A 57-Week, Multicenter, Active-treatment, Open-label Extension Trial of CVL-865 as Adjunctive Therapy in Adults With Drug-Resistant Focal Onset Seizures
Phase: PHASE2
Conditions: Seizures
Sponsor: AbbVie

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CLINICAL PROTOCOL 
A 57-WEEK, MULTICENTER, ACTIVE-TREATMENT, 
OPEN-LABEL EXTENSION TRIAL OF CVL-865 AS ADJUNCTIVE 
THERAPY IN ADULTS WITH DRUG-RESISTANT FOCAL ONSET 
SEIZURES 
Protocol: CVL-865-SZ-002 
Compound Number: CVL-865 
Trial Phase: 2 
Short Title: An Extension Trial 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 
2019-004057-83 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Version 3.0: 14 Jul 2020 
Version 2.0: 26 Nov 2019 
Original Version 1.0: 30 Oct 2019 
MEDICAL MONITOR NAME AND CONTACT INFORMATION ARE PROVIDED 
IN THE TRIAL OPERATIONS MANUAL 
NCT #: NCT04686786

PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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PROTOCOL VERSION 3.0 SUMMARY OF CHANGES TABLE 
Document History 
Document:  
Date (Day-Month-Year) 
Version 3.0 
14 Jul 2020 
Version 2.0 
26 Nov 2019 
Original Protocol Version 1.0 
30 Oct 2019 
Amendment: Protocol Version 3.0 (dd Jul 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 
1.2 Schema 
1.3 Schedule of 
Assessments 
Changed Week 4 visit to contact 
only rather than site visit, 
remove laboratory assessments at 
this visit 
Allow flexibility and reduce burden on 
subjects 
1.3 Schedule of 
Assessments 
Added a footnote to Table 2 and 
Table 3 to provide an option for 
specific visits to be completed 
remotely; remove previous text 
regarding option for remote 
pregnancy test as no longer 
applicable 
Added option for COVID-19 
testing 
To reflect risk assessment measures by 
sponsor to prioritize trial participant safety 
1.3 Schedule of 
Assessments 
Remove PGI-C and CGI-S 
assessments at the end of the 
Taper Phase 
Reduce number of assessments and 
burden on subject 
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 
4.1 Overall Design 
Added text stating subjects who 
terminate trial during Titration 
Phase will be provided 3 weeks 
of IMP for Taper Phase 
Additional clarification regarding early 
discontinuation 

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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 use of prohibited 
medications  
Simplify language by referring to the 
respective tables that specify prohibited 
medications during the trial 
5.3.1 Meals and 
Dietary Restrictions 
Increased restriction on 
consuming grapefruit and 
grapefruit-related citrus fruits 
until end of trial 
Maintain consistency with Trial CVL-
865-SZ-001 
5.4 Screen Failures 
Added language clarifying the 
definition of screen failures  
Clarification of prior language 
6.4 Trial Treatment 
Compliance 
Removed information that IMP 
given once daily in the morning 
with or without food 
Correction of erroneous information 
6.6 Dose Modification 
7.3 Individual Subject 
Discontinuation 
Removed information regarding 
discontinuation of IMP from 
Section 6.6 and added to Section 
7.3 
Restrict Section 6.6 to information 
regarding dose interruption and Section 
7.3 for information regarding subject 
discontinuation 
7.3 Individual Subject 
Discontinuation 
Added wording to specify that 
subjects should begin Taper 
Phase at time decision made to 
discontinue trial. Added caveat 
for an alternate taper scheme for 
subjects who early terminate 
prior to Day 15.  
Further clarification on trial procedures 
8.3.1 Physical and 
Neurological 
Examinations 
Added clarification that prior 
record of genitourinary 
examination was within 12 
months of enrolling in CVL-865-
SZ-001 
Further clarification on trial procedures 
8.3.2 Vital Sign 
Measurements 
Deleted redundant text in 
paragraphs 1 and 2 
Correction of error in original protocol 
8.3.3 
Electrocardiograms 
Removed information regarding 
requirement for subjects to be 
supine prior to ECG; removed 
specification that ECG is 12-lead 
Allow flexibility in case of remote trial 
visits 
8.3.4 Clinical Safety 
Laboratory 
Assessments 
Removal of language regarding 
clinically significant laboratory 
finding 
Update to be consistent with company 
processes and avoid redundant text 
8.6 Pharmacokinetics 
Simplified wording about sample 
collection (Sections 8.6.1 and 
8.6.2) 
Remove duplication of details provided in 
other materials 

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Section # and Name 
Description of Change 
Brief Rationale 
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 
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 
10.5 Appendix 5: 
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 
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
Reflect changes to visit numbers, visit 
timing, and visit types (ie, contact visits 
changed to in-clinic visits), due to changes 
to schedule of activities  
Correct errors in original protocol 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CGI-S = Clinical Global 
Impression-Severity; CYP = cytochrome P450; ECG = electrocardiogram; IMP = investigational medicinal 
product; PGI-C = Patient Global Impression of Change; SAE = serious adverse event; WBC = white blood 
cell. 

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TABLE OF CONTENTS 
 
PROTOCOL VERSION 3.0 SUMMARY OF CHANGES TABLE .............................3 
TABLE OF CONTENTS ..................................................................................................6 
TABLE OF TABLES .........................................................................................................9 
TABLE OF FIGURES .......................................................................................................9 
1 
PROTOCOL SUMMARY .......................................................................................10 
1.1 
Synopsis .................................................................................................................10 
1.2 
Schema ..................................................................................................................13 
1.3 
Schedule of Activities ...........................................................................................15 
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 .......................................................................................................24 
4.1 
Overall Design ......................................................................................................24 
4.2 
Scientific Rationale for Trial Design ..................................................................26 
4.3 
Dosing Rationale ..................................................................................................26 
4.4 
Definition of Completed Subject ........................................................................27 
4.5 
End of Trial Definition ........................................................................................27 
5 
TRIAL POPULATION ............................................................................................27 
5.1 
Inclusion Criteria .................................................................................................27 
5.2 
Exclusion Criteria ................................................................................................28 
5.3 
Lifestyle Considerations ......................................................................................28 
5.3.1 
Meals and Dietary Restrictions .....................................................................28 
5.3.2 
Alcohol, Caffeine, and Tobacco Restrictions ...............................................29 
5.3.3 
Effects on Ability to Drive and Use Machinery...........................................29 
5.4 
Screen Failures .....................................................................................................29 
6 
TRIAL TREATMENTS ...........................................................................................29 
6.1 
Investigational Medicinal Product Administered .............................................29 
6.2 
Preparation/Handling/Storage/Accountability/Disposition .............................30 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................30 
6.4 
Trial Treatment Compliance ..............................................................................30 
6.5 
Prior and Concomitant Therapy ........................................................................31 
6.5.1 
Prior and Concomitant Medications ............................................................31 
6.5.2 
Rescue Medicine .............................................................................................32 
6.6 
Dose Modification ................................................................................................32 
6.7 
Intervention after the End of the Trial ..............................................................33 
7 
DISCONTINUATION OF TRIAL TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................33 
7.1 
Discontinuation of Entire Trial...........................................................................33 
7.2 
Discontinuation of Individual Site ......................................................................33 
7.3 
Individual Subject Discontinuation ....................................................................33 
7.4 
Procedures to Encourage Continued Trial Participation ................................35 

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7.5 
Lost to Follow up ..................................................................................................35 
8 
TRIAL ASSESSMENTS AND PROCEDURES ....................................................35 
8.1 
Screening/Baseline Assessments .........................................................................36 
8.2 
Efficacy Assessments ...........................................................................................36 
8.2.1 
Seizure Frequency and Type (eDiary) .........................................................36 
8.2.2 
Patient Global Impression of Change ..........................................................36 
8.2.3 
Clinical Global Impression-Severity Scale ..................................................37 
8.3 
Safety Assessments ...............................................................................................37 
8.3.1 
Physical and Neurological Examinations.....................................................37 
8.3.2 
Vital Sign Measurements ..............................................................................38 
8.3.3 
Electrocardiograms........................................................................................39 
8.3.4 
Clinical Safety Laboratory Assessments ......................................................39 
8.3.5 
Modified Clinical Institute Withdrawal Assessment Scale – 
Benzodiazepines .............................................................................................39 
8.3.6 
Suicidal Ideation and Behavior Risk Monitoring .......................................40 
8.4 
Adverse Events and Serious Adverse Events ....................................................40 
8.4.1 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................40 
8.4.2 
Method of Detecting AEs and SAEs .............................................................41 
8.4.3 
Follow-up of AEs and SAEs ..........................................................................41 
8.4.4 
Regulatory Reporting Requirements for SAEs ...........................................41 
8.4.5 
Pregnancy .......................................................................................................41 
8.4.6 
Adverse Events of Special Interest ...............................................................42 
8.5 
Treatment of Overdose ........................................................................................44 
8.6 
Pharmacokinetics .................................................................................................45 
8.6.1 
Blood Samples for CVL-865 Concentrations ..............................................45 
8.6.2 
Blood Samples for Anti-epileptic Drug Concentrations .............................45 
8.6.3 
Methods and Analysis ....................................................................................45 
8.7 
Pharmacodynamics ..............................................................................................45 
8.8 
Pharmacogenomics ..............................................................................................45 
8.9 
Health Economics.................................................................................................45 
9 
STATISTICAL CONSIDERATIONS ....................................................................45 
9.1 
Statistical Hypotheses ..........................................................................................45 
9.2 
Sample Size Determination .................................................................................45 
9.3 
Populations for Analyses .....................................................................................46 
9.4 
Statistical Analyses...............................................................................................46 
9.4.1 
Safety Analyses ...............................................................................................46 
9.4.2 
Exploratory Analyses.....................................................................................47 
9.4.3 
Other Analyses ...............................................................................................47 
9.5 
Interim Analyses ..................................................................................................47 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................48 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .........48 
10.1.1 
Regulatory and Ethical Considerations .......................................................48 
10.1.2 
Financial Disclosure .......................................................................................48 
10.1.3 
Informed Consent Process ............................................................................49 

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10.1.4 
Data Protection ...............................................................................................49 
10.1.5 
Dissemination of Clinical Trial Data ............................................................49 
10.1.6 
Data Quality Assurance .................................................................................50 
10.1.7 
Source Documents ..........................................................................................51 
10.1.8 
Trial and Site Closure ....................................................................................51 
10.1.9 
Publication Policy...........................................................................................52 
10.2 
Appendix 2: Clinical Laboratory Tests..............................................................52 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...........................................54 
10.3.1 
Definition of AE..............................................................................................54 
10.3.2 
Definition of SAE ...........................................................................................55 
10.3.3 
Recording and Follow-Up of AE and/or SAE .............................................56 
10.3.4 
Reporting of SAEs and AESIs ......................................................................58 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ...........................................................................................................59 
10.4.1 
Definitions .......................................................................................................59 
10.5 
Appendix 5: Inducers and Inhibitors of Cytochrome P450 3A .......................62 
10.6 
Appendix 6: Abbreviations .................................................................................63 
10.7 
Appendix 7: Protocol Amendment History .......................................................64 
11 REFERENCES .........................................................................................................66 
 

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TABLE OF TABLES 
Table 1 
Objectives and Endpoints .......................................................................11 
Table 2 
Schedule of Assessments - Double-blind Titration Phase and 
Maintenance Phase (Through Visit 12)..................................................16 
Table 3 
Schedule of Assessments - Maintenance Phase (Visits 13 Through 
15/ET Only), Taper Phase, and Post-treatment Follow-up Phase .......20 
Table 4 
Dosing Schedule .......................................................................................25 
Table 5 
Investigational Medicinal Product Administered .................................29 
Table 6 
Prohibited Concomitant Medications ....................................................32 
Table 7 
Management of Hematologic Abnormalities .........................................44 
Table 8 
Protocol-Required Safety Laboratory Assessments .............................53 
Table 9 
Definition of AE........................................................................................54 
Table 10 
Events Meeting the AE Definition ..........................................................54 
Table 11 
Definition of SAE .....................................................................................55 
Table 12 
Recording and Follow-Up of AE and/or SAE .......................................56 
Table 13 
Follow-Up of AEs and SAEs ...................................................................58 
Table 14 
SAE/AESI Reporting to the Sponsor of Designee via an Electronic 
Data Collection Tool ................................................................................58 
Table 15 
SAE/AESI Reporting to the Sponsor or Designee via Paper Form (if 
needed) ......................................................................................................59 
 
TABLE OF FIGURES 
Figure 1 
Trial Schematic ........................................................................................14 
 

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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 57-Week, Multicenter, Active-treatment, Open-label Extension Trial of 
CVL-865 as Adjunctive Therapy in Adults with Drug-Resistant Focal Onset Seizures 
Short Title: An Extension Trial of CVL-865 as Adjunctive Therapy in the Treatment of 
Focal Onset Seizures 
IND Number: 126,900 
EudraCT Number: 2019-004057-83 
Trial Phase: 2 
Treatment/Indication: Focal Onset Seizures 
Rationale: The broad therapeutic use of nonselective benzodiazepines (BZDs) in 
multiple indications clearly supports the therapeutic potential of γ-aminobutyric acid type 
A (GABAA) positive allosteric modulators (PAMs) with the potential to offer efficacy 
with fewer side effects.  
This 57-week, active-treatment, open-label extension trial is designed to assess the safety 
and tolerability of CVL-865 as adjunctive treatment in subjects with drug-resistant focal 
onset seizures. This trial is open to subjects who completed treatment with the 
investigational medicinal product (IMP) in the double-blind Phase 2 
Trial CVL-865-SZ-001 and who, in the opinion of the investigator, could potentially 
benefit from treatment with CVL-865. 
Objectives and Endpoints 
The objectives and endpoints of the trial are summarized in Table 1. 

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Table 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary: To assess the long-term safety and 
tolerability of CVL-865 as adjunctive therapy in 
subjects with focal onset seizures 
• 
Nature, frequency, and temporality of 
treatment-emergent AEs (nonserious and 
serious), including abuse-related AEs and 
AEs related to medication handling 
irregularities 
• 
Clinically significant changes in ECGs, 
vital sign measurements, clinical 
laboratory assessments, and physical and 
neurological examination results 
• 
Suicidality assessed using the C-SSRS 
• 
Withdrawal symptoms assessed using the 
mCIWA-B 
Exploratory: To assess the long-term efficacy of 
CVL-865 as adjunctive therapy in subjects with 
focal onset seizures 
• 
Focal onset seizure frequency per week 
over the Maintenance Phase 
• 
Seizure freedom 
• 
Seizure rate over time 
• 
PGI-C score at each trial visit 
• 
Change from Baseline in CGI-S score at 
each trial visit 
Exploratory: To evaluate the plasma exposure of 
CVL-865 
• 
Summary listing of CVL-865 
concentrations by dose and visit 
Abbreviations: AE = adverse event; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia-
Suicide Severity Rating Scale; ECG = electrocardiogram; mCIWA-B = Modified Clinical Institute 
Withdrawal Assessment – Benzodiazepines; PGI-C = Patient Global Impression of Change. 
Overall Design: 
This is a 57-week, active-treatment, open-label extension trial designed to assess the 
long-term safety and tolerability of CVL-865 as adjunctive therapy in subjects with focal 
onset seizures. Enrollment into the trial will consist of eligible subjects who completed 
the Maintenance Phase of Trial CVL-865-SZ-001. 
Eligible subjects will enter this trial directly after completing Visit 4 (end of Maintenance 
Phase) of Trial CVL-865-SZ-001. The efficacy and safety assessments from Visit 4 of 
Trial CVL-865-SZ-001 will serve as the baseline assessments for the open-label trial for 
any assessments that are not unique to the open-label trial. All subjects must provide 
informed consent to participate in the open-label trial before any baseline assessments 
that are unique to the open-label trial are performed.  
This trial is designed with a maximum duration of approximately 61 weeks during which 
the subjects will receive CVL-865. The trial consists of the following: 
• Up to 57-week Treatment Period consisting of the following: 

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○ 2-week double-blind Titration Phase 
○ 52-week Maintenance Phase 
○ 3-week Taper Phase 
• 4-week Follow-up Period 
Disclosure Statement: This is an open-label trial of the safety and tolerability of 
CVL-865 in subjects with focal onset seizures. To ensure that the treatment assignments 
in the Phase 2 double-blind Trial CVL-865-SZ-001 remain blinded for the subjects who 
rollover into this open-label trial, all subjects will be dispensed blinded CVL-865 tablets 
during the Titration Phase of this trial. 
Number of Subjects:  
The trial population will be derived from eligible subjects from the double-blind, 
proof-of-concept Trial CVL-865-SZ-001. Of the approximately150 subjects to be 
enrolled in Trial CVL-865-SZ-001, approximately 120 are expected to complete the trial 
and be eligible for enrollment in Trial CVL-865-SZ-002. 
Key Entry criteria:  
Men and women with a diagnosis of epilepsy with focal onset seizures who have 
completed the Maintenance Phase of Trial CVL-865-SZ-001 may be eligible for 
enrollment into this trial.  
Intervention Groups, Trial Treatment, and Duration: All subjects will receive 
CVL-865, administered orally BID during a 57-week Treatment Period. 
Statistical Methods 
Sample Size Estimation: The sample size is not based on statistical power considerations. 
The trial population will be derived from eligible subjects from the double-blind, 
proof-of-concept Trial CVL-865-SZ-001. - Approximately 120 subjects are expected to 
complete Trial CVL-865-SZ-001 and be eligible for enrollment in CVL-865-SZ-002.  
Safety Analyses: The safety analysis will be conducted on the Safety Set. The primary 
safety analysis is the frequency and severity of adverse events (AEs) during the 
Treatment Period. All AEs will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term. The incidence of treatment-emergent 
AEs (TEAEs) will include the following summaries: 
• TEAEs by severity 
• Drug-related TEAEs 

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• TEAEs with an outcome of death 
• Serious TEAEs 
• Discontinuations due to TEAEs  
• TEAEs potentially related to abuse as assessed through the active monitoring of 
adverse events related to potential abuse and AEs involving medication handling 
irregularities 
A TEAE for this study is defined as an AE that started after the first dose of IMP in the 
open-label trial or a previously reported AE that increased in intensity, became serious, 
trial drug-related, or resulted in death, discontinuation, interruption, of reduction of IMP 
after the first dose of IMP in the open-label trial.  
Other safety endpoints, including clinical laboratory assessments, vital sign 
measurements, ECGs, medication withdrawal symptoms assessed by the Modified 
Clinical Institute Withdrawal Assessment – Benzodiazepines total scores at the scheduled 
visits, and suicidality monitored during the trial using the Columbia-Suicide Severity 
Rating Scale, will be summarized with descriptive statistics. Baseline is defined as the 
last assessment prior to the initiation of IMP in CVL-865-SZ-002. Additional 
presentations may be conducted evaluating changes from the original trial baseline. These 
analyses will be detailed in the statistical analysis plan. 
Exploratory Analyses: Descriptive statistics will be provided for each efficacy endpoint 
and will be summarized at each trial visit using available data. Baseline is defined as the 
last assessment prior to the initiation of IMP in CVL-865-SZ-002. Additional 
presentations may be conducted evaluating changes from the original trial baseline. These 
analyses will be detailed in the statistical analysis plan. 
1.2 
Schema 

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Figure 1 
Trial Schematic 
 
 

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1.3 
Schedule of Activities 
Two schedules are included in this section. The Schedule of Assessments for the 
Double-blind Titration Phase and for the Maintenance Phase (through Visit 12) is 
provided in Table 2. The Schedule of Assessments for the subsequent visits during the 
Maintenance Phase (Visit 13 through Visit 15/Early Termination), for the Taper Phase, 
and for the Post-treatment Follow-up Phase is provided in Table 3. 

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Table 2 
Schedule of Assessments - Double-blind Titration Phase and Maintenance Phase (Through Visit 12) 
Trial Period/ 
Phases 
Double-blind 
Titration Phase  
(2 weeks) 
Maintenance Phase (52 weeks) 
Visits 2 through 12 
Visit/Contacta 
Visit 
1/BLb,c 
Contact 
Visit 2 
Contact 
Visit 3d 
Visit 4d 
Visit 5d 
Visit 6d 
Visit 7d 
Visit 8d 
Visit 9d 
Visit 10d Visit 11d 
Visit 
12d 
Day 
1 
8 
15 
29 
43 
71 
99 
127 
155 
183 
211 
239 
267 
295 
Week 
0 
1 
2 
4 
6 
10 
14 
18 
22 
26 
30 
34 
38 
42 
Window 
± 3 days 
Entrance and History 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign subject 
identification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of birth 
control methods 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
PGI-C 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
CGI-S 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 

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Trial Period/ 
Phases 
Double-blind 
Titration Phase  
(2 weeks) 
Maintenance Phase (52 weeks) 
Visits 2 through 12 
Visit/Contacta 
Visit 
1/BLb,c 
Contact 
Visit 2 
Contact 
Visit 3d 
Visit 4d 
Visit 5d 
Visit 6d 
Visit 7d 
Visit 8d 
Visit 9d 
Visit 10d Visit 11d 
Visit 
12d 
Day 
1 
8 
15 
29 
43 
71 
99 
127 
155 
183 
211 
239 
267 
295 
Week 
0 
1 
2 
4 
6 
10 
14 
18 
22 
26 
30 
34 
38 
42 
Window 
± 3 days 
Safety Assessments 
Physical/ 
neurological 
examinatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Vital sign 
measurements 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
C-SSRSf 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Prior/concomitant 
treatments including 
BZD useg 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Adverse event 
monitoringg 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Laboratory 
Safety laboratory 
blood sample 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety laboratory 
urine sample 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Urine pregnancy 
testh 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Trial Period/ 
Phases 
Double-blind 
Titration Phase  
(2 weeks) 
Maintenance Phase (52 weeks) 
Visits 2 through 12 
Visit/Contacta 
Visit 
1/BLb,c 
Contact 
Visit 2 
Contact 
Visit 3d 
Visit 4d 
Visit 5d 
Visit 6d 
Visit 7d 
Visit 8d 
Visit 9d 
Visit 10d Visit 11d 
Visit 
12d 
Day 
1 
8 
15 
29 
43 
71 
99 
127 
155 
183 
211 
239 
267 
295 
Week 
0 
1 
2 
4 
6 
10 
14 
18 
22 
26 
30 
34 
38 
42 
Window 
± 3 days 
Urine drug 
screeningi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
PK of CVL-865j 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Blood sample for 
PK of AEDsk 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Other 
IMP dispensing 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
IMP compliance 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AED compliance 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AED = antiepileptic drug; BL = baseline; BZD = benzodiazepine; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia-Suicide 
Severity Rating Scale; ECG = electrocardiogram; ICF = informed consent form; IMP = investigational medicinal product; PGI-C = Patient Global Impression of 
Change; PK = pharmacokinetics. 
a. 
Contact with subject via phone call, internet/web, or other acceptable means of communication to check on their status. 
b. Screening/Baseline for Trial CVL-865-SZ-002 occurs at Visit 1, which is the same day as Visit 4 in Trial CVL-865-SZ-001. Any assessments conducted for 
Visit 4 of Trial CVL-865-SZ-001 will be considered the baseline assessments for Visit 1 of Trial CVL-865-SZ-002. 
c. 
Individual sites may require subjects to have COVID-19 testing done prior to enrollment. COVID-19 testing may be performed after enrollment per the 
investigator’s discretion. 
d. 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. 

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e. 
The physical examination should include weight at all time points. Physical and/or neurological examinations can be done at any time point during the trial 
at the investigator’s discretion.  
f. 
The “Since Last Visit” C-SSRS form will be completed at all visits. 
g. Adverse events (serious and non-serious) and concomitant medications should be recorded from the time of signing the ICF through the subject’s last visit.  
h. 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. Monthly pregnancy tests will be required for all women of 
childbearing potential.  
i. 
The urine drug screen can be conducted at any time during the trial at the discretion of the investigator.  
j. 
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 5, 8, and 11. 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.  
k. One 5-mL sample for each adjunctive AED collected at Visits 5, 8, and 11. 
 

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Table 3 
Schedule of Assessments - Maintenance Phase (Visits 13 
Through 15/ET Only), Taper Phase, and Post-treatment 
Follow-up Phase 
Trial Period/ 
Phases 
Maintenance Phase (52 weeks) 
Visits 13 through 15/ET 
Taper Phase 
(3 weeks) 
Post-treatment 
Follow-up 
Visit/Contacta 
Visit 13b 
Visit 14b 
Visit 15/ETc Contact 
Contact 
Visit 
16b 
Contact 
Visit 17 
Day 
323 
351 
379 
386 
393 
400 
407 
428 
Week 
46 
50 
54 
55 
56 
57 
58 
~61 
Window 
± 3 days 
Entrance and History 
Review of birth 
control methods 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
Review eDiary 
including 
compliance with 
use of eDiary 
X 
X 
X 
X 
X 
X 
X 
X 
PGI-C 
 
 
X 
 
 
 
 
 
CGI-S 
 
 
X 
 
 
 
 
 
Safety Assessments 
Physical/ 
neurological 
examinationd 
 
 
X 
 
 
X 
 
 
ECG 
 
 
X 
 
 
X 
 
 
Vital sign 
measurements 
 
 
X 
 
 
X 
 
 
C-SSRSe 
 
 
X 
 
 
X 
 
X 
mCIWA-B 
 
 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
treatments 
including BZD usef 
---------------------------------------------------------------------------------------------------------------------------- 
Adverse event 
monitoringf 
---------------------------------------------------------------------------------------------------------------------------- 
Laboratory 
Safety laboratory 
blood sample 
X 
X 
X 
 
 
X 
 
X 
Safety laboratory 
urine sample 
 
 
X 
 
 
X 
 
 
Urine pregnancy 
testg 
X 
X 
X 
 
 
X 
 
 

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Trial Period/ 
Phases 
Maintenance Phase (52 weeks) 
Visits 13 through 15/ET 
Taper Phase 
(3 weeks) 
Post-treatment 
Follow-up 
Visit/Contacta 
Visit 13b 
Visit 14b 
Visit 15/ETc Contact 
Contact 
Visit 
16b 
Contact 
Visit 17 
Day 
323 
351 
379 
386 
393 
400 
407 
428 
Week 
46 
50 
54 
55 
56 
57 
58 
~61 
Window 
± 3 days 
Other 
IMP dispensing 
 
 
X 
 
 
 
 
 
Collect final eDiary 
device 
 
 
 
 
 
 
 
X 
IMP compliance 
assessment 
X 
X 
X 
X 
X 
X 
 
 
AED compliance 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AED = antiepileptic drug; BZD = benzodiazepine; CGI-S = Clinical Global Impression – 
Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = Early 
Termination; IMP = investigational medicinal product; mCIWA-B = Modified Clinical Institute 
Withdrawal Assessment – Benzodiazepines; PGI-C = Patient Global Impression of Change. 
a. 
Contact with subject via phone call, internet/web, or other acceptable means of communication to 
check on their status. 
b. 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. 
c. 
Subjects should begin the Taper Phase after they have completed treatment in the Maintenance Phase 
or at the time the decision is made to discontinue. All Taper Phase and Post-treatment Follow-up 
procedures should be performed as indicated. If a subject discontinues early and it is inadvisable for 
them to taper IMP (after agreement from medical monitor), the subject should complete the Visit 17 
assessments approximately 30 days following the last dose of IMP. 
d. The physical examination should include weight at all time points. Physical and/or neurological 
examinations can be done at any time point during the trial at the investigator’s discretion.  
e. 
The “Since Last Visit” C-SSRS form will be completed at all visits. 
f. 
Adverse events (serious and non-serious) and concomitant medications should be recorded from the 
time of signing the ICF through the subject’s last visit.  
g. 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. Monthly pregnancy tests will be required for all women of 
childbearing potential. 
 

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2 INTRODUCTION 
2.1 
Trial Rationale 
CVL-865 (formerly known as PF-06372865) is a potent ligand of the allosteric 
benzodiazepine (BZD) site of the γ-aminobutyric acid type A (GABAA) receptor, which 
is being developed for the treatment of epilepsy. The aim of this trial is to evaluate the 
long-term safety and tolerability of CVL-865 as adjunctive treatment of adult patients 
with drug-resistant focal onset seizures who completed the Maintenance Phase of 
Trial CVL-865-SZ-001. 
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 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 positive allosteric modulators (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-penetrable, partial PAM of α2, α3, and α5 subunit containing 
GABAA receptors, with minimal functional activity at α1 subunit-containing receptors, 
which are believed to mediate many adverse effects observed with BZDs. By reducing 
the α1 activity, CVL-865 has the potential to retain highly effective anticonvulsant 
activity, without the BZD-associated adverse effects.  
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 
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 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. 

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Currently, approximately 290 subjects have been administered CVL-865 in single doses 
ranging from 0.04 to 100 mg, and in multiple doses ranging from 2.5 mg to 42.5 mg 
twice daily (BID) administered for a total duration of up to 4 weeks. CVL-865 has been 
safe and well tolerated. 
CVL-865-SZ-001 is a 13-week, placebo-controlled, double-blind trial designed to assess 
the efficacy, safety, and tolerability profile of CVL-865 as adjunctive treatment in 
subjects with drug-resistant focal onset seizures. This 57-week, active-treatment, 
open-label extension trial is designed to assess the safety and tolerability of CVL-865 as 
adjunctive treatment in subjects with drug-resistant focal onset seizures. This trial is open 
to subjects who completed the Maintenance Phase in the double-blind 
Trial CVL-865-SZ-001 and who, in the opinion of the investigator, could potentially 
benefit from treatment with 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 trial by monitoring of 
hematologic parameters and requiring the use of appropriate contraception and regular 
pregnancy testing. 
In a Phase 2 trial using a photosensitivity model, 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 the 
lorazepam 2 mg active control.  
Based on available safety and efficacy data for CVL-865, the benefit-risk profile is 
favorable.  
More detailed information about the known and expected benefits and risks and expected 
adverse events (AEs) of CVL-865 are found in the Investigator’s Brochure. 
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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3 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary: To assess the long-term safety and 
tolerability of CVL-865 as adjunctive therapy in 
subjects with focal onset seizures 
• 
Nature, frequency, and temporality of 
treatment-emergent AEs (nonserious and 
serious), including abuse-related AEs and 
AEs related to medication handling 
irregularities 
• 
Clinically significant changes in ECGs, 
vital sign measurements, clinical 
laboratory assessments, and physical and 
neurological examination results 
• 
Suicidality assessed using the C-SSRS 
• 
Withdrawal symptoms assessed using the 
mCIWA-B 
Exploratory: To assess the long-term efficacy of 
CVL-865 as adjunctive therapy in subjects with 
focal onset seizures 
• 
Focal onset seizure frequency per week 
over the Maintenance Phase 
• 
Seizure freedom 
• 
Seizure rate over time 
• 
PGI-C score at each trial visit 
• 
Change from Baseline in CGI-S score at 
each trial visit 
Exploratory: To evaluate the plasma exposure of 
CVL-865 
• 
Summary listing of CVL-865 
concentrations by dose and visit 
Abbreviations: AE = adverse event; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia-
Suicide Severity Rating Scale; ECG = electrocardiogram; mCIWA-B = Modified Clinical Institute 
Withdrawal Assessment – Benzodiazepines; PGI-C = Patient Global Impression of Change. 
4 TRIAL DESIGN 
4.1 
Overall Design 
This is a 57-week, active-treatment, open-label extension trial designed to assess the 
long-term safety and tolerability of CVL-865 as adjunctive therapy in subjects with focal 
onset seizures. Enrollment into the trial will consist of eligible subjects who completed 
the Maintenance Phase of Trial CVL-865-SZ-001. 
Eligible subjects will enter this trial directly after completing Visit 4 (end of Maintenance 
Phase) of Trial CVL-865-SZ-001. The efficacy and safety assessments from Visit 4 of 
Trial CVL-865-SZ-001 will serve as the baseline assessments for the open-label trial for 
any assessments that are not unique to the open-label trial. All subjects must provide 
informed consent to participate in the open-label trial before any baseline assessments 
that are unique to the open-label trial are performed.  
This trial is designed with a maximum duration of approximately 61 weeks during which 
the subjects will receive CVL-865. The trial consists of the following: 
• Up to 57-week Treatment Period consisting of the following: 

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○ 2-week double-blind Titration Phase 
○ 52-week Maintenance Phase 
○ 3-week Taper Phase 
• 4-week Follow-up Period 
Following enrollment in Trial CVL-865-SZ-002, subjects will enter a 2-week 
double-blind Titration Phase. Based on the blinded treatment group subjects were 
assigned to in Trial CVL-865-SZ-001, the dose will be adjusted during the double-blind 
Titration Phase to a final dose of 25 mg BID as shown in Table 4. Subjects who 
completed the Maintenance Phase of Trial CVL-865-SZ-001 on a dose of 25 mg BID will 
remain on this dose (blinded) for the Titration Phase of Trial CVL-865-SZ-002.   
Subjects who terminate during the double-blind Titration Phase (before Day 15) should 
receive 3 weeks of IMP to complete the Taper Phase. Please refer to Section 7.3. 
Subjects will continue to receive treatment with CVL-865 25 mg BID throughout a 
52-week Maintenance Phase. However, this daily dose of CVL-865 can be reduced to 
17.5 mg BID to address tolerability issues upon investigator discretion. Following the 
Maintenance Phase, subjects will be tapered off investigational medicinal product (IMP) 
over 3 weeks. A summary of the dosing schedule is provided in Table 4.  
Table 4 
Dosing Schedule 
 
Double-blind Titration Phasea 
Maintenance 
Phasea 
Taper Phasea 
Day of Dose 
Initiation  
Day 1 
Day 8 
Day 15 
Day 
380 
Day 
387 
Day 
394 
Duration 
2 weeks 
52 weeks 
3 weeks 
Dose in Trial CVL-865-SZ-001 
Placebo 
5 mg BID 
12.5 mg BID 
25 mg BID 
17.5 mg 
BID 
10 mg 
BID 
5 mg 
BID 
CVL-865  
7.5 mg BID 
12.5 mg 
BID 
17.5 mg BID 
25 mg BID 
17.5 mg 
BID 
10 mg 
BID 
5 mg 
BID 
CVL-865 
25 mg BID 
25 mg BID 
25 mg BID 
25 mg BID 
17.5 mg 
BID 
10 mg 
BID 
5 mg 
BID 
Not applicableb 
17.5 mg BIDb 
10 mg 
BID 
5 mg 
BID 
2.5 mg 
BID 
Abbreviations: BID = twice daily; IMP = investigational medicinal product. 
a Quantity of IMP dispensed at each visit will accommodate ±3-day visit windows so subjects can remain 
on existing dose until next in-clinic visit. 
b Subjects who had their dose reduced to 17.5 mg BID due to tolerability reasons during the Maintenance 
Phase. 

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Subjects are to continue treatment with at least 1 and up to a maximum of 3 concurrent 
AEDs (as permitted; see Table 6 for prohibited medications). The type and dosage of the 
concurrent AEDs may be adjusted per investigator discretion to optimize seizure control 
and/or tolerability during the Treatment Period and/or Follow-up Period. 
Subjects will continue to record all seizures and the presence or absence of all seizure 
types experienced, in addition to recording the dosing with CVL-865 and AEDs and the 
use of seizure rescue medication in the electronic diary (eDiary) each day during the trial. 
Follow-up Period: 
Follow-up telephone contact will be performed 7±3 days after the last dose of IMP. A 
Post-treatment Follow-up Visit will be made approximately 4 weeks after last dose of 
IMP. 
4.2 
Scientific Rationale for Trial Design 
The open-label, long-term extension trial design is widely accepted as one that is 
appropriate for evaluating the safety and tolerability of a trial treatment over an extended 
trial period.  
The safety endpoints, including physical and neurological examinations, vital sign 
measurements, electrocardiograms (ECGs), laboratory evaluations, and AEs, are those 
commonly used to assess the safety and tolerability of trial treatments. The 
Columbia-Suicide Severity Rating Scale (C-SSRS) is commonly used for stringent 
monitoring of suicidality in clinical trials of neurological compounds (Posner et al, 2011).  
4.3 
Dosing Rationale 
The 25 mg BID dose of CVL-865 has been selected based on the first-in-human safety 
and tolerability data, the pharmacodynamic 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 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 25 mg BID dose is the top dose used in Trial CVL-865-SZ-001 and projected to fully 
test the therapeutic potential of CVL-865 as adjunctive therapy in the treatment of focal 
onset seizures. This provides the opportunity for all the subjects in 
Trial CVL-865-SZ-001 to be administered with the top dose in the trial, in an open-label 
fashion. At the 25 mg BID dose, 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 α2/3 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 α2 receptor occupancy within the brain, the 25 mg BID dosing regimen is 
projected to achieve steady-state exposure levels of CVL-865 within the range 
anticipated to produce approximately 80% receptor occupancy.  
4.4 
Definition of Completed Subject 
A subject is considered to have completed the trial if he/she has completed all phases of 
the trial including the last scheduled procedure (ie, Visit 17 assessments) as shown in the 
Schedules of Activities (Table 2 and Table 3). 
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. 
5 TRIAL POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
 
1. 
Subjects who completed treatment in Trial CVL-865-SZ-001 (ie, subjects who completed 
Visit 4 of Trial CVL-865-SZ-001). 
2. 
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 through 
30 days post last dose. 
A male subject with a pregnant or a nonpregnant partner of childbearing potential must agree 
to use a condom during treatment and until the end of relevant systemic exposure in the male 
subject for 94 days following the last dose with IMP.  
3. 
Subjects who are capable of giving signed informed consent as described in Section 10.1.3 
(Appendix 1) 
4. 
Subjects who are able, 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. 
Abbreviations: BID = twice daily; ICF = informed consent form 

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5.2 
Exclusion Criteria  
Subjects are excluded from participation in the trial if any of the following criteria apply: 
 
1. 
Subjects who, in the opinion of the investigator, medical monitor, or sponsor, should not 
participate in the trial. 
2. 
Subjects who, in the judgment of the investigator, experienced poor tolerability to the IMP 
during the double-blind trial or whose safety assessments resulted in new concerns that would 
suggest that the subject may not be appropriate for 57 weeks of treatment with CVL-865 in an 
extension trial. 
3. 
Subjects who experienced status epilepticus during Trial CVL-865-SZ-001. 
4. 
Subjects who have demonstrated substantial noncompliance to trial procedures in Trial 
CVL-865-SZ-001, based on the investigator’s judgement, would not be eligible for this trial. 
The medical monitor should be contacted if the investigator is unsure of a subject’s eligibility. 
5. 
Subjects who answer “yes” on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active 
Suicidal Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation 
with Specific Plan and Intent), OR 
Subjects who answer “yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, preparatory acts, or behavior), OR 
Subjects who, in the opinion of the investigator, present a serious risk of suicide. 
6. 
Subjects with any of the following abnormalities in clinical laboratory tests at Visit 1, as 
assessed by the central laboratory and confirmed by a single repeat measurement, if deemed 
necessary: 
• 
Females: Hemoglobin <10 g/dL; Males: hemoglobin <11 g/dL 
• 
White blood cell (WBC) count <3.0 × 109/L 
• 
Neutrophil count <2.0 × 109/L 
• 
Platelet count <150 × 109/L 
7. 
Subjects who would be likely to require the use of prohibited concomitant medications during 
the trial (as listed in Table 6).  
8. 
Female subjects who have a positive pregnancy test result. 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Subjects should adhere to their normal or prescribed dietary regimen during the trial, 
although subjects must refrain from ingesting preparations containing St. John’s Wort. 
Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus fruits 
(eg, Seville oranges, pomelos) from 7 days prior to the first dose of IMP until completion 
of Visit 17. 

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5.3.2 
Alcohol, Caffeine, and Tobacco Restrictions 
Subjects should adhere to their usual regimen of caffeine and tobacco, if applicable. As 
the potential for interactions between IMP and alcohol have not yet been evaluated, 
subjects are strongly discouraged from consuming alcohol for the duration of the trial.  
5.3.3 
Effects on Ability to Drive and Use Machinery 
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 subjects who consent to participate in this clinical trial but are deemed 
not eligible or withdraw consent prior to receiving IMP in Trial CVL-865-SZ-002, 
defined as any IMP taken after the ICF has been signed by the subject.  
Please refer to Section 7.3 for further guidance regarding subjects who sign the ICF but 
are deemed not eligible for Trial CVL-865-SZ-002. 
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 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) 
should not be rescreened. 
6 TRIAL TREATMENTS 
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 refers to a pharmaceutical form of 
any active substance or placebo being tested in this clinical trial and will be used to refer 
to the trial treatment in this protocol. 
6.1 
Investigational Medicinal Product Administered 
A summary of the IMP administered during this trial is presented in Table 5.  
Table 5 
Investigational Medicinal Product Administered 
Treatment 
CVL-865 25 mg BID 
CVL-865 17.5 mg BID 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strengths 
2.5 mg, 5 mg, and 7.5 mg 
2.5 mg, 5 mg, and 7.5 mg 
Route of Administration 
Oral 
Oral 

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Treatment 
CVL-865 25 mg BID 
CVL-865 17.5 mg BID 
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 blister packs with the appropriate combination of tablets necessary 
in order to achieve the required dose level. 
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.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label trial with all subjects assigned to treatment with CVL-865. To 
ensure that the treatment assignments in the Phase 2 double-blind trial CVL-865-SZ-001 
remain blinded for the subjects who rollover into the open-label trial, all subjects will be 
dispensed blinded CVL-865 tablets during the Titration Phase of this trial.  
6.4 
Trial Treatment Compliance 
All IMP will be dispensed by responsible trial personnel. Subjects will be counseled on 
the importance of taking the IMP as directed at each clinic visit and will be instructed to 
bring all used and unused blister cards to each clinic visit. Accountability and compliance 
(as assessed through self-reporting by the subject and by tablet count at each clinic visit) 
will be documented in the subject’s trial records. Deviation(s) from the prescribed dosage 
regimen should be recorded in the electronic case report form (eCRF). 
If poor compliance is encountered (eg, multiple missed doses resulting in <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 

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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. 
6.5 
Prior and 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 the time of signing the 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. 
Table 6 lists all medications prohibited during the trial, including exceptions where 
appropriate.  
Use of BZDs during trial is permitted except in cases specifically defined below.  

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Table 6 
Prohibited Concomitant Medications 
 
Prohibited Concomitant Medications 
1. 
Vigabatrin, unless administered to subject in Trial CVL-865-SZ-001  
2. 
Felbamate unless administered to subject in Trial CVL-865-SZ-001, with a stable dose for ≥49 days 
3. 
Moderate to strong inducers and inhibitors of CYP3A4 metabolism (see Section 10.5, Appendix 5).  
4. 
P-gp substrates with a narrow therapeutic index (eg, digoxin, dabigatran)  
5. 
BCRP substrate rosuvastatin 
6. 
Psychotropic agents including, but not limited to, the following: 
a) Antipsychotics 
b) Non-benzodiazepine anxiolytics, unless medically prescribed and used in a stable, 
consistent manner 
c) Non-benzodiazepine sleep medications  
1) Non-benzodiazepine sleep medications (ie, zolpidem, zaleplon, and eszopiclone) 
are permitted if medically prescribed and used no more than twice per week 
7. 
Drugs that can lower the seizure threshold: 
a) Tricyclic antidepressants and bupropion 
1) Other antidepressants may be included if medically prescribed and used in a 
stable, consistent manner 
b) Stimulants, eg, amphetamine, dextroamphetamine, and methylphenidate 
c) Other – baclofen, dalfampridine, tramadol, buspirone, lithium 
Abbreviations: BCRP = breast cancer resistance protein; CYP = cytochrome P450; P-gp = P-glycoprotein 
6.5.2 
Rescue Medicine 
All subjects who normally take BZDs for seizure rescue had an individualized Rescue 
Protocol approved by TESC in use during Trial CVL-865-SZ-001. This Rescue Protocol 
describes what rescue treatment can be administered in the event the subject requires a 
BZD. It also includes different scenarios that would prompt immediate medical attention. 
The rescue protocol will remain in place for this extension protocol. 
6.6 
Dose Modification 
The dose of CVL-865 will be titrated in a blinded manner for all subjects, as shown in 
Table 4.  
The daily dose of CVL-865 (25 mg BID) can be reduced to 17.5 mg BID to address 
tolerability issues upon investigator discretion, as described in Section 4.1. An associated 
AE must be recorded in the eCRF. 
A subject may temporarily interrupt IMP for the following reasons: 
• Adverse events 

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6.7 
Intervention after the End of the Trial 
At the end of the trial, all subjects will resume treatment with available AEDs at the 
discretion of and as determined by their physician. 
7 DISCONTINUATION OF TRIAL TREATMENT 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.  
Subjects should begin the Taper Phase at the time the decision is made to discontinue. All 
Taper Phase and Post-treatment Follow-up procedures should be performed as indicated 
in the Schedules of Assessments (Table 2 and Table 3). 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 17 should be conducted approximately 30 days following 
the last dose. 
For subjects who early terminate prior to Day 15 (prior to the Maintenance Phase), an 
alternate taper scheme may be used. This includes subjects who sign consent for CVL-
865-SZ-002 but who are then determined to not meet eligibility criteria. 
A subject will discontinue IMP for the reasons listed below: 
• Any of the following AESIs 

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○ Hemoglobin <8 g/dL  
○ WBC count <2.5 × 109/L 
○ Neutrophil count <1.5 × 109/L 
○ Platelet count <100 × 109/L 
• Female subjects who have a positive pregnancy test result during the trial 
• Withdrawal of consent 
• Investigator’s discretion (eg, including failure to comply with trial procedures or 
dosing) 
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). 

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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 
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. 
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 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 and Table 3). Protocol waivers or exemptions are not allowed. 

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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 and Table 3), is essential and required for trial conduct. 
8.1 
Screening/Baseline Assessments 
The timing for all screening/baseline assessments is provided in the Schedule of 
Assessments (Table 2 and Table 3). 
A review of all inclusion and exclusion criteria will occur at Visit 1 (screening/baseline 
visit) 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. As there may be a delay 
in obtaining all relevant assessments (eg, laboratory results) prior to subject enrollment in 
Trial CVL-865-SZ-002, if any data from assessments are obtained after enrollment and 
indicate the subject would not be eligible to continue in the extension trial, the medical 
monitor should be contacted.  
Subjects will continue to record the presence or absence of all seizure types experienced 
daily in the eDiary from Visit 1 through Visit 17 (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 benzodiazepines and dosing with CVL-865 
in the eDiary. 
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 benzodiazepine use will also be recorded in the diary.  
Seizure frequency and type will be assessed based on information recorded by the subject 
in the eDiary (see Section 8.1). 
8.2.2 
Patient Global Impression of Change 
The self-report measure Patient Global Impression of Change (PGI-C) 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 

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improved,’’ ‘‘minimally improved,’’ ‘‘no change,’’ ‘‘minimally worse,’’ ‘‘much worse,’’ 
or ‘‘very much worse.’’ 
8.2.3 
Clinical Global Impression-Severity Scale 
The Clinical Global Impression – Severity (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. 
8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of 
Assessments (Table 2 and Table 3).  
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 
• Blood pressure/heart rate, 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 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 enrolling into CVL-865-SZ-001) 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), 
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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 
• 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) 
• To the best of the subject’s and site personnel’s ability, 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.  
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. 
Any clinically relevant changes occurring during the trial will be recorded in the AE 
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8.3.3 
Electrocardiograms 
Electrocardiogram recordings will be obtained after the subject has been at rest for at 
least 5 minutes. Additional 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 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. 
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 and Table 3) 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.  
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 and Table 3). 
8.3.5 
Modified Clinical Institute Withdrawal Assessment Scale – 
Benzodiazepines 
The modified Clinical Institute Withdrawal Assessment Scale – 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 benzodiazepine 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.  

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8.3.6 
Suicidal Ideation and Behavior Risk Monitoring 
Suicidality will be monitored during the trial using the C-SSRS. This semi-structured 
interview was originally developed to evaluate the link between antidepressants and 
suicidal behavior and ideation in youth and adverse events 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. 
The “Since Last Visit” C-SSRS form will be completed at all visits. 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). 
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 until the follow-up visit 
(Visit 17 at Day 428) at the time points specified in the Schedule of Assessments (Table 2 
and Table 3). 
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 

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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). 
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 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 at Visit 17. At a minimum, 
monthly pregnancy tests will be completed throughout the trial for all women of 

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childbearing potential. During periods where monthly visits are not scheduled, female 
subjects can choose to visit the site for the test or complete the test via a remote option. 
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 
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 Food and Drug Administration 
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 

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○ 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 7.  
• Hemoglobin: females <10 g/dL; males <11 g/dL  
• 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 7: 
• Hemoglobin <8 g/dL 
• WBC count <2.5 × 109/L 
• Neutrophil count <1.5 × 109/L 
• Platelet count <100 × 109/L 

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Table 7 
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) >3 × upper limit of normal range (ULN) in combination with either an elevated 
total bilirubin >2 × 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 >3 × ULN and total bilirubin >2 × ULN 
• Treatment-emergent ALT or AST >3 × ULN in combination with clinical jaundice 
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). 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the eCRF. 

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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 and Table 3). 
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 and 
Table 3). 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 
pharmacokinetic (PK) plasma samples will be provided in a laboratory manual. All 
plasma samples 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 
Not applicable. 
8.8 
Pharmacogenomics 
Not applicable. 
8.9 
Health Economics 
Not applicable.  
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
There is no statistical hypothesis for this open-label trial. 
9.2 
Sample Size Determination 
The sample size is not based on statistical power considerations. The trial population will 
be derived from eligible subjects from the double-blind, proof-of-concept 

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Trial CVL-865-SZ001. Approximately 120 subjects are expected to complete 
Trial CVL-865-SZ-001 and be eligible for enrollment in Trial CVL-865-SZ-002.  
9.3 
Populations for Analyses 
The following data sets are defined for analysis: 
• Enrolled Set: comprises all subjects who consent to participate in the clinical trial (ie, 
sign the ICF for Trial CVL-865-SZ-002)  
• Safety Set: comprises all subjects that receive at least 1 dose of IMP in Trial 
CVL-865-SZ-002 
• Efficacy Set: comprises all subjects in the Safety Set who have at least 1 post-baseline 
efficacy evaluation 
9.4 
Statistical Analyses 
Descriptive statistical methods will be used to summarize the data from this trial. 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. 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.  
A statistical analysis plan (SAP) will be developed and finalized before database lock and 
will provide descriptions of the subject populations to be used in the analysis and 
procedures for addressing missing, unused, and spurious data. This section is a summary 
of the planned statistical analyses. 
9.4.1 
Safety Analyses 
The safety analysis will be conducted on the Safety Set. The primary safety analysis is 
the frequency and severity of AEs during the Treatment Period. All AEs will be coded 
according to MedDRA preferred term. The incidence of treatment-emergent AEs 
(TEAEs) will include the following summaries: 
• TEAEs by severity 
• Drug-related TEAEs 
• TEAEs with an outcome of death 
• Serious TEAEs 
• Discontinuations due to TEAEs  

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• TEAEs potentially related to abuse as assessed through the active monitoring of 
adverse events related to potential abuse and adverse events involving MHI 
A TEAE is defined as an AE that started after the first dose of IMP in the open-label trial 
or a previously reported AE that increased in intensity, became serious, trial drug-related, 
or resulted in death, discontinuation, interruption, of reduction of IMP after the first dose 
of IMP in the open-label trial.  
Other safety endpoints, 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, will be 
summarized with descriptive statistics. Baseline is defined as the last assessment prior to 
the initiation of IMP in CVL-865-SZ-002. Additional presentations may be conducted 
evaluating changes from the original trial baseline. These analyses will be detailed in the 
statistical analysis plan. 
9.4.2 
Exploratory Analyses 
Descriptive statistics will be provided for each efficacy endpoint and will be summarized 
at each trial visit using available data. Baseline is defined as the last assessment prior to 
the initiation of IMP in CVL-865-SZ-002. Additional presentations may be conducted 
evaluating changes from the original trial baseline. These analyses will be detailed in the 
statistical analysis plan. 
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. Any population PK analysis (if completed) will be 
presented separately from the main CSR. 
9.5 
Interim Analyses 
No interim analyses are planned. 

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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 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, Health Insurance Portability and Accountability Act of 1996 
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 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. 
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. 

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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). 
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. 

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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 reports 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. 
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: 
○ 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 

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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. 
10.2 Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 8 will be performed by the central laboratory. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5. 
Additional tests may be performed at any time during the trial as determined necessary by 
the investigator or required by local regulations. 
Urine (serum tests to confirm any positive urine test) pregnancy tests are required for 
women of childbearing potential (WOCBP) at the time points indicated in the Schedule 
of Assessments; however, a serum pregnancy test can be done anytime during the trial at 
the investigator’s discretion.  

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Table 8 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
Red Blood Cell Indices: 
Mean Corpuscular 
Hemoglobin 
Mean Corpuscular Volume 
%Reticulocytes 
White blood cell Count 
with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Blood urea 
nitrogen 
Potassium 
Aspartate 
Aminotransferase 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
Total Protein 
 
Glucose 
Calcium 
Alkaline 
phosphatase 
Chloride 
 
Bicarbonate 
 
 
 
Routine 
Urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Additional 
Required Tests  
Urine drug screen for illicit drugs 
Urine dipstick pregnancy test (at time points indicated in Schedules of Assessments 
and as needed for women of childbearing potential), followed by serum pregnancy 
test if urine dipstick test is positive. 
 
Investigators must document their review of each laboratory safety report and file 
appropriately. 
Laboratory results that could unblind the trial will not be reported to investigative sites or 
other blinded personnel until the trial has been unblinded. 

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10.3 Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
Table 9 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical trial subject, temporally 
associated with the use of trial treatment, whether or not considered related to the trial 
treatment. 
• 
NOTE: Signs and symptoms and/or abnormal laboratory test results indicating a common 
underlying pathology/diagnosis should be reported as a single AE.. 
Table 10 
Events Meeting the AE Definition 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific judgment 
of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after trial treatment administration even though it may 
have been present before the start of the trial. 
• 
Signs, symptoms, or the clinical manifestations of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical manifestations of a suspected overdose of either trial treatment 
or a concomitant medication.  
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments.  

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10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under trial, 
death due to progression of disease). 
Table 11 
Definition of SAE 
A SAE is defined as any untoward medical occurrence that, at any dose in the view of either the 
investigator or sponsor, results in any of the following outcomes: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in 
other situations such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, or blood dyscrasias. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 

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10.3.3 
Recording and Follow-Up of AE and/or SAE 
Table 12 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF.  
o 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status noted. All nonserious events (that are not considered 
AESIs) that are ongoing at the last scheduled contact will be recorded as ongoing on 
the eCRF. For any AE having been identified throughout the trial, during analysis, 
additional relevant medical history information may be requested by the sponsor to 
further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history and occupation). 
o 
If updated information (eg, resolved status) on SAE status becomes available after a 
subject’s last scheduled contact (up to last in-clinic visit for the entire trial), this must 
be reported to the sponsor according to the appropriate reporting procedures. The 
investigator will follow SAEs until the events are resolved, stabilized, or the subject is 
lost to follow-up or has died. Resolution means that the subject has returned to the 
baseline state of health and stabilized means that the investigator does not expect any 
further improvement or worsening of the subject’s condition. The investigator will 
continue to report any significant follow-up information to the sponsor up to the point 
the event has resolved or stabilized, or the subject is lost to follow-up, or has died. 
o 
Any new SAEs reported to the investigator that occur after the last scheduled contact 
and are determined by the investigator to be related to the use of the IMP, should be 
reported to the sponsor. This may include SAEs that are captured on follow-up 
telephone contact or at any other time point after the defined trial period. The 
investigator should follow SAEs identified after the defined trial period and continue 
to report any significant follow-up information to the sponsor until the events are 
resolved or stabilized, or the subject is lost to follow-up or has died. 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical records to 
the sponsor or designee in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
sponsor or designee. In this case, all subject identifiers, with the exception of the subject 
number, will be redacted on the copies of the medical records before submission to the sponsor 
or designee. 

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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the trial and 
assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
• 
The investigator will assess the relationship as either of the following: 
o 
Related: An AE will be considered “related” to the use of the IMP if there is evidence 
to suggest a reasonable possibility of a causal relationship between the IMP and the 
AE. 
o 
Not Related: An AE will be considered “not related” to the use of the IMP if there is 
no plausible causal relationship between the IMP and the AE.  
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to trial treatment administration will be 
considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 

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Table 13 
Follow-Up of AEs and SAEs 
Follow-Up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
If a subject dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide the sponsor or designee with a copy of any post-mortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours 
of receipt of the information. 
10.3.4 
Reporting of SAEs and AESIs 
Table 14 
SAE/AESI Reporting to the Sponsor of Designee via an 
Electronic Data Collection Tool 
SAE/AESI Reporting to the Sponsor or Designee via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE or AESI to the sponsor or designee will be the 
electronic data collection tool. 
• 
The site will enter the SAE/AESI data as soon as it becomes available within 24 hours of 
awareness. 
• 
If the electronic data collection tool is unavailable, then the site will use the paper SAE or AESI 
form (see next section). 
• 
After the trial is completed, the electronic data collection tool will be set to read-only to prevent 
the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE or AESI from a trial subject or receives updated data on 
a previously reported SAE or AESI after the electronic data collection tool has been taken off-
line, then the site can report this information on the paper SAE or AESI form (see next section) 
or to the sponsor or designee by telephone. 
• 
 

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Table 15 
SAE/AESI Reporting to the Sponsor or Designee via Paper Form 
(if needed) 
SAE Reporting to the Sponsor or Designee via Paper Form 
• 
If the electronic data collection tool is unavailable, then the site will use the paper SAE/AESI 
form. The SAE or AESI paper form should be used to electronically transmit this information 
to the sponsor or designee. 
• 
Contacts for electronic transmission of the paper SAE/AESI form are provided in the 
Operations Manual. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE or AESI data collection tool sent by overnight mail or 
courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the appropriate SAE or AESI form within the designated reporting time frames. 
• 
 
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 

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• 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 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. 
Collection of Pregnancy Information 
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.  
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 

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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: 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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10.6 Appendix 6: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AED 
Anti-epileptic drug 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
APMP 
Abuse Potential Monitoring Plan 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BZD 
Benzodiazepine 
CBC 
Complete blood count 
CGI-S 
Clinical Global Impression-Severity 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
ESAM 
Events Subject to Additional Monitoring 
EudraCT 
European Clinical Trials Database 
GABAA 
γ-aminobutyric acid type A 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
 
 
mCIWA-B 
Modified Clinical Institute Withdrawal Assessment–Benzodiazepines 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHI 
Medication handling irregularity 
MHP 
Mental Health Professional 
PAM 
Positive allosteric modulator 

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Abbreviation 
Definition 
PGI-C 
Patient Global Impression of Change 
PK 
Pharmacokinetic 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse event 
TESC 
The Epilepsy Study Consortium 
ULN 
Upper limit of normal range 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
10.7 Appendix 7: Protocol Amendment History 
Document History 
Document:  
Date (Day-Month-Year) 
Version 3.0 
14 Jul 2020 
Version 2.0 
26 Nov 2019 
Original Protocol Version 1.0 
30 Oct 2019 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents.  
Amendment: Protocol Version 2.0 (26 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. 
 

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Section # and Name 
Description of Change 
Brief Rationale 
1.2 Schema 
1.3 Schedule of 
Activities 
Changed Contact Only visits 
during Maintenance Phase to in-
clinic visits 
Scheduled additional safety 
laboratory blood samples during 
Maintenance Phase (ie, for visits 
that been Contact Only in 
original protocol) and at Post-
Treatment Follow-up in-clinic 
visit 
Reduced intervals between some 
Maintenance Phase visits such 
that interval between visits was 
not more than 4 weeks 
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 
added new AESI subsection 
Update relevant protocol section with new 
potential risk of bone marrow suppression 
and decrease in peripheral hematologic 
parameters 
8.3.2 Vital Sign 
Measurements 
Reworded paragraph about blood 
pressure measurement 
Simplification of vital signs collection 
procedure 
Table 9 Protocol-
Required Safety 
Laboratory 
Assessments 
Added chloride and bicarbonate 
Additional biochemistry labs for safety 
monitoring 
10.4 Appendix 4: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy Information 
Revision of definitions and 
language for pregnancy 
avoidance procedure 
Consistency with preceding double-blind 
protocol 
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
Reflect changes to visit numbers, visit 
timing, and visit types (ie, contact visits 
changed to in-clinic visits), due to changes 
to schedule of activities  
Correct errors in original protocol 
Abbreviations: AESI = adverse event of special interest; IMP = investigational medicinal product; WBC = 
white blood cell. 
 

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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. 
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. 
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 from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-
77. 
US Department of Health and Human Services (DHHS). Guidance for industry: 
Assessment of Abuse Potential of Drugs. Rockville, MD: Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER); January 2017. 
 
 

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CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR SIGNATURE 
PAGE 
A 57-WEEK, MULTICENTER, ACTIVE-TREATMENT, OPEN-
LABEL EXTENSION TRIAL OF CVL-865 AS ADJUNCTIVE 
THERAPY IN ADULTS WITH DRUG-RESISTANT FOCAL ONSET 
SEIZURES 
 
Protocol Number: CVL-865-SZ-002 
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 3.0: 14 Jul 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)