Clinical trial NCT04650204
Conditions: Intractable Epilepsy Malignant Glioma Seizure Disorder WHO Grade 2 Glioma WHO Grade 3 Glioma
Sponsor: Mayo Clinic
Start date: 2020-12-04; Completion date: 2023-04-30
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase IV trial studies the side effects and how well perampanel works in reducing seizure frequency in patients with high-grade glioma and focal epilepsy. Perampanel is a drug used to treat seizures. Giving perampanel together with other anti-seizure drugs may work better in reducing seizure frequency in patients with high-grade glioma and focal epilepsy compared to alternate anti-seizure drugs alone.

Detailed description:
PRIMARY OBJECTIVE:

I. Demonstrate the efficacy and safety of perampanel (PER) on seizure frequency in adult patients with biopsy-proven high-grade glioma and focal epilepsy compared with alternate anti-seizure drugs (ASDs).

SECONDARY OBJECTIVES:

I. To assess the change in neurocognitive function and brain magnetic resonance imaging (MRI) progression over the course of PER treatment with a daily dose of 4 mg (up to -8mg) in patients with biopsy-proven high-grade glioma and focal epilepsy compared with alternate ASDs.

II. To identify a biomarker-specific response to seizure-reduction in patients treated with PER in patients with a biopsy-proven high-grade glioma (i.e., IDH-mutant versus \[vs\] wildtype).

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP A: Patients receive perampanel orally (PO) once daily (QD) for 40 weeks in the absence of disease progression or unacceptable toxicity.

GROUP B: Patients receive ASD per standard of care for 40 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 months.

Arms: arm 1: Patients receive perampanel PO QD for 40 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive ASD per standard of care for 40 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Anticonvulsant Agent intervention 2: Perampanel intervention 3: Quality-of-Life Assessment intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Given ASD intervention 2: Given PO intervention 3: Ancillary studies intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Official Title: A Phase IV, Prospective, Randomized, Open-Label, 
Parallel Study Evaluating the Effect of an Adjunctive Anti-Seizure 
Medication using a Glutaminergic Modulator in Patients with Drug-
Resistant Focal Epilepsy and High-Grade Glioma 
 
NCT04650204 
 
Protocol Version 6.0 
23Nov2022 


Adjunctive Anti-Seizure Medication in Epilepsy and High-grade Glioma 
Version 6.0 
 
 
Revised 23NOV2022 
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William O. Tatum, IV, DO FAAN, FACNS 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
A Phase IV, Prospective, Open-Label, Parallel Study Evaluating the Effect of an Adjunctive Anti-
Seizure Medication using a Glutamatergic Modulator in Patients with Focal Epilepsy and High-
grade Glioma   
 
 
 
 
 
Regulatory Sponsor: 
William O. Tatum, IV, DO FAAN, FACNS  
Mayo Clinic Neurology 
4500 San Pablo Road 
Jacksonville, Florida 32224 
904-953-2498 
 
Study Product: 
Perampanel (PER) 
Protocol Number: (IRBe) 
19-006286  
 
 
 
 
 
 
 
 
 
Initial version: [09/06/2019] Version (2.0)  
 
Current version: [11/23/2022] Version (6.0) 
 
 


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Table of Contents 
 
Study Summary 
5 
1 
Introduction 
9 
1.1 
Background 
9 
1.2 
Investigational Agent 
10 
1.3 
Preclinical Data 
10 
1.4 
Clinical Data to Date 
10 
1.5 
Dose Rationale 
11 
1.6 
Risks and Benefits 
11 
2 
Study Objectives 
11 
3 
Study Design 
11 
3.1 
General Description 
11 
3.2 
Number of Subjects 
12 
3.3 
Duration of Participation 
12 
3.4 
Primary Endpoints 
12 
3.5 
Identification of Source Data 
12 
4 
Subject Selection Enrollment and Withdrawal 
13 
4.1 
Inclusion Criteria 
13 
4.2 
Exclusion Criteria 
13 
4.3 
Subject Recruitment, Enrollment and Screening 
14 
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 
15 
5.2 
Treatment Regimen 
15 
5.3 
Method for Assigning Subjects to Treatment Groups 
15 
5.4 
Preparation and Administration of Study Drug 
15 
5.5 
Subject Compliance Monitoring 
15 
5.6 
Prior and Concomitant Therapy 
15 
5.7 
Packaging 
15 
5.8 
Masking/Blinding of Study 
16 
5.9 
Receiving, Storage, Dispensing and Return 
16 
5.9.1 
Receipt of Drug Supplies 
16 
5.9.2 
Storage 
16 
5.9.3 
Dispensing of Study Drug 
16 
5.9.4 
Return or Destruction of Study Drug 
16 


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6 
Study Procedures 
16 
6.1 
Visit 1 (Screening) 
16 
6.2 
Visit 2 (Baseline) 
16 
7 
Statistical Plan 
23 
7.1 
Sample Size Determination 
23 
7.2 
Statistical Methods 
23 
7.3 
Subject Population(s) for Analysis 
24 
8 
Safety and Adverse Events 
25 
8.1 
Definitions 
25 
8.2 
Recording of Adverse Events 
27 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
27 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB 
27 
8.3.2 
Sponsor-Investigator reporting: Notifying the FDA 
27 
8.4 
Stopping Rules 
28 
8.5 
Medical Monitoring 
28 
9 
Data Handling and Record Keeping 
28 
9.1 
Confidentiality 
28 
9.2 
Source Documents 
29 
9.3 
Case Report Forms 
29 
9.4 
Records Retention 
30 
10 Study Monitoring, Auditing, and Inspecting 
30 
10.1 
Study Monitoring Plan 
30 
10.2 
Auditing and Inspecting 
32 
11 Ethical Considerations 
32 
12 Study Finances 
33 
12.1 
Funding Source 
33 
13 Publication Plan 
33 
14 References 
33 
15 Attachments 
35 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
 
 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
 
 
 
 
 
 


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Study Summary 
Title 
A Prospective, Open-Label, Parallel Study 
Evaluating the Effect of an Adjunctive Anti-
Seizure Medication using a Glutamatergic 
Modulator in Patients with Focal Epilepsy and 
High-Grade Glioma   
Running Title 
Adjunctive Anti-Seizure Drug (ASD) in Drug-
Resistant Focal Epilepsy and high-grade glioma  
Protocol Number 
19-006286  
Phase 
IV (investigator-initiated) 
Methodology 
This is an open-label, parallel study evaluating the 
effect of PER in patients with biopsy-proven 
high-grade glioma (grade II and above) and focal 
epilepsy. Dose ranging will be based on best 
clinical practice in patients with drug-resistant 
focal epilepsy.  
Overall Study Duration 
18 months 
Subject Participation Duration 
Subject will participate in study procedures for a 
total duration of 12 months including a 2-to-4-
week titration phase, 12-week minimum and 24-
week maximum stable treatment phase for interim 
analysis, and 40 weeks of total treatment time at 
study termination.  
Single or Multi-Site  
Single Site 
Primary Objectives 
 
To evaluate the efficacy and safety of PER on 
seizure frequency in adult patients with biopsy-
proven high-grade glioma and focal epilepsy 
compared with alternate ASDs. 
 
 
Secondary objectives 
To assess the progression of biopsy-proven high-
grade glioma in patients prescribed a daily dose of 
4-8mg of PER for 40 weeks in patients with focal 
epilepsy when compared with alternate ASD 
 
To assess the change in neurocognitive function 
and brain MRI progression over the course of 
PER treatment with a daily dose of 4 mg (up to -
8mg) in patients with biopsy-proven high-grade 
glioma and focal epilepsy compared with alternate 
ASDs. 
To identify a biomarker-specific response to 
seizure-reduction in patients treated with PER in 
patients with a biopsy-proven high-grade glioma 
(i.e., IDH-mutant vs wildtype). 


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Number of Subjects 
20 


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Diagnosis and Main Inclusion and Exclusion Criteria 
Inclusion Criteria 
The subject, or the subject’s legally 
acceptable representative is willing to 
participate in a clinical trial, provides written 
informed consent, and subject provides 
written assent, as required by the Mayo Clinic 
Institutional Review Board (IRB) policy 
involving human subjects.  
1. Subjects that satisfy the following diagnostic 
criteria: Patients with established clinical 
diagnoses, of high-grade glioma (WHO class II 
and above) and epilepsy refractory to at least 
one ASD, with a seizure frequency of at least 1 
seizure per 3-months during baseline. 
2. Subjects with body weight of ≥ 40 kg and  ≤ 
125 kg at screening 
3. Adults age 18 and older 
Exclusion Criteria 
A. Subject has serious cardiac, respiratory, renal, 
gastrointestinal, hematologic, or other medical 
condition as determined by the investigator to 
potentially interfere with the study 
B. Subjects with high-grade glioma not following 
Stupp protocol for treatment of glioblastoma. 
C. History of status epilepticus in the 6 months 
prior to screening or a history of seizure 
clusters progressing to status epilepticus. 
D. Past medical history of drug and/or alcohol 
abuse  
E. Pregnant or breast-feeding 
F. Subjects treated with PER prior to baseline  
G. Prior felony conviction disclosed by the patient 
or previously stated in medical record. 
H. History of violent behavior 
I. 
Clinically significant laboratory abnormality at 
screening or baseline visits, as determined by 
the investigators 
J. 
Use of an investigational drug or device within 
20 days prior to treatment Day 1 
K. Repeated radiation therapy for tumor regrowth 
L. Subjects that plan to undergo tumor resection 
on or after baseline visit 
M. Uncontrolled psychiatric disorder at baseline 
N. Subjects who report active suicidal attempts or 
suicidality including subjects with a history of 
suicide attempts or suicidality determined to be 


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clinically significant by investigators at 
screening. 
O.  


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Study Product, Dose, Route, Regimen 
PER is a noncompetitive AMPA glutamate 
receptor antagonist. The two phases of the 
treatment portion of this study include a titration 
phase and a stable dosing phase. This study will 
have two treatment arms consisting of PER and 
alternative ASD arm. The PER arm will begin a 
titration phase with 2mg PER PO q.d. (may be 
split to b.i.d.) for one week and increase by 
2mg/week until reaching an initial dose of 4mg 
PO q.d. (q.d. or b.i.d. dosing) is reached. Flexible 
dosing of PER above 4mg to a maximum of 8 mg 
daily will be compared to use of alternative ASDs 
and be guided by best clinical practices with 
dosing and indication within U.S. FDA 
guidelines.  
 
Duration of Administration 
Participants will be assigned to receive open label 
PER or an alternate ASD for at least 12 week and 
up to 40weeks for the remainder of the study. This 
includes 2-4 weeks of titration and up to 40 weeks 
of stable dosing. Reduction by 2 mg will be 
allowed in cases of efficacy if doses greater than 4 
mg daily result in non-idiosyncratic side-effects.  
Reference therapy 
All comparisons will use standard ASDs as the 
reference therapy using an intent to treat study 
design for patients initiating or tapering off PER 
therapy. 
Statistical Methodology 
Statistical analysis will include Student T-test, 
Chi-square for categorical differences. An interim 
analysis will be performed when half of the 
targeted subjects are enrolled. 
 
 
1 Introduction 
This document is a clinical research protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research policies 
and procedures.  
1.1 
Background 
Does the novelty of Perampanels unique mechanism of action demonstrate anti-seizure efficacy, tumor-
cidal activity, and impact progressive impairment in neurocognitive function in patients with high-grade 
glioma? The major reasons why this study should be conducted include:  
1. Seizures commonly occur in 40% to 70% of patients with a primary brain tumor/glioma.3 
2. PER is FDA approved for adults with focal seizures.7, 11 


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3. PER has novel and unique mechanisms of action that include a primary effect on excitatory 
amino acids/AMPA.7,8,11 
4. Glutamate-induced excitotoxicity and disruption of intracellular communication hold a key role 
in the progression of disease in patients with glioblastoma (altered cysteine-glutamate transport).5, 
10, 11 
5. Glutamate induced over-activity is also suspected to influence high-grade glioma growth.5, 13 
6. Studies show that isocitrate dehydrogenase 1 (IDH1) mutant gliomas are more likely to cause 
seizures than IDH1 wild-type gliomas. The IDH1 mutation has been associated with 
tumorigenesis and has implications relative to differential treatment for primary brain cancer and 
prognosis.5 
 
Because of shared pathways, current anti-seizure drugs (ASDs) may affect treatment of patients with 
brain tumor, and various antitumor therapies are valuable for seizure management. Mechanisms involving 
cysteine-glutamine transporters, for example, regulate glutamate release and return through cellular 
exchange. One explanation for the close link between seizures and glioma evolution are elevated 
extracellular glutamate levels in the peri-glial and -neuronal space with ensuing over-activity of 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) 
receptors in both conditions. Recent studies point to the role of glutamate in excitotoxic damage resulting 
in seizures as well as maintenance and invasion of malignant glioma.  Blockade of this system could lead 
to pharmaceutical development that could affect the excitotoxicity of both high-grade glioma and brain-
tumor related epilepsy. Human trials of PER demonstrate safety and efficacy as an adjunctive therapy for 
adult patients with epilepsy. Limited information is available to demonstrate effectiveness in 
subpopulations associated with excessive glutamatergic stimulation such as brain tumor. PER, a FDA 
approved AMPA antagonist cleared for clinical use, may have immediate impact in 80,000 patients with 
brain tumors, and 3.4 million Americans with epilepsy (commonly co-morbid conditions). Anecdotal 
benefit has been reported in epilepsy patients with primary brain tumor and low dose PER (Vecht et al., 
2017). Cognitive decline frequently complicates treatment of patients with high-grade glioma and also in 
patients with epilepsy impairing overall QoL. 
 
1.2 
Investigational Agent 
Participants will be assigned to receive open label PER or an alternate ASD for 40 weeks. The route of drug 
delivery will be orally administered (PO). 
1.3 
Preclinical Data 
Because of shared pathways, current anti-seizure drugs (ASDs) may affect treatment of patients with 
brain tumor, and various antitumor therapies are valuable for seizure management. Mechanisms involving 
cysteine-glutamine transporters regulate glutamate release and return through cellular exchange. Blockade 
of this system could lead to pharmaceutical development that could affect the excitotoxicity of both high-
grade glioma and other brain-tumor related epilepsy syndromes. Limited information is available to 
demonstrate effectiveness in subpopulations associated with excessive glutamatergic stimulation such as 
brain tumor.  
1.4 
Clinical Data to Date 
Human trials of PER have demonstrated its efficacy as an adjunctive therapy for adult patients with 
epilepsy. Furthermore, Anecdotal improvements in both seizure frequency and tumor progression have 
been reported in epilepsy patients with primary brain tumors on low-dose PER (Vecht et al., 2017).  


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1.5 
Dose Rationale  
We will follow FDA recommendations for dosing of PER14. As such, patients will begin on PER 2 mg PO 
and increase in weekly intervals of 2 mg/week until reaching minimum dose of at least 4 mg/day and a 
maximum of 8 mg/day per patient. Alternative ASDs will be instituted according to best clinical practice 
and without excessive dosing beyond standard doses approved by the U.S. Food and Drug 
Administration. Participants will be assigned to receive open label PER or an alternate ASD for 40 weeks. 
The frequency of oral delivery of PER will be every 24 hours but no more frequently than every 12 hours. 
The route of drug delivery will be orally administered (PO). The otherASD will be chosen and be 
administered according to prior exposure to ASDs and according to best clinical practice. 
1.6 
Risks and Benefits 
Side effects associated with PER include anxiety, dizziness, headache, irritability, problems with 
coordination and balance, sleepiness, nausea, and weight gain. Serious side effects observed in clinical trials 
for patients taking PER include psychiatric and behavioral problems consisting of aggression, hostility, 
anger, and suicidal thoughts or behavior. In response to these psychiatric and behavioral risks that have 
been associated with patients beginning PER or taking increased doses of the drug, individuals who disclose 
history of prior felony conviction or who have violent behavior present in historical review will be excluded 
from the study. Additionally, any patients with clinically significant suicide risk (e.g., suicide attempt in 
the past 5 years or active suicidality as judged by the clinician) will be excluded from the study. Patients 
will be screened and monitored for changes in psychological status and behavior using the Neurological 
Disorders Depression Inventory for Epilepsy (NDDI-E), PHQ-9, Columbia-Suicide Severity Rating Scale 
(C-SSRS), and Quality of Life in Epilepsy Inventory (QOLIE-31) throughout the study. Patients’ status 
will be closely monitored by the physicians throughout the study with the low probability of developing 
these side effects outweighed by the benefits PER can provide to patients.  
 
2 Study Objectives 
Primary Objective 
Demonstrate the efficacy and safety of PER on seizure frequency in adult patients with biopsy-proven 
high-grade glioma and focal Epilepsy compared with alternate ASDs. 
 
 
Secondary Objective 
To assess the change in neurocognitive function and brain MRI progression over the course of PER 
treatment with a daily dose of 4 mg (up to -8mg) in patients with biopsy-proven high-grade glioma and 
focal epilepsy compared with alternate ASDs. 
To identify a biomarker-specific response to seizure-reduction in patients treated with PER in patients 
with a biopsy-proven high-grade glioma (i.e., IDH-mutant vs wildtype). 
 
 
3 Study Design 
3.1 
General Description 
This study is a prospective, open-label trial evaluating the effectiveness of PER on seizure frequency in 
adult patients with brain-tumor with seizures associated with high-grade glioma. Subjects (n = 20) will be 
male and female adults with a high-grade glioma recruited from Mayo Clinic in Jacksonville, Florida-
William Tatum, DO, (PI). Participants included will have had uncontrolled seizures, on a current regimen 
of at least 1 ASD manifesting ongoing focal seizures (including focal aware motor, focal impaired 


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awareness, and focal to bilateral tonic-clonic seizures), with at least 1 seizure/month during a 
retrospective 2-month baseline, relative to the screening visit.  
All patients included in the study will follow STUPP protocol (radiotherapy plus concomitant and 
adjuvant Temozolomide) for treatment of high-grade glioma in addition to best medical practice of 
comorbidities, as is standard-of-care15.   
3.2 
Number of Subjects 
20 
3.3 
Duration of Participation 
12 months 
3.4 
Primary Endpoints 
 
A. The number of patients with a high-grade glioma who achieve a > 50% reduction in focal 
seizures with PER 4 mg daily after failing 1 or more ASDs at 3 and 6 months.   
1. The overall survival of patients with high-grade glioma treated with PER at 3 months. 
2. Decline in neuropsychological function at 6 months. 
All comparisons will use intent to treat model for patients initiated or exiting PER therapy. In event of 
patients not surviving till 12 months, most recent data prior to death will be used for correlation.  
 
3.5 
Identification of Source Data 
Electronic medical records will be maintained via a RedCAP database for consecutive and prospective 
collection of data.  
 
Efficacy measures used in the study include: clinical assessments will include serial brain MRI, EEG, 
anti-seizure drug levels and subject self-assessment at clinical follow-up; Neurological Disorders 
Depression Inventory for Epilepsy (NDDI-E), assessment for screening of depression PHQ-9;Montreal 
Outcome Cognitive Assessment (MOCA);  Clinical Global Impression of Change (CGIC) score; 
Columbia –Suicide Severity Rating Scale. Seizure calendars performed at 2 months prior to initiation of 
therapy or adequate reliable historical baseline, and then monthly during study; and QOLIE-31, (see 
schedule of events for frequency of assessment). 
 
Anatomic brain MRI with perfusion scanning/gadolinium will be obtained at 3 months and then every 3 
months, to examine the correlated progression of brain tumor, or the absence of tumor. Laboratory studies 
will be employed before and after PER initiation. EEG will be obtained at baseline and at 3 months and 
12 months to identify changes in background activity (e.g. diffuse slowing) and epileptiform discharges to 
correlate with focal seizure presence vs absence. Neuropsychological batteries will determine the 
presence or absence of significant anxiety, depression or cognitive changes over time and quality of life 
inventory will be obtained at the beginning, intermediate and end of the trial. 
 
The following source data will be directly recorded on the Case Report Form (CRF):  
● A comprehensive History and Physical examination and Neurological examination will occur at 
the initial screening/baseline. 
● Clinical visitation will occur at screening/baseline, 3, 6, and 12 months. 


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Survey questionnaires will be obtained at baseline, 3, 6, 9, and 12 months. The following source 
data will not be directly collected in the Case Report Form (CRF), but will be captured in 
supportive documentation (study source documents, EMR): 
● Laboratory studies will be employed at baseline and at each clinical visit after PER initiation.   
● Brain tumor tissue will be assessed for the usual molecular markers (i.e., IDH-mutant vs 
wildtype, MGMT methylation, ARX). 
● 12-lead ECG will be obtained at baseline and as clinically indicated 
● Anatomic brain MRI with and without gadolinium will be obtained at baseline and follow-up 
brain MRI at 3 months and 6 months during PER use. 
● EEG will be obtained at baseline and at 3 months and 12 months to identify changes in background 
activity (e.g. diffuse slowing) and epileptiform discharges to correlate with focal seizure presence 
vs absence.  
● Neuropsychological batteries will be obtained at baseline, 3 months, and 6 months to determine 
the presence or absence of significant neurocognitive decline.   
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
1.  The subject, or the subject’s legally acceptable representative is willing to participate in a 
clinical trial, provides written informed consent, and subject provides written assent, as 
required by the Mayo Clinic Institutional Review Board (IRB) policy involving human 
subjects. In the event of subject lacking the capacity or losing the ability to consent, consent 
will be deferred to subject’s legally acceptable representative 
2.  Subjects that meet the following diagnostic criteria: 
a. Patients with established clinical diagnoses of biopsy-proven high-grade glioma (Grade II 
or above) and epilepsy refractory to at least 1, drug with a seizure frequency of at least 1 
seizure episode per 3-months prior to baseline visit. 
3. Subjects with body weight of ≥ 40 kg and ≤ 125 kg at screening. 
4. Adults age 18 and older. 
 
4.2 
Exclusion Criteria 
1. Subject has serious cardiac, respiratory, renal, gastrointestinal, hematologic, or other medical 
condition as determined by the investigator to potentially interfere with the study 
2. Subjects with glioblastoma not following Stupp protocol for treatment of glioblastoma. 
3. History of status epilepticus in the 6 months prior to screening or a history of seizure clusters 
progressing to status epilepticus. 
4. Past medical history of drug and/or alcohol abuse  
5. Pregnant or breast-feeding 
6. Subjects treated with PER prior to baseline  
7. Prior felony conviction disclosed by the patient or previously stated in medical record. 
8. History of violent behavior 
9. Clinically significant laboratory abnormality at screening or baseline visits, as determined by the 
investigators 
10. Use of an investigational drug or device within 20 days prior to treatment Day 1 
11. Repeated radiation therapy for tumor regrowth 
12. Subjects that plan to undergo tumor resection on or after baseline visit 
13. Uncontrolled psychiatric disorder at baseline 


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14. Subjects who report active suicidal attempts or suicidality including subjects with a history of 
suicide attempts or suicidality determined to be clinically significant by investigators at screening. 
 
4.3 
Subject Recruitment, Enrollment and Screening 
Subjects (n = 20), will be male and female adults with a high-grade glioma recruited from Mayo 
Clinic in Jacksonville, Florida- William Tatum, DO, (PI). 10 subjects will be enrolled into an 
adjunctive Perampanel and other ASDs group, and 10 subjects will receive only alternative ASDs. 
There will be a 6-month recruitment period for screening and enrollment. The treating physician 
will decide, based on best medical practice, which patients are candidates for adjunctive 
Perampanel and other ASDs, or only alternative ASDs. Patients taking Perampanel will begin their 
titration phase upon enrollment.  
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
During this study, medical history will be taken periodically as mentioned in the schedule of events. 
Physical examinations and neurological examinations will be conducted every study visit except for 
the 4-week flexible titration (2 mg/week, up to 8mg) visit. Protocol directed screening for adverse 
events will be performed at each visit.  
 
The Principal and Co-Investigator as well as Study Coordinator are responsible for individual safety 
monitoring. Stopping or interruption of the study may be necessary if a significant number of study 
participants develop unexpected clinical flaring or significant worsening that appears temporally 
linked with PER administration to be used for the indication outlined in this protocol. 
 
The Principal Investigator and/or Investigator will review all adverse event reports to determine if 
specific reports need to be made to the IRB and FDA. For this study, all SAEs or possible UPIRTSOs 
will be reported to the IRB. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
All study data will be stored in the password protected REDCAP database. Access to the REDCAP 
database will be limited to the Principal Investigator, Investigators and Statistician. Paper documents, 
including patient seizure logs/diaries and case report forms, will be kept in a locked cabinet with 
access available only to the Investigators and Study Coordinator. 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of the 
study for a period of 2 years after completion of the study.  These will include subject case histories 
and regulatory documents. All study data will be collected and managed using REDCap electronic 
data capture tools hosted at the Mayo Clinic. REDCap (Research Electronic Data Capture) is a secure, 
web-based application designed to support data capture for research studies, providing 1) an intuitive 
interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 
3) automated export procedures for seamless data downloads to common statistical packages; and 4) 
procedures for importing data from external sources.  


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5 Study Drug  
5.1 
Description 
PER is a noncompetitive AMPA glutamate receptor antagonist.  
5.2 
Treatment Regimen 
Patients will begin on PER 2 mg PO and increase in weekly intervals of 2 mg/week until reaching 
minimum dose of at least 4 mg/day and a maximum of 8 mg/day per patient. Alternative ASDs will 
be instituted according to best clinical practice and without excessive dosing beyond standard doses 
approved by the U.S. Food and Drug Administration. Participants will be assigned to receive open 
label PER or an alternate ASD for 40 weeks. The frequency of oral delivery of PER will be every 
24 hours but no more frequently than every 12 hours. The route of drug delivery will be orally 
administered (PO). The other ASDs will be chosen and be administered according to prior 
exposure to ASDs and according to best clinical practice. 
5.3 
Method for Assigning Subjects to Treatment Groups 
Participants will be assigned to receive: 
Group A: open label arm of adjunctive PER (study drug) for patients with seizures treated with at 
least 1 ASD administered in escalating divided doses of 2 mg/week to 4 mg daily with flexible 
dosing to 8 mg/day by 4 weeks. Subjects must undergo forced titration of 2 mg/week and be able to 
tolerate 4 mg to continue in the study. Concomitant ASD will be utilized according to best clinical 
practice.  
or  
Group B: continued open label treatment for patients with seizures treated with at least 1 ASD, as 
per best medical practice, without the use of PER. 
5.4 
Preparation and Administration of Study Drug 
PER (to be used for the indication outlined in this protocol) will be shipped by Eisai to the Mayo 
Clinic research pharmacy in Florida. Upon receipt, an inventory will be performed, and a drug 
receipt log filled out by the person accepting the shipment. Designated study staff will count 
and verify that the shipment contains all the items noted on the shipping invoice. Any 
discrepancies, damaged or unusable drug in any given shipment will be documented in the 
study files. The Investigators must be notified immediately of any discrepancies, damages 
or unusable products that are received. 
5.5 
Subject Compliance Monitoring 
Anti-seizure drug levels will be evaluated at clinical follow-up (see study schema for frequency of 
assessment). 
5.6 
Prior and Concomitant Therapy 
Concomitant therapy will allow 0-3 concomitant ASDs. No specific drugs will be disallowed; 
concomitant ASDs and non-ASDs (e.g. narcotics, benzodiazepines, and barbiturates) will serve as 
exclusionary therapies when deemed clinically relevant according to best clinical practice. 
5.7 
Packaging 
Study drug will be packaged according to the manufacturer’s approval for use by the U.S. FDA. 


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Bottles containing 20 tablets of 4 mg dosages of PER are anticipated. 
Study drug will be shipped separately by subject-specific packages. 
The contents of the package will include study drug and associated approved labelling. 
5.8 
Masking/Blinding of Study  
This is an open-label study.  
5.9 
Receiving, Storage, Dispensing and Return 
Study drug will be received by the principal investigator and stored in a secured location. Unused 
medication will be returned to the study institution and returned to Eisai Pharmaceuticals. 
5.9.1 Receipt of Drug Supplies 
Perampanel (to be used for the indication outlined in this protocol) will be shipped by Eisai to the 
Mayo Clinic research pharmacy in Florida. Upon receipt, an inventory will be performed and a 
drug receipt log filled out by the person accepting the shipment. Designated study staff will count 
and verify that the shipment contains all the items noted on the shipping invoice. Any 
discrepancies, damaged or unusable drug in any given shipment will be documented in the study 
files. The investigators must be notified immediately of any discrepancies, damages or unusable 
products that are received. 
5.9.2 Storage 
Perampanel will be stored at Mayo Clinic research pharmacy in Florida. Medication will be 
stored at room temperature (between 68 and 77º F) with limited exposure to heat, moisture, and 
light.  
5.9.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug assigned, drug 
dispensed, drug returns, and drug remaining.  This reconciliation will be logged on the 
drug reconciliation form and signed and dated by the study team. 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug dispensed, 
drug returns, and drug remaining.  This reconciliation will be logged on the drug reconciliation form, 
signed and dated.  Any discrepancies noted will be documented and investigated, prior to return or 
destruction of unused study drug.  Drug destroyed on site will be documented in the study files. 
6 Study Procedures 
6.1 
Visit 1 (Screening)  
Informed consent is received, and a review of study inclusion/exclusion criteria is conducted, 
Medical history and physical examination are performed. Neurological examination is performed. 
Urine Pregnancy test is performed. Seizure Diary is reviewed.  
6.2 
Visit 2 (Baseline) 
CBC, CMP, and ASD trough levels are evaluated. An MRI of the brain with volume measurement 
is completed. An EEG is taken if there has not been one completed within 3 months of the visit.  


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Neuropsychological baseline visit. Seizure frequency is assessed. PHQ-9, NDDI-E, MOCA, CGIC, 
C-SSRS and QOLIE-31 are completed.  
 
Screening and Baseline are preferred to be on the same day, but can occur separate days if needed. 
All screening and baseline events will be completed before Visit 3. 
 
6.3 
Visit 3  
Seizure frequency is assessed. Seizure Diary is reviewed. PHQ-9, NDDI-E, MOCA, CGIC, C-
SSRS and QOLIE-31 are completed. Dispense study drug to participants in Group A (PER arm). 
 
6.4 
Visit 4  
Seizure frequency is assessed. Seizure Diary is reviewed. PHQ-9, NDDI-E, MOCA, CGIC, C-
SSRS and QOLIE-31 are completed. Dispense study drug to participants in Group A (PER arm). 
 
6.5 
Visit 5  
Seizure frequency is assessed. Seizure Diary is reviewed. CBC, CMP, and ASD trough levels are 
evaluated. MRI is reviewed. Seizure frequency is assessed. PHQ-9, NDDI-E, MOCA, CGIC, C-
SSRS and QOLIE-31 are completed. Dispense study drug to participants in Group A (PER arm).  
 
6.6 
Visit 6 
Medical history and physical examination are performed. Neurological examination is performed. 
Seizure Diary is reviewed. Seizure frequency is assessed. PHQ-9, NDDI-E, MOCA, CGIC, C-
SSRS and QOLIE-31 are completed. Dispense study drug to participants in Group A (PER arm).  
 
6.7 
Visit 7 
Visit 7 will be completed by telephone call. Seizure frequency is assessed. Seizure Diary is 
reviewed. PHQ-9, NDDI-E, CGIC, C-SSRS and QOLIE-31 are completed by asking the participant 
the questions verbally. The participant will be asked about medical history. 
 
6.8 
Visit 8 
Seizure frequency is assessed. Seizure Diary is reviewed. Medical history and physical examination 
are performed. Neurological examination is performed. CBC, CMP, and ASD trough levels are 
evaluated. An MRI of the brain with volume measurement is completed. An EEG is completed. 
PHQ-9, NDDI-E, MOCA, CGIC, C-SSRS and QOLIE-31 are completed. Neuropsychological 
follow-up assessment. Dispense study drug to participants in Group A (PER arm).  
6.9 
Visit 9 
Visit 9 will be complete by telephone call. Seizure Diary is reviewed Seizure frequency is assessed.. 
PHQ-9, NDDI-E,CGIC, C-SSRS and QOLIE-31 are completed by asking the participant the 
questions verbally. The participant will be asked about medical history.   
 
6.10 
Visit 10 
Visit 10 will be complete by telephone call. Seizure frequency is assessed. Seizure Diary is 
reviewed. PHQ-9, NDDI-E, CGIC, C-SSRS and QOLIE-31 are  
completed by asking the participant the questions verbally. The participant will be asked about 
medical history.   
 
6.11 
Visit 11 
Seizure frequency is assessed. Seizure Diary is reviewed. Medical history and physical examination 
are performed. Neurological examination is performed. An MRI of the brain with volume 


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measurement is completed. An EEG is completed. PHQ-9, NDDI-E, MOCA, CGIC, C-SSRS and 
QOLIE-31 are completed. Neuropsychological follow-up assessment. Dispense study drug to 
participants in Group A (PER arm). 
 
6.12 
Visit 12 
Visit 12 will be complete by telephone call. Seizure Diary is reviewed. Seizure frequency is 
assessed. PHQ-9, NDDI-E, CGIC, C-SSRS and QOLIE-31 are completed by asking the participant 
the questions verbally. The participant will be asked about medical history.   
 
6.13 
Visit 13 
Visit 13 will be complete by telephone call. Seizure frequency is assessed. Seizure Diary is 
reviewed. PHQ-9, NDDI-E, CGIC, C-SSRS and QOLIE-31 are completed by asking the participant 
the questions verbally. The participant will be asked about medical history. 
 
6.14 
Visit 14 
Visit 14 will be complete by telephone call. Seizure frequency is assessed. Seizure Diary is 
reviewed. PHQ-9, NDDI-E, CGIC, C-SSRS and QOLIE-31 are completed by asking the participant 
the questions verbally. The participant will be asked about medical history. 
 
6.15 
Visit 15 
Medical history and examination are performed. Neurological examination is performed. Seizure 
Diary is reviewed. CBC, CMP, and ASD trough levels are evaluated. An EEG is ordered. MRI is 
reviewed. Seizure frequency is assessed. PHQ-9, NDDI-E, MOCA, CGIC, C-SSRS and QOLIE-
31 are completed.  Neuropsychological follow-up assessment. 
 


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Schedule of Events1 
 
Procedure 
Screening & 
Baseline Visits4 
Titration Phase2 
Treatment Phase2, 8, 9 
Visit Day 
Day  
0-6 
 
Day  
7 
Day 
14 
 
Day 
21 
Day 
30 
Day 
60 
Day  
90 
Day 
120 
Day 
150 
Day 
180 
Day 
210 
Day 
240 
Day 
270 
Day 
300 
Visit Number 
14 
24 
3 
4 
5 
6 
78 
8 
98 
108 
11 
128 
138 
148 
15 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
Exclusion Criteria 
check5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical 
History 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological 
Examination 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
Physical 
Examination 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
Clinical Labs1,3 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Historical 
Anatomical Brain 
MRI review7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anatomical Brain 
MRI1, 7  
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Historical EEG 
review7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard EEG1, 7 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Neuropsychology 
visit 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
NDDI-E 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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PHQ-9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MOCA 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
CGIC 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QOLIE-31 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Seizure 
Diary 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
Seizure Diary 
Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
Drug6 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
Study Drug 
Accountability6 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
1Clinical assessments (MRI, EEG, clinical labs, and anti-seizure drug levels) 
performed before or after scheduled follow-up if deemed clinically necessary 
outside of the study protocol. 
2 ±3-day tolerance window 
3CMP to include the following blood tests: albumin, blood urea nitrogen, 
calcium, carbon dioxide, chloride, creatinine, glucose, potassium, sodium, total 
bilirubin and protein, and liver enzymes (alanine aminotransferase, alkaline 
phosphatase, and aspartate aminotransferase). 
4 Screening and Baseline are preferred to occur consecutively on the same day 
but, if this is not feasible for the patient, the Baseline Visit procedures can 
occur any time after screening and before Day 7..All screening and baseline 
results must be available for review prior to dispensing study drug on day 7. 
5 Any development to the patient’s history affecting their standing within the inclusion and exclusion criteria will be continually assessed throughout the study. 


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6As needed and only for PER arm.  
 
7 Baseline MRI and EEG performed only if one has not been performed within three months prior to baseline. , otherwise historical MRI  and/or EEG will be 
reviewed .  
 
8Visits 7, 9, 10, 12, 13, and 14 will be completed as Phone Visits (PV).  
 
9±7-day tolerance window 


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7 Statistical Plan 
7.1 
Sample Size Determination 
 
A sample size of 20 patients is targeted as part of a pilot study to determine feasibility for a larger 
prospective multi-center trial. The sample size is targeted to achieve adequate enrollment and determine 
the likelihood of supporting a larger study.  
This study is not designed to be powered to determine significance for statistical significance of 
effectiveness.  
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Statistical analysis will include Student T-test, Chi-square for categorical differences. An interim analysis 
will be performed when half of subjects are enrolled. 
 
Handling of Missing Data 
 
 
Study data will be collected and managed using REDCap electronic data capture tools hosted at 
Mayo Clinic. All data requested on the Case Report Form (CRF) will be recorded for each 
participant. A standardized CRF will be generated by REDCap. For any data query, the Principal 
Investigator and Investigators will meet to clarify the data queried and make corrections based on 
consensus. Once the study is completed, the Principal Investigator will randomly select 3 
participants and compare the data documented for each on the CRF with what is entered into the 
REDCap database. If there is any discrepancy, the Principal Investigator and/or Investigators will 
cross-reference all 20 patients to ensure accuracy. 
 
Primary Hypothesis: We hypothesize that perampanel will lead to a significant reduction in 
seizure frequency for adult patients with brain tumor-related seizures associated with high-grade 
glioma. 
We will compare seizure frequency before and 3 months after treatment with monotherapy and 
adjunctive PER and use descriptive statistics to demonstrate differences in responders. A P-value 
< 0.05 will be used to reflect statistical significance. 
 
Secondary Hypothesis 1: We hypothesize the progression of brain tumor (comparing 4 and 8 
mg/d of perampanel) based upon fusion by comparing baseline brain MRI and MRI at 12 months 
will be less for IDH-mutants. 
We hypothesize there will be minimal or no change in neurocognitive function from 0 to 3 
months on Montreal Outcome Cognitive Assessment (MOCA; higher scores indicating greater 
function); and the Clinical Global Impression of Change (CGIC; scores from 1 to 7, with lower 
scores indicating greater improvement and a score of 4 indicating no change). 
 
Chi-square and Student T-test will be used to measure differences in assessment and change 
during the study period. A P-value < 0.05 will be considered significant. 


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Interim Analysis 
 
An interim analysis will be performed when half of subjects are enrolled to assess the safety and efficacy 
of the study.  
7.3 
Subject Population(s) for Analysis 
 
Analysis of the protocol-compliant population will be conducted. 3, 6, and 12 month evaluability will be 
assessed based upon the severity of the glioma disease process associated with brain tumor-related focal 
seizures and risk of imminent death from high-grade malignant primary brain tumor. 
 
 
 
 
 


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8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
● Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
● Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
● Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
● death 
● life threatening adverse experience 
● hospitalization 
● inpatient, new, or prolonged; disability/incapacity 
● persistent or significant disability or incapacity 
● birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
 
Adverse Event Reporting Period 


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For this study, the study treatment follow-up period is defined as 12 months following the last 
administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the sponsor-investigator should instruct each subject to report, to the sponsor-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality will be documented as an adverse event if the conditions of the 
laboratory are identified as outside the normal expected range for the parameter and in the 
investigators opinion requires an intervention (e.g., repeat testing, consequences on the disease 
state, exhibit evidence of organ toxicity, or necessitate dosage reduction, discontinuation of study 
drug, or additional follow-up).  
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances:  
● Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
● Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
● Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 


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8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, also in the appropriate adverse event 
section of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should be recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriate action necessary 
to protect the study participant and then complete the Study Adverse Event Worksheet and log.  
The sponsor-investigator will evaluate the event and determine the necessary follow-up and 
reporting required. 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA 
The sponsor-investigator will report to the sponsor and the FDA all unexpected, serious 
suspected adverse reactions according to the required IND Safety Reporting timelines, formats 
and requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to 
suggest a causal relationship between the study drug/placebo and the adverse event, will be 
reported as a serious suspected adverse reaction.  This will be reported to the FDA on FDA Form 
3500A, no later than 7 calendar days after the sponsor-investigator’s initial receipt of the 
information about the event. 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious 
suspected adverse reaction.  This will be reported to the FDA on FDA Form 3500A, no later than 
15 calendar days after the sponsor-investigator’s initial receipt of the information about the 
event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those 
listed in the protocol or product insert will be reported as a serious suspected adverse reaction.  


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This will be reported to the FDA on FDA Form 3500A no later than 15 calendar days after the 
sponsor-investigator’s initial receipt of the information about the event. 
 
Findings from other studies in human or animals that suggest a significant risk in humans 
exposed to the drug will be reported.  This will be reported to the FDA on FDA Form 3500A, no 
later than 15 calendar days after the sponsor-investigators initial receipt of the information about 
the event. 
8.4 
Stopping Rules  
 
The Principal and Co-Investigators as well as Study Coordinator are responsible for individual 
safety monitoring. Stopping or interruption of the study may be necessary if a significant number 
of study participants develop unexpected clinical flaring or significant worsening, as judged by 
the principal investigator, study coordinator or sponsor, appears temporally linked with 
Perampanel administration to be used for the indication outlined in this protocol. 
 
The Principal Investigator and/or Investigators will review all adverse event reports to determine 
if specific reports need to be made to the IRB and FDA. For this study, all SAEs or possible 
UPIRTSOs will be reported to the IRB. 
8.5 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  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  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
● What protected health information (PHI) will be collected from subjects in this study? 
● Who will have access to that information and why? 
● Who will use or disclose that information? 
● The rights of a research subject to revoke their authorization for use of their PHI.  
In the event a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  
For subjects that have revoked authorization to collect or use PHI, attempts should be made to 
obtain permission to collect at least vital status (long term survival status that the subject is alive) 
at the end of their scheduled study period. 


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9.2 
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. 
9.3 
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.  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 use “white-out” for errors.  For clarification 
of illegible or uncertain entries, print the clarification above the item, then initial and date it.  If 
the reason for the correction is not clear or needs additional explanation, neatly include the 
details to justify the correction. 
 
Data Management 
 
Study data will be collected and managed using REDCap electronic data capture tools hosted at 
Mayo Clinic. All data requested on the Case Report Form (CRF) will be recorded for each 
participant. A standardized CRF will be generated by REDCap. For any data query, the Principal 
Investigator and Investigators will meet to clarify the data queried and make corrections based on 
consensus.  
 
Data Security and Confidentiality 
 
Study subjects will be consented and evaluated within the Department of Neurology at Mayo 
Clinic Florida by designated study personnel. All study data will be stored in the password 
protected REDCAP database. Access to the REDCAP database will be limited to the Principal 
Investigator, Investigators and Statistician. Paper documents, including patient logs/diaries and 
case report forms, will be kept in a locked cabinet with access available only to the Investigators 
and Study Coordinator. 
 
Data Quality Assurance 
 
Once the study is completed, the Principal Investigator will randomly select 3 participants and 
compare the data documented for each on the CRF with what is entered into the REDCap 
database.  


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Data Clarification Process 
 
If there is any discrepancy, the Principal Investigator and/or Investigators will cross-reference all 
20 patients to ensure accuracy. 
 
9.4 
Records Retention 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study for a period of 2 years after completion of the study.  These will include subject case 
histories and regulatory documents. All study data will be collected and managed using REDCap 
electronic data capture tools hosted at the Mayo Clinic. REDCap (Research Electronic Data 
Capture) is a secure, web-based application designed to support data capture for research studies, 
providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for importing data from external 
sources. 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. 
 
Subject-specific data and Case Report Forms will be coded using confidential and anonymous ID 
numbers and subject names and other identifiable information (SS, MRN, DOB) will not appear 
on any reports, publications, or other disclosures of clinical study outcomes.  
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after shipment and delivery of the drug for investigational use is 
discontinued and the FDA has been so notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717   
Whichever is longer. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 
 


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DATA AND SAFETY MONITORING PLAN (DSMP) 
 
1. Subject Safety 
During this study, medical history will be taken every study visit with the exception of the 3 
Month visit. Physical examinations and neurological examinations will be conducted every study 
visit with the exception of the 4-week flexible titration to 8 mg/d (2 mg q 2 weeks) visit. Protocol 
directed screening for adverse events will be performed at each visit.  
 
The Principal and Co-Investigator as well as Study Coordinator are responsible for individual 
safety monitoring. Stopping or interruption of the study may be necessary if a significant number 
of study participants develop unexpected clinical flaring or significant worsening that appears 
temporally linked with perampanel administration to be used for the indication outlined in this 
protocol. 
 
The Principal Investigator and/or Investigator’s will review all adverse event reports to 
determine if specific reports need to be made to the IRB and FDA. For this study, all SAEs or 
possible UPIRTSOs will be reported to the IRB. 
 
2. Data Integrity 
Study data will be collected and managed using REDCap electronic data capture tools hosted at 
Mayo Clinic. All data requested on the Case Report Form (CRF) will be recorded for each 
participant. A standardized CRF will be generated by REDCap. For any data query, the Principal 
Investigator and Investigators will meet to clarify the data queried and make corrections based on 
consensus. Once the study is completed, the Principal Investigator will randomly select 3 
participants and compare the data documented for each on the CRF with what is entered into the 
REDCap database. If there is any discrepancy, the Principal Investigator and/or Investigators will 
cross-reference all 20 patients to ensure accuracy.  
 
3. Subject Privacy 
Study subjects will be consented and evaluated within the Department of Neurology at Mayo 
Clinic Florida by designated study personnel. 
 
4. Data Confidentiality 
All study data will be stored in the password protected REDCAP database. Access to the 
REDCAP database will be limited to the Principal Investigator, Investigators and Statistician. 
Paper documents, including patient logs/diaries and case report forms, will be kept in a locked 
cabinet with access available only to the Investigators and Study Coordinator. 
 
5. Product Accountability 
perampanel (to be used for the indication outlined in this protocol) will be shipped by Eisai to the 
Mayo Clinic research pharmacy in Florida. Upon receipt, an inventory will be performed, and a 
drug receipt log filled out by the person accepting the shipment. Designated study staff will 
count and verify that the shipment contains all the items noted on the shipping invoice. Any 
discrepancies, damaged or unusable drug in any given shipment will be documented in the study 
files. The Investigators must be notified immediately of any discrepancies, damages or unusable 
products that are received. 


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6. Study Documentation 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study for a period of 2 years after completion of the study.  These will include subject case 
histories and regulatory documents. All study data will be collected and managed using REDCap 
electronic data capture tools hosted at the Mayo Clinic. REDCap (Research Electronic Data 
Capture) is a secure, web-based application designed to support data capture for research studies, 
providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for importing data from external 
sources. 
 
7. Study Coordination 
The Principle Investigator and study coordinator in Florida shall communicate the procedures 
and protocols to all participating investigators and track the number of consented subjects on a 
biweekly basis until accrual targets are met or until the study ends.  
 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, 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 compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
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.  This 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 Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
 


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A subject’s capacity for consent will be determined by the attending physician and clinical team 
per standard of care assessments in conjunction with the research staff. Patients will continue to 
be assessed for their ability to consent and will be re-consented when deemed appropriate. 
 
The study staff will not obtain assent. If a patient lacks the capacity to consent for themselves, 
they will likely be unable to fully understand the study procedures. 
 
The Legally Authorized Representative (LAR) will be identified by the attending physician 
and/or case manager in accordance with standard of care practices. Obtaining consent from the 
LAR will follow the same guidelines as if the patient themselves were being consented. 
12 Study Finances 
12.1 Funding Source 
 
Feasibility Estimation sent separately and developed by the Office of Sponsored Projects, Mayo Clinic 
Florida. 
13 Publication Plan 
Study will be conducted with the intent of the publication of findings in Neurology in 2020 or 
2021.  
14 References 
 
1.Higgins GA et al. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the 
rodent. Neuropharmacology. 2004;46:907–17. 
2.Kolker S et al. NMDA receptor activation and respiratory chain complex V inhibition contribute to 
neurodegeneration in D-2-hydroxyglutaric aciduria. Eur J Neurosci 2002;16:21–8. 
3.Neal A et al. Postoperative seizure control in patients with tumor-associated epilepsy. Epilepsia 2016;57:1779–88. 
4.Huberfeld G, Vecht CJ. Seizures and gliomas — towards a single therapeutic approach. Nat Rev Neurol 
2016;12:204–16. 
5.Dang L et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462:739–44. 
6.Avila EK et al. Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials. 
Neuro Oncol 2017;19:12–21. 
7.Rosche et al.  Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and 
without MGMT promotor methylation. Fortschr Neurol Psychiatr, 2015; 83(5):286-9.  
8.Dang L et al. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol 
2016;27:599–608. 
9.Toledo M et al. Epileptic features and survival in glioblastomas presenting with seizures. Epilepsy Res 
2017;130:1–6. 
10.Chen H et al. Mutant IDH1 and seizures in patients with glioma. Neurology 2017;88:1805–13. 
11.Vecht CJ et al.  Seizure response to perampanel in drug-resistant epilepsy with gliomas: early observations. J 
Neurooncol. DOI 10.1007/s11060-017-2473-1. 
12.Vecht et al., Seizures and Anticonvulsants in Brain Tumors: Frequency, Mechanisms and Anti-Epileptic 
Management. Current Pharmaceutical Design, 2017, 23, 1-25. 
13.Onco-Epilepsy: more than tumor and seizures. Mayo Clinic Proceedings. 2018 (in press). 
14. Faulkner, Michele A. "Perampanel: a new agent for adjunctive treatment of partial seizures." American journal 
of health-system pharmacy 71.3 (2014): 191-198. 
15. Stupp, Roger, et al. "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma." New 
England Journal of Medicine 352.10 (2005): 987-996. 
 


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15 Attachments 
 
Appendix: 
Assessment 1: The NDDI-E is a brief screening tool composed of 6 questions that can be used to rapidly 
identify patients with clinical depression. The measure removes the potential effect of confounding 
variables (such as medication effects and cognitive problems) that may influence the diagnosis of 
depression in patients with epilepsy. A score of greater than 15 has a Cut-off value > 15 for screen failure. 
 
Assessment 2: PHQ-9: a brief depression severity measure 
 
 


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Assessment 3: Columbia-Suicide Severity Rating Scale (C-SSRS) used for assessment of suicidality 
during the study by the patient duration/drug exposure to perampanel. 
 
 


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Assessment 4: MOCA. Score ≥26 is normal; scores <26 indicate mild cognitive impairment and 
possible dementia 
 
 
 


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Assessment 5: Clinician’s Global Impression of Change 
 
 
 
 
 
 
 
 
 
 


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Assessment 6: QOLIE-
31 
 
Cramer JA, Arrigo C, Van Hammee G, Bromfield EB for the N132 Study Group. Comparison between 
the QOLIE-31 and the derived QOLIE-10 in a clinical trial of levetiracetam. Epilepsy Res 2000; 41: 
29-38  
INSTITUTION 
 
 
By: 
_____________________________ 
Print:  _____________________________ 
Title: 
_____________________________ 


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Date: 
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