Clinical trial NCT03826628
Conditions: Facial Angiofibroma Tuberous Sclerosis
Sponsor: Dermatology Specialties Limited Partnership
Start date: 2019-07-28; Completion date: 2022-09-01
Enrollment: 107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study aims to compare the safety and efficacy of two different strengths of Rapamycin cream, topical and placebo over 26 weeks in the treatment of facial angiofibroma (FA) associated with Tuberous Sclerosis Complex (TSC).

Detailed description:
Topical rapamycin has previously been used to treat FA associated with TSC, reducing erythema, papule size, while flattening lesions and improving skin texture. Topical rapamycin has been reported to be well tolerated.

The efficacy and safety of a topical rapamycin cream at two strengths (0.5% and 1.0%) will be assessed during a 26 week double-blind treatment phase with assessments made at clinical visits at baseline, 2, 8, 14, 20 and 26 weeks, and at follow-up (4 weeks after the last dose of study drug).

Arms: arm 1: Rapamycin cream topical, 0.5% w/w, applied once daily before bed on affected area for 26 weeks arm 2: Rapamycin cream topical, 0.5% w/w, applied once daily before bed on affected area for 26 weeks arm 3: Placebo cream topical, applied once daily before bed on affected area for 26 weeks
Interventions: intervention 1: rapamycin intervention 2: placebo
Intervention descriptions: intervention 1: Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks intervention 2: Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Confidential-Proprietary Information 
 
DSLP 
Protocol Number: DSLP-01 
 
Page 1 of 62 
Version No 8 
Release Date:  1st March 2021 
 
  
 
 
 
DSLP-01 
 
DSLP 
Level 1, Nielsen Building 
129 Hurstmere Rd, Takapuna, Auckland 0622 
 
New Zealand 
 
 
Ph +64-9-488-0232 
 
Fax +64-9-488-0234 
 
 
 
 
Clinical Study Protocol 
Version Number: 8 
Release Date:   1st March 2021 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to investigator(s) and 
appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It may not be used, reproduced, 
published or otherwise disclosed without the written authorization from the Sponsor. 
AMENDMENT POLICY 
Protocol Amendments are to be written if any procedure in the Protocol needs to be changed. It must be signed by the 
principal investigator and the Sponsor. Only if all signatures are available, the Protocol Amendment can be considered 
approved. 
Signatures may - where necessary - be submitted by Fax or e-mail. All substantial amendments are to be sent to the 
IEC/IRB. 
All ethically relevant changes to the Study Protocol are to be reviewed and approved by the IEC/IRB. Ethically relevant 
changes could be the amount of blood taken, dosing alternatives and/or number of subjects in the study. 
The study must not begin or continue before the IEC/IRB gives its written approval. 
 
 


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Protocol Number: DSLP-01 
 
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CONFIDENTIAL – PROPRIETARY INFORMATION 
STUDY TITLE 
A Phase 2/3, multi-center, double-blind, placebo-controlled, 
randomized, parallel-group, dose-response comparison of the efficacy 
and safety of a topical rapamycin cream for the treatment of facial 
angiofibromas (FA) associated with Tuberous Sclerosis Complex (TSC) 
in patients 6 years of age and over.  
STUDY SHORT TITLE 
Dose-ranging efficacy and safety study of topical rapamycin cream 
 
PROTOCOL NUMBER 
DSLP-01 
CLINICALTRIALS.GOV ID 
NCT03826628 
INVESTIGATIONAL PRODUCT 
Rapamycin cream, topical 
DEVELOPMENT PHASE 
Phase 2/3 
INDICATION 
Facial Angiofibromas Associated with Tuberous Sclerosis Complex 
SPONSOR 
DSLP 
Level 1, Nielsen Building 
129 Hurstmere Rd,  
Takapuna, Auckland 0622, New Zealand 
STUDY CENTERS 
Dr Kate Riney 
Children's Health Queensland Hospital and Health Service 
501 Stanley Street, South Brisbane, Queensland 4101, Australia 
Phone:  +61 7 3069 7144    Fax: +61 7 3069 7169 
 
Dr Caroline Mahon 
Christchurch Hospital 
2 Riccarton Ave, Christchurch, New Zealand 8011 
Phone:  +64 3 364 1157 Fax: +64 3 364 0088 
 
Dr Harper Price 
Phoenix Children’s Hospital Dermatology Department 
1919 E. Thomas Rd., Phoenix, Arizona 85016, USA 
Phone:  +1 602 933 0895    Fax: +1 602 933 2402 
 
Dr Megha Tollefson 
Mayo Clinic 
200 First Street S.W., Rochester, Minnesota 55905, USA 
Phone: +1 507 284 2536    Fax: +1 507 266 2548    
 
Dr Doris Trauner 
University of California, San Diego Health Sciences 
9500 Gilman Drive, Mail code 0935, La Jolla CA 92093-0935, USA 
Phone: +1 858-822-6700 or +1 858-966-5819   Fax: +1 858-822-6707 
 
Dr Steven DeRoos 
Spectrum Health 
100 Michigan Street NE, Grand Rapids, Michigan 49503, USA 
Phone: +1 616-267-2807 or +1 616-391-5093  Fax: +1 616-391-5070 
 
Dr Stacie Stapleton 
All Children's Research Institute Inc.  
501 6th Avenue South, St. Petersburg, Florida 33701, USA 
Phone: +1 727-767-4176 Fax: +1 727-767-4379 
 


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DSLP 
Protocol Number: DSLP-01 
 
Page 3 of 62 
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Release Date:  1st March 2021 
 
Dr Derek Bauer 
University of Virginia 
560 Ray C. Hunt Drive, Charlottesville, VA 22903, USA 
Phone: +1 434 982 4315 Fax: +1 434 243 5782 
 
Dr Marta Ivars Lleó 
Clínica Universidad de Navarra 
C/ Marquesado de Santa Marta, 1, 28027 Madrid, Spain 
Phone:  +34 91 353 19 20    Fax: +34 91 350 86 77 
 
Dr Kinga Hadzsiev 
University of Pecs 
7 Jozsef Attila St. H-7624 Pecs, Hungary 
Phone: +36 72 535 976 Fax: +36 72 535 972 
 
Dr Jaroslava Payerova 
Narodný ústav detských chorȏb 
Limbova 1, 83340 Bratislava, Slovenská republika 
Phone: +421 2593 71 634 Fax: +421 259371 708 
 
Dr Andras Fogarasi 
Neurology Department, Bethesda Children's Hospital 
H-1143 Budapest, Ilka u. 57.  
Hungary 
Phone: +36-1-422-2873 
 
Dr Lajos Kemeny 
Department of Dermatology and Allergology, Albert Szent-Györgyi 
Medical Center, University of Szeged, H-6720 Szeged, Korányi fasor 6 
Phone: +36-62-54-52-59/60 
 
Dr Blanka Pinková 
Fakultni nemocnice Brno 
Jihlavska 20, 625 00 Brno 
Czech Republic 
Phone:  +420 532 234 538 
 
Dr Yi-Hua Liao 
National Taiwan University Hospital 
7, Chung-Shan South Road, Taipei, Taiwan 100, R.O.C 
Phone: 02 2312-3456 Fax: 02 23951950 
 
Prof. dr Milos Nikolic 
Clinic of Dermatovenereology, Clinical Center of Serbia 
Deligradska 34, 11000 Belgrade, Serbia 
Phone: +381 11 366 2465 Fax: +381 11 2682 652 
 
Prof. dr Jasna Jancic 
Clinic of Neurology and Psychiatry for Children and Youth 
Dr Subotica 6a, 11000 Belgrade, Serbia 
Phone: +381 11 265 8355 Fax: +381 11 264 5064 
SPONSOR REPRESENTATIVES 
Hartley Atkinson, PhD 
Managing Director 
AFT Pharmaceuticals Ltd. 
 
Ioana Stanescu, Phil. Lic. 
Head of Drug Development 
AFT Pharmaceuticals Ltd.,   
Ph +64-9-488-0232, Fax +64-9-488-0234 
 


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Protocol Number: DSLP-01 
 
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Release Date:  1st March 2021 
 
 
 
 
DRUG SAFETY OFFICER: 
Jennifer Zhang 
SCRA & Drug Safety Officer 
AFT Pharmaceuticals Ltd. 
Ph +64-9-488-0232, Fax +64-9-488-0234 


Confidential-Proprietary Information 
 
DSLP 
Protocol Number: DSLP-01 
 
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Release Date:  1st March 2021 
 
PROTOCOL SYNOPSIS 
Name of 
Sponsor 
DSLP 
Name of Active 
Ingredients 
Rapamycin 
Title of Study 
Dose-ranging efficacy and safety study of topical rapamycin cream: 
A Phase 2/3, multi-center, double-blind, placebo-controlled, randomized, parallel-group, 
dose-response comparison of the efficacy and safety of a topical rapamycin cream for the 
treatment of facial angiofibromas (FA) associated with Tuberous Sclerosis Complex 
(TSC) in patients 6 years of age and over. 
Phase of 
Development 
Phase 2/3 
Study Centers 
Dr Kate Riney 
Children's Health Queensland Hospital and Health Service 
501 Stanley Street, South Brisbane, Queensland 4101, Australia 
Phone:  +61 7 3069 7144    Fax: +61 7 3069 7169 
 
Dr Caroline Mahon 
Christchurch Hospital 
2 Riccarton Ave, Christchurch, New Zealand 8011 
Phone:  +64 3 364 1157 Fax: +64 3 364 0088 
 
Dr Harper Price 
Phoenix Children’s Hospital Dermatology Department 
1919 E. Thomas Rd., Phoenix, Arizona 85016, USA 
Phone:  +1 602 933 0895    Fax: +1 602 933 2402 
 
Dr Megha Tollefson 
Mayo Clinic 
200 First Street S.W., Rochester, Minnesota 55905, USA 
Phone: +1 507 284 2536    Fax: +1 507 266 2548    
 
Dr Doris Trauner 
University of California, San Diego Health Sciences 
9500 Gilman Drive, Mail code 0935, La Jolla CA 92093-0935, USA 
Phone: +1 858-822-6700 or +1 858-966-5819   Fax: +1 858-822-6707 
 
Dr Steven DeRoos 
Spectrum Health 
100 Michigan Street NE, Grand Rapids, Michigan 49503, USA 
Phone: +1 616-267-2807 or +1 616-391-5093  Fax: +1 616-391-5070 
 
Dr Stacie Stapleton 
All Children's Research Institute Inc.  
501 6th Avenue South, St. Petersburg, Florida 33701, USA 
Phone: +1 727-767-4176 Fax: +1 727-767-4379 
 
Dr Derek Bauer 
University of Virginia 
560 Ray C. Hunt Drive, Charlottesville, VA 22903, USA 
Phone: +1 434 982 4315 Fax: +1 434 243 5782 
 
Dr Marta Ivars Lleó 
Clínica Universidad de Navarra 
C/ Marquesado de Santa Marta, 1, 28027 Madrid, Spain 
Phone:  +34 91 353 19 20    Fax: +34 91 350 86 77 


Confidential-Proprietary Information 
 
DSLP 
Protocol Number: DSLP-01 
 
Page 7 of 62 
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Release Date:  1st March 2021 
 
 
Dr Kinga Hadzsiev 
University of Pecs 
7 Jozsef Attila St. H-7624 Pecs, Hungary 
Phone: +36 72 535 976 Fax: +36 72 535 972 
 
Dr Jaroslava Payerova 
Narodný ústav detských chorȏb 
Limbova 1, 83340 Bratislava, Slovenská republika 
Phone: +421 2593 71 634 Fax: +421 259371 708 
 
Dr Andras Fogarasi 
Neurology Department, Bethesda Children's Hospital 
H-1143 Budapest, Ilka u. 57.  
Hungary 
Phone: +36-1-422-2873 
 
Dr Lajos Kemeny 
Department of Dermatology and Allergology, Albert Szent-Györgyi Medical Center, 
University of Szeged, H-6720 Szeged, Korányi fasor 6 
Phone: +36-62-54-52-59/60 
 
Dr Blanka Pinková 
Fakultni nemocnice Brno 
Jihlavska 20, 625 00 Brno 
Czech Republic 
Phone:  +420 532 234 538 
 
Dr Yi-Hua Liao 
National Taiwan University Hospital 
7, Chung-Shan South Road, Taipei, Taiwan 100, R.O.C 
Phone: 02 2312-3456 Fax: 02 23951950 
 
Prof. dr Milos Nikolic 
Clinic of Dermatovenereology, Clinical Center of Serbia 
Deligradska 34, 11000 Belgrade, Serbia 
Phone: +381 11 366 2465 Fax: +381 11 2682 652 
 
Prof. dr Jasna Jancic 
Clinic of Neurology and Psychiatry for Children and Youth 
Dr Subotica 6a, 11000 Belgrade, Serbia 
Phone: +381 11 265 8355 Fax: +381 11 264 5064 


Confidential-Proprietary Information 
 
DSLP 
Protocol Number: DSLP-01 
 
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Background and 
Rationale 
DSLP have developed a topical cream containing rapamycin 0.5% and 1.0% referred to 
as Rapamycin cream, topical.  
Tuberous Sclerosis Complex (TSC) is a disorder characterized by the development of 
multiorgan benign tumor-like growths in any part of the body. TSC is caused by mutations 
in the TSC1 and TSC2 genes which encode a growth suppressor complex that inhibits the 
mTOR (mammalian Target Of Rapamycin) protein. Loss of regulation of mTOR leads to 
abnormal differentiation and development, and to the generation of enlarged cells. 
Facial angiofibromas (FA) are present in 70-80% of patients with TSC and are commonly 
developed after the first two years of life. FA are distinguished as fibrous and/or highly 
vascular papules. Facial angiofibromas in patients with TSC are thought to develop due to 
the mutational activation of the mTOR pathway. 
These growths tend to spontaneously bleed or can be affected by slight traumas that can 
also cause uncontrolled bleeding. When present around the eyes, nose and mouth 
infections become common. Due to their progressive nature, FA can impair vision and 
breathing. 
Rapamycin, a macrocyclic antibiotic produced by Streptomyces hygroscopicus, is a potent 
inhibitor of mTOR. Although the mechanism of action of rapamycin is not completely 
understood, research has shown that when rapamycin binds to mTOR, the activity 
produced by the mTOR cascade pathway is inhibited, thus restraining uncontrolled 
cellular proliferation.  
A number of clinical studies have used different concentrations (0.003-1%) of topical 
rapamycin for the treatment of FA associated with TSC. Taken as a whole, these studies 
demonstrate the potent efficacy and great tolerability of topical rapamycin for FA. All 
cases reported reduction of erythema, papule size and lesion flattening, and improved skin 
texture. 
The efficacy and safety of two rapamycin strengths (0.5% and 1.0%) will be assessed 
during a 26 week double-blind treatment phase with assessments made at clinical visits at 
baseline, 2, 8, 14, 20 and 26 weeks, and at follow-up (4 weeks after the last dose of study 
drug).  
Study 
Hypothesis 
 
It is hypothesized that the two strengths of Rapamycin cream, topical will improve the 
appearance of FA associated with TSC compared to placebo. It is also expected that both 
strengths will be well tolerated. 
Study Design 
A Phase 2/3, multi-center, double-blind, placebo-controlled, randomized, parallel-group, 
dose-response study  
Duration of 
Treatment 
26 weeks 
Test Product, 
Dose, Mode of 
Administration 
Rapamycin formulated as a topical cream (Rapamycin cream, topical) of different dose 
strengths: 0.5% and 1.0%.  
Rapamycin cream, topical will be applied once daily for 26 weeks on the surface of the 
facial angiofibroma lesions. The amount of cream required to produce a thin confluent 
layer on the skin is 6 mg/cm2. The amount to be applied will be based on the size of the 
affected area. 
Reference 
Product, Dose, 
Mode of 
Administration 
A placebo cream will be applied daily for 26 weeks on the surface of the facial 
angiofibroma lesions. 
Number of 
Participants 
40 per treatment group 
It is anticipated that no more than 10% of the placebo group will achieve the primary 
endpoint, a successful treatment according to IGA scale after 26 weeks treatment and that 
each dose of Rapamycin cream, topical will achieve at least 40% successful treatment. 
Including the Holm-Bonferroni adjustment of the type I error rate for multiple 
comparisons (α = 0.025) a sample size of 40 participants per group is required in each 
randomized group to achieve >80% power for these comparisons.   


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Protocol Number: DSLP-01 
 
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Criteria for 
Inclusion 
Inclusion Criteria 
1. Male and female patients aged ≥ 6 years and ≤ 65 years on the day informed consent 
is obtained 
2. Patients diagnosed with TSC based on the clinical diagnostic criteria of International 
Tuberous Sclerosis Complex Consensus Conference 2012 and presenting visible 
facial angiofibroma 
3. An FA severity score of 2 or 3 on the IGA scale 
4. Patients or their legal representatives capable of understanding the explanation of the 
clinical trial and who give written informed consent for participation 
5. Patients or their legal representatives able to maintain patient diaries following the 
instructions of the investigator or sub-investigator 
Exclusion Criteria 
1. Patients who cannot carry out the treatment plan or follow-up assessment 
2. Patients with serious skin lesions such as erosions or ulcers 
3. Patients with known hypersensitivity to any component of the study product 
4. Patients who have received rapamycin/sirolimus, everolimus, or temsirolimus within 
3 months of enrolment 
5. Patients who received laser therapy or surgical therapy within 6 months prior to trial 
enrolment 
6. Patients who participated in any other clinical trial within 3 months prior to the day 
of enrolment 
7. Patients judged unsuitable for this clinical trial by the investigator or sub-investigator 
8. Pregnant or lactating females 
9. Sexually active females of childbearing potential not using adequate contraception 
and sexually active males not using adequate contraception  
10. Patients with immune dysfunction or receiving any form of immunosuppression 
11. Patients with severe FA, with a score of 4 on the IGA scale 
12. Patients with an FA severity score of less than 2 on the IGA scale 
Brief 
Description 
The study can be divided into a Screening Phase, a Treatment Phase and Follow-up. 
The Screening Phase includes collection of Informed Consent and the assessment of the 
subjects’ suitability for the study. Eligible subjects will be assigned a unique 
randomization number before the first application of the study drug.  Subjects will be 
randomized to receive treatment with one of two strengths of Rapamycin cream, topical 
(0.5% and 1.0% rapamycin, respectively) or placebo. 
The Treatment Phase of the study comprises one clinical visit at baseline (V0) and 5 
subsequent clinical visits after 2, 8, 14, 20 and 26 weeks treatment (V1-5) with Rapamycin 
cream, topical or placebo.  The amount of cream will be based on the total area of the 
facial lesion(s) and patients will be instructed to apply the formulation every evening, 
about half an hour before retiring for bed, for 26 weeks. 
Follow-up will be performed 28 days after the V5 visit, or the last visit where early 
withdrawal from treatment was confirmed. 
Assessment of the extent and severity of facial angiofibroma will be performed at 
randomization, at each clinical visit (V1-5) and at follow-up using a variety of measures 
including an Investigator’s Global Assessment (IGA) scale, the facial angiofibroma 
severity index (FASI), as well as subjective and objective improvement ratings. 
The primary efficacy endpoint is based on the IGA scale, described below: 
Grade 
Short Description 
Detailed Description 
0 
Clear 
No signs of facial angiofibroma 


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1 
Almost Clear 
Few small angiofibromas (< 2 mm); normal to pink 
coloration in affected area*  
2 
Mild 
Predominantly small angiofibromas (< 2 mm) with few 
intermediate tumors (2-4 mm); pink to red coloration in 
affected area  
3 
Moderate 
Predominantly intermediate angiofibromas (2-4 mm) 
with few large tumors (> 4 mm); red coloration in 
affected area 
4 
Severe 
Mix of intermediate (2-4 mm) and large angiofibromas 
(>4 mm) present diffusely on face; intense and 
generalized redness on the whole face 
* Note: coloration refers to both the FA lesions and the background facial skin tone 
Where lesion size and coloration are discrepant within the grade, emphasis should be placed on 
lesion size. 
 
The following medications are prohibited after enrolment in this trial due to the risk of 
interference in the evaluation of efficacy/safety: 
- 
Laser and surgical treatment of the target treatment area 
- 
Administration of mTOR inhibitors (rapamycin/sirolimus, everolimus, temsirolimus 
etc.) 
- 
Application of steroidal or antibacterial agents to the target area 
- 
Administration of cyclosporine or macrolide antibiotics 
- 
Strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, 
itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of 
CYP3A4 and/or P-gp (such as rifampin or rifabutin) 


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Evaluation of 
Efficacy 
 
 
 
 
 
Primary Endpoint:   
The percentage of patients obtaining successful treatment based on a blind assessment 
using the IGA scale after 26 weeks treatment or at last visit if early 
withdrawal/discontinuation  
Secondary Endpoints:  
• 
Time to treatment success  
• 
Change from baseline in IGA after 26 weeks treatment or at last visit if early 
withdrawal/discontinuation 
• 
Change from baseline in FASI after 26 weeks treatment or at last visit if early 
withdrawal/discontinuation 
• 
Subjective (patient or parent/caregiver) improvement rating from first visit 
(V0) 
after 
26 
weeks 
treatment 
or 
at 
last 
visit 
if 
early 
withdrawal/discontinuation 
• 
Objective (clinician) improvement rating from first visit (V0) after 26 weeks 
treatment or at last visit if early withdrawal/discontinuation 
• 
Categorical Improvement of Facial Angiofibroma from first visit (V0) after 26 
weeks treatment 
Exploratory Endpoints:  
• 
The percentage of patients with successful treatment according to IGA scale 
after 2, 8, 14 and 20 weeks treatment 
• 
Change from baseline in IGA after 2, 8, 14 and 20 weeks treatment 
• 
Change from baseline in FASI after 2, 8, 14 and 20 weeks treatment 
• 
Change from baseline in each FASI component (erythema, size, extension) 
after 2, 8, 14, 20 and 26 weeks treatment 
• 
Subjective (patient or parent/caregiver) improvement rating from first visit 
(V0) after 2, 8, 14 and 20 weeks treatment 
• 
Objective (clinician) improvement rating from first visit (V0) after 2, 8, 14 
and 20 weeks treatment 
• 
Change in IGA from week 26 to Follow up (4 weeks after final dose) 
• 
Change in FASI from week 26 to Follow up (4 weeks after final dose) 
Evaluation of 
Safety 
 
Safety will be assessed at each of the visits and will include: 
• 
the local and systemic tolerability of different doses of topical rapamycin (i.e. 
reporting of adverse events), including, known topical and known oral 
rapamycin adverse events. 
• 
A physical examination, measurement of vital signs, and tests of hematology, 
biochemistry, blood lipids and urinalysis at baseline, at each visit (V1-5), and 
at follow-up 
• 
Rapamycin blood concentration, performed at baseline, at each visit (V1-5), 
and at follow-up 
Statistical 
Methods 
The Intent-To-Treat (ITT) population will consist of all subjects who receive at least one 
dose of study drug. Subjects will be included in the group to which they were 
randomized irrespective of the treatment actually taken. The ITT population is the 
primary population for the efficacy analysis. The safety population will include all 
subjects who are treated with study drug, with group determined by the actual dose of 
study drug taken. 
Primary Endpoint:   
The data for the primary endpoint, the percentage of patients obtaining successful 
treatment after 26 weeks, or at last visit if early withdrawal/discontinuation, based on 


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the blind assessment using the IGA scale, will be summarized by treatment group.  
Success is defined as clear or almost clear with an improvement of at least two grades 
from baseline, i.e. 2 to 0; 3 to 1. Statistical analysis of the primary endpoint will be 
performed using a logistic regression model which will include treatment effect and 
stratum as fixed factors and baseline IGA score as a covariate. This model will be used 
to generate the odds ratios and 95% confidence intervals of the individual dose 
treatments compared with placebo, with the p-values for these comparisons adjusted 
using the Holm-Bonferroni adjustment. 
Secondary Endpoints:  
The time-to-treatment success will be summarized using Kaplan-Meier analyses and 
compared between each dose group and placebo using the stratified log-rank test. The 
secondary endpoints change in IGA and FASI from baseline to 26 weeks/last 
assessment, and objective and subject improvement from baseline to 26 weeks/last 
assessment, will be summarized by treatment group using means, medians, standard 
deviations, interquartile ranges and minima and maxima. These changes will be 
analyzed using ANOVA including treatment and stratum as main effect fixed factors, 
with planned pairwise comparisons between each dose group and placebo. If the data is 
not adequately normally distributed the Kruskal-Wallis non-parametric ANOVA, and 
Mann-Whitney U tests comparing changes between treatment groups will be used for 
the analysis.  Baseline for the IGA and FASI scores is defined as the last pre-treatment 
assessment, whether obtained at screening, randomization or V0.  
Categorical Improvement scores will be compared amongst study groups using the 
Kruskal-Wallis non-parametric ANOVA, and Mann-Whitney U tests comparing 
changes between each dose group and placebo. 
The type I error rate associated with the testing of the six secondary endpoints will be 
strictly controlled using the Hochberg procedure. This will involve ranking the 6 p-
values derived from the testing of each dose group with placebo from highest to lowest. 
If the highest p-value is <0.05, then all six comparisons are considered statistically 
significant. If not significant then the next highest is tested at p=0.025. The p-value 
continues to reduce at each non-significant step based on the Bonferroni adjustment.  
Exploratory Endpoints:  
The exploratory endpoints, including the change in IGA and FASI from week 26 to 
follow-up, will be analyzed in the same manner as the appropriate secondary endpoints. 
The p-values for these comparisons will not be reported but the differences between each 
dose group and placebo will be summarized as odds ratios or mean differences as 
appropriate with 95% confidence intervals.  
Safety Endpoints: Safety Endpoints:  
AEs will be collected for all randomized participants and will be listed with type of AE, 
severity and relationship for each treatment group, using the safety population. Adverse 
event data will be summarized for each treatment groups using frequencies and 
percentages (% of participants with each specific AE). If frequencies permit, Chi-square 
tests or fisher’s exact tests may be used to compare the rates of occurrence between 
treatment groups.  Known AEs specific to oral or topical rapamycin will be individually 
summarized by treatment group. 
Between-treatment comparisons will be made for changes in vital signs, hematology, 
biochemistry, blood lipids and urinalysis from baseline at visits V1-5. Baseline is 
defined as the last pre-treatment assessment, whether obtained at screening, 
randomization or V0. Changes between V5 and Follow-up will also be examined.   
Blood rapamycin concentrations will be summarized for each of the treatment groups at 
all scheduled timepoints using standard descriptive statistics (means, medians, 
geometric means, ranges, standard deviations and standard errors), as appropriate. 
Adverse events will be monitored up to 4 weeks after administration of the final dose of 
study medication.  


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Protocol Number: DSLP-01 
 
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Schedule of 
assessments 
Assessment 
Screening Phase 
Treatment Phase 
Follow-Up 
Informed 
consent 
Screening 
Randomization 
V0 
Baseline 
V1 
2 
weeks 
V2 
8 
weeks 
V3 
14 
weeks 
V4 
20 
weeks 
V5 
26 
weeks 
4 weeks after 
final dose 
Tolerance 
≤3 months 
before V0 
≤14 days before V0 
NA 
±3 
days 
±3 
days 
±3 days 
±3 days 
±3 days 
±5 days 
Informed consent 
X1 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test2 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Hematology, biochemistry & lipid 
panel3 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood rapamycin concentration3,4 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Drug administration (once daily, 
evenings) 
 
 
 
X 
 
Photographs of FA 
 
 
X 
 
X 
X 
X 
X 
X 
X 
IGA 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
FASI 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Percentage improvement (subjective & 
objective) 
 
 
 
 
X 
X 
X 
X 
X 
 
Categorical improvement 
 
 
 
 
 
 
 
 
X5 
 
Concomitant medications 
 
X 
X 
X 
X 
Adverse events  
 
 
 
X 
X 
1 if more than a month passes between obtaining informed consent and randomization, then informed consent should be re-obtained 
2 only conducted for women of childbearing potential 
3 if participants are unable to provide blood samples at all timepoints, the minimum to be collected should be samples at screening, V1 or V2 and V5 
4 blood sampling collected prior to the daily evening dose 
5 categorical assessment only to be done at V5, unless early withdrawal/discontinuation, in which case categorical assessment should be completed at last visit 
 


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TABLE OF CONTENTS 
Protocol Synopsis ..................................................................................................................... 6 
Table of Contents ................................................................................................................... 14 
List of Figures ......................................................................................................................... 16 
List of Tables .......................................................................................................................... 16 
List of Abbreviations ............................................................................................................. 17 
1. 
Introduction ................................................................................................................................. 18 
1.1 
Background ..................................................................................................................................... 18 
1.2 
Study Drug Rationale ...................................................................................................................... 19 
1.3 
Study Rationale ............................................................................................................................... 22 
1.4 
Known and Potential Risks and Benefits ......................................................................................... 22 
2 
Trial Objectives ........................................................................................................................... 23 
2.1 
Hypothesis ...................................................................................................................................... 23 
2.2 
Efficacy Objectives .......................................................................................................................... 23 
2.3 
Safety Objective .............................................................................................................................. 24 
3 
Investigational Plan ..................................................................................................................... 24 
4 
Participant population ................................................................................................................ 26 
4.1 
Number of Participants ................................................................................................................... 26 
4.2 
Inclusion Criteria ............................................................................................................................. 26 
4.3 
Exclusion Criteria ............................................................................................................................ 26 
4.4 
Withdrawal Criteria ........................................................................................................................ 27 
4.5 
Study or Study Site Termination and Subject Discontinuation ....................................................... 27 
4.5.1 
Study or Study Site Discontinuation ............................................................................................ 27 
4.5.2 
Subject Discontinuation .............................................................................................................. 27 
5 
Treatments ................................................................................................................................... 28 
5.1 
Treatments to be administered ...................................................................................................... 28 
5.1.1 
Treatment Phase ........................................................................................................................ 29 
5.2 
Investigational Products ................................................................................................................. 29 
5.3 
Randomization ................................................................................................................................ 29 
5.4 
Blinding ........................................................................................................................................... 30 
5.5 
Prohibited concomitant medications ............................................................................................. 30 
5.6 
Treatment compliance .................................................................................................................... 31 
6 
Study Data and Endpoints .......................................................................................................... 31 
6.1 
Efficacy data .................................................................................................................................... 31 
6.1.1 
Primary Efficacy Endpoint ........................................................................................................... 31 
6.1.2 
Secondary and Exploratory Efficacy Endpoints ........................................................................... 32 
6.2 
Safety Data ...................................................................................................................................... 34 
6.2.1 
Evaluations of Specific AEs ......................................................................................................... 34 
6.2.2 
Overall Evaluation of Safety ....................................................................................................... 35 
6.2.3 
Systemic absorption of rapamycin ............................................................................................. 35 
7 
Experimental Procedure ............................................................................................................. 35 
7.1 
Screening Phase .............................................................................................................................. 37 
7.2 
Treatment Phase ............................................................................................................................. 38 
7.2.1 
Initial Clinical Visit (V0) ............................................................................................................... 38 
7.2.2 
Clinical Visits 1-5 (V1-5) .............................................................................................................. 39 
7.3 
Follow-Up Period ............................................................................................................................ 39 
8 
Adverse Events ............................................................................................................................ 40 
8.1 
Definitions ....................................................................................................................................... 40 
8.1.1 
Serious Adverse Event ................................................................................................................. 41 
8.1.2 
Suspected Adverse Drug Reactions (ADR) .................................................................................. 41 
8.1.3 
Unexpected Adverse Drug Reaction ........................................................................................... 41 


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8.2 
Procedure for Adverse Event Reporting ......................................................................................... 41 
8.3 
Procedure for Serious Adverse Event Reporting ............................................................................ 42 
8.3.1 
Reporting to the Sponsor ............................................................................................................ 42 
8.3.2 
Reporting to Local IEC and Regulatory Authorities .................................................................... 42 
8.3.2.1 Local Ethics Committee .......................................................................................................... 42 
8.3.2.2 Regulatory Authorities ............................................................................................................ 43 
9 
Protocol Deviations ..................................................................................................................... 43 
10 Plan for Statistical and Other Calculations .............................................................................. 44 
10.1 
Populations of Interest ................................................................................................................... 44 
10.2 
Sample Size ..................................................................................................................................... 44 
10.3 
Statistical Analyses .......................................................................................................................... 44 
10.3.1 
Primary Efficacy Endpoint ........................................................................................................... 44 
10.3.2 
Secondary Efficacy Endpoints ..................................................................................................... 45 
10.3.3 
Exploratory Efficacy Analyses ..................................................................................................... 45 
10.3.4 
Additional Analyses .................................................................................................................... 45 
10.3.5 
Safety Endpoints ......................................................................................................................... 46 
10.3.6 
Demographic and Background Characteristics .......................................................................... 46 
10.4 
Treatment Compliance ................................................................................................................... 46 
10.5 
Missing data .................................................................................................................................... 46 
10.6 
Procedure for Amendments to Statistical Plan ............................................................................... 47 
10.7 
Data collection ................................................................................................................................ 47 
11 Quality Control and Quality Assurance .................................................................................... 48 
11.1 
Monitoring ...................................................................................................................................... 48 
11.2 
Auditing ........................................................................................................................................... 48 
12 Ethics and Responsibility............................................................................................................ 48 
12.1 
Informed Consent ........................................................................................................................... 48 
12.2 
Institutional Review Board/Independent Ethics Committee .......................................................... 49 
12.3 
Governance of Study and Publication Policy .................................................................................. 49 
13 Confidentiality ............................................................................................................................. 49 
14 Investigator Agreement .............................................................................................................. 50 
15 References .................................................................................................................................... 51 
Appendix 1: Investigators Global Assessment ................................................................................. 55 
Appendix 2: Facial Angiofibroma severity index (FASI) ................................................................ 56 
Appendix 3: Subjective and Objective Improvement Ratings ........................................................ 57 
Appendix 4: Categorical improvement of Facial Angiofibroma .................................................... 58 
Appendix 5: Grading of adverse events ............................................................................................ 59 
Appendix 6: SAE Reporting Form .................................................................................................... 60 
 
 


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LIST OF FIGURES 
Figure 1: Schematic of Trial Design ..................................................................................................... 25 
 
LIST OF TABLES 
Table 1: Published Clinical Trials for Topical Rapamycin for Facial Angiofibroma ........................... 20 
Table 2: IGA scoring of Facial Angiofibroma Lesions ........................................................................ 32 
Table 3: Schedule of Assessments ........................................................................................................ 36 
 
 
 


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LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of Variance 
CRF 
Case Report Form 
DBP 
Double Blind Phase 
DCF 
Data Clarification Form 
DLC 
Differential Leukocyte Count 
ECG 
Electrocardiogram 
EXP 
Extension Phase 
FA 
Facial Angiofibroma 
FASI 
Facial Angiofibroma Severity Index 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGA 
Investigator’s Global Assessment  
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LAM 
Lymphangioleiomyomatosis 
LOCF 
Last Observation Carried Forward 
PDL 
Pulse-Dye Laser 
PP 
Per-Protocol 
RBC 
Red Blood Cell 
RH 
Relative Humidity 
SAE 
Serious Adverse Event 
SAER 
Serious Adverse Event Report 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TSC 
Tuberous Sclerosis Complex 
USFDA 
United States Food & Drug Administration 
WBC 
White Blood Cell 
 
 


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1. 
INTRODUCTION 
1.1 
Background 
Tuberous Sclerosis Complex (TSC) is an autosomal dominant inherited neurocutaneous disorder that is 
characterized by the development of multiorgan benign tumor-like growths, most usually observed in 
the skin, brain, kidney, heart and lungs that could potentially lead to organ dysfunction (2,3). 
TSC is caused by defects, or mutations, in two genes, TSC1 and TSC2. Only one of the genes needs to 
be affected for TSC to be present. The TSC1/2 genes encode the proteins hamartin and tuberin, 
respectively. These two proteins create a complex that regulates the mammalian target of rapamycin 
(mTOR). mTOR has been discovered to be a key modulator in multiple processes including cell cycle, 
cellular growth, proliferation and migration. Mutation in the TSC1 or TSC2 genes results in 
dysregulation of mTOR leading to abnormal growth and proliferation via mTOR’s downstream 
effectors (4,5). 
Facial angiofibromas (FA) are one of the major features of TSC. FA are present in 70-80% of patients 
with TSC and are commonly developed after the first two years of life (5–8). FA present as 
vesicopapular rashes with pink or bright red papules formed across the medial region of the cheeks and 
nasolabial folds. In some cases, FA may extend to the lateral cheeks, forehead and eyelids. Spontaneous 
and uncontrolled bleeding is frequent, and infections are common when the lesions are present around 
the eyes, nose and mouth. Due to progressive growth, over time FA can impair vision and breathing 
(8,9) and have psychological consequences (emotional, social and self-image disorders). 
Samples of FA from patients with TSC have shown that mTOR plays a key role in the development of 
the condition. Fundamentally, dysregulated activation of mTOR (via mutations in TSC1 and/or TSC2) 
results in continuous cell proliferation and differentiation, causing the appearance of FA (10–14). The 
clinical effect of rapamycin was discovered when a 21 year old female patient with TSC and 
angiofibromas underwent a double kidney transplant and was prescribed oral rapamycin to prevent graft 
rejection. After three months of daily intake of 3.5 mg of oral rapamycin the patient’s FA regressed in 
size and also the erythema significantly decreased, improving her facial texture (15).  
There is need for a simple, non-invasive method to treat FA. Currently, there is no standard treatment 
for FA. Patients are often subjected to a variety of different methods to clear and control the growths 
with the aim of reducing bleeding, infections and preventing/relieving disfigurement. Common methods 
include cryosurgery, curettage, dermabrasion, chemical peeling, excision, laser therapy (CO2 laser, 
argon laser, pulsed dye lasers [PDL]) and surgical excision. The painful and invasive nature of these 
methods means they often require anesthesia. Such methods are better suited for the treatment of large, 
severe and well-defined FA, which typically require a combination of therapies and/or numerous laser 
sessions (9,16). Complications such as infections, or adverse events such as hypertrophic scars or 
pigmentation disorders are common after such treatments as implementing the required “after-care” is 


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often difficult for the subset of patients with learning disabilities and/or seizures also attributable to 
TSC.  
1.2 
Study Drug Rationale 
Rapamycin is a macrolide antibiotic compound produced by Streptomyces hygroscopicus that was first 
isolated from a soil sample from Easter Island, also known as Rapa Nui. Rapamycin ligates with the 
immunophilin FK506 binding protein-12 creating a complex that inhibits the activation of the mTOR. 
mTOR is a protein kinase that regulates cell growth and cell proliferation (17). Rapamycin is currently 
commercially available only as an oral solution or as a tablet (e.g. Rapamune®).  The currently approved 
indication for rapamycin is for the prophylaxis of organ rejection in patients aged ≥ 13 years receiving 
renal transplants (maintenance immunotherapy) and for the treatment of patients with 
lymphangioleiomyomatosis (LAM), a rare, cystic lung disease (18).  
Due to its potent antiproliferative effects, rapamycin has also been investigated as a treatment for a 
series of cutaneous diseases including FA associated with TSC. Interest in the use of rapamycin for the 
treatment of FA began after the publication of a case report of a 21 year old TSC patient that underwent 
kidney transplant. After initial immunosuppression with tacrolimus, the patient was transferred to oral 
rapamycin therapy, during which time her FA improved dramatically (19).  
There is an extensive literature which supports the efficacy and safety of various topical rapamycin 
formulations for the treatment of FA. In the last 7 years, 11 clinical trials and 17 case 
reports/observational studies have been published in the literature. Overall, the outcomes obtained by 
the vast majority of patients in these studies demonstrate that topical rapamycin has potent efficacy for 
FA associated with TSC (19–43). It is difficult to determine the impact of different treatment 
frequencies in terms of efficacy (i.e. twice daily or 3 times per week) but one study noted that a twice 
daily treatment regimen could be replaced by a once daily regimen without loss of efficacy (37). In line 
with the progressive nature of the disease, there is some data that demonstrates that the positive effect 
diminishes after treatment is stopped (1,45). 
Although a range of concentrations appear to be effective, adults tended to have a poorer response to 
treatment than children for a given strength, suggesting the need for higher concentrations in this age 
group where FA are typically more severe (33,45,46). There is some data to suggest that higher 
concentrations have greater efficacy, particularly in adult patients (37,45). Moreover, most authors 
suggested the use of topical rapamycin at early stages (in younger patients) so optimal results can be 
achieved. 
 
 


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Table 1: Published Clinical Trials for Topical Rapamycin for Facial Angiofibroma 
Study 
Study Design 
Strength 
N 
Frequency and 
Duration of 
therapy 
Efficacy 
Wataya-
Kaneda 
et al., 
2018  
Multicenter, 
double-blind, 
randomized, 
placebo-
controlled, 
parallel group 
0.2% 
62 
2x daily for 12 
weeks 
Primary endpoint: composite 
improvement in angiofibromas (size and 
color at 12 weeks).  Response rate of 
angiofibromas at weeks 4, 8, and 12 of 
treatment was 0 in the placebo group in 
contrast to 20%, 43% and 60% in the 
rapamycin group. None of the 31 
assessable patients in placebo group were 
rated improved or better and 26 of them 
were rated unchanged. In contrast 17% 
and 43% patients in the rapamycin group 
were rated “markedly improved” and 
“improved”, respectively.  
In the rapamycin group the response rates 
were significantly higher in the pediatric 
patients (85%) than in adult patients 
(41%) at week 12 (p=0.03) 
Rapamycin gel, 0.2% demonstrated a 
significant clinical benefit for patients 
with TSC involving angiofibromas, thus 
providing a promising therapeutic 
modality. 
Koenig et 
al., 2018 
Multicenter, 
double-blind, 
randomized, 
vehicle-
controlled, 
parallel group 
0.1% 
1% 
179 
1x daily at bed 
time for 6 
months 
Clinically meaningful and statistically 
significant improvement in facial 
angiofibroma was observed for both 1% 
and 0.1%. At 6 months, Angiofibroma 
Grading Scale (AGS) mean improvement 
for 1% was 16.7 points compared with 
11.0 for 0.1% and 2.1 points for vehicle 
only (P<0.001 for 1% and 0.1% vs 
vehicle only). End-of-treatment photos 
were rated “better” for 81.8% of patients 
in the 1% rapamycin group, compared 
with 65.5% for those in the 0.1% 
rapamycin group and 25.5% for those in 
the vehicle-only group (P<0.001, all 3 
pairwise comparisons). 
Topical rapamycin was generally well-
tolerated with no measurable systemic 
absorption. 
Wataya-
Kaneda 
et al., 
2017 
Double-blind, 
randomized, 
placebo-
controlled, 
parallel-group 
0.05% 
0.1% 
0.2% 
36 
2x daily for 12 
weeks 
0.05%, 0.1% and 0.2% strengths resulted 
in a significant ‘improvement factor’ 
(author defined composite variable 
comprised of tumor volume a redness 
measures) at 12 weeks relative to baseline 
for children (aged 3-18). Only the 0.2% 
strength provided a statistically 
significant ‘improvement factor in adults 
(aged 19 – 65).  
Koenig et 
al., 2012 
Double-blind, 
randomized, 
placebo-
controlled, 
parallel-group 
0.003% 
0.015% 
23 
1x daily for 6 
months 
73% reported improvement regardless of 
treatment provided 


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Cinar et 
al., 2017 
Single-blind, 
left-right, 
vehicle-
controlled, 
cross-over 
0.1% 
12 
2x daily for 3 
months, followed 
by 6-9 months 
treatment 
cessation, and a 
further 3 months 
treatment 
Significant reduction on FASI seen with 
initial 3 month treatment. Treatment 
discontinuation resulted in significantly 
increased in FASI score. Final 3 month 
treatment resulted in significant decrease 
in FASI score. 
Tanaka et 
al., 2013 
Open-label, left-
right, vehicle-
controlled  
0.2% 
11 
2x daily for 12 
weeks 
General score (total of each measure) was 
higher on the rapamycin treated cheek 
that on the vehicle-treated cheek in all 
patients 
Wataya-
Kaneda 
et al., 
2011 
Open-label, left-
right, vehicle-
controlled 
0.2% 
9 
2x daily for 3 
months 
General score (total of each measure)  
significantly better on combination side 
than tacrolimus monotherapy side) 
Tu et al., 
2014 
Open-label, 
uncontrolled 
case series 
0.1% 
0.5% 
1.0% 
19 
2x daily for 8-30 
months 
All demonstrated a significant and 
sustained improvement 
Amin et 
al., 2016 
Open-label, 
uncontrolled 
case series 
0.1% 
14 
1x daily for 6 
months 
FASI scores were improved in 71% of 
patients (100% of children and 33% of 
adults) 
Salido et 
al., 2012 
Open-label, 
uncontrolled 
case series 
0.4% 
10 
3x week for 9 
months 
Median time to response was 4 weeks 
Average reduction in FASI: 60.2% 
Foster et 
al., 2012 
Open-label, 
uncontrolled 
case series 
0.1% 
4 
2x daily for 6 
months 
Rapid improvement within 1 week  
maintained for 6 months, younger patients 
completely resolved FA 
 
Despite promising literature reports of the efficacy and tolerability of topical rapamycin for the 
treatment of FA, there is only one approved topical rapamycin product, in Japan. This is in part due to 
the difficulties in producing a stable rapamycin topical formulation. A new topical cream (Rapamycin 
cream, topical) is currently under development by DSLP. The advantage of the base is that it protects 
molecules that are readily oxidized, such as rapamycin, and it also has excellent cosmetic properties, 
natural antimicrobial properties and releases the active ingredient into the skin by melting at skin 
temperature (33-34°C).  
DSLP has sponsored a series of non-clinical studies which have demonstrated that Rapamycin cream, 
topical at 0.5% and 1.0% has a good absorption and penetration profile when applied to the skin. At 
0.1%, the cream showed a variable absorption profile, so was not selected for further examination. 
Rapamycin cream, topical is not considered to be a contact sensitizer and is classified as a non-irritant 
to the eye and will not cause eye damage. A 9 month toxicity study found that mean rapamycin blood 
concentrations following daily dermal application generally increased with increasing cream 
concentration, but increases were not consistently dose proportional. Rapamycin creams were well 
tolerated and did not adversely affect any measured parameters. 


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1.3 
Study Rationale 
The planned Phase 2/3 dose-response study described in this protocol will investigate the dose-
dependent efficacy of Rapamycin cream, topical (rapamycin 0.5% and 1.0% w/w) in the treatment of 
FA associated with TSC and compare with placebo.  
1.4 
Known and Potential Risks and Benefits 
All clinical studies have risks. However, these are likely to be minimal in this study. The systemic 
absorption of rapamycin from Rapamycin cream, topical has been shown to be minimal and very few 
adverse events have been reported in the literature.   
The potential benefit of this study lies in its potential to improve the appearance of FA associated with 
TSC without the use of surgery. 
 
 


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2 
TRIAL OBJECTIVES 
2.1 
Hypothesis  
It is hypothesized that the two strengths of Rapamycin cream, topical will improve the appearance of 
FA associated with TSC compared to placebo. It is also expected that both strengths will be well 
tolerated.  
2.2 
Efficacy Objectives 
The Efficacy Objectives of the study are to determine and compare the efficacy of two different 
strengths of Rapamycin cream, topical and placebo over 26 weeks of once-daily treatment. 
The primary efficacy endpoint is the percentage of patients obtaining successful treatment after 26 
weeks or at discontinuation/withdrawal, based on the blind assessment using the IGA scale.  Success is 
defined as clear or almost clear with an improvement of at least two grades from baseline, i.e. 2 to 0; 3 
to 1. 
The secondary efficacy endpoints are: 
1. Time  to treatment success  
2. Change from baseline in IGA after 26 weeks treatment or at last visit if early 
withdrawal/discontinuation 
3. Change from baseline in FASI after 26 weeks treatment or at last visit if early 
withdrawal/discontinuation 
4. Subjective (patient or parent/caregiver) improvement rating from first visit (V0) after 26 weeks 
treatment or at last visit if early withdrawal/discontinuation 
5. Objective (clinician) improvement rating from first visit (V0) after 26 weeks treatment or at 
last visit if early withdrawal/discontinuation 
6. Categorical Improvement of Facial Angiofibroma from first visit (V0) after 26 weeks treatment 
In addition, exploratory efficacy endpoints are: 
1. The percentage of patients with successful treatment according to IGA scale after 2, 8, 14 and 
20 weeks treatment 
2. Change from baseline in IGA after 2, 8, 14 and 20 weeks treatment 
3. Change from baseline in FASI after 2, 8, 14 and 20 weeks treatment 
4. Change from baseline in each FASI component (erythema, size, extension) after 2, 8, 14, 20 
and 26 weeks treatment 
5. Subjective (patient or parent/caregiver) improvement rating from first visit (V0) after 2, 8, 14 
and 20 weeks treatment 
6. Objective (clinician) improvement rating from first visit (V0) after 2, 8, 14 and 20 weeks 
treatment 
7. Change in IGA from week 26 to Follow up (4 weeks after final dose) 


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8. Change in FASI from week 26 to Follow up (4 weeks after final dose) 
2.3 
Safety Objective 
The Safety Objective of the study is to determine and compare the incidence of treatment-emergent 
adverse events (TEAEs) over the course of the study among the three treatment groups.  
The incidence of known topical rapamycin side effects (e.g. treatment area irritation, dryness, and 
redness) and oral rapamycin side effects (e.g. hypersensitivity reaction, angioedema, fluid retention, 
wound healing disturbance, hyperlipidemia and renal function aggravation (etc.) and will be 
individually summarized by treatment group. 
Planned hospital admissions and/or surgical operations for an illness or disease which existed before 
the drug was given or the participant was randomized in a clinical study will not be considered adverse 
events. 
In addition, a physical examination, vital signs, hematology, biochemistry, blood lipids and urinalysis 
will be assessed at screening, at each visit (V1-5), and at follow-up to determine if there are any 
clinically significant changes. Blood rapamycin concentration will also be determined at screening and 
at each visit (V1-5) and at follow-up to investigate systemic absorption of the drug product.  
3 
INVESTIGATIONAL PLAN 
This is a multi-center, double-blind, randomized, placebo-controlled, dose-response clinical study 
investigating the efficacy and safety of Rapamycin cream, topical in the treatment of facial 
angiofibroma in patients with a diagnosis of TSC according to the clinical diagnostic criteria of 
International Tuberous Sclerosis Complex Consensus Conference 2012.  
The study can be divided into a Screening Phase, a Treatment Phase, and Follow-Up (Figure 1).  
During the Screening Phase, Informed Consent will be obtained for participants prior to the initiation 
of any study-specific procedures including eligibility confirmation. Following enrolment, up to two 
weeks prior to the first application of the study drug, participants will be randomly assigned to one of 
three possible treatments in a 1:1:1 ratio: 
- 
Rapamycin cream, topical (0.5% rapamycin) 
- 
Rapamycin cream, topical (1.0% rapamycin) 
- 
Placebo cream 
The Treatment Phase is divided into baseline visit (V0) and 5 subsequent clinical visits (V1-5).  
Follow-up will be performed 28 days after V5 or the last visit where early withdrawal from treatment 
was confirmed.  
 
 


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Figure 1: Schematic of Trial Design 
 


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4 
PARTICIPANT POPULATION 
4.1 
Number of Participants 
120 participants who meet all inclusion criteria and none of the exclusion criteria listed below in 
sections 4.2 and 4.3, respectively, will be enrolled at sites across the United States of America, Europe 
and Australasia. 
4.2 
Inclusion Criteria 
1. Male and female patients aged ≥ 6 years and ≤ 65 years on the day informed consent is 
obtained 
2. Patients diagnosed with TSC based on the clinical diagnostic criteria of International Tuberous 
Sclerosis Complex Consensus Conference 2012 and presenting visible facial angiofibroma 
3. An FA severity score of 2 or 3 on the IGA scale 
4. Patients or their legal representatives capable of understanding the explanation of the clinical 
trial and who give written informed consent for participation 
5. Patients or their legal representatives able to maintain patient diaries following the instructions 
of the investigator or sub-investigator 
4.3 
Exclusion Criteria 
1. Patients who cannot carry out the treatment plan or follow-up assessment 
2. Patients with serious skin lesions such as erosions or ulcers 
3. Patients with known hypersensitivity to any component of the study product 
4. Patients who have received rapamycin/sirolimus, everolimus, or temsirolimus within 3 months 
of enrolment 
5. Patients who received laser therapy or surgical therapy within 6 months prior to trial enrolment 
6. Patients who participated in any other clinical trial within 3 months prior to the day of enrolment 
7. Patients judged unsuitable for this clinical trial by the investigator or sub-investigator 
8. Pregnant or lactating females 
9. Sexually active females of childbearing potential not using adequate contraception and sexually 
active males not using adequate contraception* 
10. Patients with immune dysfunction or receiving any form of immunosuppression 
11. Patients with severe FA, with a score of 4 on the IGA scale 
12. Patients with an FA severity score of less than 2 on the IGA scale 
*Methods of contraception that are deemed adequate have failure rates of < 1%, including: established use of oral 
contraceptives in conjunction with a barrier method of contraception, injected or implanted hormonal methods of 
contraception; placement of intrauterine device (IUD) or intrauterine system (IUS); barrier methods of contraception including 
condom and/or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; sexual 
abstinence; hysterectomy; post-menopausal; sterilized; vasectomy. 


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4.4 
Withdrawal Criteria 
All participants have the right to withdraw at any point during the study without prejudice. Investigators 
can discontinue any participant at any time if it is in the opinion of the Investigator that it would not be 
in the participant’s best interest to participate in the study. Whether participant withdrawal is the 
decision of the participant, or an investigator, the following situations may occur: 
• 
The participant is withdrawn from the study and the participant withdraws consent to release 
follow-up information. 
• 
The participant is withdrawn from the study but all follow-up information can still be collected. 
4.5 
Study or Study Site Termination and Subject Discontinuation 
4.5.1 Study or Study Site Discontinuation 
If the Sponsor, Investigator, Study Monitor, Drug Safety Officer, or appropriate regulatory officials 
discover conditions arising during the study that indicate that the study should be halted or that the study 
center should be terminated this action may be taken after appropriate consultation among the Sponsor, 
Investigator, Study Monitor and Drug Safety Officer.  
Conditions that may warrant termination of the study include, but are not limited to, the following: 
• 
The discovery of unexpected, serious, or unacceptable risk to the subjects enrolled in the study 
• 
A decision on the part of the Sponsor to suspend or discontinue testing, evaluation or 
development of the product 
A study conducted at a single study site may also warrant termination under the following conditions: 
• 
Failure of the Investigator to enroll subjects into the study at an acceptable rate  
• 
Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
• 
Submission of knowingly false information from the research facility to the Sponsor, Study 
Monitor, or appropriate regulatory authority  
• 
Insufficient adherence to protocol requirements 
4.5.2 Subject Discontinuation 
Participants will be encouraged to complete the study; however, they may voluntarily withdraw at any 
time. The Investigator will provide a written report on the appropriate case report from (CRF) page 
describing the reasons for discontinuation. If a participant withdraws before completion this will be 
managed as described in Section 4.4. A participant may be removed from the study for the following 
medical or alternative reasons:  
• 
Adverse event  
o If a participant suffers an adverse event assessed as ≥ Grade 3 (≥ Grade 2 for the 
system-organ class of Cardiac Disorders; see Appendix 5: Grading of adverse events) 


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or, that, in the judgement of the Investigator or the Sponsor, presents an unacceptable 
consequence or risk to the subject, the subject should not receive additional doses. The 
participant should remain in the study and be followed until the adverse event resolves 
or stabilizes.  
• 
Intercurrent illness 
o A subject may be discontinued from the study if, in the judgement of the Investigator, 
he or she develops an intercurrent illness or complication that is not consistent with the 
protocol requirements or that, in any way, justifies his or her withdrawal from the study  
5 
TREATMENTS  
5.1 
Treatments to be administered 
Active Drug: Rapamycin cream, topical (cream preparation containing 0.5% or 1.0% rapamycin). 
Control: Placebo (cream preparation indistinguishable from the active drug and not containing any 
rapamycin). 
Details of administration are as follows: 
- 
The initial application of the study drug will be performed under medical supervision at the baseline 
clinical visit (V0). Subsequent applications will be made by the patient every evening, about half 
an hour before retiring for bed. 
- 
The participating clinician will determine the size of facial area affected and instruct the patient the 
amount of product to be applied. This will be recorded in source documents. 
- 
Prior to application, subjects should wash their face with a mild cleanser and pat dry. 
- 
The study drug is to be applied using the fingertips to the entire area of the face affected by facial 
angiofibroma. The amount of cream required to produce a thin confluent layer on the skin is 6 
mg/cm2. The amount to be applied will be based on the size of the affected area.  
For example: for an affected area of 150 cm2, dose = 900 mg (150 cm2 x 6 mg/cm2)  
- 
Squeezing the tube slowly and consistently between the thumb and index finger until the product 
emerges and falls from the tube produces a globule weighing approximately 600 mg, measuring 
16.5 mm in diameter.  
- 
Once the study treatment has been applied to the face, subjects should not wash their face or apply 
anything else to the face until morning. 
- 
After the study cream is applied, subjects should wash their hands thoroughly with soap and water. 
- 
Patients will be advised to avoid direct sunlight and ultraviolet (UV) light during the clinical trial. 
Protective clothing and a sunscreen with a high protection factor should be worn to reduce exposure. 


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5.1.1 Treatment Phase 
After informed consent has been provided, screening has been performed and participant eligibility 
confirmed, subjects will be admitted to the study site and randomized to one of three following 
treatments in a 1:1:1 ratio:  
- 
Rapamycin cream, topical (0.5% rapamycin) 
- 
Rapamycin cream, topical (1.0% rapamycin) 
- 
Placebo cream 
Patients will be instructed to apply the randomized treatment to the affected area once a day in the 
evenings (i.e. before retiring) for 26 weeks.  
5.2 
Investigational Products 
The investigational products have been manufactured by Sterling Pharmaceuticals Services, LLC in its 
GMP approved manufacturing facility. Sterling Pharmaceutical Services holds a valid GMP issued by 
the USDFDA (Establishment Identifier No. 3009705561).  
Lab scale batches of both strengths of Rapamycin cream, topical have been shown to be stable under 
room temperature conditions (25°C/60%RH) for at least 12 months. It is expected that the study drug 
will be stable long term under these conditions and stability studies are ongoing. Re-testing of the 
samples of the remaining study drugs will be conducted at the end of the study to confirm that the 
product is compliant with stability specifications.  
The study drugs are contained in aluminum tubes with screw caps. Each 35 g tube contains 30 g of the 
study drug. 
The study drug supplied for use in this study is to be prescribed only by the principal investigator or 
named co/sub-investigators and may not be used for any purpose other than that outlined in this 
protocol. Neither the investigators nor any designees may provide study drug to any patient not 
participating in the study.  
The investigator or pharmacy designee will maintain an inventory record of study drug dispensed to 
assure regulatory authorities and the Sponsor that it has not been dispensed to any person who is not a 
participant under the terms and conditions set forth in this protocol. 
At the termination of the study, all unused study drug (once it has been inventoried and accountability 
documents have been reviewed by the assigned study monitor) will be destroyed, and a destruction 
certificate will be issued by a licensed destruction company.  
5.3 
Randomization 
Randomization will occur at the study site once participant eligibility is confirmed, up to two weeks 
before the first clinical visit (V0), which includes the first application of the study drug. Participants 


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will be randomly assigned to one of three possible treatments in a balanced fashion (i.e. 1:1:1 ratio). 
Each successive subject will receive a unique study randomization number which includes both a two-
digit site prefix (e.g. 01), a single-digit age stratum identifier (e.g. 0) and two-digit subject identifier 
(e.g. 01). For example, the first patient in the first stratum (age group: 6 – 11 years) at site #1 will be 
assigned the randomization number 01-001. Randomization will be balanced by using permuted blocks 
and stratified by site and age group (6 – 11 years; 12 – 17 years; 18 – 65 years). Participants will be 
enrolled into the study until a minimum of 120 participants are randomized and have started using study 
drug.  
The randomization sequence will be computer-generated by the study statistician prior to any 
enrolment. The statistician will maintain a confidential schedule of participant IDs and treatment 
allocations. The dispensing pharmacist at each site will not be blinded, and will maintain a confidential 
schedule of participant IDs and treatment allocations for participants at their site. The pharmacist will 
be responsible for over-labelling the study medication. The randomization sequences will be maintained 
by the site pharmacist in a secure location which cannot be accessed by other staff members involved 
in the conduct of the trial. 
The sites will receive a set of sealed blinding envelopes for emergency un-blinding, with a separate 
envelope for each participant number. The principal investigator will be the first point of contact should 
the randomization code need to be broken for an individual participant during the study. The emergency 
unblinding envelopes for each participant should only be opened in an emergency when knowledge of 
the study drug may affect the management of the patient. 
5.4 
Blinding 
Double-blinding will be achieved by the use of a vehicle placebo cream that has the same composition 
as Rapamycin cream, topical, but does not contain any active ingredient (rapamycin). The placebo 
cream and Rapamycin cream, topical are visually indistinguishable and are packaged into identical 
aluminum 30 g (net) tubes. Patients and treating and assessing dermatologists will all be blind to 
randomized treatment. 
5.5 
Prohibited concomitant medications 
The following medications are prohibited after enrolment in this trial due to the risk of interference in 
the evaluation of efficacy/safety: 
- 
Laser and surgical treatment of the target treatment area 
- 
Administration of mTOR inhibitors (rapamycin/sirolimus, everolimus, temsirolimus etc.) 
- 
Application of steroidal or antibacterial agents to the target area 
- 
Administration of cyclosporine or macrolide antibiotics 


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- 
Strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, 
erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such 
as rifampin or rifabutin) 
While not prohibited, concomitant use of rapamycin with some medications may increase the risk of 
certain adverse events. The following precautions will be taken: 
- 
Patients taking drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) 
inhibitors, will be closely monitored as concomitant use of rapamycin may increase the risk of 
developing angioedema. 
- 
Patients taking statins and/or fibrates will be monitored for the possible development of 
rhabdomyolysis and other adverse effects, as described in the respective labelling for these agents. 
5.6 
Treatment compliance 
The nightly administration of study medication will be documented by the patient or caregiver in the 
patient diary. A clinical trial monitor will review patient source documents, drug accountability records 
and patient diaries on an ongoing basis to assess treatment compliance. Additionally, returned tubes 
will be weighed to determine the amount of study medication used by the participant. 
Acceptable compliance is no more than an average of one missed dose per week (26 missed doses over 
the course of the study) and no more than seven missed consecutive doses. 
6 
STUDY DATA AND ENDPOINTS 
6.1 
Efficacy data 
6.1.1 Primary Efficacy Endpoint 
At screening, each visit (V1-V5) and at follow-up a blinded dermatologist will grade each patient’s 
lesion using the Investigator’s Global Assessment (IGA) of facial angiofibroma severity developed by 
the sponsor and created solely to identify the response of a treatment in FA associated with TSC.  


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Table 2: IGA scoring of Facial Angiofibroma Lesions 
The primary efficacy endpoint is the percentage of patients obtaining successful treatment, based on the 
blind assessment using the IGA scale after 26 weeks or at discontinuation/withdrawal. Success is 
defined as clear or almost clear with an improvement of at least two grades from baseline, i.e. 2 to 0; 3 
to 1.  
To the extent possible, the same Investigator should conduct all IGA assessments per patient at each 
site throughout the study. 
6.1.2 Secondary and Exploratory Efficacy Endpoints 
The following secondary efficacy endpoints will be derived from IGA scores: 
1. Time to treatment success   
2. Change from baseline in IGA after 26 weeks treatment or at last visit if early 
withdrawal/discontinuation 
In addition, the following exploratory efficacy endpoint will be derived from IGA scores: 
1. The percentage of patients with successful treatment according to IGA scale after 2, 8, 14 and 
20 weeks treatment 
2. Change from baseline in IGA after 2, 8, 14 and 20 weeks treatment 
7. Change in IGA from week 26 to Follow-up (4 weeks after final dose) 
Lesion severity will also be graded using the Facial Angiofibroma Severity Index (FASI) [Appendix 2: 
Facial Angiofibroma severity index (FASI)]. Using the FASI, lesions are graded according to their 
erythema, size and extent. Erythema is scored from 0 to 3 and lesion size are scored from 0 to 3, while 
extent carries greater specific weight (scored from 2 to 3), as the scale’s developers consider the lesion’s 
extent to be a fundamental factor in estimating the degree of severity.  
Grade Short Description Detailed Description 
0 
Clear 
No signs of facial angiofibroma 
1 
Almost Clear 
Few small angiofibromas (< 2 mm); normal to pink coloration in 
affected area*  
2 
Mild 
Predominantly small angiofibromas (< 2 mm) with few intermediate 
tumors (2-4 mm); pink to red coloration in affected area  
3 
Moderate 
Predominantly intermediate angiofibromas (2-4 mm) with few large 
tumors (> 4 mm); red coloration in affected area 
4 
Severe 
Mix of intermediate (2-4 mm) and large angiofibromas (>4 mm) 
present diffusely on face; intense and generalized redness on the 
whole face 
* Note: coloration refers to both the FA lesions and the background facial skin tone 
Where lesion size and coloration are discrepant within the grade, emphasis should be placed on lesion size. 


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The FASI is obtained by summing the partial scores assigned to each of three relevant features of FA 
for a maximum score of 9. FASI was first described in a clinical trial of 9 months duration (33) and the 
reliability and validity was subsequently reported (16). This will provide data for the following 
secondary efficacy endpoint: 
3. The change in FASI from baseline after 26 weeks treatment or at last visit if early 
withdrawal/discontinuation  
In addition, the following exploratory efficacy endpoints will be derived from FASI scores: 
3. Change from baseline in FASI after 2, 8, 14 and 20 weeks treatment 
4.  Change from baseline in each FASI component (erythema, size, extension) after 2, 8, 14, 20 
and 26 weeks treatment 
8. Change in FASI from week 26 to Follow-up (4 weeks after final dose) 
To the extent possible, the same Investigator should conduct all FASI assessments per patient at each 
site throughout the study. 
At Visits 1-5 patients or their parents/caregivers (for patients under the age of 18) will be asked to 
estimate the percentage improvement in the FA lesion appearance from their perspective since baseline 
(V0) [Appendix 3: Subjective and Objective Improvement Ratings]. Similarly, the investigators will 
estimate the percentage improvement from a clinical perspective. Improvement will be defined as: 
minimal <30%, moderate 30-59%, good 60-89%, excellent >90%. This is similar to the objective and 
subjective improvement ratings used by Foster et al. (23) and Tu et al. (37). This will provide data for 
the following secondary efficacy endpoints: 
4. Subjective improvement rating (minimal, moderate, good or excellent) in facial angiofibroma 
from first visit (V0) after 26 weeks of treatment or at last visit if early 
withdrawal/discontinuation 
5. Objective improvement rating (minimal, moderate, good or excellent) in facial angiofibroma 
from first visit (V0) after 26 weeks of treatment or at last visit if early 
withdrawal/discontinuation 
In addition, the following exploratory efficacy endpoints will be derived from percentage improvement 
scores: 
5. Subjective (patient or parent/caregiver) improvement rating from first visit (V0) after 2, 8, 14 
and 20 weeks treatment 
6. Objective (clinician) improvement rating from first visit (V0) after 2, 8, 14 and 20 weeks 
treatment 


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To the extent possible, the same clinician should conduct all improvement rating assessments per patient 
at each site throughout the study. Similarly, the same person (patient of parent/caregiver) should report 
all improvement rating assessments throughout the study. 
Upon completion of the double-blind treatment phase, patients or their parents/caregivers (for patients 
under the age of 18) will be asked which of the following statements they agree with: 
- 
3: I got significantly better on the treatment 
- 
2: I got moderately better on the treatment 
- 
1: I got slightly better on the treatment 
- 
0: The treatment made no difference 
- 
-1: I got worse on the treatment 
This is similar to the subjective improvement rating used by Koenig et al. (47). See also Appendix 4: 
Categorical improvement of Facial Angiofibroma. This will provide data for the following secondary 
efficacy endpoint: 
6. Categorical Improvement of Facial Angiofibroma from first visit (V0) after 26 weeks treatment 
Photographs of the FA lesions will be taken at randomization, and V1-5 and at follow-up to document 
changes. These will not be used directly for any efficacy endpoints, but will be available for auditing 
purposes.  
6.2 
Safety Data 
The definitions and requirements in relation to adverse events are described in Section 8. All adverse 
events (AEs), including serious adverse events will be assessed by the Investigator according to 
Common Terminology Criteria for Adverse Events (CTCAE v 5.0) (see Appendix 5: Grading of 
adverse events) and documented up until 4 weeks after the final dose of study medication i.e. Follow-
up visit.  
Planned hospital admissions and/or surgical operations for an illness or disease which existed before 
the drug was given or the participant was randomized into the clinical study will not be considered 
adverse events. 
6.2.1 Evaluations of Specific AEs 
Known topical rapamycin adverse events will be compared between groups: 
- 
Treatment area irritation (e.g. erythema, papules, vesicles, erosion etc.) 
- 
Treatment area dryness 
Known oral rapamycin adverse events will be compared between groups: 
- 
Hypersensitivity reactions 
- 
Angioedema  


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- 
Fluid retention  
- 
Wound healing disturbance  
- 
Hyperlipidemia 
- 
Renal function decline 
- 
Proteinuria 
- 
Infections 
CRFs will not specifically list these adverse events but they will be separated for analysis.  
6.2.2 Overall Evaluation of Safety 
The overall evaluation of safety throughout the trial will be based on all adverse events observed during 
the Treatment Phase and Follow-Up.  
A physical exam, vital signs and laboratory tests (hematology, biochemistry, lipid panel and urinalysis) 
will be conducted during screening (baseline results), at each subsequent visit (V1-V5) and at follow-
up. Clinically significant changes to the test results from baseline will be evaluated and compared 
among the three study groups. If participants are unable to provide blood samples at all timepoints, the 
minimum to be collected should be samples at screening, V1 or V2 and V5. 
6.2.3 Systemic absorption of rapamycin 
 Blood rapamycin concentrations should be measured at screening and at each subsequent visit (V1-5) 
and at follow-up. If participants are unable to provide blood samples at all timepoints, the minimum to 
be collected should be samples at screening, V1 or V2 and V5. Samples will be collected by 
venipuncture by a qualified member of the study team. A total of approximately 5 mL blood will be 
collected into a lithium-heparin vacutainer. 
As blood rapamycin levels are being measured as a safety parameter (blood rapamycin levels are not 
anticipated to exceed immunosuppression levels of 8-20 ng/mL), samples should be analyzed at a local 
accredited laboratory using validated analytical methods. As blood rapamycin concentrations may be 
measured by various chromatographic and immunoassay methodologies, each site should use the same 
analytical method throughout the study.  
7 
EXPERIMENTAL PROCEDURE 
The study is intended to be carried out over a total of up to 10 months. The study consists of a Screening 
Phase (up to 3 months), a Treatment Phase (baseline and 5 clinical visits; 6 months), and Follow-Up (1 
month). For early withdrawals, the follow-up visit will be scheduled from the last visit where subject 
withdrawal was confirmed. The study assessments are summarized in Table 3.  


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Table 3: Schedule of Assessments 
Assessment 
Screening Phase 
Treatment Phase 
Follow-Up 
Informed 
consent 
Screening 
Randomization 
V0 
Baseline 
V1 
2 
weeks 
V2 
8 
weeks 
V3 
14 
weeks 
V4 
20 
weeks 
V5 
26 
weeks 
4 weeks after final 
dose 
Tolerance 
≤3 months before 
V0 
≤14 days before V0 
NA 
±3 
days 
±3 
days 
±3 days 
±3 days 
±3 days 
±5 days 
Informed consent 
X1 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test2  
 
X 
 
X 
X 
X 
X 
X 
X 
 
Hematology, biochemistry & lipid panel3 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood rapamycin concentration3,4 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Drug administration (once daily, evenings) 
 
 
 
X 
 
Photographs of FA 
 
 
X 
 
X 
X 
X 
X 
X 
X 
IGA 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
FASI 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Percentage improvement (subjective & 
objective) 
 
 
 
 
X 
X 
X 
X 
X 
 
Categorical improvement 
 
 
 
 
 
 
 
 
X5 
 
Concomitant medications 
 
X 
X 
X 
X 
Adverse events  
 
 
 
X 
X 
1 if more than a month passes between obtaining informed consent and randomization, then informed consent should be re-obtained 
2 only conducted for women of childbearing potential 
3 if participants are unable to provide blood samples at all timepoints, the minimum to be collected should be samples at screening, V1 or V2 and V5 
4 blood sampling collected prior to the daily evening dose 
5 categorical assessment only to be done at V5, unless early withdrawal/discontinuation, in which case categorical assessment should be completed at last visit


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7.1 
Screening Phase 
The screening phase will occur up to 3 months prior to the initial Clinical Visit (V0).  
Prior to the initiation of the screening assessments, potential participants will be given a complete 
explanation of the study.  
Informed Consent may be obtained up to 3 months prior to the initial Clinical Visit (V0), however if 
more than one month passes between obtaining informed consent and randomization, then informed 
consent should be re-obtained. 
Once an individual has agreed to participate and signed a copy of the Informed Consent documents the 
following assessments will be performed up to 14 days prior to V0 to assess the participant’s eligibility 
for enrolment in the study according to the Inclusion/Exclusion criteria:  
• 
Demographic data (age, sex, height, weight etc.)  
• 
Complete medical history - including past or present history of cardiac, pulmonary, 
gastrointestinal, hepatic, renal, immunological, hematological, neurological, musculoskeletal 
or psychiatric conditions (if any), allergy to food or drugs and medication history for the 
previous three months.  
• 
Physical examination  
• 
Vital signs (temperature, blood pressure [systolic and diastolic], pulse rate)  
• 
Urine pregnancy tests (females of childbearing potential only) 
• 
Hematology 
o Hemoglobin 
o Hematocrit 
o Platelet count 
o Red Blood Cell (RBC) count 
o White Blood Cell (WBC) count 
o Differential Leukocyte Count (DLC) 
• 
Biochemistry 
o Sodium 
o Potassium 
o Urea 
o Creatinine 
o Phosphate 
o Glucose 
o Albumin 
o Total protein 
o Alkaline phosphatase 


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o Gamma-glutamyl transferase 
o Aspartate transaminase 
o Alanine transaminase 
o Bilirubin  
• 
Lipid panel 
o Total cholesterol 
o High-density lipid cholesterol 
o Low-density lipid cholesterol 
o Triglycerides 
• 
Blood rapamycin concentration  
• 
Urinalysis 
• 
Clinical examination of FA lesions using the Investigators Global Assessment (IGA) 
• 
Concomitant medications 
If subjects meet all eligibility criteria, they will be assigned a unique randomization number up to two 
weeks before the first application of the study drug, at which time the following baseline assessments 
will be conducted:    
• 
Vital signs (temperature, blood pressure [systolic and diastolic], pulse rate) 
• 
Photographs of FA lesions 
• 
Clinical examination of FA lesions using the Investigators Global Assessment (IGA) and Facial 
Angiofibroma Severity Index (FASI) 
• 
Concomitant Medications 
Photographs of FA lesions will be taken using standardized methodologies as established at each site. 
Photographs at each visit will be signed and dated by the Investigator. The randomization number of 
the patient will be recorded on the photograph along with the IGA and FASI scores determined at that 
visit. Photographs will not be used directly for any efficacy endpoints, but will be available for auditing 
purposes and may be used in publications of the study results (deidentified photographs only).  
7.2 
Treatment Phase 
Once an individual’s eligibility for the trial has been confirmed and the participant has been randomized, 
the Treatment Phase can start. The Treatment Phase is divided into an initial clinical Visit (V0) and 5 
subsequent clinical visits (V1-5).  
7.2.1 Initial Clinical Visit (V0) 
During the Initial Clinical Visit (V0) the initial application of the study drug will be performed under 
medical supervision. The participating clinician will determine the size of facial area affected and 
instruct the patient the amount of product to be applied. This will be recorded in source documents. 
In addition, the following assessments will be conducted: 


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• 
Vital signs (temperature, blood pressure [systolic and diastolic], pulse rate) 
• 
Urine Pregnancy test (females of childbearing potential only) 
• 
Concomitant Medications 
• 
Adverse event monitoring 
 
7.2.2 Clinical Visits 1-5 (V1-5) 
During Clinical Visits (V1-5) the following assessments will be performed: 
• 
Physical examination 
• 
Vital signs (temperature, blood pressure [systolic and diastolic], pulse rate) 
• 
Urine Pregnancy test (females of childbearing potential only) 
• 
Hematology, Biochemistry, Lipid panel (as per screening assessments) 
• 
Urinalysis 
• 
Blood rapamycin concentration 
• 
Confirm application of study drug from the patient diary 
• 
Photographs of FA lesions 
• 
Lesion severity with IGA 
• 
Lesion severity with FASI 
• 
Percentage Improvement since V0 
o Subjective assessment 
o Objective assessment 
• 
Categorical Improvement (at V5 or visit when withdrawal is confirmed only) 
• 
Concomitant medications 
• 
Adverse event monitoring 
7.3 
Follow-Up Period 
Patients will be invited back for a follow up visit ~28 days (4 weeks) after their final visit of the 
Treatment Phase (depending on participation and withdrawal status) and the following assessments will 
be performed: 
• 
Physical examination 
• 
Vital signs (temperature, blood pressure [systolic and diastolic], pulse rate) 
• 
Hematology, Biochemistry, Lipid panel (as per screening assessments) 
• 
Urinalysis 
• 
Blood rapamycin concentration 
• 
Photographs of FA lesions 
• 
Lesion severity with IGA 
• 
Lesion severity with FASI 
• 
Adverse event monitoring 


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• 
Concomitant medications 
8 
ADVERSE EVENTS 
8.1 
Definitions 
An adverse event (AE) is defined as any unintended, unfavorable clinical sign or symptom, any new 
illness or disease or deterioration of existing illness or disease, or any clinically relevant deterioration 
in laboratory variables (e.g., hematological, biochemical, hormonal) or other clinical tests (e.g., ECG, 
X-ray), whether or not considered treatment related. 
Planned hospital admissions and/or surgical operations for an illness or disease which existed before 
using the treatment or before the participant was randomized in the clinical study will not be considered 
adverse events. 
The severity of an adverse event will be assessed by the Investigator according to Common 
Terminology Criteria for Adverse Events (CTCAE v 5.0) (see Appendix 5: Grading of adverse events). 
The relationship of an adverse event to the use of the drug will be assessed by the Investigator as 
described in Appendix 5: Grading of adverse events. 
Participants will be specifically asked about the expected side-effects (such as treatment area irritation, 
dryness and redness), as well as any other symptoms they may have experienced, at each study visit. 
Other important aspects include photosensitivity reactions and adverse events reported for the oral 
formulation of rapamycin (Rapamune) including: 
• 
Hypersensitivity reactions (including anaphylactic/anaphylactoid reactions, angioedema, 
exfoliative dermatitis and hypersensitivity vasculitis) 
• 
Angioedema 
• 
Fluid retention 
• 
Wound healing disturbance 
• 
Hyperlipidemia 
• 
Renal function decline 
• 
Proteinuria  
• 
Increased susceptibility to opportunistic infections (including tuberculosis, progressive 
multifocal leukoencephalopathy (PML), interstitial lung disease, Pneumocystis carinii 
pneumonia) 
Participants experiencing adverse events will be followed clinically until their health has returned to 
baseline status or until all abnormal values have returned to normal or have otherwise been explained. 
The investigators will provide or arrange appropriate supportive care for the participant if necessary. 
Participants will be advised to contact their doctor immediately if they develop signs or symptoms of 
hypersensitivity.  


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8.1.1 Serious Adverse Event 
A serious adverse event is an AE that: 
• 
results in death; 
• 
results in persistent or significant disability/incapacity; 
• 
is life-threatening (i.e. the participant was, in the opinion of the Investigator, at immediate risk 
of death from the event as it occurred; this does not include an event that, had it occurred in a 
more severe form, might have caused death); 
• 
requires participant hospitalization or prolongs hospitalization; 
• 
is a congenital anomaly/birth defect; or 
• 
is another medically significant event that, on the basis of appropriate medical judgment, may 
jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed above (e.g. allergic bronchospasm requiring intensive treatment in an 
emergency room or home, blood dyscrasias or convulsions that do not result in hospitalization, 
or the development of drug dependency or drug abuse). 
An adverse event fulfilling any one or more of these criteria must be reported as a serious adverse event, 
irrespective of the interventions given, and even if it is the result of an interaction or drug abuse. 
A distinction should be drawn between serious and severe adverse events. Severity is an estimate or 
measure of the intensity of an adverse event, while the criteria for serious are indications of adverse 
participant outcomes for regulatory reporting purposes. A severe adverse event need not necessarily be 
considered serious and a serious adverse event need not be considered severe. For example, nausea that 
persists for several hours may be considered severe nausea, but not a serious adverse event. On the other 
hand, a myocardial infarction that may be considered minor could also be a serious adverse event if it 
prolonged hospitalization, for example. The severity of AEs will be graded according to Common 
Terminology Criteria for Adverse Events (CTCAE v 5.0). 
8.1.2 Suspected Adverse Drug Reactions (ADR)  
According to ICH GCP 1.1, “all noxious and unintended responses to a medicinal product related to 
any dose should be considered adverse drug reactions.”  
8.1.3 Unexpected Adverse Drug Reaction  
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information. 
8.2 
Procedure for Adverse Event Reporting 
All adverse events (non-serious and serious) spontaneously reported by the participant and/or in 
response to an open question from the study personnel or revealed by observation, physical 
examination, or other diagnostic procedures will be recorded.   


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All adverse events (non-serious and serious) must be recorded on the source documents and case report 
forms provided by the Sponsor. The following information shall be included: 
• 
nature of the adverse event  
• 
the onset date of adverse event  
• 
the end date of adverse event (if applicable)  
• 
the outcome of the AE  
• 
the frequency of the AE  
• 
action taken with the investigational product 
• 
relationship to the investigational product 
• 
whether any treatment was received for this adverse event  
• 
whether this adverse event was serious  
Any adverse event or abnormal laboratory result evaluated as clinically significant by the study 
investigator shall be followed until satisfactory resolution: it becomes stable, or it can be attributed to 
other causes (existing conditions) and in the opinion of investigators that further follow-up is not 
required.  
8.3 
Procedure for Serious Adverse Event Reporting 
8.3.1 Reporting to the Sponsor 
In addition to entering each serious adverse event irrespective of causality on the appropriate page of 
the case report form (CRF), the Investigator must complete a Serious Adverse Event Report (SAER) 
for each serious adverse event regardless of causality to the investigational drug. A sample of the SAE 
form for reporting is presented in Appendix 6: SAE Reporting Form. The SAER must be faxed to the 
Drug Safety Officer at the CRO and then to AFT Pharmaceuticals Ltd (+64 9 488 0234) within 24 hours 
of the event being notified to/realized by study site staff. The Drug Safety Officer will contact the 
Investigator should it be necessary to clarify any of the event information. The Investigator should 
provide any additional follow-up information for the event to AFT Pharmaceuticals Ltd as soon as it 
becomes available and up to the point the event has been resolved. This reporting requirement is 
applicable to serious adverse events that occur during the designated study period. If the Investigator is 
notified of a serious event post study that he or she determines to be causally related to study medication, 
the event should also be reported through this process.  
8.3.2 Reporting to Local IEC and Regulatory Authorities 
Serious adverse events will be reported to the local ethics committee and the relevant health authority 
as per the requirements.  
8.3.2.1 Local Ethics Committee  
There is no general requirement for applicants to submit individual or expedited reports of SAEs or 
suspected unexpected serious adverse reactions (SUSARs) to local ethics committees who do not have 


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the expertise or resources to review them. In the case of intervention studies involving a new medicine, 
the researcher is required to submit an annual summary of safety information.  
8.3.2.2 Regulatory Authorities 
Fatal or Life-Threatening Unexpected ADRs 
An ADR is considered “fatal or life-threatening” if, in the review of either the investigator or sponsor, 
its occurrence places the participants at immediate risk of death. It does not include an adverse events 
of adverse drug reaction that, had it occurred in a more severe form, might have caused death.  
Fatal of life-threatening ADRs occurring in clinical investigations is subject to expedited reporting. 
Regulatory agencies should be notified (e.g., by telephone, facsimile, transmission, or in writing) as 
soon as possible but no later than 7 calendar days after the first knowledge by the sponsor that a case 
qualifies, followed by as complete a report as possible with 8 additional calendar days. This report must 
include an assessment of the importance and implication of the findings, including relevant previous 
experience with the same of similar medicinal products.  
All other serious, unexpected ADRs 
Serious, unexpected reaction (ADRs) that are not fatal or life-threatening must be filed as soon as 
possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the 
minimum criteria for expedited reporting.  
9 
PROTOCOL DEVIATIONS 
This study will be conducted, within reasonable limits, as described in this protocol, except for 
emergency situations in which the protection, safety, and well-being of the participant requires 
immediate intervention, based on the judgement of the Investigator (or a responsible, appropriately 
trained professional designated by the Investigator). In the event of a significant deviation from the 
protocol due to an emergency, accident, or mistake, the Investigator or designee must contact the 
Sponsor, or the Sponsor’s agent, at the earliest possible time by telephone. This will allow an early joint 
decision regarding the best way to proceed with the study. The Investigator and the Sponsor will 
document this decision. The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
will be informed of all protocol changes by the Investigator in accordance with the IRB or IEC 
established procedure. No significant planned or deliberate deviations from the protocol of any type 
will be made without the Sponsor’s agreement and complying with all the IRB or IEC established 
procedures. 


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10 PLAN FOR STATISTICAL AND OTHER CALCULATIONS 
10.1 Populations of Interest 
The Intent-To-Treat (ITT) population will consist of all subjects who receive at least one dose of study 
drug. Subjects will be included in the group to which they were randomized irrespective of the treatment 
actually taken. The ITT population is the primary population for the efficacy analysis.   
The Per-Protocol (PP) population will consist of all ITT subjects who remain in the study for at least 
26 weeks (i.e. complete the double-blind treatment period) and who do not incur a major protocol 
violation that would challenge the validity of their data.  
The safety population is the population for all safety assessments. The safety population will include 
all subjects who are treated with study drug. Subjects will be included in the treatment group according 
to the treatment actually taken.  
10.2 Sample Size 
This is the first randomized clinical trial of Rapamycin cream, topical applied to patients and the first 
time that the Investigator’s Global Assessment (IGA) scale will be used for the assessment of the 
severity of facial angiofibroma.   
It is anticipated that no more than 10% of the placebo group will achieve the primary endpoint, a 
successful treatment according to IGA scale after 26 weeks treatment and that each dose of Rapamycin 
cream, topical will achieve at least 40% successful treatment (42). Including the Holm-Bonferroni 
adjustment of the type I error rate for multiple comparisons (α = 0.025), a sample size of 40 participants 
is required in each randomized group to achieve >80% power for these comparisons.   
10.3 Statistical Analyses 
10.3.1 Primary Efficacy Endpoint 
The data for the primary endpoint, the percentage of patients obtaining successful treatment based on 
the blind assessment using the IGA scale after 26 weeks or at last visit if early 
withdrawal/discontinuation, will be summarized by treatment group.  Success is defined as clear or 
almost clear with an improvement of at least two grades from baseline, i.e. 2 to 0; 3 to 1. Statistical 
analysis of the primary endpoint will be performed using a logistic regression model which will include 
treatment effect and stratum as fixed factors and baseline IGA score as a covariate. This model will be 
used to generate the odds ratios and 95% confidence intervals of the individual dose treatments 
compared with placebo, with the p-values for these comparisons adjusted using the Holm-Bonferroni 
adjustment. 
An exploratory analysis will compare the two active groups in the same manner as the primary endpoint, 
with no adjustment for multiple comparisons. This analysis will be summarized with the Odds ratio and 
95% confidence interval. 


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10.3.2 Secondary Efficacy Endpoints 
The time-to-treatment success will be summarized using Kaplan-Meier analyses and compared between 
each dose group and placebo using the stratified log-rank test. The secondary endpoints change in IGA 
and FASI from baseline to 26 weeks/last assessment, and objective and subject improvement from 
baseline to 26 weeks/last assessment, will be summarized by treatment group using means, medians, 
standard deviations, interquartile ranges and minima and maxima. These changes will be analyzed using 
ANOVA including treatment and stratum as main effect fixed factors, with planned pairwise 
comparisons between each dose group and placebo. If the data is not adequately normally distributed 
the Kruskal-Wallis non-parametric ANOVA, and Mann-Whitney U tests comparing changes between 
treatment groups will be used for the analysis. Baseline for the IGA and FASI scores is defined as the 
last pre-treatment assessment, whether obtained at screening, randomization or V0.  
Categorical Improvement scores will be compared amongst study groups using the Kruskal-Wallis non-
parametric ANOVA, and Mann-Whitney U tests comparing changes between each dose group and 
placebo. 
The type I error rate associated with the testing of the six secondary endpoints will be strictly controlled 
using the Hochberg procedure. This will involve ranking the 6 p-values derived from the testing of each 
dose group with placebo from highest to lowest. If the highest p-value is <0.05, then all six comparisons 
are considered statistically significant if not significant then the next highest is tested at p=0.025. The 
p-value continues to reduce at each non-significant step based on the Bonferroni adjustment. 
10.3.3 Exploratory Efficacy Analyses 
The exploratory endpoints, including the change in IGA and FASI from week 26 to follow-up, will be 
analyzed in the same manner as the appropriate secondary endpoints. The p-values from these 
comparisons will not be reported but the differences between each dose group and placebo will be 
summarized as odds ratios or mean differences as appropriate with 95% confidence intervals. 
10.3.4 Additional Analyses 
A sensitivity analysis will be conducted using the Per-Protocol (PP) population to assess the robustness 
of the results for the primary endpoint.  
An additional sensitivity analysis of the primary endpoint will be conducted in the portion of the ITT 
who complete the 26 week treatment period and have a 26 week assessment, if this population differs 
from the PP population. 
A further sensitivity analysis will be conducted in which those patients who do not provide data at 26 
weeks will be considered as treatment failures.  
Analyses and summaries of the primary endpoint will also be presented by subgroup. These will include 
gender, age, site and baseline IGA score groups. As the sample sizes of subgroups are likely to be small, 


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these analyses will be presented for information purposes only, and statistically significant results are 
not anticipated. 
10.3.5 Safety Endpoints 
AEs will be collected for all randomized participants and will be listed with type of AE, severity and 
relationship for each treatment group, using the safety population. Adverse event data will be 
summarized for each treatment groups using frequencies and percentages (% of participants with each 
specific AE). If frequencies permit, Chi-square tests or fisher’s exact tests may be used to compare the 
rates of occurrence between treatment groups. Known AEs specific to oral or topical rapamycin will be 
individually summarized by treatment group. 
Between-treatment comparisons will be made for changes in vital signs, hematology, biochemistry, 
blood lipids and urinalysis from baseline at visits V1-5. Baseline is defined as the last pre-treatment 
assessment, whether obtained at screening, randomization or V0. Changes between V5 and Follow-up 
will also be examined.  
Blood rapamycin concentrations will be summarized for each of the treatment groups at all scheduled 
timepoints using standard descriptive statistics (means, medians, geometric means, ranges, standard 
deviations and standard errors), as appropriate.   
Adverse events will be monitored up to 4 weeks after administration of the final dose of study 
medication.  
10.3.6 Demographic and Background Characteristics 
Participant demographic and background characteristics will be descriptively summarized by treatment 
group using means, medians, standard deviations, ranges, frequencies and percentages as appropriate. 
No formal statistical comparisons will be made between treatment groups. 
10.4 Treatment Compliance 
To evaluate the degree of treatment compliance during the trial, tabular summaries of study drug usage 
will be presented for each randomized group.  
Participants whose study drug usage exceed the limitations provided by the study protocol will be 
included in a list of protocol deviations. The potential effect of such deviations on the resulting clinical 
evaluations will be discussed in the study report. 
10.5 Missing data 
Every effort will be made to obtain all assessments at the appropriate time points from all randomized 
participants, especially to obtain assessments from early withdrawals. Where early withdrawals occur 
between visits without a visit to confirm subject withdrawal, assessments completed at the visit 
preceding withdrawal will be considered the assessment at discontinuation/withdrawal.  


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For the exploratory analyses, intermittent missing values in the analysis of IGA, FASI and percentage 
improvement scores will be imputed by linear interpolation of adjacent scores (i.e. immediately 
preceding and immediately following the missing value). No attempt will be made to impute missing 
data for Overall Improvement/Patient Satisfaction (recorded only at V5, or at last visit where 
withdrawal was confirmed).  
10.6 Procedure for Amendments to Statistical Plan 
It is intended that all statistical analyses specified in this protocol will be performed. However, it is 
conceivable that some scheduled analyses may not be performed. In addition, study observations or 
analysis results may suggest the need for additional statistical analyses of the collected study data, or 
changes to the procedures for handling missing data. In either case, deviations (subtractions or 
additions) from the planned statistical analysis will be fully described in the final clinical study report. 
10.7 Data collection 
The Case Report Form (CRF) will be used to collect all data that will be used for evaluation of specified 
analyses.  The CRF should be completed in a timely fashion. 
As this study will be conducted under International Conference on Harmonization (ICH) GCP 
guidelines, these guidelines require all investigators participating in clinical drug trials to maintain 
detailed clinical data for one of the following periods: 
• 
A period of at least 2 years following the date after the last approval of a marketing application 
in an ICH region and until there are not any pending or contemplated marketing applications in 
an ICH region. 
• 
A period of at least 2 years after the formal discontinuation of clinical development of the 
investigational product. 
Should countries participating in this study have other guidelines for record retention, the period of 
record retention should follow the strictest guidelines, for example, New Zealand guidelines require 
documents to be retained for 10 years and Australian guidelines for 15 years. 
It is agreed that the Investigator and the Sponsor will share in the responsibility to maintain these 
records. Each will maintain a complete set. Neither the Investigator nor the Sponsor will dispose of any 
records relevant to this study without either written permission from the other and from the relevant 
authorities. The Investigator and Sponsor shall both be responsible for maintaining adequate and 
accurate hard copy source documents of all observations and data generated during this study, including 
any data clarification forms (DCFs) received from the Sponsor. Such documentation is subject to 
inspection by the Sponsor or its agents, and/or regulatory agencies. The Investigator may work with the 
Sponsor to ensure that archiving facilities are provided during the archiving period. 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Monitoring 
The Sponsor has ethical, legal, and scientific obligations to carefully follow this study in a detailed and 
orderly manner in accordance with established research principles and applicable regulations. As part 
of a concerted effort to fulfil these obligations (maintain current personal knowledge of the progress of 
the study), the Sponsor's monitor will visit the center(s) during the study in accordance with the 
Monitoring Plan set forth for this trial as well as maintain frequent telephone and written 
communication. The Investigator expects that the Sponsor will fulfil this obligation and provide early 
opportunity for the Investigator to correct any deficiencies identified in the data. 
11.2 Auditing 
The Sponsor may conduct audits at the study center(s). Audits may include, but not be limited to: drug 
supply, presence of required documents, the informed consent process, and comparison of case report 
forms with source documents. The Investigator agrees to participate with audits conducted at a 
reasonable time in a reasonable manner. 
Regulatory authorities worldwide may also audit the Investigator during or after the study. The 
Investigator should contact the Sponsor immediately if this occurs and must fully cooperate with 
regulatory authority audits conducted at a reasonable time in a reasonable manner.  
The Sponsor agrees to meet all reasonable costs that arise out of such audits, including reasonable 
remuneration of staff involved in complying with the requirements of such audits. 
12 ETHICS AND RESPONSIBILITY 
12.1 Informed Consent 
Written informed consent will be obtained from the participant before any study-related procedures 
(including any pre-treatment procedures) are performed. The Investigator(s) has both ethical and legal 
responsibility to ensure that each participant being considered for inclusion in this study is given a full 
explanation of the protocol. This shall be documented on a written informed consent form, which shall 
be approved by the same IRB or IEC responsible for approval of this protocol. Each informed consent 
form shall include the elements required by ICH GCP guidelines. The Investigator agrees to obtain 
approval from the Sponsor of any written informed consent form used in the study, preferably prior to 
submission to the IRB or IEC. 
Once the appropriate essential information has been provided to the participant and fully explained by 
the investigators (or a qualified designee) and it is felt that the participant understands the implications 
of participating, the participant and the Investigator (or a medically qualified designee) shall sign the 
IRB- or IEC-approved written informed consent form. The participants shall be given a copy of the 
signed informed consent form, and the original shall be kept in the site’s regulatory file. A second copy 
may be filed in the participant's medical record, if allowed by the institution. 


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12.2 Institutional Review Board/Independent Ethics Committee 
This protocol and the written informed consent form shall be submitted to the IRB or IEC identified 
with this responsibility at the research facility. Notification in writing of approval must come from the 
IRB or IEC chairman or secretary, to the Investigator, either as a letter or as a copy of the appropriate 
section of the IRB or IEC meeting minutes where this protocol and associated informed consent form 
were discussed. The Investigator will not participate in the decision. If the Investigator is an IRB or IEC 
member, the written approval must indicate such non-participation. The Investigator will submit status 
reports to the IRB or IEC at least annually (when applicable). The IRB or IEC must be notified by the 
Investigator in writing of the interruption and/or completion of the study; the Investigator must promptly 
report to the IRB or IEC all changes in research (protocol amendments) and will not make such changes 
without IRB or IEC approval except where necessary to eliminate apparent immediate hazards to 
participants. In these cases, the IRB or IEC must be notified within 5 days of the change. The 
Investigator will promptly report to the IRB or IEC all unanticipated problems involving risk to 
participants or others. The Investigator is required to maintain an accurate and complete record of all 
written correspondence to and received from the IRB or IEC and must agree to share all such documents 
and reports with the Sponsor. 
12.3 Governance of Study and Publication Policy 
The Governance of the study will be the responsibility of the Principal Investigator/s and the Sponsor, 
in collaboration.   
It is the intention of the Sponsor to publish the results of this study. Authorship of all publications and 
communications will reflect the contribution of the investigators and sponsors and will be inclusive 
where possible.  
13 CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and must not be disclosed 
by either the Investigator or the Sponsor to any persons not directly concerned with the study without 
written prior permission from the Sponsor and Investigator (as the case may be). However, authorized 
regulatory officials, the Investigator personnel and Sponsor personnel will be allowed full access to the 
records. All medications provided and participant bodily fluids and/or other materials collected shall be 
used solely in accordance with this protocol, unless otherwise agreed to in writing by the Sponsor and 
the Investigator, and in compliance with all relevant regulations. 
Only the unique participant number in case report forms will identify participants. Their full names 
may, however, be made known to a product regulatory agency or other authorized official if necessary. 


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14 INVESTIGATOR AGREEMENT 
Certain responsibilities devolve to the Principal Investigator (notably those of signing the Statutory 
Declarations related to the Ethics Committee, the requirement to retain records, and oversight and 
governance of the study). Other responsibilities apply to all named co-investigators. 
I have read and understand the protocol (including the Investigator’s Brochure) and agree that it contains 
all the ethical, legal, and scientific information necessary to conduct this study. I understand the 
potential risks and side effects of the drug. I will personally conduct the study as described, with the 
assistance of co-investigators and study personnel. I will only make changes in a protocol after notifying 
the sponsor, except when necessary to protect the safety, rights, or welfare of subjects. 
I will provide copies of the protocol to all physicians, nurses, and other professional personnel 
responsible to me who will participate in the study. Together with the Sponsor, I will arrange briefing 
sessions and will discuss the protocol with them, to assure myself that they are appropriately informed 
regarding the investigational new drug- Rapamycin Topical Cream, the concurrent medications, the 
efficacy and safety parameters and the conduct of the study in general. I agree to make all reasonable 
efforts to adhere to the attached protocol. I understand that this EC approved protocol will be submitted 
to the regulatory authorities by the Sponsor’s Contractor, as appropriate. I agree to allow Sponsor 
monitors and auditors full access to all medical records at the research facility for participants screened 
or randomized in the study. In return the Sponsor agrees to undertake audits regularly and assist me in 
identifying any deficiencies in the conduct of the study as early as possible, and in instituting appropriate 
measures to address these. 
I agree to inform any patients that the study drugs are being used for investigational purposes and I 
agree to provide all participants with informed consent forms, as required by government and ICH 
regulations. I further agree to report to the Sponsor any adverse experiences in accordance with the 
terms of this protocol and FDA regulation, 21 CFR 312.64. I commit to conducting this trial in 
compliance with local laws and regulations and ICH GCP. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
 
 
 
 
Principal Investigator  
 
Date  
 
 


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23.  Haemel AK, O’Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas 
in tuberous sclerosis. Arch Dermatol. 2010;146(7):715–718.  
24.  Hwang S-R, Kim J-I, Song K-H, Cho Y-S, Nam K-H, Park J, et al. Topical rapamycin for treating 
facial angiofibroma of tuberous sclerosis. Poster Session P10-12. J Dermatol. 2012 Jun 1;39:53–
280.  
25.  Kaufman McNamara E, Curtis AR, Fleischer Jr AB. Successful treatment of angiofibromata of 
tuberous sclerosis complex with rapamycin. J Dermatol Treat. 2012 Feb;23(1):46–8.  
26.  Koenig MK, Hebert AA, Roberson J, Samuels J, Slopis J, Woerner A, et al. Topical Rapamycin 
Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex: A Double-
Blind, Randomized, Controlled Trial to Evaluate the Safety and Efficacy of Topically Applied 
Rapamycin. Drugs RD. 2012 Sep;12(3):121–6.  
27.  Mutizwa MM, Berk DR, Anadkat MJ. Treatment of facial angiofibromas with topical application 
of oral rapamycin solution (1 mg mL−1) in two patients with tuberous sclerosis: Correspondence. 
Br J Dermatol. 2011 Oct;165(4):922–3.  
28.  Ott J, Gass-Jegu F, Gairard-Dory A, Gourieux B, Lipsker D. Efficacy and tolerance of topical 1 % 
rapamycin in cutaneous tuberous sclerosis patients. Symposium conducted at the 42nd ESCP  on 
clinical pharmacy: implementation of pharmacy practice; Prague, Czech Republic. Int J Clin 
Pharm. 2013 Dec;35(6):1251–351.  
29.  Park J, Yun S-K, Cho Y-S, Song K-H, Kim H-U. Treatment of Angiofibromas in Tuberous 
Sclerosis Complex: The Effect of Topical Rapamycin and Concomitant Laser Therapy. 
Dermatology. 2014;228(1):37–41.  


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30.  Pynn EV, Collins J, Hunasehally PRY, Hughes J. Successful Topical Rapamycin Treatment for 
Facial Angiofibromata in Two Children. Pediatr Dermatol. 2015 May 1;32(3):e120–3.  
31.  Rodrigo-Nicolas 
B. 
Topical 
rapamycin 
in 
facial 
angiofibromas: 
assesment 
of 
clinicalimprovement and patient satisfaction in  a series of 4 cases. (P6521). J Am Acad Dermatol. 
2013 Apr;64(2, Supplement 1):AB1–238.  
32.  Salido R, Garnacho-Saucedo G, Cuevas-Asencio I, Ruano J, Galán-Gutierrez M, Vélez A, et al. 
Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous 
sclerosis - associated facial angiofibroma: Topical sirolimus in facial angiofibroma. J Eur Acad 
Dermatol Venereol. 2012 Oct;26(10):1315–8.  
33.  Smith EV, Hunasehally PRY, Hughes JR. Successful topical rapamycin treatment for facial 
angiofibromata in a child (PA06). Br J Dermatol. 2012 Jul 2;167:127–41.  
34.  Tanaka M, Wataya-Kaneda M, Nakamura A, Matsumoto S, Katayama I. First left-right 
comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with 
tuberous sclerosis complex. Br J Dermatol. 2013 Dec;169(6):1314–8.  
35.  Truchuelo T, Díaz-Ley B, Ríos L, Alcántara J, Jaén P. Facial angiofibromas treated with topical 
rapamycin: An excellent choice with fast response. Dermatol Online J. 2012 Jan 15;18(1):15.  
36.  Tu J, Foster RS, Bint LJ, Halbert AR. Topical rapamycin for angiofibromas in paediatric patients 
with tuberous sclerosis: Follow up of a pilot study and promising future directions: Topical 
rapamycin for angiofibromas. Australas J Dermatol. 2014 Feb;55(1):63–9.  
37.  Valeron-Almazan P, Vitiello M, Abuchar A, Kerdel FA. Topical rapamycin solution to treat 
multiple facial angiofibromas in a patient with tuberous sclerosis. Actas Dermo-Sifiliográficas 
Engl Ed. 2012;103(2):165–167.  
38.  Vasani R. Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian 
patient. Indian J Dermatol. 2015;60(2):165.  
39.  Wheless JW, Almoazen H. A Novel Topical Rapamycin Cream for the Treatment of Facial 
Angiofibromas in Tuberous Sclerosis Complex. J Child Neurol. 2013 Jul 1;28(7):933–6.  
40.  Viswanath V, Thakur P, Pund P. Use of Topical Rapamycin in Facial Angiofibromas in Indian 
Skin Type. Indian J Dermatol. 2016 Feb;61(1):119.  
41.  Palmetun Ekbäck M, Wiegleb Edström D. Topical rapamycin for angiofibromas in patients with 
tuberous sclerosis: how does it work in clinical practice? Plast Aesthetic Res. 2016 Oct 
25;3(10):328.  
42.  Koenig MK, Bell CS, Hebert AA, Roberson J, Samuels JA, Slopis JM, et al. Efficacy and Safety 
of Topical Rapamycin in Patients With Facial Angiofibromas Secondary to Tuberous Sclerosis 
Complex: The TREATMENT Randomized Clinical Trial. JAMA Dermatol. 2018 Jul 
1;154(7):773.  
43.  Wataya-Kaneda M, Ohno Y, Fujita Y, Yokozeki H, Niizeki H, Ogai M, et al. Sirolimus Gel 
Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A 
Randomized Clinical Trial. JAMA Dermatol. 2018 Jul 1;154(7):781.  
44.  Wataya-Kaneda M, Nakamura A, Tanaka, Mari, Hayashi M, Matsumoto S, Yamamoto K, et al. 
Efficacy and Safety of Topical Sirolimus Therapy for Facial Angiofibromas in the Tuberous 
Sclerosis Complex A Randomized Clinical Trial. JAMA Dermatol [Internet]. 2016;Published 


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online 
November 
12, 
2016. 
Available 
from: 
http://jamanetwork.com/journals/jamadermatology/article-abstract/2580304 
45.  Cinar SL, Kartal D, Bayram AK, Canpolat M, Borlu M, Ferahbas A, et al. Topical sirolimus for 
the treatment of angiofibromas in tuberous sclerosis. Indian J Dermatol Venereol Leprol. 2017 
Jan 1;83(1):27.  
46.  Amin S, Lux A, O’Callaghan F. G259 Novel treatment option of Sirolimus ointment for facial 
angiofibromas in individuals with Tuberous Sclerosis Complex (TSC). Arch Dis Child. 2016 Apr 
1;101(Suppl 1):A143–A143.  
47.  Koenig MK, Hebert AA, Roberson J, Samuels J, Slopis J, Woerner A, et al. Topical Rapamycin 
Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex: A Double-
Blind, Randomized, Controlled Trial to Evaluate the Safety and Efficacy of Topically Applied 
Rapamycin. Drugs RD. 2012 Sep;12(3):121–6.  
 
 


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APPENDIX 1: INVESTIGATORS GLOBAL ASSESSMENT 
 
 
 
 
Grade Short Description Detailed Description 
0 
Clear 
No signs of facial angiofibroma 
1 
Almost Clear 
Few small angiofibromas (< 2 mm); normal to pink coloration in 
affected area*  
2 
Mild 
Predominantly small angiofibromas (< 2 mm) with few intermediate 
tumors (2-4 mm); pink to red coloration in affected area  
3 
Moderate 
Predominantly intermediate angiofibromas (2-4 mm) with few large 
tumors (> 4 mm); red coloration in affected area 
4 
Severe 
Mix of intermediate (2-4 mm) and large angiofibromas (>4 mm) 
present diffusely on face; intense and generalized redness on the 
whole face 
* Note: coloration refers to both the FA lesions and the background facial skin tone 
Where lesion size and coloration are discrepant within the grade, emphasis should be placed on lesion size. 


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APPENDIX 2: FACIAL ANGIOFIBROMA SEVERITY INDEX (FASI) 
 
Feature 
Presentation 
Score 
Erythema 
Skin color 
0 
Light Red 
1 
Red 
2 
Dark Red/purple 
3 
Size 
None 
0 
Small (< 5mm) 
1 
Large (> 5mm) 
2 
Confluent 
3 
Extension 
<50 % cheek surface 
2 
>50% cheek surface 
3 
The score of the predominant tumors are taken in cases in which the same patient presented lesions with 
varying degrees of severity. A patient’s FASI is the sum of scores assigned to each feature. Mild, 
moderate and severe FA corresponded score ranges on the FASI of ≤ 5, 6-7, and ≥ 8, respectively.  
The scores assigned to each feature will be recorded in the case report form, as well as the overall 
summed FASI score. Please refer to (15) for further information on the FASI. 
 


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APPENDIX 3: SUBJECTIVE AND OBJECTIVE IMPROVEMENT RATINGS 
 
The following assessments will be completed at V1-V5. The subjective improvement rating will be 
evaluated by the parent/caregiver for patients under the age of 18 years. 
 
Subjective Percentage Improvement Assessment 
Please rate the change in facial angiofibroma appearance since Visit 0: 
Percentage improved since Visit 0: ___ ___ ___ % 
(Minimal: <30%, Moderate: 30-59%, Good: 60-90%, Excellent: > 90%) 
 
Objective Percentage Improvement Assessment 
Please rate the change in the participant’s facial angiofibroma appearance since Visit 0: 
Percentage improved since Visit 0: ___ ___ ___ % 
(Minimal: <30%, Moderate: 30-59%, Good: 60-90%, Excellent: > 90%) 
 


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APPENDIX 4: CATEGORICAL IMPROVEMENT OF FACIAL ANGIOFIBROMA 
 
This will be completed at V5, or at the time of early discontinuation. The categorical improvement 
rating will be evaluated by the parent/caregiver for patients under the age of 18 years. 
 
Categorical Improvement Assessment  
Please tick ONE of the following statements that you agree with: 
 
3 
I got significantly better on the treatment 
 
2 
I got moderately better on the treatment 
 
1 
I got slightly better on the treatment 
 
0 
The treatment made no difference 
 
-1 
I got worse on the treatment 
 
 


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APPENDIX 5: GRADING OF ADVERSE EVENTS 
A copy of the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, published 
November 27 2017 will be provided to each site, and is also  available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refere
nce_5x7.pdf  
Common Terminology Criteria for Adverse Events (CTCAE v 5.0) 
Grade1 Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.2 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living.3 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to adverse event (not appropriate for some adverse events). 
1: not all grades are appropriate for all AEs. 
2: Instrumental activities of daily living (ADL) refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc.  
3: Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
Relationship 
Definition 
Not related 
A temporal (timely) relationship of the onset of the event, 
relative to the administration of the product is unlikely or not 
reasonable. Or where another cause can explain the 
occurrence of the event by itself. 
Unlikely  
A temporal (timely) relationship of the onset of the event, 
relative to the administration of the product is unlikely but 
cannot be ruled out. 
Possibly Related 
A temporal (timely) relationship of the onset of the event, 
relative to the administration of the product is reasonable, but 
the event could have been due to an equally likely cause. 
Probably Related 
A temporal (timely) relationship of the onset of the event, 
relative to the administration of the product is reasonable and 
the event is more likely to be explained by the medicinal 
product than by another cause. 
Definitely Related 
A temporal (timely) relationship of the onset of the event, 
relative to the administration of the product is reasonable and 
there is no other cause to explain the event. Cause to explain 
the event, or a re-challenge is positive. 
 
 


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APPENDIX 6: SAE REPORTING FORM 
Protocol: DSLP-01 
 
 
SAE Number: ________ 
Fax to: + 64 9 488 0234  
Site:   
_________________
_________________ 
Report Type: 
 Initial Report             
 Follow-up 
 Revised / additional 
information 
 Final Report       
Date of Initial Report: 
  ______ / ______ /_____   
     dd          mmm       yyyy 
 
Date of Follow-up Report: 
  ______ / ______ /_____   
     dd          mmm       yyyy 
PATIENT INFORMATION 
Patient #:  _________ 
Gender:   
 Male   
 Female 
 
 
DOB:_____/_______ / ____ 
           dd       mmm      yyyy 
 
Weight: _______     
 lbs   
    
 kg 
STUDY DRUG INFORMATION  
Study Drug & Dose administered:  
 
Start Date and Time: 
______/ ________ / _____ 
 dd        mmm        yyyy   
  __________: ________ 
            (24 hr clock) 
Stop Date and Time: 
_____/ _______ / _____ 
 dd       mmm  /    yyyy 
  __________: ________ 
          (24 hr clock) 
Blind broken? 
Yes 
No 
 N/A 
If yes, please specify the treatment: 
 
__________________ 
 
ADVERSE EVENT (AE)*  
* List only one adverse event. Additional serious AEs are to be reported separately.  
Adverse Event: (diagnosis) 
 
Date and Time of Event Onset:   
_____ / _______ / _____              _______ : _______ 
  dd       mmm       yyyy                        (24 hr clock)    
Date and Time of Last Dose Prior to Event Onset:   
_____ / _______ / _____              _______ : _______ 
  dd       mmm       yyyy                        (24 hr clock)                         
Serious Criteria (check all that apply): 
  Death                                                                           
  Persistent or significant disability 
  Life-threatening                                                           
  Congenital anomaly or birth defect 
  Hospitalization – initial or prolonged                      
  Medically significant (specify) __________________________________________________________  
(i.e. may require intervention to prevent permanent impairment / damage or one of the other outcomes listed) 
 
 


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Protocol: DSLP-01 
Site Name: __________________________________    
Patient No: __________    
Relationship to Study 
Drug: 
 Not related, possible 
etiology: ___________ 
 Unlikely 
 Possibly   
 Probably 
 Definitely  
Outcome of AE: (check only one) 
 Death    (dd/mmm/yyyy):  ____/ ____ / ____ 
 Resolved (dd/mmm/yyyy):____ / _____ / ____ 
 Permanent sequelae (specify in description) 
 Ongoing 
 Unknown/Lost to follow-up 
Action Taken with Study Drug: 
 None 
 Discontinued permanently 
 Temporarily interrupted 
 Dose adjusted 
 Not applicable 
Description of Event* (including symptoms, diagnosis, chronology, treatment, re-challenge / dechallenge):** 
 
* List only one adverse event. Additional serious AEs are to be reported separately. 
** Attach additional sheet if necessary 
Relevant Tests/Laboratory Data (including dates, lab units): 
 
If lab reports are attached, please tick here: 
 
Other Relevant History (including pre-existing medical conditions): 
 
 
 


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Protocol: DSLP-01 
Site Name: __________________________________    
Patient No: __________    
CONCOMITANT MEDICATION(S)* (List all administered at onset of SAE, attach additional sheet of necessary) 
Name & Indication 
Dose  
&  
Regimen 
Route 
 Of 
Administration 
Start Date/Time 
& 
 Stop Date/Time 
(dd/mm/yyyy, 24 hr clock) 
Causal 
Relationship to 
AE 
Name (generic): 
 
 
 
Indication: 
 
 
 
______ 
dose 
 
______ 
units 
 
______ 
regimen 
 iv 
 sc 
 im 
 oral 
 sublingual 
 inhalation 
 other 
(specify) 
__________ 
Start:  
            ______/ _____ / _____ 
 
dd         mmm     yyyy 
________: ______ 
                      24 hr clock 
 
Stop: ______/ _____ / _____ 
 
 dd     mmm    yyyy 
________: ______ 
                      24 hr clock 
  Not Related 
 
  Unlikely 
 
  Possibly   
  
  Probably  
 
  Definitely 
 
Name (generic): 
 
 
 
Indication: 
 
 
 
______ 
dose 
 
______ 
units 
 
______ 
regimen 
 
 iv 
 sc 
 im 
 oral 
 sublingual 
 inhalation 
 other 
(specify) 
__________ 
Start: 
            ______/ _____ / _____ 
 
  dd   mmm  yyyy 
________: ______ 
                      24 hr clock 
 
Stop: ______/ _____ / _____ 
 
 dd     mmm  yyyy 
________: ______ 
                      24 hr clock 
  Not Related 
 
  Unlikely 
 
  Possibly   
  
  Probably  
 
  Definitely 
 
Name (generic): 
 
 
 
Indication: 
 
 
 
______ 
dose 
 
______ 
units 
 
______ 
regimen 
 iv 
 sc 
 im 
 oral 
 sublingual 
 inhalation 
 other 
(specify) 
__________ 
Start:  
            ______/ _____ / _____ 
 
dd         mmm     yyyy 
________: ______ 
                      24 hr clock 
 
Stop: ______/ _____ / _____ 
 
 dd     mmm    yyyy 
________: ______ 
                      24 hr clock 
  Not Related 
 
  Unlikely 
 
  Possibly   
  
  Probably  
 
  Definitely 
  
 
INVESTIGATOR’S SIGNATURE 
 
_______________________________________            
Name 
 
________________________________________            Date ______/ _____ / _________ 
Signature 
                                                                              dd       mmm       yyyy