A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-40411813 as Adjunctive Therapy in Subjects With Focal Onset Seizures With Suboptimal Response to Levetiracetam or Brivaracetam
Phase: PHASE2
Conditions: Focal Onset Seizures
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  17 November 2022
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to
Evaluate the Efficacy, Safety, and Tolerability of JNJ-40411813 as Adjunctive Therapy in
Subjects with Focal Onset Seizures with Suboptimal Response to Levetiracetam or
Brivaracetam
Short Title:
A study to investigate JNJ-40411813
in combination with levetiracetam or brivaracetam in epilepsy.
Protocol 40411813EPY2001; Amendment INT-4; Phase 2a
JNJ-40411813
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR
Part 312)
EudraCT NUMBER: 2020-003698-24.
Status: 
Approved
Date: 
17 November 2022
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-229481, 7.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the
Company customarily holds close and treats as confidential. The information is being provided under the assurance
that the recipient will maintain the confidentiality of the information under applicable statutes, regulations, rules,
protective orders or otherwise.
NCT04836559

JNJ-40411813
Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date:  17 November 2022
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 6
1.
PROTOCOL SUMMARY..................................................................................................................... 9
1.1. 
Synopsis........................................................................................................................................... 9
1.2. 
Schedule of Activities (SoA)........................................................................................................... 16
2.
INTRODUCTION................................................................................................................................ 19
2.1. 
Study Rationale.............................................................................................................................. 19
2.2. 
Background.................................................................................................................................... 19
2.2.1. 
Nonclinical Studies ..................................................................................................................... 19
2.2.2. 
Clinical Studies ........................................................................................................................... 21
2.2.3. 
Brivaracetam............................................................................................................................... 24
2.2.4. 
Levetiracetam ............................................................................................................................. 24
2.3. 
Benefit/Risk Assessment ............................................................................................................... 25
2.3.1. 
Risks for Study Participation....................................................................................................... 25
2.3.2. 
Benefits for Study Participation .................................................................................................. 26
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 27
3.
OBJECTIVES AND ENDPOINTS..................................................................................................... 27
4.
STUDY DESIGN ................................................................................................................................ 29
4.1. 
Overall Design................................................................................................................................ 29
4.2. 
Scientific Rationale for Study Design............................................................................................. 31
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 35
4.3. 
Justification for dose ...................................................................................................................... 36
4.4. 
End of Study Definition................................................................................................................... 37
5.
STUDY POPULATION ...................................................................................................................... 37
5.1. 
Inclusion Criteria ............................................................................................................................ 37
5.2. 
Exclusion Criteria ........................................................................................................................... 40
5.3. 
Lifestyle Considerations................................................................................................................. 42
5.3.1. 
Meals and Dietary Restrictions................................................................................................... 43
5.3.2. 
Caffeine, Alcohol, and Tobacco.................................................................................................. 43
5.3.3. 
Activity......................................................................................................................................... 43
5.4. 
Screen Failures.............................................................................................................................. 43
6.
STUDY INTERVENTIONS................................................................................................................. 44
6.1. 
Study interventions Administered .................................................................................................. 44
6.2. 
Preparation, Handling, and Storage............................................................................................... 45
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 46
6.4. 
Study Intervention Compliance...................................................................................................... 48
6.5. 
Concomitant Therapy..................................................................................................................... 48
6.6. 
Recording of drug intake; overview................................................................................................ 50
6.7. 
Intervention After the End of the Study.......................................................................................... 51
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 52
7.1. 
Safety Data Review........................................................................................................................ 52
7.2. 
Completion ..................................................................................................................................... 52
7.3. 
Participant Discontinuation/Withdrawal from the Study................................................................. 52
7.4. 
Protocol Stopping Criteria .............................................................................................................. 53
7.5. 
Withdrawal from the Use of Research Samples............................................................................ 53
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Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  17 November 2022
7.6. 
Lost to Follow-up............................................................................................................................ 54
8. 
STUDY ASSESSMENTS AND PROCEDURES............................................................................... 54
8.1. 
Overview ........................................................................................................................................ 54
8.2. 
Study procedures........................................................................................................................... 55
8.2.1. 
Screening.................................................................................................................................... 55
8.2.2. 
Baseline period........................................................................................................................... 56
8.2.3. 
Treatment Period........................................................................................................................ 57
8.2.4. 
Follow-up/Early Withdrawal Visit ................................................................................................ 58
8.3. 
Efficacy Assessments .................................................................................................................... 58
8.3.1. 
Seizure count.............................................................................................................................. 58
8.3.2. 
Secondary Evaluations............................................................................................................... 59
8.3.2.1. 
........................................................................................................ 59
8.4. 
Safety Assessments....................................................................................................................... 59
8.4.1. 
Physical Examination.................................................................................................................. 59
8.4.2. 
Vital Signs................................................................................................................................... 60
8.4.3. 
Electrocardiogram (ECG) ........................................................................................................... 60
8.4.4. 
Clinical Safety Laboratory Assessments .................................................................................... 60
8.4.5. 
Suicidal Risk Monitoring ............................................................................................................. 61
8.5. 
Pharmacokinetics........................................................................................................................... 61
8.6. 
Genetics......................................................................................................................................... 62
8.7. 
Biomarkers..................................................................................................................................... 63
8.8. 
Adverse Events and Serious Adverse Events ............................................................................... 63
8.8.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 64
8.8.2. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 64
8.8.3. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 64
8.8.4. 
Pregnancy................................................................................................................................... 65
8.9. 
Treatment of Overdose .................................................................................................................. 65
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 66
9.1. 
Sample Size Determination ........................................................................................................... 66
9.2. 
Efficacy analyses ........................................................................................................................... 66
9.2.1. 
Primary........................................................................................................................................ 66
9.2.2. 
Secondary and exploratory......................................................................................................... 67
9.3. 
PK and PK/PD analyses ................................................................................................................ 68
9.4. 
Safety Analyses ............................................................................................................................. 69
9.5. 
Data Review after each cohort....................................................................................................... 70
10. ADDENDUM FOR OPEN-LABEL EXTENSION (OLE) PERIOD ..................................................... 71
10.1. 
Rationale ........................................................................................................................................ 71
10.2. 
Benefit/Risk Assessment of the OLE period.................................................................................. 71
10.2.1. 
Risks for Participation................................................................................................................. 71
10.2.2. 
Benefits for Participation............................................................................................................. 72
10.2.3. 
Benefit-Risk Assessment............................................................................................................ 72
10.3. 
Objectives and endpoints of OLE period ....................................................................................... 72
10.4. 
Design of the OLE period............................................................................................................... 72
10.4.1. 
Overall Design ............................................................................................................................ 72
10.4.2. 
Scientific Rationale for Study Design ......................................................................................... 73
10.4.3. 
Study-Specific Ethical Design Considerations ........................................................................... 74
10.4.4. 
Justification for dose................................................................................................................... 75
10.4.5. 
End of Study Definition ............................................................................................................... 75
10.5. 
Study population for the OLE period.............................................................................................. 75
10.5.1. 
Inclusion Criteria......................................................................................................................... 75
10.5.2. 
Exclusion Criteria........................................................................................................................ 76
10.5.3. 
Lifestyle Considerations.............................................................................................................. 76
10.6. 
Study interventions......................................................................................................................... 76
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JNJ-40411813
Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date:  17 November 2022
10.6.1. 
Study interventions Administered............................................................................................... 76
10.6.2. 
Preparation, Handling, and Storage ........................................................................................... 78
10.6.3. 
Measures to Minimize Bias: Randomization and Blinding.......................................................... 78
10.6.4. 
Study Intervention Compliance................................................................................................... 78
10.6.5. 
Concomitant Therapy ................................................................................................................. 78
10.6.6. 
Recording of drug intake; overview............................................................................................ 78
10.7. 
Discontinuation of study intervention and participant discontinuation/withdrawal ......................... 79
10.8. 
Study assessments and procedures for the OLE period ............................................................... 79
10.8.1. 
Overview..................................................................................................................................... 79
10.8.2. 
Study procedures........................................................................................................................ 80
10.8.2.1. 
Baseline visit............................................................................................................................ 80
10.8.2.2. 
Treatment Period..................................................................................................................... 81
10.8.2.3. 
Withdrawal Visit....................................................................................................................... 82
10.8.3. 
Efficacy Assessments in the OLE period.................................................................................... 82
10.8.3.1. 
Seizure count........................................................................................................................... 82
10.8.3.2. 
Retention on JNJ-40411813 therapy....................................................................................... 82
10.8.4. 
Safety Assessments ................................................................................................................... 82
10.8.5. 
Pharmacokinetics ....................................................................................................................... 83
10.9. 
Statistical considerations for the OLE period................................................................................. 83
10.9.1. 
Sample Size Determination ........................................................................................................ 83
10.9.2. 
Efficacy analyses........................................................................................................................ 83
10.9.3. 
PK and PK/PD analyses............................................................................................................. 83
10.9.4. 
Safety Analyses.......................................................................................................................... 83
10.10. Schedule of Activities (SoA) of the OLE period ............................................................................. 84
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS............................ 86
11.1. 
Appendix 1: Abbreviations ............................................................................................................. 86
11.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 89
11.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 91
11.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................. 102
11.5. 
Appendix 5: Drugs to be avoided................................................................................................. 107
11.6. 
Appendix 6: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 109
11.7. 
Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments................................ 112
11.8. 
Appendix 8:
) ............................... 116
11.9. 
Appendix 9: Columbia Suicide Severity Rating Scale. ................................................................ 117
11.10. Appendix 10: Guidance on Study Conduct during the COVID-19 Pandemic.............................. 121
11.11. Appendix 11: Protocol Amendment History................................................................................. 123
REFERENCES.......................................................................................................................................... 133
INVESTIGATOR AGREEMENT............................................................................................................... 135
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Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  17 November 2022
LIST OF IN-TEXT TABLES AND FIGURES
FIGURES
Figure 1: Study flow diagram ................................................................................................................... 31
TABLES
Table 1: 
Composition of tablets for expected dose levels. ..................................................................... 45
Table 2: 
Description of Interventions ...................................................................................................... 45
Table 3: 
Recording of date and time of last drug intake outside the scope of the e-diary. .................... 51
Table 4: 
Schedule of collection of 2-mL PK blood samples ................................................................... 62
Table 5: 
Doses and composition of tablets............................................................................................. 77
Table 6: 
Description of Interventions ...................................................................................................... 77
Table 7: 
Recording of date and time of last drug intake during the OLE period..................................... 79
NCT04836559

JNJ-40411813
Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date:  17 November 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment INT-4 
17-November-2022
Amendment INT-3 
12-July- 2022
Amendment INT-2 
07 April 2022
Amendment INT-1 
18 January 2021
Original Protocol 
13 November 2020
Amendment 4 (17-November-2022)
Overall Rationale for the Amendment:  This protocol amendment has been issued in order to provide
instructions for up-titration 
in Cohort 2 and to allow for dose increases in the Open
Label Extension Part of the study and to implement several different corrections and clarifications as listed
below
The changes made to the clinical protocol 40411813EPY2001 as part of Protocol Amendment 4 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 11.11 Appendix 11: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
Section 1.1 Dosage
and administration
Section 2.3.1
4.3 Justification for
dose
Added:
All patients in Cohort 2 (
 will start the double-blind phase with
a dosage of
 (or matching placebo).
Induced patients will be up titrated to 
(or matching placebo) on day 8 of the
double-blind phase.
Up-titration is expected to reduce the
number of early onset AE’s (dizziness,
incoordination, sedation, or fatigue).
Section 1.1 Dosage
and Administration
Section 2.3.1 Risk for
Study Participation
Changed:
For participants receiving dosages of 
 will
be permitted in case adverse events consisting of
dizziness, incoordination, sedation, or fatigue (or
similar descriptive terms) appear within the first 2
weeks of treatment and which, in the judgment of
the investigator, potentially limit activities of daily
living. This dosage reduction may last no longer
than 2 weeks and may not be repeated. Following
the return to the originally assigned dosage,
recurrence of intolerable adverse events would
require discontinuation of the study medication
Into:
 will be permitted in case
adverse events consisting of dizziness,
incoordination, sedation, or fatigue (or similar
descriptive terms) which, in the judgment of
the investigator, potentially limit activities of
This option for temporary and/or
permanent dose reduction will
minimize the likelihood of
discontinuation because of adverse
events, and will provide experience to
guide dosing instructions in future
studies
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NCT04836559

JNJ-40411813
Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date:  17 November 2022
Section Number
and Name
Description of Change 
Brief Rationale
daily living. The PI is encouraged to
rechallenge if the AEs resolved on the lower
dose. If rechallenge is unsuccessful, i.e., the
AEs recurred when the dose was increased,
the dose may be reduced again and kept at that
level
Section 4.2
Optional temporary
dose reduction
Deleted: ‘temporary’ 
The option for dose reduction does not
need to be temporary, i.e. if rechallenge
is unsuccessful the participant may
remain on the lower dose
Section 4.1 Overall 
design  
Added to
 
 
 
or placebo on day 8 
Up-titration is expected to reduce the
number of early onset AE’s (dizziness,
incoordination, sedation, or fatigue
1.1 Participant 
Population  
4.1 Overall design  
5. Study population 
Changed: 60 patients 
Into: 
approximately 60 patients 
Because exact number of Screen
Failures is not predictable and for
planning reasons (planning for the
Interim Reviews), it is possible that
cohorts would not have exactly 60
patients.
9.5 Data Review after 
each cohort 
This section has been revised. 
This is a correction to bring the
protocol in line with Amendment 3 (no
pause in recruitment between cohorts)
5.2 Exclusion 
Criterion  
Excl 7 
Clarification 
Participants that have not had a visual field 
examination after vigabatrin discontinuation  
could have one done at any point prior to 
randomization. 
Visual field abnormalities are common
in people that have been treated with
vigabatrin, and in themselves should
not be exclusionary. The importance
for understanding the safety of JNJ-
40411813 is that, in case visual field
abnormalities are discovered in any of
our participants, we will have a
baseline to determine if this is new
(and possibly treatment-emergent), vs
old and not related to JNJ-40411813.
Note that current treatment with
vigabatrin is still exclusionary
5.2 Exclusion Criteria 
Excl 15 
Added to Positive test result(s) for alcohol 
and/or drugs of abuse: does not apply for 
patients using medicinal cannabis to treat a 
medical condition that is documented in the
Medical History
Cannabis is not considered as a drug of
abuse if used to treat a medical
condition.
9.2.1 Primary, 
Population  
Deleted: for at least 1 year 
This is a correction to bring the
protocol in line with changes in
Amendment 2
6.1. Table 2 
Added: If visit 7 coincides with Open Label 
Extension visit 1, participants should be dosed
with double blind medication in the morning
and with open label medication in the
evening.
For clarification
8.5. Table 4 
Changed: 
With study Visit
Into
For clarification
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NCT04836559

JNJ-40411813
Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date:  17 November 2022
Section Number
and Name
Description of Change 
Brief Rationale
After dosing
6.5. Concomitant
Therapy
Added that on day of visit 7, other anti- 
epileptic drugs should be taken in the clinic 
For clarification and to be in line with
instructions for dosing of the AED on
other visit days.
10.4.1. Overall design
10.6.1 Study
interventions
administered
Text on dosing has been updated to allow dose 
increases in patients in the OLE phase 
To give patients the opportunity to be
treated, in the OLE phase, with a dose
that is expected to be the most
efficacious.
10.4.2 Combination
with levetiracetam or
brivaracetam
Added: Monotherapy with JNJ-40411813 to 
treat epilepsy is not allowed.
For clarification.
10.10 Schedule of
Activities in the OLE
period
Added to footnote i: If OLE1 coincides with
Visit 7 of the Double-Blind Phase: 
For clarification.
10.10 Schedule of
Activities in the OLE
period
Added: Visit windows in footnote ‘k’ 
Information was missing in
Amendment 3 and Amendment 4
10.8.1 Overview,
10.8.2.1 Study
Procedures
10.8.3.1 Seizure
count
Deleted: Paper diary may be provided 
Electronic Diary is in place and should
be used.
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Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  17 November 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsisa
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to
Evaluate the Efficacy, Safety, and Tolerability of JNJ-40411813 as Adjunctive Therapy in
Subjects with Focal Onset Seizures with Suboptimal Response to Levetiracetam or
Brivaracetam
Background:
JNJ-40411813 is a positive allosteric modulator (PAM) of the metabotropic glutamate receptor-2 (mGlu2),
which is abundantly expressed in the forebrain and cerebellum. The mGlu2 receptor functions as a
presynaptic auto-receptor that, upon activation, decreases the release of the excitatory neurotransmitter
glutamate. Positive allosteric modulation of a receptor will result in the direct enhancement of the agonist-
induced signal while PAMs themselves have generally no or low intrinsic activity at the receptor. The net
effect of JNJ-40411813 is hypothesized to be a normalization of hyper-glutamatergic transmission.
JNJ--40411813 is being evaluated for the treatment of disorders of the central nervous systems (CNS), such
as epilepsy, and has been evaluated in schizophrenia and anxious depression.
This study as per Amendment INT-2 and INT-3 will consist of a double-blind treatment period and
an open-label extension (OLE) period. Details about the OLE period are described in Section 10.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to evaluate the efficacy of up to 3 dose levels of adjunctive
JNJ-40411813 compared to placebo based on the time to baseline monthly seizure count in participants
with focal onset seizures who are receiving levetiracetam or brivaracetam and up to 3 other anti-epileptic
drugs (AEDs).
Secondary Objectives
 
To evaluate the overall safety and tolerability of adjunctive JNJ-40411813 compared to placebo in
participants with focal onset seizures who are receiving levetiracetam or brivaracetam and up to 3
other AEDs.
 
To evaluate the efficacy of up to 3 dose levels of adjunctive JNJ-40411813 compared to placebo based
on percent reduction in the double-blind monthly seizure count, relative to the pre-randomization
monthly seizure count, in participants with focal onset seizures.
 
To evaluate the efficacy of JNJ-40411813 over the double-blind period using percent participants with
seizure freedom and percent responders (>50% seizure rate reduction).
 
To evaluate the pharmacokinetics (PK) of JNJ-40411813 and selected metabolites and levetiracetam
or brivaracetam  in participants with  focal onset seizures who are receiving levetiracetam or
brivaracetam and up to 3 other AEDs.
Exploratory Objectives
 
a 
This section has been amended by Amendment INT-1, INT-3 and INT-4
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Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  17 November 2022
 
 
 
Hypothesis
The hypothesis of this study is that JNJ-40411813 added to treatment that includes levetiracetam or
brivaracetam significantly prolongs the time to baseline monthly seizure count compared to placebo add-
on treatment.
OVERVIEW OF STUDY DESIGN
This is a double-blind, randomized, parallel, placebo-controlled study with the option for an open-label
extension (OLE) period. The study will consist of 1 to a maximum of 3 cohorts. In each cohort, for each
participant the study consists of a screening visit, an 8-week prospective pretreatment baseline period, an
up to12-week double-blind treatment period and, for those participants electing not to enter the OLE period,
a follow-up telephone visit 2 weeks after the last dose of study intervention. Participants have the option to
enter the OLE period, in which treatment with JNJ-40411813 may be continued until the product becomes
available by prescription, or until development of JNJ-40411813 in this indication ceases. The total
maximal duration of the study is approximately 22 weeks for each participant, up to the time of entry into
the OLE period.
Participants from 18 to 69 years (inclusive) old with an established diagnosis of focal onset seizures will
be enrolled in the study. For the first cohort, approximately 80 eligible participants will be initially enrolled
to ensure that approximately 60 participants are randomly assigned in a 2:1 ratio to receive either JNJ-
40411813 
 
or placebo. For each following cohort, approximately 60 eligible participants
will be initially enrolled to ensure that approximately 50 participants are randomly assigned in a 4:1 ratio
to receive either JNJ-40411813
 or placebo.
After giving written informed consent, participants will be screened immediately prior to the start of the
pretreatment baseline period to ascertain their eligibility for the study per the inclusion and exclusion
criteria. Upon completion of all informed consent form (ICF)procedures, recording of adverse events (AEs)
and concomitant medication will start.
After the screening visit, the data of the participant will be subject to an adjudication process by independent
experts from the epilepsy consortium. In this adjudication process the experts decide whether the participant
is correctly classified to participate in the study.
After screening, if they meet the inclusion criteria and not meet the exclusion criteria for which data are
available, participants can start the 8-week prospective pretreatment baseline period pending the results of
the central laboratory and the adjudication process. However, when the results of these assessments indicate
that the participant does not meet the in- and exclusion criteria, the participant will terminate the baseline
period and will not be randomized to treatment.
During the 8-week prospective pretreatment baseline period, participants will continue to take their
prescribed AEDs (one of which must include levetiracetam or brivaracetam) without change in dosage(s);
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NCT04836559

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Clinical Protocol 40411813EPY2001, Amendment INT-4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date:  17 November 2022
new concomitant AEDs should not be added. During the baseline period, participants will record seizure
information (type and frequency of seizures) in an e-diary. Baseline monthly seizure count will be defined
as the number of observable focal onset seizures recorded during the baseline period, multiplied by 28/ XBL,
where XBL is the number of days comprising the baseline.
Participants must be compliant with the recording of information in the e-diary  throughout the study.
Seizures that will be entered during baseline and throughout the study include focal aware seizures with
and without motor signs, focal impaired awareness seizures and focal to bilateral tonic-clonic seizures.
Myoclonic, or other generalized seizures will not be entered.
Participants who meet study entry criteria at the end of the prospective pretreatment baseline period will be
randomized to JNJ-40411813 or placebo, 
. The dosage(s) of
concomitant AEDs should not be increased, and new concomitant AEDs should not be added to the
treatment regimen.
. In the following cohorts,
the dose(s) of JNJ-40411813 will be determined based on an ongoing assessment oftolerability, and safety
results from the previous cohort. 
participants. The highest dose selected to be administered by induced participants will be expected to not
exceed the 95th percentile of the plasma maximum drug concentration (Cmax) for JNJ-40411813, 
Participants are encouraged to complete at least the first 4 weeks of treatment when there are no safety
concerns. Participants who have exceeded their pre-randomization monthly seizure count at Week 4, or
within any 4-week interval after Week 4 (“4-week sliding window approach”) up to Week 12, will have the
option to discontinue the study drug for lack of efficacy and to perform the end of study/early withdrawal
visit, to continue double blind treatment, or to enter the open-label extension (OLE) period. Participants
who have not exceededthe pre-randomization seizure count will continue the double-blind treatment period
through Week 12 and will have the option to perform the end of study visit or to enter the OLE period.
Participants who continued treatment to the end of the double-blind treatment period (Week 12) or have
completed the study as per Section 7.2 will continue to collect information on the number of seizures they
experience using the e-diary until 2 weeks after the last dose of study medication. Participants entering the
optional OLE will continue to record seizures by using an e-diary.
Participants will visit the study center according to the schedule in the Schedule of Activities (SoA).
After at least 55 patients in Cohort 1 and after at least 45 patients in Cohort 2 have completed at
least 4 weeks of treatment, an interim unblinded review of all cumulative safety, PK and efficacy
data of JNJ-40411813 available to that date will be performed to decide on whether there should
be any addition or modification to the dose(s) in the following cohorts and subsequent clinical
studies. If the results of the review are inconclusive with respect to the assessment of efficacy, a
second interim review of the same cohort may be done after the last participant has completed the
12-week visit.
PARTICIPANT POPULATION
At least 60 and a maximum of 160 male and female participants are planned to be randomized in the study.
To reach these numbers it is expected that about 200 participants will start the baseline pre-randomization
period of 8 weeks.
WOCBP will use a highly effective birth control method as outlined in the in/exclusion criteria.
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Clinical Protocol 40411813EPY2001, Amendment INT-4
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Status: Approved,  Date:  17 November 2022
DOSAGE AND ADMINISTRATION
JNJ-40411813 will be supplied for this study as 25-mg and 50-mg tablets. Placebo will be supplied as
matching tablets.
The tablets will be taken 
 from Day 1 to Day 85 (or day of Visit 7 when before Day 85). All study
intervention, apart from the study intervention taken in the clinic during Visits 2, 4 and 6 will be taken at
home and intake of the intervention should be confirmed in the e-diary.
All patients in Cohort 2
).
(or matching placebo) on day
8 of the double-blind phase.
.
For participants receiving dosages 
 will be permitted in
case adverse events consisting of dizziness, incoordination, sedation, or fatigue (or similar descriptive
terms) which, in the judgment of the investigator, potentially limit activities of daily living. The PI is
encouraged to rechallenge the initial dose within 2 weeks if the AEs are resolved on the lower dose. If
rechallenge is unsuccessful, i.e., the AEs recurred when the dose was increased, the dose may be reduced
again and kept at that level.
Patients should be advised to call the site ifthey experience dizziness or somnolence in the first 2 weeks of
the double-blind phase.
Study intervention should be taken in fed condition
.
The tablets must be swallowed whole with water and not chewed, divided, dissolved, or crushed.
The 
 during Visit 2 (Day 1) of the double-blind period when the
participant is in the clinic in the morning. Dosing during the site visit will be witnessed by the study staff.
The participants will bring the study intervention and all other AEDs currently taken with them at each
study visit.
On the day of Visit 4 (Week 4) and Visit 6 (Week 8), the 
 will be taken in the study center
during the study visit
. Dosing during the site visit will be witnessed by the
study staff.
The actual dose and the composition of tablets to be taken will be determined for each cohort and stratum
within a cohort.
EFFICACY EVALUATIONS
The primary efficacy evaluation will be the time to baseline monthly seizure count. To assess this endpoint,
the number and type of seizures during the baseline period and during the double-blind treatment period
needs to be documented carefully.
The participant and/or caregiver will be provided access to an (electronic) diary to record seizures and
intake of study intervention. The e-diary will be an app downloaded on the smartphone owned by the
participant. Only if the participant and/or caregiver do not own a smartphone, a smartphone programmed
for the study will be provided.
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Clinical Protocol 40411813EPY2001, Amendment INT-4
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Status: Approved,  Date:  17 November 2022
PHARMACOKINETIC EVALUATIONS
Venous blood samples of 2 mL each will be collected for determination of plasma concentrations of
JNJ-40411813 and metabolites including but not limited to 
, levetiracetam or
brivaracetam and, when used by the participant, 
 as specified in the SoA and Table 4.
SAFETY EVALUATIONS
The collection of AEs and concomitant medications will start after the ICF  has been signed and will
continue until the final study visit.
Apart from this, the following safety assessments will be performed: physical and neurological
examination, body weight, vital signs (including temperature), 12-lead electrocardiogram (ECG),
pregnancy testing (female participants only), clinical labs (hematology, chemistry panel) and urinalysis. At
screening only: serology and testing for alcohol and drugs of abuse.
Additional blood and urine samples may be taken, or vital signs and ECGs recorded at the discretion of the
investigators.
Additionally, emergence of suicidal ideation will be assessed using the Colombia suicide severity rating
scale (C-SSRS) at screening, and during each study visit.
STATISTICAL METHODS
Sample size determination
The calculation of the maximum sample size planned for this study was simulation-based and was estimated
using a Cox’s proportional hazard regression model comparing the time to baseline seizure count between
JNJ-40411813 and placebo. A longitudinal model for individual daily seizure counts, taking into account
between-subject variability in baseline seizure rate and response to treatment, and a residual overdispersed
Poisson error was applied. The simulated daily seizure count data were then converted to time to baseline
count data and analyzed using a Cox’s proportional hazard regression model.
Assuming a placebo median percentage seizure rate reduction of 15% and a further reduction of 50%
(respectively 30%) for JNJ-40411813, a cohort with 40 participants randomized to JNJ-40411813 and 20
to placebo would achieve a power of 99% (respectively 83%) at the α=5% one-sided significance level. In
subsequent cohorts with 40:10 randomization, the power becomes 94% for a 50% reduction, with all other
assumptions unchanged.
Efficacy analyses
Primary
The intent-to-treat population will be the primary efficacy population, which includes all participants who
are randomly assigned to receive study drug and who have baseline and postbaseline seizure data. Data
from participants on placebo in cohorts 2 and 3 will be combined with those from Cohort 1 if the Kaplan-
Meier curves of the subjects treated with placebo are comparable between cohorts. The analysis for interim
review may be done including both pooled and non-pooled placebo subjects.
The individualized baseline monthly seizure count is defined as the number of observable focal onset
seizures occurring during the 8-week baseline period, multiplied by 28/ XBL, where XBL is the number of
days comprising the baseline period. Observable focal onset seizures include focal aware seizures with
motor signs, focal impaired awareness seizures and focal to bilateral tonic-clonic seizures. Focal aware
seizures will not be counted towards baseline monthly seizure count. The endpoint time to baseline monthly
seizure count is defined, for each patient, as the number of days, until the patient experienced the number
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Status: Approved,  Date:  17 November 2022
of seizures equal to baseline monthly seizure count, up to the end of the 12-week double-blind treatment
period.
Kaplan-Meier analyses will be conducted to describe the time to baseline monthly seizure count distribution
(with 95% CI) for each treatment group for all observable focal-onset seizures. A formal comparison of
time to monthly baseline seizure count will be made by a Cox proportional hazard regression model,
including factors for treatment and any other relevant covariates (details will be provided in the statistical
analysis plan). Appropriate adjustment for multiple testing, in case of subsequent cohorts, will be detailed
in the SAP.
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined by the
following 5 components:
 
Population: patients with established diagnosis of focal epilepsy, for at least 1 year (ILAE 2017
criteria) with 3 to 100 seizures per 28 days; currently on 1 to 4 AEDs with inadequate response to
levetiracetam or brivaracetam who have met the inclusion/exclusion criteria.
 
Variable: the number of days, until the patient experienced the number of seizures equal to baseline
monthly seizure count, up to the end of the 12-week double blind treatment period.
 
Intervention event: the effect of the initially randomized treatment that would have been observed
had all participants remained on their treatment throughout the double-blind treatment phase.
 
Intercurrent event (ICE): treatment discontinuation will be handled according to the hypothetical
strategy as if the ICE would not have occurred. Similar efficacy is assumed for subjects who had the
ICE as those subjects from the same treatment group who did not have the ICE.
 
Population-level summary: the difference in estimated hazard ratio between the treatments.
Sensitivity analyses for the primary estimand regarding missing data assumptions; and a supplementary
estimand to inform subsequent trials will be specified in the SAP.
Secondary and exploratory
Secondary efficacy endpoints will be subject to an exploratory analysis including descriptive statistics by
treatment arm and graphical exploration. Details of the analysis for each secondary endpoint and
exploratory endpoints will be provided in the SAP. The SAP will also describe the analysis of the endpoints
in the OLE period.
Seizure Freedom
Percent participants with seizure freedom over the complete double-blind period. Participants who exit
the study after reaching their pre-randomization baseline seizure count can be included in this analysis
without introducing bias as they were not seizure free during the study.
Secondary generalized seizures (Focal to bilateral tonic-clonic seizures)
Separate analyses (including time to baseline count and % reduction of counts) for focal to bilateral tonic-
clonic seizures will be performed if a large enough number of events is observed.
Responder rate
A responder is defined as a participant having at least a 50% reduction of the monthly seizure rate.
Participants who exit the study at Week 4 after reaching the baseline seizure count will be treated as non-
responders in this analysis. As the number of seizures they experienced is either equal or larger than their
baseline monthly seizure count, their observed % seizure rate reduction is either zero, or negative (implying
an increase).
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Pharmacokinetic Analyses
Data for all participants who receive a dose of JNJ-40411813 and have at least one measurement of plasma
concentration, will be included in the PK analysis. Plasma concentrations of JNJ-40411813 and metabolites
including 
, levetiracetam or brivaracetam and
will be listed for all participants.
Descriptive statistics will be calculated for the plasma concentrations of JNJ-40411813 and metabolites
including 
, levetiracetam or brivaracetam and 
 at each applicable time point. Statistics include
sample size (n), mean, standard deviation, coefficient of variation (CV), geometric mean, median,
minimum, and maximum.
Population PK and/or PBPK analyses of JNJ-40411813 and levetiracetam or brivaracetam  may be
performed on the data of this study in combination with data pooled from other studies. An objective of
these analyses is to investigate the potential effects of covariates, such as demographics and concomitant
drugs, on the pharmacokinetics of JNJ-40411813. The results of the population analyses may be reported
separately.
PK and pharmacodynamic (PD) relationship will be explored, if feasible. The results of population PK/PD
analyses will also be reported separately.
Safety analyses
All safety analyses will be performed based on the safety analysis set, which will include all participants
who receive at least 1 dose of study intervention. Safety summaries will be provided by treatment, unless
specified otherwise.
AEs will be coded using the current version of Medical Dictionary for Regulatory Activities (MedDRA)
and tabulated by system organ class, by severity and relationship to study intervention.  Summaries, listings
or participant narratives may be provided, as appropriate, for those participants who die, who discontinue
treatment due to an AE, or who experience a severe or a serious AE.
The safety analysis will include the incidence of AEs, actual data and changes in blood pressure, pulse rate,
laboratory safety data, 12-lead ECG and physical and neurological examination data from predose to all
postdose assessments.
The participants with suicidal ideation and/or suicidal behavior collected from the C-SSRS will be listed.
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Periods 
Screening 
Baseline 
Double-blind treatment 
Follow-up
Study Week (end of) 
-8 
-8 to 0 
- 
2 
4 
6 
8
12 (or Early
withdrawal)a 
14
Study Day  
-57 
-56 to -1c 
1 
15b 
29b 
43 b 
57b 
85b 
99b
Visitd 
1 
2e 
3 
4e 
5 
6e 
7 
8
Clinic visit (C)/ Telephone contact (TC) 
C 
TCf 
C 
TC  
C 
TC  
C 
C 
TC
Height 
X
Electrocardiogram  
r 
X 
X 
X
Pregnancy tests 
X 
X 
X 
X 
X
Adverse events
Concomitant therapy
Footnotes:
a) If a participant discontinues treatment before the end of the double-blind treatment period, early withdrawal (EW) visit should be completed
b) ± 2 days
c) When required for practical reasons, the baseline period may be up to 1 week longer or shorter than 8 weeks. Baseline monthly seizure count will be defined
as the number ofobservable focal onset seizures recorded during the baseline period, multiplied by 28/ XBL, where XBL is the number of days comprising the
baseline.
d) Participant should come to the study visit in fasted conditions (at least 4 hours) when possible
e) Visit in the morning hours before noon.
f) Participants will be contacted by phone during the baseline period to confirm correct use of the e-diary. This contact should take place at least 4 weeks after
the start of the baseline period, but multiple contacts are allowed when required.
g) After completion of all visit assessments (except post-dose PK blood sample).
h) Except in-clinic doses during visits
i) To be collected before dosing and when possible in fasting condition
j) During Visit 2, also collect a blood sample for biomarkers at 2 hours post dose (together with PK-sample)
k) Collect with clinical laboratory sample.
l) Detailed timepoints for PK sample collection are provided in Table 4: PK sampling Strategy
m) Only levetiracetam or brivaracetam and JNJ-40411813, at EW only when EW visit is after Visit 6.
n) 
o) Only seizure counts. Only subjects who continued treatment to the end of the double-blind treatment period (Week 12) or have completed the study as per
Section 7.2
p) 
.
q) Systolic and diastolic blood pressure, heart rate and body temperature (oral or tympanic)
r) Triplicate ECG at screening. Single ECG at the other timepoints.
s) In women of childbearing potential only. Serum pregnancy test at screening and a urine pregnancy test at the other visits.
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2. 
INTRODUCTION
JNJ-40411813 is a positive allosteric modulator (PAM) of the metabotropic glutamate receptor-2
(mGlu2), which is abundantly expressed in the forebrain and cerebellum. The mGlu2 receptor
functions as a presynaptic auto-receptor that, upon activation, decreases the release of the
excitatory neurotransmitter glutamate. Positive allosteric modulation of a receptor will result in
the direct enhancement of the agonist-induced signal while PAMs themselves have generally no
or low intrinsic activity at the receptor. The net effect of JNJ-40411813 is hypothesized to be a
normalization of hyper-glutamatergic transmission. JNJ-40411813 is being evaluated for the
treatment of disorders of the central nervous systems (CNS), such as epilepsy, and has been
evaluated in schizophrenia and anxious depression.
For the most comprehensive nonclinical and clinical information regarding JNJ-40411813, refer
to the latest version of the Investigator's Brochure (IB) for JNJ-40411813.
The term “study intervention” throughout the protocol, refers to JNJ-40411813 or placebo.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1. 
Study Rationale
Based on nonclinical data JNJ-40411813 is expected to show synergistic activity with
levetiracetam or brivaracetam, which is thought to bind to and regulate Synaptic Vesicle
glycoprotein 2a (SV2a), a vesicular protein in the presynaptic terminal involved in glutamate
release (Metcalf 2017, 2018). In state of hyperglutamatergic activity such as in an epileptic seizure,
coadministration of both compounds is thus expected to decrease the epileptic activity in
participants with focal onset seizures with suboptimal response to levetiracetam or brivaracetam.
The current study will be conducted to assess the efficacy, safety, tolerability, pharmacokinetics
(PK) and pharmacodynamics (PD) of adjunctive JNJ-40411813 in participants with focal onset
seizures with suboptimal response to levetiracetam or brivaracetam and to assess long term safety
and efficacy in an OLE period.
2.2. 
Background
2.2.1. 
Nonclinical Studiesa
Nonclinical pharmacology
The in vitro potency (as effective concentration [EC50]) is 100 nM on human mGlu2 based on
several cellular read-outs (Lavreysen 2015).
a 
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JNJ-40411813 antagonized the serotonin type 2A (5-HT2A) receptor with moderate potency
(Kb=1.1 M) and showed 30-fold selectivity versus other targets. M47 is the major metabolite
found in rat but not in human plasma and is equipotent to the parent drug for mGlu2.
EC50 for occupying rat mGlu2 is reached at a plasma concentration of 1,032 to 2,247 ng/mL.
JNJ-40411813 has anticonvulsant efficacy in the mouse 6 Hz model.  Median effective dose (ED50)
after subcutaneous administration was 12.2 and 21.0 mg/kg in the 6 Hz 32 mA and 44 mA stimulus
intensity model.
6 Hz 44 mA ED50 of levetiracetam was 345 mg/kg intraperitoneal when levetiracetam was dosed
alone versus 9.6 mg/kg in combination with a subprotective dose of 10 mg/kg SC JNJ-40411813,
an approximately 36-fold shift in the ED50.
JNJ-40411813 was tested in the 6 Hz model in combination with another SV2A
Ligand, brivaracetam. In the 6 Hz 44-mA assay, the subprotective dose of
JNJ-40411813 (10 mg/kg SC) shifted the ED50 of brivaracetam approximately 50-fold
A PD interaction between JNJ-40411813 and levetiracetam was observed in the rat amygdala
kindling model. For more details see the IB for JNJ-40411813.
In contrast, there was only limited benefit from combining JNJ-40411813 with diazepam or
carbamazepine in the 6 Hz model, and as such the synergy seems specific and unique for the
“mGlu2 PAM –SV2A” combination.
Toxicology
No relevant effects on cardiovascular and respiratory functioning were observed in animals. Minor
CNS findings (exaggerated pharmacology) were observed.
A benign toxicological profile was seen when dosing animals with JNJ-40411813. Decreases in
body weight were seen in rats and dogs.
Administration of JNJ-40411813
 oral gavage in the Sprague-Dawley rat for
26 weeks was well tolerated, with transient, minimal clinical signs, lower body weight sometimes
associated with lower food consumption, minimal changes in hematology and clinical chemistry
parameters. Histological changes in liver and thyroid, associated with gross findings and increased
organ weight, were indicative of enzyme induction. The No Observed Adverse Effect Level
(NOAEL) was considered to be 1000 (male rats) or 500 (female rats) mg/kg/day.
Administration of JNJ-40411813 
 oral gavage for 39 weeks was well tolerated in
beagle dog up to 160 mg/kg/day. Treatment induced clinical signs at a low incidence, decreased
body weight gain, sometimes associated with lower food consumption, and minimal changes in
clinical chemistry parameters. Histological prostate immaturity, associated with gross findings and
decreased organ weight, possibly reflected delayed maturation as an indirect effect linked to the
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test article-related body weight effects. The NOAEL in the 9-month dog study was considered to
be 160 mg/kg/day.
There were no effects on fertility in male rats; a high dose of 200 mg/kg in female rats resulted in
estrous cycle irregularities and a higher incidence of pre- and post-implantation loss, likely because
of the lower food intake and body weight performance.
There were no test article-related effects on embryo-fetal development in pregnant rats and rabbits.
No genotoxic or phototoxic liabilities have been identified.
Pharmacokinetics and Metabolism in Animals
After oral dosing 
) absorption from the gut
was fast. Using nanosuspensions, the absolute bioavailability of JNJ-40411813 was variable
between species and ranged between
 general,
JNJ-40411813 showed high and comparable plasma protein binding in all species. Tissue
distribution experiments showed a fast and moderate distribution to the tissues. The brain/plasma
area under the plasma concentration-time curve (AUC) ratio was 0.93. Elimination from tissues
appeared parallel to plasma.
Clearance of JNJ-40411813 was mainly via oxidative metabolism in vitro in nonclinical species
and man, and in vivo in rat and dog.
The potential of JN-40411813 
 enzymes is considered
limited.
JNJ-40411813 showed lowest 
 
JNJ-40411813 is a weak mechanism-based inhibitor of CYP3A4. Metabolites
did not show any potential as 
2.2.2. 
Clinical Studies
To date, 9 Phase 1 clinical studies have been completed including a total of 345 healthy subjects,
a Phase 2 study of 100 subjects with schizophrenia, and a Phase 2 study of 121 subjects with Major
Depressive Disorder (MDD) with anxiety symptoms.
Pharmacokinetics, Product Metabolism, and Pharmacodynamics
Single oral doses of 5 mg up to 1,000 mg are characterized by a rapid absorption and a biphasic
decline. With increasing doses, maximum drug concentration (Cmax) and AUC∞ increase in a less
than dose-proportional manner between 5 and 225 mg. However, between the doses of 225 and
1,000 mg, Cmax  and AUC∞ tended to increase dose proportionally. With increasing doses, time to
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achieve maximum concentration (tmax) was delayed and the mean terminal half-life increased from
10.6 hours at 5 mg, to ~27 hours at 1,000 mg. 
.
Administration of JNJ-40411813 as a nanosuspension 
 Higher exposure 
Repeated dosing between 50 and 150 mg 
 achieved steady state within 2 to
4 weeks.
CYP3A4 has a major role in the metabolic clearance of JNJ-40411813. When CYP3A4 was
inhibited with ketoconazole, JNJ-40411813 showed an approximate 43% increase in Cmax  and a
7-fold increase in AUClast. 
.
Metabolites are not expected to contribute to the mGlu2 antiepileptic activity of JNJ-40411813 in
humans.
Cognitive test results suggest that JNJ-40411813 slightly reduces reaction speed and precision but
does not interfere with memory function at dose levels associated with a decrease in alertness.
While no effect was measured on rapid eye movement (REM)sleep latency or duration, an increase
in the total time spent in deep sleep as well as a reduction in total sleeping time was observed.
JNJ-40411813 500 mg also attenuated the perceptual and behavioral changes induced by a low,
subanesthetic dose of ketamine.
JNJ-40411813 100 mg bid reduced craving in abstinent dependent smokers without significantly
affecting the negative mood states induced by nicotine abstinence.
The 40411813SCH2001 study was designed to assess compound safety and tolerability in a
schizophrenia population. The daily dose was 50 or 150 mg bid. There was no consistent pattern
or trend of change observed in the Positive and Negative Syndrome Scale (PANSS) total score,
Clinical Global Impression – Schizophrenia (CGI-SCH) scores, Subjective Well-being on
Neuroleptics Scale (SWN) scores, and self-rating regarding appetite and attitude assessments.
However, there was evidence of greater improvement on the PANSS Negative Subscale and the
PANNS Negative Symptoms Marder Factor score for JNJ-40411813-treated subjects with residual
negative symptoms.
The 40411813DAX2001 study was designed to evaluate the efficacy in patients with MDD with
anxiety symptoms. The daily dose was between 25 and 150 mg bid. No efficacy signal was
detected for JNJ-40411813 versus placebo based on change in the 6-item Hamilton Anxiety Scale
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(HAM-A6) and 14-item Hamilton Anxiety Scale (Structured Interview Guide version-SIGH-A)
total score from baseline to Week 4.
However, criteria for efficacy signal detection were reached on several key secondary measures of
anxiety (Hamilton Depression Rating Scale [HDRS17] anxiety/somatization factor score, the
Inventory of Depressive Symptomatology [IDS-C30] anxiety subscale) and depression (Hamilton
Depression Rating Scale [HDRS17], the Hamilton Depression Rating Scale-6 [HAM-D6, a six-item
core depressive symptoms subscale of the HDRS17], and the IDS-C30). See the IB for more details.
Safety and Tolerability
JNJ-40411813 was safe and well-tolerated in healthy subjects receiving single oral doses of 5 to
1,000 mg and multiple oral doses of 50 to 225 mg bid.
The most common treatment-emergent adverse events (TEAEs) over all dose levels following
single dosing with JNJ-40411813 were dizziness (25.0%), headache (12.3%), vertigo (11.9%),
dizziness postural (10.2%), ataxia (8.9%), somnolence (8.1%), fatigue (5.9%), and nausea (5.1%).
The most common TEAEs over all dose levels during multiple oral dosing with JNJ-40411813
were headache (40.5%), dizziness (35.1%), fatigue (17.6%), dyspepsia (12.2%), decreased
appetite (8.1%), dizziness postural (6.8%), nausea (6.8%), back pain (5.4%), and coordination
abnormal (5.4%).
JNJ-40411813 was well tolerated in subjects with schizophrenia when administered as an add-on
treatment to other antipsychotics with a similar TEAE profile (study 40411813SCH2001).
The 150 mg bid dose was less well-tolerated compared to placebo, with more dizziness-related
adverse events (AEs) (vertigo, coordination abnormal, dizziness, and dizziness postural) and more
TEAEs judged as severe by the investigator were reported in this dose group.
There were no deaths reported in the Phase 2 first-in-patient study (40411813SCH2001). Three
subjects (3%) reported treatment-emergent serious adverse events (TESAEs) (including
schizophrenia catatonic type, electrocardiogram abnormal, and psychotic disorder, all considered
as doubtfully or not related to study drug) during the double-blind phase. Six subjects (8%)
reported TESAEs (including anxiety, psychotic disorder, hyponatremia, and augmentation of
schizophrenia, all considered as doubtfully or not related to study drug) in the open-label phase.
JNJ-40411813 was safe and well-tolerated in the dosing range studied in subjects with MDD with
anxiety symptoms (study 40411813DAX2001), with the most common TEAEs being vertigo,
nausea, and headache.
No clinically significant effects on vital signs, 12-lead electrocardiogram (ECG), or clinical
laboratory parameters were observed in Phase 1 studies, or in the Phase 2 studies.
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2.2.3. 
Brivaracetam
Brivaracetam is an antiepileptic drug indicated as adjunctive therapy in the treatment of partial-
onset seizures in patients 16 years of age and older with epilepsy.
Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A), a
transmembrane glycoprotein found at presynaptic level in neurons and in endocrine cells.
Although the exact role of this protein remains to be elucidated it has been shown to modulate
exocytosis of neurotransmitters. Binding to SV2A is believed to be the primary mechanism for
brivaracetam anticonvulsant activity.
The recommended starting dose in adults is either 50 mg/day or 100 mg/day based on physician’s
assessment of required seizure reduction versus potential side effects. Based on individual patient
response and tolerability, the dose may be adjusted in the effective dose range of 50 mg/day to 200
mg/day.
The following adverse reactions have been reported as the most common. For details see the
Summary of product characteristics for brivaracetam.
 
Very common: may affect more than 1 in 10 people somnolence dizziness
 
Common: may affect up to 1 in 10 people influenza depression, anxiety, insomnia, irritability
decreased appetite convulsion, vertigo upper respiratory tract infections, cough  nausea,
vomiting, constipation fatigue
2.2.4. 
Levetiracetam
Levetiracetam is an antiepileptic drug. Its mechanism of action is modulation of synaptic
neurotransmitter release through binding to the synaptic vesicle glycoprotein SV2a in the brain.
Levetiracetam is a generic drug, where several different formulations are available.
The daily starting dose in adult patients is 1,000 mg/day, given as bid dosing (500 mg per intake).
Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a
maximum recommended daily dose of 3,000 mg. The actual dose is titrated for each individual
patient.
The following adverse reactions have been reported as the most common. For details see the
Summary of product characteristics for levetiracetam.
 
Very common: may affect more than 1 in 10 people nasopharyngitis sleepiness headache
 
Common: may affect up to 1 in 10 people decreased appetite depression, hostility or
aggression, anxiety, insomnia, nervousness or irritability  convulsion, balance disorder,
dizziness, lethargy (lack of energy and enthusiasm) tremor cough abdominal pain, diarrhea,
dyspepsia (indigestion), vomiting, nausea rash asthenia/fatigue (tiredness).
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2.3. 
Benefit/Risk Assessment
2.3.1. 
Risks for Study Participation
Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Unknown efficacy of 
JNJ-40411813 in epilepsy  
JNJ-40411813 has been tested in 
schizophrenia and anxious 
depression but not in epilepsy. The 
synergy between JNJ-40411813 
and levetiracetam has been 
confirmed in nonclinical studies but 
not in clinical studies. 
By selecting the “time to baseline
seizure count” as primary efficacy
parameter, participants can stop
treatment because of non-efficacy
already after 4 weeks in the study
or later as soon as this endpoint has
been reached.
Existing anti-epileptic drug (AED)
treatment will be continued
unchanged.
Non-tolerability of study treatment 
Although the safety profile of 
JNJ-40411813, brivaracetam and 
levetiracetam is generally benign, 
no information about the safety and 
tolerability of the combination is 
available. No adverse safety effects 
have been identified in nonclinical 
studies. Also, the combination with 
other AEDs has not been tested 
before. There may be unknown 
safety risks.
Experience so far in the dosage
range employed indicates that
JNJ-40411813 is well tolerated and
there is no signal for target organ
damage.  The start dose of
JNJ-40411813 in the first cohort is
relatively low. In clinical studies,
 JNJ-40411813 was well
tolerated.
JNJ-40411813 has been evaluated
as adjunctive treatment in a
schizophrenia and anxious
depression study without
exacerbation of tolerability of the
concomitant drugs.
Participants can stop their
participation any time, when the
treatment is not tolerated.
Amendment 4 introduces a dosage
up titration to minimize the
occurrence of common dose-related
adverse events, and an optional dose
reduction to minimize the likelihood
of discontinuation in those that have
adverse events:
All patients in Cohort 2 
 will start the
double-blind phase with a dosage of
 (or matching placebo).
 (or matching placebo)
on day 8 of the double-blind phase.
Up-titration is expected to reduce
the number of early onset AE’s.
For participants receiving dosages
of
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Status: Approved,  Date:  17 November 2022
 i.e., Cohort 2
and beyond, a dosage reduction to
 will be permitted in
case adverse events consisting of
dizziness, incoordination, sedation,
or fatigue (or similar descriptive
terms) which, in the judgment of
the investigator, potentially limit
activities of daily living. The PI is
encouraged to rechallenge if the
AEs are resolved on the lower dose.
If rechallenge is unsuccessful, i.e.,
the AE’s re-occurred when the dose
was increased, the dose may be
reduced again and kept at that level
The safety and tolerability of JNJ-
40411813 in combination with
levetiracetam or brivaracetam will
be reviewed after each cohort
Reduction of JNJ-40411813
may be inferred but have only been
studied in nonclinical models, not
yet in man.
Participants will be stratified into
2 groups, with and without the
concomitant use 
, and 
on physiologically based
pharmacokinetic modeling (PBPK)
of 
. Plasma
concentrations of JNJ-40411813
will be evaluated after each cohort
and doses will be adapted based on
observed interactions.
Increase in the concentration 
Based on in vitro studies, JNJ-
40411813 
Concomitant drugs with a narrow
therapeutic margin 
 Plasma concentrations of
concomitant 
 can be
reduced once if the participant
experiences Aes possibly related to
these AEDs.
2.3.2. 
Benefits for Study Participationa
Treatment resistant epilepsy has a severe impact on quality of life and risk of mortality. JNJ-
40411813 in combination with levetiracetam or brivaracetam shows promise in a nonclinical
model of epilepsy and –if proven efficacious in man too –may result in a significant positive
impact on this patient population.
a 
This section has been amended by Amendment INT-2 and INT-4
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Status: Approved,  Date:  17 November 2022
All participants may benefit from the safety evaluations performed during the study.
The sponsor has added an OLE period to this study (to be initiated when all required supplies are
available), with eligibility for all participants who completed the double-blind study period and
experienced no safety concerns.
2.3.3. 
Benefit-Risk Assessment for Study Participation
The risk/benefit of JNJ-40411813 is favorable and the currently available safety and efficacy data
support the proposed clinical trial 40411813EPY2001 to investigate efficacy and safety of JNJ-
40411813 in participants with focal onset epilepsy.
More detailed information about the known and expected benefits and risks ofJNJ-40411813 may
be found in the current IB for JNJ-40411813.
3. 
OBJECTIVESAND ENDPOINTSa
Objectives 
Endpoints
Primary
The primary objective of this study is to 
evaluate the efficacy of up to 3 dose levels of 
adjunctive JNJ-40411813 compared to 
placebo based on the time to baseline monthly 
seizure count in participants with focal onset 
seizures who are receiving levetiracetam or 
brivaracetam and up to 3 other AEDs
Time to baseline monthly seizure count is
defined, for each patient, as the number of
days until the patient experienced the number
of seizures equal to baseline monthly seizure
count, up to the end of the 12-week double-
blind treatment period.
Secondary
To evaluate the overall safety and tolerability 
of adjunctive JNJ-40411813 compared to 
placebo in participants with focal onset
seizures who are receiving levetiracetam or
brivaracetam and up to 3 other AEDs.
Adverse events, significant changes in vital
signs, ECG and safety laboratory results.
To evaluate the efficacy of up to 3 dose levels 
of adjunctive JNJ-40411813 compared to 
placebo based on percent reduction in the 
double-blind monthly seizure count, relative 
to the pre-randomization monthly seizure 
count, in participants with focal onset 
seizures. 
Percent reduction in the double-blind monthly
seizure count is defined as the double-blind
monthly seizure count minus the baseline
monthly seizure count, divided by the
baseline monthly seizure count.  The double-
blind monthly seizure count is defined as the
total number of observable focal onset
seizures occurring during the 12-week double
blind treatment period, multiplied by 28/XDB,
where is the number of days comprising the
double-blind period.
Observable seizures that will be counted
during baseline and throughout the study
a 
This section has been amended by Amendment INT-1 and INT-3
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4. 
STUDY DESIGN
4.1. 
Overall Designa
This study as per Amendment INT-2 will consist of a double-blind treatment period and an open-
label extension (OLE) period. Details about the OLE period are described in Section 10.
This is a double-blind, randomized, parallel, placebo-controlled study with the option for an OLE
period. The study will consist of 1 to a maximum of 3 cohorts. In each cohort, for each participant
the study consists of a screening visit, an 8-week prospective pretreatment baseline period, an up
to 12-week double-blind treatment period and, for those participants electing not to enter the OLE
period, a follow-up telephone visit 2 weeks after the last dose of study intervention. Participants
have the option to enter an OLE period, in which treatment with JNJ-40411813 may be continued
until the product becomes available by prescription, or until development of JNJ-40411813 in this
indication ceases. The total maximal duration of the study is approximately 22 weeks for each
participant, up to the time of entry into the OLE period.
Participants from 18 to 69 years (inclusive) old with an established diagnosis of focal onset
seizures will be enrolled in the study. For the first cohort, approximately 80 eligible participants
will be initially enrolled to ensure that approximately 60 participants are randomly assigned in a
2:1 ratio to receive either JNJ-40411813 
placebo. For each following cohort, approximately
60 eligible participants will be initially enrolled to ensure that approximately 50 participants are
randomly assigned in a 4:1 ratio to receive either JNJ-40411813
 placebo.
In each cohort, participants will be 
 
At least 20% of the participants must be included in each of the two groups.
After giving written informed consent, participants will be screened immediately prior to the start
of the pretreatment baseline period to ascertain their eligibility for the study per the inclusion and
exclusion criteria. Upon completion of all informed consent form (ICF) procedures, recording of
Aes and concomitant medication will start.
After the screening visit, the data of the participant may be subject to an adjudication process by
independent experts from the epilepsy consortium. In this adjudication process the experts may
decide whether the participant meets eligibility criteria to participate in the study.
After screening, if they meet the in- and exclusion criteria for which data are available, participants
can start the 8-week prospective pretreatment baseline period pending the results of the central
laboratory and –if applicable –the adjudication process. However, when the results of these
a 
This section has been amended by Amendment INT-1 and INT-2 and INT-3
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Status: Approved,  Date:  17 November 2022
assessments indicate that the participant does not meet the in- and exclusion criteria, the participant
will terminate the baseline period and will not be randomized to treatment.
During the 8-week prospective pretreatment baseline period participants will continue to take their
prescribed AEDs (one of which must include levetiracetam or brivaracetam) without change in
dosage(s); new concomitant AEDs should not be added. During the baseline period, participants
will record seizure information (type and frequency of seizures) in an e-diary. Baseline monthly
seizure count will be defined as the number of observable focal onset seizures recorded during the
baseline period, multiplied by 28/XBL, where XBL is the number of days comprising the baseline.
Participants must be compliant with the recording of information in the subject e-diary throughout
the study. Observable seizures that will be counted during baseline and throughout the study,
include focal aware seizures with motor signs, focal impaired awareness seizures and focal to
bilateral tonic-clonic seizures. Focal aware seizures without motor signs, myoclonic, or other
generalized seizures will not be counted.
Participants who meet study entry criteria at the end of the prospective pretreatment baseline period
will be randomized to JNJ-40411813 or placebo, 
. The
dosage(s) of concomitant AEDs should not be increased, and new concomitant AEDs should not
be added to the treatment regimen.
Dosages of JNJ-40411813 in the first cohort will be
or placebo for
,
and
 or placebo 
. Dosages of JNJ-40411813 in Cohort 2 will
be
 or placebo for
 or placebo for 7 days, dose increase
to 
or placebo on day 8) and 
. In the following
cohorts, the dose of JNJ-40411813 will be determined based on an ongoing assessment of
tolerability and safety results from the previous cohort. The highest dose in following cohorts will
be 
. The highest dose selected to be administered by
induced participants will be expected not to exceed the 95th percentile of the
fter repeated administration of
 The minimum dose that might be considered in successive cohorts
will be 
Participants are encouraged to complete at least the first 4 weeks of treatment when there are no
safety concerns. Participants who have exceeded their pre-randomization monthly seizure count at
Week 4, or within any 4-week interval after Week 4 (“4-week sliding window approach”) up to
Week 12, will have the option to discontinue the study drug for lack of efficacy and to perform the
end of study/earlywithdrawal visit, to continue double blind treatment, or to enter the OLE period.
Participants who have not exceeded the pre-randomization seizure count will continue the double-
blind treatment period through Week 12 and will have the option to perform the end of study visit
or to enter the OLE period.
Procedures performed in the OLE period are described in Section 10.
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Status: Approved,  Date:  17 November 2022
optimal treatment. This decision may be based on the incidence of serious adverse events, or
adverse events leading to discontinuation, as a cohort approaches full enrollment. Given a low
incidence of these events, decision to evaluate of a higher dosage in the following cohort can be
made, without pausing screening and enrollment.
The placebo response in studies in epilepsy may be significant (Goldenholz 2016). A placebo
control will be used to establish the change in seizure count and the change in safety endpoints
that may occur in the absence of active treatment.
Stratification
JNJ-40411813 is metabolized mainly by CYP3A4. 
Optional dosage reduction
As noted in the Investigator’s brochure, dizziness, vertigo, coordination abnormal and fatigue are
adverse drug reactions attributable to JNJ-40411813. Somnolence has also been reported. These
are adverse events commonly seen with other AEDs; their frequency and severity may be related
to dose and may be mitigated by temporary dose reduction or dose titration. Accordingly, if these
adverse events occur with increasing frequency when dosages exceed
 e.g. Cohort 2 and beyond, the investigator will have the option to reduce dosage
temporarily, followed by rechallenge. The PI is encouraged to rechallenge the initial dose within
2 weeks if the Aes are resolved on the lower dose. If rechallenge is unsuccessful, i.e., the AEs
recurred when the dose was increased, the dose may be reduced again and kept at that level.
This option will minimize the likelihood of dropout because of adverse events, and will provide
experience to guide dosing instructions in future studies
Time to baseline monthly seizure count as an endpoint
The most commonly used endpoint in studies in epilepsy is the reduction of number over seizures
over a time period during treatment compared to a baseline reference period, operationalized as
percent reduction in seizure frequency relative to baseline, or proportion of participants that have
a 50%  or greater reduction in seizure frequency relative to baseline. A post hoc analysis of
3 randomized, double-blind, placebo-controlled Phase III trials of perampanel in epilepsy
(French 2015) concluded that the time to baseline monthly seizure count as an endpoint appears to
properly differentiate efficacious and nonefficacious dosages, as defined by the traditional
endpoints.
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Status: Approved,  Date:  17 November 2022
Use of time to baseline monthly seizure count as the primary trial outcome could result in a
significant reduction in exposure to placebo or ineffective treatments if participants should exit as
soon as that time point is reached, thereby facilitating trial recruitment and improving safety.
However, participants are encouraged to remain on double-blind treatment for at least 4 weeks
when safety allows this.
Seizure count will be recorded by the participant and/or the caregiver using an e-diary. A seizure
diary has been used in multiple studies in epilepsy. It is known that the use of a diary may result
in underreporting (Blachut 2015). The e-diary  may limit underreporting by allowing entry of
seizures by a caregiver, by sending daily reminders to the participant and by allowing the
participant to use their own lay terms for seizure identification. This e-diary will allow for an
immediate feedback when the time to baseline seizure count has been reached over a period of
4 weeks. This will allow the participant to terminate the study participation if required.
The secondary endpoints will include more commonly used clinical trial endpoints which will
allow comparison against historical trials.
Combination with levetiracetam and brivaracetam.
Nonclinical models have shown a strong positive PD interaction of JNJ-40411813 with
levetiracetam and brivaracetam. These models have been confirmed with multiple mGlu2PAMs
(Metcalf2017, 2018). The mechanism of action of levetiracetam and brivaracetam is through
binding to SV2a in the brain resulting in a modification of glutamate release. By the positive
allosteric modulation of the mGlu2-receptor, JNJ-40411813 also modifies glutamate release.
However, the mechanism by which these effects synergize in presynaptic terminals has not been
clarified in detail yet.
Study population
Male and female participants with focal onset epilepsy and not having primary generalized seizures
will be enrolled in this study. The upper age limit will be 69 years, as participants over 70 years of
age have an increasing incidence of progressive neurodegenerative diseases, which would make
interpretation of longer-term changes in seizure frequency and tolerability more difficult to
interpret.
Inclusion of women of childbearing potential (WOCBP) is supported by the absence of toxicity
seen in Segment II reproductive toxicology studies. WOCBP will use a highly effective birth
control method as outlined in the inclusion criteria (see Section 5.1).
Participants may benefit from their participation during the study. In addition, an OLE period has
been added to this study to allow continued use of JNJ-40411813 in combination with
levetiracetam or brivaracetam for those participants who benefit from this treatment.
Duration of study periods
Participants will be dosed with study intervention over 12 weeks. This is a common duration of
evaluation of AED’s in clinical studies (EMA 2018, FDA 1981). After at least 55 participants in a
cohort 1 and at least 45 patients in Cohort 2 have completed 4 weeks of treatment, an interim
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unblinded review of all cumulative safety, PK and efficacy data of JNJ-40411813 available to that
date will be performed to decide on the dose in the following cohort. If the results of the review
are inconclusive, a second interim review of the same cohort may be done after the last participant
has completed the 12-week visit.
Based on an evaluation of the variability of seizure count in prior epilepsy studies completed by
the sponsor (Janssen, data on file), a baseline duration of 8 weeks was considered to give a more
accurate and representative estimate of monthly seizure count than shorter periods.
The double-blind study period will be followed by a follow-up period of 2 weeks if the participant
does not take part in the OLE period. The dose will not be tapered after completion of the double-
blind study period. Although there are no signals of a rebound effect after stopping the treatment
with JNJ-40411813 from preclinical studies or previous clinical studies, the change of seizure
count after stopping the treatment will be investigated in the follow-up period.
Safety assessments
Standard safety assessments including physical and neurological examination, vital signs, 12-lead
ECG, clinical chemistry, hematology, and urinalysis will be performed.
Additionally, emergence of suicidal ideation will be assessed using the Columbia Suicide Severity
Rating Scale (C-SSRS) (Posner 2007, See Section 11.9). The C-SSRS has been used frequently in
clinical studies and is a standard measure for suicidal ideation assessment according to Food and
Drug Administration (FDA) guidance (US FDA 2012).
Biomarkers
Blood samples will be collected to determine the plasma concentration of 
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This section has been amended by Amendment INT-1, INT-3, and INT-4
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.
Pharmacokinetics
Blood samples will be collected to determine plasma concentration of JNJ-40411813 in plasma.
The sampling days and times were selected so that population PK and/or PBPK analyses analysis
could be conducted for the parent drug. The concentrations of metabolite
 the most prominent
metabolite in human plasma after repeated administration of JNJ-40411813, 
 which is
equipotent to the parent drug for mGlu2, and
 will be measured.
The plasma concentration of levetiracetam or brivaracetam will be measured so that safety, in the
presence and absence of JNJ-40411813 may be assessed (i.e., confirm that circulating levels of
levetiracetam or brivaracetam are not altered).
 since
they were the most frequently used AEDs in the Phase 3 program of perampanel, an AED approved
for the adjunctive treatment of partial-onset and primary tonic-clonic seizures in patients ≥12 years
of age 
 (Majid 2016). In
Pharmacogenomics
It is recognized that genetic variation can be an important contributory factor to interindividual
differences in drug distribution and response and can also serve as a marker for disease
susceptibility and prognosis. 
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
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Clinical Protocol 40411813EPY2001, Amendment INT-4
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Status: Approved,  Date:  17 November 2022
. The balance of the dose between
 in
Cohorts 3 and 4 may change based on the observed plasma concentrations in a previous cohort.
4.4. 
End of Study Definitiona
End of Study Definition for the double-blind period.
The end of study for the double-blind period is considered as the last visit for Visit 7 for the last
participant in the study. The final data for the double-blind period from the study site will be sent
to the sponsor (or designee) after completion of the final participant visit at that study site, in the
time frame specified in the Clinical Trial Agreement. The double-blind study period will be
analyzed separately from the OLE period.
5. 
STUDY POPULATION
For the first cohort, approximately 80 eligible participants will be initially included to ensure that
approximately 60 participants are randomly assigned in a 2:1 ratio to receive either JNJ-40411813
or placebo. For each following cohort, approximately 60 eligible participants will be initially
enrolled to ensure that approximately 50 participants are randomly assigned in a 4:1 ratio to receive
either JNJ-40411813 
 or placebo. If 3 cohorts are studied, the total number randomized would
be 160 participants. The inclusion and exclusion criteria for enrolling participants in this study are
described in the following sections. If there is a question about the inclusion or exclusion criteria
below, the investigator should consult with the study responsible physician (SRP) before entering
the participant into the study. Exceptional and limited re-testing of abnormal screening values,
including laboratory values, that lead to exclusion are allowed only once to reassess eligibility.
This should only be considered if there is no anticipated impact on participant safety.
Participants will be enrolled after reading the participant information sheet and signing the ICF
indicating that they understand the purpose of, and procedures required for the study and are
willing to participate in the study and comply with the study procedures.
5.1. 
Inclusion Criteriab
Each potential participant must satisfy all the following criteria to be enrolled in the study.
Epilepsy related inclusion criteria
1. Participants must be men or women, 18 to 69 years of age, inclusive.
Note: Participants should be at least 18 years of age or older as per the legal age of consent in
the jurisdiction in which the study is taking place.
2. Body Mass Index (BMI) between 18 and 35 kg/m2inclusive (BMI=weight/height2). Minimum
body weight should be 40 kg.
3. Criterion modified by Amendment INT-1
a 
This section has been amended by Amendment INT-2
b 
This section has been amended by Amendment INT-2 and 3
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3.1 Criterion modified by Amendment INT-2
3.2 Established diagnosis of focal epilepsy, using the International League Against
Epilepsy (ILAE) criteria (Fisher 2017). Participants should not be enrolled if they are
known to have had fewer than 3 or more than 100 seizures in any monthly period in the
past 6 months. It is preferred that participants have experience in maintaining a seizure e-
diary.
4. Criterion modified by Amendment INT-1
4.1 Must have had a neuroimaging procedure within 10 years, including a computed
tomography (CT) scan or magnetic resonance imaging (MRI), that excluded a progressive
neurologic disorder; these procedures may be performed within the 8-week baseline
period.
5. Criterion modified by Amendment INT-2
5.1. Criterion Modified by Amendment INT-3
5.2.
5.2.1. Cohort 1: Current treatment with at least 1 and up to 4 AEDs (including
levetiracetam), administered at the appropriate dosage(s) and for a sufficient
treatment periodbefore screening. These AEDs must remain unchanged throughout
the pretreatment and double-blind treatment periods (with the exception of dosage
reductions of concomitant AEDs because of suspected elevated AED levels or side
effects).
5.2.2. Cohort 2 and beyond: Current treatment with at least 1 and up to 4 AEDs
(including levetiracetam or brivaracetam), administered at the appropriate
dosage(s) and for a sufficient treatment period before screening. These AEDs must
remain unchanged throughout the pretreatment and double-blind treatment periods
(with the exception of dosage reductions of concomitant AEDs because of
suspected elevated AED levels or side effects). Important note: screening of
patients receiving Brivaracetam will start when enrolling for Cohort 2.
 Note: One-time changes in AED dosages do not represent a change in the daily AED
regimen. For example, if the participant took an extra dose of an AED on one day, this
would not represent a change in the daily AED regimen. Benzodiazepines and barbiturates
received on a continuing basis at stable dosages for 1 month before screening should be
considered as concomitant AEDs, except if they are taken to treat anxiety.
6. This criterion has been removed per Amendment INT-2.
7. Participants who continue to meet entry criteria at the end of the baseline period must also
meet the following criteria to be randomly assigned to treatment in the double-blind treatment
period of the study:
 Have had ≥3 and ≤100 seizures* per 28 days within the first 4 weeks and also within the
second 4 weeks of the baseline period.
 No seizure-free interval for more than 21 days
* Baseline seizure count includes: focal aware seizures with motor signs, focal impaired
awareness seizures, and focal to bilateral tonic-clonic seizures.
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Do not count: Focal aware seizures without motor signs, myoclonic, or other generalized
seizures will not be counted.
Other inclusion criteria
8. Healthy on the basis of clinical laboratory tests performed at screening. If the results of the
serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the
participant may be included only if the investigator judges the abnormalities or deviations
from normal to be not clinically significant or to be appropriate and reasonable for the
population under study. This determination must be recorded in the participant's source
documents and initialed by the investigator.
9. Healthy on the basis of physical examination, medical history, vital signs, and 12-lead ECG
[means of triplicate ECG, incl. QTcF ≤ 450 msec for males and ≤ 470 msec for females; PR
interval <220 msec] performed at screening. Minor abnormalities in ECG, which are not
considered to be of clinical significance by the investigator, are acceptable. The presence of
Left Bundle Branch Block (LBBB), atrioventricular (AV) Block (second degree or higher), or
a permanent pacemaker or implantable cardioverter defibrillator [ICD] will lead to exclusion.
10. Men who are sexually active with a woman of childbearing potential and have not had a
vasectomy must agree to use a barrier method of birth control i.e., a condom with spermicidal
foam/gel/film/cream/suppository for the duration of the study plus 3 months after receiving
the last dose of study drug, and all men must not donate sperm during the study and for
3 months after receiving the last dose of study drug. In addition, male participants should also
be advised of the benefit for a female partner to use a highly effective method of contraception
as condom may break or leak.
11. Before first dosing, a woman must be either:
a. Not of childbearing potential. This may include:
i. Postmenopausal: A postmenopausal state is defined as no menses for
12 months without an alternative medical cause. A high follicle stimulating
hormone (FSH) level (>40 IU/L or mIU/mL) in the postmenopausal range
may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however
in the absence of 12 months of amenorrhea, a single FSH measurement is
insufficient). If there is a question about menopausal status in women on
HRT, the woman will be required to use one of the non-estrogen-containing
hormonal highly effective contraceptive methods if she wishes to continue
HRT during the study.
ii. Permanently sterilized. Permanent sterilization methods include
hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation
procedures, and bilateral oophorectomy.
iii. Otherwise be incapable of pregnancy.
b. Of childbearing potential and practicing a highly effective method of contraception
(failure rate of <1% per year when used consistently and correctly) consistent with
local regulations regarding the use of birth control methods for participants
participating in clinical studies and agrees to remain on a highly effective method
while receiving study intervention and until 3 months after last dose - the end of
relevant systemic exposure. Examples of highly effective methods of contraception
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are located in Section 11.6, Appendix 6. Contraceptive and Barrier Guidance and
Collection of Pregnancy Information
Note: If a woman of childbearing potential who is not heterosexually active becomes active
after the start of the study, she must begin a highly effective method of birth control, as
described in Section 11.6, Appendix 6. Contraceptive and Barrier Guidance and Collection
of Pregnancy Information.
12. A woman of childbearing potential must have a negative serum pregnancy test at screening
and a negative urine pregnancy test before the first dose.
13. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for at least 3 months after receiving the last dose of study
intervention.
14. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
15. Sign an ICF indicating that they understand the purpose of, and procedures required for the
study and are willing to participate in the study.
16. To participate in the optional pharmacogenomic component of this study, participants (or their
legally acceptable representatives) must have signed the ICF for pharmacogenomic research
indicating willingness to participate in the pharmacogenomic component of the study (where
local regulations permit). Refusal to consent for this component does not exclude a participant
from participation in the study.
5.2. 
Exclusion Criteriaa
Epilepsy related exclusion criteria
1. Have a generalized epileptic syndrome.
2. Diagnosis of Lennox-Gastaut Syndrome.
3. Currently experiencing seizures that cannot be counted accurately, for example, because of
the following reasons:
 Extreme frequency or clustering.
 Lack of clear onset and cessation between seizures.
 Lack of informant to provide a seizure count when the participant is unable to
independently recall.
4. History of any current or past nonepileptic seizures, including psychogenic seizures.
5. Criterion modified by Amendment INT-2
5.1 Recently initiated vagus nerve stimulation, deep brain and cortical stimulation (i.e.
in the last 12 months before screening).
6. Planned epilepsy surgery within the next 6 months or completed epilepsy surgery < 6 months
ago.
7. Criterion modified by Amendment INT-4
a   This section has been amended by Amendment INT-2, INT-3 and INT-4
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7.1. Current treatment with vigabatrin. In the case of history of previous use of vigabatrin, a
visual field examination must have been performed in the past after vigabatrin
discontinuation. This examination should have been reliable and performed by an
ophthalmologist or neuro-ophthalmologist. The visual field examination does not have to be
normal but must be stable. Participants that have not had the visual field examination after
vigabatrin discontinuation could have one done at any point prior to randomization.
Other exclusion criteria
8. History of malignancy within 5 years before screening (exceptions are squamous and basal
cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is
considered cured with minimal risk of recurrence).
9. Current or past (within the past year) major psychotic disorder, such as schizophrenia, bipolar
disorder, or other psychotic conditions, recent (within the past 6 months) interictal psychosis,
and MDD with psychotic features.
10. Exacerbation of MDD within the past 6 months; antidepressant use is allowed.
11. Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) at
Screening, or other clinically active liver disease (in SoA).
12. History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV
at Screening.
13. Has a current or recent history of clinically significant suicidal ideation within the past
6 months, corresponding to a score of 4 (active suicidal ideation with some intent to act,
without specific plan) or 5 (active suicidal ideation with specific plan and intent) for ideation
on the C-SSRS, or a history of suicidal behavior within the past 1 year, as validated by the C-
SSRS at screening. Participants with a prior suicide attempt of any sort, or prior serious
suicidal ideation/plan > 6 months ago, should be carefully screened for current suicidal
ideation and only included at the discretion of the investigator.
14. Participant has a history of at least mild drug or alcohol use disorder according to Diagnostic
and Statistical Manual of Mental Disorders (5th edition) (DSM-5) criteria within 1 year before
Screening.
15. Criterion modified by Amendment INT-3
15.1 Criterion modified by Amendment INT-4
15.2 Positive test result(s) for alcohol and/or drugs of abuse (opiates [including
methadone], cocaine, amphetamines, methamphetamines, cannabinoids [does not apply for
subjects using cannabidiol as AED or subjects using medical cannabis to treat a medical
condition that is part of the medical history], barbiturates, ecstasy and benzodiazepines
[does not apply for subjects using benzodiazepines or barbiturates as AED , rescue
medication in epilepsy or treatment of anxiety]) at screening.
Subjects with a positive alcohol or drug screen may have the test repeated once, based on the
investigator's discretion. This determination, and the reason for permitting a repeat test, must
be recorded in the subject's source documents and initialed by the investigator. A positive,
repeat alcohol or drug screen is exclusionary.
16. Clinically significant acute illness within 7 days prior to study intervention administration.
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17. Received an investigational intervention (including investigational vaccines) or used an
invasive investigational medical device within 90 days before the planned first dose of study
intervention or is currently enrolled in an investigational interventional study.
18. Known allergies, hypersensitivity, or intolerance to placebo, JNJ-40411813 or its excipients
(See IB).
19. Taking any disallowed therapies as noted in Section  6.5, Concomitant Therapy before the
planned first dose of study intervention.
20. Inability to swallow the study intervention whole with the aid of water.
21. Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an equivalent
amount of blood within 90 days prior to study intervention administration.
22. Pregnant, or breast-feeding, while enrolled in this study.
23. Had major surgery, (e.g., requiring general anesthesia) within 8 weeks before screening, or
will not have fully recovered from surgery, or has surgery planned during the time the
participant is expected to participate in the study or within 4 weeks after the last dose of study
intervention administration
Note: Participants with planned surgical procedures to be conducted under local anesthesia
may participate
24. Psychological and/or emotional problems, which would render the informed consent invalid,
or limit the ability of the participant to comply with the study requirements.
25. Any condition that in the opinion of the investigator would complicate or compromise the
study, or the wellbeing of the participant.
26. Employees of the investigator or study center, with direct involvement in the proposed study
or other studies under the direction of that investigator or study center, as well as family
members of the employees or the investigator.
27. Vulnerable participants (e.g., a person kept in detention).
28. Participants unable to read and understand the consent forms and patient reported outcomes,
complete study-related procedures, and/or communicate with the study staff. Participants with
mild intellectual or cognitive disability are allowed in the study when they have the capacity
to provide consent, or at least assent with consent provided by a legally authorized person.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
Ifa participant's status changes (including laboratory results) after screening but before first dose
of study intervention is given such that they now meet an exclusion criterion, they should be
excluded from participation in the study.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. Refer to Section 6.5, Concomitant Therapy for details regarding prohibited and restricted
therapy during the study.
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2. Agree to follow all requirements that must be met during the study as noted in the Inclusion
and Exclusion Criteria (e.g., contraceptive requirements).
5.3.1. 
Meals and Dietary Restrictions
1. Participants may not consume any food or beverages containing, grapefruit juice, Seville
oranges (including any orange marmalade), or quinine (e.g., tonic water) from 48 hours
(72 hours in the case of grapefruit juice and Seville oranges) before the first dose of study
intervention until the last dose of study intervention.
2. Participants may not consume food containing poppy seeds from  72 hours before to
completion of the screening visit.
5.3.2. 
Caffeine, Alcohol, and Tobacco
1. Participants should abstain from using excessive alcohol or any illegal drugs within 3 days
prior to Day 1 and at any time during the study. Current low to moderate use of alcohol as
approved by the investigator may be continued unchanged.
2. The participant will be advised not to change the current use of caffeine and current smoking
behavior.
5.3.3. 
Activity
1. Should avoid driving or operating complex machinery until the participant knows whether the
drug adversely affects reaction time or impairs judgment.
2. Participants must avoid donating blood for at least 90 days after completion (i.e., final follow-
up visit) of the study.
5.4. 
Screen Failuresa
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
Exceptional and limited re-testing of abnormal screening values, including laboratory values, that
lead to exclusion are allowed only once to reassess eligibility. However, if the participant is a
screen failure based on the adjudication process by independent experts from the epilepsy
consortium at screening, re-testing will not be allowed.
a 
This section has been amended by Amendment INT-1 and INT-3
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If the adjudication process is not possible e.g., because of technical limitations of protected data
transfer, the participant will not be a screen failure.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened one time after discussion with the sponsor representative. Rescreened participants
will be assigned a new participant number, undergo the informed consent process, and then start
a new screening and baseline phases. Rescreened individuals must meet all criteria before
entering the double-blind phase.
6. 
STUDY INTERVENTIONS
For description of the study intervention in the OLE period, see Section 10.6.
6.1. 
Study interventions Administereda
JNJ-40411813 will be supplied for this study as 25-mg and 50-mg tablets. Placebo will be supplied
as matching tablets.
The tablets will be taken 
from Day 1 to Day 85 (or day of Visit 7 when before Day 85).  All
study intervention, apart from the study intervention taken in the clinic during Visits 2, 4, and 6
will be taken at home and intake of the intervention should be confirmed in the e-diary.
Study intervention should be taken in fed condition during or immediately
. The tablets must be swallowed whole with water and not chewed, divided,
dissolved or crushed.
The
 dose will be ingested immediately 
 Visit 2 (Day 1) of the double-blind
period when the participant is in the clinic 
. Dosing during the site visit will be
witnessed by the study staff. 
The participants will bring the study intervention and all other AEDs currently taken with them at
each study visit.
On the day of Visit 4 (Week 4) and Visit 6 (Week 8), 
 will be ingested in the
study center during or 
uring the study visit and not at home. Dosing
during the site visit will be witnessed by the study staff. 
  For Visit 7,
The actual dose and the composition of tablets to be taken will be determined for each cohort and
stratum within a cohort. In Table 1 below the most likely examples are presented. However, these
examples may change based on actual dose decisions.
a 
This section has been amended by Amendment INT-1
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A description of the study interventions is presented in Table 2:
Table 2: 
Description of Interventions
Arm Name 
JNJ-40411813 
Placebo
Intervention Name 
JNJ-40411813 
Placebo
Type 
Drug 
Drug
Dose Formulation 
Tablet 
Tablet
Unit Dose Strength(s) 
25 or 50 mg JNJ-40411813 
Placebo
 
 
Route of Administration 
oral 
oral
Use 
experimental 
Placebo-comparator
Investigational Medicinal Product 
(IMP) and Non-Investigational
Medicinal Product (NIMP)
IMP  
IMP
Sourcing 
Provided centrally by the Sponsor Provided centrally by the Sponsor
Packaging and Labeling 
Provided in child-resistant 
packaging, labeled to meet 
applicable regulatory 
requirements. 
Provided in child-resistant
packaging, labeled to meet
applicable regulatory
requirements.
 
 
 
 
 
 
 
.
6.2. 
Preparation, Handling, and Storage
All study intervention will be manufactured and provided under the responsibility of the sponsor.
All study intervention will be provided in child-resistant high-density polyethylene bottles. All
study intervention will be stored in a secure area with restricted access. Tablets must be stored at
controlled room temperatures as indicated on the product specific labeling.
The investigator is responsible for ensuring that all study intervention  received at the site is
inventoried and accounted for throughout the study. The dispensing of study intervention to the
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participant, and the return of study intervention from the participant, must be documented in the
interactive web response system (IWRS) system. Participants must be instructed to return all
original study intervention kits, whether empty or containing study intervention.
Study intervention must be handled in strict accordance with the protocol and the label. Unused
study intervention, and study intervention  returned by the participant, must be available for
verification by the sponsor's study site monitor during on-site monitoring visits. The return to the
sponsor of unused study intervention, or used returned study intervention for destruction, will be
documented on the study intervention return form. When the study site is an authorized destruction
unit and study intervention supplies are destroyed on-site, this must also be documented on the
medication return form.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
6.3. 
Measures to Minimize Bias: Randomization and Blindinga
Procedures for Randomization
Central randomization will be implemented in this study. Participants will be randomly assigned
to one of two treatment groups based on computer-generated randomization schedules prepared
before the study by, or under the supervision of the sponsor.
The randomization will be balanced by using randomly permuted blocks 
The IWRS will assign a unique treatment code, which will dictate the treatment assignment and
matching study drug kits for the participant. The requestor must use his or her own user
identification and personal identification number each time when contacting the IWRS and will
then give the relevant participant details to uniquely identify the participant.
For programming of the IWRS-system, the following cohort numbers will be applied:
 
Cohort 1: first cohort with 
dose level (approximately  40 participants
receiving JNJ-40411813 and approximately 20 receiving placebo)
 
Cohort 2: second cohort with a dose level of
 (approximately 40 participants
receiving JNJ-40411813 and approximately 10 receiving placebo)
 
Cohort 3: third cohort with a higher dose if the efficacy of the higher dose used in Cohort 2 is
still insufficient (approximately 40 JNJ/ approximately 10 placebo)
a 
This section has been amended by Amendment INT-1
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 
Cohort 4: this cohort includes both a lower dose and a higher dose. This cohort will randomize
100 subjects in a ratio 40:40:20 (high dose/low dose/placebo). This cohort may follow Cohort
2.
Blinding
Blinded treatment will be used to reduce potential bias during data collection and evaluation of
clinical endpoints. Participants and investigators will be blinded for treatment (JNJ-40411813 or
placebo) but not for dose.
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the treatment assignment (e.g., study intervention  plasma
concentrations, plasma biomarkers) will be handled with special care to ensure that the integrity
of the blind is maintained and the potential for bias is minimized. This can include making special
provisions, such as segregating the data in question from view by the investigators, clinical team,
or others as appropriate until the time of database lock and unblinding. Also, the site staff should
not discuss insights on unblinding of randomization with the participants.
Under normal circumstances, the blind should not be broken until all participants have completed
the study and the database is finalized. The investigator may in an emergency determine the
identity of the treatment by contacting the IWRS. While the responsibility to break the treatment
code in emergency situations resides solely with the investigator, it is recommended that the
investigatorcontact the sponsor or its designee, if possible, to discuss the particular situation before
breaking the blind. Telephone contact with the sponsor or its designee will be available 24 hours
per day, 7 days per week. In the event the blind is broken, the sponsor must be informed as soon
as possible. The date, time, and reason for the unblinding must be documented in the appropriate
section of the electronic case report form (eCRF), and in the source document. The documentation
received from the IWRS indicating the code break must be retained with the participant's source
documents in a secure manner. Participants who have had their treatment assignment unblinded
should continue to return for required follow-up evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed. However, for the interim review in each cohort (see Section 9.5) and
for unblinded review by the data review committee (DRC, see Section 7.1), the randomization
codes and the translation of randomization codes into treatment and control groups will be
disclosed to those authorized and only for those participants included in the interim review.
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6.4. 
Study Intervention Compliancea
Study intervention will be taken by the participant at home or during a study visit in the clinic. The
first dose will be taken by the participantat Visit 2 (Day 1)of the study in the clinic. The participant
will be instructed to take their study intervention to the clinic at each study visit.
When in the clinic during visits 2 and 4, study intervention will be self-administered on site as
outlined in  Section 6.1. The administration of study intervention will be witnessed by the
investigator or a properly trained designee. The exact date and time of study intervention
administration will be recorded in the eCRF.
The participant will receive an e-diary to record –apart from seizures –the intake of the study
intervention.
For study visits 2, 4 and 6, participants are requested to record the time of last dosing of
levetiracetam or brivaracetam, their 
 and the study drug on the day before the study visit. Participants will also record
the time of last dosing of levetiracetam or brivaracetam and study drug taken at home prior to visit
7. An appointment-card will be provided for documentation.
The investigator or designated study personnel will maintain a log in IWRS of all study
interventiondispensed and returned. Study interventionsupplies will be inventoried and accounted
for throughout the study.
If appropriate, additional details may be provided in a pharmacy manual/study site investigational
product manual that is provided separately and noted in Section 8.1, Study-Specific Materials.
6.5. 
Concomitant Therapyb
All prestudy therapies administered up to 30 days before screening must be recorded at screening
(and confirmed by treating physician).
During the 8-week prospective pretreatment baseline period and during the 12-week double-blind
treatment period, participants will continue to take their prescribed AEDs (one of which must
include levetiracetam or brivaracetam) without change in dosage(s); new concomitant AEDs
should not be added. For the concomitant AEDs including levetiracetam or brivaracetam, all doses
within the limits of current clinical practice will be allowed. Concomitant AEDs will not be
provided by the study sponsor.
Two exceptions to this rule will be allowed:
a 
This section has been amended by Amendment INT-1
b 
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 
Based upon clinical judgment, a one-time dosage adjustment of concomitant AEDs is
permitted to mitigate adverse events attributable to those AEDs. Collection of blood for
plasma concentration of these AEDs is allowed, at the discretion of the investigator.
 
One-time changes in AED dosages do not represent a change in the daily AED regimen. For
example, if the participant took an extra dose of an AED on one day, this would not represent
a change in the daily AED regimen.
Rescue medication may be used as needed (PRN). Each administration of rescue medication must
be documented in the seizure e-diary. However, benzodiazepines or barbiturates received on a
continuing basis at stable dosages for 1 month before screening should be considered as
concomitant AEDs. Benzodiazepines or barbiturates used as sleep aid or to treat anxiety will be
allowed but should be documented in the eCRF.
For levetiracetam or brivaracetam drug intake on the days of study visits, the same rule applies as
for JNJ-40411813: On the day of Visits 2, 4, 6 and 7
 will be taken in the study
center during the study visit and 
. Dosing during the site visit will be witnessed by the
study staff. 
. Participants taking
levetiracetam XR should preferably take their medication in the morning and take this medication
in the clinic during Visits 2, 4, 6 and 7. If the participant takes levetiracetam XR in the evening,
this should not be changed for the study.
For study visits 2, 4, 6 and 7 participants are requested to record the time of last dosing of
levetiracetam on the day before the study visit. Participants will also record the time that
levetiracetam is taken at home prior to visit 7. An appointment-card will be provided for
documentation.
 Dosing during the site visit will be
witnessed by the study staff. 
. 
For the study visits 2, 4 and 6, participants are requested to record the date and time of last dosing
of 
 when applicable on the day before the
study visit. An appointment-card will be provided for documentation.
JNJ-40411813 is primarily metabolized by CYP3A4.
Section 11.5 includes examples of disallowed CYP3A4 inhibitors (prohibited from 14 days or at
least 5 times the drug’s half-life, whichever is longer prior to study drug administration until the
follow-up visit) and inducers (prohibited from at least 1 month prior to study drug administration
until the follow-up visit).
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Similarly, participants should avoid consumption of grapefruit, grapefruit juice and Seville oranges
(including orange marmalade) and herbal products containing St. John’s wort, ephedra, ginkgo,
ginseng, or kava.
JNJ-40411813 itself is also an inhibitor of CYP3A4 and
or CYP3A4 metabolism
and have a narrow therapeutic index with caution.
Examples of drug classes that include sensitive substrates to CYP3A4 and have a narrow
therapeutic index include opioid analgesics, chemotherapy/oncologic agents, and
immunosuppressive agents. Additional sensitive substrates that have a narrow therapeutic index
include amiodarone, clindamycin, dihydroergotamine, dofetilide, ergotamine, and theophylline.
See Section 11.5 for an overview of drugs to be avoided.
If the administration of any concomitant therapy becomes necessary, it must be reported in the
appropriate section of the eCRF.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.6. 
Recording of drug intake; overview
The participant will receive an e-diary to record the intake of the study intervention. In the e-diary,
only confirmation of intake of study medication and rescue medication are recorded. The time of
intake will not be recorded in the e-diary. Intake of rescue medication should also be recorded in
the eCRF.
For reasons of proper PK analysis of study medication, levetiracetam or brivaracetam and currently
used AEDs that are substrate of CYP3A4, at some occasions the date and time of the drug intake
needs to be recorded by the participant (using the subject participation card) or the investigator/site
staff (using the eCRF) outside the scope of the e-diary.
An overview of this specific recordings of date and time of intake of AEDs is given in Table 3.
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Table 3: 
Recording of date and time oflast drug intake outside the scope of the e-diary.
Study 
visit 
When to 
record. 
Study drug 
Levetiracetam/
brivaracetam
2
Day before 
Not applicable 
By participant 
By participant
During visit 
By investigator 
By investigator 
By investigator
4
Day before 
By participant 
By participant 
By participant
During visit 
By investigator 
By investigator 
By investigator
6
Day before 
By participant 
By participant 
By participant
During visit 
By investigator 
By investigator 
By investigator
7 
Same day, prior
to the visit
By participant 
By participant 
Not applicable
During visit 
Not applicable 
Not applicable 
Not applicable
*
6.7. 
Intervention After the End of the Studya
Investigators may re-contact the participant to obtain follow-up information regarding the
participants’ safety if there are any safety concerns at the last study visit.
Participants should continue taking the AEDs they were using during the study until such time as
changes in their treatment are recommended by their treating physician. Changes in their treatment
for epilepsy will be allowed when required during the follow-up period.
The sponsor has added an OLE period to this study (to be initiated when all required supplies are
available), with eligibility for all participants who completed the double-blind study period and
experienced no safety concerns.
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This section has been amended by Amendment INT-2
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study intervention or withdraws from the study before the end of the
double-blind period, the early withdrawal assessments (Visit 7) should be obtained.
7.1. 
Safety Data Review
Continuous or periodic blinded safety reviews will be done by the SRP. An unblinded review of
the data (on the individual participant level) will be conducted if there are safety concerns from
this blinded review as a result of severe, serious or unexpected AEs that are at least possibly related
to the study intervention or if the frequency of discontinuations due to TEAEs exceeds 10% of the
participants (see Section 7.4).
This unblinded review will be done by a DRC. A DRC will consist of at least one medical expert
in the relevant therapeutic area and at least one statistician; committee membership
responsibilities, authorities, and procedures will be documented in a separate charter.
In addition to the above, an interim unblinded review of safety, PK and efficacy data will be
performed by an internal unblinded review committee as described in Section 9.5.
7.2. 
Completion
A participant will be considered to have completed the double-blind period of the study if he or
she has completed the double-blind period up to Week 12 or has elected to exit after reaching the
baseline monthly seizure count by Day 28 or exceeding the monthly baseline seizure count during
a moving 28-day interval after Day  28. Participants who prematurely discontinue the study
intervention for any  other reason before completion  of the double-blind period will not be
considered to have completed double-blind period of the study.
Any participant who discontinues the study before Week 12 after receiving the study intervention
will have an early withdrawal evaluation as described in Section 8.2.4.
Participants who discontinued the double-blind period for reason other than safety concerns, are
allowed to enter the open-label extension period. See Section 10.
Participants who prematurely discontinue the study will not be replaced.
7.3. 
Participant Discontinuation/Withdrawal from the Studya
A participant will be withdrawn from the study for any of the following reasons. The participant
must discontinue the study intervention and, whenever possible, the early withdrawal visit must
be completed.
 
Lost to follow-up
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 
Death
 
Withdrawal of consent. When a participant withdraws consent, effort should be made to
determine if the cause of withdrawal was due to tolerability or lack of efficacy.
 
Noncompliance to take the study intervention. Noncompliance will be decided on a case-by-
case basis depending on the number of missed tablets and the interval between missed doses.
 
Experiences a severe adverse event or serious adverse event (SAE)while receiving treatment,
that is considered at least possibly related to study drug.
 
The investigator or sponsor believes (e.g., that for safety or tolerability reasons such as a SAE
at least possibly related to the study intervention) it is in the best interest of the participant to
discontinue the study intervention.
 
A participant who shows signals of clinically meaningful acute suicidal ideation at any time
during the study should be withdrawn from the study and promptly referred for appropriate
medical/psychiatric care.
 
The participant becomes pregnant.
 
If the QTcF interval is higher than 500 msec or is prolonged >60 msec from the baseline
(Screening) value. If the QTcF is not readily available, the QTcB may be used instead. The
participant will continue to be monitored (maximum 12 hours) by repeated 12-lead ECGs (at
least every 60 minutes) until the ECG normalizes.
 
Ifthe liver function tests exceed the values as presented in Section 11.7.
When a participant withdraws before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document. Study interventionassigned to the withdrawn
participant may not be assigned to another participant.
7.4. 
Protocol Stopping Criteria
Blinded medical monitoring by the sponsor will occur on a continuous basis including AEs,
laboratory and ECG data. When there is any concern about the safety of the participants as a result
of severe or serious AEs that are at least possibly related to JNJ-40411813 or if the frequency of
discontinuations due to TEAEs exceeds 10% of participants, an unblinded review of the safety
data will take place (see Section 7.1). The cohort will be stopped at any time ifsignificant safety
concerns are related to JNJ-40411813 as per the reviewers’ decision. However, if the safety
observations allow, a new cohort with a lower dose of JNJ-40411813 may be started. If safety
concerns continue, or when safety concerns are not expected to be solved by a dose reduction, the
study will be stopped. The principal investigator (PI) may decide to stop study participation at any
time when he/she estimates there is an acute risk for participants in study.
7.5. 
Withdrawal from the Use of Research Samples
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in Section 11.3). In such a case, samples will
be destroyed after they are no longer needed for the clinical study. Details of the sample retention
for research are presented in the ICF.
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7.6. 
Lost to Follow-up
If a participant is lost to follow-up, every reasonable effort must be made by the study site
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The
measures taken to follow-up must be documented. Refer to Section 7.3, Participant
Discontinuation/Withdrawal from the Study.
8. 
STUDY ASSESSMENTS AND PROCEDURES
For study assessments and procedures in the OLE period, see Section 10.8
8.1. 
Overviewa
The SoA summarizes the frequency and timing ofall assessments applicable to this study.
Repeat or unscheduled blood samples may be taken for safety reasons, additional PK samples or
for technical issues with the samples.
Additional serum (by local laboratory) or urine pregnancy tests may be performed, as determined
necessary by the investigator or required by local regulation, to establish the absence of pregnancy
at any time during the participation in the study.
The total blood volume to be collected from each participant will be approximately 76 mL.
For each participant, the maximum amount of blood drawn from each participant in this study will
not exceed 200 mL.
Volume of Blood to be Collected from Each Participant
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Participant 
Approximate
Total Volume
of Blood (mL)[a]
Hematology  
2 
5 
10
Serum chemistry  
2.5 
5 
12.5
Serology (HIV, hepatitis) 
7.5 
1 
7.5
Serum β-HCG pregnancy test 
1.5 
1 
1.5
Pharmacokinetic samples[b] 
2 
14 
28
Biomarker Sample Collection 
2 
4 
8
Pharmacogenomics 
8 
1 
8
Approximate Total[c] 
75.5
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Includes the samples for JNJ-40411813 and metabolites, levetiracetam/ brivaracetam and
.
c. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the
samples.
Note: An indwelling intravenous cannula may be used for blood sample collection.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded on the laboratory requisition
form. If blood samples are collected via an indwelling cannula, an appropriate amount (1 mL) of
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serosanguineous fluid slightly greater than the dead space volume of the lock will be removed
from the cannula and discarded before each blood sample is taken. After blood sample collection,
the cannula will be flushed and charged with a volume equal to the dead space volume of the lock.
If a mandarin (obturator) is used, blood loss due to discard is not expected.
Refer to the SoA for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual(s) that will be provided before the start of the study. The exact dates and times
of blood sampling must be recorded in the CRF.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
IB for JNJ-40411813.
 
Pharmacy manual/study site investigational product manual or equivalent document e.g.,
Investigational Product Preparation Instructions.
 
Laboratory manual.
 
(Electronic) diary for participants and/or caregivers
 
Electronic systems or paper documents for the completion of
and C-SSRS.
 
Only if available for this study: Electronic devices and manuals for remote seizure monitoring.
 
Sample ICF.
8.2. 
Study procedures
8.2.1. 
Screeninga
Participants will report to the clinical study center for the eligibility screening assessment just prior
to the start of the 8-week baseline period. Participants will be asked to bring their current AEDs
with them. Before any study specific procedures are conducted and following an explanation of
the purpose and risks of the study, participants will sign an ICF  and optionally the
pharmacogenomics ICF. Recording of AEs/concomitant medication will start following consent
and will continue until the final study visit. The screening assessments may be performed over
multiple visits if deemed necessary for logistical reasons.
The eligibility screening examination will consist of the following:
 
Complete medical history and demography
 
Review of concomitant medication including AEDs
 
Physical and neurological examination (including height and body weight)
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 
Supine vital signs (systolic and diastolic blood pressure, oral or tympanic temperature)
 
12-lead ECG
 
Clinical safety laboratory assessments under fasted conditions (at least 4 hours), when feasible
(including serology, hematology, serum chemistry and urinalysis)
 
Urine drug screen and alcohol breath test
 
Serum pregnancy test for WOCBP
 
The C-SSRS (baseline) is completed by the investigator or qualified delegate.
 
Complete the diagnostic review form to initiate the adjudication process
 
Record AEs
 
Review inclusion/exclusion criteria
Exceptional and limited re-testing of abnormal screening values, including laboratory values, that
lead to exclusion are allowed only once to reassess eligibility.
After the screening visit, the completed diagnostic review form of the participant will be sent to
the epilepsy consortium for an adjudication process by independent experts. In this adjudication
process the experts decide whether the participant meets eligibility criteria to participate in the
study. If the adjudication process is not possible e.g., because of technical limitations of protected
data transfer, the participant will not be a screen failure.
8.2.2. 
Baseline perioda
After screening, if they meet the in- and exclusion criteria for which data are available, participants
can start the 8-week prospective pretreatment baseline period pending the results of the central
laboratory and the adjudication process. However, when the results of these assessments indicate
that the participant does not meet the in- and exclusion criteria, the participant will terminate the
baseline period and will not be randomized to treatment.
When required for practical reasons, the baseline period may be up to 1 week longer or shorter
than 8 weeks.
The participant and/or caregiver will be provided access to an (electronic) diary to record seizures.
The e-diary will be an app downloaded on the smartphone owned by the participant. Only if the
participant and/or caregiver do not own a smartphone, a smartphone programmed for the study
will be provided.
During the baseline period, the participant will be contacted by phone by the investigator or study
nurse to confirm correct use of the e-diary. This contact should take place at least 4 weeks after
the start of the baseline period, but multiple contacts are allowed when required.
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Participants must be compliant with the recording of information in the diary throughout the study.
Seizures that will be entered during baseline and throughout the study include focal aware seizures
with and without motor signs, focal impaired awareness seizures and focal to bilateral tonic-clonic
seizures. Myoclonic, or other generalized seizures will not be entered.
8.2.3. 
Treatment Perioda
Participants who complete the baseline period will be asked to come to the study center for Visit 2.
Visit 2 should be planned in the morning hours, before noon (12.00 pm). Participants must report
seizures in the e-diary from Day 1 through the following double-blind treatment period. When
possible, participants have to come to the study center in fasting condition and will have a meal
after the blood collection for clinical laboratory testing and biomarkers.
Participants who continue to meet entry criteria at the end of the baseline period must also meet
the following criteria to be randomly assigned to treatment in the double-blind treatment period of
the study:
 
Have had between 3 and 100 seizures per 28 days within the first 4 weeks and also within the
second 4 weeks of the baseline period.
 
No seizure-free interval for more than 21 days
At Visit 2, before randomization and the first dose administration, all assessments (except post-
dose PK blood collection) must have been completed.
The participant will visit the study center after 4, 8 and 12 weeks. After 2 and 6 weeks, the
investigator will have a telephone call with the participant to discuss adverse events, use of the e-
diary  and concomitant medication. Visits 2 (Day  1), 4 (4 weeks), and 6 (8 weeks) should be
planned in the morning hours, before noon (12.00 pm). During the study visits, all assessments
will be completed per the SoA. At each study visit, the participant should come to the study center
in fasted condition (at least 4 hours) when possible and –during visits 2, 4, 6 and 7- will be dosed
during or immediately after a meal at the study center after predose blood collections. Dosing
should be witnessed by the study staff. At each study visit, participants should take their study
intervention with them, and return used and partly used bottles.
During each study visit the following sequence of activities is preferred (not all activities at all
visits. See the SoA for details):
 
Collection of blood samples (clinical labs, pre-dose PK, biomarkers and pharmacogenomics)
 
Pregnancy test
 
Meal
 
Scales (C-SSRS, 
 
Vital signs, 12-lead ECG
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 
Physical/neurological examination
 
Dose of study intervention, levetiracetam or brivaracetam and other AEDs when applicable
 
Review of e-diary, AEs and concomitant medication
 
Post dose PK blood sample when applicable.
Participants and caregivers should continue to report seizures, new or extra concomitant
medication and AEs during the full 12 weeks of the study when possible.
Participants are encouraged to complete at least the first 4 weeks of treatment when there are no
safety concerns. Participants who have exceeded their pre-randomization monthly seizure count at
Week 4, or within any 4-week interval after Week 4 (“4-week sliding window approach”) up to
Week 12, will have the option to discontinue the study drug for lack of efficacy and to perform the
end of study/early withdrawal visit, or to continue double-blind treatment. Participants who have
not exceeded the pre-randomization seizure count will continue the double-blind treatment period
through Week 12.
8.2.4. 
Follow-up/Early Withdrawal Visit
For participants who will participate in the OLE period, no follow-up visit will be performed. For
details see Section 10.4.
All participants who discontinue the study before Week 12 are encouraged to complete the early
withdrawal visit (Visit 7, Week 12/Early Withdrawal). The procedures to be completed during this
visit are listed in the SoA. Participants who complete all study visits (including Visit 7) will have
a follow-up telephone call with the investigator to review AEs and health status.
Participants who continued treatment to the end of the double-blind treatment period (Week 12)
or have completed the study as per Section 7.2 will continue to collect information on the number
of seizures they experience using the e-diary until 2 weeks after the last dose of study medication.
Participants can start treatment with a new AED when required during the follow-up period.
8.3. 
Efficacy Assessments
8.3.1. 
Seizure counta
The primary efficacy evaluation will be the time to baseline monthly seizure count. To assess this
endpoint, the number and type of seizures during the baseline period and during the double-blind
treatment period needs to be documented carefully.
The participant and/or caregiver will be provided access to an (electronic) diary to record seizures
and intake of study intervention. The e-diary will be an app downloaded on the smartphone owned
by the participant. Only if the participant and/or caregiver do not own a smartphone, a smartphone
programmed for the study will be provided.
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Participants must be compliant with the recording of information in the e-diary throughout the
study. Seizures that will be entered during baseline and throughout the study include focal aware
seizures with and without motor signs, focal impaired awareness seizures and focal to bilateral
tonic-clonic seizures. Myoclonic, or other generalized seizures will not be entered.
Optionally, when the systems are available for the study, during some days of the baseline and
treatment period and in a limited number of study centers, wearable devices may be used for
remote registration of seizures. This is an exploratory technique and when required, details will be
described in an addendum to the protocol.
8.3.2. 
Secondary Evaluationsa
8.3.2.1. 
 
8.4. 
Safety Assessments
The collection of AEs and concomitant medications will start after the ICF has been signed and
will continue until the final study visit. All safety assessments listed below will be performed as
specified in the SoA.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the SoA.
8.4.1. 
Physical Examination
The study investigator, or other authorized and appropriately qualified designee, will perform the
physical and neurological examinations. On Visits 2 through 6, a brief neurological examination
should be performed, including assessment of eye movements, gait, and other findings relevant to
evaluation of AEs.
Body weight will be measured as per the SoA. Body weight will be measured using a calibrated
scale. Participants will be weighed at approximately the same time of day on the same scale,
wearing underwear and a gown and without shoes; they will be instructed to empty their bladders
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before being weighed. (Note: if disrobing for weighing is logistically impossible, the participant
should be dressed as lightly as possible, with consistency from visit to visit).
8.4.2. 
Vital Signs
Blood pressure measurements will be assessed in supine positions with a completely automated
device. Manual techniques will be used only if an automated device is not available.
Supine blood pressure measurements should be preceded by at least 5 minutes of rest in a quiet
setting without distractions (e.g., television, cell phones).
In addition, oral or tympanic temperature will be measured.
Vital signs should be measured in nonfasting conditions whenever possible.
8.4.3. 
Electrocardiogram (ECG)a
At screening, a triplicate ECG recording is required, i.e., 3 individual ECG tracings should be
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of
triplicates should be completed in less than 4 minutes.
At the other visits indicated in the SoA, single twelve-lead ECGs, intended for safety monitoring,
will be recorded supine (following 5 minutes rest) so that the different ECG intervals (RR, PR,
QRS, QT) can be measured at multiple time points at screening and during the study (see SoA).
The ECG will be recorded until 4 regular consecutive complexes are available in good readable
quality.
Hot and cold drinks and food should be avoided 30 minutes before an ECG measurement whenever
possible.
Clinically relevant abnormalities occurring during the study should be recorded in the Adverse
Event section of the eCRF/eSource. During the collection of ECGs, participants should be in a
quiet setting without distractions (e.g., television, cell phones). Participants should rest in a supine
position for at least 5 minutes before ECG collection and should refrain from talking or moving
arms or legs. If blood sampling or vital sign measurement is scheduled for the same time point as
ECG recording, the procedures should be performed in the following order: ECG, vital signs, blood
draw. Please note that fasting blood draw may precede the ECG and vital signs in this study.
8.4.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will
be collected as noted in Section 11.2, Clinical Laboratory Tests. A central laboratory will be used
for testing. The investigator must review the laboratory results, document this review, and record
any clinically relevant changes occurring during the study in the AE section of the eCRF.
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8.4.5. 
Suicidal Risk Monitoring
JNJ-40411813 is considered to be a CNS-active compound. The sponsor considers it important to
monitor for such events before and during this clinical study.
Columbia Suicide Severity Rating Scale (C-SSRS)
An interview to assess the risk of suicidal ideation and behavior will be conducted at screening,
through the double-blind treatment period and at follow-up/early withdrawal. The C-SSRS is a
low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the
National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess
severity and track suicidal events through any treatment (Posner 2007). The C-SSRS is a clinical
interview providing a summary of both ideation and behavior that can be administered during any
evaluation or risk assessment to identify the occurrence and intensity of suicidal thoughts and
suicidal behaviors. It can also be used during treatment to monitor for clinical worsening. See
Section 11.9 for details.
8.5. 
Pharmacokineticsa
Blood samples (2 mL each) for the determination of plasma concentrations of JNJ40411813 and
metabolites including but not limited to 
, levetiracetam or brivaracetam and,
when used by the participant, 
will be collected according to Table 4 below.
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Table 4: 
Schedule of collection of 2-mL PK blood samples
Study
visit
Study
Day
JNJ-40411813 and 
metabolites 
Relative to in-clinic dose 
Brivaracetam or 
Levetiracetam  
Relative to in-clinic dose* 
2 
1 
 2 hours after dosing
 predose
 2 hours after dosing
 predose
4 
29
 predose 
 1 hour after dosing
 predose
 1 hour after dosing
 predose
6 
57 
 predose 
 predose 
 predose
7*** 
85***
 after dosing (combine 
with other blood
collection when
feasible)
 At the same time as
sample for
JNJ-40411813
-
*If the subject is taking levetiracetam XR once daily in the evening, then one PK sample for levetiracetam will be
collected on Visits 2 and 4 (at the same time as the postdose sample for JNJ-40411813) and Visit 6 (at the same time
as the predose sample for JNJ-40411813)
*** Also, at early withdrawal when after Visit 6.
Plasma samples will be analyzed to determine concentrations of JNJ-40411813, levetiracetam or
brivaracetam, and 
 
 using validated, specific and sensitive liquid chromatography mass
spectrometry/mass spectrometry (LC-MS/MS) methods. Some plasma samples will be analyzed
to document the presence of JNJ-40411813 metabolites 
 and perhaps other
metabolites, or may be used to determine protein binding using qualified research methods or
validated methods. If deemed necessary, the concentrations of other co-administered AEDs may
also be measured. In addition, plasma PK samples may be stored for future analysis of protein
binding, biomarkers and the metabolite profile
The exact dates and times of blood sampling must be recorded in the laboratory requisition form.
In addition, the exact dates and times of the last administration of drug (administered at home or
at the clinic) prior to collection of each pharmacokinetic sample should be documented.
Data will be listed for all participants with available plasma concentrations per treatment and study
day. All concentrations below the limit of quantification (LOQ) or missing data will be labeled as
such in the concentration data listings. Concentrations below the LOQ will be treated as zero in
the summary statistics.
8.6. 
Genetics
Blood samples (8 mL) will be collected
s
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 Participation in the
genetic/pharmacogenomic part of this study is optional.
8.7. 
Biomarkers
During the study, blood will be collected for the assessment of the biomarkers
 time points indicated in the SoA (see also Section 4.2.) Additional instructions
for collection ofbiomarker samples:
 
Blood biomarkers will be collected under fasting conditions –at least 4 hours, water permitted
with the exception of the postdose collection during Visit 2.
 
Participants should be informed not to do strenuous sports or exercises within 24 hours before
blood sample collection.
Biomarkers may be added or deleted based on scientific information or technical innovations under
the condition that the total volume of blood collected will not be increased. 
Participant data
To evaluate the biomarker results, the following information needs to be documented on each day
of collection of blood samples for biomarker analysis.
 
Diet (extremes during the previous week)
 
Any sickness or allergy in the previous 2 weeks
8.8. 
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the
participant's legally acceptable representative) for the duration of the study.
As with any CNS-active medication, investigators should monitor carefully and document any
CNS-related AE including tremor, ataxia, abnormal sensation, confusion, or possibility of seizure.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints
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(PQCs), refer to Section 11.4, Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-Up, and Reporting.
Adverse Events of Interest
AEs of interest have not yet been defined in this study. If observations of new AEs of interest
during the study require this, a protocol amendment will be issued.
8.8.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant's last study visit, which
may include contact for follow-up of safety. SAEs, including those spontaneously reported to the
investigator within 30 days after the last dose of study intervention, must be reported using the
Serious Adverse Event Form. The sponsor will evaluate any safety information that is
spontaneously reported by an investigator beyond the time frame specified in the protocol.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study-site personnel immediately, without undue delay, under no circumstances later than
24 hours after their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and the eCRF, which must be completed and reviewed by a physician from the study site
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a SAE should
be transmitted electronically or by facsimile (fax).
8.8.2. 
Follow-up of Adverse Events and Serious Adverse Events
AEs, including pregnancy, will be followed by the investigator as specified in Section 11.4,
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.8.3. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate Independent Ethics Committee
(IEC) or Institutional Review Board (IRB) that approved the protocol unless otherwise required
and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded.
Participating investigators and IEC/IRB will receive a blinded SUSAR summary, unless otherwise
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An anticipated event is an adverse event that commonly occurs in the study population independent
of exposure to the drug under investigation. For the purposes of this study the following SAEs will
be considered anticipated events:
 
Sudden Unexpected Death in Epilepsy (SUDEP)
 
Seizures leading to injuries or hospitalizations
 
Anxiety
 
Depression
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the intervention group than in the
control group and the sponsor concludes there is a reasonable possibility that the drug under
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries in which the studies are conducted.
8.8.4. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (e.g.,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered serious AEs and must be reported using the Serious Adverse Event Form. Any
participant who becomes pregnant during the study must be promptly withdrawn from the study
and discontinue further study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.9. 
Treatment of Overdose
For this study, any single dose of JNJ-40411813 greater than
 a 24-hour time period
will be considered an overdose. The sponsor does not recommend specific intervention  for an
overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities until JNJ-40411813
can no longer be detected systemically (at least 2 days).
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 
Obtain a plasma sample for PK analysis within 2 days from the date of the last dose of study
intervention if requested by the Medical Monitor (determined on a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9. 
STATISTICAL CONSIDERATIONS
The double-blind study period will be analyzed separately from the OLE period after completion
of the double-blind period for each cohort.
9.1. 
Sample Size Determination
The calculation of the maximum sample size planned for this study was simulation-based and was
estimated using a Cox’s proportional hazard regression model comparing the time to baseline
seizure count between JNJ-40411813 and placebo. A longitudinal model for individual daily
seizure counts, taking into account between-subject variability in baseline seizure rate and
response to treatment, and a residual overdispersed Poisson error was applied. The simulated daily
seizure count data were then converted to time to baseline count data and analyzed using a Cox’s
proportional hazard regression model.
Assuming a placebo median percentage seizure rate reduction of 15% and a further reduction of
50% (respectively 30%) for JNJ-40411813, a cohort with 40 participants randomized to
JNJ-40411813 and 20 to placebo would achieve a power of 99% (respectively 83%) at the α=5%
one-sided significance level. In subsequent cohorts with 40:10 randomization, the power becomes
94% for a 50% reduction, with all other assumptions unchanged.
9.2. 
Efficacy analyses
9.2.1. 
Primarya
The intent-to-treat population will be the primary  efficacy  population, which  includes all
participants who are randomly assigned to receive study drug and who have baseline and
postbaseline seizure data. Data from participants on placebo in cohorts 2 and 3 will be combined
with those from Cohort 1 if the Kaplan-Meier curves of the subjects treated with placebo are
comparable between cohorts. The analysis for interim review may be done including both pooled
and non-pooled placebo subjects.
The individualized baseline monthly seizure count is defined as the number of observable focal
onset seizures occurring during the 8-week baseline period, multiplied by 28/ XBL, where XBL is
the number of days comprising the baseline period. Observable focal onset seizures include focal
aware seizures with motor signs, focal impaired awareness seizures and focal to bilateral tonic-
clonic seizures. Focal aware seizures will not be counted towards baseline monthly seizure count.
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The endpoint time to baseline monthly seizure count is defined, for each patient, as the number of
days, until the patient experienced the number of seizures equal to baseline monthly seizure count,
up to the end of the 12-week double-blind treatment period.
Although focal aware seizures with and without motor signs are entered in the e-diary, focal aware
seizures without motor signs will not be counted in the analysis.
Kaplan-Meier analyses will be conducted to describe the time to baseline monthly seizure count
distribution (with 95% CI) for each treatment group for all observable focal-onset seizures. A
formal comparison of time to monthly baseline seizure count will be made by a Cox proportional
hazard regression model, including factors for treatment and any other relevant covariates (details
will be provided in the statistical analysis plan). Appropriate adjustment for multiple testing, in
case of subsequent cohorts, will be detailed in the SAP.
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined
by the following 5 components:
 
Population: patients with established diagnosis of focal epilepsy (ILAE 2017 criteria) with 3
to 100 seizures per 28 days; currently on 1 to 4 AEDs with inadequate response to
levetiracetam/brivaracetam who have met the inclusion/exclusion criteria.
 
Variable: the number of days, until the patient experienced the number of seizures equal to
baseline monthly seizure count, up to the end of the 12-week double blind treatment period.
 
Intervention event: the effect of the initially randomized treatment that would have been
observed had all participants remained on their treatment throughout the double-blind
treatment phase.
 
Intercurrent event (ICE): treatment discontinuation will be handled according to the
hypothetical strategy as if the ICE would not have occurred. Similar efficacy is assumed for
subjects who had the ICE as those subjects from the same treatment group who did not have
the ICE.
 
Population-level summary: the difference in estimated hazard ratio between the treatments.
Sensitivity analyses for the primary estimand regarding missing data assumptions; and a
supplementary estimand to inform subsequent trials will be specified in the SAP.
9.2.2. 
Secondary and exploratorya
Secondary  efficacy endpoints will be subject to an exploratory  analysis including descriptive
statistics by treatment arm and graphical exploration. Details of the analysis for each secondary
endpoint and exploratory endpoints will be provided in the SAP.
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Seizure Freedom
Percent participants with seizure freedom over the complete double-blind period. Participants who
exit the study after reaching their pre-randomization baseline seizure count can be included in this
analysis as they were not seizure free during the study.
Secondary generalized seizures
Separate analyses (including time to baseline count and % reduction of counts) for focal to bilateral
tonic-clonic seizures will be performed if a large enough number of events is observed.
Responder rate
A responder is defined as a participant having at least a 50% reduction of the monthly seizure rate.
Participants who exit the study at Week 4 after reaching the baseline seizure count will be treated
as nonresponders in this analysis. As the number of seizures they experienced is either equal or
larger than their baseline monthly seizure count, their observed % seizure rate reduction is either
zero, or negative (implying an increase).
.
9.3. 
PKand PK/PD analysesa
Data for all participants who receive a dose of JNJ-40411813 and have at least one measurement
of plasma concentration, will be included in the PK analysis. Plasma concentrations of
JNJ-40411813 and metabolites including 
 levetiracetam/ brivaracetam and
 will
be listed for all participants who received this active medication.
Descriptive statistics will be calculated for the plasma concentrations of JNJ-40411813 and
metabolites including 
levetiracetam/ brivaracetam  and 
at each applicable
time point. Statistics include sample size (n), mean, standard deviation, coefficient of variation
(CV), geometric mean, median, minimum, and maximum.
Population PK and/or PBPK analyses of JNJ-40411813 and levetiracetam/brivaracetam may be
performed on the data of this study in combination with data pooled from other studies. An
objective of these analyses is to investigate the potential effects of covariates, such as
demographics and concomitant drugs, on the PK of JNJ-40411813. The results of the population
analyses may be reported separately.
PK and PD relationship will be explored, if feasible. The results of population PK/PD analyses
will also be reported separately.
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9.4. 
Safety Analysesa
Statistical analysis of the safety data will be done by the sponsor or under the authority of the
sponsor. Specific details will be provided in the Statistical Analysis Plan.
All safety analyses will be performed based on the safety analysis set, which will include all
included participants who receive at least 1 dose of JNJ-40411813 or placebo. Safety summaries
will be provided by treatment and by cohort, unless specified otherwise.
AEs will be coded using the current version of Medical Dictionary for Regulatory Activities
(MedDRA) and tabulated by system organ class, by severity and relationship to study intervention
and will be presented by treatment. SAEs will be summarized separately.
The safety analysis will include the incidence of AEs, actual data and changes in blood pressure,
pulse rate, laboratory safety data, 12-lead ECG and physical/neurological examination data from
predose to all postdose assessments.
The participants with suicidal ideation and/or suicidal behavior collected from the C-SSRS will be
listed.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
MedDRA. All reported AEs with onset during the double-blind treatment period (i.e., TEAEs, and
AEs that have worsened since baseline [Day 1]) will be included in the analysis. For each AE, the
percentage of participants who experience at least one occurrence of the given event will be
summarized by treatment group. Summaries will be provided for all participants receiving at least
one dose of study intervention in this study and will include AEs from this study.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who withdraw due to an AE, or who experience a severe AE or a SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory  test. Descriptive statistics will be
calculated for each laboratory analyte at baseline (Day 1) and at each scheduled time point, and
for changes from baseline.
The number and percentage of participants experiencing a laboratory result below or above normal
reference ranges will be provided for each laboratory analyte by treatment group. Summaries will
be provided for all participants receiving at least one dose of study intervention in this study.
A listing of participants with any laboratory result outside the reference ranges will be provided.
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ECG
Heart rate and ECG intervals (RR, PR, QRS and QT) as well as corrected QT intervals according
to Bazett’s formula (QTcB) and Fridericia’s formula (QTcF) (Bazett 1920, Sagie 1992,
Hodges 1983, International Conference on Harmonization [ICH] 2005) from the 12-lead ECG will
be summarized at baseline (Screening) and at each scheduled time point and for changes from
baseline using descriptive statistics.
The number and percentage of participants with at least one occurrence of a treatment-emergent
potentially clinically important QTc measurement (QTc value >450, >480, or >500 msec) or with
a change from baseline in QTc>30 msec or 60 msec, will be summarized by treatment group.
Data listings of participants with any potentially clinically important values or with a change from
baseline in QTc will be provided.
Vital Signs
Descriptive statistics of temperature, pulse, and blood pressure (systolic and diastolic) values and
changes from baseline (Day 1) will be summarized at each scheduled time point. The percentage
of participants with values beyond clinically important limits will be summarized.
Physical and Neurological Examinations
Participants with abnormal findings will be presented in a data listing.
Other Safety Measures
C-SSRS
The suicidal ideation and behavior data collected from the C-SSRS will be summarized
descriptively at each scheduled timepoint by treatment group. Data from the participants with
suicidal ideation and behavior will be presented in data listing.
9.5. 
Data Reviewafter each cohorta
After at least 55 patients in Cohort 1 and after at least 45 patients in Cohort 2 have completed at
least 4 weeks of treatment, an interim unblinded review of all cumulative safety, PK, and efficacy
data of JNJ-40411813 available to that date will be performed to decide on whether there should be
any addition or modification to the dose(s) in the following cohorts and subsequent clinical studies. If
the results of the review are inconclusive with respect to the assessment of efficacy, a second
interim review of the same cohort may be done after the last participant has completed the 12-
week visit. If safety concerns have been observed that are not expected to be solved by a dose reduction,
the study will be stopped. This decision will be taken by an internal unblinded review committee. As
a standard, data will be unblinded at the individual level (JNJ-40411813 vs placebo).
Completed cohorts may be unblinded for review by the sponsor members, if deemed necessary.
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The procedures for the internal interim review for Cohorts 1 and 2 will be documented in a separate
charter.
10. 
ADDENDUM FOR OPEN-LABEL EXTENSION (OLE) PERIODa
10.1. Rationale
This is an OLE period to investigate the long-term safety and efficacy of JNJ-40411813 in subjects
who completed their participation in the double-blind study period. This study period will allow
study participants to continue treatment and evaluate long-term safety and efficacy of JNJ-
40411813 in epilepsy. Also study participants that have been treated with placebo may be included
in the OLE period.
Because epilepsy is a chronic condition, often requiring treatment for years, long-term data should
be generated by conducting OLE studies in order to assess for maintenance of efficacy and safety.
Treatment retention rate is recommended as a global indicator of clinical effectiveness. A one-year
study duration is considered the minimum (EMA 2018).
10.2. Benefit/Risk Assessment of the OLE period
10.2.1. 
Risks for Participation
Potential Risks of Clinical
Significance
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Limited information about the long-
term tolerability of study treatment.
Experience from former studies so 
far in the dosage range employed 
indicates that JNJ--40411813 is 
well tolerated and there is no signal 
for target organ damage.
During the double-blind treatment
period, the combination of 
levetiracetam and JNJ-40411813 
was well tolerated. The data from 
chronic toxicology studies in rat 
and dog do not show adverse
effects. However, this is the first 
study in which exposure to 
JNJ-40411813 will exceed 
3 months. There may be unknown
safety risks.
The start dose of JNJ-40411813 in
open-label extension period is the
same as used during the double-
blind treatment period.
The safety and tolerability of JNJ-
40411813 will be reviewed
continuously and every 3 months,
the participant will visit the study
center for additional safety
assessments.
Participants can stop their
participation any time when the
treatment is not tolerated.
 
 
 
 
 
 
a 
This section has been added for Amendment INT-2
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10.2.2. 
Benefits for Participation
Treatment-resistant epilepsy has a severe impact on quality of life and risk of mortality. JNJ-
40411813 in combination with levetiracetam shows promise in a nonclinical model of epilepsy
and –if proven efficacious in man too –may result in a significant positive impact on this patient
population.
For the individual participant who benefits from the participation in the double-blind treatment
phase of study 40411813EPY2001, the extended open-label treatment will be made available as
long as the participant continues to benefit during this OLE study period.
10.2.3. 
Benefit-Risk Assessment
The risk/benefit of JNJ-40411813 is favorable and the currently available safety and efficacy data
support the proposed open-label study period to investigate the long-term efficacy and safety of
JNJ-40411813 in participants with focal onset epilepsy.
More detailed information about the known and expected benefits and risks ofJNJ-40411813 may
be found in the current IB for JNJ-40411813.
10.3. Objectives and endpoints of OLE period
Objectives 
Endpoints
Primary
The primary objective ofthis open-label period is 
to evaluate the long-term efficacy and safety of 
adjunctive therapy with JNJ-40411813 in subjects 
with epilepsy.
Seizure count by using an (e-)diary, adverse
events, significant changes in vital signs, and
safety laboratory results.
Secondary
To evaluate, during long-term treatment, the 
pharmacokinetics (PK) of JNJ-40411813, 
levetiracetam/ brivaracetam, and AEDs 
 
Plasma concentrations of JNJ-40411813,
levetiracetam/ brivaracetam, and AED
Hypothesis
This is an open-label observational study period. Therefore, no formal statistical hypothesis testing
has been planned.
10.4. Design of the OLE period
10.4.1. 
Overall Design
Overview of the open-label period:
For each participant, the open-label period will start immediately after the last study drug intake
by the participant in the double-blind period. Participants participating in this open-label period
will not have the follow-up visit (Visit 8) as mentioned in the SoA in Section 1.2.
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double-blind period and the start of the open-label period. They should enter the OLE period as
soon as it becomes available in their country
Inclusion of women of childbearing potential (WOCBP) is supported by the absence of toxicity
seen in Segment II reproductive toxicology studies. WOCBP will use a highly effective birth
control method as outlined in the inclusion criteria (see Section 5.1).
Duration of the study
Participants will participate in the open-label period for a period of up to 2 years. If they still
benefit from treatment with JNJ-40411813, they will be transferred to a new central OLE study
when available, in which also participants from other (late phase) studies with JNJ-40411813 will
participate.
The participants in that central OLE study can continue their participation as long as needed with
a maximum until commercial availability of the compound in the country where the participant is
living.
The OLE extension period may be stopped when the development of the compound is stopped by
a decision of the sponsor or because of insufficient efficacy or safety concerns.
Pharmacokinetics
Data on the long term (> 3 months) pharmacokinetics of JNJ-40411813 in humans are still lacking.
For this reason, plasma concentrations of JNJ-40411813 and metabolites will be measured during
study visits up to 1 year after the start of the OLE period.
PK samples for levetiracetam/brivaracetam and, when used by the participant, 
) will be collected
only during the visits after 1 month and after 2 months to evaluate the PK profiles.
10.4.3. 
Study-Specific Ethical Design Considerations
For the open-label period: The primary ethical concern is the long-term use of JNJ-40411813 as
an experimental treatment in epilepsy. The compound has been used in several clinical studies in
healthy subjects and patient populations (see IB) and was generally well tolerated. In addition,
chronic toxicology studies have been completed in rat (6 months) and dog (9 months). These
studies did not indicate adverse toxicological effects after chronic oral administration.
Although the current data from this ongoing study 40411813EPY2001 and studies in other
indications do not indicate any serious safety risk, no studies in humans have been done before
with a duration longer than 3 months.
About 11 mL of blood will be collected during the visits after 1 and 2 months and 5 mL of blood
will be collected during the visits every 3 months thereafter for PK, clinical chemistry and
hematology. This is considered to be a limited and acceptable amount of blood.
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10.4.4. 
Justification for dose
No fixed dose schedule will be presented for this study. All participants will start with intake of
JNJ-40411813 at the same dose they used in the double-blind study period. See also Section 4.1.
10.4.5. 
End of Study Definition
End of Study Definition for the OLE period.
The end of study for the OLE period is considered as the last visit for Visit OLE 11 or OLE12 for
the last participant in the study. The final data for the OLE period from the study site will be sent
to the sponsor (or designee) after completion of the final participant visit at that study site, in the
time frame specified in the Clinical Trial Agreement. The OLE period will be analyzed separately
from the double-blind period.
10.5. Study population for the OLE period
No fixed number of participants has been defined for this OLE period.
The inclusion and exclusion criteria for enrolling participants in this open-label study period are
described in the following sections. If there is a question about the inclusion or exclusion criteria
below, the investigator should consult with the study responsible physician (SRP) before entering
the participant into the study.
Participants will be enrolled after reading the participant information sheet and signing the ICF
indicating that they understand the purpose of, and procedures required for the study and are
willing to participate in the study and comply with the study procedures.
An updated ICF including a description of the OLE period will be made available for those
participants who were already enrolled in the study before the OLE period became available.
10.5.1. 
Inclusion Criteria
Each potential participant must satisfy all the following criteria to be enrolled in the open-label
study period.
101. The participant must have participated in the double-blind treatment period. This also
includes participants who stopped during the double-blind treatment period because they
reached the time to baseline seizure count study endpoint or completed the double-blind
period before the OLE period is available.
102. The participant is expected to benefit from participation in the open-label study period in
the opinion of the Investigator.
103. When a woman of childbearing potential:
 Continues to practice a highly effective method of contraception as described in the
inclusion criteria of the double-blind period (Section 5.1) until at least 3 months after the
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 Must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
during the study and for at least 3 months after receiving the last dose of study intervention.
104. Men who are sexually active with a woman of childbearing potential and have not had a
vasectomy must continue to use a barrier method of birth control i.e., a condom with
spermicidal foam/gel/film/cream/suppository for the duration of the study plus 3 months
after receiving the last dose of study drug, and all men must not donate sperm during the
study and for 3 months after receiving the last dose of study drug. In addition, male
participants should also be advised of the benefit for a female partner to use a highly
effective method of contraception as condom may break or leak.
105. The participant has signed an ICF indicating that he/she understands the purpose of, and
procedures required for the study and are willing to participate in the OLE period.
10.5.2. 
Exclusion Criteria
106. Participant meets any of the withdrawal criteria during the double-blind period or is
experiencing an ongoing severe or serious adverse event considered related to study
medication by the investigator.
107. Participant is receiving any investigational drug or using any experimental device in
addition to JNJ-40411813 for treatment of epilepsy or any other medical condition.
108. Participant has any other condition that would prevent compliance with the study
procedures or proper reporting of adverse events.
10.5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
109. Refer to the Section 6.5 on Concomitant Therapy for details regarding prohibited and
restricted therapy during the study.
110. Participants may not consume any food or beverages containing, grapefruit juice, Seville
oranges (including any orange marmalade), or quinine (e.g., tonic water) until the last dose
of study intervention.
10.6. Study interventions
10.6.1. 
Study interventions Administered
JNJ-40411813 will be supplied for this OLE period as 25-mg and 50-mg tablets.
. Only on the days of study visits, participants will not take the study drug at
home, but will take the study drug with them to the clinic and take the study medication in the
clinic after the collection of the PK-blood sample and/or the collection of blood for safety
laboratory test. The clinic will be asked to provide a meal before intake of study medication.
Study intervention should be taken in fed condition 
The tablets must be swallowed whole with water and not chewed, divided, dissolved
or crushed.
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Table 6: 
Description of Interventions
Arm Name 
JNJ-40411813
 
 
10.6.2. 
Preparation, Handling, and Storage
See Section 6.2.
10.6.3. 
Measures to Minimize Bias: Randomization and Blinding
No randomization procedure will be applied in the open-label period.
Participants completing the double-blind period and starting the open-label period will not be
unblinded. Participants who had been receiving placebo will start with the JNJ-40411813 dose that
was used in the applicable cohort of the double-blind period; in case more than one dose was tested
in the applicable cohort, participants will start with the lower one.
10.6.4. 
Study Intervention Compliance
Study intervention will be taken by the participant at home (except for the days of the study visits)
(See Section 10.6.1). When feasible, the participant should start the treatment following the
double-blind period with no interruption or try to keep the interruption as short as possible.
Participants will not need to record their drug intake in the e-diary during the open-label period.
The investigator or designated study personnel will maintain a log in IWRS of all study
intervention dispensed and returned. Study intervention supplies will be inventoried and accounted
for throughout the study.
If appropriate, additional details may be provided in a pharmacy manual/study site investigational
product manual that is provided separately and noted in Section 10.8.1.
10.6.5. 
Concomitant Therapy
See Section 6.5.
10.6.6. 
Recording of drug intake; overview
For reasons of proper PK analysis of study medication, levetiracetam/ brivaracetam and currently
used 
 some occasions the date and time of the drug intake
needs to be recorded by the participant (using the subject participation card) or the investigator/site
staff (using the eCRF).
An overview of this specific recordings of date and time of intake of AEDs is given in Table 7.
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Table 7: 
Recording of date and time of last drug intake during the OLE period.
Study 
visit 
When to 
record. 
Study drug 
Levetiracetam/brivaracetam
OLE2
Day before 
By participant 
By participant 
By participant
During visit 
By investigator 
By investigator 
By investigator
OLE3
Day before 
By participant 
By participant 
By participant
During visit 
By investigator 
By investigator 
By investigator
OLE4 
to7 
Day before 
By participant 
na 
na
During visit 
By investigator 
na 
na
10.7. Discontinuation of study intervention and participant
discontinuation/withdrawal
Participants may withdraw from participation from the OLE period any time on their request or,
at the discretion of the investigator, when JNJ-40411813 is no longer of benefit to them.
A participant will be considered to have completed the OLE period when the participant is still in
the study 2 year after the start of the OLE period or when the OLE is stopped by the sponsor. Any
subject who withdraws before the end of the OLE has withdrawn and is not a completer.
See also Sections 7.3, 7.5 and 7.6
10.8. Study assessments and procedures for the OLE period
10.8.1. 
Overview
The SoA of the OLE period (See Section 10.10) summarizes the frequency and timing of all
assessments applicable to this study.
Repeat or unscheduled blood samples may be taken for safety reasons, or for technical issues with
the samples.
Additional serum (by local laboratory) or urine pregnancy tests may be performed, as determined
necessary by the investigator or required by local regulation, to establish the absence of pregnancy
at any time during the participation in the study.
The total blood volume to be collected from each participant during each visit will be
approximately 10.5 mL in Visits OLE 2 and 3, 6.5 mL in Visits OLE4 to OLE7 and 4.5 mL in
Visits 8 to 11.
For each participant, the maximum amount of blood drawn from each participant during each visit
will not exceed 20 mL.
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 
The last visit in the double-blind period will be considered the baseline visit of open-label
period. Assessments required for the last visit in the double-blind period and for the baseline
of the open-label-period, do not have to be completed twice.
For participants who start the open-label period with an interruption of >4 weeks after completing
the double-blind period:
 
Complete the follow-up visit when the open-label period has not been started yet.
 
The baseline visit for the open-label period should be a new visit when visit 7 of double-blind
study period was more than 4 weeks ago.
The baseline examination will consist of the following:
 
Review inclusion/exclusion criteria for the open-label period
 
Physical and neurological examination (including body weight)
 
Supine vital signs (systolic and diastolic blood pressure, heart rate and oral or tympanic
temperature)
 
Clinical safety laboratory assessments under fasted conditions (at least 4 hours), when feasible
(including hematology, serum chemistry and urinalysis)
 
Urine pregnancy test for WOCBP
 
The C-SSRS (since last visit) is completed by the investigator or qualified delegate.
 
Review of concomitant medication including AEDs
 
Record AEs
 
Dispense study medication
The participant and/or caregiver will be provided access to an (electronic) diary to record seizures.
The (e-)diary will be an app downloaded on the smartphone owned by the participant.
Participants must be compliant with the recording of information in the diary throughout the study.
Seizures that will be entered throughout the study include focal aware seizures with and without
motor signs, focal impaired awareness seizures and focal to bilateral tonic-clonic seizures.
Myoclonic, or other generalized seizures will not be entered.
10.8.2.2. 
Treatment Period
During the open-label treatment period, participants must report seizures in the (e-)diary. After 1
and 2 months and every 3 months thereafter, the participant will visit the study center. The
participants take the study medication at home with a meal. However, during the study visits, the
subjects will come to the study center in the morning hours in fasting condition (at least 4 hours)
and take the study medication with them. After collection of blood for PK (Visits OLE1 to OLE7
only) and clinical chemistry and hematology, the subject takes the study medication after a meal.
Each study visit will consist of the following:
 
Review of (e-)diary
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 
Physical and neurological examination (including body weight)
 
Supine vital signs (systolic and diastolic blood pressure, heart rate and oral or tympanic
temperature)
 
Clinical safety laboratory assessments under fasted conditions (at least 4 hours), when feasible
(including hematology, serum chemistry and urinalysis)
 
Blood collection for PK (Visits OLE2 to OLE7 only)
 
urine pregnancy test for WOCBP
 
The C-SSRS is completed by the investigator or qualified delegate.
 
Review of concomitant medication including AEDs
 
Record AEs
 
Dispense study medication
10.8.2.3. 
Withdrawal Visit
All participants who discontinue the study at any time are encouraged to complete the withdrawal
visit, OLE12. The procedures to be completed during this visit are the same as during the treatment
period but no new study medication will be dispensed.
10.8.3. 
Efficacy Assessments in the OLE period
10.8.3.1. 
Seizure count
The key efficacy evaluation is seizure count; #seizures per 28 days calculated as (28/the number
of days between visits)*(seizures counted between the visits).
The participant and/or caregiver will be provided access to an (electronic) diary to record seizures.
The e-diary will be an app downloaded on the smartphone owned by the participant. Only if the
participant and/or caregiver do not own a smartphone, a smartphone programmed for the study
will be provided.
Participants must be compliant with the recording of information in the e-diary throughout the
study. Seizures that will be entered during baseline and throughout the study include focal aware
seizures with and without motor signs, focal impaired awareness seizures and focal to bilateral
tonic-clonic seizures. Myoclonic, or other generalized seizures will not be entered.
10.8.3.2. 
Retention on JNJ-40411813 therapy
Retention of JNJ-40411813 therapy will be assessed by the time difference between the date of
first dose taken in the open-label period and the date of the last dose taken. As daily dosing will
not be recorded in the (e-)diary, a log in IWRS of all study intervention dispensed and returned
will be maintained.
10.8.4. 
Safety Assessments
See Section 8.4 of the protocol.
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medication 
.
j) This should only be performed at the Month 3 visit (OLE4).
k) Visit windows are as follows: +/- 5 days for OLE2, OLE3 and OLE4 and +/- 7 days for OLE5 and beyond
(always to be calculated from OLE1); duration of 1 month is default 31 days until OLE4’, duration of 3 months
is default 90 days from OLE5 onwards.
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
11.1. Appendix 1: Abbreviations
AE 
Adverse Event
AED  
Anti-Epileptic Drug
ALT  
alanine aminotransferase
AMA  
Anti-mitochondrial antibody
ANA  
Antinuclear antibody
Anti-HAV (IgM) 
Anti-hepatitis A virus (Immunoglobulin M)
Anti-HEV (IgM) 
Anti-hepatitis E virus (Immunoglobulin M)
AP  
Alkaline phosphatase
ASMA  
anti-smooth muscle antibodies
AST  
Aspartate aminotransferase
AUC  
Area under the plasma concentration-time curve (time period specified by
subscript).
AV  
atrioventricular
 
 
BMI 
Body mass index
BUN  
Blood urea nitrogen
CBC  
Complete blood count
CHF  
Congestive heart failure
CI 
Confidence interval
Cmax  
maximum drug concentration
CMV  
Cytomegalovirus
CNS  
Central nervous system
CPK  
Creatine phosphokinase
CRP  
C-reactive protein
CSF  
cerebrospinal fluid
CSR  
Clinical study report
C-SSRS  
Columbia Suicide Severity Rating Scale
CT  
computed tomography
CV  
coefficient of variation
CYP  
cytochrome P450
DILI 
Drug induced liver injury
DNA  
desoxyribonucleic acid
DRC  
Data Review Committee
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
EBV  
Epstein-Barr virus
EC  
Effective concentration (% responders specified by subscript).
ED  
Effective dose (% responders specified by subscript).
 
EU  
European Union
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ECG  
Electrocardiogram
(e)CRF  
(electronic) case report form
eDC  
Electronic data capture
ERCP  
endoscopic retrograde cholangiopancreatography
ESR  
Erythrocyte sedimentation rate
EW  
Early Withdrawal
FDA  
Food and Drug Administration
FSH  
follicle stimulating hormone
CGI-SCH  
Clinical Global Impression –Schizophrenia
GCP  
Good Clinical Practice
GGT  
Gamma-glutamyltransferase
HAM-A(6) 
(6-item) Hamilton Anxiety Scale
HAM-D(6) 
(6-item) Hamilton Depression Scale
HBsAg 
Hepatitis B surface antigen
HCV  
Hepatitis C antibodies
HDRS17 
Hamilton Depression Rating Scale
HIV  
Human immunodeficiency virus
HRT  
Hormonal Replacement Therapy
IB  
Investigator’s Brochure
IC  
inhibitory concentration (% inhibition specified by subscript).
ICD  
implantable cardioverter defibrillator
ICE 
Intercurrent event
ICF  
Informed consent form
ICH  
International Conference on Harmonization
IDS-C30 
Inventory of Depressive Symptomatology
IEC  
Independent Ethics Committee
ILAE 
International League Against Epilepsy
IMP  
Investigational Medical Product
INR  
International normalized ratio
IRB  
Institutional Review Board
IUD  
Intrauterine device
IUS  
Intrauterine system
IWRS  
Interactive web response system
LBBB  
Left Bundle Branch Block
LC-MS/MS  
Liquid chromatography/mass spectrometry/mass spectrometry
LDH  
Lactic acid dehydrogenase
LFT  
liver function test
LKM  
Liver kidney microsomal antibody
LKM1 
Liver kidney microsomal antibody type 1
LOQ  
Limit of quantification
LT  
Liver test
MDD  
Major Depressive disorder
MedDRA  
Medical Dictionary for Regulatory Activities
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mGlu2 
metabotropic glutamate receptor-2
MRCP  
magnetic resonance cholangiopancreatography
MRI 
Magnetic resonance imaging
NIMP  
Non-Investigational Medicinal Product
NOAEL 
no-observed-adverse-effect-level
NSAID  
non-steroidal anti-inflammatory drug
OLE 
Open-label extension
OTC  
Over the counter
PAM  
positive allosteric modulator
PANSS  
Positive and Negative Syndrome Scale
pANCA  
Anti-neutrophil cytoplasmic antibody
PBPK  
physiologically based pharmacokinetic modeling
PD 
Pharmacodynamic(s)
PgP  
P-glycoprotein
PI 
principal investigator
PK 
Pharmacokinetic(s)
PQC  
Product Quality Complaint
PRN  
pro re nata (as needed)
PRO  
Patient reported outcome
PT  
Prothrombin time
PTT  
Partial thromboplastin time
RBC  
Red blood cell
REM  
Rapid eye movement
RNA  
ribonucleic acid
SAE 
Serious adverse event
 
SoA  
Schedule of Activities
SRP  
Study responsible physician
SUDEP  
Sudden Unexpected Death in Epilepsy
SUSAR  
suspected unexpected serious adverse reaction
SV2a 
Synaptic Vesicle glycoprotein 2a
SIGH-A  
Structured Interview Guide for the Hamilton Anxiety Scale
SWN  
Subjective Well-being on Neuroleptics
Tbili 
Total bilirubin
TEAE 
Treatment-emergent adverse event
TESAE 
Treatment-emergent serious adverse events
TIBC  
Total iron binding capacity
 
ULN  
Upper Limit of Normal
US  
United States
WBC  
White blood cell
WOCBP  
women of childbearing potential
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 
Urine drug screen (opiates [including methadone], ecstasy, cocaine,
(meth)amphetamines, 
cannabinoids, 
barbiturates, 
and
benzodiazepines).
 
Alcohol breath test.
The following biomarkers will be tested in this study. Biomarkers may be added or deleted based
on the latest scientific insights without amending the protocol if the total volume of blood to be
collected will not increase as a result of adding biomarkers.
sample 
analytes
 
 
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11.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
Regulatory Ethics Compliance
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance with
the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory
and country-specific requirements.
GCP is an international ethical and scientific quality standard for designing, conducting, recording,
and reporting studies that involve the participation of human participants. Compliance with this
standard provides public assurance that the rights, safety, and well-being of study participants are
protected, consistent with the principles that originated in the Declaration of Helsinki, and that the
clinical study data are credible.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents:
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants).
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any), the ICF, applicable recruiting materials, and participant compensation
programs, and the sponsor has received a copy of this approval. This approval letter must be dated
and must clearly identify the IEC/IRB and the documents being approved.
During the study, the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
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 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB
(at least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the investigational
drug
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Annual Safety Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or trial conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this clinical study. The
re-approval should be documented in writing (excluding the ones that are purely administrative,
with no consequences for participants, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Informed Consent
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF must be signed before performance of any study-related
activity. The ICF that is used must be approved by both the sponsor and by the reviewing IEC/IRB
and be in a language that the participant can read and understand. The informed consent should be
in accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP
guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the investigational
staff must explain to potential participants the aims, methods, and potential hazards of the study,
and any discomfort that participation in the study may entail. Participants will be informed that
their participation is voluntary and that they may withdraw consent to participate at any time. They
will be informed that choosing not to participate will not affect the care that they will receive.
Finally, they will be told that the investigator will maintain a participant identification register for
the purposes of long-term follow-up if needed and that their records may be accessed by health
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authorities and authorized sponsor staff without violating the confidentiality of the participant, to
the extent permitted by the applicable law(s) or regulations. By signing the ICF, form the
participant is authorizing such access, and agrees to allow his or her study physician to recontact
the participant for the purpose of obtaining consent for additional safety evaluations, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded
by means of the participant's personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of study participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator to allow direct access to his or her original medical records
for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also
addresses the transfer of the data to other entities and to other countries.
The participant has the right to request, through the investigator, access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory PK research is not conducted under standards appropriate for the return of data to
participants. In addition, the sponsor cannot make decisions as to the significance of any findings
resulting from exploratory research. Therefore, exploratory research data will not be returned to
participants or investigators, unless required by law. Privacy and confidentiality of data generated
in the future on stored samples will be protected by the same standards applicable to all other
clinical data.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or less, according to local
regulations) for additional research. 
  The research may begin at any time during the study or the
poststudy storage period.
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Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.5, Withdrawal from the Use ofResearch Samples).
Country Selection
unless explicitly addressed as a specific ethical
consideration in Section 4.2.1, Study-Specific Ethical Design Considerations.
Administrative requirements
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for nonacceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB  and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB  must be provided to the sponsor or its
designee. When the change(s) involves only logistic or administrative aspects of the study, the
IEC/IRB only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
(see Contact Information page(s) provided separately). Except in emergency situations, this
contact should be made before implementing any departure from the protocol. In all cases, contact
with the sponsor must be made as soon as possible to discuss the situation and agree on an
appropriate course of action. The data recorded in the eCRF and source documents will reflect any
departure from the protocol, and the source documents will describe this departure and the
circumstances requiring it.
Regulatory Documentation
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the investigational site:
 
Protocol and amendment(s), if any, signed and dated by the PI.
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 
A copy of the dated and signed, written IEC/IRB approval of the protocol, amendments, ICF,
any recruiting materials, and if applicable, participant compensation programs. This approval
must clearly identify the specific protocol by title and number and must be signed by the
chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the investigational staff is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (e.g., Form FDA 1572), if applicable
 
Documentation of investigator qualifications (e.g., curriculum vitae)
 
Completed investigator financial disclosure form from the PI, where required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all clinical subinvestigators
 
Documentation of subinvestigator qualifications (e.g., curriculum vitae)
 
Name and address of any local or central laboratory conducting tests for the study, and a dated
copy of current laboratory normal ranges for these tests, if applicable
 
Local or central laboratory documentation demonstrating competence and test reliability
(e.g., accreditation/license), if applicable
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by assigned number.
The investigator must also complete a participant screening log, which reports on all participants
who were seen to determine eligibility for inclusion in the study.
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Source Documentation
At a minimum, source documentation must be available for the following to confirm data collected
in the eCRF  or database: participant identification, eligibility, and study identification; study
discussion and date of signed informed consent; dates of visits; results of safety and efficacy
parameters as required by the protocol; record of all AEs and follow-up of AEs; concomitant
medication; drug receipt/dispensing/return records; study intervention administration information;
and date of study completion and reason for early discontinuation of study intervention or
withdrawal from the study, if applicable.
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a participant should be
consistent with that commonly recorded at the study site as a basis for standard medical care.
Specific details required as source data for the study will be reviewed with the investigator before
the study and will be described in the monitoring guidelines (or other equivalent document).
Following the ICH/GCP guidelines, direct access to source documentation (medical records) must
be allowed for the purpose of verifying that the data recorded in the eCRF are consistent with the
original source data.
Case Report Form Completion
Electronic data capture (eDC) will be used for this study. The study data will be transcribed by
study-site personnel from the source documents onto an eCRF and transmitted in a secure manner
to the sponsor within the timeframe agreed upon between the sponsor and the study site. The
electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documentation. All data relating to
the study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs
in English. Study site personnel must complete the eCRF within 5 days after a participant visit,
and the forms should be available for review at the next scheduled monitoring visit.
The responsible study monitor will check data at the monitoring visits to the clinical study site.
The Investigator will ensure that the data collected are accurate, complete and legible.
All clinical work conducted under this protocol is subject to GCP regulations. This includes an
inspection by the Sponsor and Competent Authority representatives at any time. The Investigator
will agree to the inspection of study-related records by Competent Authority representatives and
the audits of the Sponsor or third parties, named by the Sponsor.
Every effort should be made to ensure that all subjective measurements (e.g., pain scale
information or other questionnaires) to be recorded in the CRF are completed by the same
individual who made the initial baseline determinations. The investigator must verify that all data
entries in the eDC system are accurate and correct.
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All eCRF entries, corrections, and alterations must be made by the investigator or other authorized
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or
an authorized member of the investigational staff must adjust the eCRF (ifapplicable) and
complete the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in
3 different ways:
 
Site personnel can make corrections in the eDC tool at their own initiative or as a response to
an auto query (generated by the eDC tool)
 
Site manager can generate a query for resolution by the investigational staff
 
Clinical data manager can generate a query for resolution by the investigational staff
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
associated personnel before the study, and periodic monitoring visits by the sponsor. Written
instructions will be provided for collection, preparation, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study personnel before the
start of the study.
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the clinical study database, they will be
verified for accuracy and consistency with the data sources.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
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If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator must permit access to such reports.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the site. The first post initiation
visit will be made as soon as possible after enrollment has begun. At these visits, the monitor will
compare the data entered into the eCRFs with the hospital or clinic records (source documents); a
sample may be reviewed. The nature and location of all source documents will be identified to
ensure that all sources of original data required to complete the eCRF are known to the sponsor
and investigational staff and are accessible for verification by the sponsor site contact. If electronic
records are maintained at the investigational site, the method of verification must be discussed
with the investigational staff.
Direct access to source documentation (medical records) must be allowed for the purpose of
verifying that the data recorded in the eCRF are consistent with the original source data. Findings
from this review of eCRFs and source documents will be discussed with the investigational staff.
The sponsor expects that, during monitoring visits, the relevant investigational staff will be
available, the source documentation will be accessible, and a suitable environment will be provided
for review of study-related documents. The monitor will meet with the investigator on a regular
basis during the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Study Completion/Termination
Study Completion
The study is considered completed with the last study visit for the last participant participating in
the study. The final data from the investigational site will be sent to the sponsor (or designee) after
completion of the final participant visit at that site, in the time frame specified in the Clinical Trial
Agreement.
Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at any time
for any reason at the sole discretion of the sponsor. Investigational sites will be closed upon study
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completion. An investigational site is considered closed when all required documents and study
supplies have been collected and a site closure visit has been performed.
The investigator may initiate site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of an investigational site by the sponsor or investigator may include
but are not limited to:
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 
Inadequate recruitment of participants by the investigator
 
Discontinuation of further drug development
On-Site Audits
Representatives of the sponsor's clinical quality assurance department mayvisit the site at any time
during or after completion of the study to conduct an audit of the study in compliance with
regulatory guidelines and company policy. These audits will require access to all study records,
including source documents, for inspection and comparison with the CRFs. Participant privacy
must, however, be respected. The investigator and staff are responsible for being present and
available for consultation during routinely scheduled site audit visits conducted by the sponsor or
its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if they have been
contacted by a regulatory agency concerning an upcoming inspection.
Use of Information and Publication
All information, including but not limited to information regarding JNJ-40411813 or the sponsor's
operations (e.g., patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study and will not use it for other purposes without the sponsor's prior written
consent.
The investigator understands that the information developed in the clinical study will be used by
the sponsor in connection with the continued development of JNJ-40411813, and thus may be
disclosed as required to other clinical investigators or regulatory agencies. To permit the
information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
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The results of the study will be reported in a clinical study report (CSR) generated by the sponsor
and will contain eCRF data from all investigational sites that participated in the study. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator. Results of exploratory biomarker
analyses performed after the CSR has been issued will be reported in a separate report and will not
require a revision of the CSR. Study participantidentifiers will not be used in publication of results.
Any work created in connection with performance of the study and contained in the data that can
benefit from copyright protection (except any publication by the investigator as provided for
below) shall be the property of the sponsor as author and owner of copyright in such work.
The sponsor shall have the right to publish such data and information without approval from the
investigator. If an investigator wishes to publish information from the study, a copy of the
manuscript must be provided to the sponsor for review at least 60 days before submission for
publication or presentation. Expedited reviews will be arranged for abstracts, poster presentations,
or other materials. If requested by the sponsor in writing, the investigator will withhold such
publication for up to an additional 60 days to allow for filing of a patent application. In the event
that issues arise regarding scientific integrity or regulatory compliance, the sponsor will review
these issues with the investigator. The sponsor will not mandate modifications to scientific content
and does not have the right to suppress information. For multicenter study designs and substudy
approaches, secondary results generally should not be published before the primary endpoints of
a study have been published. Similarly, investigators will recognize the integrity of a multicenter
study by not submitting for publication data derived from the individual site until the combined
results from the completed study have been submitted for publication, within 12 months of the
availability of the final data (tables, listings, graphs), or the sponsor confirms there will be no
multicenter study publication. Authorship of publications resulting from this study will be based
on the guidelines on authorship, such as those described in the Uniform Requirements for
Manuscripts Submitted to Biomedical Journals, which state that the named authors must have
made a significant contribution to the design of the study or analysis and interpretation of the data,
provided critical review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of, and the results of, clinical studies as
required by law.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
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Financial disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial
disclosure.
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11.4. Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal
(investigational or non-investigational) product. An AE does not necessarily have a causal
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign
(including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF  (refer to All AEs under
Section 8.8.1, Time Period and Frequency for Collecting Adverse Events and Serious Adverse
Events Information, for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and European Union (EU) Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.
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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (e.g., death from anaphylaxis), the event must be
reported as a SUSAR even if it is a component of the study endpoint (e.g., all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For JNJ-40411813, the expectedness of an AE will be determined by
whether or not it is listed in the IB.
Adverse Event Associated with the Use of the Intervention
An AE is considered associated with the use of the intervention if the attribution is possible,
probable, or very likely by the definitions listed below (see Attribution Definitions).
An AE may also be associated with one or more of the baseline AEDs. If the investigator is
suspecting such an association, the attribution will be documented separately for these AEDs.
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
SEVERITY CRITERIA
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (e.g., laboratory abnormalities).
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SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention that may require expedited reporting or
safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Medication error involving a sponsor product (with or without participant exposure to the
sponsor study intervention, e.g., name confusion)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of a SAE should be recorded on the Serious Adverse Event page of the CRF.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the CRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the CRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical staff only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the participant's participation in the study, must be followed until any of the
following occurs:
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 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a participant's participation in a study must be reported as a SAE, except hospitalizations
for the following:
 
Hospitalizations not intended to treat an acute illness or AE (e.g., social reasons such as
pending placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
[Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.]
The cause of death of a participant in a study within 30 days of the last dose of study intervention,
whether or not the event is expected or associated with the study intervention, is considered a SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or
packaging, e.g., any dissatisfaction relative to the identity, quality, durability, or reliability of a
product, including its labeling or package integrity. A PQC may have an impact on the safety and
efficacy of the product. Timely, accurate, and complete reporting and analysis of PQC information
from studies are crucial for the protection of participants, investigators, and the sponsor, and are
mandated by regulatory agencies worldwide. The sponsor has established procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of PQC
information; all studies conducted by the sponsor or its affiliates will be conducted in accordance
with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
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If the defect is combined with a SAE, the study-site personnel must report the PQC to the sponsor
according to the SAE reporting timelines (refer to Section 8.8.1, Time Period and Frequency for
Collecting Adverse Event and serious Adverse Event Information). A sample of the suspected
product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
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11.5. Appendix 5: Drugs to be avoided
Examples of Concomitant Drugs to be Avoided (Moderate or Strong Inhibitor/Inducer of
CYP3A4)
inhibitors 
inducers
Strong inhibitors 
Moderate inhibitors 
Strong inducers 
Moderate inducers
cobicistat 
conivaptan 
boceprevir 
nelfinavir 
ritonavir 
telaprevir 
danoprevir and ritonavir 
elvitegravir and ritonavir 
indinavir and ritonavir 
lopinavir and ritonavir 
paritaprevir and ritonavir 
saquinavir and ritonavir 
tipranavir and ritonavir 
ombitasvir and/or dasabuvir 
itraconazole, ketoconazole, 
voriconazole, posaconazole 
troleandomyin clarithromycin 
telithromycin
mibefradil
idelalisib
nefazodone
amprenavir 
aprepitant 
atazanavir 
cimetidine 
ciprofloxacin 
clotrimazole
crizotinib
cyclosporine
darunavir and ritonavir
diltiazem
dronedarone
erythromycin
fluconazole
fluvoxamine
imatinib
tofisopam
verapamil
apalutamide 
avasimibe 
enzalutamide mitotane 
rifampin  
St. John’s wort 
bosentan
efavirenz
etravirine
modafinil
nafcillin
Source: FDA, https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-
drug-interactions-table-substrates-inhibitors-and-inducers.
Examples of CYP3A4 substrates producing potentially serious toxicity when combined with
CYP3A4 inhibitors
 
opioid analgesics
 
chemotherapy/oncologic agents
 
immunosuppressive agents
 
amiodarone
 
clindamycin
 
dihydroergotamine
 
dofetilide
 
ergotamine
 
theophylline
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Examples of 
 substrates
 
 
 
 
 
 
 
 
 
 
 
Example of
 substrate
 
Example of PgP substrate
 
digoxin
Note: This is not an exhaustive list.
CCI
CCI
CCI
CCI
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11.6. Appendix 6: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. In
addition to the procedures described in Section 5.1, male participants must also use a condom if
their female partner becomes pregnant to avoid exposure to the unborn child.
Pregnancy information will be collected and reported as noted in Section 8.8.4, Pregnancy and
Section 11.4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
Specific considerations for the current study
 
 is part of the existing therapy, and an oral contraceptive is used,
a product containing at least 30- to 35-mcg estrogen is advised. Also, an approved barrier
method must be used in combination with each hormonal contraceptive.
 
 are use, JNJ-40411813 may inhibit CYP3A4 which may result in
increased exposure of estrogen and/or progestogen. This is not expected to result in additional
safety risk (Zhang 2018).
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high FSH level (>40 IU/L or mIU/mL) in the postmenopausal range may be used to
confirm a postmenopausal state in women not using hormonal contraception or HRT, however
in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (e.g., a premenarchal woman
experiences menarche) or the risk of pregnancy changes (e.g., a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
CCI
CCI
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Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion
 Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationbin combination with approved barrier methods.
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationbin combination
with approved barrier methods.
 oral
 injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
ALLOWED BARRIER METHODS
Please note that a barrier method on its own is not sufficient
 condom with spermicidal foam/gel/film/cream/suppository
 occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository.
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NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).
Pregnancy During the Study
If a participant becomes pregnant during the study and pregnancy is specified as an exclusion criterion,
consider adding criteria for continuation of study intervention, eg:
Continuation of study intervention will only be included if either of the following apply:
 The study intervention has an approved label that indicates it can be used safely in pregnant females
OR
 When all of the following apply:
 The participant has a high mortality disease
 The investigator determines the participant is benefitting from study participation and there is no
reasonable intervention for her
 The sponsor and the relevant IEC/IRB give written approval
 The participant gives signed informed consent
 The investigator agrees to monitor the outcome of the pregnancy and the status of the participant
and her offspring
The protocol should be amended to allow such participation on a case-by-case basis, if such
participation is not already addressed in the protocol.
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11.7. Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments
Guideline Algorithm for Monitoring, Assessment & Evaluation of Abnormal
Liver Tests in Participants with no Underlying Liver Disease and normal
baseline ALT, AST, Alkaline Phosphatase and Bilirubin
Although this algorithm is still applicable across all populations, it has been developed assuming normal liver
function at baseline.  For populations with pre-existing liver disease and/or AST/ALT increases at baseline,
product teams are strongly encouraged to consult with Hepatic Safety Group for further guidance particularly for
discontinuation criteria.
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3. If Tbili is >2x upper limit of normal (ULN), request fractionation to document the fraction
that is direct bilirubin and to rule out indirect hyperbilirubinemia indicative of Gilbert’s
syndrome, hemolysis or other causes of indirect hyperbilirubinemia. Complete blood count
(CBC) with WBC and eosinophil count platelet count, international normalized ratio (INR),
and total protein and albumin (compute globulin fraction) should also be documented.  If INR
is abnormal, prothrombin time (PT), partial thromboplastin time (PTT) should be obtained
and these values should be followed until normal, along with documentation of whether
parenteral vitamin K was given along with the effect of such treatment on INR.
4. If initial liver function tests (LFTs) and ultrasound do not suggest Gilbert’s syndrome, biliary
tract disease or obstruction, viral hepatitis serology should be obtained including anti-hepatitis
A virus immunoglobin M (anti-HAV IgM), anti-HAV total,  HBsAg, anti-HBs,  anti-HB core
total,  anti-HB core IgM, anti-HCV,  anti-hepatitis E virus IgM (anti-HEV IgM) (even if has
not traveled to an endemic area for hepatitis E), Epstein-Barr virus (EBV) and
Cytomegalovirus (CMV) screen.
If participant is immunosuppressed, test for HCV ribonucleic acid (RNA) and HEV RNA.
If HBsAg or anti-HB core IgM or anti-HB core IgG positive, also get HBV DNA to detect active
HepB, especially in participants who are immunosuppressed.
If all other hepatitis B serologic tests are negative and anti-HBc total is the only positive test, HBV
DNA should be obtained to detect reactivation of hepatitis B.
5. Assuming that the history, physical, and initial imaging and laboratory has not revealed a
cause of elevated LTs, screen for other causes of liver disease including: Total protein and
albumin (estimate globulin fraction and obtain quantitative immunoglobulins if elevated),
antinuclear antibody (ANA), anti-liver kidney microsomal antibody type 1 (anti-LKM1), anti-
liver-kidney microsomal antibodies (anti-LKM antibodies), anti-smooth muscle antibodies
(ASMA), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). If the pattern
of laboratory abnormalities is not hepatocellular, but cholestatic or a mixed pattern (see
definitions in table above), then GGT, anti-mitochondrial antibody (AMA) and anti-neutrophil
cytoplasmic antibody (pANCA) should also be tested.  If there is an indication by history or
elevated baseline LTs that there may be an underlying chronic liver disease possibly
exacerbated by exposure to the study intervention in the clinical trial or making the participant
more susceptible to DILI, test iron/Total iron binding capacity (TIBC) and ferritin
(hemochromatosis), and alpha-1-antitrypsin level.  If participant is <50 years of age,
ceruloplasmin should also be tested to screen for Wilson’s disease.  If participant is sick
enough to be hospitalized and is under age 50, a slit lamp examination to detect Kayser-
Fleischer rings and a 24-hour urine collection for copper should be measured. Consider serum
ethanol and/or acetaminophen level and urine drug screen as clinically appropriate.
6. A liver biopsy should be considered if autoimmune hepatitis remains a competing etiology
and if immunosuppressive therapy is contemplated.
A liver biopsy may be considered:
if there is unrelenting rise in liver biochemistries or signs of worsening liver function despite
stopping the suspected offending agent.
if peak ALT level has not fallen by >50% at 30-60 days after onset in cases of hepatocellular DILI,
or if peak Alk Phosphatase has not fallen by >50% at 180 days in cases of cholestatic DILI despite
stopping the suspected offending agent.
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in cases of DILI where continued use or re-exposure to the implicated agent is expected.
if liver biochemistry abnormalities persist beyond 180 days to evaluate for the presence of chronic
liver diseases and chronic DILI.
7. If pertinent, copies of hospital discharge summary, radiology, pathology and autopsy reports
should be obtained.
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(Past x years = Past 1 year)
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Appendix 9b: Columbia Suicide Severity Rating Scale (Since Last Visit)
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11.10. Appendix 10: Guidance on Study Conduct during the COVID-19 Pandemica
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgement of the
investigator to protect the health and well-being of participants and site staff. If at any time a
participant’s safety is considered to be at risk, study intervention will be discontinued, and study
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed
remotely/virtually or delayed until such time that on-site visits can be resumed. Study visits may
also be performed at home by the investigator or an appropriately trained nurse. At each contact,
participants will be interviewed to collect safety data. Key efficacy endpoint assessments should
be performed if required and as feasible. Participants will also be questioned regarding general
health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow up. Modifications to protocol-required assessments may be
permitted after consultation between the participant and investigator, and with the agreement of
the sponsor. Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the case report form (CRF).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes (e.g., delay or discontinuation in recruitment, site monitoring and audits) will be
communicated to the sites and to the health authorities according to local guidance.  If a participant
has tested positive for COVID-19, the investigator should contact the sponsor’s responsible
medical officer to discuss plans for study intervention and follow-up. Modifications made to the
study conduct as a result of the COVID-19 pandemic should be summarized in the clinical study
report.
a 
This section has been amended by Amendment INT-1
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GUIDANCE SPECIFIC TO THIS PROTOCOL:
The local study center may decide, based on local regulation, to test participants for SARS-CoV-2
at time points indicated by the study center. Any results of such a test will be documented in the
eCRF.
If for any reason related to COVID-19 a site visit has to be postponed, the following guidance
should be followed:
 
According to the protocol, visit 2 (Day 1) may be postponed for 1 week without inducing a
protocol deviation. Participants must continue to record their (baseline) seizures in the e-diary.
 
Visits 3 and 5 will be done by telephone limiting the number of site visits.
 
Visits 4, 6 and 7 may be delayed up to 2 days without inducing a protocol deviation.
Participants must continue to record their seizures in the e-diary. Participants have spare
intervention.
 
Visits 4, 6 and 7 may be delayed up to 4 days. This will be recorded as a COVID-19 related
minor protocol deviation. Participants must continue to record their seizures in the e-diary.
Participants have spare intervention for up to 4 days.
 
Only when required in the context of COVID-19, the visits 4, 6 or 7 may be cancelled and
done by telephone instead. For Visits 4 and 6, this is only allowed when the study center can
dispense the study intervention at home within 4 days after the planned visit and after
temperature-controlled transport. This missing visit will be documented in the eCRF and
recorded as a COVID-19 related major protocol deviation. Participants must continue to
record their seizures in the e-diary.
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11.11. Appendix 11: Protocol Amendment History
DOCUMENT HISTORY
Document 
Date
Amendment INT-3 
12 July 2022
Amendment INT-2 
07 April 2022
Amendment INT-1 
18 January 2021
Original Protocol 
13 November 2020
Amendment INT 3 (12-July-2022)
Overall Rationale for the Amendment:
To allow for starting enrolment in the double-blind treatment phase of the second cohort as soon
as enrolment of approxilately 60 in the first cohort has been completed so that there is no pause in
recruitment, provided that no safety concerns are observed during the continuous safety monitoring
of ongoing patients. Sections 1.1 (Overview and Study Design), 3 (Objectives), 4.1 (Overall
Design), 4.3 (Justification for Dose), 6.3 (Procedures for Randomization) and 9.5 (Data Review
after each Cohort) have been changed accordingly.
Dosages of JNJ-40411813 in Cohort 2 will be
 or placebo for
 participants and
 participants.
To also allow the evaluation of the Efficacy, Safety and Tolerability of JNJ-40411813 as
Adjunctive Therapy in Subjects with Focal Onset Seizures with Suboptimal Response to
Brivaracetam, from Cohort 2 onwards. Brivaracetam has the same Mechanism of Action as
Levetiracetam and nonclinical models have shown a strong positive PD interaction of JNJ-
40411813 with both levetiracetam and brivaracetam. Brivaracetam has been added in all relevant
sections throughout the protocol.
To also add/clarify/correct:
Section number
and Name
Description of Change 
Brief Rationale
Section 1.1. Dosage and
administration
And
Section 2.3.1: Risks for Study
Participation
And
Section 4.2: Optional
temporary dose reduction
Added: 
For participants receiving dosages of 
, i.e. Cohort 2
and beyond, a temporary dosage reduction to 
 be
permitted in case adverse events consisting of
dizziness, incoordination, sedation, or fatigue (or
similar descriptive terms) appear within the first 2
weeks of treatment and which, in the judgment of the
investigator, potentially limit activities of daily living.
This dosage reduction may last no longer than 2 weeks
and may not be repeated. Following the return to the
originally assigned dosage, recurrence of intolerable
adverse events would require discontinuation of the
study medication
To anticipate management of early
onset AEs (dizziness
incoordination, sedation, or
fatigue)
CCI
CCI
CCI
CCI
CCI
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Section number
and Name
Description of Change 
Brief Rationale
Participants should be advised to call the site it they
experience dizziness incoordination, sedation, or
fatigue in the first 2 weeks of the double-blind phase.
Section 1.1 Secondary
objectives (and Section 3)
Changed:
To evaluate the pharmacokinetics (PK) of JNJ-
40411813 and selected metabolites and levetiracetam
in participants with focal onset seizures who are
receiving levetiracetam   and up to 3 other AEDs.
Into:
To evaluate the pharmacokinetics (PK) of JNJ-
40411813 and selected metabolites and levetiracetam
or brivaracetam  in participants with focal onset
seizures who are receiving levetiracetam or
brivaracetam and up to 3 other AEDs.
Due to fact that we now allow the
use of brivaracetam as primary
AED
Section 1.1 Exploratory
objectives
Changed:
To explore the exposure-response relationship using an
estimate of individual participant exposures of JNJ-
40411813, and levetiracetam if deemed warranted,
from the population PK and/or physiologically based
pharmacokinetic (PBPK) analyses, and the primary
and secondary endpoints.
Into:
To explore the exposure-response relationship using an
estimate of individual participant exposures of JNJ-
40411813, and levetiracetam or brivaracetam  if
deemed warranted, from the population PK and/or
physiologically 
based 
pharmacokinetic 
(PBPK)
analyses, and the primary and secondary endpoints.
Due to fact that we now allow the
use of brivaracetam as primary
AED
Section 4.2 Duration of study
period
Clarification:
The double-blind study period will be followed by a
follow-up period of 2 weeks. The dose will not be
tapered after completion of the double-blind study
period. Although there are no signals of a rebound
effect after stopping the treatment with JNJ-40411813
from preclinical studies or previous clinical studies, the
change of seizure count after stopping the treatment
will be investigated in the follow-up period.
Into:
The double-blind study period will be followed by a
follow-up period of 2 weeks if the participant does not
take part in the OLE period. The dose will not be
tapered after completion of the double-blind study
period. Although there are no signals of a rebound
effect after stopping the treatment with JNJ-40411813
from preclinical studies or previous clinical studies, the
change of seizure count after stopping the treatment
will be investigated in the follow-up period.
Participants entering the OLE will
not have an interruption of dosing,
therefore a followup visit after
discontinuation of study drug does
not apply
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Section number
and Name
Description of Change 
Brief Rationale
Section 5.1:
Exclusion 15
Added: does not apply for subjects using barbiturates
as AED or rescue medication in Epilepsy
The urine drug screening test is to
exclude patients abuse alcohol
and/or drugs of abuse
Section 5.1.
Inclusion 5
Clarification:
Note: One-time changes in AED dosages do not
represent a change in the daily AED regimen. For
example, if the participant took an extra dose of an AED
on one day, this would not represent a change in the
daily AED regimen. Benzodiazepines received on a
continuing basis at stable dosages for 1 month before
screening should be considered as concomitant AEDs
Into:
Note: One-time changes in AED dosages do not
represent a change in the daily AED regimen. For
example, if the participanttook an extra dose of an AED
on one day, this would not represent a change in the
daily AED regimen. Benzodiazepines and barbiturates
received on a continuing basis at stable dosages for 1
month before screening should be considered as
concomitant AEDs, except if they are taken to treat
anxiety.
Section 5.4 
Added:
Individuals who do not meet the criteria for
participation in this study (screen failure) may be
rescreened one time after discussion with the sponsor
representative. Rescreened participants will be
assigned a new participant number, undergo the
informed consent process, and then start a new
screening and baseline phases, Rescreened
individuals must meet all criteria before entering the
double blind phase.
In some cases, those factors that
caused individuals to fail to meet
criteria are judged as likely to remit
(e.g., an unrelated intercurrent
illness)
Sections 1.1, 9.3, 10.8.5, PK  
Added:
Addition of JNJ-40411813 metabolite ‘
Section 10.10, SoA of the OLE
period
Added:
Electrocardiogram (single) at OLE1, OLE2 and OLE4
Omitted by error in Amendment 2
Amendment INT-2 (07-April-2022)
Overall Rationale for the Amendment: To add an open-label extension (OLE) treatment period after
completion of the double-blind treatment period.
Section number
and Name
Description of Change 
Brief Rationale
Section 2.2.1 
Added: Information about recently completed chronic
rodent and non-rodent toxicology studies.
Chronic toxicology studies are
required to support clinical trials of
longer duration than 3 months.
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Section number 
and Name
Description of Change 
Brief Rationale
Sections, 2.3.2, 4.1, 4.4 and 6.7 Adding an OLE treatment period for subjects 
completing the double-blind treatment period. 
Treatment resistant epilepsy has a
severe impact on quality of life and
risk of mortality. Continued use of
JNJ-40411813 in combination with
levetiracetam may result in a
significant positive impact on this
patient population.
Section 5.1, Inclusion 
criterion 3 
Removed: “for at least 1 year” 
In some regions, levetiracetam  is
started as first line therapy when
diagnosis has been confirmed less
than 1 year ago.
Section 5.1, Inclusion 
criterion 5 
Changed: 
Current treatment with at least 1 and up to 4 AEDs
(including levetiracetam), administered at stable
dosage(s) for at least 1 month before screening, and no
new AEDs added for the previous 2 months; these
AEDs must remain unchanged throughout the
pretreatment and double-blind treatment periods (with
the exception of dosage reductions of concomitant
AEDs because of suspected elevated AED levels or
side effects).
Into:
Current treatment with at least 1 and up to 4 AEDs
(including levetiracetam), administered at the
appropriate dosage(s) and for a sufficient treatment
period before screening. These AEDs must remain
unchanged throughout the pretreatment and double-
blind treatment periods (with the exception of dosage
reductions of concomitant AEDs because of suspected
elevated AED levels or side effects).
In some treatment strategies, the
time window to add or change
AEDs differs from the timelines
described before. The new wording
fits better in different treatment
strategies.
Section 5.1, Inclusion 
criterion 6 
This 
inclusion 
criterion 
“Currently 
showing 
inadequate response to levetiracetam, administered at 
the appropriate dosage(s) and for a sufficient treatment 
period, based on the judgment of the investigator” has 
been removed. 
The term “inadequate” has not been
defined in detail and clear criteria on
seizure count for inclusion have been
already 
described 
in 
inclusion
criterion 3.
Section 5.1, Exclusion 
criterion 5 
Changed: 
Current treatment with vagus nerve stimulation, deep
brain and cortical stimulation for 1 year or less
Into:
Recently initiated vagus nerve stimulation, deep brain
and cortical stimulation (i.e. in the last 12 months
before screening).
Original text caused some
confusion.
Section 7.3 
Added: “promptly” to the referral for appropriate 
medical/psychiatric care.
Medical and ethical consideration.
Section 8.4.3 
Remove the sentence “The mean values of ECG 
parameters will be calculated for entry into the eCRF.” 
The eCRF has been designed to
enter the 3 individual ECGs of the
triplicate ECG
Section 9.4 
Added that the safety analysis will be done per cohort. 
This detail was missing in the
original text.
Section 10.4.2, Duration of the 
study  
Added: Participants will participate in the open-label 
period for a period of up to 2 years. If they still benefit 
from treatment with JNJ-40411813, they will be 
transferred to a new central OLE study when
Due to unforeseen circumstances,
the open label extension period
may not be completed as planned.
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Section number
and Name
Description of Change 
Brief Rationale
available, in which also participants from other (late
phase) studies with JNJ-40411813 will participate.
and
The OLE extension period may be stopped when the
development of the compound is stopped by a decision
of the sponsor or because of insufficient efficacy or
safety concerns.
Newly added Addendum
(section 10)
Adding an OLE treatment period for subjects
completing the double-blind treatment period.
To comply with the considerations
for an OLE treatment as indicated
in Sections 2.3.2 and 6.7 of the
protocol.
Amendment INT-1 (18-January-2021)
Overall Rationale for the Amendment: To implement several different corrections as listed below.
Section number 
and Name
Description of Change 
Brief Rationale
Synopsis, secondary objectives 
Changed: 
….and up to 4 other AEDs.
Into:
…and up to 3 other AEDs.
Correction of typo
Synopsis and Section 4.1 
Change:
a 12-week double-blind treatment period….
Into
An up to 12-week double-blind treatment period….
The double-blind treatment period
may be shorter if the participant
reached the baseline seizure count
Synopsis, SoA and Sections 3, 
4.1, and 9.2.1.
Changed:
.. number of focal onset seizures…
Into
.. number of observable focal onset seizures…
To have a more precise definition
of seizures to be reported.
SoA and Section 8.2.2 
A telephone contact has been added to the baseline
period. In the SoA footnotes and Section 8.2.2 the
following text has been added:
During the baseline period, the participant will be
contacted by phone by the investigator or study nurse
to confirm correct use of the e-diary. This contact
should take place at least 4 weeks after the start of the
baseline period, but multiple contacts are allowed
when required.
A period of 8 weeks is too long to
keep the participant motivated
without support from the site team.
Section 5.1, inclusion 
criterion 4
Changed:
Must have had a neuroimaging procedure within 5
years, including a computed tomography (CT) scan or
magnetic resonance imaging (MRI), that excluded a
progressive neurologic disorder; these procedures may
be performed within the 8-week baseline period. When
one was obtained earlier and the clinical situation is not
changed, the participant may be allowed in the study
To be in line with current clinical
practice.
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Section number
and Name
Description of Change 
Brief Rationale
after approval by the epilepsy consortium in the
adjudication process.
Into:
Must have had a neuroimaging procedure within 10
years, including a computed tomography (CT) scan or
magnetic resonance imaging (MRI), that excluded a
progressive neurologic disorder; these procedures may
be performed within the 8-week baseline period.
Section 5.4. and Section 8.2.1 
Added: If the adjudication process is not possible e.g.,
because of technical limitations of protected data
transfer, the participant will not be a screen failure.
To prevent participants to be a
screening failure, when the
adjudication process should fail for
technical reasons.
Section 5.1, inclusion
criterion 3
Removed:
The diagnosis will have to be confirmed by the
Epilepsy Consortium’s Review before randomization.
May conflict with the exception
mentioned above.
Synopsis
Section 3
Section 4.1
Section 5.1 Inclusion
Criterion 7
Section 8.2.2
Section 8.3.1
Section 9.2.1
Original text:
Seizures that will be counted during baseline and
throughout the study include focal onset motor
seizures with or without impaired consciousness, focal
onset nonmotor seizures with impairment of
consciousness and focal to secondarily generalized
seizures. Focal onset nonmotor seizures without
impairment of consciousness, myoclonic, or other
generalized seizures will not be counted.
Changed into:
Participants must be compliant with the recording of
information in the e-diary throughout the study.
Observable seizures that will be entered during
baseline and throughout the study include focal aware
seizures with and without motor signs, focal impaired
awareness seizures and focal to bilateral tonic-clonic
seizures. Myoclonic, or other generalized seizures will
not be entered.
The terminology of seizures is
incorrect in several places and does
not exactly reflect the ILAE 2017
criteria.
Synopsis and Section 9.2.2,
Secondary generalized seizures
Change:
Separate analyses (including time to baseline count
and % reduction of counts) for secondary generalized
seizures only and complex focal and secondary
generalized seizures, will be performed if a large
enough number of events is observed.
Into:
Separate analyses (including time to baseline count
and % reduction of counts) for focal to bilateral tonic-
clonic seizures will be performed if a large enough
number of events is observed.
To comply with ILAE 2017 criteria.
Section 9.2.1 
Added:
Although focal aware seizures with and without motor
signs are entered in the e-diary, focal aware seizures
without motor signs will not be counted in the analysis.
For participants it is not always clear
how to differentiate between motor
and 
non-motor 
seizures. 
So,
therefore all seizures will be entered
in the e-diary, but focal aware
seizures without motor signs will not
be counted.
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Section number
and Name
Description of Change 
Brief Rationale
Section 9.3 
Change:
Population PK and/or PBPK analyses of JNJ-
40411813, levetiracetam and AED
Into:
Population PK and/or PBPK analyses of JNJ-
40411813 and levetiracetam …
Population PK and PBPK analysis
of AEDs 
Section 7.3 
Added: 
A participant who shows signals of clinically
meaningful acute suicidal ideation at any time during
the study should be withdrawn from the study and
referred for appropriate medical/psychiatric care.
A withdrawal criterion for response
to the C-SSRS was missing.
Schedule of Activities
Section 8.5
Changed Visits 3 and 5 from site visits into telephone
contacts removing blood collection, C-SSRS and
some safety assessments. Adverse events and
concomitant medication will be followed up.
Because of the potentially ongoing
COVID-19 pandemic and to limit
the burden for the study participants
in general, it has been decided to
limit Visits 3 and 5 to a telephone
contact. No blood for PK will be
collected.
SoA 
Section 8.5
Section 6
Blood collections for PK have been removed from the
screening visit but added to Visit 7. Table 3 and
several sections have been updated for consistency.
Blood collection at screening should
require pre-ICF activities. More
information on steady state PK is
required.
Section 8.1 
Blood volume to be collected reduced from 83.5 to
75.5 mL. In text formulated as approximately 76 mL.
Change volume of blood to be
collected due to changes in PK
sampling plan.
Section 8.2.3 
Original text:
The participant will visit the study center after 2, 4, 6,
8 and 12 weeks.
Changed into:
The participant will visit the study center after 4, 8
and 12 weeks. After 2 and 6 weeks, the investigator
will have a telephone call with the participant to
discuss adverse events, use ofthe e-diary and
concomitant medication.
Because of the potentially ongoing
COVID-19 pandemic and to limit
the burden for the study participants
in general, it has been decided to
limit Visits 3 and 5 to a telephone
contact. No blood for PK will be
collected.
Section 10.10. Appendix 10:
Guidance on Study Conduct
during the COVID-19
Pandemic
Original text:
 
According the protocol, visit 2 (Day 1) may be
postponed for 1 week without inducing a
protocol deviation. Participants must continue to
record their (baseline) seizures in the e-diary.
 
Visits 3 to 7 may be delayed up to 2 days without
inducing a protocol deviation. Participants must
continue to record their seizures in the e-diary.
Participants have spare intervention.
 
Visits 3 to 7 may be delayed up to 4 days. This
will be recorded as a COVID-19 related minor
protocol deviation. Participants must continue to
record their seizures in the e-diary. Participants
have spare intervention for up to 4 days.
 
Only when required in the context of COVID-
19, the visits 3, 4, 5, 6 or 7 may be cancelled and
Because of the potentially ongoing
COVID-19 pandemic and to limit
the burden for the study participants
in general, it has been decided to
limit Visits 3 and 5 to a telephone
contact
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Section number
and Name
Description of Change 
Brief Rationale
done by telephone instead. For Visits 3 to 6, this
is only allowed when the study center can
dispense the study intervention at home within 4
days after the planned visit and after
temperature-controlled transport. This missing
visit will be documented in the eCRF and
recorded as a COVID-19 related major protocol
deviation. Participants must continue to record
their seizures in the e-diary.
Changed into:
 
According the protocol, visit 2 (Day 1) may be
postponed for 1 week without inducing a
protocol deviation. Participants must continue to
record their (baseline) seizures in the e-diary.
 
Visits 3 and 5 will be done by telephone limiting
the number of site visits.
 
Visits 4, 6 and 7 may be delayed up to 2 days
without 
inducing 
a 
protocol 
deviation.
Participants must continue to record their
seizures in the e-diary. Participants have spare
intervention.
 
Visits 4, 6 and 7 may be delayed up to 4 days.
This will be recorded as a COVID-19 related
minor protocol deviation. Participants must
continue to record their seizures in the e-diary.
Participants have spare intervention for up to 4
days.
 
Only when required in the context of COVID-
19, the visits 4, 6 or 7 may be cancelled and done
by telephone instead. For Visits 4 and 6, this is
only allowed when the study center can dispense
the study intervention at home within 4 days
after the planned visit and after temperature-
controlled transport. This missing visit will be
documented in the eCRF and recorded as a
COVID-19 related major protocol deviation.
Participants must continue to record their
seizures in the e-diary.
Multiple Sections 
Removed: Sections 8.3.2.1. and 10.8.
Text removed from synopsis, SoA and Sections 3, 4.2,
8.1, 8.2.3, 9.2.2 and references.
Synopsis and Sections 4.1 and 
9.5
Original text:
If the assessment of efficacy favors JNJ-40411813,
the second cohort will receive a lower dose. If the
assessment of efficacy does not favor JNJ-40411813,
the second cohort will be enrolled at a higher dosage
if there are no safety concerns. In case of doubtful
results, it may be decided to add sub-cohorts
including a lower dose as well as a higher dose.
Changed into:
If the assessment of efficacy favors JNJ-40411813
but with concerns about tolerability, the second
cohort will receive a lower dose. If the assessment of
efficacy does not favor JNJ-40411813, the second
The procedure of decisions on the
dose levels of following cohorts has
been adapted to optimize the
efficiency of study execution.
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Section number
and Name
Description of Change 
Brief Rationale
cohort will be enrolled at a higher dose if there are no
safety concerns.
If the assessment of efficacy favors JNJ-40411813
and there are no safety concerns, the following cohort
may include both a lower dose and a higher dose.
Such a cohort will randomize 100 subjects in a ratio
40:40:20 (high dose/low dose/placebo). Subjects and
investigators will be blinded for treatment but not for
dose level.
Figure 1 in Section 4.1 has been adapted.
Section 6.3 
Added: description of the protocol numbering given
the options described above.
See above.
Section 6.3 
Added:
Participants and investigators will be blinded for
treatment (JNJ-40411813 or placebo) but not for
dose.
Multiple dose levels may be
possible in one cohort (e.g., due to
enzyme induction or different dose
levels in one cohort [see above].
Blinding for dose level is technically
not possible in this study.
Section 6.1 
Original text:
The participants will take the study intervention and
levetiracetam with them at each study visit.
Changed into:
The participants will bring the study intervention and
all other AEDs currently taken with them at each study
visit.
Added:
For Visit 7, ingest morning doses of study drug and
AED medications at home, before going to the clinic.
To give more detailed instructions
on drug intake and documentation
around study visits.
Section 6.4 
Added:
For study visits 2, 4 and 6, participants are requested
to record the time of last dosing of levetiracetam , their
 
 
 
 
 and the study drug on the
day before the study visit. Participants will also record
the time of last dosing of levetiracetam and study drug
taken at home before visit 7. An appointment-card will
be provided for documentation.
To give more detailed instructions
on drug intake and documentation
around study visits.
Section 6.5 
Added:
For study visits 2, 4, and 6 participants are requested
to record the time of last dosing of levetiracetam on the
day before the study visit. Participants will also record
the time that levetiracetam is taken at home prior to
visit 7. An appointment-card will be provided for
documentation.
Added:
For the study visits 2, 4 and 6, participants are
requested to record the date and time of last dosing of
when applicable on the day before the study visit. An
appointment-card will be provided for documentation.
To give more detailed instructions
on drug intake and documentation
around study visits.
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Status: Approved,  Date:  17 November 2022
Section number
and Name
Description of Change 
Brief Rationale
Section 6.6 
A new Section 6.6, “Recording of drug intake;
overview” has been added.
To instructions on drug intake
recording were fragmented
throughout the protocol. To clarify
this better, a new section has been
added.
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Status: Approved,  Date:  17 November 2022
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a 
This section has been amended by Amendment INT-1
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct ofthis study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04836559

Signature
User 
Date 
Reason
 
17-Nov-2022
13:13:44
(GMT)
Document Approval
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NCT04836559