Conditions: Growth and Development
Keywords: TSC-associated SEGA, height, weight, Tanner Stage, growth development, everolimus, RAD001
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
The primary objective of CRAD001M2305 was to report the long-term effects of everolimus treatment on height, weight and sexual development (using Tanner Stages) in children and adolescents with Tuberous Sclerosis Complex (TSC)-associated with Subependymal Giant Cell Astrocytoma (SEGA). The study monitored the growth and development of pediatric patients with TSC-associated SEGA, previously enrolled in CRAD001M2301 (NCT00789828) until they reach Tanner Stage V, or until age 16 for females or 17 for males whichever occurred first.

Detailed description:
CRAD001M2305 was a prospective, multi-center phase IIIb/IV study. This study investigated if the physical and sexual development of pediatric patients was affected by previous or ongoing treatment with everolimus. The study monitored the growth and development of pediatric patients with TSC-associated SEGA, previously enrolled in CRAD001M2301(NCT00789828) until they reached Tanner Stage V, or until age 16 for females or 17 for males whichever occurred first. Continued treatment with everolimus was at investigator discretion and was not required for participation in CRAD001M2305. Growth (height, weight), and sexual development (Tanner Stages, sex hormone levels, age at menarche, thelarche (females) and adrenarche (males)), and brain development (assessed by TAND Checklist, dates of brain MRI) of patients participating in this long-term follow-up study was followed at annual visits to the site until patients achieve Tanner Stage V or age 16 (females), age 17 (males) whichever occurred first. Adverse events, concomitant medication, appearance of menarche, were monitored and data collected every 3 months ("3-monthly"). Unless clinically indicated these 3-monthly visits were performed per telephone.

Arms:
arm 1: All patients will have been previously treated with everolimus as part of CRAD001M2301. Continued treatment with everolimus is allowed but not required for participation in this study.

Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: At the discretion of the investigator, pediatric patients could be treated with commercially available everolimus, as per local product information / standard of care. Treatment duration and dose modifications were at the investigator's discretion, as per the local product information.

Protocol document:
Prot_000.pdf: 
Clinical Development 
RAD001 (everolimus) 
Protocol CRAD001M2305 / NCT02338609
Long-term follow-up study to monitor the growth and 
development of pediatric patients previously treated with 
everolimus in study CRAD001M2301 (EXIST-LT) 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-003795-13 
Version number 
01 (Clean) 
Development phase 
IIIb/IV 
Document status 
Final 
Release date 
11-Aug-2014
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 4 
List of tables ........................................................................................................................ 4 
List of abbreviations ............................................................................................................ 5 
Amendment 1 ...................................................................................................................... 7 
Protocol summary: ............................................................................................................. 11 
1 
Background ........................................................................................................................ 16 
1.1 
Overview of subependymal giant cell astrocytomas (SEGA) associated with 
tuberous sclerosis complex (TSC) and growth and development ......................... 16 
1.1.1 
SEGA-associated with TSC .................................................................. 16 
1.1.2 
Treatments for SEGA-associated with TSC ......................................... 16 
1.1.3 
Growth and development ...................................................................... 17 
1.2 
Introduction to everolimus ..................................................................................... 18 
1.2.1 
Overview of everolimus (RAD001) ...................................................... 18 
2 
Rationale ............................................................................................................................ 21 
2.1 
Study rationale and purpose................................................................................... 21 
2.2 
Rationale for the study design ............................................................................... 22 
3 
Objectives and endpoints ................................................................................................... 23 
4 
Study design ...................................................................................................................... 26 
4.1 
Description of study design ................................................................................... 26 
4.2 
Timing of interim analyses and design adaptations ............................................... 29 
4.3 
Definition of end of the study ................................................................................ 29 
4.4 
Early study termination.......................................................................................... 29 
5 
Population .......................................................................................................................... 29 
5.1 
Patient population .................................................................................................. 29 
5.2 
Inclusion criteria .................................................................................................... 29 
5.3 
Exclusion criteria ................................................................................................... 30 
6 
Treatment ........................................................................................................................... 30 
6.1 
Monitoring everolimus dosing ............................................................................... 30 
6.2 
Concomitant medications ...................................................................................... 30 
6.3 
Patient numbering, everolimus exposure ............................................................... 31 
6.3.1 
Patient numbering ................................................................................. 31 
6.3.2 
Everolimus exposure ............................................................................. 31 
7 
Visit schedule and assessments ......................................................................................... 31 
7.1 
Study flow and visit schedule ................................................................................ 31 


Novartis 
Confidential 
Page 3 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
7.1.1 
Eligibility enrollment ............................................................................ 34 
7.1.2 
Study participation ................................................................................ 34 
7.1.3 
Study completion .................................................................................. 34 
7.1.4 
Post-study follow up period .................................................................. 35 
7.2 
Assessment types ................................................................................................... 35 
7.2.1 
Efficacy assessments ............................................................................. 35 
7.2.2 
Safety and tolerability assessments ....................................................... 35 
8 
Safety monitoring and reporting ........................................................................................ 38 
8.1 
Adverse events ....................................................................................................... 38 
8.1.1 
Definitions and reporting ...................................................................... 38 
8.2 
Serious adverse events ........................................................................................... 39 
8.2.1 
Definitions ............................................................................................. 39 
8.2.2 
Reporting ............................................................................................... 39 
8.3 
Pregnancies ............................................................................................................ 40 
8.4 
Warnings and precautions...................................................................................... 41 
9 
Data collection and management ....................................................................................... 41 
9.1 
Data confidentiality ............................................................................................... 41 
9.2 
Site monitoring ...................................................................................................... 41 
9.3 
Data collection ....................................................................................................... 42 
9.4 
Database management and quality control ............................................................ 42 
10 Statistical methods and data analysis ................................................................................ 42 
10.1 
Analysis sets .......................................................................................................... 43 
10.1.1 
Full Analysis Set ................................................................................... 43 
10.1.2 
Safety Set .............................................................................................. 43 
10.1.3 
Per-Protocol Set .................................................................................... 44 
10.2 
Patient demographics/other baseline characteristics ............................................. 44 
10.3 
Treatments (everolimus treatment, concomitant therapies, exposure) .................. 44 
10.4 
Primary objective ................................................................................................... 44 
10.4.1 
Variable ................................................................................................. 45 
10.4.2 
Handling of missing values/censoring/discontinuations ....................... 47 
10.4.3 
Supportive analyses ............................................................................... 47 
10.5 
Secondary objectives ............................................................................................. 47 
10.5.1 
Safety objectives ................................................................................... 47 
10.5.2 
Pharmacokinetics .................................................................................. 51 
10.6 
Exploratory objectives ........................................................................................... 51 
10.7 
Interim analysis ...................................................................................................... 51 


Novartis 
Confidential 
Page 4 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
10.8 
Sample size calculation.......................................................................................... 52 
10.9 
Power for analysis of key secondary variables ...................................................... 53 
11 Ethical considerations and administrative procedures ...................................................... 53 
11.1 
Regulatory and ethical compliance ........................................................................ 53 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 53 
11.3 
Informed consent procedures ................................................................................. 53 
11.4 
Discontinuation of the study .................................................................................. 54 
11.5 
Publication of study protocol and results............................................................... 54 
11.6 
Study documentation, record keeping and retention of documents ....................... 54 
11.7 
Confidentiality of study documents and patient records ....................................... 55 
11.8 
Audits and inspections ........................................................................................... 55 
11.9 
Financial disclosures .............................................................................................. 55 
12 Protocol adherence ............................................................................................................ 55 
12.1 
Amendments to the protocol .................................................................................. 56 
13 References (available upon request) .................................................................................. 57 
 
List of figures 
Figure 4-1 
Study flowchart ..................................................................................... 28 
 
List of tables 
Table 1-1 
Non-interventional studies .................................................................... 21 
Table 3-1 
Objectives and related endpoints .......................................................... 25 
Table 6-1 
Dose and treatment schedule (if continuing on everolimus) ................. 30 
Table 7-1 
Visit evaluation schedule ...................................................................... 32 
Table 10-1 
95% confidence interval for different number of observed patients 
with growth development abnormality during M2305 (sample size 
N = 50) .................................................................................................. 52 
Table 10-2 
Probability that the true rate of patients with growth development 
abnormality is lower or equal to 0.10 as a function of number of 
observed patients with development abnormality ................................. 53 
 


Novartis 
Confidential 
Page 5 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
List of abbreviations 
AE 
Adverse Event 
µM 
Micro mole 
AKT 
Protein Kinase B 
ATC 
Anatomical-Therapeutic-Chemical 
BMI 
Body Mass Index 
CCHMC 
Cincinnati Children’s Hospital Medical Center 
CHMP 
Committee for Medicinal Products for Human Use 
Cm 
Centimeter 
Cmax 
Maximum Concentration 
Cmin 
Minimum (trough) Concentration 
CNAE 
Clinically Notable Adverse Event 
CPO 
Country Pharmaceutical Organization 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTH 
Clinical Trial Head 
DS&E 
Drug Safety & Epidemiology 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EIAED 
Enzyme Inducing Antiepileptic Drugs 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
HUVEC 
Human Umbilical Vein Endothelial Cell 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
In 
Inch 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
Kg 
Kilogram 
Lb 
Pound 
LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mTOR 
Mammalian target of Rapamycin 
NCI 
National Cancer Institute 
nM 
Nano mole 


Novartis 
Confidential 
Page 6 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
PASS 
Post-Authorization Safety Study 
PD 
Progressive Disease 
PHI 
Protected Health Information 
PI3K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetic 
p-S6 
Phosphorylated S6 
RCC 
Renal Cell Carcinoma 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDS 
Standard Deviation Score 
SEC 
Study Evaluation Completion 
SEGA 
Subependymal Giant Cell Astrocytoma 
SEN 
Subependymal Nodule 
SI 
Système International 
SS 
Safety Set 
SUSAR 
Suspected Unexpected Serious Adverse Event 
TAND 
TSC-Associated-Neuropsychiatric-Disorders 
TDM 
Therapeutic Drug Monitoring 
TS 
Tanner Stage 
TSC 
Tuberous Sclerosis Complex 
UK 
United Kingdom 
US 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 


Novartis 
Confidential 
Page 7 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Amendment 1 
Amendment rationale 
At the time of this amendment, enrollment into this study has not yet started. 
This protocol is being amended in order to address comments received from the reviewers at 
the Committee for Medicinal Products for Human Use (CHMP). In light of these comments 
from the Health Authority, the protocol is being amended to clarify operational activities that 
are planned for each visit. Additional details regarding the analysis plan were added. 
The specific issues addressed in this amendment include: 
1. To more completely capture the trajectory of growth and sexual development, the 
maximum age of follow up is increased from age 15 years (female) and 16 years (male), to 
16 years (female) and 17 years (male). 
2. To better evaluate the physiological basis of potential delays in growth or sexual 
development, annual endocrine laboratory testing for FSH, LH, and estrogen (females) or 
testosterone (males) will be performed. 
3. To provide a more detailed description of growth and sexual development in the study 
population, the age of attainment of each Tanner stage will be evaluated. 
4. To better track everolimus exposure and dosing, investigators will be asked to estimate the 
duration of interruptions by the patient in the prior reporting period. 
5. Sample size determinations have been added as well as other clarifications of the analysis 
plan. 
6. Data collected in the follow-up M2305 study will be pooled with the corresponding 
patient’s data collected in the parent CRAD001M2301 study. Inclusion of baseline values 
collected in M2301 before the start of everolimus will be used to calculate the whole 
exposure to everolimus for patients enrolled in the M2305 study and in considerations 
pertaining to the entire growth/development course over time from the start of everolimus. 
7. To be able to differentiate the impact of the TSC condition and the impact of the 
everolimus treatment on growth and sexual development a data set from peri-pubertal 
patients with TSC, who have not been exposed to everolimus will be used as a 
reference. These patients are a subset of the patient population that is currently being 
enrolled into the TOSCA registry (CRAD001MIC03). By end of enrollment TOSCA will 
have collected the data of approximately 1700 patients from 31 countries around the 
world. The descriptive analyses will present, side by side, the results from the 
CRAD001M2305 patients and those from the TOSCA registry patients not treated with an 
mTOR inhibitor, whenever similar data are collected in both studies. Detailed definition of 
the TOSCA subset of patients that will be used as a TSC-untreated reference population is 
provided in this amendment. If the missing data pattern is not limiting, exploratory 
indirect comparisons between patients treated by everolimus (from M2305 study) and 
those who never received an mTOR inhibitor (TOSCA subset of patients) will be 
performed to evaluate the everolimus effect on growth and sexual development (through 
the use of propensity scores). 


Novartis 
Confidential 
Page 8 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
8. The WHO growth charts will be used as reference data representing the average global 
population. Since no weight-for-age references are available from the WHO above 10 
years of age, the WHO BMI-for-age references from 0 to 19 years of age will be used and 
the BMI standard-deviation scores (SDS) will be analyzed instead of weight SDS. 
9. The long-term brain development and in particular the occurrence of TSC associated 
neurocognitive disorders will be assessed through the collection of the TAND Checklist, 
whenever available. Brain MRI scans may be evaluated, provided that scientific or 
technological advancements allow these data to be used for assessing brain functions. 
10. The window to allow patients entering the study was extended from 3 to 6 months after 
end of treatment in study CRAD001M2301. 
11. The language regarding evaluation of adverse event data was aligned with Novartis data 
directory requirements. 
Changes to the protocol 
1. Section 1.1.2, Section 1.2.1: Updated with newest regulatory and approval information 
2. Section 1.1.3: Deleted sentence regarding TSC and development delays. Updated 
regarding toxicology and amenorrhea see in preclinical and clinical studies to-date 
3. Section 2.1, Figure 4-1, Section 10. Updated to clarify patient population. 
4. Section 2.1, Figure 4-1, Section 6, Section 7.1.3, Section 10.3, Section 10.4: Clarifications 
made to remove implication that everolimus/study treatment mandatory for study 
participation (including changes made to sub-section headers) 
5. Section 2.2, Section 3, Table 3-1, Section 4.1, Figure 4-1, Section 5, Table 7-1, 
Section 7.2.2.3, Section 10.4.1, Section 10.4.2.3: Added endocrine laboratory values as 
part of development monitoring 
6. Section 2.1, Section 2.2, Section 3, Table 3-1, Section 4.1, Figure 4-1, Section 4.3, 
Section 5: Updated study completion age to 16 (female) and 17 (male). 
7. Section 2.2, Section 3, Table 3-1, Section 4.1, Figure 4-1, Section 5, Section 6.3.2, 
Table 7-1, Section 10.3, Section 10.5.2: Clarified the data collection and analysis 
regarding everolimus dose exposure and dose interruptions 
8. Section 3, Section 10.4.2.2, Section 10.5.1.3: Updated the activities relating to collection 
and analysis of Tanner Stage data 
9. Section 4.1: Updated frequency and activities that will be completed at each respective 
visit 
10. Section 4.1, Section 7.2.2.1, Section 10.4.2.1: Clarified data collection and analysis for 
height and weight 
11. Section 4.3: Updated potential LPLV to 2026 since age for study completion is now later 
12. Section 7.1.3: Clarifications added regarding end of study activities. 
13. Section 10.5.3.1: Added analysis and definition for potential delayed puberty 
14. Section 10.8: Updated the analysis for sample size calculations 
15. Section 1.1.3: Deleted sentence regarding recent growth surveys and trends in growth and 
development of children. Deleted sentence stating that TSC and SEGA and not everolimus 
therapy could be the cause of delayed development. 


Novartis 
Confidential 
Page 9 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
16. Section 2.2, Section 4.1, Figure 4-1, Table 7-1, Section 7.2.2.4 and 7.2.2.5: Annual brain 
MRI status collection and TAND Checklist added. 
17. Section 2.2, Section 10: Added that data of CRAD001M2305 will be pooled with data 
from parent protocol CRAD001M2301 and clarification of how data will be reported side 
by side. 
18. Section 3, Table 3-1: Primary endpoints updated: Weight replaced by BMI, height and 
BMI SDS by year since baseline. 
19. Section 3, Table 3-1: Secondary endpoints: added brain development as assessed by 
TAND and indirect comparison of CRAD001M2305 and CRAD001MIC03 (TOSCA). 
20. Section 4.1, Figure 4-1, Section 5.1, Section 5.2: Enrolment window extended from 3 to 6 
months after last treatment in CRAD001M2301. 
21. Section 8.1.1: Updated adverse events evaluation. 
22. Section 10: Update that statistical analyses will primarily be descriptive. 
23. Section 10: Added paragraph about data comparison with data from TOSCA registry. 
24. Section 10.1.1: Definition of analysis sets updated to reflect addition of TOSCA patients 
who are younger than 17 and have not received any mTOR inhibitor. 
25. Section 10.1.2: Clarification added that all patients have received everolimus in study 
CRAD001M2301. 
26. Section 10.2: Demographics and baseline characteristics updated to reflect addition of 
TOSCA data. Baseline values were updated accordingly. 
27. Section 10.3: Updated to describe how cumulative duration and dose of everolimus will be 
calculated/estimated for the time prior to CRAD001M2305 and during CRAD001M2305. 
28. Section 10.4.2.2: Section fully revised. Weight replaced by BMI and formulas updated. 
29. Section 10.4.2.2: Safety Set replaced by FAS of both studies CRAD001M2305 and 
TOSCA. Clarification for which patients the relationship between the everolimus exposure 
and the Tanner Stage will be done. 
30. Section 10.4.2.3: Safety Set replaced by FAS of both studies CRAD001M2305 and 
TOSCA. Clarification for which patients graphs will be provided. 
31. Section 10.4.3: Updated to include data from TOSCA registry. 
32. Section 10.5.1.3: Clarified statistical analysis of age when patients reach each Tanner 
Stage. Clarification that FAS instead of Safety Set will be used. 
33. Section 10.5.1.3: Statistical section regarding TAND assessments added. 
34. Section 10.5.1.4: Section added to describe how the indirect comparison will be 
performed. 
35. Section 10.5: Addition of TAND assessments and indirect comparison with TOSCA. 
36. Section 10.5.1.1: Clarification that adverse events will be described only for 
CRAD001M2305. 
37. Section 10.5.2: Weight SDS replaced by BMI SDS in the last paragraph. 
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 underlined for insertions. 


Novartis 
Confidential 
Page 10 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
IRB 
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. In addition, if 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 amended protocol. 


Novartis 
Confidential 
Page 11 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Protocol summary: 
Protocol number 
CRAD001M2305 
Title 
Long-term follow-up study to monitor the growth and development of 
pediatric patients previously treated with everolimus in study 
CRAD001M2301 (EXIST-LT) 
Brief title 
Long-term monitoring of growth and development of pediatric patients 
previously treated with everolimus 
Sponsor and Clinical 
Phase 
Novartis 
Phase IIIb/IV 
Investigation type 
Post Authorization Safety Study (PASS) 
Study type 
Interventional 
Purpose and rationale 
The results from CRAD001M2301 have shown that a significant proportion 
of patients with advanced TSC-associated SEGA benefited from 
continuous treatment with the mTOR inhibitor everolimus which led to 
volume reduction of the SEGA lesions. Patients with TSC-associated 
SEGA are typically young children at pre-pubertal age whose physical and 
sexual maturation is ongoing. mTOR has been shown to be an important 
regulator of cell growth and proliferation. Additionally, it is possible that 
mTOR is also a regulator of sexual development and maturation. As many 
patients treated in CRAD001M2301 were young at the time of their 
exposure to everolimus (an mTOR inhibitor) and/or have experienced 
prolonged exposure to the drug from a young age, patients exposed to 
everolimus as part of CRAD001M2301 may present an appropriate study 
population in which to track the long term impact of everolimus exposure 
on growth and development. 
Therefore this safety extension-study is implemented to continue 
monitoring growth and development of pediatric patients previously 
enrolled in CRAD001M2301 who have been treated or are being treated 
with everolimus. 
Primary Objective(s) 
The primary objective of this study is to monitor the growth and 
development of pediatric patients with TSC-associated SEGA, previously 
enrolled in CRAD001M2301, who had received everolimus as part of study 
CRAD001M2301 and may or may not be continuing treatment with 
everolimus by annual assessments of: 
1. Height 
2. Weight for BMI 
3. Tanner Stage 
4. Endocrine laboratory values (FSH, LH, and estrogen or testosterone) 
Secondary Objectives 
• 
Long-term safety 
• 
Age at menarche (females) 
• 
Age at thelarche (females) 
• 
Age at adrenarche (males) 
• 
Age at Tanner Stages II-V 
• 
Assess neuropsychological development by TAND Checklist 
• 
Compare CRAD001M2305 and CRAD001MIC03 on height, BMI and 
sexual development (using Tanner Stages) 
Study design 
This is a prospective, multi-center, long-term follow-up, Post-Authorization 
Safety Study (PASS) evaluating the growth and development of pediatric 


Novartis 
Confidential 
Page 12 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
patients who are currently being treated with everolimus and have been 
treated with everolimus for TSC-associated SEGA. The study will include 
all consenting pediatric patients who at the time of completion of study 
CRAD001M2301 have not achieved Tanner Stage V and are younger than 
16 years (for females) or 17 years (for males), and were receiving 
treatment with everolimus in study CRAD001M2301 within 6 months 
before enrollment into CRAD001M2305. 
According to CRAD001M2301 enrollment figures, it is anticipated that at 
the time of the start of study CRAD001M2305, approximately 50 patients 
may be eligible for this study, if they consent to participate. 
Population 
The target population is comprised of pediatric female and male patients 
who have previously participated in the study CRAD001M2301 and have 
not, prior to enrollment into CRAD001M2305, reached age 16 for females, 
or age 17 for males. Additionally, these patients will not yet have achieved 
Tanner Stage V. Study treatment in study CRAD001M2301 must have 
been completed within 6 months prior to enrollment into CRAD001M2305. 
Inclusion criteria 
1. Pediatric female patients who were on study treatment in study 
[CRAD001M2301] within the past 6 months and have not reached 
Tanner Stage V or age 16 at the time of completion of 
[CRAD001M2301] 
or 
2. Pediatric male patients who were on study treatment in study 
[CRAD001M2301] within the past 6 months and have not reached 
Tanner Stage V or age 17 at the time of completion of 
[CRAD001M2301]. 
3. Written informed consent according to local guidelines. 
Exclusion criteria 
1. Pediatric female patients who were on study treatment in 
[CRAD001M2301] and have not reached Tanner Stage V but are 
within 3 month of turning age 16 
or 
2. Pediatric male patients who were on study treatment in 
[CRAD001M2301] and have not reached Tanner Stage V but are 
within 3 months of turning age 17 
3. Any patient who was pregnant prior to start of CRAD001M2305 
Investigational and 
reference therapy 
Not applicable 
Efficacy assessments 
Not applicable 
Safety assessments 
Safety assessments will consist of monitoring and recording adverse and 
serious adverse events. 
Other assessments 
To monitor the growth and the development of pediatric patients the 
following assessments will be performed annually: 
• 
Height 
• 
Weight 
• 
Tanner Stage 
• 
LH, FSH, and estrogen levels (female patients) 
• 
LH, FSH, and testosterone levels (male patients)Furthermore, the 
timing of menarche, thelarche (females) and adrenarche (males) and 
age at each Tanner Stage (II-V) will also be determined if achieved 
before study completion. 
• 
TAND Checklist 


Novartis 
Confidential 
Page 13 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
• 
Date of brain MRI scans 
Data analysis 
This is a long-term safety follow-up study and statistical analyses will be 
primarily descriptive for all endpoints. 
Data collected in this CRAD001M2305 study will be pooled with the 
corresponding patient’s data collected in the parent CRAD001M2301 
study, in particular, background information on the disease history, 
demographics and baseline characteristics, everolimus exposure, sexual 
and growth development data. 
To facilitate the interpretation of the CRAD001M2305 results and help 
differentiate the impact of the TSC condition versus the impact of 
everolimus on growth and sexual development, a descriptive statistical 
comparison will be performed using data from patients with comparable 
clinical characteristics, enrolled in the TOSCA registry (CRAD001MIC03) 
and not treated with any mTOR inhibitor. The descriptive analyses will 
present, side by side, the results from the CRAD001M2305 patients and 
those from the TOSCA patients not treated with any mTOR inhibitor, 
whenever similar data are collected in both studies. 
Categorical data will be presented as frequencies, percentages, and 95% 
confidence intervals. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
If the missing data pattern is not limiting, exploratory indirect comparisons 
between patients treated by everolimus (from M2305 study) and those who 
never received an mTOR inhibitor (TOSCA subset of patients) will be 
performed to evaluate the everolimus effect on growth and sexual 
development (use of propensity scores). 
In order to describe data from the CRAD001M2305 patients and those 
from the TOSCA registry side by side, the following analyses sets will be 
used. 
• 
The Full Analysis Set (FAS): 
• 
for CRAD001M2305, FAS will consist of all patients enrolled in this 
study. 
• 
for TOSCA, FAS will consist of all patients enrolled in this TOSCA 
registry whose age at study entry was below 17 years and who 
never received an mTOR inhibitor throughout the registry follow-up 
period. 
• 
The Full Analysis Set for sexual development (FAS Puberty): 
• 
for CRAD001M2305, FAS Puberty will consist of the FAS patients 
defined above. 
• 
for TOSCA, FAS Puberty will consist of the FAS patients defined 
above but restricting from the patients to those aged between 9 to 
17 years at study entry. The TOSCA registry is designed to collect 
Tanner Staging until 2017 (i.e. 4 to 6 years of follow-up). Thus it is 
considered adequate to select only TOSCA patients aged between 
9 to 17 years old at the time of entry to the registry to allow for 
obtaining puberty data corresponding to the peri-pubertal time 
frame. 
The Safety Set (SS) will include all patients enrolled in this follow-up 
CRAD001M2305 study who have at least one-post baseline safety 
assessment. It should be noted that all patients enrolled in the 
CRAD001M2305 study have been exposed to everolimus in the parent 
study CRAD001M2301 (and may or may not continue receiving 


Novartis 
Confidential 
Page 14 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
commercial everolimus while on CRAD001M2305). 
For CRAD001M2305 patients, the duration of everolimus exposure and 
cumulative everolimus dose will be described using descriptive statistics 
on the Safety Set. 
The total duration of everolimus exposure will be calculated as the total 
duration of everolimus exposure received while on CRAD001M2301 plus 
the total duration of (commercially supplied) everolimus exposure reported 
in CRAD001M2305. 
In the CRAD001M2305 study, the duration of (commercially supplied) 
everolimus exposure will be estimated using the dates of the first and last 
everolimus doses and investigator summary of treatment interruptions 
between each visit. 
The primary safety objective of this study is to report the effect of 
everolimus treatment on height, BMI and sexual development (using 
Tanner Stages) in children and adolescents with TSC-associated SEGA 
who are taking everolimus or have taken everolimus. 
The height and BMI standard deviation scores (SDS) will be calculated 
based on data collected during the study and published reference 
information. The SDS (also called z-scores) will be computed for a 
particular patient at each time point. The time-course of height and BMI 
SDS will be summarized on the FAS using descriptive statistics by year 
since the enrollment date. Growth charts for height and BMI will be 
presented for each patient. 
Percentage of patients who will have reached Tanner Stage V by age 16 
(for females) or age 17 (for males) will be provided on the FAS Puberty, 
along with 95% confidence intervals. 
Endocrine parameters such as LH, FSH, testosterone levels (in males) 
and LH, FSH, estrogen levels (in females) will be summarized descriptively 
by gender and by age over time on the Safety Set. 
The following secondary objectives will be described: the long term-safety, 
the age at Tanner Stage V, the age at thelarche and menarche for 
females, and the age at adrenarche for males. The secondary safety 
objective of the study will be based mainly on the frequency of adverse 
events. 
The overall observation period will be divided into two mutually exclusive 
segments to analyse the adverse events on the Safety Set in the M2305 
study: 
1. everolimus exposure period: from day of first commercial dose 
received in the M2305 study to 30 days after the last commercial dose 
received in the M2305 study 
2. post-everolimus exposure period: 
• 
starting at day 30+1 after the last commercial dose in the M2305 
study 
or 
• 
starting at the enrollment date for patients who will stop everolimus 
in M2301 and who will not start everolimus in M2305. 
Summary tables for adverse events (AEs) have to include only AEs that 
started or worsened during the everolimus exposure period. However, all 
safety data will be listed and those collected during the post-everolimus 
exposure period are to be flagged. 
Deaths reportable as SAEs and non-fatal serious adverse events will be 
listed by patient and tabulated by type of adverse event. 


Novartis 
Confidential 
Page 15 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Clinically notable AEs (CNAE) will be considered. Such categories consist 
of one or more well-defined safety events which are similar in nature and 
for which there is a specific clinical interest in connection with everolimus. 
The other secondary safety objectives of the study will be based on sexual 
and neuropsychological development data. 
The age when patients reach each Tanner Stage II-V will be summarized 
on the FAS Puberty. 
The following variables will be summarized on the Safety Set (those are 
only collected in the CRAD001M2305 study) using descriptive statistics: 
• 
age when females will start thelarche 
• 
age when females will have their first menses 
• 
age when males will reach adrenarche 
Potential delayed puberty will be defined based on Tanner stage and also 
on onset of menarche for girls. Potential cases identified through this 
algorithm, will then be clinically reviewed by assessing all available 
information in order to conclude the clinical relevance of the delay: 
• 
Potential delayed puberty in girls is defined as failure to attain Tanner 
Stage II by age 13, or absence of menarche by age 15 or within 5 
years of attainment of Tanner Stage II 
• 
Potential delayed puberty in boys is defined as failure to attain Tanner 
Stage II by age 14 
All responses to the individual questions from the TAND Checklist 
(collected in both studies) will be summarized using descriptive statistics 
on both studies, side by side, and over time on the FAS. 
Everolimus blood trough levels (Cmin), collected at investigator discretion 
in compliance with local product information, should be recorded if 
available. The time-normalized Cmin value will be estimated for the entire 
treatment period using recorded everolimus Cmin values and prescribed 
doses in that treatment period. Cmin will be summarized with descriptive 
statistics over time. 
No formal interim analysis is planned for this study. However, safety 
outputs may be generated for regulatory safety updates. 
Key words 
Pediatric Study, Growth and Development, Height, Weight, BMI, Tanner 
Stage, Tuberous Sclerosis Complex (TSC), TSC SEGA, Everolimus 


Novartis 
Confidential 
Page 16 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
1 
Background 
1.1 
Overview of subependymal giant cell astrocytomas (SEGA) 
associated with tuberous sclerosis complex (TSC) and growth 
and development 
The long term effects of everolimus on the growth and development of pediatric patients 
treated for TSC-associated SEGA are unknown. This study is designed to monitor the long 
term growth and development of pediatric patients who had previously been treated with 
everolimus in a randomized, placebo controlled clinical trial of everolimus in this indication 
(CRAD001M2301). 
1.1.1 
SEGA-associated with TSC 
TSC is an autosomal dominant genetic disorder caused by inactivating mutations in the TSC1 
or TSC2 genes, with a prevalence ranging from 1 in 6000 to 1 in 25,000 (Morrison 2009, 
Crino 2006, Osborne 1991). TSC affects approximately 1 million people worldwide (Anon 
2010). The disease is characterized by benign, highly vascular, hamartoma growth and 
variable clinical manifestations ranging from mild dermatologic findings to seizures (which 
affect up to 90% of patients), learning disabilities (38% to 80%), mental retardation (50% to 
70%), autism (20% to 60%), and fatal renal, cardiac, or pulmonary diseases (Curatolo 2002, 
Levine 2006). 
Despite this broad range of clinical findings, a limited number of features are responsible for 
the morbidity and decreased life expectancy associated with this disease. These include 
neurologic disorders such as SEGAs and seizures, renal diseases such as angiomyolipomas 
and renal cell carcinoma (RCC), pulmonary disease (lymphangioleiomyomatosis), and 
cardiovascular disease (rhabdomyoma) (Goh et al 2004). 
The incidence of SEGA in TSC varies from 5 to 15% (Shepherd et al 1991). SEGA lesions 
are usually associated with TSC. They arise in the subependymal layer of the lateral ventricle 
and are usually located near the foramen of Monro and enhance homogeneously with contrast 
on MRI with no evidence of surrounding edema. These are slow-growing lesions that are 
typically unapparent clinically until they reach sufficient size to produce ventricular 
obstruction and hydrocephalus. By the time symptoms are noted, they are often irreversible 
even by emergent surgical intervention. They arise deep within the brain in the region of the 
foramen of Monro, which hampers their surgical resection, as the approach to the lesion 
entails removal of substantial amounts of viable cerebral tissue. Surgery, even when 
successful, often results in significant morbidity. 
1.1.2 
Treatments for SEGA-associated with TSC 
For SEGAs that exhibit serial growth, cause hydrocephalus, or produce any clinical 
symptoms, resection, until recently, was the only recommended treatment for these patients 
(Torres 1998, Sinson 1994, Cuccia 2003). The lack of reported spontaneous regression or 
subsequent stabilization in SEGAs supported this recommendation (Franz 2007). In addition, 
SEGAs do not typically respond to radiation therapy or chemotherapy (Franz 2007). Given 


Novartis 
Confidential 
Page 17 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
the genetic basis of TSC, the risk of inducing second malignancies through utilization of 
standard chemotherapeutic agents or radiation therapy has been noted (Matsumura et al 1998). 
Everolimus first received accelerated approval from FDA on 29-Oct-2010 based on data from 
CRAD001C2485 under the trade name Afinitor® for the treatment of patients with SEGA 
associated with TSC who require therapeutic intervention but are not candidates for curative 
surgical resection based on data from CRAD001C2485. The effectiveness of Afinitor 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 FDA based on results of study 
CRAD001M2301 and with the approval of the dispersible tablet to “Afinitor® Tablets and 
Afinitor® Disperz are indicated in pediatric and adult patients with TSC for the treatment of 
SEGA that requires therapeutic intervention but cannot be curatively resected. The 
effectiveness of Afinitor Tablets and Afinitor Disperz 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 the EU, under the trade name Votubia®, everolimus first received conditional approval on 
02-Sep-2011 based on the data from CRAD001C2485 for the treatment of patients aged 3 
years and older with SEGA associated with TSC who require therapeutic intervention but are 
not amenable to surgery. Further clinical benefit, such as improvement in disease-related 
symptoms, has not been demonstrated. Based on data from CRAD001M2301, the European 
Commission decision was received on 15-Nov-2013 for removal of the age restriction and 
inclusion of the dispersible tablets. 
1.1.3 
Growth and development 
Growth 
Childhood growth and development are routinely monitored as part of child preventive health 
care in many countries. The assessment whether a child’s growth pattern deviates from that of 
the reference population is intended to detect childhood illnesses that manifest themselves 
through abnormal growth, ideally before any other signs or symptoms of the disease have 
appeared. 
Close monitoring of growth and development may be even more important when children are 
treated over long periods of time with drugs like everolimus that interfere with complex 
intracellular signaling pathways. Everolimus is an inhibitor of mTOR, a key player in a 
multifunctional, intracellular signal transduction pathway which has been shown to be 
essential for various vital processes. mTOR senses cellular nutrient and energy levels, and is 
one of many regulators of the cell cycle and proliferation. At present, it is unknown if long 
term treatment with everolimus affects the growth and development of children. Under certain 
circumstances everolimus is the only treatment option for children with SEGA associated with 
TSC. In this study, the height and weight for BMI of pediatric patients who take or have taken 
everolimus will be assessed on an annual basis to detect possible abnormalities. 


Novartis 
Confidential 
Page 18 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
WHO (World Health Organization) growth charts and other population-specific growth data 
have been used to establish cut-off values that define abnormal growth. The most commonly 
used parameter is height-for-age [expressed as height SD score (SDS) or height percentile]. 
Standard deviations scores (SDS) give an indication of the stature of the subject relative to a 
normal population of that age, a value of 0 being average and + and - values representing 
degrees of tallness and shortness, respectively. 
Development 
In animal studies it was shown that signaling through mTOR was at least partially involved in 
the control of puberty onset. Chronic blockade of mTOR by rapamycin had a strong inhibitory 
impact on puberty onset in female rats. Preliminary results suggested that also male rat 
puberty is sensitive to mTOR inactivation. Toxicology studies performed with everolimus 
demonstrate that treatment with everolimus may be associated with decreased weight in 
rodent pups and a delay in descent of testes in male pups. 
Additionally, the safety profile of everolimus in Study [CRAD001M2301] was consistent 
with that observed in the phase II study [CRAD001C2485] in patients with TSC with the 
exception of three cases of secondary amenorrhea. Secondary amenorrhea is thought to be an 
indicator of end-stage ovarian dysfunction. It has been speculated that this finding may be a 
consequence of TSC-related-mTOR over-expression or mTOR inhibition. 
Due to these preclinical and clinical findings further investigation of possible effects of long-
term everolimus treatment on the onset of puberty and development of TSC patients is 
imperative. This study is designed to address these questions. The timing of puberty onset and 
development through the different stages to full maturation will be monitored by assessment 
of Tanner Stage and if achieved prior to study completion timing of menarche and thelarche 
(females) or adrenarche (males). 
In addition, many of the patients who will be enrolled in this study have previously received 
and will be taking antiepileptic drugs (or enzyme-inducing antiepileptic drugs [EIAED]). 
While in general it is not thought that antiepileptic drugs impact ultimate height, the studies 
have not been comprehensive (Macardle et al 1986). Additionally, some antiepileptic drugs 
(e.g., valproic acid, topiramate) may affect weight in the peri-pubertal period (Novak et al 
1999). As a consequence, this study may generate some observations about the dual exposure 
of patients to antiepileptic drugs and everolimus. 
1.2 
Introduction to everolimus 
1.2.1 
Overview of everolimus (RAD001) 
Everolimus (Afinitor®/Votubia®; RAD001) is a selective inhibitor of mTOR, specifically 
targeting mTORC1. Everolimus was initially developed to prevent allograft rejection 
following solid organ transplantation, and is approved in more than 80 countries worldwide 
for use in this indication (Certican®/Zortress®). 
In the oncology setting, everolimus has been approved, under the trade name Afinitor, in the 
US, in EU and many countries worldwide for the treatment of patients with advanced renal 
cell carcinoma (>100 countries), for the treatment of patients with advanced neuroendocrine 


Novartis 
Confidential 
Page 19 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
tumors of gastrointestinal, lung or pancreatic origin (>80 countries) and for the treatment of 
postmenopausal women with hormone receptor-positive advanced breast cancer in 
combination with an aromatase inhibitor, after prior endocrine therapy (>80 counties). 
Indications vary by country. 
In the TSC setting, everolimus has received approval in more than 70 countries, under the 
trade names Afinitor and Votubia, for the treatment of patients with TSC who have SEGA not 
requiring immediate surgery and for the treatment of adult patients with renal 
angiomyolipoma associated with TSC, not requiring immediate surgery. 
1.2.1.1 
Non-clinical experience 
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 (HUVEC) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that everolimus may also act as an anti-angiogenic agent. The 
antiangiogenic 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. 
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. In 
nonclinical 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 
antiproliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 
recovery period with the exception of the changes in male reproductive organs, most notably 
testes. 
Further details can be found in the everolimus Investigator’s Brochure. 
1.2.1.2 
Clinical experience 
Interventional studies in patients with tuberous sclerosis complex: 
Everolimus has been investigated in one phase I/II study (28 patients) in patients with TSC 
who have SEGA [CRAD001C2485]. Additionally, two phase III studies have been conducted 
in patients with TSC: study [CRAD001M2301] in patients with TSC who have SEGA 
(117 patients) and study [CRAD001M2302] in patients with renal angiomyolipoma 


Novartis 
Confidential 
Page 20 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
(118 patients). [CRAD001MIC02] is an ongoing, expanded access phase IIIb study for 
patients with TSC associated SEGA. Currently there is a fourth phase III study 
[CRAD001M2304] ongoing in which everolimus will be tested to evaluate whether its use as 
adjunctive treatment results in reducing seizure frequency in patients with TSC who have 
refractory seizures. 
Data on a small series of TSC patients who had systematic SEGAs which were treated with 
daily rapamycin therapy showed tumor size reduction by 46-63% within 2.5 to 5 months 
(Franz et al 2006). All lesions exhibited regression and, in one case, necrosis. Interruption of 
therapy for one patient resulted in regrowth of the SEGA, but further regression of another 62-
75% was seen upon the resumption of therapy. These results represented a new therapeutic 
paradigm for the treatment of SEGAs in the TSC patients with rapamycin and related agents. 
Therefore, in 2007, everolimus entered clinical development for TSC. Study C2485, 
conducted by Cincinnati Children’s Hospital Medical Center (CCHMC), is a prospective, 
non-randomized, open-label, investigator-initiated, single-center 28-patient trial designed to 
evaluate the safety and efficacy of everolimus in patients ≥ 3 years of age with SEGA 
associated with TSC. The primary efficacy endpoint is the change from baseline in volume of 
primary SEGA lesion at 6 months as determined by central radiology review. At 6 months, 9 
out of 28 patients (32%, 95% CI: 16% to 52%) had a ≥ 50% reduction in the tumor volume of 
their largest SEGA lesion. The median duration of response for these 9 patients was 11.8 
months (range 3.2 to 39.1 months). Response rate continues to improve as 58.3% of patients 
(14 of 23) who took everolimus for at least four years have experienced a reduction of ≥ 50% 
in the size of their largest SEGA relative to baseline. One patient has experienced a SEGA 
progression (defined as an increase of at least 25% to a value greater than baseline). The 
median time from first response to progression/censoring was 37 months (range: 6-63 
months). No patient developed a new lesion and none required surgical resection or other 
therapy for SEGA. 
The safety and efficacy of everolimus in patients with TSC who have SEGA was studied 
further in [CRAD001M2301], a randomized (2:1), double-blind, placebo-controlled trial of 
everolimus conducted in 117 pediatric and adult patients with SEGA and TSC. The main 
efficacy outcome measure was SEGA response rate based on independent central radiology 
review. After 6-months of study treatment, 35% of the patients treated with everolimus had at 
least a 50% reduction in SEGA volume compared to none in the placebo group (Franz et al 
2013). Based on recent data, the response rate after at least 12-months of everolimus treatment 
has increased to 48%. SEGA progression was seen in nine of the all patients treated with 
everolimus (8.1%). In five patients, progression occurred after cessation of treatment or was 
associated with Cmin values which were markedly reduced or at zero. In one case of 
progression, the patient developed hydrocephalus that was successfully treated, in the absence 
of SEGA growth. In one case, progression reversed with further treatment. 
Non-interventional studies: 
A total of three non-interventional studies relevant for the TSC setting ([CRAD001MIC03], 
[CRAD001MCO05], and [CRAD001M1401]) have been initiated and are ongoing (Table 1-
1). These three studies have so far not shown any unexpected or unusual safety findings. 


Novartis 
Confidential 
Page 21 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Table 1-1 
Non-interventional studies 
Non interventional studies 
Study no. 
CRAD001MIC03 
CRAD001MCO05 
CRAD001M1401 
Title 
TOSCA 
Epidemiological follow-up 
Survey 
Population 
Patients, any age 
with TSC diagnosed 
within last 12 months 
Patients with confirmed 
diagnosis 
of TSC 
TSC Patients 
<15-years-old 
Study design 
International, 
observational 
disease registry, 
retrospective and 
prospective 
Epidemiological, 
monographic 
registry model with open 
follow-up, 
retrospective and 
prospective; 
competitive recruitment 
Observational, 
site survey; 
patient registration 
For additional efficacy and safety information, please refer to the most recent edition of the 
Investigator’s Brochure as well as the Afinitor/Votubia prescribing information. 
2 
Rationale 
2.1 
Study rationale and purpose 
The results from [CRAD001M2301] have shown that a significant proportion of patients with 
advanced TSC-associated SEGA benefited from continuous treatment with the mTOR 
inhibitor everolimus which led to volume reduction of the SEGA lesions. Patients with TSC-
associated SEGA are typically young children at pre-pubertal age whose physical and sexual 
maturation is ongoing. mTOR has been shown to be an important regulator of cell growth and 
proliferation. Additionally, it is possible that mTOR is also a regulator of sexual development 
and maturation. As many patients treated in [CRAD001M2301] were young at the time of 
their exposure to everolimus (an mTOR inhibitor) and/or have experienced prolonged 
exposure to the drug from a young age, patients exposed to everolimus as part of 
CRAD001M2301 may present an appropriate study population in which to track the long term 
impact of everolimus exposure on growth and development. 
Upon request by the EMA (during the procedure EMEA/H/C/002311/II/0004), this safety 
extension-study, classified as Post-Authorization Safety Study (PASS), is implemented to 
continue growth and development monitoring of pediatric patients enrolled in 
CRAD001M2301 who have been treated or are being treated with everolimus. 
The study will monitor the growth and development of pediatric patients with TSC-associated 
SEGA, previously enrolled in CRAD001M2301until they reach Tanner Stage V, or until age 
16 for females or 17 for males whichever occurs first. After completion of [CRAD001M2301] 
continued treatment with everolimus is at investigator discretion and is not required for 
participation in CRAD001M2305. It is expected that some patients will cease treatment with 
everolimus upon completion of study CRAD001M2301, but most will opt for continued 
treatment with everolimus. Under either circumstance, the patients will be eligible for 
enrolment in study CRAD001M2305. 


Novartis 
Confidential 
Page 22 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
The primary objective of CRAD001M2305 is to report the long-term effects of everolimus 
treatment on height, BMI and sexual development (using Tanner Stages) in children and 
adolescents with TSC-associated with SEGA. Additionally, it is possible that the presence of 
TSC and SEGA and non-everolimus therapy could affect growth and sexual development. To 
be able to differentiate the potential impact of the TSC condition and the potential impact of 
the everolimus treatment on growth and sexual development a second data set from peri-
pubertal patients with TSC, who have not been exposed to everolimus will be used as a 
reference. These patients are a subset of the patient population that is currently being enrolled 
into the TOSCA registry. 
Height and BMI data obtained in this study will be compared against the WHO reference 
growth charts (representing the average global population). Recent growth surveys in both 
developed and developing countries have reported increases in mean height and earlier sexual 
maturation, suggesting that current WHO growth charts, may not be representative of the 
general population in the future. Therefore if, over the course of the next 10 years, a more 
appropriate reference data set is developed, the study may compare the growth and sexual 
development of its subjects to such a data set. 
Monitoring of patient safety, brain development as assessed by TAND Checklist and the 
timing of menarche, thelarche (females), and adrenarche (males), and the age at Tanner Stage 
V will be determined as secondary objectives. 
2.2 
Rationale for the study design 
CRAD001M2305 is a prospective, multi-center phase IIIb/IV study. This study will 
investigate if the physical and sexual development of pediatric patients is affected by previous 
or ongoing treatment with everolimus. 
Growth (height, weight), sexual development (Tanner Stages, sex hormone levels, age at 
menarche, thelarche (females) and adrenarche (males)), and brain development (assessed by 
TAND Checklist, dates of brain MRI) of patients participating in this long-term follow-up 
study will be followed at annual visits to the site until patients achieve Tanner Stage V or age 
16 (females), age 17 (males) whichever occurs first. 
Adverse events, concomitant medication, appearance of menarche, will be monitored and data 
collected every 3 months (“3-monthly”). As per local product information, all patients should 
be receiving periodic Therapeutic Drug Monitoring (TDM) to monitor the blood trough 
concentration of everolimus, any available everolimus blood trough levels with date of sample 
collection, will be recorded every 3-months. Unless clinically indicated these 3-monthly visits 
can be performed per telephone. 
Of note: the participation in this study does not require the administration of everolimus. In 
such cases in which the patient is taking everolimus, data collection (such as TDM, trough 
level, duration of everolimus interruptions and everolimus prescribed dose) will only be 
recorded, when available. Everolimus treatment, should it be continued during 
CRAD001M2305, will be based on the local product information. 
Blood samples will be collected annually for assessment of endocrine levels at a local lab for 
all patients, starting at age 10 until study participation is ended. 


Novartis 
Confidential 
Page 23 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Data collected in this CRAD001M2305 study will be pooled with the corresponding patient’s 
data collected in the parent CRAD001M2301 study, in particular background information on 
the disease history, demographics and baseline characteristics, everolimus exposure, sexual 
and growth development data. 
To facilitate the interpretation of the CRAD001M2305 results and help differentiate the 
impact of the TSC condition versus the impact of everolimus on growth and sexual 
development, a descriptive statistical comparison will be performed using data from patients 
with comparable clinical characteristics, enrolled in the TOSCA registry and not treated with 
an mTOR inhibitor. 
CRAD001M2305 results will be reported, side by side, with those from the TOSCA registry 
patients not treated with an mTOR inhibitor, whenever similar data are collected in both 
studies. 
3 
Objectives and endpoints 
Primary objective: 
The primary objective of this study is to monitor the growth and development of pediatric 
patients with TSC-associated SEGA, previously enrolled in CRAD001M2301, who had 
received everolimus as part of study CRAD001M2301 and may or may not be continuing 
treatment with everolimus. Annual measurements of the following will be collected: 
• Height 
• Weight for BMI 
• Tanner Stage 
• Endocrine laboratory values (FSH, LH, and estrogen or testosterone) 
Secondary objectives: 
• Long-term safety 
• Age at menarche (females) 
• Age at thelarche (females) 
• Age at adrenarche (males) 
• Age at Tanner Stage II-V 
• Assess neuropsychological development by TAND Checklist 
• Compare CRAD001M2305 and CRAD001MIC03 on height, BMI and sexual 
development (using Tanner Stages) 
Primary endpoints: 
Growth and development of pediatric patients with TSC-associated SEGA who are taking 
everolimus or have previously taken everolimus will be monitored via: 
• Percentage of patients who achieved Tanner Stage V by age 16 (for females) or age 17 
(for males) 
• Height, standard deviation score by year since baseline 


Novartis 
Confidential 
Page 24 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
• BMI, standard deviation score by year since baseline 
• Mean endocrine laboratory values (FSH, LH, and estrogen or testosterone) by age 
Secondary endpoints: 
• Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events. Safety will be assessed by the National Cancer Institute’s (NCI) 
Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0 
(//ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). 
• Age at Tanner Stage II-V 
• Age at start of menses (menarche) – for females 
• Age at thelarche – for females 
• Age at adrenarche – for males 
• TAND Checklist - individual responses over time since the enrollment date 
• Indirect comparison between CRAD001M2305 and CRAD001MIC03 will be performed 
on the following endpoints: 
• Percentage of patients who achieved Tanner Stage V at or before age of 16 (females) 
or 17 (males). 
• Height/BMI standard deviation score by year since baseline 
Objectives and related endpoints are described in Table 3-1 below. 


Novartis 
Confidential 
Page 25 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary objective: 
 
 
Monitoring growth and development 
of pediatric patients with TSC-
associated SEGA who are taking 
everolimus or have taken everolimus 
by annual measurements of height, 
weight for BMI, and Tanner Stage 
Percentage of patients who achieved Tanner Stage V at or before age of 16 
(females) or 17 (males). 
Height/BMI standard deviation score by year since baseline 
Mean endocrine laboratory values (FSH, LH, and estrogen or testosterone) by 
age 
Refer to Section 10.4. 
Secondary objectives: 
 
 
Determine timing of developmental 
milestones: menarche (females), 
thelarche (females), adrenarche 
(males), Tanner Stage II-V 
Assess neuropsychological 
development 
Compare CRAD001M2305 and 
CRAD001MIC03 on height, BMI and 
sexual development (using Tanner 
Stages) 
 
Safety as assessed by the NCI 
Common Toxicity Criteria, version 
3.0. 
Age at start of menses (menarche) – for females 
Age at onset of breast development (thelarche) – for females 
Age at pubic hair development (adrenarche) – for males 
Age at Tanner Stage II-V - all patients 
TAND Checklist individual responses over time since the enrollment date 
 
Indirect comparison between CRAD001M2305 and CRAD001MIC03 will be 
performed on the following endpoints: 
Percentage of patients who achieved Tanner Stage V at or before age of 16 
(females) or 17 (males). 
Height/BMI standard deviation score by year since baseline. 
Safety will be assessed by the National Cancer Institute’s (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE), version 3.0 
(//ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.p
df). 
Notes: 
• 
Safety assessments will consist of monitoring and recording adverse and 
serious adverse events 
• 
Safety follow-up as per product information 
Refer to Section 10.5.1. 


Novartis 
Confidential 
Page 26 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
4 
Study design 
4.1 
Description of study design 
This is a prospective, multi-center, long-term follow-up, Post-Authorization Safety Study 
(PASS) evaluating the growth and development of pediatric patients who are currently being 
treated with everolimus or who have previously been treated with everolimus for TSC-
associated SEGA in [CRAD001M2301]. The study will include all consenting pediatric 
patients who at the time of completion of study CRAD001M2301 have not achieved Tanner 
Stage V and are younger than 16 years (for females) or 17 years (for males), and were 
receiving treatment with everolimus in study [CRAD001M2301] within 6 months before 
enrollment into CRAD001M2305. 
According to [CRAD001M2301] enrollment figures, it is anticipated that at the time of the 
start of study CRAD001M2305, approximately 50 patients may be eligible for this study, if 
they consent to participate. 
Enrollment 
Enrollment into CRAD001M2305 will start at the conclusion of the parent protocol 
([CRAD001M2301]). Investigators will identify study patients who qualify for enrollment 
into CRAD001M2305 and assign each a unique patient number (refer to Section 6.3). 
All pediatric patients and his/her parents or legal guardian must be thoroughly informed about 
the study. The Informed Consent Form(s) for CRAD001M2305 must be signed prior to 
performing any study procedures. 
Once Informed Consent has been obtained and eligibility is confirmed (Tanner Stage and age 
have been verified) by the investigator, the patient may be enrolled in the study. 
Monitoring 
For patients taking everolimus, dosing should follow the local product information. 
Patient visits will occur every 3 months (± 14 days) for collection of adverse events, any 
Afinitor/Votubia-related SAEs, and date of menarche (females). This information will be 
obtained from the patient or their parents/caregiver, depending on the patient’s age and 
cognitive abilities. 
Visits will also occur annually (± 30 days) for measurement of growth (height, weight), 
development (Tanner staging, age at thelarche, age at menarche for females, age at adrenarche 
for males), and pregnancy testing. Height and weight should be measured with the same 
calibrated equipment and in the same manner, preferably with the patient wearing minimal 
clothing and no shoes at every respective visit. If possible these measurements should be 
obtained by the same site personnel throughout the study. 
A blood sample will be taken at the annual visits for assessment of hormone levels at a local 
laboratory, starting at age 10 until study participation is ended. Estrogen, luteinizing hormone, 


Novartis 
Confidential 
Page 27 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
and follicular stimulating hormone will be tested for females and testosterone, luteinizing 
hormone, and follicular stimulating hormone for males. 
Adverse events should be collected, by the investigator, according to the protocol 
requirements. Afinitor/Votubia-related SAEs should be collected throughout the study until 
30 days after last everolimus dose. 
Additionally, medications and therapies/non-drug therapies should be recorded on the CRFs 
designated to record concomitant medications at every 3-month and annual visit until the end 
of the study. 
The date of the first dose and the date of the last dose of systemic everolimus treatment will 
be recorded, as available. The patient’s recent everolimus Cmin (i.e. obtained since the last 
visit as per local product information) with collection date and current prescribed everolimus 
dose should be recorded. The time-normalized Cmin value will be estimated for the entire 
treatment period using recorded everolimus Cmin values and prescribed doses in that 
treatment period (Section 10.5.2). Additionally, a summary of everolimus interruptions (an 
estimate of the duration of the interruptions) will be collected at each study visit. 
The dates of all performed brain MRI scans that are done in the scope of the regular TSC 
SEGA follow-up will be collected at the annual visits. Brain MRI data will not be collected at 
this point but may be retrieved at a later date if technological advancements pertaining to 
predicting future cognitive abilities such as the development of the working memory arise. 
Brain development will be assessed by determining the occurrence of TSC-Associated-
Neuropsychiatric-Disorders (TAND) with an appropriate TAND Checklist at each annual 
visit. 
The first study visit will occur 3 months after enrollment in CRAD001M2305 and the first 
annual visit one year (± 30 days) after enrollment in CRAD001M2305. The 3-monthly visits 
can be performed per telephone unless a visit to the site is clinically indicated. 
Patient participation in the study will be completed once the patient has achieved Tanner 
Stage V or age 16 for females, age 17 for males, whichever occurs first. 


Novartis 
Confidential 
Page 28 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Figure 4-1 
Study flowchart 
 


Novartis 
Confidential 
Page 29 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
4.2 
Timing of interim analyses and design adaptations 
No formal interim analysis is planned for this study. However, safety outputs may be 
generated for regulatory safety updates. 
4.3 
Definition of end of the study 
The study will end when all patients have either reached Tanner Stage V, or age 16 for 
females, age 17 for males, or when the last patient is discontinued. The latest possible LPLV 
date is expected to take place in September-2026. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. The investigator may be 
informed of 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 target population is comprised of pediatric female and male patients who have previously 
participated in the study [CRAD001M2301] and have not, prior to enrollment into 
CRAD001M2305, reached age 16 for females, or age 17 for males. Additionally, these 
patients will not yet have achieved Tanner Stage V. Study treatment in study 
[CRAD001M2301] must have been completed within 6 months prior to enrollment into 
CRAD001M2305. 
The investigator or designee must ensure that only patients who meet all inclusion are offered 
participation in the study. No additional exclusions can be applied by the investigator, in order 
that the study population will be representative of all eligible patients. All screening 
assessments must be completed and reviewed by the investigator (or designee) prior to 
starting study participation in CRAD001M2305. 
All pediatric study patients and their parent(s) or legal guardian must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations, and 
all regulatory requirements in order to ensure informed consent. The written informed consent 
must be obtained prior to performing any CRAD001M2305 study procedures. If the patient is 
unable to read, an impartial witness and/or the patient’s parent or legal guardian must be 
present during the entire informed consent discussion. The following criteria apply to all 
patients enrolled into the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Pediatric female patients who were on study treatment in study [CRAD001M2301] within 
the past 6 months and have not reached Tanner Stage V or age 16 at the time of 


Novartis 
Confidential 
Page 30 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
completion of [CRAD001M2301] 
or 
2. Pediatric male patients who were on study treatment in study [CRAD001M2301] within 
the past 6 months and have not reached Tanner Stage V or age 17 at the time of 
completion of [CRAD001M2301]. 
3. Written informed consent according to local guidelines. 
Tanner Staging results that were obtained and documented within 6 months prior to 
enrollment into CRAD001M2305 may be used for enrollment decisions. 
5.3 
Exclusion criteria 
1. Pediatric female patients who were on study treatment in CRAD001M2301 and have not 
reached Tanner Stage V but are within 3 month of turning age 16 
or 
2. Pediatric male patients who were on study treatment in CRAD001M2301 and have not 
reached Tanner Stage V but are within 3 months of turning age 17 
3. Any patient who was pregnant prior to start of CRAD001M2305 
6 
Treatment 
This study does not require treatment with any medication. 
6.1 
Monitoring everolimus dosing 
At the discretion of the investigator, patients may be treated with commercially available 
everolimus, as per local product information / standard of care. Dosing will be based on 
locally performed PK analyses. Novartis will not perform any PK analyses. Treatment 
duration and dose modifications will be at the investigator’s discretion, as per the local 
product information. 
Table 6-1 
Dose and treatment schedule (if continuing on everolimus) 
Everolimus 
treatments 
Pharmaceutical form 
and route of 
administration 
Dose 
Frequency and/or 
Regimen 
Commercially available 
everolimus 
Tablet for oral use or 
dispersible tablet for 
oral use 
As per local product 
information/ 
investigator discretion 
As per local product 
information / 
investigator discretion 
6.2 
Concomitant medications 
Concomitant medications should be collected, by the investigator, according to the protocol 
requirements. 


Novartis 
Confidential 
Page 31 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
6.3 
Patient numbering, everolimus exposure 
6.3.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient No. consists of the Center Number (Center 
No.) (as assigned by Novartis to the investigative site) with a 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 is assigned to the next sequential Patient No. 
available. 
6.3.2 
Everolimus exposure 
For patients being prescribed Afinitor/Votubia, the sponsor will monitor the exposure by 
requesting that the investigator record in the CRF the current prescribed dose, a summary of 
everolimus interruptions, and any available everolimus trough concentration levels 
(completed as per label) that have been recorded in the patient chart. This information must 
also be recorded in the source document at each patient visit. 
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. 
No CRF will be used as a source document. 


Novartis 
Confidential 
Page 32 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Table 7-1 
Visit evaluation schedule 
 
Day 1 / 
Enrollment 
Every 3 months after Day 1 
(3-monthly visits that 
coincide with the annual 
visits are skipped (every 4th 3-
monthly visit)) 
First 
annual visit 
Every 3 months after each 
consecutive year (3-
monthly visits that 
coincide with the annual 
visits are skipped (every 
4th 3-monthly visit)) 
Annually 
after first 
year 
Study 
completion 
Time Point (months) 
0 
3 
6 
9 
12 
15, 18, 21, 27… 
24, 36… 
Last 
Visit No. 
1 
2 
3 
4 
5 
6, 7, 8, 10… 
9, 13… 
778 
Visit Window 
 
± 14 days 
± 30 days 
± 14 days 
± 30 days 
 
Obtain Informed Consent (D) 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (D) 
X 
 
 
 
 
 
 
 
Demography (D) 
X 
 
 
 
 
 
 
 
Prior study information (D) 
X 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
Height (D) 
X 
 
 
 
X 
 
X 
X 
Weight (D) 
X 
 
 
 
X 
 
X 
X 
Tanner Staging (D) 
X 
 
 
 
X 
 
X 
X 
Developmental Milestones 
 
 
 
 
 
 
 
 
Menarche (females) (D) 
X 
X 
X 
X 
X 
X 
X 
X 
Thelarche (females) (D) 
X 
 
 
 
X 
 
X 
X 
Adrenarche (males) (D) 
X 
 
 
 
X 
 
X 
X 
Urine pregnancy testing (D) 
X 
 
 
 
X 
 
X 
X 
Endocrine assessments (D) 
X 
 
 
 
X 
 
X 
X 
Concomitant medications (D) 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events (D) 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse event reporting (D) 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy reporting (D) 
X 
X 
X 
X 
X 
X 
X 
X 


Novartis 
Confidential 
Page 33 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
 
Day 1 / 
Enrollment 
Every 3 months after Day 1 
(3-monthly visits that 
coincide with the annual 
visits are skipped (every 4th 3-
monthly visit)) 
First 
annual visit 
Every 3 months after each 
consecutive year (3-
monthly visits that 
coincide with the annual 
visits are skipped (every 
4th 3-monthly visit)) 
Annually 
after first 
year 
Study 
completion 
Time Point (months) 
0 
3 
6 
9 
12 
15, 18, 21, 27… 
24, 36… 
Last 
Visit No. 
1 
2 
3 
4 
5 
6, 7, 8, 10… 
9, 13… 
778 
Visit Window 
 
± 14 days 
± 30 days 
± 14 days 
± 30 days 
 
Any available everolimus blood trough 
levels (Cmin) as per label (D) 
(only while on everolimus treatment) 
X 
X 
X 
X 
X 
X 
X 
X 
Prescribed everolimus dose (D) 
(only while on everolimus treatment) 
X 
X 
X 
X 
X 
X 
X 
X 
Summary of dose interruptions (D) 
(only while on everolimus treatment) 
X 
X 
X 
X 
X 
X 
X 
X 
Brain MRI scan dates (as available) (D) 
 
 
 
 
X 
 
X 
 
TAND Checklist (D) 
X 
 
 
 
X 
 
X 
 
End of everolimus treatment (D) 
 
X (as applicable, complete follow-up for safety 30-days after last dose) 


Novartis 
Confidential 
Page 34 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
7.1.1 
Eligibility enrollment 
Patients have to be thoroughly informed about the study by the investigator and have to sign 
the informed consent form before study enrollment can be performed. The inclusion/exclusion 
criteria should be verified within 28 days before Day 1. If Tanner Staging was done in the 
scope of [CRAD001M2301] within 3 months prior to enrollment into CRAD001M2305, these 
results may be used for enrollment decisions. In this case, Tanner Staging does not have to be 
repeated. The patient’s age should be verified prior to enrollment into CRAD001M2305. 
7.1.1.1 
Patient demographics and other characteristics at study start 
At time of enrollment, patients’ demographic and previous study identification from the 
parent protocol (CRAD001M2301) will be collected. Furthermore patients will undergo 
Tanner Staging, height, weight, and developmental milestone (adrenarche, thelarche, 
menarche) assessments. 
Data pertaining to ongoing adverse events and concomitant medications will be transferred 
from the parent study into CRAD001M2305. 
For details of assessments, refer to Table 7-1. 
7.1.2 
Study participation 
At the discretion of the investigator, patients may continue treatment of their TSC-associated 
SEGAs with commercially-supplied everolimus. Everolimus does not need to be actively in 
use for the entire duration of the patient’s study participation. 
7.1.3 
Study completion 
Patients will meet the criteria for study completion upon demonstrating Tanner Stage V, or 
reaching age 16 (females) or age 17 (males), whichever comes first. Upon meeting the criteria 
for study completion, the patient should schedule an End of Study visit at the site. The End of 
Study visit cannot be completed via telephone contact. 
Patients who discontinue commercial everolimus should continue study participation until 
meeting any of the aforementioned criteria for study completion. The discontinuation of 
everolimus will be recorded on the End of Treatment CRF page. Safety monitoring should be 
continued for at least 30 days following the last dose of everolimus. 
Patients who complete the study, or discontinue the study early, should have the reason for 
exiting the study recorded on the Study Phase Completion Disposition CRF (SEC) page. 
7.1.3.1 
Criteria for early study discontinuation 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients must be withdrawn from the study if any of the following 
occur: 
• Protocol deviation(s) that impact eligibility 
• Patient withdrew consent 
• Lost to follow-up 


Novartis 
Confidential 
Page 35 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
• Administrative problems 
• Death 
7.1.4 
Post-study follow up period 
All patients must have safety evaluations 30 days after the last dose of everolimus. 
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Not applicable 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by collecting data about growth, development, and adverse events. 
For details on AE collection and reporting, refer to Section 8.1. 
7.2.2.1 
Height and weight 
Height and body weight (with minimal clothing, without shoes) will be measured annually. 
Note: CRFs are designed to collect the data in the units they are measured in; e.g., height in 
centimeters (cm) or inches (in) and weight in kilograms (kg) or pounds (lb). Height and 
weight should be measured with the same calibrated equipment and in the same manner at 
every respective visit. If possible these measurements should be obtained by the same site 
personnel throughout the study. 
7.2.2.2 
Tanner staging 
For all male patients, Tanner Stage V will be achieved once the patient has demonstrated 
either stage 5 genitalia development or stage 5 pubic hair development. For all female 
patients, Tanner Stage V will be achieved once the patient has demonstrated either stage 5 
breast development or stage 5 pubic hair development (Marshal 1969, Marshal 1970). 
Male: Genitalia stages: 
Stage 1: Pre-adolescent. Testes, scrotum, and penis are of about the same size and proportion 
as in early childhood. 
Stage 2: The scrotum and testes have enlarged and there is a change in the texture of the 
scrotal skin. There is also some reddening of the scrotal skin. 
Stage 3: Growth of the penis has occurred, at first mainly in length but with some increase in 
breadth. There has been further growth of testes and scrotum. 
Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and 
scrotum further enlarged. There is also further darkening of the scrotal skin. 


Novartis 
Confidential 
Page 36 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Stage 5: Genitalia adult in size and shape. No further enlargement takes place after Stage 5 is 
reached. 
Male: Pubic hair stages: 
Stage 1: Pre-adolescent. The vellus over the pubesis no further developed than that over the 
abdominal wall, i.e. no pubic hair. 
Stage 2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly 
curled, appearing chiefly at the base of the penis. 
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the 
junction of the pubes. 
Stage 4: Hair is now adult in type, but the area covered by it is still considerably smaller than 
in most adults. There is no spread to the medial surface of the thighs. 
Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically 
feminine pattern. Spread to the medial surface of the thighs but not up the linea alba or 
elsewhere above the base of the inverse triangle. 
Female: Breast stages: 
Stage 1: Pre-adolescent; elevation of papilla only. 
Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, enlargement of 
areola diameter. 
Stage 3: Further enlargement of breast and areola, with no separation of their contours. 
Stage 4: Projection of areola and papilla to form a secondary mound above the level of the 
breast. 
Stage 5: Mature stage; projection of papilla only, due to recession of the areola to the general 
contour of the breast. 
Female: Pubic hair stages: 
Stage 1: Pre-adolescent; the vellus over the pubes is not further developed than that over the 
anterior abdominal wall, i.e. no pubic hair. 
Stage 2. Sparse growth of long, slightly pigmented, downy hair, straight or only slightly 
curled, appearing chiefly along the labia. 
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the 
junction of the pubes. 
Stage 4: Hair is now adult in type, but the area covered by it is still considerably smaller than 
in most adults. There is no spread to the medial surface of the thighs. 
Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically 
feminine pattern. Spread to the medial surface of the thighs, but not up the linea alba or 
elsewhere above the base of the inverse triangle. 


Novartis 
Confidential 
Page 37 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
7.2.2.3 
Endocrine testing 
A blood sample for analysis of luteinizing hormone (LH), follicular stimulating hormone 
(FSH), and estrogen (females) or total testosterone (males) will be collected on day 1, 
annually, and at end of study for endocrine assessment at a local laboratory for all patients, 
starting at age 10 until study participation is ended. In the event that amenorrhea is reported in 
between scheduled assessments, hormone evaluations should be completed at that time. 
7.2.2.4 
Brain imaging 
The dates of all brain MRI scans that were performed since the last annual visit will be 
collected annually. Actual MRI data will only be retrieved if future technological 
advancements allow MRI data to be used for prediction of cognitive abilities, diagnosing 
neuropsychological disorders, and assessing the speed of cognitive development. 
7.2.2.5 
TSC-associated-neuropsychiatric-disorders (TAND) 
A TAND Checklist will be completed by an appropriate clinician at the clinical site at each 
annual visit. 
7.2.2.6 
Pregnancy testing 
For all female patients who have achieved Tanner Stage II or higher, urine pregnancy testing 
will be completed annually as part of the assessments for growth and development. In the 
event of positive urine pregnancy test, results should be verified by serum pregnancy testing. 
7.2.2.7 
Pregnancy and assessments of fertility 
When effective contraception is required, pregnancy testing is recommended at enrollment 
and at the end of the trial. All patients should follow instructions for contraception as per local 
label. 
There are no adequate data from the use of everolimus in pregnant women. Studies in animals 
have shown reproductive toxicity effects including embryotoxicity and foetotoxicity. The 
potential risk for humans is unknown. 
Everolimus is not recommended during pregnancy and in women of childbearing 
potential not using contraception. Discontinuation of everolimus should be considered in 
case of pregnancy. 
All pregnancies should be followed up to determine outcome (Section 8.3). Patient 
participation in this study for monitoring of growth and development should be continued. 


Novartis 
Confidential 
Page 38 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
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. 
Adverse events that begin or worsen after informed consent may be recorded in the Adverse 
Events CRF. Adverse events that were ongoing from CRAD001M2301 will be transferred to 
the AE CRFs for CRAD001M2305. Adverse event monitoring should be continued for at 
least 30 days following the last dose of everolimus 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 according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1-4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
form 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
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 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: 
• The severity grade (CTCAE Grade 1-4) 
• Its duration (start and end dates or ongoing at end of study) 
• Its relationship to the everolimus treatment (suspected/not suspected) 
• Action taken with respect to everolimus treatment (no action taken; study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication taken) 
• Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event 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 everolimus treatment, the 
interventions required to treat it, and the outcome. 


Novartis 
Confidential 
Page 39 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Progression of TSC may be reported as an adverse event. Progression of TSC will not 
necessarily end patient participation in this study unless the patient meets any of the other 
reasons for early study discontinuation. 
Adverse events separate from the progression of TSC (e.g., deep vein thrombosis at the time 
of progression or hemoptysis concurrent with finding of disease progression) will be reported 
as per usual guidelines used for such events with proper attribution regarding relatedness to 
everolimus. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
1. Is fatal or life-threatening 
2. Results in persistent or significant disability/incapacity 
3. Constitutes a congenital anomaly/birth defect 
4. 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 
5. 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 of TSC 
• 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 until at least 30 days after the patient has stopped 
everolimus must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to everolimus. Recurrent episodes, complications, 
or progression of the initial SAE 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. 
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 


Novartis 
Confidential 
Page 40 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
thorough report. The investigator must assess and record the relationship of each SAE to 
treatment with everolimus, complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours to the oncology Novartis Drug Safety and 
Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. 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 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 Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis everolimus treatment, an 
oncology Novartis Drug Safety and Epidemiology (DS&E) 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 everolimus 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 Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the commercial supply of everolimus and any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took 
everolimus treatment in this study. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 


Novartis 
Confidential 
Page 41 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
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 local product 
information. 
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, and the progress of enrollment and study conduct. 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, such as 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 


Novartis 
Confidential 
Page 42 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
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. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), 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. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) 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. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
The data will be analyzed by Novartis and/or a designated CRO. 
This is a long-term safety follow-up study and statistical analyses will be primarily descriptive 
for all endpoints. 
Data collected in this CRAD001M2305 study will be pooled with the corresponding data 
collected in the parent CRAD001M2301 study, in particular, background information on the 
disease history, demographics and baseline characteristics, everolimus exposure, sexual and 
growth development data. This pooling will allow for the following: 
• Obtaining baseline values collected in M2301 before start of everolimus 
• Calculating the whole exposure to everolimus for patients enrolled in the M2305 study 
• Considering the whole growth/development course over time from the start of everolimus. 
The descriptive analyses of data from the CRAD001M2305 study and TOSCA registry will 
be presented, side by side, whenever similar data are collected in both studies. This is 


Novartis 
Confidential 
Page 43 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
intended to facilitate the interpretation of the CRAD001M2305 results and help differentiate 
the impact of the TSC condition versus the impact of everolimus on growth and sexual 
development. 
Categorical data will be presented as frequencies, percentages and 95% confidence intervals. 
For continuous data, mean, standard deviation, median, 25th and 75th percentiles, minimum, 
and maximum will be presented. 
If the missing data pattern is not limiting, exploratory indirect comparisons between patients 
treated by everolimus (from M2305 study) and those who never received an mTOR inhibitor 
(TOSCA subset of patients) will be performed to evaluate the everolimus effect on growth 
and sexual development. The proposed statistical methodology for these indirect comparisons 
is described in Section 10.5.1.4. 
In addition to the statistical methods outlined below, further details and any additional 
exploratory analyses that may be performed will be described in the Report and Analysis Plan 
(RAP). 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
In order to describe data from the CRAD001M2305 patients and those from the TOSCA 
registry side by side, the following analyses sets will be used. 
• The Full Analysis Set (FAS): 
• for CRAD001M2305, FAS will consist of all patients enrolled in this study. 
• for TOSCA, FAS will consist of all patients enrolled in this TOSCA registry whose 
age at study entry was below 17 years and who never received an mTOR inhibitor 
throughout the registry follow-up period. 
• The Full Analysis Set for sexual development (FAS Puberty): 
• for CRAD001M2305, FAS Puberty will consist of the FAS patients defined above. 
• for TOSCA, FAS Puberty will consist of the FAS patients defined above but 
restricting from the patients to those aged between 9 to 17 years at study entry. The 
TOSCA registry is designed to collect Tanner Staging until 2017 (i.e. 4 to 6 years of 
follow-up). Thus it is considered adequate to select only TOSCA patients aged 
between 9 to 17 years old at the time of entry to the registry to allow for obtaining 
puberty data corresponding to the peri-pubertal time frame. 
10.1.2 
Safety Set 
The Safety Set (SS) will include all patients enrolled in this follow-up CRAD001M2305 study 
who have at least one-post baseline safety assessment. It should be noted that all patients 
enrolled in the CRAD001M2305 study have been exposed to everolimus in the parent study 
CRAD001M2301 (and may or may not continue receiving commercial everolimus while on 
CRAD001M2305). 


Novartis 
Confidential 
Page 44 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
10.1.3 
Per-Protocol Set 
Not applicable 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline characteristics will be described by study (CRAD001M2305 
and TOSCA), side by side, on the two Full Analysis Sets (FAS and FAS-Puberty). 
The baseline value will be the last available assessment on or before the start of everolimus 
for CRAD001M2305 patients and the first available assessment after the enrollment date for 
the TOSCA patients. 
10.3 
Treatments (everolimus treatment, concomitant therapies, 
exposure) 
For patients in Study CRAD001M2305, the duration of everolimus exposure and cumulative 
everolimus dose will be described using descriptive statistics on the Safety Set. 
The total duration of everolimus exposure will be calculated as the total duration of 
everolimus exposure received while on Study CRAD001M2301 plus the total duration of 
(commercially supplied) everolimus exposure reported in Study CRAD001M2305. 
Similarly the cumulative dose of everolimus will be calculated as the cumulative everolimus 
dose received while on CRAD001M2301 plus the cumulative everolimus (commercially 
supplied) dose reported in CRAD001M2305. 
In the CRAD001M2305 study: 
• the duration of (commercially supplied) everolimus exposure will be estimated based on 
the dates of the first and last everolimus doses and the investigator summary of treatment 
interruptions (estimation of number of missed doses) between each visit. 
• the cumulative dose will be estimated through the prescribed doses recorded at each visit. 
Between two consecutive visits, the prescribed dose will be assumed constant taking into 
account the investigator summary of treatment interruptions between each visit. 
All exposure data will be listed. 
Concomitant medications and significant non-drug therapies taken concurrently with 
everolimus will be listed and summarized by ATC class, preferred term by means of 
frequency counts and percentages. 
The Safety Set will be used for all above-mentioned tables and listings. 
10.4 
Primary objective 
The primary safety objective of this study is to report the effect of everolimus on height, BMI 
and sexual development (using Tanner Stages) in children and adolescents with TSC-
associated SEGA who are taking everolimus or have taken everolimus. 


Novartis 
Confidential 
Page 45 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
10.4.1 
Variable 
To monitor the growth and the development of pediatric patients the following measurements 
will be performed annually: 
• Height 
• Weight 
• Tanner Stage 
• LH, FSH, and estrogen levels (female patients) starting age 10 
• LH, FSH, and testosterone levels (male patients) starting age 10 
10.4.1.1 Statistical hypothesis, model, and method of analysis 
10.4.1.2 Height and BMI 
The height standard deviation score (SDS) will be calculated based on height data collected 
during the study and published reference height information. The height SDS (also called z-
score) will be computed for a particular patient at each time point. The same approach will be 
used to compute BMI SDS. BMI will be calculated as weight (in kg) / squared height (in m). 
The z-scores will allow identification of potential outliers. 
SDS will be calculated using the current formulae provided by the WHO as follows: 
1. Calculate zind = 
 
2. If | zind | ≤ 3, SDS = zind 
If zind > 3, 
SDS = 3 + (X – SD3pos) / SD23pos 
If zind < -3, SDS = -3 + (X – SD3neg) / SD23neg 
where: 
• X is height in centimeters or BMI in kilograms/m2, 
• L, M and S are height or BMI-, sex- and age-specific reference values from the WHO 
Growth Charts. 
• SD3pos is the cutoff 3SD calculated by the LMS method: 
SD3pos = M * (1 + LS*3)1/L 
• SD3neg is the cutoff -3SD calculated by the LMS method: 
SD3pos = M * (1 + LS*(-3))1/L 
• SD23pos if the difference between the cutoffs 3SD and 2SD: 
SD23pos = M * (1 + LS*3)1/L - M * (1 + LS*2)1/L 
• SD23neg if the difference between the cutoffs -2SD and -3SD: 
SD23neg = M * (1 + LS*(-2))1/L - M * (1 + LS*(-3))1/L 
Height-for-age and BMI-for-age L, M and S reference values for boys and girls are available 
under http://www.who.int/childgrowth/standards/en/ (for patients aged between 0 to 5 years 
old) and http://www.who.int/growthref/en/ (for patients aged between 5 to 19 years old). 
These correspond to the latest available international references available at the time of this 
protocol and described in the 2007 Bulletin of the World Health Organization (Mercedes de 


Novartis 
Confidential 
Page 46 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Onis et al 2007). However these references may be revised according to new available 
standards at the time of the analysis. 
The age category immediately above the patient’s exact age should be used. SDS is actually a 
Z score that measures the distance from the population mean in units of standard deviations. 
That is, SDS < 0 refers to values lower than the population mean, and for example SDS ≤ -
1.645 refers to values in the lowest 5%. (The usual percentile more commonly used in the 
clinical practice can be derived from the Z-score by a normal distribution). 
The time-course of height and BMI SDS will be summarized, side by side, on the FAS of the 
studies CRAD001M2305 and TOSCA using descriptive statistics by year since the enrollment 
date (for TOSCA patients) or since the start of everolimus (for CRAD001M2305 patients). 
The counts and frequencies of patients with height and BMI SDS values lower than the 5th 
percentile (notably low) or higher than the 95th percentile (notably high) will be described on 
the FAS, overall and by region. 
The rate of height (respectively BMI) growth notable abnormality will be calculated as the 
rate of patients with a height SDS < 5th percentile at the last time point where height is 
reported. 
If a high rate of notably height (respectively BMI) growth abnormality occurs in the 
CRAD001M2305 patients, the relationship between the everolimus exposure and the height 
growth abnormality will be further explored as detailed below: 
• The rate of height (respectively BMI) growth abnormality will be described in the 
different subgroups defined by the duration of everolimus exposure. These subgroups will 
be defined in the Report and Analysis Plan. 
• The duration of exposure and the age at start of everolimus will be summarized using 
descriptive statistics in the subgroups of patients with and without a height (respectively 
BMI) growth abnormality. 
• A logistic regression including the duration of exposure and the age at the start of 
everolimus as continuous covariates will also be used to further explore the relationship 
between the everolimus exposure and the height (respectively BMI) growth notable 
abnormality. Additional covariates (e.g. time normalized Cmin) might also be included in 
the model. 
In addition, individual patient graphs for height and BMI over time will be provided for 
CRAD001M2305 patients. 
10.4.1.3 Tanner Stage 
Tanner Stage will include two components for boys, namely testis and pubic hair; and two 
components for girls: breast development and pubic hair. 
Percentage of patients who will have reached Tanner Stage V by age 16 (for females) or age 
17 (for males) will be provided, side by side, on the FAS Puberty of the studies CRADM2305 
and TOSCA, along with 95% confidence intervals. 
The relationship between the everolimus exposure and the Tanner Stage will be further 
explored in the CRAD001M2305 patients as detailed below: 


Novartis 
Confidential 
Page 47 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
• The percentage of patients who will have reached Tanner Stage V by age 16 (for females) 
or age 17 (for males) will be described in the different subgroups defined by duration of 
everolimus exposure. These subgroups will be defined in the Report and Analysis Plan. 
• The duration of exposure and the age at start of everolimus will be summarized using 
descriptive statistics in the subgroups of patients who will reach and who will not reach 
Tanner Stage V by age 16 (for females) or age 17 (for males). 
• A logistic regression including the duration of exposure and the age at the start of 
everolimus as continuous covariates may also be used to further explore if needed the 
relationship between the everolimus exposure and the achievement of Tanner Stage V by 
age 16 (for females) or age 17 (for males). Additional covariates (e.g. time normalized 
Cmin) might also be included in the model. 
10.4.1.4 Endocrine parameters 
Endocrine parameters such as LH, FSH, testosterone levels (in males) and LH, FSH, estrogen 
levels (in females) will be summarized descriptively, side by side, by gender and by age over 
time on the FAS of the studies CRADM2305 and TOSCA. 
In addition individual patient graphs over time will be provided for the CRAD001M2305 
patients. 
All data will be listed. 
10.4.2 
Handling of missing values/censoring/discontinuations 
All missing data will simply be described as missing on appropriate tables/listings in 
particular for patients who will not have reached Tanner Stage V or the age of 16 years (for 
females) or the age of 17 years (for males) at the end of the CRAD001M2305 study or at the 
end of the TOSCA registry using the FAS Puberty. 
10.4.3 
Supportive analyses 
Not applicable 
10.5 
Secondary objectives 
The following secondary objectives will be described: the long term-safety, the age at Tanner 
Stage II-V, the age at thelarche and menarche for females, the age at adrenarche for males and 
the TAND Checklist responses. 
Additionally an indirect comparison of CRAD001M2305 and TOSCA will be performed to 
compare the height, BMI and sexual development (using Tanner Stages). 
10.5.1 
Safety objectives 
The secondary safety objective of the study will be based mainly on the frequency of adverse 
events. All safety data will be listed. 


Novartis 
Confidential 
Page 48 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
10.5.1.1 Analysis set and grouping for the analyses 
All listings and tables will be presented for all CRAD001M2305 patients using the Safety Set 
for adverse events. 
The overall observation period will be divided into two mutually exclusive segments: 
1. everolimus exposure period: from day of first commercial dose received in the M2305 
study to 30 days after the last commercial dose received in the M2305 study. 
2. post-everolimus exposure period: 
• starting at day 30+1 after the last commercial dose received in the M2305 study 
or 
• starting at the enrollment date for patients who will stop everolimus in M2301 and 
who will not start commercial everolimus. 
10.5.1.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the everolimus exposure period, the treatment-emergent AEs. However, all safety data 
will be listed and those collected during the post-everolimus exposure period are to be 
flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to everolimus treatment and by year since the enrollment date. 
The prevalence over time of treatment-emergent adverse events will be described by system 
organ class and or preferred term. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event. 
Clinically notable AEs (CNAE) will be considered. Such categories consist of one or more 
well-defined safety events which are similar in nature and for which there is a specific clinical 
interest in connection with everolimus. 
For each CNAE, number and percentage of patients with at least one event part of the CNAE 
will be reported by categories regrouping the relevant preferred terms, as appropriate. 
10.5.1.3 Other safety data 
The other secondary safety objectives of the study will be based on sexual and 
neuropsychological development data. 
The age when patients reach each Tanner Stage II-V will be summarized on the FAS Puberty 
of the studies CRADM2305 and TOSCA. 
The following variables will be summarized on the Safety Set (SS) (those are only collected 
in the CRAD001M2305 study) using descriptive statistics: 
• age when females will start thelarche 
• age when females will have their first menses 
• age when males will reach adrenarche 


Novartis 
Confidential 
Page 49 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
For the age at which Tanner Stage II will be achieved, summary statistics from the Kaplan-
Meier distribution will be determined on the FAS puberty, including the median age and the 
proportions of patients reaching this milestone at some given ages. These statistics will be 
given as point estimates with 95% confidence intervals. The same analyses will be performed 
for the following variables: age at which each Tanner Stage III, IV and V will be reached. Age 
at thelarche (females), age at menarche (females) and age at adrenarche (males) will be 
described similarly on the SS. 
Potential delayed puberty will be defined based on Tanner stage and also on onset of 
menarche for girls. Potential cases identified through this algorithm, will be then clinically 
reviewed by assessing all available information in order to conclude the clinical relevance of 
the delay. 
Potential delayed puberty in girls is defined as failure to attain Tanner Stage II (for both breast 
development and pubic hair) by age 13, or absence of menarche by age 15 or within 5 years of 
attainment of Tanner Stage II (Fenichel 2012) Potential delayed puberty in boys is defined as 
failure to attain Tanner Stage II (for both testis and pubic hair) by age 14 (Traggiai 2002, 
Tanner 1962) 
Rates of potential delayed puberty will be described for boys and girls separately among the 
patients at risk of delayed puberty along with 95% confidence intervals. The patients at risk 
are patients who may potentially present an event of potential delayed puberty at baseline. 
The rates of potential delayed puberty will be described in the different subgroups defined by 
duration of everolimus exposure. These subgroups will be defined in the Report and Analysis 
Plan. 
The duration of exposure and the age at start of everolimus will be summarized using 
descriptive statistics in the subgroup of patients with potential delayed puberty. 
If a high rate of potential delayed puberty occurs, a logistic regression including the duration 
of exposure and the age at the start of everolimus as continuous covariates will also be used to 
further explore the relationship between the everolimus exposure and the rate of potential 
delayed puberty. Additional covariates (e.g. time normalized Cmin) might also be included in 
the model. 
These patients will be clinically reviewed by assessing all available information in order to 
evaluate their puberty development. 
All responses to the individual questions from the TAND Checklist (collected in both studies) 
will be summarized using descriptive statistics on both studies, side by side, and over time on 
the FAS of studies CRAD001M2305 and TOSCA. 
Safety data from other assessments will be listed, notable values flagged, and any other 
information collected will be listed as appropriate. 
10.5.1.4 Indirect comparison 
If the missing data pattern will not limiting, an indirect comparison between patients treated 
by everolimus (from CRAD001M2305 study) and those who never received an mTOR 
inhibitor (TOSCA subset of patients) will be performed to evaluate the everolimus effect on 


Novartis 
Confidential 
Page 50 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
growth and sexual development. Due to the observational nature of the TOSCA registry and 
its limited follow-up time, the statistical analysis will be primarily descriptive. 
The following steps will be followed: 
• The following non-exhaustive list of baseline characteristics will be used to assess 
potential imbalances between the two groups of patients: age at baseline, race, country, 
gender, age at first diagnosis of TSC, height abnormality at baseline, BMI abnormality at 
baseline, TSC mutation, type of TSC lesions, endocrine abnormality at baseline, Tanner 
Stage at baseline. 
• If any imbalances that are deemed to affect the comparison of the two groups are 
identified in the step above, propensity scores will be calculated using the appropriate 
statistical model according to the observed missing data pattern. The propensity score is 
the conditional probability of being a member of one of the groups to be compared (i.e. 
probability of being from the CRAD001M2305 study) given the patient’s covariates 
(D’Agostino 1998, Rosenbaum 1984). 
• Strata defined by the propensity scores (e.g. quintiles) will be then created and the balance 
between the groups within those strata will be examined. 
• If deemed relevant, the estimated propensity scores may then be used to obtain estimates 
for the effect of everolimus on growth (respectively sexual) development, through 
matching and/or logistic regression adjustment, using the CRAD001M2305 and TOSCA 
FAS (respectively FAS-Puberty) analysis sets. Matching will be considered if there is a 
much larger sample size of untreated (TOSCA) patients as compared to the 
CRAD001M2305 patients. In regression adjustment the propensity score may be included 
either as its raw score or as per the defined strata. In addition to the propensity score a 
subset of the other baseline characteristics covariates may be included. 
The following should be noted: the above described use of propensity scores is exploratory 
and highly dependent on the observed data (observed imbalances between groups, observed 
missingness pattern) and therefore it is not possible to fully pre-specify all aspects of the 
planned analyses. In addition, whereas a formal randomization guarantees that there should be 
no systematic differences in observed and unobserved covariates between the groups to be 
compared, the propensity scores are conditional only on the observed covariates. Thus, even if 
the use of propensity scores is intended to reduce bias and increase precision of the treatment 
effect, these indirect comparisons analyses using the propensity score methodology will be 
considered exploratory only and should be interpreted with cautious. 
For each covariate used to investigate the imbalances between the two groups (and then 
calculate the propensity score) the missing-data mechanism will be explored. If relevant 
(depending on the number of patients in the TOSCA Full Analysis Sets, amount of missing 
data, missing-data mechanism), specific methods like Multiple Imputation or ECM algorithms 
may be considered to estimate the propensity scores in presence of missing data. Handling of 
missing data is an evolving field of research and additional methods may be considered at the 
time of the availability of these long-term data. This will be further detailed in the Report 
Analysis Plan. 
If the missing data pattern will not limiting, the effect of everolimus on height (respectively 
BMI) growth abnormality may also be assessed as an exploratory analysis through the use of 


Novartis 
Confidential 
Page 51 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
propensity scores in a logistic regression or matching comparison as detailed before. The 
same analysis will be performed for the achievement of Tanner Stage V by age 16 (for 
females) or age 17 (for males). 
10.5.2 
Pharmacokinetics 
Blood trough levels collected at investigator discretion in compliance with local product 
information should be recorded, if available. 
The time-normalized Cmin value will be estimated for the entire treatment period using 
recorded everolimus Cmin values and prescribed doses in that treatment period. Cmin will be 
summarized with descriptive statistics over time in the SS. 
Time-normalized Cmin (Cmin,TN) will be calculated over each assessment interval (t1, t2). 
The time-normalized Cmin is defined as: 
 
Cmin,TN = (Cmin,t1*p1 + Cmin,t2*p2) / (p1+p2) 
• Cmin is considered to be the same within the same dosing interval (Cmin,ti is the mean 
Cmins if multiple Cmins are available within a dosing interval) 
• The dosing interval Pi is number of days in which the patient is treated with the same dose 
(in mg). 
• If there is no valid Cmin value available within a dose interval, the following imputation 
rule will be applied: the last Cmin,ti value will be taken and multiplied by the ratio of the 
dose given in the current dose interval to that of the previous dose interval. 
• The dose refers to the prescribed dose. 
If a high rate of growth/puberty abnormalities occurs, the potential relationships between 
Cmin and growth/puberty data will be explored in the SS as follow: 
Percentage of patients who will have reached Tanner Stage V by age 16 (for females) or age 
17 (for males) will be presented split by exposure to everolimus, in terms of patient’s time-
normalized Cmin. As per everolimus label the target Cmin for pediatric patients is between 5 
to 15 ng/mL, the time-normalized Cmin will be categorized as < 5 ng/ml, 5-10 ng/ml and > 10 
ng/ml. Note: if there are insufficient numbers of patients in one of the groups the categories 
may be collapsed. 
The same descriptive analyses will be performed for the rates of potential delayed puberty and 
for rate of notably low BMI/height SDS. 
10.6 
Exploratory objectives 
Not applicable 
10.7 
Interim analysis 
No formal interim analysis is planned for this study. However, safety outputs may be 
generated for regulatory safety updates. 


Novartis 
Confidential 
Page 52 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
10.8 
Sample size calculation 
No formal sample size calculation has been performed in this non-comparative study which 
consists in the long-term safety follow-up of CRAD001M2301 paediatric patients. It is 
anticipated that approximately 50 patients who have participated in CRAD001M2301 would 
be eligible to enter CRAD001M2305. 
Based on the safety findings in study CRAD001M2301 in terms of growth development 
where the estimated rate of patients with growth development abnormality was between 5 – 
10% as of 11-Jan-2013 cutoff, it can be expected that the proportion of patients with growth 
development abnormality in this study would be in the same range, between 5 - 10%. The 
growth development abnormality would be defined as rate of notably low height SDS at the 
cut-off date of the analysis. 
The proposed sample size of 50 patients will allow estimating a two-sided 95% confidence 
interval for rate of patients with growth development abnormality. Table 10-1 below shows 
the exact binomial 95% confidence interval (Clopper and Pearson 1934) and the precision of 
the estimate for N=50 for various numbers of observed patients with growth abnormality. 
Note that the final interval will depend on the final sample size. 
Table 10-1 
95% confidence interval for different number of observed patients 
with growth development abnormality during M2305 (sample size N = 
50) 
Number of patients with 
growth development 
abnormality 
Rate of patients with growth 
development abnormality 
Exact binomial 95% 
confidence interval 
0 
0.00 
(0.00, 0.07) 
2 
0.04 
(0.00, 0.14) 
4 
0.08 
(0.02, 0.19) 
6 
0.12 
(0.04, 0.24) 
8 
0.16 
(0.07, 0.29) 
10 
0.20 
(0.10, 0.34) 
12 
0.24 
(0.13, 0.38) 
14 
0.28 
(0.16, 0.42) 
With this sample size of 50, if we observe 4 patients with growth development abnormality 
(which corresponds to an observed 8% rate) there will be 79% probability of true rate of 
patients with growth development abnormality ≤ 10%. Probabilities that the true rate of 
patients with growth development abnormality is lower or equal to 10% with different number 
of observed patients with development abnormality are illustrated in Table 10-2. These 
calculations are based on the binomial distribution. 


Novartis 
Confidential 
Page 53 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Table 10-2 
Probability that the true rate of patients with growth development 
abnormality is lower or equal to 0.10 as a function of number of 
observed patients with development abnormality 
Number of observed patients 
with growth development 
delay 
Observed rate of patients with 
growth development delay 
P(true rate of patients with 
growth development delay 
≤ 0.10 | observed rate) 
0 
0.00 
1.00 
2 
0.04 
0.99 
3 
0.06 
0.92 
4 
0.08 
0.79 
5 
0.10 
0.62 
6 
0.12 
0.44 
8 
0.16 
0.17 
10 
0.20 
0.05 
10.9 
Power for analysis of key secondary variables 
No power calculation was made for secondary analyses. 
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 
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, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 


Novartis 
Confidential 
Page 54 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. 
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(s), proposed informed consent 
form(s) (ICF) that are 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. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
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 all 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 


Novartis 
Confidential 
Page 55 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
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. 
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. 


Novartis 
Confidential 
Page 56 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
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. 


Novartis 
Confidential 
Page 57 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
13 
References (available upon request) 
Afinitor/Votubia Investigator’s Brochure, edition 12, released 01-Nov-2013. 
Clopper C, Pearson S (1934) The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 26: 404-413. 
Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med; 
355: 1345-56. 
Cuccia V, Zuccaro G, Sosa F, et al (2003) Subependymal giant cell astrocytoma in children 
with tuberous sclerosis. Childs Nerv Syst Apr; 19(4): 232-43. 
Curatolo P, Verdecchia M, Bombardieri R (2002) Tuberous sclerosis complex: a review of 
neurological aspects. European Journal of Paediatric Neurology; 6: 15-23. 
D’Agostino (1998) Tutorial in biostatistics: propensity score methods for bias reduction in the 
comparison of a treatment to a non-randomized control group, Statist. Med. 17: 2265-2281. 
Fenichel P (2012) Delayed puberty. Endocr Dev: 22: 138-59. 
Franz DN (2007) Tuberous Sclerosis. http://www.emedicine.com/neuro/topic386.htm. Last 
updated February 14, 2007. Accessed May 4, 2007. 
Franz DN, Belousova E, Sparagana S, et al (2013) Efficacy and safety of everolimus for 
subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): 
a multicenter, randomized, placebo-controlled phase 3 trial. The Lancet; 381: 125-132. 
Franz DN, Leonard J, Tudor C, et al (2006) Rapamycin causes regression of astrocytomas in 
tuberous sclerosis complex. Annals Neurol 2006 Feb; 59:490-498. 
Goh S, Butler W, Thiele EA (2004) Subependymal giant cell tumors in tuberous sclerosis 
complex. Neurology; 63: 1457-61. 
Levine NB, Collins J, Franz DN, et al (2006) Gradual formation of an operative corridor by 
balloon dilation for resection of subependymal giant cell astrocytomas in children with 
tuberous sclerosis: specialized minimal access technique of balloon dilation. Minim Invasive 
Neurosurg; 49: 317-20. 
Macardle BM, McGowan ME, et al (1987) Anticonvulsant drugs, growth, and development. 
Arch Dis Child. 1987 June; 62(6): 615–617. 
Marshall WA, Tanner JM (1969) Variations in pattern of pubertal changes in girls. Arch Dis 
Child; 44:291-303. 
Marshall WA, Tanner JM (1970) Variations in pattern of pubertal changes in boys. Arch Dis 
Child; 45:13-23. 
Matsumura H, Takimoto H, Shimada N, et al (1998) Glioblastoma following radiotherapy in a 
patient with tuberous sclerosis. Neurol Med Chir (Tokyo); 38: 287-91. 
Mercedes de Onis, et al (2007) Development of a WHO growth reference for school-aged 
children and adolescents, Bulletin of the WHO 2007; 85: 660-667. 
Morrison PJ (2009) Tuberous Sclerosis: Epidemiology, Genetics and Progress towards 
Treatment. Neuroepidemiology; 33(4):342-343. 


Novartis 
Confidential 
Page 58 
Amended Protocol Version 01 (Clean) 
 
Protocol No. CRAD001M2305 
 
Novak GP, Maytal J, Alshansky A, et al (1999) Risk of excessive weight gain in epileptic 
children treated with valproate. J Child Neurol. 1999 Aug: 14(8):490-5. 
Osborne JP, Fryer A, Webb D (1991) Epidemiology of tuberous sclerosis. Ann N Y Acad 
Sci ;615:125-7. 
Rosenbaum, et al (1984) Reducing bias in observational studies using subclassification on the 
propensity score, Journal of the American Statistical Association, 79: Issue 387. 
Shepherd CW, et al (1991) Subependymal giant cell astrocytoma: A clinical, pathological and 
flow cytometric study. Neurosurgery; 28: 864-868. 
Sinson G, Sutton LN, Yachnis AT, et al (1994) Subependymal giant cell astrocytomas in 
children. Pediatr Neurosurg; 20: 233-9. 
Tanner JM, Growth at adolescence 1962 (2nd edition), Thomas, Springfield, Illinois. 
Torres OA, Roach ES, Delgado MR, et al (1998) Early diagnosis of subependymal giant cell 
astrocytoma in patients with tuberous sclerosis. J Child Neurol; 13: 173-7. 
Traggiai C, Stanhope R (2002) Delayed puberty. Best Pract Res Clin Endocrinol 
Metab;16:139-51. 

SAP_001.pdf: 
Clinical Development 
CRAD001/Everolimus/Afinitor® 
CRAD001M2305 / NCT02338609
Long-term follow-up study to monitor the growth and 
development of pediatric patients previously treated with 
everolimus in study CRAD001M2301 (EXIST-LT) 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final Amendment 1 
Release date: 
23-Jan-2024
Number of pages: 
31 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Document History - Changes compared to previous version 
Date 
Time 
point 
Reason for update 
Outcome for 
update  
Section and title 
impacted 
(Current) 
13-
Mar-
2015 
Prior to DB 
lock 
Creation of final version  
N/A 
– 
First 
version  
NA  
23-
Jan-
2024 
Prior 
to 
final 
DB 
lock 
Update based on new template  
 
Amendment 1 
 
 
 
Updated “TOSCA registry” to “who 
were never exposed to any mTOR 
inhibitors on the CRAD001MIC03 
study” 
 
Section 1 
 
 
Updated baseline definition “before 
the start of everolimus” to “before 
the start of everolimus in the parent 
study CRAD001M2301”  
 
Section 2.1.4 
 
 
 
 
Added Sperate Section for the 
Baseline definition addition to the 
“Endocrine assessment and Tanner 
Staging assessments”  
 
Section 2.1.5 
 
 
Updated Time window for Endocrine 
data 
 
Section 2.1.6 
 
 
Updated Section 2.1.6.1 for the 
Endocrine assessment visits   
 
Section 2.1.6.1 
 
 
Added: 
 FAS(CRAD001M2305) definition 
“(who met the inclusion exclusion 
criteria).”  
Added to the definition of Full 
Analysis Set for TOSCA, “nor 
recorded as prior or ongoing 
treatment at the baseline visit”. 
 
Section 2.3.1 
 
 
Updated “primary safety objective” 
to “primary objective” 
 
Section 2.4.2 
 
 
Updated to add table for PDs  
 
Section 3.3 
 
 
Added separate sentence 
“Concomitant medication ongoing at 
the time of enrollment in 
CRAD001M2305 and during the 
study will be summarized. 
Medications used at time of 
CRAD001M2301 will be listed.” 
 
Section 3.7 


Novartis 
Confidential 
Page 3 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update  
Section and title 
impacted 
(Current) 
 
 
Updated “LH, FSH, and estrogen 
levels for Male/female patients (for 
the CRAD001M2305/ TOSCA study, 
collected” 
 
Section 3.8 
 
 
Added sentence “The counts and 
frequencies by region will be 
provided if sufficient sample size 
observed within the region in the 
CRAD001M2305 study.” 
 
Section 3.8.1 
 
 
Added separate sentence “If the 
number of CRAD001M2305 patients 
is sufficient” 
  
Section 3.9 
 
 
Added separate sentence “AEs 
which will be counted for a specific 
period are those which are 
treatment-emergent. These events 
are those with an onset on or after 
the start of the treatment period, or 
which were present prior to the start 
of the treatment period but 
increased in severity or developed 
into SAEs after the start of the 
treatment period.” 
 
Section 3.9.1 
 
 
Updated Sentence “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. Starting prior to treatment 
day 1 will be identified in the listings 
with a starting treatment day less 
than day 1” to  “AE summaries will 
include all AEs ongoing at the time 
of enrollment and during the Study 
(CRAD001M2305) and no later than 
30 days after the last day of 
everolimus. AEs ongoing at the time 
of enrollment and during the study 
will be listed” 
 
Section 3.9.1.3 
 
 
Updated to report Adverse events of 
Special interest instead of Clinically 
notable AEs  
 
Section 3.9.1.5 
 
 
Added section 3.9.1.6 for the AE 
reporting outputs for the legal 
requirements of ClinicalTrials.gov 
and EudraCT 
 
Section 3.9.1.6 


Novartis 
Confidential 
Page 4 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update  
Section and title 
impacted 
(Current) 
 
 
Added Separate Section 4 “Change 
to protocol specified analyses” 
 
Section 4 
 
 
Updated Section 5 Imputation rules 
of missing dates: 
“Imatinib” to “Study” 
Imputation rule for study drug/AE, 
concomitant medication and other 
safety assessment 
table 4-2 title Imputation of end 
dates (Concomitant Medications) to 
“Imputation of end dates (Adverse 
events, Concomitant Medications)” 
 
Section 5.1 
 
 
 
Added Imputation rule for the 
Endocrine LLOQ/HLOQ values 
 
Section 5.2 


Novartis 
Confidential 
Page 5 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Table of contents 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 8 
2 
Definitions and general methodology ................................................................................. 8 
2.1 
Definitions ............................................................................................................... 8 
2.1.1 
Date of first administration of everolimus .............................................. 8 
2.1.2 
Date of last administration of everolimus ............................................... 9 
2.1.3 
Treatment day / Study day ...................................................................... 9 
2.1.4 
Baseline ................................................................................................... 9 
2.1.5 
First available assessment of endocrine test and Tanner Staging for 
the CRAD001M2305 patients ................................................................. 9 
2.1.6 
Time windows ......................................................................................... 9 
Table 2-1 
Time windows for Growth data/ Endocrine data .................................. 10 
2.2 
Data included in the analysis ................................................................................. 11 
Table 2-2 
Data included in each analysis .............................................................. 11 
2.3 
Definitions of analysis populations ....................................................................... 12 
2.3.1 
Full Analysis Set ................................................................................... 12 
2.3.2 
Safety Set .............................................................................................. 13 
2.4 
General statistical methodology ............................................................................ 13 
2.4.1 
Center pooling ....................................................................................... 13 
2.4.2 
Analysis of percentage rates.................................................................. 13 
2.4.3 
Time-to-event analyses ......................................................................... 13 
3 
Statistical methods used in reporting ................................................................................. 14 
3.1 
General presentation of descriptive summaries ..................................................... 14 
3.2 
Background and demographic characteristics ....................................................... 14 
3.3 
Protocol deviation summaries................................................................................ 14 
3.4 
Grouping for analysis ............................................................................................ 14 
3.5 
Patient disposition .................................................................................................. 15 
3.6 
Study treatment ...................................................................................................... 15 
3.7 
Concomitant therapy .............................................................................................. 15 
3.8 
Primary objective ................................................................................................... 16 
3.8.1 
Height and BMI..................................................................................... 16 
3.8.2 
Tanner Stage.......................................................................................... 18 
3.8.3 
Endocrine parameters ............................................................................ 18 
3.8.4 
Handling of missing values/censoring/discontinuations ....................... 18 


Novartis 
Confidential 
Page 6 
SAP Amendment 1 
 
 
CRAD001M2305 
 
3.9 
Secondary objective ............................................................................................... 19 
3.9.1 
Adverse events ...................................................................................... 19 
3.9.2 
Other safety data ................................................................................... 21 
3.9.3 
Indirect comparison ............................................................................... 23 
3.10 
Pharmacokinetic analyses ...................................................................................... 24 
3.11 
Interim analysis ...................................................................................................... 25 
3.12 
Subgroup analysis .................................................................................................. 25 
3.13 
Sample size calculation.......................................................................................... 25 
Table 3-1 
95% confidence interval for different number of observed patients 
with growth development abnormality during CRAD001M2305 (sample size 
N = 50) 26 
Table 3-2 
Probability that the true rate of patients with growth development 
abnormality is lower or equal to 0.10 as a function of number of observed 
patients with development abnormality ................................................................. 26 
4 
Change to protocol specified analyses .............................................................................. 26 
4.1 
Pharmacokinetics data ........................................................................................... 26 
4.2 
Indirect Comparison Analysis ............................................................................... 27 
5 
Appendix ........................................................................................................................... 27 
5.1 
Imputation Rule ..................................................................................................... 27 
5.1.1 
Study drug ............................................................................................. 27 
5.1.2 
Duration of exposure ............................................................................. 28 
Table 5-1             Imputation of Last dates date of exposure ............................................ 28 
5.1.3 
Cumulative dose .................................................................................... 29 
5.1.4 
AE, concomitant medication and other safety assessment date 
imputation ............................................................................................. 29 
Table 5-2 
Imputation of start dates (Adverse events, Concomitant 
Medications) .......................................................................................................... 29 
Table 5-3 
Imputation of end dates (Adverse events, Concomitant 
Medications) .......................................................................................................... 30 
5.2 
Endocrine parameters derivations.......................................................................... 30 
5.2.1 
Handling of test values below LLOQ and above HLOQ ...................... 30 
6 
References ......................................................................................................................... 31 
  


Novartis 
Confidential 
Page 7 
SAP Amendment 1 
 
 
CRAD001M2305 
 
List of abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
Cmin 
Minimum (trough) Concentration 
CRF 
Case Report/Record Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
FAS 
Full Analysis Set 
FSH 
Follicle Stimulating Hormone 
KM 
Kaplan-Meier 
LH 
Luteinizing Hormone 
MAP 
Master Analysis Plan 
MedDRA 
Medical Dictionary for Regulatory Activities 
mTOR 
Mammalian Target of Rapamycin 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDS 
Standard Deviation Score 
SEGA 
Subependymal Giant Cell Astrocytoma 
SOC 
System Organ Class 
TAND 
TSC-Associated-Neuropsychiatric-Disorders 
TSC 
Tuberous Sclerosis Complex 
VAP 
Validation and Planning 
 


Novartis 
Confidential 
Page 8 
SAP Amendment 1 
 
 
CRAD001M2305 
 
1 
Introduction 
This Statistical Analysis Plan (SAP) is for the evaluation of the long-term follow-up study to 
monitor the effect of everolimus on the growth and development of pediatric patients previously 
treated with everolimus in study CRAD001M2301 (EXIST-LT). Statistical analyses will be 
primarily descriptive for all endpoints. The planned statistical analysis is described in Section 
10 of the protocol. 
The data will be analyzed by Novartis. 
Data collected in this CRAD001M2305 study will be pooled with the corresponding data 
collected in the parent CRAD001M2301 study, in particular, background information on the 
disease history, demographics and baseline characteristics, everolimus exposure, sexual and 
growth development data.  
This pooling will allow for the following: 
• Obtaining baseline values collected in CRAD001M2301 before start of everolimus 
• Calculating the whole exposure to everolimus for patients enrolled in the CRAD001M2305 
study 
• Considering the whole growth/development course over time from the start of everolimus. 
The data of the patients enrolled in the CRAD001M2305 study and a subset of patients who 
were never exposed to any mTOR inhibitors on the CRAD001MIC03 study (TOSCA, and these 
patients are referred to as TOSCA patients) will be presented, side by side, whenever similar 
data were collected in both studies. This is intended to facilitate the interpretation of the 
CRAD001M2305 results and help differentiate the impact of the TSC condition versus any 
potential impact of everolimus on growth and sexual development. 
If the missing data pattern is not limiting and if the number of patients in each study is sufficient, 
exploratory indirect comparisons between patients treated by everolimus (enrolled in 
CRAD001M2305 study) and patients who were never exposed to any mTOR inhibitors 
(TOSCA patients) will be performed to evaluate the everolimus effect on growth and sexual 
development. 
2 
Definitions and general methodology 
2.1 
Definitions 
2.1.1 
Date of first administration of everolimus 
For CRAD001M2305 patients, the date of first administration of everolimus is defined as the 
first date when a non-zero dose was administered in the parent study CRAD001M2301. This 
date was recorded on Study History (HIS) Case Report Form (CRF) of the CRAD001M2305 
study.  
For the sake of simplicity, the date of first administration of everolimus will also be referred to 
as the start of everolimus. 


Novartis 
Confidential 
Page 9 
SAP Amendment 1 
 
 
CRAD001M2305 
 
2.1.2 
Date of last administration of everolimus 
For CRAD001M2305 patients, the date of last administration of everolimus is defined as the 
last date when a non-zero dose was administered and was recorded on the Everolimus 
prescription record CRF of the CRAD001M2305 study. 
2.1.3 
Treatment day / Study day 
For CRAD001M2305 patients, the treatment day 1 will be the date of start of everolimus. The 
treatment day of an assessment that occurred on or after the start of everolimus will be 
calculated as (date of assessment) – (date of start of everolimus) + 1. The treatment day of an 
assessment that occurred before the start of everolimus will be calculated as (date of assessment) 
– (date of start of everolimus).  
For TOSCA patients, since they were not exposed to any mTOR inhibitors on the TOSCA study, 
the concept of study day will be used. The study day 1 will be the enrollment date.  The study 
day of an assessment that occurred on or after the enrollment date will be calculated as (date of 
assessment) – (enrollment date) + 1. The study day of an assessment that occurred before the 
enrollment date will be calculated as (date of assessment) – (enrollment date). Treatment day/ 
Study day will be displayed in the data listings. 
2.1.4 
Baseline 
For CRAD001M2305 patients, the baseline value will be the last available assessment on or 
before the start of everolimus in the parent study CRAD001M2301.  
For the TOSCA patients, the baseline value is taken from the first available assessment on or 
after the enrollment date. 
If patients have no value as defined above, the baseline value will be missing. 
2.1.5 
First available assessment of endocrine test and Tanner Staging for 
the CRAD001M2305 patients 
The original protocol of the parent study CRAD001M2301 did not require collection of the  
endocrine blood test nor the Tanner Staging data. These assessments were added in the protocol 
amendment 2 of CRAD001M2301 and required to be collected during screening and at certain 
frequency during follow-up. As per the CRAD001M2301 protocol, patients who were ongoing 
at the time protocol amendment 2 was approved should have the endocrine blood tests and 
Tanner Staging assessed at their next scheduled visit (considered baseline).  
Therefore, some CRAD001M2305 patients who were already enrolled into the parent study 
CRAD001M2301 before the protocol amendment 2 do not have the endocrine blood test nor 
the Tanner Staging data on or before the start of everolimus in the parent study, and the first 
available assessments after the protocol amendment 2 of CRAD001M2301 were considered as 
the baseline data for those patients in the parent study as well as in the CRAD001M2305 study.  
2.1.6 
Time windows 
In order to summarize data over time, the following data types will be time slotted using time 
windows. 


Novartis 
Confidential 
Page 10 
SAP Amendment 1 
 
 
CRAD001M2305 
 
2.1.6.1 
Growth data/ Endocrine data 
Height and weight were collected at screening/baseline, every 4 weeks until Week 12, every 6 
weeks until Week 24, every 12 weeks until EOT in the CRAD001M2301 study. The growth 
data (height and BMI) will be collected at the enrollment and every year until EOT in the 
CRAD001M2305 study. The growth data will be collected at the baseline and annually if 
available in the TOSCA study.  
The endocrine data (LH, FSH, testosterone (in males) and LH, FSH, estrogen (in females)) will 
be collected in the CRAD001M2305 study at the baseline and then yearly, hence corresponding 
data will be pooled from CRAD001M2301 Study. The endocrine data will be collected in the 
TOSCA study at enrollment and annually if available.  
Table 2-1 summarizes the time windows for Growth data/Endocrine data analyses, where 
windows are centered at every year after start of everolimus for CRAD001M2305 patients and 
every year after the enrollment date for TOSCA patients. 
Table 2-1 
Time windows for Growth data/ Endocrine data 
Time 
Window 
Planned Assessment Day 
Time Window Definition 
 
CRAD001M2305 
TOSCA 
CRAD001M2305 
TOSCA 
Baseline 
Last available 
assessment on or 
before the start of 
everolimus in the 
parent study 
CRAD001M2301  
First available 
assessment 
after the 
enrollment date 
Before or on Treatment Day 1  Between Study Day 1 
and Study Day 182 
Year 1 
Treatment Day 365 
Study Day 365 
Treatment Days 183 to 547  
Study Days 183 to 547  
Year 2 
Treatment Day 730 
Study Day 730 
Treatment Days 548 to 913 
Study Days 548 to 913 
Year 3 
Treatment Day 1096 
Study Day 1096 
Treatment Days 914 to 1279 
Study Days 914 to 1279 
Year 4 
Treatment Day 1461 
Study Day 1461 
Treatment Days 1279 to 1644 
Study Days 1279 to 1644 
Every year thereafter until the end of each study 
Growth data, if more than one assessment is done within the Baseline time window, the 
assessment closest to study day 1 (for TOSCA) or treatment day 1 (for CRAD001M2301) will 
be used; if two or more assessments are equidistant from 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. 
Endocrine data, if more than one assessment is done within the Baseline time window, the 
assessment closest to study day 1 (for TOSCA) or treatment day 1 (for CRAD001M2301) or 
first available assessment will be used; if two or more assessments are equidistant from 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. 
 


Novartis 
Confidential 
Page 11 
SAP Amendment 1 
 
 
CRAD001M2305 
 
2.2 
Data included in the analysis 
This Study CRAD001M2305 is a long-term safety follow-up study and statistical analyses will 
be primarily descriptive for all endpoints. The planned statistical analysis is described in Section 
10 of the protocol.  
Data collected for the patients enrolled in this CRAD001M2305 study will be pooled with the 
corresponding data previously collected in the parent CRAD001M2301 study for the same 
patients, in particular, background information on the disease history, demographics and 
baseline characteristics, everolimus exposure, sexual and growth development data. This 
pooling will allow for the following: 
• Obtaining baseline values collected in CRAD001M2301 before start of everolimus 
• Calculating the whole exposure to everolimus for patients enrolled in the    
CRAD001M2305 study 
• Considering the whole growth/development course over time from the start of everolimus. 
The descriptive analyses of data from the CRAD001M2305 study and TOSCA registry will be 
presented, side by side, whenever similar data are collected in both studies. This is intended to 
facilitate the interpretation of the CRAD001M2305 results and help describe any potential 
impact of everolimus on growth and sexual development, in the TSC population, whose growth 
and sexual development independent of exposure to systemic mTOR inhibitors is not well 
characterized. 
Table 2-2  summarizes the data which will be included in all the analyses  
described in the SAP. 
Table 2-2 
Data included in each analysis 
Endpoints 
Studies 
Analysis Set 
CRAD001M2305 
CRAD001M2301 
TOSCA 
Baseline characteristics 
X 
X 
X 
FAS and FAS 
Puberty 
Patient disposition 
X 
 
 
FAS 
Protocol deviations 
X 
 
 
FAS 
Concomitant therapy 
X 
X 
 
Safety Set 
Height and BMI  
X 
X 
X 
FAS 
Tanner stage 
X 
X 
X 
FAS puberty 
Endocrines 
X 
X 
X 
FAS 
Adverse events 
X 
X 
 
Safety Set 
Age at menarche 
X 
X 
 
Safety Set 
Age at thelarche 
X 
X 
 
Safety Set 
Age at adrenarche 
X 
X 
 
Safety Set 
Potential delayed puberty 
X 
X 
 
Safety Set 
TAND checklist 
X 
 
X 
FAS 
Indirect comparison 
X 
X 
X 
FAS and FAS 
puberty 


Novartis 
Confidential 
Page 12 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Endpoints 
Studies 
Analysis Set 
CRAD001M2305 
CRAD001M2301 
TOSCA 
Treatment exposure 
X 
X 
 
Safety Set 
Pharmacokinetics  
X 
X 
 
Safety Set 
 
In order to ensure all data in the trial is captured, the cut-off date for final analysis will be fixed 
to the date of the last patient last visit. For the purpose of the final analysis, all tables, figures 
and listings (TFLs) described in this SAP as well as in TFL shells will be produced. 
If it is required to impute an end date in order to perform a specific analysis, the imputed date 
will be displayed and flagged in the listings. For example, if there is a record in the Everolimus 
prescription record panel with missing end date (or end date after the cut-off date), the cut-off 
date needs to be imputed as the end date in order to enable treatment exposure duration to be 
calculated. 
Details of imputation of partial dates are provided in the programming specifications 
(Programming Dataset Specifications). 
2.3 
Definitions of analysis populations 
This section defines the populations applicable to this study and their use in the statistical 
analyses. 
2.3.1 
Full Analysis Set 
In order to describe data from the CRAD001M2305 patients and those from the TOSCA registry 
side by side, the following analysis sets will be used. 
• The Full Analysis Set (FAS): 
- for CRAD001M2305, FAS will consist of all patients enrolled in the CRAD001M2305 
study. 
- for TOSCA, FAS will consist of all patients enrolled in this TOSCA registry whose age 
at study entry was below 16 (for female) and 17 (for male) years and who never received 
an mTOR inhibitor throughout the registry follow-up period nor recorded as prior or 
ongoing treatment at the baseline visit. 
 
• The Full Analysis Set for sexual development (FAS Puberty): 
- for CRAD001M2305, FAS Puberty will consist of the FAS patients defined above. 
- for TOSCA, FAS Puberty will consist of the FAS patients defined above but restricting 
from the patients to those aged between 9 to 17 years (for, females 9 to 16 years, males 
9 to 17 years) at registry entry. The TOSCA registry is designed to collect Tanner 
Staging until 2017 (i.e. 4 to 6 years of follow-up). Thus it is considered adequate to 
select only TOSCA patients aged between 9 to 17 years old at the time of entry to the 
registry to allow for obtaining puberty data corresponding to the peri-pubertal time 
frame. 


Novartis 
Confidential 
Page 13 
SAP Amendment 1 
 
 
CRAD001M2305 
 
2.3.2 
Safety Set 
The Safety Set (SS) will include all patients enrolled in the CRAD001M2305 study who have 
at least one-post CRAD001M2305 baseline safety assessment. It should be noted that all 
patients enrolled in the CRAD001M2305 study have been exposed to everolimus in the parent 
study CRAD001M2301 (and may or may not continue receiving commercial everolimus while 
on CRAD001M2305). 
The safety set will be the population used in the assessments of safety, such as adverse events 
(AEs) and everolimus exposure. 
2.4 
General statistical methodology 
2.4.1 
Center pooling 
All study centers will be combined for the analysis. Due to the expected small size of centers, 
no center effect will be assessed. 
2.4.2 
Analysis of percentage rates 
The primary objective of this study is to report the effect of everolimus on height, BMI and 
sexual development (using Tanner Stages) in children and adolescents with TSC-associated 
SEGA who are taking everolimus or have taken everolimus.  
The rates of sexual maturation will be described as the percentage of patients who have reached 
Tanner Stage V by age 16 (for females) or age 17 (for males). 
2.4.2.1 
Hypothesis and test statistic 
No statistical tests are planned for any of the percentage rates. 
2.4.2.2 
Confidence interval for percentage rates 
Endpoints will be summarized in terms of percentage rates with exact 95% confidence intervals. 
An exact binomial confidence interval [Clopper & Pearson, 1934] will be used, implemented 
using SAS procedure FREQ with the EXACT statement for one-way tables. 
2.4.3 
Time-to-event analyses 
This section presents the general methodology used to analyze time-to-event variables, e.g., age 
at which each Tanner Stage will be reached, age at thelarche (females), age at menarche 
(females) and age at adrenarche (males). 
2.4.3.1 
Kaplan-Meier estimates 
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. 
Median time-to-event will be obtained along with a 95% confidence interval calculated from 
the procedure LIFETEST using the method of [Brookmeyer & Crowley, 1982]. 
Kaplan-Meier (KM) estimates of the time-to-event function with 95% confidence intervals 
every 12 months, where 12 months is defined as 365.25 days, will be presented. The confidence 


Novartis 
Confidential 
Page 14 
SAP Amendment 1 
 
 
CRAD001M2305 
 
intervals will be constructed using Greenwood’s formula [Collett, 1994 ] for the standard error 
of the KM 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 log-log transformation is implemented in the LIFETEST procedure using the option 
CONFTYPE=LOGLOG. 
3 
Statistical methods used in reporting 
3.1 
General presentation of descriptive summaries 
Qualitative data (e.g., gender, race, etc.) will be summarized by appropriate descriptive statistics 
(i.e. frequencies and percentages); a missing category will be included as applicable. 
Percentages will be calculated using the number of patients in the relevant population or 
subgroup as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum). 
3.2 
Background and demographic characteristics 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301.  
Demographic and other baseline characteristics will be described by study (CRAD001M2305 
and TOSCA), side by side, on the two Full Analysis Sets (FAS and FAS Puberty). 
The summary table will include age, sex, race, weight, height, body mass index (BMI) at 
baseline.  
Age will be summarized by age category (≤12, >12) for both the studies. 
All demographic and background data will be listed. 
3.3 
Protocol deviation summaries 
For CRAD001M2305 patients, all protocol deviations which occurred during the 
CRAD001M2305 study will be analyzed, The number (%) of participants with any protocol 
deviation will be tabulated by deviation category, PDs that are pandemic related will be 
summarized by relationship to COVID-19. 
All protocol deviations will be listed (as specified in the VAP documents) using the FAS 
population. 
3.4 
Grouping for analysis 
The number and percentage of patients in each analysis population will be summarized.  


Novartis 
Confidential 
Page 15 
SAP Amendment 1 
 
 
CRAD001M2305 
 
3.5 
Patient disposition 
For the CRAD001M2305 patients, the FAS will be used for the patient disposition summary 
tables and listings. Information from the CRF page “End of Treatment” and “End of Study” 
CRAD001M2305 study will be used to provide a summary showing: 
• Number (%) of patients who started/ongoing commercial everolimus  
• Number (%) of patients with Treatment discontinuation and their discontinuation reason 
• Number (%) of patients with study discontinuation and their discontinuation reason  
3.6 
Study treatment 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301and will be summarized using the safety set. 
The participation in this study does not require the administration of everolimus. In such cases 
in which the patient was taking everolimus, data collection (such as therapeutic drug trough 
level, duration of everolimus interruptions and everolimus prescribed dose) will only be 
recorded, when available.  
For patients in Study CRAD001M2305, the duration of everolimus exposure and cumulative 
everolimus dose will be described using descriptive statistics on the Safety Set. 
The total duration of everolimus exposure will be calculated as the total duration of everolimus 
exposure received while on Study CRAD001M2301 plus the total duration of (commercially 
supplied) everolimus exposure reported in Study CRAD001M2305. 
Similarly, the cumulative dose of everolimus will be calculated as the cumulative everolimus 
dose received while on Study CRAD001M2301 plus the cumulative everolimus (commercially 
supplied) dose reported in Study CRAD001M2305. 
All exposure data will be listed. 
3.7 
Concomitant therapy 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301. Concomitant medication ongoing at the time of enrollment 
in CRAD001M2305 and during the study will be summarized. Medications used at time of 
CRAD001M2301 will be listed. 
Concomitant therapy will be described using the safety set. 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides everolimus that were administered to a patient preceding or coinciding with everolimus 
intake.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List to allow for categorization by preferred term (PT). In addition to categorizing 
medication data by PT, drugs are classified according to their Anatomical Therapeutic 
Chemical  (ATC) classification in order to present and compare how they are being utilized. 
The ATC classification allows for a summary of medications by a high-level common drug 
class. 


Novartis 
Confidential 
Page 16 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Concomitant medications and significant non-drug therapies taken concurrently with 
everolimus will be listed and summarized by ATC class and PT 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 be only listed. 
3.8 
Primary objective 
The primary objective of this study is to report the effect of everolimus on height, BMI and 
sexual development (using Tanner Stages) in children and adolescents with TSC-associated 
SEGA who are taking everolimus or have taken everolimus. 
To monitor the growth and the development of pediatric patients the following measurements 
will be performed annually: 
• Height 
• Weight 
• Tanner Stage 
• LH, FSH, and estrogen levels for female patients (for the CRAD001M2305 study, 
collected only for patients of 10 years old or older during the study) 
• LH, FSH, and testosterone levels for male patients (for the CRAD001M2305 study, 
collected only for patients of 10 years old or older during the study) 
3.8.1 
Height and BMI 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301.  
The height standard deviation score (SDS) will be calculated based on height data collected 
during the study and published reference height information. The height SDS (also called z-
score) will be computed for a particular patient at each time point. The same approach will be 
used to compute BMI SDS. BMI will be calculated as weight (in kg) / squared height (in m). 
The z-scores will allow identification of potential outliers. 
SDS will be calculated using the current formula provided by the WHO as follows: 
1. Calculate zind = 
 
2. If | zind | ≤ 3, SDS = zind 
If zind > 3, 
SDS = 3 + (X – SD3pos) / SD23pos 
If zind < -3, SDS = -3 + (X – SD3neg) / SD23neg 
where: 
• X is height in centimeters or BMI in kilograms/m2, 
• L, M and S are height or BMI-, sex- and age-specific reference values from the WHO 
Growth Charts. 
• SD3pos is the cutoff 3SD calculated by the LMS method: 
SD3pos = M * (1 + LS*3)1/L 


Novartis 
Confidential 
Page 17 
SAP Amendment 1 
 
 
CRAD001M2305 
 
• SD3neg is the cutoff -3SD calculated by the LMS method: 
SD3pos = M * (1 + LS*(-3))1/L 
• SD23pos if the difference between the cutoffs 3SD and 2SD: 
SD23pos = M * (1 + LS*3)1/L - M * (1 + LS*2)1/L 
• SD23neg if the difference between the cutoffs -2SD and -3SD: 
SD23neg = M * (1 + LS*(-2))1/L - M * (1 + LS*(-3))1/L 
Height-for-age and BMI-for-age L, M and S reference values for boys and girls are available 
under [http://www.who.int/childgrowth/standards/en/] (for patients aged between 0 to 5 years 
old) and [http://www.who.int/growthref/en/] (for patients aged between 5 to 19 years old). 
These correspond to the latest available international references available at the time of this 
protocol and described in the 2007 Bulletin of the World Health Organization (Mercedes de 
Onis et al 2007). However, these references may be revised according to new available 
standards at the time of the analysis. 
The age category immediately above the patient’s exact age should be used. SDS is actually a 
Z score that measures the distance from the population mean in units of standard deviations. 
That is, SDS < 0 refers to values lower than the population mean, and for example SDS ≤ -
1.645 refers to values in the lowest 5%. (The usual percentile more commonly used in the 
clinical practice can be derived from the Z-score by a normal distribution). 
The time-course of height and BMI SDS will be summarized, side by side, on the FAS of the 
studies CRAD001M2305 and TOSCA using descriptive statistics by year since the enrollment 
date (for TOSCA patients) or since the start of everolimus (for CRAD001M2305 patients). The 
counts and frequencies of patients with height and BMI SDS values lower than the 5th percentile 
(notably low) or higher than the 95th percentile (notably high) will be described on the FAS, 
overall and by region. The counts and frequencies by region will be provided if sufficient 
sample size observed within the region for CRAD001M2305 study. 
The rate of height (respectively BMI) growth notable abnormality will be calculated as the rate 
of patients with a height SDS < 5th percentile at the last time point where height is reported. 
If the number of CRAD001M2305 patients is sufficient and if a high rate of notably height 
(respectively BMI) growth abnormality occurs, the relationship between the everolimus 
exposure and the height growth abnormality will be further explored as detailed below: 
• The rate of height (respectively BMI) growth abnormality will be described in the 
different subgroups defined by the duration of everolimus exposure. These subgroups are 
described in the Section 3.12. 
• The duration of exposure and the age at start of everolimus will be summarized using 
descriptive statistics in the subgroups of patients with and without a height (respectively 
BMI) growth abnormality. 
• A logistic regression including the duration of exposure and the age at the start of 
everolimus as continuous covariates will also be used to further explore the relationship 
between the everolimus exposure and the height (respectively BMI) growth notable 
abnormality. Additional covariates (e.g. time normalized Cmin) might also be included in 
the model. 


Novartis 
Confidential 
Page 18 
SAP Amendment 1 
 
 
CRAD001M2305 
 
In addition, individual patient graphs for height and BMI over time will be provided for 
CRAD001M2305 patients. 
3.8.2 
Tanner Stage 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301.  
Tanner Stage will include two components for boys (testis and pubic hair) and two components 
for girls (breast development and pubic hair). 
Percentage of patients who will have reached Tanner Stage V by age 16 (for females) or age 17 
(for males) will be provided, side by side, on the FAS Puberty of the studies CRAD001M2305 
and TOSCA, along with 95% confidence intervals. 
If the number of CRAD001M2305 patients is sufficient and notably high abnormality, the 
relationship between the everolimus exposure and the Tanner Stage will be further explored as 
detailed below: 
• The percentage of patients who will have reached Tanner Stage V by age 16 (for females) 
or age 17 (for males) will be described in the different subgroups defined by duration of 
everolimus exposure. These subgroups are described in the Section 3.12. 
• The duration of exposure and the age at start of everolimus will be summarized using 
descriptive statistics in the subgroups of patients who will reach and who will not reach 
Tanner Stage V by age 16 (for females) or age 17 (for males). 
• A logistic regression including the duration of exposure and the age at the start of 
everolimus as continuous covariates may also be used to further explore if needed the 
relationship between the everolimus exposure and the achievement of Tanner Stage V by 
age 16 (for females) or age 17 (for males). Additional covariates (e.g. time normalized 
Cmin) might also be included in the model. 
3.8.3 
Endocrine parameters 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301. Endocrine parameters such as LH, FSH, testosterone levels 
(in males) and LH, FSH, estrogen levels (in females) will be summarized descriptively, by 
study, by gender and by age over time on the FAS of the studies CRAD001M2305 and TOSCA. 
Individual patient graphs over time will be provided for the CRAD001M2305 patients. 
All data will be listed. 
3.8.4 
Handling of missing values/censoring/discontinuations 
All missing data will simply be described as missing until not specified on appropriate 
tables/listings in particular for patients who will not have reached Tanner Stage V or the age of 
16 years (for females) or the age of 17 years (for males) at the end of the CRAD001M2305 
study or at the end of the TOSCA registry using the FAS Puberty or Height, BMI analysis using 
the FAS population. 


Novartis 
Confidential 
Page 19 
SAP Amendment 1 
 
 
CRAD001M2305 
 
3.9 
Secondary objective 
The following secondary objectives will be described: the long term-safety, the age at Tanner 
Stage II-V, the age at thelarche and menarche for females, the age at adrenarche for males and 
the TAND Checklist responses. 
Additionally an indirect comparison of CRAD001M2305 and TOSCA will be performed to 
compare the height, BMI and sexual development (using Tanner Stages) if the number of 
patients in the studies are sufficient. 
The secondary safety objective of the study will be based mainly on the frequency of AEs during 
the follow-up period of the CRAD001M2305 study.  
All safety data will be listed. 
3.9.1 
Adverse events 
AEs which will be counted for a specific period are those which are treatment-emergent. 
These events are those with an onset on or after the start of the treatment period, or which were 
present prior to the start of the treatment period but increased in severity or developed into SAEs 
after the start of the treatment period. 
AEs collected during the CRAD001M2305 study will be described. All listings and tables will 
be presented for all CRAD001M2305 patients using the Safety Set. 
For CRAD001M2305 patients, using the Safety Set, the overall observation period will be 
divided into two mutually exclusive segments: 
1. everolimus exposure period: from day of first commercial dose received in the 
CRAD001M2305 study to 30 days after the last commercial dose received in the 
CRAD001M2305 study. 
2. post-everolimus exposure period: 
• starting at day 30+1 after the last commercial dose received in the CRAD001M2305 
study 
or 
• starting at the enrollment date for patients who will stop everolimus in 
CRAD001M2301 and who will not start commercial everolimus. 
The safety summary tables will include only assessments collected during the everolimus 
exposure period. The safety listings will include all assessments, with those collected during 
the post-everolimus exposure period being flagged. 
3.9.1.1 
Coding of AEs 
AEs are coded using the MedDRA terminology. 
3.9.1.2 
Grading of AEs 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) by using the latest version available at the time of the final analysis. In case of an 
update of the CTC criteria during the course of the study, some mapping may be necessary. 
 


Novartis 
Confidential 
Page 20 
SAP Amendment 1 
 
 
CRAD001M2305 
 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1-4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
form. 
3.9.1.3 
General rules for AE Reporting 
Summary tables for AEs have to include only AEs that started or worsened during the 
everolimus exposure period (treatment-emergent AEs). AE summaries will include all AEs 
ongoing at the time of enrollment and during the Study (CRAD001M2305) and no later than 
30 days after the last dose of everolimus. AEs ongoing at the time of enrollment 
(CRAD001M2305) and during the study will be listed, and AEs starting later than 30 days after 
the last dose 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 
(SOC_TXT), and for each preferred term (PT_TXT) 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 (SOC), PT, and 
maximum CTC grade (AEVGRD1C). 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. 
3.9.1.4 
AE summaries 
The following AE summaries will be produced: 
• AEs, regardless of study drug relationship, by primary SOC, PT, and maximum grade 
• AEs, regardless of study drug relationship, by PT, maximum grade 
• AEs, with suspected study drug relationship, by primary SOC, PT, and maximum 
grade 
• Serious adverse events (SAEs), regardless of study drug relationship, by primary SOC 
and PT, maximum grade 
• Adverse events leading to study drug discontinuation, regardless of study drug 
relationship by primary SOC and PT, maximum grade 
• Deaths, by primary SOC and PT 
All summaries will show ‘All grades’ (including AEs with unknown/missing grade) and 
‘Grades ≥ 3’. 
AEs will be presented in alphabetical order for SOC, and in descending order of frequency for 
PT within each SOC. 
Deaths and AEs will be listed by patient. 


Novartis 
Confidential 
Page 21 
SAP Amendment 1 
 
 
CRAD001M2305 
 
3.9.1.5 
Adverse events of special interest/ Grouping of AEs  
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound Everolimus. These groupings are defined using 
MedDRA terms, such as SMQs (standardized MedDRA queries), HGLTs (high level group 
terms), HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis 
MedDRA queries, NMQ) may also be used. A NMQ is a customized group of search terms 
which defines a medical concept for which there is no MedDRA SMQ available or the available 
MedDRA SMQ does not completely fit the need. It may include a combination of single terms 
and/or an existing SMQ, narrow or broad. These searches will be are defined in the Novartis 
tool known as eCRS (electronic Case Retrieval Strategy). The most up-to-date version of the 
eCRS at the time of analysis is used for retrieval of search terms. A listing of search terms will 
be provided in the CSR.   
For each specified AESI, number (%) of participants with at least one AESI occurring during 
on-treatment period will be summarized by safety topics, maximum grades. 
A listing of all terms down to the MedDRA PTs used to define each AESI will be generated. 
3.9.1.6 
For the legal requirements of ClinicalTrials.gov and EudraCT 
Two required tables on treatment emergent AEs which are not SAEs with an incidence greater 
than 5%, on treatment emergent SAEs and SAE suspected to be related to study treatment will 
be provided by SOC and PT 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 AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
Number of deaths resulting from SAEs suspected to be related to study treatment and number 
of deaths resulting from SAEs irrespective of causality will be provided.  
3.9.2 
Other safety data 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301 except for the TAND checklist as this assessment was not 
collected in the parent study CRAD001M2301.  
The other secondary objectives of the study will be based on sexual and neuropsychological 
(TAND checklist) development data. 
The age when patients reach each Tanner Stage II-V will be summarized on the FAS Puberty 
of Studies CRAD001M2305 and TOSCA. 


Novartis 
Confidential 
Page 22 
SAP Amendment 1 
 
 
CRAD001M2305 
 
The following variables will be summarized on the Safety Set (those are only collected in the 
CRAD001M2305 study) using descriptive statistics: 
• age when females will start thelarche 
• age when females will have their first menses 
• age when males will reach adrenarche 
For the age at which Tanner Stage II will be achieved, summary statistics from the KM 
distribution will be determined on the FAS puberty, including the median age and the 
proportions of patients reaching this milestone at some given ages. These statistics will be given 
as point estimates with 95% confidence intervals. The same analyses will be performed for the 
following variables: age at which each Tanner Stage III, IV and V will be reached. Age at 
thelarche (females), age at menarche (females) and age at adrenarche (males) will be described 
similarly on the SS. 
Potential delayed puberty will be defined based on Tanner stage and also on onset of menarche 
for girls. Potential cases identified through this algorithm, will be then clinically reviewed by 
assessing all available information in order to conclude the clinical relevance of the delay. 
Potential delayed puberty in girls is defined as failure to attain Tanner Stage II (for both breast 
development and pubic hair) by age 13, or absence of menarche by age 15 or within 5 years of 
attainment of Tanner Stage II [Fenichel 2012] Potential delayed puberty in boys is defined as 
failure to attain Tanner Stage II (for both testis and pubic hair) by age 14 ([Traggiai 2002], 
[Tanner 1962]) 
Rates of potential delayed puberty will be described for boys and girls separately among the 
patients at risk of delayed puberty along with 95% confidence intervals. The patients at risk are 
patients who may potentially present an event of potential delayed puberty at baseline. 
If the number of patients in CRAD001M2305 is sufficient, the rates of potential delayed puberty 
will be described in the different subgroups defined by duration of everolimus exposure. These 
subgroups are described in the Section 3.12. 
If a high rate of potential delayed puberty occurs and if the number of patients in the 
CRAD001M2305 study is sufficient, the duration of exposure and the age at start of everolimus 
will be summarized using descriptive statistics in the subgroup of patients with potential 
delayed puberty. 
If a high rate of potential delayed puberty occurs and if the number of patients in each study is 
sufficient, a logistic regression including the duration of exposure and the age at the start of 
everolimus as continuous covariates will also be used to further explore the relationship 
between the everolimus exposure and the rate of potential delayed puberty. Additional 
covariates (e.g. time normalized Cmin) might also be included in the model. 
These patients will be clinically reviewed by assessing all available information in order to 
evaluate their puberty development. 
All responses to the individual questions from the TAND Checklist will be summarized using 
descriptive statistics on both studies, side by side, and over time on the FAS of studies 
CRAD001M2305 and TOSCA (Research Project 4). 


Novartis 
Confidential 
Page 23 
SAP Amendment 1 
 
 
CRAD001M2305 
 
All the responses are categorical in nature from the TAND Checklist, if applicable, the 
frequency of baseline and worst-post baseline will be summarized on both studies, side by side, 
and over time on the FAS of studies CRAD001M2305 and TOSCA (Research Project 4). 
Safety data from other assessments will be listed, notable values flagged, and any other 
information collected will be listed as appropriate. 
3.9.3 
Indirect comparison 
For CRAD001M2305 patients, all data described below will be pooled with the corresponding 
data from Study CRAD001M2301.  
If the missing data pattern is not limiting and if the number of patients in each study is sufficient, 
an indirect comparison between patients treated by everolimus (from CRAD001M2305 study) 
and those who never received an mTOR inhibitor (TOSCA subset of patients) will be performed 
to evaluate the everolimus effect on growth and sexual development. Due to the observational 
nature of the TOSCA registry and its limited duration of follow-up, the statistical analysis will 
be primarily descriptive. 
The following steps will be followed: 
• The following non-exhaustive list of baseline characteristics will be used to assess 
potential imbalances between the two groups of patients: age at baseline, race, country, 
gender, age at first diagnosis of TSC, height abnormality at baseline, BMI abnormality at 
baseline, TSC mutation, type of TSC lesions, endocrine abnormality at baseline, Tanner 
Stage at baseline. 
• If any imbalances that are deemed to affect the comparison of the two groups are 
identified in the step above, propensity scores will be calculated using the appropriate 
statistical model according to the observed missing data pattern. The propensity score is 
the conditional probability of being a member of one of the groups to be compared (i.e. 
probability of being from the CRAD001M2305 study) given the patient’s covariates 
[D’Agostino 1998, Rosenbaum 1984]. 
• Strata defined by the propensity scores (e.g. quintiles) will be then created and the balance 
between the groups within those strata will be examined. 
• If deemed relevant, the estimated propensity scores may then be used to obtain estimates 
for the effect of everolimus on growth (respectively sexual) development, through 
matching and/or logistic regression adjustment, using the CRAD001M2305 and TOSCA 
FAS (respectively FAS Puberty) analysis sets. Matching will be considered if there is a 
much larger sample size of untreated (TOSCA) patients as compared to the 
CRAD001M2305 patients. In regression adjustment the propensity score may be included 
either as its raw score or as per the defined strata. In addition to the propensity score a 
subset of the other baseline characteristics covariates may be included. 
The following should be noted: the above described use of propensity scores is exploratory and 
highly dependent on the observed data (observed imbalances between groups, observed 
missingness pattern) and therefore it is not possible to fully pre-specify all aspects of the 
planned analyses. In addition, whereas a formal randomization guarantees that there should be 
no systematic differences in observed and unobserved covariates between the groups to be 


Novartis 
Confidential 
Page 24 
SAP Amendment 1 
 
 
CRAD001M2305 
 
compared, the propensity scores are conditional only on the observed covariates. Thus, even if 
the use of propensity scores is intended to reduce bias and increase precision of the treatment 
effect, these indirect comparisons analyses using the propensity score methodology will be 
considered exploratory only and should be interpreted with cautious. 
For each covariate used to investigate the imbalances between the two groups (and then 
calculate the propensity score) the missing-data mechanism will be explored. If relevant 
(depending on the number of patients in the TOSCA Full Analysis Sets, amount of missing data, 
missing-data mechanism), specific methods like Multiple Imputation or ECM algorithms may 
be considered to estimate the propensity scores in presence of missing data. Handling of missing 
data is an evolving field of research and additional methods may be considered at the time of 
the availability of these long-term data.  
If the missing data pattern is not limiting, the effect of everolimus on height (respectively BMI) 
growth abnormality may also be assessed as an exploratory analysis through the use of 
propensity scores in a logistic regression or matching comparison as detailed before. The same 
analysis will be performed for the achievement of Tanner Stage V by age 16 (for females) or 
age 17 (for males). 
3.10 
Pharmacokinetic analyses 
The pharmacokinetic (PK) analyses will be described only for CRAD001M2305 patients under 
the safety set. 
Blood trough levels collected at investigator discretion in compliance with local product 
information should be recorded, if available. 
The time-normalized Cmin value will be estimated for the treatment period using recorded 
everolimus Cmin values and prescribed doses in that treatment period. Cmin will be 
summarized with descriptive statistics over time in the SS. 
Time-normalized Cmin (Cmin,TN) will be calculated over each assessment interval (t1, t2). 
The time-normalized Cmin is defined as: 
 
Cmin,TN = (Cmin,t1*p1 + Cmin,t2*p2) / (p1+p2) 
• Cmin is considered to be the same within the same dosing interval (Cmin,ti is the mean 
Cmins if multiple Cmins are available within a dosing interval) 
• The dosing interval Pi is number of days in which the patient is treated with the same dose 
(in mg). 
• If there is no valid Cmin value available within a dose interval, the following imputation 
rule will be applied: the last Cmin,ti value will be taken and multiplied by the ratio of the 
dose given in the current dose interval to that of the previous dose interval. 
• The dose refers to the prescribed dose. 
If a high rate of growth/puberty abnormalities occurs and if the number of CRAD001M2305 
patients is sufficient, the potential relationships between Cmin and growth/puberty data will be 
explored in the Safety Set as follow: 
If the number of CRAD001M2305 patients is sufficient, the percentage of patients who will 
have reached Tanner Stage V by age 16 (for females) or age 17 (for males) will be presented 


Novartis 
Confidential 
Page 25 
SAP Amendment 1 
 
 
CRAD001M2305 
 
split by exposure to everolimus, in terms of patient’s time-normalized Cmin. As per everolimus 
label, the target Cmin for pediatric patients is between 5 to 15 ng/mL, the time-normalized Cmin 
will be categorized as < 5 ng/ml, 5-10 ng/ml and > 10 ng/ml. Note: if there are insufficient 
numbers of patients in one of the groups, the categories may be collapsed or redefined. 
The same descriptive analyses will be performed for the rates of potential delayed puberty and 
for rate of notably low BMI/height SDS, if a high rate of growth/puberty abnormalities occurs 
and if the number of CRAD001M2305 patients is sufficient. 
Pooled data will be listed. 
3.11 
Interim analysis 
No formal interim analysis is planned for this study. However, safety outputs may be generated 
for regulatory safety updates. 
3.12 
Subgroup analysis 
For the CRAD001M2305 patients, if the number of patients is sufficient, the following 
subgroups by duration of everolimus exposure will be used for some analyses: 
- 
Less than 5 years of everolimus exposure (< 5 years) 
- 
Between 5 years and 10 years of everolimus exposure (≥ 5 years - < 10 years) 
- 
Ten years or more of everolimus exposure (≥ 10 years) 
Note: if there are insufficient numbers of patients in one of the groups the categories may be 
collapsed or redefined. 
3.13 
Sample size calculation 
No formal sample size calculation has been performed in this non-comparative study which 
consists in the long-term safety follow-up of CRAD001M2301 pediatric patients. It is 
anticipated that approximately 50 patients who have participated in CRAD001M2301 would be 
eligible to enter CRAD001M2305. 
Based on the safety findings in Study CRAD001M2301 in terms of growth development where 
the estimated rate of patients with growth development abnormality was between 5 – 10% as 
of 11-Jan-2013 cutoff, it can be expected that the proportion of patients with growth 
development abnormality in this study would be in the same range, between 5 - 10%. The 
growth development abnormality would be defined as rate of notably low height SDS at the 
cut-off date of the analysis. 
The proposed sample size of 50 patients will allow estimating a two-sided 95% confidence 
interval for rate of patients with growth development abnormality. Table 3-1 below shows the 
exact binomial 95% confidence interval [Clopper and Pearson 1934] and the precision of the 
estimate for N=50 for various numbers of observed patients with growth abnormality. Note that 
the final interval will depend on the final sample size. 


Novartis 
Confidential 
Page 26 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Table 3-1 
95% confidence interval for different number of observed 
patients with growth development abnormality during CRAD001M2305 
(sample size N = 50) 
Number of patients with 
growth development 
abnormality 
Rate of patients with growth 
development abnormality 
Exact binomial 95% 
confidence interval 
0 
0.00 
(0.00, 0.07) 
2 
0.04 
(0.00, 0.14) 
4 
0.08 
(0.02, 0.19) 
6 
0.12 
(0.04, 0.24) 
8 
0.16 
(0.07, 0.29) 
10 
0.20 
(0.10, 0.34) 
12 
0.24 
(0.13, 0.38) 
14 
0.28 
(0.16, 0.42) 
With this sample size of 50, if we observe 4 patients with growth development abnormality 
(which corresponds to an observed 8% rate) there will be 79% probability of true rate of patients 
with growth development abnormality ≤ 10%. Probabilities that the true rate of patients with 
growth development abnormality is lower or equal to 10% with different number of observed 
patients with development abnormality are illustrated in Table 3-2. These calculations are based 
on the binomial distribution. 
Table 3-2 
Probability that the true rate of patients with growth 
development abnormality is lower or equal to 0.10 as a function of 
number of observed patients with development abnormality 
Number of observed patients 
with growth development 
delay 
Observed rate of patients with 
growth development delay 
P(true rate of patients with 
growth development delay 
≤ 0.10 | observed rate) 
0 
0.00 
1.00 
2 
0.04 
0.99 
3 
0.06 
0.92 
4 
0.08 
0.79 
5 
0.10 
0.62 
6 
0.12 
0.44 
8 
0.16 
0.17 
10 
0.20 
0.05 
No power calculation was made for secondary analyses. 
4 
Change to protocol specified analyses 
4.1 
Pharmacokinetics data 
PK data were collected using central lab for parent study CRAD001M2301 however local lab 
used for study CRAD001M2305. The local lab test processes are not validated by Sponsor, and 
it is varying among the local labs so the PK data from local lab are not comparable to the central 


Novartis 
Confidential 
Page 27 
SAP Amendment 1 
CRAD001M2305 
lab PK data available in CRAD001M2301. Therefore, PK analysis will be performed only on 
the data collected in CRAD001M2305 Study. 
4.2 
Indirect Comparison Analysis 
Confidence interval was so wide even for 1 patient with growth development abnormality as 
shown below in the table 1-1. Estimation was not robust due to the small sample size. Sample 
size of 15 patients is too small for any comparison, Considering the unlikelihood of making a 
robust analysis with the limited enrolment into CRAD001M2305, indirect comparison is not 
meaningful. 
5 
Appendix 
5.1 
Imputation Rule 
5.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment: 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the participant is considered as on-going:  


Novartis 
Confidential 
Page 28 
SAP Amendment 1 
 
 
CRAD001M2305 
 
The participant should be treated as on-going and the cut-off date should be used as the dose 
end date.  
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:  
Case 1: The dose end date is completely missing, and the EOT  completion 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 
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date:  
            Use last day of the Month (mm) 
Case 5: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm = the month of  EOT date:  
            Use EOT date 
All other cases should be considered as a data issue and should contact the data manager of 
the study. 
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:  
Use the treatment start date 
Participants with missing start dates are to be considered missing for all study treatment 
component related calculations and no imputation will be made. If start date is missing then 
end-date should not be imputed. 
5.1.2 
Duration of exposure 
Duration of exposure (days) = (last date of exposure to investigational drug) – (date of first 
administration of investigational drug) + 1 
Table 5-1      Imputation of Last dates date of exposure 
Scenario  
Rule 
Investigational drug 
with a period 
administration 
The planned end date of the last period in which the last non-zero dose 
of the investigational drug was last administered. 
 
Note: If the subject died or was lost to follow-up before the derived last 
date, the last date of exposure to investigational drug is the date of 
death or the date of last contact, respectively. 
If the derived last date of exposure goes beyond the data cutoff date, it 
should be truncated to the date of data cutoff. 
Daily administration of 
the investigational drug 
Date of last administration of a non -zero dose of the investigational 
drug 


Novartis 
Confidential 
Page 29 
SAP Amendment 1 
 
 
CRAD001M2305 
 
5.1.3 
Cumulative dose 
Defined as the sum over the daily doses of all days between first and last dose. 
Cumulative dose = sum of (daily dose at a visit * (end date of dose – start date of dose +1). 
• The planned cumulative dose total planned dose as per the protocol up to the last 
administration of study treatment. 
• The actual cumulative dose refers to the total actual dose administered, over the 
duration for which the subject is on the as documented in the Dose Administration 
eCRF. 
 For subjects who did not take any drug the cumulative dose is by definition equal to zero. 
The actual cumulative dose is the sum of the non-zero doses recorded over the dosing period 
and the planned cumulative dose is the planned starting dose summed over the same dosing 
period. 
 
5.1.4 
AE, concomitant medication and other safety assessment date 
imputation 
Every effort will be made to get the missing information on partial dates. However, despite best 
efforts, some partial dates might still exist in the database. They will be listed as is. If needed 
in a calculation (e.g. duration), the standard Novartis Oncology imputation rules will be used.  
Table 5-2 
Imputation of start dates (Adverse events, Concomitant 
Medications) 
Missing 
Element 
Rule 
day, month, 
and year 
No imputation will be done for completely missing dates 
day, month 
If available year = year of study treatment start date then  
If stop date contains a full date and stop date is earlier than study treatment start date then 
set start date = 01JanYYYY  
Else set start date = study treatment start date.  
If available year > year of study treatment start date then 01JanYYYY 
If available year < year of study treatment start date then 01JulYYYY 
Day 
If available month and year = month and year of study treatment start date then  
If stop date contains a full date and stop date is earlier than study treatment start date then 
set start date= 01MONYYYY.  
Else set start date = study treatment start date. 
If available month and year > month and year of study treatment start date then 
01MONYYYY   
If available month and year < month year of study treatment start date then 
15MONYYYY   
 


Novartis 
Confidential 
Page 30 
SAP Amendment 1 
 
 
CRAD001M2305 
 
Table 5-3 
Imputation of end dates (Adverse events, Concomitant 
Medications)  
Missing 
Element 
Rule  
For patients who discontinued study: 
*=last treatment date plus 30 days not > (death date, cut-off date) 
For patients still on study:  
*= last contact date on study  
day, month, 
and year 
No imputation will be done for completely missing dates 
day, month 
If partial end date contains year only, set end date = earliest of 31DecYYYY or end date 
of the on-treatment period*  
day 
If partial end date contains month and year, set end date = earliest of last day of the 
month or end date of the on-treatment period* 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘continuing’ 
rather than the end date provided.  
 
5.2 
Endocrine parameters derivations 
5.2.1 
Handling of test values below LLOQ and above HLOQ 
For numerical 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 datasets respectively, where “n” can be any number.  
The time point summary tables will follow this data handling rules: prior to conversion of 
laboratory values to SI unit, a value which shows “<n” (or “<=n”) will be handled as zero; a 
value which shows “>n” (or “>=n”) will be handled as “n”. These values will be presented in 
the listing as it is. 
 
 
 
 
 


Novartis 
Confidential 
Page 31 
SAP Amendment 1 
 
 
CRAD001M2305 
 
6 
References 
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). Model ling Survival Data in Medical Research. Texts in Statistical Science. 
Chapman & Hall, London. 
Kalbfleisch, J. D., and R. L. Prentice (1980) The statistical analysis of failure time data. John 
Wiley & Sons, New York. 
Mercedes de Onis, et al (2007) Development of a WHO growth reference for school-aged 
children and adolescents, Bulletin of the WHO 2007; 85: 660-667. 
Fenichel P (2012) Delayed puberty. Endocr Dev: 22: 138-59. 
Traggiai C, Stanhope R (2002) Delayed puberty. Best Pract Res Clin Endocrinol 
Metab;16:139-51. 
Tanner JM, Growth at adolescence 1962 (2nd edition), Thomas, Springfield, Illinois. 
D’Agostino (1998) Tutorial in biostatistics: propensity score methods for bias reduction in the 
comparison of a treatment to a non-randomized control group, Statist. Med. 17: 2265-2281. 
Rosenbaum, et al (1984) Reducing bias in observational studies using subclassification on the 
propensity score, Journal of the American Statistical Association, 79: Issue 387.