Clinical trial NCT02451696
Conditions: Epilepsy Tuberous Sclerosis Complex Focal Cortical Dysplasia
Sponsor: NYU Langone Health
Start date: 2014-01-01; Completion date: 2017-12-28
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to measure if the drug called Everolimus effects mTOR signaling (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be undergoing brain surgery. One group of patients will be treated with Everolimus, and another will not. Researchers will determine if there is a difference in mTOR signaling between the patients who were treated with Everolimus and those who were not. Previous studies have suggested that Everolimus may reduce seizure activity in TSC patients by decreasing mTOR signaling. Since patients with FCD may also have excess mTOR signaling brain activity, Everolimus may also reduce seizure activity in these patients.

The drug Everolimus is approved by the Food and Drug Administration to treat specific types of breast, pancreatic, and kidney cancer, a kidney tumor called an angiomyolipoma (common in patients with TSC), and TSC patients who have a brain tumor called a subependymal giant cell astrocytoma (SEGA). However, in this research it is considered to be an investigational since it is not approved for reduction in mTOR signaling and a decrease in seizure frequency. Researchers believe that Everolimus may be useful in reducing something called cortical hyperexcitability, which is the excess brain activity that can contribute to seizures.

Detailed description:
This is a single center open-label pilot clinical trial of patients with TRE, ages 1 to 40 years old, with TSC or FCD who are scheduled for epilepsy surgery. Patients will be treated with everolimus for 7 to 28 days prior to epilepsy surgery with extension of time from 7 to 28 days in successive cohorts of patients. The initial cohort of at least three patients will be treated for 7 days and after the safety of therapy is assured for this group, there will be an extension of the treatment to 14 days for at least three patients. This will be extended at one week intervals/three patient groups to a maximum treatment duration of 28 days. Resected brain tissue will be analyzed for activation of mTORC1 and mTORC2 signaling pathways, glutamatergic and GABA-ergic neurotransmission using histochemistry, genetic analysis, as well as extracellular field recordings in acute ex-vivo brain slices from surgery. A blood sample, collected at the time of surgery, will be analyzed for everolimus levels and VEGF-D. All patients will undergo standardized intra-operative ECoG recordings over the primary epileptogenic region and reviewed blindly.

Subjects will be in the study for 7-28 days. The investigators will study variables listed in specific aims 1 and 2 in TSC and FCD patients treated with 7 to 28 days of everolimus and compare these to untreated control patients with TRE and TSC or FCD. A concurrent comparison group of 12 subjects will also be enrolled. They will all be undergoing routine surgery for the diagnosis of TRE with TSC or FCD.

All study procedures will be performed at the Comprehensive Epilepsy Center (CEC) with the exception of the surgery, which will be performed at Tisch Hospital.

Arms: arm 1: This group will be treated with everolimus 7-28 days prior to surgery arm 2: This group will be enrolled as reference subjects, and will be undergoing routine surgery as part of standard of care treatment. No intervention will be provided to these subjects as part of the study.
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: This study will measure if the drug called Everolimus effects mTOR signaling (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be undergoing brain surgery. One group of patients will be treated with Everolimus, for 7-28 days prior to epilepsy surgery and another will not. We will determine if there is a difference in mTOR signaling between the patients who were treated with Everolimus and those who were not

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Research Protocol
Version  12/10/2018
A Pilot Study to Evaluate the Effects of Everolimus on Brain mTOR activity and Cortical 
Hyperexcitability in Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD)
IND Sponsor:
Orrin Devinsky, MD 
Department of Neurology 
NYU Langone Medical Center 
223 E 34th Street
New York, NY 10016 
Phone: 646-558-0801
Funding Sponsor:
Departmental
223 East 34th Street, New York, NY 10016 
646-558-0801
Study Agent:
Everolimus
Protocol Number:
S14-00245
IND Number:
118831
Initial version:
8/12/2014
NCT02451696


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authorized in writing by the study IND sponsor


Everolimus effects on brain mTOR and excitability
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Table of Contents
STUDY SUMMARY ......................................................................................................................................1
1
INTRODUCTION.......................................................................................................................................3
1.1
BACKGROUND......................................................................................................................................3
1.2
INVESTIGATIONAL AGENT .................................................................ERROR! BOOKMARK NOT DEFINED.
1.3
PRECLINICAL DATA ............................................................................................................................5
1.4
CLINICAL DATA RELATED TO STUDY DRUG USE...................................................................................5
1.5
DOSE RATIONALE AND RISK/BENEFITS................................................................................................8
2
STUDY OBJECTIVES............................................................................................................................9
2.1
PRIMARY OBJECTIVE .........................................................................................................................9
2.2
SECONDARY OBJECTIVES ..................................................................................................................9
3
STUDY DESIGN.....................................................................................................................................9
3.1
GENERAL DESIGN..............................................................................................................................9
3.2
PRIMARY OUTCOME MEASURES .......................................................................................................10
3.3
SECONDARY OUTCOME MEASURES ..................................................................................................10
4
SUBJECT SELECTION AND WITHDRAWAL.....................................................................................10
4.1
INCLUSION CRITERIA........................................................................................................................10
4.2
EXCLUSION CRITERIA.......................................................................................................................11
4.3
SUBJECT RECRUITMENT AND SCREENING .........................................................................................13
4.4
EARLY WITHDRAWAL OF SUBJECTS ..................................................................................................14
4.4.1
When and How to Withdraw Subjects....................................................................................14
4.4.2
Data Collection and Follow-up for Withdrawn Subjects .........................................................14
5
STUDY DRUG......................................................................................................................................15
5.1
DESCRIPTION & PACKAGING.............................................................................................................15
5.2
TREATMENT REGIMEN......................................................................................................................16
5.3
STUDY DRUG ADMINISTRATION.........................................................................................................17
5.3.1
Management of specific toxicities ..........................................................................................17
5.3.2
Dose Adjustments..................................................................................................................22
5.3.2
Serum Drug Levels
22
5.4
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS............................................................22
5.5
PRIOR AND CONCOMITANT THERAPY ................................................................................................22
5.6
BLINDING OF STUDY DRUG...............................................................................................................23
5.7
RECEIVING, STORAGE, DISPENSING AND RETURN..............................................................................23
5.7.1
Receipt of Drug Supplies .......................................................................................................23
5.7.2
Storage & Handling................................................................................................................23
5.7.3
Dispensing of Study Drug ......................................................................................................23
5.7.4
Return or Destruction of Study Drug ......................................................................................23
6
STUDY PROCEDURES .......................................................................................................................23
6.1
VISIT 1............................................................................................................................................23
6.2
VISIT 2............................................................................................................................................24
6.3
VISIT 3 – DAY OF SURGERY..............................................................................................................25
6.4
VISIT 4 (AND ALL DAYS WITH INVASIVE ELECTRODES)..........................................................................26
6.5
VISIT 5A (IF A SECOND SURGERY IS DONE AT THE END OF INVASIVE RECORDINGS) ................................26
6.6
VISIT 5B (POSTOPERATIVE DAY 2 AND ALL DAYS UNTIL DISCHARGE).....................................................27
6.7
VISIT 6............................................................................................................................................27
7
STATISTICAL PLAN............................................................................................................................27
7.1
SAMPLE SIZE DETERMINATION..........................................................................................................27


Everolimus effects on brain mTOR and excitability
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7.2
ADVERSE EVENTS ...........................................................................................................................28
7.3
SERIOUS ADVERSE EVENTS .............................................................................................................30
7.3.1
Definitions.................................................................................................................................30
7.3.2
Reporting..................................................................................................................................30
7.3.3
Investigator reporting: Notifying the -NYULMC IRB...............................................................31
7.3.4
Investigator reporting: Notifying a non-NYUMC IRB ..............................................................32
7.3.5
Sponsor reporting: Notifying the FDA ....................................................................................33
7.3.6
Sponsor reporting: Notifying participating investigators
33
7.4
UNBLINDING PROCEDURES...............................................................................................................33
7.5
STOPPING RULES ............................................................................................................................33
7.6
Source Documents
35
7.7 Case Report 
Forms………………………………………………………………………………………..35
7.8
DATA MANAGEMENT ........................................................................................................................35
7.9
RECORDS RETENTION......................................................................................................................37
8
STUDY MONITORING, AUDITING, AND INSPECTING ...................................................................37
8.1
STUDY MONITORING PLAN .............................................................................................................37
8.2
AUDITING AND INSPECTING.............................................................................................................39
9
ETHICAL CONSIDERATIONS...........................................................................................................39
10
STUDY FINANCES ............................................................................................................................39
10.1
FUNDING SOURCE .........................................................................................................................39
10.2
CONFLICT OF INTEREST .................................................................................................................39
10.3
SUBJECT STIPENDS OR PAYMENTS .................................................................................................40
11
PUBLICATION PLAN ........................................................................................................................40
12
REFERENCES .....................................................................................................................................40


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Everolimus effects on brain mTOR and excitability
Version:  09/20/18
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List of Abbreviations
AED 
Antiepileptic drug 
BMI  Body mass index 
BSA       Body surface area
CTAE
Common Terminology for Adverse Events 
EIAED
Enzyme-inducing antiepileptic drug 
FCD
Focal cortical dysplasia
mTOR
Mammalian target of rampamycin 
RMP
Risk management plan
SAE       Serious adverse event
SEGA    Subependymal giant cell astrocytoma
TNF-α Tumor necrosis factor-alpha 
TSC Tuberous sclerosis complex 
TRE       Treatment resistant epilepsy
NYULMC New York University Langone Medical Center 
SUDEP  Sudden unexpected death in epilepsy
SBMC    St Barnabas Medical Center
INN
Institute of Neurology and Neurosurgery at St Barnabas 
NYU CEC New York University Comprehensive Epilepsy Center


page 1
Everolimus effects on brain mTOR and excitability
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authorized in writing by the study IND sponsor
Study Summary
Title
A Pilot Study to Evaluate the Effects of Everolimus on Brain mTOR activity and 
Cortical Hyperexcitability in Tuberous Sclerosis Complex (TSC) and Focal 
Cortical Dysplasia (FCD)
Short Title
Everolimus effects on brain mTOR and excitability
Protocol Number
Pending
Phase
2
Methodology
This is a multi center, open-label exploratory Phase II clinical trial of patients 
with treatment resistant epilepsy (TRE), ages 2 to 50 years old, with TSC or 
FCD who are scheduled for epilepsy surgery.
Study Duration
18 months of active recruitment
Study Center(s)
NYU Langone Medical Center;
Objectives
Primary objectives: A pilot study to assess the:
1) feasibility and safety of recruiting patients into a prospective study for 
patients with TSC and FCD treated for 7-21 days before epilepsy surgery 
and 2) test the hypothesis that everolimus therapy in TSC and FCD patients 
with TRE will reduce mTOR signaling (reduced S6 phosphorylation) as 
compared to concurrent controls with TSC and FCD who did not receive 
Everolimus.
Secondary Objectives: to obtain preliminary data on the effect of everolimus 
therapy in TSC and FCD patients with TRE on mTOR signaling and cortical 
hyperexcitability by assessing 1) systemic mTOR signaling suppression 
(VEGF-D) pre- and post-treatment, 2) relation of S6 phosphorylation to specific 
genetic abnormalities, and 3) blood everolimus levels; and using historical 
controls to assess 4) markers of cortical hyperexcitability (glutamate and  
GABA receptors, levels of neuroinflammation (TNF-α), axonal abnormalities, 
myelination defects), and 5) electrocorticographic (ECoG) recordings
Number of Subjects
21 total subjects study wide; 9 treated subjects (NYU CEC) and 12 controls 
(@ NYU CEC;)
This has been a very challenging study to recruit for and therefore our total 
number of enrolled patients is fewer than expected.  This has to do with 
multiple factors, including a smaller number of eligible candidates, a smaller 
percentage of parents who have considered to participate, and the challenge 
imposed by the fact that many of the patients come from outside the NY 
Tristate area. Given this distance, enrollment of subjects 3-4 weeks before the 
surgery has not been possible, so we have shortened the length of the 
treatment phase.
Diagnosis and Main 
Inclusion Criteria
1. Female and male patients, age 2 year to 50 years
2. Diagnosis: treatment resistant epilepsy ( > 2 failed anti-epileptic drug [AED] 
treatment regimens) and either:
●Tuberous Sclerosis Complex (TSC)
●Focal Cortical Dysplasia (FCD) on MRI
Number of Subjects 
in comparison 
control group
12 subjects


E v er oli m u s  eff e ct s  on br ai n  m T O R  a nd e x cit a bilit y
V er si o n :  0 9/ 2 0/ 1 8
P a g e 2
C O N F ID E N T IA L
T hi s d o c u m e n t a n d i nf or m ati on is  t he pr o p ert y o f t he N Y U  S c h o ol o f M e di ci n e  a nd L a n g o n e  M e di c al  C e nt er.  Do  n ot di s cl o se  or u s e 
e x c e p t as a ut h ori z e d  in writi n g b y t he  st u d y I ND s p o n s or
Di a g n o si s a n d  M ai n  
I n cl u si o n Crit eri a
1 . F e m al e a n d m al e p ati e nt s, a g e 2 y e ar t o 5 0  y e ar s
2 . Di a g n o si s:  tr e at m e nt r e si st a nt e pil e p s y  ( > 2  f ail e d a nti- e pil e pti c  dr u g  
[ A E D] tr e at m e nt r e gi m e n s) u n d er g oi n g r o uti n e s ur g er y
●
T u b er o u s S cl er o si s C o m pl e x  ( T S C)
●
F o c al C orti c al D y s pl a si a ( F C D) o n  M RI
St u d y Pr o d u ct,  D o s e,  
R o ut e,  R e gi m e n
E v er oli m u s:
●
P ati e nt s N O T t a ki n g EI A E D s : T h e st arti n g d o s e of e v er oli m u s f or 
tr e at m e nt p ati e nt s  will  b e  4. 5  m g/ m
2  o n c e  d ail y;  a dj u st  t o att ai n  tr o u g h 
c o n c e ntr ati o n s of 5- 1 5 n g/ ml. T h e d o s e will b e a dj u st e d f or c ert ai n  c o- 
m e di c ati o n s ( s e e  b el o w).
●
P ati e nt s T A KI N G C Y P 3 A 4 a n d/ or P- gl y c o pr ot ei n ( P g P)  I n hi bit or s 
P ati e nt s will  b e e x cl u d e d if u si n g str o n g C Y P 3 A 4 i n hi bit or s. If t h e 
p ati e nt i s r e c ei vi n g a c o- a d mi ni st er e d dr u g wit h m o d er at e  C Y P 3 A 4  
a n d/ or P g P i n hi bit or s, t h e e v er oli m u s d o s e will b e r e d u c e d  b y  
a p pr o xi m at el y 5 0 % t o m ai nt ai n tr o u g h c o n c e ntr ati o n s of 5 t o 1 0  n g/ m L.  
N o m o d er at e or str o n g C Y P 3 A 4 a n d/ or P g P i n hi bit or will b e a d d e d  or  
di s c o nti n u e d d uri n g t h e st u d y  p eri o d.
●
P ati e nt s T A KI N G o n e c o n c o mit a nt str o n g C Y P 3 A 4 i n d u c er f or  s ei z ur e 
c o ntr ol ( e. g., p h e n yt oi n, c ar b a m a z e pi n e, p h e n o b ar bit al) will b e  all o w e d  
i n t h e st u d y. P ati e nt s t a ki n g m or e t h a n o n e str o n g C Y P 3 A 4 i n d u c er  
will b e e x cl u d e d. F or p ati e nt s r e q uiri n g a c o n c o mit a nt str o n g  C Y P 3 A 4  
i n d u c er ( a n E n z y m e-I n d u ci n g A nti e pil e pti c Dr u g ( EI A E D), w e will  
d o u bl e  t h e e v er oli m u s  d o s e  fr o m t h at pr e s cri b e d  f or p ati e nt s  n ot  t a ki n g 
EI A E D s
D ur ati o n  of  
a d mi ni str ati o n
7 t o  2 1 d a y s
R ef er e n c e  t h er a p y
N ot  a p pli c a bl e
St ati sti c al  
M et h o d ol o g y
S a m pl e si z e  c o n si d er ati o n s. F or t hi s pr eli mi n ar y st u d y, s af et y a n al y s e s ar e  
pri m ar y.  St u d y  t er mi n ati o n will  o c c ur  if, a m o n g  t h e 9  tr e at e d s u bj e ct s,  t h er e ar e  
t w o c a s e s of w o u n d h e ali n g pr o bl e m s or t hr e e c a s e s of s eri o u s i nf e cti o n, 
i n cl u di n g w o u n d sit e i nf e cti o n. I n t h e c a s e of a w o u n d sit e i nf e cti o n, a n y  
pr o bl e m s  wit h  w o u n d  h e ali n g  will  b e  c o n si d er e d  s e c o n d ar y  t o t h e i nf e cti o n a n d  
N O T a s a pri m ar y w o u n d h e ali n g pr o bl e m. T h e s e e sti m at e s ar e b a s e d  o n  
n e ur o s ur gi c al e x p eri e n c e a n d r e p ort s wit h t h e fr e q u e n c y of w o u n d  h e ali n g  
pr o bl e m s of < 2 % a n d i nf e cti o n fr o m 1. 6 t o 8. 6 % i n p u bli s h e d s eri e s, wit h  a 
m e a n i nf e cti o n r at e of  5. 3 %.
F or  t h e a n al y si s  of  S 6  p h o s p h or yl ati o n,  b a s e d  o n  a  2  s a m pl e  2  si d e d  t- t e st, 
w e c a n d et e ct a diff er e n c e of │1. 4 │-  │1. 5  │st a n d ar d  d e vi ati o n s b et w e e n t h e 
c o m p ari s o n c o ntr ol s a n d t h e tr e at e d gr o u p wit h 9  tr e at e d s u bj e ct s wit h  al p h a
= 0. 0 5 a n d  p o w er of 8 0 %. Pr eli mi n ar y d at a u si n g q u a ntit ati v e W e st er n bl ot s  
o bt ai n e d fr o m 4 r e s e ct e d t u b er s d e m o n str at e d p h o s p h o- S 6/ S 6 r ati o s  of  
2 5 7 4 2 %  of  c o ntr ol.  Wit h  9  tr e at e d s u bj e ct s,  a n d  1 2  c o ntr ol s  w e  w o ul d  b e  a bl e  
t o d et e ct  a  6 4  –  6 5 %  diff er e n c e  i n p h o s p h or- S 6/ S 6  l e v el s b et w e e n  tr e at e d a n d  
u ntr e at e d  gr o u p s,  w hi c h  i s li k el y a  bi ol o gi c all y  m e a ni n gf ul  diff er e n c e.


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1
Introduction
This document is a protocol for a human research study. This study is to be conducted in accordance with 
US government research regulations, and applicable international standards of Good Clinical Practice, 
and institutional research policies and procedures.
1.1
Background
Early onset and treatment-resistant epilepsy (TRE) commonly complicates Tuberous Sclerosis Complex 
(TSC) and focal cortical dysplasia (FCD) and can contribute to or cause severe cognitive and behavioral 
impairments in these patients. In the case of TSC, the genetic loss of TSC1/TSC2 inhibition results in 
upregulation of the mTOR signaling pathway causing multiple structural and functional alterations in the 
brain that contribute to epilepsy, although the specific alterations that cause epilepsy remain unknown. 
Many patients with TSC and FCD who have TRE benefit from epilepsy surgery if seizures are localized to 
a single epileptogenic focus. However, a multicenter study of 70 patients undergoing epilepsy surgery for 
TSC found that only 53% became seizure-free after surgery [1]. Thus, nearly half of patients experience 
seizures after surgery while many others do not qualify for epilepsy surgery because of multifocal or 
widespread epileptic networks. TRE has a high morbidity, especially for TSC patients, in which autistic 
spectrum disorder and intellectual disability are associated with frequent seizures and early life onset 
epilepsy [2] [3]. Further, the risk of sudden unexpected death in epilepsy is significantly elevated among 
patients with tonic-clonic seizures during the past year, early-onset epilepsy, long-duration of epilepsy, 
and symptomatic epilepsy. In some studies, after adolescence, sudden unexpected death in epilepsy 
rates exceed 10% per decade for individuals with multiple risk factors [4], which are present in many TRE 
patients with TSC or FCD.
mTOR inhibition in animal models of TSC has anti-epileptic and anti-epileptogenic effects, and 
preliminary data suggest that mTOR inhibitors can reduce seizure frequency in some TSC patients. The 
rationale for studying everolimus in TSC is straightforward given the known effect of TSC1 and TSC2 
mutations on mTOR activity, the effect of mTOR inhibition in animal models of TSC to reduce both the 
development (epileptogenesis) and occurrence (antiseizure) of seizures [5] [6, 7], and preliminary human 
data suggesting that everolimus can reduce seizures in TSC patients [8]. For FCD, studies from human 
brain tissue reveal that balloon cells exhibit robust phosphorylation of S6 protein in a pattern similar to 
giant cells in cortical tubers from patients with TSC [9-11]. Furthermore, brain tissue from FCD and TSC 
cases has similar cellular (e.g., balloon cells) and architectural (e.g., dyslamination) changes, further 
supporting shared pathogenetic mechanisms [12]. Additionally, FCD tissue expresses similar patterns of 
dysregulated excitatory and inhibitory neurotransmitter receptors as those observed in TSC [13, 14].
Together, these findings suggest that, as with TSC, in FCD, there is upregulation of mTOR activity in the 
brain and this may directly contribute to seizure activity. Given these brain molecular and structural 
parallels between TSC and FCD, and the significant morbidity (e.g., depression; psychosis; memory, 
language and other cognitive impairments) and mortality (e.g., sudden unexpected death in epilepsy, 
drowning, status epilepticus, suicide) associated with TRE, this pilot trial of an mTOR inhibitor has the 
potential to inform future studies in these FCD patients. Further, for the FCD group or individual patients, 
if this study finds evidence that an mTOR inhibitor can down-regulate excess mTOR activity and restore 
excitatory/inhibitory neurotransmission and reduce neuronal hyperexcitability, a subsequent trial of an 
mTOR inhibitor would have potential therapeutic benefit.
No randomized clinical trial has demonstrated efficacy of mTOR inhibitors in seizure suppression, and the 
potential mechanisms of action have not been investigated. The goal of this study is to obtain data to help 
plan an exploratory Phase II clinical trial to assess the efficacy of everolimus therapy to improve the 
molecular and electrophysiological abnormalities in the brains of TSC and FCD patients with TRE. 
Patients enrolled in this study will receive everolimus for a minimum of 7 days prior to planned epilepsy 
surgery. This short-term duration of treatment highlights the unique approach of our study, when 
compared to other investigations of the effect of mTOR inhibition in TSC patients. Other randomized 
studies gave patients everolimus for six months or longer in clinical trials of patients with TSC with 
subependymal giant cell astrocytomas (SEGAs) of the brain [8]. The effectiveness of everolimus in this 
setting was based on reduced SEGA volume. These authors noted that 16 patients for whom 24-hour


Everolimus effects on brain mTOR and excitability
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video electroencephalography data were available, seizure frequency for the 6-month study period 
decreased in 9, did not change in 6, and increased in 1 (p=0.02). However, a clinical benefit for epilepsy 
has not been definitively demonstrated thus far.
Our rationale for a short-term (7-21 days) treatment is based on prior work in animal models showing 
cellular changes in mTOR signaling (down-regulation) after only 24 hours of treatment [5]. This effect of 
mTOR inhibition on mTOR signaling and epileptiform activity in humans, however, was only demonstrated 
in patients with glioblastoma multiforme, a tumor associated with disruptions of the blood-brain barrier  
(see below) [15].
Despite lack of human “proof of concept” data for everolimus treatment in patients with TRE who have 
TSC or FCD, clinical trials of TSC patients have nevertheless been conducted. To date, no adequately 
powered, prospective studies have addressed the efficacy of everolimus in patients with TSC who have 
TRE. One small study is ongoing to assess the efficacy and safety of everolimus in TSC patients with  
TRE and we will monitor the results of this study as they become available. No studies have examined  
the effects of everolimus in TRE in patients with FCD. We believe that our study of brain tissue obtained  
at the time of epilepsy surgery in TSC and FCD patients, as well as ECoG data, will provide the first in 
vivo evidence of a biologic effect of everolimus in human epilepsy brain tissue. We have a unique 
opportunity to demonstrate this in human TSC and FCD patients undergoing epilepsy surgery by studying 
the degree of mTOR inhibition in individual patients. Defining the molecular and electrophysiological 
changes of mTOR inhibition in human brain tissue may provide critical insights into the efficacy, 
tolerability, and limitations of this therapy. A better understanding of the effects of mTOR inhibition on 
mTOR signaling, neurotransmission, and epileptogenicity in human cortical tissue is critical to develop 
more effective mTOR-targeted therapies in TSC and FCD patients, and for designing and a clinical trial. 
This study is a logical next step based for both pre-clinical studies and preliminary clinical data on the 
effect of everolimus on seizures in TSC patients. Our study may help to explain why some patients treated 
with mTOR inhibitors fail treatment, as well as help elucidate the effect of these agents on epileptogenesis 
in  human  TSC  and  FCD  patients.  Therefore,  data  obtained  from  the  proposed  studies     may                  
help guide future treatment with mTOR inhibitors.
The goals of our pilot study is to obtain the necessary data to plan a prospective, multi-center Phase II 
study of everolimus for TRE in TSC and FCD. Our pilot study would provide critical data on patient 
enrollment and retention, assess safety, identify challenges to study methodology, dosing of everolimus 
(e.g., relation of dose (mg/m2/day) to serum level, relation of serum and potentially brain levels if a reliable 
assay can be identified before this subsequent study) and cellular physiological effects of everolimus  
(e.g., inhibition of neuronal mTOR activity, changes in excitatory/inhibitory neurotransmission, reduction   
of cortical excitability), and the relation of changes in mTOR activity to different genetic abnormalities in 
brain tissue. The study may also provide initial data on the efficacy of everolimus in reducing epileptiform 
activity on electrocorticography (ECoG).  The use of biomarkers – molecular signaling, cellular  
physiology, and cortical excitability – will provide sensitive indicators of the effects of everolimus on 
seizure foci. The data we acquire may also help to inform the use of everolimus to treat SEGAs and 
potential uses in cognitive and psychiatric disorders that complicate TSC and FCD.
1.2
Overview of Everolimus
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor (Table 1, Figure 1). 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), specifically targeting the mTOR- 
raptor signal transduction complex. mTOR is a key serine-threonine kinase in the PI3K/AKT signaling 
cascade, which is known to be dysregulated in a wide spectrum of human cancers [37].
Table 1 Everolimus - Drug substance


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O
H3C
O
CH3
CH3
O
O
OH
N
H3C
O
O
H C
3
O
O
O
OH
H3C
CH3
O
O
H3C
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
Chemical structure of Everolimus
HO
CH3
CH3
Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is FDA-approved as an 
antineoplastic agent. The molecular formula is C53H83NO14 and the molecular weight is 958.2
mTOR is a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is 
dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting 
in an inhibitory complex formation with mTOR Complex 1 (mTORC1) and thus inhibition of mTOR kinase 
activity. Everolimus reduces the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation 
factor 4E-binding protein (4E-BP1), downstream effectors of mTORC1, involved in protein synthesis. In 
addition, everolimus inhibits the expression of hypoxia-inducible factor (HIF-1) and reduces the 
expression of vascular endothelial growth factor (VEGF). Inhibition of mTORC1 by everolimus has been 
shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.
Two regulators of mTORC1 signaling are the oncogene suppressors hamartin (TSC1) and tuberin 
(TSC2), which together form a complex to inhibit mTORC1. Loss or inactivation of either TSC1 or 
TSC2 leads to activation of downstream signaling. In Tuberous Sclerosis Complex (TSC), a genetic 
disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation 
throughout the body.
1.3
Preclinical Data
There are no preclinical data for the use of everolimus as planned for this protocol.
1.4
Clinical Data Related to Study Drug Use
The potential surgical risks associated with 7- to 21-day trial of everolimus treatment prior to elective 
epilepsy surgery in TSC or FCD have never been documented. The optimal data for analyzing this risk 
would be the experience treating TSC or FCD patients receiving everolimus therapy who required 
neurosurgical intervention while on the medication. However, this clinical experience has not been


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reported. Further, limited information is available regarding brain tumor patients receiving everolimus who 
undergo neurosurgery. Two studies in patients with glioblastomas are cited below. The large datasets 
available are with everolimus use in other surgical settings, typically in patients receiving organ 
transplantation (e.g., kidney, heart, pancreas). However, the transplant patients are often chronically ill 
and immunosuppressed from chronic illness and other immunosuppressive agents as part of their 
treatment protocol.
mTOR inhibition with rapamycin: Everolimus in glioblastoma multiforme
Two trials of mTOR inhibitors in the short term (~1 week) treatment of glioblastomas before brain surgery 
failed to identify any evidence of impaired wound healing, increased peri-operative infections, or bleeding 
[15,16]. Intratumoral rapamycin concentrations sufficient to inhibit mTOR in vitro occurred in all 15 
patients, but the degree of mTOR inhibition in tumor cells, as measured by reduced ribosomal S6 protein 
phosphorylation, varied substantially [15]. Thus, although the dose of rapamycin ranged from 2 to 10 mg 
per day (5-fold range), the tumor levels of rapamycin ranged from 0.3 to 36.3 nM (>100-fold range).
Further, rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative 
feedback, and this activation correlated with shorter time-to-progression during post-surgical maintenance 
rapamycin therapy (p < 0.05) [15]. In this trial, there were no grade 3 or 4 toxicities during the  
preoperative treatment or perioperatively. After recovery from surgery and resumption of therapy, 3 
patients developed grade 3 toxicities that were potentially related to therapy: hypokalemia, 
hypercholesterolemia, and cytopenias. All were managed with supportive care and none led to 
discontinuation.
In a trial of everolimus for glioblastoma multiforme one week before surgery, 11 patients were randomized 
to treatment with 5 mg daily (n=5) or 10 mg daily (n=10) [17]. None of these 11 patients had peri- 
operative infections or impaired wound healing. Further, among those who continued on everolimus post- 
operatively, none developed infections. Notably, 63% of these patients were treated with dexamethasone 
and could have been immunocompromised as a result. Although dexamethasone may be used peri- 
operatively by neurosurgeons as standard care for epilepsy surgery, the dexamethasone therapy is 
associated only with the perioperative period whereas patients with glioblastoma multiforme are often on 
dexamethasone chronically, both before and after brain surgery. The glioblastoma patients are almost 
always on AEDs perioperatively and often chronically, and many took other drugs (e.g., warfarin) that 
could complicate their perioperative course.
CCI-779, an mTOR inhibitor, was used to treat 43 patients with recurrent gilioblastomas.[17] Unlike the 
prior studies, the drug was administered as an ongoing therapy. In this study, the drug was well tolerated 
by most subjects with lymphopenia, anemia, stomatitis, and elevated lipids as the only adverse effects.
There was no reported increase in infections or wound healing problems.
Everolimus: effect on wound complications in organ transplantation
Several studies reviewed the surgical wound complications in patients receiving everolimus for organ 
transplantation, examining large, randomized, multicenter clinical trials. Some studies found an increased 
risk of wound complications in the everolimus-treated groups. Multivariate analyses reveal that this risk is 
higher in the presence of other well-known risk factors for surgical wound healing, most notably increased 
body mass index (BMI). This was most robust for patients undergoing heart transplantation, but a similar 
effect was found after renal and pancreas transplantation.
A systematic reviewed of 37 randomized control trials in solid organ transplants comparjng mTOR 
inhibitors with other therapies examined the incidence of wound complications and/or lymphocele 
formation.[18] The pooled analyses showed a higher incidence of wound complications (OR 1.77, CI 
1.31–2.37) and lymphoceles (OR 2.07, CI 1.62–2.65) for kidney transplant recipients on mTOR inhibitors 
together with calcineurin inhibitors. There was also a higher incidence of wound complications (OR 3.00, 
CI 1.61–5.59) and lymphoceles (OR 2.13, CI 1.57–2.90) for kidney transplant recipients on mTOR 
inhibitors together with antimetabolites. A retrospective study of 513 kidney transplant patients found 
wound healing problems in 19% with elevated BMI as the greatest risk factor [25]. A retrospective


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analysis of 97 liver transplant patients found no increase in poor wound healing events associated with 
mTOR inhibitory therapy [23].
Heart transplant patients receiving mTOR inhibitors together with calcineurin inhibitors also had more 
wound complications (OR 1.82, CI 1.15–2.87) [18]. A randomized study of 833 de novo kidney transplant 
recipients found a higher rate of wound healing complications in the two everolimus groups compared to  
a control group receiving mycophenolate sodium [19]. Among 634 de novo heart transplant patients, 
wound infection occurred in 6.7% of the 1.5 mg and 5.2% of the 3 mg everolimus groups; the rate was 
3.3% in the group treated with azathioprine in combination with cyclosporine and corticosteroids [20]. A 
subsequent study of everolimus in conjunction with cyclosporine in 176 cardiac transplant recipients 
reported a 6.6% wound infection rate [21]. Wound healing complications relating to surgical intervention 
were reported as serious adverse events in 8.0% of patients receiving cyclosporine with everolimus and 
steroids in de novo heart transplant patients enrolled in a multicenter, randomized trial [22] Zuckerman et 
al [22] studied risk factors associated with wound complications among 711 everolimus-treated patients 
who underwent heart transplantation: 12.3% had an incision-related wound complication. Only BMI was 
significant in a multivariate analysis (12.9% increased odds for each 1 kg/m increase in BMI). They 
conclude that the overall risk for this complication is low, but increased in patients with increased BMI  
[22]. They suggest that if a patient is obese, diabetic, or needs surgical re-exploration, a higher surgical 
wound risk exists [22].  Similar findings have emerged from other solid organ transplant studies.[23-25]
Everolimus: experience in patients with TSC
Everolimus is a kinase inhibitor indicated with FDA approval for the treatment of:
• adults with renal angiomyolipoma and TSC, not requiring immediate surgery. The effectiveness of 
everolimus in the treatment of renal angiomyolipoma is based on an analysis of durable objective 
responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to 
determine long-term outcomes.
• pediatric and adult patients with TSC who have subependymal giant cell astrocytoma (SEGA) that 
requires therapeutic intervention but cannot be curatively resected. The effectiveness is based on 
demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. 
Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC has not 
been demonstrated.
There is considerable experience with everolimus use in TSC patients. In a prospective, open-label trial of 
everolimus for SEGAs in 28 patients, everolimus was associated with few serious side effects during the 
initial 6 months [8]. Self-limited upper respiratory tract infections and stomatitis were most frequent. Four 
patients had serious adverse events during the 6-month trial but they were not clearly drug related: 
hospitalization for respiratory infection (n=2; one had a prior history of reactive airway disease; one also 
had grade 3 vomiting) and convulsion (n=2). Twenty-five of these patients continued on everolimus for an 
average of 3 years and no new serious adverse events occurred [26]. A Phase III, prospective, double 
blind, randomized, multi-center study compared everolimus (n=78) and placebo (n=39) in TSC patients 
with radiologically enlarging SEGAs [27]. Everolimus was given at 4.5 mg/m2/day and titrated to a level of 
5-15 ng/ml; MRI scans were performed at 3, 6, and 12 months after initiating treatment. The investigators 
found that 27 of 78 patients (34.6%) receiving everolimus, versus none of the placebo group, had a 
significant response of > 50% reduction in tumor volume (p<0.0001) [27]. Everolimus was generally well 
tolerated. A subsequent long-term followup study of 28 patients enrolled, 25 were still under treatment at 
the time of analysis.[28] Median dose was 5.3 mg/m(2)/day and median treatment duration was 34.2 
months (range 4.7-47.1). At all time points (18, 24, 30, and 36 months), primary SEGA volume was 
reduced by ≥30% from baseline (treatment response) in 65%-79% of patients. All patients reported ≥1 
adverse event (AE), mostly grade 1/2 in severity, consistent with that previously reported, and none led to 
everolimus discontinuation. The most commonly reported drug-related AEs were upper respiratory 
infections (85.7%), stomatitis (85.7%), sinusitis (46.4%), and otitis media (35.7%). No drug-related grade  
4 or 5 events occurred.[27a] In a larger, international multicenter study, 117 patients were randomly 
assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 
50% reduction in the volume of SEGAs versus none in the placebo group (difference 35%, 95% CI 15-52; 
p<0·0001).[29] Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of 
adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus


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group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten
[26%]), and pyrexia (17 [22%] vs six [15%]).[29]
Other studies have used rapamycin to treat angiomyolipomas over 12 months with good efficacy and 
safety [30]. Everolimus was approved to treat renal angiomyolipomas in TSC. The most common AE 
during the 48-week trial was stomatitis. The most common Grade 3-4 adverse reactions (incidence >= 
2%) were stomatitis, amenorrhea and convulsion. The most common laboratory abnormalities (incidence
>= 50%) were hypercholesterolemia, hypertriglyceridemia and anemia. (Novartis data on file. 
http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf. Accessed April 2012)
1.5
Dose Rationale and Risk/Benefits
The starting dose of everolimus for treatment patients will be 4.5 mg/m2 once daily; adjust to attain trough 
concentrations of 5-15ng/ml. The dose will be adjusted for co-medications as outlined in section 5.1.
However, these are initial doses often need to be titrated up to therapeutic everolimus serum levels (5 – 
15 ng/mL). Since our everolimus treatment duration is 7-21 days and the half-life is 30 hours, the time to 
equilibration will be approximately 150 hours (6.25 days) and will not allow the investigators to adjust 
dose to achieve therapeutic levels in the initial groups of patients who will be treated for one to two 
weeks. We will double the dose in our study for patients who are taking an enzyme-inducing antiepileptic 
drug (EIAED) since serum everolimus levels will be lower due to increased hepatic metabolism.
After a minimum of three patients are treated for one week, if there is no evidence of serious adverse 
effects and other dose-level tolerability and safety issues, we will extend the treatment duration by a 
maximum of one week. Again, after a minimum of three patients treated for two weeks without evidence 
of serious adverse effects and other dose-level tolerability and safety issues, we will extend the treatment 
duration to three weeks. . For patients treated longer than two weeks, an everolimus blood level will be 
obtained after 10-12 days and used to adjust dose to maintain a serum level of 5-10 ug/ml.
The most common adverse reactions (>30%) to everolimus treatment in TSC patients include stomatitis  
in patients with angiomyolipomas and stomatitis and respiratory tract infections in patients with SEGAs. 
Potential risks associated with 7-28 days of everolimus treatment include problems with wound healing 
and infections. Published data in patients with glioblastoma multiforme who underwent brain surgery, in a 
similar protocol to our study found no evidence of problems with wound healing or infection. There 
appears to increase the risk of infection and problems with wound healing in some patients who have 
received everolimus treatment and undergone organ transplantation but the risk of serious infection over 
control rates is not documented in patients with brain tumors or TSC.
For patients in the cardiac and renal transplant groups, much of the risk of infection and impaired wound 
healing is associated with obesity, age over 40 years old, and other factors. Further, the transplant 
groups in which wound healing issues have been identified suffer from chronic illness and treatment with 
other immunosuppressive agents. To reduce the potential risk to patients with TSC in our study, we will 
exclude patients who are 1) obese, 2) over age 50, 3) have a history of chronic medical illness, or 4) 
treatment with an immunosuppressant (other than everolimus during the 7-day trial).  These criteria 
should minimize the potential for peri-operative infection or impaired wound healing. However, we will be 
vigilant with the Data Safety Monitoring Plan to closely assess all patients postoperatively and record all 
complications, including infection and impaired wound healing. Further, we will institute a special 
surveillance system to monitor for these potential side effects.
The following are possible benefits that could occur through this research study:
1) Elimination of need for epilepsy surgery if there is a significant reduction in seizure activity;
2) Improvement in seizure control, as well as reduction of cognitive, behavioral, and physical 
injury, and sudden death risks associated with ongoing seizures;
3) Improvement in cognitive or behavioral function; and
4) Reduction in signs and symptoms of TSC (e.g., renal angiomyolipomas, 
lymphangiomyelotmatosis, facial angiofibromas).
5) Close medical follow-up care


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For patients with FCD, the potential benefits are likely less, but could include 1 through 3 above since 
increased mTOR signaling is documented in FCD and it remains uncertain if Everolimus therapy may 
provide clinical benefits.
The potential risks of everolimus must be weighed against the potential benefits, which for the patients 
with TSC include: 1) elimination of need for epilepsy surgery if there is a significant reduction in seizure 
activity, 2) improvement in seizure control and reduction of cognitive, behavioral, physical injury, and 
sudden death risks associated with ongoing seizures, 3) improvement in cognitive or behavioral function, 
and 4) reduction in systemic signs and symptoms of TSC (e.g., renal angiomyolipomas, 
lymphangiomyelotmatosis, facial angiofibromas, etc.). For patients with FCD, the potential benefits are 
likely less, but could include 1 through 3 above since abnormalities of mTORC1 signaling are 
documented in FCD and it remains uncertain if therapy may provide clinical benefits.
2
Study Objectives
2.1
Primary Objective:
The primary objectives of this pilot study are to 1) test the feasibility and safety of recruiting patients into a 
prospective study before epilepsy surgery in patients with TRE and either TSC or FCD, and 2) test the 
hypothesis that everolimus therapy in TSC and FCD patients with TRE will reduce mTOR signaling 
(reduced S6 phosphorylation) as compared to TSC and FCD who did not receive everolimus (control 
group).
2.2. Secondary Objectives:
The secondary objectives include
1) systemic mTOR signaling suppression (VEGF-D) pre-and post-treatment,
2) genetic analysis of resected brain tissue,
3) correlate blood everolimus levels with brain measures of S6 phosphorylation,
4) measure markers of cortical hyperexcitability (glutamate and GABA receptors, levels of 
neuroinflammation, axonal abnormalities, myelination defects) as compared to historical controls and
5) electrocorticographic (ECoG) recordings as compared to historical controls
3
Study Design
3.1
General Design
This is a multi center open-label pilot clinical trial of patients with TRE, ages 2 to 50 years old, with TSC or 
FCD who are scheduled for epilepsy surgery. Patients will be treated with everolimus for 7 to 21 days  
prior to epilepsy surgery with extension of time from 7 to 21 days in successive cohorts of patients. The 
initial cohort of at least three patients will be treated for 7 days and after the safety of therapy is assured 
for this group, there will be an extension of the treatment to 14 days for at least three patients.  This will   
be extended at one week intervals/three patient groups to a maximum treatment duration of 21 days.
Resected brain tissue will be analyzed for activation of mTORC1 and mTORC2 signaling pathways, 
glutamatergic and GABA-ergic neurotransmission using histochemistry, genetic analysis, as well as 
extracellular field recordings in acute ex-vivo brain slices from surgery. A blood sample, collected at the 
time of surgery, will be analyzed for everolimus levels and VEGF-D. All patients will undergo standardized 
intra-operative ECoG recordings over the primary epileptogenic region and reviewed blindly.
Subjects will be in the study for approximately 10 weeks. We will study variables listed in specific aims 1 
and 2 in TSC and FCD patients treated with 7 to 21 days of everolimus and compare these to untreated 
control patients with TRE and TSC or FCD. A concurrent comparison group of 12 subjects will also be 
enrolled. They will all be undergoing routine surgery for the diagnosis of TRE with TSC or FCD.
All study procedures will be performed at either the Comprehensive Epilepsy Center (CEC) with the 
exception of the surgery, which will be performed at Tisch Hospital


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3.2
Primary Outcome Measures
The primary outcome measures for this study are to 1) test the feasibility and safety of recruiting patients 
into a prospective study before epilepsy surgery in patients with TRE and either TSC or FCD, and 2) 
estimate S6 phosphorylation status as a measure of downstream mTOR activity in patients treated with 
Everolimus as compared to 12 control subjects’ brain tissue (FCD and TSC patients who had epilepsy 
surgery) who had not received Everolimus.
3.3
Secondary Outcome Measures
●
Other mTOR downstream/upstream markers in the brain (S6 phosophorylation) and peripheral 
VEGF-D levels.
●
Blood and brain levels of cytokines (and TNF-α) and inflammatory proteins (HMGB1)at the time of 
surgery
●
Brain glutamate and GABA receptor expression at the time of surgery
●
Blood levels of everolimus at the time of surgery
●
Electrocorticography of minimum of 10 minutes. Site of expected maximal epileptogenicity will 
be recorded with grid or strip array of at least 12 contact points. Extracellular field and 
recordings in acute ex-vivo brain slice: After resection, one brain sample will be immediately 
placed, under sterile conditions, into cold, oxygenated artificial cerebrospinal fluid (ACSF). 
Tissue will be transported to the lab and, within 5-10 min from resection, acute brain slices will be 
prepared. Extracellular field recordings, from visually identified neurons will be employed to 
assess overall cortical excitability, intrinsic neuronal firing properties and basic synaptic function.
4
Subject Selection and Withdrawal
4.1
Inclusion Criteria (Active Group)
1.
Female and male patients, age 2 years to 50 years.
2.
Diagnosis: treatment resistant epilepsy (> 2 failed anti-epileptic drug [AED] treatment regimens) 
and either:
●Tuberous Sclerosis Complex
●Focal Cortical Dysplasia on MRI or neuropathology from prior brain surgery
3.
Diagnosis of TSC confirmed by genetic testing and/or clinically definite diagnosis of TSC 
according to the modified Gomez criteria [31]. Clinically definite diagnosis is defined as:
●Two Major Features, or
●One Major Feature plus two Minor Features
4.
Adequate bone marrow function as shown by: ANC ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hb >9 
g/dL;
5.
. Adequate liver function as shown by
a. Total serum bilirubin ≤2.0 mg/dL,
b. ALT and AST ≤2.5x ULN (≤5x ULN in patients with liver metastases), 
c.INR ≤2; if applicable
6.
Adequate renal function: serum creatinine ≤1.5x ULN;
7.
Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5x ULN.if 
applicable NOTE: In case one or both of these thresholds are exceeded, the patient can only be 
included after initiation of appropriate lipid lowering medication;
8.
Signed informed consent obtained prior to any screening procedures.


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4.1.1 Inclusion Criteria (Concurent Comparison Group)
1.
Female and male patients, age 2 year to 50 years. Matched for age (+/- 7 years) and sex of 
subjects in the treatment group.
2.
Diagnosis: treatment resistant epilepsy (> 2 failed anti-epileptic drug [AED] treatment regimens) 
due to TSC or FCD. Matched for diagnosis of TSC and FCD.
3.
Brain surgery for seizure control in which tissue is banked for research utilizing an existing IRB- 
approved study.
4.2
Exclusion Criteria (Active Group)
1.
Treatment with an mTOR inhibitor (everolimus, sirolimus) during the past four weeks.
2.
Patients taking more than one strong CYP3A4 inducer will be excluded.
3.
Known hypersensitivity to an mTOR inhibitor (everolimus, sirolimus)
4.
Body mass index (BMI) > 95% for age in individuals 17 years old or younger; BMI > 30 kg/m2 in 
individuals > 17 years old
5.
Failure to establish diagnosis of treatment resistant epilepsy (i.e., adequate trials of two 
appropriately-chosen, tolerated and adequate trials of antiepileptic drugs) [32].
6.
Presence of mesial temporal sclerosis or other brain structural lesion than those identified in TSC 
and FCD, other than incidental abnormalities (e.g., pineal cyst)
7.
Exposure to any investigational agent in the month prior to study entry.
8.
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 of study 
treatment. Highly effective contraception methods include 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 or;
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;
d.
Total abstinence or;
e.
Male/female sterilization.
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 (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks prior to randomization. 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.
9.
Male patients whose sexual partner(s) are women of child-bearing potential who are not willing to 
use adequate contraception, during the study and for 8 weeks after the end of treatment
10. Positive pregnancy test
11. Patients will be excluded if using strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, 
voriconazole).
12. History of malignancy patients who are receiving anti-cancer treatments, such as radiation therapy 
and/or chemotherapy.
13. Patients with severe and/or uncontrolled medical conditions, including but not limited to cardiac 
disease, cancer, disorders requiring immunosuppressive therapy, systemic autoimmune disorders, 
or uncontrolled diabetes mellitus.
14. Patients on chronic corticosteroid therapy


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15. A history of HIV seropositivity
16. Known drug or alcohol use or dependence
17. Patients who have received live attenuated vaccines within 1 week of start of everolimus and 
during the study. Patient should also avoid close contact with others who have received live 
attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, 
mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines;
18. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral everolimus;
19. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with 
a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however 
blood glucose and antidiabetic treatment must be monitored closely throughout the trial and 
adjusted as necessary;
20. Patients who have any severe and/or uncontrolled medical conditions such as:
a.
unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months 
prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically 
significant cardiac disease
b.
Symptomatic congestive heart failure of New York heart Association Class III or IV
c.
active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, 
decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive 
HbsAg, quantifiable HCV-RNA),
4.2.1
Exclusion Criteria  (Concurrent Comparison Group)
1.
Treatment with an mTOR inhibitor (everolimus, sirolimus) during the past four weeks.
2.
Known hypersensitivity to an mTOR inhibitor (everolimus, sirolimus)
3.
Body mass index (BMI) > 95% for age in individuals 17 years old or younger; BMI > 30 kg/m2 in 
individuals > 17 years old
4.
Failure to establish diagnosis of treatment resistant epilepsy (i.e., adequate trials of two 
appropriately-chosen, tolerated and adequate trials of antiepileptic drugs) [31].
5.
Presence of mesial temporal sclerosis or other brain structural lesion than those identified in 
TSC and FCD, other than incidental abnormalities (e.g., pineal cyst)
6.
Exposure to any investigational agent in the month prior to study entry.
7.
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 of 
study treatment. Highly effective contraception methods include 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 or;
b.
Placement of an intrauterine device or intrauterine system;
c.
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/ vaginal suppository;
d.
Total abstinence or;
e.
Male/female sterilization.
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 (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks prior to randomization. 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.


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8.
Male patients whose sexual partner(s) are women of child-bearing potential who are not willing 
to use adequate contraception, during the study and for 8 weeks after the end of treatment
9.
Positive pregnancy test
10. Patients will be excluded if using strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, 
voriconazole).
11. History of malignancy patients who are receiving anti-cancer treatments, such as radiation 
therapy and/or chemotherapy.
12. Patients with severe and/or uncontrolled medical conditions, including but not limited to cardiac 
disease, cancer, disorders requiring immunosuppressive therapy, systemic autoimmune 
disorders, or uncontrolled diabetes mellitus.
13. Patients on chronic corticosteroid therapy
14. A history of HIV seropositivity
15. Known drug or alcohol use or dependence
16. Patients who have received live attenuated vaccines within 1 week of start of everolimus and 
during the study. Patient should also avoid close contact with others who have received live 
attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines;
17. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of oral everolimus;
18. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients 
with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, 
however blood glucose and antidiabetic treatment must be monitored closely throughout the 
trial and adjusted as necessary;
19. Patients who have any severe and/or uncontrolled medical conditions such as:
a.
unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 
months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other 
clinically significant cardiac disease
b.
symptomatic congestive heart failure of New York heart Association Class III or IV
c.
active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, 
decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or 
positive HbsAg, quantifiable HCV-RNA),
4.3
Subject Recruitment, Screening, and Consenting
All patients will be recruited, consented and enrolled at the NYU Comprehensive Epilepsy Center (CEC). 
The NYU CEC  is the ideal centers for recruitment since they already has a high influx of epilepsy  
patients that concomitantly have TSC or FCD. All eligible subjects have treatment resistant epilepsy with 
TSC or FCD and are planning to have their surgery in the next few months. All patients who are identified 
as potential candidates for the study will be entered into a study screening log which will document the 
individual who referred the subject to the study or if they were self-referred and if the 
subject/parents/guardian did not participate why they declined or were not eligible, and for those who were 
ineligible, the specific reason why they were ineligible.
.
The physician will explain the study during the routine visit and inform the subject and surrogate that a 
capacity assessment will be performed to determine whether the subject is capable of providing an 
informed decision to participate in the study. At this time, a capacity assessment will be conducted if the 
subject does not refuse the assessment. If there is already documentation of lack of capacity, no 
assessment will be needed. Patients who are eligible and are lacking in capacity will be allowed to 
participate  by  receiving  consent  from  a  parent/legal  guardian/health  care  proxy.  This  protocol      is


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specifically for patients with drug resistant epilepsy. If we were to only include patients with drug resistant 
epilepsy who have capacity to consent, we would have very few participants in this study, as one of the 
common co-morbidities of drug resistant epilepsy is global impairment.
. If the subject/parent/legal guardian/health care proxy agrees, they will be given the informed consent 
document and study personnel will be present to explain the study in further details the objectives and 
study procedures, risks and benefits. We will review the consent form documents with them and answer 
any questions they have. They will be given an opportunity to ask questions regarding the study and 
consent form. After all parties have signed off on the consent, we will give them a copy of the informed 
consent documents.
As the majority of our surgical patients reside outside of the NYC area, there may be circumstances in 
which patients are unable to be present at the study site for consenting due to distance and travel issues. 
In such cases, the informed consent will be faxed or emailed to the patient. The principal investigator will 
then review and obtain consent over the phone. The principal investigator will explain the study in full 
detail and ensure that all questions are answered. The patient will then sign and date the informed 
consent and return it to the principal investigator via fax or email. Once received the principal investigator 
will sign and date the informed consent. A copy of this signed and dated informed consent will then be 
faxed or emailed to the patient before beginning any study procedures. The patient will also bring the 
original signed informed consent to the study site at the first visit to again be signed by the principal 
investigator. Both the mailed informed consent and the original will be kept on file and copies will be given 
to the patient. All phone correspondence and mailings will be documented in the study file. Telephone 
consent is necessary for these long distance subjects who will be coming in for a combined visit 1 and 2 
as certain study procedures need to be completed prior to their combined visit. Particularly, in order to 
meet the inclusion criteria, patients who have not had certain bloodwork need to have it completed in 
order to be eligible for the study. Therefore, in certain cases we need to obtain consent prior to combined 
Visit 1 and 2 so that these patients can obtain bloodwork and confirm eligibility prior to this combined  
initial visit.
Consent by subject
If the subject is 18 years old and it has been determined that he/she has capacity, he/she will review and 
sign an informed consent. The study personnel will be present to explain the study in further details and 
answer questions as needed. After all parties have signed off on consent, a copy of the informed consent 
documents will be given to the subject.
Assent by subject
If the subject is 7-17 years old and it has been determined that he/she has capacity, he/she will review 
and sign an assent form. In addition, if the parent/legal guardian/health care proxy agrees, they will be 
given the informed consent document and study personnel will be present to explain in further details the 
study the objectives and study procedures, risks and benefits. After all parties have signed off on assent 
and consent, a copy of the informed assent and consent documents will be given to the subject and the 
subject’s parent/legal guardian/health care proxy.
Consent by surrogate (for subjects lacking capacity)
If the subject assents, and the parent/legally authorized representative agrees, they will be given the 
informed consent document and study personnel will be present to explain in further details the study the 
objectives and study procedures, risks and benefits. Legally authorized representative will be identified as 
per New York state law. The consent form will be reviewed and any questions they may have regarding 
the study and consent form will be answered. After all parties have signed off on the consent, a copy of 
the informed consent documents will be given to them.
Assessment
A capacity assessment will be conducted by Dr. Manisha Holmes, (NYU CEC) who is independent of the 
study to ensure the patient’s level of capacity.
She is delegated only to perform capacity assessment 
throughout the study. See is board certified Neurologist as well as a Epileptologist


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experienced in dealing with patients with drug resistant epilepsy. Capacity will be assessed through 
neurological examinations and neuropsychology reports conducted by the physician as well as learning 
and/or development delays that have been documented.
For long distance subjects, Dr. Holmes will interview the parent and child via a speaker phone if the child 
is verbal. If the child is nonverbal they will be considered incapable of capacity to consent. For those that 
are verbal, Dr. Holmes will determine if the child is able to:
a) communicate clearly in English (or another language with translation services),
b) grasp the fundamental meaning of information that is communicated,
c) acknowledge medical condition and likely consequences of involvement in the study, 
and d) engage in a rational process of manipulating relevant information.
4.4
Early Withdrawal of Subjects
4.4.1
When and How to Withdraw Subjects
A subject may withdraw from the study due to:
1) Improvement in seizure activity to an extent that the patient and/or parents/legal guardians elect to 
forego epilepsy surgery for treatment with everolimus,
2) Difficult complying with protocol requirements or
3) A decision to withdrawal for personal reasons or adverse effects that are less severe than those that 
lead to mandatory discontinuation of the treatment phase.
A subject will be withdrawn from the study if any of the following are present:
1) The subject develops a systemic bacterial or fungal infection.
2) The subject develops a CTAE grade 3 or 4 (severe) event.
3) The patient and study will be terminated if he or she is the second case of impaired surgical wound 
healing or the third case of serious infection, including infection of the wound site, among the 18 
everolimus-treated patients.
Given the short duration of treatment, there are no known or postulated safety concerns related to abrupt 
discontinuation after this duration and dosage of therapy with everolimus. Any subject who elects to 
withdraw from the study will be recommended to discontinue the everolimus therapy, but if they desire a 
tapering schedule, one will be provided with exception for those patients going forward with surgery, 
when everolimus will be completely discontinued prior to surgery.
4.4.2
Data Collection and Follow-up for Withdrawn Subjects
For any subject who withdraws from the study, we will obtain serum levels of everolimus on the last date 
they take the medication (or as close). We will also collect all safety data and seizure activity calendars. 
Since these patients will be entered into the study only 7 to 21 days before brain surgery, they typically 
have close contact with the neurosurgeon, epileptologist, and clinical staff of the epilepsy center. We will 
actively pursue with phone calls to patient, parents, and legal guardians to determine the cause for 
withdrawal and obtain as complete data as possible regarding study data elements during the baseline 
and treatment phase. We will utilize up to 5 phone calls and 2 certified letters to any patients who 
withdraw but for whom we do not have complete study records.
5
Study Drug
Everolimus will be supplied by Novartis at no charge.
5.1
Description & Packaging
Everolimus (RAD001) is an inhibitor of mTOR, and is FDA-approved as an antineoplastic agent. The 
chemical name of everolimus is (1R, 9S,12S,15R,16E,18R,19R, 21R, 23S, 24E, 26E, 28E,30S, 32S,


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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. The molecular formula is C53H83NO14 and the molecular 
weight is 958.2.
For this study, everolimus will be supplied as dispersal tablets of 2.0, 3.0, 5.0 mg strength. The drug will 
be supplied by Novartis at no charge for study enrollment to patients enrolled in treatment group at NYU 
CEC
The starting dose of everolimus for treatment patients will be 4.5 mg/m2 once daily; adjust to attain trough 
concentrations of 5-15ng/ml. The dose will be adjusted for co-medications as outlined in the section 
immediately below.
.
CYP3A4 and/or P-glycoprotein (PgP) Inhibitors
Patients will be excluded if using strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, 
voriconazole). If the patient is receiving a co-administered drug with moderate CYP3A4 and/or PgP 
inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem), 
the everolimus dose will be reduced by approximately 50% to maintain trough concentrations of 5 to 10 
ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, alternate day dosing will be used. 
Subsequent dosing will be individualized based on therapeutic drug monitoring in subject on everolimus 
for sufficient duration. No moderate or strong CYP3A4 and/or PgP inhibitor will be added or discontinued 
during the study period.
Patients taking one concomitant strong CYP3A4 inducer for seizure control (e.g., phenytoin, 
carbamazepine, phenobarbital) will be allowed in the study. Patients taking more than one r strong 
CYP3A4 inducer will be excluded. For patients requiring a concomitant strong CYP3A4 inducer (an 
Enzyme-Inducing Antiepileptic Drug (EIAED), we will double the everolimus dose from that prescribed in 
Table 2. Subsequent dosing should be individualized based on therapeutic drug monitoring if the patient 
is treated with everolimus for sufficient duration. No EIAED will be discontinued during the study.
Preparation of the everolimus dispersal:
The patient will receive everolimus tablets for oral suspension as a suspension only. The everolimus 
tablets for oral suspension will be administered orally once daily at the same time every day. It will be 
given either consistently with food or consistently without food. The suspension will be administered 
immediately after preparation. The suspension will be discarded if not administered within 60 minutes 
after preparation.
Prepare suspension in water only. 
Using an oral syringe:
• Place the prescribed dose of everolimus tablets for oral suspension into a 10-mL syringe. Do not exceed 
a total of 10 mg per syringe.
If higher doses are required, prepare an additional syringe. Do not break or crush tablets.
• Draw approximately 5 mL of water and 4 mL of air into the syringe.
• Place the filled syringe into a container (tip up) for 3 minutes, until the everolimus tablets for oral 
suspension are in suspension.
• Gently invert the syringe 5 times immediately prior to administration.
• After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into 
the same syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of 
the syringe.
Using a small drinking glass:
• Place the prescribed dose of everolimus tablets for oral suspension into a small drinking glass 
(maximum size 100 mL) containing
approximately 25 mL of water. Do not exceed a total of 10 mg of everolimus tablets for oral suspension 
per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets.
• Allow 3 minutes for suspension to occur.
• Stir the contents gently with a spoon, immediately prior to drinking.


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• After administration of the prepared suspension, add 25 mL of water
Everolimus tablets for oral suspension should NOT be taken with grapefruit or Seville orange juice or with 
other effectors of CYP3A4 (other than known AEDs or other medications identified at Visit 1 as one of 
their baseline medications).
NOTE: Everolimus should be opened only at the time of administration as drug is both hygroscopic and 
light-sensitive.
5.2
Treatment Regimen
Everolimus will be self-administered (by the patient or parent at home during the 7-21 days prior to 
neurosurgery). The investigator will instruct the patient to take the study drug exactly as specified in the 
protocol.
Patients who are eligible for the active treatment group with TSC or FCD only will receive everolimus. 
After a minimum of three patients are treated for 7 days (Table 2), if there is no evidence of serious 
adverse effects or other dose-level tolerability and safety issues, we will extend the treatment duration by 
a maximum of one week. Again, after a minimum of three patients are treated for two weeks without 
evidence of serious adverse effects or other dose-level tolerability and safety issues, we will extend the 
treatment duration to three weeks. . For patients treated longer than two weeks, an everolimus  blood 
level will be obtained after 10-12 days and used to adjust dose to maintain a serum level of 5-10 ug/ml. to 
revisit escalation and numbers If one patient at a dose duration has a serious adverse effect during a 
treatment cohort period (e.g., 7 days), then up to 6 patients are treated with that dose duration. If there are 
2 or more serious adverse events among the 6 patients, then the duration is dropped back to the prior 
level. If there are no events in 3 patients or 1 event in 6 patients, then the dose duration is escalated to the 
next level. At the 3 week dose duration, 6 patients will be treated even if there are no events among the 
first 3 patients.
Table 2: Dosing Escalation for Serial Cohorts
Serial 
Cohort 
Number
Minimum # of 
patients if no 
Grade 3 or 4 
adverse event 
or serious 
adverse 
events
Minimum # of 
patients if one 
Grade 3 or 4 
adverse event 
or serious 
adverse 
events^
Duration of 
everolimus 
therapy
Result of one 
serious adverse 
events including 
wound healing 
problem and 
serious infection
Result of two serious 
adverse events 
including wound 
healing problem and 
serious infection
1
3
9
7 days
2
3
6
14 days
Add additional 
patients to Cohort 1
Return to cohort one, 
no potential for longer 
treatment duration
3
1-3
6
21 days
Add additional 
patients to Cohort 2
Return to cohort two, 
no potential for longer 
treatment duration
^ Adverse events as defined by CTAE v.4.0
Dosing:
●
Patients NOT taking EIAEDs or other drugs know to inhibit or induce CYP34A or PgP: The 
dose will be administered according to the criteria in Section 5.1.
●
Patients taking EIAEDs: The dose will be administered according to criteria in Section 5.1.
●
Patients taking moderate CYP3A4 and/or PgP inhibitors: The dose will be administered 
according to criteria in Section 5.1.


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Dose adjustments will be permitted based on safety findings or serum everolimus levels for patients on 
treatment for 3 or 4 weeks. A detailed explanation of permitted dose adjustments and the process that will 
be implemented are found in Section 5.3.1 Dose Adjustments.
5.3
Study Drug Administration
Patients will be instructed to take the prescribed dose of everolimus (or no treatment in the comparison 
group) orally with a glass of water at regular intervals, and each taken dose should be at the same time in 
the morning after a light, nonfat breakfast. Body Surface Area (in m2) should be calculated using the 
following formula where weight (W) is in kilograms and height (H) is in centimeters *(Dubois and Dubois, 
1916): BSA= (W 0.425 x H0.725) x 0.007184. The dose will be 4.5 mg/m2 once daily; adjust to attain 
trough concentrations of 5-15ng/ml and exceptions for patients taking EIAEDs based on section 5.1.
Subjects will take the medication as specified in Section 5.1.
Dietary habits around the time of everolimus intake should be as consistent as possible throughout the 
study, and in particular, on the day when sample is being taken for pharmacokinetic analysis.
NOTE: Everolimus should NOT be taken with grapefruit or Seville orange juice. Patients with taking drugs 
that inhibit or induce CYP3A4 /450 or P-glycoprotein (P-gp) will be identified and doses adjusted  for   
those who are taking EIAEDs.
Patients will receive treatment with study drug for 7 to 21days or until the occurrence of unacceptable 
toxicity as defined by the patient or guardian, or if a Grade 3 or 4 Adverse Event occurs as defined by 
Common Terminology for Adverse Events (CTAE) v.4.0 occurs, or the investigator or patient decides that 
continuation is not in the best interest of the patient. Interruption for toxicity will lead to discontinuation of 
the medication.
Overall, safety data available from completed, controlled and uncontrolled studies indicate that 
everolimus is generally well tolerated at weekly or daily dose schedules. The safety profile is 
characterized by manageable adverse events (AEs). These AEs are generally reversible and non- 
cumulative.
5.3.1 Management of specific toxicities:
Overall, safety data available from completed, controlled and uncontrolled studies indicate that 
everolimus is generally well tolerated at weekly or daily dose schedules. The safety profile is 
characterized by manageable adverse events (AEs). These AEs are generally reversible and non- 
cumulative.
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 for non-hematologic 
and hematologic adverse events are summarized in Tables 3 and 4.
Table 3: Dosing guidelines for Everolimus-related non-hematologic toxicities


C O N F ID E N T IA L
T hi s d o c u m e n t a n d i nf or m ati on is  t he pr o p ert y o f t he N Y U  S c h o ol o f M e di ci n e  a nd L a n g o n e  M e di c al  C e nt er.  Do  n ot di s cl o se  or u s e 
e x c e p t as a ut h ori z e d  in writi n g b y t he  st u d y I ND s p o n s or
E v er oli m u s  eff e ct s  on br ai n  m T O R  a nd e x cit a bilit y
V er si o n :  0 9/ 2 0/ 1 8
P a g e 1 9
T o xi cit y
A cti o n
A S T or  A L T el e v ati o n
Gr a d e 1  ( > U L N - 3. 0 x U L N)  
Gr a d e 2 ( > 3. 0 - 5. 0 x  U L N)
A S T or  A L T el e v ati o n  
Gr a d e 3 ( > 5. 0 - 2 0. 0  U L N)*
A S T or  A L T el e v ati o n  
Gr a d e 4 ( > 2 0 x  U L N)*
R e c urr e n c e of  gr a d e 4 aft er d o s e  
r e d u cti o n or t o xi cit y r e q uiri n g 
E v er oli m u s i nt err u pti o n f or >  2 1  
d a y s
I nt ol er a bl e gr a d e 2 m u c o siti s, or  
gr a d e 3 A E, e x c e pt  h y p er gl y c e mi a  
or h y p ertri gl y c eri d e mi a  or  
h y p er c h ol e st er ol e mi a
M ai nt ai n c urr e nt  d o s e l e v el
I nt err u pt E v er oli m u s a d mi ni str ati o n u ntil r e s ol uti o n t o ≤ gr a d e 1 
( or ≤ gr a d e 2 if b a s eli n e v al u e s w er e wit hi n t h e r a n g e of gr a d e  
2). If r e s ol uti o n o c c ur s ≤ 7 d a y s, E v er oli m u s s h o ul d b e r e- st art e d 
at t h e d o s e l e v el pri or t o  i nt err u pti o n.
If r e s ol uti o n t a k e s > 7 d a y s, or if e v e nt r e c ur s wit hi n 2 1 d a y s,  
h ol d E v er oli m u s u ntil r e c o v er y t o ≤ gr a d e 1 or b a s eli n e gr a d e / 
v al u e a n d r ei ntr o d u c e E v er oli m u s at o n e d o s e l e v el l o w er,  if 
a v ail a bl e.
I nt err u pt E v er oli m u s a d mi ni str ati o n u ntil r e s ol uti o n t o ≤ gr a d e 1 
( or ≤ gr a d e 2 if b a s eli n e v al u e s w er e wit hi n t h e r a n g e of gr a d e  
2). If r e s ol uti o n o c c ur s ≤ 7 d a y s, E v er oli m u s s h o ul d b e r e- st art e d 
at  o n e  d o s e  l e v el l o w er. If r e s ol uti o n t a k e s >  7  d a y s,  di s c o nti n u e  
E v er oli m u s.
Di s c o nti n u e  E v er oli m u s.
I nt err u pt E v er oli m u s a d mi ni str ati o n u ntil r e s ol uti o n t o ≤ gr a d e 1 
or b a s eli n e gr a d e /  v al u e.
If r e s ol uti o n o c c ur s wit hi n ≤ 7 d a y s, E v er oli m u s s h o ul d b e r e- 
st art e d at t h e d o s e l e v el pri or t o  i nt err u pti o n.
If r e s ol uti o n t a k e s > 7 d a y s, or if e v e nt r e c ur s wit hi n 2 1 d a y s,  
h ol d E v er oli m u s u ntil r e c o v er y t o ≤ gr a d e 1 or b a s eli n e gr a d e / 
v al u e a n d r ei ntr o d u c e E v er oli m u s at o n e d o s e l e v el l o w er,  if 
a v ail a bl e.
P ati e nt s  will  b e  wit h dr a w n  fr o m t h e st u d y  if t h e y f ail t o r e c o v er t o
 gr a d e  1  or  b a s eli n e  gr a d e  / v al u e  wit hi n  2 1  d a y s.
A n y ot h er gr a d e  4
H ol d  E v er oli m u s  u ntil  r e c o v er y t o gr a d e   1  or  b a s eli n e  v al u e 
R ei ntr o d u c e  E v er oli m u s  at  o n e  d o s e  l e v el l o w er, if a v ail a bl e.
Gr a d e 3  or 4 cli ni c al li v er f ail ur e 
( a st eri xi s or e n c e p h al o p at h y/ c o m a)
R e c urr e n c e of  i nt ol er a bl e gr a d e 2 
m u c o siti s or gr a d e 3 e v e nt  aft er  
d o s e  r e d u cti o n
R e c urr e n c e of  gr a d e 4 aft er d o s e  
r e d u cti o n
A n y n o n- h e m at ol o gi c  t o xi cit y 
r e q uiri n g E v er oli m u s i nt err u pti o n 
f or > 2 1 d a y s
Di s c o nti n u e  E v er oli m u s
R e d u c e d o s e  t o t h e n e xt l o w er d o s e l e v el, if a v ail a bl e. T h e  
l o w e st p o s si bl e  d o s e  l e v el of  E v er oli m u s  i s 2. 5  m g  d ail y.  B el o w  
t hi s l e v el, E v er oli m u s m u st b e di s c o nti n u e d.
Di s c o nti n u e  E v er oli m u s  
Di s c o nti n u e  E v er oli m u s
T a bl e  4:  D o si n g  g ui d eli n e s  f or E v er oli m u s-r el at e d  h e m at ol o gi c  t o xi citi e s


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Toxicity
Action
Grade 1 thrombocytopenia 
(platelets 0-75, ≥ 75 x109/L)
Grade 2 thrombocytopenia (platelets
<75, ≥ 50x109/L)
Grade 3 thrombocytopenia (platelets
<50,) OR
Grade 4 thrombocytopenia (platelets
< 25 x109/L)
Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x109/L)
No action.
Temporary dose interruption until recovery to Grade ≤1.
    Re-initate treatment at the same dose.
Interrupt Everolimus until resolution to grade ≤1
Re-initate treatment at a lower dose.
     Interrupt Everolimus until recovery to grade ≤2. Then  
     reintroduce Everolimus at the same dose.
Grade 4 neutropenia or anemia
     Interrupt Everolimus until recovery to grade ≤2. Then 
 reintroduce Everolimus at a lower dose.
Febrile neutropenia
Interrupt Everolimus until resolution to grade 1 (or baseline 
value) and no fever. Reintroduce Everolimus at one dose 
level lower, if available.*
Recurrence of grade 3 toxicity after 
dose reduction
*Recurrence of grade 4 toxicity 
(including febrile neutropenia) after 
dose reduction
*Any hematologic toxicity requiring 
Everolimus interruption for > 21 
days
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of Everolimus is 5 mg every other 
day (2.5 mg daily). Below this level, Everolimus must be 
discontinued.
Discontinue Everolimus
Discontinue Everolimus


C O N F ID E N T IA L
T hi s d o c u m e n t a n d i nf or m ati on is  t he pr o p ert y o f t he N Y U  S c h o ol o f M e di ci n e  a nd L a n g o n e  M e di c al  C e nt er.  Do  n ot di s cl o se  or u s e 
e x c e p t as a ut h ori z e d  in writi n g b y t he  st u d y I ND s p o n s or
E v er oli m u s  eff e ct s  on br ai n  m T O R  a nd e x cit a bilit y
V er si o n :  0 9/ 2 0/ 1 8
P a g e 2 1
5 .3 .1 .1 . M a n a g e m e nt of st o m atiti s / or al m u c o siti s / m o ut h  ul c er s
P ati e nt s wit h  a cli ni c al hi st or y of st o m atiti s/ m u c o siti s/ m o ut h ul c er s a n d t h o s e wit h g a str oi nt e sti n al  
m or bi dit y 
a s s o ci at e d 
wit h 
m o ut h/ d e nt al 
i nf e cti o n s, 
irrit ati o n 
of 
e s o p h a g e al 
m u c o s a 
e. g.  
g a str o e s o p h a g e al  r efl u x di s e a s e ( G E R D) a n d pr e- e xi sti n g st o m atiti s/ m u c o siti s m u st b e m o nit or e d e v e n 
m or e  cl o s el y. P ati e nt s s h o ul d b e i n str u ct e d t o r e p ort t h e fir st o n s et of b u c c al m u c o s a irrit ati o n/r e d d e ni n g 
t o t h eir st u d y p h y si ci a n  i m m e di at el y.
St o m atiti s/ or al  m u c o siti s/ m o ut h  ul c er s  d u e  t o e v er oli m u s  s h o ul d  b e  tr e at e d u si n g  l o c al s u p p orti v e  
c ar e. Pl e a s e  n ot e  t h at i n v e sti g at or s i n e arli er  tri al s h a v e  d e s cri b e d  t h e or al  t o xi citi e s a s s o ci at e d  wit h  
e v er oli m u s  a s m o ut h ul c er s, r at h er t h a n m u c o siti s or st o m atiti s. If y o ur e x a mi n ati o n r e v e al s m o ut h ul c er s 
r at h er t h a n a m or e g e n er al i nfl a m m ati o n of t h e m o ut h, pl e a s e cl a s sif y t h e a d v er s e e v e nt a s s u c h. W e 
will f oll o w  t h e p ar a di g m b el o w f or tr e at m e nt of st o m atiti s/ or al m u c o siti s/ m o ut h  ul c er s:
1 .
F or mil d t o xi cit y ( gr a d e 1), u s e c o n s er v ati v e m e a s ur e s s u c h a s n o n- al c o h oli c m o ut h w a s h or  
s alt w at er ( 0. 9 %) m o ut h w a s h s e v er al ti m e s a d a y u ntil  r e s ol uti o n.
2 .
F or  m or e  s e v er e  t o xi cit y ( gr a d e 2)  i n w hi c h  c a s e  p ati e nt s  h a v e  p ai n  b ut  ar e  a bl e  t o m ai nt ai n  
a d e q u at e  or al ali m e nt ati o n ( s e e T a bl e 5), m a n a g e wit h t o pi c al  a n al g e si c  m o ut h  tr e at m e nt s (i. e., 
l o c al a n e st h eti c s  s u c h a s, b e n z o c ai n e, b ut yl a mi n o b e n z o at e, t etr a c ai n e h y dr o c hl ori d e, m e nt h ol, 
or p h e n ol) wit h  or  wit h o ut  t o pi c al c orti c o st er oi d s,  s u c h  a s  tri a m ci n ol o n e or al  p a st e  0. 1 %  
( K e n al o g i n Or a b a s e ® ). T e m p or aril y i nt err u pt d o s e u ntil r e c o v er y t o Gr a d e ≤1.   R e-i niti at e 
Afi nit or ® at t h e s a m e d o s e.   If st o m atiti s r e c ur s at Gr a d e 2, i nt err u pt d o s e u ntil r e c o v er y t o 
Gr a d e ≤1.   R e-i niti at e Afi nit or® at a l o w er d o s e.  
3 .
F or gr a d e 3 i n w hi c h c a s e p ati e nt s c a n n ot m ai nt ai n a d e q u at e  or al ali m e n ati o n, m a n a g e wit h 
t o pi c al a n al g e si c  m o ut h  tr e at m e nt s (i. e., l o c al a n e st h eti c s  s u c h a s, b e n z o c ai n e, b ut yl 
a mi n o b e n z o at e, t etr a c ai n e h y dr o c hl ori d e, m e nt h ol, or p h e n ol) wit h  or  wit h o ut  t o pi c al 
c orti c o st er oi d s,  s u c h  a s  tri a m ci n ol o n e or al  p a st e  0. 1 %  ( K e n al o g i n Or a b a s e ® ). T e m p or aril y 
i nt err u pt d o s e u ntil r e c o v er y t o Gr a d e ≤1 .  R e-i niti at e Afi nit or ® at a l o w er d o s e.
4 .
F or gr a d e 4 i n w hi c h s y m pt o m s ar e a s s o ci at e d wit h lif e-t hr e at e ni n g c o n s e q u e n c e s, di s c o nti n u e 
Afi nit or a n d tr e at wit h a p pr o pri at e m e di c al t h er a p y.
5 .
A g e nt s  c o nt ai ni n g  al c o h ol,  h y dr o g e n  p er o xi d e,  i o di n e, a n d  t h y m e d eri v ati v e s  m a y  t e n d t o w or s e n  
m o ut h ul c er s. It i s pr ef er a bl e t o a v oi d t h e s e  a g e nt s.
T a bl e  5:  Tr e at m e nt  f or P ati e nt s  wit h  I nt ol er a bl e Gr a d e  2  M u c o siti s  
I nt ol er a bl e gr a d e 2 m u c o siti s
I nt err u pt e v er oli m u s  a d mi ni str ati o n  u ntil  r e s ol uti o n t o ≤ gr a d e  1
 or b a s eli n e gr a d e / v al u e.
If r e s ol uti o n o c c ur s wit hi n ≤ 7 d a y s, E v er oli m u s s h o ul d b e r e- 
st art e d at t h e d o s e l e v el pri or t o  i nt err u pti o n.
If r e s ol uti o n t a k e s > 7 d a y s, or if e v e nt r e c ur s wit hi n 2 1 d a y s,  
h ol d e v er oli m u s u ntil r e c o v er y t o ≤ gr a d e 1 or b a s eli n e gr a d e / 
v al u e a n d r ei ntr o d u c e e v er oli m u s at o n e d o s e l e v el l o w er,  if 
a v ail a bl e.
P ati e nt s  will  b e  wit h dr a w n  fr o m t h e st u d y  if t h e y f ail t o r e c o v er t o
 gr a d e  1  or  b a s eli n e  gr a d e  / v al u e  wit hi n  2 1  d a y s.
5 .3 .1 .2 . M a n a g e m e nt of s ki n  t o xi cit y
F or  p ati e nt s  wit h  gr a d e  1  t o xi cit y, n o  s p e cifi c  s u p p orti v e  c ar e  i s u s u all y  n e e d e d  or  i n di c at e d. R a s h  
m u st b e r e p ort e d a s a n A E. P ati e nt s wit h gr a d e 2 or hi g h er t o xi cit y m a y b e tr e at e d wit h t h e f oll o wi n g  
s u g g e st e d s u p p orti v e  m e a s ur e s  at  t h e di s cr eti o n  of  t h e i n v e sti g at or: or al  mi n o c y cli n e,  t o pi c al 
t etr a c y cli n e, t o pi c al cli n d a m y ci n, t o pi c al sil v er s ulf a di a zi n e, di p h e n h y dr a mi n e, or al pr e d ni s ol o n e ( s h ort 
c o ur s e),  t o pi c al c orti c o st er oi d s, or  pi m e cr oli m u s.
5 .3 .1 .3 . M a n a g e m e nt of  di arr h e a


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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).
5.3.1.4. 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 everolimus and periodically thereafter. Patients with diabetes mellitus 
will be excluded from the study.
5.3.1.5 Management of infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or 
protozoal infections, including infections with opportunistic pathogens. Localized and systemic infections, 
including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis 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 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.
5.3.2 Dose Adjustments
There only planned dose adjustments will be in patients taking the drug for 3.  Patients will be started on   
a set dose of everolimus based on their BSA (m2) and whether or not they are taking an EIAED. For those 
subjects taking everolimus for 3 weeks, a serum level will be obtained between days 10-12.  If the result  
is in desired range (5-10 ng/ml) for patient receiving study medication, the recommendation will be no 
change. If the value is between 3-5 ng/ml, the dose will be increased by 2.0 mg/m2/day and if the value is 
less than 3 ng/ml, the recommendation will be dose will be increased by 3.0 mg/ m2/day. If the value is 
between 10-13 ng/ml, the dose will be decreased by 2.0 mg/m2/day. If the value is above 13 ng/ml, the 
dose will be decreased by 3.0 mg/m2/day.
5.3.3 Serum drug levels
The target range for everolimus serum levels in this study is between 5-10 mg/ml. For patients taking 
everolimus for 1 or 2 weeks, the only time an everolimus level will be assessed is on the morning of 
surgery from the reference laboratory. For those subjects taking everolimus for 3 weeks, a serum level 
will be obtained between days 10-12. All labwork will be performed at Tisch hospital, 560 First Avenue 
New York, NY 10016 or St Barnabas Medical Center 94 Old Short Hills Rd.Livingston, NJ 07039 and the 
subjects taking everolimus for 3 weeks, the bloodwork will be done at the outpatient lab at Tisch Hospital 
as St Barnabas will only enroll controls


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5.4 Method for Assigning Subjects to Treatment Groups
All eligible patients will have TSC and FCD and will tentatively be scheduled or planning to have surgery. 
These eligible patients will be decided by Dr. Orrin Devinsky, or Dr. Doyle. Dr. Devinsky, Dr Yaun, Dr 
Harter or Dr.Doyle will also review their patient’s charts to ensure they meet the inclusion criteria (review 
section 4.1 for all inclusion criteria). Once an eligible patient is decided upon, it will be presented to the 
patient if they would like to participate in this study. Anyone who declines at the NYU CEC will be asked 
to be take part in the control part of the study. Therefore it is up the patient to choose whether or not they 
will participate in the study and if they would like to be a part of the intervention or the control group.
The objective of this study is to show that everolimus can suppress mTOR signaling in patients. A control 
group is necessary for this study to compare the mTOR with patients who do not take the everolimus.
Subject Compliance Monitoring
Patients should be requested to bring their unused study drug and packaging to the clinic at each visit. 
Compliance should be verified by the investigator’s staff through counting the number of tablets 
consumed between at the end of the study period.
5.4
Prior and Concomitant Therapy
Data will be collected on detailed information on all concomitant medical and over-the-counter 
medications taken by the patients. The dosage and time(s) of administration will be recorded at the start 
of the study and throughout the study period. For patients taking an EIAED or moderate CYP3A4 and/or 
PgP inhibitors, the dose of everolimus will be adjusted as specified in section 5-2.


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Patients are permitted to take their regular medications for epilepsy, including rescue medications (e.g., 
rectal Diastat, oral clonazepam) during the study period. Patients are also permitted to take medications for 
medical conditions that are not exclusionary (e.g., propranolol for migraine will be permitted but prednisone 
for systemic lupus erythematosus will NOT be allowed). Patients are not permitted to take 
immunosuppressive drugs (other than everolimus as a blinded medication) during the study period.
Patients will be asked to avoid drugs known to affect coagulation or platelet adhesion for 14 days before 
surgery.
5.5
Blinding of Study Drug
Not applicable.
5.6
Receiving, Storage, Dispensing and Return
5.6.1
Receipt of Drug Supplies
Upon receipt of the study treatment supplies, an inventory must be performed and a drug receipt log filled 
out and signed by the person accepting the shipment.  The designated study staff will count and verify 
that the shipment contains all the items noted in the shipment inventory. Any damaged or unusable study 
drug in a given shipment (active drug or comparator) will be documented in the study files. The 
investigator must notify study sponsor of any damaged or unusable study treatments that were supplied  
to the investigator’s site.
5.6.2
Storage & Handling
Study drug must be stored at 25°C (77°F); excursions permitted between 15°–30°C (59°–86°F); protect 
from light and moisture. Procedures for proper handling and disposal of anticancer drugs should be 
considered.
5.6.3
Dispensing of Study Drug
After a subject with FCD or TSC is consented and entered into the study, they will be instructed on the 
dosage and administration times of the study medication. All subjects will receive a specific quantity of 
tablets and they will be asked to record the time that each dose is given. At each follow-up visit, they will 
be asked to bring back the medication that was not used so it can be reconciled with expected number of 
tablets to be used. This reconciliation will be logged on the drug reconciliation form, and signed and dated 
by the study team
5.6.4
Return or Destruction of Study Drug
The site will 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. The patient will return all unused study drug at each 
dispensing visit and at the end of the study
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, 
and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and 
dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study drug. Drug destroyed on site will be documented in the study files.
6
Study Procedures
5.7
Visit 1 (Active/Control Patients)
NOTE: This visit will occur within 6 weeks of Visit 2, which will be when patient will be entered into the 
study.


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After Informed Consent is obtained and study consent form is signed, Study Visit 1 will include the 
following, from interaction with the subject, and/or as applicable the subject’s parents or guardian:
●
A detailed review of the research subject’s medical records and interview to ensure that the 
subject meets inclusion criteria and does NOT meet any of the exclusionary criteria.
●
History of current seizure types and frequencies, concomitant medical or psychiatric disorders, 
and all prescribed and over-the-counter medications taken.
●
Complete review of systems.
●
Subject physical examination, including recording of vital signs, including height and weight to 
compute body mass index (BMI; see above) and body surface area (BSA), and neurological 
examination.
●
Subject will be instructed to begin a daily seizure diary today that will be maintained and collected 
at the next visit.
5.8
Visit 2 – (Active patients- ‘NOTE: This visit will occur 7-21 days before surgery; 
patients/caretakers will be given Everolimus. )
The following activities will be conducted and research subject information will be collected by interaction 
with the subject, and/or as applicable the subject’s parents or guardian:
●
Recent history will be reviewed for any change in their medical status or change in intake of 
prescribed or over-the-counter medication.
●
Vital signs, physical and neurological examination.
●
Collect and review seizure diary kept since Visit 1 and give new diary to be recorded until date of 
surgery.The protocol for study medication administration will be reviewed with the subject, and/or 
parent/guardian as applicable.
●
Explanation of potential adverse events will be reviewed, as will the reporting of adverse events.
●
Blood work: CBC and C-reactive protein (CRP). If not done prior to visit as part of PST (pre 
surgical testing)
●
Review of the specific protocol for medication administration. (Active Patients Only at NYU CEC)
o
They will be instructed on the dosage and administration times of the study medication. 
All subjects will receive a specific quantity of tablets and they will be asked to record the 
time that each dose is given. They will be asked to bring back the medication that was 
not used so it can be reconciled with expected number of tablets to be used. This 
reconciliation will be logged on the drug reconciliation form, and signed and dated by the 
study team
6.2a  Visit 2a – For patients taking the Everolimus for 3 weeks, at NYU CEC, they will have serum levels 
of everolimus drawn after 10-12 days on the medication. A trough level will be obtained. The study nurse 
or doctor will contact the patient with the results when available and will adjust the dose as described 
above. The nurse or doctor will also ask the patient to report any adverse events.
For active patients who reside outside of the NYC area and are unable to arrive at NYU CEC due to 
distance and travel issues prior to pre-admission testing, Visits 1 and 2 will be combined as one visit to be 
completed at least 7 days prior to Visit 3. For these patients with a combined Visit 1 and 2, this could 
mean a treatment window of 7-21 days depending both on which cohort they are in and how soon they 
can begin treatment.
Pre-surgical evaluation:  Visit 2- Control Group
●
Recent history will be reviewed for any change in medical status or change in intake of prescribed 
or over-the-counter medication.


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●
Vital signs, physical and neurological examination
●
A detailed seizure history during the prior week.
●
Medication reconciliation.
Blood work: (pre surgical eval) CBC and C-reactive protein (CRP).
For control patients who reside outside of the NYC area and are unable to arrive at the study site due to 
distance and travel issues prior to pre-admission testing, Visits 1 and 2 will be combined as one visit and 
can be completed one day prior to Visit 3 if not earlier.
5.9
Visit 3 (Active/Control patients)– Day of Surgery NYU CEC
The following activities will be conducted and research subject information will be collected:
Study drug dosing: (ACTIVE PATIENTS ONLY)
●
On the day of surgery, the patient will take their last dose of everolimus with a 30 cc or less of water 
shortly after awakening and at least 3 hours before surgery
●
A detailed seizure history during the prior week. A blood sample will be used for investigation per 
the IRB-approved protocol. This will include everolimus serum levels, systemic cytokines and 
mTOR activity levels. These samples will be batched and stored in -80 freezer until requested for 
analysis. )
During surgery:  (NYU Tisch Hospital)
●
Intraoperative electrocorticography, performed in accordance with a standard protocol (see below).
●
Resected tissue will be processed by the Pathology Departments at NYU Medical Center and a 
sample will be used for investigation per the IRB-approved protocol. This tissue will be used for 
primary analysis of biochemical, molecular, electrophysiological, and genetic measures.
Corticography Protocol:
Equipment Needed:
1.
Nicolet EEG Portable Acquisition unit
2.
C64 Amplifier
3.
2 x sterile Grass monopolar needle electrodes (1 – ground, 1 – reference)
4.
2 x Touch-proof adapters for needle electrodes
5.
64-lead sterile Ad-tech electrode cable
6.
4 x sterile 16-contact Ad-tech connector blocks
7.
64-contact (8x8) Ad-tech electrode; spacing as follows:
a.
If lesion is <=2 cm in maximal dimension, use grid with 5mm spacing
b.
If lesion is 2.1-3 cm in maximal dimension, use grid with 7.5mm spacing
c.
If lesion >3cm in maximal dimension, use grid with 10mm spacing
Anesthesia:
Remifentanil/propofol. If using volatile anesthesia, turn off 15 minutes prior to beginning 
recording.
Procedure:
1.
Wheel portable EEG station into room, turn on and enter patient demographics as per routine
2.
Configure 64-electrode montage in NicOne
3.
Neurosurgeon to place ground and reference electrodes in scalp muscle adjacent to craniotomy
4.
Neurosurgeon to photograph lesion


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5.
Neurosurgeon to place selected subdural grid electrode with center of grid overlying approximate 
center of the lesion
6.
Neurosurgeon to connect and pass 64-contact Ad-tech adapter to neurophysiologist who will 
connect it to C64 amplifier
7.
Record ECoG for a minimum duration of 10 minutes using the following settings: High Pass Filter 
1 Hz, Low Pass Filter 70 Hz, Gain 70uV/mm, notch filter off.
8.
Neurosurgeon to place paper markers on 4 corners of grid then remove the grid and photograph 
the brain again.
9.
Save ECoG file as anonymized file without video to external hard drive using subject number as 
file name.
10. Obtain intraoperative photos from neurosurgeon and relabel by subject number, XXXX_pregrid, 
XXXX_grid and XXXX_postgrid. Save files to external hard drive
5.10
Visit 4 (and all days with invasive electrodes) NYU Tisch Hospital
The day after surgery, and every day thereafter if invasive electrodes are utilized:
●
The research subject will be seen by a board-certified neurosurgeon or study designee and 
evaluated for evidence of infection and abnormal wound healing as per the protocol (including 
digital photographs of the surgical site dressing) in both treated and untreated comparison 
groups.
o
We will take photographs of the surgical site dressing and subject’s face will not be in the 
photo. All photos will be de-identified in the same manner all of their clinical information 
for this study will be de-identified. Consent for the photographs are part of the consent 
form. The photographs will not be shared with anyone outside of the research team or 
anyone who is not a part of the patient’s medical care.
●
A board-certified neurologist/epileptologist will also evaluate the subject daily while invasive 
electrodes are used.
–
All seizures and subclinical electrographic seizure discharges will be reviewed and the type 
(e.g., simple v. complex partial v. subclinical electrographic discharge), onset region(s), 
spread zone(s), and duration.
–
Each day a standard portion of the awake and sleep EEG records and all seizures, including 
the period for one minute before seizure onset and 5 minutes after seizure offset will be 
stored and available for subsequent analysis.
The neurologist/epileptologist or study designee will record vital signs and perform a physical and 
neurological examination and inquire about potential adverse events.
5.11
Visit 5a (Active and concurrent comparison group) (if a second surgery is done at the 
end of invasive recordings) NYU Tisch Hospital
Resected tissue at the time of surgery will be distributed by the Pathology Departments at the local 
institutions and samples will be used for investigation per the IRB-approved protocol. This tissue will be 
used for research analysis of biochemical, molecular, electrophysiological, and genetic measures.
6.5a Resected brain tissue will be distributed at the Pathology Department of the NYU Medical 
Center then stored in the Alexandria Center for Life Sciences, located at 450 East 29th Street on 9th  floor 
a -80 freezer until requested to be analyzed.. 
The samples will be de identified and coded so that Dr. Devinsky will have access to the key. The samples 
will be stored and used only for analysis for this study. All tissue remaining after this study will be kept in 
our bank or destroyed per individual patient voluntary consent.
Samples will be stored secure labs in the above addresses. Our 3 NYU Pathologists-internal 
collaborators, Dr. Kasthuri, Dr. Leitner, and Dr. Snuderl) will perform analysis of brain resection 
specimens from patients on this study, and will be used for preparation of DNA/RNA assays.  They will be 
looking for mutations in  mTOR pathway genes. The samples will be studied using next gen sequencing, 
proteomics and/or Micro RNA assays, to search for mutations which may have caused the tuber or 
cortical dysplasia (CD). This analysis will focus on genes known to be involved in tuber/CD development 
including TSC1, TSC2, AKT1, AKT2, AKT3, MTOR, PTEN. Any variants that are found will be compared 


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with those found in blood DNA samples from the same subjects.  If subjects have indicated an interest in 
learning of the genetic findings, the findings will  be provided to them. This information will be offered to 
the patients and their families through a physician or genetics counselor experienced with tuberous 
sclerosis. As this is not a clinical grade (CLIA-certified) analysis, the findings will be presented as 
research findings, which must be confirmed by a CLIA lab if  any clinical action were considered based 
upon the information.  The results of the genetic analysis will not be shared with anyone outside of the 
research team. The use of samples for this study is required.
Our 3 pathologists mentioned above will be assaying mTOR pathway activation using immunochemistry, 
western blotting analysis, and capture ELISA and other biochemical and molecular biology techniques o], 
in order to  obtain such results. He will be looking at levels of mTOR signaling proteins in lymphocytes of 
human blood specimens. 2 mls in purple cap EDTA tube will suffice. For all Biochemical assays we will 
utilize fresh frozen tissue, For Immunohistochemistry fixed frozen tissue in 4% PFA and sucrose sank 
48hrs and frozen using OCT blocks can be used. The panel of Abs used for detection will be a panel of 
set-fixed 6 to 10 antibodies. Up to 5mg of tissue will be adequate for MTA purposes and research result 
solidity.
They will be looking for biomarkers of inflammation, and cytokines. She will measure the changes in 
serum HMBG1 with brain tissue expression. She will also measure miRNAs in serum  using additional 
100-200 microliters of serum from each patient, as well as brain tissue from specified  post – resection 
pathological TSC, or / and Epilepsy patients, and collected under an Approved ICF and under the 
supervision of the BRC of NYULMC (in order to distribute), 
If subjects wish to withdraw from this portion of the study, they will need to write a formal letter to the 
Principal Investigator stating why they would like to withdraw and we will withdraw them after that, having 
their sample destroyed. The withdrawal procedures will be explained to them when they are signing the 
consent form.
5.12
Visit 5b Active and concurrent comparison group) (postoperative day 2 and all days 
until discharge) NYU Tisch Hospital
Each postoperative day while the research subject is in the hospital, they will
●
Be seen by a board-certified neurosurgeon or study designee and evaluated for evidence of 
infection and abnormal wound healing as per the protocol (including digital photographs of the 
surgical site dressing).
●
Be seen by a board-certified neurologist/epileptologist or study designee who will also evaluate 
the subject daily each day to inquire about potential adverse events.


C O N F ID E N T IA L
T hi s d o c u m e n t a n d i nf or m ati on is  t he pr o p ert y o f t he N Y U  S c h o ol o f M e di ci n e  a nd L a n g o n e  M e di c al  C e nt er.  Do  n ot di s cl o se  or u s e 
e x c e p t as a ut h ori z e d  in writi n g b y t he  st u d y I ND s p o n s or
E v er oli m u s  eff e ct s  on br ai n  m T O R  a nd e x cit a bilit y
V er si o n :  0 9/ 2 0/ 1 8
P a g e 2 9
5. 1 3
Vi sit  6 ( A cti v e a n d c o n c urr e nt c o m p ari s o n gr o u p) N Y U C E C
3 t o  1 0 d a y s aft er di s c h ar g e, t h e r e s e ar c h s u bj e ct will:
●
B e  e x a mi n e d  b y  a  b o ar d- c ertifi e d  n e ur o s ur g e o n  or  st u d y  d e si g n e e  a n d  e v al u at e d  f or e vi d e n c e  of  
i nf e cti o n a n d  a b n or m al  w o u n d  h e ali n g  a s  p er  t h e pr ot o c ol  (i n cl u di n g di git al  p h ot o gr a p h s  of  t h e 
s ur gi c al sit e  dr e s si n g).
●
B e  e x a mi n e d  b y  a  b o ar d- c ertifi e d  n e ur ol o gi st/ e pil e pt ol o gi st  or  st u d y  d e si g n e e  t o r e vi e w c urr e nt 
m e di c ati o n s, a n y a d v er s e e v e nt s, a n d p erf or m a p h y si c al a n d n e ur ol o gi c al  e x a mi n ati o n.
6 
St ati sti c al  Pl a n
6. 1 
S a m pl e  Si z e  D et er mi n ati o n
St ati sti c al  M et h o d s
Di stri b uti o n s  of  p ati e nt  a n d  di s e a s e  c h ar a ct eri sti c s  will  b e  s u m m ari z e d  d e s cri pti v el y  at  st u d y  e ntr y  b y  d o s e  
d ur ati o n c o h ort a n d a cr o s s c o h ort s i n t h e e v er oli m u s gr o u p a n d i n t h e c o m p ari s o n gr o u p.  Fr e q u e n c y  
di stri b uti o n s a n d cr o s s t a b ul ati o n s will b e pr e s e nt e d f or c at e g ori c al v ari a bl e s. F or c o nti n u o u s  v ari a bl e s, 
s u m m ar y  st ati sti c s  ( m e a n s, m e di a n s,  i nt er q u artil e r a n g e s, st a n d ar d  d e vi ati o n s,  et c)  will  b e  pr o vi d e d  al o n g  
wit h  gr a p hi c al  di s pl a y s  ( e. g., b o x pl ot s)  b y  tr e at m e nt gr o u p.
S af et y  will  b e  s u m m ari z e d  wit hi n  a n d  a cr o s s  d o s e  d ur ati o n c o h ort s  a n d  c o m p ar e d  wit h  t h e e v e nt s  i n t h e 
c o m p ari s o n  gr o u p.
S 6  p h o s p h or yl ati o n  l e v el s i n br ai n  ti s s u e s a m pl e  at  s ur g er y  will  b e  s u m m ari z e d  d e s cri pti v el y  f or e a c h  d o s e  
d ur ati o n  c o h ort  a n d  a cr o s s  c o h ort s  i n t h e tr e at e d gr o u p  a n d  i n t h e c o m p ari s o n  gr o u p.  F urt h er,  l e v el s      
will b e c o m p ar e d b et w e e n t h e tr e at e d a n d c o m p ari s o n gr o u p u si n g 2 s a m pl e 2 si d e d t-t e st s  ( wit h 
a p pr o pri at e  tr a n sf or m ati o n s of  l e v el s if r e q uir e d t o m e et  t h e a s s u m pti o n s  of  t h e m et h o d.
Si mil ar  a n al y s e s  will  b e  c arri e d  o ut  f or all  a d diti o n al  c o nti n u o u s  e n d p oi nt s  of  i nt er e st. N o  a dj u st m e nt s  f or 
m ulti pli cit y will b e m a d e i n t hi s s m all st u d y. Bi v ari at e s c att er pl ot s a n d c orr el ati o n c o effi ci e nt s will al s o  b e  
pr o vi d e d  t o e x a mi n e  t h e a s s o ci ati o n s  b et w e e n  t h e m ulti pl e  e n d p oi nt s.
7. 3 S u bj e ct  P o p ul ati o n( s) f or A n al y si s
All  p ati e nt s  w h o  r e c ei v e o n e  or  m or e  d o s e s  of  dr u g  will b e  i n cl u d e d i n t h e a n al y s e s  of  s af et y.  T h o s e  
p ati e nt s w h o u n d er g o s ur g er y will b e i n cl u d e d i n t h e a n al y s e s of S 6 p h o s p h or yl ati o n a n d  ot h er  
m e a s ur e m e nt s o bt ai n e d at t h e ti m e of s ur g er y. A d diti o n al a n al y s e s will b e c o n d u ct e d t o c o m p ar e  t h o s e 
s u bj e ct s w h o di d n ot c o m pl et e tr e at m e nt a n d s ur g er y wit h r e s p e ct t o di s e a s e a n d p ati e nt  c h ar a ct eri sti c s 
t o i d e ntif y a n y  p ot e nti al  diff er e n c e s  b et w e e n  t h e s e gr o u p s  of  p ati e nt s.
7.  S a m pl e  si z e  c o n si d er ati o n s.  F or  t hi s pr eli mi n ar y  st u d y,  s af et y  a n al y s e s  ar e  pri m ar y.  St u d y  t er mi n ati o n 
will  o c c ur  if, a m o n g  t h e 9  tr e at e d s u bj e ct s,  t h er e ar e  t w o c a s e s  of  w o u n d  h e ali n g  pr o bl e m s  or  t hr e e c a s e s 
of s eri o u s i nf e cti o n, i n cl u di n g w o u n d sit e i nf e cti o n. I n t h e c a s e of a w o u n d sit e i nf e cti o n, a n y  pr o bl e m s  
wit h  w o u n d  h e ali n g  will  b e  c o n si d er e d  s e c o n d ar y  t o t h e i nf e cti o n a n d N O T  a s  a  pri m ar y  w o u n d  h e ali n g  
pr o bl e m. T h e s e e sti m at e s ar e b a s e d o n n e ur o s ur gi c al e x p eri e n c e a n d r e p ort s wit h t h e fr e q u e n c y  of  
w o u n d h e ali n g pr o bl e m s of < 2 % a n d i nf e cti o n fr o m 1. 6 t o 8. 6 % i n si x p u bli s h e d s eri e s, wit h a  m e a n 
i nf e cti o n r at e of 5. 3 %.[ 3 3- 3 8]
F or  t h e a n al y si s  of  S 6  p h o p h or yl ati o n,  b a s e d  o n  a  2  s a m pl e  2  si d e d  t- t e st, w e  c a n  d et e ct  a  diff er e n c e  of
│1. 4 │-  │1. 5  │st a n d ar d  d e vi ati o n s b et w e e n t h e c o m p ari s o n c o ntr ol s a n d t h e tr e at e d gr o u p wit h 9 tr e at e d 
s u bj e ct s  wit h  al p h a  = 0. 0 5  a n d  p o w er  of  8 0 %.  Pr eli mi n ar y  d at a  u si n g  q u a ntit ati v e  W e st er n  bl ot s  o bt ai n e d  
fr o m 4  r e s e ct e d t u b er s d e m o n str at e d  p h o s p h o- S 6/ S 6  r ati o s of  2 5 7 4 2 %  of  c o ntr ol.  Wit h  9  tr e at e d 
s u bj e ct s,  a n d  1 2  c o ntr ol s,  w e  w o ul d  b e  a bl e  t o d et e ct  a  6 2  –  6 5 %  diff er e n c e  i n p h o s p h or- S 6/ S 6  l e v el s 
b et w e e n  tr e at e d a n d  u ntr e at e d  gr o u p s,  w hi c h  i s li k el y a  bi ol o gi c all y  m e a ni n gf ul  diff er e n c e.  Pri or  st u di e s  i n 
m uri n e m o d el s of T S C tr e at e d wit h r a p a m y ci n h a v e d e m o n str at e d 9 0 % r e d u cti o n i n p h o s p h o- S 6  l e v el s 
[r ef]


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Safety monitoring and reporting
Information about all adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected 
and recorded and followed as appropriate.
6.2
Adverse events
6.2.1
Definitions and reporting
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 
Medical History page of the patient’s CRF. Adverse event monitoring should be continued for at least 30 
days (or 5 half-lives, whichever is longer) 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.
The occurrence of adverse events should be sought by non-directive questioning of the patient at each 
visit during the study. Adverse events also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test, or other assessments. As far as 
possible, each adverse event should be evaluated to determine:
1.
The severity grade (CTAE Grade 1-4)
2.
Its duration (Start and end dates or if continuing at the Safety Follow-up Visit)
3.
Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4.
Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, hospitalized, unknown, not applicable)
5.
Whether medication or therapy was given (no concomitant medication/non-drug therapy, concomitant 
medication/non-drug therapy)
6.
Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved 
with sequalae, fatal, unknown)
7.
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. Such treatment may include changes in study drug 
treatment including possible interruption or discontinuation, starting or stopping concomitant treatments, 
changes in the frequency or nature of assessments, hospitalization, or any other medically required 
intervention. Once an adverse event is detected, it should be followed until its resolution, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study drug, the interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be found in the 
[Investigators’ Brochure]. This information should be included in the patient informed consent and should 
be discussed with the patient during the study as needed.
Adverse event monitoring should be continued for at least 30 days following the last dose of study 
treatment
6.2.2
Laboratory test abnormalities
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


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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 CTAE 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 and is still, by definition, an 
adverse event.
6.2.3
Adverse events of special interest (optional)
In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including 
fatal outcome. 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. In clinical trials everolimus has been associated with certain adverse events (Table 6).
Table 6. Specific Adverse Events
Clinically Notable AE 
grouping
Risk Definition in 
Risk 
Management 
Plan (RMP)
Comment
Amenorrhea
Amenorrhea
Included under potential risk in RMP
Cytopenia
N/A
Included under clinically notable AEs
Hemorrhages
Hemorrhages
Included as important identified risk in the RMP
Hyperglycemia/ 
new 
onset 
of 
diabetes 
mellitus
N/A
Included under clinically notable AEs
Hypersensitivity 
reactions 
(anaphylactic reaction)
N/A
Included under clinically notable AEs
Infections
and 
infestations
N/A
Included under clinically notable AEs
Intestinal 
obstruction/ileus
Intestinal 
obstruction/ileus
Included under potential risk
N/A
Cardiac Failure
Not reported in the MAP. (important identified risk- RMP 
specific
N/A
Increased 
creatinine
Please note that this RMP specific identified risk is based 
on lab data and is defined as newly occurring or 
worsening increase to CTC grade 3 or 4
Non
infectious 
pneumonitis
Non
infectious 
pneumonitis
Name changed from pulmonary events to non infectious 
pneumonitis in the MAP. Included under important 
identified risk in RMP
Rash
and
similar 
events
N/A
Not included in the RMP
Renal events
Renal 
failure/proteinuri
a
The names in RMP and MAP are different but the search 
terms are the same. It is included important identified risk 
in RMP


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Stomatitis/oral 
mucositis/ulcers
N/A
Included under clinically notable AEs
Thromboembolism
Thromboembolism
Included as important identified risk in the RMP
6.3
Serious Adverse Events
6.3.1
Definitions
A serious adverse event is an undesirable sign, symptom or medical condition which:
●
is fatal or life-threatening
●
results in persistent or significant disability/incapacity
●
constitutes a congenital anomaly/birth defect
●
requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is 
for:
●
routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition (specify what this includes)
●
elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under 
study and has not worsened since the start of study drug
●
treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE 
given above and not resulting in hospital admission
●
social reasons and respite care in the absence of any deterioration in the patient’s general condition
●
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
6.3.2
Reporting
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E).
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA  3500A 
(MedWatch Form).
To ensure patient safety, every SAE, regardless of suspected causality, occurring
●
after the patient has provided informed consent and until atl east 30 days after the patient has 
stopped study treatment/participation
●
after protocol-specified procedures begin and 30 days after the patient has stopped study treatment
●
after the start of any period in which the study protocol interferes with the standard medical treatment 
given to a patient (e.g., treatment withdrawal during washout period, change in treatment to a fixed 
dose of concomitant medication) and until 30 days after the patient has stopped study treatment
must be reported to Novartis within 24 hours of learning of its occurrence (fax: 877-778-9739). This 
includes serious, related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. All deaths during treatment or within 30 days following completion of active protocol therapy 
must be reported within 5 working days.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator 
suspects a causal relationship to the study drug. 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. A 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.  The 
end date of the first event must be provided.
The original copy of the SAE Report and the fax confirmation sheet must be kept within the Trial Master 
File at the study site.


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Follow-up information is sent to the same fax number as the original SAE Report Form was sent, using a 
new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and giving the date of 
the original report. Each re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Everolimus Investigator Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study drug, a DS&E 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.
6.3.3
Investigator reporting: notifying the NYULMC IRB
This section describes the requirements for safety reporting by investigators who are NYULMC faculty, 
affiliated with a NYULMC research site, or otherwise responsible for safety reporting to the NYULMC IRB. 
The NYU Langone Medical Center IRB (NYULMC IRB) requires expedited reporting of those events 
related to study participation that are unforeseen and indicate that participants or others are at increased 
risk of harm. The NYULMC IRB will not acknowledge safety reports or bulk adverse event submissions 
that do not meet the criteria outlined below. The NYULMC IRB requires researchers to submit reports of 
the following problems within 5 working days from the time the investigator becomes aware of the event:
A reportable event is an event that occurs at any time during or after the research study, which in the 
opinion of the principal investigator is:
●
Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document and 
other relevant sources of information, such as product labeling and package inserts.
AND
●
Related to the research procedures: An event is “related to the research procedures” if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused 
by the research procedures.
AND
●
Harmful: Harmful includes causing harm to participants or others, or placing them at increased 
risk of harm.
Reporting Process
Unanticipated problems posing risks to subjects or others as noted above will be reported to  the   
NYULMC IRB or St Barnabas Medical Center IRB using the form: “Reportable Event Form” or as a written 
report of the event (including a description of the event with information regarding its fulfillment of the 
above criteria, follow-up/resolution and need for revision to consent form and/or other study 
documentation).
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file.
Other Reportable events:
For clinical drug trials, the following events are also reportable to the NYULMCIRB:


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●
Any adverse experience that, even without detailed analysis, represents a serious unexpected 
adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic 
necrosis, Stevens-Johnson syndrome).
●
Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
subjects.
●
Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example:
–
An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected.
–
Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected.
–
A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value.
●
Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in 
a research protocol.
●
Breach of confidentiality
●
Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant.
●
Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study.
●
Complaint of a participant when the complaint indicates unexpected risks, or the complaint cannot 
be resolved by the research team.
●
Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, or 
affects the rights or welfare of subjects.
6.3.4
Investigator reporting: Notifying a non-NYULMC/ IRB
Not Applicable
6.3.5
Sponsor reporting: Notifying the FDA
The study IND sponsor is required to report certain study events in an expedited fashion to the FDA. 
These written notifications of adverse events are referred to as IND safety reports. The following 
describes the safety reporting requirements by timeline for reporting and associated type of event:
●
Within 7 calendar days (via telephone or facsimile report)
Any study event that is:
–
associated with the use of the study drug,
–
unexpected,
–
fatal or life-threatening
●
Within 15 calendar days (via written report)
Any study event that is:
–
associated with the use of the study drug,
–
unexpected, and
–
serious, but not fatal or life-threatening
-or-
–
a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable).
Any finding from tests in laboratory animals that:


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except as authorized in writing by the study IND sponsor
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–
suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, 
or carcinogenicity.
Additional reporting requirements
Sponsors are also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports.
Reporting Process
Adverse events may be submitted on FDA Form 3500A or in a narrative format. If supplied as in a 
narrative format, the minimum information to be supplied is noted above at the beginning of section 8.3. 
The contact information for submitting IND safety reports is noted below:
6.3.6
Sponsor reporting: Notifying participating investigators
Not Applicable
6.4
Unblinding Procedures
Not applicable.
6.5
Stopping Rules
A Data Safety Monitoring Program (DSMP) will be established to monitor adverse events and study 
safety. Prior to commencement of the study, the rate of infection and impaired wound healing associated 
with routine two-stage epilepsy surgeries as will be performed in this study over the past 5 years will be 
determined for each epilepsy surgeon (Amanda Yaun and Werner Doyle). A statistician from the NYU 
School of Medicine Biostatistics Department will provide blinded reports to the Data Safety Monitoring 
Committee (DSMC). The PI, Dr. Orrin Devinsky,Dr.Amanda Yaun, David Harter and Dr. Doyle (co- 
investigators) will aid in reviewing all patients during the treatment period and throughout the post- 
treatment monitoring period. They will review all cases and if it is deemed that the serious adverse 
event(s) are related to study drug, the study will be terminated for that subject. If two patients among the 
9 treated with everolimus develop a) impaired surgical wound healing or if three patients among the 9 
develop b) serious infection, including wound site infection. Any case of wound site infection complicated 
by a wound healing problem will NOT be considered a wound healing problem.
Medical Monitoring
It is the responsibility of the Principal Investigator to oversee research subject safety. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10. 
Auditing, Monitoring and Inspecting). Medical monitoring will include a regular assessment of the number 
and type of serious adverse events..
It is the responsibility of the IND Sponsor to assess research subject safety.
Data Safety Monitoring Program (DSMP), Data Safety Monitoring Committee (DSMP): The investigators 
will review all safety data after each three subject treatment cohort has completed the trial. All safety data 
will be sent to the DSMB after every 3 patients have completed the protocol or if there is any serious 
adverse event that may possibly be related to the study.
For this pilot, open-label exploratory clinical trial, given the potential risk that may be associated with a 7- 
21 day trial of everolimus treatment prior to elective epilepsy surgery in TSC and FCD patients, a DSMP 
will be established. Monitoring will be performed on a regular basis throughout the participant accrual, 
treatment, and follow-up. Dose Limiting Toxicity is not anticipated to be an issue since the doses used 
are standard in prior research studies and now FDA approved for patients with TSC. However, all 
adverse events will be recorded and reviewed.


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except as authorized in writing by the study IND sponsor
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Version:  09/20/18
Page 35
Any adverse event occurring during, or after 30 days of last treatment will be documented by the epilepsy 
neurologist member of the DSMP, including fatigue, rash, anorexia, mucositis, edema, cough, 
thromboembolism, nausea, vomiting, stomatitis, sinusitis, bronchitis, pneumonia, abscess, leukopenia, or 
hyperlipidemia.
Because of the specific concern regarding potential wound healing problems and wound infection 
resulting from treatment with everolimus prior to elective epilepsy surgery, wound status will be carefully 
monitored, specifically by a neurosurgeon.
The site of the planned surgical incision will be inspected by both of the DSMP members 5 days after 
initiating therapy (prior to surgery), and then at weekly intervals, beginning one week after surgery until 
six weeks after surgery. The neurosurgeon will document wound status with digital photography.
Blood test surveillance for possible infection will be performed at the same time intervals (7-10 days 
before starting everolimus, 7-21 days after starting everolimus, and 3-10 days after discharge from the 
hospital, and then 3 and 6 weeks after surgery if any evidence of infection is identified on examination or 
the post-hospital discharge blood test) consisting of a complete blood count (CBC) with differential and 
C-reactive protein (CRP).
Any abnormality will be documented for review by the DSMP. Since no ideal objective scoring system 
exists for assessing surgical site adverse events [39,40], any wound breakdown, dehiscence or infection 
will be considered a serious adverse event, and will be reported to the participating site IRB and to the 
NINDS, and the decision will be made as to whether the study should be terminated.
Individual subject participation in the study will be terminated if the DSMC finds any of the following 
unexpected new findings in a subject:
1) Documented wound infection requiring surgery
2) Documented wound dehiscence requiring surgery
3) Persistent fever above 101 degrees F and abnormally elevated serum wbc count and ESR and CRP in 
the absence of a known cause
4) Documented bacterial meningitis
6.6
Source Documents
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: 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, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial.
6.7
Case Report Forms
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded in a digital RedCap database system. All missing data must be 
explained. If a space on the CRF is left blank because the procedure was not done or the question was 
not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should 
be printed legibly in black ink. If any entry error has been made, to correct such an error, draw a single 
straight line through the incorrect entry and enter the correct data above it. All such changes must be 
initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it.


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except as authorized in writing by the study IND sponsor
Everolimus effects on brain mTOR and excitability
Version:  09/20/18
Page 36
6.8
Data Management
Data Management
The data for this study will be entered into the REDCap, a research data management system. The 
reports, record locking at case report form (CRF) and subject level and the paperless query features allow 
for the cleaning of data throughout the clinical study. The system has extensive security features and all 
data transmitted into or out of the REDCap database will be encrypted.
Study Data Management staff will conduct data management and data quality assurance work activities 
for the A Pilot Study to Evaluate the Effects of Everolimus on Brain mTOR activity and Cortical 
Hyperexcitability in Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) study. Data 
Management staff will be responsible for the integrity of all study data. They will review and monitor the 
completeness and accuracy of data thought out the duration of the study. Final data clean up will be 
completed shortly after the last subject visit and the study database will be locked and provided to the 
study statistician for analyses.
A CRF will be completed for each subject. This CRF has proven successful in previous studies. It is the 
investigator’s responsibility to ensure the accuracy, completeness, clarity, and timelines of the data 
reported in the subject’s CRF. Source documentation supporting the CRF data should indicate the 
subject’s participation in the study and should document the dates and details of study procedures, 
adverse events, other observations, and subject status.
The investigator, or designated representative, should complete the CRF as soon as possible 
after information is collected. An explanation should be provided for all missing data.
The PI, Dr. Devinsky, will provide the study site with CRF training sufficient to permit site personnel to 
enter or correct information in the CRFs for the subjects for which they are responsible.
6.8.1
Data Collection Forms: To be submitted by study coordinator
Within 48 hours of registration completion: On-study CRF, Signed, Dated Consent, On-Study Lab 
Reports, Medical History CRF, Eligibility Checklist; Within two weeks of registration: Pre-Operative 
Evaluation CRF, Completed Subject Diaries, Complete Lab test results; Within two weeks post surgery: 
Post-Op evaluation CRF, Off-Study Evaluation CRF; Within two weeks post-surgery, within 30 days for all 
other AE’s: Toxicity CRFs; Within 24 hours of event occurrence: SAE’s Hospitalization 
Admission/Discharge Summaries
6.8.2
Subject Identifiers
Each patient will be given a unique identifier (study number) in the order of enrollment. Each blood and 
tissue sample will be placed in an individual cryotube labeled with study number, date of surgery, and 
time of collection.
6.8.3
Confidentiality
Each subject enrolled will, from that point forward, be identified by a unique identifier (study number). This 
study number will also be used for research specimens collected and shipped to collaborating 
laboratories. Clinical information will be accessed, according to HIPAA requirements, by study personnel 
to complete study documents, as needed. Only the PI and the study coordinator will have access to the 
log linking the study number to the patient name, birth date, and medical record number. The log will be 
kept in a secure file.


C O N F ID E N T IA L
T hi s d o c u m e n t a n d i nf or m ati on is  t he pr o p ert y o f t he N Y U  S c h o ol o f M e di ci n e  a nd L a n g o n e  M e di c al  C e nt er.  Do  n ot di s cl o se  or u s e 
e x c e p t as a ut h ori z e d  in writi n g b y t he  st u d y I ND s p o n s or
E v er oli m u s  eff e ct s  on br ai n  m T O R  a nd e x cit a bilit y
V er si o n :  0 9/ 2 0/ 1 8
P a g e 3 7
M e di c al  a n d  st u d y  r e c or d s will  b e  k e pt  i n a c c or d a n c e  wit h  st at e  a n d  f e d er al l a w s c o n c er ni n g  t h e pri v a c y  
a n d c o nfi d e nti alit y of m e di c al i nf or m ati o n. T h e c o nfi d e nti alit y of e a c h s u bj e ct’ s m e di c al r e c or d i s  al s o  
pr ot e ct e d b y f e d er al pri v a c y  r e g ul ati o n s.
S u bj e ct s  will  b e  i nf or m e d of  all  pr ot e ct e d  h e alt h  i nf or m ati o n u s e d  i n t hi s st u d y.  T h e  c o n s e nt  f or m will  s e e k 
writt e n  p er mi s si o n  fr o m t h e p ati e nt  t o u s e  a n d  di s cl o s e  i nf or m ati o n f or t hi s r e s e ar c h. T h e  p ati e nt  or  p ar e nt  
i s r e q uir e d t o si g n  t hi s f or m. T hi s  A ut h ori z ati o n  will  n ot  e x pir e  u nl e s s  t h e p ati e nt  wit h dr a w s  it i n writi n g.
T h e  v ol u nt e er  h a s  t h e ri g ht t o wit h dr a w  a ut h ori z ati o n  at  a n y  ti m e, e x c e pt  t o t h e e xt e nt  t h at N Y U  h a s  
alr e a d y  r eli e d u p o n  it or  m u st  c o nti n u e  t o u s e  t h e i nf or m ati o n t o c o m pl et e  d at a  a n al y si s  or  t o r e p ort d at a  
f or t hi s st u d y.
6. 8. 4
Di s p o siti o n  of D at a
R e s e ar c h fi n di n g s  will b e st or e d i n a p a s s w or d pr ot e ct e d c o m p ut er. Writt e n a n d el e ctr o ni c r e c or d s, 
r e p ort s, a n d d at a r e s ulti n g fr o m t hi s cli ni c al tri al will b e k e pt i n t h e v ol u nt e er’ s r e s e ar c h r e c or d f or at l e a st 
si x  y e ar s  or  u ntil  t h e st u d y  i s c o m pl et e d,  w hi c h e v er  i s l o n g er. At  t h at ti m e, eit h er  t h e r e s e ar c h i nf or m ati o n 
n ot  alr e a d y  i n t h e m e di c al  r e c or d will  b e  d e str o y e d  or  i nf or m ati o n i d e ntif yi n g t h e p ati e nt  will  b e  r e m o v e d 
fr o m s u c h  st u d y  r e s ult s at  N Y U.  A n y  r e s e ar c h i nf or m ati o n i n t h e m e di c al  r e c or d will  b e  k e pt  i n d efi nit el y.
6. 8. 5
S h ari n g St u d y  R e s ult s
W e  pl a n  t o m a k e  all  d at a  a n d  r e s o ur c e s g e n er at e d  u n d er  t hi s gr a nt  a v ail a bl e  t o t h e a c a d e mi c  c o m m u nit y 
i m m e di at el y aft er w e r e p ort t h e m f or t h e fir st ti m e i n a p e er-r e vi e w e d p u bli c ati o n. R e s ult s u s e d i n 
p u bli c ati o n s  will  n ot  b e  i d e ntifi a bl e or  a bl e  t o b e  tr a c e d b a c k  t o e nr oll e d  s u bj e ct s.
6. 9
R e c or d s  R et e nti o n
It i s t h e i n v e sti g at or’ s r e s p o n si bilit y t o r et ai n st u d y  e s s e nti al  d o c u m e nt s  f or at  l e a st 6  y e ar s  aft er  t h e st u d y 
i s c o m pl et e d a n d t h e d at a b a s e i s l o c k e d f or a n al y si s.
7 
St u d y  M o nit ori n g, A u diti n g, a n d I n s p e cti n g
7. 1 
St u d y  M o nit ori n g Pl a n
T h e  Pri n ci p al  I n v e sti g at or ( Dr. Orri n  D e vi n s k y)  will  f oll o w t h e d at a  s af et y  m o nit ori n g  pl a n  b el o w  t o e n s ur e  
t h at all s af et y m e a s ur e s ar e t a ki n g pl a c e i n t h e b e st i nt er e st of t h e s u bj e ct s.
D at a S af et y  M o nit ori n g Pl a n ( D S M P)
W h o will  d o t h e d at a m o nit ori n g f or t hi s st u d y:
●
T h e PI, Orri n D e vi n s k y,  M D.
●
T h e s u b i n v e sti g at or, A m a n d a Y a u n,  M D
●
T h e i n d e p e n d e nt m o nit or, Di mitri o Ar kil o a s,  M D
E x pl ai n h o w d at a  s af et y will b e m o nit or e d:
●
Dr u g  t ol er a bilit y a n d  s af et y  will  b e  m o nit or e d  d uri n g  cli ni c al  e v al u ati o n s  a n d  p h o n e  vi sit s  b y  
i n v e sti g at or/ st u d y t e a m m e m b er t h at will s e e k i nf or m ati o n o n a d v er s e e v e nt s b y s p e cifi c 
q u e sti o ni n g a n d, a s a p pr o pri at e, b y  e x a mi n ati o n.

.
●
Dr.  D e vi n s k y,  Dr.  Y a u n  a n d  Dr.  D o yl e  will  r e vi e w all  p ati e nt s  d uri n g  t h e tr e at m e nt p eri o d  a n d  
t hr o u g h o ut t h e p o st-tr e at m e nt p eri o d.  T h e y will r e vi e w all c a s e s a n d if it i s d e e m e d t h at t h e 
s eri o u s  a d v er s e  e v e nt( s)  ar e  r el at e d t o st u d y  dr u g,  t h e st u d y will  b e  t er mi n at e d f or t h at s u bj e ct.  If 
t w o p ati e nt s  a m o n g  t h e 9  tr e at e d wit h  e v er oli m u s  d e v el o p  a)  i m p air e d s ur gi c al  w o u n d  h e ali n g  or  if 
t hr e e p ati e nt s a m o n g t h e 9 d e v el o p b) s eri o u s i nf e cti o n, i n cl u di n g w o u n d sit e i nf e cti o n, st u d y 
t er mi n ati o n will o c c ur. A n y c a s e of w o u n d sit e i nf e cti o n c o m pli c at e d b y a w o u n d h e ali n g, t h e 
pr o bl e m will N O T b e c o n si d er e d a w o u n d h e ali n g pr o bl e m, b ut s e c o n d ar y t o t h e  i nf e cti o n.


C O N F ID E N T IA L
T hi s d o c u m e n t a n d i nf or m ati on is  t he pr o p ert y o f t he N Y U  S c h o ol o f M e di ci n e  a nd L a n g o n e  M e di c al  C e nt er.  Do  n ot di s cl o se  or u s e 
e x c e p t as a ut h ori z e d  in writi n g b y t he  st u d y I ND s p o n s or
E v er oli m u s  eff e ct s  on br ai n  m T O R  a nd e x cit a bilit y
V er si o n :  0 9/ 2 0/ 1 8
P a g e 3 8
●
T h er e i s a ri s k of P HI di s s e mi n ati o n. All p er s o n al h e alt h i nf or m ati o n ( o n p a p er) will b e st or e d  at  
N Y U C o m pr e h e n si v e E pil e p s y C e nt er l o c at e d at 2 2 3 E a st 3 4 t h Str e et, N e w Y or k, N Y i n a  l o c k e d 
fili n g c a bi n et. P ati e nt i nf or m ati o n m a y al s o b e st or e d i n R E D C a p, a s e c ur e r e s e ar c h d at a  
m a n a g e m e nt s y st e m. O nl y p er s o n n el li st e d o n t h e st u d y will h a v e a c c e s s t o  P HI.
D e s cri b e  a n y  p ot e nti al  c o nfli ct  of  i nt er e st t h e D S M  c o nt a ct  m a y  h a v e:
N o n e.
D at a S af et y  M o nit or D et ail s:
T h e e nr oll e d s u bj e ct s  will b e m o nit or e d:
Dr u g
●
P ati e nt s will b e r o uti n el y m o nit or e d f or a d v er s e e v e nt s vi a cli ni c al e v al u ati o n s a n d p h o n e  vi sit s
●
S u bj e ct s will h a v e t h e r e s e ar c h c o or di n at or’ s p h o n e n u m b er t o c all i n c a s e of n e e d t o r e p ort  si d e 
eff e ct s o n d a y s n ot s c h e d ul e d f or cli ni c al e v al u ati o n or p h o n e  vi sit.
P HI
●
All P HI will b e k e pt i n l o c k e d fili n g c a bi n et at N Y U C o m pr e h e n si v e E pil e p s y C e nt er  a n d/ or  
e nt er e d i nt o R E D C a p ( N Y U s e c ur e d at a m a n a g e m e nt s y st e m) wit h a c c e s s gi v e n o nl y t o  st u d y 
p er s o n n el
Dr o p o ut s will  b e m o nit or e d:
●
Dr o p o ut s  will  h a v e  a  fi n al vi sit  t o c o m pl et e  t h eir e nr oll m e nt  a n d  r e c ei v e i n str u cti o n s f or t a p eri n g 
off of  E v er oli m u s.

.
Pri m ar y a n d  s e c o n d ar y effi c a c y e n d p oi nt s will b e m o nit or e d:
T h e  pri m ar y  st u d y  e n d p oi nt s  of  t h e s af et y  a n d  t ol er a bilit y of  e v er oli m u si n  c hil dr e n  a n d  y o u n g  a d ult s  a n d  
t h e e st a bli s h m e nt of o pti m al d o s e will b e m o nit or e d vi a:
●
Si d e Eff e ct s i n c hil dr e n a n d s u bj e ct s w h er e c ar e gi v er r e p ort s a n d i n a d ult s t h at ar e a bl e t o  s elf 
r e p ort.
●
E v al u ati o n of s ei z ur e di ar y at cli ni c al e v al u ati o n s a n d p h o n e  vi sit s
T h e  s e c o n d ar y  st u d y  e n d p oi nt  of  c h a n g e  i n fr e q u e n c y fr o m b a s eli n e  will  b e  m o nit or e d  vi a:
●
E v al u ati o n of s ei z ur e di ar y at cli ni c al e v al u ati o n s a n d p h o n e  vi sit s
R e p ort a bl e e v e nt s  will b e m o nit or e d u si n g a n a c c e pt e d s c al e:
N o,  t h er e will  b e  n o  a c c e pt e d  s c al e  f or m o nit ori n g  r e p ort a bl e e v e nt s.  All  r e p ort a bl e e v e nt s  will  b e  f oll o w e d 
u ntil  r e s ol uti o n, st a bili z ati o n,  or  u ntil  it h a s  b e e n  d et er mi n e d  t h at t h e st u d y  tr e at m e nt or  p arti ci p ati o n  i s n ot  
t h e c a u s e. If t h e r e p ort a bl e e v e nt i s still o n g oi n g at t h e e n d of t h e st u d y, it will b e f oll o w e d u ntil fi n al 
o ut c o m e h a s b e e n  r e a c h e d.
D e s cri b e t h e  fr e q u e n c y of m o nit ori n g:
T h e  I n d e p e n d e nt m o nit or  will  e v al u at e  e v er y  1 2  m o nt h s  aft er  t h e fir st p ati e nt  r e c ei v e s t h e i niti al d o s a g e  of  
e v er oli m u s
I nt eri m a n al y si s will t a k e pl a c e:
N o,  i nt eri m a n al y si s  will  n ot  t a k e pl a c e  u nl e s s  r e q u e st e d b y  t h e I R B.
R e p ort a bl e  e v e nt s
T hi s  pr ot o c ol  will  a d h er e  t o N Y U  S O M  I R B p oli c y  f or r e p ort a bl e e v e nt s  r e p orti n g: Y e s,  w e  will  a d h er e  t o 
t h e p oli c y  f or r e p ort a bl e e v e nt s.  W e  will  al s o  b e  r e p orti n g t o N o v arti s  P h ar m a c e uti c al s  C or p or ati o n.
D e s cri pti o n of  D at a S af et y M o nit ori n g
1 . T y p e s of d at a a n d e v e nt s t h at will b e c a pt ur e d u n d er t h e  D S M P
T h e  o nl y  t y p e of  e v e nt  t h at w e  a nti ci p at e  t o c a pt ur e  i s fr o m s u bj e ct s  w h o  h a v e  a d v er s e  si d e  eff e ct s  fr o m 
dr u g or w h o s e P HI w a s a c ci d e nt all y  di s s e mi n at e d.


CONFIDENTIAL
This document and information is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use 
except as authorized in writing by the study IND sponsor
Everolimus effects on brain mTOR and excitability
Version:  09/20/18
Page 39
2. Responsibilities and roles for gathering, evaluating and monitoring data
Dr. Devinsky, Dr.Yaun, and Dr. Arkiloas (the independent monitor) will be responsible for evaluating and 
monitoring data.  They will oversee the DSMP and DSMR.
3. Information about the monitoring entity
The independent monitor, Dr. Dimitrio Arkiloas, is the monitoring entity.
4. Reportable events that will be reported to the monitoring entity and when the events will be reported 
Yes, all reportable events will be immediately reported to the PI by the independent monitor, study 
personnel, co-investigators or anyone who is aware of a reportable event. Reportable events may be 
reported by email or by phone to the PI.
5. Assessment for the frequency of monitoring
We will submit a Data Safety Monitoring Report every 12 months, at the same time as the annual 
renewal. If there is a reportable event, the independent monitor or other study personnel will report it to 
the IRB immediately.
6. Stopping rules and criteria for withdrawal of subjects
Subjects may withdraw from the study at the request of the parent or legal guardian for side effects that 
impair function or quality-of-life, assuming they do not want to lower the dose to a tolerable range.
Subjects will also have drug discontinued by investigator if any serious adverse effect is identified and 
considered as a possible or definite result of the study medication. These include rash, other signs of 
hypersensitivity, or liver function tests that exceed baseline or normal measures by 50%. Clinical 
judgment will be used when determining need for everolimus therapy to be terminated. Other reasons for 
withdrawal include non-compliance with study procedures, seizure exacerbation, or interaction with 
current concomitant AED therapy. The method termination of everolimus therapy will be determined 
based on type of reaction and/or reason for withdrawal.
7. Communication and dissemination of information
If any accidental dissemination of PHI occurs, the independent monitor, Dr. Arkiloas, will communicate 
with the IRB immediately.
7.2
Auditing and Inspecting
The Investigator will permit study-related monitoring, audits, and inspections by the IRB, government 
funding and regulatory bodies, and NYULMC compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.). The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.).
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable NYULMC compliance and quality assurance offices.
8
Ethical Considerations
This study is to be conducted accordance with applicable: US government regulations, international 
standards of Good Clinical Practice, and institutional research policies and procedures.
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB) in agreement with local legal prescriptions, for formal approval of the study conduct.  The decision  
of the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this 
decision will be provided to the sponsor before commencement of this study. The investigator should 
provide a list of IRB members and their affiliate to the sponsor.


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All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. Assent will 
not be required since all of the children in this study will be cognitively impaired. All consent will be 
coming from their legal guardians/parents/health care proxy. A consent form will be submitted with the 
protocol for review and approval by the IRB for the study. The formal consent of a subject, using the 
IRB/EC-approved consent form, must be obtained before that subject undergoes any study procedure. 
The consent form must be signed by the subject or legally acceptable surrogate, and the investigator- 
designated research professional obtaining the consent.
9
Study Finances
9.1
Funding Source
The collection of preliminary data for this study at NYU Langone Medical Center will be funded through a 
grant from Novartis. Study drug and funding will be supplied by Novartis For the randomized study, 
funding will be requested from the National Institutes of Health using an RO1 grant application.
9.2
Conflict of Interest
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must report this to the study IND Sponsor  
and have the conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee- 
sanctioned conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study. All NYULMCinvestigators will follow the applicable University conflict of interest 
policies.
9.3
Subject Stipends or Payments
Subjects will not be compensated for travel for any study-related expenses.
10
Publication Plan
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.
12
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except as authorized in writing by the study IND sponsor
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Version:  09/20/18
Page 41
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except as authorized in writing by the study IND sponsor
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This document and information is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use 
except as authorized in writing by the study IND sponsor
Everolimus effects on brain mTOR and excitability
Version:  09/20/18
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