Phase 2 Multi Center Prospective Rand. Double Blind Placebo Cont. Parallel Design Study to Evaluate Safety & Efficacy of Topical Sirolimus for Cutaneous Angiofibromas in Subjects W/ Tuberous Sclerosis Complex Followed by Opt. Open Label
Phase: PHASE2
Conditions: Angiofibroma of Face, Tuberous Sclerosis
Sponsor: Aucta Pharmaceuticals, Inc

Aucta Pharmaceuticals, Inc. 
 
AUCTA-UAP006-PH2 
 
 
Study Title: 
A Phase 2, Multi-Center Prospective, Randomized, Double-
Blind, Placebo-Controlled, Parallel-Design Study to 
Evaluate the Safety and Efficacy of a Topical Formulation 
of Sirolimus for Cutaneous Angiofibromas in Subjects with 
Tuberous Sclerosis Complex (TSC) Followed by an 
Optional Open-label Phase  
 
Drug Name/Dosage: 
Sirolimus Ointment 
Protocol No: 
AUCTA-UAP006-PH2 
IND Number: 
125130 
 
Author(s): 
Carol Udell 
 
Senior Director  
 
Clinical Data Management and Biostatistics 
 
TKL Research, Inc. 
 
 
Development phase: 
2 
 
Document status: 
FINAL 
 
Document version  
Version 8 – 16April2021 
and date: 
 
Sponsor: 
 
 
Aucta Pharmaceuticals, Inc. 
71 Suttons Lane 
Piscataway, NJ 08854 
 
(732) 640-0030 
 
Medical Monitor: 
Yunrong Wei, MD 
 
dMed Biopharmaceutical Co., Ltd 
 
298 Xiangke Road, 3/F, 301-305 
Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China 
+86-21-6875 5515 
 
 
 
 
Property of Aucta Pharmaceuticals, Inc. 
Confidential 
The confidential information provided in this document is for use by parties directly involved 
in this investigation. By accepting this document, you agree that the information contained 
herein will not be disclosed to any person not directly involved in this investigation without 
written authorization from Aucta Pharmaceuticals, Inc.  

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SIGNATURE PAGE 
Protocol number: AUCTA-UAP006-PH2 
The signatures of the representatives below constitute their approval of this protocol and 
provide the necessary assurances that this study will be conducted according to all stipulations 
stated in the protocol, including all statements as to confidentiality. It is also agreed that the 
study will not be initiated without the approval of an appropriate Institutional Review Board 
or Ethics Review Committee. 
 
Signatures: 
 
 
 
 
Shoufeng Li 
Chief Executive Officer 
Aucta Pharmaceuticals 
Signature 
 
Date 
 
 
 
 
Yunrong Wei, MD 
Medical Monitor 
dMed Biopharmaceutical Co., Ltd 
Signature 
 
Date 
 
 
April 28, 2021
April 29, 2021

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SIGNATURE PAGE FOR INVESTIGATOR(S) 
 
Product:  
 
Sirolimus Ointment 
Protocol number:  
AUCTA-UAP006-PH2 
Protocol title:   
A Phase 2, Multi-Center Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Design Study to Evaluate the Safety 
and Efficacy of a Topical Formulation of Sirolimus for Cutaneous 
Angiofibromas in Subjects with Tuberous Sclerosis Complex 
(TSC) Followed by an Optional Open-label Phase 
 
The signature of the study investigator below constitutes his/her approval of this protocol and 
provides the necessary assurances that this study will be conducted according to all 
stipulations, clinically and administratively, as detailed in the protocol. It is agreed that the 
conduct and results of this study will be kept confidential.  
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................................9 
1.0 
SYNOPSIS ..........................................................................................................................11 
2.0 
INTRODUCTION ..............................................................................................................21 
2.1 
Background ..............................................................................................................21 
2.2 
Nonclinical Safety ....................................................................................................22 
2.3 
Name and Description of the Investigational Product..............................................22 
2.4 
Rationale of the Study ..............................................................................................22 
2.5 
Benefit-risk Assessment ...........................................................................................23 
3.0 
TRIAL OBJECTIVES AND PURPOSE ..........................................................................23 
4.0 
STUDY DESIGN ................................................................................................................24 
4.1 
Overall Study Design ...............................................................................................24 
4.2 
Study Endpoints .......................................................................................................25 
5.0 
SELECTION OF STUDY POPULATION ......................................................................27 
5.1 
Subject Population ....................................................................................................27 
5.2 
Inclusion Criteria ......................................................................................................27 
5.3 
Exclusion Criteria .....................................................................................................28 
5.4 
Discontinuation of Treatment ...................................................................................29 
5.5 
Replacement Policy ..................................................................................................29 
5.6 
Dietary and Lifestyle Restrictions ............................................................................29 
6.0 
STUDY TREATMENTS ...................................................................................................30 
6.1 
Investigational Products and Controls ......................................................................30 
6.2 
Dosing Regimen .......................................................................................................30 
6.3 
Packaging, Labeling and Storage .............................................................................30 
6.4 
Assignment to Treatment .........................................................................................31 
6.4.1 
Randomization .............................................................................................31 
6.4.2 
Blinding ........................................................................................................31 
6.5 
Study Drug Dispensation .........................................................................................32 
6.6 
Replacement Procedure for Study Drug ...................................................................32 
6.7 
Prior and Concomitant Therapy ...............................................................................32 

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6.8 
Rescue Medications ..................................................................................................34 
6.9 
Treatment Compliance .............................................................................................34 
7.0 
VISIT SCHEDULE AND ASSESSMENTS .....................................................................35 
7.1 
Study Procedures ......................................................................................................35 
7.2 
Study Visits and Assessments ..................................................................................35 
7.2.1 
Visit 1 Screening (Visit 1, up to Day –28) ...................................................35 
7.2.2 
Visit 2 Randomization/Baseline (Day 1) .....................................................36 
7.2.3 
Blinded Phase ...............................................................................................37 
7.2.3.1 
Visit 3 (Week 4 ± 7 days).................................................................37 
7.2.3.2 
Telephone Visit 4 (Week 8 ± 7 days) ...............................................38 
7.2.3.3 
Visit 5 (Week 12 ± 7 days) ...............................................................38 
7.2.4 
Open-label Phase ..........................................................................................40 
7.2.4.1 
Visit 6 (Week 16 ± 7 days) ...............................................................40 
7.2.4.2 
Telephone Visit 7 (Week 20 ± 7 days) .............................................40 
7.2.4.3 
Visit 8 (Week 24 ± 7 days) ...............................................................41 
7.2.5 
Telephone End of Study Visit (14 ± 3 days after final dose of IP) – 
Both Blinded and Open-Label Participants ..................................................42 
7.2.6 
Early Termination (Blinded and Open-Label) .............................................42 
7.3 
Efficacy Assessments ...............................................................................................43 
7.3.1 
Primary Efficacy Assessment: Investigator’s Global Assessment ...............43 
7.3.2 
Secondary Efficacy Assessment: Facial Angiofibroma Severity Index 
(FASI) ...........................................................................................................44 
7.3.3 
Secondary Efficacy Assessment: Lesion Count ...........................................45 
7.3.4 
Secondary Efficacy Assessment: Lesion Elevation .....................................46 
7.3.5 
Secondary Efficacy Assessment: Subject Self-Assessment Survey ............46 
7.3.6 
Secondary Efficacy Assessment: Modified Nobel Scoring System .............47 
7.3.6.1 
Response for Target Lesions ...........................................................47 
7.3.6.2 
Response for Non-Target Lesions ...................................................48 
7.3.6.3 
Overall Response for Target and Non-Target Lesions ...................49 
7.3.7 
Independent Review Committee (IRC) on Photograph Assessment............49 
7.3.7.1 
Members of the IRC ........................................................................49 
7.3.7.2 
Transmission, Control, Compensation, Masking, and Checking 
of Image Files ..................................................................................50 
7.4 
Assessment of Safety ...............................................................................................50 
7.4.1 
Adverse Events .............................................................................................50 
7.4.1.1 
Adverse Events Assessments ...........................................................50 

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7.4.1.2 
Timing .............................................................................................52 
7.4.1.3 
Severity of Adverse Events ..............................................................52 
7.4.1.4 
Relationship of an Adverse Event to Study Treatment ....................52 
7.4.1.5 
Unexpected Adverse Events ............................................................53 
7.4.1.6 
Adverse Events of Special Interest ..................................................53 
7.4.1.7 
Adverse Events Causing Treatment Discontinuation ......................53 
7.4.2 
Serious Adverse Events ................................................................................53 
7.4.3 
Dermatologic Stopping and Follow-up Criteria ...........................................55 
7.4.4 
Safety Laboratory Assessments ...................................................................55 
7.4.5 
Pregnancy Testing ........................................................................................56 
7.4.6 
Vital Signs ....................................................................................................56 
7.4.7 
Physical Examination ...................................................................................56 
7.4.8 
Pharmacokinetics .........................................................................................56 
7.5 
Appropriateness of Measurements ...........................................................................57 
8.0 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
STATISTICAL AND ANALYTICAL PLANS ...............................................................57 
8.1 
General Considerations for Data Analysis ...............................................................57 
8.2 
Sample Size and Power Considerations ...................................................................58 
8.3 
Analysis Populations ................................................................................................58 
8.4 
Interim Analysis .......................................................................................................58 
8.5 
Analysis of Efficacy .................................................................................................59 
8.5.1 
Primary Efficacy Endpoint(s) .......................................................................59 
8.5.2 
Secondary Efficacy Endpoints .....................................................................59 
8.6 
Analysis of Safety ....................................................................................................60 
8.6.1 
Adverse Events .............................................................................................60 
8.6.2 
Other Safety Variables .................................................................................61 
8.7 
Quality of Life Analysis ...........................................................................................61 
9.0 
CHANGES IN THE PLANNED STUDY ........................................................................61 
9.1 
Protocol Amendments ..............................................................................................61 
9.2 
Termination or Suspension of the Study ..................................................................61 
10.0 DATA HANDLING AND RECORD KEEPING ............................................................62 
10.1 
Recording of Data ....................................................................................................62 
10.1.1 
Source Documents ........................................................................................62 
10.1.2 
Case Report Forms .......................................................................................62 
10.2 
Retention of Documents ...........................................................................................63 

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11.0 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................63 
11.1 
Direct Access to Source Documents ........................................................................63 
11.2 
Monitoring Procedures .............................................................................................63 
11.3 
Audit and Inspection ................................................................................................64 
12.0 ETHICS ...............................................................................................................................64 
12.1 
Ethical Conduct of the Study ...................................................................................64 
12.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) ...........64 
12.3 
Subject Information and Consent .............................................................................64 
12.4 
Disclosure and Confidentiality .................................................................................64 
12.4.1 
Confidentiality of Study Documentation .....................................................64 
12.4.2 
Privacy of Individual Health Information ....................................................65 
13.0 EMERGENCY PROCEDURES .......................................................................................65 
13.1 
Emergency Unblinding ............................................................................................65 
13.2 
Reporting of Serious Adverse Events and Pregnancies ...........................................65 
13.2.1 
Contact Person(s) and Number(s) ................................................................65 
13.2.2 
Reporting Procedures ...................................................................................66 
Serious Adverse Events ........................................................................................................66 
14.0 PUBLICATION POLICY .................................................................................................66 
15.0 REFERENCE LIST ...........................................................................................................66 
16.0 APPENDICES ....................................................................................................................69 
16.1 
APPENDIX 1: Potential Drug Interactions ..............................................................69 
16.2 
APPENDIX 2: Standardized Operation Procedure for Obtaining Digital 
Images in Sirolimus Ointment Clinical Trials for Cutaneous Angiofibromas in 
Subjects with Tuberous Sclerosis Complex .............................................................69 
 
LIST OF TABLES 
Table 1-1   Visit Schedule and Assessments .................................................................................19 
Table 7-1    Investigator’s Global Assessment (IGA)....................................................................44 
Table 7-2    Scoring for Erythema, Size, and Extension ................................................................45 
Table 7-3    Lesion Count Categories ............................................................................................46 
Table 7-4    Lesion Elevation Categories .......................................................................................46 
Table 7-5    Subject Self-Assessment Survey ................................................................................47 
Table 7-6    Color Scale for Color Assessment ..............................................................................48 

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Table 7-7    Scale for Response Assessment of Target Lesions ....................................................48 
Table 7-8    Scale for Response Assessment of Non-Target Lesions ............................................48 
Table 7-9    Scale for Overall Response Assessment .....................................................................49 
 
LIST OF FIGURES 
Figure 4-1  Study Design ...............................................................................................................25 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
CRO 
Contract Research Organization 
DMC 
Data Monitoring Committee 
DMSO 
Dimethyl sulfoxide  
eCRF 
Electronic case report form 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
EU 
European Union 
FASI 
Facial Angiofibromas Severity Index 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IGA 
Investigator’s Global Assessment 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
Intent to treat 
MCH 
Mean corpuscular hemoglobin  
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mTOR 
Mammalian target of rapamycin 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
Over the counter 

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Abbreviation 
Definition 
PgP inhibitor 
Permeability glycoprotein 1 inhibitors 
PIND 
Pre-IND (meeting with FDA) 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected adverse reaction 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TSC 
Tuberous sclerosis complex 
UPT 
Urine pregnancy test 
US  
United States 
WBC 
White blood cell 
 

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1.0 
SYNOPSIS 
Study Title: 
A Phase 2, Multi-Center Prospective, Randomized, Double-
Blind, 
Placebo-Controlled, 
Parallel-Design 
Study 
to 
Evaluate the Safety and Efficacy of a Topical Formulation of 
Sirolimus for Cutaneous Angiofibromas in Subjects with 
Tuberous Sclerosis Complex (TSC) Followed by an Optional 
Open-label Phase 
Protocol Number: 
AUCTA-UAP006-PH2 
Sponsor:  
Aucta Pharmaceuticals, Inc. 
Development Phase: 
Phase 2 
Study Objectives: 
The objective of this study is to evaluate the safety and 
efficacy of sirolimus (0.2% and 0.4% formulations) and its 
vehicle when applied topically once daily for 12 weeks for 
the treatment of cutaneous angiofibromas in pediatric 
subjects with tuberous sclerosis complex (TSC). 
Study Design: 
This is a Phase 2, randomized, double-blind, placebo-
controlled, multicenter study designed to assess the safety 
and efficacy of topically-applied sirolimus for the treatment 
of cutaneous angiofibromas in pediatric subjects with TSC. 
Approximately 45 subjects will be enrolled at investigational 
sites in the United States (US) and China, though other 
countries may be added in the future. Approximately 45 
subjects who meet the study entry criteria will randomly be 
assigned in a 1:1:1 ratio to receive 1 of 3 treatments: 
sirolimus 0.2% ointment, sirolimus 0.4% ointment, or 
placebo ointment. The randomization is stratified by site. 
Subjects, or a parent/guardian, will apply the study 
medication topically to the cutaneous angiofibromas on the 
face once daily at night before going to bed for 12 weeks. 
Subjects who complete the double-blind phase of the study, 
with an overall compliance rate >80% as determined by the 
dosing diary, will be offered entry into an open-label period 
for an additional 12 weeks. 
 

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The maximum study duration for each subject will be 
approximately 30 weeks and includes a screening period of 
up to 4 weeks, a blinded treatment period of 12 weeks, 
optional open-label period of 12 weeks, and a follow-up 
period of 2 weeks. 
 
Planned Sample Size: 
45 subjects evaluable for analysis 

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Study Population: 
Subjects must meet all of the following criteria to be eligible for 
participation in the study: 
1. 
Generally healthy males or non-pregnant females aged 2 
to 21 years, inclusive, at the time of screening.   
2. 
Diagnosis of TSC with visible facial angiofibromas of at 
least grade 3 up to grade 5, inclusive, based on the IGA. 
3. 
Subjects with 3 or more isolated, measurable lesions of 
facial angiofibroma, with color grading score ≥2 for each 
of the 3 lesions. 
4. 
Females of childbearing potential must have a negative 
urine pregnancy test (or a negative serum pregnancy test 
if a urine pregnancy test cannot be obtained) (For China, 
different pregnancy test procedure would be followed) 
and if sexually active or become sexually active during 
the study, must agree to use an effective form of birth 
control for the duration of the study. Females using oral 
contraceptives must also use a barrier method of 
contraception during the study. Sexually active male 
subjects and/or their female partners should also use 
appropriate contraception. 
Effective contraception is defined as follows: 
• 
Oral/implant/injectable/transdermal/estrogenic 
vaginal ring contraceptives, intrauterine device, 
condom 
with 
spermicide, 
diaphragm 
with 
spermicide.  
• 
Abstinence or partner’s vasectomy are acceptable 
if the female agrees to implement one of the other 
acceptable methods of birth control if her partner 
changes. 
5. 
The subject and/or their parent or guardian must be 
willing and able to provide written informed 
consent/assent. 
6. 
Willing and able to comply with all trial requirements. 

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7. 
Subject or parent/guardian must be able to complete the 
subject self-assessment survey and subject diary in 
English or another language into which the documents 
have been officially translated. 
8. 
Subjects should be in good general health based on the 
subject’s medical history, physical exam, and impression 
of the study doctor. 
A subject who fulfills any of the following criteria will be 
ineligible to participate in the study: 
9. 
Has any chronic or acute medical condition, that in the 
opinion of the investigator, may pose a risk to the safety 
of the subject during the trial period, or may interfere 
with the assessment of safety or efficacy in this trial. 
10. 
Has received oral or topical therapy with an mTOR 
inhibitor (sirolimus, temsirolimus, or everolimus) within 
1 month of Baseline or other dermatologic treatment to 
facial angiofibromas within 1 month of Baseline. 
(Sunscreen is expected to be used in this patient 
population and is not considered treatment). 
11. 
Is currently receiving any form of immunosuppression 
therapy or has previously experienced significant 
immune dysfunction. 
12. 
Has a history of sensitivity to any component of the 
investigational product. 
13. 
Is pregnant, plans to become pregnant during the course 
of the study, or is breastfeeding. 
14. 
Has other dermatologic conditions, pigmentation, 
scarring, pigmented lesions or sunburn in the treatment 
area that would preclude or prevent adequate assessment 
of changes to their facial angiofibromas. 
15. 
Has facial hair (e.g., beard, sideburns, mustache) that 
could interfere with study assessments. 
16. 
Has had laser surgery or cryotherapy to facial 
angiofibromas, within 6 months preceding study entry. 

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17. 
Requires the use of any concomitant medication that, in 
the investigator’s opinion, has the potential to cause an 
adverse effect when given with the investigational 
product or will interfere with the interpretation of the 
study results (see Section 16.1 Appendix 1 for Potential 
Drug Interactions). 
18. 
Has participated in another clinical trial or received an 
investigational product within 3 months prior to 
screening.   
Investigational Product(s): 
The investigational product is sirolimus (0.2% and 0.4%) 
administered as an ointment formulation for topical 
administration during the double-blind treatment period.  
Subjects entering the open-label treatment period will receive 
sirolimus 0.2% administered as an ointment formulation for 
topical administration.  
Reference Product(s): 
Not applicable. 
Control Product(s): 
Placebo ointment that contains the same ingredients as the 
active formulations without the active ingredient.  
Efficacy Evaluation Criteria: 
The primary efficacy endpoint will be the proportion of subjects 
with a clinical response of treatment success at Week 12. 
Treatment success is defined as: 
• At least a 2-grade improvement on the Week 12 
Investigator Global Assessment (IGA) of the facial skin 
lesions assessed by investigator. 
Secondary efficacy endpoints will be the following: 
• The proportion of subjects with an investigator assessed 
IGA score of clear or almost clear with at least a 2-grade 
improvement on the Week 12 IGA of the facial skin 
lesions; 
• The 
proportion 
of 
subjects 
with 
at 
least 
30% improvement at Week 12 as compared to Baseline 
in the Facial Angiofibromas Severity Index (FASI) 

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score, which is based on lesion erythema, size, and 
extension (Salido et.al. 2012);20 
• The time to reach at least 30% improvement from 
Baseline in the FASI score for angiofibroma severity; 
• The proportion of subjects with at least 2-grade 
improvement at Week 12 as compared to Baseline in 
categorical lesion counts (scored as follows: No lesion 
= 0; <25 lesions = 1; 25-50 lesions = 2; 51-75 lesions = 
3, >75 lesions = 4); 
• The proportion of subjects with at least 2-grade 
improvement at Week 12 as compared to Baseline in 
lesion elevation score; 
• The proportion of subjects with at least 2-grade 
improvement at Week 12 as compared to Baseline in 
the subject self-assessment survey; 
• Overall Response of angiofibroma assessed by the 
investigator at Week 12 as compared to baseline based 
on Modified Nobel Scoring System; 
• Overall Response of angiofibroma assessed by the IRC 
at Week 12 as compared to baseline based on Modified 
Nobel Scoring System; 
• The proportion of subjects with at least Moderate 
Improvement (a score of 2) on Modified Nobel Scoring 
System assessed by the investigator at Week 12; 
• The proportion of subjects with at least Moderate 
Improvement (a score of 2) on Modified Nobel Scoring 
System assessed by the IRC at Week 12; 
• The proportion of subjects with at least a 2-grade 
improvement on the Week 12 Investigator Global 
Assessment (IGA) of the facial skin lesions assessed by 
IRC. 

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Safety Evaluation Criteria: 
Adverse event incidence and severity, laboratory test results 
(hematology, clinical chemistry, urinalysis), vital signs (systolic 
and diastolic blood pressure, heart rate, respiratory rate), 
physical examination. 
Statistical Methods: 
Primary efficacy endpoint: The primary efficacy endpoint will 
be the proportion of subjects with a clinical response of 
treatment success on Week 12, defined as: 
• At least a 2-grade improvement on the Week 12 
Investigator Global Assessment (IGA) of the facial skin 
lesions assessed by investigator. The primary efficacy 
endpoint will be analyzed using Fisher’s exact test, 
making all pairwise treatment comparisons. 
Secondary efficacy endpoints: Treatment comparison of the 
proportion of treatment success with clear or almost clear will be 
conducted using Fisher’s exact test at each time point, making all 
pair-wise comparisons. Descriptive statistics for observed values, 
absolute changes and percent changes from Baseline for Facial 
Angiofibromas Severity Index [FASI] lesion score, and Number and 
percentage of subjects reached overall response level for Modified 
Nobel Scoring System score will be summarized by treatment group 
at each time point during the double-blind period. Student’s t-test 
will be used for pairwise comparison of continuous endpoints at 
each time point. Wilcoxon rank sum test will be used to compare 
Modified Nobel Scoring System score. Fisher’s exact test will be 
used for categorical endpoints. Time to reach at least 30% 
improvement from Baseline in the Composite score or FASI score 
will be analyzed using Kaplan-Meier method, making all pairwise 
treatment comparisons. Proportion of subjects with at least Moderate 
Improvement on Modified Nobel Scoring System will be analyzed 
using Fisher’s exact test, making all pair-wise comparison. 
Proportion of subjects with at least a 2-grade improvement on the 
Week 12 IGA will be analyzed using Fisher’s exact test, making all 
pair-wise comparisons. Hazard ratio and 95% CI will be calculated 
using Cox model. Blood samples for pharmacokinetic analyses will 
be collected to confirm systemic pharmacokinetics. 
Safety: The assessment of safety will be based mainly on the 
frequency of adverse events (AEs) and on the number of 
laboratory values that fall outside of predetermined ranges. 

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Adverse events will be presented in data listings and 
summarized by frequency and severity for each treatment 
group. Laboratory and vital sign data will be presented in data 
listings. Abnormal laboratory findings will be presented.   
Study Sites: 
Up to 15 sites in United States and China, though other countries 
may be added in the future 
Planned Dates of Study: 
5 Feb 2018 to 31 Dec 2021 
 

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Table 1-1   Visit Schedule and Assessments  
 
 
 
Blinded Phase 
Open-label Phase 
 
 
 
Visit  
1 
Visit  
2 
Visit  
3 
Telephone 
Visit 4 
Visit  
5  
Visit  
6 
Telephone  
Visit 7 
Visit  
8 
Telephone 
End of 
Study 
(EOS) 
Early 
Termination  
Examination 
Screening 
Baseline 
Week 
4 
Week 8 
Week 12 
(EOT DB) 
Week 16 
Week 20 
Week 24 
(EOT OL) 
Up to Day 
–28  
Day 1 
Day 28 
± 7 d 
Day 56  
± 7 d 
Day 84  
± 7 d 
Day 112 
± 7 d 
Day 140  
± 7 d 
Day 168 ± 
7 d 
14 ± 3 days 
after final 
dose of IPa 
 
Informed consent/assent 
Photographic consent/assent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Xb 
 
 
 
 
 
Demographics/background 
information 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
Prior and concomitant medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
X 
 
X 
Vital signs 
X 
X 
X 
 
X 
X 
 
X 
 
X 
Samples (blood and urine) for 
clinical laboratory assessment 
X 
 
X 
 
X 
X 
 
X 
 
X 
Pharmacokinetics  
 
 
X 
 
 
 
 
 
 
 
Urine pregnancy test, if applicablec  
X 
X 
X 
 
X 
X 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Weigh study product; dispense to 
subject 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 

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Blinded Phase 
Open-label Phase 
 
 
 
Visit  
1 
Visit  
2 
Visit  
3 
Telephone 
Visit 4 
Visit  
5  
Visit  
6 
Telephone 
Visit 7 
Visit  
8 
Telephone 
End of 
Study 
(EOS) 
Early 
Termination  
Examination 
Screening 
Baseline 
Week 
4 
Week 8 
Week 12 
(EOT DB) 
Week 16 
Week 20 
Week 24 
(EOT OL) 
Up to Day 
–28  
Day 1 
Day 28 
± 7 d 
Day 56 ± 7 
d 
Day 84 ± 7 
d 
Day 112 
± 7 d 
Day 140 ± 
7 d 
Day 168 ± 
7 d 
14 ± 3 days 
after final 
dose of IPa 
 
Dispense subject diary 
 
X 
X 
 
X 
X 
 
 
 
 
IGA 
X 
X 
X 
 
X 
X 
 
X 
 
X 
FASI (assessment of erythema, 
size, extension)  
X 
X 
X 
 
X 
 
 
X 
 
X 
Modified Nobel Scoring System 
 
X 
X 
 
X 
X 
 
X 
 
X 
Lesion count 
X 
X 
X 
 
X 
 
 
X 
 
X 
Assessment of lesion elevation 
X 
X 
X 
 
X 
 
 
X 
 
X 
Photography 
X 
X 
X 
 
X 
X 
 
X 
 
X 
Subject self-assessment survey 
X 
X 
X 
 
X 
X 
 
X 
 
X 
Collect used study medication; 
weigh the medication tube 
 
 
X 
Query 
Compliance 
X 
X 
Query 
Compliance 
X 
 
X 
Review subject diary 
 
 
X 
Query 
Compliance 
X 
X 
Query 
Compliance 
X 
 
X 
Record adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EOT = End of Treatment; EOS = End of Study; DB = Double-blind; OL = Open-label; IGA = Investigator’s Global Assessment; FASI = Facial 
Angiofibromas Severity Index; IP = Investigational product. 
a: Subjects who do not enter the open-label phase of the trial will complete the End of Study visit 14 ± 3 days after the final double-blind dose at Visit 5 
(Week 12). Subjects who do enter the open-label phase of the trial will complete the End of Study visit 14 ± 3 days after the final open-label dose at Visit 
8 (Week 24). 
b:  Inclusion criteria only are assessed for entry into the Open-label phase. 
c: Urine pregnancy tests are to be performed on females of childbearing potential. In the unlikely event that a urine pregnancy test cannot be obtained, a 
serum pregnancy test should be conducted using the serum sample collected (For China, different pregnancy test procedure would be followed).  

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2.0 
INTRODUCTION   
2.1 
Background 
Tuberous sclerosis complex (TSC) is a rare genetic disease that causes benign tumors to grow in 
vital organs such as the brain, kidneys, heart, lungs, and skin. The disorder affects as many as 
25,000 to 40,000 individuals in the United States (US) and about 1 to 2 million individuals 
worldwide, with an estimated prevalence of one in 6,000 newborns.1  
Patients with TSC commonly have skin abnormalities which can be disfiguring, especially if they 
occur on the face. It is estimated that approximately 75% of TSC patients have facial 
angiofibromas,2 which consist of blood vessels and fibrous tissue.1 Facial angiofibromas can lead 
to bleeding, chronic irritation, and cosmetic disfigurement.3 
The disease is caused by mutations on the TSC1 gene, the TSC2 gene, or both. The TSC1 gene 
produces hamartin and TSC2 produces tuberin. It is thought that these proteins inhibit the activity 
of mTOR (mammalian target of rapamycin), a kinase that regulates cellular metabolism, growth, 
and proliferation, and that the absence of these proteins leads to abnormal cellular differentiation 
and development.1,4 mTOR is aberrantly activated in patients with TSC. This occurs in fibroblast-
like cells located within the dermal layer of the skin; these cells produce an epidermal growth 
factor, epiregulin, which stimulates epidermal cell proliferation.5 When epidermal cells are 
produced faster than dead cells are shed, the overproduction of skin cells in conjunction with 
angiogenesis result in initialization and progression of facial angiofibromas over time. 
Current treatment options for facial angiofibromas include destructive approaches such as 
dermabrasion, surgical excision, and laser therapy.6 The angiofibromas often recur, requiring 
repeated procedures and are unsuitable for early intervention. A more targeted therapeutic 
approach is needed because the invasive approaches have poor compliance, often need to be 
repeated, are not suitable for early intervention, and are not accessible for many patients. 
Rapamycin (or sirolimus) binds to and inhibits the activity of mTOR. Everolimus is a derivative 
of rapamycin) that acts in a similar fashion to rapamycin.7 There are a number of reports in the 
literature of small case studies in which sirolimus or everolimus was used to treat facial 
angiofibromas.8-18 In these reports, improvement in the facial skin tumors was noted in all cases, 
although complete clearance of the skin tumors is not possible due to the underlying mechanism 
of the disease (i.e., the aberrant activation of mTOR) and the treatment was well tolerated. Salido 
et al14 reported that subjects with TSC-associated facial angiofibroma treated with topical 
sirolimus ointment (0.4%) once daily, 3 times a week for 9 months showed improvement in 
erythema and in the size and extension of tumors with no local or systemic adverse events.  
 

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2.2 
Nonclinical Safety 
Repeated dermal application up to 13.6 mg/kg/day with 0.8% (w/w) Sirolimus Ointment or the 
vehicle to male and female minipigs once daily for 13 weeks was well tolerated did not cause any 
adverse effect in mortality, clinical signs, skin reaction, body weight, food consumption, body 
temperature, ophthalmic examinations, electrocardiography and clinical pathology.   
Considering that the current GLP dermal toxicology study was given at a dose level 50-100 
times higher than the anticipated clinical dose (1-2mg applied topically), and based on the oral 
sirolimus label where whole blood sirolimus trough concentration for 2mg/day is about 8.59 
ng/mL (n=226), we expect the clinical plasma concentration to be close or below 0.1 ng/mL 
range, well below the observed oral sirolimus plasma concentration.  
      
2.3 
Name and Description of the Investigational Product 
The investigational products are sirolimus formulated as an ointment for topical administration 
and the placebo ointment. 
The chemical structure for sirolimus is 
 
The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S, 
15E,17E,19E,21S,23S,26R,27R,34aS)9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-
hexadecahydro-9,27-dihydroxy-3-[(1R)-2[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-
methylethyl]-10,21-dimethoxy6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] 
oxaazacyclohentriacontine1,5,11,28,29(4H,6H,31H)-pentone. Its molecular formula is 
C51H79NO13 and its molecular weight is 914.2. 19 
2.4 
Rationale of the Study 
Facial angiofibromas are a common symptom in patients with TSC. They can be disfiguring and 
can have a negative psychological effect on pediatric patients. The current treatment options, such 
as dermabrasion, surgical removal, and laser treatment, can be painful, may require general 
anesthesia, and likely will need to be repeated. A medical treatment, such as a topically-applied 
medication, would be an easy long-term treatment option for a chronic disease. Such a treatment 

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option would improve patient compliance and reduce the healthcare burden since untreated skin 
tumors can progress until hospitalization and surgery are required. 
Reports in the literature indicate that sirolimus is a promising candidate for the treatment of TSC-
related cutaneous angiofibromas. Concentrations of 0.2% and 0.4% sirolimus were chosen based 
on literature reports and recommendations from experts in the field. 
The study is designed to evaluate the safety and efficacy of sirolimus ointment (0.2% and 0.4% 
formulations), applied once daily to facial angiofibromas, for 12 weeks. Subjects who complete 
the double-blind treatment period, who are eligible and willing, will have the option of entering an 
open-label treatment period of 12 weeks. 
2.5 
Benefit-risk Assessment 
Sirolimus (Rapamune), an immunosuppressant, is approved in the US as an orally administered 
agent for the prophylaxis of organ rejection. The package insert reports that the most common 
(> 30%) adverse reactions are peripheral edema, hypertriglyceridemia, hypertension, 
hypercholesterolemia, creatinine increased, abdominal pain, diarrhea, headache, fever, urinary 
tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. There is also a boxed 
warning that increased susceptibility to infection and the possible development of lymphoma and 
other malignancies may result from immunosuppression. 
In the current study with topical administration of sirolimus, systemic exposure to sirolimus is 
expected to be very low. In literature reports of topically-applied sirolimus and everolimus for 
the treatment of facial angiofibromas,8-18 only 1 subject had a detectable blood levels of 
sirolimus (0.8 mmol/L).17 Additionally, the topical treatment was well tolerated and no systemic 
or local adverse effects were reported. 
Patients might benefit from the trial, because it is expected that the facial angiofibromas will 
improve. There is currently no FDA approved pharmaceutical treatment for this disease condition. 
The risks of participation in the trial include the risks associated with the study procedures (e.g., 
blood drawing) which are similar to other trials of investigative agents. No systemic or local 
adverse effects were reported in previous clinical experience with topical sirolimus, although these 
studies were small. The study has been designed and will be conducted in such a manner as to 
minimize risks as much as possible. Therefore, the benefit-risk assessment is considered 
acceptable for a first multiple-dose trial in human. 
3.0 
TRIAL OBJECTIVES AND PURPOSE 
The objective of this study is to evaluate the safety and efficacy of sirolimus (0.2% and 0.4% 
formulations) and its vehicle when applied topically once daily for 12 weeks for the treatment of 
cutaneous angiofibromas in pediatric subjects with tuberous sclerosis complex (TSC). 

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4.0 
STUDY DESIGN 
4.1 
Overall Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study designed to 
assess the safety and efficacy of topically-applied sirolimus for the treatment of cutaneous 
angiofibromas in pediatric and adolescent subjects with tuberous sclerosis complex (TSC) with an 
option to enter an open-label treatment phase. Study subjects will be enrolled at investigational 
sites in the United States (US) and China, though other countries may be included. Approximately 
45 subjects who meet the study entry criteria will be randomly assigned in a 1:1:1 ratio to receive 
1 of 3 treatments: sirolimus 0.2% ointment, sirolimus 0.4% ointment, or placebo ointment. The 
randomization is stratified by site. Subjects will apply the study medication topically to the 
cutaneous angiofibromas on the face once daily at night for 12 weeks. Subjects who complete the 
double-blind phase of the study, with an overall compliance rate >80% as determined by the dosing 
diary, will be offered entry into the open-label period for an additional 12 weeks. 
The maximum study duration for each subject will be approximately 30 weeks and includes a 
screening period of up to 4 weeks, a blinded treatment period of 12 weeks, optional open-label 
period of 12 weeks, and a follow-up period of 2 weeks. After the parent/guardian has provided 
written informed consent and the subject has assented (for subjects younger than 18 years) or after 
the subject has provided informed consent (for subjects 18 years of age), the subject will undergo 
screening procedures.  
At the end of the screening period, eligible subjects will be randomly assigned to one of the study 
treatment groups on Day 1 (Baseline) of the treatment period. The randomization is stratified by 
site. 
During the double-blind treatment period, subjects will return to the study site according to the 
study schedule for interim efficacy assessments and review of concomitant medications, the dosing 
diary, vital signs, and adverse events (AEs). At each clinic visit, subjects will be rated by the 
investigator on an Investigator’s Global Assessment (IGA) as well as undergo specified safety 
assessments. At each clinic visit, subjects (or their parent/guardian) will be asked to complete a 
subject self-assessment questionnaire. Blood samples for pharmacokinetic analyses will be 
collected. In addition, a telephone visit will be conducted at Week 8 (Visit 4) for a review of 
concomitant medications, IP compliance and adverse events (AEs). 
The study design is summarized in Figure 4-1. 
 

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Figure 4-1  
Study Design  
 
      Double-Blind 12 Week Treatment period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Days -27 to 0 
Visit 1 
 
 
Baseline 
Day 1 
Visit 2 
 
 
  Weeks 4 and 8 
Days 28 and 56 (±7 d) 
   Visits 3 and 4 
 
 
End of 
Treatment (DB) 
Week 12 
Day 84 (± 7 d) 
Visit 5 
 
  End of Study 
(14 ± 3 days 
after final dose 
of DB IP)* 
 
*Subjects participating in the open-label treatment period will not enter into the follow-up period or have an End of 
Study visit until the completion of the open-label treatment period.  
 
Open-Label 12 Week Treatment Period 
 
 
Week 12 
 
 
Weeks 16 and 20  
 
 
End of   
End of Study 
Day 84 (± 7 d) 
 
 
Days 112 and 140 (±7 d)  
      Treatment (OL) 
(14 ± 3 days 
Visit 5  
 
 
Visits 6 and 7 
 
 
 
Week 24 
after final dose 
 
 
 
 
 
 
 
 
      Day 168 (± 7 d) 
of OL IP) 
 
 
 
 
 
 
 
 
 
Visit 8 
4.2 
Study Endpoints 
The primary efficacy endpoint will be the proportion of subjects with a clinical response of 
treatment success at Week 12. Treatment success is defined as: 
• At least a 2-grade improvement on the Week 12 Investigator Global Assessment (IGA) of 
the facial skin lesions assessed by the investigator. 
Secondary efficacy endpoints will be the following: 
Sirolimus 0.2% 
Placebo
Screening Period 
Follow-up Period 
Sirolimus 0.4% 
Sirolimus 0.2% 
Follow-up Period 
Eligibility review 

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• The proportion of subjects with an investigator assessed IGA score of clear or almost clear 
with at least a 2-grade improvement on the Week 12 IGA of the facial skin lesions;  
• The proportion of subjects with at least 30% improvement at Week 12 as compared to 
Baseline in the Facial Angiofibromas Severity Index (FASI) score, which is based on 
lesion erythema, size, and extension (Salido et.al. 2012);20 
• The time to reach at least 30% improvement from Baseline in the FASI score for 
angiofibroma severity; 
• The proportion of subjects with at least 2-grade improvement at Week 12 as compared to 
Baseline in categorical lesion counts (scored as follows: No lesion = 0; <25 lesions = 1; 
25-50 lesions = 2; 51-75 lesions = 3, >75 lesions = 4); 
• The proportion of subjects with at least 2-grade improvement at Week 12 as compared to 
Baseline in lesion elevation score; 
• The proportion of subjects with at least 2-grade improvement at Week 12 as compared to 
Baseline in the subject self-assessment survey; 
• Overall Response of angiofibroma assessed by the investigator at Week 12 as compared 
to baseline based on Modified Nobel Scoring System; 
• Overall Response of angiofibroma assessed by the IRC at Week 12 as compared to 
baseline based on Modified Nobel Scoring System; 
• The proportion of subjects with at least Moderate Improvement (a score of 2) on Modified 
Nobel Scoring System assessed by the investigator at Week 12; 
• The proportion of subjects with at least Moderate Improvement (a score of 2) on Modified 
Nobel Scoring System assessed by the IRC at Week 12; 
• The proportion of subjects with at least a 2-grade improvement on the Week 12 
Investigator Global Assessment (IGA) of the facial skin lesions assessed by the IRC. 
Blood samples for pharmacokinetic analyses will be collected to confirm systemic 
pharmacokinetics. 
Safety will be assessed through the monitoring of AEs, laboratory test results, vital signs, and 
physical examinations. 

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5.0 
SELECTION OF STUDY POPULATION 
5.1 
Subject Population 
A sufficient number of subjects will be enrolled in order to provide 45 subjects randomized. An 
individual subject will be allowed to participate in the study one time only. A rationale for the 
choice of sample size is provided in Section 8.2 of this protocol. 
Each potential subject will sign and date an informed consent document before any study-specified 
procedures are performed. For subjects younger than age 18, the parent/guardian must provide 
written informed consent and the subjects will provide assent in conformance with the Institutional 
Review Board (IRB) requirements.  
5.2 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for participation in the study: 
1. 
Generally healthy males or non-pregnant females aged 2 to 21 years, inclusive, at the time 
of screening.   
2. 
Diagnosis of TSC with visible facial angiofibromas of at least grade 3 up to grade 5, 
inclusive, based on the IGA, at the time of screening. 
3. 
Subjects with 3 or more isolated, measurable lesions of facial angiofibroma, with color 
grading score ≥2 for each of the 3 lesions. 
4. 
Females of childbearing potential must have a negative urine pregnancy test (or a negative 
serum pregnancy test if a urine pregnancy test cannot be obtained) (For China, different 
pregnancy test procedure would be followed) and if sexually active or become sexually 
active during the study, must agree to use an effective form of birth control for the duration 
of the study. Females using oral contraceptives must also use a barrier method of 
contraception during the study. Sexually active male subjects and/or their female partners 
should also use appropriate contraception. 
Effective contraception is defined as follows: 
• Oral/implant/injectable/transdermal/estrogenic vaginal ring contraceptives, 
intrauterine device, condom with spermicide, diaphragm with spermicide.  
• Abstinence or partner’s vasectomy are acceptable if the female agrees to implement 
one of the other acceptable methods of birth control if her partner changes. 
 
5. 
The subject and/or their parent or guardian must be willing and able to provide written 
informed consent/assent. 
6. 
Willing and able to comply with all trial requirements. 

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7. 
Subject or parent/guardian must be able to complete the subject self-assessment survey and 
subject diary in English or another language into which the documents have been officially 
translated.   
8. 
Subjects should be in good general health based on the subject’s medical history, physical 
exam, and impression of the study doctor. 
5.3 
Exclusion Criteria 
A subject who fulfills any of the following criteria will be ineligible to participate in the study: 
9. 
Has any chronic or acute medical condition, that in the opinion of the investigator, may 
pose a risk to the safety of the subject during the trial period, or may interfere with the 
assessment of safety or efficacy in this trial. 
10. 
Has received oral or topical therapy of an mTOR inhibitor (sirolimus, temsirolimus, or 
everolimus) within 1 month of Baseline or dermatologic treatment for facial angiofibromas 
within 1 month of Baseline. (Note: Sunscreen is not considered treatment for this condition 
and is expected to be used for skin protection in this patient population.) 
11. 
Is currently receiving any form of immunosuppression therapy or has previously 
experienced significant immune dysfunction. 
12. 
Has a history of sensitivity to any component of the investigational product. 
13. 
Is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.  
14. 
Has other dermatologic conditions, pigmentation, scarring, pigmented lesions or sunburn 
in the treatment area that would preclude or prevent adequate assessment of changes to their 
facial angiofibromas. 
15. 
Has facial hair (e.g., beard, sideburns, mustache) that could interfere with study 
assessments. 
16. 
Has had laser surgery or cryotherapy to facial angiofibromas within 6 months preceding 
study entry. 
17. 
Requires the use of any concomitant medication that, in the investigator’s opinion, has the 
potential to cause an adverse effect when given with the investigational product or will 
interfere with the interpretation of the study results (see Section 16.1 Appendix 1 for 
Potential Drug Interactions). 
18. 
Has participated in another clinical trial or received an investigational product within 
3 months prior to screening.   

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5.4 
Discontinuation of Treatment 
In accordance with legal requirements and International Conference on Harmonization (ICH) – 
Good Clinical Practice (GCP) guidelines, every subject has the right to refuse further participation 
in this study at any time and without providing reasons (see also Section 9.2). A subject's 
participation is to be terminated immediately upon his/her request. The investigator should seek to 
obtain the reason and record this on the case report form (CRF) whenever possible. 
If, at the time of refusal, a study product has already been administered, the subject should be 
advised on follow-up safety investigations.  
The termination of an individual's participation should be considered in case of a serious adverse 
event (SAE). Should a subject develop conditions during the course of the study that would have 
prevented his/her entry into the study according to the safety-related medical exclusion criteria, 
he/she must be withdrawn immediately.  
A subject may be withdrawn from the study at any time at the discretion of the investigator for 
medical reasons and/or due to non-adherence to the treatment scheme and other duties stipulated 
in the study protocol. The reasons for early termination are to be fully documented on the CRF. 
In addition, the sponsor reserves the right to end or suspend the study at any time or a subject’s 
participation due to a protocol amendment (see Section 9.2). 
If a subject withdraws from the study, all efforts will be made to bring the subject in for completion 
of an Early Withdrawal visit.  
Subjects discontinued for an AE will be monitored until the AE is resolved, a reasonable 
explanation is provided for the event, or the subject is referred to his/her own primary medical 
doctor. The specific AE in question will be recorded on the appropriate CRF. 
5.5 
Replacement Policy 
There will be no replacements in this study.  Dropouts will be addressed by additional enrollment 
if necessary. 
5.6 
Dietary and Lifestyle Restrictions 
Subjects should avoid alterations to their diet, level of activity and lifestyle that would affect their 
participation during the study.   
Subjects should avoid excessive sun exposure to the face. 

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6.0 
STUDY TREATMENTS 
6.1 
Investigational Products and Controls 
The study product under investigation in this study is sirolimus administered as an ointment 
formulation for topical administration. Two concentrations/dosages of sirolimus (0.2% and 0.4%) 
will be studied.   
The ointment contains sirolimus (0.2% and 0.4%) as API, 4~10% white mineral oil as emollient, 
~5% Labrasol® as surfactant, 2-6% Compritol® 888 ATO as thickener, 4.5% propylene carbonate 
(PC) and dimethyl sulfoxide (DMSO) as solvent and the remaining ingredients will be white 
petrolatum as the ointment base. 
The placebo/vehicle contains the same ingredients as the active formulation(s) without the active 
ingredient.  
For the open-label treatment period, sirolimus 0.2% will be administered as an ointment 
formulation for topical administration.  
6.2 
Dosing Regimen 
Subjects are to apply the study product topically to the affected areas on the face, once daily at 
bedtime after thorough washing of the face. The study medication should be applied in sufficient 
quantity to cover the facial lesion. The typical dose of the medication is about 1.0 cm of ointment, 
which is about a pea-size or fingertip amount of medication. The recommended dose for 
application to the lesions on the face is a minimum of 0.5 cm.  Subjects are to continue to apply 
study medication for the entire treatment period.   
If subjects are night workers, they may apply the medication in the morning after they have 
showered and are preparing for sleep. Medication application should be consistently applied at 
near the same time each day. 
Detailed application instructions will be provided in the subject instructions. 
If a subject misses a dose >4 hours, that dose should be counted as missed and the subject should 
wait to apply investigational product at the next scheduled time of dosing. 
Should the study product come in contact with the eyes, the eyes should be flushed with tepid to 
warm water for approximately five minutes.  
6.3 
Packaging, Labeling and Storage 
The investigational product will be packaged and distributed by Bellwyck Packaging Solutions 
and will be labeled according to all applicable federal regulations.     

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The study medication will be supplied to the clinical site(s) as tubes containing 30 g of ointment.  
For the double-blind treatment period, study medication will be packaged as kits containing seven 
(7) tubes. For the open-label treatment period, appropriately labeled study medication will be 
supplied to each site. 
Study medication will be refrigerated in a secure environment under the control of the investigator, 
pharmacist, or a study coordinator/nurse, and maintained at a controlled temperature (35.6°F to 
46.4°F or 2°C to 8°C). Excursions up to 86°F or 30°C are permitted. 
Study medication will be kept by the subject in a refrigerator. When traveling and during 
application, the study medication may be kept at room temperature.  
6.4 
Assignment to Treatment 
6.4.1 
Randomization 
At the Screening Visit and throughout the trial, subjects will be identified by a subject number that 
will consist of the three-digit site number and a three-digit sequential number, beginning with 001. 
Site numbers will be 100-1500.  
A subject who fulfills the trial eligibility requirements will be randomly assigned to treatment at 
the Baseline visit. Treatment assignment to randomization numbers will be stratified at the site 
level. Both the kit and treatment tubes within a kit will have a label containing the randomization 
number for the double-blind treatment period. When a subject is to be randomized, site personnel 
will sequentially choose the kit with the lowest randomization number from their stock of double-
blind kits, unless otherwise instructed by the study team.  
Randomization data will be kept strictly confidential, accessible only to authorized persons as 
defined below, until the time of unblinding.   
6.4.2 
Blinding 
This is a double-blind study with the treatment assignment concealed from the subjects, the 
investigators and their staff, and the clinical research team. All active and placebo investigational 
products will be of identical appearance, regardless of the dose, during the double-blind phase. 
Study materials will be packaged and issued in a manner designed to maintain the blind.   
In an emergency, when knowledge of the subject’s treatment assignment is essential for the clinical 
management or welfare of the subject, the investigator must contact the Medical Monitor (or 
designee).  Since there is no antidote to sirolimus, the knowledge of treatment is unlikely to be 
medically valuable. 

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Prior to unblinding the subject’s treatment assignment, the investigator should assess the 
relationship of an AE to the administration of the study drug. The investigator must then follow 
the unblinding procedures outlined for the study. If the blind is broken for any reason, the 
investigator must record the date and reason for breaking the blind on the appropriate CRF and 
source documents. 
If the treatment assignment is unblinded during the double-blind period, the subject will not be 
allowed participation in the open-label treatment period of the study. 
 
For details of the procedure for unblinding of individual subjects in cases of emergency see Section 
13.1.  
6.5 
Study Drug Dispensation 
Two tubes of sirolimus/placebo from the kit assigned to the subject based on the randomization 
number will be dispensed at Baseline during the double-blind treatment period. Four tubes of 
sirolimus/placebo from the kit assigned to the subject based on the randomization number will be 
dispensed at Week 4. One additional tube will be provided in each double-blind kit to be used as 
a replacement tube should the subject lose or misplace a dispensed tube.  
Two tubes of sirolimus 0.2% will be dispensed at Week 12 during the open-label treatment period. 
Four tubes of sirolimus 0.2% will be dispensed at Week 16. For the open-label treatment period, 
tubes will be available as open stock. At the time of dispensation to the subject, the clinical site 
will record the Subject Number, Study Visit and sequential number of tube dispensed on the label 
and drug accountability record. 
6.6 
Replacement Procedure for Study Drug 
For the double-blind treatment period, one additional tube will be packaged in each kit for the 
purpose of replacing a lost or misplaced tube. For the open-label treatment period, a tube from the 
open stock may be used as a replacement. 
6.7 
Prior and Concomitant Therapy 
All medications, including over-the-counter (OTC) drugs, taken within 30 days prior to the start 
of the study will be recorded at Screening. Thereafter, a record of all medications and supportive 
therapy taken during the course of the study will be made. Information regarding the total daily 
dose, route of administration, start and discontinuation dates, and indication are to be recorded on 
the subject’s CRF. 
Restrictions regarding prior and concomitant therapies as listed in the Exclusion Criteria must be 
observed during the study, including the double-blind and open-label treatment and follow-up 
periods. Subjects that are screen failures due to prohibited concomitant medications, may be re-

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screened at a later time if they are no longer exposed to the prohibited products and are otherwise 
eligible. 
Use of the following medication within 1 month prior to the Baseline visit will exclude a potential 
subject from participation and is prohibited during the study:  
• oral therapy with an mTOR inhibitor (sirolimus, temsirolimus, or everolimus) 
• topical therapy with an mTOR inhibitor. 
Use of the following medications within 1 month prior to the Baseline visit will exclude a potential 
subject from participation and is prohibited during the study:  
• retinoids. 
Use of the following medications within 1 month prior to the Baseline visit should be used with 
caution during the study, though not exclusionary. Subjects on stable doses of these medications 
must be discussed in advance with the medical monitor prior to inclusion in the study: 
• medications that are strong CYP3A4/PgP inhibitors (see Appendix 16.1). 
The use of any topical anti-acne agents on the face must be discontinued from at least 1 month 
prior to the start of study drug dosing through 1 month after the last dose of study drug. Use of the 
following medications within 1 month prior to the screening visit will exclude a potential subject 
from participation and is prohibited during the study:  
• salicylic acid,  
• corticosteroids,  
• topical antibiotics,  
• other topical treatment in the treatment area. 
Laser surgery or cryotherapy to the facial angiofibromas within 6 months prior to the screening 
visit will exclude a subject from participation and is prohibited during the study.  
(Note: Sunscreen is not considered treatment for this condition and is expected to be used for skin 
protection in this patient population.) 
 
Questions regarding concomitant drugs or therapies should be discussed with the Medical Monitor.  

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6.8 
Rescue Medications 
There are no rescue medications for this study. 
6.9 
Treatment Compliance 
Records of study product used and dosages administered will be kept during the study. Product 
accountability will be checked by the study monitor during site visits and at the completion of the 
trial. 
The tubes of study medication will be weighed prior to dispensation to the subject. Subjects will 
be asked to return all unopened, partially used and empty ointment tubes to the study site at each 
clinic visit. The tubes will be weighed and the weight difference will be analyzed as a measure of 
product usage. Subjects or their parent/guardian will be asked to complete a simple dosing diary 
on a daily basis recording the times at which they administered the treatments. A missed dose 
should also be recorded upon realization that the dose was missed. 
Compliance at each visit will be determined as follows: 
(# of Dose Days / Total # of Days between visits) * 100  
Subjects who are estimated to have missed on average >1.5 doses per week, as recorded in the 
dosing diary, will be considered non-compliant. All attempts should be made to improve the 
subject’s compliance, including counseling. Subjects may be withdrawn/early terminated from the 
study due to non-compliance.  
An overall compliance rate will be calculated for the double-blind treatment period, at the 
conclusion of Visit 5, to determine the subject’s eligibility for the open-label treatment period. 
Subjects with an overall compliance rate that is > 80%, as determined by the dosing diary, will be 
allowed to continue on to the open-label phase of the trial.  
Investigators may temporarily suspend dosing at their discretion, however the time subject is off 
study drug should be minimized. If study drug use is suspended more than 7 days (consecutive or 
in aggregate in either the double-blind or open-label phase of the trial), the investigator should 
contact the Medical Monitor to review medical reasons and steps to be taken to assure patient’s 
adherence to study requirements. The exact dates of investigator approved stopping and re-starting 
study drug will be recorded in the CRF. Investigator initiated suspension of study drug will not 
count toward overall compliance. 
Subjects will be asked to return all unused product at the end of the study. 

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7.0 
VISIT SCHEDULE AND ASSESSMENTS 
7.1 
Study Procedures 
The visit schedule and assessments are summarized in Table 1-1   Visit Schedule and Assessments  
 
 
 
Blinded Phase 
Open-label Phase 
 
 
 
Visit  
1 
Visit  
2 
Visi
t  
3 
Teleph
one 
Visit 4 
Visit  
5  
Visit  
6 
Teleph
one  
Visit 7 
Visit  
8 
Teleph
one 
End of 
Study 
(EOS) 
Early 
Termina
tion  
Examination 
Screeni
ng 
Baseli
ne 
Wee
k 4 
Week 8 
Week 
12 
(EOT 
DB) 
Week 
16 
Week 
20 
Week 
24 
(EOT 
OL) 
Up to 
Day –
28  
Day 1 
Day 
28 ± 
7 d 
Day 56  
± 7 d 
Day 84  
± 7 d 
Day 
112 ± 
7 d 
Day 
140  
± 7 d 
Day 
168 ± 7 
d 
14 ± 3 
days 
after 
final 
dose of 
IPa 
 
Informed consent/assent 
Photographic 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
Xb 
 
 
 
 
 
Demographics/backgrou
nd information 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
X 
 
X 
Vital signs 
X 
X 
X 
 
X 
X 
 
X 
 
X 
Samples (blood and 
urine) for clinical 
laboratory assessment 
X 
 
X 
 
X 
X 
 
X 
 
X 
Pharmacokinetics  
 
 
X 
 
 
 
 
 
 
 
Urine pregnancy test, if 
applicablec  
X 
X 
X 
 
X 
X 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Weigh study product; 
dispense to subject 
 
X 
X 
 
X 
X 
 
 
 
 
 

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7.2 
Study Visits and Assessments 
7.2.1 
Visit 1 Screening (Visit 1, up to Day –28) 
Screening procedures should be completed no more than 28 days prior to the randomization visit 
(Day 1). The following screening procedures are to be performed: 
• 
Review study information with subject and his/her parent/guardian (for subjects <18 years of 
age). Obtain written informed consent (including photographic consent) and, for subjects <18 
years of age, assent in accordance with the IRB requirements.    
• 
Review inclusion and exclusion criteria with the subject to determine the subject’s eligibility. 
• 
Collect medical history and demographic information. 
• 
Review and record prior medication (used within the previous 30 days) and concomitant 
medication (medications currently used). 
• 
Perform a physical examination, including height and weight. 
• 
Measure vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate) 
with subject in a seated position. 
• 
Perform the following efficacy assessments: 
o Investigator’s Global Assessment (IGA); 
o Facial Angiofibroma Severity Index (FASI) (assessment of erythema, size, and 
extension); 
o Categorical lesion count using the following categories: (0) no lesion; (1) <25 lesions; 
(2) 25-50 lesions; (3) 51-75 lesions; (4) >75 lesions; 
o Assessment of lesion elevation.  
• 
Have the subject (or parent/guardian for subjects under the developmental age of 7 years) 
complete the subject self-assessment survey. 
• 
Obtain blood samples and optional urine samples for a laboratory profile including 
hematology, clinical chemistry, and urinalysis.  
• 
Perform a urine pregnancy test (UPT) in female subjects of childbearing potential. Instruct 
all sexually-active female subjects to use approved form(s) of contraception. Instruct sexually 
active male subjects that they (and/or their female partners) should use appropriate 
contraception. (In the unlikely event that a urine pregnancy test cannot be obtained, a serum 
pregnancy test can be run from the serum sample collected.) (For China, different pregnancy 
test procedure would be followed). 

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• 
If subject meets the inclusion/exclusion criteria, schedule Visit 2. 
• 
Take a photograph of the angiofibroma according to the Standardized Operation Procedure 
(Appendix 2).  
• 
Record any AEs. 
7.2.2 
Visit 2 Randomization/Baseline (Day 1) 
• 
Review inclusion and exclusion criteria to ensure that the subject is qualified for study 
participation, including laboratory test results from Visit 1. 
• 
Review and record medication used since the Screening visit. 
• 
Record any new medical history since the Screening visit. 
• 
Measure vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate) 
with subject in a seated position. 
• 
Perform a UPT for females of childbearing potential. Remind sexually-active female subjects 
of childbearing potential to use approved method(s) of contraception. Remind sexually active 
male subjects that they (or their female partners) should use appropriate contraception. (In 
the unlikely event that a urine pregnancy test cannot be obtained, a serum pregnancy test can 
be run from the serum sample collected.) (For China, different pregnancy test procedure 
would be followed). 
• 
Perform the following efficacy assessments: 
o Investigator’s Global Assessment (IGA); 
o Facial Angiofibroma Severity Index (FASI) (assessment of erythema, size, and 
extension); 
o Modified Nobel Scoring System (assessment of target lesions and non-target lesions 
response); 
o Categorical lesion count using the following categories: (0) no lesion; (1) <25 lesions; 
(2) 25-50 lesions; (3) 51-75 lesions; (4) >75 lesions. 
o Assessment of lesion elevation.  
• 
Have the subject (or parent/guardian for subjects under the developmental age of 7 years) 
complete the subject self-assessment survey. 
• 
Take a photograph of the angiofibroma according to the Standardized Operation Procedure 
(Appendix 2).  
• 
Record any AEs. 

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• 
Perform randomization by sequentially choosing the kit with the lowest randomization 
number.   
• 
Weigh the study medication and dispense to the subject or their parent/guardian with dosing 
instructions. 
• 
Dispense the dosing diary to the subject or parent/guardian. 
• 
Schedule the next visit; instruct the subjects to bring the study medication to the study visit. 
7.2.3 
Blinded Phase 
7.2.3.1 
Visit 3 (Week 4 ± 7 days) 
• 
Collect the used tubes of study medication from the subject (or parent/guardian) and weigh 
the tubes. 
• 
Collect and review the dosing diary. 
• 
Review any concomitant medication used since the previous study visit. 
• 
Measure vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate) 
with subject in a seated position. 
• 
Obtain blood samples and optional urine samples for a laboratory profile including 
hematology, clinical chemistry, and urinalysis.  
• 
Obtain blood sample for pharmacokinetic analysis. 
• 
Perform a UPT for females of childbearing potential. Remind sexually-active female subjects 
of childbearing potential to use approved method(s) of contraception. Remind sexually active 
male subjects that they (or their female partners) should use appropriate contraception. (In 
the unlikely event that a urine pregnancy test cannot be obtained, a serum pregnancy test can 
be run from the serum sample collected.) (For China, different pregnancy test procedure 
would be followed). 
• 
Perform the following efficacy assessments: 
o Investigator’s Global Assessment (IGA); 
o Facial Angiofibroma Severity Index (FASI) (assessment of erythema, size, and 
extension); 
o Modified Nobel Scoring System (assessment of target lesions and non-target lesions 
response); 
o Categorical lesion count using the following categories: (0) no lesion; (1) <25 lesions; 
(2) 25-50 lesions; (3) 51-75 lesions; (4) >75 lesions. 

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o Assessment of lesion elevation. 
• 
Have the subject (or parent/guardian for subjects under the developmental age of 7 years) 
complete the subject self-assessment survey. 
• 
Take a photograph of the angiofibroma according to the Standardized Operation Procedure 
(Appendix 2).  
• 
Record any AEs. 
• 
Weigh the study medication and dispense to the subject (or parent/guardian). 
• 
Dispense the dosing diary to the subject. 
• 
Schedule the next study visit; instruct the subjects (or their parent/guardian) to bring the 
study medication to the study visit. 
7.2.3.2 
Telephone Visit 4 (Week 8 ± 7 days) 
• 
Review any concomitant medication used since the previous study visit. 
• 
Record any AEs. 
• 
Assess subject’s compliance with study medication.  
• 
Assess subject’s compliance with maintaining the dosing diary. 
• 
Schedule the next visit; instruct the subject (or parent/guardian) to bring the study medication 
to the study visit. 
7.2.3.3 
Visit 5 (Week 12 ± 7 days) 
• 
Collect and review the dosing diary.  
• 
Collect all study materials from the subject (or parent/guardian), including unused study 
medication, etc. 
• 
Weigh the used tubes of study medication collected from the subject (or parent/guardian). 
• 
Review any concomitant medication used since the previous study visit. 
• 
Measure vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate) 
with subject in a seated position. 
• 
Obtain blood samples and optional urine samples for a laboratory profile including 
hematology, clinical chemistry, and urinalysis.  
• 
Perform a UPT for females of childbearing potential. Remind sexually-active female subjects 
of childbearing potential to use approved method(s) of contraception. Remind sexually active 
male subjects that they (or their female partners) should use appropriate contraception. (In 

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the unlikely event that a urine pregnancy test cannot be obtained, a serum pregnancy test can 
be run from the serum sample collected.) (For China, different pregnancy test procedure 
would be followed). 
• 
Perform the following efficacy assessments: 
o Investigator’s Global Assessment (IGA); 
o Facial Angiofibroma Severity Index (FASI) (assessment of erythema, size, and 
extension); 
o Modified Nobel Scoring System (assessment of target lesions and non-target lesions 
response); 
o Categorical lesion count using the following categories: (0) no lesion; (1) <25 lesions; 
(2) 25-50 lesions; (3) 51-75 lesions; (4) >75 lesions; 
o Assessment of lesion elevation. 
• 
Have the subject (or parent/guardian for subjects under the developmental age of 7 years) 
complete the subject self-assessment survey. 
• 
Take a photograph of the angiofibroma according to the Standardized Operation Procedure 
(Appendix 2).  
• 
Record any AEs. 
• 
If subject will not be participating in the open-label treatment period, schedule the End of 
Study Visit. 
• 
If the subject will be participating in the open-label treatment period: 
o Subject must have completed the double-blind treatment period, with an overall 
compliance rate that is > 80%, as determined by the dosing diary.   
o Weigh the open-label study medication and dispense to the subject or their 
parent/guardian. 
o Dispense the dosing diary to the subject. 
o Schedule the next visit; instruct the subject to bring the study medication to the study visit. 
7.2.4 
Open-label Phase 
7.2.4.1 
Visit 6 (Week 16 ± 7 days)  
• 
Collect the used tubes of study medication from the subject (or parent/guardian) and weigh 
the tubes. 
• 
Collect and review the dosing diary.  

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• 
Review any concomitant medication used since the previous study visit. 
• 
Measure vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate) 
with subject in a seated position. 
• 
Obtain blood samples and optional urine samples for a laboratory profile including 
hematology, clinical chemistry, and urinalysis. 
• 
Perform a UPT for females of childbearing potential. Remind sexually-active female subjects 
of childbearing potential to use approved method(s) of contraception. Remind sexually active 
male subjects that they (or their female partners) should use appropriate contraception. (In 
the unlikely event that a urine pregnancy test cannot be obtained, a serum pregnancy test can 
be run from the serum sample collected.) (For China, different pregnancy test procedure 
would be followed). 
• 
Perform the Investigator’s Global Assessment (IGA). 
• 
Perform the Modified Nobel Scoring System (assessment of target lesions and non-target 
lesions response). 
• 
Have the subject (or parent/guardian for subjects under the developmental age of 7 years) 
complete the subject self-assessment survey. 
• 
Take a photograph of the angiofibroma according to the Standardized Operation Procedure 
(Appendix 2).  
• 
Record any AEs. 
• 
Weigh the study medication and dispense to the subject (or parent/guardian). 
• 
Dispense the dosing diary. 
• 
Schedule the next visit; instruct the subjects (or parent/guardian) to bring the study 
medication to the study visit. 
7.2.4.2 
Telephone Visit 7 (Week 20 ± 7 days)  
• 
Review any concomitant medication used since the previous study visit. 
• 
Record any AEs. 
• 
Assess subject’s compliance with study medication.  
• 
Assess subject’s compliance with maintaining the dosing diary. 
• 
Schedule the next visit; instruct the subjects (or parent/guardian) to bring the study 
medication to the study visit. 

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7.2.4.3 
Visit 8 (Week 24 ± 7 days)  
• 
Collect and review the dosing diary.  
• 
Collect all study materials from the subject (or parent/guardian), including unused study 
medication, etc. 
• 
Weigh the used tubes of study medication collected from the subject (or parent/guardian). 
• 
Review any concomitant medication used since the previous study visit. 
• 
Perform a physical examination, including height and weight. 
• 
Measure vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate) 
with subject in a seated position. 
• 
Obtain blood samples and optional urine samples for a laboratory profile including 
hematology, clinical chemistry, and urinalysis.  
• 
Perform a UPT for females of childbearing potential. Remind sexually-active female subjects 
of childbearing potential to use approved method(s) of contraception. Remind sexually active 
male subjects that they (or their female partners) should use appropriate contraception. (In 
the unlikely event that a urine pregnancy test cannot be obtained, a serum pregnancy test can 
be run from the serum sample collected.) (For China, different pregnancy test procedure 
would be followed). 
• 
Perform the following efficacy assessments: 
o Investigator’s Global Assessment (IGA); 
o Facial Angiofibroma Severity Index (FASI) (assessment of erythema, size, and 
extension); 
o Modified Nobel Scoring System (assessment of target lesions and non-target lesions 
response); 
o Categorical lesion count using the following categories: (0) no lesion; (1) <25 lesions; 
(2) 25-50 lesions; (3) 51-75 lesions; (4) >75 lesions; 
o Assessment of lesion elevation. 
• 
Take a photograph of the angiofibroma according to the Standardized Operation Procedure 
(Appendix 2).  
• 
Have the subject (or parent/guardian for subjects under the developmental age of 7 years) 
complete the subject self-assessment survey. 
• 
Record any AEs. 

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• 
Schedule the End of Study Visit. 
7.2.5 
Telephone End of Study Visit (14 ± 3 days after final dose of IP) – Both Blinded 
and Open-Label Participants 
• 
Review any concomitant medication used since the previous study visit. 
• 
Record any AEs. 
• 
Inform Subjects that they may be approached to participate in future trials with this product. 
• 
Dismiss the subject from the study. 
7.2.6 
Early Termination (Blinded and Open-Label) 
If a subject withdraws from the study prior to the End of Study visit, the subject is to return to the 
site. The early termination procedures should be performed, as specified below:  
• 
Collect all study materials from the subject (or parent/guardian), including used and unused 
study medication, subject dosing diary, etc. 
• 
Weigh the used tubes of study medication collected from the subject. 
• 
Review any concomitant medication used since the previous study visit. 
• 
Perform a physical examination, including height and weight. 
• 
Measure vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate) 
with subject in a seated position. 
• 
Obtain blood samples and optional urine samples for a laboratory profile including 
hematology, clinical chemistry, and urinalysis.  
• 
Perform a UPT for females of childbearing potential. Remind sexually-active female subjects 
of childbearing potential to use approved method(s) of contraception. Remind sexually active 
male subjects that they (or their female partners) should use appropriate contraception. (In 
the unlikely event that a urine pregnancy test cannot be obtained, a serum pregnancy test can 
be run from the serum sample collected.) (For China, different pregnancy test procedure 
would be followed). 
• 
Perform the following efficacy assessments: 
o Investigator’s Global Assessment (IGA); 
o Facial Angiofibroma Severity Index (FASI) (assessment of erythema, size, and 
extension); 
o Modified Nobel Scoring System (assessment of target lesions and non-target lesions 
response); 

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o Categorical lesion count using the following categories: (0) no lesion; (1) <25 lesions; 
(2) 25-50 lesions; (3) 51-75 lesions; (4) >75 lesions; 
o Assessment of lesion elevation. 
• 
Have the subject (or parent/guardian for subjects under the developmental age of 7 years) 
complete the subject self-assessment survey. 
• 
Take a photograph of the angiofibroma according to the Standardized Operation Procedure 
(Appendix 2).  
• 
Record any AEs. 
• 
Inform Subjects that they may be approached to participate in future trials with this product. 
• 
Dismiss the subject from the study. 
7.3 
Efficacy Assessments 
Efficacy will be assessed using the Investigator’s Global Assessment (IGA) of the facial skin 
lesions; the facial angiofibromas severity index (FASI), a composite score based on erythema, size, 
and lesion extension scores; time to and proportion of subjects with a 30% improvement of the 
composite score (FASI); lesion counts; proportion of subjects with at least 2-grade improvement 
in categorical lesion counts; proportion of subjects with at least 2-grade improvement in lesion 
elevation score; and proportion of subjects with at least 2-grade improvement in the subject self-
assessment survey; overall response assessment of target lesions and non-target lesions including 
the size and color based on Modified Nobel Scoring System; proportion of subjects with at least 
Moderate Improvement on Modified Nobel Scoring System; and proportion of subjects with at 
least a 2-grade improvement on the Week 12 IGA. Photographs will be taken of the involved area 
for documentation purposes at clinic visits. 
7.3.1 
Primary Efficacy Assessment: Investigator’s Global Assessment 
The investigator will perform the IGA at Screening, Visit 2 (Baseline), Visit 3 (Week 4), Visit 5 
(Week 12), Visit 6 (Week 16), Visit 8 (Week 24) and Early Withdrawal. The scale in Table 7-1 
will be used; the IGA was developed based on discussion with FDA during the PIND meeting, the 
agency’s guidance for Acne Vulgaris and recent FDA approved products (i.e., Mirvaso):    
Reference:  http://www.fda.gov/downloads/Drugs/.../Guidances/UCM071292.pdf 

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Table 7-1    Investigator’s Global Assessment (IGA) 
Description 
Grade 
Disease Status 
Clear 
0 
Clear skin with no signs of erythema and no disease related lesions 
Almost clear 
1 
Slight redness with few disease related lesions,  
Mild 
2 
Greater than Grade 1; definite redness with scattered, some disease 
related lesions 
Moderate 
3 
Greater than Grade 2; marked redness, concentrated, many disease 
related lesions 
Severe 
4 
Greater than Grade 3; Very bright redness, confluent, highly 
concentrated disease related lesions  
Very severe 
5 
Greater than Grade 4; fiery redness, very extensive disease related 
lesions covering very large area of the face 
 
7.3.2 
Secondary Efficacy Assessment: Facial Angiofibroma Severity Index (FASI) 
At study visits (Visit 1 through Visit 3, Visit 5 Visit 8 and Early Termination), the investigator 
will grade the treatment area for erythema, average size, and degree of involved skin (lesion 
extension). The grades for erythema, size, and extension are presented in Table 7-2. A composite 
score, the Facial Angiofibromas Severity Index (FASI), will be derived from these measurements.   
 

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Table 7-2    Scoring for Erythema, Size, and Extension 
Score 
Description 
Erythema  
 
0 
Clear skin with no signs of erythema 
1 
Almost clear; slight redness 
2 
Mild erythema; definite redness 
3 
Moderate erythema; marked redness 
4 
Severe erythema; very bright redness 
 
 
 
 
Size 
 
0 
No lesions 
1 
Few lesions, average lesion size ≤ 2mm 
2 
Scattered, some lesions, average lesion size >2 to ≤5mm 
3 
Concentrated, many lesions, average lesion size >5mm to ≤10mm 
4 
Confluent, highly concentrated lesions 
 
 
 
 
Extension 
 
 
0 
No lesions 
2 
≤ 50% of the cheek surface 
3 
> 50% of the cheek surface 
 
 
7.3.3 
Secondary Efficacy Assessment: Lesion Count 
At Visit 1 through Visit 3, Visit 5 Visit 8 and Early Termination the investigator will perform a 
lesion count, based on the categories presented in Table 7-3. 

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Table 7-3    Lesion Count Categories 
Score 
Description 
0 
No lesion 
1 
< 25 lesions 
2 
25 to 50 lesions 
3 
51 to 75 lesions 
4 
>75 lesions 
 
7.3.4 
Secondary Efficacy Assessment: Lesion Elevation 
At Visit 1 through Visit 3, Visit 5, Visit 8 and Early Termination, the investigator will assess the 
degree of lesion elevation in the area of interest.  
Table 7-4    Lesion Elevation Categories 
Score 
Description 
0 
No elevation over normal skin 
1 
Possible but difficult to ascertain whether there is slight 
elevation above normal skin 
2 
Slight but definite elevation 
3 
Moderate elevation  
4 
Marked elevation  
 
7.3.5 
Secondary Efficacy Assessment: Subject Self-Assessment Survey 
Subjects, or their parent/guardian for subjects under the developmental age of 7 years, will be 
asked to complete the subject self-assessment survey, displayed in Table 7-5, at each clinic visit.   

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Table 7-5    Subject Self-Assessment Survey 
Circle the number that best describes the status of your facial bumps RIGHT NOW. 
0 
No redness and no disease-related bumps 
1 
Very mild redness with few very small bumps 
2 
Mild redness with some scattered bumps 
3 
Moderate redness with many small and medium sized bumps 
4 
Severe redness with numerous small, medium and large sized bumps 
 
7.3.6 
Secondary Efficacy Assessment: Modified Nobel Scoring System 
At study visits (Visit 2, Visit 3, Visit 5, Visit 6, Visit 8 and Early Termination), the investigator 
will perform response assessment of target lesions and non-target lesions including the size and 
color based on Modified Nobel Scoring System. 
7.3.6.1 
Response for Target Lesions 
Before scoring, the investigator should choose 3 of the largest isolated lesions as target lesions, 
then measure both the Volume and Color of each lesion as indicated below, using provided label: 
 
Measure lesion dimensions to the nearest 0.1 mm; 
 
Assess color of the lesion using provided color panel; 
 
Take a close-up photo of each lesion, including the color panel and mm scale label on the 
same plane; 
 
Volume of one lesion = (long diameter) x (short diameter) x (short diameter)/2. 
Color scale of 1-6 as displayed in Table 7-6: 

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Table 7-6    Color Scale for Color Assessment 
 
The investigator will calculate total volume and total color score of all 3 target lesions at baseline 
visit and each post-baseline visit, and calculate the percent change from baseline in total volume 
and percent change from baseline in total color then average these two percent change from 
baseline values to give improvement score. The scale in Table 7-7 will be used for response 
assessment of target lesions. 
Table 7-7    Scale for Response Assessment of Target Lesions 
Score 
Response Category 
Criterion 
-1 
Worsened 
20% or more increase 
0 
Unchanged 
Less than 20% reduction 
1 
Slight improvement 
≥20% - <50% reduction 
2 
Moderate improvement 
≥50% - <75% reduction 
3 
Remarkable improvement 
≥75% reduction 
 
7.3.6.2 
Response for Non-Target Lesions 
All lesions that are not selected as target lesions are defined as non-target lesions. Only three 
response categories will be defined.  
The scale for non-target lesions response assessment as listed in Table 7-8. 
Table 7-8    Scale for Response Assessment of Non-Target Lesions 
Score 
Response Category 
Criterion 

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-1 
Worsened 
Overall color increased by 1 
grade or overall size/extent 
increased by 20% or new 
lesions 
0 
Not worsened, not remarkable 
improvement 
 
1 
Remarkable improvement 
Overall color decreased by at 
least 2 grades and overall 
size/extent decreased by 75% 
 
7.3.6.3 
Overall Response for Target and Non-Target Lesions 
Before assessment, the investigator should add the scores from both target and non-target lesions 
evaluation. Overall response for Target and Non-Target lesions can be performed using the 
following scale in Table 7-9. 
Table 7-9    Scale for Overall Response Assessment 
Score 
Response Category 
-1 or less 
Worsened 
0 
Unchanged 
1 
Slight improvement 
2 
Moderate improvement 
3 or more 
Remarkable improvement 
 
All measurements and scoring will be performed by investigator at each post-screening visit. At 
the baseline visit, only the measurements will be taken for comparison. 
7.3.7 
Independent Review Committee (IRC) on Photograph Assessment  
7.3.7.1 
Members of the IRC 
Independently of the assessment of IGA and Modified Nobel Scoring System by the investigator, 
an independent review committee will blindly assess and judge the status of each lesion from the 
medical and technical viewpoints, using the photographs of the skin lesions of individual subjects 
collected from investigational sites. The independent review committee members will be blinded 

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to treatment assignment. The members of the IRC will consist of two dermatologists who are 
independent from persons involved in the sponsorship or the conduct of the study, such as the 
investigator, sub-investigators, study collaborators, coordinating investigators, medical experts, 
and the sponsor, and who treat patients with angiofibroma in everyday practice and have no direct 
conflict of interest with the sponsor. In the event there is a discrepancy between the two members 
of the IRC, a third dermatologist will perform adjudication and select dermatologist 1 or 
dermatologist 2. 
7.3.7.2 
Transmission, Control, Compensation, Masking, and Checking of Image Files 
Canfield Scientific, Inc. will be responsible for transmission, control, compensation, masking, and 
checking of image files and will supply a written Work Instruction detailing the specific 
Photographic Review process in separate document. In accordance with separately prepared 
written procedures, the investigator or study collaborators will take the photographs of each lesion 
with provided label and color panel, mask images in the image files of the photographs if 
necessary, and transmit the image files to the CRO in charge of the control and compensation of 
the image files via a dedicated server. In accordance with separately prepared written procedures, 
the CRO in charge of the control and compensation of the image files will check, retain, and control 
the photographic image files stored on the dedicated server and store the image files that were 
compensated for color tone in the prescribed location on the dedicated server. The sponsor will 
periodically access the dedicated server as appropriate and ascertain if photographing and the 
transfer, retention, control, compensation, etc., of image files are being performed appropriately. 
7.3.7.3 
IRC 
The sponsor, the CRO in charge of the control and disposition of image files, and the members of 
the IRC will hold meetings of the IRC in accordance with the written procedure for holding 
meetings of the IRC, which is separately prepared. 
7.4 
Assessment of Safety 
7.4.1 
Adverse Events 
7.4.1.1 
Adverse Events Assessments 
An adverse event (AE) is an untoward medical occurrence in any subject during the study which 
does not necessarily have a causal relationship with the study drug treatment. Adverse events can 
be categorized as treatment-emergent or treatment-related. All AEs will be recorded and will be 
documented in the CRFs.  
AEs will be collected from the time the subject signs informed consent/assent until 30 days after 
the last investigational product administration. Serious adverse events (SAEs) must be reported to 
the sponsor within 24 hours of awareness. The condition of the subject will be monitored 

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throughout the study for any signs or symptoms. The occurrence of AEs should be sought by 
nondirective questioning of the subject at each visit during the study. All AEs will be collected as: 
• 
The subject’s positive response to questions about their health. 
• 
Symptoms spontaneously reported by the subject. 
• 
Clinically relevant changes and abnormalities observed by the investigator (e.g., local and 
systemic tolerability, laboratory measurements, results of physical examinations, 
monitoring for infections and noninfectious pneumonitis). 
If an AE worsens in intensity, it should be recorded as a new AE. Otherwise, it continues as the 
first report (counted as the same AE) until the subject is recovered. 
The investigator or designee will record the following on the AE CRF: 
• 
Adverse event and relevant clinical findings 
• 
Time/date of onset 
• 
Time/date of recovery 
• 
Intensity 
• 
Action taken on study drug/treatment 
• 
Other action taken to treat the event 
• 
Relation to study drug/treatment 
• 
Seriousness of the AE 
Adverse events requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the subject. Treatment due to an AE will be recorded. 
All AEs with moderate or greater intensity and/or possibly or probably related to the study drug(s) 
or study procedure must be followed by the investigator until it is resolved or until the medical 
condition of the subject is stable; all relevant follow-up information will be reported to the sponsor. 
The outcome of an AE will be classified as recovered/resolved, recovered/resolved with sequelae, 
recovering/resolving, not recovered/not resolved, fatal or unknown. 
Safety assessment will include assessment of local safety (e.g., through active assessment of local 
signs and symptoms, such as scaling, itching etc.) as well as systemic safety. If a subject 
experiences a generalized rash or other health issue in the treatment area, the subject (or 

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parent/guardian) should contact the study site and the subject should report to the study center for 
examination. 
7.4.1.2 
Timing 
Adverse events will be assessed after the subject signs informed consent/assent and at all study 
visits.  
Treatment-emergent AEs include any untoward medical occurrence in a subject or clinical 
investigation subject after administration of an investigational study treatment, which does not 
necessarily have to have a causal relationship with this treatment. A treatment-emergent AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the product, whether or not related to 
the medicinal (investigational) product. It could also include accidents and reasons for changes in 
medication (drug and/or dose). 
Treatment-related AEs are all treatment-emergent AEs that are considered by the investigator as 
causally related to administration of the study drug. 
7.4.1.3 
Severity of Adverse Events 
The investigator is to classify the severity (intensity) of an AE according to the following 
definitions: 
• Mild – The subject was aware of the signs and symptoms but the signs and symptoms were 
easily tolerated. 
• Moderate – The signs and symptoms were sufficient to restrict, but did not prevent, usual 
daily activity for the subject. 
• Severe – The subject was unable to perform usual daily activity. 
The maximum intensity of an AE (mild, moderate, or severe) will be assessed taking into 
account the possible range of intensity of the symptom(s). 
7.4.1.4 
Relationship of an Adverse Event to Study Treatment 
The investigator is to classify the relationship of an AE to the investigational product using good 
clinical judgment and the following definitions: 
Not Related 
The AE is clearly explained by another cause not related to the study 
product. 
 

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Probably Not Related 
A potential relationship between study product and the AE could exist 
(i.e., the possibility cannot be excluded), but the AE is most likely 
explained by causes other than the study agent. 
 
Possibly Related 
The AE and administration of study product are temporally related, but 
the AE can be explained equally well by causes other than the study 
product. 
 
Probably Related 
The AE and use of study product are temporally related, and the AE is 
more likely explained by study product than by other causes. 
 
Related 
The AE and use of study product are related in time, and a direct 
association can be demonstrated. 
 
7.4.1.5 
Unexpected Adverse Events 
See the Investigator’s Brochure to determine expectedness of serious adverse events for expedited 
reporting. An AE is considered “unexpected” if it is not listed in the Package Insert of the marketed 
sirolimus oral products or in the Investigator’s Brochure, or is not listed at the specificity or 
severity that has been observed; or, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended.  
7.4.1.6 
Adverse Events of Special Interest 
There are currently no known adverse events of special interest. The investigator should evaluate 
any reactions in the treatment area. If a subject has any reaction in the treatment area, the subject 
should return to the site for evaluation. 
7.4.1.7 
Adverse Events Causing Treatment Discontinuation 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and 
reason provided in the eCRF, and the patient must be followed until the resolution of the AE or as 
instructed by the Medical Monitor. 
7.4.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• is life-threatening 
• results in death 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 

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• is an important medical event. 
The death of a subject enrolled in a study is per se not an event, but an outcome. Any event resulting 
in a fatal outcome must be fully documented and reported, regardless of the causality relationship 
to the investigational product. 
The term life-threatening refers to an AE in which the subject was at immediate risk of death at 
the time of the event. It does not refer to an event, which may have caused death, if it was more 
severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. Examples of important medical events include AEs, which suggest 
a significant hazard, contraindication or precaution, occurrence of malignancy, or development of 
drug dependency or drug abuse. 
Any SAE, whether or not deemed drug-related or expected, must be reported immediately to the 
sponsor or designee via email as soon as it becomes known to the investigator and not later than 
within 24 hours of his/her knowledge of the occurrence of an SAE. The investigator will document 
such events in the best possible detail on the SAE Report Form to be transmitted by email. SAEs 
will be collected from the time the subject signs informed consent/assent until 30 days after the 
last investigational product administration. 
A pre-scheduled elective procedure is not to be considered an SAE, even if the subject is 
hospitalized, provided the condition requiring the pre-scheduled elective procedure was present 
before and did not worsen or progress between the subject’s consent to participate in the study and 
the time of the procedure. In addition, the pre-scheduled elective procedure must be the sole reason 
for admission and intervention. An adverse event occurring during the pre-scheduled elective 
procedure should be recorded as an AE or SAE.  
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that is both unexpected (not 
consistent with the current Investigator’s Brochure/product information) and for which there is 
evidence to suggest a causal relationship between the drug and the AE. As a minimum requirement, 
the Investigator must report all SUSARs to their IRB.  All investigators participating in the trial 
will also be notified appropriately of SUSARs. The sponsor will report SUSARs and other events 
requiring expedited reporting to regulatory authorities as required.  
Investigator instructions for reporting SAEs are provided in Section 13.2. 

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7.4.3 
Dermatologic Stopping and Follow-up Criteria 
Dermatologic stopping criteria are defined below: 
If a subject has worsening angiofibromas where the investigator feels the worsening has a causal 
relationship to the study drug, the study drug should be stopped. If the investigator would like to 
restart the drug within 7 days as a re-challenge, they can do this in consultation with the Medical 
Monitor. A second re-challenge will not be allowed and the subject should be discontinued.  
If the investigator feels that the angiofibromas are worsening (such as 2 grades higher on the IGA) 
that is abnormal in disease progression and the investigator feels it is not in the subject’s best 
medical interest to continue in the study, they can schedule an early termination visit and 
discontinue the subject. 
7.4.4 
Safety Laboratory Assessments 
Blood samples and optional urine samples will be collected for routine safety laboratory tests 
(hematology, serum biochemistry, and urinalysis) at Visit 1 (Screening), Visit 3 (Week 4), Visit 
5/End of Double-blind Treatment, Visit 6 (Week 16), Visit 8 (Week 24) or at early termination 
from the study. Clinical laboratory specimens will be analyzed by a central licensed and accredited 
laboratory facility according to the laboratory’s standard operating procedures (For China, clinical 
laboratory specimens will be analyzed by local lab). The following tests will be performed: 
Hematology:  hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) 
count with differential, and platelet count, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) 
Serum chemistry:  glucose (non-fasting, but for China, glucose will be tested under fasting 
state), blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, sodium, potassium, chloride, calcium, 
phosphorus, bicarbonate, uric acid, lactic dehydrogenase (LDH), total protein, albumin, 
bilirubin (total and direct), total cholesterol, triglycerides  
Urinalysis:  color/appearance, pH, specific gravity, glucose, ketones, protein, and microscopic 
appearance. 
The investigator may collect additional blood or urine samples to repeat any laboratory test that 
was abnormal post-dosing, was within normal limits at Baseline, and is considered clinically 
significant. Abnormal laboratory results at the last scheduled visit may require additional 
collection of samples on an “as needed” basis until: a) the values return to the baseline value, b) 
the values are within normal limits, c) the values are clinically stable, or d) the investigator 
determines that further follow-up is unnecessary. The investigator will record the date and time of 

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all additional samples collected. If the investigator establishes a clear explanation for the 
laboratory abnormality, he or she will record this explanation in the CRFs. 
7.4.5 
Pregnancy Testing 
Female subjects of child-bearing potential will undergo a UPT at the screening visit before any 
study-specific procedures are performed. If the UPT is positive, the subject will not be permitted 
to enroll in the study. In the unlikely event that a urine pregnancy test cannot be obtained, a serum 
pregnancy test can be run from the serum sample collected.   
Pregnancy tests will be performed at all clinic study visits on female subjects of child-bearing 
potential. The pregnancy tests must have a sensitivity of at least 25 mIU/mL. If there is a suspicion 
of pregnancy at any time during the study, a urine sample will be obtained and tested. Should a 
subject become pregnant during the study, treatment must be discontinued. Subjects should 
continue with non-treatment and/or follow-up visits. For China, different pregnancy test procedure 
would be followed. 
All pregnancies should be immediately reported to the sponsor/Contract Research Organization 
(CRO)/Medical Monitor and followed through to resolution (i.e., delivery, miscarriage, or 
abortion). The report should be submitted within the same timelines as an SAE (within 24 hours 
of knowledge), although a pregnancy per se is not considered an SAE. Information on the status 
of the fetus and the mother may be requested (see Section 7.4.2) to include outcome of delivery.  
If the pregnancy is associated with an SAE (e.g., if the mother is hospitalized for dehydration), in 
addition to the pregnancy report form, a separate SAE report form must be filed. Miscarriage, 
stillbirth and any malformation/disease must be reported as a SAE. Any pregnancy leads to the 
immediate cessation of the study treatment. 
7.4.6 
Vital Signs 
Measurements of vital signs, including blood pressure, pulse rate, and respiratory rate, will be 
taken at every clinic visit with the subject seated. 
7.4.7 
Physical Examination 
At the screening visit, Visit 8, and Early Termination visits, the investigator or designee will 
complete an abbreviated general physical examination including measurements of weight (in 
pounds) and height (inches). 
7.4.8 
Pharmacokinetics 
A single blood sample will be collected at Visit 3 (Week 4/Day 28) during the double-blind 
treatment period for plasma sirolimus determination.  

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The actual collection time of the blood sample must be recorded in the source data, collection tube 
and in the eCRF. Exact prior dosing must be recorded in the source data and in the eCRF.  
 
The central laboratory will provide all materials and supplies to be used for the collection and 
shipment of biological samples.  
 
Plasma samples for study medication measurements will be stored at the investigational site and 
shipped as specified in the study lab manual. Plasma samples will be packaged and shipped directly 
to the bioanalytical laboratory. Specific details on sample collection, processing, aliquoting, 
storage, and shipping instructions are provided in the laboratory manual. 
 
Plasma sample PK analysis will be performed using validated procedures and methods. 
 
7.5 
Appropriateness of Measurements 
The safety evaluations are the standardized and most widely accepted methods for evaluating 
safety in clinical trials. Methodology for evaluating efficacy in the treatment of TSC-related facial 
angiofibromas are not well established; the methodology in this study was developed according to 
reports in the literature.8-18  
8.0 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
STATISTICAL AND ANALYTICAL PLANS 
8.1 
General Considerations for Data Analysis 
The methodology presented below represents a brief overview of the statistical methods that will 
be fully detailed in the statistical analysis plan (SAP). The SAP will be finalized before the 
database is locked and unblinded. Any changes to the methods described in the final SAP will be 
described and justified in the clinical study report. It is planned that the data from all centers that 
participate in this protocol will be combined so that an adequate number of subjects will be 
available for analysis. All statistical analyses will be performed using SAS statistical software 
(Version 9.2 above).  
Statistical significance will be tested at the 2-sided 5% level. No adjustments for multiplicity are 
planned.  
All efficacy and safety analyses will be performed on observed data with no imputation unless 
otherwise specified. For the analyses of treatment response, subjects having a missing responder 
status will be analyzed as non-responders.  

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8.2 
Sample Size and Power Considerations 
This study is exploratory in nature and the sample size is not based on a statistical rationale. For 
sample size calculation, reliable assumptions on the difference between treatments for the 
primary efficacy parameter must be present. However, currently no such data in subjects with 
TSC are available for sirolimus. Therefore, practical considerations were used for sample size 
calculation. The planned number of 45 subjects is considered to be sufficient to provide a reliable 
answer on the efficacy of sirolimus in concentrations of 0.2% and 0.4% in subjects with TSC 
compared to placebo (in a 1:1:1 ratio) and to achieve insight into the safety of sirolimus. 
8.3 
Analysis Populations 
The primary statistical analyses will be performed on the Intent-to-Treat (ITT) population 
(efficacy), Per-Protocol population (efficacy) and Safety population (safety). The analysis 
populations are defined as:  
• Intent-to-Treatment (ITT) population will include all randomized subjects. This will be the 
population for efficacy analysis. 
• The Per-Protocol (PP) population will include all ITT subjects with no major protocol 
deviation and with >80% study drug compliance rate, where the drug compliance will only 
apply to active treatment groups. Efficacy analyses will be repeated on this population as 
a sensitivity analysis.  
• Safety population will include all subjects who were randomized and dispensed the study 
medication at Randomization / Day 1, excluding subjects who return all of the study 
medication unused. This will be the population for safety analysis. 
8.4 
Interim Analysis 
One interim analysis will be performed. 
The  interim analysis will be conducted by the study team when all subjects have completed the 
double-blind phase (Visit 5 - Week 12). The database will be locked and unblinded to assess for 
efficacy and safety. The results will be reported in the clinical study report (CSR).  
In the event of early stopping due to interim analysis results, subjects will be brought to the 
investigational sites for a final visit.  The final analysis will include all data collected up to and 
including the final visit. 
 

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8.5 
Analysis of Efficacy 
All original and derived efficacy parameters as well as population characteristics will be described 
using summary statistics. All primary and secondary efficacy endpoints will be analyzed for 
pairwise differences between treatment groups. 
8.5.1 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint will be the proportion of subjects with a clinical response of 
treatment success on Week 12. Treatment success is defined as: 
At least a 2-grade improvement on the Week 12 Investigator Global Assessment (IGA) of the 
facial skin lesions assessed by investigator. The primary efficacy endpoint will be analyzed using 
Fisher’s exact test, making all pairwise treatment comparisons. 
8.5.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be the following: 
• The proportion of subjects with an investigator assessed IGA score of clear or almost clear 
with at least a 2-grade improvement on the Week 12 IGA of the facial skin lesions; 
• The proportion of subjects with at least 30% improvement at Week 12 as compared to 
Baseline in the Facial Angiofibromas Severity Index (FASI) score, which is based on 
lesion erythema, size, and extension (Salido et.al. 2012);20 
• The time to reach at least 30% improvement from Baseline in the FASI score for 
angiofibroma severity; 
• The proportion of subjects with at least 2-grade improvement at Week 12 as compared to 
Baseline in categorical lesion counts (scored as follows: No lesion = 0; <25 lesions = 1; 
25-50 lesions = 2; 51-75 lesions = 3, >75 lesions = 4); 
• The proportion of subjects with at least 2-grade improvement at Week 12 as compared to 
Baseline in lesion elevation score; 
• The proportion of subjects with at least 2-grade improvement at Week 12 as compared to 
Baseline in the subject self-assessment survey; 
• Overall Response of angiofibroma assessed by the investigator at Week 12 as compared 
to baseline based on Modified Nobel Scoring System; 
• Overall Response of angiofibroma assessed by the IRC at Week 12 as compared to 
baseline based on Modified Nobel Scoring System; 

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• The proportion of subjects with at least Moderate Improvement (a score of 2) on Modified 
Nobel Scoring System assessed by the investigator at Week 12; 
• The proportion of subjects with at least Moderate Improvement (a score of 2) on Modified 
Nobel Scoring System assessed by the IRC at Week 12; 
• The proportion of subjects with at least a 2-grade improvement on Week 12 Investigator 
Global Assessment (IGA) of the facial skin lesions assessed by the IRC. 
Treatment comparison of the proportion of treatment success with clear or almost clear will be 
conducted using Fisher’s exact test at each time point, making all pair-wise comparisons. 
Descriptive statistics for observed values, absolute changes, and percent changes from Baseline 
(for FASI lesion score) and Number and percentage of subjects reached each overall response level 
for Modified Nobel Scoring System score will be summarized by treatment group at each time 
point. Student’s t-test will be used for pairwise comparison of continuous endpoints at each time 
point. Wilcoxon rank sum test will be used to compare Modified Nobel Scoring System score. 
Fisher’s exact test will be used for categorical endpoints. Time to reach at least 30% improvement 
from Baseline in the FASI score will be analyzed using Kaplan-Meier method, making all pairwise 
treatment comparisons. Proportion of subjects with at least Moderate Improvement on Modified 
Nobel Scoring System will be analyzed using Fisher’s exact test, making all pair-wise comparison. 
Proportion of subjects with at least a 2-grade improvement on the Week 12 IGA will be analyzed 
using Fisher’s exact test, making all pair-wise comparisons. 
8.6 
Analysis of Safety 
The assessment of safety will be based mainly on the frequency of AEs and on the number of 
laboratory values that fall outside of predetermined ranges. Adverse events will be presented in 
data listings and summarized by frequency and severity for each treatment group. Laboratory and 
vital sign data will be presented in data listings. Abnormal laboratory findings will be presented. 
The analysis of safety will be described in the SAP. 
8.6.1 
Adverse Events  
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of subjects having any AE, having an AE in an individual body system, and having 
each individual AE. Any other information collected (e.g., severity or relatedness to study 
medication) will be listed as appropriate. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term. The incidence of AEs (percent of subjects 
reporting the AE at least once) will be tabulated separately for each treatment group by severity 
and relationship to drug.  

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8.6.2 
Other Safety Variables 
Clinical laboratory values will be reported as complete listings of individual subject data. Clinical 
laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw data and 
change from baseline values (means, medians, standard deviations, ranges), and by the flagging of 
notable values in data listings. 
Data from other tests (e.g., vital signs, special tests) will be considered as appropriate and listed. 
Notable values will be flagged, and any other information collected will be listed as appropriate. 
Any statistical tests performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration. 
8.7 
Quality of Life Analysis 
Not applicable. 
 
9.0 
CHANGES IN THE PLANNED STUDY 
9.1 
Protocol Amendments 
With the exception of administrative changes, any changes or additions to this clinical study 
protocol require a written protocol amendment that must be approved by the sponsor, the Contract 
Research Organization (CRO), and the investigator(s) before implementation. Amendments 
significantly affecting the safety of subjects, the scope of the investigation, or the scientific quality 
of the study, require additional approval by the IRB for each study center.   
These requirements for approval should in no way prevent any immediate action from being taken 
by the investigator or the sponsor in the interests of preserving the safety of all subjects included 
in the trial. If an immediate change to the protocol is felt to be necessary by the investigator and is 
implemented for safety reasons, the sponsor should be notified and the IRB should be informed 
according to their reporting requirements. 
9.2 
Termination or Suspension of the Study 
The sponsor reserves the right to terminate or suspend the study at any time or a subject’s 
participation due to a protocol amendment. In case of premature termination or suspension of the 
study, the CRO project manager will promptly inform the investigators, regulatory authorities, and 
IRBs about the premature termination or suspension, including the reason for it. In terminating the 
study, the sponsor and the investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 

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10.0 
DATA HANDLING AND RECORD KEEPING 
10.1 
Recording of Data 
10.1.1 
Source Documents 
Source data are all the information in original records and copies of original records of clinical 
findings, observations, or other activities in the study, which are necessary for the reconstruction 
and evaluation of the study. The identification of any data to be recorded directly on the CRFs is 
to be considered source data.  
Study data collection procedures must ensure that each data element can be traced with a high level 
of confidence from its originator or recorder to its representation in the study database and then to 
its place in the analysis and report of study results. Once recorded, the study data must be protected 
from unauthorized modification or deletion, and all authorized modifications and deletions must 
be securely linked in the permanent record with their author, time of change, and reason for change 
(i.e., the audit trail must be maintained). 
The investigator will permit study-related monitoring, audit(s), IRB/IEC review(s) and regulatory 
inspection(s), with direct access to all the required source records. 
The principal investigator will certify the data to be accurate and complete and will release the 
data for transmittal to the sponsor or CRO. 
Source records need to be preserved for the maximum period of time permitted by local 
requirements (see Section 10.2). For each subject enrolled, the investigator will indicate in the 
source record(s) that the subject participated in the study. 
10.1.2 
Case Report Forms 
The primary data collection tool for the study is an electronic case report form (eCRF) designed 
specifically for the study. For each subject enrolled in the study, an eCRF will be completed by 
the study coordinator and signed by the investigator or his/her designate.  
The investigator will be responsible for ensuring the accuracy of all data entered in the eCRFs. All 
eCRFs are to be completed in a timely manner. 
Errors occurring in the eCRFs will be queried. Queries raised by data reviewers must be addressed 
by site personnel. 
On request, the investigator will provide the sponsor with additional data relating to the study, or 
copies of relevant source records, duly anonymized (i.e., subject’s name is redacted). 

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10.2 
Retention of Documents 
The United States Food and Drug Administration (FDA)/ ICH regulations require all investigators 
participating in clinical drug trials to maintain detailed clinical data for one of the following 
periods: 
• 
at least two years following the date on which a Marketing Application is approved by the 
FDA/applicable regulatory or health authority, or 
• 
two years after the sponsor notifies the investigator that no further application is to be filed 
with the health authorities 
Similarly, ICH guidelines require that essential documents be retained until at 
least two years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in 
an ICH region, or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product. European Union (EU) 
Directive 2001/63/EC requires that essential documents be retained for at least 
15 years after completion or discontinuation of the trial. 
To comply with these requirements, the investigator will not dispose of any records relevant to 
this study without either (1) written permission from the sponsor, or (2) providing an opportunity 
for the sponsor to collect such records. The investigator shall take responsibility for maintaining 
adequate and accurate hard copy source documents of all observations and data generated during 
this study, including any data clarification forms received from the sponsor. Such documentation 
is subject to inspection by the sponsor or its agents, the FDA and/or other regulatory agencies. 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Direct Access to Source Documents 
As specified in the investigator’s agreement, the investigator agrees to allow study-related 
monitoring, audit(s), IRB/IEC review(s) and regulatory inspection(s), with direct access to all the 
required source records, and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues.   
11.2 
Monitoring Procedures 
The Clinical Study Monitor will contact and/or visit the investigator site periodically to verify the 
adherence to the protocol, the maintenance of study-related source records, and the completeness 
and accuracy of all CRF entries compared to source data. The investigator will cooperate with the 
study monitor to ensure that any discrepancies that may be identified are resolved. 

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11.3 
Audit and Inspection 
The investigator will make all the study-related source data and records available to a quality 
assurance auditor mandated by the sponsor, or to domestic or foreign regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights and 
well-being of the subjects have been adequately protected, and that all data relevant for the 
evaluation of the investigational product have been processed and reported in compliance with 
GCP/ICH and applicable regulatory requirements. 
The investigator is to notify the sponsor/CRO immediately of any inspection by regulatory 
authorities or IRBs. 
12.0 
ETHICS 
12.1 
Ethical Conduct of the Study 
This study must be carried out in compliance with the protocol and the applicable laws and 
regulatory requirements of the US Food and Drug Administration (FDA) as well as CFDA (China 
Food and Drug Administration). The study must be conducted in accordance with the ethical 
principles originating from the Declaration of Helsinki and amendments and the International 
Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines. 
12.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
This protocol, the proposed informed consent form, and other information for subjects must be 
reviewed and approved by an IRB or IEC, before the start of the trial, in compliance with local 
regulations. This committee must also approve any amendments to the protocol, other than 
administrative ones, before initiation of the amendment procedures. 
12.3 
Subject Information and Consent 
Before participation in the study, each subject and/or their parent/guardian is required to provide 
written consent to participate in the study. Subjects under the age of 18 years are required to 
provide assent, in accordance with IRB specifications. No study-specific procedures will be 
performed before a subject’s informed consent/assent is obtained.   
12.4 
Disclosure and Confidentiality 
12.4.1 
Confidentiality of Study Documentation 
By signing the protocol, the investigator agrees to keep all information provided by the sponsor in 
strict confidence and to request similar confidentiality from his/her staff and the IRB or IEC.  Study 
documents provided by the study sponsor (i.e., protocols, Investigators' Brochures, CRFs and other 
material) will be stored appropriately to ensure their confidentiality. The information provided by 
the sponsor to the investigator may not be disclosed to others without direct written authorization 

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from the sponsor, except to the extent necessary to obtain informed consent from subjects who 
wish to participate in the trial. 
12.4.2 
Privacy of Individual Health Information  
The investigator will undertake to protect the privacy of all individually identifiable health 
information except as specifically authorized by each individual subject through the written 
informed consent. The Informed Consent document will include a request of the subject’s consent 
to release the collected data for research purposes in such a way that the individual’s identity 
remains masked. While all data records will be identified by the corresponding subject number, 
the identity of the subject will be held in confidential source documents at the study site. All study 
personnel with access to this information are legally bound not to disclose such information. 
13.0 
EMERGENCY PROCEDURES 
13.1 
Emergency Unblinding 
Unblinding should only be performed in emergencies where knowledge of the subject’s treatment 
assignment is essential for further management of the subject’s medical care. Unblinding a 
subject’s treatment assignment under any other circumstances will be considered a protocol 
violation.  
The investigator should assess the relationship of any AEs to administration of the investigational 
product prior to unblinding. 
The investigator is required to contact the study Medical Monitor before unblinding any subject’s 
treatment assignment. Instructions for “breaking the blind” will be provided to the Investigator.  
The subject’s treatment code should not be communicated to the Medical Monitor or designee. 
The unblinding will be documented by the investigator.  
If the treatment assignment is unblinded during the double-blind treatment period, the subject 
will not be allowed participation in the open-label treatment period of the study. 
13.2 
Reporting of Serious Adverse Events and Pregnancies 
13.2.1 
Contact Person(s) and Number(s) 
Serious adverse events and pregnancies must be reported immediately (i.e., not later than 24 hours 
after first knowledge) to the sponsor or designee. 
Contact Information: 
Email for reporting initial SAE: DRUGSAFETY-AUCTA@DMEDGLOBAL.COM  
Email for reporting SAE follow-up information:  

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DRUGSAFETY-AUCTA@DMEDGLOBAL.COM   
13.2.2 
Reporting Procedures 
Serious Adverse Events 
For each SAE, the investigator will complete a Serious Adverse Event Report Form and assess the 
relationship of each SAE to study treatment. The completed form(s) should be sent electronically 
to the designated SAE email within 24 hours of first knowledge of the SAE.   
Follow-up reports regarding the status of the SAE and the subject’s subsequent course should be 
submitted until the SAE has subsided, the condition stabilized (in the case of persistent 
impairment), the subject receives alternative therapy, or the subject dies. The form and email 
confirmation will be retained. Contacts for reporting SAEs and other safety concerns are provided 
to each site.  
14.0 
PUBLICATION POLICY 
Written permission must be obtained from the Sponsor prior to submission to a publication or 
presentation. 
If the data merit, the Investigator and the Sponsor will discuss the preparation of a manuscript for 
publication in a peer-reviewed professional journal or an abstract for presentation, oral or written, 
to a learned society or symposium. Authorship should reflect work done by the Investigators and 
personnel of the Sponsor, in accordance with generally recognized principles of scientific 
collaboration. 
15.0 
REFERENCE LIST 
1. 
National Institute of Neurological Disorders and Stroke (NINDS). Tuberous sclerosis fact 
sheet, located at 
http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm. 
Accessed 17 May 2016. 
2. 
Northrup H, Koenig MK, Pearson DA, Au K-S. Tuberous Sclerosis Complex, located at 
http://www.ncbi.nlm.nih.gov/books/NBK1220/?report=printable. Accessed 23 May 
2016. 
3. 
NINDS Tuberous Sclerosis Complex Conference Summary, located at 
http://www.ninds.nih.gov/news_and_events/proceedings/2002_tsc_conference.htm#invol
vement. Access 17 May 2016. 
4. 
Madke B. Topical rapaymycin (sirolimus) for facial angiofibromas. Indian Dermatol 
Online J. 2013 Jan-Mar; 4(1): 54–57. 

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5. 
Li S, Takeuchi F, Wang J, et al. Mesenchymal-epithelial interactions involving epiregulin 
in tuberous sclerosis complex hamaratomas. PNAS 2008; 105: 3539-44 
6. 
Song MG, Park KB, Lee ES. Resurfacing of facial angiofibromas in tuberous sclerosis 
patients using CO2 laser with flashscanner. Dermatol Surg. 1999;25(12): 970-973. 
7. 
Rapamycin. Medscape website: http://emedicine.medscape.com/article/1177711-
treatment updated Oct 14, 2015. Accessed 02 June 2016. 
8. 
Koenig, Mary; Hebert, Adelaide; Roberson, Joan; Samuels, Joshua; Slopis, John; 
Woerner, Audrey; Northrup, Hope. Drugs in R&D. 2012, Vol. 12 Issue 3, p121-126. 
9. 
Haemel, A.K.; Teng, J.M.; O'Brian, A.L. Archives of Dermatology, July 2010, 
146(7):715-718. 
10. 
Wheless, JW; Almoazen, H. Journal of Child Neurology; JUL, 2013; 28; 7; p933-p936. 
11. 
Tanaka, M.; Wataya-Kaneda, M.; Nakamura, A.; Matsumoto, S.; Katayama, I. British 
Journal of Dermatology. Oct 2011, Vol. 165 Issue 4, p912-916. 
12. 
Tanaka, M.; Wataya-Kaneda, M.; Katayama, I.; Nakamura, A.; Matsumoto, S.. British 
Journal of Dermatology, December 2013, 169(6):1314-1318. 
13. 
Anadkat, M.J.; Mutizwa, M.M.; Berk, D.R.; British Journal of Dermatology, October 
2011, 165(4):922-923 Language: English. DOI: 10.1111/j.1365-2133 
14. 
Salido R., Gamacho G., Godoy E., Llorca D., Gomez C. and Moreno C.  Facial 
Angiofibroma Severity Index (FASI): reliability assessment of a new tool developed to 
measure severity and responsiveness to therapy in tuberous sclerosis-associated facial 
angiofibroma Clinical and Experimental Dermatology (2014) 39, pp 888-893. 
15. 
McNamara, K.; Curtis, A.R.; Fleischer Jr., A.B. Journal of Dermatological Treatment, 
February 2012, 23(1):46-48. 
16. 
Truchuelo, T.; Díaz-Ley, B.; Ríos, L.; Alcántara, J.; Jaén, P. Dermatology online journal, 
January 2012, 18(1):15. 
17. 
Foster, R.S.; Halbert, A.R.; Bint, L.J. Australasian Journal of Dermatology, February 
2012, 53(1):52-56. 
18. 
Dill PE, Bernardis GD, Weber P, Losch U.  Clinical Observations: Topical Everolimus 
for Facial Angiofibromas in the Tuberous Sclerosis Complex. A First Case Report.  
Pediatric Neurology. 2014; 51: 109-113 

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19. 
Rapamune (sirolimus) complete prescribing information. Wyeth Pharmaceuticals Inc. 
October 2009. 
20. 
Salido R, Gamacho-Saucedo G, Cuevas-Asencio I, Ruano J, Galán-Gutierrez M, Vélez 
A, Moreno-Giménez JC. Sustained clinical effectiveness and favorable safety profile of 
topical sirolimus for tuberous sclerosis-associated facial angiofibroma. JEADV. 
2012;26:1315-1318. 

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16.0 
APPENDICES 
16.1 
APPENDIX 1: Potential Drug Interactions 
Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The package insert 
for Rapamune (sirolimus) oral solution and tablets reports some known and potential drug 
interactions with orally-administered sirolimus. While the systemic absorption of topically-applied 
sirolimus in this study is expected to be negligible, co-administration of oral sirolimus with other 
known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, 
telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such 
as rifabutin), though not necessarily exclusionary,  should be used with caution, during the study. 
Subjects on stable doses of these medications should be discussed in advance with medical monitor 
prior to inclusion in the study.    
Drugs shown to increase sirolimus blood concentrations in drug-interaction studies included:  
• Cyclosporine.  
• Diltiazem.  
• Erythromycin.  
• Ketoconazole.  
• Verapamil. 
Other drugs with the potential to increase sirolimus blood concentrations include (but are not 
limited to): 
• Antifungal agents: clotrimazole, fluconazole. 
• Antibiotics: troleandomycin. 
• Gastrointestinal prokinetic agents: cisapride, metoclopramide. 
• Other drugs: bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, 
 
indinavir). 
16.2 
APPENDIX 2: Standardized Operation Procedure for Obtaining Digital Images in 
Sirolimus Ointment Clinical Trials for Cutaneous Angiofibromas in Subjects with 
Tuberous Sclerosis Complex  
 
For all eligible subjects providing photographic consent, photographs of the target lesion areas will 
be taken at every visit including screening and baseline, end of the study or early termination at 
any time points for documentation purpose. All the photographs are required to be of high quality 

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and resolution upon enlargement of the image, correct prospective, neutral background and even 
lighting. The following procedure should be followed and checked each time when the image is 
obtained in order to ensure the precision and objectivity of recording.  
I. Quick check for equipment and camera settings  
• Before capturing pictures, make sure the location has adequate lighting (i.e. with celling 
light above subject) and all the equipment (refer to Table I.).  
• Confirm the information written on the identification card, check camera for the right 
settings to ensure standardization (refer to Table II.). 
II. Positioning of subjects 
• For consistency, photography should be taken from the same place in the facility. 
• Remove anything that could hinder the direct and authentic photography of the lesion, such 
as a mask, hair or cosmetics. 
• Gently cleanse the lesion with saline and dry face with tissue. 
• Position the subject to stand in front of the background in a comfort way. 
III. Photography techniques 
• Take a picture of the subject with identification card to preserve blinding. 
• The camera lens should be oriented parallel to the plane of the lesion. 
• Photos were taken between 1-2 feet distance from the lesion from three directions, front, 
right 45° and left 45° (see Figure 1. for an example).  
• Make sure the face is centered, press the shutter button halfway to focus. When the aligning 
focus frame turns green, hold camera still and tight, press the button all the way to record. 
• At least two photos were taken from each direction.  
• Check the photos immediately to ensure at least one photo from each direction is focused 
and clear after enlargement, otherwise additional photos should be taken. 
• Photos of target lesions for Modified Nobel Scoring System should be close-up with mm 
scale label and color panel on the same plane as the lesion being measured. 
IV. Photograph processing and storage (For China, photograph processing and storage will 
follow canfield capture instructions provided by Canfield Scientific, Inc. and details will be 
supplied in a separate document) 
• Upload and save photos to the secure location with the cable provided. 
• Rename the photos in the following format:  
Participant Number Site_Day&Visit_Date_Orientation 
Example: 
49_BostonChildren_Day30Visit3_8May17_Front or Right45 or Left45 
• Delete photos from camera. 
 Table I.  Equipment and Materials 
Items 
Specific Choice 
Features 

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Digital 
Camera 
Panasonic LUMIX 
DMC-ZS5 
12x optical zoom lens (35mm camera 
equivalent: 25-300mm), built in flash, lithium 
ion rechargeable battery, 8GB memory card 
Background 
Blue surgical drapes 
Light weight and transportable 
Identification 
card 
Cardboard 
handwritten card 
Pre-formatted to add participant number, date 
and time of image, location, study day/visit, 
i.e. 
Participant No: 
49 
Site: 
Boston Children 
Day: 30 
Visit: 3 
Date:8-May-
2017 
Time: 2:28 PM 
 
Table II. Camera Settings* and Lighting Conditions 
Settings 
Details 
Program Mode (P)  
Taking pictures with the following setting  
Macro Zoom  
(down cursor button)  
For taking close up photographs of the subjects  
Picture Size 
12M 
Quality 
High quality 
White Balance (WB) 
Set to AWB for appropriate light compensate 
International Organization for 
Standardization (ISO) 
Set to 100  
Auto Focus Mode (AF mode)  
Set to face detection 
Metering Mode  
Set to multiple 
Stabilizer  
Set to Auto 
AF Assist Lamp 
On 
Flash (right cursor button) 
Set to forced flash on 
*Unless specified in the Table II., all the settings should be set to off, auto or standard. 
Figure 1. An Example of Capturing Photos from Three Directions 

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-Front 
 
 
 
-Right 45° 
 
 
 
-Left 45° 
 
 
Note: This figure is solely used for the purpose of providing an example of capturing subject photos 
from three directions. Panels labelled 0, 3, 6, and 9 signify months after treatment from a separate 
study, and has no relation to this study.3 
 
 
References:  
1. Bowen AC, Burns K, Tong SYC, et al. Standardising and Assessing Digital Images for 
Use in Clinical Trials: A Practical, Reproducible Method That Blinds the Assessor to 
Treatment Allocation. Soyer HP, ed. PLoS ONE. 2014;9(11):e110395. 
doi:10.1371/journal.pone.0110395. 
2. Rennert, Robert et al. "Standardization Of Wound Photography Using The Wound 
Electronic Medical Record". Advances in Skin & Wound Care 22.1 (2009): 32-38. Web. 
3. Hofbauer, G.F.L. et al. "The Mtor Inhibitor Rapamycin Significantly Improves Facial 
Angiofibroma Lesions In A Patient With Tuberous Sclerosis". British Journal of 
Dermatology 159.2 (2008): 473-475. Web. 
4. Panasonic Operating Instructions for advanced features Digital Camera Model No. DMC-
ZS5 https://data2.manualslib.com/pdf2/37/3609/360857-
panasonic/lumix_dmczs5.pdf?c64eb539351e068cae30df17407344a6