Clinical trial NCT03525834
Conditions: Renal Angiomyolipoma
Keywords: TSC tuberous sclerosis complex AML afinitor everolimus RAD001 mTOR kidney lymphangioleiomyomatosis renal angiomyolipoma
Sponsor: Novartis Pharmaceuticals
Start date: 2018-11-09; Completion date: 2020-09-25
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the safety and efficacy of everolimus (Afinitor®) in Chinese patients with renal angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC).

Detailed description:
This was an open label, single arm, multi-center, Phase IV Post-Approval Commitment (PAC) study with once daily oral dose of 10 mg everolimus in participants with renal AML associated with TSC. There were three separate phases in this study: a Screening phase, an Open-label treatment phase where participants received everolimus for 48 weeks or until disease progression, and a Treatment discontinuation follow-up phase for patients who discontinue study drug for reasons other than disease progression. Every participant had an End of Treatment visit within 28 days after last dose and a safety follow-up visit 30 days after last dose.

Arms: arm 1: Participants targeted to receive Everolimus tablets 10 mg orally once daily for 48 weeks.
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: Everolimus 2.5 mg and 5 mg tablets with dosage regimen of 10 mg orally once daily.

Protocol documents:
Prot_000.pdf: 
Clinical Development
Afinitor® (everolimus)
Oncology Clinical Protocol CRAD001M2401 / NCT03525834
Phase IV, single arm study of safety and efficacy of 
everolimus in Chinese adults with Tuberous Sclerosis 
Complex who have renal angiomyolipoma not requiring 
immediate surgery 
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
02 (Clean)
Development phase
IV
Document status
Final
Release date
06-Dec-2019
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 6-Apr-2017


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................5
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
Protocol summary:...............................................................................................................9
Amendment 2 (06-Dec-2019)............................................................................................11
Amendment 1 (24-Apr-2018)............................................................................................13
1
Background........................................................................................................................15
1.1
Overview of Tuberous Sclerosis Complex (TSC) and renal Angiomyolipoma 
(AML)....................................................................................................................15
1.2
Introduction to investigational treatment...............................................................18
1.2.1
Overview of everolimus........................................................................18
1.2.2
Non-clinical experience of everolimus .................................................23
1.2.3
Clinical experience of everolimus.........................................................24
2
Rationale............................................................................................................................26
2.1
Study rationale and purpose...................................................................................26
2.2
Rationale for the study design ...............................................................................27
2.3
Rationale for dose and regimen selection..............................................................27
2.4
Risks and benefits..................................................................................................27
3
Objectives and endpoints...................................................................................................27
4
Study design ......................................................................................................................29
4.1
Description of study design ...................................................................................29
4.2
Definition of end of study......................................................................................31
4.3
Early study termination..........................................................................................32
5
Population..........................................................................................................................32
5.1
Patient population..................................................................................................32
5.2
Inclusion criteria ....................................................................................................32
5.3
Exclusion criteria...................................................................................................33
6
Treatment...........................................................................................................................34
6.1
Study treatment......................................................................................................34
6.1.1
Dosing regimen.....................................................................................34
6.1.2
Treatment duration................................................................................35
6.1.3
Guidelines for continuation of treatment ..............................................35
6.2
Dose modifications................................................................................................35
6.2.1
Starting dose rationale...........................................................................35


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6.2.2
Dosing modifications ............................................................................35
6.2.3
Management of specific toxicities ........................................................38
6.3
Concomitant medications ......................................................................................41
6.4
Patient numbering and treatment assignment........................................................43
6.4.1
Patient numbering .................................................................................43
6.4.2
Treatment assignment ...........................................................................44
6.4.3
Treatment blinding................................................................................44
6.5
Study drug preparation and dispensation...............................................................44
6.5.1
Study treatment packaging and labeling ...............................................44
6.5.2
Drug supply and storage........................................................................44
6.5.3
Study drug compliance and accountability ...........................................45
6.5.4
Disposal and destruction .......................................................................45
7
Visit schedule and assessments .........................................................................................45
7.1
Study flow and visit schedule................................................................................45
7.1.1
Molecular pre-screening........................................................................51
7.1.2
Screening...............................................................................................51
7.1.3
Treatment period...................................................................................54
7.1.4
Discontinuation of study treatment .......................................................54
7.1.5
Withdrawal of consent ..........................................................................55
7.1.6
Follow up for safety evaluations...........................................................55
7.1.7
Lost to follow-up...................................................................................56
7.2
Assessment types...................................................................................................56
7.2.1
Efficacy assessments.............................................................................56
7.2.2
Safety and tolerability assessments.......................................................61
7.2.3
Resource utilization...............................................................................64
7.2.4
Patient reported outcomes.....................................................................64
8
Safety monitoring and reporting........................................................................................65
8.1
Adverse events.......................................................................................................65
8.1.1
Definitions and reporting ......................................................................65
8.1.2
Laboratory test abnormalities................................................................66
8.1.3
Adverse events of special interest.........................................................66
8.2
Serious adverse events...........................................................................................67
8.2.1
Definitions.............................................................................................67
8.2.2
Reporting...............................................................................................67
8.3
Pregnancies............................................................................................................68
8.4
Warnings and precautions......................................................................................68


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8.5
Data Monitoring Committee..................................................................................68
8.6
Steering Committee ...............................................................................................68
9
Data collection and management.......................................................................................69
9.1
Data confidentiality ...............................................................................................69
9.2
Site monitoring ......................................................................................................69
9.3
Data collection.......................................................................................................70
9.4
Database management and quality control............................................................70
10 Statistical methods and data analysis ................................................................................71
10.1
Analysis sets ..........................................................................................................71
10.1.1
Full Analysis Set ...................................................................................71
10.1.2
Safety set ...............................................................................................71
10.1.3
Other analysis sets.................................................................................71
10.2
Patient demographics/other characteristics............................................................71
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................71
10.4
Primary objective...................................................................................................72
10.4.1
Analysis set and grouping for the analyses...........................................72
10.4.2
Adverse events (AEs)............................................................................72
10.4.4
Other safety data ...................................................................................73
10.5
Secondary objectives .............................................................................................73
10.5.1
Angiomyolipoma response rate.............................................................73
10.5.2
Angiomyolipoma progression...............................................................73
10.5.3
Renal function change from screening..................................................73
10.5.4
Pharmacokinetics ..................................................................................74
10.5.5
Biomarkers............................................................................................74
10.5.6
Resource utilization...............................................................................74
10.5.7
Patient-reported outcomes.....................................................................74
10.6
Exploratory objectives...........................................................................................74
10.7
Final analysis .........................................................................................................74
10.8
Sample size calculation..........................................................................................74
10.9
Power for analysis of key secondary variables......................................................74
11 Ethical considerations and administrative procedures ......................................................74
11.1
Regulatory and ethical compliance........................................................................74
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................74
11.3
Informed consent procedures.................................................................................75
11.4
Discontinuation of the study..................................................................................75
11.5
Publication of study protocol and results...............................................................75


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11.6
Study documentation, record keeping and retention of documents.......................76
11.7
Confidentiality of study documents and patient records .......................................77
11.8
Audits and inspections...........................................................................................77
11.9
Financial disclosures..............................................................................................77
12 Protocol adherence ............................................................................................................77
12.1
Amendments to the protocol..................................................................................77
13 References (available upon request)..................................................................................78
List of figures
Figure 1-1
Chemical structure of Everolimus.........................................................22
List of tables
Table 1-1
Everolimus – Drug substance................................................................21
Table 3-1
Objectives and related endpoints ..........................................................28
Table 6-1
Dose and treatment schedule.................................................................34
Table 6-2
Study treatment schedule adjustments and dose levels.........................35
Table 6-3
Dosing guidelines for study drug-related non-hematologic 
toxicities................................................................................................36
Table 6-4
Dosing guidelines for study drug-related hematologic toxicities .........37
Table 6-5
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A4..............................................................................42
Table 6-6
PgP substrates, inducers, inhibitors.......................................................42
Table 6-7
Preparation and dispensing ...................................................................44
Table 6-8
Packaging and labeling .........................................................................44
Table 7-1
Visit evaluation schedule ......................................................................47
Table 7-2
Diagnostic criteria for Tuberous Sclerosis Complex ............................51
Table 7-3
Imaging collection plan.........................................................................57
Table 7-4
Performance Status WHO grade:..........................................................62
Table 7-5
Central clinical laboratory parameters collection plan..........................63


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List of abbreviations
AE
Adverse Event
ACE
Angiotensin converting enzyme
ADL
Activities of daily living
ADR
Adverse drug reaction
AESI
Adverse events of special interest
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute neutrophil count
AACR
American Association for Cancer Research
AML 
Angiomyolipoma
APTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology 
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under curve
BAL 
Bronchoalveolar lavage
BCG
Bacillus Calmette-Guérin (Vaccine)
b.i.d.
bis in diem/twice a day
BOR
Best overall response
BUN
Blood urea nitrogen
CBR
Clinical benefit rate
CFDA
Chinese Food and Drug Administration
CPK
Creatine phosphokinase
CRF
Case Report/Record Form
CRO
Contract Research Organization
CSP
Clinical Study Protocol
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events 
CT
Computed Tomography
CYP3A4
Cytochrom P450 3A4
DDI
Drug Drug Interaction
DDS
Dose Determining Set
DNA
Deoxyribonucleic acid
DOR
Duration of response
DLCO
Diffusing capacity factor of the lung for carbon monoxide
DLT
Dose limiting toxicity
DM
Diabetes Mellitus
EC
European Commission
ECG
Electrocardiogram
EOT
End of treatment
ESRD
End-stage renal disease
FAS
Full Analysis Set
FDA
Food and drug administration
FEV1
Forced expiratory volume per second
GERD
Gastroesophageal reflux disease
GI
Gastrointestinal
HBcAb
Hepatitis B virus core antibody


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HBcAg
Hepatitis B virus core antigen
HBsAb
Hepatitis B virus surface antibody
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HER2-
human epidermal growth factor receptor 2 negative
HIF-1
Hypoxy induced factor
HIV
Human Immunodeficiency Virus
HR+
Hormone receptor-positive
HRCT
High resolution computed tomography
HUVECS
Human umbilical vein endothelial cells
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
LAM
Lymphangioleiomyomatosis
NCI
National Cancer Institute
NDA
NMPA
New drug application
National Medical Products Administration
MRI
Magnetic Resonance Imaging
mTOR
Mammalian target of rapamycin
o.d.
omnia die/once a day
ORR
Overall response rate
OS
Overall survival
PCR
Polymerase chain reaction
PFS
Progression free survival
PFT
Pulmonary function test
PgP
P-glycoprotein
PI3K/AKT
Phosphoinositide 3-kinase/protein kinase
PJP
Pneumocystis jirovecii pneumonia
PNET
Pancreatic neuroendocrine tumor 
p.o.
Per os/by mouth/orally
PPS
Per-Protocol Set
PR
Partial response
PTEN
Phosphatase and tensin homolog
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SD
Stable Disease
SEGA
Subependymal Giant Cell Astrocytoma
SOP
Standard Operating Procedure
TSC
Tuberous Sclerosis Complex
TTR
Time to response
ULN
Upper limit of normal (range)


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VEGF-D
Vascular endothelial growth factor-D
WBC
White blood cell count
WHO
World Health Organisation


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Protocol summary:
Title
Phase IV, single arm study of safety and efficacy of everolimus in Chinese adults 
with Tuberous Sclerosis Complex who have renal angiomyolipoma not requiring 
immediate surgery
Brief title
Study of safety and efficacy of everolimus in adult Chinese Tuberous Sclerosis
patients who have renal angiomyolipoma not requiring immediate surgery
Sponsor and Clinical 
Phase
Novartis Pharma AG, Phase IV
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to assess the safety and efficacy of Afinitor® in 
Chinese patients with renal angiomyolipoma associated with TSC. The study will 
evaluate the safety and anti-tumor activity of Afinitor® given at a dose of 10 mg per 
day.
Primary Objective
To evaluate the safety of Afinitor® in Chinese adults with TSC-renal AML not 
requiring immediate surgery by determining the incidence of adverse events and
laboratory abnormalities within 48 weeks of treatment.
Secondary Objective
To evaluate the efficacy of Afinitor® in Chinese adults with TSC-renal AML not 
requiring immediate surgery as assessed by AML response and progression rates 
and renal function change from baseline in 12 weeks intervals up to 48 weeks.
Study design
Open label, single arm, multi-center phase IV post approval commitment study 
(PAC) of treatment with one daily oral dose of 10 mg everolimus (Afinitor®) for 48 
weeks.
Population
The study patient population consists of 40 male or female adult patients (18 years 
of age or older) who have been diagnosed with renal AML associated with TSC not 
requiring immediate surgery.
Inclusion criteria
● Eligible for treatment with everolimus as per the locally approved label.
● Presence of at least one AML ≥ 3 cm in its longest diameter using CT or MRI.
Exclusion criteria
● AML related bleeding or embolization during the 6 months prior to enrollment.
● History of myocardial infarction, angina or stroke related to atherosclerosis.
● Impaired lung function
● Significant hematological or hepatic abnormality (e.g. hemoglobin ≤9g/dL, 
platelets < 100×10^9/L, or absolute neutrophil count (ANC) < 1.5×10^9/L without 
supportive treatment of hematopoietic growth factor, transaminase levels > 2.5× 
the upper limit of normal (ULN), serum bilirubin > 2 × ULN).
● Prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus).
● Fasting serum cholesterol > 300 mg/dL (or > 7.75 mmol/L) AND fasting 
triglycerides > 2.5 × ULN. NOTE: In case one or both of these thresholds are 
exceeded, the patient can only be included after initiation of appropriate lipid 
lowering medication.
● Inadequate renal function: Serum creatinine > 1.5 × ULN.
● Any severe and/or uncontrolled medical conditions 
Investigational and 
reference therapy
10 mg RAD001 (everolimus) once daily
Patients with impaired liver function 
● Child-Pugh grade A: 7.5 mg RAD001 (everolimus) once daily
● Child-Pugh grade B: 5.0 mg RAD001 (everolimus) once daily
Efficacy assessments
● Renal angiomyolipoma lesion volume as assessed by kidney CT/MRI scans at 
Screening, 12, 24, 48 weeks, and End of Treatment.
● Blood chemistry and urinalysis clinical laboratory assessments at Screening, 4, 
12, 24, 48 weeks, and End of Treatment.


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Safety assessments
● Incidence of adverse events during treatment until 30 days after End of 
Treatment.
● Hematology, blood chemistry, and urinalysis clinical laboratory assessments at 
Screening, 4, 12, 24, 48 weeks, and End of Treatment.
Other assessments
● WHO performance status at Screening, 4, 12, 24, 48 weeks, and End of 
Treatment.
● If indicated, photographic skin lesion assessment at Screening, 12, 24, 48 
weeks, and End of Treatment.
● If indicated chest CT scans at Screening, 12, 24, 48 weeks, and End of 
Treatment.
● If indicated brain MRI/CT scans at 12, 24, 48 weeks, and End of Treatment.
● If indicated coagulation test at 4, 12, 24, 48 weeks, and End of Treatment.
● For patients with LAM: pulmonary function test and blood gas analysis at 12, 24, 
48 weeks, and End of Treatment.
● For female patients of child bearing potential urine pregnancy tests from 
treatment Day 1 every 4 weeks until End of Treatment.
Data analysis
Analysis population
The Full Analysis Set (FAS) comprises all patients who received at least one dose 
of study treatment. 
The Safety Set comprises all patients who received at least one dose of study 
treatment. The Safety set and FAS are identical in this study, and will be used for 
all analysis.
Safety analysis (primary objective) 
Safety data including adverse events, laboratory abnormalities, and vital signs will 
be summarized and listed.
The incidence of treatment-emergent adverse events (new or worsening from 
screening) will be summarized by MedDRA system organ class and/or preferred 
term, severity (based on CTCAE grades), seriousness, and relation to study 
treatment. All deaths (on-treatment and post-treatment) will be summarized.
Laboratory values will be graded by CTCAE v4.03. Shift tables to compare 
screening to the worst on-treatment value will be presented. 
Efficacy analysis (secondary objective)
AML response and progression rates, and renal function change from baseline 
(using the calculated creatinine clearance and NCI CTCAE grade 3/4 serum 
creatinine) will be summarized and listed.
Rationale for Sample Size
Approximately 40 patients will be enrolled to meet the NMPA post approval 
requirements. The sample size is based on feasibility; there is no hypothesis 
testing and statistical power consideration.
Key words
Tuberous Sclerosis Complex, TSC, angiomyolipoma, AML, Afinitor®, everolimus


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Amendment 2 (06-Dec-2019) 
Amendment rationale
At the time of this amendment study enrollment was completed with 40 patients enrolled and 
treated. Currently all 40 patients are on treatment.
The reason for this protocol amendment is to eliminate the interim analysis.
The intent of the interim analysis was to use the limited available data from CRAD001M2401 
for the Chinese Afinitor® license renewal package which was planned at the end of 2020.  
However, due to swift enrollment (12m actual vs 24m planned) the final analysis will be 
delivered in time to support the Afinitor® license renewal for the TSC associated renal AML 
indication thus eliminating the need for the interim analysis.
The protocol also describes a cut-off date for the interim analysis and a submission date for 
the Afinitor® license renewal, which under new circumstances are not being pursued. 
Therefore this information will be removed from the protocol.
In addition, some clarifications will be made in the visit evaluation schedule (VES) table and 
the patient re-screening section. 
Major change
1. Elimination of the interim analysis
Minor changes
1. New subject number will be assigned to patients that are re-screened
2. HIV history is sourced documented. Table 7-1 is updated with appropriate category “S”
3. TSC diagnosis has been added to Table 7-1
4. Unscheduled ECGs have been added to Table 7-1
5. The appropriate category “D”, is now assigned to all imaging assessments
6. Protocol reference hyperlinks will be added to the VES Table 7-1 so the reader can link to 
specific assessments described in Table 7-1
7. Within several sections. Chinese Food and Drug Administration (CFDA) has been 
replaced with NMPA (National Medical Products Administration), which is the new name 
for the Chinese Health Authority
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 4.2 Timing of Interim Analysis: entire section removed describing an interim 
analysis

Section 6.4.1 Statement added, “If a patient fails screening and is re-screened a new 7 
digit subject number will be assigned”.

Table 7-1 changes to the VES table include; protocol reference hyperlinks added to each 
assessment, unscheduled ECGs added, TSC diagnosis added, HIV history data source 


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updated to source, visit numbers added to efficacy follow up visits, imaging assessments 
data source updated to documented in database “D”. 

Section 7.1.2 sub section “Rescreening” paragraph 2 updated to state “In this case the 
Subject Number assigned to the patient will not be used and the patient will be assigned a 
new 7 digit subject number. If the patient has been enrolled and treated, re-screening of 
the patient is not allowed.”

Section 10 entire section updated to state the following: One safety and efficacy analysis 
(Final Analysis) will be conducted on all patients after they complete their treatment and 
efficacy follow-up (after 48 weeks of treatment or earlier).

Section 10.7 Interim analysis: This section now updated to state the following:

Final Analysis

The final analysis will be performed after all patients have completed Week 48 (or 
discontinued earlier but were followed up for efficacy up to Week 48) and their safety 
follow-up visit.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein do not affect the Informed Consent. The informed Consent will not be 
updated.  


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Amendment 1 (24-Apr-2018)
Amendment rationale 
No patients have yet been enrolled and no patients are planned to be enrolled until after this 
amendment is approved and in place. The changes identified in this protocol amendment 
address the omission of an important laboratory parameter and include clarifications of 
instructions and corrections of typographical errors. Furthermore the language concerning 
withdrawal of consent was aligned with Novartis’ latest guidelines.
Protocol amendment 1 to this study has been prepared for the following reasons:
Minor changes
1. To add fasting serum cholesterol to the parameters to be tested in all laboratory
biochemistry assessments of the study. The serum cholesterol value is required to confirm 
exclusion criteria #10. Furthermore, elevated serum cholesterol (hypercholesterolemia) is 
a very common adverse drug reaction to everolimus treatment and should be monitored 
throughout the study.
2. To reflect the patient’s legal rights regarding their data and samples collected during the 
study when they discontinue or withdraw consent.
3. To add clarification which radiological imaging modalities for brain, chest, abdomen, and 
pelvis are preferred and accepted.
4. To add clarification that for coagulation tests either prothrombin time (PT) or international 
normalized ratio (INR) should be determined. Both tests are not required.
5. To add clarification that a serum pregnancy test is not required on study Day 1 if it was 
completed within 28 days prior to Day 1. In this case a urine pregnancy test is sufficient 
on Day 1.
6. To add clarification that the safety follow-up visit has to be done 30 days after last dose of 
everolimus with an allowed window of +7 days. The visit should not be done sooner.
7. To add clarification that results of serum pregnancy tests will be recorded in the database 
of the assigned central lab vendor.
8. To add clarification that reasons why a patient is not eligible for enrollment into the study 
are to be recorded on the disposition CRF and not the screening CRF.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Minor changes

Changes due to the addition of the serum cholesterol test to all lab biochemistry 
evaluations:

Table 7-5

Changes to reflect the patient’s legal rights regarding their data and samples collected 
during the study when they discontinue or withdraw consent:

Section 7.1.5


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
Changes due to clarification of preferred and allowed radiological imaging modalities:

Section 4.1, Section 7.2.1, Table 7-1, Table 7-3

Changes due to clarification of requirements of coagulation test:

Section 7.2.2.5.4

Changes due to clarification of requirements of serum pregnancy test on study Day 1:

Sections 4.1, 7.2.2.5

Changes due to clarification of timing of the safety follow-up visit:

Section 4.1, Table 7-1

Changes due to clarification of recording of serum pregnancy test results:

Sections 7.1.2.3, 7.2.2.5.5

Changes due to clarification of CRF for recording of screening failure reasons:

Section 6.4.1
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs).
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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1
Background
1.1
Overview of Tuberous Sclerosis Complex (TSC) and renal 
Angiomyolipoma (AML)
Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder caused by 
inactivating mutations in the tuberous sclerosis complex tumor suppressor genes, TSC1 or 
TSC2, affecting tuberin and hamartin respectively. The results of second somatic mutation in 
the heterozygous background include benign, highly vascular, hamartomatous growths. 
Lesions occur in the brain, kidneys, heart, liver, lungs and skin, and phenotypically can 
manifest with renal and/or pulmonary complications, autism, mental retardation and epilepsy 
(Gomez 1999, Astrinidis 2005, Inoki 2005, Kwiatkowski 2005).
Angiomyolipomata are the most common renal manifestation of TSC (Gomez et al 1999) 
developing during later childhood and adolescence. As the name implies, they are composed 
of blood vessels, smooth muscle and adipose tissue. The majority of adults affected by the 
disease have multiple bilateral lesions which are usually asymptomatic but can cause life-
threatening hemorrhage or impaired renal function. Angiomyolipomata can occur in the liver 
but these are rarely of clinical significance (Yates 2006). Renal cysts are also a common 
finding (Gomez et al 1999). They are usually asymptomatic except in the rare case of patients 
with both TSC and polycystic kidney disease owing to contiguous deletions of the TSC2 and 
PKD1 genes who usually present with severe early onset renal cystic disease and progress to 
end-stage renal failure by early adult life (Sampson et al 1997). Patients with TSC appear to 
be at increased risk of renal cell carcinoma, estimated at 1-3% (Nelson and Sanda 2002).
There are two morbidities associated with renal angiomyolipomata. The first and more 
dramatic is Wunderlich syndrome (Chesa Ponce et al 1995), a retro-peritoneal hemorrhage 
originating in the angiomyolipoma. As they enlarge, angiomyolipomata frequently develop 
both micro- and macro-aneurysms which can rupture (Adler 1984, Bissler 2002). Patients 
with this sudden, painful, and often life-threatening event are most often first seen in the 
emergency department (Bissler and Kingswood 2004). It was estimated that up to 20% of 
patients with such hemorrhages present in shock (Pode et al 1985). With such a presentation, 
the treatment may be a total nephrectomy, and this approach complicates the patient’s long-
term care. Angiomyolipomata associated with TSC are usually bilateral and a nephrectomy 
would result in a significant loss of functional renal tissue, thus hastening the need for renal 
replacement therapy (Bissler and Kingswood 2004). A population study suggests that the 
cumulative risk of a hemorrhage is 18% for females and 8% for males (Webb et al 1994). 
However, among a clinic population of approximately 310 adult and pediatric TSC patients in 
Cincinnati, only nine cases of hemorrhage (3%) were observed (Bissler and Kingswood 2004). 
This difference may be, at least in part, due to an aggressive embolization program, 
population age differences or length of follow-up. Angiomyolipomata appear to grow over 
time, and there is an association between lesion size and hemorrhage (Steiner 1993, Dickinson 
1998).
The second morbidity of renal angiomyolipomata is the insidious encroachment of the 
angiomyolipoma on normal renal tissue, which may lead to renal failure (Schillinger 1996,


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Clarke 1999). The precise incidence of end-stage renal disease (ESRD) in the tuberous 
sclerosis population has not been well defined. However, European surveys suggest that 
approximately 1% of the TSC patient population with normal intellect is receiving dialytic 
renal replacement therapy (Schillinger 1996, Clarke 1999), leading to an estimate that over
30,000 TSC patients are on dialysis worldwide. Shepherd et al examined death certificates of
patients in their TSC clinic and found that of 355 patients, 40 died as a result of their TSC, 
most commonly due to renal failure (Shepherd et al 1991). The percentage of TSC patients 
developing ESRD because of polycystic kidney disease, multiple interventions for 
hemorrhage, 
or 
replacement 
of 
renal 
tissue 
by 
angiomyolipomata 
is 
unclear 
(Bissler and Kingswood 2004).
Approximately 35% of patients with TSC will have renal cysts (Cook et al 1996). Although 
these lesions may be large, they usually are not numerous and rarely cause problems 
(Bissler and Kingswood 2004).
The primary reason to intervene in patients with renal angiomyolipomata has been to alleviate 
symptoms such as pain or hemorrhage. The recent urological literature has embraced a renal 
sparing approach for angiomyolipomata (Nelson and Sanda 2002). Key to the long-term 
outcome of patients with multiple renal angiomyolipomata is the preservation of renal 
function. Indications for a total nephrectomy are limited and include a non-functioning kidney 
resulting in uncontrolled hypertension, local tissue invasion, tumor in the renal vein, or very 
strong evidence of malignancy (Bissler and Kingswood 2004). Partial or nephron-sparing 
nephrectomies run the risk of significant hemorrhage, and therefore should be undertaken 
only if unequivocally indicated (Bissler and Kingswood 2004). Embolization is currently 
regarded as a suitable alternative to such invasive procedures. The procedure obliterates the 
blood supply to the angiomyolipoma and thus reduces the risk of hemorrhage. Nevertheless, 
embolization also has significant side effects. In a review of published series, it was estimated 
that 85% of patients develop post-embolization syndrome, including significant fever and pain 
(Bissler and Kingswood 2004). In addition, although embolization and surgical therapies can 
successfully treat solitary lesions, the much more vexing clinical problem of coalescent renal 
angiomyolipomata that replace renal parenchyma has remained largely unaddressed. When 
bleeding occurs in this circumstance, it can be impossible to identify which lesion is the 
source.
A compelling argument can be made for treatment with pharmacological mTOR inhibitors. 
Loss of TSC1and TSC2 leads to increased mTOR activity and downstream activation of S6-
kinase-dependent gene expression, including the lymphangiogenic factor VEGF-D.. Study 
CRAD001M2302 (also referred as M2302) is the pivotal Phase III study that investigated the 
use of everolimus in treating renal angiomyolipoma associated with TSC. In this international 
multi-center study, 118 patients were 2:1 randomized to everolimus or placebo. The primary 
endpoint, angiomyolipoma response rate, was defined as the proportion of patients with a 
reduction in angiomyolipoma volume of at least 50% relative to baseline. At the primary 
analysis data cut-off date (30-Jun-2011) with a median follow up duration of 8.8 months, the 
angiomyolipoma response rate was statistically significantly higher in the everolimus arm 
compared to the placebo arm (33/79 patients, 41.8% vs 0/39 patients, 0.0%; p<0.0001). 33 
patients in the placebo arm transferred to everolimus treatment after study unblinding or 
disease progression. At the time of the final analysis data cut-off date (04-Feb-2015), all 112 


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patients with at least one dose of everolimus had discontinued treatment as per protocol. The
median (range) duration of study follow-up was 47.2 months (0.9 to 65.3). Cumulative
response rate was 58% (65/112; 95% CI: 48.3, 67.3). The study data also showed that 
everolimus was associated with a clinically relevant SEGA response rate of 48.0% (n=24/50,
95% CI: 33.7, 62.6). The overall skin lesion response rate was 68.2% (73/107 patients) with 
one patient reporting a confirmed complete clinical skin lesion response and no patients 
experiencing progressive disease as their best response.
Results from a one year non-interventional follow-up phase indicated that clinically 
significant treatment effects were attenuated in the evaluable patients following everolimus 
discontinuation, as shown by an increase in the volume of angiomyolipoma lesions previously 
reduced in size as a result of everolimus treatment. While in some cases post-discontinuation 
growth plateaued following discontinuation of everolimus and while lesion volumes did not 
return to pre-treatment values, profound reduction in volumes were no longer detectable in the 
majority of patients within approximately one year of everolimus discontinuation. These 
findings suggest that persistence of clinically significant angiomyolipoma volume reduction 
requires ongoing treatment in most patients. 
Choice of a minimum angiomyolipoma size
Angiomyolipomata appear to grow over time, and there is an association between lesion size 
and hemorrhage (Steiner 1993, Van Baal 1994, Oesterling 1986, Dickinson 1998).
Conservative clinical practice varies between a watchful waiting policy to an aggressive 
embolization program. Patients eligible for the current study should have at least one 
angiomyolipoma 3 cm or more in the largest dimension. The choice of 3 cm is aligned with 
the criteria that were used in the pivotal study CRAD001M2302 and reflects the vague limits 
between a justified wait and watch policy and the more proactive surgical intervention 
approaches.
Volumetric assessment of tumor response
Assessment of tumor response to therapy is a critical component for drug development and for 
the clinical management of patients. Current approaches for classifying tumor response are 
based on anatomical measurements in either one dimension (Response Evaluation Criteria in 
Solid Tumors [RECIST] (Therasse et al 2000)) or two dimensions (World Health 
Organization [WHO] (Miller et al 1981)). However, response rates as determined from these 
criteria may not always be sufficiently accurate.
As tumors grow in three dimensions, shrinkage can thus be accurately defined as a decrease in 
tumor volume. RECIST and WHO measurements are essentially surrogates for volume. With 
developing state-of-the-art imaging techniques providing a 3-D information set and computer 
algorithm development, it is now possible to obtain accurate and true tumor measurements 
using volume (Twombly 2006), rather than only one or two dimensional measurements. Also, 
for the changes in uni- and bi-dimensional measurements to be a good surrogate for changes 
in volume, one should assume that target lesions are spherical in shape, which may not be true 
for all tumor types. As shown in a study by Mayr et al 2006 three-dimensional volumetry, 
which can optimally measure irregular volumes, may provide better response assessment 
during treatment than diameter-based measurement.


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Finally, in a public workshop on brain tumor clinical trial endpoints organized by the FDA, 
AACR and ASCO on January 20, 2006, it was recognized that measuring tumor diameter is 
probably an outdated methodology, as small percentage changes in diameter can reflect much 
larger changes in tumor volume. It was also mentioned that both manual and automated 
segmentation techniques provide more accurate measurements of tumor volume than diameter 
measurement. In addition, the regional distribution of the lesion was considered an important 
issue; a 1 mm3 reduction in tumor volume in a certain part of the brain might have a dramatic 
clinical effect whereas a larger volume reduction elsewhere in the brain might be clinically 
meaningless.
1.2
Introduction to investigational treatment
1.2.1
Overview of everolimus 
Organ transplantation 
Everolimus was initially developed for the prophylaxis of organ transplant rejection. It was 
originally approved in Europe on 18-Jul-2003 under the trade name Certican® for the 
prophylaxis of organ rejection in adult patients at low to moderate immunological risk, 
receiving an allogenic renal or cardiac transplant, in combination with cyclosporine for 
microemulsion and corticosteroids, and has since been granted approval in 107 countries 
worldwide. In the United States (US), everolimus was approved by the Food and Drug 
Administration (FDA) on 20-Apr-2010 under the trade name Zortress® (NDA 21-560) for 
prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a 
kidney transplant. Certican®/Zortress® is also approved for the prophylaxis of organ rejection 
in adult patients receiving a liver transplant in 83 countries worldwide (approval in Europe 
received 17-October-2012 and FDA approval on 15-February-2013). Additional registrations 
for use of Certican® in organ transplantation are pending in Africa, South America, Middle 
East, and Asia-Pacific region.
Oncology 
Everolimus first entered clinical development for one of numerous oncology indications in 
2002. 
It was approved by the FDA on 30-Mar-2009 under the trade name Afinitor® for the treatment 
of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib 
or sorafenib. The European Commission (EC) approved it on 03-Aug-2009 for the treatment 
of patients with advanced RCC, whose disease has progressed on or after treatment with 
vascular endothelial growth factor (VEGF)-targeted therapy. Since then, everolimus has 
received approvals in more than 120 countries worldwide for the treatment of patients with 
advanced RCC. 
On 05-May-2011, FDA approved Afinitor® for the treatment of progressive neuroendocrine 
tumors of pancreatic origin (pNET) in patients with unresectable, locally advanced or 
metastatic disease. The EC approved it on 24-Aug-2011 for the treatment of unresectable or 
metastatic, well- or moderately-differentiated neuroendocrine tumors of pancreatic origin in 
adults with progressive disease. 


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Furthermore, on 26-Feb-2016, FDA approved Afinitor® for advanced non-functional NET of 
gastrointestinal (GI) or lung origin followed by the EC on 26-May-2016 for the treatment of 
unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional NET of GI 
or lung origin in adults with progressive disease. Overall, Afinitor® has been approved in 
more than 110 countries worldwide for the treatment of patients with pNET/neuroendocrine 
tumors.
On 20-Jul-2012, FDA approved Afinitor® for the treatment of postmenopausal women with 
advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2 
negative (HER2-) breast cancer in combination with exemestane, after failure of treatment 
with letrozole or anastrozole. The EC granted approval on 23-Jul-2012 for the treatment of 
HR+, HER2- advanced breast cancer, in combination with exemestane, in postmenopausal 
women without symptomatic visceral disease after recurrence or progression following a non-
steroidal aromatase inhibitor. To-date, everolimus has been approved in more than 110 
countries worldwide for the treatment of patients with advanced HR+, HER2- breast cancer.
In China, everolimus was first approved by the NMPA on 22-Jan-2013 under the trade name 
Afinitor® for the treatment of adult patients with advanced renal cell carcinoma after failure of 
treatment with sunitinib or sorafenib.
On 13-Feb-2014, NMPA also approved Afinitor® for the treatment of adult patients with 
progressive neuroendocrine tumors of pancreatic (pNET) origin that are unresectable, locally 
advanced or metastatic, well differentiated (moderately differentiated or highly differentiated). 
On 17-Oct-2018, NMPA also approved Afinitor® for adult patients with progressive, well 
differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung 
origin that are unresectable, locally advanced or metastatic.
Tuberous Sclerosis 
To-date, everolimus has been developed and received regulatory approvals for three 
manifestations of TSC: subependymal giant cell astrocytoma associated with TSC, renal 
angiomyolipoma associated with TSC, and refractory seizures associated with TSC.
On 29-Oct-2010, everolimus received accelerated approval from FDA on the basis of data 
from the Phase II study CRAD001C2485 (also abbreviated C2485) for the “treatment of 
patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis 
who require therapeutic intervention but are not candidates for curative surgical resection. The 
effectiveness is based on an analysis of change in SEGA volume. Clinical benefit such as 
improvement in disease-related symptoms or increase in overall survival has not been 
demonstrated.” Subsequently on 29-Aug-2012, the indication was revised by the FDA based 
on the results of the Phase III study CRAD001M2301 (also abbreviated M2301) to the 
“treatment of pediatric and adult patients with TSC for the treatment of SEGA that requires 
therapeutic intervention but cannot be curatively resected. The effectiveness is based on 
demonstration of durable objective response, as evidenced by reduction in SEGA tumor 
volume. Improvement in disease-related symptoms and overall survival in patients with 
SEGA and TSC have not been demonstrated”. 
In Europe the EC conditionally approved everolimus on 02-Sep-2011 based on the data of 
study C2485 under the trade name Votubia® for the “treatment of patients aged 3 years and 


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older with SEGA associated with TSC who require therapeutic intervention but are not 
amenable to surgery. The evidence is based on analysis of change in SEGA volume. Further 
clinical benefit, such as improvement in disease-related symptoms, has not been 
demonstrated”. On 15-Nov-2013, based on the results of study M2301, the indication was 
revised with the removal of the age restriction to “Votubia is indicated for the treatment of 
patients with SEGA associate with TSC who require therapeutic intervention but are not 
amendable to surgery. The evidence is based on analysis of change in SEGA volume. Further 
clinical benefit, such as improvement in disease-related symptoms, has not been 
demonstrated”. 
The follow-up data from studies C2485 and M2301 demonstrated sustained efficacy and 
safety of everolimus in this patient population. In 2015/2016, these data allowed the 
conversion of the conditional marketing authorization to full approval in the EU (on 16-Nov-
2015) and fulfillment of the Subpart H requirement and the Post Marketing Requirements in 
the US (on 29-Jan-2016). The limitation statement was also removed from the indication in 
the US. 
Overall, everolimus has been approved in more than 100 countries worldwide for the 
treatment of patients with TSC who have SEGA. 
On the basis of the results of the Phase III study M2302, everolimus received accelerated 
approval from the FDA on 26-Apr-2012 for the “treatment of adult patients with renal 
angiomyolipoma and TSC, not requiring immediate surgery. The effectiveness of Afinitor® in 
the treatment of renal angiomyolipoma is based on an analysis of durable objective responses 
in patients treated for a median of 8.3 months”.
On 31-Oct-2012, the EC granted approval to Votubia® for the “treatment of adult patients 
with renal angiomyolipoma associated with TSC who are at risk of complications (based on 
factors such as tumor size or presence of aneurysm, or presence of multiple or bilateral 
tumors) but who do not require immediate surgery”. 
On 18-Feb-2016, the FDA considered the Subpart H requirement and the Post Marketing 
Requirement related to Study M2302 as fulfilled based on the final study results and the 
limitation statement was removed from the indication.
Overall, everolimus has been approved in more than 90 countries for the treatment of renal 
angiomyolipoma associated with TSC. 
Finally, on 27-Jan-2017, the EC granted a decision for Votubia for the “adjunctive treatment 
of patients aged 2 years and older whose refractory partial-onset seizures, with or without 
secondary generalization, are associated with TSC”. This approval was based on the results of 
the Phase III Study CRAD001M2304. So far, everolimus has been approved in 31 countries 
for the treatment of TSC-associated refractory seizures.
In China, NMPA approved Afinitor® on 13-Feb-2014 for pediatric and adult patients with 
tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) 
that requires therapeutic intervention but cannot be curatively resected. This approval was 
based on the results of global studies C2485 and M2301. The effectiveness is based on the 
demonstration of durable objective response, as evidenced by reduction in SEGA tumor 


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volume. Improvement in disease-related symptoms and overall survival in patients with 
SEGA and TSC has not been demonstrated.
On 29-Nov-2016, NMPA
also approved Afinitor®
for adult patients with renal 
angiomyolipoma and tuberous sclerosis complex (TSC-AML) not requiring immediate 
surgery. This approval was based on the results of the global study M2302 and the local 
investigator initiated study MCN30T. 
Approximately 136,053 patients have been enrolled in studies with everolimus as of 31-Mar-
2019 (this number excludes patients who received marketed Afinitor®/Votubia®/Afinitor 
DISPERZ, those on planned and roll over studies as well as those on investigator-sponsored 
studies):

133,748 patients in Novartis-sponsored clinical trials

2,305 patients in the individual patient program
Approximately 49,988 patients were enrolled globally in all investigator-sponsored studies as of 
31-Mar-2019.
The following is a brief summary of the main characteristics of everolimus (Afinitor®). More 
complete information can be obtained from the Chinese product information for Afinitor®.
Mechanism of action 
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor (Table 1-
1, Figure 1-1). Everolimus selectively inhibits mammalian target of rapamycin (mTOR), 
specifically targeting the mTOR-raptor signal transduction complex. mTOR is a key serine-
threonine kinase in the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling 
cascade, which is known to be dysregulated in a wide spectrum of human cancers (Boulay and 
Lane 2007). 
Everolimus is being investigated as an anticancer agent based on its potential to act 

directly on the tumor cells by inhibiting tumor cell growth and proliferation; 

indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF production and VEGF-induced proliferation of endothelial 
cells). 
Table 1-1
Everolimus – Drug substance
Chemical name 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-
12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-
19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone 
International non-
proprietary name 
Everolimus 


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Figure 1-1
Chemical structure of Everolimus
mTOR pathway and cancer 
At the cellular and molecular level, everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR, a key protein kinase which regulates cell growth, proliferation and 
survival. The mTOR kinase is mainly activated via the PI3K pathway through AKT/PKB and 
TSC1/2. Mutations in these components or in phosphatase and tensin homolog (PTEN), a 
negative regulator of PI3K, may result in their dysregulation. Abnormal functioning of 
various components of the signaling pathways contributes to the pathophysiology of 
numerous human cancers. Various preclinical models have confirmed the role of this pathway 
in tumor development (Cohen et al 2005). 
The main known functions of mTOR include the following (Bjornsti and Houghton 2004): 

mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels; 

Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions; 

The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors; 

PI3K mutations have been reported in the primary tumor in 10-20% of human colorectal 
cancers (Frattini 2005, Velho 2005); 

The loss of PTEN protein, either through gene deletion or functional silencing (promoter 
hypermethylation), is reported in approximately 60% of primary human colorectal cancers 
(Goel et al 2004); 

The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) 
and inhibition of endothelial cell growth and proliferation; 

Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 
40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, including 
the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased expression of 
HIF-1. 
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1.2.2
Non-clinical experience of everolimus
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including 
lines originating from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range 
from sub/low nM to μM. Everolimus also inhibits the proliferation of human umbilical vein 
endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that everolimus may also act as an anti-angiogenic agent. The anti-
angiogenic activity of everolimus was confirmed in vivo. Everolimus selectively inhibited 
VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and 
metastatic tumors treated with everolimus showed a significant reduction in blood vessel 
density when compared to controls. 
The potential of everolimus as an anti-cancer agent was shown in rodent models. Everolimus 
is orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse 
xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor model. 
The pharmacokinetic profile of everolimus indicates sufficient tumor penetration, above that 
needed to inhibit the proliferation of endothelial cells and tumor cell lines deemed sensitive to 
everolimus in vitro. 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated 
doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, lung 
and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic melanoma). 
These models included tumor lines considered sensitive and “relatively resistant” in vitro. In 
general, everolimus was better tolerated in mouse xenograft models than standard cytotoxic 
agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity. 
Additionally, activity in a VEGF-impregnated subcutaneous implant model of angiogenesis 
and reduced vascularity (vessel density) of everolimus-treated tumors (murine melanoma) 
provided evidence of in vivo effects of angiogenesis. 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
everolimus. Molecular analysis has revealed that relative sensitivity to everolimus in vitro 
correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase and 
the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a correlation with 
PTEN status. 
In vivo studies investigating the anti-tumor activity of everolimus in experimental animal 
tumor models showed that everolimus monotherapy typically reduced tumor cell growth rates 
rather than produced regressions. These effects occurred within the dose range of 2.5 mg to 10 
mg/kg, orally once a day. 
In preclinical models, the administration of everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (p-S6) 
and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein upstream 
of mTOR signaling pathway. 
All significant adverse events observed in toxicology studies with everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-
proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 


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recovery period with the exception of the changes in male reproductive organs, most notably 
testes. 
1.2.3
Clinical experience of everolimus
Clinical Safety, Tolerability and Efficacy
Phase III study CRAD001M2302 in renal angiomyolipoma associated with TSC (EXIST-2)
A total of 118 patients with renal angiomyolipoma associated with TSC were enrolled to this 
study between 2009 and 2014 (01-Apr-2014 cut-off). 79 were initially treated with everolimus 
and 39 with placebo. Upon disease progression or study unblinding, patients were allowed to 
crossover from placebo to everolimus. A total of 112 patients were treated with at least 1 dose 
of everolimus. The data described below represent the cumulative experience of 112 patients 
treated with everolimus at the time of the final treatment cut-off date, 04-Feb-2015.
Efficacy
At the primary analysis cut-off date (30-Jun-2011), the angiomyolipoma response rate was 
statistically significantly higher in the everolimus arm compared to the placebo arm (33/79 
patients, 
41,8% 
vs 
0/39 
patients, 
0.0%; 
p<0.0001). 
Cumulative 
experiencefor 
angiomyolipoma response at the final cut-off date (04-Feb-2015) demonstrated that the 
tumors in 65/112 patients had responded to treatment (response rate = 58.0%; 95% CI: 48.3, 
67.3). The percentage of patients achieving ≥30% reduction in angiomyolipoma volume was 
sustained while the degree of reduction (≥50% volume reduction and median percentage 
reduction) improved over the course of the study:

78/104 patients (75%) experienced reductions of ≥30% at Week 12, 79/98 patients 
(80.6%) at Week 96, and 52/61 patients (85.2%) at Week 192;

46/104 patients (44.2%) experienced reductions of ≥50% at Week 12, 62/98 patients 
(63.3%) at Week 96, and 42/61 patients (68.9%) at Week 192;

The median percentage reduction in angiomyolipoma volume at Week 12, 96 and 192 was
46.4%, 58.9% and 61.9%, respectively.
The efficacy results confirmed that everolimus treatment effects in patients with TSC-
associated angiomyolipoma were sustained over a period of time.
Everolimus was associated with a clinically relevant SEGA response rate of 48.0% (n=24/50,
95% CI: 33.7, 62.6). 
The overall skin lesion response rate was 68.2% (73/107 patients) with one patient reporting a
confirmed complete clinical skin lesion response and no patients experiencing progressive
disease as their best response. Of 73 patients who had a response of the skin lesions, the 
median time to skin lesion response was 8.41 months (95% CI: 5.59, 11.53).
Results from the non-interventional follow-up phase indicate that clinically significant 
treatment effects were attenuated in the evaluable patients following everolimus 
discontinuation, as shown by an increase in the volume of angiomyolipoma lesions previously 
reduced in size as a result of everolimus treatment. While in some cases post-discontinuation 
growth plateaued following discontinuation of everolimus and while lesion volumes did not 


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return to pre-treatment values, profound reduction in volumes were no longer detectable in the 
majority of patients within approximately one year of everolimus discontinuation. 
Safety
The most common AEs (≥30% of patients) regardless of study drug relationship were
nasopharyngitis (44.6%), stomatitis (42.9%), hypercholesterolemia (35.7%), headache 
(33.0%), acne (32.1%), and urinary tract infection (31.3%). Stomatitis, which is a known 
identified risk of everolimus treatment, was the most frequently reported individual AE 
suspected by the Investigator to be study-drug related in everolimus-treated patients (42.0%).
Other frequently reported AEs (≥20% of patients) with suspected relationship to study drug
included hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis (21.4%), and
nasopharyngitis (21.4%). Amenorrhea (n=18/71, 25.4%) was frequently reported in the 
female population at risk (10-55 years of age).
Ten patients (8.9%) discontinued study drug due to the AEs. 
Phase II study RAD001MCN30T in renal angiomyolipoma associated with TSC 
18 Chinese adult patients with TSC-AML were enrolled in this single site investigator 
initiated study. A preliminary analysis was done with cut-off date 10-Oct 2015 when 15 
patients were enrolled and 13 patients had received 10 mg everolimus per day for 3 months.  
Out of the 13 patients with at least 3 months treatment, 4 patients met the primary endpoint, 
which was defined as 50% or more reduction of renal AML volume relative to baseline in the
absence of new renal AML >1cm and no renal AML-related bleeding of grade ≥2.  The mean 
volume decrease at 3 months and 6 months was 30.78% and 50.22%, respectively. 
Mouth ulceration, nasopharyngitis, hypercholesterolemia and irregular menstruation in 
females were the most common adverse events of which only 2 events had a CTCAE grade of
3 in the first 3 months. 
Clinical Pharmacodynamics
Results of a linear mixed model analysis in study M2302 indicated a 10.37% (95% CI= -15.96,
-4.40) reduction in AML volume from baseline for a 2-fold Cmin increase, which was 
statistically significant at 5% level. No apparent relationship was observed between absolute 
or percent change from baseline in SEGA volume and time-normalized Cmin. This was 
attributed to interpatient variability in the exposure-response relationship and the relatively 
narrow concentration range reported within individual patients as a result of the fixed daily 
dosing regimen. Box plot analysis of time-normalized Cmin in patients with skin lesion 
responses of partial response (PR) and stable disease (SD) indicated that the median time-
normalized Cmin was higher in patients with PR than in patients with SD response at Week 
12, while the median Cmin was comparable in patients with PR and SD at week 24. Higher 
Cmin or C2h was not indicative of a higher probability/risk for stomatitis and infections 
events of all grades within the Cmin and C2h ranges observed in the study.
Clinical Pharmacokinetics
After administration of Afinitor® Tablets in patients with advanced solid tumors, peak 
everolimus concentrations are reached 1 to 2 hours after administration of an oral dose of 5 to 


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70 mg everolimus under fasting conditions or with a light fat-free snack. Cmax is dose-
proportional with daily dosing between 5 and 10 mg. AUC shows dose-proportionality over 
the 5 to 70 mg dose range. 
After administration of Afinitor® Tablets in patients with advanced solid tumors, steady-state 
AUC0-τ was dose-proportional over the range of 5 to 10 mg with a daily dosing regimen. 
Steady-state was achieved within two weeks. Cmax is dose-proportional between 5 and 10 mg 
daily. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between
AUC0-τ and pre-dose trough concentration at steady-state on a daily regimen. The mean 
elimination half-life of everolimus is approximately 30 hours.
Pharmacokinetics in the TSC patient population is comparable to what was observed in the 
approved oncology indications (e.g. RCC, pNET).
In healthy subjects, high fat meals reduced systemic exposure to 10 mg Afinitor Tablets (as 
measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Low-fat meals 
reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post 
absorption phase concentration-time profile 24 h post-dose of either dosage form.
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, it is the main 
circulating component in human blood. Elimination of everolimus is mainly through faeces.
2
Rationale
2.1
Study rationale and purpose
The purpose of this study is to assess the safety and efficacy of Afinitor® in Chinese patients 
with renal angiomyolipoma associated with TSC. The study will evaluate the safety and anti-
tumor activity of Afinitor® given at a dose of 10 mg per day. Study CRAD001M2302 has 
shown that the volume of TSC-AML lesions was reduced in a significant portion of TSC renal 
AML patients that received treatment with Afinitor®. CRAD001M2302 was conducted at 24 
sites in 11 countries but China was not a participating country and no Chinese patients were 
enrolled.  The overall angiomyolipoma response rate was 41.8% (95% CI: 30.8, 53.4) for the 
everolimus arm and 0% (95% CI: 0.0, 9.0) for the placebo arm (p < 0.0001) in the FAS.
Study CRAD001MCN30T enrolled 18 Chinese adult patients with TSC-AML. At the
preliminary analysis 4 out of 13 patients with at least 3 months Afinitor® treatment (10 mg per 
day) had an angiomyolipoma response. 
Based on these results NMPA approved Afinitor® on 29-November 2016 for the treatment of 
TSC-renal AML patients not requiring immediate surgery.
This study is conducted to fulfill a post approval commitment (PAC) to assess the safety and 
efficacy of Afinitor® in adult Chinese patients with TSC associated renal AML lesions based 
on Chinese current clinical practice. The patient population in this study represents the 
population of the approved indication which is at significant risk for renal morbidities and is 
therefore well-suited for testing the effect of everolimus on tumor burden.
TSC is an autosomal dominant genetic disorder that is caused by inactivating mutations in the 
TSC1 or TSC2 genes, and characterized by benign, highly vascular, hamartoma growth. The 


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TSC1/TSC2 protein complex is a negative regulator of the mTOR pathway and mutations in 
one of the two genes causes loss of function and leads to increased mTOR pathway activation. 
Everolimus is an inhibitor of the mTOR pathway and has a similar effect as the TSC1/TSC2 
protein complex. The rationale of using everolimus in TSC patients is that it compensates the
missing inhibitory effect of TSC1/TSC2 on mTOR. 
2.2
Rationale for the study design
This single arm, open label, phase IV PAC study will evaluate the safety and efficacy of 
Afinitor® (10 mg/day) in 40 Chinese adult patients with renal angiomyolipoma associated 
with TSC. The study design is based on the positive outcome of the pivotal study 
CRAD001M2302. 
Patients eligible for the study should have a confirmed diagnosis of TSC and at least one renal 
angiomyolipoma lesion of 3 cm or more in the largest dimension.
2.3
Rationale for dose and regimen selection
The dose in this phase IV study will follow the recommended dose approved as per the 
Chinese product information of Afinitor®.  The starting dose will be 10mg/day. For patient 
with abnormal liver function, starting dose will be 7.5mg/day, or 5mg /day if Child-Pugh 
grade is A or B，respectively. 
2.4
Risks and benefits
Appropriate eligibility criteria and specific dose modification and stopping rules are included 
in this protocol. Recommended guidelines for prophylactic or supportive management of 
study-drug induced adverse events are provided in Section 6.2.3 and Table 6-3. The risk to 
subjects in this study may be minimized by compliance with the eligibility criteria and study 
procedures, as well as, close clinical monitoring. There may be unforeseen risks with
Afinitor® which could be serious. Please refer also to the Chinese product information for 
Afinitor®.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate the safety of Afinitor® in Chinese adults with 
TSC-AML not requiring immediate surgery.
● Incidence of adverse events, laboratory
abnormalities.
Secondary
Refer to Section 10.5.1
To evaluate the efficacy of Afinitor® in Chinese adults with 
TSC-renal AML not requiring immediate surgery.
● AML response
Other Secondary
Refer to Section 10.5.2 and 10.5.3
To further evaluate the efficacy of Afinitor® in Chinese 
adults with TSC-renal AML not requiring immediate 
surgery.
● AML progression
● Renal function change from screening 
Exploratory
None


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4
Study design
4.1
Description of study design
This is an open label, single arm, multi-center phase IV study of treatment with one daily oral 
dose of 10 mg everolimus (Afinitor®) in 40 patients with renal angiomyolipoma associated 
with TSC.
There are three separate phases in this study: a “Screening phase”, an “Open-label treatment 
phase”, and a “Treatment discontinuation follow-up phase” for patients who discontinue study 
drug for other reasons than disease progression.
Screening phase
At screening, the investigator or his/her designee will assign a unique number (refer to
Section 6.4.1) to patients being considered for the study. Patients are required to sign an 
Informed Consent Form prior to any study screening evaluations. Once the patient 
provides a signed informed consent form and eligibility is confirmed (all 
inclusion/exclusion criteria have been verified), the investigator can enroll the patient
and start treatment with Afinitor®.
During the 28-day screening period, all patients will have a CT/MRI of the kidneys and 
MRI/CT of the brain performed for identification of angiomyolipoma and SEGA lesions; the 
kidney CT/MRI will be used to assess patient eligibility. Although the study will use an 
Independent Central Radiology Review to measure tumor volume, the decision to enroll the 
patient will be made based on the judgment of the investigator and local radiologist. Once the 
patient is enrolled, the baseline kidney CT/MRI and brain MRI/CT should be sent within 2 
business days by the study site to the Independent Central Radiology Reviewer to assess the 
tumor volume. 
Prior to start of study drug, all patients should be tested for hepatitis B viral load and serologic 
markers: HBV-DNA, HBsAg, HBsAb, and HBcAb. All patients should also be tested for 
hepatitis C using quantitative RNA-PCR. Patients with quantifiable HBV DNA and/or 
positive HbsAg or quantifiable HCV-RNA are excluded from the study.
Other screening tests include blood sampling, urinalysis, WHO performance status, and ECG. 
If safety laboratory collections are collected more than 14 days prior to Treatment Day 1 (i.e.
day of first dose of study drug) they will need to be repeated prior to the patient’s first dose of 
study drug. The central laboratory collections that must be repeated are: hematology, 
biochemistry and lipid profile, coagulation and urinalysis.
Patients with LAM will have a lung function test (FEV1, DLCO) and blood gas analysis
performed during screening.
Patients with skin lesions at screening will have digital photos of these lesions taken during 
screening. 
Screening evaluations will also include demography, inclusion/exclusion criteria, relevant 
medical history/current medical conditions, a physical examination, and vital signs. All 


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screening evaluations should be completed in the 28 days prior to Treatment Day 1 and after 
signing the informed consent. A complete list of screening evaluations is provided in the visit 
evaluation schedule (Table 7-1). All of the above assessments/procedures must be conducted 
prior to enrollment.
Open label treatment phase
Patients who meet the study eligibility criteria will start treatment with Afinitor®. The 
treatment duration will be 48 weeks. Patients will have their first daily dose of Afinitor® at 
Day 1 and will continue on treatment until angiomyolipoma progression (as defined in 
Section 7.2.1.1, an unacceptable toxicity, occurrence of serious protocol deviations, 
withdrawal of consent or investigator decision to discontinue the patient from study treatment.
Patients with normal liver function will start with a dose of 10 mg/day. Patients with hepatic 
impairment will start with a dose of 7.5 mg/day (Child-Pugh grade A) or 5 mg/day (Child-
Pugh grade B). Dose adjustments (reduction, interruption) will occur based on safety findings. 
All doses taken by the patient and all dose changes during the study must be recorded on the
study treatment CRF.
Safety evaluations are routinely performed at each visit according to the visit schedule (Table 
7-1). Patients must be in a fasting state (at least 12 hours) at the time of blood sampling for all 
laboratory evaluations including the lipid profile. Hematology, biochemistry and urinalysis 
evaluations will be performed according to the visit schedule (Table 7-1). Note that 
hematology, biochemistry and urinalysis assessments are performed at screening and do not 
need to be repeated on Day 1 if Day 1 occurs within 14 days of the screening visit. Otherwise, 
the patient will need to repeat the screening visit blood and urine collections. All blood 
samples obtained at each visit will be sent to a Central Laboratory for analysis. Urinalysis will 
be performed locally. If laboratory results are requested on an urgent basis, the attending 
physician will use the local laboratory results for treatment decisions. Complete details 
regarding all study required safety assessments are provided in Section 7.
All patients will have a CT/MRI of the kidney performed at 12, 24 and 48 weeks in the open-
label treatment phase, after the start of study treatment, until angiomyolipoma progression. A 
CT/MRI of the kidneys should be repeated at the End of Treatment (EOT) visit if the patient 
has discontinued for any reason other than angiomyolipoma progression, and if it has been 
more than 8 weeks since their most recent kidney CT/MRI.
In addition to the CT/MRI of the kidney, patients with a SEGA lesion having a longest 
diameter ≥ 1.0 cm documented at screening will also have a MRI/CT of the brain at 12, 24 
and 48 weeks in the open-label treatment phase. For each patient, the same imaging modality 
should be used throughout the study. All kidney CT/MRIs and brain MRI/CTs will be sent to 
the central radiologist for an independent centralized radiology review. The central radiologist 
will determine the angiomyolipoma volume and verify whether the radiological criteria for 
angiomyolipoma response have been met (Section 7.2.1.1). Since not all study centers will 
have the technical capability to measure angiomyolipoma volume, there is no plan to collect 
data from the local radiologist at each site. MRI and CT scans must be digitized and sent to 
Central Radiology within 2 business days of the scan date. The central review of the CT/MRIs 
will be conducted at the agreed upon frequency between Novartis and the assigned Imaging 


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Vendor after its receipt by the central radiology vendor. Once the data is available, the results 
will be sent immediately to the study site and to Novartis. Clinical suspicion of 
angiomyolipoma progression at any time requires a physical examination and expedited 
radiological confirmation by the Independent Central Radiology Reviewer.
Other tests that will be conducted routinely include laboratory tests for safety, physical 
examinations, vital signs, and WHO performance status. In addition, for LAM patients, 
pulmonary function tests will be carried out at 12, 24, 48 weeks, in the open-label treatment 
phase. Patients with skin lesions will have digital photos of their skin lesions taken at 12, 24, 
and 48 weeks, in the open-label treatment phase. A complete list of evaluations can be found 
in Table 7-1. If unforeseen circumstances (i.e., unexpected personal reasons) prevent the 
patient from complying with the established visit schedule, the site can re-schedule the visit 
within the prescribed visit window as noted in Table 7-1. The reason(s) for any visit or 
treatment delays will be documented for the appropriate visit.
All female patients of child bearing potential should perform urine pregnancy tests at home
every 4 weeks ±7 days from Day 1 to end of treatment (EOT), and enter the result in the 
pregnancy diary. 
Every patient will have end of treatment (EOT) visit within 28 days after last dose. Laboratory
tests and imaging will be done at the EOT visit as described in Table 7-1. Laboratory tests that 
were done within 1 week and imaging that was done within 8 weeks don’t have to be repeated 
at EOT.
All patients will have a safety follow-up visit 30 days after last dose to capture AEs and SAEs 
that may have occurred after EOT. 
Treatment Discontinuation Follow-up phase
Patients without angiomyolipoma progression at the time of early discontinuation of study 
treatment will enter the Treatment Discontinuation follow-up phase and will be followed with 
CT/MRI tumor assessments 12, 24 and 48 weeks after Day1, until eventual angiomyolipoma 
progression, the start of any non-study systemic anti-angiomyolipoma therapy, or withdrawal 
of consent, whichever occurs first. Patients with SEGA lesions should be followed for routine 
follow-up with brain MRI/CT scans 12, 24 and 48 weeks after Day1. During this follow up 
period, the site will continue to send CT/MRIs for central review, and use of non-study 
systemic anti-angiomyolipoma therapies will be recorded in CRF. Patients with skin lesions 
will also be followed with digital photography during Treatment Discontinuation follow-up 
phase.
4.2
Definition of end of study
The study will end when 40 patients will have completed all scheduled visits as per protocol. 
At the end of the study，patients who in the opinion of the Investigator still derive clinical 
benefit can transfer to prescribed commercial medication. Afinitor® is commercially available 
in China for the studied indication. It is listed on the national reimbursement plan. Patients 
will need to obtain the medication with a prescription and pay for it per related reimbursement 
policy after the study ends.  


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4.3
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The study patient population consists of 40 male or female adult patients (18 years of age or 
older) who have been diagnosed with renal AML associated with TSC that do not require 
immediate surgery.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. Patients 
enrolled in this study are not permitted to participate in additional parallel investigational drug 
studies.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Eligible for treatment with everolimus as per the locally approved label.
2. Presence of at least one AML ≥ 3 cm in its longest diameter using CT or MRI. 
3. If female of child bearing potential, documentation of negative pregnancy test at time of 
Screening. Females of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, must use highly effective methods of contraception during 
dosing and for 8 weeks after stopping medication. Highly effective contraception methods 
include:

Total abstinence: When this is in line with the preferred and usual lifestyle of the
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception]

Female sterilization: have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment

Male partner sterilization (at least 6 months prior to screening). The vasectomized
male partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
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In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment
4. Sexually active males must use a condom during intercourse while taking the drug during 
treatment, and for 8 weeks after stopping treatment. They should not father a child in this 
period. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner in order to prevent delivery of the drug via semen.
5. Written informed consent according to local guidelines must be obtained prior to any
screening procedures.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. AML related bleeding or embolization during the 6 months prior to enrollment.
2. History of myocardial infarction, angina or stroke related to atherosclerosis.
3. Impaired lung function, defined as any of the following:
For patients without LAM 

Known impaired lung function (e.g. FEV1 or DLCO ≤ 70% of predicted)
Note: pulmonary function testing at screening is not required for patients without 
LAM
For patients with LAM

DLCO ≤35%, or

O2 saturations below 90% at rest, or

O2 saturation ≤88% on 6 minute walking test with up to 6 liter O2/minute nasal 
Oxygen
4. Chylous ascites sufficient to affect diaphragmatic function or pulmonary function testing.
5. Significant hematological or hepatic abnormality (e.g. hemoglobin ≤9g/dL, platelets < 
100×10^9/L, or absolute neutrophil count (ANC) < 1.5×10^9/L without supportive 
treatment of hematopoietic growth factor, transaminase levels > 2.5× the upper limit of 
normal (ULN), serum bilirubin > 2 × ULN).
6. Pregnancy or breast feeding.
7. Prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus).
8. Patients who cannot discontinue CYP3A4 strong inhibitors or inducers 2 weeks before 
study treatment.
9. Use of an investigational drug within the 30 days prior to enrollment.
10. Fasting serum cholesterol > 300 mg/dL (or > 7.75 mmol/L) AND fasting triglycerides > 
2.5 × ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can 
only be included after initiation of appropriate lipid lowering medication.
11. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 × ULN despite 
adequate therapy. Patients with a known history of impaired fasting glucose or diabetes 
mellitus (DM) may be included, however blood glucose and antidiabetic treatment must 
be monitored closely throughout the trial and adjusted as necessary.
12. Known impairment of gastrointestinal (GI) function or GI disease that may significantly 
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13. Known history of HIV seropositivity.
14. Inadequate renal function: Serum creatinine > 1.5 × ULN.
15. Patients who have a history of another primary malignancy, with the exceptions of non-
melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the 
patient has been disease free for ≥3 years.
16. Any severe and/or uncontrolled medical conditions such as:
a.
unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia,
b.
active or uncontrolled severe infection,
c.
liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. 
quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA),
d.
known severely impaired lung function (DLCO ≤70% for patients without LAM or 
≤35% for patients with LAM),
e.
active, bleeding diathesis
6
Treatment
6.1
Study treatment
The investigational drug used in the course of this study will be relabeled local commercial 
Afinitor® (everolimus).
Definition of terms: Study treatment / Study drug = RAD001 = Afinitor® = everolimus
6.1.1
Dosing regimen
This is a single arm study. All patients except those with impaired liver function will be 
administered a dose of 10 mg Afinitor® orally once daily (Table 6-1) at the same time every 
day, either consistently with or without food. 
Medication labels for study drug will comply with the legal requirements in China and be 
printed in local language. They will supply no information about the patient. The storage 
conditions for study drug will be described on the medication label.
Table 6-1
Dose and treatment schedule
Study 
treatment
Pharmaceutical form and 
route of administration
Dose
Frequency 
and/or Regimen
Afinitor®
Tablet for oral use
10 mg for patients without hepatic impairment;
7.5 mg for patients with mild hepatic impairment 
(Child-Pugh grade A)
5 mg for patients with moderate hepatic 
impairment (Child-Pugh grade B)
Daily 
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed. 
Tablets 


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Everolimus will be supplied as 2.5 mg and 5-mg Afinitor® tablets. The tablets are packaged in 
blisters. The tablets should be swallowed whole with a glass of water and should not be 
chewed or crushed. 
For patients with TSC who have SEGA and are unable to swallow tablets whole, the tablet(s) 
can be dispersed completely in a glass of water (containing approximately 30 mL) by gently 
stirring until the tablet(s) are fully disintegrated (approximately 7 minutes), immediately prior 
to drinking. The glass should be rinsed with the same volume of water and the rinse 
completely swallowed to ensure the entire dose is administered.
6.1.2
Treatment duration
The planned duration of treatment is 48 weeks. Patients may be discontinued from treatment 
with the study drug earlier due to unacceptable toxicity, disease progression and/or treatment 
is discontinued at the discretion of the investigator or the patient. 
6.1.3
Guidelines for continuation of treatment 
Not applicable.
6.2
Dose modifications
6.2.1
Starting dose rationale
The starting dose for Afinitor®, for patients enrolled in this study, is set at 10 mg /day p.o. 
administered continuously once daily. This starting dose was selected to be in accordance 
with the starting dose used in the pivotal study CRAD001M2302 and recommended starting 
dose in the approved Chinese product information of Afinitor®. Patients with mild hepatic 
impairment (Child-Pugh grade A) will start with 7.5 mg per day and patients with moderate 
hepatic impairment (Child-Pugh grade B) will start with 5 mg per day.
6.2.2
Dosing modifications
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Details of study 
treatment schedule adjustments and dose levels are provided in Table 6-2.
Table 6-2
Study treatment schedule adjustments and dose levels
Afinitor® Starting dose level - 0
Dose level - 1
Dose level - 2
Patients without hepatic impairment
10 mg daily 
5 mg daily
5 mg every 
other day
Patients with mild hepatic impairment 
(Child-Pugh grade A)
7.5 mg daily
5 mg daily
5 mg every 
other day
Patients with moderate hepatic 
impairment (Child-Pugh grade B)
5 mg daily
5 mg every 
other day
Not permitted
Notes:
● Dose reduction should be based on the worst toxicity demonstrated after the most recent dose received.
● Dose reduction below 5 mg every other day is not allowed. Treatment must be discontinued.
Management of severe or intolerable adverse drug reactions (ADRs) may require temporary 
dose interruption (with or without dose reduction) or discontinuation of Afinitor® therapy. If 


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dose reduction is required, the suggested dose is approximately 50% lower than the daily dose 
previously administered.    
The lowest permitted Afinitor® dose in this study is 5 mg every other day. Patients who don’t 
tolerate 5 mg Afinitor® every other day must be discontinued permanently.
Table 6-3 and Table 6-4 summarize the recommendations for dose interruption, reduction, or 
discontinuation of Afinitor®
in the management of ADRs. General management 
recommendations are also provided as applicable. Clinical judgment of the treating physician 
should guide the management plan of each patient based on individual benefit/risk assessment. 
Table 6-3
Dosing guidelines for study drug-related non-hematologic toxicities 
Adverse drug 
reaction
Severity1
Afinitor® dose adjustment2 and management 
recommendations 
Non-infectious 
pneumonitis
Grade 1
Asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated
No dose adjustment required.
Initiate appropriate monitoring.
Grade 2
Symptomatic, medical 
intervention indicated; 
limiting instrumental 
ADL3
Consider interruption of therapy, rule out infection and consider 
treatment with corticosteroids until symptoms improve to Grade
≤ 1.
Re-initiate Afinitor® at a lower dose.
Discontinue treatment if failure to recover within 4 weeks.
Grade 3
Severe symptoms; 
limiting self-care ADL3
O2 indicated
Interrupt Afinitor® until symptoms resolve to Grade ≤ 1. Rule out 
infection and consider treatment with corticosteroids. 
Consider re-initiating Afinitor® at a lower dose. 
If toxicity recurs at Grade 3, consider discontinuation.
Grade 4
Life-threatening 
respiratory 
compromise; urgent 
intervention indicated 
(e.g. tracheotomy or 
intubation)
Discontinue Afinitor®, rule out infection, and consider treatment 
with corticosteroids.
Stomatitis
Grade 1
Asymptomatic or mild 
symptoms; 
intervention not 
indicated
No dose adjustment required.
Manage with non-alcoholic or salt water (0.9%) mouthwash 
several times a day.
Grade 2
Moderate pain; not 
interfering with oral 
intake; modified diet 
indicated
Temporary dose interruption until recovery to Grade 1.
Re-initiate Afinitor® at the same dose.
If stomatitis recurs at Grade 2, interrupt dose until recovery to 
Grade 1.  Re-initiate Afinitor® at a lower dose.
Manage with topical analgesic mouth treatments (e.g., 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol or phenol) with or without topical corticosteroids (i.e. 
triamcinolone oral paste).4


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Adverse drug 
reaction
Severity1
Afinitor® dose adjustment2 and management 
recommendations 
Grade 3
Severe pain; 
interfering with oral 
intake
Temporary dose interruption until recovery to Grade 1. 
Re-initiate Afinitor® at a lower dose.
Manage with topical analgesic mouth treatments (e.g., 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol or phenol) with or without topical corticosteroids (i.e. 
triamcinolone oral paste).4
Grade 4
Life-threatening
consequences; urgent 
intervention indicated
Discontinue Afinitor® and treat with appropriate medical therapy.
Other non-
hematologic 
toxicities
(excluding 
metabolic events)
Grade 1
If toxicity is tolerable, no dose adjustment required.
Initiate appropriate medical therapy and monitor.
Grade 2
If toxicity is tolerable, no dose adjustment required.
Initiate appropriate medical therapy and monitor.
If toxicity becomes intolerable, temporary dose interruption until 
recovery to Grade 1. Re-initiate Afinitor® at the same dose.
If toxicity recurs at Grade 2, interrupt Afinitor® until recovery to 
Grade 1. Re-initiate Afinitor® at a lower dose.
Grade 3
Temporary dose interruption until recovery to Grade 1. 
Initiate appropriate medical therapy and monitor.
Consider re-initiating Afinitor® at a lower dose. 
If toxicity recurs at Grade 3, consider discontinuation.
Grade 4
Discontinue Afinitor® and treat with appropriate medical therapy.
Metabolic events
(e.g. hyper-
glycemia, dys-
lipidemia)
Grade 1
No dose adjustment required.
Initiate appropriate medical therapy and monitor.
Grade 2
No dose adjustment required.
Manage with appropriate medical therapy and monitor.
Grade 3
Temporary dose interruption. 
Re-initiate Afinitor® at a lower dose.
Manage with appropriate medical therapy and monitor.
Grade 4
Discontinue Afinitor® and treat with appropriate medical therapy.
1 Severity Grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-
threatening symptoms.
2 If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously 
administered.
3 Activities of daily living (ADL)
4 Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers.
Table 6-4
Dosing guidelines for study drug-related hematologic toxicities
Adverse event
Severity1
Afinitor® Dose Adjustment
Thrombocytopenia 
(Platelet count 
Grade 1
(<LLN-75.0x109/L)
No dose adjustment required.


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Adverse event
Severity1
Afinitor® Dose Adjustment
decreased)
Grade 2
(<75.0-50.0x109/L)
Temporary dose interruption until recovery to Grade 1.
Re-initiate Afinitor® at the same dose.
Grade 3
(<50.0-25.0x109/L)
Temporary dose interruption until recovery to Grade 1.
Re-initiate Afinitor® at a lower dose.
Grade 4
(<25.0x109/L)
Temporary dose interruption until recovery to Grade 1.
Re-initiate Afinitor® at a lower dose.
Neutropenia 
(Neutrophil count 
decreased) 
Grade 1
(<LLN-1.5x109/L)
No dose adjustment required.
Grade 2
(<1.5-1.0x109/L)
No dose adjustment required.
Grade 3
(<1.0-0.5x109/L)
Temporary dose interruption until recovery to Grade 2 
(ANC≥1.0x109/l).
Re-initiate Afinitor® at the same dose.
Grade 4
(<0.5x109/L)
Temporary dose interruption until recovery to Grade 2 
(ANC≥1.0x109/l).
Re-initiate Afinitor® at a lower dose.
Febrile neutropenia
Grade 3
(ANC<1.0x109/L with 
single 
temperature >38.3°C 
(101°F)
or sustained 
temperature ≥38°C 
(100.4°F) for >1h)
Temporary dose interruption until recovery to Grade 2 
(ANC≥1.25x109/l) and no fever.
Re-initiate Afinitor® at a lower dose.
Grade 4
(Life-threatening 
consequences; urgent 
intervention indicated)
Discontinue Afinitor®.
Any hematologic toxicity requiring study drug 
interruption for >28 days
Discontinue Afinitor®.
1 Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03
All dose changes must be recorded on the Dosage Administration Record CRF.
6.2.3
Management of specific toxicities
6.2.3.1
Management of infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis, candidiasis or pneumocystis jirovecii pneumonia 
(PJP) and viral infections including reactivation of hepatitis B virus, have been described in 
patients taking everolimus. Some of these infections have been severe (e.g. leading to sepsis,
including septic shock, respiratory or hepatic failure) and occasionally have had a fatal 
outcome.


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Physicians and patients should be aware of the increased risk of infection with everolimus. 
Treat pre-existing infections prior to starting treatment with everolimus. While taking 
everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation of 
everolimus.
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat 
with appropriate antifungal therapy.
Cases of PJP, some with fatal outcome, have been reported in patients who received 
everolimus. PJP may be associated with concomitant use of corticosteroids or other 
immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use 
of corticosteroids or other immunosuppressive agents is required.
6.2.3.2
Management of stomatitis / oral mucositis / mouth ulcers
Patients with a clinical history of stomatitis/oral mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis 
must be monitored even more closely. Patients should be instructed to report the first onset of 
buccal mucosa irritation/reddening to their study physician immediately.
Stomatitis/oral mucositis/mouth ulcers due to study drug should be treated using local 
supportive care. Please note that investigators in earlier studies have described the oral 
toxicities associated with everolimus as mouth ulcers, rather than mucositis or stomatitis. If 
the clinical examination reveals mouth ulcers rather than a more general inflammation of the 
mouth, please classify the adverse event as such. Please refer to Table 6-3 for management of 
stomatitis/oral mucositis/mouth ulcers. 
In addition agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may 
tend to worsen mouth ulcers. It is recommended to avoid these agents.
Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be 
avoided in all patients due to their strong inhibition of everolimus metabolism, therefore 
leading to higher everolimus exposure. Therefore, topical antifungal agents are preferred if a 
fungal infection is diagnosed.
6.2.3.3
Management of hyperlipidemia and hyperglycemia
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) 
or grade 2 hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 
3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, 
fluvastatin) or appropriate triglyceride-lowering medication, in addition to diet.
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy should 


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be determined for individual patients based on their risk of cardiovascular complications of 
hyperlipidemia.
Hyperglycemia has been reported in patients taking everolimus. Monitoring of fasting serum 
glucose is recommended prior to the start of study drug and periodically thereafter. More 
frequent monitoring is recommended when everolimus is co-administered with other drugs 
that may induce hyperglycemia.
6.2.3.4
Management of renal failure events
Cases of renal failure (including acute renal failure), some with a fatal outcome, have been 
observed in patients treated with everolimus. Renal function of patients should be monitored 
particularly where patients have additional risk factors that may further impair renal function.
Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary 
protein, and serum creatinine, is recommended prior to the start of study drug and periodically 
thereafter.
6.2.3.5
Management of non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus. Some of these have been severe and on rare occasions, a fatal outcome was 
observed.
A diagnosis of non-infectious pneumonitis should be considered in patients presenting with 
non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or 
dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have been 
excluded by means of appropriate investigations. Opportunistic infections such as PJP should 
be ruled out in the differential diagnosis of non-infectious pneumonitis. Patients should be 
advised to report promptly any new or worsening respiratory symptoms. 
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have 
few or no symptoms may continue everolimus therapy without dose alteration.
If symptoms are moderate (grade 2), consideration should be given to interruption of therapy 
until symptoms improve. The use of corticosteroids may be indicated. Everolimus may be 
reintroduced at a daily dose approximately 50% lower than the dose previously administered.
For cases of grade 3 non-infectious pneumonitis, interrupt everolimus until resolution to less 
than or equal to grade 1. Everolimus may be re-initiated at a daily dose approximately 50% 
lower than the dose previously administered depending on the individual clinical 
circumstances. If toxicity recurs at grade 3, consider discontinuation of everolimus. For cases 
of grade 4 noninfectious pneumonitis, everolimus therapy should be discontinued. 
Corticosteroids may be indicated until clinical symptoms resolve.
For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, 
prophylaxis for PJP may be considered.
Individuals participating in this study will be routinely questioned as to the presence of new or 
changed pulmonary symptoms consistent with lung toxicity. Moreover, potential lung 
radiological changes can be detected by the chest CT/MRI scans that are performed on all 


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patients with LAM for tumor assessment according to the schedule of events (Table 7-1). In 
addition, pulmonary function tests (PFTs), including spirometry, DLCO, and room air O2
saturation at rest should be performed. Bronchoscopy with biopsy and/or bronchoalveolar 
lavage (BAL), should be conducted, if clinically indicated, to monitor for pneumonitis. If non-
infectious pneumonitis develops, the guidelines in Table 6-3 should be followed. Consultation 
with a pulmonologist is recommended for any case of pneumonitis that develops during the 
study.
6.3
Concomitant medications
Concomitant medications and therapies for adverse events or supportive treatments are
permitted. Some medications may however have drug-drug interactions with everolimus and 
the guidelines below should be followed.
In clinical studies and post-marketing spontaneous reports, angioedema has been reported 
with and without concomitant use of angiotensin-converting-enzyme (ACE) inhibitors. The 
risk of angioedema events may be increased with concomitant administration of ACE 
inhibitors. 
Cytochrome P450 and P-glycoprotein (PgP) inhibitors/inducers/substrates
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall.
Therefore, the following are recommended:

Co-administration with strong inhibitors of CYP3A4/PgP should be avoided and may 
cause increased everolimus concentrations.

Co-administration with moderate CYP3A4/PgP inhibitors should be used with caution. If 
a patient requires co-administration of moderate CYP3A4/PgP inhibitors, reduce the dose 
of study drug to half the currently used dose. Additional dose reductions may be required 
to manage toxicities. If the inhibitor is discontinued, consider a washout period of at least 
2-3 days (average for the most commonly used moderate inhibitors), before the study drug 
dose is returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor.

Co-administration with strong inducers of CYP3A4 should be avoided. 

If a patient requires co-administration of strong CYP3A4 inducer, an increase in the dose 
of study drug up to twice the currently used daily dose should be considered, using 5 mg 
increments or less. This dose adjustment of study drug is predicted to achieve similar 
AUC to the range observed without inducers. However, there are no clinical data with this 
dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is 
discontinued, consider a washout period of at least 3-5 days (reasonable time for 
significant enzyme de-induction), before the study drug dose is returned to the dose used 
prior to initiation of the strong CYP3A4/PgP inducer.
Please refer to Table 6-5 listing relevant inducers and inhibitors of CYP3A and to Table 6-6
for a list of relevant substrates, inducers, and inhibitors of PgP.


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Table 6-5
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A4
Inducers
Strong inducers:
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort (HYPERICUM PERFORATUM), rifabutin, 
phenobarbital, mitotane, enzalutamide 
Moderate inducers:
bosentan, efavirenz, etravirine, modafinil, nafcillin, genistein, ritonavir, thioridazine, tipranavir, semagacestat, 
talviraline, lopinavir, lersivirine, 
Weak inducers:
amprenavir, aprepitant, armodafinil bexarotene, clobazam, danshen5, dexamethasone, echinacea, gingko (ginkgo 
biloba), glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone, prednisone, pleconaril, 
primidone, raltegravir, rufinamide, sorafenib, telaprevir, terbinafine, topiramate, troglitazone, vinblastine, 
eslicarbazepine, ginseng, vemurafenib, boceprevir, sulfinpyrazone, ticagleror, vicriviroc/ritonavir, ritonavir, 
ticlopidine, brivacetam, stribild (combo of elvitegravir, cobicistat, emtricitabine, and tenofovir), quercetin. honey,yin 
zhi huang
Inhibitors
Strong inhibitors:
VIEKIRA PAK, indinavir/ritonavir, tipranavir/ritonavir, ritonavir, cobicistat (GS-9350) ,indinavir, ketoconazole, 
troleandomycin, telaprevir, danoprevir/ritonavir, elvitegravir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir, 
itraconazole, voriconazole,mibefradil, LCL161, clarithromycin, posaconazole, telithromycin, grapefruit juice, 
conivaptan, nefazodone, nelfinavir, saquinavir, idelalisib, boceprevir, darunavir/ritonavir 
Moderate inhibitors:
Erythromycin, fluconazole, darunavir, diltiazem, dronedarone, crizotinib, atazanavir, aprepitant, casopitant, 
amprenavir, faldaprevir, imatinib, verapamil, netupitant, nilotinib, tofisopam, cyclosporine, ACT-178882, 
ciprofloxacin, schisandra, sphenanthera, isavuconazole, cimetidine, FK1706Ferula asafetida resin (Ferula assa-
foetida) 
Weak inhibitors:
Tabimorelin, ranolazine, amlodipine,lomitapide, fosaprepitant (IV), Seville orange juice, amiodarone, 
chlorzoxazone, M100240, fluvoxamine8, ranitidine, fostamatinib, goldenseal, clotrimazole, tacrolimus, palbociclib, 
cilostazol, ticagrelor, peppermint oil, ivacaftor, GSK2248761, Guan Mai Ning, AZD2327, resveratrol, 
roxithromycin, suvorexant, propiverine, isoniazid, berberine, oral contraceptives, delavirdine, daclatasvir, 
simeprevir, atorvastatin, tolvaptan, almorexant, GSK1292263, evacetrapid, linagliptin, lacidipine, cranberry juice, 
pazopanib, everolimus, blueberry juice, AMD070, alprazolam, Tong Xin Luo, bicalutamide, sitaxentan, 
azithromycin, ginkgo, teriflunomide, Garden Cress seeds (Lepidium sativum)
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated May2016  which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the University of Washington’s Drug Interaction Database, and Indiana University School of Medicine's Drug 
Interaction Table.
Table 6-6
PgP substrates, inducers, inhibitors 
Category
NTI substrates of P-gp1:
digoxin, quinidine, paclitaxel, cyclosporine, sirolimus, tacrolimus, fentanyl, phenytoin 
Substrates of Pgp (≥2X AUC change)2
aliskiren, ambrisentan, atorvastatin, atorvastatin acid, azithromycin, cerivastatin, colchicine, CP-481,715, 
cyclosporine, dabigatran, digoxin, docetaxel, domperidone, doxorubicin, fentanyl, fexofenadine, lapatinib, linezolid, 
loperamide, maraviroc, nevirapine, paclitaxel, proguanil, quinidine, ranolazine, ritonavir, saquinavir, simvastatin, 
sirolimus, sofosbuvir, tacrolimus, ticagrelor, topotecan, voclosporin
Substrates of Pgp mentioned in US label3


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afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, aprepitant, boceprevir, bosentan, 
carvedilol, carvedilol, caspofungin, ceritinib, citalopram, colchicine, cyclosporine, dabigatran, digoxin, doxepin, 
doxorubicin, eribulin, everolimus, fidaxomicin, fluvastatin, fosamprenavir, gatifloxacin, idelalisib, iloperidone, 
indacaterol, irbesartan, lacosamide, lapatinib, levetiracetam, levofloxacin, linagliptin, losartan, maraviroc, 
mirabegron, moxifloxacin, naloxegol, nateglinide, nintedanib, olodaterol, pantoprazole, paroxetine, pazopanib, 
posaconazole, pravastatin, quinine, ranolazine, riociguat, risperidone, rivaroxaban, saquinavir, silodosin, 
simeprevir, sirolimus, sitagliptin, sorafenib, telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, vincristine, voriconazole
P-gp Inhibitors
alogliptin, amiodarone4, azithromycin, canaglifozin, captopril, carvedilol, clarithromycin, clopidrogel, conivaptan, 
cremophor RH0, curcumin, diltiazem, dronedarone, elacridar, eliglustat, erythromycin, felodipine, fluvoxamine, 
fostamatinib, ginko, indinavir, isavuconazole, itraconazole, ivacaftor, ketoconazole, lapatinib, lopinavir, mibefradil, 
milk thistle (silymarin, silibinin), mirabegron, nelfinavir, nifedipine, nitredipine,ombitasvir, paritaprevir, paroxetine, 
propafenone, quercetin, quinidine, quinine, ranolazine, rifampin, ritonavir, sequinavir, schisandra chinesis extract, 
simepravir, St. John’s wort extract (HYPERICUM PERFORATUM), survorexant, talinolol, telaprevir, telmisartan, 
ticagrelor, tipranavir, tolvaptan, valspodar, vandetanib, verapamil, voclosporin, vorapaxar. 
P-gp Inducers
avasimibe, carbamazepine, danshen (Salvia miltiorhiza), efavirenz, genistein2, phenytoin, quercetin2, rifampin, St. 
Johns wort extract. garlic extract 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated May2016  which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the University of Washington’s Drug Interaction Database, and Indiana University School of Medicine's Drug 
Interaction Table.
1 These drugs have both a narrow therapeutic index and an in vivo DDI outcome ascribed at least in part ascribed 
to Pgp (inhibition or induction) that exceeds a 20% change in AUC. 
2 These drugs have in vivo DDI outcomes (inhibition) which are ≥2x increase in AUC and are at least in part 
ascribed to Pgp.
3 The US labels for these drugs have specific language on in vivo Pgp substrate status.
4 Dual P-gp and CYP3A4 inhibitor
Vaccinations
Immunosuppressants may affect the response to vaccination and vaccination during treatment 
with everolimus may therefore be less effective. The use of live vaccines should be avoided 
during treatment with everolimus. 
Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella, and TY21a typhoid vaccines.
Other prohibited concomitant therapy
Patients may not take any other mTOR inhibitors or other investigational treatments while on 
study treatment.
6.4
Patient numbering and treatment assignment 
6.4.1
Patient numbering
Each patient is identified in the study by a 7 digit subject number, that is assigned when the 
patient is first enrolled for screening and is retained as the primary identifier for the patient
throughout his/her entire participation in the trial. The subject number consists of the 4-digit 
center number (as assigned by Novartis to the investigative site) with a 3-digit sequential 
patient number suffixed to it, so that each subject is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient will be assigned the next 


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available sequential patient number by the investigator or designee. Once assigned to a patient, 
a patient number will not be reused. If a patient fails screening and is re-screened a new 7 
digit subject number will be assigned.  If after signing the informed consent, it is determined 
that the patient does not qualify for the study, reason(s) will be entered on the disposition CRF
and Novartis notified.
6.4.2
Treatment assignment
All patients who fulfill all inclusion/exclusion criteria will start receiving study treatment with 
Afinitor®. The investigator will assign patients to the 10 mg, 7.5 mg, or 5 mg O.D. Afinitor®
dose depending on their hepatic function (no liver impairment, Child-Pugh grade A, Child-
Pugh grade B).
6.4.3
Treatment blinding
Not applicable.
6.5
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Study Treatment CRF.
Table 6-7
Preparation and dispensing
Study treatment
Dispensing
Preparation
RAD001 (everolimus)
Afinitor® tablets including instructions for administration are dispensed by 
study personnel on an outpatient basis.
Patients will be provided with adequate supply of study treatment for self-
administration at home until at least their next scheduled study visit.
Not 
applicable
6.5.1
Study treatment packaging and labeling
Study treatment, Afinitor®, will be sourced as local commercial supply (in the locally 
approved formulation and packaging configuration) and re-labeled as study drug. Study 
treatment labels will comply with the legal requirements in China and will include storage 
conditions, a unique medication number (corresponding to strength).
Table 6-8
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
RAD001 (everolimus)
Tablets in blister
Labeled as ‘Afinitor®/RAD001/everolimus’
Study treatment packaging has a 2-part label. A unique medication 
number is printed on each part of this label.
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug label.


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6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. The Afinitor® dose that each patient is taking will be recorded on the 
Study Treatment CRF. This information must also be captured in the source document at each 
patient visit.
The investigator and/or assigned study personnel will also collect any information about 
concomitant medications and non-drug therapies at each patient visit and enter it on the 
‘Concomitant Medication / Non-drug Therapies’ CRF page.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. If study medication is to be destroyed by a third party or at the 
investigational site this must be approved by the sponsor and destruction certificates must be 
provided.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation.
The table indicates which assessments produce data to be entered into the clinical database (D) 
or remain in source documents only (S) (“Category” column). No CRF will be used as a 
source document. 
Allowed visit windows are specified as follows: 

Screening assessments as listed in Table 7-1 should occur within 28 days prior to Day 1. 

The 4, 12, 24, and 48 weeks visits should be performed within a ± 7 day window.


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
The 12, 24, and 48 weeks efficacy follow-up visits, where applicable, should be performed 
within a ± 7 day window. 

Urine pregnancy tests (when applicable) should be performed every 4 weeks during the 
treatment phase within a ± 7 day window. 

The End of Treatment (EOT) visit should be performed within 28 days of last dose.

All patients should be followed for at least 30 days for AEs and SAEs after last dose.
Every effort should be made to follow the schedule outlined in Table 7-1.


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Section 
Screening
Open Label Treatment
Treatment 
Discontin
uation 
Follow-up
Visit Name
Screening
Day 1
Week 4
Week 12
Week 24
Week 48
Every 4 
weeks after 
Week 4 until 
EOT
End of study 
treatment 
(EOT)
Safety 
follow-up
(Last 
dose
+30days)
Efficacy 
follow-up
(Week 12, 
24, 48)
Visit number
1
100
110
120
130
140
1999
1010,1020
,1030
Visit window 
-28 to -1 
days
±7days
±7days
±7days
±7days
±7days
Within 28 
days from 
last dose
+7 days
±7days
Obtain Informed 
Consent
D
11.3
X
Demography
D
7.1.2.3
X
Inclusion/exclusion 
criteria
D
5.2
5.3
X
X
TSC diagnosis
D
7.1.2
X
Relevant medical 
history 
D
7.1.2.3 
X
HIV history
S
7.1.2.3 
X
Prior/concomitant 
medications
D
7.1.2.3
X
X
X
X
X
X
X
X
Physical 
examination
S
7.2.2.1 
X
X
X
X
X
X
X
WHO Performance 
status
D
7.2.2.4  
X
X
X
X
X
X
X
Height 
D
7.2.2.3 
X
Weight
D
7.2.2.3 
X
X
X
X
X
X
X


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Category
Protocol 
Section 
Screening
Open Label Treatment
Treatment 
Discontin
uation 
Follow-up
Visit Name
Screening
Day 1
Week 4
Week 12
Week 24
Week 48
Every 4 
weeks after 
Week 4 until 
EOT
End of study 
treatment 
(EOT)
Safety 
follow-up
(Last 
dose
+30days)
Efficacy 
follow-up
(Week 12, 
24, 48)
Visit number
1
100
110
120
130
140
1999
1010,1020
,1030
Visit window 
-28 to -1 
days
±7days
±7days
±7days
±7days
±7days
Within 28 
days from 
last dose
+7 days
±7days
Vital signs
D
7.2.2.2 
X
X
X
X
X
X
X
Hematology
D
7.2.2.5 
X
X
X
X
X
X
X
Biochemistry
D
7.2.2.5
X
X
X
X
X
X
X
Coagulation
D
7.2.2.5 
X
If clinically indicated
If clinically 
indicated
Pulmonary function 
tests (FEV1, 
DLCO) for LAM 
patients only
D
7.2.2.6 
X
X
X
X
X
Blood gas analysis 
(O2 saturation) for 
LAM patients only
D
7.2.2.6 
X
X
X
X
X
HCV-RNA, HBV-
DNA, HBsAg, HBs-
Ab, HBc-Ab
D
7.1.2 
X
Urinalysis
D
7.2.2.5 
X
X
X
X
X
X
X
ECG
D
7.1.2
X
If clinically indicated
Serum pregnancy 
test 
D
7.1.2.3 
X
X


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Category
Protocol 
Section 
Screening
Open Label Treatment
Treatment 
Discontin
uation 
Follow-up
Visit Name
Screening
Day 1
Week 4
Week 12
Week 24
Week 48
Every 4 
weeks after 
Week 4 until 
EOT
End of study 
treatment 
(EOT)
Safety 
follow-up
(Last 
dose
+30days)
Efficacy 
follow-up
(Week 12, 
24, 48)
Visit number
1
100
110
120
130
140
1999
1010,1020
,1030
Visit window 
-28 to -1 
days
±7days
±7days
±7days
±7days
±7days
Within 28 
days from 
last dose
+7 days
±7days
Urine pregnancy 
test
S
7.2.2.5.5 
X
X
X
X
X
X
Abdomen and 
pelvis CT/MRI
D
7.2.1 
X
X
X
X
X
X
Brain MRI/CT
D
7.2.1 
X
If clinically indicated
If clinically 
indicated
If clinically 
indicated
Chest CT
D
7.2.1 
If clinically 
indicated
If clinically indicated
If clinically 
indicated
If clinically 
indicated
Digital 
photography of 
skin lesions 
D
7.2.1 
If present
If identified at screening
If identified 
at screening
If identified 
at 
screening
Adverse events
D
8.1 
X
X
X
X
X
X
X
X
Serious adverse 
events
D
8.2 
X
X
X
X
X
X
X
X
Study Drug 
administration 
D
6.1.1 
X
X
X
X
X
X
End of phase 
Disposition
D
X
X


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Category
Protocol 
Section 
Screening
Open Label Treatment
Treatment 
Discontin
uation 
Follow-up
Visit Name
Screening
Day 1
Week 4
Week 12
Week 24
Week 48
Every 4 
weeks after 
Week 4 until 
EOT
End of study 
treatment 
(EOT)
Safety 
follow-up
(Last 
dose
+30days)
Efficacy 
follow-up
(Week 12, 
24, 48)
Visit number
1
100
110
120
130
140
1999
1010,1020
,1030
Visit window 
-28 to -1 
days
±7days
±7days
±7days
±7days
±7days
Within 28 
days from 
last dose
+7 days
±7days
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
X
X
X


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7.1.1
Molecular pre-screening 
Molecular pre-screening is not required to fulfill the inclusion criteria. If patients have 
undergone genetic testing for TSC in the course of their routine care this information can be 
used to confirm the TSC diagnosis (refer to Table 7-2).
7.1.2
Screening
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to Day 1 (see Table 7-1 for list of assessments to be performed). All inclusion and exclusion 
criteria will be evaluated and the investigator verifies that all patients have a clinically definite 
diagnosis of TSC according to the criteria described below. 
Clinically definite diagnosis of TSC
All patients should have a clinically definite diagnosis of TSC according to the updated 
diagnostic criteria for TSC 2012 (Holpe Northrup, Darcy A. Krueger on behalf of the 
international TSC consensus (Hyman 2013) to be eligible. Clinically definite diagnosis of 
tuberous sclerosis according to the updated criteria is defined as either of the following:

Two major features or one major feature with ≥2 minor features from Table 7-2.

Genetic diagnostic criteria: The identification of either a TSC1 or TSC2 pathogenic 
mutation in DNA from normal tissue is sufficient to make a definite diagnosis of TSC. A 
pathogenic mutation is defined as a mutation that clearly inactivates the function of the 
TSC1 or TSC2 proteins, prevents protein synthesis, or is a missense mutation whose effect 
on protein function has been established by functional assessment. Other TSC1 or TSC2 
variants whose effect on function is less certain do not meet these criteria, and are not 
sufficient to make a definite diagnosis of TSC.
Note: In this study TSC genetic testing is not mandated. Patients who don't meet criteria in 
Table 7-2 can be regarded as fulfilling TSC diagnosis criteria if previous TSC1 or TSC2 
pathogenic mutation is documented in medical history.
Table 7-2
Diagnostic criteria for Tuberous Sclerosis Complex
Major Features
1. Hypomelanotic macules (≥3, at least 5-mm diameter)
2. Angiofibromas (≥3) or fibrous cephalic plaque
3. Ungual fibromas (≥2)
4. Shagreen patch
5. Multiple retinal hamartomas
6. Cortical dysplasiasa
7. Subependymal nodules
8. Subependymal giant cell astrocytoma
9. Cardiac rhabdomyoma
10. Lymphangioleiomyomatosis (LAM) b
11. Angiomyolipomas (≥2) b


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Minor Features
1. “Confetti” skin lesions
2. Dental enamel pits (>3)
3. Intraoral fibromas (_2)
4. Retinal achromic patch
5. Multiple renal cysts
6. Nonrenal hamartomas
a Includes tubers and cerebral white matter radial migration lines.
b A combination of the two major clinical features (LAM and angiomyolipoma) without other features does not 
meet criteria for a definite diagnosis.
Screening for hepatitis B and C
At screening all patients have to be tested for hepatitis B viral load and serologic markers, that 
is, HBV-DNA, HBsAg, HBs Ab, and HBc Ab. Additionally, all patients have to be tested for 
hepatitis C using quantitative RNA-PCR.
Please note that patients who test negative for HBV-DNA, HBsAg, and HBcAb but positive 
for HBs Ab, due to prior history of vaccination against Hepatitis B will be eligible. The fact 
that the patient had been vaccinated should be entered into the patient’s Medical History CRF.
Patients with serological markers indicative of chronic hepatitis B infection or measurable 
hepatitis C RNA will be excluded from the study.
Electrocardiogram (ECG)
A standard 12-lead ECG is to be performed at screening. Tracings must be dated and signed 
by the investigator (or his/her designee) and filed with the subject’s source documentation. 
Results from 12-lead ECG should be captured on the ECG Evaluation CRF. Significant 
findings must be recorded as Relevant Medical History. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically 
significant findings should be collected in triplicate. ECG assessments may also be performed 
at any time during the study at the discretion of the investigator.
Paper ECGs should be labeled with the study number, patient initials (where regulations 
permit), patient number, date and time and be kept in the source documents at the study site.
Rescreening
Reassessment of any screening criteria is permitted once for previously screen failed patients.
In this case the Subject Number assigned to the patient will not be used and the patient will be 
assigned a new 7 digit subject number. If the patient has been enrolled and treated, re-
screening of the patient is not allowed.
In case rescreening occurs, all evaluations re-assessed should meet the eligibility criteria. A 
new informed consent form must be signed only if there is an interruption in the patient’s 
eligibility evaluation and the investigator chooses to re-screen the patient following screen 
failure; the 28 day screen period does not apply to the informed consent process. If a new 
informed consent form is signed, AEs and medical history will be assessed relative to the new 


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informed consent date. Patients who did not have the required AML lesion size would need to 
wait at least 3 months before re-screening. For laboratory evaluations used to determine 
eligibility, a repeated evaluation within the screening window is permitted for screening 
results out of the defined range before screen failing the patient. If the repeated laboratory 
result meets the criteria, that result may be used to determine eligibility. If the repeated 
laboratory result does not meet the criteria, the patient will be considered a screening failure. 
For details of assessments see Table 7-1.
7.1.2.1
Eligibility screening 
The investigator is responsible to ensure only subjects who meet all inclusion and do not meet 
any exclusion criteria are included in the study.
7.1.2.2
Information to be collected on screening failures
Subjects who signed an Informed Consent Form but failed to be started on treatment for any 
reason will be considered screen failures. Subjects who are found not eligible after signing the 
study consent will also be considered as screening failures. The screening failure will be 
entered on the Disposition Page.
The subject ID, visit date, subject status-screening, demographic information, informed 
consent, Inclusion/Exclusion and Disposition pages must also be completed for Screen Failure 
subjects. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced a Serious Adverse Event during the Screening Phase 
(see Section 8 for SAE reporting details). If a screen failure patient experiences an AE which 
does not meet the SAE criteria, details about the AE will be recorded only in the 
investigator’s source documents. In case of an SAE after signing of main study informed 
consent, data must be recorded on both the AE and SAE forms.
7.1.2.3
Patient demographics and other baseline characteristics
During the Screening visit data will be collected on patient characteristics including 
demographic information (age, sex, race) and other background or relevant medical history 
(TSC diagnosis, prior anti-angiomyolipoma and TSC therapies), hepatitis and HIV history and 
any other assessments that are done for the purpose of determining eligibility for inclusion in 
the study (i.e. complete physical examination, height, weight, vital signs, WHO performance 
status, hematology, blood chemistries including coagulation and a serum lipid profile, 
urinalysis, CT/MRI of abdomen and pelvis, MRI/CT of brain, CT of chest (for patients with 
lymphangioleiomyomatosis), and ECG). 
A serum pregnancy test must be completed for all female patients of child bearing potential 
within 28 days of Day 1 and a urine pregnancy test follow-up on Day 1 (prior to first dosing)
to confirm eligibility. 
The results of urine pregnancy tests will only be recorded in the patient source documents
(pregnancy diary, patient records) whereas serum pregnancy test results will be recorded in 
the database of the assigned central lab vendor.
Prior and current concomitant medication use will also be collected and recorded. 


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For further details on eligibility assessments, please see Table 7-1.
Baseline assessments of kidney AML
A CT/MRI assessment of the kidneys will be performed for all patients at baseline to confirm 
presence of at least one angiomyolipoma lesion with longest diameter ≥ 3.0 cm. The CT/MRI 
images will be sent to the independent radiology service for measuring of kidney tumor 
volume at each time point. For information regarding the scan acquisition protocol, please 
refer to the Independent Radiology Review Charter provided by the assigned Imaging Vendor. 
The presence or absence of polycystic kidney disease will also be documented by the central 
reviewer.
A MRI/CT of the brain will be performed at baseline to identify any SEGA lesions. These 
images will be centrally collected and held with no independent assessment.
7.1.3
Treatment period
Patients will receive the first dose of study drug on Day 1 and continue to be treated per 
protocol until documentation of angiomyolipoma progression, unacceptable toxicity, 
pregnancy, withdrawal of consent or investigator decision to stop the study. However, study 
treatment may prematurely be discontinued for other reasons as well; please refer to Section 
7.1.4. The maximum treatment duration is 48 weeks. Patients will visit the investigator site 4, 
12, 24, and 48 weeks from Day 1 (±7days) and be followed as per the schedule of assessments. 
At these visits sufficient study drug will be dispensed to the patients to last until the next 
scheduled visit and unused drug will be returned to the site. Compliance will be assessed by 
the investigator and/or study personnel at each visit using pill counts and information 
provided by the patient or caregiver. This information should be captured in the source 
document at each visit.
7.1.4
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If
a patient decides to discontinue from the study treatment, the investigator should make a  
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for
visits, or become lost to follow-up for any other reason.
The investigator may discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being.
In addition to mandatory discontinuation reasons for study treatment listed in Section 6.2, 
study treatment must also be discontinued under the following circumstances:

Pregnancy

Death

Subject/Guardian decision

Adjustments to study treatment due to toxicity that result in treatment discontinuation 
(see Section 6.2)

Any other protocol deviation that results in a significant risk to the patient’s safety. 


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Patients who discontinue study treatment should NOT be considered withdrawn from the
study. They should return for the assessments indicated in Section 7.2.1. If they fail to return
for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) should
be made to contact them as specified in Section 7.1.7.
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, kidney lesion assessments must continue to 
be performed as per the schedule of assessments until documented disease progression (per 
independent radiology review), death, lost to follow-up, or withdrawal of consent.
7.1.4.1
Replacement policy
Not applicable.
7.1.5
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
All biological samples not yet analyzed at the time of withdrawal will no longer be used, 
unless permitted by applicable law. They will be stored according to applicable legal 
requirements.
7.1.6
Follow up for safety evaluations
All patients must have safety evaluations for 30 days after the last dose of study treatment.
Safety information can be collected during a visit to the site or per telephone.
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
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7.1.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Each center must have a designated radiologist or other physician who is responsible for the 
interpretation of CT scan or multiphase MRI. The same radiologist/physician should perform 
the evaluation for the entire duration of the study. All radiology evaluations will be performed 
initially by the local radiologist, but designation of AML response and progression will be 
based only on the evaluations made by the Independent Central Radiology Review. The 
results of the central evaluations will be used for analysis purposes. 
CT/MRIs of the kidneys and brain must be digitized and sent to central radiology within 2 
business days of the scan date. Following receipt of each scan, the Independent Central 
Radiology Review will be completed and the results of the kidney lesion assessments will be 
communicated back to the participating center and to Novartis. Details of the central review 
process will be described in the independent review charter developed between Novartis and 
the assigned imaging vendor.
Although the study will use an Independent Central Radiology Review to measure tumor 
volume, the decision to enroll the patient will be made based on the judgment of the 
investigator and local radiologist. The vendor will not decide whether patients should be 
removed from study treatment. This decision remains solely with the investigator.
Screening imaging assessments
Imaging assessments will be performed at screening within 28 days of start of treatment (Day 
-28 to Day -1 prior to Day 1).
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after 
treatment start cannot be considered baseline images. The same imaging modality that was 
performed at screening should be used for all assessments throughout the course of the study.
The following assessments are required at screening (see imaging collection plan, Table 7-3):

Kidney (abdomen and pelvis)
Preferred modalities: CT or MRI with contrast medium. 
If intravenous injection of either CT or MRI contrast medium is not tolerated by the 
patient the respective other modality with contrast medium should be performed. In case 
of intolerance to both CT and MRI contrast media it is accepted to perform MRI without 


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contrast. CT without contrast medium is not a recommended modality but accepted if 
none of the other modalities can be performed.
For instructions regarding screening assessments of angiomyolipoma lesions, please refer 
to Section 7.1.2.3.

Brain
A brain scan should be completed at screening to identify if any SEGA lesions are present.
Preferred modality: MRI with contrast medium.
If MRI contrast medium is not tolerated a contrast enhanced CT or MRI/CT without 
contrast are acceptable.

Lung (thorax)
A thorax scan at screening is only required if clinically indicated for patients with LAM.
Preferred modality: CT with contrast medium.
If a patient is known to have a contraindication to intravenous CT contrast media or 
develops a contraindication during the trial, a non-contrast CT can be performed. MRI is 
not recommended due to respiratory artifacts, however if CT is not feasible per local 
regulations, MRI can be performed instead.

Skin lesions
If skin lesions are present at screening, digital color photographs should be taken using a 
high resolution digital camera (≥3 megapixels) in clear focus, including a caliper, scale or 
ruler, in such a way that the size of the lesion(s) can be determined from the photograph.
Imaging assessments during treatment and treatment discontinuation follow-
up phase
Imaging assessments as described in Table 7-3 should be performed using the same imaging 
modality used at screening, irrespective of study treatment interruption or actual dosing (see 
Table 7-1). Imaging assessments for response evaluation will be performed 12, 24, and 48 
weeks after start of treatment and at End of Treatment. The End of Treatment assessments can
be omitted if the most recent assessment was done less than 8 weeks ago. Imaging 
assessments should be scheduled using the treatment start date as the reference date, and 
should be respected regardless of whether treatment with study treatment is temporarily 
withheld or unscheduled assessments performed.
Table 7-3
Imaging collection plan
Procedure (see below for the 
preferred imaging modalities, 
requirements to use contrast 
medium)
Screening
”Open-Label treatment” phase and ”Treatment 
Discontinuation Follow-up” phase where applicable
Abdomen and pelvis CT or MRI 
(pelvis only if required due to kidney 
size)
Mandated
Mandated at 12, 24, 48 weeks and at EOT
Brain MRI or CT
Mandated
Mandated at 12, 24, 48 weeks and EOT if SEGA lesion 
with longest diameter ≥1cm present at screening
Chest CT
If clinically 
indicated
At 12, 24, 48 weeks and EOT if clinically indicated
Digital photography of skin lesions
If skin lesions 
present
Mandated at 12, 24, 48 weeks and EOT if skin lesions 
present at screening


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The preferred and allowed radiological imaging modalities are the same as at screening.

Kidney (abdomen and pelvis)
Preferred modalities: CT or MRI with contrast medium. 
If intravenous injection of either CT or MRI contrast medium is not tolerated by the 
patient the respective other modality with contrast medium should be performed. In case 
of intolerance to both CT and MRI contrast media it is accepted to perform MRI without 
contrast. CT without contrast medium is not a recommended modality but accepted if 
none of the other modalities can be performed.

Brain
Preferred modality: MRI with contrast medium.
If MRI contrast medium is not tolerated a contrast enhanced CT or MRI/CT without 
contrast are acceptable.

Lung (thorax), only performed if clinically indicated for LAM patients
Preferred modality: CT with contrast medium.
If a patient is intolerant to intravenous CT contrast media or develops a contraindication 
during the trial, a non-contrast CT can be performed. MRI is not recommended due to 
respiratory artifacts, however if CT is not feasible per local regulations, MRI can be 
performed instead.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment.
All study kidney imaging (including any off-schedule imaging studies) should be submitted to 
the designated imaging CRO for quality control and volumetric measurement of AML lesions.
Brain MRI/CT images, chest CT scans and digital photographs of skin lesions (including any 
off-schedule imaging studies) should be sent to the designated imaging CRO for quality 
control and archiving. Any chest CT scans, brain imaging and photographs of skin lesions 
should be evaluated by the local radiologist/physician as per standard care.
All patients being discontinued from the study for angiomyolipoma progression must have 
their progression documented using the criteria specified in Section 7.2.1.1. In particular, a 
discontinuation reason of “angiomyolipoma progression” will not be sufficient to establish 
that angiomyolipoma progression actually occurred.
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be 
performed as per imaging collection plan (Table 7-3) until documented disease progression 
(per central radiology), end of study (week 48), death, lost to follow-up, or withdrawal of 
consent.
7.2.1.1
Angiomyolipoma response evaluation
Angiomyolipoma response and progression evaluation will be performed according to the 
criteria outlined below.


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Screening requirement:
At baseline, all measurable angiomyolipomata with longest diameter ≥ 1.0 cm should be 
identified from each kidney. Only patients with at least one angiomyolipoma ≥ 3.0 cm in 
longest diameter will be eligible to be randomized into the trial. All baseline evaluations 
should be performed as close as possible to the beginning of treatment and never more than 28
days before the beginning of treatment. The same imaging modality must be used throughout 
the trial.
Target lesions:
Up to five of the largest measurable lesions on each kidney seen at screening should be 
identified as target angiomyolipoma, where measurable means at least 1.0 cm in longest 
diameter. The volume of these lesions will be measured at each kidney CT/MRI assessment 
during the trial. The same imaging modality must be used throughout the trial. 
Angiomyolipoma volume is defined as the sum of the volumes of the individual target 
angiomyolipoma, and it is angiomyolipoma volume that is used directly in the definition of 
angiomyolipoma response and angiomyolipoma progression.
Kidney volume:
All other angiomyolipoma (i.e., lesions other than the target angiomyolipoma as defined 
above) present at screening are non-target angiomyolipoma. In some cases there may be many 
non-target angiomyolipoma (e.g., >20), including non-measurable lesions (i.e., with longest 
diameter <1.0 cm). Instead of attempting to individually assess each non-target 
angiomyolipoma during the trial, the volume of each kidney will be measured. Increases in 
the volume of either kidney will then be taken as evidence of worsening angiomyolipoma. 
This is expected to be particularly useful when target angiomyolipoma are relatively stable, 
but non-target angiomyolipoma are clearly progressing.
Angiomyolipoma response assessment:
Angiomyolipoma response will be defined as:

a reduction in angiomyolipoma volume of at least 50% relative to screening, where 
angiomyolipoma volume is the sum of the volumes of all target angiomyolipoma 
identified at screening.
In addition, angiomyolipoma response requires satisfying all of the following criteria:

no new angiomyolipoma ≥ 1.0 cm in longest diameter are identified

neither kidney increases in volume by more than 20% from nadir (where nadir is the 
lowest kidney volume obtained for the patient, separately for each kidney, previously in 
the trial including screening)

the patient does not have any angiomyolipoma-related bleeding of grade ≥2 (as defined by 
NCI CTCAE, version 4.03).
Angiomyolipoma progression will be defined as one or more of the following:

an increase from nadir of 25% or more in angiomyolipoma volume to a value greater than 
screening (where angiomyolipoma volume is the sum of the volumes of all target 


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angiomyolipoma identified at screening and where nadir is the lowest angiomyolipoma 
volume achieved by the patient previously in the trial (including screening))

the appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter

an increase from nadir of 20% or more in the volume of either kidney to a value greater 
than screening, where nadir is the lowest kidney volume obtained for the patient, 
separately for each kidney, previously in the trial (including screening)

angiomyolipoma-related bleeding grade ≥2 as defined by NCI CTCAE, version 4.03.
Note: In some instances, disease that is measurable as a target lesion at screening and appears 
to be one mass can split to become two or more smaller sub-lesions. When this occurs, the 
image review system allows the central reviewer to identify the separate sub-lesions as unique 
and non-overlapping so that the volume of each sub-lesion can be determined. The combined 
volumes of the sub-lesions will be reported as the volume of the lesion that has split. The 
individual split lesions will not be considered as new lesions, and will not automatically 
trigger an angiomyolipoma progression.
Conversely, it is also possible that two or more lesions which were distinctly separate at 
screening become confluent at subsequent visits. The central reviewer will be required to 
separate the confluent mass into regions relating to the original several distinct lesions. These 
regions will continue to be measured as separate lesions. Although this raises the possibility 
of increased variability in the measurements of the individual lesions due to the lack of 
distinct borders within the confluent mass, the primary endpoint (sum of lesion volumes) will 
still be accurately measured so long as the confluent mass itself has distinguishable borders.
7.2.1.2
SEGA evaluation
SEGA lesions
should be assessed as per local standard practice by the site
radiologist/physician at the scheduled time points (week 12, 24, 48, EOT). 
In the unlikely event that a patient has SEGA lesion progression and does not meet the criteria 
for angiomyolipoma progression, it will be up to the investigator to determine if the patient 
should remain on study or be discontinued.
SEGA response assessment
The SEGA response assessment is not part of the efficacy assessments in this study and is not 
required. However, since clinical decisions may have to be made on SEGA response，these
lesions need to be followed during the study by the local investigator. 
7.2.1.3
Evaluation of skin lesions
Skin lesions resulting from TSC include hypomelanotic macules, the shagreen patch, 
periungual or subungual fibromas, facial angiofibromas and/or forehead plaques. Descriptions 
of each are given below.
Hypomelanotic macules are flat areas of skin that appear lighter than the surrounding skin. 
They can be any size or shape or may be the classic “ash-leaf” shape. Skin cells in this 
areacontain less pigment, so the area appears lighter than the surrounding skin.


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The shagreen patch is a patch of skin that is similar in color to surrounding skin, but may be 
tough and dimpled like an orange peel. The shagreen patch is usually found on the lower back 
and nape of the neck, but they may also be seen on other parts of the body.
Periungual or subungual fibromas are small fibrous growths that appear around the fingernails 
or toenails and are usually not seen until adult life.
Facial angiofibromas are benign tumors of the face that often appear across the cheeks and 
nose and on the chin. They are initially small reddish spots or bumps that may increase in size 
with age.
Lastly, a forehead plaque is similar to the angiofibroma but is found on the forehead and scalp. 
These flesh-colored plaques are soft or compressible of doughy to hard lesions.
Digital photographs of all skin lesions will be taken at screening and then at 12, 24, 48 weeks 
and EOT. The investigator should document the presence of all relevant skin lesions in the 
patient records. There will not be any efficacy analysis concerning skin lesions but the 
photographic scans should be sent to the assigned Imaging Vendor.
7.2.1.4
Evaluation of renal function
Renal function will be assessed by the central lab using creatinine clearance calculated from 
the formula of Cockcroft and Gault (1976) at screening and at subsequent time points as 
specified in Table 7-1. For further details see Section 7.2.2.5.2.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examinations, vital signs, laboratory 
assessments including hematology, chemistry, coagulation, urine analysis as well as collecting 
of the adverse events at every visit. For details on AE collection and reporting, refer to 
Section 8.
7.2.2.1
Physical examination
The physical examination must be performed by the Investigator as scheduled in Table 7-1.
The complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s CRF.
7.2.2.2
Vital signs
Vital signs include blood pressure, pulse measurement, and body temperature.


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7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1.
7.2.2.4
Performance status
WHO Performance status scale will be used as described in the Table 7-1 and Table 7-4.
Table 7-4
Performance Status WHO grade:
Grade 0:
Fully active, able to carry out all normal activity without restriction.
Grade 1:
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work.
Grade 2:
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.
Grade 3:
Capable of only limited self care, confined to bed or chair more than 50% of waking hours.
Grade 4:
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
Grade 5:
Dead
7.2.2.5
Laboratory evaluations
Clinical laboratory analyses (hematology, chemistry, coagulation, hepatitis markers, serum 
pregnancy) are to be performed centrally according to the schedule of assessments and 
collection plan outlined in Table 7-1 and Table 7-5. Details on the collection, shipment of 
samples and reporting of results by the central laboratory are provided to investigators in the 
Central Laboratory Manual/Flowchart.  The urinalysis will only be performed by the local 
laboratory using dipstick analysis.
If at any time a patient has laboratory parameters obtained from a different (outside) 
laboratory, Novartis must be provided with a copy of the certification and a tabulation of the 
normal ranges and units for this laboratory. The investigator is responsible for reviewing all 
laboratory reports for patients in the study and evaluating any abnormalities for clinical 
significance.
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used (except in case of re-sampling and the results from the central 
laboratory are not yet available or are partial at Day 1, then eligibility may be based on the 
results from the local laboratory. In such case the results of the local laboratory will need to be 
recorded in the eCRF unplanned pages and a copy of the local lab normal ranges must be 
provided). Screening safety laboratory tests (hematology, biochemistry, lipid profile, 
urinalysis, and coagulation) will need to be repeated at Treatment Day 1 if they were collected 
more than 14 days prior to Treatment Day 1. 
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) AE or when the treating physician cannot wait for central laboratory 
results for decision making. In this particular situation, if possible, the blood sample obtained 
at the same time point should be submitted to the central laboratory for analysis in parallel 


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with local analysis. The results of the local laboratory will be recorded in the eCRF if any the 
following criteria are met: 

A treatment decision was made based on the local results, or

There are no concomitant central results available, or

Local lab results document an AE not reported by the central lab, or

Local lab results document an AE where the severity is worse than the one reported by the 
central lab, or

Eligibility had to be based on the local lab results due to pending / missing central lab 
results.
At any time during the study up to 30 days safety follow-up, abnormal laboratory parameters 
which are clinically relevant and require an action to be taken with study treatment (e.g., 
require dose modification and/or interruption of study treatment, lead to clinical symptoms or 
signs, or require therapeutic intervention), whether specifically requested in the protocol or 
not, will be recorded on the AE CRF page. The severity of laboratory data will be graded 
using the Common Terminology Criteria for Adverse events (CTCAE) version 4.03. 
Additional analyses are left to the discretion of the investigator.
Table 7-5
Central clinical laboratory parameters collection plan
Test category
Test name
Hematology
Hemoglobin, platelets, total white blood cell count (WBC), absolute & differential 
including neutrophils, lymphocytes, monocytes, eosinophils and basophils
Chemistry
Total LDH, fasting glucose, sodium, magnesium, phosphate, potassium, creatinine, 
BUN, albumin, SGOT (AST), SGPT (ALT), total bilirubin, direct bilirubin, triglycerides, 
cholesterol, alkaline phosphatase, uric acid, calcium
Urinalysis
(Local Lab)
Standard urinalysis dipstick assessment must include: pH, protein, glucose, blood, 
ketones, and leukocytes.
Coagulation (mandated 
at screening, then only 
if indicated)
Prothrombin time (PT) or International normalized ratio [INR])
Hepatitis markers 
HCV-RNA, HBV-DNA, HBsAg, HBs-Ab, HBc-Ab
Pregnancy test
Serum pregnancy test 
7.2.2.5.1 Hematology
Hematology tests are to be performed centrally according to the schedule of assessments and 
collection plan outlined in Table 7-1. Detailed hematology panel is described on Table 7-5.
7.2.2.5.2 Chemistry
Chemistry tests are to be performed centrally according to the schedule of assessments and 
collection plan outlined in Table 7-1. Detailed chemistry panel is described in Table 7-5.
The creatinine clearance should be calculated from the formula of Cockcroft and Gault.


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7.2.2.5.3 Urinalysis
Macroscopic urinalysis dipstick analysis (pH, protein, glucose, blood, ketones, and 
leukocytes) will be performed locally according to the schedule of assessments and collection 
plan outlined in Table 7-1. Detailed urinalysis panel is described in Table 7-5.
7.2.2.5.4 Coagulation
Prothrombin time (PT) or International normalized ratio (INR) will be assessed centrally 
according to the schedule of assessments and collection plan outlined in Table 7-1.
7.2.2.5.5 Pregnancy
Female patients of child bearing potential will perform urine pregnancy tests as outlined in 
Table 7-1 every 4 weeks (±7days) while receiving study drug until study drug discontinuation. 
The urine tests will be performed at the patient’s home or at clinical site when a visit is 
scheduled. Patients should be instructed to inform site of a positive urine pregnancy result. A 
serum hCG pregnancy test should be performed by the central lab at screening and at end of 
treatment. 
The results of urine pregnancy tests will be recorded in the patient source documents 
(pregnancy diary, patient records) whereas serum pregnancy test results will be recorded in 
the database of the assigned central lab vendor.
7.2.2.6
Pulmonary function test
Individuals participating in this trial will be questioned at each visit as to the presence of new 
or changed pulmonary symptoms consistent with lung toxicity. If an investigator suspects a 
patient may be developing pneumonitis, investigations such as pulmonary function tests, CT 
chest and referral to a pulmonologist should be considered.
Pulmonary function tests (spirometry [FEV1, FVC], DLCO and room air O2 saturation at rest 
or O2 saturation on 6 minute walking test with up to 6 liters O2/minute nasal oxygen) will be 
performed at screening on all patients with LAM. For these patients, PFTs will be performed 
at week 12, 24 and 48. In addition, PFTs should be performed as medically necessary in any 
patient with evidence of non-infectious pneumonitis.
A bronchoscopy with biopsy and/or a bronchoalveolar lavage (BAL) will be performed only 
when medically necessary for ensuring patient care (details are provided in Section 6.2.3.5
and Table 6-3).
Other assessments
No additional tests will be performed on patients entered into this study.
7.2.3
Resource utilization
Not applicable.
7.2.4
Patient reported outcomes
Not applicable.


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Relevant Medical History page of the patient’s CRF. Adverse event 
monitoring should be continued for at least 30 days following the last dose of study treatment. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 will be used to characterize the 
severity of the Adverse Event.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be 
collected through a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-5)
2. Its duration (start and end dates or ongoing at end of study)
3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met 


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7. Outcome (not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequalae, fatal, unknown) 
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the concomitant medication CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may 
be appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data.


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8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to 
study treatment, complete the SAE Report Form in English, and submit the completed form 
within 24 hours to Novartis. Detailed instructions regarding the SAE submission process and 
requirements for signatures are to be found in the investigator folder provided to each site
Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should 


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describe whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not, and whether the patient continued or withdrew from study 
participation.
If the SAE is not previously documented in the Package Insert (new occurrence) and is 
thought to be related to the Novartis study treatment, an oncology Novartis Chief Medical 
Office and Patient Safety (CMO&PS) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue 
an Investigator Notification (IN), to inform all investigators involved in any study with the 
same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the product label. 
Additional safety information will be communicated in the form of Investigator Notifications. 
This information will be included in the patient informed consent and should be discussed 
with the patient during the study as needed.
8.5
Data Monitoring Committee
Not applicable.
8.6
Steering Committee 
Not applicable.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.


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9.3
Data collection
The designated investigator staff will enter the data required by the protocol into the 
Electronic Case Report Forms (eCRF). The eCRFs have been built using fully validated 
secure web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site 
staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs and, allow modification or 
verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
Safety labs will be collected centrally and data transferred to the study database at regular 
intervals.
The radiological imaging scans performed for this trial will be submitted by the sites to the 
CRO (designated by Novartis) to undergo central radiological review. The results of the 
radiological kidney assessments will be transferred from the CRO to the study database at 
regular intervals (as agreed upon between Novartis and the designated CRO).
Results from at home pregnancy tests will be recorded in patient diaries for source 
documentation only.
9.4
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries 
and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Lab samples (hematology, chemistry, coagulation, serum pregnancy tests) and/or imaging 
data (kidney CT/MRI scans) will be processed centrally and the results will be sent 
electronically to Novartis. Digital photographs, brain and chest MRI/CT scans will only be 
quality checked and archived by the assigned imaging vendor.  No central review will take 
place for the digital photographs, brain, and chest scans.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked. Authorization is required prior to making any 
database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development.
After database lock, the investigator will receive a CD-ROM of the patient data for archiving 
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10
Statistical methods and data analysis
One safety and efficacy analysis (Final analysis) will be conducted on all patients after they 
complete their treatment and efficacy follow-up (after 48 weeks of treatment or earlier).
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of study 
treatment. 
10.1.2
Safety set
The Safety Set comprises all patients who received at least one dose of study treatment. The 
Safety set and FAS are identical in this study, and will be used for all analysis.
10.1.3
Other analysis sets 
Not applicable
10.2
Patient demographics/other characteristics
Demographic and other screening data including disease characteristics will be listed and 
summarized descriptively using the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, 25th and 75th percentiles median, minimum, and maximum will be 
presented.
Relevant medical histories and current medical conditions at screening will be summarized by 
system organ class and preferred term for all patients.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in weeks to everolimus as well as the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics.
The number of patients with dose adjustments (reduction, interruption, possible dose re-
escalation to starting dose, or permanent discontinuation) and the reasons will be summarized 
for all patients and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for all patients.


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10.4
Primary objective
The primary objective in this study is to evaluate the safety of Afinitor® in Chinese adults 
with TSC-renal AML not requiring immediate surgery.
10.4.1
Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented for 
all patients together.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 30+1 after last dose of study medication.
10.4.2
Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the Open-label Treatment phase, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from screening) will 
be summarized by system organ class and/or preferred term, severity (based on CTCAE 
version 4.03), type of adverse event, relation to study treatment
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from Screening phase and 30 
days safety follow-up visit) will be listed and those collected during the pre-treatment and 
post-treatment period will be flagged.
10.4.3
Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade
5 will not be used.
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03


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
Worst post- screening CTCAE grade (regardless of the screening status). Each patient will 
be counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v4.03  grades to compare screening to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE v4.03,

Shift tables using the low/normal/high/ (low and high) classification to compare screening
to the worst on-treatment value.
10.4.4
Other safety data
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.
10.4.4.1 Supportive analyses for primary objective 
Not applicable
10.4.4.2 Tolerability
Not applicable
10.5
Secondary objectives
The secondary objectives in this study are to evaluate the efficacy of Afinitor® in Chinese 
adults with TSC-renal AML not requiring immediate surgery with respect to angiomyolipoma 
response rate, angiomyolipoma progression, and renal function change from screening.
10.5.1
Angiomyolipoma response rate
Angiomyolipoma response rate, is defined as the proportion of patients with an 
angiomyolipoma response, as defined in Section 7.2.1.1, using data from the Independent 
Central Radiology Review of CT/MRIs and the Adverse Events CRF page (to identify 
angiomyolipoma-related bleeding of grade 2 or worse as defined by NCI CTCAE version 
4.03).
Angiomyolipoma response rate will be calculated based on the FAS and presented together 
with its 95% confidence interval for all patients. 
10.5.2
Angiomyolipoma progression
Patients with angiomyolipoma progression, as defined in Section 7.2.1.1, will be listed and 
described in narratives.
10.5.3
Renal function change from screening
Renal function will be assessed using the calculated creatinine clearance (CrCl) from the 
Cockcroft-Gault formula (Cockcroft et al 1976). The proportions of patients with severe renal 
impairment (defined as calculated CrCl < 30 mL/min), and in addition the proportion of 
patients with NCI CTCAE grade 3/4 serum creatinine will be determined. 


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10.5.4
Pharmacokinetics
Not applicable
10.5.5
Biomarkers
Not applicable
10.5.6
Resource utilization 
Not applicable
10.5.7
Patient-reported outcomes 
Not applicable
10.6
Exploratory objectives 
Not applicable
10.7
Final analysis
The final analysis will be performed after all patients have completed Week 48 (or 
discontinued earlier but were followed up for efficacy up to Week 48) and their safety follow-
up visit.
10.8
Sample size calculation
Approximately 40 patients will be enrolled to meet the CFDA post approval requirements. 
The sample size is based on feasibility, there is no hypothesis testing.
10.9
Power for analysis of key secondary variables
Not applicable
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 


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protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form 
Not applicable.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study 
start. In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted


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Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no 
honorarium provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are call information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.


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Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Adler J, Greweldinger J, Litzky G (1984) Macroaneurysm in renal angiomyolipoma: Two 
cases, with therapeutic embolization in one patient. Urol Radiol; 6: 201-3.
Astrinidis A, Henske EP (2005) Tuberous sclerosis complex: linking growth and energy 
signaling pathways in human disease. Oncogene; 24: 7475-7481.
Bissler JJ, Kingswood JC (2004) Renal angiomyolipomata Kidney Int; 66: 924-34.
Bissler JJ, McCormack FX, Young LR, et al (2008) Sirolimus for Angiomyolipoma in 
Tuberous Sclerosis Complex or Lymphangioleiomyomatosis. New England Journal of 
Medicine; 358: 140-51.
Bissler JJ, Racadio J, Donnelly LF, et al (2002) Reduction of postembolization syndrome after 
ablation of renal angiomyolipoma. Am J Kidney Dis; 39: 966-71.
Bjornsti MA, Houghton PJ (2004) The TOR pathway. A target for cancer chemotherapy. 
Nature Reviews Cancer; 4:335-338.
Boulay A, Lane HA (2007) The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res. 2007;172:99-124
Chesa Ponce N, Artiles Hernandez JL, Ponce Socorro JM, et al (1995) Wunderlich’s 
syndrome as the first manifestation of a renal angiomyolipoma. Arch Esp Urol; 48: 305-308.
Clarke A, Hancock E, Kingswood C, et al (1999) End-stage renal failure in adults with the 
tuberous sclerosis complex. Nephrol Dial Transplant; 14: 988-91.
Cockcroft DW, Gault MH, et al (1976) Prediction of creatinine clearance from serum 
creatinine. Nephron; 16: 31-41.
Cohen HT, McGovern FJ, et al (2005) Renal-cell carcinoma. N Engl J Med, 353:2477-90.
Cook JA, Oliver K, Mueller RF, et al (1996) A cross sectional study of renal involvement in 
tuberous sclerosis. J Med Genet; 33: 480-484.
Dickinson M, Ruckle H, Beaghler M, et al (1998) Renal angiomyolipoma: Optimal treatment 
based on size and symptoms. Clin Nephrol; 49: 281-286.
Duvic M, Martin AG, Kim Y, Olsen E, Wood GS, Crowley CA, Yocum RC (2001) Phase 2 
and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or 
persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol; 137: 581-593.
Frattini M, Signoroni S, Pilotti S, et al (2005) Phosphatase protein homologue to tensin 
expression and phosphatidylinositol-3 phosphate kinase mutations in colorectal cancer. 
Cancer Res. 1;65 (23)::11227.
Goel A, Arnold CN, Niedzwiecki D, et all (2004) Frequent inactivation of PTEN by promoter 
hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 
2004 May 1;64: 3014-21.
Gomez MR, (1999) An overview the tuberous sclerosis complex. Gann Monograph on Cancer 
Research; 46: 17-25.
Gomez MR, Sampson JR, Whittemore VH (eds) (1999) Tuberous Sclerosis Complex. Oxford: 
Oxford University Press.


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Heald P, Mehlmauer M, Martin AG, Crowley CA, Yocum RC, Reich SD (2003) Topical
bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell 
lymphoma: results of the phase III clinical trial. J Am Acad Dermatol; 49: 801-815.
Inoki K, Corradetti MN, Guan K-L (2005) Dysregulation of the TSC-mTOR pathway in 
human disease. Nature Genetics; 37: 19-24.
Kwiatkowski DJ, Manning BD (2005) Tuberous sclerosis: a GAP at the crossroads of 
multiple signaling pathways. Hum Mol Genet; 14 (suppl 2): R251-8
Mayr NA, Yuh WT, Taoka T, et al (2006) Serial therapy-induced changes in tumor shape in 
cervical cancer and their impact on assessing tumor volume and treatment response. Am J 
Roentgenol, 187:65-72.
Miller AB, Hoogstraten B, Staquet M, et al (1981) Reporting results of cancer treatment, 
Cancer, 47:207-214.
Nelson CP, Sanda MG (2002) Contemporary diagnosis and management of renal 
angiomyolipoma. J Urol; 168: 1315-25.
Oesterling JE, Fishman EK, Goldman SM, et al (1986) The management of renal 
angiomyolipoma. J Urol; 135: 1121-24.
Pode D, Meretik S, Shapiro A, et al (1985) Diagnosis and management of renal 
angiomyolipoma. Urol; 25: 461-7.
Sampson JR, Maheshwar MM, Aspinwall R, et al (1997) Renal cystic disease in tuberous 
sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet; 61: 843- 851.
Schillinger F, Montagnac R (1996) Chronic renal failure and its treatment in tuberous 
sclerosis. Nephrol Dial Transplant; 11: 481-5.
Shepherd CW, Gomez MR, Lie JT, et al (1991) Causes of death in patients with tuberous 
sclerosis. Mayo Clin Proc; 66: 792-6.
Steiner MS, Goldman SM, Fishman EK, et al (1993) The natural history of renal 
angiomyolipoma. J Urol; 150: 1782-6.
Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New guidelines to evaluate the response 
to treatment in solid tumors. J Natl Cancer Inst; 92: 205-16.
Twombly R (2006) Criticism of Tumor Response Criteria Raises Trial Design Questions, 
JNCI, 98: 232.
Van Baal JG, Smits NJ, Keeman JN, et al (1994) The evolution of renal angiomyolipomata in 
patients with tuberous sclerosis. J Urol; 152: 35-38.
Velho S, Oliveira C, Ferreira A, et al (2005) The prevalence of PIK3CA mutations in gastric 
and colon cancer. Eur J Cancer. 2005 Jul;41:1649-54
Webb DW, Kabala J, Osborne JP (1994) A population study of renal disease in patients with 
tuberous sclerosis. Br J Urol; 74: 151-4.
Yates JRW (2006) Tuberous sclerosis. Europ J Hum Gen; 14: 1065-73.

SAP_001.pdf: 
 
 
Clinical Development 
RAD001/Everolimus /Afinitor® 
CRAD001M2401 / NCT03525834 
Phase IV, single arm study of safety and efficacy of 
everolimus in Chinese adults with Tuberous Sclerosis 
Complex who have renal angiomyolipoma not requiring 
immediate surgery 
Statistical Analysis Plan (SAP) 
 
Author: 
Trial Statistician, 
  
Document type: 
SAP Documentation 
Document status: 
Addendum 1 
Release date: 
19-Feb-2021 
Number of pages: 
31 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis


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                                                        CRAD001M2401 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
10-
Sep-
2018 
Prior to DB lock 
Creation of final 
version 
N/A - First version 
NA 
 
 
 
 
 
02-
Dec-
2019 
Prior to DB lock 
Protocol 
amendment 
Elimination of interim 
analysis  
Section 1 
Section 1.1 
Section 2.1 
Section 2.14 
Section 5.1.1 
 
 
 
Change in threshold for 
subgroup analyses 
Section 2.2.1.1 
Section 2.2.1.2 
 
 
 
Elimination of forest plot 
Section 2.2.1.2 
 
 
 
Elimination of frequency 
figure for daily dose 
Section 2.4.1 
 
 
 
 
 
08-Apr-
2020 
Prior to DB lock 
Protocol 
amendment 
Addition of potential 
supportive analyses due 
to COVID-19 
Section 2.5.4 
 
 
 
Addition of handling of 
missing values of 
secondary efficacy 
objective 
Section 2.7.3 
 
 
 
Addition of CTC Grade 5 
for AE coding 
Section 5.2 
 
 
 
Addition of handling rules 
for test values below 
LLOQ and above HLOQ 
Section 5.3.1 
19-
Feb-
2021 
Post-DBL 
Addendum 1 
Update the Kaplan-Meier 
analysis method for time 
to angiomyolipoma 
progression (TTAP) 
calculation 
Section 2.7.1 


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                                                        CRAD001M2401 
 
 
Table of contents 
Document History – Changes compared to previous final version of SAP ........................ 2 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
 
Study design ............................................................................................................ 6 
 
Study objectives and endpoints ............................................................................... 6 
2 
Statistical methods ............................................................................................................... 8 
 
Data analysis general information ........................................................................... 8 
2.1.1 
General definitions .................................................................................. 8 
 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroup of interest .............................................................................. 11 
 
Patient disposition, demographics and other baseline characteristics ................... 12 
2.3.1 
Patient disposition ................................................................................. 13 
 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 14 
2.4.1 
Study treatment / compliance ................................................................ 14 
2.4.2 
Prior, concomitant and post therapies ................................................... 15 
 
Analysis of the primary objective .......................................................................... 16 
2.5.1 
Primary endpoint ................................................................................... 16 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 16 
2.5.4 
Supportive analyses ............................................................................... 16 
 
Analysis of the key secondary objective ............................................................... 16 
 
Analysis of secondary efficacy objective(s) .......................................................... 16 
2.7.1 
Secondary endpoints ............................................................................. 16 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 21 
 
Safety analyses....................................................................................................... 22 
2.8.1 
Adverse events ...................................................................................... 22 
2.8.2 
Deaths .................................................................................................... 24 
2.8.3 
Laboratory data ..................................................................................... 24 
2.8.4 
Other safety data ................................................................................... 25 
 
Pharmacokinetic endpoints .................................................................................... 26 


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                                                        CRAD001M2401 
 
 
 
PD and PK/PD analyses ........................................................................................ 27 
 
Patient-reported outcomes ..................................................................................... 27 
 
Biomarkers ............................................................................................................. 27 
 
Other Exploratory analyses.................................................................................... 27 
 
Final analysis ......................................................................................................... 27 
3 
Sample size calculation ..................................................................................................... 27 
4 
Change to protocol specified analyses .............................................................................. 27 
5 
Appendix ........................................................................................................................... 27 
 
Imputation rules ..................................................................................................... 27 
5.1.1 
Study drug ............................................................................................. 27 
5.1.2 
AE date imputation ............................................................................... 28 
5.1.3 
Concomitant medication date imputation ............................................. 29 
 
AEs coding/grading ............................................................................................... 29 
 
Laboratory parameters derivations ........................................................................ 30 
5.3.1 
Handling of test values below LLOQ and above HLOQ ...................... 30 
 
Statistical models ................................................................................................... 30 
5.4.1 
Primary analysis .................................................................................... 30 
5.4.2 
Key secondary analysis ......................................................................... 30 
 
Rule of exclusion criteria of analysis sets.............................................................. 31 
6 
Reference ........................................................................................................................... 31 


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                                                        CRAD001M2401 
 
 
List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
AML 
Angiomyolipoma 
ATC 
Anatomical therapeutic classification 
BMI 
Body mass index 
BSA 
Body surface area 
CFDA 
China Food and Drug Administration 
CRF 
Case Report/Record Form 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DI 
Dose intensity 
DLCO 
Diffusing capacity factor of the lung for carbon monoxide 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FEV1 
Forced expiratory volume per second 
FVC 
Forced vital capacity 
LAM 
Lymphangioleiomyomatosis 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
OS 
Overall survival 
PDI 
Planned dose intensity 
PK 
Pharmacokinetics 
PRO 
Patient-reported outcomes 
PT 
Preferred erm 
RAP 
Report and Analysis Process 
RDI 
Relative dose intensity 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SMQ 
Standardized MedDRA Queries  
SOC 
System Organ Class 
TSC 
Tuberous Sclerosis Complex 
TTAP 
Time to angiomyolipoma progression 
WHO 
World Health Organisation 
 


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                                                        CRAD001M2401 
 
 
1 
Introduction 
This document provides the detailed statistical analysis plan for study CRAD001M2401, which 
is referenced in the RAP documentation and/or study report. 
This document supports one final analysis for safety and efficacy. Final analysis will be reported 
in a final  CSR to support the license renewal submission and fulfill a post approval commitment 
(PAC). 
The current analysis plan is based on the final protocol (Version 02) and original mock CRF 
draft ver0.3. 
 
Study design 
This is an open label, single arm, multi-center phase IV study of treatment with one daily oral 
dose of 10 mg everolimus (Afinitor®) in 40 patients with renal angiomyolipoma associated 
with TSC. 
There are three separate phases in this study: a “Screening phase”, an “Open-label treatment 
phase”, and a “Treatment discontinuation follow-up phase” for patients who discontinue study 
drug for other reasons than disease progression. 
A final analysis will be performed after all patients have completed Week 48 (or discontinued 
earlier but were followed up for efficacy up to Week 48) and their safety follow-up visit. 
 
 
 
Study objectives and endpoints 
Objectives and related endpoints are described in Table 1.2-1 below. 
 
 
 
 
 
 
 
 
 


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                                                        CRAD001M2401 
 
 
Table 1.2-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
 
To evaluate the safety of Afinitor® in 
Chinese adults with TSC-AML not 
requiring immediate surgery. 
• 
Incidence of adverse events, lab 
abnormalities 
Refer to Section 
2.8 
Secondary 
 
 
To evaluate the efficacy of Afinitor® 
in Chinese adults with TSC-renal 
AML not requiring immediate 
surgery. 
• 
AML response 
 
Refer to Section 
2.7.1 
Other Secondary 
 
 
To further evaluate the efficacy of 
Afinitor® in Chinese adults with 
TSC-renal AML not requiring 
immediate surgery. 
• 
AML progression 
• 
Renal function change from screening 
Refer to Section 
2.7.1 
Exploratory 
 
 
None 
 
 


 
 
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                                                         CRAD001M2401 
 
 
2 
Statistical methods 
 
Data analysis general information 
Novartis will be performing the final analysis. 
SAS version 9.4 or higher will be used to conduct the analysis.  
Categorical data will be presented as frequencies and percentages. For continuous data, the 
number of patients with assessable data, mean, standard deviation, median, minimum, 
maximum, lower quartile, and upper quartile will be presented. For time-to-event analyses, the 
number of patients at risk, the number and percentage of patients at risk with the event, the 
number and percentage of patients censored with the reason for censoring, Kaplan-Meier 
survival estimates with 95% CIs every 3 months, the median survival estimate and the 25th and 
75th percentiles survival estimates with their 95% CI will be presented. 
2.1.1 
General definitions  
2.1.1.1 
Study drug and study treatment 
The investigational drug used in the course of this study will be relabeled local commercial 
Afinitor® (everolimus). 
Definition of terms: Study treatment = RAD001 = Afinitor® = everolimus. 
2.1.1.2 
Date of first administration of study treatment 
The date of first administration of RAD001 is defined as the first date when a non-zero dose of 
RAD001 was administered, as per the Study Treatment CRF. For the sake of simplicity, the 
date of first administration of study drug will also be referred to as the start of study drug. 
2.1.1.3 
Date of last administration of study treatment 
The date of last administration of RAD001 is defined as the last date when a non-zero dose of 
RAD001 was administered and recorded on the Study Treatment CRF. 
2.1.1.4 
Study day 
The study day for safety assessments (e.g., adverse event (AE) onset date, laboratory 
abnormality occurrence, vital sign measurement, dose interruption) will be calculated using the 
start date of study treatment as the origin. 
Safety assessments that occur on or after the start date of study treatment will have study day 
calculated as 
(date of safety assessment) – (start date of study treatment) + 1. 
Safety assessments that occur before the start date of study treatment will have study day 
calculated as 
(date of safety assessment) – (start date of study treatment). 


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Then study day 1 will be the first day of study treatment and study day -1 will be the day before 
the first day of study treatment. 
The study day for all other, i.e., non-safety assessments (e.g., Magnetic Resonance Imaging 
[MRI] assessment, angiomyolipoma progression, angiomyolipoma response, World Health 
Organization [WHO] performance status) will be calculated as same as safety assessments. 
Study day will be displayed in the data listings. 
2.1.1.5 
Baseline 
The baseline will be defined when appropriate as the last available assessment on or before the 
start date of RAD001. 
2.1.1.6 
On-treatment assessment/event 
Adverse event summaries will present only on-treatment assessments, where on-treatment 
means that the AE started in the following time interval in the open-label period (including the 
lower and upper limits): 
<date of first administration of open-label RAD001; date of last administration of open-
label RAD001 + 30 days>. 
Other safety summaries will present baseline and on-treatment assessments, where on-treatment 
means that the assessment occurred in the following time interval in the open-label period 
(including the lower and upper limits): 
<date of first administration of open-label RAD001 + 1; date of last administration of 
open-label RAD001 + 30 days>. 
2.1.1.7 
Time windows 
In order to summarize data over time, the following data types will be time slotted using time 
windows. 
CT/MRI assessments for efficacy 
CT/MRI assessments for efficacy will be performed at screening/baseline, and at 12, 24 and 48 
weeks after the start of study treatment, and at the End of Treatment visit. 
• The baseline time window is defined as being any time on or before the start of study 
treatment. 
• The first on-study time window is from study day 2, i.e., the day after the start of study 
treatment, until study day 126 (i.e., week 18). The upper limit of this time window is 
midway between the first and second planned post baseline CT/MRI assessments, i.e., 
at weeks 12 and 24. 
• The second on-study time window is from study day 127 until study day 252 (i.e., week 
36). The lower limit of this time window is midway between the first and second planned 
post baseline CT/MRI assessments, i.e., at weeks 12 and 24, and the upper limit is 
midway between the second and third planned CT/MRI assessments, i.e., at weeks 24 
and 48. 


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• The third on-study time window is from study day 253 until study day 343 (i.e., week 
48 + 7 days).  The lower limit of this time window is midway between the second and 
third planned post baseline CT/MRI assessments, i.e., at weeks 24 and 48, and the upper 
limit is day between the third assessment and its 7 day window, i.e., at weeks 48 and 
weeks 48 + 7 days. 
Table 2.1-1 summarizes the time windows for CT/MRI assessments for efficacy. 
Table 2.1-1 
Time windows for CT/MRI assessments for efficacy 
Time Window 
Planned Visit Timing  
Time Window Definition 
Baseline 
On or before Study Day 1 
≤ Study Day 1 
Week 12 
Study Day 84  
Study Days 2 – 126 (Baseline to Week 18) 
Week 24 
Study Day 168 
Study Days 127 – 252 (Week 18 to Week 36) 
Week 48 
Study Day 336 
Study Days 253 – 343 (Week 36 to Week 48 + 7 
days) 
 
 
 
Study Day 1 = Start date of study treatment 
If more than one assessment is done within the Baseline time window, the assessment closest 
to study day 1 (i.e., the start of study treatment) will be used; if two or more assessments are 
equidistant from study day 1, then the mean value will be used.  For all other time windows, the 
assessment closest to the planned assessment date will be used; if two or more assessments are 
equidistant from the planned date, then the mean value will be used. 
Pulmonary function tests 
Pulmonary function tests (PFT) will be performed on sporadic LAM and LAM patients at 
screening/baseline, and at 12, 24 and 48 weeks after the start of study treatment, and at the End 
of Treatment visit. 
Table 2.1-2 summarizes the time windows for pulmonary function tests. 
Table 2.1-2 
Time windows for pulmonary function tests 
Time Window 
Planned Visit Timing  
Time Window Definition 
Baseline 
On or before Study Day 1 
≤ Study Day 1 
Week 12 
Study Day 84  
Study Days 2 – 126 (Baseline to Week 18) 
Week 24 
Study Day 168 
Study Days 127 – 252 (Week 18 to Week 36) 
Week 48 
Study Day 336 
Study Days 253 – 343 (Week 36 to Week 48 + 7 
days) 
 
 
 
Study Day 1 = Start date of study treatment 
If more than one assessment is done within the Baseline time window, the assessment closest 
to study day 1 (i.e., the start of study treatment) will be used; if two or more assessments are 
equidistant from study day 1, then the mean value will be used.  For all other time windows, the 
assessment closest to the planned assessment date will be used; if two or more assessments are 
equidistant from the planned date, then the mean value will be used. 


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WHO performance status 
WHO performance status will be collected at screening/baseline, on the start date of study 
treatment, at 4, 12, 24 and 48 weeks, and at the End of Treatment visit. 
Table 2.1-3 summarizes the time windows for WHO performance status. 
Table 2.1-3 
Time windows for WHO performance status 
Time Window 
Planned Visit Timing  
Time Window Definition 
Baseline 
On or before Study Day 1 
≤ Study Day 1 
Week 4 
Study Day 28 
Study Days 2 – 42 (Baseline to Week 6) 
Week 12 
Study Day 84  
Study Days 43 – 126 (Week 6 to Week 18) 
Week 24 
Study Day 168 
Study Days 127 – 252 (Week 18 to Week 36) 
Week 48 
Study Day 336 
Study Days 253 – 343 (Week 36 to Week 48 + 
7 days) 
 
 
 
Study Day 1 = Start date of study treatment 
If more than one assessment is done within the Baseline time window, the assessment closest 
to study day 1 (i.e., the start of study treatment) will be used; if two or more assessments are 
equidistant from study day 1, then the mean value will be used.  For all other time windows, the 
assessment closest to the planned assessment date will be used; if two or more assessments are 
equidistant from the planned date, then the mean value will be used. 
 
Analysis sets 
This section defines the populations applicable to this study and their use in the statistical 
analyses. 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose of study 
treatment. The FAS will be the primary population in the assessment of efficacy analysis. 
Safety Set 
The Safety Set comprises all patients who received at least one dose of study treatment. The 
Safety Set and FAS are identical in this study. The Safety Set will be the population used in the 
assessments of safety analysis. 
2.2.1 
Subgroup of interest 
2.2.1.1 
Safety 
The main analyses on adverse events and abnormal laboratory values will be repeated on the 
Safety Set in the following subgroups: 
• Gender 
• Age (< 65 years and ≥ 65 years) 
The objective of carrying out these subgroup analyses is to identify safety problems that are 
limited to a subgroup of patients, or that are more commonly observed in a subgroup of patients. 


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Summary tables will only be performed on the Safety Set and only if at least 10% of patients 
are present in each class. 
2.2.1.2 
Efficacy 
For the primary efficacy variable of angiomyolipoma response rate, subgroup analyses will also 
be performed using the following: 
• Gender 
• Age (< 65 years and ≥ 65 years) 
Efficacy analyses in subgroups are intended to explore the uniformity of any treatment effects 
found overall.  Summary tables will present response rates with the exact 95% confidence 
interval. 
The efficacy analyses in subgroups will be performed on the FAS and only if at least 10% of 
patients are present in each class (some grouping of classes will be considered for race). 
 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other screening data including disease characteristics will be listed and 
summarized descriptively using the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, 25th and 75th percentiles, median, minimum, and maximum will be 
presented. 
Basic demographic and background data 
All demographic and background data will be listed. The summary table will include age, sex, 
weight, height, body mass index (BMI), body surface area (BSA), race, ethnicity and WHO 
performance status.  
Qualitative data will be summarized by means of contingency tables, and quantitative data will 
be summarized by appropriate descriptive statistics (mean, standard deviation, 25th and 75th 
percentiles, median, minimum, and maximum).  
Body surface area in m2 will be presented and is calculated using the (Dubois and Dubois, 1916) 
formula: 
BSA = (W0.425 × H0.725) × 0.007184, 
where W is weight in kilograms and H is height in centimeters. 
Diagnosis of TSC disease at Baseline 
The diagnosis of TSC-related conditions or symptoms will be documented at the time of 
screening. 
Diagnosis of TSC at baseline will be summarized according to the criteria listed in Table 2.3-1 
below. 


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Table 2.3-1 Diagnostic Criteria for Tuberous Sclerosis Complex (TSC) 
Major Features 
1. Hypomelanotic macules (≥3, at least 5-mm diameter) 
2. Angiofibromas (≥3) or fibrous cephalic plaque 
3. Ungual fibromas (≥2) 
4. Shagreen patch 
5. Multiple retinal hamartomas 
6. Cortical dysplasiasa 
7. Subependymal nodules 
8. Subependymal giant cell astrocytoma 
9. Cardiac rhabdomyoma 
10. Lymphangioleiomyomatosis (LAM) b 
11. Angiomyolipomas (≥2) b 
Minor Features 
1.  “Confetti” skin lesions 
2.  Dental enamel pits (>3) 
3.  Intraoral fibromas (_2) 
4.  Retinal achromic patch 
5.  Multiple renal cysts 
6.  Nonrenal hamartomas 
a. Includes tubers and cerebral white matter radial migration lines. 
b. A combination of the two major clinical features (LAM and angiomyolipoma) without other 
features does not meet criteria for a definite diagnosis. 
Time since initial diagnosis of TSC-related conditions or symptoms will be summarized in years 
(defined as 365.25 days), and will be measured until the time of baseline (i.e., start date of 
everolimus). 
Medical history 
Medical history, including TSC-related conditions and symptoms, will be summarized and 
listed.  
Summaries will be presented by primary system organ class and preferred term. Medical 
history/current medical conditions are coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. 
2.3.1 
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings. Information from 
the “End of study treatment” will be used to provide a summary showing: 
1. 
Number (%) of patients still on everolimus. 
2. 
Number (%) of patients completed everolimus. 
3. 
Number (%) of patients discontinued everolimus. 
4. 
Primary reason for study treatment discontinuation. 
5. 
Number (%) of patients completed follow-up phase. 


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6. 
Primary reason for discontinuation from follow-up phase 
 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The duration of study treatment (i.e., everolimus) exposure, cumulative dose, dose intensity (DI) 
and relative dose intensity (RDI) will be summarized. In addition, the duration of exposure to 
study treatment will be categorized into time intervals, and frequency counts and percentages 
will be presented for the number of patients in each interval. The number of exposed patients 
will be summarized by gender and age. The number of patients with dose reductions or 
interruptions, and the reasons, will also be summarized. 
Listings of all doses of the study treatment along with dose change reasons will be produced. 
The Safety Set will be used for all summaries and listings of study treatment. 
Duration of study treatment exposure 
The following algorithm will be used to calculate the duration of study treatment exposure: 
Duration of exposure (days) = (date of last administration of study treatment) – (date of 
first administration of study treatment) + 1. 
The duration includes periods of temporary interruption of study treatment, for any reason. 
“Date of last administration of study treatment” and “date of first administration of study 
treatment” were defined in Sections 2.1.1.3 and 2.1.1.2, respectively. 
Cumulative dose 
Cumulative dose is defined as the total dose given during study treatment exposure, expressed 
in units of mg. For patients who did not take any study drug, the cumulative dose is by definition 
equal to zero. 
Dose intensity and relative dose intensity 
Dose intensity is defined as follows: 
DI (mg/m2/day) = Cumulative dose (mg/m2) / Duration of exposure (days). 
For patients who did not take any study drug, the DI is by definition equal to zero. 
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to patients 
as per protocol in the same dose unit and unit of time as that of the DI. The PDI in this study is 
10 mg/day. 
Relative dose intensity is defined as follows: 
RDI = DI (mg/day) / PDI (mg/day). 
Cumulative dose, dose intensity and relative dose intensity will be summarized. 
Dose reductions and interruptions 


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The number of patients with dose reductions or interruptions, and the reasons, will be 
summarized. Dose reductions and interruptions will be determined programmatically using the 
rules defined below. 
Interruption: An interruption is defined as a 0 mg/0 tablets dose given on one or more days. 
If the start and end dates of dose interruption are incomplete (partial date), no imputation 
method will be applied to the date. It will be considered as no dose interruption. 
Reduction: A reduction is defined as a decrease in dose to a non-zero dose from the protocol 
planned dose (10 mg/day), or a decrease from the previous non-zero dose, even if this decrease 
has been directly preceded by an interruption.  For example, in the sequence 10 mg daily – 0 
mg – 5 mg daily, the 5 mg daily dose will be counted as a reduction.  In the sequence 10 mg 
daily – 2.5 mg daily – 5 mg daily, two reductions will be counted since the 5 mg daily dose is 
still lower than the protocol planned dose and is, therefore, counted as a second reduction.  A 
decrease in frequency of administration which results in a lower cumulative dose is also counted 
as a reduction, e.g., in the sequence 10 mg daily – 5 mg daily – 5 mg every other day, two 
reductions will be counted. 
If a patient moves from a higher than protocol planned dose down to the planned dose then this 
is not counted as a reduction.  However, if they move directly from a higher than planned dose 
down to a lower than protocol planned dose, or the planned dose on a less frequent regimen, 
then this is counted as a reduction. 
The number of dose reductions and interruptions per patient will be tabulated. The reasons for 
reductions and interruptions will be summarized, where only reasons that correspond to 
programmatically determined dose reductions and interruptions will be presented. 
2.4.2 
Prior, concomitant and post therapies 
Prior, concomitant and post therapies entered into the database will be coded using the WHO 
Drug Reference List to allow for categorization by preferred term. In addition to categorizing 
therapies data by preferred term, drugs are classified according to their ATC classification in 
order to present how they are being utilized. The ATC classification allows for a summary of 
medications by a high-level common drug class. 
Concomitant medications and significant non-drug therapies/procedures taken concurrently 
with the study drug everolimus will be listed and summarized by ATC class and preferred term 
by means of frequency counts and percentages.  
These summaries and listings will include medications starting on or after the start date of 
everolimus, or medications starting prior to the start date of everolimus and continuing after the 
start date of everolimus. Medications starting more than 30 days after the last day of everolimus 
will not be included. Any prior concomitant medications or significant non-drug 
therapies/procedures starting and ending prior to the start of everolimus will be listed. 
Systemic anti-angiomyolipoma medication since discontinuation of study treatment will be 
listed and summarized by ATC class and preferred term by means of frequency counts and 
percentages.  
The Safety Set will be used for all the above-mentioned tables and listings. 


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Analysis of the primary objective 
The primary objective in this study is to evaluate the safety of Afinitor® in Chinese adults with 
TSC-renal AML not requiring immediate surgery. For further details on safety analysis, please 
see safety analyses in section 2.8. 
2.5.1 
Primary endpoint 
The primary endpoints are incidence of adverse events and laboratory abnormalities. For further 
details, please see safety analyses in section 2.8. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Not applicable 
2.5.3 
Handling of missing values/censoring/discontinuations 
Not applicable 
2.5.4 
Supportive analyses 
Additional sensitivity analyses might be further conducted if needed to assess the impact of 
missing assessments and/or evaluate the effect of baseline demographic and disease 
characteristics of potential prognostic value on study objectives.  
Additional sensitivity analysis can be done to assess the impact of COVID19. 
 
Analysis of the key secondary objective 
There is no key secondary objective. 
 
Analysis of secondary efficacy objective(s) 
The secondary objectives in this study are to evaluate the efficacy of Afinitor® in Chinese adults 
with TSC-renal AML not requiring immediate surgery with respect to angiomyolipoma 
response rate, angiomyolipoma progression, and renal function change from baseline. 
2.7.1 
Secondary endpoints 
The efficacy endpoints will be based on the independent central radiology review of CT/MRI 
assessments of the kidneys to determine the volumes of target lesions in the kidneys.  
The efficacy analysis will be performed using the FAS. 
Definition 
Each post baseline CT/MRI assessment of the kidneys will be classified by the Independent 
Central Radiology Review as either angiomyolipoma response, stable disease, angiomyolipoma 
progression or not evaluable, based on the combined radiological assessments of target 
angiomyolipoma volume, kidney volumes and new angiomyolipoma lesions. 
An overall angiomyolipoma response will then be calculated by Novartis combining the 
angiomyolipoma radiological assessment as provided by the Independent Central Radiology 
Review and angiomyolipoma-related bleeding reported by the investigator on the Adverse 


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Events CRF page. Clinical review is required in order to identify all occurrences of 
angiomyolipoma-related bleeding reported by the investigators. 
Angiomyolipoma response is defined as: 
• A reduction in angiomyolipoma volume of at least 50% relative to screening, where 
angiomyolipoma volume is the sum of the volumes of all target angiomyolipomata 
identified at screening. 
In addition, angiomyolipoma response requires satisfying all of the following criteria: 
• No new angiomyolipomata  ≥ 1.0 cm in longest diameter are identified 
• Neither kidney increases in volume by more than 20% from nadir (where nadir is the lowest 
kidney volume obtained for the patient, separately for each kidney, previously in the trial 
including baseline) 
• The patient does not have any angiomyolipoma-related bleeding of grade ≥ 2 (as defined by 
NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03). 
Angiomyolipoma progression is defined as one or more of the following: 
• An increase from nadir of 25% or more in angiomyolipoma volume to a value greater than 
screening, where angiomyolipoma volume is the sum of the volumes of all target 
angiomyolipomata identified at baseline and where nadir is the lowest angiomyolipoma 
volume achieved by the patient previously in the trial (including screening) 
• The appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter 
• An increase from nadir of 20% or more in the volume of either kidney to a value greater 
than screening, where nadir is the lowest kidney volume obtained for the patient, separately 
for each kidney, previously in the trial (including screening) 
• Angiomyolipoma-related bleeding grade ≥ 2 as defined by NCI CTCAE, version 4.03. 
Stable disease (SD): insufficient shrinkage in angiomyolipoma volume to qualify for response 
and the absence of progression. 
Not evaluable (NE): CT/MRI performed but not readable (e.g., not all designated target lesions 
are included in a follow up image due to technical error). 
The best overall angiomyolipoma response is the best response recorded from treatment until 
the first to occur out of (i) angiomyolipoma progression, (ii) the cut-off date for the final 
analysis, (iii) the date when a further systemic anti-angiomyolipoma medication is started, (iv) 
the date of an angiomyolipoma-related surgery, or (v) the date of death. 
Angiomyolipoma response rate 
Angiomyolipoma response rate, is defined as the proportion of patients with best overall 
angiomyolipoma response status of “angiomyolipoma response” (as defined as above) during 
maximum treatment duration of 48 weeks using data from the Independent Central Radiology 
Review of CT/MRIs and the Adverse Events CRF page (to identify angiomyolipoma-related 
bleeding of grade 2 or worse as defined by NCI CTCAE version 4.03). Angiomyolipoma 
response rate will be calculated based on the FAS and presented together with an exact 95% 
confidence interval for all patients. 


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Overall angiomyolipoma response (either angiomyolipoma response, stable disease, 
angiomyolipoma progression or not evaluable) at each assessment will be summarised by 
frequency and percentage. 
Supportive analyses will include descriptive summaries of the sum of the volumes of target 
angiomyolipoma lesions from both kidneys (mean, standard deviation, 25th and 75th 
percentiles, median, minimum and maximum) at each assessment, using the time windows 
defined in Section 2.1.1.7. Change from baseline (actual and percentage) in the sum of volumes 
of target angiomyolipoma lesions will also both be summarized descriptively at each 
assessment. 
A waterfall plot will present the best percentage change from baseline in target angiomyolipoma 
volume at each assessment. 
Note that patients with best overall angiomyolipoma response of Not Evaluable will be treated 
as non-responders in the calculation of the best overall angiomyolipoma response rate in the 
FAS, but will be excluded from the denominator for the waterfall plots. 
Angiomyolipoma progression 
Angiomyolipoma progression, is defined as the proportion of patients with an angiomyolipoma 
progression during maximum treatment duration of 48 weeks, as defined as above, using data 
from the Independent Central Radiology Review of CT/MRIs and the Adverse Events CRF 
page (to identify angiomyolipoma-related bleeding of grade 2 or worse as defined by NCI 
CTCAE version 4.03). 
Angiomyolipoma progression rate will be calculated based on the FAS and presented together 
with an exact 95% confidence interval for all patients. 
Time to angiomyolipoma progression 
Time to angiomyolipoma progression (TTAP) is defined as the time from the start date of 
everolimus to the date of the first documented angiomyolipoma progression, where 
angiomyolipoma progression is defined as above. TTAP will be censored if angiomyolipoma 
progression is not observed before the first to occur out of  
(i) 
the cut-off date for the analysis, or  
(ii) 
the date when a further systemic anti-angiomyolipoma medication is started, or  
(iii) 
the date of a angiomyolipoma-related surgery or  
(iv) 
the date of death. 
The censoring date will be the date of the last adequate CT/MRI assessment occurring before 
the first of any of these four events to have occurred, or treatment day 1 if there were no 
adequate CT/MRI assessments performed post-baseline.  
TTAP will be presented in months and is calculated as: 
(Date of angiomyolipoma progression/censoring – Start date of everolimus + 1) × 12 ÷ 
365.25. 
The TTAP distribution will be presented descriptively in the FAS using a Kaplan-Meier curve. 
Summary statistics from the Kaplan-Meier distribution will be determined, including the 


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median TTAP and the proportions of patients remaining progression-free at 3, 6, and 12 months. 
These statistics will be given as point estimates with 95% confidence intervals.  
Per protocol, tumor assessment was done at Week 4, 12, 24 and 48. At database lock, it was 
observed that most patients were censored at treatment completion at the time of their Week 48 
assessment, and only 3 out of the 40 patients had angiomyolipoma progression observed. 9 
patients were discovered to have TTAP greater than the maximum treatment duration of 48 
weeks + 7 day window, among which one patient had progressed; this patient had the longest 
TTAP in the analysis set.   
Kaplan-Meier estimates up to 48 weeks can be interpreted as fully valid. However, beyond that 
point where censoring was occurring due to treatment completion, the estimates are extremely 
undependable due to the high variability introduced by the small number of patients remaining 
in the risk set. In particular, the progression event in the patient with the longest TTAP causes 
the KM curve to drop to zero which is not meaningful;  it is just an artifact of the KM calculation. 
In order to perform a somewhat interpretable analysis at this late timepoint, a revised analysis 
was introduced in which all patient outcomes (censoring or event) occurring after the maximum 
treatment duration will be considered to have occurred at the same timepoint. Specifically:  
For TTAP exceeding the maximum treatment duration of 48 weeks + 7day window (11.268 
months), the TTAP will be reassigned to 11.268 months. Then the Kaplan-Meier curve will be 
re-computed using this revised time definition. 
It should be kept in mind that the KM event rate at the end of the study using this approach is 
very likely still over-estimated: the KM curve still drops noticeably because there were only 9 
patients in the risk set beyond the end of treatment. Nevertheless, there was no signal in the data 
of a likely large increase in that narrow timeframe. Although this revised estimate ignores an 
event when it actually occured, it does allow incorporation of that single late event in a more 
reasonable manner than using the raw data. Therefore, it is reasonable to say that the estimates 
up to the end of the Week 48 assessment window can be interpreted as fully valid. 
 
Time to angiomyolipoma response 
Time to angiomyolipoma response is defined as the time from the start date of everolimus until 
the date of the first documented angiomyolipoma response, where angiomyolipoma response is 
as defined as above. Time to angiomyolipoma response applies only to patients who achieve an 
angiomyolipoma response, i.e., patients in the analysis will have known times to 
angiomyolipoma response and there will be no censored times. 
Time to angiomyolipoma response is calculated in months as 
(Date of first AML response – Start date of everolimus + 1) × 12 ÷ 365.25. 
The median time to angiomyolipoma response will be presented along with a 95% confidence 
interval, and the proportions of angiomyolipoma responders who respond by 3, 6, and 12 
months will be provided. 
Duration of angiomyolipoma response 


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Duration of angiomyolipoma response is defined as the time from the date of the first 
documented angiomyolipoma response until the date of the first documented angiomyolipoma 
progression, where angiomyolipoma response and angiomyolipoma progression are as defined 
as above. Duration of angiomyolipoma response applies only to patients who achieve an 
angiomyolipoma response.  
Duration of angiomyolipoma response will be censored if angiomyolipoma progression is not 
observed before the first to occur out of 
(i) 
the cut-off date for the analysis, or 
(ii) 
the date when a further systemic anti-angiomyolipoma medication is started, or 
(iii) 
the date of a angiomyolipoma-related surgery, or 
(iv) 
the date of death. 
The censoring date will be the date of the most recent CT/MRI assessment before the first of 
any of these four events occurred. 
Duration of angiomyolipoma response is calculated in months as 
(Date of angiomyolipoma progression/censoring – Date of first angiomyolipoma 
response + 1) × 12 ÷ 365.25. 
A Kaplan-Meier curve will be constructed, and the median duration of angiomyolipoma 
response will be presented along with 95% confidence intervals. In addition, the Kaplan-Meier 
estimates with 95% confidence intervals will be presented at 3, 6, and 12 months. 
Change from baseline in renal function 
Renal function will be assessed using the calculated creatinine clearance (CrCl) from the 
Cockcroft-Gault formula (Cockcroft et al 1976). 
The proportions of patients with severe renal impairment (defined as calculated CrCl < 30 
mL/min). In addition, the proportion of patients with NCI CTCAE grade 3/4 serum creatinine 
will be determined. 
For creatinine clearance, changes from baseline will be summarized descriptively (mean, 
standard deviation, 25th and 75th percentiles, median, minimum and maximum) at each 
assessment in FAS. The proportions of patients with severe renal impairment and NCI CTCAE 
grade 3/4 serum creatinine will be summarized by means of frequency counts and percentage 
at each assessment. Creatinine and CrCl values will be listed at patient level by visit from FAS.  
2.7.2 
Statistical hypothesis, model, and method of analysis 
This study has a single treatment arm and there are no statistical tests planned for any of the 
response rates. 
Response rates 
Responses will be summarized in terms of percentage rates with exact 95% confidence intervals. 
An exact binomial confidence interval (Clopper and Pearson, 1934) will be used, implemented 
using SAS procedure FREQ with the EXACT statement for one-way tables. 


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Time-to-event analyses 
This section presents the general methodology used to analyze time-to-event variables, e.g., 
TTAP, time to angiomyolipoma response and duration of response. 
An estimate of the time-to-event function will be constructed using the Kaplan-Meier (product-
limit) method as implemented in the procedure LIFETEST with the METHOD=KM option. 
The Kaplan-Meier curve will be displayed. 
Median time-to-event will be obtained along with a 95% confidence interval calculated from 
the procedure LIFETEST using the method of (Brookmeyer and Crowley, 1982). 
Kaplan-Meier estimates of the time-to-event function with 95% confidence intervals at 3, 6, 
and 12 months, where 1 month is defined as (365.25/12)=30.4375 days, will be presented. The 
confidence intervals will be constructed using Greenwood’s formula (Collett, 1994) for the 
standard error of the Kaplan-Meier estimate. The log-log transformation of the survivor 
function (Kalbfleisch and Prentice, 1980) will be used in order to ensure that the confidence 
limits remain in the interval [0, 1]. The complementary log-log transformation is implemented 
in the LIFETEST procedure using the option CONFTYPE=LOGLOG. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Patients with unknown angiomyolipoma response status will be treated as non-responders in 
the calculation of the angiomyolipoma response rate in the Full Analysis Set at the end of the 
trial. 
If an AML progression is documented after two or more missing assessments or non-adequate 
assessments, then the date of AML progression will be censored at the date of the last adequate 
assessment. If an AML response is observed after a single missing or non-adequate assessment, 
the actual date of event will be used. 
TTAP will be censored if angiomyolipoma progression is not observed before the first to occur 
out of (i) the cut-off date for the analysis, or (ii) the date when a further systemic anti-
angiomyolipoma medication is started, (iii) the date of a angiomyolipoma-related surgery or  
(iv) the date of death. The censoring date will be the date of the most recent MRI assessment 
before the first of any of these four events occurred. 
Time to angiomyolipoma response applies only to patients who achieve an angiomyolipoma 
response, i.e., patients in the analysis will have known times to angiomyolipoma response and 
there will be no censored times. 
Duration of angiomyolipoma response will be censored if angiomyolipoma progression is not 
observed before the first to occur out of (i) the cut-off date for the analysis, or (ii) the date when 
a further systemic anti-angiomyolipoma medication is started, (iii) the date of a 
angiomyolipoma-related surgery or  (iv) the date of death. The censoring date will be the date 
of the most recent MRI assessment before the first of any of these four events occurred. 
Other missing data will simply be noted as missing on appropriate tables/listings. 


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Safety analyses 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., 
vital signs and special tests) will be considered as appropriate. 
All safety outputs will use the Safety Set. 
The safety summary tables will include only assessments collected no later than 30 days after 
the date of last administration of everolimus. The safety summary listings will include all 
assessments, with those collected later than 30 days after date of last everolimus being flagged. 
2.8.1 
Adverse events 
General rules for AE Reporting 
AE summaries will include all AEs starting on or after treatment day 1 (i.e., on or after the start 
date of everolimus) and no later than 30 days after the last day of everolimus. All AEs will be 
listed. AEs starting prior to treatment day 1 will be identified in the listings with a starting 
treatment day less than day 1, and AEs starting later than 30 days after the last day of everolimus 
will be specifically flagged. 
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, and having at least one AE in each body system/primary system organ class, and for 
each preferred term using MedDRA coding. A patient with multiple occurrences of an AE will 
be counted only once in the AE category. 
Separate AE summaries will be presented by primary system organ class, preferred term, and 
maximum common toxicity criteria (CTC) grade. A patient with multiple CTC grades for an 
AE will be summarized under the maximum CTC grade recorded for the event. 
The frequency of CTC grade 3 and 4 AEs will be summarized separately. 
Any information collected (e.g., CTC grades, relationship to study drug, action taken) will be 
listed as appropriate. 
AE summaries 
The following adverse event summaries will be produced: 
• Adverse events, regardless of study drug relationship, by primary system organ class 
and preferred term 
• Adverse events, with suspected relationship to study drug, by primary system organ 
class and preferred term 
• Adverse events, regardless of study drug relationship, by preferred term 
• Adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and maximum CTC grade 
• Adverse events, with suspected study drug relationship, by primary system organ class, 
preferred term and maximum CTC grade 


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• CTC grade 3 or 4 adverse events, regardless of study drug relationship, by primary 
system organ class and preferred term 
• CTC grade 3 or 4 adverse events, with suspected study drug relationship, by primary 
system organ class and preferred term 
• Deaths, by primary system organ class and preferred term 
• Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term 
• Serious adverse events, with suspected study drug relationship, by primary system organ 
class and preferred term 
• Adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by preferred term 
• Adverse events requiring dose adjustment or study drug interruption, regardless of study 
drug relationship, by preferred term 
• Adverse events requiring additional therapy, regardless of study drug relationship, by 
preferred term 
Adverse events will be presented in alphabetical order for system organ class, and in descending 
order of frequency for preferred term within each system organ class. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables for on 
treatment emergent AEs which are not SAEs with an incidence greater than and equal to 5% 
and on treatment emergent SAEs and SAEs suspected to be related to study treatment will be 
provided by system organ class and preferred term on the safety set. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.1.1 
Adverse events of special interest (AESI)/ grouping of AEs 
For each specified AESI, the number and percentage of patients with at least one event of the 
AESI occurring during the on-treatment period will be summarized. Summaries of these AESIs 
will be provided grouped by CTCAE grades, SAE, relationship, leading to treatment 
discontinuation, leading to dose adjustment/interruption, etc. 


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Such groups consist of adverse events for which there is a specific clinical interest in connection 
with everolimus treatment (i.e., where everolimus may influence a common mechanism of 
action responsible for triggering them), or adverse events which are similar in nature (although 
not identical). A non-exhaustive list of AE groupings includes “Stomatitis and related events”, 
“Infections”, “Amenorrheas” and “Non-infectious pneumonitis”. All notable adverse event 
groupings are defined through the use of Standardized MedDRA Queries (SMQ), Preferred 
Terms (PT), High Level Terms (HLT), or System Organ Classes (SOC), or through a 
combination of these four components. At the project level, a SAS dataset named eCRS contains 
the exact composition of the adverse events groupings will be used to map reported adverse 
events to the notable adverse events groupings. This dataset may be updated (i.e., it is a living 
document) based on review of accumulating trial data, and it is the most up to date version at 
the time of DB lock that will be used. Note that certain adverse events may be reported within 
multiple groupings. 
2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by system organ class and preferred term. 
All deaths will be listed for the safety set, post treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened subjects. 
2.8.3 
Laboratory data 
The laboratory assessments include hematology, biochemistry, coagulation , urinalysis, 
hepatitis markers, and pregnancy test. Data from all sources (central and local laboratories) will 
be listed, but summary tables will only include data from the central laboratory (except 
urinalysis, where most assessments were done in local lab). 
The frequency of notable laboratory abnormalities will be displayed by parameter. 
The following summaries will be produced for laboratory data (by laboratory parameter – 
except for coagulation parameters): 
• Number and percentage of patients with worst post-baseline CTC grade (regardless of 
the baseline status). Each patient will be counted only for the worst grade observed post-
baseline. 
• Shift tables using CTC grades to compare baseline to the worst post-baseline value will 
be produced for hematology and biochemistry laboratory parameters with CTC grades. 
• For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based on 
laboratory reference ranges. 
Note: As a project standard, shift tables using the low/normal/high classifications based on 
laboratory reference ranges to compare baseline to the final on-treatment laboratory value will 
not be produced. 
The following listings will be produced for laboratory data: 


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• Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges. 
• Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
A standard 12-lead ECG is to be performed at screening. Tracings must be dated and signed by 
the investigator (or his/her designee) and filed with the subject’s source documentation. 
Results from 12-lead ECG should be captured on the ECG Evaluation CRF. Significant findings 
must be recorded as Relevant Medical History. 
Data from electrocardiogram will be listed at screening and unscheduled visits. 
2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
parameters collected are height (cm), weight (kg), body temperature (°C), respiratory rate 
(breaths per minute), pulse (beats per minute) and both systolic and diastolic blood pressure 
(mmHg). 
The criteria for clinically notable abnormalities are defined below in Table 2-1. 
The following summaries will be produced for each vital sign parameter: 
• Number and percentage of patients with at least one post-baseline vital sign abnormality 
(in both directions, i.e., both elevated and below normal values). 
In addition, the following two listings will be produced: 
• Patients with clinically notable vital sign abnormalities. 
• All vital sign assessments listed by patient and vital sign parameter. 
In both listings, the clinically notable values will be flagged and the assessments collected later 
than 30 days after the last treatment date will also be flagged. 
Table 2-1 
Clinically notable values for vital signs  


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Vital Sign 
 
Criteria for clinically notable abnormalities 
Systolic BP (mmHg) 
High 
>=180 mmHg and increase >=20 mmHg from baseline 
 
Low 
<= 90 mmHg and decrease >=20 mmHg from baseline 
Diastolic BP (mmHg) 
High 
>=105 mmHg and increase >=15 mmHg from baseline 
 
Low 
<= 50 mmHg and decrease >=15 mmHg from baseline 
Body temperature (°C) 
High 
>=39.1°C 
 
Low 
<=35.0°C 
Weight (kg) 
High 
Increase from baseline of >= 10% 
 
Low 
Decrease from baseline of >= 10% 
Pulse (beats per minute [bpm]) 
High 
 120 bpm with increase from baseline of  15 bpm 
 
Low 
 50 bpm with decrease from baseline of  15 bpm 
2.8.4.3 
WHO performance Status 
The WHO performance scale (Table 2-2) is an instrument designed by the World Health 
Organization and is used to describe the physical health of patients, ranging from 0 (most active) 
to 4 (least active). 
Table 2-2 
WHO Performance Scale 
Score 
Description 
0 
Able to carry out all activity without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to do 
light work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
The WHO performance status will be analyzed for patients from the safety set. Frequency 
counts and percentages will be used to summarize performance status descriptively over time. 
A Listing of performance status will be presented. 
2.8.4.4 
Pulmonary function test 
Change from baseline in pulmonary function tests by time point will be presented. Lung 
function parameters including FEV1, FVC and DLCO  and changes from baseline will be 
summarized descriptively (mean, standard deviation, 25th and 75th percentiles, median, 
minimum and maximum) at each assessment in sporadic LAM and LAM patients only from 
safety set. Listing of pulmonary function test will also be presented for LAM patients. 
 
Pharmacokinetic endpoints   
Not applicable 


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PD and PK/PD analyses 
Not applicable 
 
Patient-reported outcomes 
Not applicable 
 
Biomarkers 
Not applicable 
 
Other Exploratory analyses 
Not applicable  
 
Final analysis 
A final analysis will be performed after all patients have completed Week 48 (or discontinued 
earlier but were followed up for efficacy up to Week 48) and their safety follow-up visit. 
3 
Sample size calculation 
Approximately 40 patients will be enrolled to meet the CFDA post approval requirements. The 
sample size is based on feasibility, there is no hypothesis testing. 
4 
Change to protocol specified analyses 
No change to protocol.  
5 
Appendix 
 
Imputation rules 
5.1.1 
Study drug 
The following rule should be used for the imputation of date of last administration for a given 
study treatment component: 
Scenario 1: If the date of last administration is completely or partially missing and the end of 
treamtent (EOT) eCRF page is available (prior to any death date or withdrawl of consent date, 
if available): 
Case 1: The date of last administration is completely missing, and the EOT visit date is complete, 
then this latter date should be used. 
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date: 
Use Dec31yyyy 
Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date: 
Use EOT date 


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Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy = the year of EOT date and mm < the month of EOT visit: 
Use last day of the Month (mm). 
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record 
Use the start date of that record. 
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations described in Section 2.4.1 and no imputation will be made. If the date of 
first administration is missing, then the date of last administration should not be imputed. 
5.1.2 
AE date imputation 
Adverse event end date 
No imputation of partial date or missing date was done except for imputation to handle events 
spreading over the cut-off date. 
Adverse event start date 
If the adverse event start date was missing no imputation was done. 
If the adverse event start date was partial (missing day) and the month occurred prior to the 
study medication start month and the year occurred prior to the study medication start year, the 
15th of the specified month was used.   
If the adverse event start date was partial (missing day), and the adverse event start month was 
greater than or equal to the study medication start month and the adverse event start year was 
greater than or equal to the study medication start year, the maximum of the first of the month 
of the adverse event start date or the study medication start date plus one day was used. 
The table below presents the algorithm used to impute the partial AE start date: 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
_null_ 
_null_ 
_null 
_null_ 
YYYY < 
TRTY 
01JULYYYY 
15MONYYYY 
15MONYYYY 
15MONYYYY 
YYYY = 
TRTY 
TRTSTD+1 
15MONYYYY 
MAX(01MONYYYY, 
TRTSTD+1) 
MAX(01MONYYYY, 
TRTSTD+1) 
YYYY > 
TRTY 
01JANYYYY 
MAX(01MONYYYY, 
TRTSTD+1) 
MAX(01MONYYYY, 
TRTSTD+1) 
MAX(01MONYYYY, 
TRTSTD+1) 
Where: 
MON = Month of Partial Adverse Event Start Date 
YYYY =Year of Partial Adverse Event Start Date 
TRTM= Month of Treatment Start Date 


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TRTY= Year of Treatment Start Date 
TRTSTD = Treatment Start Date 
5.1.3 
Concomitant medication date imputation 
Medication/therapy end date 
If the medication/therapy end day or day/month was missing and the partial date indicated that 
the medication/therapy clearly started prior to or equal to the year of study treatment start - 
Impute the last day of the month or 31 December. 
If the medication/therapy end date is completely missing - Check to see if medication is still 
ongoing before imputing a date and also when it started in relation to study drug. If the ongoing 
flag is missing then we assume that medication is still being taken (i.e. no imputation is done).  
If the medication is not ongoing and medication start date is prior to first dose date of study 
treatment then impute the study treatment end date as medication end date. Similarly, if 
medication started on or after first dose date then impute the last date of either the last dose date 
of study treatment or a day after medication/therapy start date. 
Medication/therapy start date 
If the medication/therapy start day or day/month was missing and the partial date indicated that 
the medication/therapy clearly started prior to or equal to the year of study treatment start, the 
1st of the month or January 1 was used as the medication/therapy start date.   
If the medication/therapy start day was missing, and the partial date did not indicate if the date 
was before or after first dose of study treatment, the medication/therapy start date was imputed 
to: 
• 01JAN CMDEND1Dyyyy if the medication/therapy end date was before the start of 
study treatment (where CMDEND1D is the medication/therapy end date). 
• Start of study treatment otherwise. 
5.1.3.1 
Prior therapies date imputation 
Not applicable 
5.1.3.2 
Post therapies date imputation 
Not applicable 
5.1.3.3 
Other imputations 
Not applicable 
 
AEs coding/grading 
Coding of AEs 
Adverse events are coded using the MedDRA terminology. 
Grading of AEs 


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AEs will be assessed according to the CTCAE version 4.03. In case of an update of the CTC 
criteria, some mapping may be necessary. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of TSC treatments. CTCAE v4.03 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). Grade 1 
to 5 will be used to characterize the severity of the Adverse Event. 
If CTCAE grading does not exist for an adverse event, grades 1 – 5 corresponding to the severity 
of mild, moderate, severe, life-threatening, and death related to the AE will be used.  
 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI CTCAE 
version 4.03. The calculation of laboratory CTC grades will be based on the observed laboratory 
values only, clinical assessments will not be taken into account. The criteria to assign CTC 
grades are given in <Novartis internal criteria for CTC grading of laboratory parameters>. The 
latest available version of the document based on the underlying CTCAE version 4.03 at the 
time of analysis will be used. 
For laboratory tests where grades are not defined by CTCAE version 4.03, results will be graded 
by the low/normal/high (or other project-specific ranges, if more suitable) classifications based 
on laboratory normal ranges. 
A severity grade of 0 will be assigned when the value is within normal limits. In the case when 
a local laboratory normal range overlaps into the higher (i.e., non-zero) CTC grade, the 
laboratory value will still be taken as within normal limits and assigned a CTC grade of zero. 
Grade 5 will not be used. 
5.3.1 
Handling of test values below LLOQ and above HLOQ 
For numeric laboratory parameters, test values below the lower limit of quantification (LLOQ) 
and above the higher limit of quantification (HLOQ) may show “<n” (or “<=n”) and “>n” (or 
“>=n”) in the database respectively, where n can be any number. The classification of CTC 
grades, the low/normal/high groups, and time point summary tables will follow this data 
handling rule: a value which shows “<n” (or “<=n”) will be handled as zero; a value which 
shows and “>n” (or “>=n”) will be handled as n. These values will be presented in the listing 
as it is. 
 
Statistical models 
5.4.1 
Primary analysis 
Primary analysis is safety analysis, so no model will be used for analysis.  
5.4.2 
Key secondary analysis 
Not Applicable 


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Rule of exclusion criteria of analysis sets  
Not Applicable  
6 
Reference 
DuBois D and DuBois EF (1916). A formula to estimate the approximate surface area if height 
and weight be known. Arch Intern Medicine, 17, 863-71. 
Cockcroft DW, Gault MH, et al (1976) Prediction of creatinine clearance from serum creatinine. 
Nephron; 16: 31-41. 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika, 26, 404-413. 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics, 38, 29 - 41. 
Collett D (1994). Modelling survival data in medical research. Chapman & Hall, London. 
Kalbfleisch JD and Prentice RL (1980). The Statistical Analysis of Failure Time Data, New 
York: John Wiley & Sons, Inc. 
Hyman MH and Whittemore VH (2000). National Institutes of Health consensus conference: 
tuberous sclerosis complex. Arch Neurol, 57, 662-5 
International Conference on Harmonization. E9: Statistical Principles for Clinical Trials. 
Roach ES, Gomez MR, Northrup H (1998). Tuberous sclerosis complex consensus conference: 
revised clinical diagnostic criteria. J Child Neurol, 13, 624-8.