Clinical trial NCT03406702
Conditions: Epilepsy
Keywords: Epilepsy, Idiopathic Generalized Epilepsy, Absence Seizures
Sponsor: Jazz Pharmaceuticals
Start date: 2018-02-25; Completion date: 2019-03-29
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2a, open-label study consisting of a screening period of up to 4 weeks and a 4-dose-titration treatment period to a dose of up to 10 mg twice daily (BID) of CX-8998, followed by a 1-week safety follow-up period after the last dose of study medication.

Detailed description:
This is a Phase 2a, open-label study consisting of a screening period of up to 4 weeks and a 4-dose-titration treatment period to a dose of up to 10 mg twice daily (BID) of CX-8998, followed by a 1-week safety follow-up period after the last dose of study medication.

Subjects will participate for a total of up to 9 weeks, including screening, the 4-week treatment period and follow-up.

Arms: arm 1: T-type calcium channel blocker
Interventions: intervention 1: CX-8998
Intervention descriptions: intervention 1: T-type calcium channel blocker

Protocol documents:
Prot_000.pdf: 
Cavion, Inc. 
CX-8998 for Absence Seizures
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019
CONFIDENTIAL AND PROPRIETARY 
Page 1 of 91 
TITLE PAGE 
Clinical Study Protocol 
Main Title: 
A Phase 2a, Safety, Tolerability, Pharmacokinetics, and Quantitative EEG 
Study of CX-8998 in Adolescents and Adults with Idiopathic Generalized 
Epilepsy with Absence Seizures
Protocol Number: 
CX-8998-CLN2-002
Original Version Number: 1.0 Date: 23 Oct 2017 
Amendment 1, Version Number: 2.0 Date: 12 Dec 2017 
Amendment 2, Version Number: 3.0 Date: 30 April 2018 
Amendment 3, Version Number: 4.0 Date: 24 September 2018 
Amendment 4, Version Number: 5.0 Date: 29 April 2019 
Amendment 5, Version Number: 6.0 Date: 30 May 2019 
IND #: 130296 
Official Short Title: 
CX-8998 for Absence Seizures
Confidentiality Statement:
This document contains information proprietary to Cavion, Inc, and is intended solely for the 
purpose of this clinical investigation. It should be kept securely, and its contents should not be 
disclosed to any third party without the prior written consent of Cavion, Inc. 
NCT03406702


Cavion, Inc. 
 
CX-8998 for Absence Seizures 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 2 of 91 
SIGNATURE PAGE FOR SPONSOR 
 
Study No.  
 
CX-8998-CLN2-002 
 
Protocol Title:  
A Phase 2a, Safety, Tolerability, Pharmacokinetics, and Quantitative EEG 
Study of CX-8998 in Adolescents and Adults with Idiopathic Generalized 
Epilepsy with Absence Seizures 
 
 
 
Approved by the following: 
 _______________________  
Date 
Cavion, Inc. 
One Broadway 
Cambridge, MA 02142 
 
31MAY2019
PI


Cavion, Inc. 
 
CX-8998 for Absence Seizures 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 3 of 91 
SIGNATURE PAGE FOR INVESTIGATOR 
 
Study No.  
 
CX-8998-CLN2-002 
 
Protocol Title:  
A Phase 2a, Safety, Tolerability, Pharmacokinetics, and Quantitative EEG 
Study of CX-8998 in Adolescents and Adults with Idiopathic Generalized 
Epilepsy with Absence Seizures 
 
 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with all applicable regulations, ICH and the Declaration of Helsinki. 
 
 __________________________________  
 __________________________________  
 _______________________  
Investigator Name 
Signature 
 
Date 
 
 


Cavion, Inc. 
 
CX-8998 for Absence Seizures 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 4 of 91 
STUDY ORGANIZATIONAL STRUCTURE 
Sponsor: 
Cavion, Inc. 
One Broadway 
Cambridge, MA 02461 
+1.434.200.8442 
Study Safety Representative: 
24-Hour Serious Adverse Event (SAE) Reporting 
Primary contact: Premier Research Pharmacovigilance 
Reporting email: GlobalPV-US@premier-research.com 
Backup reporting fax number: +1.215.972.8765 
 
COMPLIANCE STATEMENT 
This study will be conducted in full accordance with the International Conference on Harmonisation 
(ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and 
local laws and regulations (eg, Title 21 Code of Federal Regulations [21CFR] Parts 11, 50, 54, 56, 
312, and 314, European Union [EU] Directive 20/EC and 28/EC). Any episode of noncompliance 
will be documented. 
The investigators are responsible for performing the study in accordance with this protocol and the 
applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of each investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national authorities. 
Each investigator is responsible for ensuring the privacy, health, and welfare of the subjects during 
and after the study and must ensure that trained personnel are immediately available in the event 
of a medical emergency. Each investigator and the applicable study staff must be familiar with the 
background to, and requirements of, the study and with the properties of the study drug(s) as 
described in the Investigator’s Brochure or prescribing information.  
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities. 
 


Cavion, Inc. 
 
CX-8998 for Absence Seizures 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 5 of 91 
PROTOCOL SYNOPSIS 
Study Title: A Phase 2a, Safety, Tolerability, Pharmacokinetics, and Quantitative EEG Study of 
CX-8998 in Adolescents and Adults with Idiopathic Generalized Epilepsy with Absence 
Seizures 
Name of Finished Product: CX-8998 
Protocol Number: CX-8998-CLN2-002 
Study Phase: 2a 
Clinical Sites: 
Multiple sites in the United States 
Primary Objective 
• 
To assess the safety and tolerability of CX-8998 in adolescents and adults with idiopathic 
generalized epilepsy (IGE) with absence seizures. 
Secondary Objectives 
• 
To evaluate the pharmacokinetics (PK) of CX-8998 and its metabolites (including, but not 
limited to, M01 and M02) in the plasma of subjects with IGE with absence seizures. 
Exploratory Objectives 
• 
To assess the exposure-response and exposure-safety relationships for plasma CX-8998 and its 
metabolites (including, but not limited to, M01 and M02); results to be reported separately 
from the clinical study report. 
• 
To evaluate the pharmacodynamic effects of CX-8998 as measured by electroencephalogram 
(EEG) 
Study Design: 
This is a Phase 2a, open-label study consisting of a screening period of up to 4 weeks and a 4-dose-
titration treatment period to a dose of up to 10 mg twice daily (BID) of CX-8998, followed by a 
1-week safety follow-up period after the last dose of study medication. 
Study Population:  
Inclusion Criteria 
1. Signed informed consent form (ICF) indicating that the subject has been informed of the 
procedures to be followed, the experimental nature of the therapy, alternatives, potential 
benefits, side effects, risks, and discomforts. 
2. Men or nonpregnant, non-breastfeeding women 16 to 55 years of age who are able to read and 
understand written and spoken local language.  
3. Clinical diagnosis of IGE (including, but not limited to, childhood absence epilepsy, juvenile 
absence epilepsy, juvenile myoclonic epilepsy, or Jeavons syndrome) with absence seizures 
consistent with the International League against Epilepsy Revised Classification of Seizures 
(2017). 
4. Absence seizures, by history on average once per hour, persisting despite standard of care 
(SOC) treatment, defined as treatment with at least 2 antiepileptic drugs (AEDs) appropriate for 
the patient’s epilepsy syndrome. SOC failure, per investigator discretion, will be defined as 
insufficient clinical response or intolerable side effects, which precludes the use of the 
appropriate AED. 
5. Observation of at least 1 provoked absence seizure during at least 1 of the hyperventilation 
(HV) periods and at least 3 absence seizures during the 6.5-hour video-EEG. Absence seizures 


Cavion, Inc. 
 
CX-8998 for Absence Seizures 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 6 of 91 
are defined on EEG as typical generalized 3-Hz spike and wave lasting ≥3 seconds during 
wakefulness. Hyperventilation should be carried out in the following manner: 5 minutes of HV 
(HV period 1), followed by 5 minutes of relaxation, followed by a second 5 minutes of HV (HV 
period 2). Subjects who have an induced seizure during HV period 1 do not need to undergo HV 
period 2. At least 75% of the background should be normal. 
6. On stable doses of one or more antiepileptic medication(s) for at least 30 days. If a subject is not 
on medication, adequate documentation justifying lack of therapy may be acceptable for the 
subject after sponsor review. Ketogenic, modified Atkins diet (MAD), or low glycemic diet with 
stable carbohydrate ratio for at least 30 days before screening is an acceptable antiepileptic 
therapy. Vagal nerve stimulation at stable settings (for at least 30 days before screening), 
without use of the magnet, is also acceptable. 
7. Body weight ≥45 kg at screening. 
8. Subjects with reproductive capability, including all males and women of childbearing potential 
(WOCBP), must agree to practice continuous abstinence or adequate contraception methods 
(appropriate double barrier method or oral, patch, implant, or injectable contraception) from as 
soon as feasible during screening period until at least 30 days after the last dose (i.e., 
intermittent abstinence based on “rhythm,” temperature monitoring, or other means of timing 
is not acceptable). WOCBP include any woman who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, and/or 
bilateral oophorectomy) or is not postmenopausal. Postmenopausal is defined as amenorrhea 
for ≥12 consecutive months without another cause, and a documented serum follicle-
stimulating hormone (FSH) level ≥35 mIU/mL.  
9. Male subjects with a partner of childbearing potential must be surgically sterilized or be willing 
to use condoms with spermicide from as soon as feasible during screening period until at least 
30 days after the last dose.  
10. Able and willing to comply with scheduled visits, treatment plan, laboratory tests, and other 
study procedures. 
11. Approval by the sponsor medical personnel or delegate as to final eligibility for the study. 
Exclusion Criteria 
1. History of surgical intervention for treatment of epilepsy. 
2. Additional seizure (clinical and electrographic) types, including, but not limited to, epileptic 
spasms, generalized tonic seizures, atonic seizures, or focal seizures. Subjects with generalized 
tonic-clonic seizure (GTCS) or myoclonic seizures are eligible for the study. 
3. Inadequately treated psychotic or mood disorder (e.g., schizophrenia, major depression, bipolar 
disorder). 
4. Presence of severe intellectual disability, severe autism spectrum disorder, or severe 
developmental disorder such that the subject cannot sign the ICF or cannot cooperate with the 
study procedures. 
5. Presence of positive urine drug screen for drugs of abuse, except if this is explained by use of an 
allowed prescription medicine.  
6. Regular use of more than 2 standard drinks of alcohol per day (28 grams of pure alcohol). 
7. Hypersensitivity/allergic reaction to other T-type calcium agents, such as (but not limited to) 
ethosuximide and zonisamide. 
8. Use of strong CYP3A4 inhibitors, including prescription or nonprescription drugs or other 
products (e.g., grapefruit juice), which cannot be discontinued at least 2 weeks prior to Day 1 of 


Cavion, Inc. 
CX-8998 for Absence Seizures
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019
CONFIDENTIAL AND PROPRIETARY 
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dosing and throughout the study (Appendix B). 
9.
Concurrent illnesses that would be a contraindication to trial participation, including, but not
limited to:
a) Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris,
stroke) less than 6 months before screening.
b) New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular
arrhythmias or uncontrolled hypertension.
c)
Clinically significant electrocardiographic (ECG) abnormality per the investigator
assessment or any of the following:
i)
QTcF ≥450 msec (males) or ≥470 msec (females).
ii) PR interval ≥250 msec.
iii) Atrioventricular block of second degree or higher, including Mobitz I.
iv) Persistent sinus bradycardia of ≤50 beats per minute; persistent means the bradycardia
is present on the first ECG and on one repeat ECG performed on another day.
v) For other ECG findings (including, but not necessarily limited to, tachycardia, bundle
branch block, frequent ectopic beats, etc) the investigator should send a scanned,
identity-blinded copy of the ECG tracing to the Study Safety Representative for review.
10. Positive result for human immunodeficiency virus (HIV), hepatitis B [indicating ongoing
infection], or hepatitis C at screening or otherwise known ongoing infection with HIV, hepatitis
B, or hepatitis C, unless curative therapy completed; for hepatitis C curative therapy is defined
as negative polymerase chain reaction (PCR) for hepatitis C virus (HCV) RNA.
11. Significant hepatic (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] or
bilirubin ≥2 times the upper limit of normal) or renal disease (creatinine clearance
≤39 mL/min) at screening.
12. History of alcohol or substance abuse within the last year.
13. A current Columbia-Suicide Severity Rating (C-SSRS) score of 4 or 5 at screening or history of
suicide attempt.
14. Psychological, social, familial, or geographical reasons that would hinder or prevent compliance
with the requirements of the protocol or compromise the informed consent process.
15. Any other condition and/or situation that causes the investigator or Study Safety
Representative to deem a subject unsuitable for the study (including, but not limited to,
expected study medication noncompliance, inability to medically tolerate the study procedures,
or a subject’s unwillingness to comply with study–related procedures).
16. Treatment with an investigational agent within 30 days prior to the first dose of CX-8998 or
planning to receive an investigational agent during the study.
17. Subjects who do not experience a provoked absence seizure during either HV period and who
have fewer than 3 typical absence seizures during the baseline video-EEG (considered to be
screen failures).
Planned Number of Patients: 
Up to approximately 15 
Test Product, Dose, and Mode of Administration: 
CX-8998, 2 mg capsule, oral


Cavion, Inc. 
 
CX-8998 for Absence Seizures 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
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Reference Product, Dose, and Mode of Administration:  
None 
Duration of Treatment:  
26 days 
Administration:  
CX-8998 will be administered as: 
1. Days 1 – 2: 
2 mg (1 capsule) BID (4 mg/d);  
2. Days 3 – 8: 
4 mg (2 capsules) BID (8 mg/d); 
3. Days 9 – 14: 
6 mg (3 capsules) BID (12 mg/d); 
4. Days 15 – 20:  8 mg (4 capsules) BID (16 mg/d);  
5. Days 21 – 26:  10 mg (5 capsules) BID (20 mg/d). 
  
Study drug should be administered with food. Subjects should be instructed to take their daily dose 
at approximately the same times each day. Consecutive doses should be taken no closer than 10 
hours and no later than 14 hours (every 12 hours ± 2 hours). Subjects will remain under 
observation for at least 4 hours post-dosing prior to discharge at Visit 1.  
At the Day 26 clinic visit at which 2 postdose PK blood draws, >2 hours apart, are scheduled to be 
obtained, subjects will take the morning dose at the appropriate time. Both the time of the morning 
dose and the time of the PK blood draw will be recorded. 
A missed dose (>14 hours since the prior dose) should be skipped and should not be “doubled-up” 
or “made up”; the next dose should be taken 24 hours from the last administered dose. If the subject 
experiences emesis following the dose, that dose should not be retaken; instead the next dose 
should be taken 24 hours from the last administered dose without emesis. If emesis occurs, the 
subject should contact the investigator or qualified designee at the study site for guidance on 
management of the emesis. 
Subjects who experience specified adverse events (AEs) will have their dose adjusted. Subjects 
suspected of experiencing neuropsychiatric AEs may be asked to return to the clinic for an 
unscheduled visit prior to further dose escalation. 
Duration of Subject Study Participation: 
Subjects will participate for a total of up to 9 weeks, including screening, the 4-week treatment 
period and follow-up. 
Endpoints: 
Primary Endpoint:  
Safety and tolerability endpoints:  
• 
Treatment-emergent adverse events (TEAE),  
• 
Changes from baseline in QTcF and other ECG parameters,  
• 
Changes from baseline in clinical safety laboratory assessments (clinical chemistry, 
hematology, and urinalysis),  
• 
Changes from baseline in vital signs,  
• 
Number (%) of subjects who did not complete the study due to TEAEs 
• 
Number (%) of subjects with serious adverse events (SAEs)  


Cavion, Inc. 
 
CX-8998 for Absence Seizures 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
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• 
Number (%) of subjects with adverse events of special interest (AESI): 
o Increased seizure frequency 
o New seizure types 
o Status epilepticus 
• 
C-SSRS 
• 
University of Miami Parkinson's Disease Hallucinations Questionnaire (UM-PDHQ) 
Secondary Endpoints: 
• 
Plasma PK parameters: Cmax, Tmax, Cmin, and partial AUC0-4h for CX-8998 and metabolites 
(including, but not limited to, M01 and M02) 
• 
Additional CX-8998 PK parameters (CL/F, Vz/F, t1/2) may be estimated, pending 
performance of a population PK analysis with data pooled from several studies (to be 
reported separately from the clinical study report) 
Exploratory Endpoints:  
• 
Change in frequency (number of seizures per hour) of absence seizures as defined by a 3-Hz 
spike and wave lasting ≥3 seconds as determined by HV (HV period 1 + HV period 2) 
• 
Change in frequency (number of seizures per hour) of absence seizures as defined by 3-Hz 
spike and wave lasting ≥3 seconds during wakefulness as determined by 6.5-hour 
video-EEG 
• 
Time to absence seizure occurrence during HV (HV period 1 + HV period 2) 
• 
Percent of subjects with a shift in occurrence of absence seizure during HV (e.g., shift for 
seizure occurring in HV period 1 or HV period 2 to no seizures occurring during either HV 
period; shift from absence seizure occurring to HV period 1 to HV period 2) 
• 
Change from baseline to end of treatment in absence seizure-free days based on seizure 
diary 
• 
Absence of photic response in subjects who had photic response during the baseline 
video-EEG 
• 
Change in the Seizure-related Disability Assessment Scale (SERDAS) 
• 
Relationship between the EEG parameters and the PK of CX-8998  
• 
Exposure-response and exposure-safety relationships using plasma concentrations of 
CX-8998 and its 2 primary metabolites (M01 and M02) in population 
pharmacokinetic/pharmacodynamic (PK/PD) analyses (to be reported separately from the 
clinical study report) 
Pharmacokinetic Variables and Endpoints: 
Plasma concentrations of CX-8998 and its metabolites (including, but not limited to, M01 and M02) 
will be determined at various visits and doses of CX-8998. Concentrations will also be incorporated 
into a population PK/PD model that will estimate peak exposure (Cmax) and overall exposure (AUC) 
of CX-8998. 
Statistical Methods:  
Sample size justification:  
The sample size was not based on statistical considerations, but rather chosen to provide safety and 
efficacy information on CX-8998 when administered  according to this protocol 
Safety analyses: 


Cavion, Inc. 
CX-8998 for Absence Seizures
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019
CONFIDENTIAL AND PROPRIETARY 
Page 10 of 91 
Adverse events will be mapped to a MedDRA (Medical Dictionary for Regulatory Activities) 
preferred term and system organ classification. Severity will be assessed by investigator. The 
occurrence of TEAEs will be summarized using MedDRA preferred terms, system organ 
classifications, and severity. All AEs will be listed for individual subjects; both verbatim and 
preferred terms will be listed. Separate summaries of treatment-emergent SAEs, AESIs, and AEs 
leading to discontinuation of study or study drug will be generated. 
Descriptive summaries of vital signs and clinical laboratory results will be prepared. The number 
and percentage of subjects experiencing treatment-emergent laboratory abnormalities and 
laboratory abnormality shifts from baseline to postbaseline assessments will be summarized. 
Concomitant medications will be mapped to a World Health Organization (WHO) Drug Dictionary 
preferred term and drug classification. The number and percent of subjects taking concomitant 
medications will be summarized using preferred terms and drug classifications.  
Changes from baseline in ECGs during study will be evaluated. Results from the C-SSRS, UM-PDHQ, 
and physical examinations will be listed.  
Efficacy analyses: 
The change in frequency (number of seizures per hour) of absence seizures as defined by a 3-Hz 
spike and wave lasting for ≥3 seconds as determined by HV, the frequency (number of seizures per 
hour) of absence seizures (based on 6.5-hour video-EEG), the time to absence seizures during HV, 
the percent of subjects with a shift in the occurrence of absence seizure (e.g., from HV period 1 to 
HV period 2), the percent of subjects with an absence of photic response, the actual and change 
from baseline in SERDAS scores, and the change from baseline to end of treatment in absence 
seizure-free days as collected by seizure diary will be summarized. Ninety-five percent (95%) 
confidence intervals will be constructed. 


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Cavion, Inc. 
Protocol Number: CX-8998-CLN2-002 
TABLE OF CONTENTS 
TITLE PAGE ....................................................................................................................................................................................1 
SIGNATURE PAGE FOR SPONSOR ..................................................................................................................................... 2 
SIGNATURE PAGE FOR INVESTIGATOR ......................................................................................................................... 3 
STUDY ORGANIZATIONAL STRUCTURE ......................................................................................................................... 4 
COMPLIANCE STATEMENT .................................................................................................................................................. 4 
PROTOCOL SYNOPSIS ............................................................................................................................................................. 5 
TABLE OF CONTENTS .......................................................................................................................................................... 11 
TABLE OF TABLES ................................................................................................................................................................ 16 
TABLE OF FIGURES............................................................................................................................................................... 17 
GLOSSARY OF TERMS AND ABBREVIATIONS ........................................................................................................... 18 
1 
BACKGROUND INFORMATION AND RATIONALE .......................................................................... 21 
1.1 
Introduction .................................................................................................................................................... 21 
1.1.1 
Absence Epilepsy .......................................................................................................................................... 21 
1.1.2 
Treatments for Absence Seizures .......................................................................................................... 21 
1.2 
Rationale for Evaluating CX-8998 in Idiopathic Generalized Epilepsy with 
Absence Seizures .......................................................................................................................................... 23 
1.2.1 
CaV3 and its Role in Neurological Disorders with Excessive or Abnormal 
Rhythmicity .................................................................................................................................................... 23 
1.2.2 
Role of Cav3 in Epilepsy ............................................................................................................................ 23 
1.3 
Nonclinical Pharmacology ........................................................................................................................ 24 
1.3.1 
Primary Pharmacology Studies .............................................................................................................. 24 
1.3.2 
Safety Pharmacology and Toxicology Studies .................................................................................. 25 
1.4 
CX-8998 Clinical Experience .................................................................................................................... 27 
1.4.1 
Clinical Pharmacokinetics......................................................................................................................... 29 
1.4.2 
Clinical Pharmacodynamics ..................................................................................................................... 30 
1.4.3 
Clinical Safety ................................................................................................................................................. 30 
1.5 
Rationale for Selected Dose ..................................................................................................................... 31 
2 
STUDY OBJECTIVES ..................................................................................................................................... 35 


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CX-8998 for Absence Seizures
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019
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2.1 
Primary Objective ........................................................................................................................................ 35 
2.2 
Secondary Objectives .................................................................................................................................. 35 
2.3 
Exploratory Objectives ............................................................................................................................... 35 
3 
STUDY DESIGN AND ENDPOINTS ......................................................................................................... 35 
3.1 
Study Type ...................................................................................................................................................... 35 
3.2 
Schematic of Study Design ........................................................................................................................ 35 
3.3 
Endpoints ......................................................................................................................................................... 37 
3.3.1 
Primary Endpoint ......................................................................................................................................... 37 
3.3.2 
Secondary Endpoints .................................................................................................................................. 37 
3.3.3 
Exploratory Endpoints ............................................................................................................................... 37 
4 
STUDY DRUG .................................................................................................................................................. 38 
4.1 
Supply and Storage ...................................................................................................................................... 38 
4.2 
Packaging and Labeling ............................................................................................................................. 38 
4.3 
Administration .............................................................................................................................................. 39 
4.4 
Subject Stopping Rules ............................................................................................................................... 39 
4.5 
Study Drug Accountability and Compliance ...................................................................................... 40 
4.5.1 
Study Drug Accountability ........................................................................................................................ 40 
4.5.2 
Subject Compliance with Study Drug ................................................................................................... 40 
4.6 
Dose Adjustments / Toxicity Management ....................................................................................... 41 
4.7 
Overdose Management .............................................................................................................................. 41 
5 
INVESTIGATORS, SITES, AND DURATION ......................................................................................... 42 
5.1 
Investigators and Sites ............................................................................................................................... 42 
5.2 
Central Reviewers ........................................................................................................................................ 42 
5.3 
Duration of Study ......................................................................................................................................... 42 
5.4 
Termination of Study .................................................................................................................................. 42 
6 
STUDY POPULATION .................................................................................................................................. 42 
6.1 
Number of Subjects ..................................................................................................................................... 42 
6.2 
Inclusion Criteria .......................................................................................................................................... 42 
6.3 
Exclusion Criteria ......................................................................................................................................... 43 


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Protocol Number: CX-8998-CLN2-002 
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6.4 
Withdrawal of Subjects and/or Discontinuation of Treatment ................................................ 45 
6.4.1 
Follow-up Procedures for Subjects Who Withdraw/Discontinue Prematurely ................ 45 
6.4.2 
Procedures for Replacing Subjects Who Withdraw/Discontinue Prematurely ................. 46 
7 
TREATMENT PLAN AND METHODS .................................................................................................... 46 
7.1 
Schedule of Assessments ........................................................................................................................... 46 
7.2 
Summary of Treatment Visits ................................................................................................................. 50 
7.2.1 
Screening ......................................................................................................................................................... 50 
7.2.2 
Visit 1 (Day 0 - Baseline) ........................................................................................................................... 50 
7.2.3 
At Home Dose Titration (Days 1-26) .................................................................................................... 50 
7.2.4 
Telephone Safety Check (Day 2) ............................................................................................................ 50 
7.2.5 
Telephone Safety Check (Day 8) ............................................................................................................ 50 
7.2.6 
Telephone Safety Check (Day 14) .......................................................................................................... 51 
7.2.7 
Telephone Safety Check (Day 20) .......................................................................................................... 51 
7.2.8 
End of Study Visit (Day 26) ...................................................................................................................... 51 
7.2.9 
Telephone Safety Check (Day 33) .......................................................................................................... 51 
7.2.10 
Follow-up Phone Call .................................................................................................................................. 51 
7.3 
Concomitant Medications and Other Restrictions .......................................................................... 52 
7.3.1 
Concomitant Medications ......................................................................................................................... 52 
7.3.2 
Other Restrictions ........................................................................................................................................ 52 
8 
EFFICACY ASSESSMENTS ......................................................................................................................... 52 
8.1 
Electroencephalogram ............................................................................................................................... 52 
8.2 
Seizure-related Disability Assessment Scale .................................................................................... 52 
8.3 
Daily Seizure Diary ...................................................................................................................................... 52 
9 
PHARMACOKINETIC AND PHARMACOGENOMIC ASSESSMENTS .......................................... 53 
9.1 
Blood Sample Collection for Pharmacokinetic Assessments ..................................................... 53 
9.2 
Pharmacokinetic Parameters .................................................................................................................. 53 
9.3 
Pharmacogenomics of Drug Response ................................................................................................ 53 
10 
SAFETY ASSESSMENTS .............................................................................................................................. 54 
10.1 
Assessment of Safety ................................................................................................................................... 54 


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CX-8998 for Absence Seizures
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019
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10.1.1 
Adverse Events .............................................................................................................................................. 54 
10.1.2 
Physical and Neurological Examinations ........................................................................................... 54 
10.1.3 
Vital Signs ........................................................................................................................................................ 54 
10.1.4 
Clinical Laboratory Tests .......................................................................................................................... 55 
10.1.5 
Urine Drug Screen ........................................................................................................................................ 55 
10.1.6 
Pregnancy Tests ............................................................................................................................................ 55 
10.1.7 
Electrocardiogram ....................................................................................................................................... 55 
10.1.8 
Columbia-Suicide Severity Rating Scale .............................................................................................. 56 
10.1.9 
University of Miami Parkinson’s Disease Hallucinations Questionnaire .............................. 56 
10.2 
Adverse Events .............................................................................................................................................. 57 
10.2.1 
Definitions ....................................................................................................................................................... 57 
10.2.2 
Collection and Rating of Adverse Events ............................................................................................ 58 
10.2.3 
Adverse Event Follow-up .......................................................................................................................... 59 
10.3 
Serious and Other Significant Adverse Events ................................................................................. 60 
10.3.1 
Definition of a Serious Adverse Event ................................................................................................. 60 
10.3.2 
Serious Adverse Event Reporting by the Investigator to the Sponsor ................................... 61 
10.3.3 
Handling of Follow-up Information ...................................................................................................... 61 
10.3.4 
Reporting and Follow-up of Pregnancy .............................................................................................. 62 
10.3.5 
Expedited Reporting of Serious Adverse Events ............................................................................. 62 
10.4 
Safety Monitoring and Risk Mitigation Plan ...................................................................................... 63 
11 
STATISTICAL METHODS ........................................................................................................................... 64 
11.1 
Statistical Analysis Plans ........................................................................................................................... 64 
11.2 
Study Hypothesis .......................................................................................................................................... 64 
11.3 
Determination of Sample Size ................................................................................................................. 64 
11.4 
Analysis Populations ................................................................................................................................... 64 
11.5 
Data Analysis .................................................................................................................................................. 65 
11.5.1 
Efficacy Analyses .......................................................................................................................................... 65 
11.5.2 
Safety Analyses .............................................................................................................................................. 65 
11.5.3 
Pharmacokinetic Analyses ....................................................................................................................... 65 


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11.6 
Missing, Unused, and Spurious Data .................................................................................................... 65 
12 
STUDY MANAGEMENT .............................................................................................................................. 66 
12.1 
Protocol Amendment and Protocol Deviation ................................................................................. 66 
12.1.1 
Protocol Amendment .................................................................................................................................. 66 
12.1.2 
Protocol Deviations and Waivers .......................................................................................................... 66 
12.2 
Ethics and Regulatory Aspects ................................................................................................................ 66 
12.2.1 
Ethical Conduct of the Study and Regulatory Guidelines ............................................................ 66 
12.2.2 
Institutional Review Board and Regulatory Approval .................................................................. 66 
12.2.3 
Subject Informed Consent ........................................................................................................................ 67 
12.3 
End of Study and Regulatory Notification .......................................................................................... 67 
12.4 
Data Protection and Confidentiality ..................................................................................................... 68 
12.5 
Monitoring ....................................................................................................................................................... 68 
12.6 
Quality Assurance and Quality Control ............................................................................................... 68 
12.7 
Source Data ..................................................................................................................................................... 68 
13 
DATA AND RECORD KEEPING ................................................................................................................ 69 
13.1 
Case Report Forms ....................................................................................................................................... 69 
13.2 
Record Keeping ............................................................................................................................................. 69 
14 
REFERENCES .................................................................................................................................................. 70 
15 
APPENDICES .................................................................................................................................................. 74 
APPENDIX A1 – COLUMBIA SUICIDE SEVERITY RATING SCALE ...................................................................... 75 
APPENDIX A2 – UNIVERSITY OF MIAMI PARKINSON’S DISEASE HALLUCINATIONS 
QUESTIONNAIRE (UM-PDHQ) ................................................................................................................ 81 
APPENDIX B – CYTOCHROME P450 DRUG INTERACTION TABLE................................................................... 83 
APPENDIX C – SUMMARY OF CX-8998 TOXICOLOGY STUDIES ......................................................................... 84 
APPENDIX D - SUMMARY OF PREVIOUS CLINICAL TRIAL EXPERIENCE WITH CX-8998 
(MK-8998) ....................................................................................................................................................... 86 


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TABLE OF TABLES 
Table 1 
Completed Clinical Studies ....................................................................................................................... 28 
Table 2 
Study Drug Dose Reduction for Intolerable AEs ............................................................................. 41 
Table 3 
Schedule of Assessments ........................................................................................................................... 47 


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TABLE OF FIGURES 
Figure 1 
Chemical Structure of CX-8998 .............................................................................................................. 24 
Figure 2 
Effect of CX-8998 on Seizure time in Male WAG/Rij Rats ........................................................... 25 
Figure 3 
Percentage (%) Occurrence of CNS Adverse Events Correlated with Average 
Cmax of CX-8998 (nM) .................................................................................................................................. 31 
Figure 4 
Relationship between the Dose-normalized AUCinf (dnAUC) of CX-8998 and 
Subject Age and Weight (Pooled data across studies PN001, PN002, PN003, 
and PN005) ..................................................................................................................................................... 33 
Figure 5 
Simulated Plasma Concentrations of CX-8998 following Stepwise Dose 
Escalation of CX-8998 Administered Every 12 Hours under Fed Conditions ..................... 34 
Figure 6 
Schematic of Study Design ........................................................................................................................ 36 


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GLOSSARY OF TERMS AND ABBREVIATIONS 
Abbreviation 
Description 
ABV 
alcohol by volume 
ADL 
activity(ies) of daily living 
AE 
adverse event  
AED 
antiepileptic drug(s) 
AESI 
adverse events of special interest 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CaV 
voltage-dependent calcium channels 
CAE 
childhood absence epilepsy 
CNS 
central nervous system 
Cmax 
maximum (peak) concentration 
Cmin 
minimum concentration 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CHO 
Chinese hamster ovary 
CK 
creatine kinase 
CL/F 
oral clearance 
CNS 
central nervous system 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
dnAUC 
dose-normalized area under the concentration-time curve 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 


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Abbreviation 
Description 
EOS 
end of study 
ET 
end of treatment 
FDA 
Food and Drug Administration 
FLIPR 
Fluorometric Imaging Plate Reader 
FOB 
functional observation battery 
FSH 
follicle-stimulating hormone 
FU 
follow-up 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GTCS 
generalized tonic clonic seizure 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HV 
hyperventilation 
IC 
inhibition concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IGE 
idiopathic generalized epilepsy 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat population 
JAE 
juvenile absence epilepsy 
LDH 
lactate dehydrogenase 
MAD 
modified Atkins diet 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHV 
normal healthy volunteer 
NIH 
National Institutes of Health 
NOEL 
no-observed-effect level 
NYHA 
New York Heart Association 
PCP 
phencyclidine 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PGES 
postictal generalized electroencephalography suppression 
PK 
pharmacokinetic 


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Abbreviation 
Description 
PS 
photic stimulation 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SERDAS 
Seizure-related Disability Scale 
SOC 
standard of care 
t1/2 
terminal half life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
UM-PDHQ 
University of Miami Parkinson's Disease Hallucinations Questionnaire 
Vz/F 
volume of distribution 
Vh 
holding potential 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 


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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
1.1.1 
Absence Epilepsy 
Generalized epilepsies constitute nearly one-third of all epilepsies. Idiopathic generalized epilepsies 
(IGEs) manifest with absences seizures, myoclonic jerks, and generalized tonic–clonic seizures, 
alone or in varying combinations and severity (Panayiotopoulos, 2005). Absence seizures are the 
hallmark seizure type in absence epilepsy (a form of generalized epilepsy) but can also be a 
predominant seizure type in other generalized epileptic syndromes. Absence seizures are 
characterized by a transient impairment in consciousness generally not followed by a notable post-
ictal state. Absence seizures are characterized clinically and electroencephalographically as typical 
and atypical types. Typical absence seizures show abrupt onset and resolution and are often 
accompanied by other features, including staring, behavioral arrest, eyelid fluttering or hand/face 
automatisms (Penry, 1969). Electroencephalogram (EEG) findings of a typical absence seizure 
show generalized spike-and-wave complexes in the 3-4.5 Hz range lasting at least 3 seconds 
(Holmes, 1987, Frank, 1999, Panayiotopoulos, 2008). Age of onset for typical absence seizures is 
bimodal with a peak at 6-7 years of age and a second peak at 12 years of age (Loiseau, 1995). 
Atypical absence seizures last longer than typical absences, have less abrupt onset and offset, more 
pronounced changes in tone and variable impairments of consciousness (Proposal for revised 
clinical and electroencephalographic classification of epileptic seizures, 1981). EEG findings for 
atypical absence seizures are more heterogeneous, often showing irregular spike-and-wave 
complexes that are slower (<2.5 Hz), asymmetrical, and often associated with diffuse fast activity 
(Holmes, 1987).  
Absence epilepsy syndromes include childhood absence epilepsy (CAE), juvenile absence epilepsy 
(JAE), epilepsy with myoclonic absences, juvenile myoclonic epilepsy, and Jeavons syndrome. CAE 
is the most common pediatric epilepsy syndrome, affecting females more than males and 
characterized by very frequent (several to many per day) absences in school-age children, with age 
of onset between 4 and 10 years (Proposal for revised clinical and electroencephalographic 
classification of epileptic seizures, 1981; Camfield, 1996; Berg, 2000; Jallon, 2001; Fisher, 2005). 
CAE is self-limiting in many cases with reported remission rates ranging from 21% to 74% (Tenney, 
2013) by age 12 or sooner (Posner, 2013) but with roughly 40% developing generalized tonic 
clonic seizures (GTCS), often 5-10 years after the initial onset of absence seizures (Loiseau 1983). 
JAE has a later age of onset with most cases beginning between 10 and 17 years (Loiseau, 1995). 
JAE is distinguished from CAE by more common incidence of GTCS which eventually occur in nearly 
80% of JAE patients (Wolf, 1984) and by a higher likelihood of persistence into adulthood (Tenney, 
2013). In general, later onset of absence seizures is associated with more severe, persistent and 
drug resistant epilepsy.  
1.1.2 
Treatments for Absence Seizures  
Current treatments for absence seizures include ethosuximide, valproate, and the sodium channel 
blocker lamotrigine. Prior to 2010, a total of 6, short duration, small randomized controlled trials 
had examined ethosuximide, valproic acid, and lamotrigine initial monotherapy in children with 


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absence epilepsy. Due to multiple methodological limitations, none of these trials met the criteria 
for either a Class I or II study, providing insufficient evidence to inform clinical practice (Glauser et 
al., 2006). In 2010, a National Institutes of Health (NIH)-funded randomized controlled trial of 446 
children with CAE, ethosuximide and valproate resulted in the best efficacy with 53% and 58% of 
patients achieving freedom-from-treatment-failure respectively, while lamotrigine showed lower 
efficacy with seizure free rates of 29% (Glauser et al., 2010). Other treatments less frequently used 
to treat absence epilepsy include clonazepam, clobazam, zonisamide, and topiramate. 
Nearly a quarter of patients receiving front-line drugs experience intolerable side effects (Glauser 
et al., 2010). Ethosuximide is commonly associated with gastrointestinal (GI) disturbances, 
anorexia, weight loss, drowsiness, photophobia, headache, and behavioral and psychiatric 
disturbances and is rarely associated with aplastic anemia, skin reactions, and renal and hepatic 
impairment (Posner, 2013). Common adverse events (AEs) associated with valproate include GI 
disturbances, weight gain, and tremor and, rarely, behavioral and cognitive abnormalities and 
potentially fatal liver necrosis and pancreatitis; its use is limited clinically by weight gain and in 
women of childbearing potential (WOCBP) because of fetotoxicity (Posner, 2013). Lamotrigine is 
associated with dizziness, somnolence, nausea, vomiting and headache and can cause serious skin 
reactions and aseptic meningitis (Posner, 2013). 
No randomized, controlled, double-blind trials have been conducted in JAE or in other generalized 
epilepsy syndromes with absence seizures. Separate expert opinion surveys in the US and Europe 
found valproic acid and lamotrigine  to be the top initial treatment choice for JAE (as they treat both 
absences and tonic-clonic seizures) (Wheless et al., 2005; Wheless et al., 2007). Second-line (or 
later) treatments with evidence of modest efficacy for JAE include ethosuximide, amantadine, and 
the ketogenic diet (Fattore et al., 2011; Groomes et al., 2011).  
While a proportion of patients diagnosed with absence seizures will respond to first-line 
antiepileptic drugs (AEDs) and have a generally good prognosis, a significant proportion will fail to 
achieve adequate seizure control with existing therapeutics or will experience intolerable side 
effects that limit therapy (Connock, 2006). For these patients the goal is to achieve seizure control 
while limiting side effects and negative impacts, especially on cognitive outcomes. Drug-resistant 
epilepsy has been defined as the “failure of adequate trials of 2 tolerated, appropriately chosen and 
used antiepileptic drug schedules (whether as monotherapy or in combination) to achieve 
sustained seizure freedom.” This operational definition, established by an International League 
Against Epilepsy commission, (Kwan et al., 2010) relies upon the observation that adults and 
children rarely achieve sustained seizure freedom once 2 agents have failed to control seizures 
(Mohanraj & Brodie, 2006; Kwan et al, 2010). 
Despite the development of nearly a dozen new drugs for epilepsy in the 1990s and 2000s and, 
although many newer drugs have superior pharmacokinetic (PK) and side effect profiles than older 
AEDs, they possess the same degree of effectiveness (Krauss & Sperling, 2011). These AEDs rarely 
stop seizures once older agents have failed. Innovative pharmaceutical approaches with new 
antiepileptic drugs, especially those with greater potency, selectivity and a defined mechanism of 
action are needed to offer treatment options to these patients and yield better response rates. 


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1.2 
Rationale for Evaluating CX-8998 in Idiopathic Generalized 
Epilepsy with Absence Seizures 
1.2.1 
CaV3 and its Role in Neurological Disorders with Excessive or Abnormal 
Rhythmicity 
Calcium is a ubiquitous intracellular second messenger critical for cellular functions. The elevation 
of free intracellular Ca2+ levels triggers various responses, including the activation of Ca2 + 
dependent enzymes, the secretion of neurotransmitters, and muscle contraction. Multiple calcium 
ion channels regulate calcium influx in response to membrane depolarization, voltage changes, or 
substrate, which include the pore-forming alpha1 subunit Cav3 channel (Catterall, 2005; Adams & 
Snutch, 2007).  
The T-type calcium channel, Cav3, its 3 isoforms (3.1, 3.2 and 3.3), and their genes CACNA1G, 
CACNA1H, and CACNA1I were discovered and cloned in the early 1990s, where their function as 
low-threshold, voltage-gated calcium channel was elucidated (Cribbs et al., 1998). T-type (“T” is for 
transient) calcium channels are low voltage-activated channels predominantly found in neurons. As 
stated previously, a unique and discriminating property of T-type channels (CaV3) is their ability to 
activate upon small depolarization of the membrane, contributing to the setting of the resting 
membrane potential and allowing a surge of calcium entry into excitable cells at the beginning of an 
action potential. In pathologic states, CaV3 is either upregulated or found to have increased activity, 
becoming a selective target for specific neurologic diseases (Bourinet et al., 2005; Park et al., 2010; 
Tai et al., 2011). 
Isoforms of Cav3 are expressed throughout the central nervous system (CNS) and the peripheral 
nervous system, including the thalamocortical pathway1 (Ertel et al., 2000). Deep cerebellar nuclei, 
substantia nigra, globus pallidus externa, globus pallidus interna, subthalamic nucleus, have been 
noted to have oscillations in healthy hosts and excessive rhythmicity in animals and humans with 
pathologic conditions of the nervous system. It has been discovered that Cav3 is a mediator of 
subthreshold oscillations and excessive rhythmicity in pathophysiologic states found in tremor, 
neuropathic pain, epilepsy and Parkinson’s disease (Llinás et al., 1999; Llinás, 2003; Handforth et 
al., 2005; Park et al., 2013).  
1.2.2 
Role of Cav3 in Epilepsy 
It is well established that T-type calcium channels are a pharmacological target for absence 
seizures. Neuronal burst-firing, a key pathophysiologic contributor to epileptic seizures, is 
generated by low threshold calcium potentials initiated by Cav3 channel opening (Cain & Snutch, 
2013). In particular, rodent models of absence epilepsy show enhanced Cav3 currents in 
thalamocortical relay neurons and enhanced burst-firing during seizures that correlate with spikes 
in spike-and-wave discharges. A number of single nucleotide mutations in Cav3.2 have been 
reported in patients with childhood absence epilepsy (Chen et al., 2004), some of which result in 
gains of function in channel gating and in elevated channel expression (Khosravani et al., 2004; 
                                                             
1 Cav3.1 is the most common isoform in the thalamocortical pathway 


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Vikto et al., 2005; Peloquin et al., 2006; Vikto et al., 2007). In addition, overexpression of Cav3.1 
results in an absence-like seizure phenotype in mice (Ernst, et al., 2009) and mice lacking Cav3.1 
show reduced thalamocortical burst firing and resistance to pharmacologically induced absence 
seizures (Kim et al., 2001). A number of antiepileptic drugs have been reported to have 
nonselective Cav3 blocking activity, including ethosuximide, valproate, zonisamide, and phenytoin 
(Powell et al., 2014). These drugs are thought to act in part through suppression of Cav3 activity 
although all have substantial effects on other types of channels, including sodium, potassium, and 
potassium-activated calcium currents. Current treatments for absence seizures include 
ethosuximide, valproate, and the sodium channel blocker lamotrigine. In CAE, ethosuximide and 
valproate result in the best efficacy, with approximately 50% of patients achieving freedom from 
seizures, however, nearly a quarter of patients receiving these drugs experience intolerable side 
effects (Glauser et al., 2010). Thus, selective targeting Cav3 channels may offer a more efficacious 
and better-tolerated treatment option. 
1.3 
Nonclinical Pharmacology  
 
 
 
 
Figure 1 
Chemical Structure of CX-8998 
 
1.3.1 
Primary Pharmacology Studies 
 
 
 
 
 
 
 
 


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1.3.2 
Safety Pharmacology and Toxicology Studies 
 
 
 
 
 
  


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1.4 
CX-8998 Clinical Experience 
 
 
  
 
 
 
 
 


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Table 1 
Completed Clinical Studies 
Study 
Number 
Phase 
Population 
Design;  
endpoints 
Dose CX-8998, control 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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randomized; TETRAS = The Essential Tremor Rating Assessment Scale 
1.4.1 
Clinical Pharmacokinetics 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4.2 
Clinical Pharmacodynamics 
 
  
 
 
 
  
 
  
 
 
 
  
 
  
1.4.3 
Clinical Safety 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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.  
1.5 
Rationale for Selected Dose 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
To assess the safety and tolerability of CX-8998 in adolescents and adults with IGE with absence 
seizures 
2.2 
Secondary Objectives 
• 
To evaluate the PK of CX-8998 and its metabolites (including, but not limited to, M01 and M02) 
in the plasma of subjects with IGE with absence seizures 
2.3 
Exploratory Objectives 
• 
To assess the exposure-response and exposure-safety relationships for plasma CX-8998 and its 
metabolites (including, but not limited to, M01 and M02); results to be reported separately 
from the clinical study report  
• 
To evaluate the PD effects of CX-8998 as measured by EEG  
3 
STUDY DESIGN AND ENDPOINTS 
3.1 
Study Type 
This is a Phase 2a, multicenter, open-label study consisting of a screening period of up to 4 weeks, a 
4-week dose-titration treatment period to dose of up to 10 mg BID of CX-8998, and a 1-week safety 
follow-up period following the last dose of study medication. 
3.2 
Schematic of Study Design 
The study design schematic is shown in Figure 6.  
 
 


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Figure 6 
Schematic of Study Design 
 
 


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3.3 
Endpoints 
3.3.1 
Primary Endpoint 
Safety and tolerability endpoints:  
• 
Treatment-emergent adverse events (TEAE),  
• 
Changes from baseline in QTcF and other ECG parameters,  
• 
Changes from baseline in clinical safety laboratory assessments (clinical chemistry, 
hematology, and urinalysis),  
• 
Changes from baseline in vital signs,  
• 
Number (%) of subjects who did not complete the study due to TEAEs 
• 
Number (%) of subjects with SAEs  
• 
Number (%) of subjects with adverse events of special interest (AESI): 
o Increased seizure frequency 
o New seizure types 
o Status epilepticus 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
• 
University of Miami Parkinson's Disease Hallucinations Questionnaire (UM-PDHQ) 
3.3.2 
Secondary Endpoints 
• 
Plasma PK parameters: Cmax, Tmax, Cmin, and partial AUC0-4h for CX-8998 and metabolites 
(including, but not limited to, M01 and M02) 
• 
Additional CX-8998 PK parameters (CL/F, Vz/F, t1/2) may be estimated, pending 
performance of a population PK analysis with data pooled from several studies (to be 
reported separately from the clinical study report). 
3.3.3 
Exploratory Endpoints 
• 
Change in frequency (number of seizures per hour) of absence seizures as defined by a 3-Hz 
spike and wave lasting ≥3 seconds as determined by HV (HV period 1 + HV period 2) 
• 
Change in frequency (number of seizures per hour) of absence seizures as defined by 3-Hz 
spike and wave lasting ≥3 seconds during wakefulness as determined by 6.5-hour 
video-EEG 
• 
Time to absence seizure occurrence during HV (HV period 1 + HV period 2) 
• 
Percent of subjects with a shift in occurrence of absence seizure during HV (e.g., shift for 
seizure occurring in HV period 1 or HV period 2 to no seizures occurring during either HV 
period; shift from absence seizure occurring to HV period 1 to HV period 2) 
• 
Change from baseline to end of treatment in absence seizure-free days based on seizure 
diary 
• 
Absence of photic response in subjects who had photic response during the baseline 
video-EEG 


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• 
Change in the Seizure-related Disability Assessment Scale (SERDAS) 
• 
Relationship between the EEG parameters and the PK of CX-8998  
• 
Exposure-response and exposure-safety relationships using plasma concentrations of 
CX-8998 and its 2 primary metabolites (M01 and M02) in population PK/PD analyses (to be 
reported separately from the clinical study report) 
4 
STUDY DRUG 
4.1 
Supply and Storage 
CX-8998 will be supplied as 2 mg capsules. All manufacturing and packaging activities will be 
performed according to current Good Manufacturing Practices (cGMP) guidelines.  
Study drug supplies will be stored securely in a temperature-controlled storage area (a locked 
cupboard or pharmacy with limited access). Only authorized personnel will have access to the 
study drug. The study site personnel at each site will be responsible for correct storage and 
handling of the study drug. 
Supplies of study drug should be stored at 20°C to 25°C. Temperature excursions are permitted 
between 15°C to 30°C. 
4.2 
Packaging and Labeling 
Study medication will be supplied in 60-cc white HDPE bottles with 33-mm polypropylene, white, 
child-resistant closures. Bottles will contain 62 capsules per bottle. The bottles will be 
appropriately labeled. The affixed label will have spaces for entering the subject number and 
subject initials. At the time of dispensing, the subject number and subject initials will be entered 
onto the appropriate lines on the label.  
The product label will contain the following information in the English language: 
• 
Protocol number: CX-8998-CLN2-002 
• 
Kit number (and bottle number) 
• 
Storage conditions 
• 
The sentence, “Caution: New Drug – Limited by Federal (or United States) law to investigational 
use”  
• 
Name and address of the sponsor 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
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CONFIDENTIAL AND PROPRIETARY 
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4.3 
Administration 
CX-8998 will be administered as: 
1. Days 1 – 2: 2 mg (1 capsule) BID (4 mg/d);  
2. Days 3 – 8: 4 mg (2 capsules) BID (8 mg/d); 
3. Days 9 - 14:  
6 mg (3 capsules) BID 12 mg/d); 
4. Days 15 – 20: 
8 mg (4 capsules) BID (16 mg/d);  
5. Days 21 - 26:  
10 mg (5 capsules) BID (20 mg/d).  
Study drug should be administered with food. Subjects should be instructed to take their daily dose 
at approximately the same times each day. Consecutive doses should be taken no closer than 10 
hours and no later than 14 hours (every 12 hours ± 2 hours). Subjects will remain under 
observation for at least 4 hours post-dosing prior to discharge at Visit 1.  
At the Day 26 clinic visit at which 2 postdose PK blood draws, >2 hours apart, are scheduled to 
be obtained, subjects will take the morning dose at the appropriate time. Both the time of the 
morning dose and the time of the PK blood draw will be recorded. 
A missed dose (>14 hours since the prior dose) should be skipped and should not be “doubled-up” 
or “made up”; the next dose should be taken 24 hours from the last administered dose. If the subject 
experiences emesis following the dose, that dose should not be re-taken; instead the next dose 
should be taken 24 hours from the last administered dose without emesis. If emesis occurs, the 
subject should contact the investigator or qualified designee at the study site for guidance on 
management of the emesis. 
Treatment compliance will be assessed as described in Section 4.5.1.  
Subjects experiencing specified AEs will have their dose adjusted. See Section 4.6 for details on dose 
adjustments. 
4.4 
Subject Stopping Rules 
Study drug dosing for an individual subject will be permanently discontinued for intolerable AEs 
that do not resolve to mild in severity (as defined in Section 10.2.2.2) or baseline within 48 hours of 
suspension of dosing and for study drug-related SAEs.  
Administration of the study treatment will be discontinued if any of the following liver chemistry 
stopping criteria is met:  
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × 
ULN (upper limit of normal) and total bilirubin level ≥2 × ULN  
NOTE: Serum bilirubin fractionation should be performed if testing is available. If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury). 
• Serum ALT or AST ≥5 × ULN 
• Serum ALT or AST ≥3 × ULN if associated with the appearance or worsening of rash 
or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia) 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
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Any laboratory value that exceeds these limits should be repeated as soon as possible and, if 
confirmed, study treatment should be immediately discontinued. If a repeat laboratory assessment 
cannot be obtained within 3 days after receipt of the result showing the abnormal value, study drug 
should be discontinued. 
A subject who meets the following ECG criteria will have study treatment discontinued: 
• QTcF >500 msec or uncorrected QT >600 msec  
• an increase in QTcF by ≥60 msec from Day 1 predose (baseline) with an absolute 
value of QTcF ≥450 msec (males) or ≥470 msec (females) 
Treatment must be discontinued immediately in any subject who experiences a GTCS during the 
study if the subject had not had a GTCS prior to study entry. Subjects with worsening of seizures 
during the study should have treatment discontinued per investigator discretion. Unless consent for 
further follow-up is withdrawn, subjects who discontinue study drug for safety reasons should be 
followed in accordance with the schedule detailed in Table 3. 
Other reasons for treatment termination are provided in Section 6.4.  
4.5 
Study Drug Accountability and Compliance 
4.5.1 
Study Drug Accountability 
The investigator or an appointed designee is responsible for ensuring that deliveries of study drug 
are correctly dispensed and recorded, that the product is handled and stored safely and properly, 
and that it is only given to subjects in accordance with this protocol.  
Sites will keep a current log of drug accountability recording:  
• 
What drug supply was received from the sponsor 
• 
What drug supply was dispensed to each subject 
• 
What drug supply is current in inventory 
• 
What drug supply was destroyed or returned to the sponsor for destruction 
Note: Drug accountability is the responsibility of the investigator; a written account will be 
required for all discrepancies. 
If the study drug supplies appear to be damaged/missing upon arrival at the investigational site, the 
sponsor should be contacted immediately. 
The sponsor’s designated monitor must verify all accountability records during periodic monitoring 
visits. Unused and used study drug must be stored on site until such accountability has taken place 
and authorization is received from the sponsor or sponsor’s designee that the study drug may be 
returned or destroyed. 
4.5.2 
Subject Compliance with Study Drug 
Compliance will be assessed by capsule counts. Subjects will be instructed to bring all used empty 
bottles and unused study drug with them to the clinic visit on Day 26.  
 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
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4.6 
Dose Adjustments / Toxicity Management  
Adverse events will be graded for intensity by the investigator (see Section 10.2.2.2).  
Dosing will be discontinued for all study drug-related SAEs. 
A member of the study staff will contact any subject who is suspected of experiencing 
neuropsychiatric AEs to determine the need for an unscheduled visit before further dose escalation 
may proceed. Subjects who are experiencing any AEs may also be asked to return for an 
unscheduled visit. Subjects who are suspected of experiencing a neuropsychiatric event should be 
seen in person. 
In all subjects with intolerable AEs (as defined in Section 10.2.1) that are considered related to 
study drug, treatment should be suspended for up to 48 hours or until the AE resolves to a tolerable 
level of severity, whichever is earlier. In subjects who are unable to tolerate 6 mg BID, 8 mg BID or 
10 mg BID, dosing may then be resumed at a previously tolerated lower dose. Only a single dose-
step reduction (i.e., 10 mg BID to 8 mg BID, 8 mg BID to 6 mg BID, or 6 mg BID to 4 mg BID) is 
permitted. Reescalation of the dose is NOT permitted. Dosing should be discontinued if there is 
recurrence of intolerable AEs after the dose reduction. Subjects who experience intolerable AEs 
while receiving the 2 mg BID or 4 mg BID dose will be discontinued from treatment. Table 2 details 
dose reductions by dose level. 
Table 2 
Study Drug Dose Reduction for Intolerable AEs 
Dose and Schedule of Study Drug 
Dose Reduction 
2 mg BID 
Remove from treatment 1 
4 mg BID 
Remove from treatment 
6 mg BID 
4 mg BID 
8 mg BID 
6 mg BID 
10 mg BID 
8 mg BID 
1 – Subjects who are removed from treatment for AE(s) should be followed for resolution of the AE(s) and 
should complete all assessments scheduled for the End-of Study (EOS)/Follow-up (FU) Visit, as well as all 
assessments that they are capable of completing on the scheduled visit day if the decision to remove from 
treatment is made on a scheduled visit day. Likewise, if the investigator plans to temporarily interrupt dosing 
because of an AE and the decision is made on a scheduled visit day, then the subject should complete all 
scheduled assessments that they are capable of completing on the visit day on which they appear.  
All subjects who discontinue treatment due to AEs will be followed for AE outcome. All AEs should 
be followed for resolution or for 30 days from the last dose of study drug, whichever is shorter. 
The Study Safety Representative should be notified of all dose reductions as soon as is feasible.  
All subjects who discontinue treatment due to AEs will be followed for AE outcome. All AEs should 
be followed for resolution or for 30 days from the last dose of study drug, whichever is shorter. 
4.7 
Overdose Management 
To date, no overdoses of CX-8998 in humans have occurred. Therefore, specific information 
regarding treatment of overdose is not currently available. In case of an acute overdose, it is 
recommended that the stomach be emptied and oral gavage with activated charcoal be used to help 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
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CONFIDENTIAL AND PROPRIETARY 
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reduce absorption of CX-8998. In the event of an overdose, the Study Safety Representative should 
be contacted immediately. 
5 
INVESTIGATORS, SITES, AND DURATION 
5.1 
Investigators and Sites 
The study will be conducted at multiple sites in the United States. 
5.2 
Central Reviewers 
A central reviewer and the sponsor will review eligibility criteria for all subjects. The site will 
submit an eligibility checklist for evaluation of each subject. No subject may be enrolled or receive 
study drug prior to receipt of notification that the central reviewer and review process have 
deemed the subject eligible. 
5.3 
Duration of Study 
Subjects will participate for a total of up to 9 weeks, including screening, the 4-week treatment 
period, and follow-up. 
5.4 
Termination of Study 
This study may be terminated at the discretion of the sponsor or the Food and Drug Administration 
(FDA) or in accordance with the recommendations set forth in the Safety Monitoring Plan (Section 
10.4). 
6 
STUDY POPULATION 
6.1 
Number of Subjects 
Up to approximately 15 eligible subjects will receive treatment.  
6.2 
Inclusion Criteria 
Subjects may be included in the study only if they meet all of the following criteria. Subjects may 
undergo rescreening following consultation with and approval of the Study Safety Representative. 
1) Signed informed consent form (ICF) indicating that the subject has been informed of the 
procedures to be followed, the experimental nature of the therapy, alternatives, potential 
benefits, side effects, risks, and discomforts. 
2) Men or nonpregnant, non-breastfeeding women 16 to 55 years of age who are able to read 
and understand the written and spoken local language. 
3) Clinical diagnosis of IGE (including, but not limited to, CAE, JAE, juvenile myoclonic epilepsy, 
or Jeavons syndrome) with absence seizures consistent with the International League 
against Epilepsy Revised Classification of Seizures (2017). 
4) Absence seizures, by history on average once per hour, persisting despite standard of care 
(SOC) treatment, defined as treatment with at least 2 AEDs appropriate for the patient’s 
epilepsy syndrome. SOC failure, per investigator discretion, will be defined as insufficient 
clinical response or intolerable side effects, which precludes use of the appropriate AED. 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
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5) Observation of at least 1 provoked absence seizure during at least 1 of the hyperventilation 
(HV) periods and at least 3 absence seizures during the 6.5-hour video-EEG. Absence 
seizures are defined on EEG as typical generalized 3-Hz spike and wave lasting ≥3 seconds 
during wakefulness. Hyperventilation should be carried out in the following manner: 
5 minutes of HV (HV period 1), followed by 5 minutes of relaxation, followed by a second 
5 minutes of HV (HV period 2). Subjects who have an induced seizure during HV period 1 do 
not need to undergo HV period 2. At least 75% of the background should be normal. 
6) On stable doses of one or more antiepileptic medication(s) for at least 30 days. If a subject is 
not on medication, adequate documentation justifying lack of therapy may be acceptable for 
the subject after sponsor review. Ketogenic, modified Atkins diet (MAD), or low glycemic 
diet with stable carbohydrate ratio for at least 30 days before screening is an acceptable 
antiepileptic therapy. Vagal nerve stimulation at stable settings (for at least 30 days before 
screening), without use of the magnet, is also acceptable. 
7) Body weight ≥45 kg at screening. 
8) Subjects with reproductive capability, including all males and WOCBP, must agree to 
practice continuous abstinence or adequate contraception methods (appropriate double 
barrier method or oral, patch, implant, or injectable contraception) from as soon as feasible 
during screening period until at least 30 days after the last dose (i.e., intermittent 
abstinence based on “rhythm,” temperature monitoring, or other means of timing is not 
acceptable). WOCBP include any woman who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, and/or 
bilateral oophorectomy) or is not postmenopausal. Postmenopausal is defined as 
amenorrhea for ≥12 consecutive months without another cause, and a documented serum 
follicle stimulating hormone (FSH) level ≥35 mIU/mL.  
9) Male subjects with a partner of childbearing potential must be surgically sterilized or be 
willing to use condoms with spermicide from as soon as feasible during screening period 
until at least 30 days after the last dose.  
10) Able and willing to comply with scheduled visits, treatment plan, laboratory tests, and other 
study procedures. 
11) Approval by the sponsor medical personnel or delegate as to final eligibility for the study. 
6.3 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following conditions apply. Subjects may 
undergo rescreening following consultation with and approval of the Study Safety Representative. 
1) History of surgical intervention for treatment of epilepsy. 
2) Additional seizure (clinical and electrographic) types, including, but not limited to, epileptic 
spasms, generalized tonic seizures, atonic seizures, or focal seizures. Subjects with GTCS or 
myoclonic seizures are eligible for the study. 
3) Inadequately treated psychotic or mood disorder (e.g., schizophrenia, major depression, 
bipolar disorder). 
4) Presence of severe intellectual disability, severe autism spectrum disorder, or severe 
developmental disorder such that the subject cannot sign the ICF or cannot cooperate with 
the study procedures. 


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CX-8998 in Absence Epilepsy 
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5) Presence of positive urine drug screen for drugs of abuse, except if this is explained by use 
of an allowed prescription medicine. 
6) Regular use of more than 2 standard drinks of alcohol per day (28 grams of pure alcohol). 
7) Hypersensitivity/allergic reaction to other T-type calcium agents, such as (but not limited 
to) ethosuximide and zonisamide.  
8) Use of strong CYP3A4 inhibitors, including prescription or nonprescription drugs or other 
products (e.g., grapefruit juice), which cannot be discontinued at least 2 weeks prior to Day 
1 of dosing and throughout the study (Appendix B). 
9) Concurrent illnesses that would be a contraindication to trial participation, including, but 
not limited to:  
a) Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, 
stroke) less than 6 months before screening. 
b) New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular 
arrhythmias or uncontrolled blood pressure.  
c) Clinically significant ECG abnormality per the investigator assessment or any of the 
following: 
i. QTcF ≥450 msec (males) or ≥470 msec (females). 
ii. PR interval ≥250 msec. 
iii. Atrioventricular block of second degree or higher, including Mobitz I. 
iv. Persistent sinus bradycardia of ≤50 beats per minute; persistent means the 
bradycardia is present on the first ECG and on one repeat ECG performed on 
another day. 
v. For other ECG findings (e.g., including, but not necessarily limited to, 
tachycardia, bundle branch block, frequent ectopic beats) the investigator 
should send a scanned, identity-blinded copy of the ECG tracing to the Study 
Safety Representative for review. 
10) Positive result for human immunodeficiency virus (HIV), hepatitis B [indicating ongoing 
infection], or hepatitis C at screening or otherwise known ongoing infection with HIV, 
hepatitis B, or hepatitis C, unless curative therapy has been completed; for hepatitis C 
curative therapy is defined as negative polymerase chain reaction (PCR) for hepatitis C 
virus (HCV) RNA. 
11) Significant hepatic (AST/ALT or bilirubin ≥2 × ULN) or renal disease (creatinine clearance 
≤39 mL/min). 
12) History of alcohol or substance abuse within the last year. 
13) A current C-SSRS score of 4 or 5 at screening or history of suicide attempt.  
14) Psychological, social, familial, or geographical reasons that would hinder or prevent 
compliance with the requirements of the protocol or compromise the informed consent 
process. 


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15) Any other condition and/or situation that causes the investigator or Study Safety 
Representative to deem a subject unsuitable for the study (including, but not limited to, 
expected study medication noncompliance, inability to medically tolerate the study 
procedures, or a subject’s unwillingness to comply with study–related procedures) 
16) Treatment with an investigational agent within 30 days prior to the first dose of CX-8998 or 
planning to receive an investigational agent during the study. 
17) Subjects who do not experience a provoked absence seizure during either HV period and 
who have fewer than 3 typical absence seizures during the baseline video-EEG (considered 
to be screen failures). 
6.4 
Withdrawal of Subjects and/or Discontinuation of Treatment 
A subject should be withdrawn from the study for any of the following: 
1) Withdrawal of subject consent. 
2) Subject is lost to follow-up. 
3) Investigator determines that withdrawal from the study is in the best interest of the subject.  
4) Subject is noncompliant with protocol-mandated activities.  
5) Occurrence of any intercurrent condition, injury, or disease that becomes apparent during the 
study and necessitates the termination of the subject from the study. 
6) Administrative reason (e.g., termination of the clinical study by a regulatory agency or the 
sponsor). 
A subject should be discontinued from treatment for any of the following (see also Section 4.4): 
1) Occurrence of defined unacceptable toxicity (Section 4.6). 
2) Investigator determines that discontinuation of treatment is in the best interest of the subject. 
3) Occurrence of any intercurrent condition, injury, or disease that becomes apparent during the 
study and necessitates the discontinuation of treatment. 
4) Pregnancy. 
5) Subjects who answer “yes” to Suicidal Ideation item 4 or 5 on the C-SSRS during the study must 
be withdrawn from the study treatment. Investigators should also withdraw subjects from 
treatment if, in the judgment of the investigator, the subject develops other indicators of 
significant risk of suicide. In the event that suicidal ideation is observed in any study subject, the 
investigator will manage the situation as he/she deems medically and psychiatrically 
appropriate. 
6.4.1 
Follow-up Procedures for Subjects Who Withdraw/Discontinue Prematurely 
If a subject withdraws from the study, attempts should be made to contact the subject to determine 
the reason(s) for discontinuation. If a subject does not return to the clinic for follow-up visits, 
attempts should be made to contact the subject via phone, email, or mail. At least 3 documented 
attempts (one of which should be a certified letter) should be made to contact the subject before 
declaring a subject lost to follow-up. The Study Safety Representative must be informed as soon as 
possible if a subject discontinues or withdraws early. 


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The date and the reason for study drug discontinuation or subject withdrawal from the study must 
be recorded on the case report form (CRF) In case of early discontinuation or withdrawal of a 
subject, every effort must be made to report all study-mandated observations up to the time of 
discontinuation/withdrawal as completely as possible.  
Subjects who are removed from treatment for AE(s) should be followed for resolution of the AE(s) 
(see Section 10.2.3) and should complete all assessments scheduled for the End-of-Study (EOS) 
Visit, as well as all assessments that they are capable of completing on the scheduled visit day if the 
decision to remove from treatment is made on a scheduled visit day. Likewise, if the investigator 
plans to temporarily interrupt dosing because of an AE and the decision is made on a scheduled 
visit day, the subject should complete all scheduled assessments that they are capable of completing 
on the visit day on which they appear. 
If the reason for discontinuation/withdrawal is medical and the subject has not withdrawn consent, 
the subject should remain under the supervision of the investigator until the medical issue is 
resolved or otherwise declared stable.  
6.4.2 
Procedures for Replacing Subjects Who Withdraw/Discontinue Prematurely 
Subjects who withdraw from the study or discontinue treatment prematurely will not be replaced. 
7 
TREATMENT PLAN AND METHODS 
7.1 
Schedule of Assessments 
The schedule of assessments is presented in Table 3.


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Table 3 
Schedule of Assessments 
Visit 
Screening 
Dosing Period 
EOT 
EOS 
FU 
Day 
-28 to -1 
1 
2 
3-7 
8 
9-13 
14 
15-19 
20 
21-25 
26  
33 
57 
Visit Window 
 
- 
0 
 
-2 d 
 
-2 d 
 
-2 d 
 
±1 d 
±1 d 
±2 d 
CX-8998 daily dose 
- 
4 mg 
8 mg 
12 mg 
16 mg 
20 mg  
 
 
Clinic visit 
X 
X 
 
 
 
 
 
 
 
 
X1 
 
 
Telephone call3 
 
 
X 
 
X2 
 
X2 
 
X2 
 
 
X1 
X 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/medical 
history5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Targeted physical exam6  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Neurological exam 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital signs7 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Electrocardiogram8 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Clinical laboratory tests9  
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Urine (+/- serum) pregnancy 
test10 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum FSH 11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screening 12 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacogenomics sample13 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PK14 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Video EEG + HV and PS15 
X 
 
 
 
 
 
 
 
 
 
X 
 
Video-EEG16 
X 
 
 
 
 
 
 
 
 
 
X 
 
Seizure-related Disability 
Assessment Scale 
 
X 
 
 
 
 
 
 
 
 
X 
 
 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
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CONFIDENTIAL AND PROPRIETARY 
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Visit 
Screening 
Dosing Period 
EOT 
EOS 
FU 
Day 
-28 to -1 
1 
2 
3-7 
8 
9-13 
14 
15-19 
20 
21-25 
26  
33 
57 
Visit Window 
 
- 
0 
 
-2 d 
 
-2 d 
 
-2 d 
 
±1 d 
±1 d 
±2 d 
CX-8998 daily dose 
- 
4 mg 
8 mg 
12 mg 
16 mg 
20 mg  
 
 
Clinic visit 
X 
X 
 
 
 
 
 
 
 
 
X1 
 
 
Telephone call3 
 
 
X 
 
X2 
 
X2 
 
X2 
 
 
X1 
X 
Daily Seizure Diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
C-SSRS17 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
UM-PDHQ18 
 
As needed 
 
 
Prior / concomitant meds 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
AE review19 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X19 
Study drug admin. in clinic 
 
X20 
 
 
 
 
 
 
 
 
X20 
 
 
Study drug admin. outpatient 
 
X20 
X 
X 
X 
X 
X 
X 
X 
X 
X20 
 
 
Drug compliance 
 
 
 
 
 
 
 
 
 
 
X21 
 
 
AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EEG = electroencephalogram; EOS = end of study; EOT = end 
of treatment; FSH = follicle-stimulating hormone; FU = follow-up; HIV = human immunodeficiency virus; HV = hyperventilation, PK = pharmacokinetic; 
PS = photic stimulation; UM-PDHQ – University of Miami Parkinson’s Disease Hallucinations Questionnaire. 
1. Visit window ± 1 day as needed for scheduling. 
2. Visit window +0, -2 days as need for scheduling. 
3. Before initiating dose escalation, study staff will contact the subjects by telephone and will question them about their health status, including about the 
occurrence of any AEs. Subjects who report AEs may be asked to return to the clinic for an unscheduled visit. Subjects who are suspected of 
experiencing a neuropsychiatric event should be seen in person. 
4. Informed consent must be signed prior to initiation of all other screening procedures. 
5. Medical history will include seizure history. 
6. A targeted physical exam will be based on subject reports of signs and symptoms and investigator’s observations. 
7. Vital signs include body temperature, systolic and diastolic blood pressures, pulse rate and respiration rate. Vital signs will be collected predose and 
postdose (1-2 hours) at the Baseline (Day 1) Visit and during the Day 26 clinic visit. Blood pressure and pulse rate will be measured in the recumbent 
position after at least 2 minutes of recumbency, and both will be measured again after approximately no less than 1 minute of standing. 
8. At baseline (Day 1), a 12-lead ECG will be performed predose and approximately 1-2 hours after the dose as convenient between other required visit 
procedures. All ECGs should be performed after at least 10 minutes of recumbency. 


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9. Clinical chemistry, and hematology. Urinalysis to be performed only as clinically indicated. Additional lab tests are obtained at the screening visit to 
verify eligibility (including HIV, hepatitis B and C). A positive drug screen will result in exclusion from the study unless it is explained by use of an 
allowed prescription medication. 
10. A urine pregnancy test will be performed, and if the result is positive a serum pregnancy test should be completed. 
11. Serum FSH only as needed to determine menopausal status in females <62 years old with history of ≥12 months of amenorrhea without another cause. 
12. Laboratory urine testing for phencyclidine (PCP), cocaine, cannabinoids, opiates, barbiturates, benzodiazepines, amphetamines, methadone, and MDMA 
(Ecstasy). 
13. Optional sample that requires additional informed consent. 
14. On Day 1, PK samples will be taken at time 0 (predose; before subject takes first dose of study drug in the clinic) and at 1, 2, and 4 hours after 
administration of study drug. Two postdose PK samples, separated by >2 hours, will be obtained on Day 26. The time of the last dose of study drug and 
the time of the blood draw will be recorded. 
15. A standard multi-lead 6.5-hour video EEG will be obtained using HV and PS. The first 30 minutes will consist of HV and PS. For HV, subjects will be 
hyperventilated for 5 minutes or until the subject has an absence seizure (HV period 1). If no absence seizure occurs during HV period 1, the subject will 
rest for 5 minutes and then perform hyperventilation for an additional 5 minutes (HV period 2). Photic stimulation will be performed as described in 
the EEG charter. The EEG will be centrally evaluated by a qualified rater. 
16. After completion of the above 30-minute video-EEG during which HV and PS are conducted, the video-EEG will continue, and the subjects will be 
monitored during wakefulness for an additional 6 hours. The EEG recording will be centrally evaluated by a qualified rater.  
17. The “Lifetime” version of the C-SSRS will be used at screening, and the “Since Last Visit” version will be completed at all other visits. 
18. The UM-PDHQ is a 20-item clinician-administered questionnaire that quantitatively and qualitatively assesses hallucinations. The UM-PDHQ will be 
completed for any subject who reports hallucinations. 
19. All AEs, irrespective of the relatedness to the study drug, will be captured from the time the ICF is signed through the EOS visit. All AEs should be 
followed until resolution, for 30 days after onset, for 30 days after the last dose of study drug, until the subject is lost to follow-up (as defined in 
Section 6.4.1), or the subject withdraws consent, whichever occurs first. Serious adverse events (SAEs) will be reported up to 30 days after the last dose 
of study drug. A follow-up phone call will be made 30 days after the last dose of study drug for evaluation of any SAEs. 
20. Study drug will be administered in the clinic on the morning of Day 1. Study drug will be administered on an outpatient basis on the evening of Day 1 
through the morning of Day 26. Subjects will be instructed to bring all used empty bottles and unused study drug, with them to the end-of-study visit on 
Day 26. 
21. Drug compliance will be assessed by capsule count. 


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Protocol Number: CX-8998-CLN2-002 
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7.2 
Summary of Treatment Visits 
7.2.1 
Screening 
The Screening Visit must be performed within 28 days of Visit 1/baseline. Subject informed 
consent must be obtained prior to initiation of any study-specified procedures. A central 
reviewer and the sponsor will review eligibility criteria for all subjects. 
A standard multi-lead video-EEG with HV and photic stimulation (PS) will be obtained over 
30 minutes and will be followed by an additional 6-hour awake video-EEG (total, 6.5 hours). 
Subjects will undergo HV for 5 minutes (HV period 1). If no absence seizure occurs, the 
subject will rest for 5 minutes and then undergo HV for an additional 5 minutes (HV period 
2). Further details, including procedures for HV and PS will be elaborated in the EEG 
Charter.  
Subjects will begin documenting absence seizure-free days in a daily diary and will continue 
to do so for the duration of the study. See Table 3 for a detailed list of assessments to be 
performed.  
7.2.2 
Visit 1 (Day 0 - Baseline) 
Subjects will return to the clinic within 28 days of screening. Following confirmation of 
continued eligibility by the central reviewer and sponsor, subjects will receive the first dose 
of study drug (2 mg or placebo) with food and undergo assessments as detailed in Table 3. 
Subjects will be followed for adverse events, orthostatic vital signs, and ECG for at least 
2 hours prior to discharge. The investigator or qualified designee will make the 
determination of whether it is safe to release the subject from the clinic. Subjects will be 
instructed to take the second daily dose of study drug no sooner than 10 hours and no later 
than 14 hours (every 12 hours ± 2 hours) from the time of their first dose.  
7.2.3 
At Home Dose Titration (Days 1-26) 
Subjects will continue twice daily dosing for 4 weeks according to the dose titration 
schedule detailed in Section 4.3. 
7.2.4 
Telephone Safety Check (Day 2) 
Prior to initiating the 4 mg BID dose, study staff will contact subjects by telephone to query 
the subject on their health status, including the occurrence of any AEs. Subjects who are 
experiencing any AEs may be asked to return to the clinic for an unscheduled visit. Subjects 
who are experiencing nervous or psychiatric system-related AEs should return to the clinic 
for an unscheduled visit. 
7.2.5 
Telephone Safety Check (Day 8) 
Prior to initiating the 6 mg BID dose, the study staff will contact the subjects by telephone to 
query them about their health status, including the occurrence of any AEs. Subjects who are 
experiencing any AEs may be asked to return for an unscheduled visit. Subjects who are 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
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experiencing nervous or psychiatric system-related AEs should return to the clinic for an 
unscheduled visit. The telephone call may take place on Day 6, 7, or 8. 
7.2.6 
Telephone Safety Check (Day 14) 
Prior to initiating the 8 mg BID dose, study staff will contact subjects by telephone to query 
the subject on their health status, including the occurrence of any AEs. Subjects who are 
experiencing any AEs may be asked to return for an unscheduled visit. Subjects who are 
experiencing any nervous or psychiatric system-related AEs should return to the clinic for 
an unscheduled visit. This call may take place on Day 12, 13, or 14. 
7.2.7 
Telephone Safety Check (Day 20) 
Prior to initiating the 10 mg BID dose, the study staff will contact the subjects by telephone 
to query them about their health status, including the occurrence of any AEs. Subjects who 
are experiencing any AEs may be asked to return for an unscheduled visit. Subjects who are 
experiencing any nervous or psychiatric system-related AEs should return to the clinic for 
an unscheduled visit.  The telephone call may take place on Day 18, 19, or 20. 
7.2.8 
End of Study Visit (Day 26) 
Subjects will return to the clinic for the final visit assessments detailed in Table 3. This visit 
may take place on Day 25, 26, or 27 as needed for scheduling. Subjects will be instructed to 
take their dose of study drug before reporting to the clinic. 
A standard multi-lead video-EEG with HV and photic stimulation (PS) will be obtained over 
30 minutes and will be followed by an additional 6-hour awake video-EEG (total, 6.5 hours). 
During this time, safety assessments, as shown in Table 3, will be conducted, and 2 PK blood 
samples, separated by >2 hours, will be obtained. Subjects will undergo HV for 5 minutes 
(HV period 1). If no absence seizure occurs, after a 5-minute rest, subjects will undergo HV 
for an additional 5 minutes (HV period 2). Further details, including procedures for HV and 
PS will be elaborated in the EEG Charter. Adverse events that are unresolved at the visit will 
continue to be followed by study staff as detailed in Section 10.2.3. 
7.2.9 
Telephone Safety Check (Day 33) 
One week after the End of Study Visit, the study staff will contact the subjects by telephone 
to query them about their health status, including the occurrence of any AEs. Subjects who 
are experiencing any AEs may be asked to return for an unscheduled visit. Subjects who are 
experiencing any nervous or psychiatric system-related AEs should return to the clinic for 
an unscheduled visit. Any AEs that remain unresolved at this visit will be noted as ongoing. 
This telephone call may take place on Day 32, 33, or 34. 
7.2.10 
Follow-up Phone Call 
Study staff will contact each subject by phone 30 days after the last dose of study drug for 
evaluation of the occurrence of any SAEs. 


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7.3 
Concomitant Medications and Other Restrictions 
7.3.1 
Concomitant Medications 
The use of prescription or nonprescription drugs or other products (e.g., grapefruit juice) 
known to be strong inhibitors or inducers of CYP3A4 must be discontinued 2 weeks prior to 
Day 1 of dosing and withheld throughout the study. See Appendix B for a complete list of 
restricted inhibitors and inducers. 
7.3.2 
Other Restrictions 
Regular use of more than 2 standard drinks of alcohol per day is prohibited. In the United 
States, a standard drink contains about 14 grams of alcohol. This roughly corresponds to a 
12-fluid ounce (350 mL) glass of beer (5% alcohol by volume [ABV]), a 5-fluid ounce 
(150 mL) glass of wine (12% ABV), or a 1.5-fluid ounce (44 mL) glass of a spirit (40% ABV). 
Use of any illicit drugs is prohibited throughout the study period. 
8 
EFFICACY ASSESSMENTS 
8.1 
Electroencephalogram 
 
A standard multi-lead video-EEG with HV and photic stimulation (PS) will be obtained over 
30 minutes and will be followed by an additional 6-hour awake video-EEG (total, 6.5 hours). 
HV will be conducted under the protocol used in the NIH-sponsored childhood absence 
study (Glauser et al., 2010). The first 30 minutes will consist of  HV and PS. For HV, subjects 
will be hyperventilated for 5 minutes or until the subject has an absence seizure (HV 
period 1). If no absence seizure occurs during HV period 1, the subject will rest for 
5 minutes and then perform hyperventilation for an additional 5 minutes (HV period 2). 
Photic stimulation will be performed as described in the EEG charter. The EEG will be 
centrally evaluated by a qualified rater. After completion of the above 30-minute video-EEG 
during which HV and PS are carried out, the video-EEG will continue, and the subjects will 
be monitored during wakefulness for an additional 6 hours (total, 6.5 hours). The EEG 
recording will be centrally evaluated by a qualified rater.  Procedures for VH, PS and video-
EEG will be elaborated in the EEG Charter. 
8.2 
Seizure-related Disability Assessment Scale 
The SERDAS was developed to assess functional impairment in work/school, social, and 
family life. The SERDAS is a 6-item self-report tool on which the patient rates the extent to 
which work/school, social life, and homelife or family responsibilities are impaired by his or 
her symptoms on a 10-point visual analog scale. 
8.3 
Daily Seizure Diary 
Beginning at the screening visit and continuing each day until the End of Study Visit, 
subjects will document if they had any absence seizures on that day (absence seizure-free 


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day). The number of absence seizure-free days will be calculated during both the baseline 
period and the treatment period. 
9 
PHARMACOKINETIC AND PHARMACOGENOMIC 
ASSESSMENTS 
9.1 
Blood Sample Collection for Pharmacokinetic 
Assessments 
For details on the timing, volume, handling, storage, and methods of analysis of blood 
samples see the Laboratory Manual. 
9.2 
Pharmacokinetic Parameters  
Plasma concentrations of CX-8998 and its metabolites (including, but not limited to, M01 
and M02) will be determined. 
The concentrations of CX-8998 and its metabolites (including, but not limited to, M01 and 
M02) in plasma will be summarized by visit, timepoint and dose using descriptive statistics.  
The concentration data will also be used as part of an exploratory population PK/PD 
analysis intended to evaluate the exposure-response and exposure-safety relationships, 
which will be reported separately from the clinical study report. 
9.3 
Pharmacogenomics of Drug Response 
Genomic and metabolomic variation may help to explain some of the variability in response 
seen with some drugs among different individuals. This is referred to as 
pharmacogenomics. Comparing the DNA, 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 and retaining samples for pharmacogenomic analyses makes it possible to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study.  
An optional 4-mL blood sample will be collected at Visit 1/baseline and retained for 
potential pharmacogenomic analyses related to drug response for subjects who consent to 
provide sample for these potential analyses. For example, putative safety biomarkers, drug 
metabolizing enzyme genes, drug transport protein genes, or genes thought to be related to 
the mechanism of drug action may be examined. Detailed collection, processing, storage and 
shipment instructions are provided in the Laboratory Manual. 


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10 
SAFETY ASSESSMENTS 
10.1 
Assessment of Safety 
10.1.1 
Adverse Events  
Adverse events (AEs) will be captured from the time the ICF is signed through the EOS 
telephone safety check on Day 33. SAEs will be reported up to 30 days after the last dose of 
study drug. A follow-up phone call will be made 30 days after the last dose of study drug for 
evaluation of any SAEs. See Section 10.2 for definitions and instructions on the rating and 
collection of AEs. 
10.1.2 
Physical and Neurological Examinations  
A complete physical examination includes measurement of height (screening only), weight, 
and examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, heart, lungs, abdomen, lymph nodes, and extremities. Genital, rectal, and breast 
examination may be excluded if not clinically indicated. Weight should be measured on the 
same scale each time. A neurological examination includes testing mental status, gait, 
cerebellar function, cranial nerves, motor functioning (including strength and reflexes), and 
sensation. 
The targeted physical examination is at the investigator’s discretion based on subject 
reported signs and symptoms and investigator observations. 
10.1.3 
Vital Signs 
Vital signs include body temperature, systolic and diastolic blood pressures, pulse rate, and 
respiration rate.  
Blood pressure and pulse rate will be measured in the recumbent position after at least 
2 minutes of recumbency, and both will be measured again after approximately no less than 
1 minute of standing. Subjects should be observed carefully for dizziness or unsteadiness 
while standing and allowed to sit if such occurs. Blood pressure and pulse rate should be 
recorded as soon as possible after sitting if the subject cannot stand for 1 full minute.  
Recumbent and standing recordings of blood pressure and pulse rate will be made at the 
Screening Visit and at the Day 26 Visit. Orthostatic blood pressure and pulse rate will be 
measured before dosing (recumbent and standing) on Day 1. During any visit (screening, 
baseline, or Day 26 or an unscheduled clinic visit), blood pressure and pulse rate are to be 
assessed at any time subjects appear faint or complain of dizziness or other symptoms 
suggestive of hypotension.  
Respiratory rate and temperature will be measured in the recumbent position and need 
only be measured one time (with the first set of blood pressure/pulse measurements) 


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10.1.4 
Clinical Laboratory Tests 
The following screening/safety laboratory tests (hematology, chemistry, and urinalysis) will 
be performed after 4 to 6 hours of fasting: 
• 
Hematology testing will include hematocrit, hemoglobin, red blood cell count, white 
blood cell (WBC) count with differential, absolute neutrophil count (ANC), and 
absolute lymphocyte count (ALC), and platelet count.  
• 
Serum chemistry analyses will include sodium, potassium, chloride, calcium, 
magnesium, phosphorus, bicarbonate, albumin, total protein, glucose, blood urea 
nitrogen (BUN), creatinine, creatine kinase (CK), uric acid, lactate dehydrogenase 
(LDH), ALT, AST, alkaline phosphatase, triglycerides, total cholesterol, and total 
bilirubin.  
• 
Urinalysis will be performed only as clinically indicated.  
10.1.5 
Urine Drug Screen 
Subjects will undergo urine drug screening for the presence of phencyclidine (PCP), cocaine, 
cannabinoids, opiates/barbiturates, benzodiazepines, amphetamines, methadone, and 
MDMA (Ecstasy) at the Screening Visit and at the Day 26 Visit. Subjects who have a positive 
urine drug screen will be excluded from the study unless the positive result is explained by 
the use of an approved prescription medication. 
10.1.6 
Pregnancy Tests 
A urine pregnancy test will be performed for all WOCBP. See Section 6.2, inclusion criterion 
#10 for the definition of WOCBP.  
Positive urine tests will be confirmed with a serum pregnancy test. Subjects may not enter 
the study if pregnant and must be immediately be discontinued from dosing when a positive 
pregnancy test is reported during study participation. 
10.1.7 
Electrocardiogram 
A 12-lead ECG will be obtained according to the Schedule of Assessments (Table 3). Subjects 
must rest in the supine position for at least 10 minutes before the ECG recording is started. 
The ECG should be recorded during the period of rest required before blood collection and 
the measurements of orthostatic blood pressure, pulse rate, and respiratory rate. A 
qualified physician will review the ECGs and any clinically important finding will be 
recorded on the appropriate CRF. The investigator is responsible for providing 
interpretation of all ECGs. The results will include heart rate, PR interval, QRS interval, QT 
interval, and QTc interval, and assessment of rhythm and morphology. If necessary, (e.g., 
suspected QTc prolongation), a manual reading of the ECG data will be performed. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in 
the same positions each time in order to achieve precise ECG recordings. If a machine-read 
QTc value is prolonged, as defined above, repeat measurements may not be necessary if a 


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qualified physician’s interpretation determines that the QTc values are in the acceptable 
range. 
10.1.8 
Columbia-Suicide Severity Rating Scale  
The C-SSRS is a suicidal ideation rating scale created by researchers at Columbia University 
(Posner, 2011). It rates an individual's degree of suicidal ideation on a scale, ranging from 
"wish to be dead" to "active suicidal ideation with specific plan and intent." 
The scale identifies behaviors that may be indicative of an individual's intent to commit 
suicide. The C-SSRS is used extensively across primary care, clinical practice, surveillance, 
research, and institutional settings. It is available in more than 100 country-specific 
languages and is part of a national and international public health initiative involving the 
assessment of suicidal ideation and behavior.  
The C-SSRS requires no mental health training to administer. An electronic patient-reported 
version of the C-SSRS is also available in tablet, interactive voice response, and web versions 
(Mundt 2010; Mundt 2013).  
Subjects with a history of attempted suicide within the past year or a C-SSRS score of 4 or 5 
at screening will be excluded from the study. Subjects who answer “yes” to Suicidal Ideation 
item 4 or 5 on the C-SSRS during the study must be withdrawn from study treatment. 
Investigators should also withdraw subjects from treatment if, in the judgment of the 
investigator, the subject develops other indicators of significant risk of suicide. In the event 
that suicidal ideation is observed in any study subject, the investigator will manage the 
situation as he/she deems medically and psychiatrically appropriate. 
The “lifetime” version of the C-SSRS will be used at screening, and the “since last visit” 
version will be used at all other visits.  
Samples of the C-SSRS are provided in Appendix A1. 
10.1.9 
University of Miami Parkinson’s Disease Hallucinations Questionnaire 
The UM-PDHQ was specifically developed to quantitatively and qualitatively assess 
hallucinations in patients with Parkinson’s disease (Papapetropoulos, 2008). The UM-PDHQ 
is a 20-item clinician-administered questionnaire that is completed during a structured 
interview. Questions are divided into 2 groups: a quantitative group that consists of 6 
questions (modality, frequency, duration, insight, emotional burden) and a qualitative 
group that consists of 14 questions. The first item is a gating question to assess the presence 
or absence of hallucinations. 
The investigator will complete the UM-PDHQ for any subject who experiences visual 
hallucinations during the study. The investigator should discuss the continued participation 
of any subject developing visual hallucinations during the study with the study safety 
representative. 
A copy of the UM-PDHQ is provided in Appendix A2. 


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10.2 
Adverse Events  
10.2.1 
Definitions  
Adverse Event  
An AE is any unfavorable or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or 
procedure that may or may not be considered related to the medical treatment or 
procedure. 
Seizure should not be reported as an AE or SAE unless it is a new seizure type, the 
frequency of seizure increases, status epilepticus occurs, or the investigator considers the 
seizure to be an AE or SAE. 
Adverse Events of Special Interest 
The following are considered AESIs: increase in seizure frequency, new seizure type, and 
status epilepticus. 
Laboratory Abnormality 
A laboratory abnormality is any clinically significant laboratory abnormality that suggests a 
disease or organ toxicity and that is of a severity to require active management (i.e., changes 
of dose, discontinuation of drug, more frequent follow-up, medical treatment, diagnostic 
investigation). Laboratory abnormalities are also considered AEs. 
Treatment-emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) are all AEs occurring during the treatment 
period or a pretreatment event that worsens in intensity during the treatment period. 
Treatment Period 
The treatment period is the period during which a subject receives study drug (i.e., first 
dose through Day 26). 
Intolerable Adverse Event 
An intolerable AE is one that is considered by the investigator to be related to study drug 
(Section 10.2.2.3) AND is either a severe or life-threatening event (Section 10.2.2.2) OR is a 
mild or moderate event that prompts the subject to express a desire to discontinue dosing. 
Dose adjustments for intolerable AEs are described in Section 4.6. 
Serious Adverse Event 
An SAE is any adverse event that results in death, is life threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, is a congenital anomaly/birth defect observed in any 
offspring of the subject conceived during treatment with the study drug, or is an important 
medical event. See Section 10.3 for more details on SAEs. 


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10.2.2 
Collection and Rating of Adverse Events  
All AEs, irrespective of the relatedness to the study drug, will be captured from the time the 
ICF is signed through the telephone safety check on Day 33. SAEs will be reported up to 
30 days after the last dose of study drug. A follow-up phone call will be made 30 days after 
the last dose of study drug for evaluation of any SAEs. In case of an SAE, an SAE Report 
Form must be completed and transmitted to the sponsor or designee within 24 hours.  
Overdoses and medication errors in the presence of clinical consequences should be 
recorded as AEs. The clinical consequence should be reported as “[enter AE] due to 
overdose.” See Section 4.7 for overdose management. 
10.2.2.1 
Onset Date 
The onset date is the date when the first sign(s) or symptom(s) were first noted. For 
example, if the AE is an abnormal laboratory test (such as “platelets low”), the onset date is 
the date when the sample was taken. If the subject was hospitalized for meningitis, and 
symptoms such as fever, headache, and nausea started the day before the hospitalization, 
the onset date is the day symptoms presented versus day of hospitalization. 
10.2.2.2 
Assessment of Intensity 
Each adverse event will be graded according to the following definitions: 
• 
Mild:  
asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
• 
Moderate:  
minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
[Instrumental ADL refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc]; 
• 
Severe:  
medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL [self-care ADL refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden]  
10.2.2.3 
Relationship to Study Drug 
The assessment of the relationship of an AE to the administration of study drug is a clinical 
decision based on all available information at the time of the completion of the CRF.  
The causal relationship of the study drug to an AE will be rated as follows:  
• 
Related:  
The AE has at least a possible or stronger causal relationship to the 
study drug, i.e., there are facts in evidence to suggest a causal 
relationship to the study drug. The study treatment and the AE are 
reasonably related in time, and any alternative etiology is equally or 
less likely.  


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• 
NOT Related: 
Exposure to study treatment did not occur; or the occurrence of the AE 
is not reasonably related in time, or is due to an 
underlying/intercurrent illness, or to other medication or procedure; 
or the AE is considered unlikely to be related to the study treatment.  
10.2.2.4 
Action Taken  
The action taken toward the study drug in response to an AE will be listed as one of the 
following:  
• 
None:  
 
No change in study drug dosage was made. 
• 
Reduced:  
 
Dose of study drug was reduced, with or without a period of 
temporary suspension of dosing. 
• 
Discontinued:  
The study drug was permanently stopped. 
10.2.2.5 
Outcome of Adverse Event  
The outcome of an AE will be recorded as one of the following:  
• 
Recovered:  
 
fully recovered or the condition has returned to the level 
observed at baseline 
• 
Recovered with sequelae:  resulted in persistent or significant disability or 
incapacity; the nature of the sequelae should be specified 
• 
Not yet recovered 
• 
Death 
10.2.3 
Adverse Event Follow-up 
Adverse events requiring therapy must be treated with recognized standards of medical 
care to protect the health and well-being of the subject. 
Any subject who has any AE (whether serious or non-serious) or clinically significant (in the 
investigator’s opinion) abnormal laboratory test values will be evaluated by the investigator 
or qualified designee and will be treated and followed up until the symptoms or values 
return to normal or acceptable levels, as judged by the investigator and the sponsor.  
All AEs, whether serious or non-serious, will be collected beginning at the time the ICF is 
signed through the telephone safety check on Day 33. All AEs should be followed until 
resolution or: 
1. 30 days from onset; or 
2. 30 days after the last dose of study drug; or  
3. the subject is lost to follow-up (as defined in Section 6.4.1); or  
4. the subject withdraws consent,  
whichever occurs first.  
SAEs will be reported up to 30 days after the last dose of study drug. A follow-up phone call 
will be made 30 days after the last dose of study drug for evaluation of any SAEs. 


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Any follow-up information available at the time of the subject’s end of study will be included 
in the clinical study report. 
10.3 
Serious and Other Significant Adverse Events  
10.3.1 
Definition of a Serious Adverse Event 
A serious adverse event is any adverse event that  
• 
Results in death. Death is not an event per se but rather an outcome. Note that any AE 
resulting in a fatal outcome must be fully documented and reported, including deaths 
that occur within 30 days after treatment ends and irrespective of the causal 
relationship to the study drug. 
• 
Is life threatening. Life threatening refers to an AE in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, which may 
have caused death, if it was more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization means that the subject was admitted to hospital or that existing 
hospitalization was extended as a result of an AE. Hospitalization describes a period of 
at least 24 hours. Over-night stays for observation, stays at the emergency room or 
treatment on an outpatient basis do not constitute a hospitalization. However, medical 
judgment must always be exercised and, when in doubt, the case should be considered 
serious (i.e., if the case fulfills the criterion for a medically important event). 
Hospitalization for administrative or social purposes does not constitute an SAE. 
Hospital admissions and/or surgical operations planned before study inclusion are not 
considered AEs if the illness or disease existed before the subject was enrolled in the 
study, provided that the condition did not deteriorate during the study. 
• 
Results in persistent or significant disability/incapacity. Disability/incapacity 
means a substantial disruption of a person’s ability to conduct normal life functions. If in 
doubt, the decision should be left to medical judgment by the investigator. 
• 
Is a congenital anomaly/birth defect. Any congenital anomaly or birth defect 
observed in any offspring of the subject that was conceived during treatment with the 
study drug. 
• 
Is an important medical event. Important medical events are events that may not be 
immediately life threatening or result in death or hospitalization but that may 
jeopardize the subject or require intervention to prevent one of the other outcomes 
listed in the definition above. Examples of important medical events include AEs that 
suggest a significant hazard, contraindication, or precaution; occurrence of malignancy; 
or development of drug dependency or drug abuse. Medical and scientific judgment 
should be exercised in deciding whether events qualify as medically important. 
An AE caused by an overdose or medical error is considered serious if a criterion listed in 
the definitions above is fulfilled. 


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The following are not considered SAEs: 
• 
A preexisting condition that is present prior to or at the start of the study that did not 
worsen. 
• 
Hospitalizations for treatment, which were elective or preplanned, for a preexisting 
condition unrelated to the indication under study that did not worsen. 
• 
Admission to a hospital or other institution for general care not associated with any 
deterioration in condition. 
10.3.2 
Serious Adverse Event Reporting by the Investigator to the Sponsor 
Any SAE that occurs after a subject has entered the study, whether or not related to study 
drug, must be reported to the sponsor or the sponsor’s agent immediately (within 24 hours) 
via telephone or email. If initially reported via telephone, this must be followed-up by a 
written SAE report. The investigator must report all SAEs that occur from the time the 
subject signs the ICF until 30 days after last dose of the study drug. 
A completed SAE Report Form with the best possible details must be transmitted to the 
sponsor representative within 24 hours of knowledge of the SAE according to contact 
details as specified below:  
Sponsor Representative and Contact Information for SAE Reporting: 
SAE Reporting Primary Contact:  
Premier Research Pharmacovigilance 
Reporting email:  
 
 
GlobalPV-US@premier-research.com  
Back-up reporting fax number:  
+1.215.972.8765 
10.3.3 
Handling of Follow-up Information 
Follow-up information may be required, or additional information may be requested by the 
sponsor (e.g., evolution of the SAE, other signs or symptoms, final diagnosis, final outcome, 
hospital discharge summary, autopsy report). The same procedures and timelines as for 
initial reporting, listed above, should be followed for any follow-up information. If 
necessary, the study site will be visited to collect additional information. 
Follow-up information is required on all SAEs until one the following criteria is satisfied: 
۰ 
The final outcome of the case is known. 
۰ 
The event is resolved or the medical condition of the subject is stabilized. 
۰ 
No further information is available. 
۰ 
Sponsor assessment has been finalized. 
۰ 
The subject has withdrawn consent for further follow-up; information obtained up 
to the date and time of withdrawal of consent will remain a part of the study record. 


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10.3.4 
Reporting and Follow-up of Pregnancy 
When an investigator becomes aware of the pregnancy of a female subject (or female 
partner of a male subject), the investigator must withdraw the subject from the study 
treatment and follow the pregnancy until termination or until the child is 1 month old. The 
pregnancy will be reported immediately by telephone and by faxing a completed Pregnancy 
Report to the sponsor within 24 hours of knowledge of the event. The pregnancy will not be 
processed as an SAE; however, the investigator should notify the sponsor or the sponsor’s 
agent of the outcome of the pregnancy by submitting a follow-up Pregnancy Report. 
Additionally, if the outcome of the pregnancy meets the criteria for immediate classification 
of an SAE (e.g., spontaneous or therapeutic abortion, stillbirth, neonatal death, congenital 
anomaly), the investigator will report the event by phone and by faxing a completed SAE 
Report Form to the sponsor within 24 hours of knowledge of the event. 
10.3.5 
Expedited Reporting of Serious Adverse Events  
10.3.5.1 
Responsibilities 
The sponsor is responsible for ensuring the timely reporting of SAEs to regulatory 
authorities and to all investigators who participate in the clinical development program of 
the study drug. It is the responsibility of the investigator to provide the sponsor with the 
case information such that reporting timeline demands of applicable regulatory authorities 
can be met. 
10.3.5.2 
Expedited Reporting 
All AEs that are serious, unexpected, and considered related to the study drug judged by the 
sponsor will undergo expedited reporting. All available information relevant to the 
evaluation of the SAE will be reported. Serious AEs will be considered reportable regardless 
of whether or not the study drug was used in accordance with the provisions in the 
protocol. 
Adverse events that are serious, but expected, or those that are not associated with the 
study drug will only be subjected to expedited reporting if they are required to be reported 
to an authority according to national requirements.  
10.3.5.3 
Timelines 
Fatal or life-threatening serious unexpected related cases require rapid reporting. 
regulatory authorities shall be notified as soon as possible but no later than 7 calendar days 
after first knowledge by the sponsor representative, followed by as complete a report as 
possible within 8 additional calendar days.  
Serious unexpected related cases that are not fatal or life threatening must be submitted as 
soon as possible, but no later than 15 calendar days after first knowledge by the sponsor 
representative that the case meets the minimum criteria for expedited reporting. 
It is the responsibility of the investigator to support sponsor activities needed to meet the 
aforementioned timelines for regulatory authority reporting in the event of an SAE. 


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10.4 
Safety Monitoring and Risk Mitigation Plan 
Measures to minimize the risks to subjects enrolled in this clinical trial have been taken 
with respect to the following study design elements: 
• 
Subject safety and tolerability will be monitored in this study across multiple 
dimensions by tracking clinical AEs; vital signs (including orthostatic pulse and 
blood pressure); general and neurological physical examinations; standard clinical 
laboratory safety panels for complete blood counts, chemistry, coagulation, and 
urinalysis; standard 12-lead ECGs; the C-SSRS; and the UM-PDHQ.  
• 
The specified inclusion/exclusion criteria have been carefully considered to avoid 
enrollment of subjects for whom exposure to the study drug might pose a hazard. 
• 
This study will perform a careful dose titration in which dosing of CX-8998 will be 
initiated at 2 mg BID for 2 days and then increased to 4 mg BID for 6 days, to 6 mg 
BID for 6 days, to 8 mg BID for 6 days, and, finally, if tolerated, to the target dose of 
10 mg BID for 6 days. The study is designed to allow for flexible titration. The dose 
should only be increased if the previous dose level is well tolerated. Should subjects 
experience intolerable AEs (see Section 10.2.1) at 6 mg, 8 mg, or 10 mg BID, study 
drug may be discontinued, or the dose may be decreased to the previous lower dose. 
Subjects who experience intolerable AEs at 2 mg or 4 mg BID will be discontinued 
from treatment.  
• 
Dose modification and stopping rules are in place for individual subjects (see 
Section 4.4). Near real-time safety and tolerability monitoring for individual subjects 
is the primary responsibility of the principal investigators and sub-investigators. 
• 
All SAEs meeting criteria for expedited reporting to the US FDA will be reported to 
the FDA and all institutional review boards (IRBs) in accordance with regulatory 
timelines. 
• 
The sponsor’s Study Safety Representative will monitor aggregate study level safety 
and tolerability after approximately 50% of the projected sample size of subjects 
have completed the EOS Visit. These reviews will be based on blinded, select listings 
and summary tables of the evolving safety and tolerability data for each arm of the 
study. Decision-making will depend on the specifics of the safety and tolerability 
data reviewed.  
• 
In the event of a treated subject’s death within 30 days of the last dose of study drug 
that is assessed by the treating principal investigator/sub-investigator or the Study 
Safety Representative as at least possibly related to study drug, further enrollment 
in the study will be immediately suspended until a safety review can be conducted 
by the Study Safety Representative, the actively participating principal 
investigators/sub-investigators, and the sponsor. As required by regulation, all 
deaths that meet the criteria for expedited reporting to the US FDA will be reported 
to the FDA and all IRBs within regulatory timelines. A final decision to reopen the 
study to new enrollment without modification(s), reopen with modification(s), or 


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terminate the study will be made by the overall study principal investigator, and the 
sponsor’s Study Safety Representative.  
11 
STATISTICAL METHODS 
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 0.05. 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.  
11.1 
Statistical Analysis Plans 
A statistical analysis plan (SAP) will be created and approved prior to database lock. This 
document will provide a more technical and detailed description of the proposed data 
analysis methods and procedures.  
11.2 
Study Hypothesis 
No formal statistical hypotheses will be tested in this exploratory study. Statistical testing 
may be utilized to inform hypothesis generation for subsequent studies. 
11.3 
Determination of Sample Size 
Up to approximately 15 eligible subjects will receive CX-8998. The sample size was not 
based on statistical considerations but rather chosen to provide safety and efficacy 
information on CX-8998 when administered according to this protocol. 
11.4 
Analysis Populations 
The populations defined for analysis will include the intent-to-treat (ITT) population, safety 
population, and a PK population. Additional analysis populations may be defined to evaluate 
study results; these populations will be defined in the SAP.  
• 
Intent-To-Treat Population: The ITT population will include all subjects who are 
enrolled in the study. The ITT population will be used for analyses of accountability, 
demographics, and efficacy.  
• 
Safety Population: The safety population will include all subjects who are enrolled in 
the study and receive at least 1 dose of CX-8998 The safety population will be the 
primary population for all analyses of safety data. 
• 
PK Population: The PK population will consist of all subjects who received study 
treatment and for whom PK samples were obtained and sufficient plasma 
concentrations are available. 


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Individual data for all enrolled subjects will be presented in data listings, sorted by subject 
identifier. 
11.5 
Data Analysis 
11.5.1 
Efficacy Analyses 
The change in frequency (number of seizures per hour) of absence seizures as defined by a 
3-Hz spike and wave lasting for ≥3 seconds as determined by HV, the frequency (number of 
seizures per hour) of absence seizures (based on 6.5-hour video-EEG), the time to absence 
seizures during HV, the percent of subjects with a shift in the occurrence of absence seizure 
(e.g., from HV period 1 to HV period 2), the percent of subjects with an absence of photic 
response, the actual and change from baseline in SERDAS scores, and the change from 
baseline to end of treatment in absence seizure-free days as collected by seizure diary will 
be summarized. Ninety-five percent (95%) confidence intervals will be constructed. 
11.5.2 
Safety Analyses 
Adverse Events will be mapped to a MedDRA preferred term and system organ 
classification. Severity will be assessed by investigator. The occurrence of TEAEs will be 
summarized using MedDRA preferred terms, system organ classifications, and severity. All 
AEs will be listed for individual subjects; both verbatim and preferred terms will be listed. 
Separate summaries of treatment-emergent SAEs, AESIs, and AEs leading to discontinuation 
of study or study drug will be generated. 
Descriptive summaries of vital signs and clinical laboratory results will be prepared. The 
number and percentage of subjects experiencing treatment-emergent laboratory 
abnormalities and laboratory abnormality shifts from baseline to postbaseline assessments 
will be summarized. 
Concomitant medications will be mapped to a World Health Organization (WHO) Drug 
Dictionary preferred term and drug classification. The number and percent of subjects 
taking concomitant medications will be summarized using preferred terms and drug 
classifications.  
Changes from baseline in ECGs during study will be evaluated. Results from the C-SSRS, 
UM-PDHQ, and physical examinations will be listed.  
11.5.3 
Pharmacokinetic Analyses 
Individual plasma concentrations and actual time of collection will be listed by visit and 
dose of CX-8998.  
11.6 
Missing, Unused, and Spurious Data  
Every effort will be made to obtain required data at each scheduled visit from all subjects 
who have been randomized. In situations where it is not possible to obtain all data, it may 
be necessary to impute missing data. Details of imputation methods will be presented in the 
SAP. 


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12 
STUDY MANAGEMENT 
12.1 
Protocol Amendment and Protocol Deviation 
12.1.1 
Protocol Amendment 
Administrative amendments to the protocol will be classed as amendment of typographical 
errors, clarifications of confusing wording, and other minor modifications, including, but 
not limited to, name, address, and contact information changes that have no impact on the 
safety of the subject or the science of the study. Administrative amendments will be 
submitted to the IRB for information only. The sponsor will ensure that acknowledgement 
is received and filed. Otherwise, an amendment will be classed as a substantial amendment 
and will be submitted to the appropriate regulatory authorities and the IRB for approval. 
12.1.2 
Protocol Deviations and Waivers 
Requests for waivers will generally not be granted in advance by the sponsor. Should a non-
anticipated protocol deviation occur, the sponsor must be informed as soon as possible. All 
deviations and the reasons for the deviation will be documented by the investigator or 
designated staff. Reporting of protocol deviations to the IRB and in accordance with 
applicable regulatory authority mandates is an investigator responsibility. 
12.2 
Ethics and Regulatory Aspects 
12.2.1 
Ethical Conduct of the Study and Regulatory Guidelines 
To ensure the ethical conduct of this clinical study, each investigator is expected to conduct 
the study in accordance with the protocol; the US investigational new drug (IND) 
regulations specified under 21 CFR 11, 50, 54, 56, and 312; the International Conference on 
Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP); and 
the Guidelines of the Declaration of Helsinki. The investigator will conduct all aspects of the 
study in accordance with all national, state and local laws of applicable regulatory 
authorities.  
The responsibilities of the sponsor, the monitor and the investigator will be as defined in 
the ICH GCP consolidated guideline and applicable regulatory requirements in the country 
where the study takes place. The investigator is responsible for adhering to the GCP 
responsibilities of investigators, for dispensing the study drug in accordance with the 
approved protocol or a signed amendment, and for secure storage and safe handling of the 
study drug throughout the study. 
12.2.2 
Institutional Review Board and Regulatory Approval 
The study protocol and any amendments will be reviewed by an IRB. The IRB will review 
the written subject information sheet and the ICF, their updates (if any), and any written 
materials given to the subjects. A listing of the membership of the IRB consulted and the 
name of the committee chair(s) or IRB registry (accreditation) number will be documented 
within the Investigator File and Trial Master File of the sponsor. 


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Regulatory permission to perform the study must be obtained in accordance with 
applicable regulatory requirements. All ethics approvals must be obtained, and all 
regulatory obligations must be met before a subject is exposed to any study-related 
procedure, including screening tests for eligibility. 
12.2.3 
Subject Informed Consent 
Subjects will be informed about the study both verbally and in writing. Each subject will be 
provided with a written subject information sheet that has been approved by the IRB and 
will be given a reasonable time to consider the study and to ask any questions regarding the 
study. The written subject information sheet and ICF must be in a language that the subject 
can understand.  
Only the investigator, a medically qualified sub-investigator, or a suitably qualified and 
trained authorized person may be involved in the informed consent process.  
The investigator or suitable designee will obtain a freely given, written consent from each 
subject after an appropriate explanation of the aims, methods, potential hazards, and any 
other aspects of the study that are relevant to the decision of the subject to participate. The 
investigator will explain that the subject is completely free to refuse to enter the study or to 
withdraw from it at any time, without any consequences for further care and without the 
need to justify.  
The ICF must be signed and dated by the subject before any study-related procedure is 
performed, including screening tests for eligibility. The subject will receive a copy of the 
written subject information sheet and the ICF. 
Each subject will be informed that a monitor, a quality assurance auditor mandated by the 
sponsor, or a health authority inspector, in accordance with applicable regulatory 
requirements, may review his or her source records and health data. Data protection will be 
handled in compliance with national and local regulations. 
If new safety information becomes available and results in significant changes in the 
risk-to-benefit assessment, the written subject information sheet will be revised or updated 
where necessary. Under these circumstances, all subjects (including those already being 
treated) should be informed of the new information, given a copy of the revised form, and 
allowed to reevaluate their consent to continue in the study. 
12.3 
End of Study and Regulatory Notification 
The study can be terminated in part or in whole at the discretion of the FDA, an applicable 
regulatory authority, or the sponsor.  
At the end of the study, the IRBs and regulatory authorities will be notified by the sponsor 
according to applicable regulatory requirements. 


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12.4 
Data Protection and Confidentiality 
The confidentiality of records that could identify subjects should be protected, respecting 
the privacy and confidentiality rules in accordance with applicable regulatory 
requirement(s). 
12.5 
Monitoring 
The study will be monitored to ensure that the study is conducted and documented 
properly according to the protocol, GCPs, and all applicable regulatory requirements.  
On-site visits will be made at appropriate times during the study. Monitors must have direct 
access to source documentation in order to check the consistency of the data recorded in 
the CRFs. 
The investigator will make available to the monitor source documents, medical records, and 
source data necessary to complete CRFs. In addition, the investigator will work closely with 
the monitors and, as needed, provide them appropriate evidence that the conduct of the 
study is being done in accordance with applicable regulations and GCP guidelines. 
Monitoring of safety data will be conducted in accordance with the safety monitoring plan 
outlined in Section 10.4. 
12.6 
Quality Assurance and Quality Control 
The sponsor or its designee will perform the quality assurance and quality control activities 
of this study; however, responsibility for the accuracy, completeness, and reliability of the 
study data presented to the sponsor lies with the principal or qualified investigator 
generating the data.  
Prior to the study initiation, the sponsor will explain the protocol, Investigator’s Brochure, 
and CRFs to investigators. In addition, the monitor will be available to explain applicable 
regulations and to answer any questions regarding the conduct of the study. 
At its discretion, the sponsor may conduct audits as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the protocol, 
standard operating procedures, GCPs, and all applicable regulatory requirements. Audits 
will be independent of and separate from the routine monitoring and quality control 
functions. 
The study center may also be compelled to an inspection by a regulatory authority. 
12.7 
Source Data 
Source data are defined as information in original records and certified copies of original 
records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study.  
Source documents are the original data, documents, and records. Examples include hospital 
records, laboratory reports, clinical and office charts, laboratory notes, memoranda, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 


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instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, other 
radiographic depictions or displays, subject files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical study. All source 
documents must be reviewed by the principal investigator and the sponsor (or designee) 
for compliance with GCP. 
The investigator will permit study-related monitoring, audit(s), IRB review(s), and 
regulatory inspection(s), with a direct access to all the required source documents and 
associated records. 
13 
DATA AND RECORD KEEPING 
13.1 
Case Report Forms 
Study sites will be provided access to an electronic data capture (EDC) system that has been 
fully validated and conforms to 21 CFR Part 11 requirements. The sponsor or designee will 
train designated study site staff on the EDC system. Study site staff will not be given access 
to the EDC system until they have been trained. Designated study site staff will enter the 
data required by the protocol into the electronic CRFs (eCRFs). The investigator must 
certify that the data are complete and accurate prior to database lock. After database lock, 
the investigator will receive a CD-ROM copy of the subject data for archiving at the study 
site. 
Designated Cavion personnel will review the data on the eCRFs entered by study site staff 
for completeness and accuracy. Authorized study site staff will respond to queries sent to 
their site and make any necessary changes to the data. 
13.2 
Record Keeping 
The investigator must arrange for retention of study records (“Essential Documents for the 
Conduct of a Trial” are listed in the ICH “Guideline for Good Clinical Practice,” Section 8, E6) 
at the site, in a secure location, for 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or for at least 2 years after the formal discontinuation of clinical development 
of the investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by agreement with the 
sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained. The investigator should take 
measures to prevent any accidental or premature destruction of these documents. 


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14 
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Tenney JR, Glauser TA. The current state of absence epilepsy: can we have your attention? 
Epilepsy Curr. 2013;13:135-40. 


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CONFIDENTIAL AND PROPRIETARY 
Page 73 of 91 
Tai C, Yang Y, Pan M, Huang C, Kuo C. Modulation of subthalamic T-type Ca2+ channels 
remedies locomotor deficits in a rat model of Parkinson disease. J Clin Invest. 2011;121(8): 
3289-3305. 
Vitko I, Bidaud I, Arias JM, et al. The I-II loop controls plasma membrane expression and 
gating of Ca(v)3.2 T-type Ca2+ channels: a paradigm for childhood absence epilepsy 
mutations. J Neurosci. 2007; 27:322–30. 
Vitko I, Chen Y, Arias JM, et al. Functional characterization and neuronal modeling of the 
effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J 
Neurosci. 2005;25:4844–55.  
Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: 
European expert opinion, 2007. Epileptic Disord. 2007;9:353–412.  
Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion, 2005. J 
Child Neurol. 2005;20:S1–56. 
Wolf P, Inoue Y. Therapeutic response of absence seizures in patients of an epilepsy clinic 
for adolescents and adults. J Neurol. 1984;231:225–9. 
 


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Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 74 of 91 
15 
APPENDICES 
Appendix A1 – Columbia Suicide Severity Rating Scale 
Appendix A2 – University of Miami Parkinson’s Disease Hallucinations Questionnaire 
(UM-PDHQ) 
Appendix B – Cytochrome P450 Interaction Table  
Appendix C - Summary of CX-8998 Toxicology Studies 
Appendix D - Summary of Previous Clinical Trial Experience with CX-8998 (MK-8998) 


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Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 75 of 91 
Appendix A1 – Columbia Suicide Severity Rating Scale 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline/Screening Version 
Version 1/14/09 
Posner, K; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P; Zelazny, J.; 
Burke, A.; Oquendo, M; Mann, J. 
Disclaimer. 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
Defrnitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide Histo,y form 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, I 05 I Riverside Drive, New York, NY, I 0032. (Oquendo M. A., 
Halberstam B. & Mann J. )., Risk factors for suicidal behavior. utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practic~ pp. /03-130 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, I 051 Riverside Drive, New 
York, New York, I 0032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
C-SSRS Bas~ine Screening - United States/Eng ish - Mapi 
c-SSR s-8 asel n es c re eni'lg_A tJ51 _ ena-l.JSori.d o c 


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Protocol Number: CX-8998-CLN2-002 
Version 6.0 
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CONFIDENTIAL AND PROPRIETARY 
Page 76 of 91 
 
 
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to "[llicidal Behavior" section. If the answer to 
Lifetime: Time 
Part 
questw n 2 is "yes", ask questwns 3, 4 and 5. Jfthe answer to question 1 and/or 2 is "yes", complete 
He/She Felt 
-
"Intensity o{Ideatwn" sectwn below. 
:Most Suicidal 
:Months 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead er not alive anymore, or wish to fall asleep and not wake up. 
Yes 
No 
Yes 
N o 
Han you wished you were dead orwishedyou could go to sleep and rwtwake up? 
D 
D 
D 
D 
If yes. describe 
2. Non-Specific Active Suicidal Thoug)lts 
General non-specific thoughts of wanting to end one's life/commit suicide (e.g., "I'w thought about. killing rr{)'Selj' ) without thoughts of 
Yes 
No 
Yes 
N o 
ways to kill oneself/associated methods, intent, cr plan dlring the assessment period 
D 
D 
D 
D 
Have you actually had any thoughts of killing yourself? 
If yes, describe 
3. Active Snicidel Ideation with Any Methods (Not Plmi) withont Intent to Act 
Subject endorses thoughts cf suicide and has thought of at least one method during the assessment period. This is different than a specific 
Yes 
No 
Yes 
No 
plan with time, place or method details worked out (e.g .. thought of method to kill self but not a specific plan). Includes person who would 
D 
D 
D 
D 
say, "I thought about, taking an owrdosebut I nt2w r rna.df! a spf!cific plan as to whf!n, whf!rf! or how l wouldactua.lly do it and I would 
new r go through 1-Vith iL " 
Have you been thinking about how you might do this? 
If yes, describe 
4. Active Snicidal Ideation with Some Intent to Act, without Specific Plan 
Acnve suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to "I have the thougf.Jts 
Yes 
No 
Yes 
N o 
but I de.finitely ½'ill not do anything about them " 
D 
D 
D 
D 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe 
5. Active Snicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or part1ally worked out and subject has some intent to carry it out. 
Yes 
No 
Yes 
No 
Have you storied to ·work out orworked out the details of how to killyourse!f? Do you intend to carry outthispkm? 
D 
D 
D 
D 
If yes, describe 
INTENSITY OF IDEATION 
The fcUowingfeatures should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being 
the least severe and 5 being the most severe). Ask about time he/she was feeling the m ost suicidal. 
Lifetime• 
JHost Severe Ideation: 
Most Severe 
Most 
T>-pe # (I.SJ 
Description if ltkdon 
Severe 
Past X Months • 
JHost Severe Ideation: 
Type# (I.SJ 
Description if ltkdon 
Frequency 
How mm,y times hare you had Duse thoughts? 
(1) Less than once a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Daily or almost daily 
(5) Many times each day 
-
-
Duration 
When you hare the thoughis how long do they last? 
(1 ) Fleeting - few seccnds or minutes 
(4) 4-8 hours/most of day 
-
-
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or ccntinuous 
(3) 1-4 hours/a lot of time 
Controllability 
Coukllcanyou stop thinking about1dllingyoune!formmting to die ffyou m,nt to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
-
-
(2) Can control thoughts with little diffi culty 
(5) Unable to control thoughts 
(3) Con control thO\lghts with some difficulty 
(0) Does not attempt to control thoughts 
DeteITents 
Are there things-"'!)'one or anything (e.g.,jamizy, religion, pain '!{'death) -tlwtsloppedyoufrom wanting to /lie or 
acting on thoughls of committing sukide? 
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not step you 
-
-
(2) Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped vou 
(0) Does not applv 
Reasons for Ideation 
Wltatsortofreasonsilidyou lunv,jbrthinldngabouJmmting to die orkiIJingyoune!f? Was itto end the pain or 
stop the mw you »v,re feeling (in other »vras you coukln't go on living with this pain or how you m,re feeling) or 
was it to get attention, revenge or a reaction.from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others 
(4) Mostly to end or stop the pam (you couldn't go on 
-
-
(2) Mostly to get attention, revenge or a reacticn from ethers 
living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others and to 
(5) Completely to end or stop the pain (you couldn't g,:, on 
end/stop the pain 
living with the pain or how you were feeling) 
(0) Does not apply 
0 2008 Research Foundation for Mental Hygiene, Inc 
C-SSRS- Baseline/Screening0fersion 1/14/00) 
Page I of2 


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CONFIDENTIAL AND PROPRIETARY 
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SUICIDAL BEHAVIOR 
Past -
{Check all that apply, so long as these are separate events; must ask about ail types) 
Lifetime 
Years 
Actual Attempt: 
Ye, 
No 
Ye, 
No 
A potentially self-injunous act committed with at least some wish to che, as a result of act. Behavitt was m part thought of as method to kill 
□ □ 
□ □ 
oneself. Intent does not have to be 100'%. If there is any intent/desire to de associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be 419' -inj,uy or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun 1s broken so no injury results, this is considered an attempt. 
Inf erring Intent: Even if an individual denies intent/..vish to die, it may be inferred clinically from the behavior or circumstances. For example, 
a highly lethal act that is clearly not an accident sono other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of 
a high floor/stcry) . .Also, if someooe denies intent to die, but they thought that what they did could b e lethal, intent may be inferred 
Haveyou ltlll(kasuidile attempt? 
Have you done "'!)'thing to hannyour.self? 
Have you done a'!)'thing dangeroJIS ,mere you could have dkd? 
Total # of 
Total# of 
What diilyou do? 
Attempts 
Attempts 
Didyou ___ as amzy to end your life? 
Did you ffl'.tnt to die (even a li11Je) v.nenyou __ ? 
--
--
Were you hying to end your l!fewhenyou __ ? 
Or diilyou think itmis JJDS$ibleyou couklhaw: dkd.from __ ? 
Or did you do it purely far other reasons / without ANY intention Qfldllingyourse!f (liki, to relieve Jtress,feel better, 
gelJYmpathy, or get so~thingelse "lo happen)? (Self♦Injurious Behavior without suicidal intent) 
ff yes, describe 
Ye, 
No 
Ye, 
No 
Has subiect en<>~<>ed in Non-Suicidal Self-Iniurious Behavior? 
□ □ 
□ □ 
InteITUpted Attempt: 
Ye, 
No 
Ye, 
No 
When the person is interrupted (by an outside circumstance) from starting the potentially self♦injurious act (if not for that, actual attempt 
□ □ 
□ □ 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger 
Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from 
l edge. Hangrng: Person has noose around neck but has not yet started to hang + i s stopped from doing so 
Ha. there been a time when you started to do something to end your life blli someone or something stopped you 
Total# of 
Total# of 
before you actually diil anything? 
interrupted 
interrupted 
ff yes, describe 
--
--
Aborted Attempt: 
Ye, 
No 
Yes 
No 
When person begins to take steps toward making a suicide attempt, but stops themselves befcre they actually have engaged in any self♦ 
□ □ 
□ □ 
desb"uctive behavior. Examples are sim il ar to interrupted attempts, except that the individ..al stops him/herself, instead of being stopped by 
something else 
Ha. there been a time when you started to do something to try to end your life but you stopped your.se!fbefare you 
Total# of 
Total# of 
actual/y did anything? 
aborted 
aborted 
ff yes , describe 
--
--
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalizatioo or thought, such as 
Ye, 
No 
Yes 
No 
assembling a specific method (e.g. , buying pills, purchasing a gun) or preparing for ooe· s death by suicide (e.g., giving thmgs away, writing a 
□ □ 
□ □ 
suicide note) 
Have you taken ti'!)' step, IDwards making a suicide attempt or preparing to ldll your.self (such as collecting pills, 
getting a gun, giving valllilbles """'!I' or writing a suicide note)? 
ff yes , describe 
Suicidal Behavior: 
Ye, 
No 
Ye, 
No 
Suicidal behavior was present during the assessment period? 
□ □ 
□ □ 
Answer for Actual Attempr; Only 
M ost Recent 
Most Lethal 
InitialfFirst 
Attempt 
Attempt 
Attempt 
D ate: 
Date 
Date 
Actual Lethality/1\fedical Damage: 
Enter Code 
Enter Code 
EnrerCcxie 
0 N o physical damage or very minor physical damage (e.g., surface scratches) 
I Minor physical damage (e.g ., lethargic speech; first♦degree bums; mild bleeding; sprains) 
2 Moderate physical damage; medical attentioo needed (e.g., conscious but sleepy, somewhat responsive; second--degree 
bums; bleeding of major vessel) 
3 Moderately severe physical damage; medjcal hospitalization and likely intensive care required (e.g., comatose with 
--
--
--
reflexes intact; third-degree bums less than 20% of body; extensive blood loss but can recover; major fractures) 
4 Severe physical damage; n1,uiical hospitalization with intensive care required (e.g, comatose without reflexes; third♦ 
degree burns over 20% of body; extensive blood loss with unstable vital signs; maj or damage to a vital area) 
5 Death 
Potential Lethality: Only AnswEr if Actual Lethality=0 
Enter Code 
Enter Code 
EnrerCcxie 
Likely lethality of actual attempt if no medical damage (the f cllowing examples, while having no octual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train trocks with oncoming train but pulled away before run over) 
0 = Behavior not likely to result in injury 
--
--
--
1 = Behaviorlikely toresult ininjury but not likely to cause death 
2 = Behavior likelv to result in death despite available medical care 
0 2008 Research Foundation for Mental Hygiene, Inc 
C-SSRS- Baseline/Screening0fersion 1/14/00) 
Page 2 of2 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 78 of 91 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
Posner, K; Brent, D.; Lucas, C.; Gould, M; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J. 
Disclaimer. 
This scale is intended tD be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severitoj Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, I 051 Riverside Drive, New York, NY, I 0032. (Oquendo M. A., 
Halberstam B. & Mann J. }., Risk facwrs for suicidal behavior. utilitoj and limitations of research instruments. In M. B First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. I 03 -130, 2003.) 
For reprints of the C-SSRS contaa Kelly Posner, Ph.D., New York State Psychiatric lnstiWte, /05 I Riverside Drive, New 
York, New York, I 0032; inquiries and training requirements contaa posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
C-SSRS Since Last Visit - United SW:es/English. Mai:,. 
C-SSRS-Sincelasf\/i9t_AU5.1 _eng-USori.doc 


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CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 79 of 91 
 
 
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to "Swcidal Behavior" section. If the answer to question 2 is "yes ", 
Since Last 
ask quest,ons 3, 4 and 5. If the answer to question 1 and/or 2 is "yes", complete "Intensity of Ideat,on " sect,on below. 
Visit 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Yes 
No 
Haveyouwishedyouweredeadorwishedyoucouldgo tc sleep and not-wake up? 
□ □ 
If yes, describe 
2. Non-Specific Active Suicidal Thoughts 
General noo-specific thoughts of wanting to end one' s life/commit suicide (e.g ., "I've thought ahouthlling myself) without thoughts of ways to kill 
Yes 
No 
oneself/associated methods. intent, or plan during the assessm ent period 
□ □ 
Have you actJJalJ, had any thoughts of JG//jng yourself? 
If yes, describe 
3, Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Yes 
No 
Subject endorses thoughts of suicide and has thought cf at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would say, '1 thought about taking an 
□ □ 
overdose but I never made a specific plan as ta when, where or how I would actually do it .. and I would never go throu#i with it" 
Have you been ihinkmg alJout how yon might. do ibis? 
If yes, describe 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to "I have the thought.s but 1 defmiWly 
Yes 
No 
Y-.'ill not do anything about them" 
□ □ 
Have you had these thoughts and had someinJentwn of ac.tingon them? 
If yes, describe 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Yes 
No 
Have you started to workoutorworkedoutthe details of hawk> kill.yourself? Do you inlendw carry outihisplan? 
□ □ 
If yes, describe 
INTENSITY OF IDEATION 
1he f olfowmg f eatures shou.J.d be rated w1th respect to the most severe 'type of ideation (i.e.,1-5 from above, w1th 1 being the least seLJere 
and 5 being the m ost severe). 
Most 
Most Severe Idea/ion: 
---
Severe 
I)!pe # (1-5) 
Description of Idea/ion 
Frequency 
Huw many Innes have you had these thoughJs? 
(1) Less than ooce a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Dailv or almost daily 
(5) :Manv times each day 
-
Duration 
When you have the thoughts huw long /lo they la.st? 
(I) Fleetrng • few seconds or minutes 
(4) 4 -8 hours/most of day 
-
(2) Lessthan lhour/someofthetime 
(5) More than 8 hours/persistent or cootinuous 
(3) 1-4 hours/a lot of time 
Controllability 
Coulillcanyoustop thinking abouJ kiHing you~e!J"ormmting to die if"youlWIIII to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficu lty 
-
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some dl.fficulty 
(0) Does not attempt to control thoughts 
Deterrents 
Are there thingr- anyone or mwthing (e.g.,fmni!f, religion, pain qfdealh) - lhatstoppedyoujrom »unllng to die or acting on 
thoughJs ofcommi11ing suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stq:> you 
-
(2) Deterrents probably stq:>ped you 
(5) Deterrents definitely di.cl not stq:> you 
(3) Uncettam that deterrents stopped you 
(0) Does not apply 
Reasons for Ideation 
Wlwt sorl '!{reasons did you /un,e fer thinking aboutwanting to die or ldlling yoUJ'Se!f? W a,-it to end the pain or stop the '"'!I' 
you m,refteling (in othenwrds-you couldn't go on living with this pain or how you m,refteling) ormzs itto get attention, 
ret."enge or a reaction.from others? Or both? 
(1) Completely to get attention. revenge or a reaction from others 
(4) Mostly to end or stop the pain (you couldn' t go on living with the pain oc 
(2) Mostly to get attention. reveng e or a reaction from others 
how you were feeling) 
-
(3) Equally to get attentioo, revenge or a reaction from others and to 
(5) Completely to end or stop the pc\n (you coul<tl't go on living with the 
end/stop the pain 
pain or how you were feeling) 
(0) Does not applv 
Cl 2008 Research Foundation fur Merta! Hygiene, loc. 
C-SSRS-SinceLast Visit(Version 1/1411)9) 
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Protocol Number: CX-8998-CLN2-002 
Version 6.0 
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CONFIDENTIAL AND PROPRIETARY 
Page 80 of 91 
 
SUICIDAL BEHAVIOR 
Since 
(Greek alf that apply, so lonz as these are separate events; must ask about all ty_pes) 
Last Visit 
Actual Attempt: 
A potentially self-injurioos act committed with at least some wish to die, asa result afacl Behavior was in part thought of as method to kill oneself. Intent 
Ye, 
No 
does not have to be 100%. If there is tutJ,' mtent/desire to die associated with the act, then it co11 be considered an actual suicide attempt. There does not 
□ □ 
have to be a,w injwy or harm,just thepotc:ntial for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury 
results, this is considered an attempt. 
Infemng Intent: Even if an indivtdual denies intent/wish to d e, it may be 1nferred clinically from the behav1or or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, Jumping from window cf a hi.gh floor/story) 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you coulil haw: died'! 
Total # of 
What did you do? 
Attempts 
Didyou ___ arawqi• to end your /!ft? 
Did you mint to die (even a llJtk) when you __ ? 
--
Were you trying to end your lffe »ttenyou __ ? 
Or Did you thinkitwar possible you could haw: diedfrom __ ? 
Or did you do il purel,yfer other rearons l wilhoul ANY intention ofkiJJingyourse!f(liu to relieve stress,ftel better, get 
,sympathy, or get something else to happen)? (Self -Injuri ous Behavior without suicidal intent) 
If yes, describe 
Ye, 
No 
Has subject emrn.,ed in Non-Suicidal Self-lnjwious Behavior? 
□ □ 
Interrupted Attempt: 
When the persoo is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not.for t,hat,, actual atf£mpt would havrJ 
Ye, 
No 
occurred) 
□ □ 
Overdose: Person has pills in hand l::ut is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an int errupted attempt 
Shooting: Person has gun pointed toward self, gun is taken away by someooe else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt Jumping: Persoo is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck l::ut has not yet started to hang - is stowed from doing so. 
Total # of 
Har there been a time »ttenyou started to do something to end your lifr but someone or something stopped you bejbreyou 
intemipted 
aetuany did a,wthing? 
If yes, describe 
--
Aborted Attempt: 
Ye, 
No 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior 
□ □ 
E xamples are similar to intemipted attempts, ~ cept that the individual stops him/herself. instead of being stopped by something else 
Har there been a time mrenyou started to do something to t,y to end your /!ft butyoustoppedyourse!fbeforeyou aetuaJJydid 
Total# of 
anything? 
aborted 
If yes, describe 
--
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
Ye, 
No 
specific method (e.g., l::uying pills, purchasing a gun) oc preparing for one's death by suicide (e.g., giving things away, writing a suicide note) 
□ □ 
Have you taken any steps lomlrds making a suicide attempt or preparing to kill yourself (such as collecting pills, geliing a gun, 
giving valu.ables amzy or writing a suicide note)? 
If yes, describe 
Suicidal Behavior: 
Ye, 
No 
Suicidal behavior was present during th.e assessment period? 
□ □ 
Suicide: 
Ye, 
No 
□ □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date 
Actual Lethality/Medical Damage: 
Enter Code 
0. No physical damage or very minor physical damage (e.g., surface scratches) 
1. M:mor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains) 
2 Moderate physical damage; medical attention needed (e.g., cooscious but sleepy, somew hat responsive; second-degree bums; bleeding of maj or vessel) 
3 Moderately severe physical damage; med:cal hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree \::urns 
less than 2(1'/o cf body; extensive blood loss l::ut can recover; m ajor fractures) 
--
4 Severe physical damage; 11'1t2dical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; maj or damage to a vital area) 
5 Death 
Potential Lethality: Only Answer if Actual Lethality=0 
Enter Code 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying oo train tra cks with oncoming train l::ut pulled away 
before run over) 
0 = Behav1or not hkely to result m in Jury 
--
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likelv to result in death desoite available medical care 
Cl 2008 Research Foundation fur Merta! Hygiene, loc. 
C-SSRS-SinceLast Visit(Version 1/1411)9) 
Page 2 of2 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 81 of 91 
Appendix A2 – University of Miami Parkinson’s Disease 
Hallucinations Questionnaire (UM-PDHQ) 
 
 
 
 
Th• Uninrsity of Miami Parkinson's diseas• Hallucinations Qu•stioooaire (UM-PD HQ) 
I 
~ 
C 
.2 
~ 
·! • 
'; ... -
0 
b 
"C 
~ t 
"' 
I 
I 
Patient identifier: 
_DATE: 
I Ouestion 
I . Do you experience hallucinations? 
(Have you noticed anything unusual 
about your vision? Have you had 
any unusual visual experiences? Or 
ever see/hear/feel/smell/taste things 
that are not really there or that other 
-nJe do not see?) 
2. How often do you experience 
hallucinations? 
3. On average, how Jong do the 
experiences last? 
4. Do you think what you are 
seeing/experiencing is real? 
5. How many types of 
images/sensations do you 
.,...,...._.;ence? 
6. How severe/emotionally distressing 
do you find these images/sensations 
or visions? 
I Total Score(min= 0; max = 14) 
Comments: 
A:Future,/Commeots B:Score <circle annronriate) 
Type: (awt apptopriale) 
0. No hallucinations (skip to Am>ex) 
I. Visual 
2. Auditory 
I. One type only 
3. Somatic/Cutaneous 
2. Combination 
4. Gustatory 
5. Olfactory 
C: Not within the past month, but it has 
(assess each separately) 
ha~n..! in the Dasi 
0 = Only a few times 
I = Occasionally Oess than once a 
week, but continuously) 
2 = Often (about once per week) 
3 = Frequently (several times per week 
but < than once per day) 
4 = V erv freauentlv "'°nee ner dav) 
0 = Short Duration(< !sec) 
I = Medium Duration(< !0secs) 
2 = Prolon•edDuration /> !Osecsl 
O= Notreal 
I = Sometimes real 
2 = Alwavs real 
! = One 
2 = Few(2or3) 
3 - Several /more than 3l 
0 = No effect/Friendly 
I = Mildly- produce little distress 
2 = Moderately- produce distress and 
are disturbing and disruptive 
3 = Severely- very disturbing 
(medications mav be = JrHI\ 
Page 1 ofZ 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 82 of 91 
 
Please circle the appropriate answer and provide information 
7. Have you been diagnosed with any eye 
Yes (please describe) No 
disease? (i.e. near or far sight problems, double 
vision, cataract, glaucoma, retinitis, retinal 
detachment, diabetic or hypertensive eye 
disease) 
8. Was there a recent change in your 
Yes (please describe) No 
treahnent? Pl ease describe. 
9. Was this change related to the 
Yes 
appearance or change in the 
No 
characteristics of hallucinations? 
I cannot tell 
NIA 
10. Do you experience hallucinations while 
On 
"mf' or ''off"? 
Off 
Anytime-not related to on-offs 
11. What do you normally 
Not formed/cannot describe 
se e/fe el/hear ism el I/taste? 
Whole Faces 
If not visual describe here: 
Fragmented faces 
□Familiar 
Voices, Music, tastes, smells, skin related: 
Whole people 
□Unfamiliar 
Animals 
Insects/reptiles 
Objects 
a 
12. Is there anything you can do to make the 
Yes 
Q 
images/sensations disappear? 
No 
-c .. = 
13. Al what time of the day or under which 
A. Specific time During 
·c = 
lighting conditions do you experience 
the day/Bright During the 
'; 
.c 
hallucinations 
night/Dark Dim 
'<I 
B. Anytime 
f 
14. \Vhen are the images most present? 
\Vhen eyes are open 
= 
0 
\Vhen eyes are closed 
No difference 
NI A (for non-visual hallucinations) 
15 . Do the images ever make any sound or noise 
Yes 
(for visual hallucinations)? 
No 
NIA (for non-visual hallucinations) 
16. Do images move (for visual 
Yes 
hallucinations)? 
No 
NIA (for non-visual hallucinations) 
17. Are the images normal size? 
Yes 
No, smaller than normal No, 
larger than normal 
NIA (for non-visual hallucinations) 
18. Are the images transparent or solid? 
Transparent 
Solid 
NI A (for non-visual hallucinations) 
19. Are the images colored? 
Yes 
No, (black and white) 
NIA (for non-visual hallucinations) 
20. Is the onset of hallucinations gradual or 
Gradual (appear-disappear slowly) 
sudden? 
Sudden ( appear-disappear suddenly) 
I cannot tell 
Page2 of2 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 83 of 91 
Appendix B – Cytochrome P450 Drug Interaction Table  
PROHIBITED CYP3A4 INHIBITORS* 
PROHIBITED CYP2C9 INHIBITORS* 
HIV antivirals (delaviridine, indinavir, 
nelfinavir, ritonavir) 
amiodarone 
cimetidine  
clarithromycin 
diltiazem 
erythromycin  
fluvoxamine 
grapefruit juice  
itraconazole 
ketoconazole 
nefazodone 
suboxone 
troleandomycin 
verapamil 
amiodarone 
fluconazole 
izoniazid 
 
 
 
Prohibited moderate and strong inhibitors of CYP3A4 and CYP2C9 include the lists above, but are not 
limited to the medications and agents listed 
PROHIBITED CYP3A4 INDUCERS* 
PROHIBITED CYP2C9 INDUCERS* 
carbamazepine 
efavirenz 
nevirapine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin 
rifampin 
St. John's Wort 
troglitazone 
rifampin 
secobarbital 
Prohibited moderate and strong inducers of CYP3A4 and CYP2C9 include the lists above, but are not 
limited to the medications and agents listed 
From: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007). "/clinpharm/ddis/clinical-table/" Accessed [6 Dec 2016]. 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 84 of 91 
Appendix C – Summary of CX-8998 Toxicology Studies 
Summary of Preclinical Toxicology Studies 
Study No. 
Study Type 
Dose (mg/kg/day) - Toxicologic Finding 
Total/Free 
AUC 
Exposurea 
(µM∙hr)  
Total/Free 
Margin  
(Animal/ 
Humanb) 
06-1088 
Rat 4-Week 
Toxicity Study 
30, 300 and 2000 
mg/kg/day 
2000 – mortality, adverse clinical signs, nasopharyngeal 
inflammation, renal tubular degeneration, stomach ulcer, 
reduced seminal vesicle secretion 
≥ 300 – adverse FOB changes; reduced prostate weight / 
secretion, reduced pituitary weight (M, F) 
≥ 30 – reversible female reproductive organ changes 
indicating extended diestrus; NOAEL for FOB changes 
including increased number of urine pools and foot splay, 
decreased body temperature and number of rears, and 
abnormal gait 
546/4.4  
 
 
385/3.1  
 
43.6c/0.35d 
40.1/81.5 
 
 
28.3/57.4 
 
3.2/6.5 
07-0034 
Rat 4-Week 
Investigative 
Female Histology 
Study with 8-
Week Recovery 
10 and 1000 
mg/kg/day 
1000 – reversible female reproductive organ changes 
(extended diestrus); adverse clinical signs 
10 – NOEL for female reproductive organ changes 
751e/6.0f  
 
13.7g/0.11h 
55.2/111 
 
1.0/2.0 
08-7370 
Rat Female 
Fertility Study 
10, 30, 100, and 
1000 mg/kg/day 
1000 – NOEL for mating, reproductive and fertility 
effects;  
100 – Toxicokinetic (TK) assessment 
751i/6.0j 
 
247/2.0 
55.2/111 
 
18.2/37 
08-7175 
Rat Embryo Fetal 
Development 
Study 
10, 30, 100, 300, 
and 1000 
mg/kg/day 
1000 - Excessive maternal toxicity resulting in the 
early termination of this dose group 
≤ 300 - Transient, dose-related maternal toxicity 
≥ 100 – Reduced fetal body weight 
No TK 
NA 
08-7185 
Rabbit Embryo 
Fetal 
Developmental 
Study 
30, 100, 300, and 
1000 mg/kg/day 
1000 - Excessive maternal toxicity resulting in the 
early termination of this dose group 
≤ 300 - Transient, dose-related maternal toxicity  
≤ 300 - No evidence of developmental toxicity 
No TK 
NA 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
 
CONFIDENTIAL AND PROPRIETARY 
Page 85 of 91 
Summary of Preclinical Toxicology Studies 
Study No. 
Study Type 
Dose (mg/kg/day) - Toxicologic Finding 
Total/Free 
AUC 
Exposurea 
(µM∙hr)  
Total/Free 
Margin  
(Animal/ 
Humanb) 
06-1087 
Dog 4-Week 
Toxicity Study 
2, 20 and 800 
mg/kg/day 
800 – mortality, adverse clinical signs, decreased testis 
and prostate weight, testicular seminiferous tubular 
degeneration and reduced spermatogenesis, immature 
prostate 
20 - NOEL 
1780/5.3 
 
 
467/1.4 
130.9/98.1 
 
 
34.3/25.9 
a M/F combined values unless otherwise indicated 
b Based on anticipated human total exposure of 13.6 µM∙hr (free 0.054 µM∙hr) at the 10 mg BID dose; Free CX-
8998 in human, rat and dog plasma is 0.4%, 0.8% and 0.3% respectively. 
c/0.35d Female AUC value 
i/6.0j 
AUC data from study 07-0034 
M – male, F- female, NOEL – no effect level; NOAEL – no adverse effect level; TK – toxicokinetic 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
CONFIDENTIAL AND PROPRIETARY 
Page 86 of 91 
Appendix D - Summary of Previous Clinical Trial Experience with CX-8998 
(MK-8998) 
Study PN001 
Title 
(population) 
Part I: A Double-Blind, Randomized, Placebo-Controlled, Multiple Period, Alternating-Panel, Single-Rising-Oral- Dose Study to Assess the 
Safety, Tolerability, and Pharmacokinetics of MK-8998 (24 healthy males, 18-45 years old) 
Part II: A Double-Blind, Randomized, Placebo-Controlled Three Period Crossover Study to Assess the Effects of MK-8998 on Awake EEG in 
Healthy Adult Male Subjects (12 healthy males, 18-45 years old) 
Design 
Single oral doses of CX-8998 1-24 mg or placebo, fasted; included fasted vs. fed comparison for 1 mg po dose 
Summary of 
findings 
Safety: 
• 
Mild to moderate, transient central nervous system (CNS) AEs observed at 
all doses ≥3 mg, including drowsiness, relaxation, mood changes 
(euphoria), poor concentration, visual changes, and paresthesias 
• 
Single doses up to 16 mg generally well tolerated 
• 
20 and 24 mg doses less well tolerated due to poor concentration, 
headache, mood changes, anxiety, and restlessness; and vivid dreams with 
night-time dosing 
PK:  
• 
Dose proportional increase in Cmax and AUC0-inf 
• 
Tmax fasted 0.5-2 hrs; fed 4 hrs; food decreases 
Cmax but AUC is similar to fasted 
• 
Biphasic elimination; terminal T½ = 9.7-13.2 hrs 
• 
Single 8 mg dose produced Cmax 522-580 nM 
PD: 
• 
Awake EEG demonstrated 25% or greater 
reduction in absolute power for alpha band in a 
dose dependent manner at CX-8998 
concentrations 200-800 nM  


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
CONFIDENTIAL AND PROPRIETARY 
Page 87 of 91 
Study PN002 
Title 
(population) 
Part I: A Double-Blind, Randomized, Placebo-Controlled, Rising-Single-Dose Study in Healthy Elderly Male Subjects (9 healthy males, 55-
75 years old) 
Part II: A Double-Blind, Randomized, Placebo-Controlled, Serial-Panel, Rising-Multiple-Dose Study in Healthy Young Male Subjects (40 
healthy males, 18-45 years old) 
Design 
Single oral doses 2-18 mg or placebo, fasted 
 
Summary of 
findings 
Safety, Part I (elderly males, single dose): 
• 
Single doses up to 18 mg of CX-8998 were generally well tolerated 
• 
TEAE were temporary and generally mild or moderate in intensity. The 
most frequent TEAE included general, nervous system, and psychiatric 
disorders: relaxation, fuzzy head, tiredness, headache, lightheadedness, 
dizziness, mood alteration  
• 
No dose dependent, treatment related effects were observed on safety labs, 
ECGs, ECG telemetry monitoring or vital signs 
PK (elderly males, single oral dose): 
• 
Dose proportional increase in Cmax and AUC0-
inf 
• 
Tmax 0.5-1 hr (fasted) 
• 
Biphasic elimination; terminal T½ = 18.8-22.6 
hrs 
 
 
Safety, Part II (young males, multiple dosing once QD X 7 days): 
• 
Multiple oral doses up to 12-mg daily X 7 days were generally well 
tolerated; TEAEs of mood or perceptual disturbance became more frequent 
and intense at the 18-mg once daily dose 
• 
Most common TEAE's considered at least possibly drug related were 
headache, lightheadedness, tiredness, feeling happy or pleasant, feeling 
emotional, tiredness, somnolence, relaxation, abnormal or vivid dreams or 
day dreams, and paresthesia/hypoesthesia. No subjects treated with CX-
8998 at doses < 18 mg po QD X 7 days discontinued treatment for AEs  
• 
For subjects experiencing CNS AE's, these were generally observed at or 
near Tmax; late occurrence (e.g., days after dosing) was not observed in the 
absence of CNS AE's near Tmax 
 
PK, Part II 
• 
Dose proportional Day 1 and Day 7 Cmax and 
AUC0-24hr  
• 
Terminal T½ = 11 hrs 
• 
Steady state trough attained after 2 days of 
dosing 
• 
Day 7/Day 1 geometric mean accumulation 
ratios for CX-8998 were 1.31 (AUC0-24hr) and 
1.15 (Cmax) for the 8 mg dose;  
• 
Day 7 mean (±SD) Cmax = 665 (156) nM and  
AUC0-24hr = 4679(1495) nMhr 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
CONFIDENTIAL AND PROPRIETARY 
Page 88 of 91 
 
• 
Two syncopal episodes occurred: 1) A subject fainted after standing 2 hours 
after the first dose of CX-8998 2 mg po; assessed as vasovagal probably not 
related to CX-8998, and the subject continued through the full 7 days of 
dosing without further events of syncope or dose related blood pressure, 
heart rate or orthostatic changes; and 2) A subject experienced syncope 2 
hours after the first dose of CX-8998 18 mg po; the event was judged by the 
investigator as moderate in intensity and probably study drug related. Due 
to ongoing nausea and feeling weak/lethargic, this subject was 
discontinued from the study after the first dose 
• 
One subject experienced a serious adverse event (SAE) of mood swings 
following the first dose of 18 mg CX-8998; no additional doses were given 
and the event was assessed as moderate in intensity and probably study 
drug related 
 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
CONFIDENTIAL AND PROPRIETARY 
Page 89 of 91 
Study PN003 
Title 
(population) 
A 2-Part, Adaptive Design, Randomized, Double-Blind, Placebo-Controlled Crossover Polysomnogram (PSG) Study to Evaluate the Effects 
of Single Doses of MK-8998 on Slow Wave Activity and Rapid Eye Movement Sleep in Healthy Middle Aged and Elderly Subjects (28 
healthy males, 40-80 years old) 
Design 
Single oral doses of 4, 8, or 12 mg CX-8998 or placebo prior to bedtime 
Summary of 
findings 
Safety: 
• 
Single oral doses of 4, 8, or 12 mg CX-8998 were well tolerated 
• 
The most common AE's were headaches, vivid dreams, and visual 
and/or auditory disturbances/hallucinations. The dose of CX-8998 was 
administered at bedtime for this sleep study. The visual and auditory 
disturbances/hallucinations were typically described as seeing 
geometric shapes, colors, lights and/or movement, and hearing tones 
similar to a telephone or electronic music. These were generally not 
disturbing to subjects. These events had onset about 30 minutes after 
dosing or generally near Tmax, and resolved within minutes or during the 
night. 
PK, PD: 
PK data was not yet available for this study 
PD, polysomnogram (PSG) study: 
• 
The hypothesis that sleep slow wave activity 
(SWA) would increase following dosing with 
CX-8998 was not supported: SWA decreased 
by 30% after 12 mg of CX-8998; delayed sleep 
onset and decreased sleep maintenance were 
also observed after 12 mg single doses of CX-
8998 
• 
Results of the PSG study with 4 and 8 mg of 
CX-8998 are not yet available 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
CONFIDENTIAL AND PROPRIETARY 
Page 90 of 91 
Study PN005 
Title 
(population) 
A Single Dose Clinical Trial to Test the Safety, Tolerability, and Pharmacokinetics of MK-8998 in Healthy Female Subjects of Non-
Childbearing Potential (9 healthy females of non-childbearing potential, 55-75 years old) 
Design 
Single oral doses of 8 mg CX-8998 or placebo, fasted 
 
Summary of 
findings 
Safety: 
• 
Single doses of 8 mg CX-8998 in healthy middle-aged and elderly 
females were generally well tolerated 
• 
Mild laughter, nervousness, and racing thoughts were observed in 2, 1, 
and 1 subject administered CX-8998, respectively 
One subject receiving CX-8998 had elevated serum alanine aminotransferase 
(ALT) deemed as possibly drug related by the investigator. This subject's pre-
dose ALT was 28 IU/L and increased to 41 and 59 IU/L at one and 4 days post-
dose, returning to 33 IU/L by two weeks post-dose (normal range: 6 – 40 IU/L). 
All serum aspartate aminotransferase, alkaline phosphatase and total bilirubin 
values were within the normal range for this subject 
PK: 
• 
Tmax = 0.5 hrs 
• 
Terminal T½ = 30.3 hrs 
• 
Mean Cmax was 582 nM and AUC0-inf was 9420 
nMhr 
 


Cavion, Inc. 
 
CX-8998 in Absence Epilepsy 
Protocol Number: CX-8998-CLN2-002 
Version 6.0 
Issue Date: 30 May 2019 
CONFIDENTIAL AND PROPRIETARY 
Page 91 of 91 
Study PN004 
Title 
(population) 
A Phase IIa, Randomized, Multicenter, Double-Blind, Active Comparator- and Placebo-Controlled, Clinical Trial to Study the Safety and 
Efficacy of MK-8998 in Acutely Psychotic Patients with Schizophrenia (216 adult males (N=126) and females (N=90) 20-55 years old) 
Design 
CX-8998 (8 mg BID) was compared with olanzapine and with placebo. N=86 randomized to CX-8998, including 49M/37F, 21-55 years old 
(mean age 37.4 years) 
Summary of 
findings 
Safety: 
• 
The most frequent TEAEs without regard to causality classified by MedDRA 
System Organ Class (SOC) in the CX-8998 group were Psychiatric Disorders 
(19/86 [22.1%] CX-8998 vs. 10/83 [12.0%] placebo); Nervous System 
Disorders (10/86 [11.66%] CX-8998 vs 6/83 [7.2%] placebo); and 
Gastrointestinal Disorders (9/86 [10.5%] CX-8998 vs 5/83 [6.0%] placebo). 
Among CX-8998 treated subjects, insomnia was the only TEAE that rose to a 
frequency of ≥ 5% (13/86 [15.1%] vs. 7/83 [8.4%] placebo).  
• 
No treatment-emergent SAE’s occurred in CX-8998 treated subjects 
TEAE’s led to treatment discontinuation in 9/86 (10.5%) of CX-8998 
treated subjects vs. 1/83 (1.2%) placebo treated subjects. Four of the CX-
8998 discontinuations for AE were for worsening or exacerbation of 
schizophrenia, only one of which was assessed by the investigator as 
causally related to CX-8998. 
Anti-Psychotic Efficacy: 
• 
Primary endpoint measure was mean change 
from baseline in the Positive and Negative 
Syndrome Scale (PANSS) total score at Week 4 
• 
CX-8998 was not statistically significantly 
different from placebo in the mean change from 
baseline in PANSS total score at Week 4 (Mean 
changes from baseline: CX-8998, -13.3; 
olanzapine -17.0; placebo -12.7)  
• 
For one of the secondary endpoints, responders 
were defined as those who demonstrated ≥ 20% 
improvement from baseline on the PANSS total 
score. CX-8998 was not statistically significantly 
different from placebo in the responder rate after 
4 weeks of treatment (responder rates were: CX-
8998, 57.4%; olanzapine, 66.7%; placebo, 48.3%) 
 
Reported safety observations in this table are limited to those that occurred in CX-8998 treated subjects more frequently than in placebo treated 
subjects. Serious adverse events occurring in placebo treated subjects are not included. Complete details of the safety results are contained in the 
latest edition of the CX-8998 Investigator’s Brochure. 
 

SAP_001.pdf: 
Cavion, Inc. 
CX-8998-CLN2-002
Statistical Analysis Plan
Final Version 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 2a, Safety, Tolerability, Pharmacokinetics and 
Quantitative EEG Study of CX-8998 in Adolescents and Adults 
with Idiopathic Generalized Epilepsy with Absence Seizures 
Phase: 
2a 
Protocol No.: 
CX-8998-CLN2-002
Protocol Date: 
Original Version 1.0: 23OCT2017 
Amendment 1 Version 2.0: 12DEC2017 
Amendment 2 Version 3.0: 30APR2018 
Amendment 3 Version 4.0: 24SEP2018 
Amendment 4 Version 5.0: 29APR2019 
Amendment 5 Version 6.0: 30MAY2019 
Analysis Plan Version and 
Date: 
Final Version: 21APR2020 
Prepared By: 
PharPoint Research, Inc. 
Prepared For: 
Cavion, Inc. 
One Broadway 
Cambridge, MA 02461 
PI
PI
NCT03406702


Cavion, Inc. 
CX-8998-CLN2-002 
Statistical Analysis Plan 
Final Version 
 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION


Cavion, Inc. 
CX-8998-CLN2-002 
Statistical Analysis Plan 
Final Version 
 
 
 
CONFIDENTIAL 
Page 3 
21APR2020 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL 
This Statistical Analysis Plan has been prepared in accordance with team reviewers’ specifications.   
 
PharPoint Research, Inc. 
 
Date 
 
 
PharPoint Research, Inc. 
 
Date 
 
 
 
 
 
 
 
Jazz Pharmaceuticals 
 
Date 
 
 
 
 
 
 
 
Jazz Pharmaceuticals 
 
Date 
21-Apr-2020 | 14:09 PM EDT
22-Apr-2020 | 09:16 AM PDT
21-Apr-2020 | 10:43 AM PDT
21-Apr-2020 | 13:37 PM EDT
PI
PI
PI
PI
PI
PI


Cavion, Inc. 
CX-8998-CLN2-002 
Statistical Analysis Plan 
Final Version 
 
 
 
CONFIDENTIAL 
Page 4 
21APR2020 
TABLE OF CONTENTS 
1. 
INTRODUCTION .................................................................................................................. 6 
1.1. 
Study Overview .................................................................................................................. 6 
1.2. 
Schedule of Assessments .................................................................................................... 8 
1.3. 
Glossary of Abbreviations ............................................................................................... 12 
2. 
OBJECTIVES ...................................................................................................................... 13 
2.1. 
Primary Objective............................................................................................................ 13 
2.2. 
Secondary Objectives ...................................................................................................... 13 
2.3. 
Exploratory Objectives .................................................................................................... 13 
3. 
GENERAL STATISTICAL CONSIDERATIONS............................................................ 13 
3.1. 
Sample Size and Power .................................................................................................... 13 
3.2. 
Randomization and Masking .......................................................................................... 13 
3.3. 
Handling of Data .............................................................................................................. 13 
3.3.1. Strata and Covariates ..................................................................................................... 13 
3.3.2. Examination of Subject Subsets .................................................................................... 14 
3.3.3. Multiple Testing and Comparisons ................................................................................ 14 
3.3.4. Missing Data and Outliers ............................................................................................. 14 
3.3.5. Imputation of Incomplete Dates .................................................................................... 14 
3.3.6. Presentations by Study Visit .......................................................................................... 15 
3.3.7. Definitions and Terminology ......................................................................................... 15 
3.4. 
Timing of Analyses........................................................................................................... 18 
4. 
ANALYSIS POPULATIONS .............................................................................................. 18 
4.1. 
Intent-To-Treat (ITT) Population .................................................................................. 18 
4.2. 
Safety Population ............................................................................................................. 18 
4.3. 
PK Population .................................................................................................................. 18 
5. 
STATISTICAL METHODS ................................................................................................ 18 


Cavion, Inc. 
CX-8998-CLN2-002 
Statistical Analysis Plan 
Final Version 
 
 
 
CONFIDENTIAL 
Page 5 
21APR2020 
5.1. 
Subject Disposition, Demographic and Baseline Characteristics, and Extent of 
Exposure ........................................................................................................................................ 18 
5.2. 
Concomitant Medications and Non-Drug Therapies .................................................... 19 
5.3. 
Safety and Tolerability .................................................................................................... 19 
5.3.1. Safety and Tolerability Endpoints ................................................................................. 19 
5.3.2. Safety Analysis .............................................................................................................. 20 
 
Vital Signs and ECGs ....................................................................................................... 20 
 
Clinical Laboratory Assessments ...................................................................................... 21 
 
Adverse Events ................................................................................................................ 22 
 
Physical and Neurological Examinations .......................................................................... 22 
 
Columbia Suicide Severity Rating Scale ........................................................................... 22 
 
Epworth Sleepiness Scale ................................................................................................. 22 
 
UM-PDHQ ....................................................................................................................... 22 
5.4. 
Pharmacokinetic Analyses .............................................................................................. 23 
6. 
PROTOCOL DEVIATIONS ............................................................................................... 23 
7. 
CHANGES IN THE PLANNED ANALYSES FROM THE PROTOCOL ..................... 23 
8. 
REFERENCES ..................................................................................................................... 24 
9. 
PROGRAMMING CONVENTIONS ................................................................................. 25 
10. PROPOSED TABLES, LISTINGS, AND FIGURES ........................................................ 27 
 


Cavion, Inc. 
CX-8998-CLN2-002 
Statistical Analysis Plan 
Final Version 
 
 
 
CONFIDENTIAL 
Page 6 
21APR2020 
1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary 
and analysis of data from Protocol CX-8998-CLN2-002. Background information is provided for 
the overall study design and objectives.  The reader is referred to the study protocol and electronic 
case report forms (eCRFs) for details of study conduct and data collection. 
1.1. 
STUDY OVERVIEW 
CX-8998-CLN2-002 is a Phase 2a, open-label study consisting of a screening period of up to 4 
weeks and a 4- dose-titration treatment period to dose of up to 10 mg twice daily (BID) of CX-
8998, followed by a 1-week safety follow-up period after the last dose of study medication.  
 
Eligible subjects will receive titrating doses of CX-8998 up to 10 mg BID as follows: 
1. Days 1 – 2: 
2 mg (1 capsule) BID (4 mg/d);  
2. Days 3 – 8: 
4 mg (2 capsules) BID (8 mg/d); 
3. Days 9 – 14: 
6 mg (3 capsules) BID (12 mg/d); 
4. Days 15 – 20:  8 mg (4 capsules) BID (16 mg/d);  
5. Days 21 – 26:  10 mg (5 capsules) BID (20 mg/d); 
6. Day 27: 
10 mg (5 capsules) (10 mg/d) (once, morning dose only).  
 
Study drug should be administered with food. Subjects should be instructed to take their daily dose 
at approximately the same times each day. Consecutive doses should be taken no closer than 10 
hours and no later than 14 hours (every 12 hours ± 2 hours). Subjects will remain under 
observation for at least four hours post-dosing prior to discharge at Visit 1. 
At clinic visits at which PK blood draws are scheduled in the afternoon, subjects will take the 
morning dose at the appropriate time. Both the time of the morning dose and the time of the PK 
blood draw will be recorded. 
A missed dose (>14 hours since the prior dose) should be skipped and should not be “doubled-up” 
or “made up”; the next dose should be taken 24 hours from the last administered dose. If the 
subject experiences emesis following the dose, that dose should not be re-taken; instead the next 
dose should be taken 24 hours from the last administered dose without emesis. If emesis occurs, the 
subject should contact the investigator or qualified designee at the study site for guidance on 
management of the emesis. 
Subjects experiencing specified adverse events will have their dose adjusted. 
A member of the study staff will contact any subject who is suspected of experiencing 
neuropsychiatric adverse events to determine the need for an unscheduled visit before further dose 
escalation may proceed. 
Though amendments 4 and 5 of the protocol were executed, no subjects enrolled under these 
amendments. Amendment 4 changed the target population and replaced the use of ambulatory 
electroencephalograms (EEG) withstandard multi-lead video EEGs. Amendment 5 removed dosing 


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on Day 27. Since no subjects enrolled under these amendments, this schedule of assessments below  
and the data included in listings will be presented based on amendment 3.


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1.2. 
SCHEDULE OF ASSESSMENTS 
Visit 
Screening 
 
Dosing Period 
EOT 
 
EOS 
FU 
Day 
-28 to -1 
1 
2 
3-7 
8 
9-13 
14 
15-19 
20 
21-25 
26  
27 
33 
57 
Visit Window 
 
- 
0 
 
-2 d 
 
- 2 d 
 
- 2 d 
 
±1 d 
 
±1 d 
±2 d 
CX-8998 daily dose 
- 
4 mg 
8 mg 
12 mg 
16 mg 
20 mg 
 
 
Clinic visit 
X 
X 
 
 
 
 
 
 
 
 
X1 
 
 
 
Nurse home visit 
 
 
 
 
X2 
 
 
 
X2 
 
 
 
X1 
 
Telephone call 3 
 
 
X 
 
 
 
X2 
 
 
 
 
 
 
X 
Informed consent 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/medical history 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam6 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Targeted physical exam  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Neurological exam 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital Signs 7 
X 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Electrocardiogram 8 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Clinical laboratory tests 9 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Urine (+/- serum) pregnancy 
test10 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum FSH 11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screening 12 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pharmacogenomics sample 13 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PK 14 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 


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Visit 
Screening 
 
Dosing Period 
EOT 
 
EOS 
FU 
Day 
-28 to -1 
1 
2 
3-7 
8 
9-13 
14 
15-19 
20 
21-25 
26  
27 
33 
57 
Visit Window 
 
- 
0 
 
-2 d 
 
- 2 d 
 
- 2 d 
 
±1 d 
 
±1 d 
±2 d 
CX-8998 daily dose 
- 
4 mg 
8 mg 
12 mg 
16 mg 
20 mg 
 
 
Clinic visit 
X 
X 
 
 
 
 
 
 
 
 
X1 
 
 
 
Nurse home visit 
 
 
 
 
X2 
 
 
 
X2 
 
 
 
X1 
 
Telephone call 3 
 
 
X 
 
 
 
X2 
 
 
 
 
 
 
X 
Ambulatory EEG 15 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Seizure-Related Disability 
Assessment Scale 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Daily Seizure Diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Epitel device (based on device 
availability)16 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Epworth Sleepiness Scale 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
C-SSRS 17 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
UM-PDHQ 18 
 
As needed 
 
 
 
Prior / Concomitant meds 
X 
X 
 
 
X20 
 
X 
 
X20 
 
X 
 
 
 
AE review19 
 
X 
 
 
X20 
 
X 
 
X20 
 
X 
 
X 
X19 
Study drug admin. in clinic 
 
X21 
 
 
 
 
 
 
 
 
X21 
 
 
 
Study drug admin. outpatient 
 
X21 
X 
X 
X 
X 
X 
X 
X 
X 
X21 
X21 
 
 
Drug compliance  
 
X22 
X23 
X22 
X23 
X22 
X24 
 
 
AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EEG = electroencephalogram; EOS = end of study; 
EOT = end of treatment; FSH = follicle-stimulating hormone; FU = follow-up; HIV = human immunodeficiency virus; PK = pharmacokinetic; UM-PDHQ – 
University of Miami Parkinson’s Disease Hallucinations Questionnaire.. 
1. Visit window ± 1 day as needed for scheduling. 
2. Visit window +0, -2 days as need for scheduling. 


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3. Before initiating dose escalation, study staff will contact the subjects by telephone and will question them about their health status, including about 
the occurrence of any AEs. Subjects who report AEs may be asked to return to the clinic for an unscheduled visit. 
4. Informed consent must be signed prior to initiation of all other screening procedures. 
5. Medical history will include seizure history. 
6. A targeted physical exam will be based on subject reports of signs and symptoms and investigator’s observations 
7. Vital signs include body temperature, systolic and diastolic blood pressures, pulse rate and respiration rate. Vital signs will be collected predose and 
postdose (1-2 hours) at the Baseline (Day 1) Visit and on Day 26. Blood pressure and pulse rate will be measured in the recumbent position after at 
least 2 minutes of recumbency, and both will be measured again after approximately no less than 1 minute of standing. 
8. At baseline (Day 1) and EOT, a 12-lead ECG will be performed predose and approximately 1-2 hours after the dose as convenient between other 
required visit procedures. All ECGs should be performed after at least 10 minutes of recumbency. 
9. Clinical chemistry, and hematology. Urinalysis to be performed only as clinically indicated. Additional lab tests are obtained at the screening visit 
to verify eligibility (including HIV, hepatitis B and C). A positive drug screen will result in exclusion from the study unless it is explained by use of 
an allowed prescription medication. 
10. A urine pregnancy test will be performed, and if the result is positive a serum pregnancy test should be completed. 
11. Serum FSH only as needed to determine menopausal status in females <62 years old with history of ≥12 months of amenorrhea  without another 
cause. 
12. Laboratory urine testing for phencyclidine (PCP), cocaine, cannabinoids, opiates, barbiturates, benzodiazepines, amphetamines, methadone, and 
MDMA (Ecstasy). 
13. Optional sample that requires additional informed consent. 
14. PK samples will be taken at time 0 (predose) and at 2 and 4 hours after administration of study drug. The time of the last dose of study drug and the 
time of the blood draw will be recorded. 
15. Multi-lead EEG will be recorded for 24 hours using an ambulatory system. The EEG will be centrally evaluated by a qualified rater. 
16. A single lead EEG will be bipolarly recorded for 5 days using a wearable EEG patch (Epitel device). The EEG recording will be centrally evaluated 
by a qualified rater. Subjects will be trained in the use of the device by site personnel and will replace the EEG patch every 7 days. Subjects will 
receive the device at screening. On Days 8 and 20, the nurse who conducts the home visit will check positioning of the device. The device will be 
returned on the Day 26 clinic visit.  This assessment is based on device availability. 
17. The “lifetime” version of the C-SSRS will be used at screening, and the “since last visit” version will be completed at all other visits. 
18. The UM-PDHQ is a 20-item clinician-administered questionnaire that quantitatively and qualitatively assesses hallucinations. The UM-PDHQ will 
be completed for any subject who reports hallucinations. 
19. All AEs, irrespective of the relatedness to the study drug, will be will be captured from the time the ICF is signed through the EOS visit. All AEs 
should be followed until resolution, for 30 days after onset, for 30 days after the last dose of study drug, until the subject is lost to follow-up, or the 
subject withdraws consent, whichever occurs first. Serious adverse events (SAEs) will be reported up to 30 days after the last dose of study drug. A 
follow-up phone call will be made 30 days after the last dose of study drug for evaluation of any SAEs. 
20. Concomitant medications and adverse events will be recorded by the visiting nurse on Days 8 and 20. 


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21. Study drug will be administered in the clinic on the morning of Day 1 and Day 26. Study drug will be administered on an outpatient basis on the 
evening of Day 1 and Day 26 and on the morning of Day 27. 
22. Drug compliance will be assessed by a remote mobile technology monitoring application (AiCure). 
23. Evaluation of drug compliance and dosing accuracy will be assessed by the visiting nurse. 
24. Subjects will return all remaining study drug (including empty bottles) to the site via a prepaid mailer. 


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1.3. 
GLOSSARY OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
BID 
twice daily 
BLQ 
below limit of quantification 
CRF/eCRF 
case report form/electronic case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CX-8998 
investigational product 
d 
day 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
EOS 
end of study 
EOT 
end of treatment 
ESS 
Epworth Sleepiness Scale 
FSH 
follicle stimulating hormone 
GSW 
generalized spike and wave 
HIV 
human immunodeficiency virus 
hr 
hour 
HV 
hyperventilation 
ITT 
intent-to-treat 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
M01 
a primary metabolite of CX-8998 
M02 
a primary metabolite of CX-8998 
M03 
a metabolite of CX-8998 
M04 
a metabolite of CX-8998 
MDMA 
3,4-Methylenedioxymethamphetamine, ecstasy 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
msec 
millisecond 
n 
number of subjects 
PK 
pharmacokinetic 
QTcF 
Fridericia corrected QT 
SAE 
serious adverse event 
SERDAS 
Seizure-related Disability Assessment Scale 
s, SD 
standard deviation 
t* 
critical value from the t distribution 
TEAE 
treatment emergent adverse events 
ULN 
upper limit of normal 
UM-PDHQ 
University of Miami Parkinson’s Disease Hallucinations Questionnaire 
WHO 
World Health Organization 


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2. 
OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
To assess the safety and tolerability of CX-8998 in adolescents and adults with idiopathic 
generalized epilepsy with absence seizures. 
 
2.2. 
SECONDARY OBJECTIVES 
To evaluate the pharmacokinetics of CX-8998 and its metabolites (including, but not limited to, 
M01 and M02) in the plasma of subjects with idiopathic generalized epilepsy with absence 
seizures. 
2.3. 
EXPLORATORY OBJECTIVES 
To assess the exposure-response and exposure-safety relationships for plasma CX-8998 and its 
metabolites (including, but not limited to, M01 and M02); results to be reported separately from the 
Clinical Study Report.  
To evaluate the pharmacodynamic effects of CX-8998 as measured by electroencephalogram 
(EEG). 
3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1. 
SAMPLE SIZE AND POWER 
Up to 15 eligible subjects will be enrolled in the study and receive CX-8998. The sample size was 
not based on statistical considerations, but rather chosen to provide preliminary safety and efficacy 
information on CX-8998 when administered according to this protocol. 
 
3.2. 
RANDOMIZATION AND MASKING 
This is an open-label study.   
 
3.3. 
HANDLING OF DATA 
3.3.1. 
Strata and Covariates 
There are no planned analyses by stratification factors or covariates. Should there be notable 
differences between the treatment groups for the exploratory efficacy parameters.  Analyses may be 
repeated adjusting for the baseline (i.e., analysis of covariance with effects for treatment and 
baseline). 


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3.3.2. 
Examination of Subject Subsets 
Given the relatively small sample size, there are no planned examinations of subsets. 
3.3.3. 
Multiple Testing and Comparisons  
No adjustments will be made for multiple testing. 
3.3.4. 
Missing Data and Outliers 
Every effort will be made to obtain all data at each scheduled visit from all enrolled subjects. No 
imputation for missing data will be implemented in this exploratory study. 
 
3.3.5. 
Imputation of Incomplete Dates 
An incomplete date is any date for which either the day, month or year is unknown, but all three 
fields are not unknown.  An incomplete date occurs when the exact date an event occurred or ended 
cannot be obtained from a subject.  For many of the analyses, a complete date is necessary to 
determine if the event should be included in the analysis (i.e., if the event is treatment-emergent) or 
to establish the duration of an event.  In such cases, incomplete dates may be imputed. 
In particular, treatment-emergence for AEs with missing start or stop dates will be defined using 
the following additional criteria: 
• 
if the start date for a particular event is after the date of first dose, then that event will be 
considered treatment-emergent; 
• 
if the start date for a particular event is missing and the stop date was after the date of first 
dose, then that event will be considered treatment-emergent; and 
• 
if both the start and stop dates for a particular event are missing, then that event will be 
considered treatment-emergent. 
 
‘Concomitant’ for medications or non-drug therapies with missing start or stop dates, will be 
defined using the following criteria: 
• 
if both the start and stop dates of a particular therapy are missing, then that therapy will be 
considered concomitant, 
• 
if the start date of a therapy is missing and the stop date of that therapy falls on or after the 
date of the first dose, then that therapy will be considered concomitant,  
• 
if the start date of a therapy is prior to the date of the first dose and the stop date of that 
therapy is missing and the therapy was listed as continuing, that therapy will be considered 
concomitant, and 
• 
if the start date of a therapy is prior to the date of the first dose and the stop date of that 
therapy is completely missing and the therapy is listed as not continuing, that therapy will 
be considered not concomitant. 
If other missing dates need to be imputed, the project statistician will impute dates in a systematic, 
but reasonable manner to minimize bias using the following algorithm: 


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• 
If the month/year is the same as the Day 1 month/year then the date will be set to the date 
of Day 1. 
• 
In other cases, missing days will be imputed as the day component of Day 1; missing 
months/years will be imputed as the month/year of Day 1.   
A list of incomplete and imputed dates will be prepared by the project statistician or statistical 
programmer(s) and will be submitted for review by the clinical project manager and sponsor prior 
to database lock. 
3.3.6. 
Presentations by Study Visit 
When data are collected serially over time, individual data presentations may include by-visit or 
by-assessment displays.  For these presentations, assessments will be presented according to the 
nominal assessment time as obtained from the eCRF.  If the planned visit from the schedule of 
events is present, it will be used.  If it is not present, then the closest assessment to the planned visit 
will be used.  If two assessments have the same distance to the expected study assessment, the 
earlier value will be used.   
All assessments will be presented in the listings.  
3.3.7. 
Definitions and Terminology  
Age 
The age of a subject is defined as the number of whole years between the subject’s birth date and 
the date of informed consent. 
 
Day 1 (Baseline) 
Day 1 is the earliest day that study drug is initiated. 
 
Study Day  
Study Day is defined relative to Day 1 as follows: Study Day = Date of event – Date of Day 1 
+1*(1 if date of event ≥ Date of Day 1, 0 otherwise). 
 
Study Visit  
Study Visit is the nominal visit as recorded on the eCRF.   
 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last non-missing value obtained prior 
to initiation of study drug. 
 
Change from Baseline  
Change from baseline for a given endpoint is defined as the Study Day X value minus the baseline 
value. 
 


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Percent Change from Baseline  
Percent change from baseline for a given endpoint is defined as the Study Day X value minus the 
baseline value, quantity divided by the baseline value, multiplied by 100. 
Percent Change from Baseline = (Study Day X – Baseline)/Baseline*100 
 
Days on Study 
Days on study is defined as the number of days from the date of study drug initiation to the final 
study visit (includes in home or in clinic assessments). 
 
Completer 
A subject is defined as a completer if he/she completes the Day 26 EEG and Day 27 dosing 
regardless of completing the Day 33 visit.  
Treatment Period 
The treatment period is the period during which a subject receives study drug (i.e., first dose 
through Day 27). 
Days on Study Drug 
Days on study drug is defined as the number of days in the treatment period.  The date of the last 
dose of study drug as recorded on the End of Study Visit form or from the AICure electronic data 
transfer. 
 
Total Study Drug Expected (capsules) 
The total study drug expected is defined as the total number of capsules expected to be taken as 
recorded from all sources and reported from the AICure system. 
 
Total Study Drug Received (capsules) 
The total study drug received is defined as the total number capsules of taken as recorded from all 
sources and reported from the AICure system. 
 
Total Study Drug Received (mg) 
The total study drug received (mg) amount will be multiplied by 2 for subjects receiving CX-8998 
to calculate the amount of study drug received in mg (i.e., each capsule is 2 mg). 
 
Treatment Compliance 
Treatment compliance will be calculated for each subject as a percentage using the following 
formula: 
 
total study drug received (capsules)/total study drug expected(capsules)*100 
 
Adverse Event 
An adverse event is any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure that may or may not be considered related to the medical treatment or procedure.


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Serious Adverse Event 
A serious adverse event (SAE) is any adverse event that results in death, is life-threatening, 
requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, is a congenital anomaly/birth defect observed in any offspring of 
the subject conceived during treatment with the study drug or is an important medical event. 
 
Treatment-emergent Adverse Event  
Treatment-emergent adverse events (TEAEs) are all AEs occurring during the treatment period or a 
pretreatment event that worsens in intensity during the treatment period. 
Laboratory Abnormality 
Per protocol, a laboratory abnormality is any clinically significant laboratory abnormality 
suggesting a disease or organ toxicity and which is of a severity requiring active management (i.e., 
changes of dose, discontinuation of drug, more frequent follow-up, medical treatment or a 
diagnostic investigation). Laboratory abnormalities may also be recorded as adverse events.  While 
laboratory values are available in the clinical database, assessment of clinical significance is not 
captured.  As such, for analysis purposes, laboratory abnormalities are considered to be any values 
that are outside of the reported normal range for a given laboratory test.  
 
Treatment-emergent Laboratory Abnormality 
Treatment-emergent laboratory abnormalities are all analysis defined laboratory abnormalities 
occurring in the treatment period that were not within the normal range at baseline. 
 
Concomitant Medications 
Concomitant medications are those medications or non-drug therapies taken on or after the 
initiation of study drug.  This definition includes medications started prior to the initiation of study 
drug that continue to be used concomitantly with study drug. 
 
Orthostatic Blood Pressure 
Orthostatic blood pressure is defined as the difference from recumbent to standing in the systolic 
and diastolic blood pressure measurements. 
 
Seizure Duration 
Seizure duration is calculated as the sum of the individual durations of seizures of any type 
(absence seizures, generalized spike and wave [GSW], focal seizures, focal epileptiform patterns, 
seizure [other] and electrographic seizure). This is measured in hours. 
 
Absence Seizure Duration 
Absence seizure duration is calculated as the sum of the individual durations of absence seizures.  
This is measured in hours. 
 
Seizure (other) Duration 
Seizure (other) duration is calculated as the sum of the individual durations of seizures of any type 
other than absence seizures (generalized spike and wave [GSW], focal seizures, focal epileptiform 
patterns, seizure [other] and electrographic seizure ). This is measured in hours. 
 


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3.4. 
TIMING OF ANALYSES 
The final analysis will be completed after the last subject completes or discontinues the study and 
the resulting clinical database has been cleaned, quality checked, and locked. 
 
4. 
ANALYSIS POPULATIONS 
The populations defined for analysis will include the intent-to-treat (ITT) population, safety 
population, and a pharmacokinetic (PK) population.  
4.1. 
INTENT-TO-TREAT (ITT) POPULATION 
The ITT population will include all subjects enrolled. This analysis population reflects the full 
analysis set for this study.  The ITT population will be used for analyses of accountability, 
demographics, and efficacy.  
 
4.2. 
SAFETY POPULATION 
The safety population will include all subjects who are enrolled and receive at least one dose of 
study drug. The safety population will be the primary population for all analyses of safety data. 
4.3. 
PK POPULATION 
The PK population will consist of all subjects in Safety Population who have at least one 
nonmissing plasma concentration data for CX-8998 and /or its metabolites 
5. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study. 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. Presentations of data will be summarized in an overall manner.  All available data 
for enrolled subjects will be listed in the data listings. Unless otherwise noted, the data will be 
sorted first by subject number and then by date within each subject number. 
The statistical analyses will be conducted with the SAS® System version 9.4 or higher. 
5.1. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS, AND EXTENT OF EXPOSURE 
Subject disposition will be presented for all enrolled subjects.  The number of subjects enrolled will 
be presented for each study population and site.  The number of subjects who completed the study 
and discontinued from the study will be provided.  The primary reasons for discontinuation from 
the study at any point also will be presented.  Days on study will be summarized.  


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Demographic data and baseline characteristics including age, gender, race, ethnicity, height, weight 
will be summarized using descriptive statistics for the ITT population.  
Extent of exposure will be summarized for the safety population using the following measures: 
days on study drug and total study drug received (in mg), as estimated by the number of capsules 
dispensed and returned. Treatment compliance also will be summarized.  The number and 
percentage of subjects requiring a dose reduction will be summarized. 
5.2. 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 
Concomitant medications and non-drug therapies will be mapped to a World Health Organization 
(WHO) preferred term and drug classification (Anatomic Therapeutic Chemical Classification 
level 4): WHODrug March 2018.  The number and percent of subjects taking concomitant 
medications or undergoing non-drug therapies will be summarized using preferred terms and drug 
classifications and sorted by descending total number of subjects.  Determination of concomitant 
status will be determined according to the rules outlined in Section 3.3.5. 
5.3. 
SAFETY AND TOLERABILITY 
5.3.1. 
Safety and Tolerability Endpoints 
The primary objective of this study is to assess the safety and tolerability of CX-8998.  The 
following endpoints will be captured and evaluated: 
• 
TEAEs  
• 
changes from baseline in QTcF and other electrocardiogram (ECG) parameters  
• 
changes from baseline in clinical safety laboratory assessments (clinical chemistry, 
hematology, and urinalysis)  
• 
changes from baseline in vital signs  
• 
number (%) of subjects who did not complete the study due to TEAE 
• 
number (%) of subjects with SAE  
• 
number (%) of subjects with Adverse Events of Special Interest (AESI) from the AE pages 
of the CRF: 
o Increased seizure frequency 
o New seizure types 
o Status epilepticus 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Epworth Sleepiness Scale (ESS) 


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• 
University of Miami Parkinson’s Disease Hallucinations Questionnaire (UM-PDHQ) 
 
 
5.3.2. 
Safety Analysis 
 
Vital Signs and ECGs 
Descriptive statistics will be presented for actual values and for the change from baseline values for 
systolic and diastolic blood pressure, pulse rate, respiration rate, and weight by study visit. Blood 
pressure summaries will include recumbent and standing measurements, as well as the change from 
recumbent to standing (orthostatic changes). 
Incidence of vital signs outliers will be presented by visit and time point, where applicable.  
Outliers for recumbent and standing vital sign parameters will be determined using the criterion in 
Table 1. 
Descriptive statistics will be presented for actual values and for the change from baseline values for 
the ECG parameters of heart rate (bpm), PR interval (msec), QRS duration (msec), QT interval 
(msec), QTc interval (msec), and QTcF interval (msec) will be summarized by treatment group and 
study visit.  
The incidence of ECG outliers will also be summarized by visit according to the following criteria:  
• 
QT > 500 msec 
• 
QTcF > 450 msec for males or QTcF > 470 msec for females 
• 
QTcF increases from baseline or pre-dose:  
o ≤ 30 msec 
o > 30 msec to ≤ 60 msec 
o > 60 msec 


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Table 1.  Outliers for recumbent and standing vital sign parameters 
 
Vital Sign 
 
Criteria 
 
 
Temperature 
>38°C and ≥1°C increase from baseline 
 
 
Pulse 
>120 bpm and >30 bpm increase from baseline 
 
<50 bpm and >20 bpm decrease from baseline 
 
≥ 20 bpm increase from baseline 
 
≥ 40 bpm increase from baseline 
 
≥ 20 bpm decrease from baseline 
 
≥ 40 bpm decrease from baseline 
 
 
Systolic blood pressure 
>180 mmHg and with >40 mmHg increase from baseline 
 
<90 mmHg and with >30 mmHg decrease from baseline 
 
≥ 20 mmHg increase from baseline 
 
≥ 40 mmHg increase from baseline 
 
≥ 20 mmHg decrease from baseline 
 
≥ 40 mmHg decrease from baseline 
 
 
Diastolic blood pressure 
>105 mmHg and with >30 mmHg increase from baseline 
 
<50 mmHg and with >20 mmHg decrease from baseline 
 
≥ 10 mmHg increase from baseline 
 
≥ 20 mmHg increase from baseline 
 
≥ 10 mmHg decrease from baseline 
 
≥ 20 mmHg decrease from baseline 
 
 
Clinical Laboratory Assessments 
Actual values and changes from baseline in clinical laboratory assessments will be summarized by 
study visit. 
Laboratory values outside the normal range for each parameter will be identified using shift tables.  
Each subject’s hematology and blood chemistry values will be flagged as “low” (below the lower 
limit of normal/LLN), “normal” (within the normal range), or “high” (above the upper limit of 
normal/ULN) relative to the normal ranges of the central laboratory.  Each subject’s urinalysis 
values will be flagged as “normal” or “abnormal.” 
Shifts from baseline to high/normal/low status for hematology and blood chemistry parameters will 
be presented by study visit. Shifts from baseline to normal/abnormal status for urinalysis will be 
presented by study visit.   


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Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification, version 21.0. If a subject experiences multiple 
events that map to a single preferred term, the greatest severity grade and strongest assessment of 
relationship to study medication, as determined by the investigator, will be assigned to the 
preferred term for the appropriate summaries. Adverse events that have a missing severity will be 
classified as having the greatest severity. Adverse events that have a missing relationship will be 
classified as having the strongest relationship to study medication.   
A summary of TEAEs will be presented to show the number and percentage of subjects with at 
least one AE, SAE, AESI, related AE, or Grade 3 or higher AE.   
The occurrence of TEAEs will be summarized by treatment group using system organ class, 
preferred term, and severity. Separate summaries of treatment-emergent SAEs, AESI, TEAEs 
related to study drug, and TEAEs leading to the discontinuation of study treatment, and TEAEs by 
CX-8998 dose administered will be generated.  Adverse events will be assigned to a respective 
CX-8998 according to the start date of the adverse event. 
All TEAEs will be listed for individual subjects. The listing will show both verbatim and preferred 
terms, along with the system organ class and other data gathered regarding the event. All AEs that 
have start dates prior to the initiation of study treatment will be excluded from the tables but will be 
included in the listings.  
Determination of treatment emergence will be determined according to the rules outlined in Section 
3.3.5. 
The following are considered AEs of special interest: increase in seizure frequency, new seizure 
type, and status epilepticus.  Otherwise; seizures are not reported as AEs or SAEs. 
 
Physical and Neurological Examinations 
Data from the physical and neurological examinations will be listed.  
 
Columbia Suicide Severity Rating Scale 
Data from the C-SSRS will be listed.  
 
Epworth Sleepiness Scale 
Results from ESS will be listed. 
 
UM-PDHQ 
Data from the UM-PDHQ will be listed.  
 


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5.4. 
PHARMACOKINETIC ANALYSES 
Descriptive statistics of analyte concentrations will be prepared by analyte (CX-8998, including, 
but not limited to, M01 and M02), visit, time point, and dose. Plasma concentration values reported 
as below the limit of quantification (BLQ) will be presented as “BQL” in the concentration data 
listing. Values that are BLQ will be treated as 0 at predose time points, and set to one-half of the 
lower limit of quantification (LLOQ) at post-baseline time points for summary purposes.  
The following conventions will be used for the presentation of summary statistics: 
• 
If at least 1 subject has a concentration data value of BLQ for the time point, the minimum 
value will be displayed as “BLQ”. 
• 
If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ”. 
• 
If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1 and median values will be displayed as “BLQ”. 
• 
If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median and Q3 values will be displayed as “BLQ”. 
• 
If all subjects have a concentration data values of BLQ for a given time point, all order 
statistics will be displayed as “BLQ” and SD will be suppressed. 
Individual plasma concentrations of all measured analytes, visit, dose, nominal time point, date and 
time of actual collection, and actual time elapsed will be listed by subject for all subjects in PK 
population analysis set.  
6. 
PROTOCOL DEVIATIONS 
Protocol deviations will be documented by the investigator or assigned staff. All deviations and 
reasons for deviations will be reported to the Sponsor as soon as possible. Deviations will be 
presented in a data listing. 
 
7. 
CHANGES IN THE PLANNED ANALYSES FROM THE PROTOCOL 
Changes to the planned analysis from protocol: 
The following endpoints will not be summarized:  
• 
The change in frequency (number of seizures per hour) of absence seizures as defined by a 
3-Hz spike and wave lasting for ≥3 seconds as determined by hyperventilation (HV) 
• 
The frequency (number of seizures per hour) of absence seizures (based on 6.5-hour video-
EEG) 
• 
The time to absence seizures during HV  


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• 
The percent of subjects with a shift in the occurrence of absence seizure (e.g., from HV 
period 1 to HV period 2) 
• 
The percent of subjects with an absence of photic response. 
• 
Change in seizure duration (determined by ambulatory EEG) 
• 
Change in spike-wave run duration (determined by ambulatory EEG) 
• 
Change in spike-wave density (spike-wave %) (determined by ambulatory EEG) 
• 
Proportion of subjects with 30% and 50% reduction in seizure frequency (responder 
rate)and proportion of seizure-free subjects (determined by ambulatory EEG) 
• 
Seizure-free intervals in minutes (maximum and average determined by ambulatory EEG) 
• 
Change in the Seizure-related Disability Assessment Scale (SERDAS) 
• 
Change in the average weekly seizure frequencyfor each type of seizure self-reported by 
subjects inthe daily seizure diary 
• 
Changes in the number of seizures recorded with the Epitel device (based on device 
availability) 
• 
Relationship between the EEG parameters and the PK of CX-8998 
• 
Exposure-response and exposure-safety relationships using plasma concentrations of CX-
8998 and its 2 primary metabolites (M01 and M02) in population PK/PD analyses 
 
Should any additional deviations from the analyses specified in the authorized statistical analysis 
plan arise, such deviations will be documented in the final clinical study report. 
 
8. 
REFERENCES 
None. 


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9. 
PROGRAMMING CONVENTIONS 
• 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation. There should be a minimum of a 1.25” boundary on the upper (bound) 
edge, and a minimum of a 1.0” boundary on the remaining three edges. Output should be 
printed in Courier New with a point size of 8. Titles may be printed using a larger font (e.g., 
point size 10). 
• 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized. Listings will be prepared for the ITT Population. 
• 
Group headers: In the summary tables, the group headers will identify the summary group and 
the sample size for the indicated analysis population. Of note, the header’s sample size does 
not necessarily equal the 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 due to missing data. 
 
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.  The number of missing observations, if any, will be noted. 
 
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. The number of missing observations, if any, will be noted. 
• 
Sorting: Listings will be sorted by subject number, date, and parameter, if applicable.  If a 
listing is sorted in a different manner, a footnote will indicate as such.  
• 
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:  
 
Raw measurements will be reported to the number of decimal places as captured 
electronically or on the eCRFs, not to exceed 4 decimal places.   
 
Standard deviations will be reported to one decimal place beyond the number of decimal 
places the original parameter is presented, not to exceed 5 decimal places. 


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 
Means will be reported to the same number of decimal places as the parameter, not to 
exceed 4 decimal places.  
 
Calculated percentages will be reported with no decimals. 
• 
Dates will be formatted as DDMONYYYY.  Partial dates will be presented on data listings as 
recorded on CRFs. 
 
Time will be presented according to the 24-hour clock (HH:MM). 


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10. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
Summary Tables 
Accountability and Baseline Characteristics 
 All Subjects Screened 
14.1.1.1 
Subject Disposition and Termination from Study 
 ITT Population 
14.1.1.2 
Protocol Deviations 
14.1.2.1 
Demographics and Baseline Characteristics 
 Safety Population 
14.1.2.2 
Demographics and Baseline Characteristics 
14.1.3 
Summary of Concomitant Medications and Non-Drug Therapies 
14.1.4 
Extent of Exposure and Percent Compliance 
 PK Population 
14.1.5 
Summary of Plasma Concentrations of CX-8998 and Metabolites  
Safety – Safety Population 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events 
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class, Preferred  
 
 
Term, and Greatest Severity 
14.3.1.3 
Treatment-Emergent Adverse Events Related to Study Drug by System Organ  
 
 
Class and Preferred Term  
14.3.1.4 
Treatment-Emergent Adverse Events by CX-8998 Dose Administered, System 
 
 
Organ Class, and Preferred Term 
14.3.2.1 
Treatment-Emergent Serious Adverse Events by System Organ Class and  
 
 
Preferred Term 
14.3.2.2 
Treatment-Emergent Adverse Events Leading to the Discontinuation of Study 
Drug by System Organ Class and Preferred Term 
14.3.2.3 
Treatment-Emergent Adverse Events of Special Interest by System Organ 
Classification and Preferred Term 
14.3.4.1 
Summary of Hematology Assessments 
14.3.4.2 
Summary of Serum Chemistry Assessments 
14.3.4.3 
Summary of Coagulation Assessments 
14.3.4.4 
Summary of Urinalysis Assessments 
14.3.4.5 
Shift from Baseline of Laboratory Abnormalities 
14.3.5.1.1 Summary of Electrocardiogram Parameters 
14.3.5.1.2 Summary of Electrocardiogram Outliers 
14.3.5.2.1 Summary of Respiration Rate, Temperature, and Weight 
14.3.5.2.2  Summary of Blood Pressure and Pulse 
14.3.5.2.3 Summary of Vital Signs Outliers 
 
 
 
 
Data Listings – ITT Population 
16.2.1.1 
Subject Disposition 
16.2.1.2 
Informed Consent and Eligibility 


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16.2.2 
Protocol Deviations 
16.2.3 
Reasons for Exclusion from Study Populations 
16.2.4.1 
Demographics and Baseline Characteristics 
16.2.4.2 
Medical and Surgical History 
16.2.4.3 
Prior and Concomitant Medications and Non-Drug Therapies 
16.2.5.1 
Study Drug Dose Change Log 
16.2.5.2 
AICure Dose Compliance 
16.2.5.3 
Pharmacokinetic Samples 
16.2.6.1 
Ambulatory EEG 
16.2.6.2 
Subject Diary Information 
16.2.6.3 
Seizure-Related Disability Assessment Scale 
16.2.7 
Adverse Events 
16.2.8.1.1 Laboratory Tests – Hematology 
16.2.8.1.2 Laboratory Tests – Serum Chemistry 
16.2.8.1.3 Laboratory Tests – Coagulation 
16.2.8.1.4 Laboratory Tests – Urinalysis 
16.2.8.1.5 Pregnancy Test 
16.2.8.1.6 Laboratory Tests – Other 
16.2.8.2 
Vital Signs, Height, and Weight 
16.2.8.3 
Physical Examination 
16.2.8.4 
Neurological Examination 
16.2.8.5 
Electrocardiogram 
16.2.9.1 
Epworth Sleepiness Scale 
16.2.9.2 
Columbia Suicide Severity Rating Scale 
16.2.9.3 
UM-PDHQ