A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Trial of CVL-865 as Adjunctive Therapy in Adults With Drug-Resistant Focal Onset Seizures (REALIZE Trial)
Phase: PHASE2
Conditions: Seizures
Sponsor: AbbVie

 
 
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CLINICAL PROTOCOL 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP, MULTICENTER TRIAL OF CVL-865 AS 
ADJUNCTIVE THERAPY IN ADULTS WITH DRUG-RESISTANT 
FOCAL ONSET SEIZURES (REALIZE TRIAL) 
Protocol Number: CVL-865-SZ-001 
Compound Number: CVL-865 
Trial Phase: 2 
Short Title: A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in 
the Treatment of Focal Onset Seizures 
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 131 Dartmouth Street, Suite 502, Boston, MA 02116 
United States 
Regulatory Agency Identifier Number 
Regulatory Agency File 
Identifying # 
IND:  
126,900 
EudraCT 
2019-002576-14 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Version 4.0: 30 Jun 2020 
Version 3.0: 15 Nov 2019 
Version 2.0: 03 Oct 2019  
Original Version 1.0: 24 Jul 2019 
MEDICAL MONITOR NAME AND CONTACT INFORMATION IS PROVIDED IN 
THE TRIAL OPERATIONS MANUAL 
 
NCT04244175

 
 
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PROTOCOL VERSION 4.0 SUMMARY OF CHANGES TABLE 
Document History
Document: 
Date (Day-Month-Year) 
Version 4.0 
30 Jun 2020 
Version 3.0 
15 Nov 2019 
Version 2.0 
03 Oct 2019 
Original Protocol Version 1.0 
24 Jul 2019 
Amendment: Protocol Version 4.0 (30 Jun 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
incorporate measures into the protocol to ensure the safety of the trial subjects and the 
validity of the trial data in the environment of the COVID-19 pandemic and to clarify 
other aspects of trial conduct unrelated to the COVID-19 pandemic.
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3 Objectives and 
Endpoints 
9.4.1 Efficacy Analyses 
Changed the order of the 2 key 
secondary endpoints 
To reflect the sponsor’s decision to allow 
a hierarchical testing sequence 
1.1 Synopsis 
9.2 Sample Size 
Determination 
Added provision to extend 
enrollment to maintain the 
planned statistical power in 
the event of higher than 
expected early terminations 
due to COVID-19 or other 
reasons 
Unknown effect of COVID-19 pandemic 
on trial enrollment 
1.3 Schedule of 
Assessments 
Added a footnote to Table 2 to 
provide an option for specific 
visits to be completed 
remotely  
Added option for COVID-19 
testing 
To reflect risk assessment measures by 
sponsor to prioritize trial participant 
safety 
 
Deleted portion of footnote in 
Table 2 about obtaining PK 
sample at Visit 6 
Correct typographical error  
2.3 Benefit/Risk 
Assessment 
Added a statement regarding 
sponsor risk assessment 
related to COVID-19 
To reflect measures implemented by the 
sponsor to prioritize trial participant 
safety and data validity 
 

 
 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
7.3 Individual Subject 
Discontinuation 
8.4.6.2 Hematologic 
Abnormalities 
Changed decimal places for 
WBC and neutrophil counts 
Correct typographical errors 
5.2 Exclusion Criteria 
Modified the wording related 
to current and prior use of 
prohibited medications  
Simplify language by referring to the 
respective tables that specify prohibited 
medications before and during the trial 
5.2 Exclusion Criteria 
8.3.3 Electrocardiograms 
Specify that QTcF 
interpretation at screening is 
according to central ECG 
service reading  
Align ECG exclusion criterion 
with methods for obtaining 
ECGs 
Address inconsistency in previous version 
of the protocol and provide clarification 
regarding results interpretation 
6.7 Intervention  after the 
End of the Trial 
Deleted sentence about 
subjects who require 
withdrawal from the trial 
being potentially eligible for  
entry into the open-label 
extension trial 
Correct error (subjects who do not 
complete the trial are not eligible for the 
open-label extension) 
8.6 Pharmacokinetics 
Simplified wording about 
sample collection (Sections 
8.6.1 and 8.6.2) 
Remove duplication of details provided in 
other materials 
 
Revised sample analysis 
wording (Section 8.6.3) 
Clarify that only treatment samples will 
be analyzed 
10.1.3 Informed Consent 
Process 
Removed references to legally 
authorized representative 
Correct inconsistency with inclusion 
criteria  
10.2 Appendix 2: Clinical 
Laboratory Tests 
Added section on additional 
required tests, which includes 
serum and urine pregnancy 
tests 
Correct inconsistency with Schedule of 
Assessments 
10.3 Appendix 3: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, 
and Reporting 
 
Revised section to remove 
redundant language and to 
clarify AE and SAE/AESI 
reporting procedures 
Align wording with actual processes that 
will be followed in trial and for 
consistency across Cerevel clinical 
development programs 
10.6 Appendix 6: 
Inducers and Inhibitors of 
Cytochrome P450 3A 
Added eslicarbazepine as CYP 
3A inducer 
Add to prohibited medications, due to 
potential for reduction of CVL-865 
concentrations 
Signature Page 
Changes to signatories 
Reflect changes in sponsor personnel 
Reflect consistency of roles across 
protocols 
 

 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Overall 
Minor grammatical and 
wording corrections or 
clarifications throughout 
protocol 
Correct errors in the previous version of 
the protocol 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CYP = cytochrome P450; 
ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event; WBC = white blood cell 
 

 
 
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TABLE OF CONTENTS 
PROTOCOL VERSION 4.0 SUMMARY OF CHANGES TABLE .............................3
TABLE OF CONTENTS ..................................................................................................6
TABLE OF TABLES .........................................................................................................9
TABLE OF FIGURES .....................................................................................................10
1 
PROTOCOL SUMMARY .......................................................................................11
1.1
Synopsis .................................................................................................................11
1.2
Schema ..................................................................................................................15
1.3
Schedule of Assessments ......................................................................................16
2 
INTRODUCTION ....................................................................................................22
2.1
Trial Rationale .....................................................................................................22
2.2
Background ..........................................................................................................22
2.3
Benefit/Risk Assessment ......................................................................................23
3 
OBJECTIVES AND ENDPOINTS .........................................................................24
4 
TRIAL DESIGN .......................................................................................................25
4.1
Overall Design ......................................................................................................25
4.2
Scientific Rationale for Trial Design ..................................................................27
4.3
Dosing Rationale ..................................................................................................27
4.4
Definition of Completed Subject ........................................................................28
4.5
End of Trial Definition ........................................................................................28
5 
TRIAL POPULATION ............................................................................................28
5.1
Inclusion Criteria .................................................................................................29
5.2
Exclusion Criteria ................................................................................................30
5.3
Lifestyle Considerations ......................................................................................32
5.3.1
Meals and Dietary Restrictions .....................................................................32
5.3.2
Alcohol, Caffeine, and Tobacco Restrictions ...............................................32
5.3.3
Effects on Ability to Drive and Use Machines .............................................33
5.4
Screen Failures .....................................................................................................33
6 
TRIAL TREATMENT .............................................................................................33
6.1
Trial Treatments Administered ..........................................................................34
6.2
Preparation/Handling/Storage/Accountability/Disposition .............................34
6.3
Measures to Minimize Bias: Randomization and Blinding..............................35
6.3.1
Subject Assignment to Treatment ................................................................35
6.3.2
Blinding ...........................................................................................................35
6.4
Trial Treatment Compliance ..............................................................................35
6.5
Concomitant Therapy ..........................................................................................36
6.5.1
Prior and Concomitant Medications ............................................................36
6.5.2
Prohibited Medications .................................................................................36
6.5.3
Rescue Medicine .............................................................................................38
6.6
Dose Modification ................................................................................................38
6.7
Intervention after the End of the Trial ..............................................................38
7 
DISCONTINUATION OF TRIAL INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................39
7.1
Discontinuation of Entire Trial...........................................................................39
7.2
Discontinuation of Individual Site ......................................................................39
 

 
 
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7.3
Individual Subject Discontinuation ....................................................................39
7.4
Procedures to Encourage Continued Trial Participation ................................41
7.5
Lost to Follow up ..................................................................................................41
8 
TRIAL ASSESSMENTS AND PROCEDURES ....................................................41
8.1
Screening and Baseline Assessments ..................................................................42
8.2
Efficacy Assessments ...........................................................................................42
8.2.1
Seizure Frequency and Type (eDiary) .........................................................42
8.2.2
Patient’s Global Impression of Change .......................................................43
8.2.3
Clinical Global Impression-Severity of Symptoms Scale ...........................43
8.2.4
Clinical Global Impression-Improvement Scale .........................................43
8.2.5
Quality of Life in Epilepsy – 31 ....................................................................43
8.2.6
Health Utilities Index .....................................................................................44
8.3
Safety Assessments ...............................................................................................44
8.3.1
Physical and Neurological Examinations.....................................................44
8.3.2
Vital Sign Measurements ..............................................................................45
8.3.3
Electrocardiograms........................................................................................45
8.3.4
Clinical Safety Laboratory Assessments ......................................................46
8.3.5
Modified Clinical Institute Withdrawal Assessment – 
Benzodiazepines .............................................................................................47
8.3.6
Suicidal Ideation and Behavior Risk Monitoring .......................................47
8.4
Adverse Events and Serious Adverse Events ....................................................47
8.4.1
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................48
8.4.2
Method of Detecting AEs and SAEs .............................................................48
8.4.3
Follow-up of AEs and SAEs ..........................................................................48
8.4.4
Regulatory Reporting Requirements for SAEs ...........................................49
8.4.5
Pregnancy .......................................................................................................49
8.4.6
Adverse Events of Special Interest ...............................................................49
8.5
Treatment of Overdose ........................................................................................52
8.6
Pharmacokinetics .................................................................................................52
8.6.1
Blood Samples for CVL-865 Concentrations ..............................................52
8.6.2
Blood Samples for Anti-epileptic Drug Concentrations .............................52
8.6.3
Methods and Analysis ....................................................................................52
8.7
Pharmacodynamics ..............................................................................................52
8.8
Future Biospecimen Research ............................................................................53
8.9
Health Economics.................................................................................................53
9 
STATISTICAL CONSIDERATIONS ....................................................................53
9.1
Statistical Hypotheses ..........................................................................................53
9.2
Sample Size Determination .................................................................................53
9.3
Populations for Analyses .....................................................................................54
9.4
Statistical Analyses...............................................................................................54
9.4.1
Efficacy Analyses ...........................................................................................55
9.4.2
Safety Analyses ...............................................................................................56
9.4.3
Other Analyses ...............................................................................................56
9.5
Interim Analysis ...................................................................................................57
 

 
 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................58
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .........58
10.1.1
Regulatory and Ethical Considerations .......................................................58
10.1.2
Financial Disclosure .......................................................................................58
10.1.3
Informed Consent Process ............................................................................59
10.1.4
Data Protection ...............................................................................................59
10.1.5
Dissemination of Clinical Trial Data ............................................................60
10.1.6
Data Quality Assurance .................................................................................60
10.1.7
Source Documents ..........................................................................................61
10.1.8
Trial and Site Closure ....................................................................................61
10.1.9
Publication Policy...........................................................................................62
10.2
Appendix 2: Clinical Laboratory Tests..............................................................63
10.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...........................................65
10.3.1
Definition of AE..............................................................................................65
10.3.2
Definition of SAE ...........................................................................................65
10.3.3
Recording and Follow-Up of AE and/or SAE .............................................67
10.3.4
Reporting of SAEs and AESIs ......................................................................69
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ...........................................................................................................71
10.4.1
Definitions .......................................................................................................71
10.4.2
Collection of Pregnancy Information ...........................................................72
10.5
Appendix 5: Future Biospecimen Research ......................................................73
10.6
Appendix 6: Inducers and Inhibitors of Cytochrome P450 3A .......................74
10.7
Appendix 7: Abbreviations .................................................................................75
10.8
Appendix 8: Protocol Amendment History .......................................................78
11 REFERENCES .........................................................................................................82
 
 

 
 
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TABLE OF TABLES 
Table 1 
Objectives and Endpoints .......................................................................12
Table 2 
Schedule of Assessments ..........................................................................16
Table 3 
Objectives and Endpoints .......................................................................24
Table 4 
Dosing Schedule .......................................................................................26
Table 5 
Trial Treatments Administered ..............................................................34
Table 6 
Prohibited Prior Medications .................................................................37
Table 7 
Prohibited Concomitant Medications ....................................................38
Table 8 
Management of Hematologic Abnormalities .........................................51
Table 9 
Protocol-Required Safety Laboratory Assessments .............................63
Table 10 
Definition of AE........................................................................................65
Table 11 
Events Meeting the AE Definition ..........................................................65
Table 12 
Definition of SAE .....................................................................................66
Table 13 
Recording and Follow-Up of AE and/or SAE .......................................67
Table 14 
Follow-Up of AEs and SAEs ...................................................................69
Table 15 
SAE Reporting to the Sponsor of Designee via an Electronic Data 
Collection Tool .........................................................................................69
Table 16 
SAE Reporting to the Sponsor or Designee via Paper Form (if needed)
....................................................................................................................70
 
 

 
 
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TABLE OF FIGURES 
Figure 1
Trial Schematic ........................................................................................15
 

 
 
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1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Sponsor Name: Cerevel Therapeutics, LLC 
Name of Investigational Medicinal Product: CVL-865 
Protocol Title: A Randomized, Double-blind, Placebo-controlled, Parallel group, 
Multicenter Trial of CVL-865 as Adjunctive Therapy in Adults with DRug-REsistAnt 
FocaL Onset SeIZurEs (REALIZE Trial) 
Short Title: A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the 
Treatment of Focal Onset Seizures 
IND Number: 126,900 
EudraCT Number: 2019-002576-14 
Trial Phase: 2 
Treatment/Indication: Focal Onset Seizures 
Rationale: This placebo-controlled, double-blind trial is designed to assess the efficacy, 
safety, and tolerability profile of CVL-865 as adjunctive treatment in subjects with 
drug-resistant focal onset seizures. 
The broad therapeutic use of nonselective benzodiazepines (BZDs) in multiple 
indications clearly supports the therapeutic po
-aminobutyric acid type A 
(GABAA) positive allosteric modulators (PAMs) with the potential to offer efficacy with 
fewer side effects. 
A double-blind, placebo-controlled trial is an appropriate design in which to assess initial 
efficacy with CVL-865. This proof-of-concept trial will assess whether CVL-865 
demonstrates efficacy compared with placebo, as measured by a decrease in seizure 
frequency in subjects with a diagnosis of epilepsy with drug-resistant focal onset 
seizures. 
 
 
  

 
 
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electrocardiogram; HUI = Health Utilities Index; mCIWA-B = Modified Clinical Institute Withdrawal 
Assessment – Benzodiazepines; MHI = Medication Handling Irregularities; PGIC = Patient’s Global 
Impression of Change; QOLIE-31 = Quality of Life in Epilepsy-31; RRatio = Response Ratio; TEAE = 
treatment-emergent adverse event. 
Overall Design: 
This is a double-blind, parallel-group, placebo-controlled trial with subjects randomized 
to 1 of the following 3 arms in a 1:1:1 ratio: 
 CVL-865 25 mg twice daily (BID) maintenance 
 CVL-865 7.5 mg BID maintenance 
Placebo 
Subjects who satisfy all inclusion/exclusion criteria and thus are eligible for the trial will 
be randomly assigned to 1 of the 3 treatment arms at Visit 1, the start of the 13-week 
Treatment Period (10 weeks for subjects enrolling into the open-label extension trial, see 
below). 
At the completion of the Maintenance Phase in this trial, the investigator will evaluate the 
subject’s eligibility to continue treatment with CVL-865 in the open-label extension trial 
CVL-865-SZ-002.  
Disclosure Statement: This is a parallel group treatment trial with 3 arms that are 
blinded to the subjects and the investigator.   
Number of Subjects: Approximately 214 subjects will be screened to achieve 
150 subjects randomly assigned to treatment (50 per group) and 120 evaluable subjects 
for an estimated total of 40 evaluable subjects per treatment group. 
In the event of higher than anticipated early terminations due to COVID-19 or other 
reasons, Cerevel may extend enrollment in order to maintain the planned statistical 
power. 
Key Entry Criteria: Men and women 18 to 75 years of age, inclusive, with a diagnosis 
of epilepsy with focal onset (as defined in the 2017 ILAE Classification of Seizures), 
focal aware (except subjects with only focal aware seizures without a motor component), 
focal impaired awareness, and focal to bilateral tonic-clonic seizures for at least 2 years 
prior to signing the ICF will be enrolled into this trial. A history of an average of 4 or 
more spontaneous and observable focal onset, focal aware, focal impaired awareness, and 
focal to bilateral tonic-clonic seizures (as defined in previous sentence) per 28-day period 
for at least 3 months (84 days) prior to signing the ICF along with a minimum of 8 of 
these seizure types during the 8-week Baseline Period with no 21-day period free of any 
of these seizure types is also required for entry into the trial. 
 
 
 
 

 
 
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Intervention Groups, Trial Treatment, and Duration: This trial is designed with a 
maximum duration of approximately 25 weeks. The trial consists of the following: 
 8-week Screening/Baseline Period 
 10- or 13-week Treatment Period, including an initial 2-week Titration Phase, an 
8-week Maintenance Phase, and a 3-week Taper Phase (only for subjects not 
continuing treatment in the open-label extension trial). The tablets (including the 
number of tablets given) will be the same between the placebo and both CVL-865 
dose arms during the Titration, Maintenance, and Taper Phases to maintain the blind. 
All tablets will be administered orally. 
 4-week Follow-up Period 
 The daily dosing schedule will start at Day 1 with a 2-week Titration Phase during 
which time the subject’s dose will be increased in a blinded fashion up to the 
randomized dose level (CVL-865 25 mg BID, CVL-865 7.5 mg BID, or placebo). In 
the high-dose group, CVL-865 will be administered as 
 
 
 during the Titration Phase, and then 25 mg BID during 
the 8-week Maintenance Phase. In the low-dose group, CVL-865 will be administered 
as 
 during the 
Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For 
subjects not enrolling into the open-label extension trial, following the Maintenance 
Phase, dose will be gradually decreased over a 3-week Taper Phase.  
Statistical Methods: 
A sample size of 50 subjects per group (total of 150 subjects) will provide at least 80% 
power to detect a difference in the means of the primary outcome measure (RRatio) of -
20 (PASS 2008 Tests of Two Means, Two Sample T-Test, 2-sided alpha level = 0.1, 
Standard Deviation=34, and a 20% dropout rate). 
The primary efficacy endpoint is the Rratio over the Maintenance Phase. This is 
calculated as Rratio=(T B)/(T B) 
 where T represents the seizure frequency rate 
per week in the Maintenance Phase and B represents the seizure frequency rate per week 
in the Baseline Period. The Rratio is between -100 and 100. Negative values will indicate 
reduction in seizure rate and positive values indicate increase in seizure rate during 
treatment. Values of Rratio will be analyzed for the modified intent-to-treat population 
using an analysis of covariance model, including treatment and the baseline seizure 
frequency per week as a covariate. 
 
 
 
 
 
 
 

 
 
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1.3 
Schedule of Assessments 
Table 2 
Schedule of Assessments
Trial Periods/ 
Phases 
Screening/ Baseline 
Perioda 
(8 weeks) 
Treatment Period 
Post-treatment Follow-up 
Titration Phase 
(2 weeks)
Maintenance Phase 
(8 weeks)
Taper Phase
(3 weeks)
Visit/Contactb 
Screen-
ing 
Contact 
Visit 1a 
Contact 
Visit 2c Contact Visit 3c Contact Visit 4d  Contact Contact Visit 5c 
ETe 
Contact 
Visit 6 
Day 
-56 
-28 
1 
8 
15 
29 
43 
57 
71 
78 
85 
92 
NA 
~99 
120 
Window 
± 3 days 
 
± 3 days 
 
Entrance and History 
Informed consentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign subject 
identification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Record medical 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record seizure 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Head MRI/CTg 
X 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of drug 
and alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of birth 
control methods 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

 
 
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Trial Periods/ 
Phases 
Screening/ Baseline 
Perioda 
(8 weeks) 
Treatment Period 
Post-treatment Follow-up 
Titration Phase  
(2 weeks) 
Maintenance Phase  
(8 weeks) 
Taper Phase 
(3 weeks) 
 
Visit/Contactb 
Screen-
ing 
Contact 
Visit 1a 
Contact 
Visit 2c Contact Visit 3c Contact Visit 4d  Contact Contact Visit 5c 
ETe 
Contact 
Visit 6 
Day 
-56 
-28 
1 
8 
15 
29 
43 
57 
71 
78 
85 
92 
NA 
~99 
120 
Window 
± 3 days 
 
± 3 days 
 
Complete and send 
SIF/DRF 
paperwork to 
TESCh
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Rescue 
Protocol for 
subjects who 
normally receive 
BZDi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
based on TESCj 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense eDiary 
and train on use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense medical 
bracelet 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
Review eDiary 
including 
compliance with 
use of eDiary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGIC
X 
X 
X 
X 
CGI-S 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 

 
 
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Trial Periods/ 
Phases 
Screening/ Baseline 
Perioda 
(8 weeks) 
Treatment Period 
Post-treatment Follow-up 
Titration Phase  
(2 weeks) 
Maintenance Phase  
(8 weeks) 
Taper Phase 
(3 weeks) 
 
Visit/Contactb 
Screen-
ing 
Contact 
Visit 1a 
Contact 
Visit 2c Contact Visit 3c Contact Visit 4d  Contact Contact Visit 5c 
ETe 
Contact 
Visit 6 
Day 
-56 
-28 
1 
8 
15 
29 
43 
57 
71 
78 
85 
92 
NA 
~99 
120 
Window 
± 3 days 
 
± 3 days 
 
Safety laboratory 
urine sample 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Serum pregnancy 
testo
X 
<--------> 
X 
<--------------------------------------------------------------------------------------------------------> 
X 
<--------> 
X 
Serology (HIV, 
HBV, HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testo 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Urine drug 
screeningp 
X 
 
Blood sample for 
PK of CVL-865 
 
 
 
 
Xq 
 
Xq 
 
Xq 
 
 
Xq 
Xq 
 
 
Blood sample(s)
for PK of AEDr
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
Future 
biospecimen 
research blood 
samples
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
IMP dispensing
X 
X 
X 
X 
Collect final 
eDiary device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

 
 
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Trial Periods/ 
Phases 
Screening/ Baseline 
Perioda 
(8 weeks) 
Treatment Period 
Post-treatment Follow-up 
Titration Phase  
(2 weeks) 
Maintenance Phase  
(8 weeks) 
Taper Phase 
(3 weeks) 
 
Visit/Contactb 
Screen-
ing 
Contact 
Visit 1a 
Contact 
Visit 2c Contact Visit 3c Contact Visit 4d  Contact Contact Visit 5c 
ETe 
Contact 
Visit 6 
Day 
-56 
-28 
1 
8 
15 
29 
43 
57 
71 
78 
85 
92 
NA 
~99 
120 
Window 
± 3 days 
 
± 3 days 
 
Provide 
individualized 
rescue protocol 
and train subjecti
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IMP compliance 
assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adjunctive AED 
compliance 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AED = anti-epileptic drug; BID = twice daily; BZD = benzodiazepine; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression – 
Severity of Symptoms; C-SSRS = Columbia-Suicide Severity Rating Scale; CT = computed tomography; ECG = electrocardiogram; ET = Early Termination; 
HBV = hepatitis B virus; HCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; 
IMP = investigational medicinal product; mCIWA-B = Modified Clinical Institute Withdrawal Assessment – Benzodiazepines; MRI = magnetic resonance 
imaging; PGIC = Patient Global Impression of Change; PK = pharmacokinetic; QOLIE-31 = Quality of Life in Epilepsy-31; SIF/DRF = Seizure Identification 
and Diagnostic Review Form; TESC = The Epilepsy Study Consortium. 
a. 
Individual sites may require subjects to have COVID-19 testing done prior to randomization. COVID-19 testing may be performed after randomization per 
the investigator’s discretion. 
b. Contact with subject via phone call or other means of communication to check on their status.  
c. 
In the event that a subject is unable to attend a clinic visit in person due to restrictions related to COVID-19, this visit may be completed remotely. Please 
refer to the Trial Operations Manual for further instructions related to remote visits. 
d. At Visit 4, the investigator will evaluate the subject’s eligibility to continue treatment with CVL-865 in the open-label extension trial CVL-865-SZ-002. If 
the investigator determines the subject is eligible for the trial, he/she will discuss with the subject if they would like to continue into Trial CVL-865-SZ-002. 
If the investigator determines the subject is eligible and the subject agrees to continue participation in Trial CVL-865-SZ-002, consent will be obtained and 
unique procedures for Visit 1 of Trial CVL-865-SZ-002 will be completed. Subjects who do not continue into Trial CVL-865-SZ-002 will begin the Taper 
Phase. 
 

 
 
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e. 
Subjects who require early termination should begin the Taper Period at the time the decision is made to discontinue. All indicated procedures should be 
performed per protocol. If a subject discontinues early and it is inadvisable for them to taper IMP (after agreement from medical monitor), the subject should 
complete Visit 6 assessments approximately 30 days following the last dose of IMP.  
f. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be rescreened after consultation with the medical monitor. 
Rescreened subjects should receive a unique subject number for each screening. 
g. Unless procedure has been performed within 10 years prior to signing the ICF. This procedure, if necessary, should be conducted as soon as possible during 
the Screening/Baseline Period (per local guidelines) with the report available prior to randomization. 
h. A SIF/DRF will need to be completed by site personnel for every subject. This information will be faxed or emailed to TESC after the Screening Visit for 
review and approval. The SIF/DRF will be used by TESC to ensure that the seizures are classified accurately, the subject is appropriate for the trial, and will 
help to confirm the diagnosis. 
i. 
All subjects who normally take BZDs for seizure rescue will be required to have an individualized Rescue Protocol approved by TESC. The Rescue Protocol 
will be submitted along with the SIF/DRF and will describe what rescue treatment can be administered in the event the subject requires a BZD. It will also 
include different scenarios that will prompt immediate medical attention. 
j. 
 Subjects cannot be enrolled until site personnel have received the TESC approval notification. 
k. All responses will be relative to the subject’s condition at Day 1, prior to the first dose of IMP. 
l. 
Full physical and neurological examinations should be completed at Screening Visit 4, and Visit 5/ET. The physical examination should include weight at all 
time points and height at the Screening Visit only. Physical and/or neurological examinations can be done at any time point during the trial at the 
investigator’s discretion.  
m. The “Baseline/Screening” C-SSRS form will be completed for all subjects at Screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the Baseline Visit to ensure that the subject continues to qualify for the trial. The “Since Last Visit” C-SSRS form will also be completed at 
all visits after Baseline. 
n. Adverse events (serious and non-serious) and concomitant medications should be recorded from screening through the subject’s last visit.  
o. For women of childbearing potential only. All positive urine pregnancy test results must be confirmed by a serum test. Pregnancy tests can be performed at 
any time during the trial at the discretion of the investigator if pregnancy is suspected.  
p. A urine drug screen is required at screening; see the exclusion criteria for exclusions based on the urine drug screen. The urine drug screen can be conducted 
at any time during the trial at the discretion of the investigator.  
q. With subjects maintaining their normal BID dosing routine, a single daytime blood sample for determination of plasma CVL-865 concentration will be 
collected at Visits 2, 3, 4, and 5. The date and time of the PK sample, as well as the time of ingestion of the morning dose of IMP (on the same day), will be 
recorded in the source documentation.  
r. 
One 5-mL sample for each individual adjunctive AED. 
s. Future biospecimen research sample is optional and is to only be collected if signed consent is obtained from the subject. 
 

 
 
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2 INTRODUCTION 
2.1 
Trial Rationale 
This placebo-controlled, double-blind trial is designed to assess the efficacy, safety, and 
tolerability profile of CVL-865 as adjunctive treatment in subjects with drug-resistant 
focal onset seizures. 
The broad therapeutic use of nonselective benzodiazepines (BZDs) in multiple 
indications clearly supports the therapeutic potential of -aminobutyric acid type A 
(GABAA) positive allosteric modulators (PAMs) with the potential to offer efficacy with 
fewer side effects.  
A double-blind, placebo-controlled trial is an appropriate design in which to assess initial 
efficacy with CVL-865. This proof-of-concept trial will assess whether CVL-865 
demonstrates efficacy compared with placebo, as measured by a decrease in seizure 
frequency in subjects with a diagnosis of epilepsy with drug-resistant focal onset 
seizures. 
2.2 
Background 
Epilepsy is the most common serious neurological condition in the world affecting 
approximately 60 million people worldwide. In the United States (US), more than 3 
million people have been diagnosed with epilepsy or have experienced an unprovoked 
seizure. Approximately 20% to 30% of patients with focal onset seizures have seizures 
that are refractory to currently available anti-epileptic drugs (AEDs). Drug-resistant 
seizures have been defined by the International League Against Epilepsy (ILAE) as 
“failure of adequate trials of 2 tolerated and appropriately chosen and used AED 
schedules to achieve sustained seizure freedom” (Kwan et al, 2010). Furthermore, current 
AEDs possess undesirable toxicity for many patients; therefore, there remains a clear 
medical need for the development of improved anti-epileptic therapies that are more 
efficacious, easy to use, and better tolerated than those already on the market. 
Benzodiazepines are nonselective PAMs of GABAA receptors with widespread utility in 
neurology and psychiatry, but their use is limited by sedation, psychomotor impairment, 
and other adverse effects. In the treatment of epilepsy, chronic use of BZDs can result in 
loss of efficacy, which precludes its use in many epilepsy populations. 
CVL-865 is a novel, brain-
subunit containing GABAA receptors, w
-
containing receptors, which are believed to mediate many adverse effects observed with 
BZDs. By reducing the 1 activity, CVL-865 has the potential to retain highly effective 
anticonvulsant activity, without the BZD-associated adverse effects.  
CVL-865 has been shown to be anticonvulsant in several nonclinical models of epilepsy 
including the pentylenetrazol model in mice, the amygdala kindling model of temporal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

 
 
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lobe epilepsy in rats, and in the genetic absence epilepsy rat from Strasbourg. The strong 
efficacy across a broad spectrum of models is suggestive of potential clinical utility of 
CVL-865 in epilepsy. 
Clinically, the first investigation of the anticonvulsant potential of CVL-865 was 
demonstrated in a Phase 2 photosensitive epilepsy model trial (Gurrell et al, 2019). In this 
proof-of-principle trial, photosensitive subjects were exposed to intermittent photic 
stimulation and the reduction in sensitivity was measured. CVL-865 showed robust 
suppression of the generalized photoparoxysmal electroencephalogram (EEG) response, 
following single doses of 17.5 and 52.5 mg, raising the possibility that CVL-865 may 
have potential efficacy in other epilepsy populations. 
Currently, approximately 290 subjects have been administered CVL-865 in doses ranging 
from 0.04 to 100 mg single dose, and 2.5 mg to 42.5 mg twice daily (BID) multiple dose. 
CVL-865 has been safe and well tolerated. 
Please refer to the Investigator’s Brochure for a summary of available nonclinical and 
clinical safety data for CVL-865.  
2.3 
Benefit/Risk Assessment 
There are no important identified risks for CVL-865. Fetal toxicity, bone marrow 
suppression and decrease in peripheral hematologic parameters are important potential 
risks; however, these risks will be minimized during the study by monitoring of 
hematologic parameters and requiring the use of appropriate contraception and regular 
pregnancy testing. 
Results from a recently completed Phase 2a trial using a photosensitivity model as a 
proof-of-concept for CVL-865 demonstrated highly robust efficacy. This was shown by a 
marked and statistically significant mean reduction in standardized photosensitivity 
ranges to intermittent photic stimulations for single doses of 17.5 mg and 52.5 mg 
CVL-865 compared with placebo, which was similar to lorazepam 2 mg active control.  
Based on available safety and efficacy data for CVL-865, the benefit-risk profile is 
favorable.  
In response to the COVID-19 pandemic, Cerevel has performed a risk assessment of this 
trial and the investigator of each individual trial site and has implemented measures 
throughout the protocol, which prioritizes trial participant safety and data validity. 
 

 
 
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Impression of Change; QOLIE-31 = Quality of Life in Epilepsy-31; RRatio = Response Ratio; TEAE = 
treatment-emergent adverse event. 
4 TRIAL DESIGN 
4.1 
Overall Design 
This is a double-blind, parallel-group, placebo-controlled trial with subjects randomized 
to 1 of the following 3 arms in a 1:1:1 ratio: 
 CVL-865 25 mg BID maintenance 
CVL-865 7.5 mg BID maintenance
Placebo
This trial is designed with a maximum duration of approximately 25 weeks. The trial
consists of the following: 
8-week Screening/Baseline Period
 10- or 13-week Treatment Period, including an initial 2-week Titration Phase, an 
8-week Maintenance Phase, and a 3-week Taper Phase (only for subjects not 
continuing treatment in the open-label extension trial). The tablets (including the 
number of tablets given) will be the same between the placebo and both CVL-865 
dose arms during the Titration, Maintenance, and Taper Phases to maintain the blind 
 4-week Follow-up Period 
Screening/Baseline Period: 
Only subjects who have signed an informed consent form (ICF) and are expected to 
fulfill the inclusion/exclusion criteria enter into the Screening/Baseline Period for 
evaluation at the Screening Visit. Subjects are to continue on their current AEDs at the 
same dosages throughout the Screening/Baseline Period. If a subject has a vagus nerve 
stimulator (VNS), a deep brain stimulator (DBS), or a responsive neurostimulator (RNS), 
the settings must remain stable throughout the Screening/Baseline Period. 
During this Screening/Baseline Period, subjects will be required to complete electronic 
seizure diaries (eDiary) and record all seizures in the eDiary for each day. The presence 
or absence of all seizure types experienced by each subject will be recorded daily in the 
eDiary. 
Treatment Period: 
Subjects who satisfy all inclusion/exclusion criteria and thus are eligible for the trial will 
be randomized to 1 of 3 treatment arms at Visit 1.  
 
 
 
 
 
 
 

 
 
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Follow-up Period: 
See Figure 1 for a schematic of the trial design and Table 2 for the schedule of 
assessments.  
4.2 
Scientific Rationale for Trial Design 
CVL-865 is a novel small molecule with a first-in-class mechanism of action, which, 
based on the nonclinical and clinical data, has the potential to be highly efficacious in a 
broad spectrum of patients with epilepsy via modulation of GABAA receptors. As an 
5 subtype selective partial PAM with minimal 
, CVL-865 
would be expected to maintain efficacy whilst overcoming many of the adverse events 
(AEs) that limit the use of BZDs, such as cognitive impairment, sedation, withdrawal 
symptoms, abuse potential, and tolerance. 
The clinical development of anti-epileptic agents in focal onset epilepsy in the adjunctive 
setting is well established. Usually, focal seizures in adults represent the first patient 
population, since they are the most frequent seizure type, and a substantial percentage of 
patients have seizures that are not well controlled using current medications. The initial 
evaluation process for a new AED involves determination of its efficacy in reducing the 
frequency of seizures in patients who continue to have seizures despite therapy with an 
adequate dosage of appropriate drug(s) and thus represent a drug-resistant population.  
This trial includes a randomized, double-blind, placebo-controlled parallel group design, 
which are the key features recommended by the European Medicines Agency draft 
guidelines 2018 on the clinical investigation of medicinal products in the treatment of 
epileptic disorders (EMA 2018).  
4.3 
Dosing Rationale 
The 2 arms of CVL-865 have been selected based on the first-in-human safety and 
tolerability data, the pharmacodynamic (PD) profile, and the efficacious doses used in the 
clinical photosensitive epilepsy Trial B7431005. Single doses up to 100 mg have been 
safe and well tolerated and associated with mild adverse effects. No changes in 
electrocardiograms (ECGs) or vital sign measurements have been observed at doses up to 
100 mg. Multiple doses of CVL-865 up to 42.5 mg BID have been found to be safe and 
well tolerated in healthy adult subjects.   
The top maintenance dose of 25 mg BID is designed to fully test the therapeutic potential 
of CVL-865 as adjunctive therapy in the treatment of focal onset seizures. At that dose 
level the steady-state exposure levels of CVL-865 are expected to be comparable with 
those at which the peak effects in saccadic peak velocity, a reliable biomarker of 2/3 
activity, were observed following single dose (65 mg) administration (Trial B7431001). 
Likewise, the exposure levels are expected to be comparable with those at which efficacy 
was observed in a single-dose (52.5 mg) photosensitive epilepsy trial (Trial B7431005).  
 
 
  
   
 
 

 
 
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The relationship between GABAA receptor occupancy in the whole brain and plasma 
exposure levels of CVL-865 was characterized in an open-label, single-dose (10 and 
65 mg) trial in healthy volunteers (Trial B7431004). Pharmacodynamic analysis of the 
GABAA receptor occupancy data indicated that nearly complete (ie, >80%) receptor 
occupancy was achieved at the peak exposure level of the 65 mg dose. More specifically, 
with respect to 2 receptor occupancy within the brain, the 25 mg BID dosing regimen is 
anticipated to achieve steady-state exposure levels of CVL-865 within the range 
anticipated to produce approximately 80% receptor occupancy. In addition, 
pharmacokinetic (PK)/PD modeling of saccadic peak velocity and 2 receptor occupancy 
data also suggests that no additional benefit would come from increasing the dose above 
25 mg BID.  
The lower dose of 7.5 mg of CVL-865 administered BID is anticipated to result in 
exposures with limited overlap with the high dose and a submaximal effect based on the 
same neurofunctional endpoints described above. The 7.5 mg BID and 25 mg BID doses 
will facilitate evaluation of a wide exposure and target occupancy range in this trial to 
facilitate appropriate dose selection for future clinical trials. Exposures from both dosing 
regimens are not expected to exceed the no observed adverse effect level (NOAEL) 
established based on the pivotal 13-week toxicological studies in rats and dogs. 
4.4 
Definition of Completed Subject
Subjects continuing treatment with CVL-865-SZ-001 in the open-label extension trial are 
considered to have completed this trial if he/she has completed the Maintenance Phase of 
the trial (ie, completed Visit 4) as shown in the Schedule of Assessments.  
Subjects not continuing in the open-label extension trial, are considered to have 
completed this trial if he/she has completed all phases of the trial including the last 
scheduled procedure (Day 120 phone contact) shown in the Schedule of Assessments. 
4.5 
End of Trial Definition 
The end of the trial is defined as the date of the last visit (including phone contact) of the 
last subject in the trial globally. 
5 TRIAL POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
A Seizure Identification and Diagnostic Review Form (SIF/DRF) will need to be 
completed by site personnel for every subject. This information will be faxed or emailed 
to The Epilepsy Study Consortium (TESC) after the Screening Visit for review and 
approval. The SIF/DRF will be used to ensure that the seizures are classified accurately, 
the subject is appropriate for the trial, and will help to confirm the diagnosis. Subjects 
cannot be enrolled until the TESC review and feedback of the SIF/DRF has been 
completed and the site personnel have received final notification. 
 
 
 

 
 
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5.1 
Inclusion Criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
 
1. 
Male and female subjects, ages 18 to 75 years, inclusive, at the time of signing the ICF. 
2. 
A diagnosis of epilepsy with focal onset (as defined in the 2017 ILAE Classification of 
Seizures [Fisher et al, 2017]), focal aware (except subjects with only focal aware seizures 
without a motor component), focal impaired awareness, and focal to bilateral tonic-clonic 
seizures for at least 2 years prior to signing the ICF. Diagnosis will be based on the 
investigator’s assessment of available clinical, radiographic, and EEG data and the review by 
TESC. 
3. 
A history of an average of 4 or more spontaneous and observable focal onset (as defined in 
the 2017 ILAE Classification of Seizures [Fisher et al, 2017]), focal aware (except subjects 
with only focal aware seizures without a motor component), focal impaired awareness, and 
focal to bilateral tonic-clonic seizures per 28-day period for at least 3 months (84 days) prior 
to signing the ICF. 
4. 
A minimum of 8 focal onset (as defined in the 2017 ILAE Classification of Seizures [Fisher et 
al, 2017]), focal aware (except subjects with only focal aware seizures without a motor 
component), focal impaired awareness, or focal to bilateral tonic-clonic seizures during the 8-
week Baseline Period with no 21-day period free of any of these seizure types. 
5. 
Subjects who have tried and failed at least 2 appropriate AEDs in the past. 
6. 
Subjects currently taking 1 to 3 permitted AEDs (see concomitant medication exclusions) at a 
stable dose for 4 weeks prior to the Screening Visit. VNS, DBS, and RNS is permitted and is 
not considered an AED. The VNS, DBS, and RNS settings should remain stable for 4 weeks 
prior to the Screening Visit. Note: Should a subject require a change of AED therapy/dose or 
VNS, DBS, or RNS settings between the Screening Visit and Visit 1, that subject should not 
continue in the trial at that time but must remain on the new regime for at least 4 weeks and 
then may repeat the screening process. 
7. 
An MRI or CT scan of the head within 10 years prior to Screening Visit to demonstrate no 
progressive structural abnormality. If a scan is not available, one should be conducted during 
the Baseline Period with a report that demonstrated no progressive structural abnormality 
available prior to randomization. 
8. 
BMI of 17.5 to 40.0 kg/m2 and a total body weight >50 kg (110 lbs). 
9. 
A female subject of childbearing potential (see Section 10.4, Appendix 4) who is sexually 
active with a nonsterilized male partner must agree to use a highly effective method of 
contraception (see Section 10.4, Appendix 4) from signing of informed consent throughout 
the duration of the study and for 30 days post last dose. 
A male subject with a pregnant or a nonpregnant partner of childbearing potential must agree 
to use condom during treatment and until the end of relevant systemic exposure in the male 
subject for 94 days following the last dose with IMP. 
10. 
Capable of giving signed informed consent as described in Section 10.1.3 (Appendix 1), 
which includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 
11. 
Ability, in the opinion of the investigator, to understand the nature of the trial and comply 
with protocol requirements, including the prescribed dosage regimens, scheduled visits, 
laboratory tests, and other trial procedures. 
 

 
 
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Abbreviations: AED = anti-epileptic drug; BMI = body mass index; CT = computed tomography; DBS = 
deep brain stimulator; EEG = electroencephalogram; ICF = informed consent form; ILAE = International 
League Against Epilepsy; IMP = investigational medicinal product; MRI = magnetic resonance imaging; 
RNS = responsive neurostimulator; TESC = The Epilepsy Study Consortium; VNS = vagus nerve 
stimulator 
5.2 
Exclusion Criteria
Subjects are excluded from the trial if any of the following criteria apply: 
 
Target Disease 
1. 
Subjects with (genetic) idiopathic generalized epilepsies or combined generalized and focal 
epilepsies, including a history of Lennox-Gastaut Syndrome. 
2. 
Subjects with only focal aware seizures without a motor component. 
3. 
Subjects with a history of seizures over the past 12 months that occur at such a high frequency 
they cannot be counted (eg, repetitive seizures, cluster seizures). 
4. 
Subjects with a history of psychogenic non-epileptic seizures within the year prior to signing 
the ICF. 
5. 
Subjects with a history of status epilepticus within 5 years prior to signing the ICF. 
6. 
Subjects with a history of neurosurgery for seizures less than 1 year prior to signing the ICF, 
or radiosurgery less than 2 years prior to signing the ICF. 
Medical History and Concurrent Diseases 
7. 
 
Subjects with a current history of significant cardiovascular, pulmonary, gastrointestinal, 
renal, hepatic, metabolic, hematological, immunological, or neurological (excluding focal 
onset epilepsy) disease that, in the opinion of the investigator or medical monitor, could 
compromise either subject safety or the results of the trial. In addition, subjects with a 
psychiatric illness of sufficient severity as to make them inappropriate for the trial are 
excluded. 
Medical conditions that are minor or well-controlled may be considered acceptable if the 
condition does not expose the subject to an undue risk of a significant AE or interfere with the 
assessments of safety or efficacy during the course of the trial. The medical monitor should be 
contacted in any instance where the investigator is uncertain regarding the stability of a 
subject’s medical conditions(s) and the potential impact of the condition(s) on trial 
participation. 
8. 
Subjects with an active CNS infection, demyelinating disease, degenerative neurological 
disease or any CNS disease deemed to be progressive during the course of the trial that may 
confound the interpretation of the trial results. 
9. 
Subjects with a history of substance or alcohol-use disorder (excluding nicotine; DSM-5 
criteria) within 2 years prior to signing the ICF. 
10. 
Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation 
with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting 
criteria for this C-SSRS Item 4 occurred within the last 6 months, OR  
Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation 
with Specific Plan and Intent) and whose most recent episode meeting criteria for this C-
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5.3.3 
Effects on Ability to Drive and Use Machines
The effect of CVL-865 on the ability to drive and use machines has not been 
systematically evaluated.  
5.4
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are not subsequently randomly assigned to treatment in the trial. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure subjects to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) may 
be rescreened after consultation with the medical monitor. Rescreened subjects should 
receive a unique subject number for each screening. 
If the subject fails screening due only to safety laboratory results, the Investigator may, at 
their discretion, decide to repeat the safety laboratory tests and perform additional tests as 
appropriate. In this case, no other screening procedures need to be repeated, as long as the 
procedures stay within the protocol-specified timelines. 
If a subject requires a change in AED dose, type or number of AEDs, or a change in the 
settings on their VNS, DBS, or RNS, the subject may be rescreened with medical monitor 
approval at a time when they have been a stable dose and/or setting for a period of a least 
4 weeks. 
6 TRIAL TREATMENT 
Trial treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a trial subject according to 
the trial protocol. Investigational medicinal product (IMP) refers to a pharmaceutical 
form of any active substance or placebo being tested in this clinical trial. 
 

 
 
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6.1 
Trial Treatments Administered 
Table 5 
Trial Treatments Administered 
Treatment 
Group 
CVL-865 25 mg BID 
CVL-865 7.5 mg 
BID 
Placebo 
Dose Formulation 
Tablet 
Tablet 
Matching tablet 
Unit Dose 
Strengths 
2.5, 5 mg, and 7.5 mg 
2.5, 5 mg, and 7.5 mg 
2.5, 5 mg, and 7.5 mg (matching) 
Dosage Levels 
25 mg BID 
7.5 mg BID 
Placebo 
Route of 
Administration 
Oral 
Oral 
Oral 
Sourcing 
Provided to the site by Cerevel
Packaging and 
Labeling 
IMP will be provided in blister packs and should be stored in its original pack in 
accordance with the drug label. Blister packs will be labeled according to local 
regulatory requirements. 
Abbreviations: BID = twice daily; IMP = investigational medicinal product 
Subjects will receive the appropriate combination of tablets necessary in order to achieve 
the required dose level. In order to maintain the blind, subjects assigned to the placebo 
treatment group will receive the same number of tablets as subjects in the CVL-865 
groups.  
6.2 
Preparation/Handling/Storage/Accountability/Disposition 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit (original shipment and/or moving of IMP supply from one 
office or facility to another within the sites network) for all IMP received and any 
discrepancies are reported and resolved before use of the IMP. 
Only subjects enrolled in the trial may receive IMP and only authorized site staff may 
supply or administer IMP. All IMP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. 
The investigator is responsible for IMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the preparation, handling, storage, accountability, 
and disposition of IMP are provided in appropriate protocol-specific manuals. 
 

 
 
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6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Subject Assignment to Treatment 
During the entire trial, treatment will be double-blind, ie, neither the investigator nor the 
subject will have knowledge of the treatment assignment at any visit.  
Treatment assignments will be based on a computer-generated randomization code 
provided by Cerevel or designee. Sponsor personnel, including those involved in 
monitoring, data management, and data analysis, will not have access to the treatment 
codes during the trial. Access to the treatment codes will be restricted to personnel 
charged with generating and maintaining randomization files, packaging IMP, operating 
the interactive response technology (IRT), and reporting SAEs to regulatory agencies.  
Once a randomization number has been assigned, it must not be reassigned.  
6.3.2 
Blinding 
At the initiation of the trial, investigators and site personnel will be instructed on the 
method for breaking the blind. The IRT will be programmed with blind-breaking 
instructions. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a subjects’ treatment assignment is warranted. Subject safety 
must always be the first consideration in making such a determination. If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact 
the medical monitor prior to unblinding a subject’s treatment assignment unless this 
could delay emergency treatment of the subject. If a subject’s treatment assignment is 
unblinded, the medical monitor must be notified within 24 hours after breaking the blind. 
Documentation of breaking the blind should be recorded on the subject’s medical record 
and in the electronic case report form (eCRF) with reason for breaking the blind, the date 
and time the blind was broken, and the names of the personnel involved. Once the blind 
is broken for a subject, reinitiation of treatment with IMP cannot occur for that subject.  
6.4 
Trial Treatment Compliance 
Responsible trial personnel will dispense the IMP. The time and dose of each IMP 
administration, along with information on any missed or inappropriately administered 
dose, will be recorded in source documents and the eCRF. 
Subjects must be counseled on the importance of taking the IMP as directed. If poor 
compliance is encountered (eg, multiple missed doses resulting in less than 80% overall 
compliance at any point in the trial), discontinuation of the subject from the trial should 
be considered. Subjects who habitually miss visits or habitually attend visits outside of 
the protocol-defined visit window are also defined as noncompliant and should be 
considered for discontinuation. The medical monitor should be contacted if the 
investigator is uncertain whether a subject’s lack of compliance merits discontinuation 
from the trial. 
 

 
 
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6.5 
Concomitant Therapy 
6.5.1 
Prior and Concomitant Medications 
The investigator will record all medications and therapies (including vaccines, over-the-
counter or prescription medicines, vitamins, and/or herbal supplements) taken by the 
subject from 30 days prior to signing of informed consent through the end of the 
evaluation period (defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives) on the eCRF. The investigator will also record all 
medications and therapies taken by the subject for treatment of an AE or which caused an 
AE until the end of the trial (defined as the last date of contact or date of final contact 
attempt) on the eCRF. 
For concomitant medications, the following will be recorded in the eCRF: medication, 
indication, dose, frequency, route, start date and end date. For concomitant therapy, the 
following will be recorded in the eCRF: therapy, indication, start date, and end date. 
All subjects should be counselled on the importance of taking background medications as 
prescribed. 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.2 
Prohibited Medications 
All subjects must agree to discontinue all prohibited medications per defined washout 
times in table below. 
 

 
 
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7 DISCONTINUATION OF TRIAL INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs), and regulatory authorities in accordance with regulatory 
requirements.
7.2 
Discontinuation of Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and Good Clinical Practice (GCP). 
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site. 
7.3 
Individual Subject Discontinuation 
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator.  
Under certain circumstances, when subjects leave the trial early, dosing with the taper 
medication or continuing with the taper phase medication may be inadvisable. The 
decision not to taper the subject is upon agreement from the medical monitor. If the taper 
will not be utilized, then all assessments required at Visit 6 should be conducted 30 days 
following the last dose. 
A subject will discontinue IMP for the reasons listed below: 
 Any of the following AESIs 
 Hemoglobin <8 g/dL  
 WBC count <2.5  109/L 
 Neutrophil count <1.5  109/L 
 Platelet count <100  109/L
 Failure to comply with trial procedures or dosing 
 Withdrawal of consent 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 Investigator’s discretion 
If the subject temporarily interrupts or discontinues IMP due to an AE, the investigator or 
other trial personnel, will make every effort to follow the event until it has resolved or 
stabilized.  
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible. 
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up: 
 Participation in all follow-up procedures specified in the protocol (whether in-
clinic, by telephone, or by an in-home visit). 
 Participation in a subset of protocol specified follow-up procedures (by a 
frequency schedule and method, as agreed by subject and staff). 
 Contact of the subject by trial personnel, even if only by telephone, to assess 
current medical condition, and obtain necessary medical or laboratory reports 
relevant to the trial’s objectives. 
 Contact of alternative person(s) who have been designated in source records as 
being available to discuss the subject’s medical condition, even if only by 
telephone, mail, or e-mail (eg, family, spouse, partner, legal representative, friend, 
neighbor, or physician). 
 Access to medical information from alternative sources (eg, hospital/clinic 
medical records, referring doctor’s notes, public records, dialysis, transplantation 
or vital registries, social media sources). 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to interrupt or modify or discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation. A subject may, however, indicate that further trial participation is creating a 
burden on their work, school, or social schedule. Therefore, the investigator should 
determine if the subject can continue participation in the trial if modifications to his/her 
treatment and/or schedule of assessments can be accommodated. Only subjects who 
 
 
 
 
 
 
 

 
 
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withdraw their permission for all of the above methods of follow-up are considered to 
have completely withdrawn their consent to participate in the trial.
Details on the withdrawal of consent from the optional pharmacogenomic (PGx) 
assessment and/or optional future biospecimen research sample are provided in the ICF. 
7.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss (without undue coercion) with the subject their options 
of continuing in the trial, preferably on therapy. The investigator should ensure 
understanding and documentation of the reasons for the subject’s desire to withdraw 
consent. 
7.5 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the trial site personnel. 
The following actions must be taken if a subject fails to return to the site for a required 
trial visit: 
• 
The site personnel must attempt to contact the subject and reschedule the missed 
visit as soon as possible and counsel the subject on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the trial 
• 
Before a subject is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record
• 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the trial 
8 TRIAL ASSESSMENTS AND PROCEDURES 
Trial procedures and their timing are summarized in the Schedule of Assessments (Table 
2). Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the medical monitor immediately 
upon occurrence or awareness to determine if the subject should continue or discontinue 
IMP. 
Adherence to the trial design requirements, including those specified in the Schedule of 
Assessments (Table 2), is essential and required for trial conduct. 
 

 
 
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8.1 
Screening and Baseline Assessments 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Assessments (Table 2). 
As part of the screening procedures, a head magnetic resonance imaging or computed 
tomography scan will be completed to demonstrate no progressive structural abnormality, 
unless the procedure has been performed within 10 years prior to signing the ICF. This 
procedure, if necessary, should be conducted as soon as possible during the 
Screening/Baseline Period (per local guidelines) with the report available prior to 
randomization. 
Subjects will be dispensed an electronic diary (eDiary) and be trained on its use at the 
screening visit. The presence or absence of all seizure types experienced by each subject 
will be recorded daily in the diary from the Screening Visit through Visit 6 (end of 
follow-up period). Site personnel should classify the seizure type based upon the 
description provided by the subject in the eDiary and, if needed, via further discussion 
with the subject. If a new seizure type occurs during the trial, the seizure category will be 
evaluated by the investigator and, if confirmed to be new, and not reported previously, it 
will be submitted to TESC for review. If seizures do not occur on any given day, lack of 
seizures is also recorded. Subjects will also record any use of BZDs.  
As described in Section 5.1, a minimum of 8 focal onset (as defined in the 2017 ILAE 
Classification of Seizures [Fisher et al, 2017]), focal aware (except subjects with only 
focal aware seizures without a motor component), focal impaired awareness, or focal to 
bilateral tonic-clonic seizures during the 8-week Baseline Period with no 21-day period 
free of any of these seizure types should be confirmed by site personnel in order for the 
subject to be eligible for the trial. 
A medical bracelet with subject and trial information will be dispensed at Visit 1.  
8.2 
Efficacy Assessments 
8.2.1 
Seizure Frequency and Type (eDiary) 
Subjects will record details regarding their seizures (frequency and type) in an eDiary. 
Any BZD use will also be recorded in the diary.  
Seizure frequency and type will be assessed based on information recorded by the subject 
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8.2.2 
Patient’s Global Impression of Change 
The self-report measure Patient’s Global Impression of Change (PGIC) reflects a 
patient’s belief about the efficacy of treatment. It is a 7-point scale depicting a patient’s 
rating of overall improvement. Patients rate their change as “very much improved,” 
“much improved,” “minimally improved,” “no change,” “minimally worse,” “much 
worse,” or ‘‘very much worse.” 
8.2.3 
Clinical Global Impression-Severity of Symptoms Scale 
The CGI-S is an observer-rated scale that will be used to measure symptom severity. It is 
important to note that the observer or rater will provide their assessment of the subject’s 
symptoms at the time of the current visit. 
To perform this assessment, the investigator (or designee) will answer the following 
question: “Considering your total clinical experience with this particular population, how 
ill is the subject at this time?” Response choices are 0 = not assessed; 1 = normal, not at 
all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely 
ill; and 7 = among the most extremely ill subjects. 
8.2.4 
Clinical Global Impression-Improvement Scale 
The CGI-I is an observer-rated scale that will be used to measure the subject’s symptom 
severity compared with before initiation of treatment with IMP. It is important to note 
that the observer or rater will provide their assessment of the subject’s current level of 
symptoms compared with their symptoms at baseline (Visit 1).   
The investigator (or designee) will rate the subject’s change from baseline in symptom 
severity (as related to seizure frequency and severity) using the following response 
choices: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally 
improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much 
worse. 
8.2.5 
Quality of Life in Epilepsy – 31 
The Quality of Life in Epilepsy – 31 (QOLIE-31) was developed in cooperation with 
professional postgraduate services, a division of Physicians World Communications 
Group and the QOLIE Development Group. The 31-item QOLIE-31 (Version 1.0) has 
been derived from the longer QOLIE-89 (Rausch & Crandall, 1982; Cramer et al, 1998). 
The QOLIE-31 contains 7 multi-item scales that tap the following health concepts: 
emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure 
worry, medication effects, and overall quality of life. A QOLIE-31 overall score is 
obtained using a weighted average of the multi-item scale scores. The QOLIE-31 also 
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8.2.6 
Health Utilities Index 
The Health Utilities Index (HUI) is a rating scale used to measure general health status 
and health-related quality of life. The HUI questionnaires are designed to map onto 2 
classification systems, HUI-2 and HUI-3, capable of measuring 24,000 and 972,000 
unique health states, respectively. The HUI classifications measure a range of health 
domains with examples including sensation, mobility, pain, cognition, ambulation, and 
emotion (Horsman et al, 2003). 
8.3 
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of 
Assessments (Table 2).  
For the assessments described below, when multiple procedures are scheduled on the 
same visit, the following chronology of events should be adhered to, where possible: 
 ECGs, obtain prior to vital sign measurements 
 Vital sign measurements, obtain prior to procurement of blood specimens 
 Blood specimen collection 
 Other procedures: all other procedures may be obtained before or after blood 
specimen collection 
8.3.1 
Physical and Neurological Examinations 
A complete physical examination will consist of measurement of height (screening only) 
and weight and a review of the following body systems: head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, gastrointestinal, genitourinary, and 
musculoskeletal systems. If the investigator/designee is unable to perform a genitourinary 
examination, special attention will be given to the genitourinary medical history. A prior 
record (within 12 months) of a recent genitourinary examination from a gynecologist or 
family doctor can substitute for a genitourinary examination.  
A full neurological examination will include an assessment of the subject’s mental status 
(level of consciousness, orientation, speech, memory, etc.), cranial nerves, motor (muscle 
appearance, tone, strength and reflexes), sensation (including Romberg sign), 
coordination, and gait. 
Height will be measured at screening only.  
The following guidelines will aid in the standardization of body weight measurements: 
 The same scale should be used to weigh a given subject each time, if possible 
 
 
 
 
 
 

 
 
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 Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session
 A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments) 
 Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit 
The investigator (or designee) is responsible for performing the physical and neurological 
examinations. If the appointed designee is to perform these examinations, he or she must 
be permitted by local regulations and his or her name must be included on the delegation 
of authority log. Whenever possible, the same individual should perform all physical and 
neurological examinations.  
Any condition present at the post-treatment physical and neurological examinations that 
was not present at the baseline examination should be documented as an AE and followed 
to a satisfactory conclusion. 
8.3.2 
Vital Sign Measurements 
Vital sign measurements will include body temperature, respiratory rate, systolic blood 
pressure, diastolic blood pressure, and heart rate.  
Vital signs will be measured with the subject in a sitting/semi-recumbent position after 5 
minutes rest and will include temperature, systolic and diastolic blood pressure, and heart 
rate.  
A properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time. The use of an automated device for measuring blood pressure and 
heart rate is acceptable, although, when done manually, heart rate will be measured in the 
brachial/radial artery for at least 30 seconds. When the timing of these measurements 
coincides with a blood collection, blood pressure and heart rate should be obtained prior 
to the nominal time of the blood collection. 
Body temperature will be measured with either an oral (temperature taken at floor of the 
mouth) or tympanic thermometer. The same method (ie, oral or tympanic) must be used 
for all measurements for each individual subject and should be the same for all subjects at 
each investigational site. 
8.3.3 
Electrocardiograms
Electrocardiogram recordings will be obtained after the subject has been supine and at 
rest for at least 5 minutes. Additional 12-lead ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of early termination. The ECG 
results will be evaluated at the investigational site to determine the subject’s eligibility 
and to monitor safety during the trial. The investigator (or qualified designee) will 
 
 
 
 

 
 
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review, sign, and date each ECG reading, noting whether or not any abnormal results are 
of clinical significance. Any clinically relevant changes occurring during the trial will be 
recorded in the AE section of the eCRF. The ECG will be repeated if any results are 
considered to be clinically significant. A central ECG service will be used for reading all 
ECGs in order to standardize interpretations for the safety analysis. 
If, during screening, an abnormal ECG finding is deemed medically significant according 
to the investigator’s judgment (impacting the safety of the subject or the interpretation of 
the trial results) or meets an exclusion criterion (see Section 5.2), the subject should be 
excluded from the trial. At screening, triplicate ECG recordings should be taken 
approximately 1 minute apart. The central ECG service will provide the QT interval 
corrections based on Fridericia’s formula (QTcF) for the 3 screening ECGs. A mean 
QTcF >450 msec as assessed by the central reader from the screening triplicate ECGs 
will be exclusionary. 
Exclusion criteria for screening do not apply as mandatory discontinuation criteria for 
subjects who are already randomized. A repeat ECG should be performed to confirm any 
clinically significant abnormality that is identified in a randomized subject during the 
treatment period (which will be confirmed by central service read) and, in these cases, the 
medical monitor should be consulted on the appropriateness of the subject continuing in 
the trial. 
8.3.4 
Clinical Safety Laboratory Assessments 
See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed and 
to the Schedule of Assessments (Table 2) for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the trial in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
subject’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the trial should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the medical monitor notified. 
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2), 
must be conducted in accordance with the laboratory manual and the Schedule of 
Assessments (Table 2). 
 

 
 
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8.3.5 
Modified Clinical Institute Withdrawal Assessment – 
Benzodiazepines 
The modified Clinical Institute Withdrawal Assessment – Benzodiazepines (mCIWA-B) 
is a sensitive instrument to measure withdrawal under conditions where there is a taper of 
medication (rather than abrupt discontinuation). It consists of 17-items that monitor the 
type and severity of BZD withdrawal symptoms such as irritability, fatigue, appetite, and 
sleeplessness (Busto et al, 1989). The clinician-observed assessments of sweating, 
restlessness (pacing), and tremor that are included in the overall version have been 
removed from this modified version. The total score ranges from 1 to 68 with higher 
scores indicating more severe withdrawal.  
8.3.6 
Suicidal Ideation and Behavior Risk Monitoring 
Suicidality will be monitored during the trial using the Columbia – Suicide Severity 
Rating Scale (C-SSRS). This semi-structured interview was originally developed to 
evaluate the link between antidepressants and suicidal behavior and ideation in youth and 
AEs from pediatric clinical trials (Posner et al, 2011). It was designed to quantify the 
severity of suicidal ideation and behavior. Trial personnel administering the C-SSRS 
must have completed the appropriate training and have valid certification. Training on the 
scale will be provided via the sponsor or designee. 
This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale. 
The “Baseline/Screening” version, which assesses the lifetime experience of the subject 
with suicide events and suicidal ideation and the occurrence of suicide events or ideation 
within a specified time period prior to entry into the trial, will be completed for all 
subjects at screening to determine eligibility and confirmed at baseline. Any subject with 
active suicidal ideation or suicidal behaviors within the last 6 months, suicidal behaviors 
within the last 2 years, or who in the clinical judgment of the investigator presents a 
serious risk of suicide should be excluded from the trial (see Section 5.2).  
The “Since Last Visit” C-SSRS form will be completed at all visits after screening and 
Visit 1. The investigator will review the results of the “Since Last Visit” C-SSRS during 
the trial to determine whether it is safe for the subject to continue in the trial. If a subject 
demonstrates potential suicidal ideation associated with actual intent or method or plan as 
indicated by “YES” answers on item 4 or 5 of the C-SSRS, the investigator will need to 
evaluate whether a risk assessment by a qualified mental health professional (MHP, or 
the investigator alone if the investigator is a qualified MHP) is needed and whether the 
subject should continue in the trial or be discontinued. 
8.4 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.3 (Appendix 3). 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, 
surrogate, or the subject’s legally authorized representative). 
 

 
 
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The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the IMP or trial procedures, or 
that caused the subject to discontinue IMP (see Section 7) 
8.4.1 
Time Period and Frequency for Collecting AE and SAE 
Information 
All AEs and SAEs will be collected from the signing of the ICF through the subject’s last 
visit at the time points specified in the Schedule of Assessments (Table 2). 
Adverse events that begin before the start of IMP but after obtaining informed consent 
will be recorded and categorized as pretreatment AEs. Any AE occurring after initiation 
of IMP are defined as treatment-emergent AEs (TEAEs). 
All SAEs will be recorded and reported to the medical monitor immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). The 
investigator will submit any updated SAE data to the medical monitor within 24 hours of 
it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the trial 
participation. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the trial, and he/she considers the event to 
be reasonably related to the IMP or trial participation, the investigator must promptly 
notify the sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 
(Appendix 3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up (as 
defined in Section 7.5). Further information on follow-up procedures is given in 
Section 10.3 (Appendix 3). 
 

 
 
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8.4.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the medical monitor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of an IMP under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of an IMP under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/ IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review, acknowledge, and then file it along with the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate according to local requirements.
8.4.5 
Pregnancy 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of IMP and until the final contact on Day 120. 
If a pregnancy is reported, the investigator should inform the medical monitor within 24 
hours of learning of the pregnancy and should follow the procedures outlined in 
Section 10.4 (Appendix 4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4.6 
Adverse Events of Special Interest 
8.4.6.1
Adverse Events Potentially Related to Abuse or Dependence 
A key objective of the Abuse Potential Monitoring Plan (APMP) is to monitor for 
instances of abuse or diversion of the trial medication and other psychoactive substances. 
In addition to monitoring for irregularities in medication handling, AEs that may be 
suggestive of a developing abuse issue will also receive special attention. As part of the 
APMP, medication handling irregularities (MHIs) must be reported, and AEs related to 
abuse potential and AEs involving MHIs must be reported as AEs of special interest 
(AESIs) with 24 hours to the sponsor with detailed narratives. 
Investigators and site staff at each trial site will be trained on reporting potentially abuse 
related AEs (eg, recording a description of the event in the subject’s own words in the 
 

 
 
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source documents as well as the eCRF, in addition to the clinical term, and to be aware 
that a subject’s report may encompass more than one event and that these should be 
recorded separately). The investigators will be provided with examples of potentially 
abuse-related AEs and trained on how to handle such events (eg, additional monitoring). 
While the investigators will be provided with examples of AE terms as a guide during 
trial conduct, the analysis of potentially abuse-related AEs by the sponsor will be based 
on a search of all relevant Medical Dictionary for Regulatory Activities (MedDRA) 
terms, all verbatim terms, and any open text fields within the AE data to identify text 
strings suggestive of abuse potential, in line with the 2017 FDA guidance (Guidance for 
Industry, 2017). Refer to the separate APMP documentation for complete details on 
MHIs and Events Subject to Additional Monitoring (ESAMs), including documenting 
and reporting procedures, examples of potentially abuse-related AE terms that meet the 
criteria for ESAM reporting, and guidance for the training of investigators and trial site 
staff. 
The following AEs are considered indicative of potential abuse for the CVL-865 
mechanism of action: 
 Abnormal behavior 
 Abnormal dreams 
 Amnesia 
 Any reports of altered perception or hallucinations 
 Apathy 
 Balance disorder 
 Cognitive disorder 
 Depressed level of consciousness 
 Depressed mood 
 Dizziness 
 Euphoric mood 
 Feeling drunk 
 Feeling of relaxation 
 Sedation 
 Somnolence 
Narratives will be completed for the above terms; information included in the narratives 
will consist of time to onset/offset, time course of severity, all concurrent events, 
concurrent medications, and time of onset of events relative to ingestion of IMP.  
8.4.6.2 
Hematologic Abnormalities 
The occurrence of any of the following hematologic abnormalities must be reported as 
AESI to the sponsor with 24 hours and the clinical course must be discussed with the 
medical monitor. Management of AESIs should follow instructions described in Table 8.  
 Hemoglobin: females <10 g/dL; males <11 g/dL  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 WBC count <3.0  109/L
 Neutrophil count <2.0  109/L 
 Platelet count <150  109/L
Treatment with study drug must be discontinued if a subject develops any of the 
following hematologic abnormalities and should be managed as described in Table 8: 
 Hemoglobin <8 g/dL 
 WBC count <2.5  109/L
 Neutrophil count <1.5  109/L 
Platelet count <100 
109/L
Table 8 
Management of Hematologic Abnormalities 
Hematologic Abnormalities 
Management 
Hemoglobin: females <10 g/dL;  
males <11 g/dL 
WBC count <3.0  109/L 
Neutrophils <2.0  109/L 
Platelet count <150 
109/L 
Concomitant therapies and medical history should be reviewed
CBC should be rechecked regularly until CBC returns to near 
baseline value 
The finding must be reported as an AESI and must be discussed 
with the medical monitor 
Hemoglobin <8 g/dL 
WBC count <2.5  109/L 
Neutrophils <1.5  109/L 
Platelet count <100 
109/L 
Treatment with study drug should be permanently discontinued
Concomitant therapies and medical history should be reviewed 
CBC should be rechecked regularly until CBC returns to near 
baseline value 
The finding must be reported as an AESI and must be discussed 
with the medical monitor 
Abbreviations: AESI = adverse event of special interest; CBC = complete blood count; WBC = white blood 
cell 
8.4.6.3 
Abnormal Liver Function Tests
The finding of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) 
 upper limit of normal range (ULN) in combination with either an elevated 
total bilirubin 
ULN or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, 
investigators must report the occurrence of either of the following as an AESI to the 
sponsor with 24 hours: 
 Treatment-emergent ALT or AST 
ULN and total bilirubin 
 
 Treatment-emergent ALT or AST 
ULN in combination with clinical jaundice
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
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8.5 
Treatment of Overdose 
For this trial, any dose of CVL-865 greater than 80 mg within a 24-hour time period 
( 2 hours) will be considered an overdose. 
There is no specific antidote for overdose with CVL-865. Treatment of overdose should 
consist of general supportive measures.  
In the event of an overdose, the investigator should complete the following: 
1. 
Contact the medical monitor immediately. 
2. 
Closely monitor the subject for any AE/SAE and laboratory abnormalities until 
CVL-865 can no longer be detected systemically (at least 3 days). 
4. 
Document the quantity of the excess dose as well as the duration of the 
overdose 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 subject. 
8.6 
Pharmacokinetics 
8.6.1 
Blood Samples for CVL-865 Concentrations 
Samples for determination of CVL-865 concentrations will be collected in appropriately 
labeled tubes as specified in the Schedule of Assessments (Table 2). Additional 
instructions are provided in the Laboratory Flow Chart. 
8.6.2 
Blood Samples for Anti-epileptic Drug Concentrations 
Samples for determination of concentrations of adjunctive AEDs will be collected in 
appropriately labelled tubes as specified in the Schedule of Assessments (Table 2). 
Additional instructions are provided in the Laboratory Flow Chart. 
8.6.3 
Methods and Analysis 
Additional details regarding the collection, processing, storage, and shipping of all PK 
plasma samples will be provided in a laboratory manual. Plasma samples from treatment 
groups will be analyzed for analyte using a validated bioanalytical method. CVL-865 
plasma samples collected in this trial may be used for other exploratory purposes, eg, 
method development, identification of metabolites and metabolite scouting. Results of 
such analyses will not be reported in the Clinical Study Report (CSR). 
8.7 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this trial. 
 
 

 
 
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8.8 
Future Biospecimen Research 
Studying the variation in genetic markers and other biomarkers may help to explain some 
of the variability in response seen with some drugs among different individuals. This is 
referred to as pharmacogenomic/biomarker research. Comparing the deoxyribonucleic 
acid (DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of 
subjects who respond well and those who respond poorly to treatment may help to better 
define the most appropriate group of subjects in which to target a given treatment. 
Collecting biospecimens for exploratory pharmacogenomic/biomarker analyses and 
retaining them at Cerevel makes it possible to better understand the drug’s mechanism of 
action and to seek explanations for differences in, for example, exposure, efficacy, 
tolerability, or safety not anticipated prior to the beginning of this trial. 
Future biospecimen research samples will be collected from subjects who provide 
additional consent specifically for this sample collection. Research performed on these 
samples may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics and/or the measurement of other analytes. Such research is for 
biomarker testing to address emergent questions not described elsewhere in the protocol 
(as part of the main trial) and will only be conducted on specimens from appropriately 
consented subjects.  
8.9 
Health Economics 
Health economics will be assessed using the QOLIE-31 and the HUI, which are described 
in Section 8.2.5 and Section 8.2.6, respectively. 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The primary efficacy endpoint is the Response ratio (Rratio), defined as 
Rr
week in the Maintenance Phase and B represents the focal onset seizure frequency rate 
per week in the Baseline Period. 
The hypotheses of interest are 2-sided tests of superiority comparing each active 
CVL-865 dose (CVL1, CVL2) to placebo. 
H01: µ placebo = rCVL1 vs H11: µ placebo 
CVL1   
H02: µ placebo = rCVL2 vs H12: µ placebo 
CVL2
9.2 
Sample Size Determination 
A sample size of 50 subjects per group (total of 150 subjects) will provide at least 80% 
power to detect a difference in the means of the primary outcome measure (Rratio) of -20 
(PASS 2008 Tests of Two Means, Two Sample T-Test, 2-sided alpha level = 0.1, 
Standard Deviation=34, and a 20% dropout rate). 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
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Therefore, approximately 214 subjects will be screened to achieve 150 subjects randomly 
assigned to treatment and 120 evaluable subjects for an estimated total of 40 evaluable 
subjects per treatment group. 
In the event of higher than anticipated early terminations due to COVID-19 or other 
reasons, Cerevel may extend enrollment in order to maintain the planned statistical 
power. 
9.3 
Populations for Analyses 
The following data sets are defined for analysis: 
Screen Failures (SFs): comprises all subjects who consent to participate in the clinical 
trial but are not subsequently randomly assigned to treatment in the trial.   
Intent-to-Treat (ITT): comprises all randomized subjects 
Full Analysis Set (FAS): comprises all randomized subjects who receive at least 1 dose of 
IMP
Modified ITT (mITT) Set: comprises all randomized subjects who receive at least 1 dose 
of IMP and have at least 1 entry in the seizure diary. 
9.4
Statistical Analyses 
Descriptive statistical methods will be used to summarize the data from this study, with 
statistical testing performed for the efficacy endpoints. Unless stated otherwise, the term 
“descriptive statistics” refers to number of subjects (n), mean, median, standard 
deviation, minimum, and maximum for continuous data, and frequencies and percentages 
for categorical data. Statistical testing, if performed, will be 2-sided and will be 
performed using a significance (alpha) level of 0.1. All available data for enrolled 
subjects will be listed by subject. Unless otherwise noted, the data will be sorted first by 
subject number and then by date within each subject number.  
All statistical analyses will be conducted with the SAS® System, version 9.4 or higher.  
The remainder of this section is a summary of the planned statistical analyses of the 
primary and secondary endpoints as well as a description of planned safety analyses. Full 
details of these analyses will be included in the statistical analysis plan (SAP). The SAP 
will be developed and finalized before database lock and will describe the subject 
populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. 
 

 
 
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9.4.1 
Efficacy Analyses 
Seizure frequency is defined as the total number of focal onset seizures over the treatment 
period of interest divided by the total number of days with no missing seizure counts in 
the corresponding period multiplied by 7.   
The primary efficacy endpoint is the Rratio over the Maintenance Phase. This is 
calculated as Rratio=(T B)/(T B)
 where T represents the seizure frequency rate 
per week in the Maintenance Phase and B represents the seizure frequency rate per week 
in the Baseline Period. The Rratio is between -100 and 100. Negative values will indicate 
reduction in seizure rate and positive values indicate increase in seizure rate during 
treatment. 
Values of Rratio will be analyzed for the mITT population using an analysis of 
covariance model, including treatment and the baseline seizure frequency per week as a 
covariate. This estimand will include response data that occur before discontinuation of 
treatment. The differences between the treatment groups will be based on the least square 
mean (LSMean) difference between each CVL-865 group and placebo. A separate 
comparison of the combined CVL-865 groups and placebo may be conducted. The 
corresponding 95% confidence interval (CI) will be presented. Sensitivity analyses will 
be conducted by including all available data (de facto estimand). 
A key secondary efficacy endpoint is the change from baseline in focal onset seizure 
frequency per week over the Maintenance Phase. These data will be log-transformed 
log-transformed values will be analyzed using an analysis of covariance model, including 
treatment as a factor and the log-transformed baseline focal onset seizure frequency per 
week as a covariate. The differences between the treatment groups will be based on the 
LSMean difference between each CVL-865 group and placebo. The percent reduction 
relative to placebo will be constructed by exponentiating the LSMean difference between 
each CVL-865 treatment group and placebo using the following formula: 
%Reduction/Placebo = 100 exp
exp(
)
exp
1
 
The corresponding 95% CI will be calculated. A secondary analysis of this endpoint will 
be conducted using a Poisson Regression model on the untransformed data. 
An additional key secondary endpoint is the 50% responder rate, defined as the 
percentage of subjects with at least a 50% reduction in the Maintenance Phase focal onset 
seizure frequency relative to the Baseline Period. This key secondary endpoint will be 
analyzed for the mITT population using a logistic regression model with effects for 
treatment. Odds ratios representing the odds of being a responder compared with placebo 
will be constructed for each CVL-865 treatment group. Subjects with missing or 
incomplete seizure information will be treated as non-responders for this analysis. 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
 

 
 
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Continuous endpoints with repeated post-baseline assessments (CGI-S, CGI-I, PGIC) 
will be analyzed for the mITT population using a Mixed Model for Repeated Measures 
(MMRM). This estimand will include available post-baseline response data that occur 
before discontinuation of treatment. The baseline score (if applicable) will be included as 
the covariate, and treatment group (CVL-865 7.5 mg, CVL-865 25 mg, or placebo), visit, 
and the interaction between treatment group and visit will be included as fixed factors in 
the MMRM. The difference between each CVL-865 level versus placebo at each visit 
will be estimated based on the LSMeans from the MMRM. Changes from baseline in 
QOLIE-31 Domain and Overall Scores and HUI Utility Function scores will be analyzed 
using an analysis of covariance model (ANCOVA) with the baseline score and treatment 
group included in the model as fixed effects. The difference between each CVL-865 level 
versus placebo will be estimated based on the LSMeans from the ANCOVA model. 
9.4.2 
Safety Analyses 
The safety analysis will be conducted on the FAS. Should there be any subjects that 
receive a treatment other the randomized treatment, the treatment as received will be used 
for safety presentations. Treatment-emergent adverse events will be coded according to 
MedDRA and summarized by treatment group, system organ class, and preferred term. 
Further summaries will be done by seriousness, severity, relationship to IMP, and dose at 
the time of onset.  
The number of subjects withdrawing from IMP due to AEs, as well as the number of 
subjects with treatment-emergent AEs potentially related to abuse will be summarized by 
treatment group. Abuse potential will be assessed through the active monitoring of AEs 
related to potential abuse and AEs involving MHI. 
Other safety endpoints will be summarized with descriptive statistics by treatment group, 
including laboratory assessments, vital sign measurements, ECGs, medication withdrawal 
symptoms assessed by the mCIWA-B total scores at the scheduled visits, and suicidality 
monitored during the trial using C-SSRS.  
All data collected for subjects in the SF data set will be listed separately. 
9.4.3 
Other Analyses  
The CVL-865 concentration data will be used to determine the extent to which subjects 
attain exposure levels within the range predicted at each dosing regimen. Likewise, the 
AED concentration data will be used to review the exposure levels of AED taken with or 
without CVL-865. Appropriate tabular and/or graphical summaries of all PK 
concentration data will be generated as detailed in the SAP. 
Concentration data from this trial may be used to update the previously established 
population PK model for CVL-865. In addition, the relationship between the exposure 
levels (or dose) of CVL-865 and one or more efficacy/safety endpoints may be evaluated 
for the purpose of exploratory PK/PD analyses.  Any population PK analysis and 
 

 
 
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exploratory biomarker analyses (if completed) will be presented separately from the main 
CSR.
9.5
Interim Analysis  
The sponsor may perform an interim analysis to obtain preliminary information on safety 
and efficacy. Interim analysis results may be used for internal business decisions 
regarding future trial planning or stopping for futility. Before any interim analysis is 
instigated, the details of the objectives, decision criteria, and method of maintaining the 
trial blind will be documented and approved in an interim SAP or final SAP (as 
applicable). 
 

 
 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This trial will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 Applicable International Council for Harmonisation (ICH) GCP Guidelines 
 Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
hazard to trial subjects. 
The investigator will be responsible for the following: 
 Providing written summaries of the status of the trial to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical trials (if applicable), and all other applicable local 
regulations 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested 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 trial and for 1 year after completion of the trial. 
 
 
 
 
 
 
 

 
 
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10.1.3 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the trial to the subject
and answer all questions regarding the trial. 
Subjects must be informed that their participation is voluntary. Subjects will be required 
to sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC or 
trial center. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the trial and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial. 
A copy of the ICF(s) must be provided to the subject. 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 4 weeks from the previous ICF signature date. 
A separate and similar consent process will be followed for the optional future 
biospecimen research samples. The investigator or authorized designee will explain to 
each subject the objectives of the exploratory research. Subjects will be told that they are 
free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to document a 
subject's agreement to allow specimens to be used for exploratory research. Subjects who 
decline to participate in this optional research will not provide this separate signature. 
10.1.4 
Data Protection 
Subjects will be assigned a unique identifier by the sponsor or designee. Any subject 
records or datasets that are transferred to the sponsor will contain the identifier only; 
subject names or any information which would make the subject identifiable will not be 
transferred. 
The subject must be informed that his/her personal trial-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject and outlined in the ICF. 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 

 
 
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10.1.5 
Dissemination of Clinical Trial Data 
Cerevel fulfills its commitment to publicly disclose clinical trial results through posting 
trial results on ClinicalTrials.gov, the European Clinical Trials Database (EudraCT), and 
other public registries in accordance with applicable local laws/regulations. 
In all cases, trial results are reported by Cerevel in an objective, accurate, balanced, and 
complete manner and are reported regardless of trial outcome or the country in which the
trial was conducted. 
Clinical trial US Basic Results are posted on Clinicaltrials.gov for all Cerevel-sponsored 
interventional trials conducted in subjects that evaluate the safety and/or efficacy of a 
Cerevel product, regardless of the geographical location in which the trial is conducted. 
US Basic Results are submitted for posting within 1 year of the primary completion date 
as defined in Section 4.5 for trials in adult populations or within 6 months of the primary 
completion date for trials in pediatric populations. 
Cerevel posts European Union (EU) Basic Results on EudraCT for all Cerevel-sponsored 
interventional trials that are in scope of EU requirements. EU Basic Results are submitted 
for posting within 1 year of the primary completion date as defined in Section 4.5 for 
trials in adult populations or within 6 months of the primary completion date for trials in 
pediatric populations. 
10.1.6 
Data Quality Assurance 
All subject data relating to the trial will be recorded on the eCRF unless transmitted to the 
sponsor or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Clinical Monitoring Plan. 
The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
 

 
 
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Trial monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
trial is being conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial 
must be retained by the investigator for the longest of the following periods: 
 At least 2 years after the date on which approval to market the drug is obtained (or if 
IMP developments is discontinued, the date regulatory authorities were notified of 
discontinuation 
 At least 3 years after the sponsor notified the investigator that the final report has 
been filed with regulatory authorities  
 A longer period if required by local regulations or institutional policies 
No records may be destroyed during the retention period without the written approval of 
the sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
10.1.7 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available.
Definition of what constitutes source data can be found in the Clinical Monitoring Plan.
10.1.8 
Trial and Site Closure 
The sponsor or designee reserves the right to close the trial site or terminate the trial at 
any time for any reason at the sole discretion of the sponsor. Trial sites will be closed 
upon trial completion. A trial site is considered closed when all required documents and 
trial supplies have been collected and a trial-site closure visit has been performed. 
The investigator may initiate trial-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 a trial site by the sponsor or investigator may include but 
are not limited to: 
 
 
 
 

 
 
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 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the investigator 
 Discontinuation of further trial treatment development 
10.1.9 
Publication Policy 
The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
The sponsor will comply with the requirements for publication of trial results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 
 
 

 
 
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10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1 
Definitions 
10.4.1.1 
Highly Effective Form of Contraception 
A highly effective form of contraception is defined as follows:
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
10.4.1.2 
Contraception and Pregnancy Avoidance Procedures
The following definitions apply for contraception and pregnancy avoidance procedures: 
A woman is considered a woman of childbearing potential (WOCBP) following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy and bilateral oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
Sterilized male subjects should be at least 1 year postbilateral vasectomy and have 
confirmed that they have obtained documentation of the absence of sperm in the ejaculate 
or have had bilateral orchidectomy. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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10.4.2 
Collection of Pregnancy Information 
10.4.2.1 
Male subjects with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this trial. This 
applies only to male subjects who receive IMP. 
 After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
10.4.2.2 
Female subjects who become pregnant 
 The investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this trial. Information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a 
subject's pregnancy.  
 The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-trial pregnancy related SAE considered reasonably related to the 
trial treatment by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former trial subjects, he or she may learn of an SAE through spontaneous 
reporting. 
 Any female subject who becomes pregnant while participating in the trial will 
discontinue trial treatment and be withdrawn from the trial. 
 
 
 
 
 
 
 

 
 
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10.5 Appendix 5: Future Biospecimen Research 
Use/Analysis of DNA 
• 
Genetic variation may impact a subject’s response to IMP, susceptibility to, and 
severity and progression of disease. Variable response to IMP may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis from 
consenting subjects. 
• 
DNA samples will be used for research related to CVL-865 or epilepsy and 
related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to CVL-865 or interventions of this drug class and 
epilepsy. Genetic research may consist of the analysis of one or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the 
entire genome (as appropriate). 
•
There are no planned analyses of DNA samples. Analyses may be conducted if it 
is hypothesized that this may help further understand the clinical data. 
• 
The samples may be analyzed as part of a multi-trial assessment of genetic factors 
involved in the response to CVL-865 or IMPs of this class to understand trial 
disease or related conditions. 
• 
The results of genetic analyses may be reported in the CSR or in a separate trial 
summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 
The samples will be retained while research on CVL-865 or interventions of this 
class or epilepsy continues but no longer than 15 years or other period as per local 
requirements. 
 

 
 
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10.6 Appendix 6: Inducers and Inhibitors of Cytochrome P450 3A 
CYP 3A Inhibitors 
CYP 3A Inducers 
HIV antivirals 
HIV antivirals
Indinavir 
Efavirenz 
Nelfinavir 
Nevirapine 
Ritonavir 
Etravirine 
Saquinavir
Miscellaneous 
Boceprevir
Barbiturates 
Lopinavir/ritonavir 
Carbamazepine 
Amprenavir 
Eslicarbazepine 
Atazanavir 
Glucocorticoids (systemic) 
Telaprevir 
Modafinil 
Darunavir/ritonavir 
Oxcarbazepined 
Fosamprenavir 
Phenobarbital 
Antibiotics
Phenytoin 
Clarithromycin 
Pioglitazone
Erythromycin
Rifabutin 
Telithromycin 
Rifampin 
Ciprofloxacin
St. John’s wort 
Anti-infectives 
Troglitazone 
Itraconazole 
Bosentan 
Ketoconazole
Nafcillin 
Fluconazole 
Avasimibe 
Posaconazole
Voriconazole
Anti-anginal therapy
Diltiazem
Verapamil
Anti-cancer therapy
Crizotinib
Imatinib
Miscellaneous
Nefazodone
Aprepitant
Grapefruit juicea,b
Conivaptan
Mibefradilc
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” 
when a certain preparation was used (eg, high dose, double strength) or as a “moderate CYP3A 
inhibitor” when another preparation was used (eg, low dose, single strength). 
b 
A 2-week washout prior to dosing is required if grapefruit juice was being consumed continually. 
c 
Withdrawn from the United States market. 
d 
Doses >900 mg/day. 
 

 
 
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10.7 Appendix 7: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AED 
Anti-epileptic drug 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APMP 
Abuse Potential Monitoring Plan 
AST
Aspartate aminotransferase 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily 
BMI 
Body mass index 
BZD 
Benzodiazepine 
CBC 
Complete blood count 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity of Symptoms 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences
CONSORT 
Consolidated Standard of Reporting Trials 
CSR
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Computed tomography 
CYP 
Cytochrome P450 
DBS 
Deep brain stimulator 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EEG 
Electroencephalogram 
ESAM
Events Subject to Additional Monitoring 
ET 
Early Termination 
EU 
European Union
 

 
 
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Abbreviation 
Definition 
EudraCT 
European Clinical Trials Database 
FAS 
Full Analysis Set 
GABAA 
-aminobutyric acid type A 
GCP 
Good Clinical Practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HUI 
Health Utilities Index
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
K2EDTA 
Dipotassium ethylenediamine tetraacetic acid 
LSMean 
Least square mean 
mCIWA-B 
Modified Clinical Institute Withdrawal Assessment–Benzodiazepines 
mITT 
Modified Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHI 
Medication handling irregularity 
MHP 
Mental Health Professional 
MMRM 
Mixed Model for Repeated Measures 
MRI
Magnetic resonance imaging 
NOAEL
No observed adverse effect level 
OLE 
Open-label extension 
PAM 
Positive allosteric modulator
PD 
Pharmacodynamic 
PGIC 
Patient’s Global Impression of Change 
 
 

 
 
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Abbreviation 
Definition 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetic 
QOLIE-31 
Quality of Life in Epilepsy-31 
QTcF 
QT interval as corrected for heart rate by Fridericia’s formula 
RNA 
Ribonucleic acid 
RNS 
Responsive neurostimulator 
RRatio 
Response ratio
SAE
Serious adverse events 
SAP 
Statistical Analysis Plan 
SF 
Screen Failures 
SIF/DRF
Seizure Identification and Diagnostic Review Form 
SUSAR 
Suspected Unexpected Serious Adverse Reaction
TEAE 
Treatment-emergent adverse event 
TESC 
The Epilepsy Study Consortium 
ULN 
Upper limit of normal range
US 
United States 
VNS 
Vagus nerve stimulator 
WBC 
White blood cell
WOCBP 
Women of childbearing potential 
 

 
 
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10.8 Appendix 8: Protocol Amendment History 
Document History 
Document:  
Date (Day-Month-Year) 
Version 4.0 
30 Jun 2020 
Version 3.0 
15 Nov 2019 
Version 2.0 
03 Oct 2019 
Original Protocol Version 1.0 
24 Jul 2019 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents.  
Amendment: Protocol Version 3.0 (15 Nov 2019) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: To revise relevant sections of the protocol to 
minimize potential risk to subjects. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Table 1 Objectives 
and Endpoints 
Table 3 Objectives 
and Endpoints 
Reworded secondary endpoint 
for TEAEs 
Consistency with open-label extension 
protocol 
Table 2 Schedule of 
Assessments 
Addition of time points for 
safety laboratory blood samples 
(Visits 3, 5, and 6) 
Monitoring of new potential risk of bone 
marrow suppression and decrease in 
peripheral hematologic parameters 
2.3 Benefit/Risk 
Assessment 
5.2 Exclusion Criteria 
7.3 Individual Subject 
Discontinuation 
8.4.6.2 Hematologic 
Abnormalities 
Added potential risk of bone 
marrow suppression and 
decrease in peripheral 
hematologic parameters 
Updated relevant risk 
minimization measures, 
exclusion criterion, criteria for 
discontinuation of IMP, and 
new AESI subsection 
Update relevant protocol section with new 
potential risk of bone marrow suppression 
and decrease in peripheral hematologic 
parameters 
5.2 Exclusion Criteria 
Revised criterion for HIV, 
hepatitis B, and hepatitis C 
Exclude subjects regardless of LFT results 
8.3.2 Vital Sign 
Measurements 
Reworded paragraph about 
blood pressure measurement 
Simplification of vital signs collection 
procedure 
 

 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule 
of Assessments 
Footnote regarding rescreening 
was modified to indicate 
subjects would not retain their 
subject number in the event 
they were rescreened. 
Correction of inaccurate information 
Section 1.3 Schedule 
of Assessments 
Footnote regarding timing of 
physical/neurological 
examinations was modified. 
Correction of inaccurate information and 
addition of examination at Visit 4 
Section 1.3 Schedule 
of Assessments 
Removal of language stating 
female subjects with 
exclusively same sex partners 
are not required to have 
pregnancy tests 
Change made to be consistent with sponsor 
standard practices 
Section 4.4 Definition 
of Completed Subject 
Modified text to indicate 
subjects who continued into 
Trial CVL-865-SZ-002 were 
considered to have completed 
Trial CVL-865-SZ-001 at Visit 
4.  
In order to avoid unnecessary taper and re-
titration of investigational medicinal 
product for subjects entering Trial CVL-
865-SZ-002, the point of entry into that trial 
was moved to the end of the Maintenance 
Phase (Visit 4) 
Section 5.2 Exclusion 
Criteria 
Section 8.3.3 
Electrocardiograms 
Exclusion criterion 13 modified 
to exclude subjects with QTcF 
values >450 msec, regardless of 
sex 
Change made to be consistent with ICH E14 
Section 5.4 Screen 
Failures 
Text regarding rescreening was 
modified to indicate subjects 
would not retain their subject 
number in the event they were 
rescreened 
Correction of inaccurate information 
Section 6.7 
Intervention after the 
End of the Trial 
Modified text to indicate 
subjects who were eligible 
would enter Trial CVL-865-SZ-
002 after completion of the 
Maintenance Phase (Visit 4) of 
Trial CVL-865-SZ-001  
In order to avoid unnecessary taper and re-
titration of investigational medicinal 
product for subjects entering Trial CVL-
865-SZ-002, the point of entry into that trial 
was moved to the end of the Maintenance 
Phase (Visit 4) 
Section 8.3.1 Physical 
and Neurological 
Examinations 
Removed specifications on 
methods to measure height at 
screening 
No standard method to measure height will 
be required 
Section 8.3.2 Vital 
Sign Measurements 
Added respiratory rate to list of 
vital signs to be measured; 
clarified vital signs would be 
measured with subject in 
sitting/semi-recumbent 
position; removed requirement 
for triplicate blood pressure and 
heart rate measurements; added 
specifications for measurement 
of body temperature 
Further clarification on how to assess vital 
signs 
 

 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.3 
Electrocardiograms 
Added language stating 
clinically relevant changes in 
ECGs will be recorded in the 
AE section of eCRF 
Inadvertent omission in original protocol 
Section 8.6.3 Methods 
and Analysis 
Added language to provide 
flexibility to use CVL-865 
samples for future exploratory 
analyses for potential 
metabolites and method 
development activities 
Judicious use of collected human samples 
for future use towards potential method 
development activities and understanding 
metabolic fate of CVL-865 
Section 8.6.3 Methods 
and Analysis 
Moved text regarding use of 
CVL-865 concentration data to 
Section 9.4.3 Other Analyses 
Text was moved to a more appropriate 
location within protocol 
Overall
Minor grammatical and 
wording 
corrections/clarifications made 
throughout protocol 
Correct errors in original protocol
 
 

 
 
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11 REFERENCES 
Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J 
Clin Psychopharmacol. 1989;9(6):412-6. 
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. 
Development and cross-cultural translations of a 31-item quality of life in epilepsy 
inventory. Epilepsia. 1998;39(1):81-8.  
European Medicines Agency. Guideline on clinical investigation of medicinal products in 
the treatment of epileptic disorders. Available at: 
https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-clinical-
investigation-medicinal-products-treatment-epileptic-disorders-revision-3_en.pdf. 26 July 
2018. 
Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational 
classification of seizure types by the International League Against Epilepsy: position 
paper of the ILAE Commission for Classification and Terminology. Epilepsia. 
2017;58(4):522-30.  
Gurrell R, Gorman D, Whitlock M, Ogden A, Reynolds DS, DiVentura B, et al. 
Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator. 
Neurology. 2019; 92(15):e1786-e1795. 
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Methern G, et al. 
Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the 
ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-77. 
Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): 
concepts, measurement properties and applications. Health Qual Life Outcomes. 
2003;1:54. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77. 
Rausch R, Crandall PH. Psychological status related to surgical control of temporal lobe 
seizures. Epilepsia. 1982;23(2):191-202. 
Guidance for Industry: Assessment of abuse potential of drugs (January 2017). Available 
at: https://www.fda.gov/media/116739/download. Accessed: 01 October 2019. 
 
 
 

 
 
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CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR SIGNATURE 
PAGE 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP, MULTICENTER TRIAL OF CVL-865 AS 
ADJUNCTIVE THERAPY IN ADULTS WITH DRUG-RESISTANT 
FOCAL ONSET SEIZURES (REALIZE TRIAL) 
 
Protocol Number: CVL-865-SZ-001 
Compound Number: CVL-865 
Trial Phase: 2
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 131 Dartmouth Street, Suite 502, Boston MA 02116 
United States 
Version 4.0: 30 Jun 2020 
 
I, the undersigned principal investigator, have read and understand the protocol 
and agree that it contains the ethical, legal, and scientific information necessary to 
conduct this trial in accordance with the principles of Good Clinical Practices and 
as described herein and in the sponsor’s (or designee’s) Clinical Research 
Agreement. 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
Principal Investigator Signature 
 
 
Date (DD MMM YYYY)