Clinical trial NCT04244175
Conditions: Seizures
Keywords: CVL-865 Anti-epileptic drugs (AEDs) Focal epilepsy γ-aminobutyric acid (GABA) Partial seizure PF-06372865 Darigabat
Sponsor: AbbVie
Start date: 2020-01-27; Completion date: 2024-05-21
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to learn if CVL-865, when taken regularly with other anti-seizure medicines, works to prevent seizures in adults with drug-resistant focal onset seizures. It will also learn about the safety of CVL-865.

The main question it aims to answer is whether CVL-865, when taken regularly with other anti-seizure medicines, lowers the number of seizures in those with a diagnosis of epilepsy with drug-resistant focal onset seizures.

This study has an 8-week Screening/Baseline Period, a 13-week Treatment Period (including a 2-week Titration Phase, an 8-week Maintenance Phase, and a 3-week Taper Phase), and a 4-week Safety Follow-Up Period.

Participants will take CVL-865 or a placebo twice a day during the 10-13 week Treatment Period, visit the clinic every few weeks for checkups, tests, and surveys, and fill out an e-Diary.

Detailed description:

Arms: arm 1: Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase. arm 2: CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase. arm 3: CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
Interventions: intervention 1: Placebo intervention 2: CVL-865
Intervention descriptions: intervention 1: Participants received CVL-865 matched placebo tablets orally twice a day (BID) during the Treatment Period. intervention 2: Participants received CVL-865 tablets orally twice a day (BID) up to the maximum dose of 7.5 mg BID or 25 mg BID during the Treatment Period.

Protocol documents:
Prot_000.pdf: 
 
 
Protocol CVL-865-SZ-001
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CLINICAL PROTOCOL 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP, MULTICENTER TRIAL OF CVL-865 AS 
ADJUNCTIVE THERAPY IN ADULTS WITH DRUG-RESISTANT 
FOCAL ONSET SEIZURES (REALIZE TRIAL) 
Protocol Number: CVL-865-SZ-001 
Compound Number: CVL-865 
Trial Phase: 2 
Short Title: A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in 
the Treatment of Focal Onset Seizures 
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 131 Dartmouth Street, Suite 502, Boston, MA 02116 
United States 
Regulatory Agency Identifier Number 
Regulatory Agency File 
Identifying # 
IND:  
126,900 
EudraCT 
2019-002576-14 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Version 4.0: 30 Jun 2020 
Version 3.0: 15 Nov 2019 
Version 2.0: 03 Oct 2019  
Original Version 1.0: 24 Jul 2019 
MEDICAL MONITOR NAME AND CONTACT INFORMATION IS PROVIDED IN 
THE TRIAL OPERATIONS MANUAL 
 
NCT04244175




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


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


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


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


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


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


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


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


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




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


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




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


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




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


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


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


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


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




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




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


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


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


 
 
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Abbreviations: AED = anti-epileptic drug; BMI = body mass index; CT = computed tomography; DBS = 
deep brain stimulator; EEG = electroencephalogram; ICF = informed consent form; ILAE = International 
League Against Epilepsy; IMP = investigational medicinal product; MRI = magnetic resonance imaging; 
RNS = responsive neurostimulator; TESC = The Epilepsy Study Consortium; VNS = vagus nerve 
stimulator 
5.2 
Exclusion Criteria
Subjects are excluded from the trial if any of the following criteria apply: 
 
Target Disease 
1. 
Subjects with (genetic) idiopathic generalized epilepsies or combined generalized and focal 
epilepsies, including a history of Lennox-Gastaut Syndrome. 
2. 
Subjects with only focal aware seizures without a motor component. 
3. 
Subjects with a history of seizures over the past 12 months that occur at such a high frequency 
they cannot be counted (eg, repetitive seizures, cluster seizures). 
4. 
Subjects with a history of psychogenic non-epileptic seizures within the year prior to signing 
the ICF. 
5. 
Subjects with a history of status epilepticus within 5 years prior to signing the ICF. 
6. 
Subjects with a history of neurosurgery for seizures less than 1 year prior to signing the ICF, 
or radiosurgery less than 2 years prior to signing the ICF. 
Medical History and Concurrent Diseases 
7. 
 
Subjects with a current history of significant cardiovascular, pulmonary, gastrointestinal, 
renal, hepatic, metabolic, hematological, immunological, or neurological (excluding focal 
onset epilepsy) disease that, in the opinion of the investigator or medical monitor, could 
compromise either subject safety or the results of the trial. In addition, subjects with a 
psychiatric illness of sufficient severity as to make them inappropriate for the trial are 
excluded. 
Medical conditions that are minor or well-controlled may be considered acceptable if the 
condition does not expose the subject to an undue risk of a significant AE or interfere with the 
assessments of safety or efficacy during the course of the trial. The medical monitor should be 
contacted in any instance where the investigator is uncertain regarding the stability of a 
subject’s medical conditions(s) and the potential impact of the condition(s) on trial 
participation. 
8. 
Subjects with an active CNS infection, demyelinating disease, degenerative neurological 
disease or any CNS disease deemed to be progressive during the course of the trial that may 
confound the interpretation of the trial results. 
9. 
Subjects with a history of substance or alcohol-use disorder (excluding nicotine; DSM-5 
criteria) within 2 years prior to signing the ICF. 
10. 
Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation 
with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting 
criteria for this C-SSRS Item 4 occurred within the last 6 months, OR  
Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation 
with Specific Plan and Intent) and whose most recent episode meeting criteria for this C-
SSRS Item 5 occurred within the last 6 months OR  
 






 
 
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5.3.3 
Effects on Ability to Drive and Use Machines
The effect of CVL-865 on the ability to drive and use machines has not been 
systematically evaluated.  
5.4
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are not subsequently randomly assigned to treatment in the trial. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure subjects to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) may 
be rescreened after consultation with the medical monitor. Rescreened subjects should 
receive a unique subject number for each screening. 
If the subject fails screening due only to safety laboratory results, the Investigator may, at 
their discretion, decide to repeat the safety laboratory tests and perform additional tests as 
appropriate. In this case, no other screening procedures need to be repeated, as long as the 
procedures stay within the protocol-specified timelines. 
If a subject requires a change in AED dose, type or number of AEDs, or a change in the 
settings on their VNS, DBS, or RNS, the subject may be rescreened with medical monitor 
approval at a time when they have been a stable dose and/or setting for a period of a least 
4 weeks. 
6 TRIAL TREATMENT 
Trial treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a trial subject according to 
the trial protocol. Investigational medicinal product (IMP) refers to a pharmaceutical 
form of any active substance or placebo being tested in this clinical trial. 
 


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


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


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






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


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


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


 
 
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8.1 
Screening and Baseline Assessments 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Assessments (Table 2). 
As part of the screening procedures, a head magnetic resonance imaging or computed 
tomography scan will be completed to demonstrate no progressive structural abnormality, 
unless the procedure has been performed within 10 years prior to signing the ICF. This 
procedure, if necessary, should be conducted as soon as possible during the 
Screening/Baseline Period (per local guidelines) with the report available prior to 
randomization. 
Subjects will be dispensed an electronic diary (eDiary) and be trained on its use at the 
screening visit. The presence or absence of all seizure types experienced by each subject 
will be recorded daily in the diary from the Screening Visit through Visit 6 (end of 
follow-up period). Site personnel should classify the seizure type based upon the 
description provided by the subject in the eDiary and, if needed, via further discussion 
with the subject. If a new seizure type occurs during the trial, the seizure category will be 
evaluated by the investigator and, if confirmed to be new, and not reported previously, it 
will be submitted to TESC for review. If seizures do not occur on any given day, lack of 
seizures is also recorded. Subjects will also record any use of BZDs.  
As described in Section 5.1, a minimum of 8 focal onset (as defined in the 2017 ILAE 
Classification of Seizures [Fisher et al, 2017]), focal aware (except subjects with only 
focal aware seizures without a motor component), focal impaired awareness, or focal to 
bilateral tonic-clonic seizures during the 8-week Baseline Period with no 21-day period 
free of any of these seizure types should be confirmed by site personnel in order for the 
subject to be eligible for the trial. 
A medical bracelet with subject and trial information will be dispensed at Visit 1.  
8.2 
Efficacy Assessments 
8.2.1 
Seizure Frequency and Type (eDiary) 
Subjects will record details regarding their seizures (frequency and type) in an eDiary. 
Any BZD use will also be recorded in the diary.  
Seizure frequency and type will be assessed based on information recorded by the subject 
in the eDiary (see Section 8.1). 
 


 
 
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8.2.2 
Patient’s Global Impression of Change 
The self-report measure Patient’s Global Impression of Change (PGIC) reflects a 
patient’s belief about the efficacy of treatment. It is a 7-point scale depicting a patient’s 
rating of overall improvement. Patients rate their change as “very much improved,” 
“much improved,” “minimally improved,” “no change,” “minimally worse,” “much 
worse,” or ‘‘very much worse.” 
8.2.3 
Clinical Global Impression-Severity of Symptoms Scale 
The CGI-S is an observer-rated scale that will be used to measure symptom severity. It is 
important to note that the observer or rater will provide their assessment of the subject’s 
symptoms at the time of the current visit. 
To perform this assessment, the investigator (or designee) will answer the following 
question: “Considering your total clinical experience with this particular population, how 
ill is the subject at this time?” Response choices are 0 = not assessed; 1 = normal, not at 
all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely 
ill; and 7 = among the most extremely ill subjects. 
8.2.4 
Clinical Global Impression-Improvement Scale 
The CGI-I is an observer-rated scale that will be used to measure the subject’s symptom 
severity compared with before initiation of treatment with IMP. It is important to note 
that the observer or rater will provide their assessment of the subject’s current level of 
symptoms compared with their symptoms at baseline (Visit 1).   
The investigator (or designee) will rate the subject’s change from baseline in symptom 
severity (as related to seizure frequency and severity) using the following response 
choices: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally 
improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much 
worse. 
8.2.5 
Quality of Life in Epilepsy – 31 
The Quality of Life in Epilepsy – 31 (QOLIE-31) was developed in cooperation with 
professional postgraduate services, a division of Physicians World Communications 
Group and the QOLIE Development Group. The 31-item QOLIE-31 (Version 1.0) has 
been derived from the longer QOLIE-89 (Rausch & Crandall, 1982; Cramer et al, 1998). 
The QOLIE-31 contains 7 multi-item scales that tap the following health concepts: 
emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure 
worry, medication effects, and overall quality of life. A QOLIE-31 overall score is 
obtained using a weighted average of the multi-item scale scores. The QOLIE-31 also 
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8.2.6 
Health Utilities Index 
The Health Utilities Index (HUI) is a rating scale used to measure general health status 
and health-related quality of life. The HUI questionnaires are designed to map onto 2 
classification systems, HUI-2 and HUI-3, capable of measuring 24,000 and 972,000 
unique health states, respectively. The HUI classifications measure a range of health 
domains with examples including sensation, mobility, pain, cognition, ambulation, and 
emotion (Horsman et al, 2003). 
8.3 
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of 
Assessments (Table 2).  
For the assessments described below, when multiple procedures are scheduled on the 
same visit, the following chronology of events should be adhered to, where possible: 
 ECGs, obtain prior to vital sign measurements 
 Vital sign measurements, obtain prior to procurement of blood specimens 
 Blood specimen collection 
 Other procedures: all other procedures may be obtained before or after blood 
specimen collection 
8.3.1 
Physical and Neurological Examinations 
A complete physical examination will consist of measurement of height (screening only) 
and weight and a review of the following body systems: head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, gastrointestinal, genitourinary, and 
musculoskeletal systems. If the investigator/designee is unable to perform a genitourinary 
examination, special attention will be given to the genitourinary medical history. A prior 
record (within 12 months) of a recent genitourinary examination from a gynecologist or 
family doctor can substitute for a genitourinary examination.  
A full neurological examination will include an assessment of the subject’s mental status 
(level of consciousness, orientation, speech, memory, etc.), cranial nerves, motor (muscle 
appearance, tone, strength and reflexes), sensation (including Romberg sign), 
coordination, and gait. 
Height will be measured at screening only.  
The following guidelines will aid in the standardization of body weight measurements: 
 The same scale should be used to weigh a given subject each time, if possible 
 
 
 
 
 
 


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


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


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


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


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


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


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


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


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


 
 
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Therefore, approximately 214 subjects will be screened to achieve 150 subjects randomly 
assigned to treatment and 120 evaluable subjects for an estimated total of 40 evaluable 
subjects per treatment group. 
In the event of higher than anticipated early terminations due to COVID-19 or other 
reasons, Cerevel may extend enrollment in order to maintain the planned statistical 
power. 
9.3 
Populations for Analyses 
The following data sets are defined for analysis: 
Screen Failures (SFs): comprises all subjects who consent to participate in the clinical 
trial but are not subsequently randomly assigned to treatment in the trial.   
Intent-to-Treat (ITT): comprises all randomized subjects 
Full Analysis Set (FAS): comprises all randomized subjects who receive at least 1 dose of 
IMP
Modified ITT (mITT) Set: comprises all randomized subjects who receive at least 1 dose 
of IMP and have at least 1 entry in the seizure diary. 
9.4
Statistical Analyses 
Descriptive statistical methods will be used to summarize the data from this study, with 
statistical testing performed for the efficacy endpoints. Unless stated otherwise, the term 
“descriptive statistics” refers to number of subjects (n), mean, median, standard 
deviation, minimum, and maximum for continuous data, and frequencies and percentages 
for categorical data. Statistical testing, if performed, will be 2-sided and will be 
performed using a significance (alpha) level of 0.1. All available data for enrolled 
subjects will be listed by subject. Unless otherwise noted, the data will be sorted first by 
subject number and then by date within each subject number.  
All statistical analyses will be conducted with the SAS® System, version 9.4 or higher.  
The remainder of this section is a summary of the planned statistical analyses of the 
primary and secondary endpoints as well as a description of planned safety analyses. Full 
details of these analyses will be included in the statistical analysis plan (SAP). The SAP 
will be developed and finalized before database lock and will describe the subject 
populations to be included in the analyses, and procedures for accounting for missing, 
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9.4.1 
Efficacy Analyses 
Seizure frequency is defined as the total number of focal onset seizures over the treatment 
period of interest divided by the total number of days with no missing seizure counts in 
the corresponding period multiplied by 7.   
The primary efficacy endpoint is the Rratio over the Maintenance Phase. This is 
calculated as Rratio=(T B)/(T B)
 where T represents the seizure frequency rate 
per week in the Maintenance Phase and B represents the seizure frequency rate per week 
in the Baseline Period. The Rratio is between -100 and 100. Negative values will indicate 
reduction in seizure rate and positive values indicate increase in seizure rate during 
treatment. 
Values of Rratio will be analyzed for the mITT population using an analysis of 
covariance model, including treatment and the baseline seizure frequency per week as a 
covariate. This estimand will include response data that occur before discontinuation of 
treatment. The differences between the treatment groups will be based on the least square 
mean (LSMean) difference between each CVL-865 group and placebo. A separate 
comparison of the combined CVL-865 groups and placebo may be conducted. The 
corresponding 95% confidence interval (CI) will be presented. Sensitivity analyses will 
be conducted by including all available data (de facto estimand). 
A key secondary efficacy endpoint is the change from baseline in focal onset seizure 
frequency per week over the Maintenance Phase. These data will be log-transformed 
log-transformed values will be analyzed using an analysis of covariance model, including 
treatment as a factor and the log-transformed baseline focal onset seizure frequency per 
week as a covariate. The differences between the treatment groups will be based on the 
LSMean difference between each CVL-865 group and placebo. The percent reduction 
relative to placebo will be constructed by exponentiating the LSMean difference between 
each CVL-865 treatment group and placebo using the following formula: 
%Reduction/Placebo = 100 exp
exp(
)
exp
1
 
The corresponding 95% CI will be calculated. A secondary analysis of this endpoint will 
be conducted using a Poisson Regression model on the untransformed data. 
An additional key secondary endpoint is the 50% responder rate, defined as the 
percentage of subjects with at least a 50% reduction in the Maintenance Phase focal onset 
seizure frequency relative to the Baseline Period. This key secondary endpoint will be 
analyzed for the mITT population using a logistic regression model with effects for 
treatment. Odds ratios representing the odds of being a responder compared with placebo 
will be constructed for each CVL-865 treatment group. Subjects with missing or 
incomplete seizure information will be treated as non-responders for this analysis. 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
 


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


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


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


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


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


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


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


















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


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


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


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


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


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


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


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




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


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


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


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

SAP_001.pdf: 
 
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STATISTICAL ANALYSIS PLAN 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL 
GROUP, MULTICENTER TRIAL OF CVL-865 AS ADJUNCTIVE THERAPY IN 
ADULTS WITH DRUG-RESISTANT FOCAL ONSET SEIZURES (REALIZE TRIAL) 
Protocol Number: CVL-865-SZ-001 
Compound: Darigabat (CVL-865) 
Trial Phase: 2 
Short Title: A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the 
Treatment of Focal Onset Seizures 
Sponsor Name: Cerevel Therapeutics, LLC 
Protocol Version: 
Version 4.0:  30 Jun 2020 
 
 
Version 3.0:  15 Nov 2019 
 
Version 2.0:  03 Oct 2019 
 
Original Version 1.0:  24 Jul 2019 
Analysis Plan Version: 
Final 1.0: 17 July 2024 
 
 
 
 
 
 
NCT04244175


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STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL
specifications. 
Prepared by:
PharPoint Research, Inc.
Date
Reviewed by: 
PharPoint Research, Inc.
Date
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 




 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................................2 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................9 
1. 
INTRODUCTION ......................................................................................................10 
1.1. 
Study Overview ..........................................................................................................10 
1.2. 
Sample Size Considerations .......................................................................................11 
1.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................12 
1.3.1. 
Subject Assignment to Treatment ...............................................................................12 
1.3.2. 
Blinding ......................................................................................................................12 
1.4. 
Treatment Period ........................................................................................................12 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................14 
3. 
KEY ASSESSMENTS AND DERIVATIONS ..........................................................16 
3.1. 
Efficacy Assessments .................................................................................................16 
3.1.1. 
Seizure Frequency and Type (eDiary) ........................................................................16 
3.1.2. 
 ......................................................................16 
3.1.3. 
Clinical Global Impression-Severity of Symptoms Scale ..........................................16 
3.1.4. 
Clinical Global Impression-Improvement Scale ........................................................16 
3.1.5. 
Quality of Life in Epilepsy  31 .................................................................................17 
3.1.6. 
Health Utilities Index ..................................................................................................17 
3.2. 
Safety Assessments .....................................................................................................17 
3.2.1. 
Adverse Event (AE) ....................................................................................................17 
3.2.1.1. 
Treatment-emergent Adverse Event (TEAE) .............................................................17 
3.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................18 
3.2.1.3. 
Adverse Events of Special Interest .............................................................................18 
3.2.2. 
Clinical Safety Laboratory Assessments ....................................................................18 
3.2.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................18 
3.2.4. 
Vital Signs ..................................................................................................................19 
3.2.5. 
Electrocardiograms .....................................................................................................19 
3.2.6. 
Modified Clinical Institute Withdrawal Assessment  Benzodiazepines ...................19 
 
 
 
 
 
 
 
 
 
 
 


 
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3.2.7. 
Concomitant Medications and Non-Drug Therapy/Procedures .................................19 
3.2.8. 
Rescue Medicine .........................................................................................................20 
3.2.9. 
Physical and Neurological Examinations ...................................................................20 
3.3. 
Pharmacokinetics ........................................................................................................20 
4. 
DATA CONVENTIONS AND VISIT WINDOWS ..................................................21 
4.1. 
Data Conventions ........................................................................................................21 
4.1.1. 
Age ..............................................................................................................................21 
4.1.2. 
Day 1 ...........................................................................................................................21 
4.1.3. 
Study Day of an Event ................................................................................................21 
4.1.4. 
Days on Study .............................................................................................................21 
4.1.5. 
Days on IMP ...............................................................................................................21 
4.1.6. 
Baseline Value ............................................................................................................21 
4.1.7. 
Change from Baseline .................................................................................................21 
4.1.8. 
Last Dose of IMP ........................................................................................................21 
4.1.9. 
Average Daily Dose by Period ...................................................................................22 
4.1.10. 
Compliance with Study Drug .....................................................................................22 
4.1.11. 
Handling of Incomplete or Missing Dates Associated with an Event ........................22 
4.1.12. 
Handling of Alphanumeric Data .................................................................................23 
4.2. 
Analysis Periods .........................................................................................................23 
4.3. 
Visit Windows ............................................................................................................24 
5. 
STATISTICAL ANALYSIS METHODS ..................................................................27 
5.1. 
GENERAL CONSIDERATIONS ..............................................................................27 
5.2. 
Populations for Analyses ............................................................................................27 
5.3. 
Statistical Hypotheses .................................................................................................28 
5.4. 
Multiplicity Adjustment..............................................................................................28 
5.5. 
Strata and Covariates ..................................................................................................28 
5.6. 
Subject Disposition, Demographic and Baseline Characteristics ...............................28 
5.6.1. 
Medical History ..........................................................................................................28 
5.6.2. 
History of Epilepsy .....................................................................................................29 
5.7. 
Exposure to Treatment ................................................................................................29 
5.7.1. 
eDiary compliance ......................................................................................................29 
 
 
 
 
 
 


 
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5.8. 
Primary Efficacy Analysis ..........................................................................................30 
5.8.1. 
Derivation of Primary Efficacy Endpoint ...................................................................30 
5.8.2. 
Primary Estimand .......................................................................................................30 
5.8.3. 
Main Analytical Approach .........................................................................................30 
5.8.4. 
Sensitivity Analyses ....................................................................................................31 
5.8.4.1. 
Treatment Effect based on Actual Treatment Received .............................................31 
5.8.4.2. 
Impact of Low eDiary Entry Compliance ..................................................................31 
5.8.4.3. 
Impact of Discontinuation Potentially Related to Treatment .....................................31 
5.8.5. 
Subgroup Analyses .....................................................................................................32 
5.9. 
Key Secondary Efficacy Analyses ..............................................................................32 
5.9.1. 
Derivation of Key Secondary Efficacy Endpoints ......................................................32 
5.9.1.1. 
Change in Log-Transformed Seizure Frequency from Baseline ................................32 
5.9.1.2. 
50% Responder ...........................................................................................................32 
5.9.2. 
First Key Secondary Estimand ...................................................................................33 
5.9.3. 
Main Analytical Approach for First Key Secondary Endpoint ..................................33 
5.9.4. 
Sensitivity Analyses ....................................................................................................34 
5.9.5. 
Subgroup Analysis ......................................................................................................34 
5.9.6. 
Supplemental Analysis ...............................................................................................34 
5.10. 
Second Key Secondary Efficacy Analysis .................................................................34 
5.10.1. 
Second Key Secondary Estimand ...............................................................................34 
5.10.2. 
Main Analytical Approach for Second Key Secondary Endpoint ..............................35 
5.10.3. 
Sensitivity Analyses ....................................................................................................35 
5.11. 
Other Efficacy Analyses .............................................................................................35 
5.11.1. 
Other Secondary Efficacy Endpoints ..........................................................................35 
5.12. 
Additional Exploratory Analyses ...............................................................................37 
5.13. 
Interim and Final Analysis..........................................................................................37 
5.14. 
Safety Analyses ..........................................................................................................37 
5.14.1. 
Adverse Events ...........................................................................................................37 
5.14.2. 
Concomitant Medications and Non-Drug Therapy/Procedures .................................38 
5.14.2.1. 
Non-AED Concomitant Medications and Non-Drug Therapy/Procedures ................38 
5.14.2.2. 
Concomitant AED Medication and Therapy/Procedures ...........................................38 
 
 
 
 
 
 


 
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5.14.3. 
Clinical Laboratory Assessments ...............................................................................38 
5.14.4. 
Vital Signs ..................................................................................................................39 
5.14.5. 
Electrocardiograms (ECGs) ........................................................................................40 
5.14.6. 
Physical and Neurological Examinations ...................................................................41 
5.14.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................41 
5.14.8. 
Modified Clinical Institute Withdrawal Assessment  Benzodiazepines 
(mCIWA-B) ................................................................................................................41 
5.15. 
Pharmacokinetics ........................................................................................................41 
5.15.1. 
Pharmacokinetic Data Analysis ..................................................................................41 
5.16. 
Protocol Deviations ....................................................................................................42 
6. 
CHANGES IN THE PLANNED ANALYSES ..........................................................43 
7. 
REVISION HISTORY ...............................................................................................44 
8. 
REFERENCES ...........................................................................................................45 
9. 
APPENDICES ............................................................................................................46 
9.1. 
Schedule of Assessments ............................................................................................46 
9.2. 
Quality of Life in Epilepsy  31 (QOLIE-31) ............................................................53 
9.3. 
Health Utilities Index (HUI) .......................................................................................59 
9.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation and 
Suicidal Behavior Scores ............................................................................................71 
9.5. 
MNAR Cases Identified Prior to Database Lock .......................................................73 
9.6. 
CTCAE Based Laboratory Test Results Grading Specifications ...............................74 
9.7. 
Programming Conventions .........................................................................................98 
9.8. 
Abbreviations ............................................................................................................100 
 
 
 
 
 
 
 
 


 
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LIST OF TABLES 
Table 1: 
Dosing Schedule .........................................................................................................13 
Table 2: 
Objectives and Endpoints ...........................................................................................14 
Table 3: 
Definition of Analysis Periods for Seizure Frequency and Average Daily 
Dose Data ....................................................................................................................24 
Table 4: 
Visit Windows for Early Termination and Unscheduled Visits - ECGs and 
Vital Signs ..................................................................................................................25 
Table 5: 
Visit Windows for Early Termination and Unscheduled Visits - Safety Labs 
and C-SSRS ................................................................................................................25 
Table 6: 
Visit Windows for Early Termination and Unscheduled Visits  CGI-S ...................25 
Table 7: 
Visit Windows for Early Termination and Unscheduled Visits  PGIC and 
CGI-I ...........................................................................................................................26 
Table 8: 
Visit Windows for Early Termination and Unscheduled Visits  QOLIE-31 
and HUI ......................................................................................................................26 
Table 9: 
Visit Windows for Early Terminations and Unscheduled  mCIWA-B ....................26 
Table 10: Populations for Analysis .............................................................................................27 
Table 11: Summary of Other Secondary Efficacy Analyses ......................................................36 
Table 12: Schedule of Assessments ............................................................................................47 
Table 13: QOLIE-31 Scoring Form ............................................................................................53 
Table 14: Formula for Calculating QOLIE-31 Overall Score ....................................................58 
Table 15: HUI-3 Vision Attribute Level Decision Table ...........................................................64 
Table 16: HUI-3 Hearing Attribute Level Decision Table .........................................................65 
Table 17: HUI-3 Speech Attribute Level Decision Table ..........................................................65 
Table 18: HUI-3 Cognition Attribute Level Decision Table ......................................................65 
Table 19: Ambulation, Dexterity, Emotion and Pain Attribute Level Decision Table ...............66 
Table 20: HUI-2 Sensation Attribute Level Decision Table ......................................................67 
Table 21: HUI-2 Mobility Attribute Level Decision Table ........................................................67 
Table 22: HUI-2 Cognition Attribute Level Decision Table ......................................................68 
Table 23: HUI-2 Self-Care, Emotion, and Pain Attributes Level Decision Table .....................68 
Table 24: HUI-2 Fertility Attributes Level Decision Table ........................................................68 
 
 
 
 
 
 
 
 


 
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LIST OF FIGURES 
Figure 1: 
Trial Schematic ...........................................................................................................11 
 
 
 
 
 
 
 


 
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1. 
INTRODUCTION 
This document describes the statistical methods and data presentations planned for the analysis 
of the efficacy and safety data from Protocol CVL-865-SZ-001. Background information is 
provided for the study designs and objectives. Further details of study conduct, and data 
collection are provided in the study protocol and electronic case report forms (eCRFs) 
1.1. 
Study Overview 
This is a double-blind, parallel-group, placebo-controlled trial with subjects randomized to 1 of 
the following 3 arms in a 1:1:1 ratio: 
 CVL-865 25 mg BID maintenance 
 CVL-865 7.5 mg BID maintenance 
 Placebo 
This maximum duration is to be approximately 25 weeks, consisting of the following: 
 8-week Screening/Baseline Period 
 10- or 13-week Treatment Period, including an initial 2-week Titration Phase, an 
8-week Maintenance Phase, and a 3-week Taper Phase (only for subjects not 
continuing treatment in the open-label extension trial). The tablets (including the 
number of tablets given) will be the same between the placebo and both CVL-865 
dose arms during the Titration, Maintenance, and Taper Phases to maintain the blind 
 4-week Follow-up Period (only for subjects not continuing treatment in the open-
label extension trial)  
Subjects are to continue on their current AEDs at the same dosages throughout the 
Screening/Baseline Period. If a subject has a vagus nerve stimulator (VNS), a deep brain 
stimulator (DBS), or a responsive neurostimulator (RNS), the settings must remain stable 
throughout the Screening/Baseline Period. 
During this Screening/Baseline Period, subjects will be required to complete electronic seizure 
diaries (eDiary) and record all seizures in the eDiary for each day and days free of seizures. The 
presence or absence of all seizure types experienced by each subject will be recorded daily in the 
eDiary. 
Subjects who satisfy all inclusion/exclusion criteria and thus are eligible for the trial will be 
randomized to 1 of 3 treatment arms at Visit 1 (Day 1). The daily dosing schedule will start at 
Day 1 with a 2-
blinded fashion up the randomized dose level (CVL-865 25 mg BID, CVL-865 7.5 mg BID, or 
placebo). In the high-dose group, CVL-865 will be administered as 
 
 during the Titration Phase, and then 25 mg BID during 
the 8-week Maintenance Phase. In the low-dose group, CVL-865 will be administered as 
 
 during the Titration Phase, and then 
7.5 mg BID during the 8-week Maintenance Phase. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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eligibility to continue treatment with CVL-865 in the open-label extension trial 
CVL-865-SZ-002. If the investigator determines the subject is eligible for the trial, he/she will 
discuss with the subject if they would like to continue into Trial CVL-865-SZ-002. If the 
investigator determines the subject is eligible and the subject agrees to continue participation in 
Trial CVL-865-SZ-002, consent will be obtained and unique procedures for Visit 1 of Trial 
CVL-865-SZ-002 will be completed.
For subjects who do not continue into Trial CVL-865-SZ-002, following the Maintenance Phase, 
the dose will be gradually decreased over a 3-week Taper Phase.
The trial design is depicted in Figure 1 and details of schedule of assessments are provided in
Section 9.1.
Figure 1:
Trial Schematic
Abbreviations: AED = anti-epileptic drug; BID = twice daily; OLE = open-label extension; Wk = week.
1.2.
Sample Size Considerations
Approximately 214 subjects will be screened to achieve 150 subjects randomly assigned to 
treatment (50 per group) and 120 evaluable subjects for an estimated total of 40 evaluable 
subjects per treatment group.
A sample size of 50 subjects per group (total of 150 subjects) will provide at least 80% power to 
detect a difference in the means of the primary outcome measure (RRatio) of -20 (PASS 2008 
Tests of Two Means, Two Sample T-Test, 2-sided alpha level = 0.1, Standard Deviation=34, and 
a 20% dropout rate). Approximately 214 subjects will be screened to achieve 150 subjects
randomized.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
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In the event of higher than anticipated early terminations due to COVID-19 or other reasons, 
Cerevel may extend enrollment in order to maintain the planned statistical power.  
1.3. 
Measures to Minimize Bias: Randomization and Blinding 
1.3.1. 
Subject Assignment to Treatment 
All subjects will be centrally randomized in a 1:1:1 ratio to 3 treatment arms (CVL-865 7.5 mg 
BID, 25 mg BID, or placebo) at the Visit 1 (Day 1) via an Interactive Voice Response 
System/Interactive Web Response System (IVRS/IWRS), according to a computer generated 
randomization scheme generated by a non-study statistician and be kept strictly confidential. 
Subjects will be sequentially assigned to the next available randomization number and will 
receive the IMP that corresponds to that randomization number. Once a randomization number 
has been assigned, it will not be reassigned. 
1.3.2. 
Blinding 
The CVL-865 and placebo tablets will be identical in appearance. Subjects will receive the 
appropriate combination of tablets necessary in order to achieve the required dose level. In order 
to maintain the blind, subjects assigned to the placebo treatment group will receive the same 
number of tablets as subjects in the CVL-865 groups.  
Treatment assignments will be blinded to the investigators and other trial site personnel, the 
subjects, and all sponsor personnel who are involved in the conduct of the trial (including trial 
monitoring, data management, and data analysis). Access to the treatment codes will be restricted 
to personnel who are responsible for generating and maintaining the randomization code, 
packaging the IMPs, operating the IVRS/IWRS, analyzing the PK blood samples, or reporting 
serious adverse events (SAEs) or adverse events of special interest (AESI) to regulatory 
agencies. 
If the investigator decides that unblinding is warranted, the investigator should make every effort 
atment assignment is unblinded, 
the medical monitor must be notified within 24 hours after breaking the blind. 
eCRFs, with the reason for breaking the blind, the date and time the blind was broken, and the 
names of the personnel involved. Once the blind is broken for a subject, treatment with the IMP 
may not be reinitiated for that subject. 
1.4. 
Treatment Period 
The dose of CVL-865 will be titrated to the assigned dose over the first 2 weeks of the trial 
during the Dose Titration Phases followed by 8 weeks of Maintenance Phase at the assigned dose 
level. At the end of Maintenance Phase, eligible subjects have the option to continue treatment 
with CVL-865 in the open-label extension trial CVL-865-SZ-002. If for subjects who do not 
continue into Trial CVL-865-SZ-002, following the Maintenance Phase, the dose will be 
gradually decreased over a 3-week Taper Phase. 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
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Objectives 
Endpoints 
Secondary (PK): To evaluate the plasma exposure of 
CVL-865 
 
Summary listing of CVL-865 concentrations 
by dose and visit 
Abbreviations: AE = adverse event; CGI-I = Clinical Global Impression  Improvement; CGI-S = Clinical Global 
Impression  Severity of Symptoms; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; 
HUI = Health Utilities Index; mCIWA-B = Modified Clinical Institute Withdrawal Assessment  Benzodiazepines; 
-31 = Quality of 
Life in Epilepsy-31; RRatio = Response Ratio; TEAE = treatment-emergent adverse event. 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 


 
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3. 
KEY ASSESSMENTS AND DERIVATIONS 
3.1. 
Efficacy Assessments 
3.1.1. 
Seizure Frequency and Type (eDiary) 
Subjects will record details regarding their seizures (frequency and type) in an eDiary. Any BZD 
use will also be recorded in the diary. Seizure frequency and type will be assessed based on 
information recorded by the subject in the eDiary.  
Seizure frequency is defined as the total number of focal onset seizures over the analysis period 
of interest divided by the total number of days with no missing seizure counts in the 
corresponding period multiplied by 7. For cluster seizures, which are a group of seizures too 
numerous to count, the number of cluster episodes will be included as one seizure event. Unless 
otherwise specified, Seizure frequency will only be calculated for focal onset seizures, which 
include focal aware seizures without motor signs, focal aware seizures with motor signs, focal 
impaired awareness seizures and focal to bilateral tonic-clonic seizures. 
3.1.2. 
ange 
The self-
about the efficacy of treatment. It is a 7-
 
3.1.3. 
Clinical Global Impression-Severity of Symptoms Scale 
The CGI-S is an observer-rated scale that will be used to measure symptom severity. It is 
symptoms at the time of the current visit. 
To perform this assessment, the investigator (or designee) will answer the following question: 
clinical experience with this particular population, how ill is the subject 
3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most 
extremely ill subjects. 
3.1.4. 
Clinical Global Impression-Improvement Scale 
The CGI-I is an observer-
compared with before initiation of treatment with IMP. It is important to note that the observer or 
their symptoms at baseline (Visit 1).   
(as related to seizure frequency and severity) using the following response choices: 0 = not 
assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 
5 = minimally worse, 6 = much worse, and 7 = very much worse. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
  
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.1.5. 
Quality of Life in Epilepsy  31 
The Quality of Life in Epilepsy  31 (QOLIE-31) was developed in cooperation with 
professional postgraduate services, a division of Physicians World Communications Group and 
the QOLIE Development Group. The 31-item QOLIE-31 (Version 1.0) has been derived from 
the longer QOLIE-89 (Rausch & Crandall, 1982; Cramer et al, 1998). 
The QOLIE-31 contains 7 multi-item scales that tap the following health concepts: emotional 
well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, medication 
effects, and overall quality of life. A QOLIE-31 overall score is obtained using a weighted 
average of the multi-item scale scores. The QOLIE-31 also includes a single item that assessed 
overall health. 
Details of QOLIE-31 categories are provided in Section 9.2. 
3.1.6. 
Health Utilities Index 
The Health Utilities Index (HUI) is a rating scale used to measure general health status and 
health-related quality of life. The HUI questionnaires are designed to map onto 2 classification 
systems, HUI-2 and HUI-3, capable of measuring 24,000 and 972,000 unique health states, 
respectively. The HUI classifications measure a range of health domains with examples 
including sensation, mobility, pain, cognition, ambulation, and emotion (Horsman et al, 2003). 
Details of HUI categories are provided in Section 9.3. 
3.2. 
Safety Assessments 
3.2.1. 
Adverse Event (AE)  
An adverse event 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of trial treatment. All adverse events will be recorded on the ADVERSE EVENTS eCRF. 
tabulations. Adverse events with missing relationship to IMP will have the relationship imputed 
e AE started on or after the first dose of IMP. However, 
in the data listings these missing severity and/or relationship will be presented as missing. 
3.2.1.1. 
Treatment-emergent Adverse Event (TEAE) 
Any event reported on the eCRF that occurs on or after the initiation of IMP through the last 
follow up contact is considered treatment emergent. Additionally, it is assumed that an Adverse 
Event which was reported to have started on Day 1 without an associated onset time is assumed 
to be treatment emergent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   


 
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3.2.1.2. 
Serious Adverse Event (SAE) 
Adverse events that meet the definition of SAE in the protocol will be captured in the 
ADVERSE EVENTS eCRF. 
3.2.1.3. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) will be captured and monitored during this study. 
AESI include Adverse Events Potentially Related to Abuse or Dependence, Hematologic 
Abnormalities and Abnormal Liver Function Tests as defined in the protocol. These events will 
be noted by the investigator in the ADVERSE EVENTS eCRF. 
3.2.2. 
Clinical Safety Laboratory Assessments 
The clinical laboratory tests as listed in the protocol will be performed in accordance with the 
laboratory manual and the Schedule of Assessments. All results, including repeats, will be 
included in the laboratory reports. 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. 
3.2.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the trial using the C-SSRS. It was designed to quantify the 
severity of suicidal ideation and behavior. 
e of the subject with suicide 
events and suicidal ideation and the occurrence of suicide events or ideation within a specified 
time period prior to entry into the trial, will be completed for all subjects at screening to 
determine eligibility and confirmed at baseline. Any subject with active suicidal ideation or 
suicidal behaviors within the last 6 months, suicidal behaviors within the last 2 years, or who in 
the clinical judgment of the investigator presents a serious risk of suicide should be excluded 
from the trial. 
-SSRS form will be completed at all visits after screening and baseline. 
-SSRS during the trial to 
determine whether it is safe for the subject to continue in the trial. If a subject demonstrates 
answers on item 4 or 5 of the C-SSRS, the investigator will evaluate whether a risk assessment 
by a qualified mental health professional (or the investigator alone if the investigator is a 
qualified mental health professional) is needed and whether the subject should continue in or be 
discontinued from the trial. 
Details of C-SSRS categories as well as definition of treatment emerging events are provided in 
Section 9.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.2.4. 
Vital Signs 
Vital sign measurements will include body temperature, respiratory rate, systolic blood pressure, 
diastolic blood pressure, and heart rate. 
3.2.5. 
Electrocardiograms 
Electrocardiogram recordings will be obtained after the subject has been supine and at rest for at 
least 5 minutes. Additional 12-
 discretion and 
should always be obtained in the event of early termination. The ECG results will be evaluated at 
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.  
At screening, triplicate ECG recordings should be taken approximately 1 minute apart. The 
(QTcF) for the 3 screening ECGs. A mean QTcF >450 msec as assessed by the central reader 
from the screening triplicate ECGs will be exclusionary.  
A repeat ECG should be performed to confirm any clinically significant abnormality that is 
identified in a randomized subject during the treatment period (which will be confirmed by 
central service read) and, in these cases, the medical monitor should be consulted on the 
appropriateness of the subject continuing in the trial. 
3.2.6. 
Modified Clinical Institute Withdrawal Assessment  Benzodiazepines 
The modified Clinical Institute Withdrawal Assessment  Benzodiazepines (mCIWA-B) is a 
sensitive instrument to measure withdrawal under conditions where there is a taper of medication 
(rather than abrupt discontinuation). It consists of 17-items that monitor the type and severity of 
BZD withdrawal symptoms such as irritability, fatigue, appetite, and sleeplessness (Busto et al, 
1989). The clinician-observed assessments of sweating, restlessness (pacing), and tremor that are 
included in the overall version have been removed from this modified version. The total score 
ranges from 1 to 68 with higher scores indicating more severe withdrawal. 
3.2.7. 
Concomitant Medications and Non-Drug Therapy/Procedures 
Concomitant medications are those medications taken on or after the initiation of IMP. These 
medications include those medications started before the initiation of IMP and continuing post 
Day 1. Medications that start and stop before the first dose of IMP will be classified as prior 
medications and will not be considered concomitant. Medications that start after the last dose of 
IMP will be classified as taken post last dose and will not be considered concomitant. These 
medications will be recorded in the eCRF. The investigator will record all medications and 
therapies (including vaccines, over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that are used by the subject from 30 days before the informed consent form (ICF) 
is signed through the end of Post-treatment Safety Follow-up Period. The investigator will also 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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record all medications and therapies taken or received by a subject for treatment of an AE or that 
cause an AE through the end of Post-treatment Safety Follow-up Period. 
Non-drug therapy/procedures will also be recorded as medications described above. 
3.2.8. 
Rescue Medicine 
All subjects who normally take BZDs for seizure rescue will be required to have an 
individualized Rescue Protocol approved by TESC (The Epilepsy Study Consortium). The 
Rescue Protocol will be submitted along with the SIF/DRF (Seizure Identification and 
Diagnostic Review Form) and will describe what rescue treatment can be administered in the 
event the subject requires a BZD. It will also include different scenarios that will prompt 
immediate medical attention. 
3.2.9. 
Physical and Neurological Examinations 
Full physical and neurological examinations should be completed at Screening Visit 4, and Visit 
5/ET. The physical examination should include weight at all time points and height at the 
Screening Visit only.  
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. 
3.3. 
Pharmacokinetics 
To evaluate the plasma exposure of CVL-865 (and adjunctive AEDs, if appropriate) over time, a 
single daytime blood sample will be collected as specified in the Schedule of Assessments 
(Section 9.1). 
 
 
 
 
 
 


 
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4. 
DATA CONVENTIONS AND VISIT WINDOWS 
4.1. 
Data Conventions 
4.1.1. 
Age 
Age is the age at the time of informed consent and is as captured on the eCRF (note: date of birth 
is not captured on the eCRF). 
4.1.2. 
Day 1  
Day 1 is the day IMP is first initiated. 
4.1.3. 
Study Day of an Event 
Study day of an event is defined relative to Day 1 as: 
 
Study Day = event date  
 
This calculation will result in negative study days for an event occurring prior to the start of IMP 
and positive study days for an event on or after the start of IMP.  There will be no Day 0 value to 
match the schedule of events. 
4.1.4. 
Days on Study 
Days on Study is the number of days from Day 1 to the date of study completion or early 
termination as recorded on the END OF STUDY eCRF. 
4.1.5. 
Days on IMP 
Days on IMP is the number of days from Day 1 to the date of last dose of IMP as recorded on the 
EXPOSURE eCRF. 
4.1.6. 
Baseline Value 
For purposes of analysis of safety assessments and efficacy assessments outside of eDiary, the 
baseline value is defined as the last value obtained prior to initiation of IMP. Should the Day 1 
visit value be obtained after the first dose of IMP or if this value is not available at Day 1, then 
the most recent value obtained prior to earliest initiation of IMP will be used for the baseline 
value.  
4.1.7. 
Change from Baseline 
Change from baseline for a given variable is defined as the value on a given Study Day (Time 
Point) minus the Baseline Value. 
4.1.8. 
Last Dose of IMP 
Last Dose of IMP is defined as the last date that the subject received IMP. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
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4.1.9. 
Average Daily Dose by Period 
The cumulative dose of IMP, calculated in milligrams and based on the daily dose of IMP as 
recorded in the EXPOSURE eCRF for each Period defined in Table 3 will be used to derive 
average daily dose for the period. 
4.1.10. 
Compliance with Study Drug 
Dosing compliance, based on daily dose of IMP as recorded in the EXPOSURE eCRF, will be 
defined by the ratio of the number of doses actually taken by the subject divided by the number 
of doses that were expected to be taken during the same period multiplied by 100. Subjects could 
be considered for discontinuation of the trial for non-compliance if poor study drug compliance 
is observed. 
4.1.11. 
Handling of Incomplete or Missing Dates Associated with an Event 
An incomplete date occurs when the exact date an event (e.g. an adverse event) occurred or 
ended cannot be obtained from a subject. The database contains data fields for month, day, and 
year. A date is incomplete if at least one of these three fields is not known.  
For many of the planned analyses, a complete date is necessary to determine if the event should 
be included in the analysis (e.g. if the event is treatment-emergent) or to establish the duration of 
an event. In such cases, incomplete dates will be imputed. 
For the purposes of handling partially reported start and stop dates for an event the following 
algorithm will be applied: 
 Missing start day, but month and year present: 
If the event occurs same month and year as the occurrence of IMP, then the start day of 
the event will be assigned to the day of first dose of IMP (i.e., Day 1). 
Otherwise the start day will be set to the first day of the month. 
 Missing start day and month, but year present: 
If event occurs in the same year as IMP, then the start date of the event will be assigned 
to Day 1. 
Otherwise the start day and month will be set to 01 January. 
 In the unlikely event of a completely missing start date (year not present), the start 
date will be imputed as Day 1. 
 Missing end day, but month and year present: 
The day will be set to the last day of the month. 
 Missing end day and month, but year present: 
The end day and month will be set to the date of study completion. However, if study 
completion year is greater than the year of the event, then the day and month will be set 
to 31 December. 
 
 
 
 
 
 
 
 
 
 
 


 
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 Missing all components of an end date and the event is not marked as ongoing: 
-emergent if 
the start date is on or after Day 1. 
For completely missing date of epilepsy diagnosis in medical history, the first start date 
of anti-epilepsy medication(s) will be used to impute the diagnosis date. 
If any imputed start date causes the start date to occur after the end date, the end date will be 
used for the imputation of the start date. If any imputed end date causes the end date to occur 
prior to the start date of the event, the start date of the event will be used for the imputation of the 
end date. If the imputed date is later than the date of study withdrawal, then the date of study 
withdrawal will be imputed for the date. In subject data listings, start and stop date of events will 
be displayed as reported on the eCRF (i.e., imputed values will not be listed). 
4.1.12. 
Handling of Alphanumeric Data  
Should there be instances where a clinical laboratory parameter is reported with imbedded non-
summaries. The actual values as reported in the database will be presented in data listings. 
For incorporation in quantitative summaries (except for concentration data), the following 
imputation rules will be employed: 
 The values < LLN will be replaced with ½ the value of the lower limit. For example, 
< 0.1  will be replaced with 0.05 if the LLN is 0.1.   
 The values > ULN will be replaced by values of increased precision by one level. For 
 if the 
ULN is 10. 
4.2. 
Analysis Periods 
The start and end dates of each analysis period (following the study design) are used for the 
classification of efficacy data. The exact start and end of each of these periods is described for 
calculation purposes in Section 4.3. Seizure frequency and average daily dose for each analysis 
period will be calculated based on Table 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
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Table 3: 
Definition of Analysis Periods for Seizure Frequency and Average Daily Dose 
Data 
Analysis Period 
Duration 
Start Date 
End Date 
Baseline Period 
~8 Weeks 
The greater of: 
Study Day, -56  
or 
Informed consent 
Study Day, -1 
Titration Phase 
~2 Weeks 
Study Day, 1 
The lesser of: 
 Day 15 (Visit 2) minus 1  
or 
*Early termination (minus 
1)  
or 
End of Treatment 
Maintenance Phase 
~8 Weeks 
Day 15 (Visit 2) 
The lesser of: 
**Day 71 (Visit 4) minus 1 
or 
*Early termination (minus 
1) 
or 
End of Treatment 
Taper Phase 
~3 Weeks 
Day 71 (Visit 4) 
or 
*Early termination 
End of Treatment 
* If a subject experiences early termination from the study and continues to Taper Phase, end dates will be bound 
by early termination minus 1 while the start of Taper Phase will begin on the date of early termination. 
** For subjects continues to Taper Phase from Maintenance Phase
4.3. 
Visit Windows 
Data collected longitudinally across visits will be summarized and analyzed by visit. Visits will 
be presented according to the nominal study day and visit as obtained from the eCRF or 
laboratory data unless the visit is an early termination or unscheduled visit. Early termination and 
unscheduled visits will be assigned visit windows based on the study day completed according to 
Table 4 -Table 9. 
If assessments are collected multiple times within a given visit, the scheduled visit, if available, 
will be used for summary presentations. If no scheduled visit is available, then the result closest 
to the scheduled visit date will be used for summary presentations. If two unscheduled 
measurements (discharge or unscheduled visit) have the same distance to the expected date, the 
earlier value will be used. If a subject has multiple non-missing unscheduled values on the same 
date, then the last one is used, as determined by the time collected, if available. 
 
 
 
 
 
 


 
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Table 4: 
Visit Windows for Early Termination and Unscheduled Visits - ECGs and 
Vital Signs 
Study Day of Early Termination or 
Unscheduled Visit  
Analysis Visit  
Analysis Visit 
Target Day 
1 (pre-dose) or earlier 
Baseline 
 
1* to 15 
Day 1 (Visit 1) 
1 
16 to 57 
Day 43 (Visit 3) 
43 
58 to 82 
Day 71 (Visit 4) 
71 
83 to 106 
Day 92 (Visit 5) 
92 
107 and higher 
Day 120 (Visit 6) 
120 
*Only post-dose values at Day 1 will be windowed to Day 1. 
Table 5: 
Visit Windows for Early Termination and Unscheduled Visits - Safety Labs 
and C-SSRS 
Study Day of Early Termination or 
Unscheduled Visit  
Analysis Visit 
Analysis Visit 
Target Day 
1 or earlier 
Baseline 
 
2 to 8 
Day 1 (Visit 1) 
1 
9 to 29 
Day 15 (Visit 2) 
15 
30 to 57 
Day 43 (Visit 3) 
43 
58 to 82 
Day 71 (Visit 4) 
71 
83 to 106 
Day 92 (Visit 5) 
92 
107 and higher 
Day 120 (Visit 6) 
120 
Table 6: 
Visit Windows for Early Termination and Unscheduled Visits  CGI-S 
Study Day of Early Termination or 
Unscheduled Visit  
Analysis Visit 
Analysis Visit 
Target Day 
1 or earlier 
Baseline 
 
2 to 8 
Day 1 (Visit 1) 
1 
9 to 29 
Day 15 (Visit 2) 
15 
30 to 57 
Day 43 (Visit 3) 
43 
58 or higher 
Day 71 (Visit 4) 
71 
 
 
 
 
 
 


 
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Table 7: 
Visit Windows for Early Termination and Unscheduled Visits  PGIC and 
CGI-I 
Study Day of Early Termination or 
Unscheduled Visit  
Analysis Visit 
Analysis Visit 
Target Day 
29 or earlier 
Day 15 (Visit 2) 
15 
30 to 57 
Day 43 (Visit 3) 
43 
58 or higher 
Day 71 (Visit 4) 
71 
Table 8: 
Visit Windows for Early Termination and Unscheduled Visits  QOLIE-31 
and HUI 
Study Day of Early Termination or 
Unscheduled Visit  
Analysis Visit 
Analysis Visit 
Target Day 
1 or earlier 
Baseline 
 
2 or greater 
Day 71 (Visit 4) 
71 
Table 9: 
Visit Windows for Early Terminations and Unscheduled  mCIWA-B 
Study Day of Early Termination or 
Unscheduled Visit  
Analysis Visit 
Analysis Visit 
Target Day 
1 to 74 (on treatment, prior to Taper 
Phase) 
Baseline 
 
1 to 82 (off treatment) 
Day 78 (Contact) 
78 
83 to 89 
Day 85 (Contact) 
85 
90 to 96 
Day 92 (Visit 5) 
92 
97 to 110 
Day 99 (Contact) 
99 
110 and higher 
Day 120 (Visit 6) 
120 
 
 
 
 
 
 
 






 
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5.6.2. 
History of Epilepsy 
The number and percentage of subjects who received epilepsy surgery and the type of surgeries 
will be summarized. 
Epileptic seizure profile is based on the historical seizure types reported by the subject on the 
Seizure History form. The number and percentage of subjects experiencing each seizure type at 
any time in the past will be summarized.  
The number and percentage of subjects with each category of focus localization will be 
summarized. Subjects may be counted in more than one category of focal localization. The 
average number of seizures for each category of focus localization will be summarized. 
The date of diagnosis of epilepsy is collected on Seizure History eCRF. If the date of diagnosis 
date is missing, the date will be imputed as the earliest start date of any Anti-Epileptic Drug 
taken. The duration of epilepsy will be derived as the years between informed consent date and 
diagnosis date as reported on the Seizure History eCRF. The duration of epilepsy and age at 
epilepsy diagnosis will be summarized descriptively.  
The background AEDs and history of RNS/VNS procedures at study entry will also be 
summarized. 
5.7. 
Exposure to Treatment 
The number of days on study drug, reasons for premature discontinuation of IMP, treatment 
compliance, days in each phase (Titration, Maintenance, and Taper), average dose in each phase, 
will be summarized by treatment group for the FAS Population. 
5.7.1. 
eDiary compliance 
Primary and secondary, and other efficacy variables are based on diary-collected seizure 
frequencies, and as such, diary compliance will be evaluated along with treatment compliance. 
Subjects are instructed to complete their diary entries at least once a day during the study. A 
diary day will be considered missing for compliance if a seizure diary record is missing for that 
day. Diary compliance will be evaluated during the Baseline Period, during the entire Treatment 
Period, and during the Maintenance Period. 
Diary compliance will be calculated as 100 times the number of diary days (days with diary 
completed) during the period and dividing this quantity by the expected number of diary days 
that should have been completed during this period of time. Compliance is only computed for 
actual time of participation in the study up to the end of the Treatment Period. Only data prior to 
and on the date of last dose of study medication will be included in the compliance calculation. If 
calculated. 
Diary compliance data will be listed by treatment then subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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5.8. 
Primary Efficacy Analysis 
5.8.1. 
Derivation of Primary Efficacy Endpoint 
The primary efficacy endpoint is the response ratio (RRatio) over the Maintenance Phase: 
 
 
 
where  T = focal onset seizure frequency rate per week in the Maintenance Phase and 
B = focal onset seizure frequency rate per week in the Baseline Period 
It ranges between -100 and 100 where negative values will indicate reduction in seizure rate and 
positive values indicate increase in seizure rate during treatment. 
5.8.2. 
Primary Estimand 
The key research question for the primary endpoint will be addressed with an estimand based on 
the following attributes:  
1. Treatments: treatments as randomized regardless of the actual treatment received.  
2. Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population.  
3. Endpoint (variable) of interest: RRatio over the Maintenance Phase. 
4. Population level summary of interest: difference between CVL-865 treated and placebo 
subjects in RRatio over the Maintenance Phase. 
5. Strategy for Intercurrent events (ICEs): a hypothetical strategy will be used to address 
intercurrent events (ICEs) of potential death, and treatment discontinuations. The data 
after treatment discontinuations will typically be missing or be treated as missing even if 
collected. Under the hypothetical strategy, these missing values as the result of ICEs of 
discontinuation will be assumed to follow the observed trajectory of the subject and thus 
the endpoint will include only eDiary based response data that occur before 
discontinuation of treatment. It should be noted that the use of protocol defined rescue 
medication will not be considered as an ICE. 
5.8.3. 
Main Analytical Approach 
Primary efficacy endpoint will be summarized using descriptive statistics by treatment group and 
visit, if appropriate. Statistical comparisons for each endpoint will be constructed without 
adjustment for multiplicity. 
The RRatio will be analyzed using an analysis of covariance (ANCOVA) model including 
treatment and the baseline seizure frequency per week as a covariate. The differences between 
the treatment dose group and placebo will be estimated based on the least square mean 
(LSMean) difference between each CVL-865 dose group vs placebo and combined CVL-865 
dose groups vs placebo with corresponding 90% confidence interval (CI) and P-value. 
 
 
 
 
 
 
 
  
 
 
 


 
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5.8.4. 
Sensitivity Analyses 
5.8.4.1. 
Treatment Effect based on Actual Treatment Received 
Should a discrepancy between the study treatment received and the randomized treatment 
assignment occurred in 4 or more subjects, a sensitivity analysis may be conducted based on the 
study treatments that subjects actually received using the analysis method described in 
Section 5.8.3. 
5.8.4.2. 
Impact of Low eDiary Entry Compliance 
To evaluate the impact of 
s from the main 
analysis, a sensitivity analysis that treat these cases as missing at random will be performed. 
Specifically, if a subject has more than 50% of their diary entries missing over a period (baseline, 
maintenance, etc), the seizure frequency for that period will be treated as missing. Multiple 
imputations under missing at random assumption will be performed. The Markov chain method 
implemented in SAS PROC MI will be utilized based on the mITT population. The imputations 
will be performed on the logarithmic scale (ln(X+1)), where X represents the 7 day average 
seizure frequency for a period, and back transformed to conform to the multivariate normality 
distribution and the imputed values will then be back transformed to the original scale. SAS 
PROC MI will be used to generate 10 possible imputed datasets using the following SAS code:  
proc mi data=mcmc1 seed=SEED1 nimpute=10 minimum=0 out=Out1X; 
mcmc chain=multiple displayinit initial=em(itprint); 
var TRT y0 y; 
run; 
Where TRT is an indicator variable representing treatment with the two treatment groups of 
-
-
ln(7 day average 
seizure frequency over maintenance period + 1), y0 is ln(7 day average seizure frequency over 
the baseline period+1), and SEED1 is a random number. 
Each of these datasets will be analyzed using the same ANCOVA model through SAS PROC 
MIXED as described in Section 5.8.3. The results of the analyses of the datasets will be 
combined using PROC MIANALYZE to produce an inferential result. 
5.8.4.3. 
Impact of Discontinuation Potentially Related to Treatment 
The seizure frequency data of subjects who discontinue of from the trial on or before Week 6 
(Visit 3) for the following reasons are potentially missing not at random (MNAR). 
 AE with AEHLGT eq 'Seizures (incl subtypes)'   
 WITHDRAWAL BY SUBJECT  
 LACK OF EFFICACY  
 LOST TO FOLLOW-UP  
In this assessment, the subjects with MNAR (to be identified and documented in Section 9.5 
before database lock) will be imputed by jump to reference approach. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


 
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Specifically, the missing values in each of the active group will be imputed using the multiple 
imputation procedure described above except that the missing observations in CVL-865 group 
are not constructed from the observed data in the respective groups, but rather from the observed 
data in the placebo group. Any missing data from the placebo group is imputed using the 
observed data from the placebo group.   The data will be log transformed using convention 
log(X+1) and back transformed to conform to the multivariate normality distribution. The 
proc mi data = mcmc1 (where=( ((y = . or y0=.) and trt 
)  or (trt=
 and (y0  ne . 
and y ne .)) )) seed = SEED1 nimpute = 10 minimum =0 minmaxiter = 1000 out= Out1X; 
mcmc chain = multiple displayinit initial=em(itprint); 
 var  y0 y;  
run; 
Where y represents ln(7 day average seizure frequency over maintenance period + 1), y0 is 
ln(7 day average seizure frequency over the baseline period+1), and SEED1 is a random number. 
Each of these datasets will be analyzed using the same ANCOVA model through SAS PROC 
MIXED as described in Section 5.8.3. The results of the analyses of the datasets will be 
combined using PROC MIANALYZE to produce an inferential result. 
5.8.5. 
Subgroup Analyses 
The mITT population is defined as all randomized subjects who receive at least 1 dose of IMP 
seizure diary during maintenance phase. To further assess the impact of the eDiary compliance, 
 
In addition, the following subgroup analyses will be conducted: 
1. subjec
 
2. subgroup analysis of baseline disease characteristics based on seizure frequency, defined: 
Low frequency= up to 20 seizures a week; High frequency = 21 and above, including all 
will be conducted. 
5.9. 
Key Secondary Efficacy Analyses 
5.9.1. 
Derivation of Key Secondary Efficacy Endpoints 
5.9.1.1. 
Change in Log-Transformed Seizure Frequency from Baseline 
The 7-day adjusted seizure frequency will be log-transformed using the convention ln(X+1), 
where X represents the focal onset seizure frequency. This will be summarized for the Titration 
Phase and Maintenance Phase. 
5.9.1.2. 
50% Responder 
Responder status (yes or no) for a subject is determined by the percent reduction in 7-day 
adjusted seizure frequency during the Maintenance Phase from Baseline. A subject is defined as 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 


 
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a 50% responder if subject has at least a 50% reduction in the focal onset seizure frequency 
during the Maintenance Phase relative to the Baseline Period. 
5.9.2. 
First Key Secondary Estimand  
The key research question for the first secondary efficacy variable will be addressed with an 
estimand based on the following attributes:  
1. Treatments: treatments as randomized regardless of the actual treatment received.  
2. Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population.  
3. Endpoint (variable) of interest: change from baseline in focal onset seizure frequency in 
logarithmic scale. 
4. Population level summary of interest: estimated mean difference between CVL-865 
treated and placebo subjects in change from baseline in focal onset seizure frequency per 
week in logarithmic scale during the Maintenance Phase. 
5. Strategy for Intercurrent events (ICEs): a hypothetical strategy will be used to address 
intercurrent events (ICEs) of potential death, and treatment discontinuations. The data 
after treatment discontinuations will typically be missing or be treated as missing even if 
collected. Under the hypothetical strategy, these missing values as the result of ICEs of 
discontinuation will be assumed to follow the observed trajectory of the subject and thus 
the endpoint will include only eDiary based response data that occur before 
discontinuation of treatment. It should be noted that the use of protocol defined rescue 
medication will not be considered as an ICE. 
5.9.3. 
Main Analytical Approach for First Key Secondary Endpoint 
The change from baseline in log-transformed seizure frequency will be analyzed using an 
ANCOVA, including treatment as a factor and the log-transformed baseline focal onset seizure 
frequency per week as a covariate. The comparisons between the treatment groups will be based 
on the LS Mean difference between each CVL-865 dose group and placebo with corresponding 
90% CI and P-value.  
The LS Mean and 90%CI for each treatment group in log scale will be exponentiated to derive 
the model-estimated mean percent change from baseline using the following formula: 
Estimated Mean % Change from Baseline=100*[1-exp(LSMean)] 
The percent reduction relative to placebo and 90%CI will be constructed by exponentiating the 
LSMean difference and 90%CI between each CVL-865 treatment group and placebo from the 
ANOCOVA model using the following formula: 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 


 
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5.9.4. 
Sensitivity Analyses 
The sensitivity analyses to assess the impact of low eDiary compliance and that of 
discontinuation potentially related to treatment described in Section 5.8.4 for the primary 
estimand will also be performed for the key secondary efficacy estimand. 
Two additional sensitivity analyses will be performed to assess the impact of the logarithmic 
transformation ln(X+1) of seizure frequency. The first one will be based on a slightly modified 
logarithmic transformation ln(X+0.1). This sensitivity analysis is to assess if the correction for 
zero in seizure frequency may have undue effect on other low seizure frequencies. In addition, 
the percent change from baseline in seizure frequency in Titration Phase and Maintenance Phase 
will also be analyzed using a nonparametric approach (in the original scale) of Wilcoxon rank 
sum test followed by the Mann-Whitney test for the comparison of each active treatment group 
to placebo. 
5.9.5. 
Subgroup Analysis 
The following subgroup analyses will be conducted: 
1. 
 
2. subgroup analysis of baseline disease characteristics based on seizure frequency, defined: 
Low frequency= up to 20 seizures a week; High frequency = 21 and above, including all 
 
5.9.6. 
Supplemental Analysis 
A supplemental analysis will be conducted using a Poisson Regression model on the 
untransformed data for the raw number of seizures. A generalized linear model assuming a 
Poisson distribution and canonical log link function will be applied to the raw seizure count over 
the Maintenance Phase. The model will have an off-set parameter for the number of non-missing 
eDiary days (i.e., ln(days)) the subject was in the maintenance phase. Independent variables will 
include treatment and baseline seizure count. 
5.10. 
Second Key Secondary Efficacy Analysis 
The second key secondary efficacy endpoint is the 50% responder rate, defined as the percent of 
subjects with at least a 50% reduction in the Maintenance Phase focal onset seizure frequency 
rate relative to the Baseline Period. 
5.10.1. 
Second Key Secondary Estimand 
The key research question for the second key secondary efficacy variable will be addressed with 
an estimand based on the following attributes: 
1. Treatments: treatments as randomized regardless of the actual treatment received.  
2. Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population.  
3. Endpoint (variable) of interest: 50% responder rate in the Maintenance Phase. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4. Population level summary of interest: the 50% responder rate in the Maintenance Phase 
relative to the baseline period between CVL-865 treated and placebo subjects. 
5. Strategy for Intercurrent events (ICEs): a hypothetical strategy will be used to address 
intercurrent events (ICEs) of potential death, and treatment discontinuations. The data 
after treatment discontinuations will typically be missing or be treated as missing even if 
collected. These missing values as the result of ICEs of discontinuation will be assumed 
to follow the observed trajectory of the subject and thus the endpoint will include only 
eDiary based response data that occur before discontinuation of treatment. However, 
subjects with greater than 80% missing seizure diary entries will be treated as 
non-responders. It should be noted that the use of protocol defined rescue medication will 
not be considered as an ICE. 
5.10.2. 
Main Analytical Approach for Second Key Secondary Endpoint 
The second key secondary endpoint, 50% responder rate, will be analyzed for the mITT 
population using a logistic regression model with effects for treatment and baseline seizure 
frequency. The binary outcome will be defined as having at least a 50% reduction in the 
maintenance phase relative to the baseline period or not having a 50% reduction. Odd ratios will 
be constructed for each CVL-865 treatment dose group compared with placebo and will be 
summarized with 90% confidence intervals. Subjects with greater than 80% missing seizure 
diary entries will be treated as non-responders for this analysis. Should a logistic regression 
model fail to converge, pai
 
5.10.3. 
Sensitivity Analyses 
The sensitivity analyses to assess the impact of low eDiary compliance and that of 
discontinuation potentially related to treatment described in Section 5.8.4 for the primary 
estimand will also be performed for the second key secondary efficacy estimand. The 50% 
responder rate will be constructed off the results from the primary sensitivity analysis. This will 
be conducted for the two different sensitivity assessments will be conducted to assess the impact 
of this missingness (data are missing at random and data are not missing at random). 
5.11. 
Other Efficacy Analyses 
5.11.1. 
Other Secondary Efficacy Endpoints 
Other protocol-defined secondary efficacy endpoints will be summarized using descriptive 
statistics by treatment group and visit, if appropriate. Statistical analysis method for each 
endpoint is described below in Table 11. Statistical comparisons for each endpoint will be 
constructed without adjustment for multiple endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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Endpoint 
Analysis 
Population 
Analysis Method 
Activities, Mental Activity, Medication Effects, Seizure Worry, and 
Overall Quality of Life. 
HUI Utility Score - 
Change from Baseline to 
Visit 4 
mITT 
Overall Health-Related Quality of Life (HRQL) Utility Scores (HUI-3 
and HUI-2) will be analyzed using an ANCOVA model as described 
above for QOLIE-31 Overall Scores. 
5.12. 
Additional Exploratory Analyses 
An exploratory analysis may be conducted to evaluate the percentage of subjects reaching 75% 
seizure frequency reduction from baseline during the maintenance period if sample size warrants. 
 
A second exploratory analysis may also be conducted to evaluate the percentage of subjects with 
use of protocol defined rescue medications. 
5.13. 
Interim and Final Analysis 
No interim analysis is planned for this trial. 
A final analysis will be conducted once the last subject completes or discontinues the study, and 
the resulting clinical database has been cleaned, quality checked, the pre-analysis meeting has 
occurred, and the database has been locked. 
5.14. 
Safety Analyses 
All safety analyses will be performed on the Safety analysis set (FAS). Should any subjects 
receive a treatment other than their randomized treatment, the treatment as received will be used 
in the safety presentation.  
5.14.1. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
version 27.0 or higher preferred term and system organ class. If a subject experiences multiple 
events that map to a single preferred term, the greatest intensity and strongest investigator 
assessment of relation to IMP will be assigned to the preferred term for the appropriate 
summaries.  Events with missing intensity or relationship will be classified as outlined in 
Section 3.2.1.  Summaries of treatment-emergent AEs will include any AEs reported beginning 
with the initiation of study drug on Day 1 through last follow up contact.  The occurrence of 
TEAEs will be summarized by treatment group using preferred terms, system organ classes, and 
severity.  Separate summaries of treatment-emergent serious adverse events (TESAEs), TEAEs 
related to IMP, AESIs, AESIs not leading to discontinuation of IMP, TEAEs leading to death 
and events leading to the discontinuation of IMP will be generated respectively. A presentation 
of AEs by phase, by dose at event onset and AESIs by dose at event onset will be prepared. All 
adverse events reported will be listed for individual subjects showing both verbatim and 
preferred terms. All adverse events that occurred prior to the initiation of study will be excluded 
from the tables but will be included in the listings.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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placebo group will be summarized by treatment group using preferred term in descending order 
of the incidence in the treatment group. 
Missing onset dates will be imputed as previously outlined in Section 4.1.11 as required to 
determine treatment-emergent events. 
5.14.2. 
Concomitant Medications and Non-Drug Therapy/Procedures 
5.14.2.1. Non-AED Concomitant Medications and Non-Drug Therapy/Procedures 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
dictionary (Version: Global B3, March 2020 or higher). Each concomitant medication will be 
classified as either an AED or a non-AED medication. Non-AED concomitant medications will 
be summarized by treatment group, frequency of drug classification and generic drug name. 
Prior and concomitant medications will be presented in a data listing. The drug classification will 
be the anatomic therapeutic chemical (ATC) classification 4. If this classification is not present, 
the next available classification will be utilized. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
drug dictionary (WHODrug Version: Global B3 September 2019 or later). Concomitant 
medications will be summarized by treatment group, frequency of drug classification, and 
generic drug name. Incidence of dosage adjustment of levodopa (L-Dopa) or equivalent, 
prohibited by the protocol, for duration longer than one week will be summarized. Prior and 
concomitant medications will be presented in a data listing.  
Prior and concomitant non-drug therapy/procedures will be coded using MedDRA Version 26.1 
or higher. Concomitant non-drug therapy/procedures will be summarized by treatment group, 
frequency of system organ class and preferred term. Prior and concomitant non-drug 
therapy/procedures will be presented in a data listing. 
5.14.2.2. Concomitant AED Medication and Therapy/Procedures 
Concomitant AED medications will be summarized by treatment group, frequency of drug 
classification and generic drug name. Number of AEDs taken at study entry and number of 
subjects with RNS/VNS will also be summarized by treatment group. 
5.14.3. 
Clinical Laboratory Assessments 
Descriptive summaries of selected (quantitative) clinical laboratory results will be presented by 
treatment group and study visit. Laboratory values outside the normal range for each 
systematically collected hematology, blood chemistry, and urinalysis parameter will be 
ative to the normal ranges of the central 
the severity of laboratory abnormality will be graded based on toxicity 
criteria specified in Section 9.6 in reference to Common Terminology Criteria for Adverse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Events (CTCAE) Version 5.0. The result of each laboratory test for individual subjects will be 
presented in a listing with the normal range defined by the central laboratory, the status relative 
to the normal range, and the toxicity grade. 
Shift table will be used to summarize shifts from baseline toxicity grades to greatest (worst) 
treatment-emergent laboratory toxicity. For hematology and, blood chemistry, and quantitative 
urinalysis parameters that toxicity grade was not defined, a shift table for each laboratory test 
will be based on the shift from baseline high/normal/low status to the status of the maximum 
post-baseline value and the minimum post-baseline value (including test results from 
unscheduled visits, if any). Similarly, for qualitative urinalysis parameters, shifts from baseline 
normal/abnormal status to the worst post-baseline status will be summarized. 
The number and percentage of subjects who have post-baseline elevations in liver transaminase 
(alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) or bilirubin abnormalities 
in relation to fold above the upper limit of normal will be summarized according to the Food and 
Drug Administration's Premarketing Clinical Evaluation on Drug-Induced Liver Injury Guidance 
for Industry (FDA 2009). Abnormal hepatic laboratory values will be categorized and evaluated 
for any occurrence among all post-
indicates elevations occurring at the same visit). Within each laboratory parameter grouping, a 
subject may be counted once per elevation criteria using the worst-case result. That is, a subject 
with a worst case ALT elevation > 5 × the ULN would be counted once in the ALT > 3 × ULN 
category and once in the ALT > 5 × ULN category, regardless of how many ALT elevations the 
subject had that met the > 3 × ULN and > 5 × ULN elevation criteria. 
 ALT and/or AST > 3 × ULN and total bilirubin > 1.5 or 2 × ULN 
 AST > 3, 5, 10, 20 × ULN 
 ALT > 3, 5, 10, 20 × ULN  
 Total bilirubin > 1.5, 2 × ULN  
 Alkaline phosphatase (ALP) > 1.5 × ULN 
In addition, an eDISH plot, a shift plot showing liver safety panel tests over time (baseline vs. 
post-baseline), and distribution plots of ALT, AST, ALP, and bilirubin over time will be 
produced to aid identification of any potential cases (Merz M. et. al. 2014). The plots to be 
included are the scatter plot of maximum transaminase versus maximum bilirubin, the liver test 
safety panel over time, and the distribution of ALT by time. The distribution plots for AST, ALP, 
and bilirubin will use the same format as used for ALT. 
Other tests (drug screen, pregnancy testing, serology) will be presented in listings. 
5.14.4. 
Vital Signs 
Vital sign measurements will include body temperature (oral or tympanic), respiratory rate, body 
weight, systolic blood pressure, diastolic blood pressure, and heart rate. Body temperature, blood 
pressures, and heart rate will be measured with the subject in a sitting/semi-recumbent position 
after a 5-minute rest. For the body temperature, the same method must be used for all 
measurements for each individual subject and should be the same for all subjects at each 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
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investigational site. Vital signs and corresponding changes from baseline will be summarized by 
visit and treatment group using descriptive statistics. 
Number and percent of subjects with out-of-range post-baseline vital signs will be summarized 
based on the following criteria: 
 Systolic Blood Pressure  
 < 90 mmHg,  
 > 140 mmHg 
 Diastolic Blood Pressure 
 < 50 mmHg  
 > 90 mmHg 
 Heart Rate (Supine) 
 < 60 bpm 
 > 100 bpm 
 Respiratory Rate 
 < 12 bpm 
 > 20 bpm 
 Temperature 
 < 36° C 
 > 38° C 
Vital signs results will also be presented as listing with the out-of-range value flagged based on 
the above criteria. 
5.14.5. 
Electrocardiograms (ECGs) 
Electrocardiogram recordings will be obtained after the subject has been supine and at rest for at 
least 5 minutes. If during screening, any abnormal ECG finding is deemed medically significant 
or meets and exclusion criteria, it will be repeated once at screening with 3 consecutive ECG 
recordings to ensure reproducibility of the abnormality before excluding the subject. Any 
clinically relevant changes occurring during the trial will be recorded in the AE section of the 
eCRF. If a subject in the FAS population has more than one ECG within a time point, an average 
of each ECG measurement at that time point will be used for summary analysis.  
ECGs measurements and corresponding changes from baseline will be listed. ECG variables will 
include heart rate, PR interval, QRS interval, QT interval, and QTc interval corrected for heart 
.  
The number and proportion of subjects having a worst post-baseline QTcF value from 
> 450 msec to 480 msec, > 480 msec to 500 msec, and > 500 msec will be summarized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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In addition, subjects with an increase from baseline of > 30 msec to 60 msec and > 60 msec will 
be summarized.  
Important abnormalities in ECG waveform that are changes from baseline readings will also be 
reported in a listing. 
5.14.6. 
Physical and Neurological Examinations 
Physical and Neurological examination data will be listed. 
5.14.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The maximum post-baseline results from the C-SSRS will be summarized. The maximum of 
each subscale (suicidal ideation [Categories 1-5], suicidal behavior [Categories 6-10], suicidal 
ideation or behavior [Categories 1-10], and self-injurious behavior without suicidal intent) will 
be presented. The number of patients with suicide-related treatment-emergent events, 
treatment-emergent suicidal ideation, and suicidal behavior, based on a comparison of the 
C-SSRS at baseline and/or previous lifetime experience to maximum C-SSRS scores across all 
post-baseline assessments will be provided. All C-SSRS elements will be reflected in a listing. 
5.14.8. 
Modified Clinical Institute Withdrawal Assessment  Benzodiazepines 
(mCIWA-B) 
The clinician-observed assessment section has been removed for the modified version of Clinical 
Institute Withdrawal Assessment  Benzodiazepines (CIWA-B), and the total scores of 
mCIWA-B ranges from 1 to 68. The total score will be summarized descriptively at the 
scheduled visits and contacts by treatment group in addition to change from last on treatment 
assessment prior to or on Day 71 (Visit 4). 
5.15. 
Pharmacokinetics 
To evaluate the plasma exposure of CVL-865 (and anti-epileptic drug, if appropriate), a single 
daytime blood sample will be collected at Visits 2, 3, 4, and 5. The date and time of the PK 
sample, as well as the time of ingestion of the morning dose of IMP (on the same day), will be 
recorded in the source documentation. An additional PK sample will be obtained at Visit 6 to 
document complete washout of IMP. 
5.15.1. 
Pharmacokinetic Data Analysis 
Plasma concentrations of CVL-865 in unit as reported by the analytical laboratory will be 
summarized by treatment and nominal time point using descriptive statistics. Summaries will 
include mean, standard deviation and coefficient of variation, median, minimum, maximum, and 
geometric mean. The mean concentration (SD) plot over time in the original scale and log-scale 
will be plotted based on nominal visit week. 
Concentration values that are below the level of quantification (BLQ) will be set to zero for 
summary tables. The geometric mean, however, will be calculated by imputing BLQ values as ½ 
BLQ. 
listing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Concentration data from this trial may be used to update the previously established population 
PK model for CVL-865. In addition, the relationship between the exposure levels (or dose) of 
CVL-865 and one or more efficacy/safety endpoints may be evaluated for the purpose of 
exploratory PK/PD analyses. Any population PK analysis and exploratory biomarker analyses (if 
completed) will be presented separately from the main CSR. 
5.16. 
Protocol Deviations 
All protocol deviations will be reviewed by the project team prior to unblinding to identify 
subjects with important protocol deviations. The number and percentage of subjects with 
important deviations will be tabulated by treatment and further tabulated by category and 
treatment. All deviations from the protocol will be listed by category along with a description 
and any additional comments. 
 
 
 
 
 
 
 


 
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6. 
CHANGES IN THE PLANNED ANALYSES 
Should any deviations from the analyses specified in the final approved (prior to database lock 
and unblinding) statistical analysis plan arise, such deviations will be documented in the final 
clinical study report. 
 
 
 
 
 
 
 


 
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7. 
REVISION HISTORY 
 
Date 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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8. 
REFERENCES 
Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J Clin 
Psychopharmacol. 1989;9(6):412-6. 
Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): concepts, 
measurement properties and applications. Health Qual Life Outcomes. 2003;1:54. 
Merz M, Lee KR, Kullak-Ublick GA, Brueckner A, Watkins PB. Methodology to Assess 
Clinical Liver Safety Data. Drug Saf (2014) 37 (Suppl 1):S33 S45 
National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials; 
2010. 
Rausch R, Crandall PH. Psychological status related to surgical control of temporal lobe 
seizures. Epilepsia. 1982;23(2):191-202. 
US Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation; 2009. 
 
 
 
 
 
 


 
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9. 
APPENDICES 
9.1. 
Schedule of Assessments 
 
 
 
 
 
 


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Table 12: 
Schedule of Assessments 
Trial Periods/ 
Phases 
Screening/ Baseline 
Perioda 
(8 weeks) 
Treatment Period 
Post-treatment Follow-up 
Titration Phase  
(2 weeks) 
Maintenance Phase  
(8 weeks) 
Taper Phase 
(3 weeks) 
 
Visit/Contactb 
Screen-
ing 
Contact 
Visit 1a 
Contact 
Visit 2c Contact Visit 3c Contact Visit 4d  Contact Contact Visit 5c 
ETe 
Contact 
Visit 6 
Day 
-56 
-28 
1 
8 
15 
29 
43 
57 
71 
78 
85 
92 
NA 
~99 
120 
Window 
± 3 days 
 
± 3 days 
 
Entrance and History 
Informed consentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign subject 
identification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Record medical 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record seizure 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Head MRI/CTg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of drug 
and alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of birth 
control methods 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 


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




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


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Trial Periods/ 
Phases 
Screening/ Baseline 
Perioda 
(8 weeks) 
Treatment Period 
Post-treatment Follow-up 
Titration Phase  
(2 weeks) 
Maintenance Phase  
(8 weeks) 
Taper Phase 
(3 weeks) 
 
Visit/Contactb 
Screen-
ing 
Contact 
Visit 1a 
Contact 
Visit 2c Contact Visit 3c Contact Visit 4d  Contact Contact Visit 5c 
ETe 
Contact 
Visit 6 
Day 
-56 
-28 
1 
8 
15 
29 
43 
57 
71 
78 
85 
92 
NA 
~99 
120 
Window 
± 3 days 
 
± 3 days 
 
Other 
IMP dispensing 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Collect final 
eDiary device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Provide 
individualized 
rescue protocol 
and train subjecti 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IMP compliance 
assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adjunctive AED 
compliance 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 


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AED = anti-epileptic drug; BID = twice daily; BZD = benzodiazepine; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression  Severity of Symptoms; C-SSRS = 
Columbia-Suicide Severity Rating Scale; CT = computed tomography; ECG = electrocardiogram; ET = Early Termination; HBV = hepatitis B virus; HCG = human chorionic gonadotropin; HCV = 
hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; IMP = investigational medicinal product; mCIWA-B = Modified Clinical Institute Withdrawal Assessment  
Benzodiazepines; MRI = magnetic resonance imaging; PGIC = Patient Global Impression of Change; PK = pharmacokinetic; QOLIE-31 = Quality of Life in Epilepsy-31; SIF/DRF = Seizure Identification 
and Diagnostic Review Form; TESC = The Epilepsy Study Consortium. 
a. 
Individual sites may require subjects to have COVID-19 testing done prior to randomization. COVID-
 
b. 
Contact with subject via phone call or other means of communication to check on their status.  
c. 
In the event that a subject is unable to attend a clinic visit in person due to restrictions related to COVID-19, this visit may be completed remotely. Please refer to the Trial Operations Manual for 
further instructions related to remote visits.  
d. 
-865 in the open-label extension trial CVL-865-SZ-002. If the investigator determines the subject is 
eligible for the trial, he/she will discuss with the subject if they would like to continue into Trial CVL-865-SZ-002. If the investigator determines the subject is eligible and the subject agrees to 
continue participation in Trial CVL-865-SZ-002, consent will be obtained and unique procedures for Visit 1 of Trial CVL-865-SZ-002 will be completed. Subjects who do not continue into Trial 
CVL-865-SZ-002 will begin the Taper Phase.  
e. 
Subjects who require early termination should begin the Taper Period at the time the decision is made to discontinue. All indicated procedures should be performed per protocol. If a subject 
discontinues early and it is inadvisable for them to taper IMP (after agreement from medical monitor), the subject should complete Visit 6 assessments approximately 30 days following the last dose of 
IMP.  
f. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be rescreened after consultation with the medical monitor. Rescreened subjects should receive a unique 
subject number for each screening.  
g. 
Unless procedure has been performed within 10 years prior to signing the ICF. This procedure, if necessary, should be conducted as soon as possible during the Screening/Baseline Period (per local 
guidelines) with the report available prior to randomization.  
h. 
A SIF/DRF will need to be completed by site personnel for every subject. This information will be faxed or emailed to TESC after the Screening Visit for review and approval. The SIF/DRF will be 
used by TESC to ensure that the seizures are classified accurately, the subject is appropriate for the trial, and will help to confirm the diagnosis.  
i. 
All subjects who normally take BZDs for seizure rescue will be required to have an individualized Rescue Protocol approved by TESC. The Rescue Protocol will be submitted along with the SIF/DRF 
and will describe what rescue treatment can be administered in the event the subject requires a BZD. It will also include different scenarios that will prompt immediate medical attention.  
j. 
Subjects cannot be enrolled until site personnel have received the TESC approval notification.  
k. 
 
l. 
Full physical and neurological examinations should be completed at Screening Visit 4 and Visit 5/ET. The physical examination should include weight at all time points and height at the Screening 
Visit only. Physical and/or neurological examinations can be done at any time point during the trial at the investigat
 
m. 
-
-SSRS form will be completed at the Baseline Visit to 
ensure that the subject continues to qualify f
-SSRS form will also be completed at all visits after Baseline.  
n. 
Adverse events (serious and non-
 
o. 
For women of childbearing potential only. All positive urine pregnancy test results must be confirmed by a serum test. Pregnancy tests can be performed at any time during the trial at the discretion of 
the investigator if pregnancy is suspected.  
p. 
A urine drug screen is required at screening; see the exclusion criteria for exclusions based on the urine drug screen. The urine drug screen can be conducted at any time during the trial at the 
discretion of the investigator.  
q. 
With subjects maintaining their normal BID dosing routine, a single daytime blood sample for determination of plasma CVL-865 concentration will be collected at Visits 2, 3, 4, and 5. The date and 
time of the PK sample, as well as the time of ingestion of the morning dose of IMP (on the same day), will be recorded in the source documentation.  
r. 
One 5-mL sample for each individual adjunctive AED.  
s. 
Future biospecimen research sample is optional and is to only be collected if signed consent is obtained from the subject.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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Response 
  
  
  
Scale 
Question   
1 
2 
3 
4 
5 
6 
Subtotal 
 
Final Scale 
Score (0-100) 
(Domain Score) 
  
 
 
 
 
 
 
 
 
D. Mental Activity (thinking, concentrating, memory) 
 
 
 
 
 
 
 
 
  
How much of the time during the past 4 weeks... 
 
 
 
 
 
 
 
 
 
     Did you have difficulty reasoning and solving problems 
     (such as making plans, making decisions, learning new  
     things)?1 
0 
20 
40 
60 
80 
100 
  
 
  
     In the past 4 weeks, have you had any trouble with  
     your memory?4 
0 
33.3 
66.7 
100 
-- 
-- 
  
 
  
In the past 4 weeks, how often have you had... 
 
 
 
 
 
 
 
 
 
     Trouble remembering things people tell you?1 
0 
20 
40 
60 
80 
100 
  
 
  
     Trouble concentrating on reading?1 
0 
20 
40 
60 
80 
100 
  
 
  
     Trouble concentrating on doing one thing at a time?1 
0 
20 
40 
60 
80 
100 
  
 
  
     How much do your memory difficulties bother you?3  
100 
75 
50 
25 
0 
-- 
  
 
  
  
 
 
 
 
 
TOTAL: 
  
÷ 6 = 
  
     How much do the above problems and worries about  
     energy distress you overall?9 
100% 
75% 
50% 
25% 
10% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Response 
  
  
  
Scale 
Question   
1 
2 
3 
4 
5 
6 
Subtotal 
 
Final Scale 
Score (0-100) 
(Domain Score) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E. Medication Effects (physical, mental) 
 
 
 
 
 
 
 
  
During the past 4 weeks... 
 
 
 
 
 
 
 
 
     How much do physical effects of antiepileptic  
     medication bother you?3 
100 
75 
50 
25 
0 
-- 
  
 
  
     How much do mentals effects of antiepileptic  
     medication bother you?3 
100 
75 
50 
25 
0 
-- 
  
 
  
     How worried are you that medications you are  
     taking will be bad for you if taken for a long time?5 
0 
33.3 
66.7 
100 
0 
-- 
  
 
  
  
 
 
 
 
 
TOTAL: 
  
÷ 3 = 
  
     How much do the above problems and worries about  
     energy distress you overall?9 
100% 
75% 
50% 
25% 
10% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F. Seizure Worry (impact of seizures) 
 
 
 
 
 
 
 
 
How much of the time during the past 4 weeks... 
 
 
 
 
 
 
 
 
     Have you worried about having another seizure?1 
0 
20 
40 
60 
80 
100 
  
 
  
     How fearful are you of having a seizure during  
     the next month?6 
0 
33.3 
66.7 
100 
-- 
-- 
  
 
  
     Do you worry about hurting yourself during a seizure?7 
0 
50 
100 
-- 
-- 
-- 
  
 
  
     How worried are you about embarrassment or other  
     social problems resulting from having a seizure  
     during the next month?5 
0 
33.3 
66.7 
100 
-- 
-- 
  
 
  
     How much do your seizures bother you?3 
100 
75 
50 
25 
0 
-- 
  
 
  
  
 
 
 
 
 
TOTAL: 
  
÷ 5 = 
  
     How much do the above problems and worries about  
     energy distress you overall?9 
100% 
75% 
50% 
25% 
10% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Response 
  
  
  
Scale 
Question   
1 
2 
3 
4 
5 
6 
Subtotal 
 
Final Scale 
Score (0-100) 
(Domain Score) 
  
 
 
 
 
 
 
 
  
G. Overall Quality of Life 
 
 
 
 
 
 
  
     Overall, how would you rate your quality of life? (10 = Best  
     Possible Quality of Life; 0 = Worst Possible Quality of Life) 
(multiply response by 10) 
 
 
 
 
  
     How has the quality of life been during the past 4 weeks?8 
100 
75 
50 
25 
0 
-- 
  
 
  
  
 
 
 
 
 
TOTAL: 
  
÷ 2 = 
  
How much does the state of your quality of life distress you 
overall?9 
100% 
75% 
50% 
25% 
10% 
 
 
 
 
 
Note: The total number of items in each scale is listed as the divisor for each subtotal. However, due to missing data, the divisor might actually be less than that 
as noted. The divisor should be the number of items that the respondent answered within the scale. 
 
11=All of the time, 2=Most of the time, 3=A good bit of the time, 4=Some of the time, 5=A little of the time, 6=None of the time 
21=A great deal, 2=A lot, 3=Somewhat, 4=Only a little, 5=Not at all 
31= Not at all bothersome and 5 = Extremely bothersome 
41= Yes, a great deal, 2=Yes, somewhat, 3=Only a little, 4=No, not at all 
51=Very worried, 2=Somewhat worried, 3=Not very worried, 4=Not at all worried 
61=Very fearful, 2=Somewhat fearful, 3=Not very fearful, 4=Not fearful at all 
7
 
81=Very well: could hardly be better, 2=Pretty good, 3=Good and bad parts about equal, 4=Pretty bad, 5=Very bad: could hardly be worse 
91=Not at all, 2=Somewhat, 3=Moderately, 4=A lot, 5=Very Much 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 


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A QOLIE-31 overall score is obtained using a weighted average of the multi-item scale scores found in the table below (Table 15). If a 
value for Final Scale Score or Distress Score % is missing, the Weighted Subtotal cannot be calculated. However, if the Distress Score 
% is available, it can be used for the Sum Distress 
Table 14: 
Formula for Calculating QOLIE-31 Overall Score 
 
QOLIE-31 Scale 
Final Scale Score 
(Domain Score) 
 
Distress 
Score % 
 
Weighted 
Subtotal 
  
A. Energy 
_____ 
x 
_____ 
= 
_____ 
 
B. Emotions 
_____ 
x 
_____ 
= 
_____ 
 
C. Daily Activities 
_____ 
x 
_____ 
= 
_____ 
 
D. Mental Activity 
_____ 
x 
_____ 
= 
_____ 
 
E. Medication Effects 
_____ 
x 
_____ 
= 
_____ 
 
F. Seizure Worry 
_____ 
x 
_____ 
= 
_____ 
 
G. Overall QoL 
_____ 
x 
_____ 
= 
_____ 
 
  
 
 
 
 
 
  
  
Sum Distress= 
_____ 
Sum Weights= 
_____ 
  
 
 
 
OVERALL QOLIE-31-P SCORE = Sum Weights/Sum Distress * 100 = _____ 
  
 
 
 
 
 
 


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9.3. 
Health Utilities Index (HUI) 
HUI Utility Score 
The HUI is a rating scale used to measure general health status and health-related quality of life. 
The HUI questionnaires are designed to map onto 2 classification systems, HUI-2 and HUI-3, 
capable of measuring 24,000 and 972,000 unique health states, respectively. The HUI 
classifications measure a range of health domains with examples including sensation, mobility, 
pain, cognition, ambulation, and emotion. The HUI-3 health status classification system evolved 
from applications of the HUI-2 system and is considered to be complementary to the HUI-2 
health status classification system. They both provide a descriptive measure of ability or 
disability for each subject on each HUI-2 and HUI-3 attribute, as well as a composite description 
of overall health status according to both systems.  
The 15-item family of questionnaires for self-completion have been designed to collect the 
minimum amount of information required to classify subjects' health status according to both the 
HUI-2 and HUI-3 classification systems. The standard HUI 15-item questionnaires for 
self-completion are as follows: 
1. Which one of the following best describes your ability, during the past week, to see well 
enough to read ordinary newsprint? 
a) Able to see well enough without glasses or contact lenses 
b) Able to see well enough with glasses or contact lenses 
c) Unable to see well enough even with glasses or contact lenses 
d) Unable to see at all 
 
2. Which one of the following best describes your ability, during the past week, to see well 
enough to recognize a friend on the other side of the street? 
a) Able to see well enough without glasses or contact lenses 
b) Able to see well enough with glasses or contact lenses 
c) Unable to see well enough even with glasses or contact lenses 
d) Unable to see at all 
 
3. Which one of the following best describes your ability, during the past week, to hear what 
was said in a group conversation with at least three other people? 
a) Able to hear what was said without a hearing aid 
b) Able to hear what was said without a hearing aid 
c) Unable to hear what was said even with a hearing aid  
d) Unable to hear what was said, but did not wear a hearing aid 
e) Unable to hear at all 
 
4. Which one of the following best describes your ability, during the past week, to hear what 
was said in a conversation with one other person in a quiet room? 
a) Able to hear what was said without a hearing aid 
b) Able to hear what was said without a hearing aid 
c) Unable to hear what was said even with a hearing aid  
d) Unable to hear what was said, but did not wear a hearing aid 
e) Unable to hear at all 
 
 
 
 
 
 
 


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5. Which one of the following best describes your ability, during the past week, to be 
understood when speaking your own language with people who do not know you? 
a) Able to be understood completely 
b) Able to be understood partially 
c) Unable to be understood 
d) Unable to speak at all 
 
6. Which one of the following best describes your ability, during the past week, to be 
understood when speaking with people who know you well? 
a) Able to be understood completely 
b) Able to be understood partially 
c) Unable to be understood 
d) Unable to speak at all 
 
7. Which one of the following best describes how you have been feeling during the past week? 
a) Happy and interested in life 
b) Somewhat happy 
c) Somewhat unhappy 
d) Very unhappy 
e) So unhappy that life was not worthwhile 
 
8. Which one of the following best describes the pain and discomfort you have experienced 
during the past week? 
a) Mild to moderate pain or discomfort that prevented no activities 
b) Moderate pain or discomfort that prevented no activities 
c) Moderate to severe pain or discomfort that prevented no activities 
d) Severe pain or discomfort that prevented most activities 
 
9. Which one of the following best describes your ability, during the past week, to walk? 
Note: Walking equipment refers to mechanical supports such as braces, a cane, crutches 
or a walker. 
a) Able to walk around the neighborhood without difficulty, and without walking 
equipment. 
b) Able to walk around the neighborhood with difficulty; but did not require walking 
equipment or the help of another person 
c) Able to walk around the neighborhood with walking equipment, but without the help 
of another person 
d) Able to walk only short distances with walking equipment, and required a wheelchair 
to get around the neighborhood 
e) Unable to walk alone, even with walking equipment. 
f) Able to walk short distances with the help of another person, and required a 
wheelchair to get around the neighborhood 
g) Unable to walk at all 
 
 
 
 
 
 
 


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10. Which one of the following best describes your ability, during the past week, to use your 
hands and fingers?  
Note: Special tools refers to hooks for buttoning clothes, gripping devices for opening 
jars or lifting small items, and other devices to compensate for limitations of hands or 
fingers. 
a) Full use of two hands and ten fingers 
b) Limitations in the use of hands or fingers, but did not require special tools or the help 
of another person 
c) Limitations in the use of hands or fingers, independent with use of special tools (did 
not require the help of another person) 
d) Limitations in the use of hands or fingers, required the help of another person for 
some tasks (not independent even with use of special tools) 
e) Limitations in the use of hands or fingers, required the help of another person for 
most tasks (not independent even with use of special tools) 
f) Limitations in the use of hands or fingers, required the help of another person for all 
tasks (not independent even with use of special tools) 
 
11. Which one of the following best describes your ability, during the past week, to remember 
things? 
a) Able to remember most things 
b) Somewhat forgetful 
c) Very forgetful 
d) Unable to remember anything at all 
 
12. Which one of the following best describes your ability, during the past week, to think and 
solve day to day problems? 
a) Able to think clearly and solve day to day problems 
b) Had a little difficulty when trying to think and solve day to day problems. 
c) Had some difficulty when trying to think and solve day to day problems. 
d) Had a great difficulty when trying to think and solve day to day problems. 
e) Unable to think or solve day to day problems. 
 
13. Which one of the following best describes your ability, during the past week, to perform basic 
activities? 
a) Eat, bathe, dress and use the toilet normally 
b) Eat, bathe, dress or use the toilet independently with difficulty 
c) Required mechanical equipment to eat, bathe, dress or use the toilet independently 
d) Required the help of another person to eat, bathe, dress or use the toilet 
 
14. Which one of the following best describes how you have been feeling during the past week? 
a) Generally happy and free from worry 
b) Occasionally fretful, angry, irritable, anxious or depressed 
c) Often fretful, angry, irritable, anxious or depressed 
d) Almost always fretful, angry, irritable, anxious or depressed 
e) Extremely fretful, angry, irritable, anxious or depressed; to the point of needing 
professional help 
 
 
 
 
 
 
 


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15. Which one of the following best describes the pain or discomfort you have experienced 
during the past week? 
a) Free of pain and discomfort. 
b) Occasional pain or discomfort. Discomfort relieved by non-prescription drugs or self-
control activity without disruption of normal activities. 
c) Frequent pain or discomfort. Discomfort relieved by oral medicines with occasional 
disruption of normal activities 
d) Frequent pain or discomfort; frequent disruption of normal activities Discomfort 
required prescription narcotics for relief. 
e) Severe pain or discomfort. Pain not relieved by drugs and constantly disrupted 
normal activities. 
 
16. Overall, how would you rate your health during the past week? 
a) Excellent 
b) Very good 
c) Good 
 
17. How did you complete the questionnaire? Please select the one answer that best describes 
your situation 
a) By myself, without any help from anyone else 
b) By myself, except someone else circled the answers on the questionnaire form for me 
c) With the help of someone else 
d) This questionnaire was completed by a family member, without help from the subject 
or patient 
e) This questionnaire was completed by a nurse or other health professional, without 
help from the subject or patient 
f) This questionnaire was completed by another person, without help from the subject 
or patient 
 
 
 
 
 
 
 
 


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The mappings of the self-complete questions to the HUI-3 and HUI-2 attribute levels are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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From the standard HUI 15-item questionnaire data we are able to determine 8 scores (with differing 
number of variables in the scoring) which are used to calculate an overall utility score for HUI-3 and 
HUI-2:  
 
1. HUI-3 attribute levels (8 variables; calculated from HUI 15-item questionnaire data) 
2. HUI-3 single-attribute utility scores (8 variables; calculated from the HUI-3 attribute levels) 
3. HUI-3 comprehensive health state (1 variable; 8-element vector from HUI-3 attribute levels) 
4. HUI-3 overall multi-attribute utility score (1 variable; calculated from single-attribute utility scores) 
5. HUI-2 attribute levels (7 variables; calculated from the HUI-3 attribute levels) 
6. HUI-2 single-attribute utility scores (7 variables; calculated from the HUI-2 attribute levels) 
7. HUI-2 comprehensive health state (1 variable; 7-element vector from HUI-3 attribute levels) 
8. HUI-2 overall multi-attribute utility score (1 variable; calculated from single-attribute utility scores) 
 
The statistical analysis will be completed utilizing the OVERALL MULTI-ATTRIUBUTE UTILITY 
SCORES for HUI-3 and HUI-2. 
 
The HUI-2 and HUI-3 multi-attribute utility score scales are each defined such that the score for dead is 
set to 0.00. The score for perfect health (defined as the state having all attributes at level 1) is set to 1.00. 
The HUI-2 multi-attribute utility scale is defined for the interval -0.03 to 1.00; the HUI-3 multi-attribute 
utility scale is defined for the interval -0.36 to 1.00. Negative scores represent states considered worse 
than dead. 
 
The following instructions guide the user in the determination of HUI-3 and HUI-2 attribute levels and 
overall multi-attribute utility scores for each subject: 
 
1. Determining HUI-3 Attribute Levels (8 variables) 
The levels are Vision, Hearing, Speech, Emotion, Pain, Ambulation, Dexterity, and Cognition. 
Four of these attributes (vision, hearing, speech, and cognition) each require input from sets of 
two questions to determine the attribute level.  
 
The scoring methods for HUI-3 Attribute Levels can be found in Tables 15-19: 
Table 15: 
HUI-3 Vision Attribute Level Decision Table 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 16: 
HUI-3 Hearing Attribute Level Decision Table 
 
 
Table 17: 
HUI-3 Speech Attribute Level Decision Table 
 
Table 18: 
HUI-3 Cognition Attribute Level Decision Table 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 19: 
Ambulation, Dexterity, Emotion and Pain Attribute Level Decision Table 
 
 
The standard, and somewhat arbitrary, HUB attribute levels for comatose study subjects are 
defined as follows: Vision= Level 6; Hearing= Level 6; Speech= Level 5; Ambulation= Level 6; 
Dexterity= Level 6; Emotion= Level 3; Cognition= Level 6; and Pain= Level 3.  
 
2. Determining HUI-2 Attribute Levels (7 variables)  
The levels are Sensation, Mobility, Cognition, Self-Care, Emotion, Pain, and Fertility. HU1-2 
level codes for sensation and mobility attributes are derived directly from previously determined 
HUI-3 attribute level codes. Note: To distinguish clearly previously determined HUI-3 levels 
from HUI-2 levels being determined, the HUI-3 levels are printed as words and the HUI-2 levels 
are specified using numerals. 
 
The scoring methods for HUI-2 Attribute Levels can be found in Tables 20-24: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 20: 
HUI-2 Sensation Attribute Level Decision Table 
 
Table 21: 
HUI-2 Mobility Attribute Level Decision Table  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 22: 
HUI-2 Cognition Attribute Level Decision Table  
 
 
Table 23: 
HUI-2 Self-Care, Emotion, and Pain Attributes Level Decision Table  
 
 
Table 24: 
HUI-2 Fertility Attributes Level Decision Table  
 
 
The standard, and somewhat arbitrary, HUI-2 attribute levels for comatose study subjects are as 
follows: Sensation= Level 4; Mobility= Level 5; Emotion= Level 3; Cognition Level 4; Self-
Care= Level 4; Pain= Level 3; and Fertility= Level 1.  
 
3. Determining Single-Attribute HUI-3 Utility Scores (8 variables) 
Single-attribute utility functions provide preference scores of relative desirability for functional 
capacity within single attributes defined by the HUI-3 health status classification system. The 
HUI-3 levels are labelled using integers. Each single-attribute utility function is defined on a 
scale from 0.00 to 1.00. 
 
The most disabled level of an attribute has a single-attribute utility score of 0.00, and no disability 
of an attribute has a single-attribute utility score of 1.00. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  


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Scoring is as follows: 
Attribute 
Level 
Vision 
u1 
Hearing 
u2 
Speech 
u3 
Ambulation
u4 
Dexterity
u5 
Emotion
u6 
Cognition
u7 
Pain 
u8 
1 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
2 
0.95 
0.86 
0.82 
0.83 
0.88 
0.91 
0.86 
0.92 
3 
0.73 
0.71 
0.67 
0.67 
0.73 
0.73 
0.92 
0.77 
4 
0.59 
0.48 
0.41 
0.36 
0.45 
0.33 
0.70 
0.48 
5 
0.38 
0.32 
0.00 
0.16 
0.20 
0.00 
0.32 
0.00 
6 
0.00 
0.00 
n/a 
0.00 
0.00 
n/a 
0.00 
n/a 
Legend: ux: single-attribute utility function for attribute x, n/a: not applicable 
Note: The mean single-attribute utility score for level 3 cognition is greater than the mean single-attribute 
utility score for level 2 cognition. 
 
4. Determining Single-Attribute HUI-2 Utility Scores (7 variables) 
Single-attribute utility functions provide preference scores of relative desirability for functional 
capacity within single attributes defined by the HUI-2 health status classification system. The 
HUI-2 levels are labelled using integers. Each single-attribute utility function is defined on a 
scale from 0.00 to 1.00.   
 
The lack of functional capacity, or most disabled level, in an attribute has a single-attribute utility 
score of 0.00, and full function, or no disability, for an attribute has a single-attribute utility score 
of 1.00. 
 
Scoring is as follows: 
Attribute 
Level 
Sensation 
u1 
Mobility 
u2 
Emotion 
u3 
Cognition 
u4 
Self-Care 
u5 
Pain 
u6 
Fertility 
u7 
1 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
2 
0.87 
0.92 
0.86 
0.86 
0.85 
0.95 
0.75 
3 
0.65 
0.61 
0.60 
0.66 
0.55 
0.75 
0.00 
4 
0.00 
0.34 
0.37 
0.00 
0.00 
0.42 
n/a 
5 
n/a 
0.00 
0.00 
n/a 
n/a 
0.00 
n/a 
Legend: ux: single-attribute utility function for attribute x, n/a: not applicable 
 
5. Determining Overall Health-Related Quality of Life (HRQL) Utility Scores Using HUI-3 Utility 
Function (1 variable) 
To calculate the HUI-3 HRQL Utility Score, the above-determined single-attribute levels are 
entered into the following health utility formula or subjects who do not have missing data from 
the 15-item questionnaire: 
U=1.371(Vison*Hearing*Speech*Ambulation*Dexterity*Emotion*Cognition*Pain) 0.371 
 
 
 
 
 
 
 


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HUI-3 allows for negative scores of HRQL that represent health states considered worse than 
dead. The lowest possible HUI-3 score is -0.3. Note that the overall HRQL utility score for 
deceased subjects cannot be calculated using the HUB multi-attribute utility function and that this 
variable should be assigned a score of 0.00. (Dead is an anchor state of the conventional 
dead=0.00 to perfect health=1.00 overall HRQL utility scale and, therefore, the score for dead is 
0.00 by definition.) 
 
6. Determining Overall Health-Related Quality of Life (HRQL) Utility Scores Using HUI-2 Utility 
Function (1 variable) 
To calculate the HUI-2 HRQL Utility Score, the above-determined single-attribute levels are 
entered into the following health utility formula for subjects who do not have missing data 
from the 15-item questionnaire: 
U=1.06(Sensation*Mobility*Emotion*Cognition*Self-Care*Pain*Fertility) 0.06 
 
HUI-2 allows for negative scores of HRQL that represent health states considered worse than 
dead. The lowest possible HUI-2 score is -0.03. Note that the overall HRQL utility score for 
deceased subjects cannot be calculated using the HUB multi-attribute utility function and that this 
variable should be assigned a score of 0.00. (Dead is an anchor state of the conventional 
dead=0.00 to perfect health=1.00 overall HRQL utility scale and, therefore, the score for dead is 
0.00 by definition.) 
 
 
 
 
 
 
 
 


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9.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation 
and Suicidal Behavior Scores 
The C-SSRS is comprised of 10 categories with binary responses. The 10 categories include: 
Category 1  Wish to be Dead  
Category 2  Non-specific Active Suicidal Thoughts  
Category 3  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Category 4  Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
Category 5  Active Suicidal Ideation with Specific Plan and Intent  
Category 6  Preparatory Acts or Behavior  
Category 7  Aborted Attempt  
Category 8  Interrupted Attempt  
Category 9  Actual Attempt (non-fatal)  
Category 10  Completed Suicide 
Categories 1-5 represent Suicidal Ideation and categories 6-10 represent Suicidal Behavior. Each 
category is scored as 1 if there is a positive response in the category and a 0 if there are no 
positive responses in the category.    
 Self-Injurious Behavior Without Suicidal Intent During Treatment 
A subject will be categorized as having self-injurious behavior without suicidal intent if there is 
an occurrence of non-suicidal self-injurious behavior on the C-SSRS  Since Last Visit eCRF at 
any post-baseline visit. 
 Baseline C-SSRS Score  
Baseline represents the pre-treatment assessment of recent history, with elements of suicidal 
ideation assessed over the prior 6 months and elements of suicidal behavior assessed over the 
prior 2 years. It is scaled from 0 (no suicidal ideation or behavior) to 10 (completed suicide) 
 Treatment-Emergent Suicide-Related Event  
A subject will be categorized as having a treatment-emergent suicide-related event if at least one 
post-baseline suicidal ideation or suicidal behavior score is greater than 0.  
 Treatment-Emergent Suicidal Ideation Compared to Recent History 
A subject will be categorized as having treatment-emergent suicidal ideation compared to recent 
history when there is at least one post-baseline suicidal ideation score > 0 and is an increase from 
baseline. Lifetime scores are not considered for baseline suicidal ideation responses. 
 Treatment-Emergent Serious Suicidal Ideation Compared to Recent History 
A subject will be categorized as having treatment-emergent serious suicidal ideation compared to 
recent history if the baseline score was < 4 and the post-baseline suicidal ideation score increases 
to 4 or 5. Lifetime scores are not considered for baseline suicidal ideation responses. 
 
 
 
 
 
 
 
 
 
 
 


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 Emergence of Serious Suicidal Ideation Compared to Recent History 
A subject will be categorized as having emergence of serious suicidal ideation compared to 
recent history if baseline score was 0 (no suicidal ideation) and post-baseline C-SSRS suicidal 
ideation score is either 4 or 5. Lifetime scores are not considered for baseline suicidal ideation 
responses.  
 Emergence of Suicidal Behavior Compared to all Prior History 
A subject will be categorized as having emergence of suicidal behavior compared to all prior 
history if there had been no suicidal behavior in Categories 6-10 reported at any pre-treatment 
assessment, including responses to lifetime history questions, and there is at least one positive 
post-baseline C-SSRS assessment in Categories 6-
 
history. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




















































 
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9.7. 
Programming Conventions 
 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in landscape 
urier New 
with a point size of 8.  
 
Identification of analysis population: Every summary table, listing, and figure will clearly specify the 
analysis population being summarized/listed. Listings will be prepared for all subjects randomized. 
 
Group headers: In the summary tables, the group headers will identify the within-group sample size 
number of subjects actually summarized within any given summary module; some subjects in the 
analysis population may have missing values and thus may not be summarized. 
 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when the 
count is zero in order to draw attention to the non-zero counts. 
 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the number 
of subjects actually contributing to the summary statistics presented in any given summary module. 
As mentioned above, this may be less than the number of subjects in the analysis population. 
 In the quantitative modules describing continuous variables (and thus presenting sample size, 
means, and standard deviations), the sample size should be the number of non-missing 
observations 
 For categorical variables that are presented in frequency tables, the module should present the 
total count in addition to the count in each category. Percentages should be calculated using this 
total as the denominator, and the percentage corresponding to the sum itself (that is, 100%) 
should be presented so as to indicate clearly to a reviewer the method of calculation. 
 
Sorting: Listings will be sorted by treatment, subject number and date, if applicable. If a listing is 
sorted in a different manner, it will be indicated on the listing shells.  
 
General formatting rules: Rounding for all variables will occur only as the last step, immediately prior 
to presentation in listings, tables, and figures. No intermediate rounding will be performed on derived 
variables. The standard rounding practice of rounding numbers ending in 0-4 down and numbers 
ending in 5-9 up will be employed.  
 
The presentation of numerical values will adhere to the following guidelines (exceptions may be 
necessary in some circumstances for derived analysis variables to allow readability):  
 Raw measurements will be reported to the number of significant digits as captured electronically 
or on the eCRFs.  
 Standard deviations will be reported to two decimal places beyond the number of decimal places 
the original parameter is presented. 
 Means will be reported to the one decimal place beyond the number of decimal places the original 
parameter is presented. 
 Calculated percentages will be reported with one decimal place.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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 Coefficient of variation will be reported to the same number of decimal places as the standard 
deviation.  
 
Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data listings as 
recorded on eCRFs. 
 
Time will be presented according to the 24-hour clock (HH:MM). 
 
Verification of Results: All analyses will be subject to formal verification procedures. Specifically, 
results will be verified utilizing independent programming prior to issuance of the draft statistical 
report. All documents will be verified by the lead statistician to ensure accuracy and consistency of 
analyses. 
 
 
 
 
 
 
 
 
 
 
 


 
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9.8. 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AED 
Anti-epileptic drug 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST  
Aspartate aminotransferase 
ATC  
Anatomic Therapeutic Chemical 
BID 
Twice daily 
BMI 
Body mass index 
BZD 
Benzodiazepine 
CGI-S 
Clinical Global Impression  Severity of Symptoms 
CGI-I 
Clinical Global Impression  Improvement 
CI 
Confidence interval 
CRF 
Case Report Form 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVL-865 
Study drug 
DBS 
Deep brain stimulator 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HUI 
Health Utilities Index 
ICF 
Informed consent form 
ILAE 
International League Against Epilepsy 
IMP 
Investigational medicinal product 
LLN 
Under the lower limit of normal 
LOQ 
Limit of quantification 
mCIWA-B 
Modified Clinical Institute Withdrawal Assessment  Benzodiazepines 
MedDRA 
Medical Dictionary for Regulatory Activities