Conditions: Tuberous Sclerosis Complex-associated Refractory Seizures
Keywords: TSC seizures TSC epilepsy mTOR inhibitor RAD001 Everolimus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 366
Healthy volunteers: no

Brief summary:
This study evaluated the efficacy and safety of two trough-ranges of everolimus given as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who had refractory partial-onset seizures.

The study consisted of 4 phases for each patient Baseline phase:\[From Screening Week -8 (V1) to randomization visit at Week 0 (V2)\], Core phase \[from randomization at Week 0 (V2) to Week 18 (V11)\], Extension phase \[from Week 18 (V11) until 48 weeks after the last patient had completed the core phase\] and Post Extension phase \[from end of Extension phase to end of study\].

Detailed description:

Arms:
arm 1: Participants received everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL plus 1 to 3 antiepileptic drugs. arm 2: Participants received everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL plus 1 to 3 antiepileptic drugs. arm 3: Participants received placebo plus 1 to 3 antiepileptic drugs.

Interventions: intervention 1: RAD001 intervention 2: Placebo intervention 3: Antiepileptic drug (1 to 3 only) intervention 4: open label RAD001 (only used for post-extension phase)
Intervention descriptions: intervention 1: Everolimus tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister packs and placed in boxes with color-coded labels, color 1 or color 2. intervention 2: Placebo tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister packs and placed in boxes with color-coded labels, color 1 or color 2. intervention 3: no more than any 3 of the listed antiepileptic drugs could be taken with the study drug or placebo. List of allowed antiepileptic drugs were: valporic acid, carbamazepine, clobazam, N-desmethylclobazam, topiramate,TRI477, TRI476, clonazepam, zonisamide, phenobarbital, phenytoin intervention 4: everolimus tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister backs in boxes with open label design and were taken during the Post-Extension phase, where all the participants, including those who were previously on placebo, took the 2mg tablets.

Protocol document:
Prot_000.pdf: 
Clinical Development
Afinitor®/Votubia® (everolimus)
Clinical Trial Protocol CRAD001M2304 / NCT02962414
A three-arm, randomized, double-blind, placebo-controlled 
study of the efficacy and safety of two trough-ranges of 
everolimus as adjunctive therapy in patients with tuberous 
sclerosis complex (TSC) who have refractory partial-onset 
seizures
Authors
Document type
Amended Protocol Version
EUDRACT number
2011-000860-90
Version number
03 (Clean)
Development phase
III
Document status
Final
Release date
25-Mar-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................10
Amendment 3 (25-Mar-2016) ...........................................................................................11
Summary of previous amendments ...................................................................................13
Protocol summary..............................................................................................................23
1
Background........................................................................................................................25
1.1
Overview of Tuberous Sclerosis and current treatment options............................25
1.1.1
Epilepsy associated with TSC...............................................................25
1.1.2
Role of mTOR in TSC and epileptogenesis..........................................26
1.1.3
Rapamycin and everolimus (RAD001) in TSC-epilepsy......................29
1.2
Introduction to investigational treatment(s) and other study treatment(s).............32
1.2.1
Overview of everolimus (RAD001)......................................................32
2
Rationale............................................................................................................................35
2.1
Study rationale and purpose...................................................................................35
2.2
Rationale for the study design ...............................................................................36
2.3
Rationale for dose and regimen selection..............................................................37
3
Objectives and endpoints...................................................................................................37
4
Study design ......................................................................................................................40
4.1
Description of study design ...................................................................................40
4.1.1
Baseline phase.......................................................................................41
4.1.2
Core phase.............................................................................................42
4.1.3
Extension phase.....................................................................................43
4.1.4
Post Extension Phase.............................................................................46
4.1.5
Definition of end of the study ...............................................................47
4.2
Early study termination..........................................................................................47
5
Population..........................................................................................................................47
5.1
Patient population..................................................................................................47
5.2
Inclusion criteria ....................................................................................................47
5.3
Exclusion criteria...................................................................................................51
6
Treatment...........................................................................................................................53
6.1
Study treatment......................................................................................................53
6.1.1
Dosing Regimen....................................................................................53


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6.1.2
Rescue medication ................................................................................57
6.1.3
Treatment duration................................................................................57
6.2
Dose modification guidelines ................................................................................58
6.2.1
Starting dose rationale...........................................................................58
6.2.2
Dose Titration........................................................................................59
6.2.3
Rounding of doses.................................................................................60
6.2.4
Dose reduction or delay ........................................................................61
6.2.5
Management of specific toxicity...........................................................63
6.3
Concomitant medications ......................................................................................68
6.3.1
Permitted concomitant therapy requiring caution and/or action...........68
6.3.2
Prohibited concomitant therapy ............................................................70
6.4
Patient numbering, treatment assignment or randomization .................................71
6.4.1
Patient numbering .................................................................................71
6.4.2
Treatment assignment or randomization...............................................71
6.4.3
Treatment blinding................................................................................72
6.5
Study Drug Supply ................................................................................................72
6.5.1
Study drug preparation and dispensation ..............................................72
6.5.2
Study drug packaging and labeling.......................................................73
6.5.3
Drug supply and storage........................................................................75
6.5.4
Study drug compliance and accountability ...........................................75
6.5.5
Disposal and destruction .......................................................................76
7
Visit schedule and assessments .........................................................................................76
7.1
Study flow and visit schedule................................................................................76
7.1.1
Screening...............................................................................................87
7.1.2
Baseline phase.......................................................................................89
7.1.3
Core phase.............................................................................................90
7.1.4
Extension phase.....................................................................................90
7.1.5
Post Extension phase.............................................................................91
7.1.6
End of treatment visit and premature withdrawal.................................91
7.1.7
Follow up/Study completion.................................................................93
7.2
Assessment types...................................................................................................94
7.2.1
Eligibility assessments ..........................................................................94
7.2.2
Efficacy assessments.............................................................................95
7.2.3
Safety and tolerability assessments.......................................................95
7.2.4
Pharmacokinetics ................................................................................104
7.2.5
Patient reported outcomes...................................................................111


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8
Safety monitoring and reporting......................................................................................111
8.1
Adverse events.....................................................................................................111
8.1.1
Definitions and reporting ....................................................................111
8.1.2
Laboratory test abnormalities..............................................................113
8.1.3
Adverse events of special interest.......................................................113
8.2
Serious adverse events.........................................................................................113
8.2.1
Definitions...........................................................................................113
8.2.2
Reporting.............................................................................................114
8.3
Emergency unblinding of treatment assignment .................................................115
8.4
Pregnancies..........................................................................................................115
8.5
Warnings and precautions....................................................................................116
8.6
Data Monitoring Committee................................................................................116
8.7
Steering Committee .............................................................................................116
9
Data collection and management.....................................................................................116
9.1
Data confidentiality .............................................................................................116
9.2
Site monitoring ....................................................................................................117
9.3
Data collection.....................................................................................................117
9.4
Database management and quality control..........................................................118
10 Statistical methods and data analysis ..............................................................................119
10.1
Analysis sets ........................................................................................................119
10.1.1
Full Analysis Set .................................................................................119
10.1.2
Safety Set ............................................................................................119
10.1.3
Per-Protocol Set ..................................................................................120
10.1.4
Long-Term Evaluation Set..................................................................120
10.2
Patient demographics/other baseline characteristics ...........................................120
10.3
Treatments (study treatment, concomitant therapies)..........................................120
10.3.1
Study medication.................................................................................120
10.3.2
Concomitant medication .....................................................................121
10.4
Primary objective.................................................................................................121
10.4.1
Variable...............................................................................................121
10.4.2
Statistical hypothesis, model, and method of analysis........................122
10.4.3
Handling of missing values/censoring/discontinuations.....................123
10.4.4
Supportive and sensitivity analyses ....................................................123
10.5
Secondary objectives ...........................................................................................124
10.5.1
Efficacy objectives..............................................................................124
10.5.2
Safety objectives .................................................................................126


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10.5.3
Pharmacokinetics ................................................................................128
10.5.4
Patient-reported outcomes...................................................................129
129
129
129
10.7
Interim analysis....................................................................................................130
10.8
Sample size calculation........................................................................................130
11 Ethical considerations and administrative procedures ....................................................131
11.1
Regulatory and ethical compliance......................................................................131
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................131
11.3
Informed consent procedures...............................................................................132
11.4
Discontinuation of the study................................................................................132
11.5
Publication of study protocol and results.............................................................132
11.6
Study documentation, record keeping and retention of documents.....................132
11.7
Confidentiality of study documents and patient records .....................................133
11.8
Audits and inspections.........................................................................................133
11.9
Financial disclosures............................................................................................133
12 Protocol adherence ..........................................................................................................134
12.1
Amendments to the protocol................................................................................134
13 References (available upon request)................................................................................135
14 Appendix A: Using Diffusion Tensor Imaging (DTI) with Tractography to Measure 
the Treatment Effect of Everolimus in Tuberous Sclerosis Complex (TSC) Patients 
with Epilepsy: An EXIST-3 Sub-study...........................................................................142
14.1
SUMMARY OF DTI SUB-STUDY OBJECTIVES AND RATIONALE .........142
14.2
BACKGROUND .................................................................................................142
14.3
RESEARCH STRATEGY...................................................................................144
14.3.1
Sub-Study Subjects .............................................................................144
14.3.2
Sub-Study Participation Criteria .........................................................145
14.3.3
Sub-Study Procedures .........................................................................145
14.3.4
Sub-Study Analysis and Statistical Considerations ............................146
14.4
POTENTIAL BENEFITS, RISKS, AND PRECAUTIONS ...............................147
14.4.1
Potential Benefits of the DTI Sub-study.............................................147
14.4.2
Potential Risks of the DTI Sub-study..................................................148
14.4.3
Additional Precautions........................................................................148
14.4.4
Cost .....................................................................................................148
14.4.5
Analysis of Benefit and Risk for DTI Sub-study Participation...........148


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List of figures
29
 
30
30
Figure 1-4
Chemical Structure of Everolimus........................................................33
Figure 4-1
Study Design .........................................................................................41
List of tables
Table 1-1
Everolimus – Drug Substance...............................................................33
Table 3-1
Objectives and related endpoints ..........................................................38
Table 4-1
PK sampling and dose titration events during Core phase....................43
Table 4-2
PK sampling and dose titration events during Extension phase ...........44
Table 4-3
Dose transition of everolimus to 6-10 ng/ml beginning at Week 26 ....46
Table 5-1
Diagnostic Criteria for Tuberous Sclerosis Complex ...........................48
Table 6-1
Dose and Treatment Schedule...............................................................53
Table 6-2
Starting dose..........................................................................................56
Table 6-3
Predicted pre-dose concentrations in patients of different age 
groups after the per protocol starting dose............................................59
Table 6-4
Examples for how to dose a patient ......................................................60
Table 6-5
Everolimus dose modification guidelines for non-hematologic 
toxicities................................................................................................62
Table 6-6
Dosing guidelines for study drug-related hematologic toxicities .........63
Table 6-7
Management of non-infectious pneumonitis.........................................66
Table 6-8
Action to be taken based on screening hepatitis B results ....................67
Table 6-9
Guidelines for the management of hepatitis B reactivation..................67
Table 6-10
Guidelines for the management of hepatitis C flare..............................68
Table 6-11
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A4..............................................................................70
Table 6-12
Clinically relevant drug interactions: substrates, inducers, 
inhibitors of PgP and PgP/CYP3A4 dual inhibitors .............................70
Table 6-13
Core Phase Treatment ...........................................................................74
Table 6-14
Extension Phase Treatment...................................................................74
Table 6-15
Post Extension Phase Treatment ...........................................................75
Table 7-1
Visit evaluation schedule ......................................................................77


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Table 7-2
Visit Evaluation Schedule: Post Extension Phase.................................84
Table 7-3
Central Clinical laboratory parameters collection plan.......................101
Table 7-4
Everolimus/Placebo PK Sample Log Table for Study core phase, 
Visits 0-11(777) ..................................................................................105
Table 7-5
Everolimus PK Sample Log Table for Study extension phase, 
starting at Visit 12 ...............................................................................106
Table 7-6
Everolimus PK Sample Log Table for Study Post-Extension phase ..106
Table 7-7
PK Sample Log Table for Carbamazepine..........................................107
Table 7-8
PK Sample Log Table for Oxcarbazepine ..........................................107
Table 7-9
PK Sample Log Table for Clonazepam ..............................................107
Table 7-10
PK Sample Log Table for Diazepam ..................................................107
Table 7-11
PK Sample Log Table for Clobazam ..................................................108
Table 7-12
PK Sample Log Table for Felbamate..................................................108
Table 7-13
PK Sample Log Table for Phenobarbital ............................................108
Table 7-14
PK Sample Log Table for Phenytoin ..................................................109
Table 7-15
PK Sample Log Table for Primidone..................................................109
Table 7-16
PK Sample Log Table for Topiramate................................................109
Table 7-17
PK Sample Log Table for Valproic acid.............................................110
Table 7-18
PK Sample Log Table for Zonisamide................................................110
Table 10-1
Supportive and sensitivity analyses for primary objective .................124
Table 10-2
Sample size and power for primary objective.....................................130


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List of abbreviations
AE
Adverse Event
AED
Anti-epileptic drug
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AMH
Anti-Mullerian Hormone
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BSA
Body surface area
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
Cmin
Minimum (trough) pre-dose concentration
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
C-SSRS
Columbia Suicide Severity Reporting Scale
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
Human cytochrome P450 3A4
DDI
Drug-drug interaction
DMC
Data Monitoring Committee
DMPK/BA
Drug Metabolism and Pharmacokinetics / Bioanalytics
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
EEG
Electroencephalogram
EIAED
Enzyme inducing anti-epileptic drug
EMA
European Medicines Agency
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GI
Gastrointestinal
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL 
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
HRQoL
Health Related Quality of Life
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IUD
Intrauterine Device
IUS
Intrauterine System
LDL
Low Density Lipoprotein
mTOR
mammalian Target Of Rapamycin
PgP
P-glycoprotein
PK
Pharmacokinetics
PPS
Per Protocol Set
QOL
Quality of life
QOLCE
Quality of Life in Childhood Epilepsy
QOLIE-31-P
Quality of Life in Epilepsy Inventory-31-Problems


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QOLIE-AD-48
Quality of Life in Epilepsy Inventory for Adolescents-48
RAD001
Everolimus
RAP
Report and Analysis Plan
RBC
Red blood cell
SAE
Serious Adverse Event
SC
Steering Committee
SDQ
Strengths and Difficulties Questionnaire
SEC
Safety event category
SEGA
Subependymal giant cell astrocytoma
SOP
Standard Operating Procedure
TDM
Therapeutic drug monitoring
TSC
Tuberous sclerosis complex
ULN
Upper limit of normal
VABS-II
Vineland Adaptive Behavior Scales 2nd Edition
VEGF
Vascular endothelial growth factor
VNS
Vagal nerve stimulator
WBC
White blood cell
WNV
Wechsler Non-Verbal Scale of Ability


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient randomization into the study; informed consent must be obtained 
prior to screening (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new 
drug.”
Investigational 
treatment
Drug whose properties are being tested in the study as well as their associated placebo 
and active treatment controls (when applicable). This also includes approved drugs 
used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by the 
protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to one 
of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that was 
not included in the investigational treatment
Patient number
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all 
study treatment administration and/or assessments; at this time all study treatment 
administration is discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the patient 
(subject) as part of the required study procedures, including placebo and active drug 
run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason; may 
or may not also be the point/time of premature patient withdrawal
Treatment group
A treatment group defines the dose and regimen or the combination, and may consist 
of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points


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Amendment 3 (25-Mar-2016)
Amendment rationale
As of February 26, 2016, 366 patients have been randomized, 87 patients discontinued 
treatment and 279 patients are still ongoing in the Extension phase.
In December 2015, the primary analysis of study data (data cutoff: October 2, 2015) was 
performed. The primary endpoint of the study was met when a clinically and statistically 
significant reduction in seizure frequency and increase in response rate, during the 
maintenance period of the Core Phase, was observed among patients randomized to the high 
everolimus Cmin range treatment arm (HT) and to patients randomized to the low everolimus 
Cmin range arm (LT), when compared to patients randomized to placebo. Safety for the 3 
treatment arms was also assessed. The Study Steering Committee assessed the results and 
concluded that everolimus treatment offered study patients a positive and compelling 
Benefit/Risk.
Protocol Amendment 3 to this Study has been prepared for the following reasons:
Major changes
1. To create a new phase of the study (Post-Extension phase) that will permit the opportunity 
for patients remaining in the study to receive ongoing treatment with everolimus and for 
the study to extend the monitoring and collection of everolimus exposure, as well as safety 
measures during this longer study participation and drug exposure phase.

As patients were receiving a benefit from participation in the study, it was decided to 
extend the End of the Study until a date when either, everolimus could be 
commercially available to study participants or until it would be reasonable to expect 
that a roll over protocol could be opened at study sites, so that patients benefiting 
from continued treatment with everolimus, prior to the commercial availability of the 
drug, could exit this study, and enter the rollover protocol (as referenced in Sections 
4.1.3 and 4.1.4). This strategy will allow closure of this study by October 30, 2017 
(approximately 13 months after what would have been the end of study, had the study 
been closed at the completion of the Extension phase), and the creation of a final CSR.

To permit the completion of the Extension Phase and the generation of a Clinical 
Study Report covering Extension phase, as originally envisioned.
2. To provide investigators with independent control of patient dosing, targeting a trough 
level within 5-15 ng/ml, subject to safety and tolerability. This allows for more 
personalized and clinically relevant increases or decreases in dose titrations to more 
rapidly and effectively permit titration of the everolimus dose to a level that creates a 
desired Cmin.
Minor changes
1. While making the necessary changes in the protocol to facilitate the objectives described 
above, some additional clarifying language was included.
2. To clarify protocol text
3. To update pregnancy section based on the revised pregnancy follow up language.


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4. To update the DTI sub-study to take account of the fact that only about 15 patients were 
enrolled, somewhat less than the planned number of 50 patients. As a consequence, the 
originally planned statistical analyses have been simplified to descriptive analyses only, 
and no attempt will now be made to correlate findings with the primary outcome measure 
of seizure frequency.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Major changes

Changes due to the addition of the Post Extension phase and continued monitoring of 
dosing, exposure, and safety as a result of the extension of treatment

Protocol summary, Section 2.2, 4.1, 4.1.3, 4.1.4, 4.1.5, 6.1.1, 6.1.2, 6.1.3, 6.2.2, 6.2.4, 
6.5.2, 7.1, 7.1.5, 7.1.6, 7.1.6.1, 7.2.3, 7.2.3.4, 7.2.3.5, 7.2.3.6, 7.2.3.7, 7.2.3.8, 7.2.3.10, 
7.2.3.11.1, 7.2.3.11.2, 7.2.3.11.3, 7.2.3.11.4, 7.2.3.11.6, 7.2.4, 10, 10.1.4, Figure 4-1,
Table 7-1, Table 7-2, Table 7-5, Table 7-6

Updates to allow Investigators to request more personalized and clinically relevant dosing

Section 4.1.4, 6.1.1, 6.2.2, 6.2.4, 7.1.5
Minor changes

Corrections made related to clarify protocol text

Glossary of terms, Section 4.1, 4.1.3, 6.2.3, 6.3.1.1, 7.1.2, 7.1.4, 7.2.1.2, 7.2.3.1, 
7.2.3.11.6, 7.2.3.4, 7.2.4, 7.2.5, 8.6, Table 6-11, Table 6-12

Updates to pregnancy language

Section 7.2.3.11.6

Corrections made to update the DTI sub-study to take account of the lower than expected 
sample size (n≈15 instead of n=50)

Appendix A, Section 14.1, 14.2, 14.3.1, 14.3.4.1, 14.4.1.1
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Summary of previous amendments
Amendment 2
Amendment rationale
As of February 27, 2014, 116 patients have been randomized, 3 patients discontinued 
treatment and with 36 patients still in the baseline phase.
Amendment 2 has been prepared for the following reasons.
Major Changes
1. To include an additional 10 patients to the everolimus 9 to 15 ng/ml trough range arm, to 
account for a potential loss in power

A human error was identified resulting in the failure of the IRT system to perform 
dose titrations in the presence of Cmin values outside the targeted trough ranges for 
patients randomized to everolimus (high trough range: 9-15ng/ml and low trough 
range: 3-7ng/ml). The error was corrected, but it is estimated that some patients 
randomized to the high trough range may not have achieved the targeted exposure to 
everolimus. As a result, it was decided to increase the sample size in the everolimus 9 
to 15 ng/ml trough range arm by 10 patients, to account for the potential loss of power 
in comparing this arm to the placebo arm for the primary efficacy endpoint. In 
addition, an independent PK expert will be appointed to oversee interaction between 
PK vendor and IRT vendor to ensure appropriate dose titration recommendations are 
being made by the IRT system through the rest of the study.
2. Inclusion criteria 3 updated to expand the definition of partial onset seizures (POS) and 
include sensory seizures as the sole seizure type if confirmed to be partial onset by ictal 
EEG

Associated eligibility criteria are updated as a result of this change which include the 
updated definition of partial onset seizures for Inclusion criteria 4 and the removal of 
Exclusion criteria 2

Sensory seizures had been excluded from the counting of partial onset seizures. The 
intent for this exclusion was to limit seizure counting to objectively assessable 
seizures (i.e., motor events that can be observed by another person). Yet, investigators 
have noted that sensory events confirmed to be seizures by ictal EEG would represent 
a seizure as least as “probable” as a motor event, not confirmed by ictal EEG. As a 
consequence, this amendment includes the expansion of the definition of partial onset 
seizures suitable for counting in this study, to include sensory seizures confirmed by 
ictal EEG. By permitting the counting of these events, it has become necessary to 
expand the definition of sensory seizures to two subcategories (those confirmed by 
ictal EEG and those not confirmed by EEG).


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3. Exclusion criteria 4 clarified to exclude patients < 2 years of age with untreated infantile 
spasms

It has been recognized over the course of the trial that many patients with epileptic 
spasms, following effective treatment for infantile spasms, may be inadvertently 
excluded from the study, based on the exclusion criteria of “infantile spasms” 
Therefore, the exclusion is herein modified to “untreated infantile spasms”. This 
modification will clarify the eligibility of patients with residual epileptic spasms to be 
included in the study, as originally intended.
4. Addition of Exclusion criteria 26 related to patients on a ketogenic diet defined as < 40g 
of carbohydrate a day

The amendment adds ketogenic diet, defined as “< 40 g of carbohydrate/day”.
Ketogenic diet, a type of anti-epilepsy therapy, may mediate its effect through mTOR 
inhibition. Because the potential interaction of similarly acting therapies may pose 
risks to patients, it was determined that treatment with a low carbohydrate ketogenic 
diet should be an exclusion criterion.
5. Allowing investigator discretion to manage everolimus titrations in the extension phase.

The modifications preserve blinding of the Core Phase randomization among patients, 
investigators and the sponsor, and provide freedom for dose adjustments that 
neurologists are typically accustomed to (in the extension phase of multi-dose vs 
placebo randomized trials of anti-epileptic drugs).

Investigators have expressed a desire to know the everolimus Cmin values of their 
patients after the Core phase of the study, and to be permitted to make dose 
adjustments (increases or decreases), during the Extension phase. To accomplish this, 
patients are first transitioned towards an everolimus trough concentration range of 6-
10 ng/ml, which preserves the blinding of the original randomization. After this 
transition (week 26 for newly enrolled patients) Cmin values will be revealed to 
investigators who will have the option to modify the dose of study drug. If 
investigators choose not to modify dosing, the dose will be determined by the IRT to 
maintain the everolimus trough concentration range between 3-15 ng/ml for all 
patients.
6. Updates to Exclusion Criteria 25 and additional assessment of self-injury and mood and/or
behavior changes

The study requires patients 13 years and over to complete the eC-SSRS themselves 
and for caregivers to complete the eC-SSRS on behalf of patients under the age of 13
or patients with cognitive impairment. The amendment now requires that the 
investigator discuss episodes of self-injury and changes in the patient’s mood and/or
behavior with the patient and caregiver, for all patients. For patients ≥13 years of age 
who do not complete the scale via IRT, the investigator will proactively assess the 
patient for the presence of suicidality. These changes help ensure a relevant mental 
safety assessment has been performed on behalf of patients for whom the eC-SSRS 
has not been completed. The exclusion criteria was also updated to harmonize with 
the guidance provided throughout the protocol, namely that a score of 4 or 5 could be 
addressed in a discussion with a healthcare professional.


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7. Updates to Data collection, Data management and quality control

The Vineland scale raw scores would be collected in a separate database and not in 
clinical OC-RDC database. This is the first protocol amendment since the final license 
agreement for the Vineland scale, therefore additional information regarding the 
collection of the Vineland data has been included in this amendment.
8. Correction to definition of Safety Population

The Safety Population in the original protocol was planned to be defined using actual 
Cmin values, however that approach has since been recognized as inappropriate. That 
is, there will be no attempt to reassign patients from one everolimus arm to the other 
everolimus arm based on observed everolimus concentrations during the Core phase. 
This is because increases in the dose of everolimus would have been recommended 
during the Core phase in order to reach the targeted trough range of 9-15 ng/ml, and 
any associated toxicity should therefore be attributed to the 9-15 ng/ml arm and not 
the 3-7 ng/ml arm.
Minor Changes
1. To provide corrections to protocol text
2. To include clarifications related to Study Procedures, Timing of Visits and Assessments, 
updated Reference list and other typographical Errors
3. To include anti-Mullerian Hormone (AMH) in all newly enrolled female patients ≥10 
years of age

AMH is a gonadotrophin independent, paracrine hormone, involved in the recruitment 
of primordial follicles. It measures ovarian function and may be useful in assessing 
conditions such as polycystic ovary syndrome and premature ovarian failure. One of 
the noted risk factors of everolimus is amenorrhea, and whether amenorrhea 
represents a consequence of endocrine dysfunction related to everolimus, remains 
unclear. It has been suggested that patients with tuberous sclerosis may have, as a 
consequence of mTOR over-activation, a higher rate of primordial follicle recruitment, 
with premature ovarian failure leading to amenorrhea. In short, it is unclear whether 
amenorrhea is a comorbid condition associated with TSC or a consequence of 
everolimus treatment. The measurement of AMH before and during treatment with 
everolimus, in female patients near puberty can help address this question. Only 
female patients ≥10 years of age will be evaluated for AMH, because the goal is to 
capture baseline and post-treatment levels in TSC patients near puberty until 
menopause.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Major Changes

Sample size increase of 10 additional patients

Section 5.1, 6.4.2, 10.8


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
Updates to Inclusion criteria 3 and 4

Section 5.2

Updates to Exclusion criteria 2, 4 and 26

Section 5.3

Investigator-led titration

Section 4.1, 4.1.3, 4.1.4, Fig. 4-1, Table 4-3, 6.1.1, 6.2.2, 6.5.2, Table 6-14, Table 7-1, 
7.1.4, Table 7-4

Updates to Exclusion criteria 25 and additional assessment of self-injury and mood 
and/or behavior changes

Section 5.3 and 7.2.3.10

To include Data collection and Database management language relating to the paper 
component of the trial

Section 9.3, 9.4

Correction to definition of Safety Population

Section 10.1.2
Minor Changes

Corrections related to Protocol Text

Section 6.1.3, 6.2.5.8, 7.1.1, 7.1.2, 7.1.3, 7.1.4, 7.1.6, 7.2.2.3, 7.2.3.6, 7.2.3.11.6, 7.2.4, 
7.2.4.1, 10.1.3, 10.5.1, 10.5.2.1, Table 7-2

Clarifications related to Study Procedures, Timing of Visits and Assessments and 
updated Reference list

Section 2.2, 4.1.1, 4.1.3, 4.1.5, 5.2, 5.3, 6.1.1.1, , 6.2.2, 6.2.5.1, 6.3, 6.3.1, 6.4.3, 6.5.1, 
6.5.4.1, 7.1.5.1, 7.2.1.5, 7.2.2.1, 7.2.3.1, 7.2.3.8, 7.2.3.9, 7.2.3.10, 7.2.4.2.2, 7.2.5, 
8.1.3, 10.5.2.4, 13, 14, Table 6-5, Table 6-6, Table 6-7, Table 7-1, Table 7-3, Table 7-
4

To include anti-Mullerian Hormone (AMH) in all newly enrolled female patients ≥10 
years of age

Section 7.2.3.11.7, Table 7-1, Table 7-2

Corrections of typographical errors

Figure 1-1, Fig 1-3, Table 3-1, Table 7-6, and throughout the protocol
IRB/IEC
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.


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Amendment 1
Amendment Rationale
This study is still in planning stages, and no patients have yet been enrolled. No patients are 
planned to be enrolled until after this amendment is approved and in place. The changes 
identified in this protocol amendment address feedback to the protocol provided by the EMA 
(European Medicines Agency) and FDA, and includes clarifications of instructions and 
corrections of typographical errors. The rationale for the major changes are as follows:
The exclusion criterion regarding Lennox Gastaut Syndrome (LGS) is removed. Patients with 
TSC may have multiple seizure types that must include partial onset seizure to be enrolled in 
the study. The diagnosis of LGS includes multiples seizure types, intellectual disability and a 
slow-spike wave pattern on EEG. Therefore, because patients carrying the diagnosis of TSC 
and LGS are viewed as patients with TSC whose disease has progressed to cause intellectual 
disability and a characteristic LGS EEG wave pattern, there is no reason to exclude patients 
who have LGS as long as they have an underlying diagnosis of TSC and partial onset seizures.
The volume of blood drawn in the study was reviewed and modified to make it compliant 
with the “ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON MEDICINAL 
PRODUCTS CONDUCTED WITH THE PAEDIATRIC POPULATION: Recommendations 
of the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC 
relating to good clinical practice in the conduct of clinical trials on medicinal products for 
human use” The volume of blood collected from pediatric patients during all phases of the is 
now limited to ensure that not more than 1% of the patient’s total blood volume (i.e.,
0.8mL/kg) is collected on any visit, and not more than 3% of the patients total blood volume 
(i.e., 2.4mL/kg is collected in any 3 week period. To accomplish this two changes are 
incorporated:

Patients weighing less than 12 kg will not be enrolled in the study, because of the inability 
to collect adequate volumes of blood to monitor their safety and evaluate PK

Patients weighing 12 to 20 kg will not be required to provide PK AED and it will be 
recommended that TSC1/2 genetic mutation samples instead be collected on Visit 4 to 
decrease the collection of blood on Visit 2.
EMA requested that the study include patients down to age 1 year of age. Inclusion criteria, 
and all stratification specifications are changed to reflect this. The protocol now includes 
patients age 2 to 65, except for Europe, where the inclusion is 1 to 65. For stratifications, the 
first group is 1 to <6.
FDA specifically requested a sensitivity analysis of the primary endpoint where seizure 
frequency is determined across the entire Core phase (i.e., titration period as well as 
maintenance period). This analysis is already included in Section 10.4.4 of the protocol, 
however the wording is improved to make it more explicit.
In order to ensure that patients remain in their target trough range, clarification was made that 
titration may occur during both the Core and the Extension Phases. Language is added to 
Section 4.1.3, and rows in Tables 4-1 and 4-2 to indicate that titration may occur outside a 
‘scheduled’ time, and what actions must happen if this occurs.


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Missing information about whether or not patients may take rescue medication during the 
Baseline Phase is updated in the exclusion criteria, and in withdrawal criteria.
To improve internal consistency in the protocol the dosing age group for the >18 is changed to 
≥ 18.
Clarifications on the inclusion criteria have been added. These focus primarily on the 
definition of partial onset seizures. Seizures in patients with TSC are focal in origin, due to the 
underlying pathophysiology of the disease which drives neuronal hyperexcitability in or near 
tubers and possibly other areas of the brain. Therefore, for the purpose of this study being 
conducted in patients with TSC, any seizure with a motor component is deemed to be a partial 
onset seizure, unless that seizure type is demonstrated to be a primary generalized seizures on 
an ictal EEG. Clarification to the definition of partial onset seizures have been captured in 
Inclusion Criteria 3. Additionally, further subcategories to categories IB (Complex partial 
seizures) and IC (secondarily generalized partial seizures) were added in order to capture the 
different clinical presentations of this seizure type.
Three items are added under criteria for premature withdrawal (7.1.5.1) to ensure that patients 
who should no longer be included in the study are removed. 1) an interruption from study 
drug that lasts for more than 28 days; 2) an interruption of one or more of the concomitant 
AEDs for more than 7 days; 3) In patients who have their dose interrupted for toxicity, if 
restarting study drug upon resolution of the toxicity requires dose reduction, and that 
reduction results in instruction to take 0 tablets for placebo patients during the core phase, or 0 
mg of everolimus for active drug patients in the Core phase, or 0 mg everolimus for all 
patients in the Extension phase.
Appendix A is replaced with an updated Substudy summary that includes the collection of 
HFO EEGs.
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.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through red font for deletions and red underlined for insertions.
1. Changes to List of Abbreviations and Glossary of Terms

Abbreviations updated to reflect deletion of C-SSRS.

Terms updated to clarify patient number.
2. Changes to Study Design (Protocol section 4)

Figure 4-1: Footnote changed to clarify that after the titration period, patients are 
maintained on their treatment for 12 weeks.

Section 4.1.1: Randomization stratification updated to include patients starting at age 
1.

Section 4.1.2: Description of titration and PK sampling updated for clarity. The 
volumes of PK blood samples per age group were also added to this section.

Table 4-1: Table on PK sampling and dose titration updated to reflect the possibility 
of additional PK sampling and potential for titrations.


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
Section 4.1.3: Text regarding length of extension phase clarified.

Section 4.1.3: Description of titration and PK sampling in the extension phase 
updated for clarity. Blood volume to be taken was clarified and a sentence was added 
to specify that patients weighing 12-20 kg would not be required to provide blood 
samples for PK AED testing.

Table 4-2: Table on PK sampling and dose titration in extension phase updated to 
reflect the possibility of additional PK sampling and potential for titrations.

Table 4-2: The heading of “table” is changed to “week”.
3. Changes to Patient Population (Protocol section 5)

Section 5.1: Patient population was changed to include patients starting at age 1 for 
Europe and patients starting at age 2 for rest of world.

Section 5.2: Inclusion criteria number 1 modified to include patients starting at age 1 
for Europe and patient starting at age 2 for rest of world.

Section 5.2: Inclusion Criterion #1, the minimum number of pediatric patients to be 
randomized in the age group 1 to <6 years has changed to 40 patients, in the age 
group 6 to <12 years has changed to 40 patients, and in the age group 12 to <18 years
has changed to 40 patients.

Section 5.2: Inclusion Criterion #7, the requirement for sexually active males to use a 
condom during intercourse has been increased to 8 weeks after stopping study 
treatment.

Section 5.3: The exclusion criteria have been modified to exclude patients who 
require rescue medication during the Baseline Phase for 7 or more consecutive days 
or 7 or more cumulative days.

Section 5.3: The exclusion criteria regarding Lennox Gastaut Syndrome (LGS) has 
been removed.

Section 5.3: Additional exclusion criteria was added stating that patients who weigh 
less than 12kg cannot be enrolled.
4. Changes to Treatment (Protocol section 6)

Section 6.1.1: The change allows for clarification regarding color coding of the study 
medication in order to maintain the blind.

Section 6.1.1: Packaging of medication boxes clarified as color labeled boxes will be 
provided separately and not as a “kit”.

Table 6-2: The age of the patients that receive a starting dose of 5.0 mg/m2/day has 
been changed to patients aged 10 to less than (<) 18 and age of patients receiving a 
starting dose of 3.0 mg/m2/day has been modified to greater than or equal to (≥) 18 
years.

Section 6.1.2: Clarification added to rescue medication section that they are only 
allowed for a period that does not exceed 6 days during the baseline period.

Section 6.1.3: Dose reduction due to toxicity to zero tablets during the core phase and 
pregnancy were added to possible reasons for treatment withdrawal.


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
Table 6-3: The changes allow for clarification on the age group of patients whose pre-
dose concentrations have been predicted after the per protocol starting dose. The 
middle age group was changed to 10 to less than (<) 18 years age group and ≥ 18 
years for the highest age group.

Section 6.2.3: Under titration the change allows for further clarification on the 
different age groups listed in table 6-4.

Section 6.2.4: Reason of interruption of study drug for more than 28 days was added 
as a possible reason for treatment withdrawal.

Tables 6-5, 6-6, 6-7, and 6-9: Clarification on the guidelines for Everolimus dose 
modification for patients that do, or do not take CYP3A4 inducers.

Section 6.2.5.5: Additional section was added for the management of amenorrhea.

Table 6-10: The guideline for the management of hepatitis C flare has changed to the 
patient being excluded from the study.

Section 6.4.2: Randomization stratification updated to include patients starting at age 
1.

Section 6.5.2: Packaging of medication boxes clarified as color labeled boxes will be 
provided separately and not as a “kit”.

Table 6-13 and Table 6-14: Packaging of medication boxes clarified as color labeled 
boxes will be provided separately and not as a “kit”. Additional option added for low 
trough range group.
5. Changes to Visit Schedule and Assessments (Protocol Section 7)

Table 7-1: In the visit evaluation schedule, the inclusion and exclusion criteria that 
will be recorded, has been changed to category “D” indicating that this data will be 
entered into the database.

Table 7-1: Seizure history has been added to the visit evaluation schedule to be 
performed at screening.

Table 7-1: Further clarification in the form of a footnote was added for timing of 
WNV, Vineland, and QOL after the end of core visit.

Table 7-1: Assessment for endocrine tests at EOT Core was added.

Table 7-1: Clarification added to study drug administration assessment.

Table 7-1: A footnote was added to give the option for patients between 12-20 kg to 
have the TSC 1/2 genetic sampling on visit 4, to decrease the blood collection amount 
on visit 2. This information is also included in section 7.1.2 under the description of 
the baseline visit.

Table 7-1: AED PK sampling was added at the screening visit.

Section 7.1.1: The section on screening has been amended to further clarify the 
requirements for certain procedures, collection of patient data, and the methods of 
maintaining and recording this data, including IRT procedures.

Section 7.1.1: The statement on permitting reassessment of screening criteria has been 
moved from the sub-heading of screening for hepatitis C to the main heading of 
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
Section 7.1.2: The baseline phase and baseline visit has been amended to further 
clarify the requirements during this phase, especially seizure diaries, the use of rescue 
medication, data recording and collection, requirements for determining eligibility, 
IRT procedures and MRI sub-study details.

Section 7.1.2: The paragraph detailing the screening visit has been removed from the 
baseline phase section as the details are covered under section 7.1.1.

Section 7.1.3: The core phase section has been amended to further clarify the 
requirements during this phase, including procedures performed during this phase.

Section 7.1.4: The extension phase section has been amended to further clarify the 
requirements during this phase, including procedures performed during this phase.

Section 7.1.5: The end of treatment section has been amended to further clarify the 
requirements during this visit.

Section 7.1.5.1: Three additional criteria for premature withdrawal of the patient from 
the study have been added - An interruption of study drug that lasts for more than 28 
days, an interruption of one or more of the concomitant AEDs for more than 7 days, 
and in patients who have their dose interrupted for toxicity, if restarting study drug 
upon resolution of the toxicity requires dose reduction, and that reduction results in 
instruction to take 0 tablets for placebo patients during the core phase, or 0 mg of 
everolimus for active drug patients in the Core phase, or 0 mg everolimus for all 
patients in the Extension phase.

Section 7.2.1.1: Seizure history and TSC history added to patient history description.

Section 7.2.3.1: Clarifications made to descriptions of neurobehavioral, 
neurodevelopmental, and neurocognitive assessments.

Section 7.2.3.4: The tanner staging section regarding pubic hair stages has been 
amended to provide further clarity on this assessment.

Section 7.2.3.6: Pregnancy history, menstrual history and monitoring section was 
updated to include description of the menstruation diaries and how data will be 
collected.

Section 7.2.3.8: Clarification was added for collection of pre-baseline height and 
weight and collection of parental height.

Section 7.2.3.10: Instructions for who completed the eC-SSRS was clarified.

Table 7.2.3.11: The table detailing the central clinical laboratory parameters 
collection plan and the following test-categories have been amended to accurately list 
all the laboratory evaluations that are required.

Section 7.2.3.11.2: Description of clinical chemistry was amended to reflect the 
laboratory evaluations to be performed.

Section 7.2.3.11.5: Description of urinalysis was amended to reflect the laboratory 
evaluations to be performed.

Section 7.2.3.11.6. Timing and procedures for monthly pregnancy tests were clarified.


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
Section 7.2.4: The pharmacokinetic section was updated to include blood sample 
clarifications for pediatric patients, and to define the timing of a trough sample

Section 7.2.5: Clarification statement was added indicating that the parent/caregiver 
of patients <10 years old will be completing the three quality of life questionnaires on 
behalf of the patient.
6. Changes to Statistical Methods and Data Analysis (Protocol section 10)

Section 10.4.1: Changed the word supportive to sensitivity when describing the 
analysis of the primary outcome.

Section 10.4.1.1: The change to the EMA primary variable: response rate includes the 
change of “exclusion criteria” to “inclusion criteria” as the criteria where counting of 
partial-onset seizures is defined.

Section 10.4.4: “Supportive analyses” has been changed to “Sensitivity analyses”.
7. Changes to References (Protocol section 13)

Changes to this section include re-formatting of all the reference articles.
8. Changes to Appendix A (Protocol section 14)

Changes were made to Appendix A to include EEGs and clarifications were made to 
the MRI section.
IRB/IEC
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.


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Protocol summary
Study title: A three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety 
of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex 
(TSC) who have refractory partial-onset seizures
Study phase: III
Study objectives:
Primary objective: To compare the reduction in frequency of partial-onset seizures on each of two 
trough ranges of everolimus (3-7 ng/mL and 9-15 ng/mL) versus placebo in patients with TSC who are 
taking one to three AEDs.
Key secondary objective: To compare each of the two everolimus trough ranges versus placebo with 
respect to:
1.
Ability to completely suppress partial-onset seizures.
2.
Proportion of patients with ≥ 25% reduction from baseline in average weekly frequency of 
partial-onset seizures.
3.
Distribution of reduction from baseline in seizure frequency
4.
Seizure-free days
5.
Treatment duration
6.
Quality of life
Study population: The target population is comprised of approximately 355 male or female patients, 
with TSC who have refractory partial-onset seizures. Patients between ages of 1 and 65 years will be 
enrolled.
Number of patients: 355
Overview of study design: This is a three-arm, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of two trough-ranges of everolimus given as adjunctive therapy in 
patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures.
The study consists of 4 phases for each patient [Baseline phase: From Screening Week -8 (V1) to 
randomization visit at Week 0 (V2)], Core phase [Double-blind, placebo-controlled, from randomization 
at Week 0 (V2) to Week 18 (V11)], Extension phase [All patients receiving everolimus from Week 18
(V11) until 48 weeks after the last patient has completed the core phase], and Post Extension Phase 
[after the end of the Extension phase until October 30, 2017].
Eligibility criteria will be assessed subsequently at the end of the baseline phase (V2, Week 0), prior to 
randomization. All patients who continue to meet eligibility criteria, including demonstrating the 
minimum seizure frequency during the 8-week baseline phase (see Section 5.2 and 5.3), will be 
randomized in a 1:1:1.09 ratio to one of the three treatment arms as described in Section 6.1. 
Randomization will be stratified by age subgroup at randomization as follows: 1 to <6 years; (ii) 6 to 
<12 years; (iii) 12 to <18 years; and (iv) ≥ 18 years.
Statistical considerations: The data cut-off date for the primary efficacy and safety analyses will be 
when all patients have completed the Core phase or have discontinued early. At that time, all data 
from the Core phase will be available as will a part of the Extension phase data. The analyses for the 
reports will thus cover both periods:

The main focus will be on descriptive and inferential comparisons of both everolimus arms 
versus placebo on efficacy and safety in the Core phase.

Descriptive efficacy and safety analyses on Extension phase data will also be conducted in 
order to explore the longer term effects of everolimus.


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The second data cut-off will be at the end of the extension phase, which is planned 48 weeks after the 
last patient completes the Core phase, and which will be used for the study report of the Extension 
phase. Earlier updates of the Extension phase data are not currently planned, but may be performed if 
needed. The final data cut off will be at the end of the Post Extension phase (October 30, 2017).


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1
Background
1.1
Overview of Tuberous Sclerosis and current treatment options
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). Clinical disease spectrum is highly variable, with manifestations ranging from mild 
skin 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 disease (Curatolo et al 2002, Levine et al 2006). Despite this broad range of 
clinical findings, a limited number of features are responsible for the decreased life 
expectancy associated with the disease. These include neurologic disorders (SEGAs and 
seizures), renal disease (angiomyolipomas and renal cell carcinoma [RCC]), pulmonary 
disease (lymphangioleiomyomatosis), and cardiovascular disease (rhabdomyoma) (Goh et al 
2004).
1.1.1
Epilepsy associated with TSC
TSC represents one of the most common genetic causes of epilepsy. Eighty to 90% of 
individuals with TSC are affected by epilepsy that manifests usually very early during the first 
year of life. In a retrospective study of 291 TSC patients treated at Massachusetts General 
Hospital, 84.5% of the patients developed epilepsy (Chu-Shore et al 2010).
Seizures with partial-onset are observed in most TSC patients. A variety of seizure types have 
been reported including infantile spasms, simple partial, complex partial and generalized 
tonic-clonic seizures (Holmes 2007; Wong 2010; Orlova and Crino 2010). In the 
Massachusetts General Hospital study that included both children and adults, the most 
common seizures observed were complex partial seizures (86.9%, including those with 
secondary generalization) and infantile spasms (46.4%) (Chu-Shore et al 2010).
Patients with seizure onset before the age of 4 years, particularly when the seizures are 
frequent or refractory to treatment, have a substantially increased risk of subsequent mental 
retardation or autism. In a study that evaluated the intellectual abilities in 108 patients with 
TSC using standardized assessment tools and compared these with other features of TSC, 
including seizures, reported that infantile spasms and severe intractable seizures are highly 
correlated with global intellectual impairment (Joinson et al 2003). Studies have also found a 
higher incidence of autism in children with TSC who have intractable epilepsy at early onset
(Bolton et al 2002). Children with TSC are particularly prone to epileptic encephalopathies 
such as Lennox-Gastaut syndrome. Goh evaluated intellectual outcomes in children with TSC 
and infantile spasms and found that the length of uncontrolled seizure activity and poor 
control of other seizure types after infantile spasms were associated with increased risk of 
mental retardation (Goh et al 2005).
A retrospective chart review of all patients with TSC seen between January 2002 and October 
2008 by (Chu-Shore, et al 2010) reported that the onset of seizures typically occurred in the 
first year of life (with 82% before 3 years of age); however, adults remain at risk. Notably, in 


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this review 12% of adult patients with TSC without prior history of seizure developed 
epilepsy subsequently, indicating that TSC patients are at an increased risk of epilepsy 
throughout their lifetime.
Seizure control
Seizures may be controlled by medication such as antiepileptic drugs (AEDs) or methods such 
as epilepsy surgery, vagal nerve stimulation (VNS) or ketogenic diet (Wong 2010; Jobst 
2009). However, between 20-60% of patients with TSC-associated epilepsy fail to 
demonstrate improvement in seizure frequency with available therapies (Franz 2000; Franz 
2001; Collins 2006). One study found only 14% of epilepsy remission rate in its TSC 
population; furthermore, of these patients, about 25% relapsed after a mean follow-up of 5.5 
years (Sparagana 2003).
Refractory seizures
Refractory or intractable epilepsy is generally defined as failure to control partial-onset
seizures despite having been treated with two or more sequential regimens of single or 
combined antiepileptic drugs (Berg 2006; Chu-Shore 2010; Kwan 2010). Many patients with 
TSC continue to have intractable seizures with a poor response to both established and new 
anti-epileptic therapies. In the (Chu-Shore study 2010), 155 out of 248 (62.5%) TSC patients 
with epilepsy developed refractory epilepsy. Furthermore, in patients with a history of 
infantile spasms, 75.4% developed refractory epilepsy compared to 39.8% in patients without 
a history of infantile spasms (p < 0.0001).
Surgery may constitute a valuable option for refractory seizures, however, surgery is not 
feasible for all patients either because the removal of epileptic zone will result in unacceptable 
deficit (for example when motor or language areas are involved) or because of the multifocal 
origin of seizures (Granata 2009). Furthermore, it is reported that around one third of patients 
with TSC still experience seizures even after surgical treatment (Curatolo 2006; Jansen 2007; 
Napolioni 2009).
Attempts to determine why some TSC patients fail to respond to conventional AEDs and 
develop intractable epilepsy have been inconclusive. One possible explanation is that the 
available AEDs target neuronal over-excitability through alteration in neurotransmitter release, 
receptor activation, or ion channel function; therefore such AEDs act primarily on the 
molecular mechanism that mediates the end stage of epilepsy (i.e., seizures). Such AEDs are 
considered “antiepileptic” therapies that suppress seizures and thus affect symptoms only, and 
not “antiepileptogenic” therapies that affect the underlying cause of epilepsy.
1.1.2
Role of mTOR in TSC and epileptogenesis
Neurological manifestations associated with TSC including epilepsy are thought to be caused 
by cerebral cortical tubers, which are present in over 80% of patients (Crino, et al 2006).
However the relationship between tubers and seizures is not totally well understood. Among 
other questions still unanswered, it is not known whether seizures originate within or near 
tubers, whether the pathophysiology of seizures in TSC differs from other epilepsy syndromes, 
or how the development of tubers affects the maturation of brain circuits. Unresolved 


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questions also include how the specific gene mutation leads to tuber formation, the exact cells 
of tuber origin, and the factors that determine tuber location and number.
The protein products of the TSC1 (hamartin) and TSC2 (tuberin) genes are part of the 
PI3K/PKB(Akt)/S6K1 signaling pathway that regulates cell growth and proliferation via the 
mammalian target of rapamycin (mTOR) (Dan et al 2002; El-Hashemite et al 2003;
Goncharova et al 2002; Manning et al 2002). A precise interaction between tuberin and 
hamartin appears to be critical at different stages of central nervous system development, 
including morphogenesis, cell adhesion/migration, and cell fate determination (Wong 2009).
In the brain, TSC1 and TSC2 messenger RNA (mRNA) and proteins have been detected in 
cerebral cortex, hippocampus, cerebellum, brainstem, choroid plexus epithelium, and spinal 
cord of immature and mature brain (Marcotte and Crino 2006).
mTOR exists as two complexes, designated mTORC1 (mammalian target of rapamycin 
complex 1) and mTORC2 (mammalian target of rapamycin complex 2). The hamartin/tuberin 
complex targets specifically regulation of mTORC1 through the inhibition of Ras homolog 
enriched in brain (Rheb) (Zhang et al 2003). Rheb is a small GTP-binding protein whose 
activation results in upregulation of mTORC1. Cortical tubers and other hamartomatous 
lesions found in patients with TSC demonstrate abnormal mTORC1 activation and 
upregulation of downstream targets including p70 S6 kinase (S6K1), 4E binding protein 
(4EBP1), and S6 ribosomal protein (Baybis et al 2004; Ma et al 2005). These proteins play a 
major role in the translational regulation of mRNAs in diverse processes, including proteins 
involved in G1-phase cell cycle progression in many different cell types (Huang et al 2008).
Less is known regarding the mTORC2 complex, but evidence suggests hamartin and tuberin 
have a role in mTORC2-mediated signaling as well (Huang et al 2008).
In addition to contribution to cortical tuber formation, emerging evidence suggests a major 
role of mTOR in neuronal function and neuronal disease pathogenesis. Widespread 
neuropathological changes have been shown to be present in radiologically normal 
parenchymal structures in addition to TSC cerebral hamartomas (such as SEGA or 
subependymal nodules (SENs)). mTOR is known to regulate cell size, arborization and 
function of dendritic spines, as well as synthesis and density of glutamate receptors (Meikle et 
al 2007; Kwon et al 2006; Lenz 2005; Wiersma-Meems et al 2005). Tavazoie identified 
anatomic changes in dendritic spines in neurons, more severe in homozygous and less severe 
in heterozygous neurons for TSC mutations, indicating a so-called genetic “dose effect” 
(Tavazoie et al 2005). This is relevant for the potential epileptic involvement of peri-tuberal 
cortex. Individual progenitor neurons sharing a common mutation in either TSC1 or TSC2 
give rise to cortical tubers. The process responsible for inactivation of the other copy of the 
TSC gene can differ for each neuronal progenitor cell, resulting in the markedly different 
biologic activity of various tubers, even within the same patient.
Nutrient deprivation, specifically that of carbohydrates, serves to inhibit mTOR and results in 
many of the same effects as treatment with rapamycin (Peng et al 2002). This may be one of 
the mechanisms of action of the ketogenic diet, a therapy that is particularly efficacious in 
TSC patients (Kossoff et al 2005).


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Neurotransmitter responses are also impacted by mTOR-dependent signaling in addition to 
morphological changes in neurons. TSC2+/- rats exhibited memory differences compared to 
wild-type controls and also more rapidly developed stage five seizures in one model of 
chemically-induced kindling (Waltereit et al 2006). Glutamatergic neurotransmission has been 
shown to enhance activity of mTOR and S6K1 that serve to stimulate protein synthesis, 
including the synthesis of glutamate receptors (Gong et al 2006). In another study, mTOR 
inhibition by rapamycin altered synaptic protein synthesis during induced plasticity of 
cultured neurons and long-term consolidation of auditory cortex-dependent memory in gerbils 
(Tischmeyer et al 2003). Protein synthesis and microanatomic changes that underlie both 
synaptic long term potentiation and long term depression, processes thought to contribute to 
epileptogenesis and seizure susceptibility, are also regulated by mTOR (Ess 2006).
Alterations in glutamatergic neurotransmission are associated with these changes, as is 
modulation of voltage-dependent potassium channels (Raab-Graham et al 2006). Additionally, 
glutamate itself can activate mTOR and S6K1 (Narayanan et al 2007). In this way subclinical 
epileptiform discharges, such as are those commonly seen in TSC children, could cause 
epileptogenesis through a localized activation of mTOR independent of TSC1 or TSC2 
mutation. This is supported by study reporting inhibition of kindling in wild type mice by 
mTOR inhibition (Zeng et al 2008). Finally, activation of mTOR is important in the 
development of chronic epilepsy after closed head injury in animal models not having TSC 
mutations (Erlich et al 2007).
Apart from the direct effect of mTOR signaling on epileptogenesis, de Vries and Howe
proposed that the molecular disruption caused by TSC mutations are sufficient to lead to the 
neurocognitive and neurodevelopmental deficits seen in tuberous sclerosis, given that many of 
the upstream and downstream protein targets have key roles in the neurobiology of learning 
and memory (de Vries and Howe 2007). As illustrated in the figure below (Napolioni et al 
2009), the mutation of TSC genes, through downstream effect on neuronal and synaptic 
structures/neurotransmission, results in fundamental alterations in network properties as well 
as an imbalance in excitation and inhibition, acting as a common pathway toward epilepsy, 
intellectual development, and autism.


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Impact of seizures on neurodevelopment and cognition is also well recognized. Poorly 
controlled seizures represent significant risk factors for adverse neurocognitive and 
neurodevelopmental outcome. Recent findings in an Eker Rat model of TSC2 showed an 
additive effect between molecular and seizure factors. In the study by (Waltereit et al 2011), 
Eker rats showed some specific social deficits, and gained additional social deficits through 
the onset of seizures. The combination of poorly controlled seizures and TSC genotype 
therefore represents a significant risk factors for poor neurocognitive and neurodevelopmental 
outcomes in TSC. It is well known that the neuropsychiatric manifestations of TSC (including 
intellectual disability, autism and other neurocognitive deficits) represent some of the greatest 
contributions to the burden of care in TSC (Hunt et al 1983; de Vries 2010).
1.1.3
Rapamycin and everolimus (RAD001) in TSC-epilepsy
1.1.3.1
Nonclinical investigation
Nonclinical research using animal models, either due to genetic modification or treatment 
with seizure-inducing agents, has demonstrated a reduction in seizure activity with mTOR 
inhibitors. For example, a neuronal-specific conditional knockout of TSC1 experienced 
spontaneous seizure activity that caused death by day 35 (Figure 1-2). This could be 
completely blocked by treatment with the mTOR inhibitors rapamycin or everolimus 
(RAD001), allowing survival to more than 100 days (Meikle 2007 and Meikle 2008).


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Zeng et al also reported that early treatment with rapamycin prevented the development of 
epilepsy and premature death observed in Tsc1GFAPCKO mice. Late treatment with 
rapamycin suppressed seizures and prolonged survival in Tsc1GFAPCKO mice that had 
already developed epilepsy (Zeng 2008).
In summary, the nonclinical research demonstrates that mTOR inhibitors, rapamycin and 
everolimus, have efficacy for preventing seizures and prolonging survival in TSC mice. The 
effects of mTOR inhibition in mouse models of TSC are considered to be extremely important 
as they are more consistent with an anti-epileptogenic effect rather than seizure suppression 
alone (Wong 2010).
1.1.3.2
Clinical experience in TSC
Everolimus has been investigated in one phase II study (28 patients) in patients with TSC who 
have SEGA ([RAD001C2485]). Additionally two phase III studies have been conducted in 
patients with TSC: study [RAD001M2301] in patients with TSC who have SEGA (117
patients) and study [RAD001M2302] in patients with renal angiomyolipoma (118 patients), of 
which 113 had TSC.
Study RAD001C2485, 
an 
open-label 
phase 
II 
study 
(Clinicaltrials.gov 
Identifier 
NCT00411619) of everolimus in patients with TSC who have SEGA, is ongoing at the 
 
Twenty-eight patients between the ages of 3 and 34 years with TSC 
who have SEGA were enrolled between 07-Jan-2007 and 18-Dec-2008. The starting daily 
dose of everolimus was 3.0 mg/m2, with subsequent titration to attain a target trough level of 
5-15 ng/mL. The primary efficacy endpoint of the trial is reduction in SEGA volume. The 
effect of everolimus on seizure frequency was assessed as a secondary endpoint (Krueger 
2010).
A 24-hour video electroencephalogram (EEG) was performed at baseline and at 24 weeks on 
all patients with uncontrolled epilepsy (defined as those having at least one seizure per month 
prior to study enrollment), and seizure frequency was also assessed and followed using 
patient/caregiver report at study visits. Neuro-psychometric function was assessed using a 
battery of age appropriate tests. Eighteen out of the 28 enrolled patients (64%) had active 
seizures at baseline. Mean (median) number of seizures/24 hours (by video-EEG) was 6.3 (1.0) 
at baseline and 2.75 (0.0) at 6 months (median change: -0.99, P=0.022). Nine patients 
experienced decreases in seizure frequency (across all types of seizure) relative to baseline. 
Furthermore, the proportion of patients experiencing seizures on a daily basis (caregiver 
observation) improved from 27% at baseline to 8% at Month 6 (Krueger 2010).
Preliminary data from another ongoing phase II trial that included 23 patients, [average age 
8.3 years (range 2-21)], has shown that everolimus can reduce seizure frequency in TSC 
patients with medically-refractory epilepsy, and may allow concurrent AEDs to be reduced or 
discontinued 
 
Clinicaltrials.gov Identifier NCT00411619).
Change in seizure frequency using video EEG was evaluated as a secondary endpoint in Study 
M2301, a randomized, double-blind, placebo-controlled trial of everolimus in 117 patients 
with TSC who have SEGA (median age 9.5 years; range 0.8 to 26.6). Frequency of seizures 


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was measured at baseline and at Week 24 by 24-hour EEG. There was no observed difference 
between the two treatment arms in change from baseline in total seizure frequency. However, 
from a clinical viewpoint, analysis of the change in seizure frequency was inconclusive, as 
seizure diary was not used and a single 24-hour EEG did not appropriately capture the high 
variability in daily seizure frequency. Although 103 patients (88%) were receiving AEDs at 
study entry, only 40 patients (34.2%) were captured as having clinical or sub -clinical seizures 
using single 24-hour EEG
 Clintrials.gov Identifier NCT00789828).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
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®).
Everolimus was approved by the United States (US) Food and Drug Administration (FDA) 
under the trade name Afinitor for the treatment of patients with advanced renal cell carcinoma 
(RCC) after failure of treatment with sunitinib or sorafenib, and for the treatment of 
progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, 
locally advanced or metastatic disease. The European Commission approved Afinitor for the 
treatment of patients with advanced RCC, whose disease has progressed on or after treatment 
with vascular endothelial growth factor-targeted therapy, and for the treatment of unresectable 
or metastatic, well- or moderately-differentiated neuroendocrine tumors (NET) of pancreatic 
origin in adults with progressive disease.
More recently, an application was submitted for Afinitor in the treatment of patients with 
hormone receptor-positive advanced breast cancer in combination with an aromatase inhibitor, 
in postmenopausal women previously treated with endocrine therapy. On 21-Jan-2012, 
Afinitor was approved in Argentina for this indication.
In addition, everolimus received accelerated approval for the treatment of patients with 
tuberous sclerosis (TSC) who have subependymal giant cell astrocytoma (SEGA) who require 
therapeutic intervention but are not candidates for curative surgical resection (as Afinitor) in 
the US, and received conditional approval in the EU (as Votubia) for the treatment of patients 
aged 3 years and older with TSC who have SEGA who require therapeutic intervention but 
are not amenable to surgery.
Furthermore, marketing authorization applications have been submitted for Afinitor/Votubia 
in the treatment of patients with TSC who have renal angiomyolipoma not requiring 
immediate surgery.


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Table 1-1
Everolimus – Drug Substance
Chemical name
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-
{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-
dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone
International non-
proprietary name
Everolimus
Figure 1-4
Chemical Structure of Everolimus
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 (HUVECS) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that everolimus may also act as an anti-angiogenic agent. The anti-
angiogenic activity of everolimus was confirmed in vivo. Everolimus selectively inhibited 
VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and 
metastatic tumors treated with everolimus showed a significant reduction in blood vessel 
density when compared to controls.
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 
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All significant adverse events observed in toxicology studies with everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-
proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 
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
Pharmacokinetics of RAD001 in patients with TSC
During Study RAD001M2301, in patients with TSC who have SEGA, pre-dose (Cmin) and 2-
hour post-dose (C2h) PK blood samples were collected at steady-state. Ages of patients in the 
everolimus arm of study ranged from 1 to 23.9 years. Patients in this study received a starting 
dose of 4.5 mg/m2 daily which was subsequently titrated to a whole blood trough 
concentration of 5-15 ng/mL. This was the starting dose and trough range approved for this 
indication.
Everolimus Cmin within individual patients was approximately dose-proportional (dose-
proportionality coefficient = 1.107; 90% CI = 1.03, 1.19). This was based on fitting the 
mixed-effect model to data in the dose range of 1.35 mg/m2-14.43 mg/m2.
The geometric mean Cmin values normalized to mg/m2 dose in patients of ages < 10 years and 
10-18 years were statistically lower than that of adults (> 18 years), suggesting that 
everolimus clearance normalized to body surface area was higher in younger patients:

Geometric mean Cmin (for values not associated with co-administration of CYP3A4/PgP 
inhibitor and/or inducer):

18 years of age (A): 2.13 ng/mL per mg/m2 dose (n=46)

10-18 years of age (B): 1.27 ng/mL per mg/m2 dose (n=92)

< 10 years of age (C): 0.97 ng/mL per mg/m2 dose (n=194)

B:A geo-mean ratio [90% CI] = 0.60 [0.38, 0.92]

C:A geo-mean ratio [90% CI] = 0.46 [0.31, 0.68]
Co-administration of inducer of CYP3A4 decreased everolimus exposure as indicated by the 
geometric mean Cmin values normalized to mg/m2 dose in patients with TSC who have SEGA 
in different age groups:

Geometric mean computed out of Cmin associated with co-administration of CYP3A4/PgP 
inducer (without inhibitor of CYP3A4):

18 years of age: 0.72 ng/mL per mg/m2 dose (n=7)

10-18 years of age: 0.80 ng/mL per mg/m2 dose (n=118)

< 10 years of age: 0.61 ng/mL per mg/m2 dose (n=122)
Results of a linear mixed model analysis indicated that the relationship between absolute 
change from baseline in SEGA volume and Cmin was statistically significant with a slope of -
0.304 (95%CI= -0.42, -0.19), corresponding to a 0.211 cm3 reduction in SEGA volume with a 
2-fold increase in Cmin. Results of another linear mixed model analysis indicated that the 
relationship between percent change from baseline in SEGA lesion volume and C min was 
statistically significant with a 12.98% (95% CI= 7.46%, 18.16) further tumor size reduction 


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for a 2-fold Cmin increase. Subgroup analysis of selected AEs by everolimus trough 
concentration was not indicative of an increased risk with higher C min within the Cmin range 
observed in the studies.
2
Rationale
2.1
Study rationale and purpose
The primary goal of this study is to assess the efficacy and safety of everolimus as adjunctive 
therapy in patients with TSC who have partial-onset refractory seizures. Such seizures (often 
“refractory”) are known to be experienced commonly in patients with TSC, as described in 
Section 1.1.1. Epileptogenesis in these patients has been attributed in part to the 
overexpression of mTOR. As noted above, the TSC1/TSC2 protein complex is a negative 
regulator of the mTOR pathway. Hence, mutation or loss of either of these gene products in 
nonclinical models is associated with increased mTOR pathway activation and heightened 
sensitivity to mTOR inhibitors (Astrinidis and Henske 2005; Inoki et al 2005; Kwiatkowski 
and Manning 2005). mTOR pathway upregulation has also been observed in lesions derived 
from TSC patients (Astrinidis and Henske 2005; Kwiatkowski and Manning 2005), and TSC1 
or TSC2 defective experimental animal models exist which recapitulate the pathology, 
behavioral and neurological aspects of the TSC disease (Onda et al 1999; Kwiatkowski and 
Manning 2005; Uhlmann et al 2002; Kenerson et al 2005) and are sensitive to mTOR 
inhibition (Kenerson et al 2005; Astrinidis and Henske 2005; Kwiatkowski and Manning 
2005).
Encouraging anti-epileptogenic and antiepileptic, nonclinical and preliminary clinical 
evidence, discussed in Section 1.1.3, illustrates that two different mTOR targeting drugs 
(rapamycin and everolimus), can limit the development of new onset seizures and increase 
survival in genetically engineered models of TSC associated seizures. Rapamycin has been 
shown to decrease the seizure frequency after the development of seizures in these animals. In 
the clinical setting, although the M2301 phase III findings were inconclusive, 2 phase II 
studies provided proof of concept for the activity of everolimus in seizure control. These 
findings justify the clinical evaluation of the mTOR inhibitor, everolimus, for an indication of 
seizure reduction. Traditionally, seizure reduction can be most accurately described when an 
individual seizure type, such as Partial Onset Seizures is pre-defined as the seizure type of
interest in the primary endpoint of the study. Finally, because epilepsy in TSC often seems to 
follow a progressive, intractable course, TSC patients with seizures are in high need of a 
novel type of intervention that is not only symptomatic “anti-seizure” but may be “anti-
epileptogenic” by targeting the primary signaling pathway that triggers epileptogenesis in this 
group of patients (Crino 2010; Wong 2010; Marcotte and Crino 2006). Taking all these data 
into account, there is strong rationale for evaluating the use of mTOR inhibitors such as 
everolimus for the treatment of refractory partial-onset seizures associated with TSC.


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2.2
Rationale for the study design
This study will investigate the efficacy and safety of everolimus, as adjunctive treatment, in 
patients with TSC who have refractory partial-onset seizures. This is a randomized, double-
blind, parallel-group study comparing two target trough concentration ranges of everolimus
versus placebo.
The use of placebo as the control arm is ethically acceptable because study treatment will be 
added to other anti-epileptic medications already used by the patients (1-3 AEDs). The 
presence of a placebo arm allows efficacy/safety changes attributable to treatment to be 
differentiated from those attributable to underlying disease, with any possible placebo effect 
being taken into account. Moreover, this design is consistent with clinical trial methodology 
used for evaluation of other AEDs as adjunctive treatment for refractory partial onset seizures.
Therapeutic dose monitoring is being used since it is expected that most of the patients 
enrolled will be pediatric, with a broad age range, hence, it will allow to tailor the dose based 
on BSA and potential concomitant use of medications that interact with everolimus 
metabolism.
The use of two trough ranges of everolimus is based on the following rationale: in a previous 
trial of everolimus in TSC patients (Study M2301), therapeutic drug monitoring was used to 
individualize the dose of everolimus to a targeted trough range of 5 to 15 ng/mL. However, 
results of this study indicated that acceptable efficacy (defined as > 50% reduction in total 
target SEGA volume in at least 40% of patients) was obtained with trough levels as low as 3 
ng/mL below which efficacy is not expected. Therefore, the lower limit of the trough range in 
the proposed study is 3 ng/mL, with an upper limit of 15 ng/mL. In order to determine the 
most appropriate trough level range, and to gain insight into whether C min values at the lower 
end of this range are as effective as higher values, this trial will assess two separate ranges (3-
7 ng/mL and 9-15 ng/ mL). The primary comparisons will be between each everolimus arm 
and placebo.
Additionally, safety will be presented by treatment arm thus allowing for determination of 
whether tolerability differs between the two everolimus trough levels.
The study includes a prospective baseline phase during which patients complete a seizure 
diary for a total of 8 weeks, which is considered long enough to provide reliable data on the 
baseline seizure frequency of patients taking one to three AEDs. At the end of this baseline 
phase, if all eligibility criteria are still met (lab results from the Screening visit), patients will 
continue their baseline phase AED medications and be randomized in a 1:1:1.09 fashion to 
receive adjunctive: 1) placebo; 2) everolimus to attain a trough level 3-7 ng/mL; or 3) 
everolimus to attain a trough level 9-15 ng/mL. Following randomization, patients enter a 
core phase, which starts with a 6 week titration period during which up to 3 dose adjustments
could be made in order to reach the targeted everolimus trough range. This is followed by a 
maintenance period of 12 weeks’ duration, as recommended in the EMA guidance on anti-
epileptics (EMA 2010) as being long enough to establish efficacy. After completing the 
maintenance period, patients will be offered to continue in an extension phase; this extension 
phase will allow for longer-term safety and efficacy data to be obtained. Once the Extension 
phase is completed, patients deriving clinical benefit will be offered continued treatment in 


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the Post Extension phase which will allow for additional long term safety data to be obtained, 
while ensuring availability of everolimus.
For the primary efficacy variable of this study, the regulatory requirements differ between 
Europe and US, with EMA preferring response rate and FDA preferring percentage reduction 
in seizure frequency. Therefore, both variables will be analyzed for the primary objective, and 
without correction for multiplicity since it is understood that each Agency will only use their 
preferred variable to make a decision on the primary objective.
Both primary efficacy variables are based on the change from baseline in seizure frequency 
during the 12-week maintenance phase, with sensitivity analyses included that count seizures 
over the entire core phase (titration period plus maintenance period).
2.3
Rationale for dose and regimen selection
The starting dose in both Study C2485 and M2301 was based on the patients’ body surface 
area (BSA). Therapeutic drug monitoring (TDM) of everolimus was used with a targeted 
trough concentration range in whole blood to determine the optimal therapeutic dose.
In Study M2301, an everolimus trough (Cmin) level of 3-15 ng/mL has shown superior 
efficacy versus placebo in patients with TSC who have SEGA, with an acceptable safety 
profile. In addition, there was a significant correlation between SEGA volume reduction and 
Cmin while higher Cmin did not result in more adverse events. However, it is unknown if a Cmin
in the range of 3-15 ng/mL will lead to a reduction in seizure frequency, or if a correlation 
between reduction in seizure frequency and Cmin exists. Therefore, two trough levels, 3-7 
ng/mL (low) and 9-15 ng/mL (high), will be investigated.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below. Note that for the primary 
objective there are separate primary variables and analyses planned for EMA and FDA, in 
accordance with their differing preferences for demonstrating efficacy of an anti-epileptic 
medication. See Section 10.4.1 for further details.
Also note that the analyses provided in Table 3-1 mainly apply to data from the core phase of 
the trial, and at the data cutoff the extension phase will not be complete (see Section 10).


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To compare the reduction in frequency of partial-onset 
seizures on each of two trough ranges of everolimus 
(3-7 ng/mL and 9-15 ng/mL) versus placebo in 
patients with TSC who are taking one to three AEDs.
EMA: Response rate, where response means at least 
a 50% reduction from baseline in partial-onset seizure 
frequency during maintenance period of the core 
phase
FDA: Percentage reduction from baseline in partial 
onset seizure frequency during maintenance period of 
the core phase
EMA: Cochran-Mantel-Haenszel (CMH) chi-square 
tests
FDA: Rank analysis of covariance (ANCOVA)
Secondary
Refer to Section 10.5
To compare each of the two everolimus trough ranges 
versus placebo with respect to:
(1) Ability to completely suppress partial-onset 
seizures.
(2) Proportion of patients with ≥ 25% reduction from 
baseline in average weekly frequency of partial-onset 
seizures.
(3) Distribution of reduction from baseline in seizure 
frequency
(4) Seizure-free days
(5) Treatment duration
(6) Quality of life
(1) Seizure-free rate, where seizure-free means a 
100% reduction in partial-onset seizure frequency 
during maintenance period of the Core phase
(2) Proportion of patients with at least a 25% reduction 
from baseline in partial-onset seizure frequency during 
maintenance period of the core phase
(3) Categorical variable of six levels of reduction from 
baseline in partial-onset seizure frequency during 
maintenance period of the core phase (≤ -25% 
(exacerbation); > -25% to < 25% (no change); ≥ 25% 
to < 50%; ≥ 50% to < 75%; ≥ 75% to < 100%; 100% 
(seizure-freedom)).
(4) Frequency of seizure-free days during 
maintenance period of the Core phase
(5) Time from randomization until treatment 
discontinuation in the Core phase
(6) Overall QOL global scores from the 3 age-specific 
questionnaires
Descriptive statistics


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Objective
Endpoint
Analysis
To assess everolimus in relation to neurocognitive, 
neurobehavioral and neurodevelopmental measures
using the Vineland Adaptive Behavior Scales-II and 
the Wechsler Non-Verbal Scale of Ability
Change from baseline of sub-test scores 
Descriptive statistics
To assess the relationship between everolimus 
concentration and efficacy / safety endpoints
Percentage reduction in seizure frequency / frequency 
of selected AEs
Mixed models and descriptive statistics
To evaluate the impact of everolimus on the pre-dose 
exposure of antiepileptic drugs 
Pre-dose concentrations of AEDs at Baseline (AEDs 
alone) and at post-Baseline (AEDs plus everolimus)
Mixed models and descriptive statistics
To evaluate the effect of everolimus on long-term 
seizure reduction 
50% response rate, percent reduction from Baseline 
and seizure free-days in partial onset seizure by time 
interval over the extension phase
Descriptive statistics
To evaluate the safety and tolerability of each 
everolimus trough range in the study population
Frequency of AEs / abnormal laboratory values
Descriptive statistics
To evaluate the impact of everolimus on the risk of 
suicidality using the Columbia Suicide Severity Rating 
Scale (C-SSRS)
Frequency C-SSRS outcomes, frequency of SAEs 
referring to a positive suicidal evaluation
Descriptive statistics


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4
Study design
4.1
Description of study design
This is a three-arm, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of two trough-ranges of everolimus given as adjunctive therapy in patients 
with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures.
The study consists of 4 phases for each patient (see Figure 4-1 below):

Baseline phase: From Screening Week -8 (V1) to randomization visit at Week 0 (V2). For 
baseline seizure frequency calculations, the 8-week prospective period counts will be 
totaled.

Core phase: Double-blind, placebo-controlled, from randomization at Week 0 (V2) to 
Week 18 (V11).

Extension phase: From Week 18 (V11) until 48 weeks after the last patient has completed 
the core phase, with all patients receiving everolimus.

Post Extension phase: From the end of the extension phase until everolimus is 
commercially available for the indication, a rollover protocol is available locally, or 
October 30, 2017, whichever occurs first (on a per patient basis).


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Figure 4-1
Study Design
4.1.1
Baseline phase
The Baseline phase is 8 weeks/56 days (+ 2 weeks for scheduling purposes) and begins with 
the Screening Visit and ends with the Baseline Visit. Patients/caregivers will record seizures 
in a seizure diary beginning at the Screening Visit. The most recent 56 days prior to the 
baseline visit must be used for determining eligibility.
Screening visit
During the Screening visit (V1, Week -8), the history of prior seizure type and antiepileptic 
drug use will be assessed.
The patient must provide a signed informed consent form (ICF) prior to any study related 
procedure.
Baseline visit
Patients who meet the eligibility criteria will then enter a prospective, eight-week Baseline 
phase during which the seizure type and frequency and antiepileptic drug use will be assessed.
Patients are required to be on a stable dose of 1-3 AEDs (stable dose defined as no change for 
at least 4 weeks prior to the screening visit and through the entire study). Patients/caregivers 


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will be instructed on how to count seizures and to complete a daily seizure diary for the entire 
eight-week Baseline phase.
Eligibility criteria will be assessed subsequently at the end of the baseline phase (V2, Week 0), 
prior to randomization. All patients who continue to meet eligibility criteria, including 
demonstrating the minimum seizure frequency during the last 8-weeks of the baseline phase 
(see Section 5.1), will be randomized in a 1:1:1.09 ratio to one of the three treatment arms as 
described in Section 6.1. Randomization will be stratified by age subgroup at randomization 
as follows: (i) 1 to <6 years; (ii) 6 to <12 years; (iii) 12 to <18 years; and (iv) ≥ 18 years.
4.1.2
Core phase
The Core phase of the study includes both a titration period (V2, Week 0 to V8, Week 6) and 
a maintenance period (V8, Week 6 to V11, Week 18).
During the Core phase of the study, there will be visits at weeks 0 (V2), 1 (V3), 2 (V4), 3 
(V5), 4 (V6), 5 (V7), 6 (V8), 10 (V9), 14 (V10), and 18 (V11).
Everolimus will be dosed based on TDM with dose titration to attain one of the two target 
Cmin ranges (3 to 7 ng/mL or 9 to 15 ng/mL). Starting doses of study drug are defined in 
Section 6.1.1.1.
During the 6 week titration period, three pre-dose PK blood samples (0.5 mL for 1 to < 2 
years of age; 1 mL for 2 to ≤6 years of age; and 2 mL for > 6 years of age) will be taken for 
potential dose adjustments as described in Table 4-1. The high frequency of visits during the 
beginning of the Core phase is essential to ensure that titration is being performed effectively, 
and also helps to ensure that seizures are being counted properly, and provides an opportunity 
to remind patients of the importance of good compliance.
The titrations are implemented as follows. A local lab (at the treating center) will collect the 
blood samples and send them to a central laboratory for determination of everolimus 
concentrations. The site will receive recommendations from the central Interactive Response 
Technology (IRT) on dose adjustment (to maintain, increase or decrease the number of the 2-
mg tablets) for each patient, based on concentration values of the pre-dose PK samples. It is 
expected that all patients will achieve the planned target pre-dose trough level (Cmin) during 
this period. In order to keep the blind, the IRT will also instruct the site to adjust the dose for 
patients in the placebo arm based on a random scheme of dose changes.
After the completion of the titration period, the vast majority of patients are expected to 
continue at their current dose level during the entire 12 week maintenance period. However, 
the possibility of further titration does still exist, based on the planned pre-dose PK blood 
samples that will be collected every 4 weeks during the maintenance period. In addition, pre-
dose PK blood samples should be collected two weeks after any everolimus dose 
adjustment, and so a patient having a titration at week 6 (end of titration period) would need 
to have a pre-dose PK sample collected at week 8 (2 weeks into the maintenance period). This 
PK sample could then lead to a dose adjustment at the next planned visit at week 10, which if 
implemented would then necessitate a further pre-dose PK sample at week 12. Few patients 
are expected to need these extra titrations, but the possibility exists in order to keep patients in 
their targeted trough range as assigned at randomization.


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Table 4-1
PK sampling and dose titration events during Core phase
Week
Action
Potential for titration
0
Start dosing
1
PK sample 1
2
PK result
X
3
PK sample 2
4
PK result
X
5
PK sample 3
6
PK result
X
8 (only if titration occurred at week 6)
Additional PK sample
10
Preplanned PK sample 4
X
12 (only if titration occurred at week 10)
Additional PK sample
14
Preplanned PK sample 5
X
16 (only if titration occurred at week 14)
Additional PK sample
18
Preplanned PK sample 6
X
4.1.3
Extension phase
The extension phase of this study will allow further evaluation of the long-term safety profile 
and efficacy of everolimus in this patient population.
All patients who complete the Core phase will be offered continuation on the extension phase, 
during which all the patients will receive everolimus at Week 18 [(V11) same visit as end of 
Core and start of Extension)]. Patients will enter into this phase upon completion of the core 
phase, and will continue until 48 weeks after the last patient completes the core phase.
(Patients enrolled earlier in the study may remain in the Extension phase for more than 48
weeks.)
The intention is to allow investigators to decide appropriate dose changes themselves, based 
on everolimus concentrations at trough (Cmin) obtained during the extension phase. However, 
in order to avoid compromising the blinded nature of the study (including for the investigator, 
patient and sponsor) in the earlier Core phase, all patients will first be transitioned towards a 
common targeted trough range of 6 to 10 ng/ml before any Cmin value is shared with the 
investigator. Note that no individual patient unblinding will be performed at entry into 
extension.
During the Extension phase, visits will be at Weeks 18 (V11), 19 (V12), 20 (V13), 22 (V14), 
26 (V15), and 30 (V16), and then every 12 weeks thereafter, unless additional visits are 
clinically indicated. Pre-dose blood samples will be collected at weeks 19 and 22 to allow 
possible titrations at Weeks 20 and 26. In addition, patients randomized to one of the two 
everolimus arms will be transitioned at week 18. Patients are expected to approach or be 
within the planned target trough range of 6 to 10 ng/ml after the week 20 titration. This will 
serve to preserve the blinding of the prior Core phase. At the Week 26 visit, investigators will 
be provided with the Cmin result from Week 22 PK, and they will be permitted to make their 
own dose titration decisions. Further titrations are possible based on the planned pre-dose PK 
samples collected every 12 weeks from Week 30, and any additional pre-dose PK blood 
sample collected two weeks after any everolimus dose adjustment (see Table 4-2).


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Table 4-2
PK sampling and dose titration events during Extension phase
Week
Action
Potential for titration
18
Switch to extension
19
Pre-planned PK sample E1
20
PK result
X
22
Pre-planned PK sample E2
26
Pre-planned PK sample E3
X
28 (only if titration occurred at week 26)
Additional PK sample
30
Pre-planned PK sample E4
X
32 (only if titration occurred at week 30)
Additional PK sample
42, 54, 66, etc.
PK sample E5, E6, E7, etc.
X
For patients who signed informed consent for Amendment 2 of the protocol after completing 
their week 18 visit, a modified transition schedule will be permitted in the Extension Phase.
This schedule will begin at week 26, 30 or at any subsequent scheduled visit (every 12 weeks
thereafter). At the first such visit, the everolimus dose will be transitioned based on the prior 
PK value using a targeted trough range of 6-10 ng/ml. The patient will return the following 
week for an everolimus PK sample, and the following week, for disclosure of the PK value. 
The investigator may begin to make his/her own dose adjustment decisions or rely on the IRT 
system to prescribe a dose that will maintain the everolimus trough within 3-15 ng/ml. (see
Section 4.1.3.1).
At the start of the Extension Phase, during the transition to investigator control of everolimus 
dosing, and while the everolimus Cmin value is still not shared with the investigator, the 
investigator should consider managing clinical deterioration in seizure control (as judged by 
the investigator) by modifying AED doses or adding or subtracting AEDs. Starting at week 26, 
when everolimus Cmin values are made available to the investigator, the investigator may 
manage a patient’s clinical deterioration by modifying AED doses, adding and or subtracting 
AEDs and modifying everolimus dosing in whatever order or combination the investigator 
chooses.
When the last patient completes the Core phase, the data will be analyzed. If the results are 
positive, patients will continue on study treatment until the end of the Extension phase.
Patients deriving clinical benefit will also be offered continued treatment in a Post Extension 
phase. If the results are negative, the study will be terminated.
When results of the Core phase of the study become available, if a more favorable risk-benefit 
ratio is identified for one of the two trough ranges, the protocol may be amended and patients 
will be offered to be titrated to the preferred trough range.
The last Extension phase visit for a patient will be the last scheduled visit that occurs prior to 
or on September 2, 2016, at which point the patient will then enter the Post Extension phase.
After the Post Extension phase is completed, if the Core study results are positive and patients 
continue to receive benefit, everolimus will continue to be provided free of charge in a roll 
over protocol until the drug is approved and commercially available for use in TSC-associated 
refractory partial onset seizures, or until the patient stops receiving everolimus for any reason, 
whichever occurs first. If this is prohibited by local regulations (e.g., in UK and Norway) the 
patient will exit the study when the Post Extension phase is completed (see Section 4.1.4).


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Additional Everolimus PK sampling
In addition to the time points described above in the Core, Extension and Post Extension 
sections, pre-dose blood samples for everolimus concentration determination should be 
collected two weeks after the following events:

Any everolimus dose adjustment

Starting or changing the dose of a CYP3A4/PgP inducer/inhibitor
Anti-epileptic drug PK sampling
Everolimus is metabolized by the CYP3A4 pathway in the liver, and to some extent in the 
intestinal wall. Many of the concomitantly administered AEDs are also metabolized by the 
CYP3A4 pathway, which results in a potential for drug-drug interaction between the AEDs 
and everolimus. Therefore, levels of the AEDs listed below (considered to be CYP3A4 
substrates and /or inducers) will be measured to investigate the effect of everolimus on the 
AED level (i.e., if AED + everolimus leads to higher levels of AED compared to AED alone).
Inducers:

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

Primidone
Substrates:

Clobazam

Clonazepam

Diazepam

Felbamate

Topiramate

Valproic acid

Zonisamide
Pre-dose blood samples of 6 mL (5.2 mL for patients 6 and under) will be collected at Visits 1, 
2, 3, and 5 for the measurement of antiepileptic drug (AED) concentration. Patients weighing 
12 to 20 kg will not be required to provide PK AED blood samples due to the high overall 
blood volume required at the early visits. Effects of everolimus on the exposure of anti-
epileptic drugs will be assessed by comparing the anti-epileptic drug concentrations at Visits 1
and 2 (AEDs alone) and at Visits 3 and 5 (AEDs plus everolimus). A list of commonly 
prescribed AEDs that are used in this population is provided in Section 6.1.1.1.
4.1.3.1
Investigator-led dosing in patients past week 22
Patients who have completed week 18 of the study at the time of signing informed consent for 
protocol amendment 2, will have an opportunity to have their everolimus concentrations 
revealed after a transition process that can begin at any scheduled visit beginning from week 


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26. At week 26, 30 or any other scheduled visit (every 12 weeks), the patient would first be 
transitioned using a targeted trough range of 6-10 ng/ml (Transition visit A). The IRT system 
would recommend dose instructions using the previous PK result (week 22, 26, etc). The 
patient would return at least 5 days later to provide an additional transition PK trough sample 
(Transition visit B), and then again at least one week later for a clinic visit (Transition visit C), 
when the investigator would be informed of the everolimus concentration. The investigator 
would then be permitted to modify the patient’s dose of study drug by 2mg daily (patients not 
on CYP3A4/PgP inducers) or 4mg daily (patients on CYP3A4/PgP inducers) to a minimum 
dose of 2 mg/day. A dose increase will not be permitted if the everolimus concentration 
exceeds 15 ng/ml. If the investigator chooses not to modify dosing, the dose will be 
maintained by the IRT system in the range of 3-15 ng/ml. Table 4-3 outlines the visits and 
actions to be taken. Additional assessments to be performed at unscheduled Transition visit C 
are outlined in Table 7-1.
Table 4-3
Dose transition of everolimus to 6-10 ng/ml beginning at Week 26
Visit
Week
Action
14
22
Pre-planned PK sample
15
26 transition visit A
Transition dose change by IRT based on PK from W22
201
27 transition visit B
Additional transition PK sample
202
28 transition visit C
Cmin revealed, Investigator-led dosing may begin
16
30 transition visit A
Transition dose change by IRT based on PK from W26
201
31 transition visit B
Additional transition PK sample
202
32 transition visit C
Cmin revealed, Investigator-led dosing may begin
17+
42, 54, 66, etc. transition visit A
Transition dose change by IRT based on PK from W30, 42, 54, etc
201
43, 55, 67, etc. transition visit B
Additional transition PK sample
202
44, 56, 68, etc. transition visit C
Cmin revealed, Investigator-led dosing may begin
4.1.4
Post Extension Phase
All patients who complete the Extension phase will be offered continued participation in the 
Post Extension phase. Investigators will determine patient’s daily dosing at their sole 
discretion based on guidance provided (see Section 6). The IRT system will respond to the 
investigator’s request and provide kit numbers to be dispensed to supply the patient. In the 
Post Extension phase, the IRT system will no longer provide daily dosing recommendations.
During the Post Extension phase, visits will occur every 12 weeks, unless additional visits are 
clinically indicated. The first scheduled Post Extension phase visit will occur 12 weeks after 
the patient’s last scheduled Extension phase visit. Additional pre-dose blood samples for 
everolimus concentration determination should be collected two weeks after the following 
events:

Any everolimus dose adjustment

Starting or changing the dose of a CYP3A4/PgP inducer/inhibitor
Investigators will confirm the Cmin value from the last PK drawn and make a decision on 
dosing. The investigator will enter the chosen daily dose into the IRT system and the IRT 
system will dispense the appropriate number of kits to supply the patient until the next 
scheduled visit.


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4.1.5
Definition of end of the study
The end of the Core phase of the study will occur when the last patient reaches Visit 11 
(Week 18). At this point, the core data will be analyzed and, if the results are positive, all 
patients in the Extension phase will continue. If one trough level is found to be superior to the 
other, the protocol may be amended and all patients will be offered to be titrated to that trough 
level. The Extension phase of the study will end 48 weeks after the last patient enters the 
Extension Phase. At that point, long term safety and efficacy data will be analyzed. The last 
treatment in a patient’s Post Extension phase will be on or before September 29, 2017, and the 
end of the study will be on or before October 30, 2017.
A follow up visit should be performed by either phone or in person, depending on whether 
adverse events are ongoing at time of the previous visit for all patients who permanently 
discontinue treatment. Patients will be followed for 30 days after end of treatment for 
continuing or new adverse events and for serious adverse events until resolution of the AE. At 
the time when the last patient completes their follow-up visit, the data will be cleaned and 
locked, and a final study report written.
4.2
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient will be contacted, requested to discontinue taking study treatment, and be seen as 
soon as possible. The same assessments should be performed as described in Section 7.1.6 for 
a prematurely withdrawn patient. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing IRBs and/or ECs of the 
early termination of the trial according to ICH-GCP and local regulations.
5
Population
5.1
Patient population
The target population is comprised of approximately 355 male or female patients, with TSC 
who have refractory partial-onset seizures. Patients between the ages of 2 and 65 years will be 
enrolled, except in Europe where the minimum age will be 1 based on EMA request.
Refractory seizures are defined as prior history of failure to control partial-onset seizures 
despite having been treated with two or more sequential regimens of single or combined 
antiepileptic drugs.
Partial-onset seizures are defined as simple partial seizures with motor signs, complex partial 
seizures, and complex partial seizures with secondary generalization or a combination of these 
types.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:


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1. Male or female between the ages of 2 and 65 years (except in Europe where the minimum 
age will be 1 at the request of the EMA). (A minimum number of pediatric patients will be 
randomized in the following age groups: 1 to <6 years [40 patients], 6 to <12 years [40 
patients], and 12 to <18 years [40 patients].)
2. Clinically definite diagnosis of TSC see Table 5-1 (modified Gomez criteria, Gomez 
1999). Note: positive genetic test without definite diagnosis of TSC as per the modified 
Gomez criteria is not allowed.
Table 5-1
Diagnostic Criteria for Tuberous Sclerosis Complex
Major Features
Facial angiofibromas or forehead plaque
Nontraumatic ungual or periungual fibroma
Hypomelanotic macules (three or more)
Shagreen patch (connective tissue nevus)
Multiple retinal nodular hamartomas
Cortical tubera
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma, single or multiple
Lymphangiomyomatosisb
Renal angiomyolipomab
Minor Features
Multiple, randomly distributed pits in dental enamel
Hamartomatous rectal polypsc
Bone cystsd
Cerebral white matter radial migration linesa,d
Gingival fibromas
Non-renal hamartomac
Retinal achromic patch
‘Confetti’ skin lesions
Multiple renal cystsc
Definite Tuberous Sclerosis Complex:
Either two Major Features or one Major Feature plus two Minor Features.
a. The co-occurrence of cerebral cortical dysplasia and cerebral white matter radial migration lines should be 
considered as one major feature of TSC.
b. In patients with both lymphangiomyomatosis and renal angiomyolipoma, another feature of TSC must be 
identified before a definite diagnosis is assigned.
c. Histological confirmation of these features is suggested.
d. Radiographic confirmation of these features is sufficient.


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3. Diagnosis of partial-onset epilepsy according to the classification of the International 
League Against Epilepsy (Commission on Classification and Terminology of the 
International League Against Epilepsy, 1989) and revised in 2009 (Berg 2010). This 
classification is further modified for the purpose of capturing clinical details, and defines 
partial onset seizures in patients with TSC on the basis of the pathophysiology of TSC as 
either:

any seizure that has been definitively shown to be partial onset on ictal EEG, or

any probable seizure with motor signs (non-sensory) that has NOT been documented 
to be a primary generalized seizure on ictal EEG.
Seizure Classification:
I.
Partial Onset Seizures
A. Without impairment of consciousness or awareness
1. With observable motor or autonomic components. (Formerly known as “simple 
partial seizures”) ‘‘Focal motor’’ and ‘‘autonomic’’ are terms that may 
adequately convey this concept depending on the seizure manifestations
2. Involving subjective sensory or psychic phenomena only.(This corresponds to the 
concept of an aura).
a. With ictal EEG confirmation
b. Without ictal EEG confirmation
B. With impairment of consciousness or awareness. (Formerly known as “complex 
partial seizures”, or partial onset seizures with Absence-like features)
1. Typical Absence features
2. Atypical Absence features
3. NOS (not otherwise specified)
C. Evolving to a bilateral, convulsive seizure (Formerly known as “secondarily 
generalized seizure”)
1. Myoclonic features
2. Clonic features
3. Tonic features
4. Tonic-clonic features (Older term: grand mal)
5. Atonic features
6. NOS
II
Primary Generalized seizures
A. Absence seizures
1. Typical absence seizures
2. Atypical absence seizures
B. Myoclonic seizures
C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures (Older term: grand mal)
F. Atonic seizures


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G. NOS
4. Uncontrolled partial-onset seizures; must meet the following:
a. At least 16 reported quantifiable (no cluster or innumerable seizures) partial-onset 
seizures (as defined in Inclusion Criteria 3) over the Baseline period (56 days, 8 
weeks) with no continuous 21-day seizure-free period between Visit 1 (Screening 
Visit) and Visit 2 (Randomization visit), as per data captured in daily seizure diaries.
b. Prior history of failure to control partial-onset seizures despite having been treated 
with two or more sequential regimens of single or combined antiepileptic drugs
c. Prior or concurrent use of vagal nerve stimulator (VNS) is allowed. If the patient is 
using VNS, device stimulator parameters must remain constant throughout the study.
d. Prior epilepsy surgery is allowed if performed at least 12 months before study entry.
5. Must be receiving one, two, or three AEDs at a stable dose for at least 4 weeks at the start 
of the 8-week prospective Baseline phase, remain on the same regimen throughout the 
Baseline phase, and intend to continue the same regimen throughout the 18-week double 
blind Core phase (rescue medications are permitted, as defined in the Rescue Medications 
Section 6.1.2). No more than one of these can be a strong CYP3A4 inducer (e.g., 
Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin, Primidone)
6. If female of child bearing potential, documentation of negative pregnancy test at time of 
informed consent. Females of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, must use highly effective contraception 
during the study and for 8 weeks after stopping treatment. Highly effective contraception 
is defined as either:

Total abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception]

Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) 
or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment

Male partner sterilization, at least 6 months prior to screening visit, (with the 
appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). 
[For female subjects on the study, the vasectomized male partner should be the sole 
partner for that subject].

Use of a combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the oral agent before 
taking study treatment for at least 3 months.


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7. Sexually active males must use a condom during intercourse while taking study drug, and 
for 8 weeks after stopping study treatment. They should not father a child during this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid.
8. Hepatic, renal and blood laboratory values within the following range at screening:

AST and ALT levels < 2.5 x ULN

serum bilirubin <1.5 × ULN (this limit does not apply to patients with an elevated 
indirect bilirubin, if they have Gilbert’s Syndrome),

serum creatinine < 1.5 x ULN,

hemoglobin ≥ 9 g/dL,

platelets ≥ 80,000/mm3,

absolute neutrophil count ≥ 1,000/mm3
9. Written informed consent. Subjects or their legal guardians must have the ability to 
comprehend the informed consent form and be willing to provide informed consent. For 
subjects who are too young or unable to comprehend the written consent, a legal guardian
who is able to describe and provide an understanding of the informed consent to the 
subject must sign the consent form on behalf of the subject. In all cases, the informed 
consent process will follow the local rules and regulations.
10. Patient or caregiver must be able to reliably record seizures and keep a daily diary and 
recall adverse events.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or 
drug abuse or current seizures related to an acute medical illness.
2. Presence of only non-motor partial seizures (Criteria Not Applicable per Amendment 2)
3. Patients with TSC who have SEGA in need of immediate surgical intervention.
4. Patients under 2 years of age with untreated infantile spasms.
5. Within 52 weeks prior to study entry, an episode of status epilepticus, defined as:
a.
in adults and children 5 years and older -- continuous or intermittent, convulsive 
seizures lasting more than 10 minutes and requiring additional medical intervention 
such as with rescue medication not commonly used in the home (i.e., a convulsive 
seizure or series of convulsive seizures not within the patient’s typical seizure pattern 
and management).
b.
in children less than 5 years of age -- continuous or intermittent, convulsive seizures 
lasting more than 10 minutes and requiring significant additional medical 
intervention such as hospitalization (note: It is recognized that some young patients 
may be sent for emergency care despite having experienced a seizure within their 
typical seizure pattern and management. Only the more severe episodes of prolonged 
convulsive seizures in such patient, such as those leading to hospitalization, would 
qualify as status epilepticus).


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6. Patients with history of seizure clusters (where individual seizures cannot be accurately 
counted according to the judgment of the investigator) occurring within 26 weeks prior to 
study entry.
7. Patients who require rescue medication during the Baseline phase for more than 6 days.
8. Patients with non-TSC related progressive encephalopathy.
9. Patients who weigh less than 12 kg.
10. Patients with coexisting malignancies within the 3 years prior to randomization, except for 
adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the 
skin.
11. Patients with any severe and/or uncontrolled medical conditions at randomization such as:
a. Symptomatic congestive heart failure of New York Heart Association Class III or IV, 
history of left ventricular ejection fraction (LVEF) < 50%, QTc interval >460ms, 
congenital QT syndrome, unstable angina pectoris, myocardial infarction within 6 
months of study entry, serious uncontrolled cardiac arrhythmia or any other clinically 
significant cardiac disease.
b. Significant symptomatic deterioration of lung function. If clinically indicated, 
pulmonary function tests including measures of predicted lung volumes, DLco, O2
saturation at rest on room air should be considered to exclude restrictive pulmonary 
disease, pneumonitis or pulmonary infiltrates.
c. Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of everolimus (e.g., ulcerative disease, malabsorption 
syndrome or small bowel resection).
d. liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. 
quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA),
e. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN.
f.
Active skin, mucosa, ocular or GI disorders of Grade > 1.
g. Active (acute or chronic) or uncontrolled severe infections.
h. A known history of HIV seropositivity or other active viral infections.
12. Patients with an active, bleeding diathesis.
13. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL 
OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
14. Patients who have had a major surgery or significant traumatic injury within 4 weeks of 
study entry. Patients who have not recovered from the side effects of any major surgery 
(defined as requiring general anesthesia), or patients that may require major surgery 
during the course of the study.
15. Patients with a prior history of organ transplant.
16. Patients receiving more than 3 antiepileptic drugs at any time in the baseline phase or at 
randomization or who change the dose of the AEDs during 4 weeks before screening or 
during the baseline period.
17. Patients being treated with felbamate, unless treatment has been continuous for ≥ 1 year.
18. Patients currently receiving anticancer therapies or who have received anticancer therapies 
within 4 weeks of study entry (including chemotherapy, radiation therapy, antibody based 
therapy, etc.).


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19. Prior treatment with any investigational drug within the preceding 4 weeks prior to study 
entry.
20. Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed.
21. Patients who have received prior treatment with a systemic mTOR inhibitor (sirolimus, 
temsirolimus, everolimus) within 24 months of study entry. Patients who have received 
prior treatment with a topical mTOR inhibitor (sirolimus, temsirolimus, everolimus) 
within 4 weeks of study entry.
22. Patients with a known hypersensitivity to everolimus or other rapamycin-analogues 
(sirolimus, temsirolimus) or to its excipients.
23. Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study.
24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
25. Patients with a Score of 4 or 5 on the Suicidal Ideation item within 2 years of Screening, 
or any “yes” on the Suicidal Behavior item of the Columbia-Suicide Severity Rating Scale 
at Screening or Baseline who upon follow up with a healthcare professional are found to 
be severely depressed or suicidal.
26. Maintenance of a diet consisting of <40 g of carbohydrate per day within 3 months of 
screening.
6
Treatment
6.1
Study treatment
Patients will be randomized to one of the following three treatment arms:
Investigational therapy:

Everolimus tablets for oral suspension (dispersible tablets) with titration to trough range of
3-7 ng/mL

Everolimus tablets for oral suspension with titration to trough range of 9-15 ng/mL
Control therapy:

Placebo
6.1.1
Dosing Regimen
Table 6-1
Dose and Treatment Schedule
Study drugs
Pharmaceutical form and route of administration
Frequency
Route of administration
Everolimus
2 mg tablets for oral suspension
daily (qd)
Oral
Placebo
Matching placebo tablets
daily (qd)
Oral


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Study drug (everolimus or matching placebo) will be dispensed by study center personnel on 
an outpatient basis at Weeks 0, 2, 4, 6, 10, 14 in the Core phase, and at 18, 20, 22, 26, 30 and 
every twelve weeks thereafter in the Extension phase and Post Extension phase. Patients will 
be provided with an adequate supply of study drug for self-administration at home, with 
exception of the days when PK sampling will be performed and drug will be administered at 
the site after the blood draw. The investigator should instruct the patient to take the study drug 
exactly as prescribed (promote compliance). The patient will take the first dose of study drug 
(Day 1) at the center. All dosages prescribed and administered to the patient and all dose 
changes during the study must be recorded on the Dosage Administration Record CRF.
Study drug will be packaged in blister packs, and placed in boxes with color-coded labels of 
color 1 or color 2 in order to maintain the blind. At each visit a patient will receive one or 
multiple boxes of medication of one or both color labeled boxes with either active drug or 
placebo, depending on the arm they were randomized to. During the Post Extension phase, 
only everolimus will be dispensed. See Section 6.5.2.
At the start of the Core phase, IRT will inform the investigator how many tablets from each of 
the Color 1 and Color 2 labeled boxes should be taken to administer the starting dose, as per 
Section 6.1.1.1. Then at Weeks 1, 3 and 5 of the Core phase, all patients will have blood 
samples drawn and sent to a PK lab for determination of the trough level of everolimus, with 
results forwarded to IRT. In turn, IRT will inform the investigator of the dosing for the 
following 2 weeks, in terms of number of tablets to be taken from each of the Color 1 and 
Color 2 labeled boxes, based on the observed everolimus trough level and the targeted trough 
range of the patient’s randomization arm. That is, the dose could be increased, maintained or 
decreased in order to reach and maintain the targeted trough range. For patients in the placebo 
arm, the starting dose will be increased, maintained or decreased according to a randomization 
list, designed to resemble possible titrations on the everolimus arms. PK samples will also be 
taken at weeks 10 and 14 for all patients to monitor whether the targeted trough level is being 
maintained with IRT giving appropriate instructions to change the dose if necessary.
The potential for unmasking the blind is minimized because all patients in each treatment arm 
can receive either or both Color 1 and Color 2 labeled boxes at each visit except 
Randomization, and because patients randomized to the Everolimus Low group (target trough 
3-7 ng/mL) will sometimes have placebo in the Color 1 labeled box and sometimes in the 
Color 2 labeled box. At Randomization only one color labeled box will be dispensed because 
it would be possible to ascertain which box contained active drug due to the formula for the 
starting dose.
At the start of the Extension phase, patients will be assigned to new kit types 
(see Section 6.5.2). From Weeks 18-26 all patients will be transitioned towards a common
targeted trough range of 6 to 10 ng/ml to avoid compromising the blind in the earlier Core 
phase. Starting at Week 26, investigators will be provided with the Cmin results and will be 
permitted to make their own titration decisions.
Patients randomized to one of the two everolimus arms will be transitioned at Week 18 based 
on the prior PK value.


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Placebo patients will start everolimus at Week 18, and be dosed according to the starting dose 
instructions in Section 6.1.1.1. The targeted trough range will be 6 to 10 ng/mL. PK will be 
taken at Week 19 with appropriate titration dosing instructions given at the Week 20 visit.
Patients are expected to approach or be within the planned target trough range of 6 to 10 
ng/ml after the Week 20 titration.
At the Week 26 visit, investigators will be provided with the Week 22 Cmin result, and IRT 
will recommend a dose change using a wider targeted trough range of 3 to 15 ng/ml. 
Investigators will be able to override the IRT recommendation subject to the rules defined in 
Section 6.2.2, although dose increases will not be allowed if Cmin >= 15 ng/ml. Investigator-
led titrations will be possible at all future visits in the extension phase, based on PK samples 
taken at Weeks 26, 30 and every 12 weeks thereafter, until the Core phase results are available, 
and a preferred trough range can be recommended.
For patients who sign informed consent for Amendment 2 of the protocol after completing 
their Week 18 visit, a modified transition schedule will be permitted in the Extension Phase.
This schedule may begin at week 26, 30 or at any subsequent scheduled visit (every 12 weeks
thereafter). At the first such visit, the everolimus dose will be transitioned based on the prior 
PK value using a targeted trough range of 6-10 ng/ml (Transition visit A). The patient will 
return the following week for an everolimus PK sample (Transition visit B), and the following 
week, for disclosure of the PK value (Transition visit C). The investigator may begin to make 
his/her own dose adjustment decisions or rely on the IRT system to prescribe a dose.
For any patient participating in the Post Extension phase, the investigator will have complete 
control over the dosing, although dose increases should not be made if Cmin > 15 ng/ml. 
Investigators will confirm the Cmin value from the last PK drawn and make a decision on 
dosing. The investigator will enter into the IRT, the chosen total daily dose in mg units and 
the IRT system will calculate how many and which kits to dispense to supply the patient until 
the next scheduled visit.
The results of the Core phase analysis should be considered by investigators participating in 
investigator led titrations in the Extension phase and/or Post Extension phase. Based on the 
analysis of the Core phase, it is recommended that the everolimus trough be maintained 
within 5-15 ng/ml, subject to safety and tolerability.
Dosing
Tablets for oral suspension are to be taken as a suspension only, and should not be swallowed 
whole, chewed, or crushed. The suspension can be prepared in an oral syringe or in a small 
drinking glass. Care should be taken to ensure the entire dose is administered. 
See Section 6.5.1.
Everolimus and/or the matching placebo should be administered after a light breakfast in the 
morning. If vomiting occurs, no attempt should be made to replace the vomited dose.
On the days of PK sampling, patients should not take the daily study drug dose until AFTER 
blood work is drawn so that an accurate trough level of everolimus can be obtained. On days 
of scheduled visits, patients should bring their daily dose of study drug into the clinic 
with them for administration after blood work is drawn.


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During the titration periods, in absence of any other reason for holding study drug, study drug 
will be continued for up to 2 weeks while awaiting central PK lab results, which will be used 
to determine if a modification of the dosing regimen is indicated.
Patients should be requested to bring their unused study drug, including the empty blister 
packs, to the clinic at each visit. Compliance should be verified by the investigator’s staff by 
counting the number of tablets consumed between visits. The investigator (or his/her designee) 
will document dosage administration and all dose changes during the study in the eCRF. The 
site must maintain an overall drug accountability log for the study, as well as individual 
accountability records for each patient. The dose, amount dispensed, amount received, and 
amount remaining unused must be recorded in the source document. Drug accountability will 
be noted by the field monitor during site visits and at the completion of the study. The patient 
will return all unused study drug at each dispensing visit and at the end of the study.
6.1.1.1
Starting Dose
Everolimus or matching placebo will be provided to the patient, and the first dose will be 
taken at the site on the day of the Baseline visit (V2) after eligibility is confirmed. Starting 
dose will be determined by the IRT based on the patient’s age and concomitant use of 
CYP3A4/PgP inducers is presented below in Table 6-2.
Patients with TSC associated epilepsy are often treated with CYP3A4 enzyme-inducing 
antiepileptic drugs (EIAEDs) which lead to an increase of everolimus apparent clearance. 
Some of these EIAEDs could also be inducers of PgP.
Different starting doses, taking into account increased everolimus clearance in young patients 
and the use CYP3A4/PgP inducers (regardless of number), will be used as follows:
Table 6-2
Starting dose
Age
Not receiving CYP3A4/PgP inducer
Receiving CYP3A4/PgP inducer
Patients under the age of 10
6.0 mg/m2/day
9.0 mg/m2/day
Patients age 10 to 18
5.0 mg/m2/day
8.0 mg/m2/day
Patients age ≥18
3.0 mg/m2/day
5.0 mg/m2/day
The investigator will enter the patient’s age, height, weight, and CYP3A4/PgP inducer status 
into the IRT system, and the system will calculate the appropriate starting dose. Body surface 
area (BSA), in m2, will be calculated by IRT using the following formula, where weight (W) 
is in kilograms and height (H) is in centimeters (Dubois and Dubois 1916):
BSA = (W0.425 X H0.725) X 0.007184
Once the dose is calculated, the system will instruct the investigator which kit number to 
assign to the patient, and how many tablets should be taken from each color labeled box.
Commonly prescribed EIAEDs that are used in this population include:

Phenytoin (Dylantin®, Dilantin® Kapseals®, Dilantin® Infatabs®, Eptoin®, Epanutin®, 
Diphenin®, Dipheninum®, Phenytek®)

Carbamazepine (Tegretol®, Biston®, Calepsin®, Carbatrol®, Epitol®, Equetro®, Finlepsin®, 
Sirtal®, Stazepine®, Telesmin®, Teril®, Timonil®, Trimonil®, Epimaz®, and Degranol®)

Phenobarbital (Luminal®)


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
Pentobarbital (Nembutal®)

Primidone (Mysoline®)

Oxcarbazepine (Trileptal®)
6.1.2
Rescue medication
In patients with refractory epilepsy, it is known that sometimes patients experience transient 
increases in seizure activity despite best medical management. In such cases, rescue 
medications are permitted.
No new AEDs or changes to existing AED treatment (medication, dose, or frequency) are 
permitted from 28 days prior to screening and throughout the Baseline and Core phase of the 
study. In addition, the study drug should not be increased beyond the protocol-defined limits 
to treat any emerging/increasing epilepsy symptoms.
The choice of rescue medications (e.g., buccal midazolam, rectal diazepam and other 
benzodiazepines) to provide additional seizure control should follow the local institution’s 
practice. For the purpose of this study, rescue medications are only allowed for a period that 
does not exceed 6 cumulative days during the Baseline phase of the study; and does not 
exceed 7 consecutive days or a total of 14 cumulative days during the Core phase of the study. 
During the Extension and Post Extension phases, rescue medications should not be taken for 
more than 14 cumulative days in any 12 week period. Use of rescue medications for a longer 
duration will be considered as a treatment failure and the patient will be discontinued from 
trial therapy.
All rescue medications will be captured on the rescue medications eCRF page.
6.1.3
Treatment duration
Treatment will continue until any of the following take place during the Core Phase the study:
1. Loss of seizure control defined as an increase of 100% in the average weekly number of 
partial-onset seizures for a minimum of 4 consecutive weeks as compared to the average
weekly number of partial-onset seizures during the 8 weeks baseline period.
2. An episode of status epilepticus, defined as:
a. in adults and children 5 years and older -- continuous or intermittent, convulsive 
seizures lasting more than 10 minutes and requiring additional medical intervention 
such as with rescue medication not commonly used in the home (i.e., a convulsive 
seizure or series of convulsive seizures not within the patient’s typical seizure pattern 
and management).
b. in children less than 5 years of age -- continuous or intermittent, convulsive seizures 
lasting more than 10 minutes and requiring significant additional medical intervention 
such as hospitalization (note: It is recognized that some young patients may be sent 
for emergency care despite having experienced a seizure within their typical seizure 
pattern and management. Only the more severe episodes of prolonged convulsive 
seizures in such patient, such as those leading to hospitalization, would qualify as 
status epilepticus)


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3. A single generalized tonic clonic seizure (non-febrile), if none occurred during the 
baseline period, and if one has not occurred within the past year.
4. Use of rescue medications longer than the maximum duration described in Section 6.1.2.
5. Treatment duration completed as per protocol: completion of the Core phase (if patients 
do not accept to start the extension phase), completion of the Extension phase or 
completion of the Post Extension phase.
6. An interruption of one or more of the concomitant AEDs for more than 7 days
Other criteria for withdrawal from the study at any time are:

Discovery of failure of randomization or blinding

Discovery of patient ineligibility

An interruption of study drug that lasts for more than 28 days

Intolerable toxicity.

Pregnancy.

Withdrawal of consent.

In patients who have their dose interrupted for toxicity, if restarting study drug upon 
resolution of the toxicity requires dose reduction, and that reduction results in instruction 
to take 0 tablets for placebo patients during the core phase, or 0 mg of everolimus for 
active drug patients in the Core phase, or 0 mg everolimus for all patients in the Extension
phase and Post Extension phase.
6.2
Dose modification guidelines
6.2.1
Starting dose rationale
The starting doses shown in Table 6-2 for patients in the different age groups were estimated 
based on data from Study M2301. In this study, the geometric mean Cmin values normalized to 
mg/m2 dose were 0.97, 1.27, and 2.13 ng/mL per mg/m2 dose for patients not taking 
CYP3A4/PgP inducer and of ages < 10 years, 10 to <18 years, and ≥18 years, respectively, 
suggesting a higher clearance of everolimus (normalized to BSA) in younger children. Based 
on these dose normalized Cmin values, starting doses of 6.0, 5.0, and 3.0 mg/m2/day for 
patients in the respective age groups are expected to lead to Cmins of 5.82, 6.35, and 6.39 
ng/mL, respectively.
Table 6-3 presents the predicted pre-dose concentration by actual starting dose in each of the 
three age groups for different levels of BSA, for patients not taking CYP3A4/PgP inducers. 
The starting dose is calculated based on BSA and then rounded to the nearest multiple of 2 
(everolimus is provided in 2-mg tablets) as described in Section 6.2.3.
The starting dose for patients receiving CYP3A4/PgP inducers will be increased as per
Table 6-4.


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Table 6-3
Predicted pre-dose concentrations in patients of different age groups 
after the per protocol starting dose
For patients without concomitant use of CYP3A4/PgP Enzyme Inducers (EI):
Age group
BSA 
m2
Starting 
dose 
(mg/m2)
Starting dose 
in mg 
(calculated 
dose)
Starting dose rounded to 
the nearest multiple of the 
2-mg tablet (actual dose)*
Predicted Cmin after 
the rounded 
starting dose 
(ng/mL)
< 10 yr
0.4
6
2.40
2 mg (1 x 2-mg tablet)
4.85
< 10 yr
0.5
6
3.00
4 mg (2 x 2-mg tablet)
7.76
< 10 yr
0.6
6
3.60
4 mg (2 x 2-mg tablets)
6.47
< 10 yr
0.7
6
4.20
4 mg (2 x 2-mg tablets)
5.54
< 10 yr
0.8
6
4.80
4 mg (2 x 2-mg tablets)
4.85
< 10 yr
0.9
6
5.40
6 mg (3 x 2-mg tablets)
6.47
< 10 yr
1.0
6
6.00
6 mg (3 x 2-mg tablets)
5.82
< 10 yr
1.1
6
6.60
6 mg (3 x 2-mg tablets)
5.29
< 10 yr
1.2
6
7.20
8 mg (4 x 2-mg tablets)
6.47
< 10 yr
1.3
6
7.80
8 mg (4 x 2-mg tablets)
5.97
10 to <18 yr
0.9
5
4.50
4 mg (2 x 2-mg tablets)
5.64
10 to <18 yr
1
5
5.00
6 mg (3 x 2-mg tablets)
7.62
10 to <18 yr
1.1
5
5.50
6 mg (3 x 2-mg tablets)
6.93
10 to <18 yr
1.2
5
6.00
6 mg (3 x 2-mg tablets)
6.35
10 to <18 yr
1.3
5
6.50
6 mg (3 x 2-mg tablets)
5.86
10 to <18 yr
1.4
5
7.00
8 mg (4 x 2-mg tablets)
7.26
10 to <18 yr
1.5
5
7.50
8 mg (4 x 2-mg tablets)
6.77
10 to <18 yr
1.6
5
8.00
8 mg (4 x 2-mg tablets)
6.35
10 to <18 yr
1.7
5
8.50
8 mg (4 x 2-mg tablets)
5.98
10 to <18 yr
1.8
5
9.00
10 mg (5 x 2-mg tablets)
7.06
10 to <18 yr
1.9
5
9.50
10 mg (5 x 2-mg tablets)
6.68
10 to <18 yr
2.0
5
10.00
10 mg (5 x 2-mg tablets)
6.35
≥18 yr
1.5
3
4.50
4 mg (2 x 2-mg tablets)
5.68
≥18 yr
1.6
3
4.80
4 mg (2 x 2-mg tablets)
5.33
≥18 yr
1.7
3
5.10
6 mg (3 x 2-mg tablets)
7.52
≥18 yr
1.8
3
5.40
6 mg (3 x 2-mg tablets)
7.10
≥18 yr
1.9
3
5.70
6 mg (3 x 2-mg tablets)
6.73
≥18 yr
2.0
3
6.00
6 mg (3 x 2-mg tablets)
6.39
*This is the dose of active drug. During the study patients may have placebo tablets added and subtracted to 
maintain the blind.
6.2.2
Dose Titration
Table 6-2 describes the starting dose and the dose levels that may be evaluated during this
trial.
Dose will be titrated via Interactive Response Technology (IRT) in a blinded fashion until 
each patient reaches their assigned target trough range. The IRT will indicate from which of 
the 2 labeled boxes (color 1 or color 2) the tablet/s should be titrated or down titrated (to attain 
trough level or adverse events management).


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The titration will be performed as follows:

Any age, NO CYP3A4/PgP inducers: one tablet (2 mg) total increments, regardless of 
BSA

Any age, WITH CYP3A4/PgP inducers: two tablets (4 mg) total increment, regardless of 
BSA. (In cases where a patient is taking 4 mg/day and requires a dose reduction, the 
reduction would be by one tablet (2 mg).)
For example, a 4 year old patient not taking CYP3A4/PgP inducers with a BSA of 0.65:
calculated as 0.65 × 6.0 = 3.9 mg, rounded up to 4 mg (2 tablets). If this patient’s first Cmin is 
below 3 ng/mL, his dose would be adjusted up from 4 mg (2 tablets) by one increment of 2 
mg (1 tablet), for a total daily dose of 6 mg (3 tablets).
Patients on placebo will have random increases and decreases in number of tablets taken to 
simulate titration and to maintain the blind. Patients in the low trough group will also have 
random increases and decreases in placebo tablets to simulate titration for the high trough 
group.
During the extension phase, placebo dose changes will be possible at the start of dose 
transition. Starting at the visit at which everolimus concentrations may be disclosed, placebo 
tablets will no longer be dispensed.
In the Extension phase, from Week 26 onwards when investigator-led dose titration is 
possible, dose changes should continue to be in units of 1 tablet (2 mg) for patients not taking 
CYP3A4/PgP inducers, and 2 tablets (4 mg) for patients taking CYP3A4/PgP inducers. The 
investigator will be allowed full discretion to increase the dose, as long as Cmin does not 
exceed 15 ng/ml and to decrease the dose to a minimum of 1 tablet (2mg) per day. A dose and 
frequency of less than 2 mg/day requires study treatment discontinuation (see Section 7.1.6.1).
In the Post Extension phase, the investigator will have independent control over the dosing to 
increase or decrease the dose. Dose increases should not be attempted if Cmin is ≥15 ng/ml.
6.2.3
Rounding of doses
Starting dose
The starting dose should be rounded up or down to the nearest multiple of 2 mg in order to 
use whole 2-mg tablets. For example:
Table 6-4
Examples for how to dose a patient
Patient 
age
BSA 
m2
CYP3A4/PgP 
inducers?
Starting 
dose 
(mg/m2)
Calculation
Starting 
dose in 
mg
Round
Starting dose rounded 
to nearest multiple 2-
mg tablet*
2
0.5
No
6
0.5 x 6
3.0
Up
4 mg (2 x 2-mg tablet)
9
1.2
Yes
9
1.2 x 9
10.8
Down
10 mg (5 x 2-mg tablets)
22
1.8
No
3
1.8 x 3
5.4
Up
6 mg (3 x 2-mg tablets)
*This will be the active dose. Additional placebo tablets may be added or subtracted to maintain the blind.
If the starting dose in mg is an odd integer (i.e., 1, 3, 5, etc.), then the dose should be rounded 
up to the nearest multiple of 2 mg tablets (e.g., a starting dose of 3 mg would be rounded up to 
4 mg, corresponding to two 2 mg tablets).


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Titration
Titration will be done by whole increments of 2 mg (patients not taking CYP3A4/PgP
inducers) and 4 mg (patients taking CYP3A4/PgP inducers), so rounding will not be necessary.
In the examples above in Table 6-4, patients illustrated in rows 1 and 3 (2 and 22 years of age) 
will be titrated by 1 tablet, whereas the patient in row 2 (9 years old) will be titrated by 2 
tablets.
During the Core phase and Extension phase, trough PK levels will be assessed for the purpose 
of dose titration and assessment of any potential interactions with antiepileptic drugs. For the 
first 6 weeks of the core phase, bi-weekly PK samples are to drawn and analyzed to assist in 
titration. However, in the absence of adverse events requiring a site visit (as assessed by the 
investigator and the patient through telephone contact), and if there are circumstances that 
make it difficult for the patient to go to the site, the PK samples can be taken at a local facility 
and sent to the central laboratory for analysis, provided the study PK kit is used and proper 
labeling, handling, and shipment procedures are followed. This will be done on an exception 
basis only.
6.2.4
Dose reduction or delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Please see Table 6-5,
Table 6-6 and Table 6-7 below for specific guidelines. In all cases, intended dose adjustments 
must be communicated to the IRT. The IRT will give instructions as to the new number of 
tablets to be taken from each blister pack in order to implement the dose adjustment through 
the end of the Extension phase.
The following guidelines need to be applied:

All changes in dose must be recorded on the Dosage Administration Record eCRF.

The study drug at the day of treatment can be administered at full dose, at reduced dose or 
held according to the below dose adjustment Table 6-5, Table 6-6, Table 6-7, Table 6-8, 
Table 6-9 and Table 6-10 and according to the actual instructions from IRT as to the new 
number of tablets to be taken from each blister pack (Core and Extension phases only).
During the Post Extension phase, IRT will dispense kit packs based on the dose 
determined by the investigator.

If the study drug cannot be administered on the scheduled day, the administration of the 
study drug will be skipped until the next day.

If the interruption of study drug lasts for more than 28 days, the patient must be withdrawn 
from the study.


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Table 6-5
Everolimus dose modification guidelines for non-hematologic 
toxicities
Toxicity
Action
Pneumonitis
Please refer to Section 6.2.5.7
Reactivation of HBV or HCV flare
Please refer to Section 6.2.5.8
AST or ALT elevation
Grade 1 (> ULN - 3.0 x ULN)
Grade 2 (> 3.0 - 5.0 x ULN)
Maintain current dose level
AST or ALT elevation
Grade 3 (> 5.0 - 20.0 ULN)*
Interrupt study drug administration until resolution to ≤ grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤ 7 days, study drug should be re-started at the dose 
level prior to interruption.
If resolution takes > 7 days, or if event recurs within 28 days, hold study 
drug until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce study drug 2 tablets less for patients taking CYP3A4/PgP
inducers, or 1 tablet less for patients NOT taking CYP3A4/PgP inducers
AST or ALT elevation
Grade 4 (> 20 x ULN)*
Recurrence of grade 4 after dose 
reduction or toxicity requiring study 
drug interruption for > 28 days
Interrupt study drug administration until resolution to ≤ grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤ 7 days, study drug should be re-started at 2 tablets 
less for patients taking CYP3A4/PgP inducers, or 1 tablet less for 
patients NOT taking CYP3A4/PgP inducers. If resolution takes > 7 
days, discontinue study drug.
Discontinue study drug.
Intolerable grade 2 mucositis (see 
Section 6.2.5.3), or grade 3 AE, except 
hyperglycemia or hypertriglyceridemia 
or hypercholesterolemia (see Section 
6.2.5.6)
Interrupt study drug administration until resolution to ≤ grade 1 or 
baseline grade / value.
If resolution occurs within ≤ 7 days, study drug should be re-started at 
the dose level prior to interruption.
If resolution takes > 7 days, or if event recurs within 28 days, hold study 
drug until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce study drug 2 tablets less for patients taking CYP3A4/PgP
inducers, or 1 tablet less for patients NOT taking CYP3A4/PgP
inducers, if available.
Patients will be withdrawn from the study if they fail to recover to 
grade 1 or baseline grade / value within 28 days.
Any other grade 4
Hold study drug until recovery to grade 1 or baseline value
Reintroduce study drug at one 2 tablets less for patients taking 
CYP3A4/PgP inducers, or 1 tablet less for patients NOT taking 
CYP3A4/PgP inducers, if available.
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma)
Discontinue study drug
Recurrence of intolerable grade 2 
mucositis or grade 3 event after dose 
reduction
Reduce dose by 2 tablets less for patients taking CYP3A4/PgP
inducers, or 1 tablet less for patients NOT taking CYP3A4/PgP
inducers. The lowest possible dose level of study drug is 2 mg daily. 
Below this level, study drug must be discontinued.
Recurrence of grade 4 after dose 
reduction
Discontinue study drug
Any non-hematologic toxicity requiring 
study drug interruption for > 28 days
Discontinue study drug
* Should HCV flare be confirmed, the guidelines for flare must take precedence


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Table 6-6
Dosing guidelines for study drug-related hematologic toxicities
Toxicity
Action
Grade 2 thrombocytopenia
No action
Grade 3 thrombocytopenia
Interrupt study drug until resolution to grade 1
If resolution occurs ≤ 7 days, reintroduce study drug at the dose level 
prior to interruption.
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce study drug reduced 2 tablets less for patients taking 
CYP3A4/PgP inducers, or 1 tablet less for patients NOT taking 
CYP3A4/PgP inducers, if available.
Grade 4 thrombocytopenia
Interrupt study drug until recovery to grade 1. Then reintroduce study 
drug at 2 tablets less for patients taking CYP3A4/PgP inducers, or 1 
tablet less for patients NOT taking CYP3A4/PgP inducers, if available.
Grade 3 neutropenia or anemia
Interrupt study drug until resolution to grade ≤1 or baseline value
If AE resolution occurs ≤ 7 days, reintroduce study drug at the same 
dose level.
If AE resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce study drug 2 tablets less for patients taking CYP3A4/PgP
inducers, or 1 tablet less for patients NOT taking CYP3A4/PgP
inducers, if available.
Grade 4 neutropenia or anemia
Interrupt study drug until recovery to grade 1 or baseline value. 
Reintroduce study drug at 2 tablets less for patients taking 
CYP3A4/PgP inducers, or 1 tablet less for patients NOT taking 
CYP3A4/PgP inducers, if available.
Febrile neutropenia
Interrupt study drug until resolution to grade 1 (or baseline value) and 
no fever. Reintroduce study drug 2 tablets less for patients taking 
CYP3A4/PgP inducers, or 1 tablet less for patients NOT taking 
CYP3A4/PgP inducers, if available.
Recurrence of grade 3 toxicity after 
dose reduction
Reduce dose 2 tablets less for patients taking CYP3A4/PgP inducers, 
or 1 tablet less for patients NOT taking CYP3A4/PgP inducers. The 
lowest possible dose level of study drug is 2 mg. Below this level, study 
drug must be discontinued.
Recurrence of grade 4 toxicity 
(including febrile neutropenia) after 
dose reduction
Discontinue study drug
Any hematologic toxicity requiring 
study drug interruption for > 28 days
Discontinue study drug
6.2.5
Management of specific toxicity
Adverse events most frequently observed with everolimus are rash, stomatitis /oral mucositis, 
non-infectious pneumonitis, fatigue, headache, anorexia, nausea, vomiting, diarrhea, and 
infections. Overall, the most frequently observed laboratory abnormalities include neutropenia, 
thrombocytopenia, hypercholesterolemia, and/or hypertriglyceridemia. The majority of these 
AEs have been of mild to moderate severity (NCI CTC grade 1-2). Recommendations for 
dose adjustments, should any of these treatment-related adverse events occur, are given in
Table 6-5, Table 6-6, Table 6-7, Table 6-9 and Table 6-10.
6.2.5.1
Management of infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 


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fungal infections, such as aspergillosis or candidiasis and viral infections including 
reactivation of hepatitis B virus, have been described in patients taking everolimus. Some of 
these infections have been severe (e.g. leading to sepsis, respiratory or hepatic failure) and 
occasionally have had a fatal outcome.
Physicians and patients should be aware of the increased risk of infection with everolimus. 
Treat pre-existing infections prior to starting treatment with everolimus. While taking 
everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation of 
everolimus.
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat 
with appropriate antifungal therapy.
6.2.5.2
Management of skin toxicity
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with 
the following suggested supportive measures at the discretion of the investigator: oral 
minocycline, topical tetracycline, topical
clindamycin, topical silver sulfadiazine, 
diphenhydramine, oral prednisolone (short course), topical corticosteroids, or pimecrolimus.
6.2.5.3
Management of stomatitis / oral mucositis / mouth ulcers
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis 
must be monitored even more closely. Patients should be instructed to report the first onset of 
buccal mucosa irritation/reddening to their study physician immediately.
Stomatitis/oral mucositis/mouth ulcers due to study drug should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with everolimus as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, 
please classify the adverse event as such. Please follow the paradigm below for treatment of 
stomatitis/oral mucositis/mouth ulcers:
1. For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution.
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate 
oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., 
local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®).
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents.
Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be 


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avoided in all patients due to their strong inhibition of everolimus metabolism, therefore 
leading to higher everolimus exposures. Therefore, topical antifungal agents are preferred if 
an infection is diagnosed.
6.2.5.4
Management of diarrhea
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
supportive care such as loperamide, initiated at the earliest onset (for example 4 mg orally 
followed by 2 mg orally every 2 hours until resolution of diarrhea).
6.2.5.5
Management of amenorrhea
Investigators should be aware of the identified risk of secondary amenorrhea in post-
adolescent females. No changes in study drug treatment or treatment with concomitant 
medications was implemented in prior cases. Nearly all previous cases of amenorrhea for 
patients on study resolved without treatment action. Amenorrhea did not result in any 
treatment discontinuations. If an amenorrhea event of at least 6 months is seen, consultation 
with an endocrinologist, gynecologist or other appropriate medical personnel is recommended.
6.2.5.6
Management of hyperlipidemia and hyperglycemia
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) 
or grade 2 hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 
3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, 
fluvastatin) or appropriate triglyceride-lowering medication, in addition to diet.
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy should 
be determined for individual patients based on their risk of cardiovascular complications of 
hyperlipidemia.
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of study drug and periodically thereafter. Optimal glycemic 
control should be achieved before starting a patient on study drug.
6.2.5.7
Management of non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus. Some of these have been severe and on rare occasions, a fatal outcome was 
observed.
Individuals participating in this trial will be routinely questioned as to the presence of new or 
changed pulmonary symptoms consistent with lung toxicity. Chest X-ray or CT/MRI scan can
be performed if clinically indicated. If non-infectious pneumonitis develops, the guidelines in 
Table 6-7 should be followed. Consultation with a pulmonologist is recommended for any 
case of pneumonitis that develops during the study.


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
A diagnosis of non-infectious pneumonitis should be considered in patients presenting 
with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough 
or dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have been 
excluded by means of appropriate investigations. Patients should be advised to report 
promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and 
have few or no symptoms may continue everolimus therapy without dose alteration.
Table 6-7
Management of non-infectious pneumonitis
Worst grade 
pneumonitis
Required investigations
Management of 
pneumonitis
Study drug dose adjustment
Grade 1
CT scans with lung windows.
No specific 
therapy is required
Administer 100% of study 
treatment dose.
Grade 2
CT scan with lung windows. 
Consider pulmonary function testing 
includes: spirometry, DLCO, and 
room air O2 saturation at rest. 
Consider a bronchoscopy with 
biopsy and/or BAL. Monitoring at 
each visit until return to ≤ grade 1. 
Return to initial monitoring 
frequency if no recurrence.
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy 
if symptoms are 
troublesome.
Reduce study treatment dose by 2 
tablets less for patients taking 
CYP3A4/PgP inducers, or 1 tablet 
less for patients NOT taking 
CYP3A4/PgP inducers until 
recovery to < Grade 1. Study 
treatment may also be interrupted 
if symptoms are troublesome. 
Patients will discontinue study 
treatment if they fail to recover to ≤
Grade 1 within 4 weeks.
Grade 3
CT scan with lung windows and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2
saturation at rest. Monitoring at 
each visit until return to ≤ grade 1. 
Return to initial monitoring 
frequency if no recurrence. 
Bronchoscopy with biopsy and/or 
BAL is recommended.
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as
medically 
indicated.
Hold treatment until recovery to ≤
Grade 1. May restart study 
treatment within 4 weeks at a 
reduced dose (2 tablets less for 
patients taking CYP3A4/PgP
inducers, or 1 tablet less for 
patients NOT taking CYP3A4/PgP
inducers) if evidence of clinical 
benefit.
If toxicity recurs at grade 3, 
consider discontinuation of study 
drug.
Grade 4
CT scan with lung windows and 
required pulmonary function testing, 
if possible, includes: spirometry, 
DLCO, and room air O2 saturation at 
rest. Monitoring at each visit until 
return to ≤ grade 1. Return to initial 
monitoring frequency if no 
recurrence. Bronchoscopy with 
biopsy and/or BAL is recommended 
if possible.
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated.
Discontinue treatment.


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6.2.5.8
Management of hepatitis reactivation / flare
Monitoring and prophylactic treatment for hepatitis B reactivation
Table 6-8 provides details of monitoring and prophylactic therapy according to the screening 
results of viral load and serologic markers testing.
Table 6-8
Action to be taken based on screening hepatitis B results
Test
Result
Result
Result
Result
Result
HBV-DNA
+
+ or -
-
-
-
HbsAg
+ or -
+
-
-
-
HbsAb
+ or -
+ or -
+
and no prior HBV 
vaccination
+ or -
-
or + with prior HBV 
vaccination
HbcAb
+ or -
+ or -
+ or -
+
-
Recommendation
Excluded from the study
No prophylaxis
Monitor HBV-DNA every 4 weeks 
(from Visit 2 and onwards)
No specific action
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug. 
For HBV reactivation definition and management guidelines, see Table 6-9.
Table 6-9
Guidelines for the management of hepatitis B reactivation
HBV reactivation (with or without clinical signs and symptoms)*
For patients with baseline 
results: 
Positive HBV-DNA
OR
positive HBsAg
--------------------------------------
reactivation is defined as:
[Increase of 1 log in HBV-DNA 
relative to baseline HBV-DNA 
value OR new appearance of 
measurable HBV-DNA]
Excluded from study
For patients with baseline 
results:
Negative HBV-DNA and HBsAg
AND
[Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb]
-------------------------------------
Reactivation is defined as:
New appearance of 
measurable HBV-DNA
Treat : Start first antiviral medication
AND
Interrupt study drug administration until resolution:
≤ undetectable (negative) HBV-DNA levels
If resolution occurs within ≤ 28 days, study drug should be re-started at 2 
tablets less for patients taking CYP3A4/PgP inducers, or 1 tablet less for 
patients NOT taking CYP3A4/PgP inducers, if available. If the patient is 
already receiving the lowest dose of study drug according to the protocol, the 
patient should restart at the same dose after resolution. Antiviral therapy 
should continue at least 4 weeks after last dose of study drug.
If resolution occurs > 28 days Patients should discontinue study drug but 
continue antiviral therapy at least 4 weeks after last dose of study drug.
* All reactivations of HBV are to be recorded as grade 3 (CTCAE Version 4.03 - Investigations/Other: Viral 
Reactivation), unless considered life threatening by the investigator, in which case they should be recorded as 
grade 4. Date of viral reactivation is the date on which the rise or reappearance of HBV-DNA was recorded.


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Monitoring for hepatitis C flare
The following category of patients should be monitored every 8 to 12 weeks for HCV flare:

Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’)
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to 
Table 6-10.
Table 6-10
Guidelines for the management of hepatitis C flare
Baseline results
HCV flare definition*
HCV flare management
Detectable HCV-RNA
> 2 log10 IU/mL increase in HCV-RNA
AND
ALT elevation > 5 x ULN or 3 x baseline level, 
whichever is higher.
Excluded from study
Knowledge of past hepatitis C 
infection with no detectable HCV-
RNA
New appearance of detectable HCV-RNA
AND
ALT elevation > 5 x ULN or 3 x baseline level, 
whichever is higher.
Discontinue study drug
* All flares of HCV are to be recorded as grade 3 (CTCAE Version 4.03 - Investigations - Other: Viral Flare), 
unless considered life threatening by the investigator; in which case they should be recorded as grade 4. Date of 
viral flare is the date on which both the clinical criteria described above were met. (e.g., for a patient whose HCV-
RNA increased by 2 logs on 01 JAN 2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the date of viral 
flare is 22 JAN 2011).
6.3
Concomitant medications
Patients must be instructed not to take any medications (over-the-counter or other products) 
during the protocol treatment period without prior consultation with the investigator. The 
investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and blood transfusions) taken from 
the screening visit through the 30-day safety follow up visit must be reported on the
Concomitant Medication/Significant Non Drug Therapies eCRF.
6.3.1
Permitted concomitant therapy requiring caution and/or action
6.3.1.1
CYP3A4 and P-glycoprotein inhibitors/inducers/substrates
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall.
Everolimus is also a substrate of PgP.
For this study patient population, many patients will be taking concomitant CYP3A4/PgP
enzyme inducing drug. Therefore, their PK trough levels will be monitored closely.
Therefore:

Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided.


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
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution. If a patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of study drug to half the 
currently used dose. If the inhibitor is discontinued, consider a washout period of at least 
2-3 days (average for the most commonly used moderate inhibitors), before the study drug 
dose is returned to the dose used prior to initiation of the moderate CYP3A4 and/or PgP 
inhibitor.

Seville oranges, star fruit, grapefruit and their juices affect CYP3A4 and PgP activity. 
Concomitant use should be avoided.

For patients who require co-administration of strong CYP3A4/PgP inducers (i.e., 
phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s wort), the starting 
dose will be increased per Section 6.1.1.1, and titration will be done by 4 mg increments.

This dose adjustment of study drug is intended to achieve similar AUC to the range 
observed without inducers. However, there are no clinical data with this dose adjustment 
in patients receiving CYP3A4/PgP inducers. If the inducer is discontinued, consider a 
washout period of at least 3-5 days (reasonable time for significant enzyme de-induction), 
before the study drug dose is returned to the dose used prior to initiation of the 
CYP3A4/PgP inducer.

Anytime there is a change in inducers or inhibitors of CYP3A4 and/or PgP, trough PK 
levels will be checked and study drug dose will be adjusted accordingly.
Please refer to Table 6-11 listing relevant inducers and inhibitors of CYP3A4 and to Table 6-
12 for a list of relevant substrates, inducers, and inhibitors of PgP. These tables are not all 
inclusive and are only provided as guidance to the investigator.
Everolimus may affect the response to vaccinations making the response to the vaccination 
less effective. Live vaccines, or contact with other who recently received live vaccines, should 
be avoided while a patient is treated with study drug. Everolimus should not be administered 
within 2 weeks of receiving a live vaccine, //cdc.gov/mmwr/pdf/rr/rr6002.pdf.


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Table 6-11
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A4
Inducers
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort, rifabutin, phenobarbital, mitotane, enzalutamide, 
bosentan, efavirenz, etravirine, modafinil, nafcillin, genistein, ritonavir, thioridazine, tipranavir, semagacestat, 
talviraline, lopinavir, lersivirine, amprenavir, aprepitant, armodafinil bexarotene, clobazam, danshen, 
dexamethasone, echinacea, garlic, gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, 
oxcarbazepine, pioglitazone, prednisone, pleconaril, primidone, raltegravir, rufinamide, sorafenib, telaprevir, 
terbinafine, topiramate, troglitazone, vinblastine, eslicarbazepine, ginseng, vemurafenib, boceprevir, 
sulfinpyrazone, ticagleror, vicriviroc/ritonavir, ritonavir, ticlopidine, brivacetam, Stribild (combo of elvitegravir, 
cobicistat, emtricitabine, and tenofovir), quercetin.
Inhibitors
Strong inhibitors:
boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, sequinavir/ritonavir, telaprevir, 
telithromycin, voriconazole, indinavir/ritonavir, tipranoavir/ritonavir, cobicistat, troleandomycin, danoprevir/ritonavir, 
eltegravir/ritonavir
Moderate inhibitors:
amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, 
fosamprenavir, grapefruit juice, nilotinib imatinib, tofisopam, cyclosporin, ciprofloxacin, verapamil, dronedarone, 
crizotinib, casopitant, amprenavir, atazanavir/ritonavir, duranavir, netupitant, schisandra sphenanthera, cimetidine, 
lomitapide
Table 6-12
Clinically relevant drug interactions: substrates, inducers, inhibitors 
of PgP and PgP/CYP3A4 dual inhibitors
Substrates
digoxin, quinidine, paclitaxel, cyclosporine, sirolimus, tacrolimus, fentanyl, pphenytoin
Inducers
avasimibe, carbamazepine, efavirenz, genistein, phenytoin, quercetin, rifampin, St. John’s wort extract
PgP Inhibitors and PgP/CYP3A Dual Inhibitors
alogliptin, amiodarone, azithromycin, canaglifozin, captopril, carvedilol, clarithromycin, conivaptan, cremophor 
RH40, curcumin, diltiazem, dronedarone, elacridar, erythromycin, felodipine, fluvoxamine, ginko, indinavir, 
indinavir/ritonavir, itraconazole, ketoconazole, lapatinib, lopinavir/ritonavir, mibefradil, milk thisle, mirabegron, 
nelfinavir, nifedipine, nitredipine, paroxetine, propafenone, quercetin, quinidine, ranolazine, rifampin, ritonavir, 
sequinavir/ritonavir, schisandra chinesis extract, simepravir, St. John’s wort extract, talinolol, telaprevir, 
telmisartan, ticagrelor, tipranavir/ritonavir, tolvaptan, valspodar, vandetanib, verapamil voclosporin
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated 2015, which summarizes 
DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, the University 
of Washington’s Drug Interaction Database, and Indiana University School of Medicine's Drug Interaction Table.
6.3.2
Prohibited concomitant therapy
No new AEDs or changes to existing AED treatment (medication, dose, or frequency) are 
permitted from 28 days prior to screening and throughout the Baseline and Core phase of the 
study. In addition, the study drug should not be increased beyond the protocol-defined limits 
to treat any emerging/increasing epilepsy symptoms.
Patients may not take any other mTOR inhibitors while on study.


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6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the study. 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 to the investigator.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 
not be reused for any other patient and the Patient No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for 
any reason, the reason will be entered into the Screening Log eCRF. IRT must be notified 
within 2 days of the Baseline visit, that the patient was not randomized.
6.4.2
Treatment assignment or randomization
Patients will be assigned to one of the three treatment arms (Section 6.1) in order to obtain 
115 patients in the placebo arm, 115 patients in the everolimus 3-7 ng/ml trough arm and 125 
patients in the everolimus 9-15 ng/ml trough arm, which corresponds to a ratio of 
approximately 1 : 1 : 1.09. See Section 10.8 for explanation of why 10 additional patients will 
be randomized in the everolimus 9-15 ng/ml arm.
Randomization will be stratified by age subgroup at randomization as follows: (i) 1 to <6 
years; (ii) 6 to <12 years; (iii) 12 to <18 years; and (iv) ≥ 18 years.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization 
list will be produced by or under the responsibility of Novartis Drug Supply Management 
using a validated system that automates the random assignment of medication numbers to 
medication packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and will enter the patient’s age, height, weight, and CYP3A4/PgP inducer status. The IRT 
system will then calculate the appropriate starting dose. The IRT will assign a randomization 
number to the patient, which will be used to link the patient to a treatment arm and will 
specify a unique medication number for the first package of study treatment to be dispensed to 
the patient. The randomization number will not be communicated to the caller.


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6.4.3
Treatment blinding
This is a double-blind study. Patients, investigators, site personnel and the Novartis trial team 
will make every effort to remain blinded to the identity of the treatment from the time of 
randomization until database lock for the Core phase, using the following methods: (1) 
randomization data are kept strictly confidential until the time of treatment unblinding. This 
information will not be accessible to anyone involved in the conduct of the study with the 
exception of the DMC who will perform periodic safety reviews. The DMC independent 
statistician and programmers, producing outputs for the DMC, will remain semi-blinded to the 
treatment groups. (2) the identity of the treatments will be concealed by the use of study 
treatments that are all identical in packaging, labeling, schedule of administration and 
appearance. The following Novartis personnel, all non-members of the study team, will be 
unblinded: PK DMPK/BA (BA monitor), Drug Supply Manager, IRT Trials Account 
Manager, Independent Randomization Expert and Independent PK Expert. In addition, the 
following CRO vendors will be unblinded: for IRT 
 and for PK bioanalysis (
 
.
Unblinding will only occur in the case of patient emergencies (Section 8.3), during safety 
review in the DMC if required (Section 8.6), for regulatory reporting purposes (if requested) 
and at the conclusion of the study.
6.5
Study Drug Supply
6.5.1
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
Everolimus Dispersible Tablets are to be taken as a suspension only and should not be 
swallowed whole, chewed, or crushed. The suspension can be prepared in an oral syringe or in 
a small drinking glass. Care should be taken to ensure the entire dose is administered. Enteric 
feeding tubes may be used.
Administer the suspension immediately after preparation. Discard the suspension if not 
administered within 60 minutes of preparation. Prepare the suspension in water only.
1. Using an oral syringe: The required number of tablets for oral suspension (maximum of 
five 2-mg tablets) should be placed into a 10 mL oral syringe. Do not break or crush 
tablets. The plunger should be inserted and pushed inward to make contact with the
dispersible tablet(s).
2. A sufficient volume of water (approximately 5 mL) should be drawn up from a glass to 
cover the dispersible tablet(s). In addition, approximately 4 mL of air should be drawn up 
into the oral syringe. The filled oral syringe should be placed in a glass (tip up) and the 
contents left to disintegrate for 3 minutes, until the Everolimus Dispersible Tablets are in 
suspension.


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3. Prior to administration, the oral syringe should be inverted gently five times. While 
holding the oral syringe in an upright position (tip up), excess air should be removed 
carefully. The full contents of the oral syringe should be immediately dispensed into the 
mouth of the patient, slowly and gently.
4. The same volume of water and air should then be drawn up into the oral syringe, and the 
contents should be swirled to suspend any remaining particles. The full contents of the 
syringe should be dispensed into the mouth of the patient, slowly and gently.
If more than five tablets are to be dispersed, steps 1 and 2 should be repeated with the 
additional tablets to ensure the entire dose is administered. Step 3 should be repeated after the 
last dispersion.
Using a small drinking glass or cup:
1. The required number of tablets for oral suspension (maximum of five 2-mg tablets) should 
be placed into a small drinking glass (maximum size 100 mL or 3.38 oz.) containing 
approximately 25 mL (.85 oz.) of water. Do not break or crush tablets.
2. The tablets should be left to disintegrate for 3 minutes. The contents should be stirred 
gently with a spoon, immediately prior to drinking.
3. After administering the suspension, the glass should be rinsed with the same volume of 
water and stirred with the same spoon to suspend any remaining tablet particles. The rinse 
should be swallowed to ensure the entire dose is administered.
If more than five tablets are to be dispersed, steps 1 and 2 should be repeated with the 
additional tablets to ensure the entire dose is administered. Step 3 should be repeated after the 
last dispersion.
Of note, anyone who prepares the suspensions for another person should wear gloves to avoid 
possible contact with the drug.
6.5.2
Study drug packaging and labeling
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms. Responsible site 
personnel will identify the study treatment package(s) to dispense to the patient by using the 
IRT and obtaining the medication number(s). Site personnel will add the patient number on 
the labels. Immediately before dispensing the package to the patient, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document (Drug 
Accountability Log) for that patient’s unique patient number.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient.
Study drug will be packaged in blister packs, and placed in boxes with color-coded labels 
color 1 or color 2 in order to maintain the blind. At each visit a patient will receive one or 
multiple boxes of medication of one or both color labels and the contents of each labeled box
will be as follows:


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Table 6-13
Core Phase Treatment
Patients randomized to:
Core Phase Treatment
Everolimus High (target 
trough 9-15 ng/ml)
Color 1 Labeled box = everolimus 2mg tablets & Color 2 Labeled box = everolimus 
2mg tablets
Everolimus Low (target 
trough 3-7 ng/ml)
Color 1 Labeled box = everolimus 2mg tablets & Color 2 Labeled box = matching 
placebo tablets, or
Color 1 Labeled box = matching placebo tablets & Color 2 Labeled box = 
everolimus 2mg tablets
Placebo
Color 1 Labeled box = placebo 2mg tablets & Color 2 Labeled box = matching 
placebo tablets
The potential for unmasking the blind is minimized because all patients in each treatment arm
receive either one or both Color 1 and Color 2 labeled boxes at each visit, and because 
patients randomized to the Everolimus Low group (target trough 3-7 ng/ml) will sometimes 
have placebo in the Color 1 labeled boxes and sometimes in the Color 2 labeled box.
At the start of the Extension phase, patients who were receiving placebo will receive
everolimus. At Week 26 and thereafter, investigators will be permitted to make their own dose 
titrations and only everolimus tablets will be dispensed.
For patients already having completed week 18 of the study at the time of signing the 
informed consent for protocol amendment 2, investigators will also be permitted to make their 
own dose changes, but only after a 2 week titration process that can begin at any upcoming 
scheduled visit on or after week 26. Such patients may continue to receive everolimus and 
placebo tablets, although only everolimus tablets will be dispensed once the Cmin value has 
been shared with the investigator.
Table 6-14
Extension Phase Treatment
Patients originally 
randomized to:
Dispensing Visit
Extension Phase Treatment
Any treatment arm
Before the first visit when 
Cmin is provided to the 
investigator
Color 1 Labeled box = everolimus 2mg tablets & Color 2 
Labeled box = matching placebo tablets
or
Color 1 Labeled box = matching placebo tablets & Color 2 
Labeled box = everolimus 2mg tablets
or
Color 1 Labeled box = everolimus 2mg tablets & Color 2 
Labeled box = everolimus 2mg tablets
On or after the first visit 
when Cmin is provided to 
the investigator
Color 1 Labeled box = everolimus 2mg tablets
or
Color 2 Labeled box = everolimus 2mg tablets
The dosing in the extension phase is designed to minimize the potential for unmasking the 
blind in the earlier Core phase. This is achieved by transitioning all patients to a common 
trough range of 6 to 10 ng/ml before any Cmin value is provided to the investigator, and by 
adding the possibility of placebo tablets being administered to patients in any of the three 
treatment groups during the transition period.


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Table 6-15
Post Extension Phase Treatment
Patients originally 
randomized to:
Dispensing Visit
Extension Phase Treatment
Any treatment arm
Any dispensing visit
everolimus 2mg tablets with Open Label design
As soon as the site is approved for the Post Extension Phase and the patient has signed the 
Informed Consent Form for the Post Extension Phase and related actions are completed in the 
IRT, the system will assign only Open Label boxes to patients based on the selected dose. The 
system is managing the number of kits needed by the patient.
6.5.3
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the [Investigator’s Brochure].
6.5.4
Study drug compliance and accountability
6.5.4.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Log. Information will be collected on the DAR eCRF as to how many tablets 
each patient is taking from the Color 1 blister and the Color 2 blister. This information must 
be captured in the source document at each patient visit. Study site personnel will also affix 
the medication labels to the appropriate source document each time drug is dispensed to a 
patient.
6.5.4.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the field monitor or to the Novartis address provided in 
the investigator folder at each site.


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6.5.4.3
Handling of other study treatment
Not applicable.
6.5.5
Disposal and destruction
Upon approval from Novartis personnel, the study drug supply can be destroyed at the local 
Novartis facility, Drug Supply group or third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-2 list all of the assessments and indicate 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 eCRF will be used as a source document. The category in 
table indicates which data are entered into the database (D) or remain in source documents 
only (S).
Tests, procedures and visits should occur on schedule whenever possible. However, test, 
procedures and visit that occur within the prescribed allowance windows indicated in Table 7-
1 and Table 7-2 will not constitute protocol deviations.


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Section
Screening
Baseline
Core Phase
EoT 
Core
(11)
Extension Phase 
(visits every 12 weeks 
after #16)
Transition
Visits8
End of 
treatment 
Extensio
n (EoT)
Follow 
up/Study 
Completio
n
Visit Number
1
2
3
4
5
6
7
8
9
10
777
12
13
14
15
16+
201
202
778
779
Study Week
-8
0
1
2
3
4
5
6
10
14
18
19
20
22
26
8
308+
within 7 days of 
stopping study 
drug
30 days after EOT
-2 to +4 wks*
56 to 70 days 
after V1*
± 2 days
± 7 
days
± 2 days5
± 2 
days
± 7 days
Obtain Informed 
Consent
D
11.3
X
IRT Registration
S
7.2.4.2.1
X
Demography
D
7.1.1.3
X
Inclusion/exclusion 
criteria
D
7.2.1.5
X
X4
Screen failure log 
as needed
D
7.1.1.2
X
X
Relevant medical 
history/current 
medical conditions
D
7.2.1.1
X
Diagnosis of TSC
D
7.2.1.2
X
Prior anti-TSC 
therapy
D
7.2.1.3
X
Seizure history
D
7.2.1.1
X
Previous AED 
therapy
D
7.2.1.4
X


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Category
Protocol 
Section
Screening
Baseline
Core Phase
EoT 
Core
(11)
Extension Phase 
(visits every 12 weeks 
after #16)
Transition
Visits8
End of 
treatment 
Extensio
n (EoT)
Follow 
up/Study 
Completio
n
Visit Number
1
2
3
4
5
6
7
8
9
10
777
12
13
14
15
16+
201
202
778
779
Study Week
-8
0
1
2
3
4
5
6
10
14
18
19
20
22
26
8
308+
within 7 days of 
stopping study 
drug
30 days after EOT
-2 to +4 wks*
56 to 70 days 
after V1*
± 2 days
± 7 
days
± 2 days5
± 2 
days
± 7 days
Current AED 
therapy
D
7.2.2.3
X
Concomitant 
medications
D
7.2.3.9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue 
medications
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IRT Randomization
S
7.2.1.6
X
Physical 
examination
S
7.2.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological exam
S
7.2.3.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact Epilepsy 
Study Consortium
S
7.1.1
X
Distribute Seizure 
Diary
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
Seizure data from 
diary
D
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
Height7
D
7.2.3.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Parental height
D
7.2.3.6
X
Weight
D
7.2.3.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Category
Protocol 
Section
Screening
Baseline
Core Phase
EoT 
Core
(11)
Extension Phase 
(visits every 12 weeks 
after #16)
Transition
Visits8
End of 
treatment 
Extensio
n (EoT)
Follow 
up/Study 
Completio
n
Visit Number
1
2
3
4
5
6
7
8
9
10
777
12
13
14
15
16+
201
202
778
779
Study Week
-8
0
1
2
3
4
5
6
10
14
18
19
20
22
26
8
308+
within 7 days of 
stopping study 
drug
30 days after EOT
-2 to +4 wks*
56 to 70 days 
after V1*
± 2 days
± 7 
days
± 2 days5
± 2 
days
± 7 days
Vital signs
D
7.2.3.7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tanner Staging6
D
7.2.3.4
X
X
X
X2
X2
Developmental 
milestones6
D
7.2.3.5
X
X
X
X2
X2
EOT (Core and 
Extension)
D
7.1.6
X
X
Pregnancy History, 
Menstrual History 
D
7.2.3.6
X
Distribute 
Menstrual Diary
S
7.2.3.6
X
X
X
X
X
X
X
X
X
X
X
X
Menstrual 
Monitoring
D
7.2.3.6
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
assessments
7.2.3.11
Hematology
D
7.2.3.11.
1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.3.11.
2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endocrine tests
D
7.2.3.11.
3
X
X
X
X
X


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Category
Protocol 
Section
Screening
Baseline
Core Phase
EoT 
Core
(11)
Extension Phase 
(visits every 12 weeks 
after #16)
Transition
Visits8
End of 
treatment 
Extensio
n (EoT)
Follow 
up/Study 
Completio
n
Visit Number
1
2
3
4
5
6
7
8
9
10
777
12
13
14
15
16+
201
202
778
779
Study Week
-8
0
1
2
3
4
5
6
10
14
18
19
20
22
26
8
308+
within 7 days of 
stopping study 
drug
30 days after EOT
-2 to +4 wks*
56 to 70 days 
after V1*
± 2 days
± 7 
days
± 2 days5
± 2 
days
± 7 days
Lipid Panel
D
7.2.3.11.
4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis testing
D
7.2.3.12, 
7.2.3.13
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
D
7.2.3.11.
5
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy 
test
D
7.2.3.11.
6
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
test
D
7.2.3.11.
6
X
X
X
Anti-Mullerian 
Hormone
D
7.2.3.11.
7
X
X
X9
X9
ECG
D
7.2.3.16.
1
X
MRI1
D
7.2.3.14
X
X
EEG1
D
7.2.3.15
X
X
Safety
Adverse events
D
8.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient reported 
Outcomes
7.2.5


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Category
Protocol 
Section
Screening
Baseline
Core Phase
EoT 
Core
(11)
Extension Phase 
(visits every 12 weeks 
after #16)
Transition
Visits8
End of 
treatment 
Extensio
n (EoT)
Follow 
up/Study 
Completio
n
Visit Number
1
2
3
4
5
6
7
8
9
10
777
12
13
14
15
16+
201
202
778
779
Study Week
-8
0
1
2
3
4
5
6
10
14
18
19
20
22
26
8
308+
within 7 days of 
stopping study 
drug
30 days after EOT
-2 to +4 wks*
56 to 70 days 
after V1*
± 2 days
± 7 
days
± 2 days5
± 2 
days
± 7 days
Seizure diaries
S
7.2.2.1
X
X
X
X
X X
X X
X
X
X
X
X
X
X
X
X
X
X
WNV2
D
7.2.3.1
X
X
X2
X
Vineland2
D
7.2.3.1
X
X
X2
X
QOL
D
7.2.5
X
X
X
eC-SSRS
D
7.2.3.10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
administration via 
IRT recorded on 
Everolimus/Placeb
o DAR
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
AED administration 
recorded on AED 
DAR
D
7.2.2.3
X`
X
X
X
X
X
X
X
X
X
X
X
X
Everolimus PK 
sampling 
D
7.2.4
X
X
X
X
X
X
X
X
X
X
X
X
AED PK sampling
D
7.2.4
X
X
X
X


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Category
Protocol 
Section
Screening
Baseline
Core Phase
EoT 
Core
(11)
Extension Phase 
(visits every 12 weeks 
after #16)
Transition
Visits8
End of 
treatment 
Extensio
n (EoT)
Follow 
up/Study 
Completio
n
Visit Number
1
2
3
4
5
6
7
8
9
10
777
12
13
14
15
16+
201
202
778
779
Study Week
-8
0
1
2
3
4
5
6
10
14
18
19
20
22
26
8
308+
within 7 days of 
stopping study 
drug
30 days after EOT
-2 to +4 wks*
56 to 70 days 
after V1*
± 2 days
± 7 
days
± 2 days5
± 2 
days
± 7 days
Offer inclusion into 
extension phase
S
4.1.3,
7.1.4
X
Offer inclusion into 
the post extension 
phase
S
4.1.4,
7.1.5
X


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Category
Protocol 
Section
Screening
Baseline
Core Phase
EoT 
Core
(11)
Extension Phase 
(visits every 12 weeks 
after #16)
Transition
Visits8
End of 
treatment 
Extensio
n (EoT)
Follow 
up/Study 
Completio
n
Visit Number
1
2
3
4
5
6
7
8
9
10
777
12
13
14
15
16+
201
202
778
779
Study Week
-8
0
1
2
3
4
5
6
10
14
18
19
20
22
26
8
308+
within 7 days of 
stopping study 
drug
30 days after EOT
-2 to +4 wks*
56 to 70 days 
after V1*
± 2 days
± 7 
days
± 2 days5
± 2 
days
± 7 days
Study completion 
CRF
D
7.1.7
X
* All procedures for screening visit must be performed within -2 weeks to + 4 weeks of Visit 1. All procedures for Baseline visit must be performed within -2 days of 
Baseline visit (V2) and occur prior to first dose.
1 MRI and EEG will only be performed at select sites during the study. Please refer to protocol Appendix A for more information
2 WNV, Vineland, Tanner Staging, Developmental milestones, will be completed every 6 months after End of Core, i.e., Week 42, Week 66 etc. Although there is an “X” in 
the Visit 16+ column, these assessments will not be done at Visit 16 because 6 months will not have passed since EOT Core Visit 11 (777).
3
4 Eligibility related to lab criteria will be based on central lab results from the Screening visit.
5 +/- 7 days for permanent discontinuation. 
6 Tanner staging is not required after 2 consecutive assessment scores of Stage 5 on both assessments. Tanner Staging will occur at Baseline only for patients who enter 
the study with Stage 5 for both assessments. Developmental milestones will be completed at the same time and frequency as Tanner Staging.
7 Height is to be performed for adults at full development only at screening visit. Patients who are still growing will measure height at all visits.
8 Please refer to Section 4.1.3 for details and actions to be performed when transitioning patients to 6 to 10 ng/ml starting at visits 26, 30+ in the Extension Phase
9 AMH will be tested in females ≥10 years of age at Baseline, EOT core, Week 54 and every 48 weeks thereafter.


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Table 7-2
Visit Evaluation Schedule: Post Extension Phase
Category
Protocol 
Section 
Post Extension Phase Visits
(every 12 weeks)
End of treatment
Post Extension (EoT)
Follow up/Study Completion
Visit Number
401, 402, 403+
±7 days
780
±7 days
779
Obtain Informed 
Consent 1
S
11.3
X
Physical examination
S
7.2.3.2
X
X
Tanner Staging2
D
7.2.3.4
X
Development 
Milestones2
D
7.2.3.5
X
Neurological exam
S
7.2.3.3
X
X
Height
D
7.2.3.8
X
X
Weight
D
7.2.3.8
X
X
Vital signs
D
7.2.3.7
X
X
EOT (Post Extension)
D
7.1.6
X
Laboratory 
assessments
7.2.3.11
Hematology
D
7.2.3.11.1
X
X
Chemistry
D
7.2.3.11.2
X
X
Endocrine tests
D
7.2.3.11.3
X
X
Lipid Panel
D
7.2.3.11.4
X
X
Hepatitis testing
(if indicated)
D
7.2.3.12, 
7.2.3.13
X
X
X
Urinalysis
D
7.2.3.11.5
X
X


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Category
Protocol 
Section 
Post Extension Phase Visits
(every 12 weeks)
End of treatment
Post Extension (EoT)
Follow up/Study Completion
Visit Number
401, 402, 403+
±7 days
780
±7 days
779
Urine Pregnancy test
D
7.2.3.11.6
X
X
Serum Pregnancy 
test3
D
7.2.3.11.6
X*
X
Anti-Mullerian 
Hormone
D
7.2.3.11.7
X
X
ECG
D
7.2.3.16.1
If clinically indicated
Safety
Adverse events
D
8.1
X
X
X
eC-SSRS/ 
Assessment of Mood 
and behavior
D
7.2.3.10
X
X
Assessment of 
changes in seizure 
presentation
D
7.2.3
X
Study Drug 
administration via IRT 
recorded on 
Everolimus DAR
D
7.2.2.2
X
AED administration 
recorded on AED 
DAR
D
7.2.2.3
X
X
Everolimus PK 
sampling 4
D
7.2.4
X
Concomitant 
medications
D
7.2.3.9
X
X
X


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Category
Protocol 
Section 
Post Extension Phase Visits
(every 12 weeks)
End of treatment
Post Extension (EoT)
Follow up/Study Completion
Visit Number
401, 402, 403+
±7 days
780
±7 days
779
Rescue medications
D
7.2.2.4
X
X
X
Study completion 
CRF
D
7.1.7
X
1 Amendment 3 informed consent to be signed prior to first Post Extension phase visit.
2 Tanner staging is not required after 2 consecutive assessment scores of Stage 5 on both assessments. Tanner staging and developmental milestones will continue to 
be completed every 6 months.
3 Serum pregnancy test required to confirm any positive urine test
4 Additional PK required as per Section 4.1.4


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7.1.1
Screening
The informed consent must be signed prior to any screening procedure. The informed consent 
will provide information on study requirements and study procedures.
During the Screening visit (V1 /Week -8), the patient demographics and medical history, 
including TSC diagnosis, prior anti-TSC therapy, seizure history and prior AED use will be 
assessed. A physical and neurological examination will be performed, as well as assessments 
for height, weight, vital signs, and risk of suicide using the eC-SSRS. Laboratory tests for 
hematology, chemistry, hepatitis, lipids, urinalysis, and pregnancy will be assessed. Also, PK 
sampling for the specified AEDs will be collected. An ECG will also be performed at 
screening. For applicable patients, all available pre-baseline height and weight data should be 
collected in order to adequately represent the patient’s rate of growth prior to starting the 
study.
In addition, inclusion and exclusion criteria will be evaluated. The patient should also be 
registered into the IRT system as described in the IRT Manual.
The Epilepsy Study Consortium
As part of screening, investigators will be asked to complete a detailed description of each patient’s 
seizures along with the seizure classification on a form that will be faxed to the Epilepsy Study 
Consortium.
A reviewer at the Consortium will review the form and provide feedback about the patient’s 
seizure classification to the Investigator.
Rescreening
Reassessment of any screening criteria is permitted for previously screen failed patients.
Patients who did not meet the required seizures counts during the baseline phase would need 
to wait at least 3 months before re-screening. Reassessment of screening criteria is permitted 
for patients whose laboratory values changed since initial screening as long as all screening 
procedures are performed within the specific screening time window. The re-test value must 
be normal at least two weeks prior to randomization.
Screening for hepatitis B
Prior to randomization, the following three categories of patients should be tested for hepatitis 
B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc Ab:

All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal and Greece.
[nc.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849]

Patients with any of the following risk factors:

known or suspected past hepatitis B infection,

blood transfusion(s) prior to 1990,

current or prior IV drug users,

current or prior dialysis,


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
household contact with hepatitis B infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos,

mother known to have hepatitis B,

history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper 
quadrant pain.

Additional patients at the discretion of the investigator
Patients with serological markers indicative of prior hepatitis B will be excluded from the 
study.
The management guidelines, in Section 6.2.5.8, are provided according to the results of the 
baseline assessment of viral load and serological markers for hepatitis B.
Screening for hepatitis C
Patients with any of the following risk factors for hepatitis C should be tested using 
quantitative RNA-PCR:

known or suspected past hepatitis C infection (including patients with past interferon 
‘curative’ treatment),

blood transfusions prior to 1990,

current or prior IV drug users,

current or prior dialysis,

household contact of hepatitis C infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos.
At the discretion of the investigator, additional patients may also be tested for hepatitis C.
The management guidelines, in Section 6.2.5.8, are provided according to the results of the 
baseline assessment of hepatitis C viral load.
For other screening assessments refer to Table 7-1.
7.1.1.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT 
system. Please refer and comply with detailed guidelines in the IRT manual.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be randomized for any reason will be 
considered a screen failure. The reason for not being randomized will be entered on the 
Screening 
Failure 
Log. 
The 
demographic 
information, 
informed 
consent, 
and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Baseline Phase (see Section 8 for SAE 


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reporting details). Any data other than these that are entered by the site into the database will 
not be deleted, but they will not be included for analysis. If the patient fails to be randomized, 
the IRT must be notified within 2 days of the screen fail that the patient was not randomized.
7.1.1.3
Patient demographics and other baseline characteristics
Data will be collected on patient characteristics, including demographic information (age, sex, 
ethnicity, race, weight) and other background or relevant medical history (seizure type and 
frequency, date of epilepsy diagnosis, and treatment history). Information will also be 
collected regarding child-bearing potential, TSC diagnosis, TSC genetic testing, and any other 
assessments that are done for the purpose of eligibility for inclusion into the study (physical 
and neurological examination, vital signs, hematology and blood chemistry, urinalysis, 
pregnancy test, ECG, and suicide risk assessed by the eC-SSRS). The prior and current AED 
and concomitant medication use, including VNS and ketogenic diet, will also be collected and 
recorded. For further details on eligibility assessments, please see Table 7-1.
7.1.2
Baseline phase
The baseline phase consists of a screening visit (V1) at week -8 through the baseline visit (V2) 
at week 0. For more information on the screening visit, please see Section 7.1.1. During this 
phase, patients should keep track of any seizures in the seizure diaries and any change in 
AEDs taken during this time.
Baseline visit
During the baseline visit, inclusion and exclusion criteria will be re-assessed, (central lab 
results from the Screening visit), along with other assessments outlined in Table 7-1.
performed prior to first dose The use of seizure rescue medication from time of screening to 
baseline will also be collected. If a patient requires rescue medication for 7 or more
cumulative days during the Baseline phase, they will not be able to continue to the Core phase 
of the study. A physical and neurological exam will be performed, as well as assessments for 
height, weight, vital signs, tanner staging, and laboratory tests (hematology, chemistry, lipids, 
hepatitis, endocrine function, urinalysis, and pregnancy). 
 
 
 
The patient’s seizure history 
and AED use from screening to baseline will be assessed from the seizure diaries. In addition, 
assessments for developmental milestones, suicidality, quality of life and neuropsychological 
assessments will be performed. Also, pregnancy history, menstrual history, and mother’s 
reproductive history, and assessment of parental height will be conducted.
Adverse events and concomitant medications will also be assessed at this visit. For patients 
participating in the MRI substudy, an MRI and EEG will also be conducted at the Baseline 
visit. For more information on the MRI and EEG substudy, please see Appendix A.
All patients who continue to meet eligibility criteria at the baseline visit (V2), including 
demonstrating the minimum seizure frequency during the 8-week baseline phase (see Section 
5.2), will be randomized in a 1:1:1.09 ratio to one of the three treatment arms as described in 
Section 6.1. The patient should be randomized via the IRT system as described in the IRT 


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manual. At that time, study medication pack details and administration guidelines will be 
provided. Also, the first dose of study drug should be administered.
7.1.3
Core phase
The Core phase begins at the baseline visit (Visit 2) and continues up to and includes Visit 11 
(week 18), at which time the patient would be offered inclusion into the extension phase.
At Weeks 2 (V4), 4 (V6), 6 (V8), 10 (V9), 14 (V10), and 18 (V11); assessments will include 
seizure diaries, use of AED medications, and suicidality risk. Other assessments include use 
of rescue medications, physical and neurological exams, and height, weight, vital signs, and 
laboratory tests (hematology, chemistry, lipids, hepatitis, and urinalysis). If applicable, 
pregnancy testing and/or hepatitis testing will be assessed approximately every month.
Endocrine testing will be done every 12 weeks.
At each visit during the Core phase, study drug titration (if applicable) and dosing will also 
occur. Adverse events, concomitant medications, and drug accountability will also be assessed 
at each visit.
Pharmacokinetic testing will be performed at various visits throughout the core phase for 
dosing and titration purposes. For more information on PK testing, see Section 7.2.4. Only at 
the Week 14 (V10) visit during the Core Phase, development milestones and Tanner staging 
will be assessed.
The end of treatment (EOT) in the Core Phase is at Week 18 (Visit 11). In addition to the 
assessments above, at this visit, neuropsychological and quality of life assessments will be 
performed.
For more information about assessments, please see Table 7-1.
7.1.4
Extension phase
All patients who complete the Core phase will be offered continuation on the Extension phase, 
during which all the patients will receive everolimus at Week 18 [(V11) same visit as end of 
Core and start of extension)]. Patients will enter into this phase upon completion of the core 
phase, and will continue in the Extension phase until 48 weeks after the last patient completes 
the core phase. (Patients enrolled earlier in the study may remain in the Extension phase for 
more than 1.5 years.)
During the Extension phase, visits will be at Weeks 18 (V11), 19 (V12), 20 (V13), 22 (V14), 
26 (V15), and 30 (V16), and then every 12 weeks thereafter, unless additional visits are 
clinically indicated. For patients signing the informed consent for Amendment 2 after 
completing the week 18 visit, at least two additional visits will be added for the purpose of 
transitioning towards a trough concentration range of 6-10 ng/ml.
Assessments during the extension phase should be performed pre-dose and include seizure 
diaries, use of AED medications, and suicidality risk will also be assessed and recorded. Other 
assessments include use of rescue medications, physical and neurological exams, and height, 
weight, 
vital 
signs, 
and 
laboratory 
measurements
(including 
pregnancy 
tests).
Pharmacokinetic testing for everolimus will be performed at all visits throughout the 
extension phase, except at Week 20.


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In the Extension phase, development milestones and Tanner staging will be done as outlined 
in Table 7-1. Menstrual monitoring will be assessed every month (if applicable).
At each visit during the Extension phase, study drug titration (if applicable) and dosing will 
also occur. Adverse events, concomitant medications, and drug accountability will also be 
assessed at each visit.
At the end of the Extension phase, an end of treatment visit will occur as described in Section 
7.1.6 and Table 7-1.
For more information about assessments, please see Table 7-1.
7.1.5
Post Extension phase
All patients continuing to receive clinical benefit at the completion of the Extension phase 
will be offered continued treatment in the Post Extension phase. During the Post Extension 
phase, visits will occur every 12 weeks unless additional visits are clinically indicated. 
Investigators will have control over patient dosing and should follow the guidance outlined in 
Section 6. Modified safety assessments will be performed as described in Table 7-2.
7.1.6
End of treatment visit and premature withdrawal
Premature withdrawal
Patients may voluntarily withdraw from the study or be dropped from the study at the 
discretion of the investigator at any time. For more detailed information, please see Section 
7.1.6.1
End of treatment (EOT)
There are three time points at which an EOT eCRF can be completed for each patient. One 
will be at Visit 11/Week 18, marking the end of the Core phase of the study. A second will be 
when the patient completes the study treatment in the Extension Phase and the third will be 
when the patient completes the Post Extension phase. At the time patients discontinue study 
treatment, a visit should be scheduled as soon as possible, at which time all of the assessments 
listed for the End of Treatment (EOT) visit will be performed (Core,  Extension or Post 
Extension as applicable). An End of Treatment eCRF page should be completed, giving the 
date and reason for stopping the study treatment.
During the EOT visits, assessments will include collection of concomitant and rescue 
medications, physical and neurological exam, height, weight, vital signs, and laboratory tests 
assessments, including a pregnancy test, the use of AED medications, and the risk of 
suicidality. For the Core and Extension phase EOT visits, seizure diary review,  quality of life 
and neuropsychological assessments will also be performed, and menstrual monitoring will be 
reviewed as applicable.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment.


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Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
If a study withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the End of Treatment eCRF.
The Investigator must contact the IRT to register the subject’s discontinuation.
End of treatment/Premature withdrawal visit is not considered as the end of the study.
7.1.6.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients should be withdrawn from the study if any of the 
following occur:

Pregnancy

Discovery of failure of randomization or blinding

Discovery of patient ineligibility

An interruption of study drug that lasts for more than 28 days.

Intolerable toxicity

Withdrawal of Consent

In patients who have their dose interrupted for toxicity, if restarting study drug upon 
resolution of the toxicity requires dose reduction, and that reduction results in instruction 
to take 0 tablets for placebo patients during the core phase, or 0 mg everolimus for active 
drug patients in the Core phase, or 0 mg everolimus for all patients in the Extension and 
Post Extension phases.
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation during the Core Phase:

Loss of seizure control defined as an increase of 100% in the average weekly number of 
partial-onset seizures for a minimum of 4 consecutive weeks as compared to the average 
weekly number of partial-onset seizures during the 8 weeks baseline period.

An episode of status epilepticus, defined as: in adults and children older than 5 years --
continuous or intermittent, convulsive seizures lasting more than 10 minutes and requiring 
additional medical intervention such as with rescue medication not commonly used in the 
home (i.e., a convulsive seizure or series of convulsive seizures not within the patient’s 
typical seizure pattern and management).

A single generalized tonic clonic seizure (non-febrile), if none occurred during the 
baseline period, and if one has not occurred within the past year.

Use of rescue medications longer than the maximum duration described in Section 6.1.2.

An interruption of one or more of the concomitant AEDs for more than 7 days.


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
Treatment duration completed as per protocol: completion of the Core phase (if patients 
do not accept to start the extension phase), completion of the Extension phase (if patients 
do not accept to start the post extension phase) or completion of the Post Extension phase.
At the start of the Extension Phase, during the transition to investigator control of everolimus 
dosing, and while the everolimus Cmin value is still not shared with the investigator, the 
investigator should consider managing clinical deterioration in seizure control (as judged by 
the investigator), if it should occur, by modifying AED doses or adding or subtracting AEDs.
Starting at week 26, when everolimus Cmin values are made available to the investigator, the 
investigator may manage a patient’s clinical deterioration by modifying AED doses, adding 
and or subtracting AEDs and modifying everolimus dosing in whatever order or combination 
the investigator chooses.
Patients who are withdrawn prematurely will have an End of Treatment visit as close as 
possible to the day that study drug is stopped. There will then be a follow-up visit 30 days 
after study drug is stopped.
7.1.7
Follow up/Study completion
All patients will be followed for adverse events and serious adverse events for at least 30 days 
following the last dose of study treatment. At the end of this period, the investigator should 
follow up with the patient about any adverse event observed/concomitant medication taken 
during this period either in person (for patients who have continuing adverse events) or via a 
phone visit (for patients who do not have continuing adverse events. Also, patients who are 
being followed for possible hepatitis flare ups will have an office visit where they will be 
tested for hepatitis for the final time in the study. Female patients of child bearing potential 
will perform a urine pregnancy test at home and report the results at this follow up.
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first. In case the patient has any abnormal laboratory values at end of 
treatment that are considered clinically significant by the investigator, the patient needs to 
come to the site for repeat blood analysis until resolution or stabilization including at least a 
site visit with respective analyses 30 days after end of treatment.
For more information on follow up procedures, please refer to Table 7-1.
Patients lost to follow up should be recorded as such on the eCRF. 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.


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7.2
Assessment types
7.2.1
Eligibility assessments
7.2.1.1
Patient History
A detailed patient history will be taken, to include seizure history, TSC history and any TSC-
related problems, major illness, surgeries, concomitant conditions. This information, including 
dates of diagnosis and whether or not the condition is still present will be recorded on the 
Relevant Medical History eCRF.
7.2.1.2
Diagnosis of TSC
Each patient must have a documented diagnosis of TSC per the modified Gomez criteria. See
Section 5.2, Inclusion criterion #2. This diagnosis will be recorded on the TSC Diagnosis 
eCRF.
7.2.1.3
Prior anti-TSC therapy
A history should be taken from each patient to document any previous anti-TSC therapy taken.
This information will be recorded on the Prior TSC therapy eCRF. Patients may not have been 
on prior anti-TSC therapy within 24 months of randomization, unless they were treated with a 
topical mTOR inhibitor, in which case the washout time is 4 weeks.
7.2.1.4
Prior AED therapy
Each patient will be questioned to get a history of prior anti-epileptic drug therapy to ensure 
that the inclusion criterion 4B is met, and the failed therapies recorded. These prior therapies 
will be documented on the Prior AED therapy eCRF.
7.2.1.5
Inclusion/Exclusion criteria
Once all screening procedures have been completed, and the laboratory results are back from 
the central lab, the patient’s results should be compared with the list of Inclusion/Exclusion 
Criteria in Section 5.2 and Section 5.3. If all criteria aremet at the Baseline visit (using lab 
results from screening visit), the patient may be randomized to receive study drug. The 
eligibility questionnaire must be completed per the IRT manual in order to initiate therapy.
7.2.1.6
IRT randomization
When screening procedures are complete, and eligibility is confirmed, the patient will be 
entered into the IRT system to be randomized and have their first drug package assigned. This 
will be done per the IRT manual.


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7.2.2
Efficacy assessments
7.2.2.1
Seizure diaries and counts
The investigator will review patient-specific seizure types and descriptions with the patient or 
caregiver at the screening visit, in order to ensure that all events are appropriately recorded 
throughout the study (the investigator may believe that some stereotypical events are not 
likely to be seizures, but for patient safety, and to limit patient confusion, the investigator may 
instruct the patient to record and count such events as well). Events will be counted daily by 
the patient or caregiver, following the Screening Visit, and entered into the diary by date, with 
seizures lasting more than 10 minutes being noted. The investigator will define a list of 
“probable seizures” in consultation with the Epilepsy Study Consortium (see Section 7.1.1) 
after the Screening Visit. Only events characterized as “probable seizures” by the investigator 
will be entered with their frequencies into the investigator portion of the diary, which will 
then be entered into the eCRF.
7.2.2.2
Study drug administration
At each study visit, the site will log into the IRT system to get the next drug assignment for 
each patient. The assigned number package will be dispensed to the patient. The tear off 
portion of the label will be affixed to the patient-specific drug accountability log. The 
specifics of the drug administration will be recorded on DAR eCRF.
7.2.2.3
AED therapy and administration
Patients must be taking one to three concomitant AEDs during the baseline and core phases of 
the study. These medications will be recorded on the AED DAR eCRF. The specific drugs 
and doses of these medications may not change 28 days prior to the screening visit and
through the core phase of the study.
The name, dose, and frequency of concomitant AED therapy will be asked about at every visit.
Any changes will be recorded on the AED DAR eCRF.
7.2.2.4
Rescue medications
Rescue medications are permitted as per Section 6.1.2. Any use of rescue medications will be 
recorded on the Rescue Medications eCRF.
7.2.3
Safety and tolerability assessments
Safety will be monitored by assessing as well as collecting the adverse events at every visit
until the study completion visit. For details on AE collection and reporting, refer to Section 8.
Risk of suicide will be assessed at each visit until the End of Treatment Visit of the Post 
Extension phase. Neurobehavioral, neurodevelopment, and neurocognitive assessments, will 
also be collected and assessed as part of safety monitoring during the Core and Extension 
phases only. In the Post Extension phase, as part of safety monitoring, assessments of changes 
in seizure presentation (i.e. frequency, intensity and/or development of new seizure types) will 
be collected.


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7.2.3.1
Neurobehavioral, neurodevelopmental, and neurocognitive 
assessments
Wechsler Non-Verbal Scale of Ability
All patients aged >4 and <22 will undergo three subtests from the WNV 4-Subtest Battery at 
Baseline, at completion of the Core phase (EoT Core/Visit 11/Week 18), and then every 6 
months (24 weeks)  through the End of Treatment Visit of the Extension phase. If the last 
assessment before the EOT Visit of the Extension phase was less than 3 months prior to the 
EOT visit, the assessment does not need to be repeated.
For children >4 and <8 years of age, the following 3 subtests will be administered at the 
aforementioned visits in the following order: Matrices, Coding, and Recognition.
For children and young adults >8 and <22 years of age, the following 3 subtests will be 
administered at the aforementioned visits in the following order: Matrices, Coding, and 
Spatial Span.
The instructions for this scale will be provided in English, German, Spanish, French, Chinese 
and Dutch.
Vineland II Adaptive Behavior Scale
The Vineland is a scale that measures changes in certain behaviors. There are two forms 
which can be used to complete this scale. One is the Survey Interview Form, which a 
physician completes while interviewing/observing the patient. This form will be used when 
the investigator assesses that the patient is able to provide the information for the scale. The 
preference is for the Survey Interview Form to be used. The second form is the 
Parent/Caregiver Form which is completed by the Parent or Caregiver. This form will be 
used when the physician assesses that the patient cannot provide the information for the scale.
The Parent/Caregiver Form should only be considered for parents/caregivers who are likely to 
complete the form accurately. Whichever form is used for the first assessment will be used 
throughout the study.
The appropriate Vineland Scale (Survey Interview or Parent/Caregiver) will be completed at 
Baseline (Visit 2), completion of the Core phase (EOT Core/Visit 11/Week 18), and then 
every 6 months (24 weeks)through the End of Treatment Visit of the Extension phase. If the 
last assessment before the EOT Extension were to be less than 3 months prior to the EOT visit, 
the assessment need not be repeated. The Vineland aids in diagnosing and classifying 
intellectual and developmental disabilities and other disorders, such as Autism, Asperger 
Syndrome, and developmental delays. The Vineland will be provided in the following 
languages: Dutch, Dutch (BELG), English (Australian), English (UK), English (US), English 
(CA), French, French (BELG), French (CA), German, German (BELG), Italian, Japanese, 
Polish, Spanish, Spanish (COL), and Spanish (US). These are the only countries in which the 
Vineland Scale will be used. Other countries will skip the Vineland, and only complete the 
other scales. Scoring by the site is not required for Vineland scales.


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7.2.3.2
Physical examination
Physical examination must include a total body examination including: general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, and basic neurological exam. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the eCRF.
7.2.3.3
Neurological examination
Neurological examination must include level of consciousness, mental status, speech, vision,
cranial nerves III, IV, and VI, motor, sensory and gait/limb ataxia assessments.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the eCRF.
7.2.3.4
Tanner staging
Tanner staging will be performed as described in Table 7-1 and Table 7-2 and will consist of 
the parameters below for both males and females.
7.2.3.4.1 Males
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.
Stage 5: Genitalia adult in size and shape. No further enlargement takes place after Stage 5 is 
reached.
Pubic Hair Stages:
Stage 1: Pre-adolescent, 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.


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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 pattern and present along the inner borders of the thighs.
7.2.3.4.2 Females
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.
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.
7.2.3.5
Developmental milestones
Developmental milestones will be assessed at the visits listed in Table 7-1 and Table 7-2 and 
will include questions related to the expected secondary sexual characteristics such as body 
hair, breast development and voice change. Females will also be assessed on date of thelarche, 
which is the first stage of secondary (postnatal) breast development. Males will be assessed on 
date of adrenarche, which includes changes in sweat composition, pubic hair growth, and 
increasing skin oiliness or acne.


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7.2.3.6
Pregnancy History, Menstrual History and Monitoring
In order to provide additional follow-up on cases of amenorrhea, increased hormonal 
evaluation will be performed and supplemental medical history will be collected.
Additional menstrual history (previous cases of amenorrhea or menstrual disorders, biological 
mother’s age at menopause) and pregnancy history (pregnancies, full-term gestations, 
abortions, live births, living children) will be collected at baseline. Patients will be distributed 
menstrual diaries starting at the screening visit. Menstrual monitoring will be collected 
monthly at baseline and then every 4 weeks through Week 30. After Week 30, menstrual 
status will be collected monthly until the End of Treatment Extension via patient menstrual 
diary for source documentation, data from the patient menstrual diary will be collected during 
patient’s visit at clinical site for eCRF entry. Pregnancy testing will be performed as described 
in Table 7-1 and Table 7-2. It is recommended that study coordinators contact patients 
monthly for the first 3 months to remind patients to document menstrual status in patient diary.
7.2.3.7
Vital signs
Vital signs include blood pressure, temperature, pulse and respiratory rate measurements. The 
results will be recorded on source documents, repeated at each visit and entered in eCRF 
starting at the screening visit and until the 30-day Safety Follow-up as described in 
Table 7-1 and Table 7-2.
7.2.3.8
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured as described in Table 7-1 and Table 7-2. Weight 
will be recorded on the eCRF at each visit starting at the Screening Visit until the Post 
Extension Phase End of Treatment Visit. Pre-baseline height and weight will also be collected 
with a goal of collecting a minimum of three data points each 6 months apart for patients who 
enter the study with a Tanner Stage of less than 5. Parental height will also be captured at 
baseline for purposes of comparing children’s height.
7.2.3.9
Concomitant medications
Each patient will be queried at each visit regarding the use of any medication other than study 
drug. These drugs will be listed on the Concomitant Medications eCRF. The start date, stop 
date, and reason for each drug should be recorded. If the reason for a concomitant medication 
constitutes an adverse event after signing informed consent, this AE should be added to the 
AE eCRF.
7.2.3.10 Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior using a semi-structured interview to probe 
patient responses. The electronic version of this scale (eC-SSRS) will be administered via the 
IVR system and will be completed at every visit as outlined in Table 7-1 and Table 7-2.


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Patients 13 years and over will complete this scale for themselves. Patients under 13 years, or 
with cognitively impairment which renders them unable to understand and complete the scale, 
will have it completed by their Parent/Caregiver.
If at any assessment after Screening and/or Baseline the score is 4 or above on the Suicidal 
Ideation item or any “yes” on the Suicidal Behavior item, the patient must be referred to a 
health care professional for further assessment and/or treatment. The decision on whether the 
study treatment should be discontinued is to be taken by the health care professional to whom 
the patient is referred.
Per health authority recommendations, it is important to closely monitor the mental well-
being of patients taking medications actively targeting their central nervous system. In the 
event that a patient ≥13 years of age does not complete the scale via the IVR system, the 
investigator will proactively assess the patient for the presence of suicidality and mood 
disturbance as part of the monitoring of adverse events. The investigator should ask the 
patient whether he or she has thought about hurting himself/herself and whether the patients 
wished they were dead, using words appropriate to the understanding of the individual patient. 
For all patients, the investigator will also ask the caregiver whether the patient has done 
anything to seriously injure himself/herself (but excluding behaviors previously associated 
with frustration, like hand biting, head banging etc.), or has expressed or exhibited significant 
changes in mood or behavior. These questions will be asked at every visit during the study as 
described in Table 7-1 and Table 7-2, with the caregiver also present in the room, so that both 
parties can answer. Any positive response will be further investigated, and appropriate 
medical treatment initiated and recorded as an adverse event on the AE eCRF
In the event of a successful suicide, the investigator will complete the Supplemental Data for 
Suicidal Ideation and Behavior Categories eCRF.
The use of the eC-SSRS to detect suicidal ideation or behavior is currently mandated in 
studies of CNS active drugs.
The eC-SSRS system is available in various languages including but not limited to Chinese, 
Danish, Dutch, Dutch (BELG), English (Australian), English (UK), English (US), English 
(CA), French, French (BELG), French (CA), German, German (BELG), Greek, Hungarian, 
Italian, Japanese, Korean, Norwegian, Polish, Russian, Spanish, Spanish (MEX), Spanish 
(US), Swedish, Turkish and Thai.


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7.2.3.11 Laboratory evaluations
Table 7-3
Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, WBC Morphology with
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils), ANC
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, Chloride, 
Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol (fasting), LDL, 
HDL, Glucose (fasting), LDH (lactate dehydrogenase), Magnesium, Phosphate, Potassium, 
Total Protein, Sodium, Triglycerides, Blood Urea Nitrogen (BUN), Uric Acid, Creatinine 
Clearance (calculated)
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, Protein, pH, Urobilinogen)
Hepatitis markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR
Endocrine tests
FSH, LH, estradiol, β-HCG and testosterone, Anti-Mullerian Hormone
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the [Laboratory Manual]. If a central lab result comes back that 
requires stat re-testing for safety, a local lab may be used. However, the central lab must be 
used for all study visits.
7.2.3.11.1
Hematology
Hematology tests are to be performed as indicated in Table 7-1 and Table 7-2. These must 
include: hemoglobin, hematocrit, platelets, red blood cell (RBC) count, total white blood cell 
(WBC) count and differential including lymphocytes, monocytes, neutrophils, eosinophils, 
basophils. Absolute Neutrophil Count (ANC) will be calculated by the laboratory.
7.2.3.11.2
Clinical chemistry
The following tests will be performed as indicated in Table 7-1 and Table 7-2: sodium, 
potassium, chloride, bicarbonate, creatinine, LDH, albumin, total protein, SGOT (AST), 
SGPT (ALT), total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, uric acid, 
BUN, calcium, magnesium, phosphate, and fasting glucose. Creatinine clearance will also be 
calculated.
7.2.3.11.3
Endocrine tests
Endocrine tests will be performed at baseline, Visit 10, every 12 weeks, and EOT visits (Core,
Extension and Post-Extension). Tests will include LH, FSH, estradiol, and testosterone. Please 
refer to Table 7-1 and Table 7-2 for more information.
7.2.3.11.4
Lipid profile
A lipid profile (total cholesterol, triglycerides, LDL, HDL) will be determined at screening 
and repeated at the same time points in Table 7-1 and Table 7-2. A final assessment will be 
performed at EOT Visits. The patient must be in a fasting state at the time of blood sampling 
for the lipid profile evaluation.


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7.2.3.11.5
Urinalysis
Dipstick measurements for
protein, ketones, bilirubin, leukocyte esterase, nitrites, 
urobilinogen, glucose, pH and blood will be performed. Any significant findings on dipstick 
will be followed up with a microscopic evaluation, where WBC and RBC sediments will also 
be measured. In the case where a urine sample cannot be obtained, this test can be omitted.
7.2.3.11.6
Pregnancy and assessments of fertility
Pregnancy testing is required for females of childbearing potential at screening, baseline and 
monthly until the end of the trial. β-HCG serum pregnancy testing will be performed at 
baseline and at the end of the treatment for the Core, Extension and Post-Extension phases. 
Urine pregnancy testing will be performed at screening, monthly at clinic visits, and at home 
when visits are greater than one month apart. Patients should be instructed to inform the site 
of a positive urine pregnancy result. β-HCG serum pregnancy testing will be performed for 
confirmation of a positive urine pregnancy test. Patients with a positive serum pregnancy test 
should be withdrawn from the study. For further guidance see Section 8.4.
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during dosing and 
for 8 weeks after stopping study treatment. Highly effective contraception methods include:

Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception]

Female Sterilization: Have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male partner 
should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception

or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormonal contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
Sexually active males unless they use a condom during intercourse while taking drug
treatment  for 8 weeks after stopping treatment and should not father a child in this period.


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A condom is required to be used also by vasectomized men as well as during intercourse with 
a male partner in order to prevent delivery of the drug via semen.
7.2.3.11.7
Anti-Mullerian Hormone test
Female patients ≥10 years of age will perform AMH at Baseline, EOT core, Week 54 and 
every 48 weeks thereafter. Patients who are beyond the Baseline visit at the time of signing 
the Amendment 2 informed consent should not collect AMH.
7.2.3.12 HBV testing
Prior to randomization, the categories of patients listed in Section 7.1.1 should be tested for 
hepatitis B serologic markers and viral load (local results are acceptable for screening only):

HBV-DNA, HBsAg, HBc Ab, and HBs Ab.

During the treatment period, HBV DNA monitoring should be done depending on results 
from serologic markers and viral load as listed in Table 6-8.

The final monitoring visit for HBV will be at the 30-day safety follow-up.
7.2.3.13 HCV testing
Patients with hepatitis C risk factors and at the discretion of the investigator should be tested 
for HCV RNA prior to randomization (local results are acceptable for screening only). For a 
list of hepatitis C risk factors, refer to Section 7.1.1.
Follow-up testing will be performed, as per the visit schedule, only if the patient has a history 
of Hepatitis C. The final monitoring visit for HCV will be at the 30-day safety follow-up.
7.2.3.14 Radiological examinations
Magnetic Resonance Imaging (MRI) with diffuse tensor imaging (DTI) will be performed at 
select sites during the study. These scans will be performed at baseline, or within 7 days prior 
to the baseline visit and again at the end of the Core phase (V11) or within 7 days prior to the 
end of Core phase. Please refer to protocol Appendix A for more information.
7.2.3.15 Electroencephalogram (EEG) assessments
High frequency oscillation EEGs will be performed at selected sites during the study. These 
tests will be performed at baseline, or within 7 days prior to baseline visit, and again at the 
end of Core phase (V11) or within 7 days prior to the end of Core phase. Please refer to 
protocol Appendix A for more information.


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7.2.3.16 Cardiac assessments
7.2.3.16.1
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed during screening and if medically indicated during 
the treatment period.
Interpretation of the tracing must be made by a qualified physician. Each ECG tracing should 
be labeled with the study number, patient initials (where regulations permit), patient number, 
date, and kept in the source documents at the study site. Clinically significant abnormalities 
present when the patient signed informed consent should be reported on the Medical History 
eCRF. Clinically significant findings must be discussed with the Novartis Medical Monitor 
prior to enrolling the patient in the study. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the Adverse Events eCRF.
7.2.4
Pharmacokinetics
During the 6 week titration period, three pre-dose PK blood samples will be taken for 
potential dose adjustments as described in Table 4-1. A local lab (at the treating center) will 
collect the blood samples and send them to a central laboratory for determination of 
everolimus concentrations. The site will receive recommendations from the central Interactive 
Response Technology (IRT) on dose adjustment (to maintain, increase or decrease the number 
of the 2-mg tablets) for each patient, based on concentration values of the pre-dose PK 
samples. A sample of blood collected immediately prior to dosing on the study day and at 
22-26 hours after the patient’s last daily dose of study drug following 5 days of consistent 
(daily dose and timing of dose) dosing is a valid trough PK blood sample. Any sample 
collected outside of these parameters is not considered a true trough and therefore 
should not be used as a basis for adjusting the patient's dose. It is expected that all the 
patients will achieve the desired target pre-dose trough level (Cmin) during this period. In 
order to keep the blind, the IRT will also instruct the site to adjust the dose for patients in the 
placebo arm.
After the completion of the titration period, patients will continue their current dose level 
during a 12 weeks maintenance period. Pre-dose PK blood samples will be collected every 4 
weeks during the maintenance period.
In order to minimize total blood samples taken from pediatric patients, the amount of blood 
required for everolimus PK samples will be 0.5 mL for patients from 1 to < 2 years of age, 
and 1 mL for patients 2 to ≤ 6 years of age. For patients > 6 years of age, the amount will be 2 
mL.
Additional Everolimus PK sampling
In addition to the time points described above in the Core, Extension and Post Extension 
phase sections, pre-dose blood samples for everolimus concentration determination should be 
collected two weeks after the following events:

Any everolimus dose adjustment

Starting or changing the dose of a CYP3A4/PgP inducer/inhibitor


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Anti-epileptic drug PK sampling
Everolimus is metabolized by the CYP3A4 pathway in the liver, and to some extent in the 
intestinal wall. Many of the concomitantly administered AEDs are also metabolized by the 
CYP3A4 pathway, which results in a potential for drug-drug interaction between the AEDs 
and everolimus. Therefore, levels of the AEDs listed in Section 4.1.3 (considered to be 
CYP3A4 substrates and /or inducers) will be measured to investigate the effect of everolimus 
on the AED level (i.e., if AED + everolimus leads to higher levels of AED compared to AED 
alone).
Pre-dose plasma samples will be collected at Visits 1, 2, 3, and 5 for the measurement of 
antiepileptic drug (AED) concentration. Effects of everolimus on the exposure of anti-
epileptic drugs will be assessed by comparing the anti-epileptic drug concentrations at Visits 1 
and 2 (AEDs alone) and at Visits 3 and 5 (AEDs plus everolimus). A list of commonly 
prescribed AEDs that are used in this population is provided in Section 6.1.1.For a list of 
inducers and inhibitors, please refer to Section 4.1.3 and Table 6-11 and Table 6-12.
Table 7-4
Everolimus/Placebo PK Sample Log Table for Study core phase, Visits 
0-11(777)
Study visit
Study 
Week
Time
PK Collection 
Numberb
PK Sample 
Numberc
Sample Volumed
(mL)
Visit 3
Week 1
Pre-dose
401/501
401
2 mL (blood)
Visit 5
Week 3
Pre-dose
402/502
402
2 mL (blood)
Visit 7
Week 5
Pre-dose
403/503
403
2 mL (blood)
Visit 9
Week 10
Pre-dose
404/504
404
2 mL (blood)
Visit 10
Week 14
Pre-dose
405/505
405
2 mL (blood)
Visit 11(777)
Week 18
Pre-dose
406/506
406
2 mL (blood)
Additionala
Pre-dose
40401/50501 
40402/50502 
40403/50503 . . .
3001, 3002, 
3003, . . .
2 mL (blood)
a additional visit at two weeks after any everolimus dose adjustment or start/change in dose of the CYP3A4/PgP
inhibitor/inducer
b The first PK collection number refers to the first dose of everolimus received after collection of the PK sample, 
while the second PK collection number is the last dose the subject received prior to the collection of the PK 
sample
c The PK sample number uniquely identifies the PK sample for a particular visit and should be written on the tube 
label of samples sent to the central PK lab. 
d Sample volume is dependent on patient’s age. 0.5 mL for 1 to <2, 1 mL for 2 to ≤ 6, and 2 mL for > 6
During the Extension phase, Everolimus PK samples will be drawn at Weeks 19 (V12), 22 
(V14), 26 (V15), and 30 (V16), and then every 12 weeks thereafter, unless additional visits 
are clinically indicated. Pre-dose blood samples will be collected per Table 4-2. After the 
target trough level is achieved, PK blood draws will be performed every 12 weeks through the 
Post Extension phase.


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Table 7-5
Everolimus PK Sample Log Table for Study extension phase, starting 
at Visit 12
Study visit
Study Week
Time
PK Collection 
Numberb
PK Sample 
Numberc
Sample Volumed
(mL)
Visit 12
Week 19
Pre-dose
601/701
601
2 mL (blood)
Visit 14
Week 22
Pre-dose
602/702
602
2 mL (blood)
Visit 15
Week 26
Pre-dose
603/703
603
2 mL (blood)
Visit 16
Week 30
Pre-dose
604/704
604
2 mL (blood)
Every 12 weeks 
after
Pre-dose
605/705, 606/706, 
607/707….
605,606, 
607….
2 mL (blood)
End of 
Treatment 
Extension (V778)
Pre-dose
699/799
699
2 mL (blood)
Visit 201
Transition B: 
Week 27, 31, 
43, 55, 67, etc
Pre-dose
801/901
801
2 mL (blood)
Additionala
Pre-dose
60601/70701,
60602/70702,
60603/70703,…
4001, 4002, 
4003, . . .
2 mL (blood)
a additional visit at two weeks after any everolimus dose adjustment or start/change in dose of the CYP3A4/PgP 
inhibitor/inducer
b The first PK collection number refers to the first dose of everolimus received after collection of the PK sample, 
while the second PK collection number is the last dose the subject received prior to the collection of the PK 
sample
c The PK sample number uniquely identifies the PK sample for a particular visit and should be written on the tube 
label of samples sent to the central PK lab. 
d Sample volume is dependent on patient’s age. 0.5 mL for 1 to <2, 1 mL for 2 to ≤ 6, and 2 mL for > 6
Table 7-6
Everolimus PK Sample Log Table for Study Post-Extension phase
Study visit
Study Week in 
Post-
Extension 
Phasee
Time
PK Collection 
Numberb
PK Sample 
Numberc
Sample Volumed
(mL)
Visit 401
Week n+12
Pre-dose
1101/1201
1101
2 mL (blood)
Visit 402
Week n+24
Pre-dose
1102/1202
1102
2 mL (blood)
Visit 403
Week n+36
Pre-dose
1103/1203
1103
2 mL (blood)
Visit 404
Week n+48
Pre-dose
1104/1204
1104
2 mL (blood)
Visit 405
Week n+60
Pre-dose
1105/1205
1105
2 mL (blood)
Additionala
Pre-dose
11801/12901,
11802/12902,
11803/12903,…
11001, 11002, 
11003, . . .
2 mL (blood)
a Additional visit at two weeks after any everolimus dose adjustment or start/change in dose of the CYP3A4/PgP 
inhibitor/inducer
b The first PK collection number refers to the first dose of everolimus received after collection of the PK sample, 
while the second PK collection number is the last dose the subject received prior to the collection of the PK 
sample
c The PK sample number uniquely identifies the PK sample for a particular visit and should be written on the tube 
label of samples sent to the central PK lab. 
d Sample volume is dependent on patient’s age. 0.5 mL for 1 to <2, 1 mL for 2 to ≤ 6, and 2 mL for > 6
e n = the week at which the patient’s last scheduled Extension phase visit occurred


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Table 7-7
PK Sample Log Table for Carbamazepine
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample 
Volumeb
Visit 1
Week -8
Pre-dose
1/201
1
~1mL (plasma)
Visit 2
Week 0
Pre-dose
2/202
2
~1mL (plasma)
Visit 3
Week 1
Pre-dose
3/203
3
~1mL (plasma)
Visit 5
Week 3
Pre-dose
4/204
4
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-8
PK Sample Log Table for Oxcarbazepine
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample 
Volumeb
Visit 1
Week -8
Pre-dose
11/211
11
~1mL (plasma)
Visit 2
Week 0
Pre-dose
12/212
12
~1mL (plasma)
Visit 3
Week 1
Pre-dose
13/213
13
~1mL (plasma)
Visit 5
Week 3
Pre-dose
14/214
14
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-9
PK Sample Log Table for Clonazepam
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample 
Volumeb
Visit 1
Week -8
Pre-dose
21/221
21
~1mL (plasma)
Visit 2
Week 0
Pre-dose
22/222
22
~1mL (plasma)
Visit 3
Week 1
Pre-dose
23/223
23
~1mL (plasma)
Visit 5
Week 3
Pre-dose
24/224
24
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
bSample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-10
PK Sample Log Table for Diazepam
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample 
Volumeb
Visit 1
Week -8
Pre-dose
31/231
31
~1mL (plasma)
Visit 2
Week 0
Pre-dose
32/232
32
~1mL (plasma)
Visit 3
Week 1
Pre-dose
33/233
33
~1mL (plasma)
Visit 5
Week 3
Pre-dose
34/234
34
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.


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Table 7-11
PK Sample Log Table for Clobazam
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample 
Volumeb
Visit 1
Week -8
Pre-dose
41/241
41
~1mL (plasma)
Visit 2
Week 0
Pre-dose
42/242
42
~1mL (plasma)
Visit 3
Week 1
Pre-dose
43/243
43
~1mL (plasma)
Visit 5
Week 3
Pre-dose
44/244
44
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-12
PK Sample Log Table for Felbamate
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample Volumeb
Visit 1
Week -8
Pre-dose
51/251
51
~1mL (plasma)
Visit 2
Week 0
Pre-dose
52/252
52
~1mL (plasma)
Visit 3
Week 1
Pre-dose
53/253
53
~1mL (plasma)
Visit 5
Week 3
Pre-dose
54/254
54
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-13
PK Sample Log Table for Phenobarbital
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample Volumeb
Visit 1
Week -8
Pre-dose
61/261
61
~1mL (plasma)
Visit 2
Week 0
Pre-dose
62/262
62
~1mL (plasma)
Visit 3
Week 1
Pre-dose
63/263
63
~1mL (plasma)
Visit 5
Week 3
Pre-dose
64/264
64
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.


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Table 7-14
PK Sample Log Table for Phenytoin
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample Volumeb 
Visit 1
Week -8
Pre-dose
71/271
71
~1mL (plasma)
Visit 2
Week 0
Pre-dose
72/272
72
~1mL (plasma)
Visit 3
Week 1
Pre-dose
73/273
73
~1mL (plasma)
Visit 5
Week 3
Pre-dose
74/274
74
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-15
PK Sample Log Table for Primidone
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample Volumeb
Visit 1
Week -8
Pre-dose
81/281
81
~1mL (plasma)
Visit 2
Week 0
Pre-dose
82/282
82
~1mL (plasma)
Visit 3
Week 1
Pre-dose
83/283
83
~1mL (plasma)
Visit 5
Week 3
Pre-dose
84/284
84
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-16
PK Sample Log Table for Topiramate
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample Volumeb
Visit 1
Week -8
Pre-dose
91/291
91
~1mL (plasma)
Visit 2
Week 0
Pre-dose
92/292
92
~1mL (plasma)
Visit 3
Week 1
Pre-dose
93/293
93
~1mL (plasma)
Visit 5
Week 3
Pre-dose
94/294
94
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.


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Table 7-17
PK Sample Log Table for Valproic acid
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample 
Volumeb
Visit 1
Week -8
Pre-dose
101/301
101
~1mL (plasma)
Visit 2
Week 0
Pre-dose
102/302
102
~1mL (plasma)
Visit 3
Week 1
Pre-dose
103/303
103
~1mL (plasma)
Visit 5
Week 3
Pre-dose
104/304
104
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
Table 7-18
PK Sample Log Table for Zonisamide
Study visit
Study Week
Time
PK Collection 
Numbera
PK Sample 
Number
Sample 
Volumeb
Visit 1
Week -8
Pre-dose
111/311
111
~1mL (plasma)
Visit 2
Week 0
Pre-dose
112/312
112
~1mL (plasma)
Visit 3
Week 1
Pre-dose
113/313
113
~1mL (plasma)
Visit 5
Week 3
Pre-dose
114/314
114
~1mL (plasma)
a The first PK collection number is for current dose, while the second PK collection number is for last dose the 
subject received prior to the collection of the PK sample
b Sample collection is dependent on patient’s weight. Patients weighing ≥ 12 kg to ≤ 20 kg will not have AED PK 
samples taken. Patients ≤ 6 will have 5.2 mL blood taken to yield 2.6 mL plasma for three .87 mL aliquots of 
plasma. Patients > 6 will have 6 mL blood taken to yield 3 mL plasma for 3 1 mL aliquots of plasma.
7.2.4.1
Analytical method
Everolimus concentrations in whole blood will be determined by a LC-MS/MS method 
following solid phase extraction. The method has a lower limit of quantification (LLOQ) of 
0.300 ng/mL.
Plasma concentrations of Clobazam, N-desmethyl Clobazam; Clonazepam and Diazepam will 
be measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS)
assay with a lower limit of quantification (LLOQ) 1, 1, 1 and 2 ng/mL, respectively.Plasma 
concentrations of Felbamate, Phenytoin will be measured using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay with a lower limit of 
quantification (LLOQ) 50 and100 ng/mL, respectively.
Plasma concentrations of Primidone and Zonisamide will be measured using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay with a lower limit of 
quantification (LLOQ) 10 and 20 ng/mL, respectively.
Concentrations below the LLOQ will be reported as 0 ng/mL or 0 μM or 0 μg/mL and missing 
samples will be labeled accordingly.
Additional details regarding the analytical Method for quantification of everolimus (and other 
analytes, as applicable) shall be described in the Bioanalytical Report issued at the final of the 
Clinical Study Report.


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7.2.4.2
Other assessments
7.2.4.2.1 IRT Registration
After a patient signs the informed consent form, they must be registered into the IRT system 
to obtain the patient number, and enter the patient to the study. Instructions should be 
followed as per the IRT manual.
7.2.4.2.2 TSC genetic testing
In addition to the safety and efficacy assessments described above, blood will be taken at the 
Baseline visit to measure TSC genetic markers (TSC1 / TSC2) if they have not been tested 
prior to entering the trial. If these tests have been analyzed and reported prior to study start, 
the date of testing, results of those tests, and the lab that performed the test will be collected.
7.2.5
Patient reported outcomes
The following scales will be completed used to assess all health-related quality of life
(HRQoL) issues. One instrument will be used per subject determined by the subject’s 
chronological age at Baseline. These questionnaires should be completed only by the person 
who has epilepsy or the parent/caregiver for children <10 years old. The same questionnaires 
completed at Baseline will continue to be completed throughout the study. This will be 
collected at Baseline, Week 18 (End of Core) and End of Treatment for the Extension phase, 
see Table 7-1.

Quality of Life in Childhood Epilepsy Questionnaire (QOLCE) for children ≤10 years old 
with epilepsy

Quality of Life in Epilepsy Inventory for Adolescents – 48 (QOLIE-AD-48) for 
Adolescents 11-17 years old with epilepsy

Quality of Life in Epilepsy Inventory -31- Problems (QOLIE-31-P) for adults > 18 years 
old with epilepsy
In situations where completion of the instrument (QOLIE-AD-48 and QOLIE-31-P) by the 
subject is required, but the subject is either a) unable to sign the instrument, or b) capable of 
indicating the correct response but physically incapable of marking the score sheet, the subject 
may be assisted by a parent or caregiver in completing the instrument. No other assistance is 
permissible in order to maintain the validity of the results.
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.


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Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Except for screening failures, adverse events that begin or worsen after informed consent 
should be recorded in the Adverse Events CRF. Conditions that were already present at the 
time of informed consent should be recorded in the Relevant Medical History/Current 
Medical Conditions page of the patient’s CRF. Adverse event monitoring should be continued 
for at least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
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 the EOT
eCRF.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments.
As far as possible, each adverse event should be evaluated to determine:

The severity grade (CTCAE Grade 1-4)

Its duration (Start and end dates or ongoing at end of study)

Its relationship to the study treatment (suspected or not suspected)

Action taken with respect to study or investigational treatment (no action taken, study 
drug dosage adjusted/ temporarily interrupted or permanently discontinued).

Whether medication or therapy was given (concomitant medication/non-drug therapy
given)

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 the study treatment, the 
interventions required to treat it, and the outcome.


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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
In clinical trials, everolimus has been associated with infections (including exacerbation, 
aggravation or reactivation of pre-existing infections), and serious cases of hepatitis B 
reactivation, including fatal outcome. Infections and reactivation of infections is an expected 
event during periods of immunosuppression.
In clinical trials and post-marketing spontaneous reports, everolimus has been associated with 
renal failure events (including fatal ones) and proteinuria. Renal function will be monitored 
throughout the study.
Also in clinical trials, everolimus has been associated with noninfectious pneumonitis, 
stomatitis, hyperglycemia, hypophosphatemia, and dyslipidemia. These events will be 
monitored throughout the study as described in Section 6.2.5.
Additional events associated with everolimus in clinical trials include hemorrhages, 
thrombotic and embolic events, cytopenias, cardiac failure, amenorrhea, male infertility, and 
hypersensitivity reactions. Potential risks also include intestinal obstruction/ileus, pancreatitis, 
and cholelithiasis.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect


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
Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. 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 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, except for countries applied with local Novartis operation procedure in local 
languages, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department as managed by local 
organizations.
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 investigator folder 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 


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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 study 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
Emergency unblinding of treatment assignment
Emergency unblinding should only be undertaken when it is essential for effective treatment 
of the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator 
contacts the IRT to unblind a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Lead that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The protocol number, study
treatment name if available, patient number, and instructions for contacting the local Novartis 
CPO (or any entity to which it has delegated responsibility for emergency code breaks) will 
be provided to the patient in case emergency unblinding is required at a time when the 
investigator and backup are unavailable. However, if a mechanism is already in place to 
ensure that the investigator and/or back-up can always be reached in case of emergency then 
the procedure above is not required.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis 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 study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.


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Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
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 provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be constituted prior to the randomization of the 
first patient. The DMC is an external independent group including at least two physicians with 
expertise in epilepsy and/or TSC and one statistician. The DMC will perform the first safety 
review using a data cutoff 6 months after randomization of the first patient or when 100 
patients have received treatment for 4 weeks (whichever occurs first), and every 6 months 
thereafter until the Core Database Lock, unless otherwise requested by the Chairman of the 
DMC. The DMC will also receive reports on a regular basis on all SAEs reported for this trial. 
No interim analysis is planned. Recruitment will not be interrupted unless otherwise requested 
by the Chairman of the DMC.
Details on the membership, responsibilities and working procedures of the DMC will be 
described in the DMC Charter.
8.7
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial (i.e., not members of the DMC) and Novartis representatives from the Clinical Trial 
Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in the SC Charter.
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


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


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part, non-carbon-required paper. Field monitors will review the Vineland Scales for completeness 
and accuracy and instruct site personnel to make any required corrections or additions. The 
harvested Vineland Scales will be forwarded to Novartis (or designated CRO). The carbon copies 
will remain on site as source document.
The Principal Investigator is responsible for assuring that the data entered into eCRFs and on
Vineland Scales is complete, accurate, and that entry and updates are performed in a timely 
manner.
An IRT system will be used for drug dispensing and titration purposes for this study. There 
will be regular reports of enrollment at site activity. In order to maintain the blind, there will 
data transfers of operational details only from IRT until analysis of the Core data. After the 
Core data have been analyzed, regular full data transfers will be established.
Safety labs will be collected centrally and data transferred to the study database, at regular 
intervals. The C-SSRS will be administered via IVRS, and there will be regular transfers of 
these data. PK analysis will also be done at a central lab. In order to maintain the blind, the 
PK results will only be transferred at the time of analysis of the Core data. DTI MRI and EEG 
performed will be transmitted by the sites to the CRO designated by Novartis to undergo 
central review. Refer to Appendix A for further details.
9.4
Database management and quality control
For Vineland Scales used in this study, data will be entered into a fully validated study 
database by Novartis Data Management personnel (or designated CRO). Following entry from 
the Vineland Scales, the data are systematically checked by Novartis Data Management 
personnel (or designated CRO) using programmed checks and data review tools/reports. 
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 on the corresponding eCRF. Designated investigator site staff are required to respond 
promptly to queries. Novartis Data Management personnel (or designated CRO) will make 
any necessary changes to the data.
For the eCRFs used in this study, 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.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an IRT. The system will be supplied by a 


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vendor(s), who will also manage the database. The data will be sent electronically to Novartis 
personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the treatment codes will be unblinded and 
made available for data analysis. Authorization is required prior to making any database 
changes to locked data, by joint written agreement between the Global Head of Biostatistics 
and Data Management and the Global Head of Clinical Development.
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 cut-off date for the primary efficacy and safety analyses will be when all patients 
have completed the Core phase or have discontinued early. At that time, all data from the 
Core phase will be available as well as part of the Extension phase data. The analyses for the 
reports will thus cover both periods:

The main focus will be on descriptive and inferential comparisons of both everolimus 
arms versus placebo on efficacy and safety in the Core phase.

Descriptive efficacy and safety analyses on Extension phase data will also be conducted in 
order to explore the longer term effects of everolimus.
The second data cut-off will be at the end of the extension phase, which is planned 48 weeks 
after the last patient completes the Core phase, and which will be used for the final report of 
the Extension phase. Earlier updates of the Extension phase data are not currently planned, but 
may be performed if needed. A final data cutoff will be at the end of the Post Extension phase, 
which is planned on October 30, 2017.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment and stratum they have been assigned to during the randomization 
procedure. This will be the primary analysis set for all Core phase efficacy analyses.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication in the 
Core Phase, and had at least one post-baseline safety assessment in the Core Phase (where the 
statement that a patient had no adverse event (on the Adverse Events CRF) constitutes a 
safety assessment). Patients will be analyzed according to the study treatment (regimen) they 
actually received. This will be the primary analysis set for all Core phase safety analyses.


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A precise definition of “actually received”, will be added in the Report and Analysis Plan 
(RAP).
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP.
Protocol deviations leading to exclusion from the PPS are:

Absence of diagnosis of TSC or partial-onset epilepsy.

Baseline phase with less than 16 partial-onset seizures or at least 21 days seizure-free.

Previously failed less than two sequential regimens of single or combined AEDs.

Use of more than 3 concomitant AEDs in the baseline phase or the core phase AEDs.

Non-use of concomitant AEDs in the baseline phase or the core phase.

Use of a different 1 to 3 concomitant AEDs in the Core phase to that in the Baseline phase.

Rescue medication during the Core phase modified beyond the accepted limits defining 
rescue medication.

Study treatment received different from treatment assigned by randomization.

Missing seizure information on > 50% of days in the Core phase.
10.1.4
Long-Term Evaluation Set
The Long-Term Evaluation Set is intended to capture all data on everolimus in the trial, from 
the Core Phase, the Extension Phase and the Post Extension Phase. It consists of all patients 
who received at least one dose of everolimus in the trial and have at least one efficacy/safety 
measure. Patients will be analyzed as a single everolimus group as well as separately 
according to their randomized treatment arm in the Core phase (i.e., everolimus trough ranges 
of 9-15 ng/ml and 3-7 ng/ml, or for patients originally randomized to placebo who enter the 
extension phase, everolimus trough range of 3-15 ng/ml). This analysis set will be used for 
long-term efficacy and safety analyses.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline characteristics will be summarized descriptively by treatment 
group for the FAS. Categorical data will be presented by frequencies and percentages. For 
continuous data the mean, standard deviation (SD), median, 25th and 75th percentiles, 
minimum and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies)
10.3.1
Study medication
Duration of study treatment exposure, cumulative dose (mg/m2) and dose intensity 
(mg/m2/day) will be summarized by treatment group. The number of patients with dose 
changes/interruptions will be presented by treatment group, along with reasons for the dose 
change. These analyses will be conducted over the Core phase on the Safety set, and over the 
extension phase on the Long-Term Evaluation set.


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10.3.2
Concomitant medication
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized by Anatomical Therapeutic Chemical (ATC) 
class, preferred term and treatment arm by means of frequency counts and percentages. These 
summaries will include medications starting on or after the start of study treatment or 
medications starting prior to the start of study treatment and continuing after the start of study 
treatment. These summaries will be presented separately for anti-epileptic drugs versus other 
types of concomitant medications.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. The Safety Set and the Long-Term Evaluation Set 
will be used for all above-mentioned concomitant medication tables and listings.
10.4
Primary objective
The primary objective is to compare the reduction in frequency of partial-onset seizures on 
each of two trough ranges of everolimus (3-7 ng/mL and 9-15 ng/mL) versus placebo in 
patients with TSC who have refractory partial-onset seizures and are already receiving one to 
three AEDs.
10.4.1
Variable
The regulatory requirements for demonstrating efficacy of an anti-epileptic medication differ 
between Europe and US: whereas the EMA prefers response rate to be the primary variable, 
the FDA prefers percentage reduction in seizure frequency. It is understood that each Agency
will use their preferred variable as the primary variable, with the other (non-primary) variable 
being used in a supportive analysis. As each Agency will only use their preferred primary 
variable to make a decision on the primary objective, the full alpha level can be used for each 
Agency’s primary variable, without correction for multiplicity.
10.4.1.1 EMA primary variable: response rate
The EMA primary variable is response rate in the maintenance period of the Core phase, 
determined using counts of partial-onset seizures (as defined in Inclusion Criterion 4a) from 
patient seizure diaries (see Section 7.2.2.1) and the following definitions:

Average weekly seizure frequency in the Baseline phase (SFB) = 7 × number of partial-
onset seizures recorded over the 8 week prospective Baseline phase ÷ number of days with 
evaluable seizures in the prospective Baseline phase.

Average weekly seizure frequency in the maintenance period of the Core phase (SFM):

If patient does not discontinue during the 6 week titration phase, SFM = 7 × number of 
partial-onset seizures recorded during the maintenance period of the Core phase ÷ 
number of days with evaluable seizures in the maintenance period of the Core phase.

Otherwise, SFM = 7 × number of partial-onset seizures recorded during the titration 
period of the Core phase ÷ number of days with evaluable seizures in the titration 
period of the Core phase.


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That is, patients who discontinue prior to the maintenance period have seizure frequency 
determined using their data from the titration period, thereby assuring that all patients 
with seizure data in the Core phase have a value for SFM.

Percentage reduction from baseline in average weekly seizure frequency during the 
maintenance period of the Core phase (% Red) = 100 × (SFB - SFM) ÷ SFB.
A responder is a patient with ≥ 50% reduction from baseline in average weekly partial-onset 
seizure frequency during the maintenance period of the Core phase, that is, when % Red ≥ 50.
10.4.1.2 FDA primary variable: percentage reduction in seizure frequency
The FDA primary variable is percentage reduction from baseline in average weekly frequency 
of partial-onset seizures during the maintenance period of the Core phase, and is defined by 
the variable % Red in Section 10.4.1.1 above.
10.4.2
Statistical hypothesis, model, and method of analysis
10.4.2.1 EMA primary variable: response rate
Response rate in the maintenance period of the Core phase will be compared between each 
everolimus arm versus the placebo arm, according to a Bonferroni-Holm procedure, assuring 
an overall experiment-wise alpha level of 2.5% one-sided. Cochran-Mantel-Haenszel (CMH)
chi-square tests will be used (implemented via SAS procedure FREQ with CMH option in the 
TABLES statement), stratified by age subgroup at randomization (the randomization 
stratification factor, consisting of 4 subgroups: 1 to < 6, 6 to < 12, 12 to < 18, ≥18 years). The 
p-value will be obtained from the “General association” CMH statistic.
The statistical hypotheses are
H01: RREVE1 ≤ RRPLB versus H11: RREVE1 > RRPLB, and
H02: RREVE2 ≤ RRPLB versus H12: RREVE2 > RRPLB
where RREVE1 is the probability of response on the everolimus 3-7 ng/mL trough arm, RREVE2
is the probability of response on the everolimus 9-15 ng/mL trough arm, and RRPLB is the 
probability of response on the placebo arm.
Response rates will be provided with exact 95% confidence intervals (Clopper and Pearson, 
1934).
In addition, the odds ratio will be used as a measure of association between treatment and 
response. It will be derived for each everolimus arm versus placebo from a logistic regression 
model (implemented using SAS procedure LOGISTIC, with treatment specified as an 
explanatory variable in the CLASS statement), stratified by age subgroup at randomization. 
The two odds ratios will be presented with two-sided 95% Wald confidence limits.
10.4.2.2 FDA primary variable: percentage reduction in seizure frequency
Percentage reduction in seizure frequency in the maintenance period of the Core phase will be 
compared between each everolimus arm versus the placebo arm, according to a Bonferroni-
Holm procedure, assuring an overall experiment-wise alpha level of 2.5% one-sided. Rank 
ANCOVA will be used (implemented via SAS procedures RANK, REG and FREQ), with 


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baseline average weekly seizure frequency as covariate, and stratified by age subgroup at 
randomization.
The statistical hypotheses are:
H01: μEVE1 ≤ μPLB versus H11: μEVE1 > μPLB, and
H02: μEVE2 ≤ μPLB versus H12: μEVE2 > μPLB
where μEVE1 is the population mean of the reduction in seizure frequency for the everolimus 3-
7 ng/mL trough arm, and where μEVE2 and μPLB are the equivalent quantities for the 
everolimus 9-15 ng/mL trough arm and the placebo arm.
The median percentage reduction from baseline will be presented for each everolimus arm 
versus the placebo arm, along with 95% confidence intervals computed using the bootstrap 
percentile method.
10.4.3
Handling of missing values/censoring/discontinuations
Patients with no data in their seizure diary during the Core phase will be assumed to be non-
responders for the EMA primary analysis, and to have a percentage reduction from baseline in 
seizure frequency of 0% for the FDA primary analysis. In addition, in case of one or more 
individual days with missing seizure information within a period, those days are excluded 
from the period duration when computing the standardized seizure frequency over the period 
(e.g. in case 3 seizures have been reported over a period of 28 days, but one of those 28 days 
had missing seizure evaluation, the seizure frequency will be computed as 3 seizures over 27 
days and not 3 seizures over 28 days).
10.4.4
Supportive and sensitivity analyses
For the EMA primary variable on response rate, a supportive analysis will be the FDA 
primary analysis on percentage reduction in seizure frequency, and vice versa.
The primary analysis of both the EMA and FDA primary variables will be repeated in the Per 
Protocol Set.
In addition, sensitivity analyses will be conducted in the FAS to assess robustness of the 
primary analysis to (i) patient discontinuation before the end of the Core phase, and (ii) the 
calculation of seizure frequency across the entire Core phase (i.e., titration period as well as 
maintenance period).
For (i), the sensitivity analysis will assume no change from baseline in seizure frequency for
patients discontinuing in the Core phase, whereas the primary analysis uses the actual seizure 
frequency calculated up to the day of discontinuation. Response rate and percentage change 
from baseline in seizure frequency will be recalculated for this sensitivity analysis and 
analyzed per the primary analysis.
For (ii), the sensitivity analysis will use the average weekly seizure frequency over the entire 
Core phase, that is, over the 6-week titration period plus the 12-week maintenance period.
This compares with the primary analysis where titration period data is not used to calculate 
average weekly seizure frequency if the patient continues into the maintenance period. The 
variable used in the sensitivity analysis, labeled SFTM is defined as follows:


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
Average weekly seizure frequency in the entire Core phase (SFTM) = 7 × number of 
seizures recorded over the entire Core phase (titration plus maintenance) ÷ number of days 
with evaluable seizures in the entire Core phase (titration plus maintenance).
Response rate and percentage reduction in seizure frequency will be re-calculated using SFTM
instead of SFM, and analyzed as per the primary analysis.
Table 10-1
Supportive and sensitivity analyses for primary objective
Variable
Population
Time Period
Variable for seizure 
frequency
Rule for 
discontinuations
EMA
% reduction in 
seizure frequency
FAS
Maintenance
SFM
None
Response rate
PPS
Maintenance
SFM
None
Response rate
FAS
Maintenance
SFM
SFM = SFB
Response rate
FAS
Titration + 
maintenance
SFTM
None
FDA
Response rate
FAS
Maintenance
SFM
None
% reduction in 
seizure frequency
PPS
Maintenance
SFM
None
% reduction in 
seizure frequency
FAS
Maintenance
SFM
SFM = SFB
% reduction in 
seizure frequency
FAS
Titration + 
maintenance
SFTM
None
FAS = Full Analysis Set, PPS = Per Protocol Set, SFM = average weekly seizure frequency in the maintenance 
period of the Core phase, SFTM = average weekly seizure frequency in the entire Core phase (titration + 
maintenance), SFB = average weekly seizure frequency in the Baseline phase.
10.5
Secondary objectives
Secondary objectives are described below, separated into sections for efficacy, safety, 
pharmacokinetics and patient-reported outcomes.
10.5.1
Efficacy objectives
Seizure freedom
The ability to completely suppress partial-onset seizures will be assessed by determining the 
proportion of patients remaining seizure-free during the maintenance period of the Core phase. 
A patient will be considered seizure-free if the percentage reduction from baseline in average 
weekly frequency of partial-onset seizures during the maintenance period of the Core phase is 
100%, that is, if % Red = 100 using the definitions given in Section 10.4.1.1. Patients with no 
data in their seizure diary during the Core phase will be assumed not to be seizure-free.
The seizure-free rates for each treatment arm will be presented along with exact 95% 
confidence intervals (Clopper and Pearson, 1934). The odds ratio for each everolimus arm 
versus placebo, plus the Wald 95% confidence interval, will be derived from a logistic 
regression model stratified by age subgroup at randomization.
A sensitivity analysis will be performed where patients who discontinue during the Core 
phase are assumed not to be seizure-free even if % Red = 100.


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Proportion of patients with at least 25% reduction in seizure frequency
This objective is assessed by determining the proportion of patients in each treatment arm 
with at least a 25% reduction from baseline in average weekly frequency of partial-onset 
seizures during the maintenance period of the Core phase, defined by % Red ≥ 25 using the 
definitions given in Section 10.4.1.1. Patients with no data in their seizure diary during the 
Core phase will be assumed to have less than a 25% reduction.
The proportion of patients with at least a 25% reduction will be presented in each treatment 
arm along with exact 95% confidence intervals (Clopper and Pearson, 1934). The odds ratio 
for each everolimus arm versus placebo, plus the Wald 95% confidence interval, will be 
derived from a logistic regression model stratified by age subgroup at randomization.
Distribution of reduction from baseline in seizure frequency
The reduction from baseline in average weekly frequency of partial-onset seizures in the 
maintenance period of the core phase will be categorized into six levels using the variable % 
Red defined in Section 10.4.1.1. The six levels will be: (≤ -25% (exacerbation); > -25% to < 
25% (no change); ≥ 25% to < 50%; ≥ 50% to < 75%; ≥ 75% to < 100%; 100% (seizure-
freedom)). Patients with no seizure diary data in the Core phase will be assigned as missing.
The proportions of patients in each category will be presented for each treatment arm.
Seizure-free days
The frequency of partial-onset seizure-free days per 28 days during the maintenance period of 
the Core phase will be obtained for each patient, calculated as 28 × number of partial-onset 
seizure-free days in the maintenance period of the Core phase ÷ number of non-days with 
evaluable seizures in the maintenance period of the Core phase. A similar quantity will be 
calculated for the Baseline phase. Patients with no seizure data in the Core phase will be 
assumed to have the same number of seizure-free days as during the Baseline phase.
The change from baseline in frequency of partial-onset seizure-free days per 28 days will be 
summarized by treatment arm (mean, standard deviation, range). Mean differences between 
each everolimus arm and the placebo arm in change from baseline in frequency of seizure-free 
days will presented, along with 95% confidence intervals.
Treatment duration
Treatment duration is defined as the time from randomization until the date of permanent 
study treatment discontinuation (for any reason) during the entire Core phase (i.e., including 
the titration period and the maintenance period). Patients who complete the Core phase 
without discontinuing will have treatment duration censored on the last day of the Core phase.
The treatment duration distributions in each arm will be presented descriptively in the FAS 
using Kaplan-Meier curves, from which summary statistics will be determined, including the 
median treatment duration and the proportions of patients on treatment at 6 and 12 weeks. 
These statistics will be given as point estimates with 95% confidence intervals. The hazard 
ratio (and two sided 95% confidence interval) for each everolimus arm versus placebo will be 
obtained from a Cox proportional hazards model stratified by age subgroup at randomization.


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Long-term efficacy evaluation over the extension phase
Descriptive statistics on percent reduction from baseline in partial onset seizure-frequency, 
responder rate and seizure-free days will be computed by time interval over the extension 
phase on the Long-Term Evaluation Set.
10.5.2
Safety objectives
10.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. The assessment of safety will be based mainly on the frequency of adverse 
events and on the number of laboratory values that fall outside of pre-determined normal 
ranges. Other safety data (e.g., electrocardiogram, vital signs) will be considered as 
appropriate. All safety data will be listed.
For the analysis of safety data from the Core phase of the study, the overall observation period 
will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication in Core phase
2. on-treatment period: from day of first dose of study medication in the Core phase until 30
days after last dose of study medication in the Core phase, except for patients who enter 
the Extension phase, for whom the on-treatment period lasts until the day before starting 
everolimus in the Extension phase
3. post-treatment period: starting the day after the end of the on-treatment period.
10.5.2.2 Adverse events (AEs)
Summary tables for AEs will only include AEs that started or worsened during the on-
treatment period, the treatment-emergent AEs. However, all safety data (including those 
from the pre and post-treatment periods) will be listed and those collected during the pre-
treatment and post-treatment 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 study treatment and by treatment group.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group.
Specific safety event categories (SECs) will be monitored during the study, consisting of one 
or more well-defined adverse events which are similar in nature and for which there is a 
specific clinical interest to epilepsy/TSC or the study treatment. SECs of interest include for 
example CNS-related events, stomatitis/oral mucositis, infections, renal events and 
amenorrhea. This list is not exhaustive and all the principles guiding the definition and use of 
those categories will be further documented in the Report and Analysis Plan (RAP).
For each specified SEC, number and percentage of patients with at least one event that is part 
of the SEC will be reported.


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10.5.2.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, the study’s biostatistical and reporting team will grade laboratory data 
accordingly. Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high

classification to compare baseline to the worst on-treatment value

listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP.
10.5.2.4 Other safety data
Neuropsychological assessments
Changes from baseline in neurodevelopmental, neurobehavioral and neurocognitive 
assessments and tests of cognitive function will be listed and summarized descriptively by 
treatment group. The instruments/questionnaires that will be used include:

Vineland Adaptive Behavior Scales 2nd Edition (VABS-II)

Wechsler Non-Verbal Scale of Ability
Vital signs
Definitions of notably abnormal results will be defined in the RAP. Analysis will consist of

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
Columbia Suicide Severity Reporting Scale (C-SSRS)
C-SSRS data will be mapped to Columbia Classification Algorithm for Suicide Assessment 
(C-CASA) as per FDA guidance on suicidality (Food and Drug Administration 2010). The 
proportion of patients who have completed suicide, suicide attempt, preparatory actions 
toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior without 


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suicidal intent will be summarized by treatment group. The number of patients with SAEs 
referring to a positive suicidal evaluation will be summarized by treatment group.
Growth Data
Growth data will only be analyzed as part of the long-term evaluation of everolimus among 
patients under the age of 18, i.e., using patients from the LTE Safety Set who were under 18 
years of age on the start date of everolimus. Growth data will be summarized descriptively for 
each treatment group at each time point. These data consist of height, height velocity, weight, 
weight velocity, the age at thelarche and menarche for girls, the age at adrenarche for boys as 
well as the Tanner stage assessment. In addition, based on height data collected during the 
study and published reference height information, the height standard deviation score (SDS, 
also called z-score) will be computed for each patient at each time point as:
(height - mean height for that age category) / SD of height for that age category.
The same approach will be used to compute height velocity SDS, weight SDS and weight 
velocity SDS.
Descriptive statistics of these endpoints will be presented by time point and the z-scores will 
allow identification of potential outliers. Growth velocity during the trial will also be 
compared with growth velocity at baseline (if sufficient pre-baseline data are available).
10.5.2.5 Tolerability
Not applicable for this study.
10.5.3
Pharmacokinetics
Biofluid concentrations will be expressed in mass per volume units. All concentrations below 
the lower limit of quantitation (LLOQ) or missing data will be reported as such in the 
concentration data listings. Concentrations below the limit of quantitation will be treated as 
zero in summary statistics.
Validity of PK samples will be confirmed by checking sampling time window and vomiting.
Only confirmed PK concentrations will be used in the analyses.
Drug concentrations for each treatment group (for core phase only) and each visit will be 
summarized by descriptive statistics. Descriptive statistics of drug concentration will include 
arithmetic and geometric mean, median, SD, coefficient of variation (CV), geometric CV, 
minimum and maximum. Zero concentrations will not be included in the geometric mean 
calculation.
To evaluate the effects of everolimus on exposure of AEDs descriptive statistics will be used
to compare the pre-dose concentrations of AEDs at Visits 1 and 2 (AED alone) with those at 
Visits 3 and 4 (AED plus everolimus).
To evaluate the impact of EIAED/CYP3A4 inducer and inhibitor on everolimus PK, a linear 
mixed model will be fitted to log-transformed Cmin concentration at steady state including log-
transformed dose, use of EIAED/CYP3A4 inducer and inhibitor and other factors as 
appropriate as covariates.


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To explore the relationship between everolimus Cmin and the response rate as defined for the 
primary analysis, a logistic regression model will be used to fit the response data using 
averaged Cmin levels in the maintenance period of the core phase, stratifying by age subgroup
at randomization and adjusting for additional risk factors if appropriate.
The relationship between everolimus Cmin and selected safety endpoints will also be explored 
by an appropriate model-based approach.
10.5.4
Patient-reported outcomes
Quality of life will be assessed using three age-specific questionnaires as follows:

Patients aged ≤ 10 years: Quality of Life in Childhood Epilepsy (QOLCE)

Patients aged 11-17 years: Quality of Life in Epilepsy Inventory for Adolescents-48 
(QOLIE-AD-48)

Patients aged ≥ 18 years: Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-
P)
Descriptive statistics for the overall quality (QOL) score and subscale scores will be presented 
by time point and treatment group in the FAS for each questionnaire.


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10.7
Interim analysis
No interim analysis is planned for this study.
10.8
Sample size calculation
The sample size was chosen to provide adequate power for the primary objective comparing 
seizure frequency between each everolimus arm and the placebo arm. The sample size 
calculation provided here is based exclusively on response rate, the primary endpoint used by 
the EMA, but it is also expected to provide sufficient patients for the power of the FDA 
primary endpoint, percentage reduction in seizure frequency. This is because response rate is 
a binary transformation of percentage reduction in seizure frequency, and therefore likely to 
be less sensitive owing to the loss of information going from a continuous variable to binary.
It was assumed that response rates would be 15% in the placebo arm and 35% in each of the 
two everolimus arms. That is, there was no a priori strong expectation that the higher targeted 
trough everolimus arm 9-15 ng/mL would deliver a higher response rate than the lower 
targeted trough everolimus arm 3-7 ng/mL, as better efficacy may be mitigated by worse 
tolerability. For this reason, the testing strategy was to simultaneously compare each pairwise 
comparison, splitting the significance level, rather than testing hierarchically starting with the 
higher trough arm for example.
Using nQuery version 6.1 it was determined that a sample size of 355 patients would ensure 
90% power for each of the primary comparisons of each everolimus arm versus placebo, 
assuming one-sided 1.25% significance levels for each CMH chi-square test, and assuming 
balanced randomization (i.e., 115 patients per randomization arm).
Table 10-2
Sample size and power for primary objective
Comparison
One-sided 
alpha
Response rates under 
alternative hypothesis
Sample Size
Power
Everolimus 3-7 ng/mL arm versus 
Placebo arm 
1.25%
35% vs. 15%
230 
(115 vs. 115)
90%
Everolimus 9-15 ng/mL arm versus 
Placebo arm 
1.25%
35% vs. 15%
230 
(115 vs. 115)
90%
Approximately 5 months after the first patient was randomized, a human error was identified 
which caused the IRT system not to perform dose titrations despite Cmin values outside the 
targeted trough range. The IRT system was updated the same day. By that time a total of 47 
patients had already passed their Week 2 assessment, the point at which the first dose titration 
could have been made.
After an investigation into the potential impact of this error on the study power, it was noted 
that placebo patients would be unaffected, and in all likelihood, the majority of patients in the 
everolimus 3 to 7 ng/ml arm would be expected to achieve everolimus concentrations within
the targeted range. However, since few patients randomized to the everolimus 9 to 15 ng/ml 
arm would be expected to achieve adequate dosing, it was decided to increase the sample size 
in the everolimus 9 to 15 ng/ml arm by 10 patients.


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The choice of 10 patients was made on the following grounds. Based on the pattern of 
complete and incomplete blocks, up to 18 of the 47 potentially affected patients may have 
been on the everolimus 9 to 15 ng/ml arm. As a worst case, assume all 18 patients were under-
dosed and achieved everolimus concentrations in the 3-7 ng/ml range, and assume that this 
trough range is no better than placebo. Then at the end of the study, among the 115 planned 
patients on the everolimus 9 to 15 ng/ml arm, 18 patients will have a 15% chance of being 
responders (i.e., as placebo arm patients) and 97 will have a 35% chance. Overall this makes 
an expected response rate in the everolimus 9 to 15 ng/ml arm of 31.9%, in which case the 
power for the comparison with the placebo arm drops to 78%. Other more realistic scenarios 
lead to a smaller loss in power, for example with 12 patients under-dosed and subject to 
placebo arm response rate, the power is 83%, with 6 patients it is 87%. The sample size 
increase was chosen to protect against loss in power for these more realistic scenarios, where 
the addition of 10 patients to the everolimus 9-15 ng/ml arm improves power to 85% for 12 
under-dosed patients and to 88% for 6 under-dosed patients.
The sample size increase of 10 patients will be made by inserting a number of blocks with 
randomization ratio of 1:1:2 in favor of the everolimus 9 to 15 ng/ml arm, with the planned 
sample size becoming 355 patients (115 on placebo arm, 115 patients on everolimus 3 to 7 
ng/ml arm and 125 patients on everolimus 9 to 15 ng/ml arm; overall randomization ratio of 
1:1:1.09). The required modification of the randomization list will be overseen by an 
Independent Randomization Expert, a Novartis employee who is not part of the study team.
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. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. 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.


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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 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 
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, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.2.
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 


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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 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.


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12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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14
Appendix A: Using Diffusion Tensor Imaging (DTI) with 
Tractography to Measure the Treatment Effect of Everolimus 
in Tuberous Sclerosis Complex (TSC) Patients with Epilepsy: 
An EXIST-3 Sub-study
14.1
SUMMARY OF DTI SUB-STUDY OBJECTIVES AND RATIONALE
Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence at birth of 1 in 6000.
This disorder is characterized by the development of benign tumors in multiple organ systems, 
including the brain. The primary neurological manifestations of TSC are epilepsy, mental 
retardation and autism. Epilepsy is most common, occurring in 80-90% of patients, and often 
the seizures are severe, unremitting, and uncontrolled by current anticonvulsant medications.
Strong preclinical evidence and more recent phase II human clinical trials reveal that 
treatment with the mTOR inhibitor everolimus can improve seizure control in TSC patients 
who are refractory to conventional anticonvulsant treatments. EXIST-3 is a phase III 
randomized, placebo-controlled, double-blind clinical trial designed to confirm these findings.
We hypothesize that improvement in white matter integrity and connectivity, in conjunction 
with reduced tuber epileptogenicity, by everolimus is an important if not essential mechanism 
of the everolimus anti-seizure effect. We propose to assess this hypothesis through analysis of 
white matter integrity and connectivity using diffusion tensor imaging (DTI) with 
tractography and advanced EEG technology in a subset of EXIST-3 participants through the 
following aims:

Assess the hypothesis that DTI measures of white matter integrity improve after 
treatment with everolimus in epilepsy patients with TSC. Regions of interest (ROI) 
will be determined and analyzed for before and after treatment changes in the everolimus 
and placebo arms. 

Assess the hypothesis that overall and specific tuber epileptogenicity improves with 
treatment with Everolimus. 1 hour EEG utilizing a customized EEG protocol for 
recording high frequency oscillations (HFO) will be obtained at time points coinciding 
with MRI DTI studies. HFO measures (gamma, ripples, fast ripples) will be determined.
14.2
BACKGROUND
Previous clinical trials have demonstrated clear efficacy and favorable clinical tolerability of 
everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR) in the treatment of 
subependymal giant cell astrocytoma (SEGA) and angiomyolipoma (AML) in patients with 
tuberous sclerosis complex (TSC)(Bissler et al 2012; Franz et al 2012). FDA approval for 
these indications occurred in 2010 and 2012, respectively. Relevant to the current proposal, 
improvement in seizure frequency and other neurological and behavioral aspects of TSC has 
been seen in SEGA patients treated with everolimus(Krueger et al 2010). We recently 
completed a phase II clinical trial confirming these earlier results in TSC epilepsy patients 
without SEGA, in which seizure frequency was reduced in 17 of 20 subjects (median 
reduction = 73%) after 12 weeks of therapy (clinicaltrials.gov: NCT01070316, Krueger et al 
2013). The current phase III double-blind randomized placebo controlled trial (EXIST-3, 
CRAD001 M2304) is designed to confirm these earlier phase II results. This sub-study of 


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EXIST-3 subjects is designed to evaluate the value of diffusion tensor imaging (DTI) 
tractography accompanied by high frequency oscillations (HFO) EEG analysis as an 
exploratory measure of clinical benefit in TSC patients with epilepsy treated with everolimus.
As our understanding of TSC matures, it is becoming clear that non-tuber abnormalities, 
especially in the white matter (WM) and subcortical areas, are strongly associated with 
neurological outcome (Wong 2008; Tsai 2011). Diffusion tensor imaging (DTI), a specialized 
type of magnetic resonance imaging (MRI) of the brain that can be combined with 
tractography to determine fascicle structures and connections in matching brain anatomy
(Ciccarelli et al 2008; Mori et al 1999), has been used to detect abnormities in TSC that 
appeared normal with conventional MRI techniques (Garaci et al 2004; Peng et al 2004; Luat 
et al 2007; Arulrajah et al 2009; Krishnan et al 2010, Simao et al 2010; Widjaja et al 2010).
Furthermore, we have shown that DTI measures, such as fractional anisotropy (FA), radial 
diffusivity (RD), and mean diffusivity (MD), improve in TSC patients with SEGA treated 
with everolimus (Tillema et al 2012). Comparing baseline values with those acquired after 12-
18 months of treatment, a significant change in FA was observed in the corpus callosum, 
internal capsule, and geniculocalcarine region (p < 0.05). Mean change in FA was 0.04 (p < 
0.01), driven primarily by a significant decrease in RD, and was independent of SEGA 
response to treatment. These findings suggest that WM integrity can be improved with mTOR 
inhibition in TSC individuals and encourage systematic analysis of the relationship between 
DTI and everolimus treatment response in epilepsy patients with TSC.
Analysis of DTI with tractography in the current context can be further enhanced when 
accompanied with current state of the art advanced EEG analysis that includes high frequency 
oscillations (HFO EEG). HFO EEG is a powerful technique for examining the energy in any 
single frequency band as an indicator of oscillatory synchrony and therefore local functional 
integration. In preliminary experiments, we examined HFO patterns in children with TSC and 
epilepsy and found that HFO EEG analysis revealed a particularly high predictive value of 
epilepsy in otherwise asymptomatic individuals in TSC when compared to traditional EEG 
(Wu, Bebin, unpublished). Specifically, traditional EEG demonstrated a sensitivity of 83% 
and specificity of 50% (n=10), whereas HFO EEG was associated with 100% sensitivity and 
specificity (n=8)
EXIST-3 (CRAD001M2304) is a three-arm, randomized, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of two trough-ranges of everolimus given as 
adjunctive therapy in patients with TSC who have refractory partial-onset seizures. The study 
consists of three phases (1) baseline observation period x 8 weeks; (2) core treatment phase 
from randomization to primary endpoint x 18 weeks; and (3) extension phase from week 18 
until up to 48 weeks after last patient has completed the core phase. Target enrollment for the 
overall study is approximately 355 subjects between ages 2 and 65 (or 1 and 65 in Europe), 
with partial-onset seizures refractory to current medical therapy (failed 2 or more anti-
epileptic regimens), and diagnosis of TSC. The study will be conducted globally, involving 
100-120 different sites. Evaluation of a subset of EXIST-3 patients (about 15 patients) will be 
used to assess the benefit of DTI tractography combined with HFO EEG analysis as an 
independent biomarker of everolimus efficacy.
A number of important considerations must be accounted for in ensuring the successful 
acquisition of comparable data at multiple sites. These include logistical factors such as study 


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protocol compliance, compliance with HIPAA regulations, and technical performance factors 
of imaging equipment (Smith et al 2004; Zhou and Liu 2005: Keator et al 2008). For MRI, 
differences in scanner make, model, field strength, field homogeneity, slew rates, and image 
reconstruction may influence data acquisition (Friedman and Glover 2006a; Friedman and 
Glover 2006b). The quantitative assessment of acquired data may be influenced by the nature 
and sophistication of the post-acquisition image analysis, including approaches for identifying 
and compensating for certain image artifacts. Recent publications have described successful 
multi-site diffusion imaging protocols, with effective assessment and management of inter-
site and intra-site variability related to site-dependent and time-varying characteristics of 
imaging equipment (Zhu et al 2011; Evans 2006). Best practice for data quality assessment is 
to estimate accuracy with respect to a gold-standard phantom, and to characterize 
measurement precision via one of test-retest imaging, imaging with multiple replications, or 
bootstrap estimation.
It became clear during the 2011 International TSC Research Conference in Washington DC 
that single site clinical trials in TSC were going to be limited in their impact and ability to 
move TSC clinical care forward, due to their limited size and scope. To address this need, the 
TSC-CRC was created, consisting of geographically-distributed medical centers across the 
USA each with a large TSC clinic directed by clinician with advanced expertise in TSC .
 
. The TS Alliance 
patient-advocacy organization provides some monetary support and also has key involvement 
aimed at helping identify areas of unmet need in TSC-related research and encouraging 
patient recruitment into TSC-CRC clinical trials. The success of the TSC-CRC is already 
demonstrated in the first 12 months of existence, having been awarded more than $12.5M 
from the National Institutes of Health for clinical trials targeting epilepsy and autism in TSC.
One of the current NIH-funded clinical trials of the TSC-CRC includes sophisticated DTI 
imaging and advanced HFO EEG analysis. As part of the study, the TSC-CRC already has 
identified personnel at each site familiar with acquisition and tasked specifically to ensure 
quality control. 3T MRI scanners at each of the sites will be calibrated every 6 months using 
both the American College of Radiology (ACR) and ‘live human’ (live volunteer who 
undergo repeated imaging at each site) phantoms to ensure DTI accuracy across all the sites
(Friedman 2006; Zhu et all 2011; Evans 2006; Nagy et al 2007; Delakis et al 2004; Tofts et al 
2000; Zou et al 2005). Similar standardization and quality assurance procedures are in place at 
each location for HFO EEG. The advantage of utilizing TSC-CRC sites to conduct this DTI 
sub-study in EXIST-3 is that this standardization across sites will not have to be newly 
created and supervised by Novartis and avoids duplicative effort and cost.
14.3
RESEARCH STRATEGY
14.3.1
Sub-Study Subjects
Up to 15 patients enrolled in EXIST-3 from US TSC-CRC sites will be eligible for 
participation in the DTI sub-study. Enrollment will be competitive across the US TSC-CRC 
sites until the target is achieved. Participation in the DTI sub-study will be considered 
optional, and not prevent enrollment into EXIST-3 if DTI sub-study participation is declined.


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14.3.2
Sub-Study Participation Criteria
Only patients enrolled in EXIST-3 will be eligible for participation in the DTI sub-study and 
same inclusion/exclusion criteria for EXIST-3 will apply for this DTI sub-study.
Inclusion criteria for participation in DTI sub-study:

Meet all inclusion criteria for enrollment in EXIST-3

Provide written, informed consent for participation in the optional DTI sub-study analysis
Exclusion criteria for participation in DTI sub-study:

Ensure no exclusion criteria for enrollment in EXIST-3 apply

Contraindications to MRI scanning, such as metal implants/non-compatible medical 
devices or medical conditions
14.3.3
Sub-Study Procedures
14.3.3.1 Overview
EXIST-3 consists of an 8 week baseline phase, 6 week titration phase, and 12 week 
maintenance phase. The DTI sub-study analysis entails two MRI sessions and two 1-hour 
EEG sessions. The first EEG and MRI will be performed prior to randomization and study 
drug initiation (visit 2, week 0) and will serve as the baseline. The follow-up EEG and MRI 
will be performed at the end of the core phase (visit 11, week 18). Blinding rules in place for 
EXIST-3 will remain in effect for the DTI sub-study analysis (DTI investigators will remain 
blinded to treatment group of participating subjects until final unblinding and analysis of 
entire EXIST-3 dataset).
14.3.3.2 Informed Consent
All prospective subjects and their families will have the DTI sub-study explained by a 
member of the research team or a member of their staff. Participation in the DTI sub-study 
will be optional and not required for participation in EXIST-3. The nature of sub-study tests 
and procedures will be explained together with potential hazards and possible adverse 
reactions. The written informed consent, and patient assent with parental permission, if 
applicable, will be obtained prior to the performance of any screening evaluation, per each 
site’s IRB guidelines.
14.3.3.3 DTI Acquisition
Both structural and diffusion images will be acquired. Sedation will be used if needed to limit 
motion artifact during image acquisition. DTI data will be pre-processed with alignment to 
T1-weighted MPRAGE images to help compensate for eddy currents and patient motion to 
ensure maximum data quality. 3-Telsa MRI scanners will be used at all sites for all subject 
imaging in the DTI sub-study. Image acquisition protocols will be the same as those for the 
TACERN (TSC Autism Center of Excellence Network) study conducted by the TSC-CRC, to 
minimize need for duplicative standardization, allow comparison of results across studies, and 
to provide recommended TSC clinical standard of care brain surveillance imaging. Specific 
sequences will include anatomical imaging, diffusion tensor imaging, functional imaging, and 
post-gadolinium imaging.


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14.3.3.4 HFO EEG Acquisition
As for DTI, EEG acquisition and recording protocols will be the same as those for the 
TACERN study conducted by the TSC-CRC, to minimize need for duplicative standardization, 
allow comparison of results across studies, and to provide recommended TSC clinical 
standard of care EEG recording. One hour of recording is generally sufficient for HFO 
analysis and negates the need for 24-hour EEG used in previous TSC everolimus clinical trials.
Data will be acquired utilizing a 23 electrode enhanced version of the International 10-20 
System, with 9mm gold-disc electrodes to yield a frequency resolution of 0.5Hz. Sedation for 
EEG is not allowed and if performed on the same day as MRI requiring sedation, EEG should 
be obtained prior to the MRI or on a different day. Subjects should be sleep-deprived as much 
as tolerated and scheduled for early to mid-morning or around subjects’ usual nap times to 
increase the likelihood of both awake and sleep epochs being captured during the recording 
session.
14.3.3.5 Data Transfer for Central Analysis
Local sites will be able to review imaging and EEG studies for clinical and safety purposes, 
where previous examinations will be available for comparison. For the DTI sub-study, 
imaging and EEG data will be transferred to 
 for centralized analysis. Prior to 
transfer, all data will be anonymized at the local site with the study type, subject ID, and 
acquisition date as the only identifiers. The local site will retain a copy of the entire study data 
(MRI and EEG) until receipt by 
 is confirmed. Standard redundancy and backup 
procedures will be followed at 
 to ensure data is not lost or compromised until 
analysis is complete. TSC-CRC investigators involved in DTI and HFO EEG analysis will be 
given secure access to 
 servers with the relevant anonymized data sets necessary for 
the analyses outlined in Section 14.3.3.4.
14.3.4
Sub-Study Analysis and Statistical Considerations
14.3.4.1
Analytical Methods
Specific, reproducible, regions of interest (ROI) will be determined, following known 
anatomy, to evaluate multiple white matter regions. These will include (i) the genu and 
splenium of the corpus callosum, (ii) anterior and posterior limb of the internal capsule, and 
(iii) the geniculocalcarine tract. The following four tensor parameters will be determined for 
each of the three ROIs: fractional anisotropy, radial diffusivity, axial diffusivity and mean 
diffusivity, making a total of 12 different analyses. HFO EEG will be quantified in three 
frequency bands, by region corresponding to electrode and frequency, for gamma (30-100Hz), 
ripple frequencies (100-250Hz), and fast ripple frequencies (250-500Hz). Data from the 
regions will be combined, providing three EEG parameters for gamma, ripple and fast ripple 
frequencies.
Change from baseline in the 12 DTI parameters and the 3 EEG parameters will be 
summarized using appropriate descriptive statistics between the pooled everolimus arms and
the placebo arm. Other endpoints include change from baseline in tuber burden, and change 
from baseline in number of regions of the brain with EEG abnormalities. 


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The sample size of about15 patients in this sub-study was chosen for practical reasons rather 
than on the basis of statistical power.
14.4
POTENTIAL BENEFITS, RISKS, AND PRECAUTIONS
14.4.1
Potential Benefits of the DTI Sub-study
14.4.1.1 Potential direct benefit to class
EXIST-3 is a randomized, placebo-controlled, double-blinded, phase III clinical trial using the 
investigational drug everolimus to evaluate its clinical effectiveness as a treatment of 
refractory epilepsy in TSC. The DTI sub-study, using advanced non-invasive imaging and 
electroencephalography (EEG) technologies, provides additional objective assessment 
approaches to assess treatment efficacy and safety. The DTI sub-study will do so without the 
need to involve the entire study population (n=15 vs n=355 for EXIST-3), improving study 
feasibility and limiting patient time and effort within the group. The results of the DTI sub-
study may further support IND application for FDA approval of everolimus for the treatment 
of refractory epilepsy in this study population by providing mechanistic and objective 
evidence of treatment effect. It would also provide supporting evidence for the use of DTI and 
HFO EEG in the future as non-invasive, objective measures of everolimus treatment effect
should everolimus be approved for this indication.
14.4.1.2 Potential direct benefit to subjects
TSC patients already undergo MRI surveillance annually to monitor for the emergence or 
progression of subependymal giant cell astrocytoma (SEGA) (2012 International TSC 
Consensus Conference, manuscript in preparation). More frequent MRI may be indicated if 
SEGA is present and being followed clinically before implementing medical or surgical 
intervention. In the process of DTI acquisition for the present study, MRI obtained has the 
potential to identify SEGA emergence or progression sooner than what would be realized 
otherwise. Like MRI, conventional EEG in TSC is recommended-at time of diagnosis and 
periodically thereafter according to clinical need in refractory epilepsy patients. The purpose 
of conventional EEG is to assess for epileptiform activity and characterize ictal events, both 
of which will be frequent in patients participating in EXIST-3. Participation in the DTI sub-
study will provide such patients two opportunities to non-invasively assess for these findings 
that in turn may have important secondary impact on development, cognitive function, and 
behavior that can directly influence medical decision-making for the same.
Participants also will have potential for benefit after DTI and HFO analysis is completed. The 
previously discussed Phase II Everolimus for SEGA in TSC clinical trial is now in extension 
phase, with patients treated now out to 5+ years. At the time of most recent analysis, in which 
all patients were treated at least 2 years, patient-reported seizure frequency demonstrated 
improvement at 12 and 24 months that was not evident in all participants at the conclusion of 
the main study phase (6 months) (Krueger et al 2013). In fact, improvement seems to be more 
evident the longer treatment is continued (Krueger et al 2013). Thus evidence of DTI or HFO 
EEG improvement within individual study participants could provide compelling evidence to 
pursue continued treatment with everolimus on a clinical basis even if clear improvement in 
seizure frequency is not immediately evident.


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14.4.2
Potential Risks of the DTI Sub-study
MRI and EEG used to acquire DTI and HFO EEG data for the sub-study are routine clinical 
procedures considered safe and carry negligible risk. Both procedures are routinely performed 
in the TSC population eligible for participation in EXIST-3.
EEG has minor risk of skin irritation from the adhesive used for application of the electrodes.
MRI utilizes electromagnetic signals to generate non-invasive images internal organs of 
patients, including the brain. MRI itself does not affect body tissues, but can interfere or cause 
discomfort in patients with non-compatible surgical implants and devices. MRI contrast agent 
(gadolinium) can rarely cause hypersensitivity or skin reactions in susceptible individuals and 
individuals with severely compromised renal clearance. In both instances (incompatible 
medical devices or medical conditions), such patients are excluded from participation in the 
EXIST-3 DTI sub-study.
EEG will be obtained without sedation. In contrast, MRI in TSC refractory epilepsy patients 
often requires sedation to obtain suitable images for clinical interpretation and analysis
(Curatolo et al 2002; Jansen et al 2008). This is particularly true for DTI acquisition, which is 
additionally susceptible to motion artifact and eddy currents and other distortions.
Complications with sedation are rare (Karian et al 2002), but include risk of over-sedation, 
respiratory depression, and post-sedation effects on mental status, behavior, and cognitive 
performance (Schulte-Uentrop and Goepfert 2010; Edwards and Arthurs 2011).
14.4.3
Additional Precautions
Inclusion and exclusion criteria already outlined in the main EXIST-3 protocol will apply to 
the DTI Sub-study as well, with the few additional criteria defined in Section 14.3.2. Adverse 
event reporting, subject removal, safety monitoring, emergency unblinding, stopping rules, 
data quality assurance and handling, patient confidentiality, and all other safety and regulatory 
rules detailed in the main EXIST-3 protocol will continue to apply and be adhered to for all 
DTI sub-study activities.
14.4.4
Cost
Neither third party payers, subjects, nor their families will be charged for the performance of 
MRI scans and EEG studies to be used for the DTI sub-study.
14.4.5
Analysis of Benefit and Risk for DTI Sub-study Participation
In summary, TSC patients with medically refractory epilepsy and having failed previously 
multiple AED medications have limited options for improved seizure control using currently 
available anticonvulsant medications and are at highest risk of poor long-term neurological 
outcome. EXIST-3 is a phase 3 clinical trial designed to evaluate the safety and efficacy of 
everolimus for seizure control in this population. EXIST-3 participation is considered to be of 
more than minimal risk with potential for direct patient benefit. The only additional risk of 
DTI sub-study participation is encountered with sedation required for MRI during the 
acquisition of DTI. This risk is countered by the DTI sub-study’s potential to provide an 
objective measures to treatment effect and establish evidence for everolimus mechanism of 
action in treating epilepsy Thus there is benefit to class while minimizing the number of 


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subjects needed for the analysis (direct benefit to overall study and indirect benefit to 
subjects). Direct benefit to DTI sub-study participants is also possible through heightened 
MRI surveillance for SEGA emergence/progression and EEG monitoring for epileptiform 
activity and seizures. DTI and HFO analysis may also provide direct evidence of treatment 
benefit on an individual basis that may prove useful for future treatment decisions involving 
patient care with everolimus after completion of EXIST-3. Altogether, both EXIST-3 main 
study and DTI sub-study represent more than minimal risk, with the potential for direct and 
indirect patient benefits.

SAP_001.pdf: 
Clinical Development
Afinitor®/Votubia®/Everolimus
CRAD001M2304 / NCT02962414
A three-arm, randomized, double-blind, placebo-controlled 
study of the efficacy and safety of two trough-ranges of 
everolimus as adjunctive therapy in patients with tuberous 
sclerosis complex (TSC) who have refractory partial-onset 
seizures
RAP Module 3 – Detailed Statistical Methodology –
Addendum 1
Author:
Document type:
RAP Documentation
Document status:
Final version 2.0
Release date:
March 16, 2016
Number of pages:
98
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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DOCUMENT CONTENT
This document describes in detail the primary analysis that will be incorporated into the CSR, 
consisting of double-blind Core phase comparative analyses between everolimus and placebo, 
plus descriptive analyses of the data from the first part of the Extension phase. The document 
also describes the analyses for the final analysis, conducted at the end of the trial, focusing on 
the long-term evaluation of everolimus using all data on everolimus from both the Core and 
Extension phases of the trial. The study will include interim safety reviews by a Data 
Management Committee, for which a separate analysis plan will be prepared.
Document History – Changes compared to previous version of RAP Module 3
Version
Date
Changes
1.0
26-Jul-2013
First approval
1.0 –
Amendment 1
20-Aug-2015
- Update of the primary endpoint calculations, following protocol 
amendment 2. Sensory seizures that have been shown to be partial 
onset with an ictal EEG will be counted in the primary endpoint 
calculations.
- Further clarifications on how to obtain one-sided p-values for the 
CMH and Rank ANCOVA test statistics are added.
-
Subgroup analyses of efficacy and safety by
number of 
concomitant AEDs added.
- Update definition of the treatment arms to be displayed for the 
Long-Term Evaluations of safety and efficacy, following the new 
study design for the extension phase of the trial introduced by the 
protocol amendment 2.
- Addition of two sensitivity analyses for the primary endpoints, to 
evaluate the potential impact of missing data in the daily seizure 
diary.
- Update of the groupings used to analyze certain types of seizure 
categories of particular interest. Particularly, sensory seizures are 
now considered of interest by protocol amendment 2. 
- Review of the definition of major protocol deviations leading to 
exclusion from the Per-protocol Set:
- Criteria for minimum duration of baseline changed from 54 days to 
49 days
- Clarifications on the major PDs related to concomitant AED 
regimens and everolimus treatment received.
- Removal of the criteria for the use of rescue medication
- Vineland data:
-
Further clarifications added on the process to obtain the 
subdomain/domain and global scores using an external software.
- Due to improper filling-out of the questionnaires, subdomain 
scores were missing frequently. An attempt is being made to 
retrospectively collect the missing information. Inclusion of a 
supportive analysis using all available data is described in this RAP 
amendment.
- Raw scores from the Wechsler Non Verbal scale will be used,
converted to a z-score. No attempt is made to derive standardized 
T-scores comparing to the reference population provided with the 
WNV evaluation tool.


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Version
Date
Changes
- Columbia Suicide Severity Rating Scale: clarification on the 
analysis of incomplete calls to the IRT when followed by a complete 
call. 
- Update of the PK/PD analyses 
- Update of the growth data analyses to use the references 
provided by the World Health Organization (WHO), rather than the 
references provided by the Center for Disease Control (CDC), 
(when WHO references are available).
- Further clarifications on reporting of prior Antiepileptic drugs 
received by patients.
- Further clarifications added on the use of the CTCAE v4.03 for the 
derivation of hematological/biochemical parameter grades.
- SAS procedure to estimate the mean difference (and its 95% CI) 
between two continuous variables is added.
- Further minor updates, clarification and corrections
2.0 -
Amendment 2
18-Nov-2015
The changes implemented in this CSR RAP-Amendment 2 are the 
following:
Changes related to efficacy analysis:
Addition of two subgroup analyses:
1)
Response rate and percentage reduction in seizure 
frequency in the subgroup of patients with at least one 
Subpendymal Astrocytoma lesion (SEGA).
2)
Response rate and percentage reduction in seizure 
frequency by considering only the Generalized Tonic Clonic 
Seizures (GTCS) (seizure code: IC4).
For the QOLIE-AD-48 and the QOLIE-31-P questionnaires, the rule 
for the derivation of the total scores in case of missing subscales 
will be updated in the RAP Module 3 in order to be consistent with 
the Scoring Manual.
Changes related to safety analysis:
The term “Clinically Notable Adverse Event (CNAE)” will be 
replaced by “Adverse Event of Special Interest (AESI)”.
Other general changes:
Minor updates, clarification and corrections added throughout the
documents.
 
 
 
 
 
 


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Version
Date
Changes
 
 
 
 
 
All other updates, clarifications and corrections arose during the 
review of dry runs and were requested in order to meet the 
requirements of submission documents (Case Study Report for 
safety updates) or to correct inconsistencies between RAP module 
3 and RAP module 7.
2.0 -
Addendum 1
16-Mar-2016
The changes implemented in this CSR RAP-Addendum 1 are the 
following:
-
Details on derivation of projected Cmin for PK analyses 
were added (section 3.13.1.2).
-
Two figures to assess the effect of everolimus in seizure 
frequency were added: waterfall plot and cumulative plot of 
percentage reductions from baseline in seizure frequency.
-
 
 
 
 
 
-
The term “Clinically Notable Adverse Event” (CNAE) was 
replaced by “Adverse Event of Special Interest” (AESI).
-
Dose-proportional tests by age range and by the use of 
CYP3A4 inducer/inhibitor (without inducer and inhibitor, 
with inducer and without inhibitor, with inhibitor and without 
inducer) will be addressed in the CSPD documents and 
removed from this statistical analysis plan.
-
For the FDA primary endpoint using a rank ANCOVA test, 
the effect size (measuring the magnitude of the everolimus 
effect) will be assessed by using a stratified bootstrap 
method to estimate the difference between median 
percentage reduction from baseline between everolimus 
treatment arms and placebo.
Statistical methods planned in the protocol and determination of sample size
Data will be analyzed by Novartis and/or a designated CRO according to the data analysis 
Section 10 of the study protocol which is available in Appendix 16.1.1 of the CSR. Important 
information is given in the following sections and details are provided, as applicable, in 
Appendix 16.1.9 of the CSR.


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Statistical and analytical plans
The planned analysis is described in Section 10 of the protocol (Appendix 16.1.1).
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented unless specified in a 
different way.
It is planned that the data from all centers that participate in this protocol will be used. 
Primary efficacy analysis will be stratified, reflecting the stratified nature of the 
randomization method.
Subjects and treatments
Analysis sets
Full Analysis Set (FAS): The FAS comprises all patients to whom study treatment has been 
assigned by randomization. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment arm and stratification factor that they were assigned to at 
randomization.
Safety Set: The Safety Set includes all patients who received at least one dose of study 
medication in the Core phase, and had at least one post-baseline safety assessment in the Core 
phase (where the statement that a patient had no adverse event (on the Adverse Events eCRF) 
constitutes a safety assessment).
There are three treatment groups in the study: everolimus titrated to a trough concentration of 
3 to 7 ng/ml, everolimus titrated to a trough concentration of 9 to 15 ng/ml, and placebo. The 
usual approach for the Safety Set would be to analyze patients according to study treatment 
received. However, that is not possible because the two everolimus arms have the same 
treatment received (i.e., everolimus), and are only differentiated by differing targeted trough 
ranges. Therefore, patients randomized to one of the two everolimus arms and who received at 
least one dose of everolimus, will be analyzed in the Safety Set according to the everolimus 
treatment arm assigned at randomization. Similarly, patients randomized to placebo and who 
received at least one dose of placebo, will be analyzed in the placebo arm of the Safety Set.
That is, only patients who received the wrong treatment regimen throughout their entire time 
in the Core phase will be reassigned to a different treatment arm in the Safety Set compared 
with the FAS, as follows:

Patients randomized to either of the two everolimus arms and who received only placebo 
tablets during the Core phase will be reassigned to the placebo arm in the Safety Set. This 
could happen for example if the first kit of study medication contained only placebo 
tablets (i.e., given in error), and the patient took at least one tablet and then subsequently 
discontinued before taking any everolimus tablets.

Patients randomized to the placebo arm and who received only everolimus tablets during 
the Core phase will be reassigned to the everolimus 3 to 7 ng/ml arm in the Safety Set. 
Again this would require a dispensing error in the first kit of study medication, followed 
by early discontinuation. Note that the reassignment is to the lower everolimus targeted 
trough arm, chosen because such an error in starting dose would be recognized via IRT 
before any dose increase could be made.


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Note that there will be no attempt to reassign patients from one everolimus arm to the other 
everolimus arm based on observed everolimus concentrations during the Core phase. For 
example, a patient randomized to the everolimus 9 to 15 ng/ml arm and whose observed 
everolimus trough concentrations ranged from 3 to 7 ng/ml during the entire Core phase 
would still be considered to have treatment received = everolimus 9 to 15 ng/ml. This is 
because increases in the dose of everolimus would have been recommended during the Core 
phase in order to reach the targeted trough range of 9 to 15 ng/ml, and any associated toxicity 
should therefore be attributed to the 9 to 15 ng/ml arm and not the 3 to 7 ng/ml arm.
Per-Protocol Set (PPS): The PPS will be a subset of the patients in the FAS who are
compliant with requirements of the protocol, who are evaluable for efficacy and who have 
completed a minimum exposure requirement. However, if a patient discontinued for lack of 
efficacy, adverse event or death before the minimum exposure requirement could be met, or 
before he/she could become evaluable for efficacy, that patient will still be included in the 
PPS.
Patients will be evaluable for efficacy if their seizure diary continues until at least day 70 of 
the Core phase, i.e., at least the first 4 weeks of the maintenance period of the Core phase.
The minimum exposure requirement is defined as receiving study treatment on ≥ 50% of days 
during the first 10 weeks of the Core phase.The following list of major protocol deviations 
will constitute reason for excluding the patient from the PPS:

Absence of diagnosis of TSC or partial-onset epilepsy.

Previously failed < 2 sequential regimens of single or combined AEDs.

Prior therapy with systemic or topical mTOR inhibitors within the exclusion criteria time 
windows.

Baseline seizure diary with < 16 ESC-approved partial-onset seizures.

Baseline seizure diary containing a seizure-free period of ≥21 consecutive days.

Baseline seizure diary < 49 days in duration.

Did not receive 1-3 AEDs at same dose from 4 weeks prior to screening visit to baseline
visit

Change in dose for more than 7 days or in number of concomitant AEDs during Core 
Phase or interruption of AED > 7 days

Missing seizure information on > 50% of days in the Core phase or the Baseline phase.

Received the wrong treatment regimen throughout their entire time in the Core phase, 
defined as:

Patients randomized to either of the two everolimus arms and who received only 
placebo tablets during the Core phase.

Patients randomized to the placebo arm and who received only everolimus tablets 
during the Core phase.
Long-Term Evaluation Efficacy Set (LTE Efficacy Set): The LTE Efficacy Set is intended 
to capture all data on everolimus in the trial, from both the Core phase and the Extension 
phase. It consists of all patients who received at least one dose of everolimus in the trial and 


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have at least one post-baseline efficacy measure. Patients will be analyzed as a single 
everolimus group as well as separately according to their randomized treatment arm in the 
Core phase (i.e., everolimus trough ranges of 3-7 ng/ml and 9-15 ng/ml, or placebo). This 
analysis set will be used for long-term efficacy analyses of everolimus.
Before protocol amendment 2, patients from the two everolimus groups were to continue in 
the Extension phase with the same targeted trough range from Core phase, while placebo 
patients were to be switched to receive everolimus during the Extension phase with a 3-15 
ng/ml targeted trough. Protocol amendment 2 introduced the possibility for investigators to 
make the dose adjustments in the Extension phase based on the Cmin value. If investigators 
choose not to modify dosing themselves, the dose was determined by the IRT system to 
maintain the everolimus trough concentration range between 3-15 ng/ml for all patients. In 
order to avoid compromising the blinded nature of the study in the earlier Core phase 
(including the investigator, patient and sponsor), all patients were to be transitioned towards a 
common targeted trough range of 6 to 10 ng/ml before any Cmin value is shared with the 
investigator. For this reason, for analyses of long-term evaluation data from the Core and 
Extension phase, patients will be analyzed as a single everolimus group (“All patients”) as 
well as separately according to their randomized treatment arm in the Core phase (i.e., 
everolimus trough ranges of 3-7 ng/ml and 9-15 ng/ml and placebo). Note that “placebo” arm
will only contain data from the Extension phase when patients received everolimus.
Long-Term Evaluation Safety Set (LTE Safety Set): The LTE Safety Set is intended to 
capture all data on everolimus in the trial, from both the Core phase and the Extension phase. 
It consists of all patients who received at least one dose of everolimus in the trial and have at 
least one post-baseline safety measure. Patients will be analyzed as a single everolimus group 
as well as separately according to their randomized treatment arm in the Core phase (i.e., 
everolimus trough ranges of 3 to 7 ng/ml and 9 to 15 ng/ml, or placebo. This analysis set will 
be used for long-term safety analyses of everolimus.
For the same reason as described above for the LTE Efficacy Set, patients will be analyzed as 
a single everolimus group (“All patients”) as well as separately according to the randomized 
treatment arm in the Core phase (i.e., everolimus trough ranges of 3 to 7 ng/ml and 9 to 15
ng/ml and placebo). Note that “placebo” arm will only contain data from the Extension phase 
when patients received everolimus.
Pharmacokinetic analysis set: There will be no formal pharmacokinetic analysis set. The 
pharmacokinetic analyses will be performed in the Safety Set and the LTE Safety Set using all 
available PK samples from the Confirmed PK Sample Set or PK Sensitivity Sample Set, as 
defined below (section 3.13.1.1).
Patient demography and other baseline characteristics
Demographic (age, gender, ethnicity, weight, height, BMI, BSA) and disease characteristics
(time since diagnosis of partial onset seizures, prior epilepsy surgery, prior VNS, prior 
ketogenic diet, seizure history (status epilepticus, simple partial seizure, complex partial 
seizure, secondarily generalized tonic clonic convulsion, primarily generalized tonic clonic 
convulsion, absence, myoclonus, tonic, clonic, other), major/minor features of TSC) will be
listed and summarized descriptively by treatment group in the FAS and in the LTE Efficacy 


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Set. Prior anti-TSC therapies and number and type of prior antiepileptic drugs (AEDs) will 
also be listed and summarized by treatment group.
Treatment (study drug, background AED regimen, other concomitant therapies)
Duration of study treatment exposure, cumulative dose and dose intensity will be summarized 
by treatment group. The numbers of patients with dose changes/interruptions will be 
presented by treatment group, along with reasons for the dose change. These analyses will be 
conducted over the Core phase on the Safety set, and over the entire study using the LTE 
Safety Set.
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drugs will be listed and summarized by ATC term, preferred term, and treatment arm by 
means of frequency counts and percentages. Of particular interest will be the medications 
used in the background AED regimen. In addition, specific tables will be produced for rescue 
medication and medications that may affect everolimus mechanism of action (i.e., CYP3A4, 
PgP).
Efficacy evaluation
Analysis of primary efficacy endpoint
The primary efficacy endpoint is the reduction from baseline in the frequency of partial-onset 
seizures during the maintenance period of the Core phase. Two separate definitions of the 
primary efficacy endpoint will be used, owing to the differing regulatory preferences between 
Europe and USA for demonstrating efficacy of an antiepileptic medication. Whereas the EMA 
prefers response rate to be the primary variable, the FDA prefers percentage reduction in 
seizure frequency. It is understood that each Agency will use their preferred variable as the 
primary variable, with the other (non-primary) variable being used in a supportive analysis. 
As each Agency will only use their preferred primary variable to make a decision on the 
primary objective, the full alpha level can be used for each Agency’s primary variable, 
without correction for multiplicity. This approach has been endorsed by both EMA and FDA.
Response rate and percentage reduction in seizure frequency will be determined using counts 
of partial-onset seizures, based on seizure diaries that are completed by the patient or 
caregiver throughout the trial. During the baseline phase the investigator will review the 
known seizure types of each patient with the Epilepsy Study Consortium (ESC), an 
independent group of experienced epileptologists charged with harmonizing the classification 
of partial-onset seizures in the trial. Only seizures approved by the ESC and agreed to by the 
investigator will be entered into the eCRF and counted as partial-onset seizures. 
The following definitions are required to calculate response rate and percentage reduction in 
seizure frequency:
1. Average weekly seizure frequency in the Baseline phase (SFB) = 7 × number of partial-
onset seizures recorded over the 8 week prospective Baseline phase ÷ number of non-
missing seizure diary days in the 8 week prospective Baseline phase.
2. Average weekly seizure frequency in the maintenance period of the Core phase (SFM):


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
If patient does not discontinue during the 6 week titration phase, SFM = 7 × number of
partial-onset seizures recorded during the maintenance period of the Core phase ÷
number of non-missing seizure diary days in the maintenance period of the Core phase.

Otherwise, SFM = 7 × number of partial-onset seizures recorded during the titration
period of the Core phase ÷ number of non-missing seizure diary days in the titration
period of the Core phase.
That is, patients who discontinue prior to the maintenance period have seizure frequency 
determined using their data from the titration period, thereby assuring that all patients with 
seizure data in the Core phase have a value for SFM.
3. Percentage reduction from baseline in average weekly seizure frequency during the
maintenance period of the Core phase (%Red) = 100 × (SFB - SFM) ÷ SFB.
Point 3 is the FDA primary variable, percentage reduction in seizure frequency, defined 
by %Red.
A responder is a patient with ≥ 50% reduction from baseline in average weekly partial-onset 
seizure frequency during the maintenance period of the Core phase, that is, when %Red ≥50.
Response rate is the percentage of responders in a treatment group.
Response rate will be compared between each everolimus arm versus the placebo arm in the 
FAS, using Cochran-Mantel-Haenszel (CMH) chi-square tests stratified by age subgroup. The
Bonferroni-Holm procedure will be used to ensure an overall family-wise Type I error rate of 
2.5% one-sided. Response rates will be provided with exact 95% confidence intervals, and the 
odds ratio for each everolimus arm versus placebo will be obtained from logistic regression
models stratified by age subgroup.
Percentage reduction in seizure frequency, the FDA primary variable, will be compared
between each everolimus arm versus the placebo arm in the FAS using rank ANCOVA, with 
baseline average weekly seizure frequency as a covariate, and stratified by age subgroup. The 
Bonferroni-Holm procedure will be used as a multiplicity correction to ensure an overall 
family-wise Type I error rate of 2.5% one-sided. The median percentage reduction from 
baseline will be presented for each treatment group, along with 95% bootstrap confidence 
intervals.
For the EMA primary variable of response rate, a supportive analysis will be the FDA primary 
analysis on percentage reduction in seizure frequency, and vice versa.
The primary analysis of both the EMA and FDA primary variables will be repeated in the Per
Protocol Set.
Descriptive statistics (n, mean, median, standard deviation, minimum and maximum) for 
average weekly seizure frequency in the Baseline phase (SFB), in the maintenance period of 
the Core phase (SFM), and percentage reduction from baseline (%Red), will be presented by 
treatment group in the FAS. The quantities for seizure frequency will also be summarized in 
units of 28 days instead of weekly, i.e., average number of partial-onset seizures per 28 days 
in the Baseline phase, and per 28 days in the maintenance period of the Core phase. 
In addition, sensitivity analyses will be conducted in the FAS to assess robustness of the
primary analysis to (i) patient discontinuation before the end of the Core phase, (ii) the


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calculation of seizure frequency across the entire Core phase (i.e., titration period as well as
maintenance period), (iii) missing daily seizure data.
For (i), the sensitivity analysis will assume no change from baseline in seizure frequency for
patients discontinuing in the Core phase, compared with the approach for the primary analysis 
where the actual seizure frequency calculated up to the day of discontinuation will be used. 
Response rate and percentage change from baseline in seizure frequency will be recalculated 
for this sensitivity analysis and analyzed per the primary analysis.
For (ii), the sensitivity analysis will use the average weekly seizure frequency over the entire
Core phase, that is, over the 6-week titration period plus the 12-week maintenance period.
This compares with the primary analysis where titration period data will not be used to 
calculate average weekly seizure frequency if the patient continues into the maintenance 
period. The variable to be used in the sensitivity analysis, labeled SFTM is defined as follows:

Average weekly seizure frequency in the entire Core phase (SFTM) = 7 × number of
seizures recorded over the entire Core phase (titration plus maintenance) ÷ number of non-
missing seizure diary days in the entire Core phase (titration plus maintenance).
Response rate and percentage reduction in seizure frequency will be re-calculated using SFTM
instead of SFM, and analyzed as per the primary analysis.
For (iii), two approaches will be considered:
- Best case scenario: this sensitivity analysis will assume that patient experienced no 
seizures (i.e. missing data imputed to 0) in the maintenance period on the days where the data 
is reported as missing in the eCRF. For the baseline phase, it will be assumed that the patient 
experienced the maximum number of seizures that she/he has experienced during the baseline 
phase (i.e. missing data imputed to maximum daily seizure count). 
- Worst case scenario: this sensitivity analysis will assume that the patient experienced 
the same maximum number of seizures that she/he experienced during the maintenance period 
on the days where the data is reported as missing in the eCRF in the maintenance period (i.e. 
missing data imputed to maximum daily seizure count). For the baseline phase, it will be 
assumed that the patient experienced no seizures (i.e. missing data imputed to 0) on these 
missing days. 
Response rate and percentage change from baseline in seizure frequency will be recalculated 
for this sensitivity analysis and analyzed per the primary analysis.
Subgroup analyses will be performed to compare each everolimus arm versus placebo on the 
primary analyses of response rate or percentage reduction in seizure frequency. The 
subgroups that will be analyzed include gender, age, race and ethnicity. Subgroup analyses of 
the main efficacy and safety endpoints will be performed on patients randomized in Japan, for 
use by the Japanese regulatory authority.
Analysis of secondary endpoints
Seizure freedom is defined as remaining seizure-free during the maintenance period of the 
Core phase (or during the titration period for patients who discontinue during the titration 
period). The seizure-free rates for each treatment arm in the FAS will be presented along with 
exact 95% confidence intervals, and the odds ratio for each everolimus arm versus placebo


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will be derived from logistic regression models stratified by age subgroup. A sensitivity 
analysis will be performed where patients who discontinue during the Core phase are assumed 
not to be seizure-free even if no seizures had been reported before they discontinued.
The proportions of patients with at least 25% reduction in seizure frequency during the 
maintenance period of the Core phase (or titration period for patients who discontinue in the 
titration period) will be presented in each treatment arm along with exact 95% confidence 
intervals, and odds ratios for each everolimus arm versus placebo from logistic regression 
models stratified by age subgroup.
The distribution of reduction from baseline in seizure frequency will be categorized into 
the following six levels using the variable %Red defined above: (≤ -25% (exacerbation); > -
25% to < 25% (no change); ≥ 25% to < 50% (25% response); ≥ 50% to < 75% (50% 
response); ≥ 75% to < 100% (75% response); 100% (seizure freedom)), and the proportions of 
patients in each category will be presented for each treatment arm.
The frequency of seizure-free days per 28 days during the maintenance period of the Core 
phase will be obtained for each patient, calculated as 28 × number of partial-onset seizure-free 
days in the maintenance period of the Core phase ÷ number of non-missing seizure diary days 
in the maintenance period of the Core phase. For patients who discontinue in the titration 
period, the number of seizure-free days per 28 days during the titration period will be used. A 
similar quantity will be calculated for the Baseline phase. Then the change from baseline in 
frequency of seizure-free days per 28 days will be summarized by treatment arm (mean, 
standard deviation, range). Mean differences between each everolimus arm and the placebo 
arm in change from baseline in frequency of seizure-free days will be presented, along with 
95% confidence intervals.
Treatment duration is defined as the time from randomization until the date of permanent
study treatment discontinuation (for any reason) at any time during the Core phase (i.e., 
titration period or maintenance period). Patients who complete the Core phase without 
discontinuing will have treatment duration censored on the last day of the Core phase. The 
treatment duration distributions in each arm will be presented descriptively in the FAS using 
Kaplan-Meier curves, from which summary statistics will be determined, including the
median treatment duration and the proportions of patients still on treatment at 6 and 12 weeks.
These statistics will be given as point estimates with 95% confidence intervals. The hazard
ratio (and two sided 95% confidence interval) for each everolimus arm versus placebo will be
obtained from a Cox proportional hazards model stratified by age subgroup.
A long-term evaluation of efficacy over the extension phase will use descriptive statistics 
of percentage reduction from baseline in partial-onset seizure frequency, response rate and 
seizure-free days, computed by time interval using the LTE Efficacy Set. For patients 
randomized to one of the two everolimus arms, all data from the Core phase and the 
Extension phase will be used, whereas for patients randomized to placebo, only the Extension 
phase data will be included. There will be 4 different treatment groups displayed: everolimus 
3 to 7 ng/ml, everolimus 9 to 15 ng/ml, placebo (i.e., extension phase data from patients 
previously randomized to placebo) and an overall everolimus arm.


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Pharmacokinetic evaluations
PK analyses will be based on evaluable samples from patients in the Safety Set, and for the 
long-term evaluation of everolimus, in the LTE Safety Set. The validity of PK samples will be 
confirmed by checking the sampling time window and whether the patient vomited within 4 
hours of taking study drug. Only confirmed PK concentrations will be used in the analyses.
For each everolimus treatment group, everolimus concentrations at trough (Cmin) will be 
summarized by descriptive statistics at each PK sampling time during the Core phase in the 
Safety Set, and during the Core and Extension phases in the LTE Safety Set. The descriptive 
statistics will be arithmetic and geometric mean, median, standard deviation, coefficient of 
variation (CV), geometric CV, minimum and maximum. 
To evaluate the impact of CYP3A4/PgP inducer and inhibitor on everolimus PK, a linear 
mixed model will be fitted to log-transformed Cmin concentration at steady state including log 
transformed dose, use of CYP3A4/PgP inducer and inhibitor and other factors as appropriate 
as covariates.
To explore the relationship between everolimus Cmin and the response rate as defined for the 
EMA primary analysis, a logistic regression model will be used to fit the response data using 
time-normalized Cmin levels in the maintenance period of the Core phase, stratifying by age 
subgroup and adjusting for additional risk factors if appropriate.
A linear regression model will be used to characterize the impact of exposure on the average 
weekly seizure frequency. The model will include baseline seizure frequency (SFB) and time-
normalized Cmin in the maintenance period of the Core phase, both in log scale.
A linear mixed model with repeated measurements will be used to link the post baseline 
average weekly seizure frequency to the time normalized Cmin in defined time intervals during 
the Core phase. The model will be adjusted by the baseline frequency of seizure (SFB). Other 
covariates will be included if appropriate.
The relationship between everolimus Cmin and selected safety endpoints will also be explored 
by an appropriate model-based approach. In addition the time to first event of selected AEs 
will be fitted with an extended Cox model with projected Cmin as a time varying covariate, 
stratified by age subgroups. 
To evaluate the effects of everolimus on the exposure of 12 different AEDs, descriptive 
statistics will be used to compare the pre-dose concentrations of AEDs at Visits 1 and 2 (AED 
alone) with those at Visits 3 and 4 (AED plus everolimus) in the two everolimus treatment 
groups. In addition, separate linear mixed models will be fitted to log transformed 
concentration levels of each of the 12 AEDs, including period (before and after everolimus 
administration) as a fixed effect and patient as random effect. Geometric mean ratios of the 
concentrations with and without everolimus (as reference) and their 90% confidence intervals
will be calculated from the model.
Safety evaluation
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data 


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including vital signs, neuropsychological scales and the Columbia Suicide Severity Rating 
Scale will also be considered.
Safety analyses will be performed on the Safety Set, and on the LTE Safety Set.
Safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. All safety assessments will be listed and those collected later 
than 30 days after study treatment discontinuation will be flagged.
Serious AEs, AEs leading to discontinuation, AEs requiring dose reduction/interruption,
related AEs and notable AEs will be summarized by system organ class, preferred term and 
treatment. Maximum grade by AEs will be also summarized. The time to first occurrence of 
selected AEs will be assessed in the double blind Core phase.
All laboratory values will be converted into SI units. Shift tables using CTCAE grades when 
available or low/normal/high/ (low and high) classification when no CTCAE grades are 
available will be used to compare baseline to the worst on-treatment value.
The Vineland-II instrument (Vineland Adaptive Behavior Scales 2nd Edition) will be 
completed by patients at baseline, end of Core phase, and then every 6 months in the 
Extension phase plus at the end of treatment in the Extension phase. Changes from baseline in 
domain and subdomain scores will be listed and summarized descriptively by treatment group
in both the Safety Set and the LTE Safety Set. 
The Wechsler Nonverbal instrument (WNV: Wechsler Nonverbal Scale of Ability) is for 
patients aged 4-21 years at baseline, and will be completed at baseline, end of Core phase, and 
then every 6 months in the Extension phase plus at the end of treatment in the Extension 
phase. Changes from baseline in overall and test scores will be listed and summarized 
descriptively by treatment group.
The Columbia Suicide Severity Rating Scale will be completed by patients at all visits 
(except weeks 1, 3, 5 and 19 when only PK samples are collected, and the End of Study visit). 
The proportions of patients in each treatment group in the Safety Set with suicidal ideation, 
suicidal behavior and suicidal ideation or behavior, will be presented by treatment group. This 
analysis will be repeated using the LTE Safety Set.
Interim analyses
No interim analysis for efficacy is planned, but there will be DMC reviews of the ongoing 
safety data as the trial progresses. The first meeting will review data from the first 6 months of 
the study, with subsequent meetings every 6 months thereafter. As outlined in the DMC 
charter, the safety review outputs will be prepared by an independent statistician and an 
independent programmer from Novartis, neither of whom will belong to the trial team or will 
be involved in any other aspects of the trial conduct. Semi-blinded results will be shared with 
the DMC members using a secured web portal to which Novartis personnel have no access
(except independent statistician/programmer). After the meeting, the DMC chair will provide 
the recommendation to Novartis Oncology global development head. Apart from the 
recommendation made, the Novartis team members will remain blinded to any study results.


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Other topics
Patient reported outcome
Quality of life will be assessed using three age-specific questionnaires: the Quality of Life in 
Childhood Epilepsy (QOLCE) for patients aged ≤ 10 years, the Quality of Life in Epilepsy 
Inventory for Adolescents-48 (QOLIE-AD-48) for patients aged 11 to ≤ 17 years, and the 
Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P) for patients aged ≥ 18 years. 
Descriptive statistics for the overall quality (QOL) score and subscale scores will be presented 
by time point and treatment group in the FAS for each questionnaire.
Growth data
Growth data will only be analyzed as part of the long-term evaluation of everolimus among 
patients under the age of 18, i.e., using patients from the LTE Safety Set who were under 18 
years of age on the start date of everolimus.
Data will be summarized descriptively for each treatment group at each time point. The data 
will consist of height, height velocity, weight and weight velocity. In addition, based on the 
data collected during the study and published reference information, the standard deviation 
score (SDS, also called z-score) will be computed for each patient at each time point for 
height, height velocity, weight and weight velocity.
Descriptive statistics of these endpoints will be presented by time point and the z-scores will 
allow identification of potential outliers. Growth velocity during the trial will also be 
compared with growth velocity at baseline (if sufficient pre-baseline data are available).
Comparison of height at 18 years with mid-parental heights will be performed, by presenting 
the number of patients with a height higher/lower than expected.
Puberty stage
Puberty stage will only be analyzed as part of the long-term evaluation of everolimus on the 
LTE Safety Set.
Tanner Stage includes two components for boys, namely testis and pubic hair, and two 
components for girls: breast development and pubic hair. It is expected that data will become 
available during the trial on a proportion of patients as they go through puberty attaining 
higher levels of the Tanner Stage. For the age at which Tanner Stages 2-5 are achieved, age at 
thelarche (females), age at menarche (females) and age at adrenarche (males), summary 
statistics from Kaplan-Meier distributions will be determined, including the median age and 
the proportions of patients reaching these milestones at some given ages. These statistics will 
be given as point estimates with 95% confidence intervals. The percentage of patients who 
will reach Tanner Stage 2 during the study will be calculated among the number of patients 
with Tanner Stage 1 at Baseline (prior to the start of everolimus). The percentage of patients 
who will reach Tanner Stage 3 during the study will be calculated among the number of 
patients with Tanner Stage 1 or 2 at Baseline.
Similar rules will be applied for the age at Tanner Stages 4 and 5. Age at thelarche, age at
menarche and age at adrenarche will be assessed among patients who have not yet reached 
these development milestones at baseline.


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Potential delayed puberty in girls is defined as failure to attain Tanner Stage 2 (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 2 (Fenichel et al. 2012). Potential delayed puberty in boys is 
defined as failure to attain Tanner Stage 2 (for both testis and pubic hair) by age 14 (Crowley 
et al. 2012). Rates of potential delayed puberty will be presented for boys and girls separately, 
along with 95% confidence intervals, on the population at risk of delayed puberty at baseline.
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.
TSC genetic testing
Proportions of patients with TSC1 and TSC2 gene mutations will be presented per treatment 
arm in the FAS.
Determination of sample size
The sample size was chosen to provide adequate power for the primary objective comparing 
seizure frequency between each everolimus arm and the placebo arm. The sample size 
calculation provided here is based exclusively on response rate, the EMA primary endpoint, 
but it is also expected to provide sufficient patients for the power of the FDA primary 
endpoint, percentage reduction in seizure frequency. This is because response rate is a binary 
transformation of percentage reduction in seizure frequency, and therefore likely to be less 
sensitive owing to the loss of information going from a continuous variable to binary.
It was assumed that response rates would be 15% in the placebo arm and 35% in each of the 
two everolimus arms. That is, there was no a priori strong expectation that the higher targeted 
trough everolimus arm 9 to 15 ng/mL would deliver a higher response rate than the lower 
targeted trough everolimus arm 3 to 7 ng/mL, as better efficacy may be mitigated by worse 
tolerability. For this reason, the testing strategy was to simultaneously compare each pairwise 
comparison, splitting the significance level, rather than testing hierarchically starting with the 
higher trough arm for example.
Using nQuery version 6.1 it was determined that a sample size of 355 patients would ensure 
90% power for each of the primary comparisons of each everolimus arm versus placebo, 
assuming one-sided 1.25% significance levels for each CMH chi-square test, and assuming 
balanced randomization (i.e., 115 patients per randomization arm). Due to a mistake in the 


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IRT system discovered early in the trial, preventing dose titrations despite Cmin values outside 
the targeted trough range, it was decided to increase the sample size in the everolimus 9 to 15 
ng/ml arm by 10 patients, i.e. 125 patients in total.


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Table of contents
Table of contents ...............................................................................................................17
List of figures ....................................................................................................................20
List of tables ......................................................................................................................20
Clinical Study Report - Appendix 16.1.9 Documentation of statistical methods .............21
List of abbreviations..........................................................................................................21
1
Introduction .......................................................................................................................23
2
Definitions, general considerations and statistical methodology ......................................25
2.1
Definitions .............................................................................................................25
2.1.1
Study drug and study treatment.............................................................25
2.1.2
Date of first administration of study drug.............................................25
2.1.3
Date of last administration of study drug..............................................25
2.1.4
Date of first administration of study treatment .....................................25
2.1.5
Date of last administration of study treatment ......................................26
2.1.6
Study day...............................................................................................26
2.1.7
Baseline.................................................................................................26
2.1.8
On-treatment assessment/event.............................................................27
2.1.9
Time windows.......................................................................................27
2.1.10
Definitions of analysis sets....................................................................30
2.2
General considerations...........................................................................................33
2.2.1
Data included in the analysis.................................................................33
2.2.2
Patient Classification.............................................................................35
2.3
Major protocol deviations......................................................................................36
2.4
Concomitant medications with specific impact on the analysis ............................36
2.4.1
Background AED regimen....................................................................36
2.4.2
Rescue medications...............................................................................37
2.4.3
Inducers and inhibitors of CYP3A4 and/or PgP ...................................37
2.5
Seizure data............................................................................................................37
2.5.1
Investigator/Patient interview at the screening visit .............................37
2.5.2
Independent review by the Epilepsy Study Consortium.......................38
2.5.3
Transcription of patient seizure diary to eCRF.....................................40
2.5.4
Seizures counted towards partial-onset seizure frequency....................40
2.6
Stratification ..........................................................................................................40
2.6.1
Stratified randomization........................................................................40
2.6.2
Stratified analysis..................................................................................40
3
Statistical methods used in reporting.................................................................................40


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3.1
General presentation of descriptive summaries.....................................................40
3.2
Enrollment status ...................................................................................................41
3.3
Background and demographic characteristics .......................................................41
3.3.1
Basic demographic and background data..............................................41
3.3.2
Stratification factors..............................................................................41
3.3.3
Protocol eligibility criteria ....................................................................41
3.3.4
Diagnosis and extent of TSC disease....................................................41
3.3.5
Diagnosis and extent of epilepsy...........................................................42
3.3.6
Medical history......................................................................................42
3.3.7
Prior anti-TSC therapy..........................................................................42
3.3.8
Prior antiepileptic therapy.....................................................................43
3.3.9
TSC genetic testing ...............................................................................43
3.3.10
Pregnancy history, menstrual history and monitoring ..........................43
3.3.11
Other......................................................................................................43
3.4
Protocol deviation summaries................................................................................43
3.5
Groupings for Analysis..........................................................................................43
3.6
Patient disposition..................................................................................................43
3.6.1
Core phase.............................................................................................43
3.6.2
Extension phase.....................................................................................44
3.7
Study treatment......................................................................................................44
3.7.1
Duration of study treatment exposure...................................................45
3.7.2
Cumulative dose....................................................................................45
3.7.3
Dose intensity........................................................................................45
3.7.4
Dose reductions, increases or interruptions ..........................................45
3.8
Concomitant therapy..............................................................................................46
3.9
Efficacy evaluation................................................................................................47
3.9.1
Primary efficacy endpoint.....................................................................47
3.9.2
Secondary efficacy endpoints ...............................................................56
61
3.10
Safety evaluation ...................................................................................................64
3.10.1
Adverse events data...............................................................................64
3.10.2
Laboratory data .....................................................................................68
3.10.3
Vital signs..............................................................................................70
3.10.4
Neuropsychological Scales ...................................................................70
3.10.5
Columbia Suicide Severity Rating Scale ..............................................74
3.10.6
Other safety data ...................................................................................76


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3.11
Other test data........................................................................................................76
3.11.1
Growth Data..........................................................................................76
3.11.2
Puberty Stage ........................................................................................78
3.12
Patient reported outcomes......................................................................................79
3.12.1
Quality of life........................................................................................79
3.13
Pharmacokinetic analysis.......................................................................................81
3.13.1
Everolimus PK ......................................................................................82
3.13.2
AED PK ................................................................................................86
3.14
Subgroup analyses .................................................................................................87
3.15
Interim analyses.....................................................................................................88
3.16
Sample size calculation..........................................................................................89
4
Details of the statistical analysis........................................................................................90
4.1
Baseline comparability ..........................................................................................90
4.2
One-sided vs. two-sided test..................................................................................90
4.3
Comparison of response rates................................................................................90
4.4
Confidence interval for response rate....................................................................92
4.5
Rank Analysis of Covariance ................................................................................92
4.6
Bonferroni-Holm method ......................................................................................93
4.7
Bootstrap method...................................................................................................94
4.8
Time-to-event analyses..........................................................................................95
4.8.1
Kaplan-Meier estimates ........................................................................95
4.8.2
Hazard ratio...........................................................................................95
4.9
Comparison of means ............................................................................................95
4.10
Linear Mixed model for Expose-Response relationship .......................................96
4.11
Stratified Cox model and Extended Cox model for Exposure-Safety 
relationship ............................................................................................................96
5
References .........................................................................................................................98


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List of figures
Figure 2-1
Example timing of data cut-off dates....................................................34
List of tables
Table 2-1
Time windows for neuropsychological assessments.............................27
Table 2-2
Time windows for everolimus PK ........................................................28
Table 2-3
Time windows for everolimus PK – patients randomized to the 
placebo arm ...........................................................................................28
Table 2-4
Time windows for AED PK..................................................................29
Table 2-5
Time windows for eC-SSRS suicide scale............................................29
Table 2-6
Time windows for growth data .............................................................30
Table 2-7
Patient classification rules.....................................................................35
Table 2-8
Seizure codes.........................................................................................38
Table 3-1
Diagnostic Criteria for Tuberous Sclerosis Complex (TSC) ................41
Table 3-2
Sensitivity analyses ...............................................................................51
Table 3-3
Analysis time points for long-term evaluation of efficacy....................60
Table 3-4
Clinically notable values.......................................................................70
Table 3-5
Content of Vineland-II..........................................................................71
Table 3-6
Subgroup analyses.................................................................................87
Table 3-7
Sample size and power for primary objective.......................................89


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Clinical Study Report -
Appendix 16.1.9 Documentation of statistical methods
List of abbreviations
AE
Adverse Event
AED
Antiepileptic Drug
ANCOVA
Analysis of Covariance
ATC
Anatomic Therapeutic Chemical (Classification)
BMI 
Body Mass Index
BSA
Body Surface Area
CMH 
Cochran-Mantel-Haenszel
Cmin
Pre-dose concentration of drug at steady-state
Cmin,TN
Time normalized Cmin
CRO 
Contract Research Organization
C-CASA
Columbia Classification Algorithm for Suicide Assessment
C-SSRS
Columbia Suicide Severity Rating Scale
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DAR 
Dosage Administration Record
DI
Dose Intensity
DMC 
Data Monitoring Committee
DRF
Diagnostic Review Form
eCRF
Electronic Case Report/Record Form
eC-SSRS
Electronic Columbia Suicide Severity Rating Scale
EEG
Electroencephalography
EMA
European Medicines Agency
ESC
Epilepsy Study Consortium
FAS
Full Analysis Set
FDA
Food and Drug Agency
HLT 
High Level Term
IRT
Interactive Response Technology 
IVRS
Interactive Voice Response System
LTE
Long-Term Evaluation
MAP 
Master Analysis Plan
MedDRA
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable
NOS
Not Otherwise Specified
PgP
P-glycoprotein
PK
Pharmacokinetic
PPS
Per Protocol Set
PT
Preferred Term
QOL
Quality of Life
QOLCE
Quality of Life in Childhood Epilepsy
QOLIE-31-P
Quality of Life in Epilepsy Inventory – 31 – Problems
QOLIE-AD-48
Quality of Life in Epilepsy Inventory for Adolescents – 48


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RAP
Report Analysis Plan
SAE 
Serious Adverse Event
SD
Standard Deviation
SDS
Standard Deviation Score
SEC
Safety Event Category
SI
Standard International
SIF
Seizure Identification Form
SOC
System Organ Class
TEAE
Treatment-Emergent Adverse Event
TSC
Tuberous Sclerosis Complex
VAP
Validation and Planning
VNS
Vagal Nerve Stimulator
WHO
World Health Organization
WNV
Wechsler Nonverbal


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1
Introduction
This Reporting and Analysis Plan (RAP) Module 3 incorporates the latest project standards 
from the Master Analysis Plan (MAP), i.e., “Module 3 – Detailed Statistical Methodology –
Amendment 4”, finalized on 06-Jan-2010.
Overview of study design and objectives 
This is a prospective, multi-center, randomized, double-blind, parallel-group, placebo-
controlled, 3-arm Phase III study comparing the efficacy and safety of two trough-ranges of 
everolimus to placebo as adjunctive therapy in patients with tuberous sclerosis complex (TSC)
who have refractory partial onset seizures. A total of 355 patients will be randomized in a 1:
1:1.09 ratio to receive 1) placebo, or 2) everolimus titrated to a trough concentration of 3 to 7 
ng/ml or 3) everolimus titrated to a trough concentration of 9 to 15 ng/ml, with all patients 
remaining on a stable background antiepileptic drug (AED) regimen (of 1-3 AEDs).
Randomization will be stratified into 4 groups according to age at baseline: < 6 years, 6 to < 
12 years, 12 to < 18 years, and ≥ 18 years. The primary objective is to compare the reduction 
from baseline in frequency of partial-onset seizures between each everolimus arm versus the 
placebo arm.
The study includes a prospective Baseline phase during which patients complete a seizure 
diary for a total of 8 weeks. At the end of the Baseline phase, eligible patients will be 
randomized and enter an 18-week double-blind Core phase. The Core phase starts with a 6 
week titration period, during which up to 3 dose adjustments can be made in order to reach the 
targeted everolimus trough range, followed by a 12-week maintenance period. Patients 
continue to record occurrence of seizures on each day throughout the Core phase. After 
completing the maintenance period of the Core phase, patients will be offered to continue in 
an Extension phase, where all patients will receive everolimus; this Extension phase allows
for a long-term evaluation of the safety and efficacy of everolimus.
The primary efficacy endpoint is the reduction from baseline in the frequency of partial-onset 
seizures during the maintenance period of the Core phase. Two separate definitions of the 
primary efficacy endpoint will be used, owing to differing regulatory preferences between 
Europe and USA for demonstrating the efficacy of an antiepileptic medication. Whereas the 
European Medicines Agency (EMA) prefers response rate to be the primary variable, the 
Food and Drug Agency (FDA) prefers percentage reduction in seizure frequency. However, 
since a response is defined as ≥ 50% reduction from baseline in seizure frequency, the two 
variables are very similar. It is understood that each Agency will only use their preferred 
primary variable to make a decision on the primary objective, and therefore the full alpha
level will be used for each variable, without correction for multiplicity.
The EMA primary analysis will compare response rates between each everolimus arm versus 
the placebo arm in the Full Analysis Set (FAS), using Cochran-Mantel-Haenszel (CMH) chi-
square tests stratified by age subgroup. In order to accommodate the simultaneous testing of 
each everolimus arm versus placebo, the Bonferroni-Holm procedure will be used to ensure 
an overall family-wise Type I error rate of 2.5% one-sided.


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The FDA primary analysis will compare percentage reduction in seizure frequency between 
each everolimus arm versus the placebo arm in the FAS, using rank analysis of covariance 
(ANCOVA), with baseline average weekly seizure frequency as a covariate, and stratified by 
age subgroup. Again, the Bonferroni-Holm procedure will be used as a multiplicity correction 
to ensure an overall family-wise Type I error rate of 2.5% one-sided.
The trial was designed to provide adequate power for the primary objective comparing seizure 
frequency between each everolimus arm and the placebo arm. With respect to the EMA 
primary endpoint of response rate, the sample size of 115 patients per arm provides 90% 
power assuming response rates of 15% on placebo and at least 35% on either everolimus arm. 
This sample size is also expected to provide at least 90% power for the FDA primary endpoint, 
percentage reduction in seizure frequency, because response rate is expected to be less 
sensitive since there is a loss of information going from a continuous variable to binary.
The secondary objectives are to compare each of the two everolimus trough ranges versus 
placebo with respect to:

Ability to completely suppress partial-onset seizures

Proportion of patients with ≥ 25% reduction from baseline in seizure frequency

Distribution of reduction from baseline in seizure frequency

Seizure-free days

Treatment duration

Quality of life
Further secondary objectives are:

To assess everolimus in relation to neurocognitive, neurobehavioral and neuro-
developmental measures using Vineland-II and Wechsler Nonverbal scales

To assess the relationship between everolimus concentration at trough and efficacy / 
safety endpoints

To evaluate the impact of everolimus on the pre-dose exposure of background AEDs 

To evaluate the effect of the two everolimus trough ranges on long-term seizure reduction

To evaluate the safety and tolerability of each everolimus trough range in the study 
population

To evaluate the impact of everolimus on the risk of suicide using the Columbia Suicide 
Severity Rating Scale (C-SSRS)
 


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A Data Monitoring Committee (DMC) will review the ongoing safety data as the trial 
progresses. The first meeting will review data from the first 6 months of the study, with 
subsequent meetings every 6 months thereafter. Efficacy data will not be reviewed.
2
Definitions, general considerations and statistical 
methodology
2.1
Definitions
2.1.1
Study drug and study treatment
Study drug refers to everolimus or matching placebo. 
Study treatment also refers to everolimus or matching placebo.
Note that a background AED regimen will be provided to all patients, but it will not be 
considered as part of the study treatment. The background AED regimen must consist of 
between 1 and 3 AEDs, with the exact choice and dose of AEDs left to each investigator’s 
discretion.
2.1.2
Date of first administration of study drug
The date of first administration of double-blind study drug is defined as the first date when a 
non-zero dose of double-blind study drug is administered and recorded on the “Dosage 
administration record - Everolimus/Placebo – Core” eCRF. For the sake of simplicity, the date 
of first administration of study drug will also be referred to as the start of study drug.
Similarly, the date of first administration of everolimus in the Extension phase is defined as 
the first date when a non-zero dose of everolimus is administered and recorded on the
“Dosage administration record – Everolimus – Extension” eCRF.
2.1.3
Date of last administration of study drug
The date of last administration of double-blind study drug is defined as the last date when a 
non-zero dose of double-blind study drug is administered and recorded on the “Dosage 
administration record - Everolimus/Placebo – Core” eCRF.
Similarly, the date of last administration of everolimus in the Extension phase is defined as 
the last date when a non-zero dose of everolimus is administered and recorded on the “Dosage 
administration record – Everolimus – Extension” eCRF.
2.1.4
Date of first administration of study treatment
The date of first administration of study treatment is the same as the date of first
administration of study drug.


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2.1.5
Date of last administration of study treatment
The date of last administration of study treatment is the same as the date of last administration 
of study drug.
2.1.6
Study day
The study day for safety assessments (e.g., start date of an adverse event (AE), dose 
interruption, neuropsychological scales, suicide scale, etc.) will be calculated using the start 
date of study treatment as the origin. Assessments that occur on or after the start date of study 
treatment will have study day calculated as (date of assessment) – (start date of study 
treatment) + 1. Assessments that occur before the start of study treatment will have study day 
calculated as (date of assessment) – (start date of study treatment). Then study day 1 for safety 
assessments will be the first day of study treatment, and study day -1 will be the day before 
the first day of study treatment.
The study day for all other assessments (e.g., seizure diary, quality of life) will be calculated 
using the randomization date as the origin. Assessments that occur on or after the 
randomization date will have study day calculated as (date of assessment) – (randomization 
date) + 1. Assessments that occur before the randomization date will have study day 
calculated as (date of assessment) – (randomization date). Then study day 1 for non-safety 
assessments will be the day of randomization, and study day -1 will be the day before the 
randomization date.
The vast majority of patients are expected to start taking study medication on the day of 
randomization, in which case the start date of study treatment will be the same as the 
randomization date.
Study day will be displayed in the data listings.
For the long-term evaluation of efficacy and safety, study day for all assessments will be 
calculated using the start date of everolimus as the origin. In particular, for patients originally 
randomized to the placebo arm, study day 1 will be the start date of everolimus in the 
Extension phase of the trial.
2.1.7
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient.
For safety evaluations (e.g., AEs, lab values, vital signs, neuropsychological scales, suicide 
questionnaire, etc.), the baseline assessment is defined as the last available assessment on or 
before the start date of study treatment.
For all other evaluations (e.g., seizure diary, quality of life), the baseline assessment is 
defined as the last available assessment on or before the randomization date. However, to 
reduce the risk of missing baselines, in rare cases when study treatment is started one or more 
days after randomization, the last available assessment prior to first treatment will be used as 
baseline.
If patients have no value as defined above, the baseline result will be missing.


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The baseline seizure frequency is calculated from the start of the seizure diary at screening 
until the day before the randomization date, as defined in Section 3.9.1.1.
For the long-term evaluation of efficacy and safety, patients originally randomized to the 
placebo arm will have baseline values taken from the last assessment on or before the start of 
everolimus in the Extension phase. For example, for the Vineland-II scale, the baseline for 
placebo patients in the LTE Safety Set could be obtained at the end of the Core phase. Further, 
such patients will have baseline seizure frequency calculated over the latest 56 days of the 
seizure diary prior to the start date of everolimus in the Extension phase (i.e., not including 
the start date of everolimus).
2.1.8
On-treatment assessment/event
AE summaries will present only on-treatment assessments or events, where on-treatment 
means that the AE started in the following time interval (including the lower and upper 
limits):

<start date of study treatment; date of last study treatment + 30 days>
Other safety summaries will present baseline and on-treatment assessments, where on-
treatment means that the assessment occurred in the following time interval (including the 
lower and upper limits):

<start date of study treatment + 1; date of last study treatment + 30 days>
2.1.9
Time windows
In order to summarize data over time, the following data types will be time slotted using time 
windows.
2.1.9.1
Neuropsychological assessments
The Vineland- II and Wechsler Nonverbal (WNV) scales will be performed at baseline, at end 
of Core phase (or end of treatment if patient discontinues), and then every 6 months (24 
weeks) in the Extension phase plus at the end of treatment in the Extension phase. 
Table 2-1 shows the defined time windows for the neuropsychological assessments.
Table 2-1
Time windows for neuropsychological assessments
Time Window
Planned Visit Timing 
Time Window Definition
Baseline
On or before Study Day 1*
≤ Study Day 1
Week 9
Study Day 64
Study Days 2 – 94
Week 18
Study Day 127
Study Days 95 – 211
Week 42
Study Day 295
Study Days 212 – 379
Week 66
Study Day 463
Study Days 380 – 547
Every 24 weeks thereafter
Week =66+24×k,
(where k=1,2,3,…)
Study Day = (66+24×k) ×7+1
Study Days (66+24×k) ×7+1 –
(12×7-1) to (66+24×k) ×7+1 + 
(12×7)
* Study Day 1 = start date of study treatment (or for long-term evaluation, study day 1 = start date of everolimus)


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Excluding the baseline, for which the last value is used, if more than one assessment is done 
within the same time window, the assessment performed closest to the target date will be 
used; if two or more assessments are equidistant from the planned date, then the mean values
will be used.
2.1.9.2
Everolimus pharmacokinetics
Blood samples will be collected for everolimus pharmacokinetic (PK) analysis at weeks 1, 3, 
5, 10, 14 and 18 during the Core phase, and at weeks 19, 22, 26, and 30, and every 12 weeks 
thereafter during the Extension phase. Additional everolimus PK samples will be collected 
approximately 2 weeks, but not less than 5 days after any change in the dose of study 
medication, or approximately 2 weeks, but not less than 5 days after after any change in use of 
concomitant CYP3A4/P-glycoprotein (PgP) inhibitors or inducers.
Table 2-2 shows the defined time windows for everolimus PK.
Table 2-2
Time windows for everolimus PK
Time Window
Planned Visit Timing 
Time Window Definition
Week 1
Study Day 8*
Study Days 2 – 15
Week 3
Study Day 22
Study Days 16 – 29
Week 5
Study Day 36
Study Days 30 – 53
Week 10
Study Day 71
Study Days 54 – 85
Week 14
Study Day 99
Study Days 86 – 113
Week 18
Study Day 127
Study Days 114 – 130
Week 19
Study Day 134
Study Days 131 – 145
Week 22
Study Day 155
Study Days 146 – 169
Week 26
Study Day 183
Study Days 170 – 197
Week 30
Study Day 211
Study Days 198 – 251
Week 42
Study Day 295
Study Days 252 – 337
Every 12 weeks thereafter
Week =42+12×k,
(where k=1,2,3,…)
Study Day = (42+12×k)×7 +1
Study Days (42+12×k)×7 +1 – (6×7 -
1) to (42+12×k)×7 +1 + (6×7)
* Study Day 1 = start date of everolimus
If more than one assessment is done within the same time window, the mean value per time 
window will be used.
For the long-term evaluation of everolimus, placebo patients who enter the Extension phase 
will be included. As the planned schedule of blood draws for everolimus PK is different in the 
Extension phase compared with the Core phase, the time windows in Table 2-3 will be used in 
some analyses for such patients. 
Table 2-3
Time windows for everolimus PK – patients randomized to the 
placebo arm
Time Window
Planned Visit Timing 
Time Window Definition
Week 1
Study Day 8*
Study Days 2 – 18
Week 4
Study Day 29
Study Days 19 – 43
Week 8
Study Day 57
Study Days 44 – 71
Week 12
Study Day 85
Study Days 72 – 127


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Time Window
Planned Visit Timing 
Time Window Definition
Week 24
Study Day 169
Study Days 128 – 211
Every 12 weeks thereafter
Week =24+12×k,
(where k=1,2,3,…)
Study Day = (24+12×k)×7 +1
Study Days (24+12×k)×7 +1 – (6×7 -
1) to (24+12×k)×7 +1 + (6×7)
* Study Day 1 = start date of everolimus
2.1.9.3
AED pharmacokinetics
Blood samples will be collected from all patients for AED pharmacokinetic (PK) analysis at 
week -8 (screening), on study day 1 (baseline), and at weeks 1 and 3 during the Core phase. 
Only samples from patients randomized to one of the two everolimus arms will be analyzed.
Table 2-4 shows the defined time windows for AED PK.
Table 2-4
Time windows for AED PK
Time Window
Planned Visit Timing 
Time Window Definition
Week -8
Study Day -56*
Study Days -70 to -8
Baseline
Study Day 1
Study Days -7 to 1
Week 1
Study Day 8
Study Days 2 to 15
Week 3
Study Day 22
Study Days 16 to 43
* Study Day 1 = start date of everolimus
If more than one assessment is done within the same time window, the mean value per time 
window will be used.
2.1.9.4
Columbia Suicide Severity Rating Scale
The electronic Columbia Suicide Severity Rating Scale (eC-SSRS) should be performed at 
every visit (except the PK visits at weeks 1, 3, 5 and 19, and the end of study visit).
Table 2-5 shows the defined time windows for eC-SSRS.
Table 2-5
Time windows for eC-SSRS suicide scale
Time Window
Planned Visit Timing 
Time Window Definition
Screening
Study Day -56*
Study Days -70 to -8
Baseline
Study Day 1
Study Days -7 to 1
Week 2
Study Day 15
Study Days 2 – 22
Week 4
Study Day 29
Study Days 23 – 36
Week 6
Study Day 43
Study Days 37 – 57
Week 10
Study Day 71
Study Days 58 – 85
Week 14
Study Day 99
Study Days 86 – 113
Week 18
Study Day 127
Study Days 114 – 141
Week 22
Study Day 155
Study Days 142 – 169
Week 26
Study Day 183
Study Days 170 – 197
Week 30
Study Day 211
Study Days 198 – 251
Week 42
Study Day 295
Study Days 252 – 337
Every 12 weeks thereafter
Week =42+12×k,
(where k=1,2,3,…)
Study Day = (42+12×k)×7 +1
Study Days (42+12*k)*7+1-(6*7-1)
to (42+12×k)×7 +1 + 6×7


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* Study Day 1 = start date of everolimus
These time windows will only be used to summarize compliance, and so no rules are required 
for cases when there is more than one assessment in the same time window.
2.1.9.5
Growth data
Growth data (height and weight) will be collected at every visit (except the PK visits at weeks 
1, 3, 5 and 19, and the end of study visit). There is also an attempt to retrospectively collect 
growth data prior to screening, and so pre-baseline time windows will be required. Note that 
for the long-term evaluation, for patients randomized to the placebo arm, pre-baseline also 
includes the double-blind Core phase of the trial, prior to the start of everolimus in the 
Extension phase.
Table 2-6 summarizes the time windows for growth data, where windows are centered at 
every 24 weeks before and after start of everolimus. Although height and weight are collected 
more frequently than every 24 weeks (post-randomization), this choice of time window length 
was made to reflect the degree of accuracy in the reference values (every 6 months) that will 
be used in the calculation of summary variables of growth (see Section 3.11.1).
Table 2-6
Time windows for growth data
Time Window
Planned Visit Timing 
Time Window Definition
Week -72
Study Day -504
Study Days -588 to -421
Week -48
Study Day -336
Study Days -420 to -253
Week -24
Study Day -168
Study Days -252 to -85
Baseline
Study Day 1
Study Days -42 to 1
Week 24
Study Day 169
Study Days 86 to 253
Week 48
Study Day 337
Study Days 254 to 421
Week 72
Study Day 505
Study Days 422 to 589
Every 24 weeks thereafter
Week =72+24×k,
(where k=1,2,3,…)
Study Day = (72+24×k)×7 +1
Study Days (72+24×k)×7 +1 – (12×7 
-1) to (72+24×k)×7 +1 + (12×7)
Study Day 1 = start date of everolimus
If more than one assessment is done within the Baseline time window, the assessment closest 
to treatment day 1 will be used; if two or more assessments are equidistant from treatment 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.
2.1.10
Definitions of analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment arm and stratification factor that they were assigned to at 
randomization. The FAS is the primary efficacy population.
Safety Set


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The Safety Set includes all patients who received at least one dose of study medication in the 
Core phase, and had at least one post-baseline safety assessment in the Core phase (where the 
statement that a patient had no AE (on the AE eCRF) constitutes a safety assessment). 
There are three treatment groups in the study: everolimus titrated to a trough concentration of 
3 to 7 ng/ml, everolimus titrated to a trough concentration of 9 to 15 ng/ml, and placebo. The 
usual approach for the Safety Set would be to analyze patients according to study treatment 
received. However, that is not possible because the two everolimus arms have the same 
treatment received (i.e., everolimus), and are only differentiated by differing targeted trough 
ranges. Therefore, patients randomized to one of the two everolimus arms and who received at 
least one dose of everolimus, will be analyzed in the Safety Set according to the everolimus 
treatment arm assigned at randomization. Similarly, patients randomized to placebo and who 
received at least one dose of placebo, will be analyzed in the placebo arm of the Safety Set.
That is, only patients who received the wrong treatment regimen throughout their entire time 
in the Core phase will be reassigned to a different treatment arm in the Safety Set compared 
with the FAS, as follows:

Patients randomized to either of the two everolimus arms and who received only placebo 
tablets during the Core phase will be reassigned to the placebo arm in the Safety Set. This 
could happen for example if the first kit of study medication contained only placebo 
tablets (i.e., given in error), and the patient took at least one tablet and then subsequently 
discontinued before taking any everolimus tablets.

Patients randomized to the placebo arm and who received only everolimus tablets during 
the Core phase will be reassigned to the everolimus 3 to 7 ng/ml arm in the Safety Set. 
Again this would require a dispensing error in the first kit of study medication, followed 
by early discontinuation. Note that the reassignment is to the lower everolimus targeted 
trough arm, chosen because such an error in starting dose would be recognized via IRT 
before any dose increase could be made.
Note that there will be no attempt to reassign patients from one everolimus arm to the other 
everolimus arm based on observed everolimus concentrations during the Core phase. For 
example, a patient randomized to the everolimus 9 to 15 ng/ml arm and whose observed 
everolimus trough concentrations ranged from 3 to 7 ng/ml during the entire Core phase 
would still be considered to have treatment received = everolimus 9 to 15 ng/ml. This is 
because increases in the dose of everolimus would have been recommended during the Core 
phase in order to reach the targeted trough range of 9 to 15 ng/ml, and any associated toxicity 
should therefore be attributed to the 9 to 15 ng/ml arm and not the 3 to 7 ng/ml arm.
Per Protocol Set
The Per-Protocol Set (PPS) consists of a subset of patients in the FAS who are compliant to 
the requirements of the protocol, who are evaluable for efficacy and who have completed a 
minimum exposure requirement. However, if a patient discontinued for lack of efficacy, AE
or death before the minimum exposure requirement could be met, or before he/she could 
become evaluable for efficacy, that patient will still be included in the Per Protocol Set.
Patients will be evaluable for efficacy if their seizure diary continues until at least day 70 of 
the Core phase, i.e., at least the first 4 weeks of the maintenance period of the Core phase.


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The minimum exposure requirement is defined as receiving study treatment on ≥ 50% of days 
during the first 10 weeks of the Core phase.
Major protocol deviations excluding patients from the PPS are described in Section 2.3.
Long-Term Evaluation Efficacy Set
The Long-Term Evaluation Efficacy Set (LTE Efficacy Set) is intended to capture all data on 
everolimus in the trial, from both the Core phase and the Extension phase. It consists of all 
patients who receive at least one dose of everolimus in the trial and have at least one post-
baseline efficacy measure (i.e., at least one day on which the number and types of seizures are 
known and documented in the “Investigator’s Seizure Classification” eCRF). Patients will be 
analyzed as a single everolimus group as well as separately according to their randomized 
treatment arm in the Core phase (i.e., everolimus trough ranges of 3 to 7 ng/ml and 9 to 15
ng/ml, or placebo). This analysis set will be used for long-term efficacy analyses of 
everolimus.
Before protocol amendment 2, patients from the two everolimus groups were to continue in 
the Extension phase with the same targeted trough range from Core phase, while placebo 
patients where switched to receive everolimus during the Extension phase with a 3-15 ng/ml 
targeted trough. Protocol amendment 2 introduced the possibility for investigators to make the 
dose adjustments in the Extension phase based on the Cmin value. If investigators chose not to 
modify dosing, the dose was determined by the IRT to maintain the everolimus trough 
concentration range between 3-15 ng/ml for all patients. In order to avoid compromising the 
blinded nature of the study (including the investigator, patient and sponsor) in the earlier Core 
phase, all patients were be transitioned towards a common targeted trough range of 6 to 10 
ng/ml before any Cmin value is shared with the investigator. For this reason, for analyses of 
long-term evaluation data from the Core and Extension phase, patients will be analyzed as a 
single everolimus group (“All patients”) as well as separately according to the randomized 
treatment arm in the Core phase (i.e., everolimus trough ranges of 3 to 7 ng/ml and 9 to 15
ng/ml and placebo). Note that “placebo” arm will only contain data from the Extension phase 
when patients received everolimus.
Long-Term Evaluation Safety Set
The Long-Term Evaluation Safety Set (LTE Safety Set) is intended to capture all data on 
everolimus in the trial, from both the Core phase and the Extension phase. It consists of all 
patients who receive at least one dose of everolimus in the trial and have at least one post-
baseline safety measure. Patients will be analyzed as a single everolimus group as well as 
separately according to their randomized treatment arm in the Core phase (i.e., everolimus 
trough ranges of 3 to 7 ng/ml and 9 to 15 ng/ml, or placebo). This analysis set will be used for 
long-term safety and pharmacokinetic analyses of everolimus.
For the same reason as described above for the LTE Efficacy Set, patients will be analyzed as 
a single everolimus group (“All patients”) as well as separately according to their randomized 
treatment arm in the Core phase (i.e., everolimus trough ranges of 3 to 7 ng/ml and 9 to 15


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ng/ml and placebo). Note that “placebo” arm will only contain data from the Extension phase 
when patients received everolimus.
Pharmacokinetic Set
There will be no formal pharmacokinetic set. The pharmacokinetic analyses will be performed 
in the Safety Set and the LTE Safety Set using all available PK samples Set or PK Sensitivity 
Sample Set, as defined below (section 3.13.1.1). 
2.2
General considerations
2.2.1
Data included in the analysis
It is planned that the data from all centers participating in the trial will be combined, so that an 
adequate number of patients are available for analysis. Novartis and/or a designated CRO will 
perform all the analyses. 
The primary data cut-off date, for the primary analysis, will be when all patients have 
completed the Core phase or have discontinued early (see Figure 2-1 below). At that time, all 
data from the Core phase will be available as will a part of the Extension phase data. The 
analyses will thus cover both periods, although the main focus will be on inferential and 
descriptive comparisons of each everolimus arm versus placebo on efficacy and safety in the 
Core phase. In addition, descriptive analyses for the long-term evaluation of everolimus will 
be presented based on data from the Core phase and the available data from the Extension 
phase. All planned analyses for the Core phase will be produced at that time. Only a subset of 
the analyses for the long-term safety and efficacy evaluation of everolimus will be produced. 
All analyses for the long-term evaluation will be produced after the final cut-off at the end of 
extension phase.
Figure 2-1 shows that the first patient was randomized on July 3, 2013, and that accrual of the 
planned 355 patients was completed on May 29, 2015. Then the data cut-off date for the 
primary analysis will be end of September/beginning of October 2015, assuming the last
patients complete the Core phase. The figure also shows the extent of Extension phase data at 
the primary cut-off date, with the first randomized patients potentially having more than 12 
months follow-up during the Extension phase.  


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Figure 2-1
Example timing of data cut-off dates
There will be a final data cut-off date at the end of the Extension phase, for the final analysis, 
which is planned 48 weeks after the last patient completes the Core phase (except if the 
primary analysis fails to show a benefit for everolimus over placebo, in which case the trial 
will be terminated). The analyses at the final data cut-off will complete the long-term 
evaluation of everolimus, using all data on everolimus from both the Core and Extension 
phases of the study. As data from the Core phase will remain unchanged since the first cut-off 
date, no new analyses comparing the everolimus arms to placebo will be undertaken at the 
final analysis.
No other analyses between the primary analysis and the final analysis are currently planned, 
but may be performed if needed.
The tables, listings and figures to be produced at each analysis (primary and final) will be 
identified in RAP Module 7. All data collected in the database will be used for the statistical 
analysis.
Only data with an assessment date or event start date on or before the data cut-off date will be 
included in the analysis. For example, if the data cut-off date is 15-Jun-2014 then an AE 
starting on 13-Jun-2014 will be reported, whereas an AE with start date on 17-Jun-2014 will 
not be reported.
3 Jul 2013
29 May 2015      Sep/Oct 2015
Q3 2016
48 weeks until end
of Extension phase
18 weeks
last Core phase
Accrual period
First
patient
randomized
Last
patient
randomized
Last
patient
End of
Core phase
End of
Extension
phase
PRIMARY
DATA
CUT-OFF
FINAL
DATA
CUT-OFF
Potential patient data (solid line = 18-week Core phase, broken line = Extension phase)
001
002
xxx
355


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All events with a start date on or before the cut-off date and with an end date after the cut-off 
date will be reported as ‘continuing at the cut-off date’. The same rule will apply to events 
starting on or before the cut-off date and without a documented end date. This approach 
applies in particular to AE and concomitant medication reports. For these events, the cut-off 
date will not be imputed and therefore will not appear in the listings.
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 Dosage 
Administration Record (DAR) 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 and dose intensity to be calculated. Details of imputation of partial dates will be
provided in the programming specifications (RAP Module 8).
2.2.2
Patient Classification
Patients are excluded from the analysis sets defined above based on protocol deviations and/or 
specific patient classification rules, as defined in Table 2-7. For example, a patient will be 
excluded from the Safety Set if they meet either of the conditions (i) no post-baseline safety 
assessment or (ii) no dose of study medication (as programmed in derived dataset noviopto).
Table 2-7
Patient classification rules
Analysis set
Protocol deviation 
severity codes 
leading to exclusion
Additional patient classification rules leading to exclusion*
Full Analysis Set
8
Patient not randomized.
Safety Set
8, 5
(i) Patient with no post-baseline safety assessment.
(ii) Patient with no dose of study medication, i.e., no non-zero 
dose in the “Dosage administration record -
Everolimus/Placebo – Core” eCRF
Per Protocol Set
8, 1
(i) Patient not randomized.
(ii) Not evaluable for efficacy (seizure diary discontinued during 
first 10 weeks of Core phase). **
(iii) Insufficient treatment exposure (received study treatment on 
< 50% of days during first 10 weeks of Core phase). **
(iv) Received the wrong treatment regimen throughout the
entire duration of the Core***
Severity code: 1=exclude from per protocol analysis, 5=exclude from all safety analyses, 8=exclude from all 
analyses (to be used only if patient has not signed informed consent prior to start of study)
* Classification rule will be determined programmatically
** However, if a patient discontinued for lack of efficacy, AE or death before the minimum exposure requirement 
could be met, or before he/she could become evaluable for efficacy, that patient will still be included in the Per 
Protocol Set.
*** This major deviation will be determined programmatically after the unblinded information of IRT is available, in 
order to determine which treatment was received by the patients. Since it cannot be known before unblinding, this 
information will not be found in dataset of protocol deviations (Viopto). This deviation, if any, will have to be added 
to the derived dataset a_viopto in order to be reported in the summary of protocol deviations.
All protocol deviations and patient classification rules will be finalized before database lock.


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2.3
Major protocol deviations
The following protocol deviations are considered as major deviations and constitute reasons
for excluding patients from the per-protocol set:

Absence of diagnosis of TSC or partial-onset epilepsy.

Previously failed < 2 AEDs given individually or combined.

Prior therapy with systemic or topical mTOR inhibitors within the exclusion criteria time 
windows.

Baseline seizure diary with < 16 ESC-approved partial-onset seizures.

Baseline seizure diary containing a seizure-free period of ≥21 consecutive days.

Baseline seizure diary < 49 days in duration.

Did not receive 1-3 AEDs at same dose from 4 weeks prior to screening visit to baseline
visit

Change in dose for more than 7 days or in number of concomitant AEDs during Core 
Phase or interruption of AED > 7 days

Missing seizure information on > 50% of days in the Core phase or the Baseline phase.

Received the wrong treatment regimen throughout their entire time in the Core*, defined 
as:

Patients randomized to either of the two everolimus arms and who received only 
placebo tablets during the Core phase.

Patients randomized to the placebo arm and who received only everolimus tablets 
during the Core phase.
* This deviation will be determined programmatically, post database lock and unblinding. If 
an occurrence is found, it will be added to the a_viopto dataset in order to be reported in 
the deviation summary tables.
Other protocol deviations will also be identified, summarized and listed. However, patients 
will not be excluded from the Per-Protocol set based on these other deviations.
2.4
Concomitant medications with specific impact on the analysis
Each of the following categories of medication or non-drug therapy will be identified based 
on a clinical review of medication and non-drug therapies listings. Details on how each list 
should be prepared for review, be updated and used to produce summary tables and listings 
will be provided in the programming specification (RAP Module 8). 
2.4.1
Background AED regimen
Patients are required to be on a stable background AED regimen consisting of between 1 and 
3 different AEDs, starting from 4 weeks prior to screening and continuing until the end of the 
Core phase. The background AED regimen will be recorded on the DAR – Antiepileptic 
Therapy eCRF page.


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2.4.2
Rescue medications
Rescue medications are allowed when patients experience transient increases in seizure 
activity 
despite 
best 
medical 
management.
Rescue 
medications 
are 
essentially 
benzodiazepines (e.g., buccal midazolam, rectal diazepam), and should be prescribed 
according to the local institution’s practice. Rescue medications will be recorded on the rescue 
medications eCRF page.
2.4.3
Inducers and inhibitors of CYP3A4 and/or PgP
Many patients will be taking concomitant CYP3A4 enzyme inducing drugs as part of their 
background regimen of antiepileptic drugs. Therefore, co-administration of strong inhibitors 
of CYP3A4 or P-glycoprotein (PgP) should be avoided and moderate inhibitors used with 
caution. These substances are listed in the Investigator’s Brochure and referenced in the study 
protocol.
However, some patients may take these substances during the trial so these concomitant 
medications will be selected via programming and will be tabulated and listed. An everolimus 
project level document lists all such known substances, and ongoing review by the Clinical 
Pharmacologist will be performed as follows:

Substances will be identified as inhibitors, inducers, or substrates

Inhibitors of CYP3A4 will be also classified as strong, moderate, weak, or other

Inhibitors of PgP will be classified as yes or no

Inducers of CYP3A4 will be classified as yes or no

Inducers of PgP will be classified as yes or no

Substrates of CYP3A4 will be classified as yes or no

Substrates of PgP will be classified as yes or no
Substances that have not been reviewed and those which are no longer available in the current 
version of the WHO dictionary will be flagged.
Review listings will be produced for this study but will always feed back into the project level 
list. This list is considered applicable at the everolimus project level and is to be used for all 
clinical indications.
A corresponding list for programming purposes will be stored in the Novartis global 
programming system (i.e., in GPS2, in the compound level CRAD001/util folder).
2.5
Seizure data
The primary efficacy endpoint of the study is change from baseline in frequency of partial -
onset seizures. This section gives more detailed information on the process of how seizure 
events are collected, reviewed and documented, and on which seizure events are included in 
counts of partial-onset seizures for the primary endpoint. 
2.5.1
Investigator/Patient interview at the screening visit
Seizures are recorded in patient seizure diaries on an ongoing basis throughout the trial. 
During the screening visit, patients and/or caregivers will be asked by the investigator to 


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describe the patient’s seizures in their own words. There may be certain events that are 
considered to be an epileptic seizure by the patient, but that are considered to be behavioral 
events by the investigator. In any case, the investigator is required to use his/her expert 
judgment to identify events that in his/her opinion have at least a 50% probability of being an 
epileptic seizure, and to request the patient or caregiver to only record such events in their 
seizure diary. These events will be defined on the first page of the patient seizure diary using a 
simple coding scheme like A, B, C, etc. The patient then embarks on the 8-week baseline 
phase, and records each occurrence of A, B, C, etc. in the patient seizure diary as they occur.
2.5.2
Independent review by the Epilepsy Study Consortium
An independent review of the seizure types being recorded by the patient will be performed 
by the Epilepsy Study Consortium (ESC) in conjunction with the investigator. The ESC is an 
independent group of scientific investigators from academic medical research, dedicated to 
accelerating the development of new therapies in epilepsy to improve patient care.
Within 48 hours of the screening visit, the investigator will complete a Diagnostic Review 
Form (DRF) which documents what information was used to determine the patient’s diagnosis 
and provides the seizure history, with supporting materials if necessary (e.g., EEGs). In 
addition, the investigator completes a Seizure Identification Form (SIF) for each seizure, 
answering questions about the event and providing a seizure code from a list that is 
reproduced below in Table 2-8.
Table 2-8
Seizure codes 
Seizure type
Protocol definition of 
partial-onset*
FOCAL SEIZURE
IA1
Motor or autonomic components, but without impairment of consciousness 
or awareness

IA2a
Subjective sensory or psychic phenomena; without impairment of 
consciousness or awareness; with ictal EEG confirmation

IA2b
Subjective sensory or psychic phenomena; without impairment of 
consciousness or awareness; without ictal EEG confirmation

IB1
Complex partial seizures, predominantly stare

IB2
Complex partial seizures, predominantly stare and facial automatisms

IB3
Complex partial seizures (Not Otherwise Specified)

SECONDARILY GENERALIZED
IC1
Convulsive seizure: Myoclonic features

IC2
Convulsive seizure: Clonic features

IC3
Convulsive seizure: Tonic features

IC4
Convulsive seizure: Tonic-clonic features

IC5
Convulsive seizure: Atonic features

IC6
Convulsive seizure: NOS 

GENERALIZED ONSET SEIZURES
IIA1
Convulsive seizure: Typical Absence seizures

IIA2
Convulsive seizure: Atypical Absence seizures

IIB
Convulsive seizure: Myoclonic seizures

IIC
Convulsive seizure: Clonic seizures

IID
Convulsive seizure: Tonic seizures



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Seizure type
Protocol definition of 
partial-onset*
IIE
Convulsive seizure: Tonic-clonic seizures

IIF
Convulsive seizure: Atonic seizures

IIG
Convulsive seizure: NOS

*: Protocol definition of partial-onset seizures: seizures with motor signs that have not been documented to be 
generalized onset seizures on EEG or sensory seizures confirmed to be partial-onset by ictal EEG – see Section 
2.5.4 below. 
*: indicates seizure type qualifying for protocol definition of partial-onset; seizure type excluded from the 
protocol definition of partial-onset
The SIF also solicits the subjective judgment of the investigator as to whether the seizure is 
Probable (greater than 80% likelihood of being an epileptic seizure) or Questionable (50-80% 
chance). In fact the aim in this study is to only record events in the eCR F that have a high 
probability of being seizures, and one of the main tasks of the ESC review is to ensure sites 
are consistently identifying such seizures.
The DRF and SIF forms are sent to the ESC for their review, and this process will be followed 
for every patient in the study. With the benefit of having this overview across all investigators, 
and in the interests of making seizure classification as consistent as possible across sites, the 
ESC can make a recommendation to an investigator to change a particular seizure 
classification, although the final decision rests with the investigator. For example, some 
seizures that were initially considered Probable by the investigator may end up not getting 
ESC approval, whereas other seizures rated as Questionable by the investigator may get 
approved.
ESC findings will be communicated to the investigator via a Feedback Form. Questions or 
requests for additional information made by the ESC will be documented using the Feedback 
Form. If corrections, clarifications or additional information are required, the site is instructed 
to respond on the Feedback Form and depending on the response, may be asked to revise and 
resubmit the DRF and/or SIF. The documents are then to be resubmitted to the ESC for a 
second review.
Once agreement has been reached between the ESC and the investigator, an Approval Form 
will be sent, containing a list of events to be counted as seizures (including the agreed upon 
seizure code as per Table 2-8), and a list of events not to be counted as seizures in the eCRF.
If a new seizure type occurs during the trial, the investigator will complete a new SIF and 
submit it to the ESC for review. If new information about a previous seizure type becomes 
available, the investigator should revise the DRF and/or SIF and resubmit to the ESC. Then a 
seizure that was originally not approved, could on the basis of new information, be 
reclassified as approved, or vice versa. In either case, the investigator would need to review 
all previous Investigator Seizure Classification eCRFs in order to make the necessary 
corrections, starting from the beginning of the Baseline phase.
If the investigator and the reviewer do not agree on the classification/diagnosis, the forms will 
be sent to a second ESC reviewer as a quality control step. In the event that the investigator 
and the ESC do not resolve their difference, the decision of the investigator is final.


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2.5.3
Transcription of patient seizure diary to eCRF
When entering the patient seizure diary into the Investigator Seizure Classification eCRF, the 
investigator should only include events counted as seizures on the Approval Form. However, 
patients should continue to track all events, as originally instructed by the investigator, in their 
seizure diaries (i.e., events counted as seizures as well as events not counted as seizures).
2.5.4
Seizures counted towards partial-onset seizure frequency
The study protocol gave a specific definition of partial-onset seizures that will be counted in 
this trial: seizures with motor signs that have not been documented to be primary generalized 
seizures on EEG. The study protocol amendment 2 further extended this definition by 
including also the sensory seizures (without motor sign) confirmed to be partial-onset by ictal 
EEG. Considering the list of seizure codes provided in Table 2-8, this excludes code IA2b 
because such seizures do not include any motor component and were not confirmed by EEG, 
and also codes IIA1 through IIG which are (primarily) generalized onset seizures. Therefore, 
the seizure codes that count towards the primary endpoint are: IA1, IA2a, IB1, IB2, IB3, IC1, 
IC2, IC3, IC4, IC5 and IC6. 
2.6
Stratification
2.6.1
Stratified randomization
The randomization will use stratified random blocks with a single stratification factor of 
patient age at randomization split into 4 distinct groups as follows: 1 to <6 years; (ii) 6 to <12 
years; (iii) 12 to <18 years; and (iv) ≥ 18 years.
2.6.2
Stratified analysis
A stratified analysis method will be used to test for treatment group differences, since the 
factor on which the randomization has been stratified should be accounted for in the analysis 
(ICH guideline E5).
The stratified CMH test and the stratified rank ANCOVA model will be the primary analyses 
for the EMA and FDA primary endpoints respectively (see Section 3.9.1).
3
Statistical methods used in reporting
3.1
General presentation of descriptive summaries
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by treatment group; 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, weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e., mean, standard deviation, median, minimum, maximum) by treatment group.


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3.2
Enrollment status
Number of patients screened will be summarized by country and center. Number of patients 
randomized will be summarized by country, center and treatment group. This information will 
also be presented separately for the FAS, Safety Set, Per-Protocol Set and the LTE Efficacy 
and Safety sets.
3.3
Background and demographic characteristics
The FAS and the LTE Efficacy Set will be used for all baseline and demographic summaries 
and listings. 
3.3.1
Basic demographic and background data
All demographic and background data will be listed. A summary table will include age, sex, 
weight, height, body mass index (BMI), body surface area (BSA), race, ethnicity and puberty 
stage at baseline.
Qualitative data will be summarized by means of contingency tables, and quantitative data 
will be summarized by appropriate descriptive statistics (mean, standard deviation, median, 
minimum, and maximum).
3.3.2
Stratification factors
The randomization stratification factor actually used to randomize patients (contained in the 
IVR dataset) will be tabulated and listed against patient age subgroups calculated from date of 
birth and randomization date as collected on the eCRFs.
3.3.3
Protocol eligibility criteria 
Protocol eligibility criteria as per eCRFs at randomization will be summarized and listed.
3.3.4
Diagnosis and extent of TSC disease
Diagnosis of TSC will be summarized according to the criteria listed in Table 3-1 below.
Table 3-1
Diagnostic Criteria for Tuberous Sclerosis Complex (TSC)
Major Features
1. Facial angiofibromas or forehead plaque 
2. Non-traumatic ungual or periungual fibroma 
3. Hypomelanotic macules (three or more) 
4. Shagreen patch (connective tissue nevus) 
5. Multiple retinal nodular hamartomas 
6. Cortical tuber a
7. Subependymal nodule 
8. Subependymal giant cell astrocytoma 
9. Cardiac rhabdomyoma, single or multiple 
10. Lymphangioleiomyomatosis b
11. Renal angiomyolipoma b
Minor Features


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1. Multiple, randomly distributed pits in dental enamel 
2. Hamartomatous rectal polyps c
3. Bone cysts d
4. Cerebral white matter radial migration lines a, d
5. Gingival fibromas 
6. Non-renal hamartoma c
7. Retinal achromic patch 
8. ‘Confetti’ skin lesions 
9. Multiple renal cysts c
Definite Tuberous Sclerosis Complex:
Two Major Features or one Major Feature plus two Minor Features.
a. The co-occurrence of cerebral cortical dysplasia and cerebral white matter radial migration lines should be 
considered as one major feature of TSC.
b. In patients with both lymphangioleiomyomatosis and renal angiomyolipoma, another feature of TSC must be 
identified before a definite diagnosis is assigned.
c. Histologic confirmation of these features is suggested.
d. Radiographic confirmation of these features is sufficient.
Time since initial diagnosis of TSC-related conditions or symptoms will be summarized in 
years (defined as 365.25 days), and will be measured until the time of baseline (i.e., start date 
of study treatment).
3.3.5
Diagnosis and extent of epilepsy
Summary statistics will be tabulated for diagnosis and extent of epilepsy. These analyses will 
include seizure history (status epilepticus, simple partial seizure, complex partial seizure, 
secondarily generalized seizure, generalized onset seizure, other) and time since initial 
diagnosis or partial-onset seizures.
3.3.6
Medical history
Medical history and ongoing medical conditions, including TSC-related conditions and 
symptoms, will be summarized and listed by treatment group. Separate summaries will be 
presented for historical medical conditions (marked as “not active” on the Medical History 
eCRF) and for ongoing medical conditions (marked as “active”). In addition, pre-treatment 
AEs will be included in the summary of ongoing medical conditions, defined as any AE 
starting between the time of signing informed consent and the day before starting study 
treatment.
The summaries will be presented by primary system organ class and preferred term. Medical 
history/current medical conditions are coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology.
3.3.7
Prior anti-TSC therapy
Prior anti-TSC therapy will be listed, and the number and percentage of patients recording any 
prior anti-TSC medications will be summarized by treatment group.
Prior anti-TSC medications will be summarized by Anatomic Therapeutic Chemical (ATC)
class, preferred term and treatment group.


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3.3.8
Prior antiepileptic therapy
The number and percentage of patients with prior epilepsy surgery, prior vagal nerve 
stimulator (VNS) and prior ketogenic diet will be summarized by treatment group.
The number of prior AEDs within 1 year prior to screening, 3 years prior to screening and 
over the patient’s lifetime will be summarized by treatment group. 
Prior AEDs will also be summarized by therapy type, ATC class, and preferred term, within 1 
year prior to screening, 3 years prior to screening, as well as throughout the entire patient’s 
life.
3.3.9
TSC genetic testing
Proportions of patients with TSC1 and TSC2 gene mutations will be presented per treatment 
arm.
3.3.10
Pregnancy history, menstrual history and monitoring
This data is collected to provide background and additional information for observed cases of 
amenorrhea (see Section 3.10.1.5), and will be listed.
3.3.11
Other
All other data collected at baseline, including source of subject referral, child bearing 
potential, pregnancy test results, and biomarker informed consent, will be listed.
3.4
Protocol deviation summaries 
The number and percentage of patients in the FAS with any protocol deviation will be 
tabulated by the deviation category (as specified in the Validation and Planning (VAP)
documents) and by treatment group. Protocol deviations will also be summarized by center.
Protocol deviations leading to exclusion from the Per Protocol Set will be tabulated separately 
by treatment group. All protocol deviations will be listed, with deviations leading to exclusion 
from the Per Protocol Set being flagged.
3.5
Groupings for Analysis
The number and percentage of patients in each analysis population will be summarized by 
treatment group. The distribution of patients at screening and in the FAS, Per Protocol Set, 
Safety Set and the LTE Efficacy and Safety Sets will also be summarized by country, center 
and treatment group. 
3.6
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings which will be 
summarized separately for the Core phase and the Extension phase.
3.6.1
Core phase
Information from the End of Treatment (Core phase) eCRF will provide a summary by 
treatment arm showing:


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1. Number (%) of patients who completed the Core phase. 
2. Number (%) of patients who discontinued double-blind study treatment:
a.
During titration period.
b. During maintenance period.
c.
Overall.
3. Reasons for study treatment discontinuation.
3.6.2
Extension phase
Information from the End of Treatment (Extension phase) eCRF will provide a summary by 
treatment arm, and using the number of patients entering the Extension phase as denominator, 
showing:
1. Number (%) of patients who completed the Extension phase.
2. Number (%) of patients who discontinued from the Extension phase.
3. Reasons for discontinuation from the Extension phase.
3.7
Study treatment
Duration of study treatment exposure, cumulative dose and dose intensity (DI) will be 
summarized by treatment group in the Core phase using the Safety Set, and separately for the 
LTE Safety Set using all data on everolimus from the Core and Extension phases. 
In addition, the duration of study treatment exposure will be categorized into time intervals,
and frequency counts and percentages will be presented for the number of patients in each 
interval. The number of patients with dose reductions or interruptions, and the reasons, will be 
summarized by treatment. 
Dose modification is planned for the study, with all dose modifications recommended by IRT 
based on everolimus trough concentrations and the targeted trough range (3 to 7 ng/ml or 9 to 
15 ng/ml depending on the treatment arm assigned at randomization). In order to maintain the 
blind, patients in the placebo arm may receive dose changes, and patients in the everolimus 3 
to 7 ng/ml arm may receive placebo tablets as dummy dose increases.
Dose of study treatment will be defined in units of mg/m2, calculated as the actual dose 
received in mg divided by the most recent determination of BSA obtained on or before the 
date of dosing. BSA is calculated using the Dubois and Dubois (1916) formula:
BSA = (W0.425 × H0.725) × 0.007184,
where W denotes weight in kilograms and H denotes height in centimeters.
All patients are started at a dose of between 3 and 9 mg/m 2 depending on three categories of 
age at randomization and whether the patient is receiving a CYP3A4/PgP inducer (see [Table 
6-2 of the study protocol] for details). Study treatment is given as 2 mg dispersible tablets, and 
the number of tablets to be administered should be calculated from the dose per mg/m 2 and 
the patient’s BSA, and using the rounding rules described in [Section 6.2.3 of the study 
protocol]. Doses at subsequent visits can be increased in order to reach the targeted 
everolimus trough concentration range, but only by one whole 2 mg tablet (or two 2 mg 
tablets for patients receiving a CYP3A4/PgP inducer). Similarly, in case of toxicity or trough 


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concentration above the target range, study treatment can also be decreased by one whole 2
mg tablet (or two 2 mg tablets for patients receiving a CYP3A4/PgP inducer).
Listings of all doses of the study treatment along with dose change reasons will be produced.
Attention will be paid to patients in the everolimus 3 to 7 ng/ml treatment group, to identify 
separately the doses of everolimus tablets and placebo tablets that may have been taken.
3.7.1
Duration of study treatment exposure
The following algorithm will be used to calculate the duration of study treatment exposure for 
patients who took at least one dose of the study treatment:
Duration of exposure (days) = (date of last administration of study treatment) – (date of first 
administration of study treatment) + 1.
The duration includes any periods of temporary interruption of study treatment for any reason. 
“Date of last administration of study treatment” and “Date of first administration of study 
treatment” are defined in Section 2.1.4 and Section 2.1.5.
The duration of exposure will be summarized both categorically and continuously in units of
weeks and/or months.
3.7.2
Cumulative dose
Cumulative dose is defined as the total dose given during the study treatment exposure, 
expressed in units of mg/m2. For patients in the everolimus 3 to 7 ng/ml trough arm, total dose 
refers to the total amount of everolimus received during the trial (i.e., excluding placebo).
3.7.3
Dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (mg/m2/day) = Cumulative dose (mg/m2) / Duration of exposure (days).
3.7.4
Dose reductions, increases or interruptions
The number of patients with dose reductions, increases or interruptions, and the reasons, will 
be summarized by treatment group.
Note that since actual dose changes in the study are made in units of 2 mg, summaries across 
patients need to be interpreted with care, because for example, a 2 mg change is a higher 
relative change in dose for a patient with a BSA=0.6 than it is for a patient with BSA=2.0. 
Therefore, differences in dose changes between treatment arms may also be influenced by 
differences in BSA.
Interruption: An interruption is defined as one or more consecutive days on which no study 
medication is taken by the patient. A specific situation could arise for patients randomized to 
the everolimus arms, when the patient was still taking pills, but, due to an error in the kits 
used, all the pills were placebo. In that case the interruption of everolimus would not be 
reported with a reason in the eCRF since it was unknown. If that specific situation happens, 
then an interruption will be reported, along with the following reason: ‘Only placebo tablets 
taken‘.
These cases will be identified programmatically, and the reason derived 
programmatically.


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Reduction: A reduction is defined as a decrease in dose by 2 mg or more to a non-zero dose, 
even if this decrease has been directly preceded by an interruption. For example, in the 
sequence 8.0 mg/day – 0 mg/day – 6.0 mg/day, the 6.0 mg/day dose will be counted as a 
reduction.
Increase: An increase is defined as an increase in dose by 2 mg, even if this increase has been 
directly preceded by an interruption. For example, in the sequence 6.0 mg/day – 0 mg/day –
8.0 mg/day, the 8.0 mg/day dose will be counted as an increase.
3.8
Concomitant therapy
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment (i.e., everolimus) that were administered to a patient preceding or 
coinciding with the study assessment period.
There will be one analysis for the double blind Core phase using the Safety Set, and a second 
analysis for all the data on everolimus from both the Core and Extension phases using the 
LTE Safety Set.
For the Core phase, concomitant includes therapy starting on or after the start date of double 
blind study treatment in the Core phase, or medications starting prior to the start date of study 
treatment in the Core phase and continuing after the start date. Therapy starting more than 30
days after the last day of study treatment in the Core phase will not be included , and neither 
will any therapy starting on or after the first day of everolimus given in the Extension phase.
Prior concomitant therapy starts and ends before the start date of study treatment in the Core 
phase.
For the long-term evaluation of everolimus, concomitant includes therapy 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. Therapy starting more than 30 days after the last day of 
everolimus will not be included. Prior concomitant therapy starts and ends before the start 
date of everolimus: note that for patients randomized to the placebo arm and who 
subsequently received everolimus in the Extension phase, this refers to the entire Core phase 
and Baseline phase.
Concomitant medications entered into the database will be coded using the WHO (World 
Health Organization) Drug Reference List to allow for categorization by preferred term. In 
addition to categorizing medication data by preferred term, drugs are classified according to 
their 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.
Concomitant medications and significant non-drug therapies taken concurrently with study 
treatment will be listed and summarized by ATC class and preferred term by means of 
frequency counts and percentages. Concomitant AEDs received as background regimen will 
also be described separately and presented for both the Baseline and Core phases, including 
number of drugs received, type of drug received, and compliance to AED treatment. 
Any prior concomitant medications (excluding prior anti-TSC therapy covered in Section
3.3.7 and prior antiepileptic therapy in Section 3.3.8) or significant non-drug therapy will be 
listed.


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Concomitant medications with a specific impact on certain analyses will be identified prior to 
database lock, as defined in Section 2.4: background AED regimen, rescue medications and 
CYP3A4/PgP inducers and inhibitors. Separate summaries of these concomitant medications 
will be produced for the Core phase using the FAS population instead of the Safety Set.
Medications will be listed and summarized by ATC class and preferred term by means of
frequency counts and percentages.
3.9
Efficacy evaluation
The efficacy evaluation is based on the seizure diaries completed by patients on each day 
throughout the trial (see Section 2.5).
3.9.1
Primary efficacy endpoint
The primary efficacy endpoint is the reduction from baseline in the frequency of partial -onset 
seizures during the maintenance period of the Core phase. Two separate definitions of the 
primary efficacy endpoint will be used, owing to the differing regulatory preferences between 
Europe and USA for demonstrating efficacy of an antiepileptic medication. Whereas the EMA 
prefers response rate to be the primary variable, the FDA prefers percentage reduction in 
seizure frequency. It is understood that each Agency will use their preferred variable as the 
primary variable, with the other (non-primary) variable being used in a supportive analysis. 
As each Agency will only use their preferred primary variable to make a decision on the 
primary objective, the full alpha level can be used for each Agency’s primary variable, 
without correction for multiplicity. This approach has been endorsed by both EMA and FDA.
3.9.1.1
Response Rate - definition
The following definitions are required to calculate response rate:
1. Average weekly seizure frequency in the Baseline phase (SFB)
Defined as:
SFB  =  7 × number of partial-onset seizures recorded over the 8 week prospective Baseline 
phase ÷ number of non-missing seizure diary days in the 8 week prospective Baseline 
phase.
Number of partial-onset seizures: The aggregate total of all seizures of codes IA1, IA2a, 
IB1, IB2, IB3, IC1, IC2, IC3, IC4, IC5 and IC6 (see Table 2-8), as reported in the 
“Investigator’s Seizure Classification” eCRF. 
8 week prospective Baseline phase: The Baseline phase for the seizure diary is from the 
first day at which the diary is completed in screening through until the day before the date 
of randomization. Most patients are expected to be randomized on the day of the baseline 
visit, which is scheduled to be 8 weeks after the screening visit, in which case there will
be a total of 56 days in the baseline phase seizure diary (assuming the diary is started on 
the day of the screening visit, as called for by the study protocol). However, due to late 
timing of the baseline visit for example, the baseline seizure diary could contain more than 
56 days; or due to a delay in starting the diary at screening, the diary could contain less 
than 56 days. In either case the diary should be used in its entirety for this calculation of 
average weekly seizure frequency in the Baseline phase.


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Number of non-missing seizure diary days: This is the number of days on which the 
number and types of seizures are known and documented in the “Investigator’s Seizure 
Classification” eCRF. That is, it excludes days on which seizure information is unknown,
coded as NA (not available) in the eCRF, which can arise when for example the patient or 
caregiver forget to count the seizures on a particular day.
2. Average weekly seizure frequency in the maintenance period of the Core phase (SFM)
Defined as:
If patient does not discontinue during the 6 week titration period of the Core phase, then 
SFM =  7 × number of partial-onset seizures recorded during the maintenance period of the 
Core phase ÷ number of non-missing seizure diary days in the maintenance period of 
the Core phase.
Otherwise 
SFM  =  7 × number of partial-onset seizures recorded during the titration period of the 
Core phase ÷ number of non-missing seizure diary days in the titration period of the 
Core phase.
That is, patients who discontinue prior to the maintenance period have seizure frequency 
determined using their data from the titration period, thereby assuring that all patients with 
seizure data in the Core phase have a value for SFM.
Number of partial-onset seizures: see point 1 above.
Titration period of the Core phase: Defined as starting on the date of randomization until 6 
weeks later, that is, from study day 1 until study day 42 inclusive; for patients who 
discontinue the study on or before study day 42, the titration period is considered to have 
ended on the last day of study treatment. Note that this rule will be the same for all 
patients, even if a visit is delayed and the final titration step occurs after study day 43.
Maintenance period of the Core phase: Defined as starting at the beginning of week 7 of 
the Core phase (i.e., study day 43) and continuing until the last day of study treatment in 
the Core phase. For patients who complete the Core phase according to the scheduled 
visits, the last day of study treatment should be study day 126, corresponding to the end of 
week 18. Seizure counts beyond study day 126 should still be counted as long as double 
blind study treatment is continued in the Core phase.
Number of non-missing seizure diary days: see point 1 above.
3. Percentage reduction from baseline in average weekly seizure frequency during the 
maintenance period of the Core phase (%Red)
Defined as:
%Red  =  100 × (SFB - SFM) ÷ SFB
In the special case where SFM is unknown, for example if a patient discontinues the trial 
without completing the patient seizure diary, then %Red is assigned equal to 0. (Note that 
SFB is not expected to be unknown because the baseline seizure diary is required before a 
patient can be randomized.)


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A responder is a patient with ≥ 50% reduction from baseline in average weekly partial-onset 
seizure frequency during the maintenance period of the Core phase, that is, when %Red ≥ 50. 
Response rate is the percentage of responders in a treatment group.
3.9.1.2
Percentage reduction in seizure frequency - definition
The FDA primary variable, percentage reduction in seizure frequency, is defined by the 
variable %Red defined in point 3 in Section 3.9.1.1 above.
3.9.1.3
Primary analysis – response rate
The primary analysis of response rate will compare each everolimus arm versus the placebo 
arm using Cochran-Mantel-Haenszel (CMH) chi-square tests (as described in Section 4.3). 
Each CMH test will be stratified by age subgroup at randomization, the randomization
stratification factor, which consists of 4 subgroups: 1 to < 6, 6 to < 12, 12 to < 18, ≥18 years.
Multiplicity will be controlled via the Bonferroni-Holm procedure (Holm 1979), which is 
described below in Section 3.9.1.4 and in detail in Section 4.6. This method allows the 
statistical significance of each treatment comparison to be assessed whilst ensuring an overall 
family-wise alpha level of 2.5% one-sided.
Response rates will be provided with exact 95% confidence intervals (see Section 4.4), and 
the odds ratio (see Section 4.3) for each everolimus arm versus placebo will be obtained from 
logistic regression models stratified by age subgroup.


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3.9.1.4
Hypothesis and test statistic - response rate 
The statistical hypotheses are
H01: RREVE1 ≤ RRPLB     versus    H11: RREVE1 > RRPLB,
and
H02: RREVE2 ≤ RRPLB     versus    H12: RREVE2 > RRPLB,
where RREVE1 is the probability of response on the everolimus 3 to 7 ng/ml arm, RREVE2 is the 
probability of response on the everolimus 9 to 15 ng/ml arm, and RRPLB is the probability of 
response on placebo.
The null hypothesis H01 will be tested against the alternative hypothesis H11 using the CMH 
test, with an associated one-sided p-value denoted by p1. At the same time, the null hypothesis 
H02 will also be tested against the alternative hypothesis H12 using the CMH test, with an 
associated one-sided p-value denoted by p2.
The Bonferroni-Holm procedure is used to ensure an overall family-wise Type I error of 2.5% 
one-sided, and it works as follows:

If the smaller of the two one-sided p-values is greater than 0.0125, then neither of the two 
everolimus arms have a statistically significant benefit in the probability of response 
compared with placebo.

Otherwise

if the smaller of the two p-values is less than or equal to 0.0125, then the everolimus 
arm associated with the smaller p-value has a statistically significant benefit in the 
probability of response compared with placebo.
AND

If the larger of the two p-values is less than or equal to 0.025, then the everolimus arm 
associated with the larger p-value also has a statistically significant benefit in the 
probability of response compared with placebo.
3.9.1.5
Primary analysis – percentage reduction in seizure frequency
The primary analysis of percentage reduction in seizure frequency will compare each
everolimus arm versus the placebo arm using rank analysis of covariance (rank ANCOVA, as 
described in Section 4.5). Each rank ANCOVA model will include baseline average weekly 
seizure frequency as covariate, and will be stratified by age subgroup at randomization, the 
randomization stratification factor, which consists of 4 subgroups: 1 to < 6, 6 to < 12, 12 to < 
18, ≥18 years. 
Multiplicity will be controlled via the Bonferroni-Holm procedure, which is described above
in Section 3.9.1.4 and in detail in Section 4.6. This method allows the statistical significance 
of each treatment comparison to be assessed whilst ensuring an overall family-wise alpha 
level of 2.5% one-sided.
The median percentage reduction from baseline will be presented for each treatment group
along with 95% bootstrap confidence intervals (see Section 4.7). Effect size will be assessed 
by calculating the difference between the median percentage reduction from baseline between


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each of everolimus treatment arms and placebo using a stratified bootstrap methodology 
(stratified by the randomization stratification factor, see Section 4.7).
3.9.1.6
Hypothesis and test statistic - percentage reduction in seizure 
frequency
The statistical hypotheses are
H03: μEVE1 ≤ μPLB     versus    H13: μEVE1 > μPLB, and
H04: μEVE2 ≤ μPLB     versus    H14: μEVE2 > μPLB,
where μEVE1 is the population mean of the reduction in seizure frequency for the everolimus 3 
to 7 ng/ml arm, μEVE2 is the population mean of the reduction in seizure frequency for the 
everolimus 9 to 15 ng/ml arm, and μPLB is the population mean of the reduction in seizure 
frequency for placebo.
The null hypothesis H03 will be tested against the alternative hypothesis H13 using rank 
ANCOVA, with an associated one-sided p-value for treatment effect denoted by p3. At the 
same time, the null hypothesis H04 will also be tested against the alternative hypothesis H14
using rank ANCOVA, with an associated one-sided p-value for treatment effect denoted by p4.
The Bonferroni-Holm procedure is used to determine whether p3 and/or p4 are statistically 
significant whilst maintaining an overall family-wise Type I error of 2.5% one-sided (see 
Section 3.9.1.4 for details).
3.9.1.7
Sensitivity and other supportive analyses
For the EMA primary variable of response rate, a supportive analysis will be the FDA primary 
analysis on percentage reduction in seizure frequency, and vice versa.
The primary analysis of both response rate and percentage reduction in seizure frequency will 
be repeated in the Per Protocol Set.
Descriptive statistics (n, mean, median, standard deviation, minimum and maximum) for 
average weekly seizure frequency in the Baseline phase (SFB), in the maintenance period of 
the Core phase (SFM), and percentage reduction from baseline (%Red), will be presented by 
treatment group in the FAS. The quantities for seizure frequency will also be summarized in 
units of 28 days instead of weekly, i.e., average number of partial-onset seizures per 28 days 
in the Baseline phase, and per 28 days in the maintenance period of the Core phase. 
Sensitivity analyses will be conducted in the FAS to assess robustness of the primary analysis 
to the 4 following conditions presented in Table 3-2:
Table 3-2
Sensitivity analyses
Number
Description
Change compared to 
primary analysis
Baseline phase
Change compared to 
primary analysis
Core phase
1
Patient discontinuation before the 
end of Week 18 of the Core phase
None
Any patient discontinuing 
before day 126 will be 
classified as a non-
responder, and for 
percentage reduction in 


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Number
Description
Change compared to 
primary analysis
Baseline phase
Change compared to 
primary analysis
Core phase
seizure frequency, the 
reduction will be 0%.
2
Calculation of seizure frequency 
across the entire Core phase
None
Uses the average weekly 
seizure frequency over the 
entire Core phase (titration 
+ maintenance)
3
‘Best case’ – Days with missing 
information considered as maximum 
seizure number for the Baseline  
phase and seizure-free for the Core 
phase
On days with missing 
information, the patient is 
considered to experience the 
same number of maximum 
daily seizures she/he has 
experienced during the 
baseline phase
Days with missing 
information considered to be 
seizure-free
4
‘Worst case’ - Days with missing 
information considered as maximum 
seizure number for the Core phase 
and seizure-free for the Baseline
phase
Days with missing information 
considered to be seizure-free
On days with missing 
information, the patient is 
considered to experience 
the same number of 
maximum daily seizures 
she/he has experienced 
during the maintenance
period
Below are the detailed calculation rules for the 4 sensitivity analyses:
1. Patient discontinuation before the end of Week 18 of the Core phase
This sensitivity analysis will assume no change from baseline in seizure frequency for 
patients discontinuing before the end of Week 18 in the Core phase (i.e., discontinuing 
before day 126). This compares with the approach for the primary analysis where the 
observed seizure frequency calculated up to the day of discontinuation is used. Therefore, 
for response rate, any patient discontinuing before day 126 will be classified as a non-
responder, and for percentage reduction in seizure frequency, the reduction will be 0%.
Response rate and percentage change from baseline in seizure frequency will be 
recalculated for this sensitivity analysis and analyzed per the primary analysis.


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2. Calculation of seizure frequency across the entire Core phase (i.e., titration period as well 
as maintenance period)
This sensitivity analysis will use the average weekly seizure frequency over the entire 
Core phase, that is, from the day of randomization until the last day of study treatment in 
the Core phase. This compares with the primary analysis where titration period data will 
not be used to calculate average weekly seizure frequency, except if the patient 
discontinues on or before study day 42 (see Section 3.9.1.1 above).
The variable to be used in the sensitivity analysis, labeled SFTM is defined as follows:
Average weekly seizure frequency in the entire Core phase (SFTM)
Defined as:
SFTM  =  7 × number of partial-onset seizures recorded over the entire Core phase ÷ 
number of non-missing seizure diary days in the entire Core phase. 
Number of partial-onset seizures: see point 1 in Section 3.9.1.1.
Entire Core phase: From the day of randomization until the last day of study treatment in 
the Core phase. For patients who complete the Core phase according to the scheduled 
visits, the last day of study treatment should be study day 126, corresponding to the end of 
week 18. Seizure counts beyond study day 126 should still be counted as l ong as double 
blind study treatment is continued in the Core phase.
Number of non-missing seizure diary days: see point 1 in Section 3.9.1.1.
Response rate and percentage reduction in seizure frequency will be re-calculated using 
SFTM instead of SFM in the formula for %Red given in Section 3.9.1.1, and analyzed as per 
the primary analysis.
3. Calculation of seizure frequency assuming days missing data imputed to the maximum 
number of seizures experienced by the patient in the Baseline phase and to 0 seizures in 
the maintenance period of the Core phase.
This sensitivity analysis will assume that the maximum number of seizures observed in the 
Baseline phase (SBmax) was observed on the days where data is reported as missing in the 
diary in this phase. For the Core phase, it will be assumed that 0 seizures were observed 
on the days where data is reported as missing in the diary. That is, there will be no missing 
seizure diary day in the Baseline and Core period phases. This compares with the primary 
analysis where days with missing seizure information are excluded from the calculations 
of the average weekly seizure frequency (see Section 3.9.1.1 above).
The variables to be used in the sensitivity analysis, labeled SBmax, SFBMAX and SFM0 are
defined as follows:
Daily maximum seizure count in the Baseline phase (SBMAX)
Defined as:
SBMAX =  maximum reported count of partial onset-seizures (see point 1 in Section 
3.9.1.1) on one day during the Baseline phase (see point 1 in Section 3.9.1.1).
Average weekly seizure frequency in the Baseline phase (SFBMAX)


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Defined as:
SFB0  =  7 × number of partial-onset seizures recorded over the 8 week prospective 
Baseline phase ÷ number of days in the 8 week prospective Baseline phase. 
Number of partial-onset seizures: The aggregate total of all seizures of codes IA1, IA2a, 
IB1, IB2, IB3, IC1, IC2, IC3, IC4, IC5 and IC6 (see Table 2-8), as reported in the 
“Investigator’s Seizure Classification” eCRF. On days where information on seizure 
counts is missing in the diary, the patient will be considered to have experienced SBmax
seizures.
8 week prospective Baseline phase: see point 1 in Section 3.9.1.1.
Number of days: This is the number of days of the Baseline phase. That is, it includes
days on which seizure information is unknown.
Average weekly seizure frequency in the maintenance period of the Core phase 
(SFM0)
Defined as:
If patient does not discontinue during the 6 week titration period of the Core phase, then 
SFM0  =  7 × number of partial-onset seizures recorded during the maintenance period of 
the Core phase ÷ number of days in the maintenance period of the Core phase.
Otherwise 
SFM0  =  7 × number of partial-onset seizures recorded during the titration period of the 
Core phase ÷ number of days in the titration period of the Core phase.
That is, patients who discontinue prior to the maintenance period have seizure frequency 
determined using their data from the titration period, thereby assuring that all patients with 
seizure data in the Core phase have a value for SFM0.
Number of partial-onset seizures: The aggregate total of all seizures of codes IA1, IA2a, 
IB1, IB2, IB3, IC1, IC2, IC3, IC4, IC5 and IC6 (s ee Table 2-8), as reported in the 
“Investigator’s Seizure Classification” eCRF. On days where information on seizure 
counts is missing in the diary, the patient will be considered to have experienced 0
seizures.
Titration period of the Core phase: see point 2 in Section 3.9.1.1.
Maintenance period of the Core phase: see point 2 in Section 3.9.1.1.
Number of days: This is the number of days of the Maintenance (or Titration) phase. That 
is, it includes days on which seizure information is unknown.
Response rate and percentage reduction in seizure frequency will be re-calculated using 
SFB0 and SFM0 instead of SFB and SFM in the formula for %Red given in Section 3.9.1.1, 
and analyzed as per the primary analysis.
4. Calculation of seizure frequency assuming days with missing data imputed to the 
maximum number of seizures experienced by the patient in the maintenance period of the 
Core phase and to 0 seizures in the Baseline phase.
This sensitivity analysis will assume that the maximum number of seizures observed in the 
Maintenance period of the Core phase (SCmax) was observed on the days where data is 


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reported as missing in the diary in this period. For the baseline phase, it will be assumed 
that 0 seizures were observed on the days where data is reported as missing in the diary. 
That is, there will be no missing seizure diary day in the Baseline and Core period phases. 
This compares with the primary analysis where days with missing seizure information are 
excluded from the calculations of the average weekly seizure frequency (see Section 
3.9.1.1 above).
The variables to be used in the sensitivity analysis, labeled SCmax, SFB0 and SFMMAX are
defined as follows:
Daily maximum seizure count in the maintenance period of the Core phase (SCMAX)
Defined as:
If patient does not discontinue during the 6 week titration period of the Core phase, then 
SCMAX = maximum reported count of partial onset-seizures (see point 1 in Section 3.9.1.1) 
on one day during the maintenance period of the Core phase (see point 1 in Section 
3.9.1.1).
Otherwise 
SCMAX = maximum reported count of partial onset-seizures (see point 1 in Section 3.9.1.1) 
on one day during the titration period of the Core phase (see point 2 in Section 3.9.1.1).
Average weekly seizure frequency in the Baseline phase (SFB0)
Defined as:
SFB0  =  7 × number of partial-onset seizures recorded over the 8 week prospective 
Baseline phase ÷ number of days in the 8 week prospective Baseline phase. 
Number of partial-onset seizures: The aggregate total of all seizures of codes IA1, IA2a, 
IB1, IB2, IB3, IC1, IC2, IC3, IC4, IC5 and IC6 (see Table 2-8), as reported in the 
“Investigator’s Seizure Classification” eCRF. On days where information on seizure 
counts is missing in the diary, the patient will be considered to have experienced 0 
seizures.
8 week prospective Baseline phase: see point 1 in Section 3.9.1.1.
Number of days: This is the number of days of the Baseline phase. That is, it includes
days on which seizure information is unknown.
Average weekly seizure frequency in the maintenance period of the Core phase 
(SFMMAX)
Defined as:
If patient does not discontinue during the 6 week titration period of the Core phase, then 
SFMMAX  =  7 × number of partial-onset seizures recorded during the maintenance period of 
the Core phase ÷ number of days in the maintenance period of the Core phase.
Otherwise 
SFMMAX  =  7 × number of partial-onset seizures recorded during the titration period of the 
Core phase ÷ number of days in the titration period of the Core phase.


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That is, patients who discontinue prior to the maintenance period have seizure frequency 
determined using their data from the titration period, thereby assuring that all patients with 
seizure data in the Core phase have a value for SFMMAX.
Number of partial-onset seizures: The aggregate total of all seizures of codes IA1, IA2a, 
IB1, IB2, IB3, IC1, IC2, IC3, IC4, IC5 and IC6 (see Table 2-8), as reported in the 
“Investigator’s Seizure Classification” eCRF. On days where information on seizure 
counts is missing in the diary, the patient will be considered to have experienced SCMAX
seizures.
Titration period of the Core phase: see point 2 in Section 3.9.1.1.
Maintenance period of the Core phase: see point 2 in Section 3.9.1.1.
Number of days: This is the number of days of the Maintenance (or Titration) phase. That 
is, it includes days on which seizure information is unknown.
Response rate and percentage reduction in seizure frequency will be re-calculated using 
SFB0 and SFMMAX instead of SFB and SFM in the formula for %Red given in Section 3.9.1.1, 
and analyzed as per the primary analysis.
3.9.1.8
Waterfall plots and cumulative plots
Waterfall graphs and cumulative plots will be used to investigate the effect of everolimus 
versus Placebo across a range of responder definitions. For the waterfall plot, the percentage 
reduction from baseline in seizure frequency during the maintenance period of the core phase 
will be presented for each patient. The cumulative plot will display the cumulative percentage 
of patients in each treatment arm for each individual value of the percentage reduction from 
baseline in seizure frequency observed in the maintenance period of the core phase.
3.9.2
Secondary efficacy endpoints
3.9.2.1
Seizure freedom
Seizure freedom is defined as not experiencing any partial-onset seizure (codes IA1, IA2a,
IB1, IB2, IB3, IC1, IC2, IC3, IC4, IC5 and IC6 (see Table 2-8), as reported in the 
“Investigator’s Seizure Classification” eCRF) during the maintenance period of the Core 
phase, where the maintenance period is from study day 43 until the last day of study 
medication in the Core phase. Note that this definition allows for patients to be classified as 
seizure-free despite experiencing partial-onset seizures during the titration period, and despite 
experiencing seizure types other than partial-onset during the maintenance phase. For patients 
who discontinue study treatment during the titration period, seizure freedom requires an 
absence of partial-onset seizures from study day 1 until the day of discontinuation. In terms of 
the variables defined in Section 3.9.1.1 above (without considering imputation rules for 
patients who discontinued the trial without completing the patient seizure diary), seizure 
freedom is when %Red = 100.
The seizure-free rates for each treatment arm in the FAS will be presented along with exact 
95% confidence intervals, and the odds ratio for each everolimus arm versus placebo will be 


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derived from logistic regression models stratified by age subgroup. In addition, a sensitivity 
analysis will be performed where patients who discontinue at any time during the Core phase 
are assumed not to be seizure-free, even if no seizures had been reported before they 
discontinued.
3.9.2.2
Proportion of patients with at least 25% reduction in seizure frequency
This variable is equivalent to the primary endpoint of response rate except with a lower 
threshold of ≥ 25% reduction from baseline rather than ≥ 50%. In terms of the variables 
defined in Section 3.9.1.1 above (without considering imputation rules for patients who 
discontinued the trial without completing the patient seizure diary), a ≥ 25% reduction 
corresponds to %Red ≥ 25. The proportions of such patients in each treatment arm will be 
presented along with exact 95% confidence intervals. In addition, odds ratios for each 
everolimus arm versus placebo from logistic regression models stratified by age subgroup will 
be determined. 
3.9.2.3
Distribution of reduction from baseline in seizure frequency
The distribution of reduction from baseline in seizure frequency will be categorized into the 
following six levels using the variable %Red defined in Section 3.9.1.1 above (without 
considering imputation rules for patients who discontinued the trial without completing the 
patient seizure diary):
%Red  ≤  -25
exacerbation
-25 < %Red < 25
no change
25 ≤ %Red < 50
25% response
50 ≤%Red < 75
50% response
75 ≤ %Red < 100
75% response
%Red  = 100
seizure freedom
The proportions of patients in each category will be presented for each treatment arm. 
3.9.2.4
Seizure-free days
Change from baseline in frequency of seizure-free days per 28 days will be presented for each 
treatment arm. The following definitions are required:
1. Frequency of seizure-free days per 28 days during the Baseline phase (SF0B)
Defined as:
SF0B  =  28 × number of seizure-free days recorded over the 8 week prospective Baseline 
phase ÷ number of non-missing seizure diary days in the 8 week prospective Baseline 
phase. 
Number of seizure-free days: The number of days on which the number and types of 
seizures were known and documented in the “Investigator’s Seizure Classification” eCRF, 
and on which there were no occurrences of any of the seizure types that are part of the 
protocol definition of partial-onset (i.e., no occurrences of seizure codes IA1, IA2a, IB1, 
IB2, IB3, IC1, IC2, IC3, IC4, IC5 or IC6, as defined in Table 2-8).


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8 week prospective Baseline phase: see point 1 in Section 3.9.1.1.
Number of non-missing seizure diary days: see point 1 in Section 3.9.1.1.


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2. Frequency of seizure-free days per 28 days in the maintenance period of the Core 
phase (SF0M)
Defined as:
If patient does not discontinue during the 6 week titration period of the Core phase, then 
SF0M  =  28 × number of seizure-free days recorded during the maintenance period of the 
Core phase ÷ number of non-missing seizure diary days in the maintenance period of 
the Core phase.
Otherwise 
SF0M  =  28 × number of seizure-free days recorded during the titration period of the Core 
phase ÷ number of non-missing seizure diary days in the titration period of the Core 
phase.
That is, patients who discontinue prior to the maintenance period have frequency of 
seizure-free days determined using their data from the titration period, thereby assuring 
that all patients with seizure data in the Core phase have a value for SF0M.
Number of seizure-free days: see point 1 above. 
Titration period of the Core phase: see point 2 in Section 3.9.1.1.
Maintenance period of the Core phase: see point 2 in Section 3.9.1.1.
Number of non-missing seizure diary days: see point 1 in Section 3.9.1.1.
Then the change from baseline in frequency of seizure-free days per 28 days is calculated as 
(SF0M - SF0B), with values greater than 0 representing improvement over baseline.
Change from baseline in frequency of seizure-free days per 28 days will be summarized by 
treatment arm (mean, standard deviation, range). Mean differences between each everolimus 
arm and the placebo arm in change from baseline in frequency of seizure-free days per 28 
days will be presented, along with 95% confidence intervals (See Section 4.9 for details on 
calculation of mean differences).
3.9.2.5
Treatment duration
Treatment duration is defined as the time from randomization until the date of permanent 
study treatment discontinuation (for any reason) at any time during the Core phase (i.e., 
titration period or maintenance period). Patients who complete the Core phase without 
discontinuing will have treatment duration censored on the last day of the Core phase. For the 
purposes of this analysis, a patient is considered to have completed the Core phase if still on 
double blind study treatment on study day 126 (where study day 1 is the randomization date).
The treatment duration distributions in each arm will be presented descriptively in the FAS 
using Kaplan-Meier curves (see Section 4.8.1), from which summary statistics will be 
determined, including the median treatment duration and the proportions of patients still on 
treatment at 6 and 12 weeks. These statistics will be given as point estimates with 95% 
confidence intervals. The hazard ratio (and two sided 95% confidence interval) for each 
everolimus arm versus placebo will be obtained from a Cox proportional hazards model 
stratified by age subgroup (see Section 4.8.2).


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3.9.2.6
Long-Term Evaluation of Efficacy
A long-term evaluation of efficacy will be conducted using the LTE Efficacy Set, including 
all data on everolimus from both the Core phase and the Extension phase.
For patients randomized to one of the two everolimus arms, all data from the Core phase and 
the Extension phase will be used, whereas for patients randomized to placebo, only the 
Extension phase data will be included. In addition, the baseline seizure frequency for patients 
randomized to placebo will be obtained from the last 56 days prior to the start of ev erolimus, 
that is, from the last 8 weeks of the Core phase (see Table 3-2 below). There will be 4 
different treatment groups displayed: everolimus 3-7 ng/ml, everolimus 9 to 15 ng/ml, placebo
(i.e., extension phase data from patients previously randomized to placebo) and an overall 
everolimus arm.
The efficacy endpoints of response rate, percentage reduction from baseline in seizure 
frequency and change from baseline in seizure-free days will be determined at 12-weekly 
intervals throughout the duration of everolimus treatment (which for some patients could 
extend to more than two years). The analysis time points are shown in Table 3-2 below.
Table 3-3
Analysis time points for long-term evaluation of efficacy
Time point
Time window
Patients randomized to 
everolimus
Patients randomized to 
placebo
Baseline
The 8 weeks immediately 
prior to the start of everolimus
Study Weeks -8 to -1
(Baseline phase)
Study Weeks 11 to 18 
(Last 8 weeks of Core 
phase)
Week 18
A 12-week window ending on 
the last day of the 18th week 
of everolimus
Study Weeks 7 to 18
(Maintenance period of Core 
phase)
Study Weeks 25 to 36
(Weeks 7-18 of Extension 
phase)
Week 30
A 12-week window ending on
the last day of the 30th week 
of everolimus
Study Weeks 19 to 30
(Weeks 1 to 12 of Extension 
phase)
Study Weeks 37 to 48
(Weeks 19-30 of Extension 
phase)
Week 42
A 12-week window ending on 
the last day of the 42nd week 
of everolimus
Study Weeks 31 to 42
(Weeks 13 to 24 of Extension 
phase)
Study Weeks 49 to 60
(Weeks 31-42 of Extension 
phase)
Every 12 weeks 
thereafter
Week 
=42+12×k,
(where 
k=1,2,3,…)
A 12-week window ending on 
the last day of the (42+12×k)th
week of everolimus
Study Weeks (31+12×k) to 
(42+12×k)
Study Weeks (49+12×k) to 
(60+12×k)
Note: Study Week 1 starts on the date of randomization
The average weekly seizure frequency per time window (denoted SFTWi for the ith time 
window, i=1, 2, …), is defined as
SFTWi  =  7 × number of partial-onset seizures recorded during the ith time window ÷ 
number of non-missing seizure diary days in the ith time window,
and following the definitions provided in Section 3.9.1.1. The percentage reduction from 
baseline in seizure frequency at each time window, denoted %Red TWi for the ith time window
(i=1, 2, …), is defined as
%RedTWi  =  100 × (SFTW1 - SFTWi) ÷ SFTW1


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where SFTW1 is the average weekly seizure frequency in the baseline time window.
The frequency of seizure-free days per 28 days for the ith time window, denoted SF0TWi (i=1, 
2, …), is defined as
SF0TWi  =  28 × number of seizure-free days recorded during the ith time window ÷ number 
of non-missing seizure diary days in the ith time window,
and the change from baseline in frequency of seizure-free days per 28 days is calculated as 
(SF0M - SF0B), with values greater than 0 representing improvement over baseline.
Descriptive statistics (n, mean, median, standard deviation, minimum and maximum) for 
average weekly seizure frequency, percentage reduction from baseline and change from 
baseline in seizure-free days will be presented by treatment group at each time window, and 
median values with 95% bootstrap confidence intervals will be plotted over time. The 
proportions of patients with 50% response at each time window, defined where %RedTWi  ≥ 50, 
will also be shown for each treatment group, with 95% exact confidence intervals. 
These analyses need to be interpreted with care because patients are permitted to change their 
background AED regimen during the Extension phase. So for example, a patient who has had 
an important reduction in partial-onset seizures during the Core phase, and who attributes that 
reduction to the use of everolimus, may reduce the dose or stop completely one or more of the 
background AEDs during the Extension phase. This in turn could lead to an increase in 
seizure frequency, which should not necessarily be interpreted as a sign of loss of efficacy of 
everolimus.
 
 
 
 
 
 
 


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3.10
Safety evaluation
The assessment of safety will be based mainly on the frequency of AEs and on the number of 
laboratory values that fall outside of pre-determined ranges. Other safety data including vital 
signs, neuropsychological scales and the Columbia Suicide Severity Rating Scale will also be 
considered.
Safety analyses will be performed on the Safety Set, and on the LTE Safety Set.
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. All safety assessments will be listed and those collected later 
than 30 days after study treatment discontinuation will be flagged.
3.10.1
Adverse events data
3.10.1.1 Coding of AEs
AEs are coded using Medical Dictionary for Regulatory Activities (MedDRA) terminology.
3.10.1.2 Grading of AEs
The severity of AEs will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting toxicity in therapeutic 
oncology trials, but it has also been used outside of oncology (see http://wiki.nci.nih.gov) and 
was used in this study to be consistent with other studies of everolimus in TSC. CTCAE 
version 4.03 grading is by definition a 5-point scale generally corresponding to mild, 
moderate, severe, life threatening and death. This grading system inherently places a value on 
the importance of an event although there is not necessarily proportionality among grades 
(Grade 2 is not necessarily twice as bad as Grade 1).
If CTCAE grading does not exist for an AE, grades 1 – 4 corresponding to the severity of 
mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) will not be 
used; death information will be collected on the “End of Treatment (Core Phase)”, “End of 
Treatment (Extension Phase)” or “Study Completion Evaluation” eCRF pages.
3.10.1.3 General rules for AE Reporting
AE summaries will include all AEs starting or worsening on or after study day 1 (i.e., on or 
after the start date of study treatment), and starting no later than 30 days after the date of last 


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study treatment (see Section 2.1.8). Such events were labeled treatment emergent AEs in the 
study protocol, but will be referred to here as AEs in order to be consistent with the approach 
taken across other everolimus studies in TSC.
Pre-treatment AEs, defined as AEs starting or worsening between the time of signing 
informed consent and the day before starting study treatment, will only be summarized as part 
of the analysis of ongoing medical conditions – see Section 3.3.6. All AEs will be listed, and 
pre-treatment AEs will be flagged, as will post-treatment AEs, defined as AEs starting more
than 30 days after the date of last study treatment.  
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, and having at least one AE in each body system/primary system organ class, and for 
each preferred term using MedDRA coding. A subject with multiple occurrences of an AE 
will be counted only once in the AE category.
Separate AE summaries will be presented by primary system organ class, preferred term, and 
maximum CTCAE grade. A patient with multiple CTC grades for an AE will be summarized 
under the maximum (i.e., worse) CTC grade recorded for the event. In the summaries 
presented by grade, all AEs will be pooled regardless of whether they are CTC gradable or not.
The frequency of CTC grade 3 and 4 AEs will be summarized separately.
Any information collected (e.g., CTC grades, relatedness to study drug, action taken, etc.) will 
be listed as appropriate.
3.10.1.4 AE summaries
The following AE summaries will be produced:

Adverse events, regardless of study drug relationship, by primary system organ class and 
preferred term

Adverse events, regardless of study drug relationship by preferred term and maximum
CTC grade

Adverse events with suspected relationship to study drug by primary system organ class, 
preferred term

Adverse events, regardless of study drug relationship by primary system organ class, 
preferred term and maximum CTC grade

On-treatment Deaths, by primary system organ class and preferred term

All Deaths

Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term

Serious adverse events with suspected study drug relationship, by primary system organ 
class and preferred term

Adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by primary system organ class and preferred term

Adverse events requiring dose adjustment or study-drug interruption, regardless of study 
drug relationship, by primary system organ class and preferred term 


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
Adverse events requiring additional therapy, regardless of study drug relationship, by 
primary system organ class and preferred term

Non serious adverse events, regardless of study drug relationship, by primary system
organ class and preferred term (>5%)

Adverse events of special interest (AESI) (see Section 3.10.1.5) , regardless of study drug 
relationship, by grouping, preferred term and maximum CTC grade


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
Adverse events of special interest (AESI), with suspected study drug relationship, by 
grouping, preferred term and maximum CTC grade

For specific adverse events, analysis of time to event onset will be considered.
3.10.1.5 Grouping of adverse events of special interest (AESI)
Specific groupings of adverse events of special interest (AESI), labeled Safety Event 
Categories (SECs) in the study protocol, will be considered and the number of patients with at 
least one event in each grouping will be reported.
Specific groupings of AESI will be considered and the number of patients with at least one 
event in each grouping will be reported. Such groups consist of AEs for which there is a 
specific clinical interest in connection with everolimus treatment (i.e., where everolimus may 
influence a common mechanism of action responsible for triggering them) or AEs which are 
similar in nature (although not identical). The groups are defined at the project level and the 
latest version of the groupings based on the project-level information available at the time of 
the analysis will be used.
All AESI groupings are defined through a combination of Preferred Terms (PT), High Level 
Terms (HLT) or System Organ Classes (SOC). AE groupings definitions will be included in 
the appendix of the Clinical Study Report (CSR).


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Amenorrhea
The proportions of patients having at least one event of amenorrhea will be summarized by 
treatment arm, using females from the Safety Set aged between 10 and 55while on treatment. 
Frequency of events, duration of the longest event, frequency of patients by duration of event
and age at onset of first event will also be summarized.
3.10.1.6 Time to first onset of specific AEs
For selected groupings of AESIs or SOC, the following analysis of time to first occurrence 
will be considered for the double-blind Core phase.
The following AE groupings will be analyzed if at least 10% of patients have the 
corresponding event:

Stomatitis (AESI)

Infections and infestations (SOC)
All Treatment-Emergent Adverse Events (TEAEs) of interest (see Section 2.1.8) will be taken
into account.
Time to first occurrence of an AE is defined as time from the start of study treatment to the 
date of first occurrence of an AE within the grouping considered in the analysis, i.e., time in 
days is calculated as (start date of first occurrence of AE) – (date of first dose of study 
treatment) +1.
A patient will be censored for time to first occurrence of an AE if:

the patient discontinues the Core phase with no event

the patient is still on-going at the end of the Core phase with no event
In the absence of an event, the censoring date applied will be the earliest from the following 
dates: end of double-blind study treatment + 30 days, start date of everolimus treatment in the 
Extension phase, data cutoff date, date of death.
Kaplan-Meier curves will be constructed by treatment group. Median time to first occurrence 
of AE together with the 95% confidence interval will be presented for each treatment group. 
The hazard ratio will be obtained from an unstratified Cox model.
The above analyses will be performed irrespective of AE grade, and may also be repeated for 
grade 3 or above.
3.10.2
Laboratory data
Laboratory assessments include hematology, biochemistry and urinalysis. Laboratory data 
from all sources (central and local laboratories) will be combined. The summaries will include 
all laboratory assessments collected no later than 30 days after the last treatment/exposure 
date (see Section 2.1.8). All laboratory assessments will be listed and those collected later 
than 30 days after the last treatment/exposure date will be flagged in the listings.

All laboratory values will be converted into SI (Standard International) units and will be 
classified programmatically into CTC grades according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.


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
Conflict between normal range and grade definition: Because many institutions have 
differences for normal ranges of metabolic laboratory, and hematology values, the 
CTCAE often uses the terms 'Upper Limit of Normal (ULN)' and 'Lower Limit of Normal 
(LLN)' in lieu of actual numerical values. In some cases, an institution's LLN might be 
beyond the range specified for a Grade. In this case, the institutional limits of normal 
should take precedence over the CTCAE values: the laboratory value will still be taken as 
within normal limits and assigned a CTC grade of zero.

For the few parameters having comparison to baseline in CTCAE grading definition 
(Fibrinogen, INR, Hemoglobin, Creatinine), the highest grade will be retained. In another 
words, in the particular case when a value is a grade x as per CTC grade definition based 
on threshold/ranges and also grade x+1 when comparing to baseline, Grade x+1 is retained. 

Grade 5 will not be used.

For calcium, CTCAE grading is based on Corrected Calcium and not on Calcium. 
Corrected Calcium (CALC) can be calculated from Albumin and Calcium. Corrected 
Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4].
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following summaries will be produced for the laboratory data (by laboratory parameter):

Number and percentage of patients by worst post-baseline CTC grade (regardless of the 
baseline status). Each patient will be counted only for the worst observed post-baseline
grade. For laboratory parameters such as blood glucose where the patient can be graded 
for a decrease or an increase, the worst post-baseline CTC grade will be presented 
separately (i.e., hypoglycemia and hyperglycemia).

Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology and biochemistry laboratory parameters that are CTC gradable.

For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based on 
laboratory reference ranges.
3.10.2.1 Listings of laboratory values
The following listings will be produced for laboratory data:

Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges

A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities).
3.10.2.2 Hepatitis B and C
All data collected on Hepatitis B and C will be listed.
The results obtained at baseline and at last examination will be summarized by treatment 
group. The number of patients followed for regular monitoring will also be provided.


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3.10.3
Vital signs
Vital signs assessments are performed in order to characterize basic body function. Height 
(cm), weight (kg), body temperature (°C), pulse (beats per minute), systolic and diastolic 
blood pressure (mmHg) and respiration rate (breaths per minute) will be collected in eCRFs.
The criteria for clinically notable abnormalities are defined below in Table 3-4.
Table 3-4
Clinically notable values
Vital Sign
Patient age at randomization
< 18 years
≥ 18 years
Systolic BP
High
≥ 95th percentile of the age and 
height group1
≥ 180 mmHg and an increase ≥ 
20 mmHg from baseline
Low
≤ 5th percentile of the age and 
height group1
≤ 90 mmHg and an decrease ≥ 
20 mmHg from baseline
Diastolic BP
High
≥ 95th percentile of the age and 
height group1
≥ 105 mmHg and an increase ≥ 
15 mmHg from baseline
Low
≤ 5th percentile of the age and 
height group1
≤ 50 mmHg and an decrease ≥ 
15 mmHg from baseline
Body temperature
High
≥ 38.4 °C
≥ 39.1 °C
Low
≤ 35.0 °C
Weight
High
increase of ≥ 2 BMI-for-age 
percentile categories2
increase from baseline of ≥ 10%
Low
decrease of ≥ 2 BMI-for-age 
percentile categories2
decrease from baseline of ≥ 10%
Pulse
High
≥ 120 bpm with increase from baseline of ≥ 15 bpm
Low
≤ 50 bpm with decrease from baseline of ≥ 15 bpm
1: The 95th percentiles for blood pressure for the appropriate age and height groups are obtained from the NHLBI 
tables (http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm).
2: Percentiles categories: P3, P5, P10, P25, P50, P75, P85, P90, P97 are obtained from the WHO Growth Charts 
(http://www.who.int/childgrowth/en/
The following summaries will be produced for each vital sign parameter:

Number and percentage of patients with at least one post-baseline vital sign abnormality 
(in both directions, i.e., both elevated and below normal values).
In addition, the following two listings will be produced by treatment group:

Patients with clinically notable vital sign abnormalities. 

All vital signs assessments will be listed by patient and vital sign parameter. 
In both listings, the clinically notable values will be flagged and also the assessments 
collected later than 30 days after the date of last study treatment will be flagged.
3.10.4
Neuropsychological Scales
3.10.4.1 Vineland-II
The Vineland-II instrument (Vineland Adaptive Behavior Scales 2nd Edition) is for patients 
of any age and will be completed at baseline, end of Core phase, and then every 6 months (24 
weeks) in the Extension phase plus at the end of treatment in the Extension phase. It will be 
used in only a subset of countries participating in the trial, where translated and validated 


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versions of the scale are available: Australia, Belgium, Canada, Colombia, France, Germany, 
Ireland, Italy, Japan, Netherlands, Poland, Spain, United Kingdom and United States. 
There are two distinct versions of the Vineland-II being used in the study, namely the Survey 
Interview Form and the Parent/Caregiver Form. The Survey Interview Form is completed by 
the investigator during a semi-structured interview with the patient and/or caregiver, whereas 
the Parent/Caregiver Form is a questionnaire that is completed by the parent or caregiver 
directly. The two forms differ only in the method of administration, although the wording is 
different on the Parent/Caregiver Form for ease of understanding. The same type of form that 
is used at the baseline assessment should be used thereafter at all subsequent assessments.
Each form contains 433 items that are scored 0 (never), 1 (sometimes) or 2 (usually). The 
items are organized into the five domains of Communication, Daily Living Skills, 
Socialization, Motor Skills and Maladaptive Behavior. The five domains consist of 15 
subdomains as shown in Table 3-5.
Table 3-5
Content of Vineland-II
Domain (number of items)
Subdomains (number of items)
Communication (99)
Receptive (20), Expressive (54), Written (25)
Daily Living Skills (109)
Personal (41), Domestic (24), Community (44)
Socialization (99)
Interpersonal Relationships (38), Play and Leisure Time (31), 
Coping Skills (30)
Motor Skills (76)
Gross (40), Fine (36)
Maladaptive Behavior (50)
Maladaptive Behavior Index – Internalizing (11), Maladaptive 
Behavior Index – Externalizing (10), Maladaptive Behavior Index 
– Other (15), Maladaptive Behavior Critical Items (14)
Within each domain, the subdomains yield so-called v-scale scores that sum to yield the 
domain composite scores. An overall Adaptive Behavior Composite (ABC) score is obtained 
by combining the first four domain scores for patients aged less than 7 years, or the first 3 
domain scores for patients aged 7 or older. 
The raw scores, v-scale scores for subdomains, standard scores for domains and overall 
Adaptive Behavior score will be obtained using the Vineland-II Survey Forms ASSISTTM
software, which provides scores based on the Vineland-II Survey Forms Manual (Sparrow et 
al. 2005). Individual item answers, as collected during administration of the questionnaire,
will be entered in the software by an external vendor. Subsequently, scores obtained from the 
software will then be printed and results entered in a dataset. This dataset containing the
derived scores (v-scale scores for subdomains, domain standard scores and ABC score) will 
then be transferred to the Novartis systems for analysis.
The 14 Maladaptive Behavior Critical Items do not yield a score and will only be listed. The 
15 Maladaptive Behavior Index – Other items do not yield a v-scale score and will not be 
analyzed separately. They will only be used for the derivation of the Maladaptive Behavior 
Index Score, and will also be listed.
Compliance to the schedule of administration of the Vineland-II will be summarized for each 
treatment arm in the FAS at baseline and end of Core phase using the following categories:
- yes, fully completed


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- yes, partly completed
- no
The precise rules to determine completeness of the forms will be described in RAP M8.
For the long-term evaluation of everolimus, the same categories will be used to summarize 
compliance in the LTE Safety Set at baseline, end of Core phase and then every 6 months (24 
weeks) in the Extension phase plus at the end of treatment in the Extension phase.
Descriptive statistics (n, mean, standard deviation, minimum and maximum) for the overall 
Adaptive Behavior Composite and domain/subdomain v-scale scores will be presented at 
baseline and at end of Core phase by treatment group in the Safety Set, using the time 
windows defined in Section 2.1.9.1. The data will also be presented separately based on the 
type of form that is used (Survey Interview Form and Parent/Caregiver Form). 
Change from baseline at the end of the Core phase in these scores will also be summarized. 
For this analysis, only patients who used the same form at baseline and end of Core phase will 
be included.
A similar descriptive approach will be used for the long-term evaluation of everolimus, 
including change from baseline in each time window through to the end of the Extension 
phase.
During the conduct of the study, it became apparent through blinded data review that 
questionnaires (caregiver forms in particular) were not being filled out correctly in some cases, 
preventing the determination of raw scores for some subdomains. For each subdomain, a basal 
and a ceiling item must be established in order to determine the patient’s score. The basal item 
is defined when a series of 4 consecutive 2’s (usually) is determined in the subdomain and the 
ceiling item is defined when a series of 4 consecutive 0’s (never) is found. The 
Parent/Caregiver Form identifies a starting point answering subdomain items, based on 
patient’s chronological age. In patients with cognitive disability, chronological age may not 
correlate with developmental age and an earlier starting point would be more appropriate. In 
that case, the basal item would be established at lower levels than what is expected for this 
age range. This would require answering items targeting skills associated with younger 
patients in an effort to establish a basal item. The same issue could be seen for the ceiling item, 
less commonly, where it might be needed to answer items from age categories above the 
patient’s chronological age. It is possible, therefore, that because questionnaires were 
completed based on a chronological age-starting point, which is often greater than the 
developmental age in the largely disabled population enrolled in this study, basal and ceiling 
items were often not established properly.
As a consequence, subdomain raw scores were often missing and, subsequently, subdomain v
-scale scores, domain standard scores and ABC scores were missing as well. To mitigate the 
impact of many missing data points, an attempt was made to retrospectively collect the 
missing information and increase the likelihood of establishing basal and ceiling items in 
patients.
It is recognized that self-reported (or third-party reported) outcomes, can be subject to recall 
bias, and therefore, the primary analyses described above will be conducted including only 
data collected on ‘real-time’, as initially planned in the protocol. Some analyses will be 


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repeated on a dataset that includes retrospectively collected data and identified as ‘real-time 
and retrospective’ in the outputs. These supportive analyses will include data from 
retrospective collection, only when the retrospective collection yielded a score that was 
previously missing.
Retrospectively collected data (individual items answers and scores) will be flagged in the 
database via a different CRF page name, to allow the conduct if the primary and supportive 
analyses as described above.
3.10.4.2 Wechsler Nonverbal
The Wechsler Nonverbal instrument (WNV: Wechsler Nonverbal Scale of Ability) is for 
patients aged 4 to 21 years at baseline (i.e., ≥ 4 and < 22), and will be completed at baseline, 
end of Core phase, and then every 6 months in the Extension phase plus at the end of 
treatment in the Extension phase. It is a non-verbal measure of general ability, with pictorial 
instructions and no requirement for respondents to speak, and will be used in all sites across 
the study.
The full version of the WNV consists of four tests for patients less than 8 years old, namely 
Matrices, Coding, Object Assembly and Recognition, and four tests for patients aged 8 to 21, 
which are Matrices, Coding, Spatial Span and Picture Arrangement. The brief version of the 
WNV includes only Matrices and Recognition for patients under 8, and Matrices and Spatial 
Span for patients aged 8 to 21. Taking into account the time required for this and other scales 
that will be collected at the same time (i.e., Vineland-II, quality of life), it was decided to use 
the brief version of WNV for this trial, but to also perform the Coding test.
Each test is scored by the investigator, and the raw scores are recorded in the eCRF, i.e., raw 
scores for Matrices and Recognition for patients aged under 8 years, and for Matrices and 
Spatial Span for patients aged 8 to 21. The raw score for Coding is also obtained, along with 
the completion time in seconds, for all patients aged 4 to 21. In addition, the following four 
quantities can be determined from the Spatial Span test for patients aged 8 to 21: Spatial Span 
Forward (SSpF), Spatial Span Backward (SSpB), Longest Spatial Span Forward (LSSpF) and 
Longest Spatial Span Backward (LSSpB). 
Based on the raw scores from the subtests, standardized z-scores will be determined for all of 
the subtests/quantities defined above.
For each of the subtests, the mean (b) and standard deviation (Sb) of the raw scores will be 
computed using data from all subjects at baseline.  Then, the z-score for a subtest for each 
subject at each visit (including baseline visit) will be computed from the raw score (X) as  
follows:   
Z = (X -  b)/Sb .
Z follows a standard normal distribution.
A composite WNV score (W) for each subject at each visit will be computed by summing up 
the Z-scores of the 3 subtests of the WNV collected in this study (i.e., Matrices, Recognition 
and Coding for patients aged under 8 years; Matrices, Spatial Span  and Coding for patients 
aged 8 to 21).


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Compliance to the schedule of administration of the WNV will be summarized for each 
treatment arm in the FAS at baseline and end of Core phase using the following categories, 
which will be determined programmatically based on presence/absence of raw scores in the 
eCRF:
- yes, fully completed
- yes, partly completed
- no
For the long-term evaluation of everolimus, the same categories will be used to summarize 
compliance in the LTE Safety Set at baseline, end of Core phase and then every 6 months in 
the Extension phase plus at the end of treatment in the Extension phase.
Descriptive statistics (n, mean, standard deviation, minimum and maximum) for the 
composite WNV score, and the individual test z-scores, will be presented at baseline and at 
end of Core phase by treatment group in the FAS, using the time windows defined in Section 
2.1.9.1. Change from baseline at the end of the Core phase in these scores will also be 
summarized.
A similar descriptive approach will be used for the long-term evaluation of everolimus, 
including change from baseline in each time window through to end of the Extension phase.
3.10.5
Columbia Suicide Severity Rating Scale
The electronic Columbia Suicide Severity Rating Scale (eC-SSRS) will be completed by 
patients at all visits except at the PK visits (weeks 1, 3, 5 and 19) and the End of Study visit. It 
will be administered by an Interactive Voice Response System (IVRS), with the patient 
making the telephone call while at the study site. For patients under 12 years of age, the 
suicide scale will be answered on their behalf by the parent or caregiver.
The scale consists of five categories of suicide ideation (Categories 1 to 5) and five categories 
of suicide behavior (Categories 6 to 10) each answered either yes or no:
Suicide Ideation:
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Suicide Behavior:
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt (non-fatal) 
Category 10 – Completed Suicide
Self-injurious behavior without suicidal intent is also an eC-SSRS outcome (although not 
suicide-related) and will also be answered either yes or no.
Three composite endpoints based on the above categories will be used:


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
Suicidal ideation is defined as a “yes” at any time on or after the first day of study 
treatment to any one of the five suicidal ideation categories (Categories 1 to 5).

Suicidal behavior is defined as a “yes” at any time on or after the first day of study 
treatment to any one of the five suicidal behavior categories (Categories 6 to 10).

Suicidal ideation or behavior is a “yes” answer at any time on or after the first day of 
study treatment to any one of the ten categories.
In addition, the eC-SSRS data will be mapped to the Columbia Classification Algorithm for 
Suicide Assessment (C-CASA) as per FDA guidance on suicidality, as follows: 
1. Completed Suicide: eC-SSRS Category 10.
2. Suicide Attempt: eC-SSRS Category 9.
3. Preparatory Actions Toward Imminent Suicidal Behavior: eC-SSRS Categories 6 to 8.
4. Suicidal Ideation: eC-SSRS Categories 1 to 5.
5. Self-Injurious Behavior without Suicidal Intent: taken directly from eC-SSRS.
Compliance to the schedule of administration of the eC-SSRS will be summarized for each 
treatment arm in the Safety Set at each of the time windows defined in Section 2.1.9.4. 
Compliance will be determined programmatically based on the responses in the eC-SSRS, and 
will use the following categories:
- yes, fully completed
- yes, partly completed
- no
A call is considered as fully completed if answers to all of the questions related to the 
categories 1 to 9 above have been given at the IRT by the respondent. Please note that 
categories 3, 4 and 5 are only inquired in case of a positive answer to question 2 ; therefore, 
calls with a negative answer to question 2 and missing results to questions 3, 4 and 5 in the 
database will be considered as fully completed calls.
In the analysis, some calls to the IRT will be considered as invalid and results not included in 
the summary tables. These calls will be flagged with a ‘*’ as invalid calls in the listings. 
These calls are defined “invalid” when the patient or caregiver calling the IRT system 
recording the answers to the questionnaire hangs up before completing the call. If the patient 
or caregiver calls back the same day and re-answer all questions and completes the call, then 
the first incomplete call is flagged as invalid and is not taken into account in the analyses. 
This situation typically arises when the patient/caregiver answered incorrectly one question 
and therefore hangs-up and calls back to correct the answers. Both calls will be listed. Please 
note that an incomplete call not followed by a complete call on the same day is still 
considered valid and is included in the analyses.
For the long-term evaluation of everolimus, the same categories will be used to summarize 
compliance in the LTE Safety Set at each of the time windows. Note that for placebo patients 
who start everolimus in the Extension phase, their compliance data will be shown using the 
Extension phase time windows (i.e., from Week 22 onwards).


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A data listing will be prepared containing all patients in the Safety Set who answered “yes” 
during the Baseline or Core phases to any of the Categories 1 through 10, or who answered 
“yes” to the outcome “Self-injurious behavior without suicidal intent”. The listing will contain 
all visits for such patients from screening through to the end of the Core phase, and the 
responses to all ten Categories and the additional outcome on self-injurious behavior will be 
shown, along with the C-CASA score. A similar listing will be presented using the LTE 
Safety Set, including patients who answered yes during Baseline, Core or Extension phases.
The proportions of patients in each treatment group in the Safety Set with suicidal ideation,
suicidal behavior and suicidal ideation or behavior, at any time during the Core phase, will be 
presented, along with the worst categories of suicidal ideation and suicidal behavior (where 
worst means the highest numbered category). The same analysis will be performed using the 
C-CASA scores of completed suicide, suicide attempt, preparatory actions toward imminent 
suicidal behavior, suicidal ideation and self-injurious behavior without suicidal intent. These
analyses will be repeated using the LTE Safety Set across the Core and Extension phases.
Upon release of protocol amendment 2, investigators were required to discuss episodes of 
self-injury and changes in the patient’s mood and/or behavior with the patient and caregiver,
for all patients.  For patients ≥13 years of age who are not able to complete the eC-SSRS
scale via IRT, the investigator was to proactively assess the patient for the presence of 
suicidality. Any positive response had to be further investigated, and appropriate medical 
treatment initiated and recorded as an adverse event on the AE eCRF.
The summary of this assessment was recorded in the eCRF and data will be listed.
3.10.6
Other safety data
Data from other tests (e.g., electrocardiogram) will be listed, notable values will be flagged, 
and any other information collected will be listed as appropriate.
All assessments collected later than 30 days after the last date of study treatment (see Section 
2.1.8) will be flagged in the listings.
3.11
Other test data
3.11.1
Growth Data
Growth data will only be analyzed as part of the long-term evaluation of everolimus. This is 
because the 18 week Core phase is not considered a long enough period of time to observe 
changes in growth. Also, analyses will be restricted to patients under the age of 18, in whom 
height/weight growth is still likely to be taking place. Therefore, all analyses will use patients 
from the LTE Safety Set who were under 18 years of age on the start date of everolimus.
Height and BMI will be summarized at 24-week intervals before and after starting everolimus, 
using the standard deviation score (SDS, also called z-score), velocity and velocity SDS. The 
relevant height and BMI values for each 24-week period are defined using time windows, as 
defined in Section 2.1.9.5. 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:


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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:
SD3neg = 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 males and females 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 this time and 
described in the 2007 Bulletin of the World Health Organization (Mercedes de Onis et al 
2007). 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).
Height velocity is defined as follows:
Height velocity (cm/6-months) = (height in time window k – height in time window k-1) 
÷ ([assessment date in time window k – assessment date in time window k-1] ÷ 
[365.25/2]),
and similarly for weight velocity. 
Velocity SDS is calculated as (velocity – mean) / SD, where mean and SD are obtained as the 
height-, weight-, sex- and age-specific values in Tables 3 to 8 in Baumgartner (1986), where 
the age category immediately above the patient’s exact age (at the assessment date in time 
window k) should be used. Velocity SDS will only be calculated for time window k if data 
also exists for time window k-1, since calculating across multiple units of 6 months requires 
more than one reference value to be taken into account.
Height/weight SDS and velocity SDS will be summarized using descriptive statistics (mean, 
standard deviation, range) for each time window (before and after starting everolimus 
allowing informal comparison of growth data), as well as by presenting number of patients 


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with SDS values lower/higher than 5th/95th percentiles respectively. Box plots will also be 
plotted for each time window. All height/weight SDS, velocity and velocity SDS data will be 
listed, and values of SDS and velocity SDS outside of the central 95% of population values 
will be flagged as either High (SDS ≥ 1.645) or Low (SDS ≤ -1.645).
Comparison of height at 18 years with mid-parental heights will be performed, by presenting 
the number of patients with a height higher/lower than expected. High/Low values are defined 
as values more extreme than mid-parental height +/- 8.5 cm. Mid-parental height= ((father’s 
height – 13) + mother’s height) ÷ 2 for girls, and ((mother’s height + 13) + father’s height) ÷ 2 
for boys (Tanner et al. 1970).
3.11.2
Puberty Stage
Puberty stage will only be analyzed as part of the long-term evaluation of everolimus on the 
LTE Safety Set. . 
Tanner Stage includes two components for boys, namely testis and pubic hair, and two 
components for girls: breast development and pubic hair. It is expected that data will b ecome 
available during the trial on a proportion of patients as they go through puberty attaining 
higher levels of the Tanner Stage. For the age at which Tanner Stages 2-5 are achieved, age at 
thelarche (females), age at menarche (females) and age at adrenarche (males), summary 
statistics from Kaplan-Meier distributions will be determined, including the median age and 
the proportions of patients reaching these milestones at some given ages (see Section 4.8.1). 
These statistics will be given as point estimates with 95% confidence intervals. The 
percentage of patients who will reach Tanner Stage 2 during the study will be calculated 
among the number of patients with Tanner Stage 1 at Baseline (prior to the start of 
everolimus). The percentage of patients who will reach Tanner Stage 3 during the study will 
be calculated among the number of patients with Tanner Stage 1 or 2 at Baseline.
Similar rules will be applied for the age at Tanner Stages 4 and 5. Age at thelarche, age at
menarche and age at adrenarche will be assessed among patients who have not yet reached 
these development milestones at baseline.
Potential delayed puberty in girls is defined as failure to attain Tanner Stage 2 (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 2 (Fenichel et al. 2012). Potential delayed puberty in boys is 
defined as failure to attain Tanner Stage 2 (for both testis and pubic hair) by age 14 (Crowley 
et al. 2012). Rates of potential delayed puberty will be presented for boys and girls separately, 
along with 95% confidence intervals, on the population at risk of delayed puberty at baseline.
Note that the denominator for analyses of delayed puberty excludes patients who were 
identified as having delayed puberty at baseline (i.e., prior to starting everolimus). 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.
Blood samples for endocrine testing will be obtained at week 14, end of treatment in the Core 
phase, every 12 weeks through the Extension phase and at end of treatment in the Extension 
phase. Parameters measured will include testosterone, follicle stimulating hormone, 
luteinizing hormone and estradiol (girls only). The data will be listed.


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3.12
Patient reported outcomes
3.12.1
Quality of life
Quality of life will be assessed using three baseline-age-specific questionnaires: the Quality of 
Life in Childhood Epilepsy (QOLCE) for patients aged ≤ 10 years, the Quality of Life in 
Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48) for patients aged 11 to ≤ 17 years, 
and the Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P) for patients aged ≥ 
18 years.
Each questionnaire will be completed at baseline, at end of Core phase (or end of treatment if 
patient discontinues), and then at the end of treatment in the Extension phase. The same 
questionnaire that is used at baseline should be used at the post-baseline visits, even if the 
patient’s age exceeds the upper age limit, so that changes from baseline can be calculated.
Details of each of the three questionnaires follow.
QOLCE
The QOLCE is completed by the patient’s parent or caregiver. It consists of 16 subscales (13 
multi-item scales and 3 single item scales) and one Overall Quality of Life Score. The 
subscale score for each individual is calculated as the mean of the items belonging to the 
subscale. The Overall Quality of Life Score is computed by adding each subscale score for 
each individual and then dividing by 16. Higher scores correspond to improved quality of life. 
The 16 subscales are as follows, where the numbers and letters following each subscale name 
refer to the section and item numbers in the questionnaire:
Quality of life item:
2.1.
Physical restrictions: 
3.1. a, b, c, d, e, f, g, h, i, j.
Energy/fatigue: 
3.2. a, b
Depression:
4.1. a, d, e, l
Anxiety:
4.1. g, j, n, o, p 
Control/helplessness:
4.1. c, f, h, i
Self-esteem:
4.1. k, m, q, r, s
Attention/concentration:
5.1. a, d, e, f, g
Memory:
5.1. j, k, l, m, n, o
Language:
5.1. p, q, r, s, t, u, v, w
Other Cognitive:
5.1. b, c, h
Social interactions:
6.1. b, c, d, f, h 
Social activities:
6.1. a, e, and 6.2.
Stigma item:
6.1. i
Behaviour:
7.1. a, b, c, f, g, h, i, j, k, l, m, o, p, q, r, t 
General health item:
8.1.
The coding of each item and subscale will be given in detail in Module 8 of the RAP 
documentation, based on the publication by Sabaz et al. 2003. Higher scores correspond to 
improved quality of life. An Overall Quality of life score can be obtained by averaging the 16 


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subscale scores. There has been doubt expressed over the reliability and validity of the tool in 
patients under 6 years of age for the cognitive subscales: Attention/concentration, Memory, 
Language, Other Cognitive  (Sabaz et al. 2003). For these patients, the Overall Quality of life 
score will be obtained as the average of the remaining 12 subscales.
QOLIE-AD-48
The QOLIE-AD-48 must be completed by the patient, and not by the parent or caregiver. It 
contains 48 items in 8 subscales as follows, where the numbers following each subscale name 
refer to the item numbers in the questionnaire:
Epilepsy impact (12 items): 
7, 26, 27, 29, 30, 31, 32, 33, 34, 35, 37, 48.
Memory/concentration (10 items): 
9, 13, 14, 15, 16, 17, 18, 19, 20, 21.
Attitudes toward epilepsy (4 items): 
44, 45, 46, 47.
Physical functioning (5 items): 
3, 4, 5, 6, 8.
Stigma (6 items): 
38, 39, 40, 41, 42, 43.
Social support (4 items): 
22, 23, 24, 25.
School behavior (4 items): 
10, 11, 12, 28.
Health perceptions (3 items): 
1, 2, 36.
The coding of each item and subscale will be given in detail in Module 8 of the RAP 
documentation, based on the publication by Cramer et al. 1999. Higher scores correspond to 
improved quality of life. An overall quality of life score is obtained by summing a linear 
combination of the subscale scores, where each subscale is multiplied by a relative weight that 
is provided in the publication.
QOLIE-31-P
The QOLIE-31-P must be completed by the patient, and not by the parent or caregiver. It 
contains 39 items, of which a total of 30 are used to make up 7 different subscales as follows, 
where the numbers following each subscale name refer to the item numbers in the 
questionnaire:
Seizure Worry (5 items): 
30, 31, 32, 33, 34.
Overall Quality of Life (2 items): 
1, 36.
Emotional well-being (5 items): 
7, 8, 9, 10, 11.
Energy/fatigue (4 items): 
2, 3, 4, 5.
Cognitive (6 items): 
19, 20, 21, 22, 23, 24.
Medication effects (3 items): 
26, 27, 28.
Social function (5 items): 
13, 14, 15, 16, 17.
A further 7 items (numbers 6, 12, 18, 25, 29, 35, 37 in the questionnaire) ask about distress, 
one for each of the 7 subscales. These distress scores provide the weights in a linear 
combination of the 7 subscale scores to give an overall quality of life score. Finally, item 38 
assesses the overall health of the patient, and item 39 requires patients to rank in order of 
importance the 7 subscale domains in the list above. The coding of each item will be given in 
detail in Module 8 of the RAP documentation, based on the publication by Cramer et al. 2003
and the QOLIE-31-P Scoring Manual (QOLIE Development Group 2013).


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QOL statistical analysis
There will be a common approach to analyzing each of the three questionnaires. The 
exception being that for the QOLCE cognitive subscales (Attention/concentration, Memory, 
Language, Other Cognitive), only patients aged 6 years and over at the baseline assessment 
will be included. First, compliance to the schedule of administration of each questionnaire 
will be summarized for each treatment arm in the FAS at baseline and end of Core phase 
using the following categories:
- yes, fully completed
- yes, partly completed
- no
For the long-term evaluation of everolimus, the same categories will be used to summarize 
compliance in the LTE Efficacy Set at baseline, end of Core phase and end of Extension 
phase. In addition, for all three QOL questionnaires, the number of items that can be missing 
for a given patient for a subscale score to still be calculated will be determined based on the 
50% or “half-scale” rule.  That is, for all three QOL questionnaires, subscores are calculated 
for a given patient only if at least 50% of the items in the subscale are completed; otherwise, 
the score for that subscale is set to missing for that patient.  Thus, for example, the Epilepsy 
Impact domain of the QOLIE-AD-48 consists of 12 items, and so a specific patient must 
answer at least 6 of those items for their Epilepsy Impact score to be calculated. If a patients 
answers less than 6 items then the subscale score is set to missing.  For the QOLIE-AD-48
and the QOLIE-31-P, the total score should not be calculated if more than one scale score is 
missing. If one scale is missing, the total score is calculated based on the subscale scores that 
are completed.  In addition, the following specific rule must be applied for the derivation of 
the QOLIE-AD-48 total score: the “Epilepsy impact” subscale score (with a weight of 0.31 in 
the total score) is always required. For the QOLCE, if less than 50% of the subscale scores are 
present then the total score is also set to missing.  
Descriptive statistics (n, mean, standard deviation, minimum, maximum) for the overall 
quality of life score and subscale scores will be presented at baseline and at end of Core phase 
by treatment group in the FAS. Change from baseline at the end of Core phase in these scores 
will also be summarized.
Change from baseline to end of Core phase in the overall quality of life scores will be 
analyzed using an analysis of covariance (ANCOVA) model including terms for treatment
and baseline overall quality of life score. The differences in least square means between each
everolimus arm and the placebo, and the corresponding two-sided 95% confidence interval 
will be presented.
A similar descriptive approach will be used for the long-term evaluation of everolimus, 
including change from baseline at end of Core phase and End of Extension phase.
3.13
Pharmacokinetic analysis
This study includes PK analyses for everolimus concentration, and also for concentrations of 
12 different AEDs. 


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3.13.1
Everolimus PK
3.13.1.1 General principle
In this study, measurement of everolimus levels at trough (Cmin) is scheduled for weeks 1, 3, 
5, 10, 14 and 18 during the Core phase, and at weeks 19, 22, 26, and 30 , and every 12 weeks 
thereafter during the Extension phase. Additional everolimus PK samples will be collected 2 
weeks after any change in the dose of study medication, or 2 weeks after any change in use of 
concomitant CYP3A4/PgP inhibitors or inducers.
Blood samples for the pre-dose sample (Cmin) should be obtained prior to dose 
administration on the same treatment day and at 20-28 hours after the previous dose. Cmin
should be collected at steady state, which means that no dose interruption or dose changes 
should have occurred in the previous 4 days. Further, the Cmin value will not be reliable if the 
patient had vomited within 4 hours of taking the previous dose. Samples collected during the 
first 4 days of dosing will be excluded from all analyses.
PK analyses will be performed on the Confirmed PK Sample Set from all everolimus patients 
in the Safety Set, which is defined as follows:
Confirmed PK Sample Set:
Cmin values collected prior to dose administration on the same treatment day and at 
20-28 hours after previous dose, at steady state, and patient did not vomit within 4 
hours of previous dose.
All analyses described below (except figures) will be repeated using a PK Sensitivity Sample 
Set if the Confirmed PK Sample Set contains less than 50% of the samples available among 
everolimus patients in the Safety Set.
PK Sensitivity Sample Set:
Cmin values collected prior to dose administration on the same treatment day and at
20-28 hours after previous dose.
Equivalent PK sample sets will be defined for the LTE Safety Set. 
Biofluid concentrations will be expressed in mass per volume units. All missing data and 
concentrations below the lower limit of quantification (i.e., < 0.3 ng/ml) will be labeled as 
such in the concentration data listings, and will be excluded from all analyses.
3.13.1.2 PK definitions
Leading dose level 
Leading dose level is the dose level that has the most immediate impact on the concentration, 
and for Cmin it is the dose of everolimus administered on the previous day. 
Projected Cmin and time-normalized Cmin
The following model-based approach will be used to calculate the projected Cmin (instant 
Cmin). Cmin will be fitted using a modified power model expressed as a linear mixed effect 
model with a random effect for subject and fixed effects for each of up to the last 5 dosing 


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days (which corresponds to 120 hours, equivalent to 4 times everolimus half-life. Everolimus 
half-life is 30 hours according to the information in the Investigator Brochure). Cmin for 
subject i at timepoint j will be calculated as:
Where

µ is the population mean

si is the random subject effect

dosej-k is the dose k days prior to the Cmin at time j

εij is the residual error

Cmin and dose will be log-transformed and the age subgroup (stratification factor) will 
be included in the model as a covariate
The best fixed effects model will be selected based on the lowest Akaike Information 
Criterion (AIC) and clinical pharmacological interpretation, using the Maximum Likelihood 
(ML) method. Correlation between the 5 variables of dose will be assessed to determine 
appropriate possible model (to avoid collinearity issues). The final estimates will be obtained 
using restricted maximum likelihood (REML). Different covariate structures will be 
investigated.  The final model will be used to predict Cmin for each subject at each day in the 
study based on the individual’s dosing record. If the predicted Cmin is negative, the projected 
Cmin will be set to zero.
Time-normalized (Cmin, TN) is an estimate of the daily Cmin for a patient i averaged over a 
time interval Δt =t2-t1 between consecutive assessment times (t1, t2). It will be calculated 
over each assessment interval (t1, t2) and will be linked to the response assessed (seizure 
frequency in this specific case) within the same interval in exposure-response analyses. For 
each patient, an overall Cmin,TN will be calculated across the maintenance period of the Core 
phase or other selected time intervals.
The time-normalized Cmin will be defined as: 
Cmin,TN = AUCC(t1-t2) ÷ (t2 – t1 ) 
where AUCC(t1-t2) denotes the area under the pre-dose concentration-time curve over the 
interval (t1, t2), with the AUC calculated using the trapezoidal rule as follows
, where pCmin(tk) is the projected Cmin at time tk,,N= the number of equally spaces panels in the 
interval. N+1 = the number of grid points. t1 = pCmin at the beginning of the interval. tN =
pCmin one day prior to t2  
If t1=t2, then Cmin,TN = pCmin(t1).
For patients with events occurring after treatment stop, projected Cmin after treatment stop 
will be computed from the last projected Cmin derived from the last dose (i.e. Cmini(tlast+1), 


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where tlast+1 is the day following the last dose). Based on the PK linear properties of 
everolimus, ie, that the elimination rate does not depend on the concentration, the overall 
elimination constant, λ, can be approximated by the estimated half-life from population PK 
model. The computation of Cmini(tp) (tp > tlast+1) will be as follows:
Cmini(tp)= Cmini(tlast+1) × exp(-λ × 24× (tp – (tlast + 1)))
3.13.1.3 PK summary statistics
Cmin will be summarized for each everolimus treatment arm by time window (as defined in 
Section 2.1.9.2). Descriptive statistics will include n, arithmetic mean, median, standard 
deviation, coefficient of variation, minimum and maximum. Geometric mean and geometric 
coefficient of variation will also be displayed (when ≥3 samples).
Cmin and dose-normalized Cmin (ng/mL per mg dose and ng/mL per mg/m2 dose) will be 
summarized for each everolimus treatment arm by time window and by age subgroups (<6, 6 
to <12, 12 to < 18, and ≥ 18 years of age) and by the use of CYP3A4 inducer.
Box plots of Cmin and dose-normalized Cmin (ng/mL per mg dose and ng/mL per mg/m2
dose) will be plotted by time window and by age subgroups (<6, 6 to <12, 12 to < 18, and ≥ 
18 years of age) (when ≥3 samples) and by the use of CYP3A4 inducer for each treatment 
arm.
Scatter plot of Cmin versus dose (mg) by age subgroups (<6, 6 to <12, 12 to < 18, and ≥ 18 
years of age) (when ≥ 3 samples) will be plotted (use all Cmin values collected during the 
core and extension phase of the study).
Scatter plot of Cmin versus dose normalized to BSA (mg/m2) by age subgroups (<6, 6 to <12, 
12 to < 18, and ≥ 18 years of age) (when ≥ 3 samples) will be plotted (use all Cmin values 
collected during the core and extension phase of the study).
Scatter plot of dose-normalized Cmin (ng/mL per mg dose and ng/mL per mg/m2 dose) versus 
age by the use of CYP3A4 inducer will be plotted (use all Cmin values collected during the 
core and extension phase of the study).
Time-normalized Cmin calculated across the maintenance period of the Core phase will be 
summarized by treatment arm.
For the long-term evaluation of everolimus, these same analyses will be repeated for the 
patients originally randomized to either of the two everolimus arms. For placebo patients who 
start everolimus in the Extension phase, Cmin will be summarized using different time 
windows that take account of the planned schedule of blood draws in the Extension phase, as 
defined in Section 2.1.9.2.
3.13.1.4 Impact of CYP3A4/PgP inducers and inhibitors
The impact of CYP3A4/PgP inducers and inhibitors on everolimus concentration by age range 
will be assessed by fitting a mixed model to log(C min), with log(leading dose [mg/m2]) as a 
fixed effect and patient as a random effect. The model will also include two indicator 
covariates and their interaction as fixed effects:


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
co-administration of a CYP3A4/PgP inducer at the time of a sample (yes/no), defined as 
the intake of a CYP3A4 inducer or a PgP inducer over each of the previous 7 consecutive 
days

co-administration of a CYP3A4/PgP inhibitor at the time of a sample (yes/no), defined as 
the intake of a CYP3A4 inhibitor or a PgP inhibitor on any one of the previous 4 days
Further covariates might be included if appropriate.
The estimate of the regression coefficients for the continuous covariates in the fitted model 
and their 90% confidence intervals will be presented. For the categorical factors, the 
geometric mean ratios and their 90% confidence intervals will be calculated. For the
CYP3A4/PgP categories, the no inducer/no inhibitor category will be the reference. Note that 
including log-dose in the model is not done in an attempt to assess dose-proportionality.
3.13.1.5 Exposure-response relationship 
The relationship between everolimus exposure and the two primary efficacy endpoints of 
response rate and percentage change from baseline in seizure frequency will be investigated.
For response rate, logistic regression will be used to model the probability of response. The 
model will include terms for time-normalized Cmin (log-transformed) in the maintenance 
period of the Core phase (defined as from study day 43 until the last day of study medication 
in the Core phase and extension phase), baseline seizure frequency (SFB defined in Section 
3.9.1.1), and will be stratified by age subgroup. Further covariates might be included if 
appropriate.
To estimate the exposure-response relationship on the seizure frequency, a multiplicative 
linear regression model will be used. The dependent variable will be the absolute seizure 
frequency during the maintenance period of the Core phase and extension phase (in log scale).
The model will include baseline seizure frequency (SFB) (in log scale) and time-normalized
Cmin (in log scale) in the maintenance period of the Core phase as fixed effects. Further 
covariates might be included if appropriate. The absolute seizure frequency change for a 2-
fold increase in Cmin will be also estimated. Box plots of percentage reduction from baseline 
in seizure frequency by range of time-normalized everolimus concentration at through 
(Cmin,TN) in steps of 1ng/mL, during the maintenance period will also be presented.
An additional analysis will be performed considering the seizure frequency (log scale) and the 
time-normalized Cmin for fixed time intervals (e.g. 2 weeks), accounting for the longitudinal 
nature of the data and the inter-patient variability. A linear mixed model with time-normalized 
Cmin, baseline seizure frequency, both log transformed as fixed effects and patient as random 
effect will be performed. Further covariates might be included if appropriate. In particular, 
CYP3A4/PgP inducers (yes/no) and use of CYP3A4/PgP inhibitors (yes/no) will be 
considered. Scatter plots of percentage change from baseline in seizure frequency versus time-
normalized Cmin with a line joining data of individual patients during the maintenance period 
of the Core phase and extension phase will be presented, separately for different values of 
baseline seizure frequency (in units of seizures per week: < 3, 3 to < 6, 6 to < 9, ≥9). Note 
that if there are insufficient numbers of patients in any of the groups these categories of 
seizure frequency might be changed. Targeted concentrations ranges of 3 to 7 ng/mL and 9 to 
15 ng/mL will be identified by lines on the graph.


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Response rate (as defined in Section 3.9.1.1) and percentage reduction in seizure frequency 
(as defined in Section 3.9.1.2) will be analyzed by time normalized Cmin across the 
maintenance phase categories (< 3, 3 to 7, > 7 to < 9, 9 to 15 and > 15 ng/ml). Response rates 
will be provided with exact 95% confidence intervals (see Section 4.4) for each category. The 
median percentage reduction from baseline will be presented for each treatment group along 
with 95% bootstrap confidence intervals (see Section 4.7) for each category.
Time-normalized Cmin values associated with ≥ 50% reduction from baseline in seizure rate 
(Cmin_responder) will be estimated for individual patients. Frequency distribution curve of 
Cmin_responder (10, 25, 50, 75, 90 percentiles of Cmin associated with ≥ 50% reduction 
from baseline in seizure rate) will be made.
Time-normalized Cmin values associated with 40% to 60% reduction from baseline in seizure 
rate (Cmin_50%) will be estimated for individual patients. Frequency distribution curve of 
Cmin_50% (10, 25, 50, 75, 90 percentiles of Cmin associated with ~ 50% reduction from 
baseline in seizure rate) will be made.
Exposure-response analyses will consider Core phase data. In addition, exposure-response 
analyses will be repeated considering all data available at the time of the cut -off, including 
data beyond the core phase. 
3.13.1.6 Exposure-safety relationship
Selected summary AE tables will be presented split by exposure to everolimus, in terms of 
time-normalized Cmin over the entire Core phase (titration period plus maintenance period), in 
order to compare the safety profiles. The selected AE will be the clinically notable AE 
groupings, as defined in Section 3.10.1.6. The tables will present the number of patients 
experiencing a given AE. Time-normalized Cmin values will be categorized in units of ng/ml
as < 3, 3 to 7, > 7 to < 9, 9 to 15 and > 15. 
In addition the time to first event of selected AEs will be fitted using an extended Cox model 
with interval time-normalized Cmin as a time varying covariate, stratified by age subgroups. 
Four time intervals will be considered to adjust relative risks by the impact of exposure on 
safety: during the 6 weeks titration period, the 12 weeks of the maintenance period of the core 
phase, the 8 weeks titration period of the extension phase and the extension phase (after week 
26). Relative risks of the AEs for a two-fold increase in exposure and its 90% confidence 
interval will be reported.
Exposure-safety analyses will be based on available data at the time of the cut-off, that means 
even data points beyond the core phase will be also considered.
3.13.2
AED PK
The concentration levels of 12 commonly prescribed AEDs that are CYP3A4/PgP inducers or 
inhibitors will be assessed, in order to investigate the possibility of drug-drug interactions
with everolimus. The 12 AEDs are of interest consist of five CYP3A4/PgP inducers: 
carbamazepine, oxcarbamazepine, phenobarbital, phenytoin and primidone, and seven
CYP3A4/PgP inhibitors: clonazepam, diazepam, clobazam, felbamate, topiramate, valproic 
acid and zonisamide. 


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All patients should be taking a background regimen of one to three AEDs at a stable dose 
from 4 weeks prior to screening through until the end of the Core phase. Blood samples for 
AED PK are scheduled to be taken at two time points in the Baseline phase, at the screening 
visit (week -8) and the baseline visit (day -1), providing two values of AED concentration in 
the absence of everolimus. Two further samples will be taken at weeks 1 and 3 of the Core 
phase, providing two values of AED concentration in the presence of everolimus. Samples 
will only be collected from patients who are taking at least one of the 12 AEDs of interest, 
and who are over 20 kg in body weight (to avoid drawing too much blood in the very 
youngest patients, given that blood draws are also required for laboratory determinations and 
everolimus PK). If a patient is taking more than one of the AEDs of interest in their 
background AED regimen, then a separate sample will be obtained for each AED.
Blood samples for AEDs must be pre-dose, obtained prior to dose administration on the same 
treatment day.
Concentrations of each AED will be summarized for each everolimus treatment arm by time
window (as defined in Section 2.1.9.3). Descriptive statistics will include n, arithmetic mean, 
median, standard deviation, coefficient of variation, minimum and maximum. Geometric 
mean and geometric coefficient of variation will also be displayed (when ≥3 samples).
The impact of everolimus on the exposure of the AEDs will be assessed via linear mixed 
models to compare the exposure of the AEDs before and after the administration of 
everolimus. Separately for each AED, a linear mixed model will be fitted to the log-
transformed
concentrations,
and will include period (before and after everolimus 
administration) as a fixed effect, and patient as a random effect. Geometric mean ratios of the 
concentrations with and without everolimus (as reference) and their 90% confidence intervals
will be calculated from the model.
The above analyses will be repeated considering only patients exposed to only one of the 12 
AEDs of interest to investigate any potential confounding effect. 
Model-based analysis will be performed only on those AEDs taken by a minimum of 6 
patients with valid concentrations for both everolimus and the corresponding AED.  
3.14
Subgroup analyses
Subgroup analyses will be performed to compare each everolimus arm versus placebo as 
detailed in Table 3-6 below.
Table 3-6
Subgroup analyses
Subgroup
Categories
Reference
Use
Age
Calculated from date of birth 
and randomization date as 
collected on the eCRF, as 
follows: 1 to <6 years, 6 to 
<12 years, 12 to <18 years 
and ≥ 18 years
Stratification factor
(1) Safety
(2) Efficacy
Gender
Male versus Female
Regulatory requirement
(1) Safety
(2) Efficacy


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Subgroup
Categories
Reference
Use
Race
As collected in eCRF if large 
enough to allow interpretable 
results. If small, grouping of 
categories might be 
considered.
Regulatory requirement
(1) Safety
(2) Efficacy
Ethnicity
As collected in eCRF if large 
enough to allow interpretable 
results. If small, grouping of 
categories might be 
considered.
Regulatory requirement
(1) Safety
(2) Efficacy
Japanese*
Japanese
Regulatory requirement
(PMDA)
(1) Safety
(2) Efficacy
(1) Main safety analysis (overall AE tables, adverse events of special interest) will be repeated.
(2) If the primary analysis of response rate or percentage reduction in seizure frequency is statistically significant, 
subgroup analyses will be performed.
* Subgroup analyses of the main efficacy and safety endpoints, as well as baseline characteristics, will be 
performed on patients randomized in Japan, for use by the Japanese regulatory authority.
 
No adjustment of alpha for multiplicity or 
any other strategy to control the family-wise error rate will be implemented.
3.15
Interim analyses
No interim analysis for efficacy is planned, but there will be DMC reviews of the ongoing 
safety data as the trial progresses. The first meeting will review data from the first 6 months of 
the study, with subsequent meetings every 6 months thereafter until the study is unblinded.
As outlined in the DMC charter, the safety review outputs will be prepared by an independent 
statistician and an independent programmer from Novartis, neither of whom will belong to the 
trial team or will be involved in any other aspects of the trial conduct. Semi-blinded results 
will be shared with the DMC members using a secured web portal to which Novartis 
personnel have no access (except the independent statistician/programmer). After the meeting, 
the DMC chair will provide a recommendation to the Novartis Oncology global development 
head. Apart from the recommendation made, the Novartis team members will remain blinded 
to any study results.


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Details of all outputs to be provided to the DMC will be described in a separate DMC RAP
document.
3.16
Sample size calculation
The sample size was chosen to provide adequate power for the primary objective comparing 
seizure frequency between each everolimus arm and the placebo arm. The sample size 
calculation provided here is based exclusively on response rate, the EMA primary endpoint, 
but it is also expected to provide sufficient patients for the power of the FDA primary 
endpoint, percentage reduction in seizure frequency. This is because response rate is a binary 
transformation of percentage reduction in seizure frequency, and therefore likely to be less 
sensitive owing to the loss of information going from a continuous variable to binary.
It was assumed that response rates would be 15% in the placebo arm and 35% in each of the 
two everolimus arms. That is, there was no a priori strong expectation that the higher targeted 
trough everolimus arm 9 to 15 ng/mL would deliver a higher response rate than the lower 
targeted trough everolimus arm 3 to 7 ng/mL, as better efficacy may be mitigated by worse 
tolerability. For this reason, the testing strategy was to simultaneously compare each pairwise 
comparison, splitting the significance level, rather than testing hierarchically starting with the 
higher trough arm for example.
Using nQuery version 6.1 it was determined that a sample size of 355 patients would ensure 
90% power for each of the primary comparisons of each everolimus arm versus placebo, 
assuming one-sided 1.25% significance levels for each CMH chi-square test, and assuming 
balanced randomization (i.e., 115 patients per randomization arm). 
Table 3-7
Sample size and power for primary objective
Comparison
One-sided 
alpha
Response rates under 
alternative hypothesis
Sample Size
Power
Everolimus 3-7 ng/mL arm versus 
Placebo arm 
1.25%
35% vs. 15%
230 
(115 vs. 115)
90%
Everolimus 9-15 ng/mL arm versus 
Placebo arm 
1.25%
35% vs. 15%
230 
(115 vs. 115)
90%
Approximately 5 months after the first patient was randomized, a human error was identified 
which caused the IRT system not to perform dose titrations despite Cmin values outside the 
targeted trough range. The IRT system was updated the same day. By that time a total of 4 7 
patients had already passed their Week 2 assessment, the point at which the first dose titration 
could have been made.
After an investigation into the potential impact of this error on the study power, it was noted 
that placebo patients would be unaffected, and in all likelihood, the majority of patients in the 
everolimus 3 to 7 ng/ml arm would be expected to achieve everolimus concentrations within 
the targeted range. However, since few patients randomized to the everolimus 9 to 15 ng/ml 
arm would be expected to achieve adequate dosing, it was decided to increase the sample size 
in the everolimus 9 to 15 ng/ml arm by 10 patients.
The choice of 10 patients was made on the following grounds. Based on the pattern of 
complete and incomplete blocks, up to 18 of the 47 potentially affected patients may have 
been on the everolimus 9 to 15 ng/ml arm. As a worst case, assume all 18 patients were under-


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dosed and achieved everolimus concentrations in the 3 to 7 ng/ml range, and assume that this 
trough range is no better than placebo. Then at the end of the study, among the 115 planned 
patients on the everolimus 9 to 15 ng/ml arm, 18 patients will have a 15% chance of being 
responders (i.e., as placebo arm patients) and 97 will have a 35% chance. Overall this makes 
an expected response rate in the everolimus 9 to 15 ng/ml arm of 31.9%, in which case the 
power for the comparison with the placebo arm drops to 78%. Other more realistic scenarios 
lead to a smaller loss in power, for example with 12 patients under-dosed and subject to 
placebo arm response rate, the power is 83%, with 6 patients it is 87%. The sample size 
increase was chosen to protect against loss in power for these more realistic scenarios, where 
the addition of 10 patients to the everolimus 9 to 15 ng/ml arm improves power to 85% for 12 
under-dosed patients and to 88% for 6 under-dosed patients.
The sample size increase of 10 patients was made by inserting a number of blocks with 
randomization ratio of 1:1:2 in favor of the everolimus 9 to 15 ng/ml arm, with the planned 
sample size becoming 355 patients (115 on placebo arm, 115 patients on everolimus 3 to 7 
ng/ml arm and 125 patients on everolimus 9 to 15 ng/ml arm; overall randomization ratio of 
1:1:1.09). The required modification of the randomization list was overseen by an 
Independent Randomization Expert, a Novartis employee who is not part of the study team.
4
Details of the statistical analysis
4.1
Baseline comparability
Baseline variables refer to characteristics of patients at the start of a study (see Section 2.1.7
for more detailed definition of ‘baseline’).
Baseline variables will be descriptively summarized by treatment group. No inferential 
analysis will be performed to compare baseline characteristics between the treatment arms.
4.2
One-sided vs. two-sided test 
Since this is a placebo controlled study where the primary objective is clearly directional, the 
hypothesis test for the primary endpoint will be one-sided at the 2.5% level of significance.
However, confidence intervals will always be two-sided and at the 95% level, since they will 
be used for estimation rather than decision-making.
4.3
Comparison of response rates
Cochran-Mantel-Haenszel test
The Cochran-Mantel-Haenszel (CMH) chi-square test (implemented via SAS procedure 
FREQ with the CMH option in the TABLES statement) will be used to test the difference in 
response rates between the treatment arms. The p-value will be obtained from the “General 
association” CMH statistic.
The one-sided p-value will be obtained using the square root of the chi-square distributed 
CMH general association statistic. As a consequence, the one-sided p-value will then be either 


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the two-sided p-value divided by two or its opposite (1 – two-sided p-value divided by two) 
depending on the direction of the Odds ratio estimate.
The following SAS code will be used:
PROC FREQ data=dataset; 
TABLES stratum*trt*response / CMH;
OUTPUT OUT=pval_cmh COMOR CMHGA;
RUN;
/* stratum represents stratum variable 
   trt represents treatment group variable 
   response represents response variable  */
DATA pval_cmh1sid;
SET pval_cmh;
IF _MHOR_>1 THEN pvalue=P_CMHGA/2; 
ELSE pvalue=1-P_CMHGA/2;
run;
* If OR is in favor of everolimus (i.e. <1) then one-sided p-
value = two-sided p-value/2 else one-sided p-value = 1- two-
sided p-value/2;
/* pvalue represents the one-sided p-value
P_CMHGA represents the two-sided p-value from the “General association” 
CMH statistic
   MHOR_represents the adjusted Mantel-Haenszel odds ratio*/
Note: The direction of the odds ratio depends on the parametrization of the model. In the 
above example, it is assumed that the probability modeled is absence of response and the 
reference arm is placebo. In other words, an odds ratio below one indicates that the 
probability of being non-responder is less in the everolimus arm compared to placebo.
Odds ratio
The odds ratio can also be used as a measure of association between treatment and response. 
It will be derived from a logistic regression model (implemented using SAS procedure 
LOGISTIC, with treatment specified as an explanatory variable in the CLASS statement) 
which allows for including not only the stratification factor but also for adjustments for other 
covariates, both categorical and continuous. The odds ratio will be presented with 95% Wald 
confidence limits.
The following SAS code will be used:
PROC LOGISTIC data=dataset; 
     CLASS trt;
MODEL response=trt stratum <covariate_1>..<covariate_k>;
RUN;
/* stratum represents stratum variable
   trt represents treatment group variable 
   response represents response variable
   covariate_i (i=1,…,k) represents the ith covariate */


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4.4
Confidence interval for response rate
An exact binomial confidence interval (implemented using SAS procedure FREQ with the
EXACT statement for one-way tables) will be used (Clopper and Pearson 1934).
4.5
Rank Analysis of Covariance
Continuous data where the normality assumption is unlikely to be valid will be analyzed using 
rank ANCOVA (rank analysis of covariance). Rank ANCOVA is a nonparametric approach 
and is preferred to classical parametric ANCOVA when the data may not be even 
approximately normally distributed. This method does not lead to much loss of power versus 
parametric ANCOVA should the data turn out to be approximately normal (Canover 1999).
Rank ANCOVA will be implemented in SAS using the procedures RANK, REG and FREQ. 
The following three steps illustrate how to compare a continuous response variable (labeled 
perc) between two treatment groups (labeled treat), adjusting for a covariate (labeled cov), 
and with an analysis stratified by a stratification factor (labeled strat).
1. Procedure RANK is used to calculate fractional ranks for the covariate and the response 
variable across the combined treatment groups separately within each stratum. Fractional 
ranks are obtained by dividing each rank by the number of patients with non-missing data 
in the stratum; fractional ranks are used because they adjust for possibly different numbers 
of patients in each stratum. In case of ties, the mean of the ranks will be assigned.
PROC RANK data=dataset FRACTION TIES=MEAN OUT=ranks; 
BY strat;
VAR cov perc;
RUN;
2. Procedure REG is then used to fit separate linear regression models for each stratum. In 
each model the fractional ranks of the response variable is the dependent variable, and the 
fractional ranks of the covariate is the independent variable. The residuals from each 
model are stored in an output dataset.
PROC REG data=dataset NOPRINT; 
BY stratum;
MODEL perc=cov,
OUTPUT OUT=residual R=resid;
RUN;
3. Then a stratified Cochran-Mantel-Haenszel mean score test is performed using the 
residuals as scores, and a p-value for the treatment comparison is obtained.
PROC FREQ data=residual; 
TABLES stratum*treat*resid / NOPRINT CMH2;
OUTPUT OUT=pval_rank CMH2;
RUN;
The p-value is taken from the SAS output labeled “Row Mean Scores Differ”.
The one-sided p-value will be obtained using the square root of the chi-square distributed 
CMH row mean score statistic. As a consequence, the one-sided p-value will then be either 
the two-sided p-value divided by two or its opposite (1 – two-sided p-value divided by two) 
depending on the sign of the mean difference estimate of the percentage change from baseline.


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The following SAS code will be used:
ODS OUTPUT DIFFS=diffs LSMEANS=lsmeans;
PROC MIXED data=residual;
CLASS strata trtreg1c;
MODEL resid=strata trtreg1c /ddfm=satterth;
LSMEANS trtreg1c /diff=control("Placebo");
run;
DATA pval_rank1sid;
      MERGE pval_rank diffs;
      IF Estimate>0 THEN pvalue=P_CMHRMS/2; 
ELSE pvalue=1-P_CMHRMS/2; 
run;
* If the mean percentage reduction is in favor of everolimus 
(i.e. the mean percentage reduction is higher in everolimus) 
then one-sided p-value = two-sided p-value/2 else one-sided p-
value = 1- two-sided p-value/2;
/* pvalue represents the one-sided p-value
P_CMHRMS represents the two-sided p-value from the “Row Mean Scores” CMH 
statistic
   Estimate represent the mean difference between everolimus and placebo*/
4.6
Bonferroni-Holm method
The Bonferroni-Holm method for multiple testing (Holm 1979) was designed to control the 
family-wise error rate, that is, the probability of incorrectly rejecting at least one of a family 
of hypotheses. It is more powerful than the Bonferroni approach, and does not require any 
assumptions (e.g., distributional, independence), and can therefore be applied to any family of 
pairwise comparisons regardless of the joint distribution of the test statistics. It is a 
conservative test and the family-wise error rate cannot exceed the planned alpha level.
The method works as follows.
Consider testing the family of hypotheses H0i, where i = 1, 2, …, k, with the intention of 
controlling the family-wise error rate to α (e.g., α = 0.05).
Let pi, i = 1, 2, …, k, denote the sample p-values of tests for H0i, i = 1, 2, …, k, where the p-
values were computed without any multiplicity adjustment.
Let [1], [2], …, [k] denote indices such that p[1]  ≤  p[2]  ≤  …  ≤  p[k].
That is, p[1] refers to the smallest p-value, and in general, [i] is the inverse rank of pi among p1, 
p2, …, pk.
The Bonferroni-Holm method then proceeds as follows.
Step 1: If p[1]  ≤  α ÷ k, reject H0[1] and go to Step 2; otherwise stop.
Step 2: If p[2]  ≤  α ÷ (k – 1), reject H0[2] and go to Step 3; otherwise stop.


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…
Step k: If p[k]  ≤  α, reject H0[k] and stop.
There is no direct procedure in SAS to run the Bonferroni-Holm method, so it will be run by
reading in the appropriate unadjusted p-values and the required alpha level, and then 
performing the steps 1 though k above.
4.7
Bootstrap method
To calculate the confidence intervals of observed medians, percentile bootstrap confidence 
intervals will be used (Efron and Tibshirani 1993).
From the original sample of size n, a total of B independent bootstrap samples are 
selected, each consisting of n data values drawn with replacement. The number of 
bootstrap samples will be B = 100 000.
The sample median is evaluated for each of the B independent bootstrap samples.
The B sample medians are ordered to obtain the 2.5th percentile and 97.5th percentile. 
The 95% confidence interval itself will then be: (2.5th percentile, 97.5th percentile).
Bootstrap methodology (Efron and Tibshirani 1993) stratified by age subgroup will be used to 
estimate the difference between the median percentage reduction from baseline between each 
of everolimus treatment arms and placebo using the following steps:
1. Let N1j, N2j, N3j denote the numbers of patients in the relevant analysis population who 
were randomized to the everolimus 3 to 7 ng/ml arm (Arm 1), the everolimus 9 to 15 ng/ml 
arm (Arm 2) and the placebo arm (Arm 3) respectively and stratum j, j=1 (1 to <6 years), 2 (6 
to <12 years), 3 (12 to <18 years) and 4 (≥ 18 years). Calculate the median percentage 
reduction from baseline in seizure frequency in the 3 arms and by stratum M1j, M2j and M3j 
(M=median). Calculate the difference between the median percentage reduction from baseline 
between each of everolimus treatment arms and placebo: Y1j as M1j-M3j and Y2j as M2j-
M3j.
2. Take a sample with replacement, of size N1j from patients in Arm 1 and stratum j, of size 
N2j from patients in Arm 2 and stratum j, and of size N3j from patients in Arm 3 and stratum 
j. Calculate an estimate of Y1j and Y2j. Repeat this resampling estimation step Nsim=10,000 
times. Denote the estimates of Y1j and Y2j obtained from these steps by Y1ij and Y2ij, i=1 to 
Nsim.
3. Calculate the variance of the estimates Y1ij and Y2ij by stratum and denote it Var(Y1j*)
and Var(Y2j*) respectively. Calculate the weight of each stratum equal to W1j=[1/Var(Y1j*)] 
/ [Σj=1 to j=4 1/Var(Y1j*)] for the comparison between the everolimus 3 to 7 ng/ml arm and 
the placebo arm, and W2j=[1/Var(Y2j*)] / [Σj=1 to j=4 1/Var(Y2j*)] for the comparison 
between the everolimus 9 to 15 ng/ml arm and the placebo arm.
4. Calculate for each sample, the stratified estimates Y1iW=Σj=1 to j=4 Y1ij*W1j and 
Y2iW=Σj=1 to j=4 Y2ij*W2j
5. Calculate the stratified estimate of comparison as Y1=Σj=1 to j=4 Y1j*W1j for everolimus 
3 to 7 ng/ml versus placebo and Y2=Σj=1 to j=4 Y2j*W2j for everolimus 9 to 15 ng/ml versus 
placebo.


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6. To obtain the 95% confidence interval, Y1 and Y2 are ordered to obtain the 2.5th percentile 
and 97.5th percentile.
4.8
Time-to-event analyses
This section presents the general methodology used to analyze time-to-event variables.
4.8.1
Kaplan-Meier estimates
An estimate of the time-to-event function in each treatment group will be constructed using 
the Kaplan-Meier (product-limit) method as implemented in the procedure LIFETEST with 
the METHOD=KM option. Kaplan-Meier curves will be displayed by treatment group.
Median time-to-event for each treatment group will be obtained along with 95% confidence 
intervals using the method of Brookmeyer and Crowley 1982.
Kaplan-Meier estimates of the time-to-event function with 95% confidence intervals at 6 and 
12 months, where 1 month is defined as (365.25/12)=30.4375 days, will be summarized by 
treatment group. Confidence intervals will be constructed using Greenwood’s formula for the 
standard error of the Kaplan-Meier estimate (Collett 1994, p.23). 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.
Kaplan-Meier graphs will be constructed using S-Plus software, although the statistics 
displayed on the graph (e.g., median, hazard ratio) will be obtained from SAS.
4.8.2
Hazard ratio
Hazard ratio as a treatment effect measure will be derived from the Cox proportional hazards 
model using the SAS procedure PHREG (with the TIES=EXACT option in the MODEL 
statement).
A stratified Cox model will be used (where the baseline hazard function is allowed to vary 
across strata). In this model the MODEL statement will include the treatment group variable
as the only covariate and the STRATA statement will include the protocol stratification 
variable (age subgroup). The hazard ratio and its two-sided 95% confidence interval will be 
based on the Wald test.
4.9
Comparison of means
The mean difference along with its 95% CI between two continuous variables will be 
calculated using a t-test assuming equal variances in the two arms. The mean difference 
(95%CI) will be obtained from the “Diff (1-2) pooled method” estimate. 
The following SAS code will be used:
PROC TTEST data=dataset TEST=DIFF;
      CLASS trt;
      VAR response;
run;
/* trt represents treatment group variable 


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   response represents response variable  */
4.10
Linear Mixed model for Expose-Response relationship 
A linear mixed model analysis will be performed to investigate the relationship between the 
frequency of seizures and the time-normalized Cmin assessed every two weeks. The linear 
mixed model allows introducing fixed as well as random effects and therefore adjusting for
the repeated measures nature of the data. Variables will be log transformed. Different 
covariance patterns will be investigated. The best model will be selected based on the lowest 
Akaike Information Criteria (AIC, BIC or AICC) and clinical pharmacology interpretation, 
under maximum likelihood (ML) method of estimation. Once the fixed effect model is 
selected, the final estimates will be obtained based on a restricted ML (REML) method.
Marginal estimates and corresponding 95% confidence interval will be presented for each 
factor in the model. Interactions among the different covariates will be investigated and kept 
in the model if the statistical significance is below the 10%.    
PROC MIXED procedure in SAS could be used. 
PROC MIXED data=dataset   method=(ML or REML); 
Class patient cov1 cov2 ;
model Y =  logCmin cov1 cov2 / DDFM=  ; 
random intercept/subject=;
RUN;
The estimate of the 2 fold increases in Cmin will be calculated as follows: 
fold2Est=100*(exp( ( log(Estimate)*log(2) ) - 1)) where the ‘Estimate’ is the one given by the 
model. The same formula will be applied for the 95% CI.
For simplicity the same procedure will be used to fit a linear regression model to investigate 
the relationship between frequency of seizures at the end of the core phase and the time-
normalized Cmin over the entire core phase period. 
4.11
Stratified Cox model and Extended Cox model for Exposure-
Safety relationship 
Hazard ratio will be derived from the Cox proportional hazards model using SAS procedure 
PHREG (with TIES=EXACT option in the MODEL statement).
Hazard ratio with two-sided 95% confidence interval will be based on Wald test. 
The Stratified Cox model adjusted for covariates will be used. Subgroup of age and other 
covariates as appropriate will be considered. 
PROC PHREG data=dataset; 
MODEL survtime*censor(1)=cov1..<covk>;/TIES=EXACT;
STRATA stratum1 .. <stratum k>;
RUN;
/* survtime represents variable containing event/censor times;   
   censor represents censoring variable (1=censored, 0=event); 


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   cov1 to covk represent covariates;
   STRATA statement to be used for stratified studies only, 
   stratum1 to stratumk represent stratification variables */
The Extended Cox model in those cases where a time varying covariate will be included. 
Subgroup of age and other covariates as appropriate will be considered. 
PROC PHREG data=dataset; 
MODEL (start stop)*censor(1)= cov1..<covk>;/TIES=EXACT;
STRATA stratum1 .. <stratum k>;
RUN;
/* censor represents censoring variable (1=censored, 0=event); 
   start and stop refers to the lower and upper limit of the given time interval. 
The lower limit of the interval is not included while the upper it is.
For a 
patient with no event, the start and stop will refer to the beginning and end of 
the interval. For a patient with an event, the start refers to the beginning of 
the interval.
   cov1 to covk represent covariates;
   STRATA statement to be used for stratified studies only, 
   stratum1 to stratumk represent stratification variables */


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5
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Scoring Manual, Pearson, Bloomington, MN.


Clinical Development
Afinitor®/Votubia®/Everolimus
CRAD001M2304 / NCT02962414
A three-arm, randomized, double-blind, placebo-controlled 
study of the efficacy and safety of two trough-ranges of 
everolimus as adjunctive therapy in patients with tuberous 
sclerosis complex (TSC) who have refractory partial-onset 
seizures
Statistical Analysis Plan (SAP) – Addendum1
to support the Clinical Study Report (CSR) of the Extension phase (02-
Sep-2016 cutoff date)
Author:
 
Document type:
SAP Documentation
Document status:
Final version 
Release date:
10-Feb-2017
Number of pages:
11
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Extension CSR – Addendum1 
CRAD001M2304
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for 
update
Section and 
title impacted 
(Current)
18-
Oct-
2016
Prior 
to 
DB 
lock
Creation of final version
N/A -
First 
version
NA
09-
Feb-
2017
After 
DBL
 Addendum 1
Sections 
2.1.5.2, 2.1.7, 
2.1.8 
and 
3.1.2 added


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................4
1
Introduction .........................................................................................................................5
..5
..5
..5
..6
..6
..6
..8
..9
..9
10
10
10
10
11
4
Reference...........................................................................................................................11


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List of abbreviations
AED
Antiepileptic drug
CSR
Clinical Study report
EEG
Electroencephalogram
FSH
Follicle Stimulating Hormone
LH
Luteinizing hormone
LTE
Long-Term Evaluation
SAP
Statistical Analysis Plan
TSC
Tuberous Sclerosis Complex


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1
Introduction
Analyses conducted at the end of the core phase, focusing on the Long-Term Evaluation (LTE) 
of everolimus using all available data from both the Core and Extension phases of the trial
were described in the Statistical Analysis Plan (SAP) “CRAD001M2304_M3: Detailed 
statistical methodology_Final analysis_Addendum 1”.
The purpose of this new (‘SAP Extension CSR’) is to describe the additional exploratory 
analyses planned to further assess the LTE of everolimus in this study population (TSC with 
refractory seizures). Both SAPs will support the writing of the Clinical Study Report (CSR) of 
the Extension phase. The cutoff date for these analyses will be on 02-Sep-2016, at the end of 
the extension phase, which is 48 weeks after the last patient completed the core phase.
The CSR of the Extension phase will include the following analyses:
-
Supportive analyses on Vineland questionnaires collected during the core phase: to 
mitigate the impact of many missing data points, analyses of Vineland questionnaires 
were planned using all available data (including questionnaires retrospectively 
collected); this analysis related to core phase data was not conducted at the time of the 
Core database lock because we were not able to retrieve all retrospective 
questionnaires at the time of the Core database lock; this analysis was described in 
“CRAD001M2304_M3: Detailed statistical methodology_Final analysis_Addendum 
1”.
-
Long term safety and efficacy analyses described in “CRAD001M2304_M3: Detailed 
statistical methodology_Final analysis_Addendum 1”.
-
Additional exploratory long term efficacy analyses described in Section 2.1 of this 
document.
Except for the two first analyses listed above, none of the results focusing on the double-blind 
Core phase with comparative analyses between everolimus and placebo will be repeated for 
this CSR.


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4
Reference
Not applicable.


Clinical Development
Afinitor®/Votubia®/Everolimus
CRAD001M2304 / NCT02962414
A three-arm, randomized, double-blind, placebo-controlled 
study of the efficacy and safety of two trough-ranges of 
everolimus as adjunctive therapy in patients with tuberous 
sclerosis complex (TSC) who have refractory partial-onset 
seizures
Statistical Analysis Plan (SAP)
to support final Clinical Study Report (CSR)
Author:
 
Document type:
SAP Documentation
Document status:
Final version 
Release date:
11-SEP-2017
Number of pages:
13
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Post-Extension CSR 
CRAD001M2304
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for 
update
Section and 
title impacted 
(Current)
11-
SEP-
2017
Prior 
to 
DB 
lock
Creation of final version
N/A -
First 
version
NA


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................4
1
Introduction .........................................................................................................................5
2
Statistical methods...............................................................................................................5
2.1
Definition of  new population analysis sets.............................................................6
2.2
Background, demographics and disposition additional/modified analyses.............7
2.2.1
Background and demographics...............................................................7
2.2.2
Patient disposition...................................................................................7
8
8
8
8
 
8
9
2.4
Additional/Modified safety analyses .......................................................................9
2.4.1
Duration of exposure...............................................................................9
2.4.2
Pharmacokinetics/ Safety analyses .........................................................9
2.4.3
On-treatment deaths, serious and non-serious adverse events..............10
10
12
12
12
12
13
3
References .........................................................................................................................13


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List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
AED
Antiepileptic drug
CSR
Clinical Study report
EudraCT
European Union Drug Regulatory Authorities Clinical Trial
LTE
Long-Term Evaluation
PEP
Post-Extension Phase
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCS
Summary of Clinical Safety: preparation document
SOC
System Organ Class
TSC
Tuberous Sclerosis Complex


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1
Introduction
Analyses conducted for the Extension CSR (cut-off date of 02SEP2016), focusing on Long-
Term Evaluation (LTE) of everolimus using all available data from both the Core and 
Extension phases of the trial, were described in “CRAD001M2304_M3: Detailed statistical 
methodology_Final 
analysis_Addendum 
1”
(Primary/ 
Original 
SAP)
and
“CRAD001M2304_SAP_Extension CSR_addendum 1” (Extension SAP). 
The purpose of this new SAP is to describe the additional analyses planned to further assess 
the LTE of everolimus in the study population, especially those linked to the Post-Extension 
Phase (PEP). 
The final CSR will include the following analyses:
-
Some 
of 
the 
long-term 
efficacy 
and 
safety 
analyses 
described 
in 
“CRAD001M2304_SAP_Extension CSR_addendum 1” on the LTE Efficacy/Safety 
populations that were deemed relevant to update with data of patients who were still 
ongoing in Extension phase at the cut-off date of 02SEP2016. These analyses will use 
Post-Extension Phase data as well, when applied on the LTE Safety Set.
-
Some long-term efficacy and safety analyses on the Long-Term Post-Extension Phase 
populations (described in the sections 2.3.1, 2.3.2, 2.3.5 and 2.4.7) to assess long-term 
evaluation of everolimus for patients who continued in PEP specifically. Regarding 
efficacy, only one analysis will combine data from Extension phase and PEP (section 
2.3.2). Other efficacy analyses will either use Core + Extension phases data only or 
PEP data only. All data from Core, Extension and PEP will be used for the safety part, 
unless a restriction is specified.
-
New additional safety/efficacy analyses on LTE Efficacy/Safety Sets:

that are required as per standards for safety clinical trial disclosure registry 
(2.4.3) or for safety evaluation (2.4.6);

that were previously needed for publications purpose (2.3.4) or to address
Health Authorities request (2.4.5);

or that are slightly modified versions of analyses described in Extension SAP
(2.3.3, 2.4.1, 2.4.2) or Summary of Clinical Safety -SCS- (2.4.4); for the 
purpose of this CSR.
2
Statistical methods
Statistical 
methods 
are 
described 
in 
“CRAD001M2304_M3: 
Detailed 
statistical 
methodology_Final 
analysis_Addendum 
1” 
and 
“CRAD001M2304_SAP_Extension 
CSR_addendum 1” except for the additional exploratory analyses described in the section 2.3,
2.4.3, 2.4.4 and 2.4.5.


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2.1
Definition of new population analysis sets
Seizure diaries are no longer collected in the Post-Extension Phase, instead, seizure
information has been collected as qualitative data through a questionnaire. Seizure diaries 
were recording, on an ongoing basis up to the end of the Extension, the patient’s seizures and 
their characteristics. From the counts of partial-onset seizures, the primary endpoints were 
determined. The questionnaire in PEP only gives information on the seizure status of the 
patient, for instance it only shows yes/no answers to the questions: “was patient seizure-free 
since last visit?”, “have seizures worsened?”, “how did they worsen?”.
Three new sets of analysis population are therefore defined: “Long-Term Post-Extension 
Phase Efficacy Set” , “Long-Term Post-Extension Phase Safety Set” and “Long-Term Post-
Extension Phase Safety Set- Confirmed PK sample Set”. 
-
LT PEP Efficacy Set includes all patients who received at least one non-zero dose of 
everolimus during the Post-Extension Phase and with the specific eCRF efficacy page 
(“Changes in seizures”) collected  at least once during the Post-Extension Phase.
-
LT PEP Safety Set includes all patients who received at least one non-zero dose of 
everolimus and who have at least one safety evaluation during PEP. LT PEP Safety 
Set will be used for exposure and concomitant medication related outputs only.
-
LT PEP Safety Set-Confirmed PK Sample Set is the same definition as the LTE Safety 
Set-Confirmed PK Sample Set, except that post-extension phase samples only are used.
These two populations are used in Pharmacokinetics/Safety analyses. 
Of note, LTE Safety Set, LTE Efficacy Set and LTE Safety Set-Confirmed PK Sample Set 
definitions have not changed compared to the primary CSR. Only the data used vary 
according to the analyses (see Table 1 below).


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Table 1  Analysis populations and the data they use
Analysis population
Data used
LTE Efficacy Set
Core + Extension (analyses with seizure diaries 
information)
LT PEP Efficacy Set
Post-Extension (except for analyses described in  2.3.2 & 
2.3.5 where Extension data for this population is also 
included)
LTE Safety set
Core + Extension + Post-Extension (unless it is 
precised that we consider data up to the end of Extension 
phase cf 2.4.1)
LT PEP Safety Set
Core + Extension + Post-Extension
LTE Safety Set-Confirmed PK Sample 
Set
Time windows up to the end of Extension phase
LT PEP Safety Set-Confirmed PK Sample 
Set
Time windows during PEP
2.2
Background, demographics and disposition 
additional/modified analyses
2.2.1
Background and demographics
Demographics, Epilepsy background and seizure history, TSC diagnosis, and Seizure history 
during the baseline phase will be summarized, as they have been defined in Primary SAP, by 
treatment group and overall but using the LT PEP Efficacy Set.
Seizure characteristics at the start of the Post-Extension Phase for patients included in the LT 
PEP Efficacy set will be presented for each treatment group and overall in order to 
characterize the seizure profile of patients that have started the PEP. 
The start of Post-Extension Phase in this analysis refers to the seizures recorded in the last 12
weeks of the Extension phase.
2.2.2
Patient disposition
In order to better interpret the patient disposition in the different everolimus treatment phases, 
the analysis suggested in the previous Extension CSR will be modified. The number of 
patients who have been treated in Core/Extension/Post-Extension phases will be presented 
separately as well as the number of patients who continued in the corresponding next 
treatment phase. For patients who did not move into the next treatment phase, the primary 
reason for end of treatment will be described. The summary of patient disposition will be 


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performed using LTE Efficacy Set and LT PEP Efficacy Set by treatment arm and over all. 
The LTE Efficacy Set will be used for the listing.


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2.4
Additional/Modified safety analyses
2.4.1
Duration of exposure
In order to link the efficacy results (i.e. percentage seizure reduction from baseline & response 
rate) with the duration of exposure on one hand, and on the other hand to link the safety 
results with the duration of exposure, two analyses of duration of exposure will be defined:
-
using data up to the end of Extension phase. The duration of exposure will be 
calculated as described in the original SAP (“CRAD001M2304_M3: Detailed 
statistical methodology_Final analysis_Addendum 1” );
-
using data up to the end of Post-Extension Phase. The duration of exposure will be 
then calculated from the first administration date to the last administration date in the 
PEP that is defined as the last date when a non-zero dose of everolimus is 
administered and recorded on the “Dosage administration record – Everolimus – Post-
Extension” eCRF. 
The duration of exposure will be summarized both categorically and continuously in units of 
weeks and/or months, by treatment arm and overall on the Long-Term Evaluation Safety Set.
2.4.2
Pharmacokinetics/ Safety analyses
As for the previous analysis, the impact of CYP3A4 inducers and inhibitors on everolimus 
concentration at trough (Cmin in ng/mL) and dose-normalized everolimus concentration at 
trough (Cmin in ng/mL per mg  and Cmin in ng/mL per mg/m²) as they are defined in section 
3.13.1.2 of  the Primary SAP, will be assessed descriptively using two different analyses:


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-
using time windows as defined in the Primary SAP up to the end of Extension phase
on the Long-Term Evaluation Safety Set-Confirmed PK Sample Set;
-
using time windows calculated only during the Post-Extension-Phase on Long-Term 
Post-Extension Phase Safety Set-Confirmed PK Sample Set.
Everolimus concentration will be summarized using the two above specifications, by 
treatment arm. And then separately by treatment arm, age subgroup, use of CYP3A4 inducers
and use of  CYP3A4 inhibitors. The corresponding boxplots will as well be presented.
2.4.3
On-treatment deaths, serious and non-serious adverse events
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events (AE) which are not serious adverse events (SAE) with an incidence 
greater than 5% and on on-treatment SAE and SAE suspected to be related to study
treatment will be provided by system organ class (SOC) and preferred term (PT) on the LTE
Safety Set population. On-treatment assessment is defined as per Primary SAP as an AE 
started in the following time interval (including the lower and upper limits): [start date of 
study treatment; date of last study treatment + 30 days].
If for a same patient, several consecutive AEs (irrespective of study treatment causality,
seriousness and severity) occurred with the same SOC and PT:
-
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE.
-
more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study
treatment /non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and
SAEs irrespective of study treatment relationship will be provided by SOC and PT.


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3
References
Not applicable.