A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of NBI-921352 as Adjunctive Therapy in Subjects With SCN8A Developmental and Epileptic Encephalopathy Syndrome (SCN8A-DEE)
Phase: PHASE2
Conditions: SCN8A Developmental and Epileptic Encephalopathy Syndrome
Sponsor: Neurocrine Biosciences

NBI-921352 CLINICAL STUDY PROTOCOL 
Amendment No. 2.0 Version Date: 30 November 2021 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy, Safety, Tolerability, and Pharmacokinetics of NBI-921352 as 
Adjunctive Therapy in Subjects with SCN8A Developmental and Epileptic 
Encephalopathy Syndrome (SCN8A-DEE) 
Study No.: NBI-921352-DEE2012 
IND 141603 
EudraCT# 2020-003140-83 
Development Phase: 2 
Sponsor 
Neurocrine Biosciences, Inc. 
 
 
Telephone: 
 
Facsimile:  
 
Study Medical Monitor 
 
 
 
 
 
 
Telephone: 
  
US toll free:
 
Email: 
 
Serious Adverse Event Reporting 
Facsimile: 
 
Email: 
 
CONFIDENTIAL 
This document contains information that is of confidential, trade secret, and/or proprietary nature 
to Neurocrine Biosciences, Inc. It is intended for your confidential review and to provide you, your 
staff, and your reviewing Institutional Review Board/Independent Ethics Committee with 
information regarding the specific clinical study in which you are participating. You may not 
disclose the contents of this document to parties, other than those previously mentioned, without 
prior written permission from Neurocrine Biosciences, Inc.; provided that you shall be entitled to 
disclose it to authorized representatives of national regulatory authorities under the condition that 
they respect its confidential nature. 
Neurocrine Biosciences, Inc., Study No. NBI-921352-DEE2012 
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NCT #: NCT04873869

PROTOCOL AMENDMENTS  
Protocol/Amendments 
Date 
Original Protocol 
16 July 2020 
Amendment 1 
09 March 2021 
Amendment 2.0 
30 November 2021 
 
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TABLE OF CONTENTS 
NBI-921352 CLINICAL STUDY PROTOCOL .............................................................................1 
PROTOCOL AMENDMENTS .......................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
1. 
SYNOPSIS .................................................................................................................10 
2. 
INTRODUCTION ......................................................................................................15 
2.1. 
Epilepsy and Voltage-Gated Sodium Channel Inhibitors ...........................................15 
2.2. 
SCN8A Developmental and Epileptic Encephalopathy .............................................15 
2.3. 
NBI-921352 ................................................................................................................17 
3. 
OBJECTIVES .............................................................................................................18 
4. 
STUDY DESIGN .......................................................................................................19 
4.1. 
Overall Design ............................................................................................................19 
4.2. 
Study and Dose Rationale ...........................................................................................24 
4.3. 
Study Duration ............................................................................................................26 
4.4. 
End of Study Definition ..............................................................................................26 
4.5. 
Benefit-Risk Assessment ............................................................................................26 
5. 
STUDY POPULATION .............................................................................................29 
5.1. 
Inclusion Criteria ........................................................................................................29 
5.2. 
Exclusion Criteria .......................................................................................................32 
6. 
STUDY TREATMENT ..............................................................................................34 
6.1. 
General Information ....................................................................................................34 
6.2. 
Study Treatment Administration ................................................................................34 
6.3. 
Study Treatment Storage and Compliance .................................................................35 
6.4. 
Study Treatment Accountability and Return ..............................................................35 
6.5. 
Direct-to-Subject Shipments of Study Treatment .......................................................35 
6.6. 
Blinding ......................................................................................................................35 
6.7. 
Procedures for Overdose .............................................................................................36 
7. 
SUBJECT RESTRICTIONS ......................................................................................36 
7.1. 
Prior and Concomitant Medications ...........................................................................36 
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7.2. 
Dietary and Other Restrictions ...................................................................................37 
8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL ........................................................................................................37 
8.1. 
Discontinuation of Study Treatment ...........................................................................37 
8.2. 
Withdrawal from Study ..............................................................................................39 
8.3. 
Sponsor’s Termination or Suspension of Study or Study Site ...................................39 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................39 
9.1. 
Screening Assessments ...............................................................................................40 
9.1.1. 
Comprehensive Epilepsy Panel Genotyping ..............................................................40 
9.1.2. 
Cytochrome P450 2D6 Genotyping ............................................................................40 
9.1.3. 
Video Electroencephalogram ......................................................................................40 
9.1.4. 
Diagnosis Confirmation Panel ....................................................................................40 
9.2. 
Efficacy Assessments .................................................................................................41 
9.2.1. 
Daily Seizure Diary ....................................................................................................41 
9.2.2. 
Clinical Global Impression of Change .......................................................................41 
9.2.3. 
Parent/Caregiver Global Impression of Change .........................................................41 
9.2.4. 
Clinical Global Impression of Severity ......................................................................41 
9.2.5. 
Parent/Caregiver Global Impression of Severity ........................................................42 
9.2.6. 
 ......................................................42 
9.2.7. 
 ..........................................42 
9.2.8. 
 ........................................................................42 
9.3. 
Safety Assessments .....................................................................................................42 
9.3.1. 
Vital Sign Measurements ............................................................................................43 
9.3.2. 
Medical History ..........................................................................................................43 
9.3.3. 
Physical and Neurological Examination Including Height/Length and Tanner 
Staging ........................................................................................................................43 
9.3.4. 
Weight .........................................................................................................................43 
9.3.5. 
Electrocardiogram .......................................................................................................44 
9.3.6. 
Clinical Laboratory Assessments ...............................................................................44 
9.3.7. 
Columbia-Suicide Severity Rating Scale ....................................................................45 
9.3.8. 
 ....................45 
9.4. 
Pharmacokinetic Assessments ....................................................................................45 
9.5. 
............................................................................46 
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9.5.1. 
 ......................................................46 
9.5.2. 
 .............................................................46 
9.5.2.1. 
 ...................................................................46 
9.5.2.2. 
 ....................................................................................................48 
9.5.3. 
 ......................................................................................................49 
9.5.3.1. 
 .....................................................................................................49 
9.5.4. 
 ............................................................................................49 
9.5.4.1. 
 .............................................................49 
10. 
ADVERSE EVENTS..................................................................................................49 
10.1. 
Definition ....................................................................................................................49 
10.1.1. 
Intensity of Adverse Events ........................................................................................50 
10.1.2. 
Relationship to Study Treatment ................................................................................51 
10.2. 
Recording Adverse Events .........................................................................................51 
10.3. 
Poststudy Follow-Up of Adverse Events ....................................................................52 
10.4. 
Serious Adverse Events ..............................................................................................52 
10.4.1. 
Definition of a Serious Adverse Event .......................................................................52 
10.4.2. 
Managing Serious Adverse Events .............................................................................53 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................53 
10.4.4. 
Expedited Safety Reports ...........................................................................................54 
10.5. 
Pregnancy ...................................................................................................................54 
11. 
STATISTICAL METHODS .......................................................................................55 
11.1. 
Sample Size Determination ........................................................................................55 
11.2. 
Analysis Sets ...............................................................................................................55 
11.3. 
Endpoints ....................................................................................................................56 
11.3.1. 
Primary .......................................................................................................................56 
11.3.2. 
Key Secondary ............................................................................................................56 
11.3.3. 
Other Secondary .........................................................................................................56 
11.3.4. 
Exploratory .................................................................................................................56 
11.3.5. 
Pharmacokinetics ........................................................................................................57 
11.3.6. 
Safety ..........................................................................................................................57 
11.4. 
Statistical Analyses .....................................................................................................57 
11.4.1. 
Missing Data ...............................................................................................................59 
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11.4.2. 
Interim Analysis ..........................................................................................................59 
12. 
SUPPORTING DOCUMENTATION ........................................................................59 
12.1. 
Case Report Forms .....................................................................................................59 
12.2. 
Data Capture, Review, and Validation .......................................................................60 
12.3. 
Coding Dictionaries ....................................................................................................60 
12.4. 
Ethics ..........................................................................................................................60 
12.5. 
General Legal References ...........................................................................................61 
12.6. 
Institutional Review Board/Independent Ethics Committee ......................................61 
12.7. 
Protocol Adherence – Amendments ...........................................................................61 
12.8. 
Required Documents ..................................................................................................61 
12.9. 
Informed Consent/Assent ...........................................................................................62 
12.10. 
Study Monitoring ........................................................................................................62 
12.11. 
Quality Assurance .......................................................................................................62 
12.12. 
Record Retention ........................................................................................................63 
12.13. 
Confidentiality ............................................................................................................63 
12.14. 
Publication Policy .......................................................................................................63 
13. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................63 
14. 
 ...........................................................................................................64 
APPENDIX A. SCHEDULE OF ASSESSMENTS ...................................................................66 
APPENDIX B. INVESTIGATORS SIGNATURE ....................................................................72 
APPENDIX C. SPONSORS APPROVAL SIGNATURE .........................................................73 
 
LIST OF TABLES 
Table 1: 
Titration Period Doses by Weight Group ...................................................................21 
Table 2: 
 .............................................25 
Table 3: 
Study Treatments ........................................................................................................34 
Table 4: 
 .................................................................................................49 
Table 5: 
Intensity of Adverse Events ........................................................................................51 
Table 6: 
Relationship of Adverse Events to Study Treatment ..................................................51 
Table 7: 
Contact Information for Drug Safety and Pharmacovigilance and Study 
Medical Monitor .........................................................................................................54 
Table 8: 
Analysis Sets ...............................................................................................................55 
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Table 9: 
Endpoints and Statistical Methods ..............................................................................57 
Table 10: 
 ............................................................................................67 
 
 
LIST OF FIGURES 
Figure 1: 
 ...........................................23 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
Adrenocorticotropin hormone 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASM 
Antiseizure medication 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration versus time curve 
AUC0-24 
Area under the concentration versus time curve for a 0 to 24 hour interval 
AUC0-24h,ss 
Steady state area under the concentration versus time curve for a 0 to 24 hour interval 
bid 
Twice a day 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CGIS 
Clinical Global Impression of Severity 
CI 
Confidence interval 
Cmax 
Maximum observed drug concentration 
Cmax,ss  
Steady state maximum concentration for a 0 to 24 hour interval 
CNS 
Central nervous system 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DCP 
Diagnosis Confirmation Panel  
DMC 
Data Monitoring Committee 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EDTA K2 
dipotassium ethylenediaminetetraacetic acid 
EEG 
Electroencephalogram 
eCRF 
Electronic case report form 
ET 
Early termination 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration (United States)  
FOS 
Focal onset seizure 
G-tube 
Gastrostomy tube 
GABA 
Gamma-aminobutyric acid  
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GCP 
Good Clinical Practice 
GDPR  
General Data Protection Regulation 
GIC 
Global Impression of Change 
GIS 
Global Impression of Severity 
GTCS 
Generalized tonic-clonic seizures 
GOF 
Gain-of-function 
HAV-IgM 
hepatitis A virus immunoglobulin M 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C antibody 
HIV-Ab 
human immunodeficiency virus antibody 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MES 
Maximal Electroshock Seizure 
NaV 
Voltage-gated sodium channel 
NBI 
Neurocrine Biosciences, Inc. 
NOAEL 
No-observed-adverse-effect level 
PK 
Pharmacokinetic(s) 
qd 
Once daily 
QoLCE 
Quality of Life-Childhood Epilepsy 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SSAS 
Symptom and Seizure Activity Scale 
SCN8A 
Sodium channel, voltage-gated, type VIII, alpha subunit 
SCN8A-DEE 
SCN8A Developmental and Epileptic Encephalopathy Syndrome 
SUDEP 
Sudden unexpected death in epilepsy 
TEAE 
Treatment emergent adverse event 
tid 
3 times a day 
 
 
Video-EEG 
Video- electroencephalogram 
VNS 
Vagus nerve stimulator 
VSD4 
Voltage sensor domain IV 
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1. 
SYNOPSIS 
Title of study: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of NBI-921352 as Adjunctive Therapy in Subjects with SCN8A Developmental 
and Epileptic Encephalopathy Syndrome (SCN8A-DEE) 
Protocol number: NBI-921352-DEE2012 
Phase of development: 2 
Study center(s): Approximately 35 study centers in regions including, but not limited to, the United States, Europe, 
and Australia.  
Objectives:  
Primary 
• 
To assess the efficacy of NBI-921352 as adjunctive therapy on the frequency of countable motor seizures 
(defined as generalized tonic-clonic seizure [GTCS], tonic, atonic or focal onset seizures [FOS] with 
noticeable motor component). 
Secondary 
• 
To evaluate the efficacy of NBI-921352 using the Clinical and Parent/Caregiver Global Impression of 
Change scales and the Clinical and Parent/Caregiver Global Impression of Severity scales. 
• 
To characterize the pharmacokinetics (PK) of NBI-921352 and determine the effect of NBI-921352 on 
plasma levels of concomitant antiseizure medications (ASMs) and evaluated metabolites. 
• 
To evaluate the safety and tolerability of NBI-921352. 
Exploratory 
• 
 
 
Methodology:  This is a Phase 2 randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, 
tolerability, and pharmacokinetics of NBI-921352 as adjunctive therapy in subjects with SCN8A Developmental and 
Epileptic Encephalopathy Syndrome (SCN8A-DEE). Approximately 52 male and female subjects will be 
randomized for study participation according to the study eligibility criteria. Subjects will be randomized 1:1 
(NBI-921352:placebo). This study will enroll approximately 52 subjects 2 to 21 years of age.  
This study will include 2 separate cohorts: 
• 
Sentinel Cohort: 8 subjects will be randomized into the Sentinel Cohort. These subjects will be considered a 
sentinel group to evaluate observed PK relative to predicted exposures as well as safety and tolerability. An 
external, independent Data Monitoring Committee (DMC) will review the Sentinel Cohort subject safety, 
tolerability, and PK data through the 
 titration period prior to randomization of subjects in the Main 
Cohort. Preliminary efficacy data will not be assessed as part of the interim Sentinel Cohort data review. 
• 
Main Cohort: Once safety, tolerability, and PK have been assessed in the Sentinel Cohort, subjects will be 
randomized into the Main Cohort.  
For both cohorts, this study will consist of 3 periods (for subjects who enroll in the separate, active extension study) 
or 5 periods (for subjects who do not enroll in the active extension study): 
• 
An up to 
 screening period that includes a baseline period of at least 
 to collect baseline daily 
seizure diary data. 
o 
The baseline period may start once the investigator has confirmed that the parent/caregiver is 
capable of and comfortable with identifying seizures. 
• 
A 
 titration period 
 at each of the 2 lowest titration dose levels and 
 at each of the 
2 highest titration dose levels) 
• 
A 
 maintenance period 
• 
A 
 taper period (for those subjects not enrolling into the active extension study) 
• 
A 
 safety follow-up period (for those subjects not enrolling into the active extension study) 
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Subjects will be eligible to enter the separate, active extension study if they have successfully completed 16 weeks of 
treatment 
 titration period and 
 maintenance period). Subjects in the active extension will receive 
active treatment; however, treatment received during Study NBI-921352-DEE2012 will remain blinded until the last 
subject ends their participation in Study NBI-921352-DEE2012 and the study database is locked.  
Screening/Baseline Period – Sentinel and Main Cohorts 
After informed consent has been provided by the parent/legal guardian or subject (if appropriate) and the subject has 
provided assent (if appropriate), subjects will be screened for eligibility to participate in the study. Prior to starting 
the baseline period, site personnel will review the seizure types with the subject and parent/caregiver and train them 
on correct seizure identification with a focus on identification of countable motor seizures 
 
 as well as noncountable seizures 
 
. Methods of training may include recent
 
 
The investigator will document that training has been completed and the parent/caregiver is capable of and 
comfortable with identifying seizures before the start of the baseline period. The investigator will also document that 
the subject has an adequate rescue medication regimen as well as a nocturnal alerting system in place. Baseline daily 
seizure diary data must be collected for at least 
, during which the parent/caregiver will complete the daily 
diary to record the number and type of countable motor seizures, as well as the occurrence of noncountable seizures 
for recording of seizure-free days. After completion of the baseline period, final eligibility will be confirmed by the 
investigator after review of the baseline diary data to ensure that parent/caregivers completed the diary according to 
instructions and that the subject has sufficient frequency of countable motor seizures (on average at least 1 countable 
motor seizure per week [4 per 28-day period]).  
A sample for comprehensive genetic epilepsy panel testing will be collected at screening and used to verify the 
diagnosis. The clinical and genetic findings supporting the diagnosis of SCN8A-DEE will be reviewed and 
confirmed by an external Diagnosis Confirmation Panel (DCP) based on guidelines outlined in the DCP charter. 
Rescreening is permitted if a subject does not meet all eligibility requirements and returns to be rescreened. A subject 
that has failed screening twice may not be rescreened again without prior permission from the Sponsor. Subjects who 
do not meet seizure frequency criteria as assessed during a completed baseline period will not be eligible for 
rescreening. Genotyping assessments do not need to be repeated for subjects who are rescreened. 
Titration Period - Sentinel Cohort  
The first 8 subjects will be randomized into the Sentinel Cohort in a 1:1 ratio (4 subjects to NBI-921352 and 
4 subjects to placebo). These subjects will be assigned to 1 of 4 weight groups based on weight at the screening visit:  
Weight Group 1 
 Weight Group 2 
 Weight Group 3 
 and Weight Group 4 
 Subjects will receive the dose for their assigned weight group at each dose level as indicated in the table 
below. The titration period will include 
 at Dose Level 1, 
 at Dose Level 2, 
 at Dose Level 3, 
and 
 at Dose Level 4. 
Weight 
Group 
Body Weight 
(kg) 
Dose Level 1 
(mg) 
tid 
Dose Level 2 
(mg) 
tid 
Dose Level 3 
(mg) 
tid 
Dose Level 4 
(mg) 
tid 
1 
2 
3 
4 
tid = 3 times a day. 
After 
 of the titration period, the investigator may decrease a subject's dose to the lower tolerated dose level 
based on safety and tolerability. In addition to the assessment of safety and tolerability at the titration period study 
visits, the study site will contact the parent/caregiver by telephone call approximately 1 week after the dose titration 
visits for Dose Levels 3 and 4 (ie, at the end of 
) to assess for any adverse events. Subjects who are 
unable to escalate to or tolerate Dose Level 2 should be discontinued from study treatment. 
Once the Sentinel Cohort titration period has completed, the DMC will review safety, tolerability, and PK data as 
described in the DMC charter. Upon completion of the review and based on recommendations from the DMC, 
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subjects may be randomized in the Main Cohort. Doses, weight groups, and dose titration targets in the Main Cohort 
may be modified based on the results of the Sentinel Cohort safety, tolerability and PK data; however, the average 
target exposures 
 
 
 
Titration Period - Main Cohort 
Approximately 44 subjects will be randomized into the Main Cohort in a 1:1 ratio (NBI-921352:placebo). Beginning 
on Day 1, subjects will receive Dose Level 1 for their assigned weight group (based on weight at the screening visit). 
The titration period will include 
 at Dose Level 1, 
 at Dose Level 2, 
 at Dose Level 3, and 
 at Dose Level 4, with subjects receiving the dose for their weight group at each dose level as indicated in the 
table above, or as determined based on the results of the Sentinel Cohort data review by the DMC. 
After 
 of the titration period, the investigator may decrease a subject's dose to the lower tolerated dose level 
based on safety and tolerability. Subjects who are unable to escalate to or tolerate Dose Level 2 should be 
discontinued from study treatment. 
Maintenance Period – Sentinel and Main Cohorts 
Subjects in both cohorts who complete the titration period will enter the 
 maintenance period. During the 
maintenance period, subjects will continue to receive their final tolerated dose from the titration period. Dose levels 
should not be changed during the maintenance period without prior Sponsor approval. Rescue medication is 
permitted at any time during the study and will not be a reason for discontinuation from study treatment; however, 
use of rescue medication will be collected in the seizure diary and must be documented in the electronic case report 
form (eCRF).  
Subjects receiving Dose Levels 3 or 4 who discontinue study treatment at any time before the end of Week 16, 
including during the titration period, should undergo dose de-escalation, if appropriate, during which the subject’s 
current dose will be reduced in a step-wise manner over a period of up to 
 Instructions for dose de-escalation 
will be provided. Subjects who withdraw from the study will not be replaced. Subjects receiving Dose Levels 1 or 2 
who discontinue study treatment do not require dose de-escalation. 
Following completion of the maintenance period, subjects will have the option to continue in the active extension 
study if they have successfully completed the 16-week treatment period 
 titration and 
 
maintenance) in the current study AND have not had a serious or severe adverse event (AE) that, in the investigator’s 
opinion, was related to study treatment and would make it unsafe for the subject to continue study treatment dosing. 
 
  
Taper Period 
If the subject completes the maintenance period and does not enroll in the active extension study, the subject will 
enter a 
 taper period where the study treatment is tapered to ensure that all subjects will be off study treatment 
by the end of the 
.  
Safety Follow-Up Period 
After the last dose of study treatment, subjects who do not enroll in the active extension study will enter a 
 
safety follow-up period which includes a follow-up telephone call approximately 1 week after the last dose of study 
treatment and a visit approximately 
 after the last dose of study treatment. 
Study population: A total of approximately 52 male and female subjects, 2 to 21 years of age, with a diagnosis of 
SCN8A-DEE reviewed and approved by the DCP will be enrolled. 
 
 Enrollment of eligible subjects will not be limited based on weight group or age 
group. 
Duration of treatment and study participation: The expected duration of study participation from screening to last 
visit for each subject is approximately 
 for subjects enrolling in the active extension study and 
approximately 30 weeks 
 plus 
 taper and 
 safety follow-up period) for subjects who choose 
not to enroll in the active extension study. 
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Investigational product, dosage and mode of administration: 
 
 
 
 
 
  
 
Reference therapy, dose and mode of administration, batch number:  Placebo capsules identical in appearance to 
the test product will be taken in the same manner and on an identical schedule as NBI-921352. 
Criteria for Evaluation: 
Efficacy: 
Daily seizure diaries (collected at each visit) will be used to determine efficacy. The site will review the daily diaries 
at each visit to confirm appropriateness of completion and re-instruct the parent/caregiver as necessary. 
Parent/caregivers will also be instructed to document days without any seizures. In addition, use of rescue medication 
will also be collected.  
Clinical Global Impression of Change (CGIC) and Parent/Caregiver Global Impression of Change (GIC) scales 
Clinical Global Impression of Severity (CGIS) and Parent/Caregiver Global Impression of Severity (GIS) scales 
 
 
  
 
 
 
Pharmacokinetics: 
Blood samples to evaluate plasma concentrations of NBI-921352 and metabolites and concomitant ASMs and 
evaluated metabolites will be collected throughout the study. 
Safety: 
Safety and tolerability will be monitored throughout the study and will include the following assessments: 
• 
AEs 
• 
Clinical laboratory tests including hematology, clinical chemistry, and urinalysis 
• 
Vital signs 
• 
Physical examinations, including height/length and weight, Tanner staging (as appropriate based on subject 
age and stage of puberty), and neurological examination 
• 
12-lead electrocardiograms 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
 
 
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Study Endpoints: For the endpoints below, countable motor seizures are defined as GTCS, tonic, atonic or FOS 
with noticeable motor component. The treatment period is defined as the
 titration period and the 
 
maintenance period combined. 
Primary: 
• 
Percentage change from baseline in 28-day seizure frequency for countable motor seizures during the 
treatment period of the study. 
Key Secondary: 
• 
Treatment response defined as a ≥50% decrease from baseline in 28-day seizure frequency for countable 
motor seizures during the treatment period of the study. 
Other Secondary: 
• 
Percentage change from baseline in 28-day seizure frequency for countable motor seizures, during the 
 of the maintenance period. 
• 
Treatment response defined as a ≥25%, ≥75%, or 100% decrease from baseline in 28-day seizure frequency 
for countable motor seizures during the treatment period of the study. 
• 
Treatment response defined as a ≥25%, ≥50%, ≥75%, or 100% decrease from baseline in 28-day seizure 
frequency for countable motor seizures during the maintenance period of the study. 
• 
CGIC and Parent/Caregiver GIC at each study visit during the treatment period of the study. 
• 
Change from baseline in CGIS and Parent/Caregiver GIS at each visit during the treatment period of the 
study. 
Pharmacokinetic: 
• 
PK parameters for NBI-921352 and metabolites will be determined by standard noncompartmental methods. 
• 
Plasma concentration data for NBI-921352 
 
 
• 
 
 
Safety: 
• 
Incidence of AEs and suicidality (as measured by either C-SSRS or clinical report of AEs of suicidality 
depending on subject's age and developmental level). 
• 
Absolute values and changes from baseline in clinical laboratory test values (hematology and clinical 
chemistry), vital signs, weight, Tanner stage, and electrocardiogram (ECG) parameters. 
• 
 
Statistical Methods 
The primary endpoint is the percentage change from baseline in 28-day seizure frequency for countable motor 
seizures during the treatment period. All subjects with any seizure data collected during the treatment period will be 
included in the primary analysis. Subjects in the Sentinel Cohort may be excluded from the primary analysis if 
changes to dosing are implemented in the Main Cohort. The null hypothesis is the percentage reduction from 
baseline in 28-day seizure frequency during the treatment period in subjects treated with NBI-921352 is equal to the 
reduction in subjects treated with placebo. The null hypothesis of no treatment effect will be tested using a Wilcoxon 
rank-sum test (2-sided test) at the 
 significance level.  
The proportion of subjects considered treatment responders, defined as a ≥50% decrease from baseline in 28-day 
seizure frequency for countable motor seizures during the treatment period, will be summarized by treatment group 
and analyzed using Fisher’s exact test.  
Safety data, plasma concentrations, and PK parameters (calculated using noncompartmental methods) will be 
summarized using descriptive statistics. 
 
 
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2. 
INTRODUCTION 
2.1. 
Epilepsy and Voltage-Gated Sodium Channel Inhibitors 
Epilepsy is one of the most common neurological disorders, affecting approximately 65 million 
people worldwide (Moshe et al., 2015). It is characterized by abnormal electrical activity in the 
brain leading to seizures. For epidemiological purposes, the definition requires more than one 
unprovoked seizure of any type. Patients with epilepsy have an increased mortality risk 
compared with the general population primarily due to the etiology of the disease. However, in 
patients with uncontrolled epilepsy, which can include up to 30% of patients who are refractory 
to conventional treatment (Chen et al., 2018), the greatest seizure-related risk of mortality is due 
to sudden unexpected death in epilepsy (SUDEP) (Hitiris et al., 2007). Uncontrolled epilepsy 
poses additional risks to pediatric patients; frequent uncontrolled seizures in young children have 
been shown to have a detrimental effect on cognitive development beyond that caused by the 
underlying disease (Encinas et al., 2019; O'Callaghan et al., 2011). 
The pathophysiology of most forms of epilepsy remains poorly understood, but it is known that 
epileptic seizures arise from an excessively synchronous and sustained firing of a group of 
neurons. Persistent increase in neuronal excitability is common to all epilepsy syndromes. 
Currently available antiseizure medications (ASMs) are considered to act by inhibition of 
synaptic vesicle glycoprotein (neurotransmitter release), potentiation of the inhibitory 
gamma-aminobutyric acid (GABA)ergic neurotransmission, reduction of glutamate-mediated 
excitatory neurotransmission, or inhibition of voltage-gated sodium or calcium channels. 
Inhibition of voltage-gated sodium channels (NaV) is a common mechanism of widely prescribed 
antiepileptic drugs, including carbamazepine, eslicarbazepine, oxcarbazepine, lacosamide, 
lamotrigine, phenytoin, rufinamide, and zonisamide.
 
 
 
 
 
  
2.2. 
SCN8A Developmental and Epileptic Encephalopathy 
SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) is a rare and severe 
genetically determined neurologic syndrome characterized by early onset developmental delay, 
cognitive impairment and intractable seizures for which no approved therapy exists. 
SCN8A-DEE is caused by de novo missense variants in the SCN8A gene, which encodes the 
pore-forming alpha subunit of NaV1.6. NaV1.6 is among the most ubiquitous sodium channels in 
the brain and slight alterations in its kinetics of opening and closing can have profound 
functional effects (O’Brien and Meisler, 2013). Mutations in SCN8A as a cause of epileptic 
encephalopathy were first described in 2012 (Veeramah et al., 2012). The vast majority of 
SCN8A mutations that cause SCN8A-DEE result in NaV1.6 gain of function (GOF) by 
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producing impaired inactivation or abnormal activation causing increased sodium current. This 
can lead to neuronal hyperexcitability resulting in epileptic seizures (Gardella et al., 2018; 
Wagnon et al., 2016). A subset of phenotypically distinct cases have been reported in which 
patients primarily present with movement disorders, developmental delay, and cognitive 
impairment, with less prevalent or no seizure symptoms, and these cases are predominately 
associated with loss-of-function (LOF) SCN8A mutations (Liu et al. 2019; Wagnon et al. 2018; 
Wagnon et al., 2017; Trudeau et al., 2006). 
Early onset seizures, which occur at a median age of 4 months, are a hallmark of SCN8A-DEE 
(Larsen et al., 2015). Seizures vary in frequency, with some patients with SCN8A-DEE 
experiencing up to several per day. SCN8A-DEE seizures may be prolonged (eg, more than 
20 minutes) and may have autonomic features of apnea, bradycardia or tachycardia, and cyanosis 
at the onset. The most common seizures are generalized motor seizures, motor and nonmotor 
focal seizures including focal to bilateral tonic-clonic, spasm-like episodes and erratic myoclonus 
and are most often poorly controlled (Gardella et al., 2018; Schreiber et al., 2020). While the 
intellectual impairment may vary as a result of SCN8A mutations, development in most children 
with SCN8A-DEE is severely delayed. The developmental delays are usually present from birth 
but may appear or become evident after the onset of severe and frequent seizures. Over 90% of 
children with SCN8A-DEE are nonverbal. Developmental regression has been reported to occur 
with seizure onset, or seizure worsening. Half of children with SCN8A-DEE are not ambulatory 
and may have eventual motor decline. Hypotonia and movement disorders consisting of 
dystonia, ataxia and choreoathetosis may be present. Gastrointestinal disorders are often present, 
such as gastric reflux, and oral feeding often poses a risk, therefore half of patients are fed 
through a gastrostomy tube (Gardella et al., 2018). Death occurs at a high rate in SCN8A-DEE; 
in a cross-sectional review of 190 patients worldwide, the overall mortality rate was 5.3% 
(10/190), comparable to other epileptic encephalopathies, with 3 of these 10 attributed to SUDEP 
(Johannesen et al., 2018). Deaths were frequently preceded by progressive neurologic decline 
accompanied by increased seizures, including status epilepticus, resulting in deaths mostly due to 
respiratory distress or pulmonary infections. 
The majority of described cases of patients with SCN8A-DEE, due to its onset in infancy, are in 
children and adolescents. This is presumably due to the relatively recent identification of genetic 
SCN8A variants linked to the infantile epileptic encephalopathy, which were first described in 
2012 (Veeramah et al., 2012). However, patients with SCN8A-DEE ≥18 years of age at the time 
of initial diagnosis have been identified, who have severe disease including frequent seizures 
similar to younger patients. Deaths due to SUDEP have also been documented in older 
adolescent and adult patients (Blanchard et al., 2015; Gardella et al., 2018; Gardella and Moller, 
2019). Available information from clinicians treating patients with SCN8A-DEE indicates that 
young adult SCN8A-DEE patients have a similar disease phenotype compared to younger 
patients and may continue to be treated by their pediatric epileptologists into early adulthood. 
Reduction of seizures associated with SCN8A-DEE is the primary goal of treatment; however, 
there are currently no therapies indicated to treat SCN8A-DEE. SCN8A-DEE seizures are 
typically very resistant to ASMs. A global dataset characterizing 22 SCN8A-DEE patients found 
that only 4 patients had significant seizure reduction with existing treatments (Gardella et al., 
2018).
 
 
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2.3. 
NBI-921352 
NBI-921352 is a potent, selective, small molecule inhibitor of NaV1.6 channels. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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A complete summary of the available clinical and nonclinical data for NBI-921352 is provided in 
the Investigator’s Brochure. 
3. 
OBJECTIVES 
The objectives for this study are: 
Primary 
• To assess the efficacy of NBI-921352 as adjunctive therapy on the frequency of 
countable motor seizures (defined as generalized tonic-clonic seizure [GTCS], tonic, 
atonic or focal onset seizures [FOS] with noticeable motor component). 
Secondary 
• To evaluate the efficacy of NBI-921352 using the Clinical and Parent/Caregiver 
Global Impression of Change scales and the Clinical and Parent/Caregiver Global 
Impression of Severity scales. 
• To characterize the pharmacokinetics of NBI-921352 and determine the effect of 
NBI-921352 on plasma levels of concomitant ASMs and evaluated metabolites. 
• To evaluate the safety and tolerability of NBI-921352. 
Exploratory 
• 
 
 
 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2 randomized, double-blind, placebo-controlled study to evaluate the efficacy, 
safety, tolerability, and pharmacokinetics of NBI-921352 as adjunctive therapy in subjects with 
SCN8A-DEE. Approximately 52 male and female subjects will be randomized for study 
participation according to the study eligibility criteria. Subjects will be randomized 1:1 
(NBI-921352:placebo). This study will enroll subjects 2 to 21 years of age. Enrollment of 
eligible subjects will not be limited based on weight group or age group.  
This study will include 2 separate cohorts: 
• Sentinel Cohort: 8 subjects will be randomized into the Sentinel Cohort. These 
subjects will be considered a sentinel group to evaluate observed pharmacokinetics 
(PK) relative to predicted exposures as well as safety and tolerability. An external, 
independent Data Monitoring Committee (DMC) will review the Sentinel Cohort 
subject safety, tolerability, and PK data through the 
 titration period prior to 
randomization of subjects in the Main Cohort. Preliminary efficacy data will not be 
assessed as part of the interim Sentinel Cohort data review. 
• Main Cohort: Once safety, tolerability, and PK have been assessed in the Sentinel 
Cohort, subjects will be randomized into the Main Cohort. 
For both cohorts, this study will consist of 3 periods (for subjects who enroll in the separate, 
active extension study) or 5 periods (for subjects who do not enroll in the active extension 
study): 
• An up to 
 screening period that includes a baseline period of at least 
 
to collect baseline daily seizure diary data 
− The baseline period may start once the investigator has confirmed that the 
parent/caregiver is capable of and comfortable with identifying seizures. 
• A 
 titration period 
 at each of the 2 lowest titration dose levels and 
 at each of the 2 highest titration dose levels) 
• A 
 maintenance period 
• A 
 taper period (for those subjects not enrolling into the active extension 
study) 
• A 
 safety follow-up period (for those subjects not enrolling into the active 
extension study) 
Subjects will be eligible to enter the separate, active extension study if they have successfully 
completed 16 weeks of treatment 
 titration period and 
 maintenance period). 
Subjects in the active extension study will receive active treatment; however, treatment received 
during Study NBI-921352-DEE2012 will remain blinded until the last subject ends their 
participation in Study NBI-921352-DEE2012 and the study database is locked. 
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Screening/Baseline Period – Sentinel and Main Cohorts 
After informed consent has been provided by the parent/legal guardian or subject (if appropriate) 
and the subject has provided assent (if appropriate), subjects will be screened for eligibility to 
participate in the study. Prior to starting the baseline period, site personnel will review the 
seizure types with the subjects and parent/caregiver and train them on correct seizure 
identification with a focus on identification of countable motor seizures (defined as GTCS, tonic, 
atonic seizure, and FOS with an identifiable motor component) as well as noncountable seizures 
(eg, myoclonic, epileptic spasms, and absence). 
 
 
The investigator will document that training has 
been completed and the parent/caregiver is capable of and comfortable with identifying seizures 
before the start of the baseline period. The investigator will also document that the subject has an 
adequate rescue medication regimen as well as a nocturnal alerting system in place. Baseline 
daily seizure diary data must be collected for at least 
, during which the parent/caregiver 
will complete the daily diary to record the number and type of countable motor seizures, as well 
as the occurrence of noncountable seizures for recording of seizure-free days. After completion 
of the baseline period, final eligibility will be confirmed by the investigator after review of the 
baseline diary data to ensure that parent/caregivers completed the diary according to instructions 
and that the subject has sufficient frequency of countable motor seizures (on average at least 
1 countable motor seizure per week [4 per 28 day period]). 
A sample for comprehensive genetic epilepsy panel testing will be collected at screening and 
used to verify the diagnosis. The clinical and genetic findings supporting the diagnosis of 
SCN8A-DEE will be reviewed and confirmed by an external Diagnosis Confirmation Panel 
(DCP) based on guidelines outlined in the DCP charter.  
Rescreening is permitted if a subject does not meet all eligibility requirements and returns to be 
rescreened. A subject that has failed screening twice may not be rescreened again without prior 
permission from the Sponsor. Subjects who do not meet seizure frequency criteria as assessed 
during a completed baseline period will not be eligible for rescreening. Genotyping assessments 
do not need to be repeated for subjects who are rescreened. 
Titration Period - Sentinel Cohort 
The first 8 subjects will be randomized into the Sentinel Cohort in a 1:1 ratio (4 subjects to 
NBI-921352 and 4 subjects to placebo). These subjects will be assigned to 1 of 4 weight groups 
based on weight at the screening visit:  Weight Group 1 
 Weight Group 2 
 
, Weight Group 3 
 and Weight Group 4 
 Subjects will receive the 
dose for their assigned weight group at each dose level as indicated in Table 1. The titration 
period will include 
 at Dose Level 1, 
 at Dose Level 2, 
 at Dose Level 3, 
and 
 at Dose Level 4. 
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Table 1: 
Titration Period Doses by Weight Group 
Weight 
Group 
Body Weight 
(kg) 
Dose Level 1 
(mg) tid 
Dose Level 2 
(mg) tid 
Dose Level 3 
(mg) tid 
Dose Level 4 
(mg) tid 
1 
2 
3 
4 
tid = 3 times a day. 
After 
 of the titration period, the investigator may decrease a subject's dose to the lower 
tolerated dose level based on safety and tolerability. In addition to the assessment of safety and 
tolerability at the titration period study visits, the study site will contact the parent/caregiver by 
telephone call approximately 1 week after the dose titration visits for Dose Levels 3 and 4 (ie, at 
the end of 
 to assess for any adverse events. Subjects who are unable to escalate 
to or tolerate Dose Level 2 should be discontinued from study treatment.  
Once the Sentinel Cohort titration period has completed, the DMC will review safety, 
tolerability, and PK data as described in the DMC charter. Upon completion of the review and 
based on recommendations from the DMC, subjects may be randomized in the Main Cohort. 
Doses, weight groups, and dose titration targets in the Main Cohort may be modified based on 
the results of the Sentinel Cohort safety, tolerability and PK data; however,
 
 
 
Titration Period - Main Cohort 
Approximately 44 subjects will be randomized into the Main Cohort in a 1:1 ratio 
(NBI-921352:placebo). Beginning on Day 1, subjects will receive Dose Level 1 for their 
assigned weight group (based on weight at the screening visit). The titration period will include 
 at Dose Level 1, 
 at Dose Level 2, 
 at Dose Level 3, and 
 at Dose 
Level 4, with subjects receiving the dose for their weight group at each dose level as indicated in 
Table 1, or as determined based on the results of the Sentinel Cohort data review by the DMC. 
After 
 of the titration period, the investigator may decrease a subject's dose to the lower 
tolerated dose level based on safety and tolerability. Subjects who are unable to escalate to or 
tolerate Dose Level 2 should be discontinued from study treatment. 
Maintenance Period – Sentinel and Main Cohorts 
Subjects in both cohorts who complete the titration period will enter the 
 maintenance 
period. During the maintenance period, subjects will continue to receive their final tolerated dose 
from the titration period. Dose levels should not be changed during the maintenance period 
without prior Sponsor approval. Rescue medication is permitted at any time during the study and 
will not be a reason for discontinuation from study treatment; however, use of rescue medication 
will be collected in the seizure diary and must be documented in the electronic case report form 
(eCRF). 
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Subjects receiving Dose Levels 3 or 4 who discontinue study treatment at any time before the 
end of Week 16, including during the titration period, should undergo dose de-escalation if 
appropriate, during which the subject’s current dose will be reduced in a step-wise manner over a 
period of up to 
. Instructions for dose de-escalation will be provided. Subjects who 
withdraw from the study will not be replaced. Subjects receiving Dose Levels 1 or 2 who 
discontinue study treatment do not require dose de-escalation. 
Following completion of the maintenance period, subjects will have the option to continue in the 
active extension study if they have successfully completed the 16 week treatment period 
 titration and 
 maintenance) in the current study AND have not had a serious or 
severe adverse event (AE) that, in the investigator’s opinion, was related to study treatment and 
would make it unsafe for the subject to continue study treatment dosing. For subjects electing to 
enroll in the active extension study, the last study visit will occur at the end of the maintenance 
period, and the first visit of the active extension study will occur at the same visit.  
Taper Period 
If the subject completes the maintenance period and does not enroll in the active extension study, 
the subject will enter a 
 taper period where the study treatment is tapered to ensure that all 
subjects will be off study treatment by the end of the 
 The dose taper procedure is 
described in Section 9.5.3. 
Safety Follow-Up Period 
After the last dose of study treatment, subjects who do not enroll in the active extension study 
will enter a 
 safety follow-up period which includes a follow-up telephone call 
approximately 1 week after the last dose of study treatment and a visit approximately 
 
after the last dose of study treatment. 
A schematic of the study design is shown in Figure 1. 
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Figure 1: 
 
 
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4.2. 
Study and Dose Rationale 
This Phase 2 randomized, double-blind, placebo-controlled study is designed to evaluate the 
efficacy, safety, tolerability, and PK of NBI-921352 doses administered tid as adjunctive therapy 
in subjects 2 to 21 years of age with SCN8A-DEE. 
The titration doses and weight groups selected for this study were identified using simulations 
based on a population PK model developed with data from the 2 NBI-921352 Phase 1 healthy 
adult studies. The NBI-921352 titration doses used in this study are predicted to provide the 
specified target average maximum plasma concentration for each dose level based on weight 
group (Table 2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2: 
 
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After 
 PK data will be assessed in the Sentinel Cohort, doses, dose titration targets, 
and/or weight groups for the Main Cohort may be adjusted; however,
 
 
 
4.3. 
Study Duration 
The expected duration of study participation from screening to last visit for each subject is 
approximately 
 for subjects enrolling in the separate active extension study and 
approximately 30 weeks (
 plus 
 taper and 
 safety follow-up period) for 
subjects who choose not to enroll in the active extension study. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last study visit of the last subject in the study. 
4.5. 
Benefit-Risk Assessment 
SCN8A-DEE is a severe and rare neurologic syndrome caused by de novo missense variants in 
the SCN8A gene, which encodes the pore-forming alpha subunit of NaV1.6. Currently no 
therapies are indicated to treat SCN8A-DEE, and seizures in SCN8A-DEE patients are typically 
very resistant to existing ASMs. SCN8A-DEE patients are at risk for developmental delay, 
cognitive impairment, and life-threatening status epilepticus and SUDEP, and the lack of an 
effective therapy for these patients establishes a clear unmet medical need. 
NBI-921352 is a potent, selective, small molecule inhibitor of NaV1.6 channels.
 
 
 
 
 
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channels and the selectivity of NBI-921352 for NaV1.6 against other human NaV isoforms. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
The DMC will monitor safety and tolerability data throughout the study. The current study 
includes a Sentinel Cohort of 8 subjects (4 NBI-921352 and 4 placebo). Once the Sentinel 
Cohort has completed the 
 titration period, an external, independent DMC will review 
safety, tolerability, and PK data before subjects are randomized in the Main Cohort. Based on the 
DMC review of the Sentinel Cohort data, the doses, weight groups, and dose titration targets in 
the Main Cohort may be modified but 
 
 
 
 
ASMs as a class are associated with potential risks, including cardiovascular effects, CNS effects 
including increased risk of seizures, an increased risk of suicidal thoughts or behavior, and 
hypersensitivity reactions. The current study includes vital signs assessments and centrally read 
12-lead ECGs throughout the study to monitor for cardiovascular abnormalities, and subjects 
with clinically significant abnormal ECG findings or vital signs at screening will be excluded 
from the study. 
 
 
 
 
 
 
Safety and 
tolerability will be assessed at each dose level by the investigator before a subject’s dose is 
increased to the next dose level. Subjects who are unable to tolerate Dose Levels 1 or 2 for their 
weight group will be discontinued from study treatment. Beginning at 
 of the titration 
period, doses may be decreased to a lower, tolerated dose level based on safety and tolerability. 
Study procedures are in place to ensure that subjects are monitored appropriately for seizure 
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exacerbations. Treatment regimens and prevention strategies are included to address serious 
events, such as status epilepticus and nocturnal seizures, which may result in SUDEP. 
Other CNS adverse events will also be monitored during the study. Suicidality will be monitored 
using the C-SSRS or clinical impression for subjects for whom the C-SSRS would be 
inappropriate due to developmental reasons. 
 
  
SCN8A-DEE is associated with increased risk of life-threatening conditions, including status 
epilepticus and SUDEP (Johannesen et al., 2018); these conditions represent potential risks for 
all subjects in the proposed Phase 2 Study NBI-921352-DEE2012 and the risk of developing 
these conditions may be higher for subjects who are randomized into the placebo treatment 
group. However, all subjects must be receiving concomitant ASM therapy, including a 
requirement for an established regimen for rescue-medication administration, and treatment with 
up to 4 ASMs is allowed during the study. Subjects in both treatment groups in 
Study NBI-921352-DEE2012 who complete the 16-week treatment period may be eligible to 
receive NBI-921352 in the separate, active extension study 
 
 
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5. 
STUDY POPULATION 
Subjects must fulfill all inclusion and exclusion criteria to participate in the study. 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria:  
1. Written or oral pediatric assent from the subject if deemed capable of providing assent, and 
written informed consent from the subject’s parent(s) or legal guardian(s) for subjects 
<18 years of age and for subjects ≥18 years of age who are not capable of providing consent 
in accordance with the governing Independent Ethics Committees (IEC)/Institutional Review 
Boards (IRB) and according to local laws and regulations. Subjects who are ≥18 years of age 
and capable of providing consent should sign an Informed Consent Form (ICF). Informed 
consent/assent may be done remotely, if allowed and remote consenting procedures are in 
place. 
2. Be a male or female 2 to 21 years of age, inclusive. 
3. Have a diagnosis of SCN8A-DEE supported by both clinical and genetic findings outlined as 
follows: 
a. Clinical findings: 
i. Required 
1. Seizure onset prior to 18 months of age 
2. Developmental delay which may have occurred either prior to or 
with onset of seizures or after 
ii. Supportive (not required): 
1. Multiple seizure types which include focal seizures (including 
focal to bilateral tonic-clonic), tonic-clonic seizures, 
epileptic/infantile spasms, tonic seizures 
2. History or ongoing motor abnormalities including hypotonia, 
dystonia, choreoathetosis, ataxia, spasticity, hyperekplexia 
3. Episodes of convulsive and nonconvulsive status epilepticus 
4. Beneficial response to sodium channel blockers such as phenytoin, 
valproate, carbamazepine, lacosamide, lamotrigine, rufinamide, 
and oxcarbazepine 
b. Genetic findings (i, ii, and iii required): 
i. 
Pathological gain of function (GOF) mutation in SCN8A defined as 
either a previously identified GOF mutation or a presumed pathological 
GOF mutation. Presumed pathological GOF mutations must be either a 
missense mutation that is not seen in either parent (de novo) OR a 
mutation which leads to a hyperfunctioning channel in in vitro function 
tests. Presumed pathological GOF mutations must not be nonsense 
mutations or other mutations likely to lead to a truncated protein. 
ii. 
Subject may not have an identified (known or newly functionally 
characterized missense variant) or presumed (ie, protein-truncating 
variant) loss-of-function variant in SCN8A. 
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iii. 
No other pathogenic mutation in an additional gene that is known to 
cause epilepsy and is more likely to cause the epilepsy experienced by 
the subject. 
 
Genetic findings required for SCN8A-DEE diagnosis may be based on genetic testing 
performed previously. The genetic mutation in the subject’s SCN8A gene (b[i] and b[ii]) 
and the absence of other pathogenic mutations that are more likely to cause the epilepsy 
experienced by the subject (b[iii]) must be confirmed at screening as part of the 
comprehensive epilepsy panel genotyping (Section 9.1.1). 
4. Have SCN8A-DEE diagnosis confirmed by the DCP. 
5. In the 90 days before screening, have a history of on average at least 4 countable motor 
seizures (defined as GTCS, tonic, atonic or FOS with noticeable motor component) per 
month. 
6. Have on average at least 1 countable motor seizure (defined as GTCS, tonic, atonic or FOS 
with noticeable motor component) per week (4 per 28-day period) and not be seizure-free for 
more than 20 consecutive days per 28-day period during the baseline period. 
7. Have at least 
 of reliably and consistently completed baseline seizure diary data. 
8. Being treated with at least 1 other ASM, but no more than 4 ASMs. Epidiolex®/Epidyolex® 
will be considered an ASM. The dose should be stable for at least 5 half-lives at screening. 
Vagus nerve stimulator (VNS) and ketogenic diet are not counted as ASMs. 
9. Have failed to achieve seizure freedom with at least 2 ASMs. 
10. The subject, if using a VNS, must have had the VNS placed at least 3 months prior to 
screening with stable settings for ≥30 days before screening; settings must remain stable 
throughout the duration of the study. 
11. The subject, if on a ketogenic diet, must have started the ketogenic diet at least 30 days prior 
to screening; diet must be stable, and continue through the duration of the study. 
12. Must be using a nocturnal alerting system or practice consistent with standards of care at the 
time of screening and continue to use this for the duration of the study. Acceptable nocturnal 
alerting systems or practices include but are not limited to: 
 
 
 
 
 
  
13. Must have an adequate rescue medication regimen per the investigator’s judgment in place at 
the time of screening and for the duration of the study. 
14. Female subjects of childbearing potential must agree to use contraception consistently from 
screening until the final study visit or 30 days after the last dose of study treatment, 
whichever is longer. 
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A female subject of childbearing potential is defined as 
 
 A male subject of childbearing potential is 
defined as a 
 
. 
Highly effective methods of contraception are required for female subjects of childbearing 
potential: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Male subjects must agree to use effective barrier contraception consistently from screening 
until 30 days after the last dose of study treatment. The acceptable method of contraception 
for male subjects,
 
15. Have a body weight of 
 
16. Be able to carry out all the appropriate assessments and take the study treatment with the help 
of the parent/caregiver in the opinion of the investigator. 
17. The subject’s parent/caregiver is able to accurately identify seizure types, especially 
countable motor seizures 
 
 and is able to complete seizure diary. 
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5.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Have previously been enrolled in this study and received blinded treatment. 
2. Have participated in an interventional clinical trial <30 days prior to screening. 
3. Have symptoms that would be more consistent with another epilepsy disorder such as Dravet 
syndrome (eg, fever-induced episodes of status epilepticus, frequent myoclonic seizures, 
worsening on sodium channel blockers, absence seizures with generalized spike-and-wave 
EEG as the sole seizure type). 
4. Are currently receiving cannabinoids or medical marijuana except Epidiolex/Epidyolex, 
unless approved by the Sponsor.  
5. Are currently taking systemic steroids (excluding inhaled medication for asthma treatments 
and intranasal steroids for allergies) such as adrenocorticotropin hormone (ACTH), high dose 
prednisolone for epileptic spasms. If subject has received these medications in the past, must 
be off these medications for at least 3 months prior to the screening visit and these drugs may 
not be initiated during the duration of the study. Intermittent steroids to treat nonepilepsy 
related diseases (such as allergies or dermatological conditions) are not exclusionary. 
6. 
 
 
7. Have a history of severe drug allergy or hypersensitivity to NBI-921352 or its excipients. 
8. Have a previous exposure to NBI-921352. 
9. Have any other disorder for which the treatment takes priority over treatment of 
SCN8A-DEE or is likely to interfere with study treatment or impair treatment compliance. 
10. Have a history of moderate or severe head trauma or other neurological disorders or systemic 
medical diseases that are, in the investigator’s opinion, likely to affect nervous system 
functioning. 
11. Have a clinically significant medical condition or chronic disease (including history of 
neurological, hepatic, renal, cardiovascular, gastrointestinal, significant malabsorption, 
hematologic, pulmonary, psychiatric, or endocrine disease) that in the opinion of the 
investigator would preclude the subject from participating in and completing the study or that 
could confound interpretation of study outcome. 
12. Are taking or have received disallowed concomitant medication (Section 7.1) or it is 
anticipated that the subject will require treatment with at least one of the disallowed 
concomitant medications during the study. 
13. Have clinically significant abnormal vital signs at the screening visit as determined by the 
investigator. 
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14. Have one or more clinical laboratory test values outside the reference range, based on blood 
samples taken at the screening visit, that are of potential risk to the subject’s safety as 
determined by the investigator, or have at the screening visit: 
• A serum creatine value >1.5 times the upper limit of the reference range. 
• A total bilirubin value >1.5 times the upper limit of the reference range. 
• A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2.5 times the upper limit of the reference range. For subjects on valproate, ALT or 
AST values up to 3 times the upper limit of the reference range are acceptable, if 
these values have remained stable over the past 3 months based on investigator 
judgement. 
15. Have, at the screening visit, an ECG finding of a corrected QT interval using Fridericia’s 
formula (QTcF) >450 msec or presence of any significant cardiac abnormality. 
16. The subject or subject’s parent/caregiver, in the investigator’s opinion, is unlikely to comply 
with the protocol, including the requirement to travel to the study sites for study visits, or is 
unsuitable for any reason. 
17. Have attempted suicide within the last year or are at significant risk of suicide (either in the 
opinion of the investigator or defined as a “yes” to suicidal ideation questions 4 or 5 or “yes” 
to suicidal behavior on the C-SSRS within the past 12-months). 
18. Females who are pregnant or currently breastfeeding. 
19. Have a history of a positive hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B 
surface antigen (HBsAg), or human immunodeficiency virus antibody (HIV-Ab) test results 
at screening. Subject with positive hepatitis C antibody (HCV-Ab) and confirmatory positive 
polymerase chain reaction (PCR) reflex test results at screening will be allowed to participate 
in the study provided that the subject is asymptomatic as assessed by the investigator and 
does not have exclusionary liver function test abnormalities (ALT, AST, and total bilirubin). 
20.
 
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6. 
STUDY TREATMENT  
6.1. 
General Information 
Study treatments are summarized in Table 3. 
Table 3: 
Study Treatments 
Group Name 
NBI-921352 
Placebo 
Doses 
Subjects will receive up to 4 dose levels 
during the study based on their 
assigned weight group. 
 
 
Placebo is administered in the same 
manner and on an identical schedule as 
NBI-921352. 
Unit Dose 
Strengths 
  
Placebo 
Dose 
Formulation 
 
Matching oral granules in sprinkle 
capsules 
Route of 
Administration 
Oral or G-tube 
Oral or G-tube 
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and 
Labeling 
Study treatment will be provided  
 
Matching placebo will be provided
 
 
 
tid=3 times a day; WG=weight group. 
6.2. 
Study Treatment Administration 
 
 
 
 
 
 
 
 
 
 
 
 
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6.3. 
Study Treatment Storage and Compliance 
The designated personnel is responsible for maintaining records of the quantity and dates of all 
study treatment supplies received, dispensed, returned, lost, and destroyed, according to 
applicable regulations and study procedures. Study treatment should be stored in a locked area 
accessible only to the designated pharmacist or qualified personnel. A detailed description of 
how study treatment should be dispensed, stored, and reconstituted, and any stability changes 
will be provided in the Pharmacy Manual.  
6.4. 
Study Treatment Accountability and Return 
Parents/caregivers will bring all unused study treatment and empty packaging material to the 
center at specified study visits for drug accountability and reconciliation by study center 
personnel. A compliance check will be performed by counting the capsules returned at each 
study visit. 
The quantity of study treatment dispensed, used, and returned will be recorded on a dispensing 
log or otherwise documented. The quantity of study treatment lost or destroyed must also be 
accounted for and documented. The designated pharmacist or qualified personnel will be 
responsible for maintaining accurate records of the quantity and dates of all study treatment 
supplies received, dispensed, and returned. 
Returns will be shipped to NBI or its designee at the completion of the study according to 
instructions provided by NBI or its designee according to applicable local and national 
regulations and study procedures. 
6.5. 
Direct-to-Subject Shipments of Study Treatment 
To ensure continued access to study treatment, if a subject is unable to go to the site when study 
treatment is to be dispensed, study treatment may be delivered from the site’s pharmacy to the 
subject’s residence by a distributor independent from the Sponsor. The subject’s name, address, 
and other contact details will not be accessible to the Sponsor, and the distributor will not have 
access to the subject’s health information. 
6.6. 
Blinding 
This is a double-blind, placebo-controlled study during which the subject, parent/caregivers, 
investigator, all study center personnel, and the Sponsor, with the exception of clinical trial 
material supply chain personnel who do not have access to study data and are not involved in 
decisions regarding subject’s treatment, will be blinded to the subject’s treatment assignment 
(NBI-921352 or placebo).  
The randomization code will be broken for an individual subject only if the subject is pregnant, 
experiences a serious adverse event (SAE) that the investigator feels cannot be adequately 
treated without knowing the subject’s treatment assignment, or for regulatory reporting 
requirements. In the case of a medical emergency in which knowledge of the identity of the 
study treatment is important for subject management, the investigator has the responsibility to 
decide whether to break the blind; treatment assignments will be unblinded following the 
interactive web response system (IWRS) process. It is recommended that the investigator contact 
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the Study Medical Monitor (or designee) before unblinding the treatment assignment if it would 
not result in unnecessary delay to the immediate medical management of the subject. The 
investigator must document the date, time, and the reason the blind was broken. 
Members of the DMC, the independent statistics group that generates the DMC reports, and the 
pharmacokineticist providing the PK analysis for the Sentinel Cohort will be unblinded 
throughout the study.  
6.7. 
Procedures for Overdose 
For this study, any dose of NBI-921352 greater than the subject’s assigned dose level within a 
24-hour time period will be considered an overdose. The current version of the Investigator’s 
Brochure should be referenced for overdose information. There is no recommended specific 
treatment for an overdose but to provide supportive care if clinically indicated. 
In the event of a suspected overdose, the investigator and/or treating physician should: 
1. Closely monitor the subject for any AE/SAE and laboratory abnormalities and follow the 
AE reporting process. The Study Medical Monitor should be contacted for adverse events 
related to an overdose. 
2. Document the quantity of the excess dose(s), as well as the date(s) on which the 
additional dose(s) were taken, if this information is available.  
Subjects who overdose will be counseled on correct dosing and administration of study 
treatment. Decisions regarding study discontinuation, dose interruptions, or dose modifications 
will be made by the investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the subject. 
7. 
SUBJECT RESTRICTIONS 
7.1. 
Prior and Concomitant Medications 
All prescription and over-the-counter medications, dietary supplements (including vitamins), and 
herbal supplements taken by the subject within 30 days before screening will be recorded on the 
Prior and Concomitant Medications page of the eCRF. All previously taken ASMs and reasons 
for discontinuation will also be recorded on a separate eCRF. 
The following medications are prohibited for all subjects beginning 30 days before the screening 
visit (unless otherwise stated) until the final study visit (or upon early discontinuation of study 
treatment):   
• Cannabinoids or medical marijuana except Epidiolex/Epidyolex, unless approved by the 
Sponsor. 
• Systemic steroids (eg, high dose prednisolone, ACTH) are prohibited for at least 
3 months before the screening visit. Inhaled steroids for asthma treatments and 
intermittent steroids to treat nonepilepsy related diseases (such as allergies or 
dermatological conditions) are allowed. 
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• Any investigational treatments received in the context of a clinical study, unless approved 
by Sponsor. 
 
 
 
ASMs must be stable throughout the study. 
Rescue Medication 
Subjects must have an adequate rescue medication regimen in place for the duration of the study. 
Short-term benzodiazepines may be used as acute treatment for prolonged seizures. If needed, 
longer-acting ASMs may be used as rescue medication based on the investigator's discretion. 
Rescue medication is permitted at any time and will not be a reason for discontinuation from 
study treatment; however, use of rescue medication will be collected in the seizure diary and 
must be documented in the eCRF. 
7.2. 
Dietary and Other Restrictions 
 
 
Subjects who are on a ketogenic diet must have started the diet at least 30 days prior to screening 
and diet must remain stable throughout the study. If using VNS, subjects must have stable 
settings for at least 30 days before screening and throughout the study. 
 
 
 
 
8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL 
Subjects can discontinue study treatment or withdraw their consent to participate in the study at 
any time. The investigator must discontinue study treatment dosing or withdraw any subject from 
the study at the parent/caregiver or subject's request. All subjects discontinuing study treatment 
dosing should continue study participation for safety and efficacy assessments through the end of 
Week 16, after which they will be withdrawn.  
8.1. 
Discontinuation of Study Treatment 
If a subject prematurely discontinues study treatment dosing, the investigator will record the 
reason for discontinuation on the relevant eCRF. Such subjects will not be automatically 
withdrawn from the study and should continue participation. Data for any outcome measures, 
particularly the primary and secondary endpoints, as well as safety follow-up, are important to 
collect. PK sampling is not required after study treatment has been discontinued; however, 
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subjects should return to the study center at the next scheduled visit for safety assessments. 
Additional study visits and assessments for subjects who discontinue study treatment but agree to 
remain in the study may be conducted remotely. Medications listed in Section 7.1 are no longer 
prohibited after study treatment discontinuation.  
Reasons for discontinuation from study treatment include but are not limited to: 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Site termination by the Sponsor 
• Study termination by the Sponsor 
• AE 
• Pregnancy 
• Lack of efficacy 
• Protocol deviation 
The investigator must discontinue study treatment dosing if the subject experiences any of the 
following: 
• If the type, frequency, or severity of any AE becomes unacceptable/intolerable. This 
includes AEs of seizures. Criteria for evaluating whether seizures should be 
considered AEs are provided in Section 10.1. 
• A clinically significant worsening in the underlying seizure disorder requiring an 
adjustment in concomitant ASM regimen to ensure subject safety, including increased 
usage of rescue medication. 
• If the subject is unable to tolerate Dose Levels 1 or 2 for the assigned weight group. 
• QTcF of >500 msec (cardiologist verified) on any ECG tracing. 
• QTcF change from baseline >60 msec (cardiologist verified) and confirmed with 
repeated ECG measure. 
• If the subject exhibits suicidal behavior, or suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal 
ideation with specific plan and intent) based on the C-SSRS. 
• If the subject is confirmed to be pregnant. 
• Withdrawal of consent/assent for study treatment administration by parent/caregiver 
or subject. 
It is crucial to obtain follow-up data for any subject who discontinues study treatment dosing 
because of an AE, abnormal laboratory test, vital sign measurement, physical examination, or 
ECG finding. In any case, every effort must be made to undertake safety follow-up procedures. 
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8.2. 
Withdrawal from Study 
If a subject prematurely withdraws from the study, the investigator will record the reason for 
withdrawal on the relevant eCRF. All subjects who withdraw from the study prematurely will be 
asked to have all early termination assessments performed and, unless consent has been 
withdrawn, will be asked to come back approximately 
 later for a follow-up visit. If a 
subject’s last dose of study treatment was 
 before the early termination visit, no 
additional visits are needed.  
Reasons for withdrawal from study include but are not limited to: 
• Withdrawal by the subject or parent/caregiver 
• AE 
• Death 
• Lost to follow-up 
• Site terminated by Sponsor 
• Study terminated by Sponsor 
• Protocol deviation 
• Investigator decision 
8.3. 
Sponsor’s Termination or Suspension of Study or Study Site 
The Sponsor or designee reserves the right to close a study site, terminate the study, or suspend 
the study overall or at the level of individual sites at any time for any reason at the sole discretion 
of the Sponsor. Reasons for terminating the study include, but are not limited to, a determination 
of unjustifiable risk or toxicity in the risk-benefit assessment based on the occurrence of adverse 
events or other safety findings that, in their nature, severity, duration, or frequency, require 
re-evaluation of the current established safety profile, or new scientific evidence (eg, results from 
other clinical studies) becomes available that may affect subject safety. If the study is 
prematurely terminated or suspended, the Sponsor shall promptly inform the investigators, the 
Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs), the regulatory 
authorities, and any contract research organizations (CROs) used in the study of the reason for 
termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject and should assure appropriate subject therapy 
and/or follow-up. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
A schedule of assessments is shown in Table 10 in Appendix A. No study procedures should be 
performed until after signed informed consent by parent(s) or legal representative(s) and, if 
applicable, informed consent for subjects ≥18 years of age or pediatric assent from subjects 
<18 years of age determined by the investigator to be capable of providing consent/assent, are 
obtained. Informed consent/assent may be done remotely, if allowed and remote consenting 
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procedures are in place. Subject-related events and activities including specific instructions, 
procedures, concomitant medications, dispensing of study treatment, and descriptions of AEs 
should be recorded in the appropriate source documents and eCRFs. 
The sponsor will store biosamples and the results of any genetic testing in a manner compliant 
with applicable national and local regulations and the requirements of Articles 25, 26, 28, and 32 
of the European Union (EU) General Data Protection Regulation (GDPR). 
9.1. 
Screening Assessments 
9.1.1. 
Comprehensive Epilepsy Panel Genotyping 
 
 
9.1.2. 
Cytochrome P450 2D6 Genotyping 
 
 
9.1.3. 
Video Electroencephalogram 
A video-EEG may be performed during screening at the discretion of the investigator, if a recent 
(within 3 years) video-EEG is not available and the subject and parent(s)/legal representative(s) 
provide consent/assent. The video-EEG is optional and will be used for parent/caregiver training 
in the detection and classification of countable seizures. The video-EEG will be obtained using 
the standard procedures for the study center. 
9.1.4. 
Diagnosis Confirmation Panel 
An external DCP, consisting of clinical and research experts in pediatric epilepsy and SCN8A, 
will review and confirm that the subject meets the clinical and genetic diagnosis of SCN8A-DEE 
to determine study eligibility. The DCP will be provided the results of the comprehensive 
epilepsy panel genotyping during screening to review in order to confirm the genetic diagnosis. 
Medical history information, as well as any further medical information supporting the diagnosis 
if available, will be provided to the DCP for review to confirm that the subject meets the clinical 
diagnosis of SCN8A-DEE. DCP confirmation of the clinical and genetic diagnosis of 
SCN8A-DEE must be provided before subject randomization. A DCP charter will describe the 
responsibilities, data review procedures, and diagnostic guidelines for the members to follow. 
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9.2. 
Efficacy Assessments 
9.2.1. 
Daily Seizure Diary 
Seizure information will be recorded in a paper daily diary throughout the study. The 
parent/caregiver will complete the daily diary to record the number and type of countable motor 
seizures 
 as well as 
the occurrence of noncountable seizures 
 for 
recording of seizure-free days. Parent/Caregivers will also be instructed to document days 
without any seizures and rescue medication use in the daily diary. 
Parent/caregivers will be instructed to bring the completed daily seizure diary to each study visit 
as noted in the Schedule of Assessments (Table 10). At the Day 1 visit prior to randomization, 
the study center will review the daily seizure diary to confirm that there are at least 4 weeks 
(28 days) of reliably and consistently completed baseline seizure diary data. At subsequent study 
visits, the study center will review the daily seizure diary to confirm appropriateness of 
completion and re-instruct the parent/caregiver as necessary.  
9.2.2. 
Clinical Global Impression of Change 
The Clinical Global Impression of Change (CGIC), which is based on a 7-point scale (range: 
1=very much improved to 7=very much worse), will be used to rate the overall global 
improvement since the initiation of study treatment dosing. This scale is a modification of a scale 
developed by the Psychopharmacology Research Branch of the National Institute of Mental 
Health to rate the subject’s overall improvement in clinical disorder and provides a global 
evaluation of improvement over time from the clinician’s perspective (Guy, 1976). 
The investigator (or qualified designee) will rate the scale at the scheduled timepoints as 
indicated in the Schedule of Assessments (Table 10); if possible, the same person should rate the 
CGIC at all timepoints. 
9.2.3. 
Parent/Caregiver Global Impression of Change 
The Parent/Caregiver Global Impression of Change (GIC) will be used to assess the 
parent/caregiver’s impression of change in the subject’s overall condition since starting study 
treatment and is rated on a 7-point scale (1=very much improved to 7=very much worse).  
The main caregiver will rate the scale at the study visits indicated in the Schedule of 
Assessments (Table 10). If the main caregiver is not available at the visit where the scale is 
collected, this information may be captured over the telephone on the day of the visit or within 
3 days. 
9.2.4. 
Clinical Global Impression of Severity 
The Clinical Global Impression of Severity (CGIS) scale will be used to assess overall severity 
on a 7-point scale (range: 1=normal, not at all ill to 7=among the most extremely ill patients). 
The CGIS will be assessed by the investigator (or qualified designee) at the scheduled timepoints 
as indicated in the Schedule of Assessments (Table 10). 
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9.2.5. 
Parent/Caregiver Global Impression of Severity 
The Parent/Caregiver Global Impression of Severity (GIS) scale will be used to assess overall 
severity on a 5-point scale (range: 1=none to 5=very severe).  
The main caregiver will rate the scale at the study visits indicated in the Schedule of 
Assessments (Table 10). If the main caregiver is not available at the visit where the scale is 
collected, this information may be captured over the telephone on the day of the visit or within 
3 days. 
9.2.6. 
 
 
 
 
 
9.2.7. 
 
 
 
 
 
 
 
 
 
 
9.2.8. 
 
 
 
 
 
 
 
9.3. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 7.1 and Section 10, respectively. Additional safety assessments are described in the 
following sections.  
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For any abnormal safety assessment deemed clinically significant, the investigator will perform 
appropriate follow-up assessments (eg, repeat analysis), until the cause of the abnormality is 
determined and/or until the value returns to baseline (or within normal limits), or the investigator 
deems the abnormality to be of no clinical significance. 
Appropriate psychiatric evaluation and intervention will be provided for any treatment-emergent 
suicidal behavior or clinically significant suicidal ideation. 
9.3.1. 
Vital Sign Measurements 
Vital sign measurements, including orthostatic systolic and diastolic blood pressure, orthostatic 
pulse rate, respiratory rate, and body temperature will be measured. Orthostatic blood pressures 
may be considered optional if the subject is unable to stand (eg, subject is in a wheelchair). If the 
investigator is unable to obtain orthostatic blood pressures, the reason for noncollection must be 
captured in the eCRF. Blood pressure and pulse rate will be measured after the subject has been 
supine for at least 5 minutes and after approximately 2 minutes standing, if possible. Body 
temperature may be measured orally or at the forehead, ear, or rectum. 
Vital sign measurements will be obtained before any scheduled blood sample collection at 
screening and then at the timepoints specified in the Schedule of Assessments (Table 10).  
9.3.2. 
Medical History 
A medical history, including family medical history and social, psychiatric, developmental, and 
neurological histories, will be taken at the screening visit and updated as needed throughout the 
study.  
9.3.3. 
Physical and Neurological Examination Including Height/Length and Tanner 
Staging  
The complete physical examination will consist of an assessment of general appearance, skin and 
mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest/lungs, 
cardiovascular, abdomen, extremities, musculoskeletal, genito-urinary, and neurological system, 
including assessment of level of consciousness, mental status, muscle strength and tone, 
coordination and gait. Height/length will be measured at the screening visit only and may be 
optional if the subject is unable to stand. If the investigator is unable to obtain height/length, the 
reason for noncollection must be captured in the eCRF. The complete physical examination will 
be performed at the study visits indicated in the Schedule of Assessments (Table 10). 
Physical signs of puberty will be assessed using Tanner staging in subjects (as appropriate based 
on subject age and stage of puberty) as part of the physical examination at screening and at the 
end of maintenance/early termination visit.  
9.3.4. 
Weight 
Weight will also be measured at the study visits indicated in the Schedule of Assessments 
(Table 10). Weight at the screening visit will be used for weight group assignment for study 
treatment dosing. 
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9.3.5. 
Electrocardiogram 
A standard 12-lead ECG will be recorded after the subject has rested supine for at least 
5 minutes. The ECG will be centrally read and parameters that will be assessed include heart 
rate, PR interval, QRS duration, QT interval, and QTcF. Additionally, the occurrence of de- and 
re-polarization and rhythm disorders or other abnormalities will be assessed. Based on the review 
of these parameters, the investigator will note if the ECG is Normal, Abnormal not Clinically 
Significant, or Abnormal Clinically Significant. If the ECG is Abnormal Clinically Significant, 
the investigator or designee will provide a description of the abnormality recorded on the AE 
eCRF.  
9.3.6. 
Clinical Laboratory Assessments 
All clinical laboratory assessments will be performed by a central laboratory. The central 
laboratory will provide instructions and supplies to the study staff before study initiation and 
instructions will be included in a laboratory manual. The laboratory test battery will include 
routine and screening laboratory tests.  
The following clinical safety laboratory assays will be performed: 
Hematology:
 
 
 
Clinical chemistry:
  
 
Urinalysis:
 
 
 
The following additional laboratory tests will be performed: 
Serology: 
 
Drug screen: 
 
Pregnancy test: Pregnancy tests will be performed for female subjects of childbearing potential. 
A serum (β-hCG) pregnancy test will be performed at the visits indicated in the Schedule of 
Assessments (Table 10). A urine pregnancy test should be performed at Day 1; however, a serum 
pregnancy test may be performed, if it is not possible to obtain urine. 
The maximum total blood volume collected during the study from screening to last visit in this 
study 
; Safety Follow-up Visit) is 
 
 
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9.3.7. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and behavior 
(http://www.cssrs.columbia.edu). There are versions of the questionnaire designed for use at 
screening (Baseline/Screening version) and at visits throughout the study (Since Last Contact 
version). All versions of the C-SSRS include a series of screening questions related to suicidal 
ideation and suicidal behavior. Subject responses of “yes” to one or more screening questions 
will prompt additional questions that evaluate frequency and intensity of suicidal ideation and/or 
behavior. 
The C-SSRS Baseline/Screening version will be administered at screening. Subjects with 
developmental impairment for whom the C-SSRS would be inappropriate will be monitored for 
suicidality based on clinical impression. 
Subjects with any suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with 
some intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and 
intent) within the last year based on the C-SSRS should be excluded (refer to exclusion criterion 
#17 in Section 5.2). 
The C-SSRS will be administered and scored by the investigator or qualified study center 
personnel at screening and throughout the study as indicated in the Schedule of Assessments 
(Table 10). 
9.3.8. 
 
 
 
 
 
9.4. 
Pharmacokinetic Assessments 
Blood samples for determination of plasma concentrations of NBI-921352 
 will 
be collected. 
 
. An intravenous catheter inserted in a peripheral vein 
may be used to collect serial PK blood samples. Timepoints for both blood samples are provided 
in the Schedule of Assessments (Table 10). 
For each sample, blood
 
 will be collected
 
 The exact time of sampling 
in hours and minutes will be recorded for all plasma PK samples. A PK sample should be 
collected from subjects who terminate early. The blood samples will be processed and stored 
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according to the procedure as specified in the laboratory manual. Samples will be shipped on dry 
ice to the central laboratory for analysis. 
9.5. 
 
 
 
9.5.1. 
 
 
 
  
 
 
 
 
 
 
 
9.5.2. 
 
 
 
 
  
 
 
 
 
 
9.5.2.1. 
 
9.5.2.1.1. 
 
 
 
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9.5.2.1.2. 
 
 
 
 
9.5.2.1.3. 
 
 
 
 
 
 
 
 
 
9.5.2.1.4. 
 
 
 
9.5.2.1.5. 
 
 
 
 
 
 
 
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9.5.2.2. 
 
9.5.2.2.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5.2.2.2. 
 
 
 
 
 
 
  
 
 
 
 
 
 
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9.5.3. 
  
 
  
Table 4: 
 
 
9.5.3.1. 
 
 
 
9.5.4. 
 
 
9.5.4.1. 
 
 
 
9.5.4.1.1. 
 
 
10. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or identified by other means, will be recorded from the time the subject has signed the 
ICF until the subject’s final study visit (or upon early termination). 
10.1. 
Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
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(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
AEs include, but are not limited to, any of the following:  
• worsening or change in nature, severity, or frequency of conditions present at the start of 
the study 
• subject deterioration beyond what would be expected due to the primary illness 
• intercurrent illness 
• drug interaction 
All suicidal behaviors and clinically significant suicidal ideations will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom. The investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms. Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
treatment, must be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice and on the AE eCRF. Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
study treatment.  
The following are not considered AEs: 
• Continuous persistent disease/symptom present before drug administration, unless 
it unexpectedly progresses, or increases in severity following drug administration.  
• Treatment failure or lack of efficacy 
• Seizures will not be considered an AE unless there is a significant increase in 
seizure frequency, a new seizure type, occurrence of status epilepticus, and/or in 
the investigator’s opinion it should be captured as an AE. 
• Pregnancy 
• Overdose of either study treatment or concomitant medication without any 
clinical signs or symptoms. 
10.1.1. 
Intensity of Adverse Events  
AEs must be graded for intensity. An intensity category of mild, moderate, or severe, as defined 
in Table 5, must be entered on the AE eCRF. It should be noted that the term “severe” used to 
grade intensity is not synonymous with the term “serious.” 
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Table 5: 
Intensity of Adverse Events 
Grade  
Intensity 
Mild 
An adverse event that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
Moderate 
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
subject. 
Severe 
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
10.1.2. 
Relationship to Study Treatment 
The investigator will document his/her opinion of the relationship of the AE to study treatment 
using the criteria outlined in Table 6. An AE is deemed associated with the use of the study 
treatment “if there is a reasonable possibility that the drug caused the AE” (otherwise referred to 
as a suspected adverse reaction). Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the AE (Title 21 Code of Federal Regulations [CFR] 
312.32 [a]).  
Table 6: 
Relationship of Adverse Events to Study Treatment 
Relationship 
Description 
Definite 
The adverse event (AE) follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized cause-effect 
relationship, and (if appropriate) reappears when the drug is reintroduced. 
Possible 
The AE follows a reasonable temporal sequence from administration of the drug and cannot 
be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental, or toxic factors, or other modes of therapy administered to the subject. There 
should be some evidence to support a causal relationship between the drug and the adverse 
event. 
Unlikely 
The temporal sequence between the AE and the drug is such that the drug is not likely to 
have any reasonable association with the AE or other plausible explanations exist for the AE 
(eg, disease, other drugs). 
Not Related 
The AE does not follow a reasonable temporal sequence from administration of the drug, 
may not abate upon discontinuation of the drug, does not follow a known or hypothesized 
cause-effect relationship, and (if applicable) may not reappear when the drug is reintroduced, 
furthermore, there may exist a clear alternative medical explanation (eg, underlying disease 
state) or association with study procedure or study conduct. 
10.2. 
Recording Adverse Events 
For randomized subjects, each AE will be listed as a separate entry on an AE eCRF. Screen 
failure subjects will have AE information noted only in the source document. The investigator 
(or designee) will provide information on dates of onset and resolution, intensity, seriousness, 
frequency, action(s) taken, changes in study treatment usage, relationship to study treatment, and 
outcome.  
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The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours to NBI or its designee: 
• SAE, including death (must be reported immediately and no later than 24 hours under 
any circumstances) 
• Pregnancy 
• Treatment unblinding for any reason. 
• Events of suicidal behavior or suicidal ideation type 4 (active suicidal ideation with 
some intent to act, without specific plan) or type 5 (active suicidal ideation with 
specific plan and intent) based on the C-SSRS. 
10.3. 
Poststudy Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up.  
AEs ongoing at the final visit or at early termination will be followed for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes, resolves, or the subject is 
lost to follow-up. The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as may be indicated to elucidate the nature and/or causality of the 
AE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals, as is practical. 
10.4. 
Serious Adverse Events 
All SAEs will be recorded from the time the subject has signed the ICF until the final study visit. 
Investigators are not obligated to actively seek SAEs after a subject has withdrawn from or 
completed the study. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been withdrawn from or has completed the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, the 
investigator must promptly notify the Sponsor as described in Section 10.4.3. 
10.4.1. 
Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcome: 
• Death. 
• A life-threatening AE. Life-threatening means that the subject was, in the view of the 
investigator or Sponsor, at immediate risk of death from the reaction as it occurred. It 
does not mean that hypothetically the event might have caused death if it occurred in 
a more serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization. Hospitalization 
for elective treatment or a pre-existing condition that did not worsen during the 
clinical investigation is not considered an AE. Hospitalization or nursing home 
admission for the purpose of caregiver respite is not considered an AE. Complications 
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that occur during hospitalization are AEs, and if a complication prolongs 
hospitalization, the event is considered serious. Treatment in a hospital emergency 
room is not a hospitalization. 
• A persistent or significant incapacity or substantial disruption of a person’s ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization. These events may be considered serious when, based on appropriate 
medical judgment, they may jeopardize the health of the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed. Any other 
event thought by the investigator to be serious should also be reported, following the 
reporting requirements detailed in this section. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias, convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
10.4.2. 
Managing Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible. The physician in attendance will do whatever is medically needed for the safety 
and well-being of the subject. The subject will remain under observation as long as medically 
indicated. Appropriate laboratory studies will be conducted until all parameters return to normal 
or are otherwise explained or stable. The subject will be followed until the SAE resolves or until 
the subject is medically stabilized. The investigator (or designee) will notify the Study Medical 
Monitor of the SAE and the outcome of the SAE immediately and no later than 24 hours under 
any circumstances and will also notify the IRB/IEC, if necessary. 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events  
SAEs must be reported immediately and no later than 24 hours under any circumstances, and 
other immediately reportable events (defined in Section 10.4) must be reported within 24 hours 
of first knowledge of the event by study personnel to the Study Medical Monitor and NBI Drug 
Safety and Pharmacovigilance (DSPV) Department. Reports of SAEs and pregnancies must be 
followed by a fax or email of the SAE or Pregnancy Form. It is important that the investigator 
provides his or her assessment of relationship to study treatment at the time of the initial SAE 
report. 
For SAEs and pregnancies, contact DSPV (Table 7). Treatment unblinding and events of suicidal 
behavior or suicidal ideation type 4 or 5 based on the C-SSRS should be reported to the Study 
Medical Monitor (Table 7). 
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Table 7: 
Contact Information for Drug Safety and Pharmacovigilance and Study 
Medical Monitor  
DSPV 
 
Facsimile 
 
Email 
 
 
Study Medical Monitor 
 
 
 
 
 
  
Telephone: 
  
 
  
US toll free: 
 
Email:  
 
 
10.4.4. 
Expedited Safety Reports 
NBI or its representatives will submit an Expedited Safety Report for any suspected adverse 
reaction (as defined in Section 10.1.2) that is considered both serious and unexpected within 
15 calendar days and for any unexpected fatal or life-threatening experience within 7 calendar 
days to the applicable regulatory authority(ies); or according to country-specific regulations. 
NBI or its representatives will send copies of each safety report submitted to regulatory 
authorities to the investigators. The safety report must be submitted to the appropriate IRB/IEC 
as soon as possible. Documentation of the submission to the IRB/IEC and receipt by the 
IRB/IEC (if applicable) must be retained for each safety report. 
10.5. 
Pregnancy 
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met. However, all 
pregnancies in subjects who received NBI-921352 will be followed to assess for congenital 
anomaly. Subjects of child bearing potential must be counseled at all visits to continue using 
contraception (inclusion criterion #13, Section 5.1) until 30 days after the last dose of study 
treatment. If a subject believes she is pregnant at any time between the time the subject signs the 
ICF and the last study visit, she should return to the study center within 24 hours and undergo a 
serum pregnancy test. Subjects confirmed to be pregnant will be unblinded. 
All confirmed pregnancies in subjects who received study treatment must be immediately 
reported to NBI (Section 10.4.3 for contact information), followed by fax or email of the 
pregnancy form to NBI DSPV. A first trimester ultrasound will be requested for all confirmed 
pregnancies. Pregnancies in subjects who received NBI-921352 will be followed until resolution 
(ie, termination [voluntary or spontaneous] or birth). 
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11. 
STATISTICAL METHODS 
This section is a summary of the planned statistical analyses of the endpoints. The statistical 
analysis plan (SAP) will be finalized prior to database lock and will include a more technical and 
detailed description of the analyses described in this section. 
11.1. 
Sample Size Determination 
 
 
 
 
 
The sample size estimates are based on the total number of subjects that will be included in the 
primary analysis.
 
11.2. 
Analysis Sets 
The analysis sets to be used for the analyses described in this protocol are defined in Table 8. 
Additional analysis sets may be specified in the SAP. 
Table 8: 
Analysis Sets  
Subject Analysis Set 
Description 
Full Analysis Set 
The FAS will include all subjects who are randomized, receive study 
treatment, and have post-baseline efficacy data. Subjects will be 
analyzed according to their randomized treatment group. 
Subjects in the Sentinel Cohort may be excluded from the primary 
analysis of efficacy data if changes to dosing are implemented in the 
Main Cohort. 
PK 
The PK analysis set will include all subjects who are administered 
NBI-921352, have at least 1 reportable plasma concentration value for 
NBI-921352, and do not have any important protocol deviations that 
exclude them from the PK analysis. 
Safety 
The safety analysis set will include all subjects who receive at least 
1 dose of study treatment. Subjects will be analyzed according to their 
randomized treatment group, unless they receive the incorrect study 
treatment for the entire treatment duration. 
FAS=full analysis set; PK=pharmacokinetics. 
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11.3. 
Endpoints 
For the endpoints below, countable motor seizures are defined as GTCS, tonic, atonic or FOS 
with noticeable motor component, and noncountable seizures include absence, myoclonic, and 
epileptic spasms. The treatment period is defined as the 
 titration period and the 
 
maintenance period combined. 
11.3.1. 
Primary 
• Percentage change from baseline in 28-day seizure frequency for countable motor 
seizures during the treatment period of the study. 
11.3.2. 
Key Secondary 
• Treatment response defined as a ≥50% decrease from baseline in 28-day seizure 
frequency for countable motor seizures during the treatment period of the study. 
11.3.3. 
Other Secondary 
• Percentage change from baseline in 28-day seizure frequency for countable motor 
seizures, during the 
 of the maintenance period. 
• Treatment response defined as a ≥25%, ≥75%, or 100% decrease from baseline in 
28-day seizure frequency for countable motor seizures during the treatment period of 
the study. 
• Treatment response defined as a ≥25%, ≥50%, ≥75%, or 100% decrease from 
baseline in 28-day seizure frequency for countable motor seizures during the 
maintenance period of the study. 
• CGIC and Parent/Caregiver GIC at each study visit during the treatment period of the 
study. 
• Change from baseline in CGIS and Parent/Caregiver GIS at each visit during the 
treatment period of the study. 
11.3.4. 
Exploratory 
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11.3.5. 
Pharmacokinetics 
• PK parameters for NBI-921352 and metabolites will be determined by standard 
noncompartmental methods. 
• Plasma concentration data for NBI-921352
 
• 
 
 
11.3.6. 
Safety 
• Incidence of adverse events and suicidality (as measured by either C-SSRS or clinical 
report of AEs of suicidality depending on subject's age and developmental level). 
• Absolute values and changes from baseline in clinical laboratory test values 
(hematology and clinical chemistry), vital signs, weight, Tanner stage, and ECG 
parameters. 
• 
 
 
11.4. 
Statistical Analyses 
Descriptive and inferential statistical methods will be used to evaluate and summarize the data 
from this study. Descriptive statistics typically refers to the number of subjects (n), mean, 
standard deviation (SD) or standard error (SE), median, first (Q1) and third (Q3) quartile, 
minimum, maximum, and confidence intervals for continuous variables; and refers to the number 
and percentage of subjects for categorical variables. Inferential statistics refers to the analysis 
results from hypothesis tests, which will be performed to assess differences between treatment 
groups (NBI-921352 and placebo). 
Statistical analyses for the study endpoints are summarized in Table 9.  
Table 9: 
Endpoints and Statistical Methods 
Endpoint 
Statistical Methodology 
Primary 
The primary endpoint is the percentage change from baseline in 
28-day seizure frequency for countable motor seizures during 
the treatment period. Percentage change from baseline will be 
calculated as ((Frequency during the treatment period – 
Frequency during baseline) ÷ Frequency during baseline) × 
100, where frequency during each period is calculated as 
(Number of seizures in the period ÷ Number of nonmissing 
days in the period) × 28. 
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Endpoint 
Statistical Methodology 
The null hypothesis is the percentage reduction from baseline in 
28-day seizure frequency during the treatment period in 
subjects treated with NBI-921352 is equal to the reduction in 
subjects treated with placebo. The null hypothesis of no 
treatment effect will be tested using a Wilcoxon rank-sum test 
(2-sided test) at the 
 significance level. An estimate of the 
median difference between NBI-921352 and placebo, 
 
, will be 
presented. 
Key Secondary 
The proportion of subjects considered treatment responders, 
defined as a ≥50% decrease from baseline in 28-day seizure 
frequency for countable motor seizures during the treatment 
period, will be summarized by treatment group and analyzed 
using Fisher’s exact test. In addition, the difference in 
proportions and the odds ratio (NBI-921352 vs. placebo) will 
be presented with 95% confidence intervals. 
Secondary 
Secondary endpoints will be compared between treatment 
groups over the 16-week treatment period using appropriate 
statistical methodology as described in the SAP. 
Safety 
A TEAE is an adverse event that started or worsened in severity 
following the first dose of study treatment. Subject incidence of 
TEAEs, serious TEAEs, TEAEs leading to discontinuation of 
study treatment, fatal TEAEs, and adverse events of special 
interest will be summarized for each treatment group by system 
organ class and preferred term. 
Clinical laboratory, vital signs, ECG, weight, height/length, 
Tanner stage, C-SSRS, 
 at baseline and 
during treatment, and the changes from baseline, will be 
summarized for each treatment group using descriptive 
statistics. The incidence of potentially clinically significant 
laboratory values will be provided. Categorical shift tables for 
selected laboratory values may also be presented. 
PK 
The plasma concentration data for NBI-921352 and metabolites 
will be summarized by sampling time point using the PK 
Analysis Set. 
 
 
 
 
 
 
 
 
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ASM=antiseizure medication; BLQ=below the level of quantification; C-SSRS=Columbia-Suicide Severity Rating 
Scale; ECG=electrocardiogram; PK=pharmacokinetics; SAP=statistical analysis plan; TEAE=treatment-emergent 
adverse event; VABS-3=Vineland Adaptive Behavioral Scales-3. 
11.4.1. 
Missing Data 
The primary and key secondary endpoints are calculated from the available data collected during 
the treatment period. Any sensitivity analyses to explore the robustness of the primary analysis 
will be specified in the SAP. Any methods of handling missing data in the secondary and 
exploratory endpoints will be specified in the SAP. 
11.4.2. 
Interim Analysis 
A review of the unblinded Sentinel Cohort data (including safety, tolerability, and PK data [PK 
data will only be assessed at 
 will be conducted by the independent DMC. The DMC 
will also conduct an ongoing review of safety and tolerability data for both the Sentinel and Main 
Cohorts. The DMC has the overall responsibility of safeguarding the interests of the subjects by 
monitoring data obtained in the study and making appropriate recommendations based on the 
reported data, thus ensuring that the study is being conducted with high scientific and ethical 
standards. Provisions will be in place to maintain the blinding of Sponsor study personnel. The 
DMC charter will describe the responsibilities, timing of meetings, and data review procedures 
for the members to follow. 
The first 8 subjects (randomized 1:1; ie, 4 subjects randomized to NBI-921352 and 4 subjects 
randomized to placebo) will be enrolled into the Sentinel Cohort for the analysis of safety, 
tolerability, and PK data through 
 by the DMC. Efficacy analyses will not be performed 
as part of this analysis. 
12. 
SUPPORTING DOCUMENTATION 
12.1. 
Case Report Forms 
The eCRF data for this study are being collected with an electronic data capture (EDC) system 
(Rave®) provided by Medidata Solutions Incorporated, NY, USA. The EDC system and the 
study-specific eCRFs will comply with FDA Title 21 CFR Part 11 and Articles 25, 26, 28, and 
32 of the EU GDPR. The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study specific eCRFs will be conducted 
by NBI and the required documentation will be maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
authorized study personnel in the EDC system, with the exception of data captured in an 
electronic format, which will be loaded electronically into the appropriate eCRFs. All data 
entered into the eCRF will be supported by source documentation. The investigator should 
review the eCRFs as soon as possible after the subject visit has occurred and should 
electronically sign the eCRFs as soon as possible after the subject completes or withdraws from 
the study.  
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The investigator or an authorized member of the investigator's staff will make any necessary 
additions/corrections to the eCRF. All change information, including the date, person performing 
the corrections, and reason for the change will be available via the electronic audit trail, which is 
part of the EDC system. The eCRFs will be reviewed periodically for completeness, legibility, 
and acceptability by NBI (or designee). NBI will also be allowed access to all source documents 
and medical records pertinent to the study in order to verify eCRF entries. The Principal 
Investigator will review the eCRFs for completeness and accuracy and enter his or her electronic 
signature on the eCRFs as evidence thereof. 
Medidata will provide access to the NBI portal of the EDC system for the duration of the study 
through a password-protected method of internet access. Such access will be removed from study 
centers at the end of the center’s participation in the study. Data from the EDC system will be 
archived on appropriate data media or uploaded to a secure location with restricted access, in 
order to provide the investigator with a durable record of the center’s eCRF data. Although not 
required, the investigator may make paper printouts from that media. 
All clinical work conducted under this protocol is subject to GCP regulations. This includes an 
inspection by NBI and/or health authority representatives at any time. The Principal Investigator 
will agree to the inspection of study-related records by health authority representatives and/or 
NBI. 
12.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or designee). 
Any discrepancies will be corrected on-line by authorized study center personnel. After data is 
entered into the EDC, automated (computer-generated) logic checks will run in order to identify 
items such as inconsistent study dates. In addition, manual review/checks may be performed by 
NBI on the data. Any inconsistencies/errors/omissions identified will be sent to the study center 
(via an electronic query) for the necessary corrections to be made to the eCRF. Once entered and 
saved in an eCRF, data immediately become part of the study database and are available to NBI. 
12.3. 
Coding Dictionaries 
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA), per NBI. Prior and concomitant medications will be coded 
using the chosen version of the World Health Organization Drug Dictionary, per NBI. 
12.4. 
Ethics 
The Sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, and with the 
laws and regulations of the country in which the study is conducted. 
The investigator and/or Sponsor/CRO will submit this protocol and any related document(s) to 
be provided to the subject to an IEC/IRB and to the national competent (health) authority (as 
applicable). Approval documentation (as applicable) from both the IEC/IRB and the national 
competent (health) authority must be obtained before starting the study. 
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12.5. 
General Legal References 
The study will be carried out according to provisions of the United States (US) CFR, the US 
Food and Drug Administration (FDA), the laws and regulations of the country in which the study 
is conducted, and the ICH Guidelines for GCP. All clinical work conducted under this protocol is 
subject to GCP regulations. This includes an inspection by the Sponsor or its representative, 
health authority, or IRB/IEC representatives at any time. The investigator must agree to the 
inspection of study related records by health authority representatives and/or the Sponsor or its 
designee. 
12.6. 
Institutional Review Board/Independent Ethics Committee 
The final approved protocol and the ICF will be reviewed by the IRB/IEC at the study center. 
The committee’s decision concerning conduct of the study will be sent in writing to the 
investigator and a copy will be forwarded to the Sponsor. The investigator must agree to make 
any required progress reports to the IRB/IEC, as well as reports of SAEs, life-threatening 
problems, or death. 
A list of members participating in the IEC/IRB meetings must be provided, including the names, 
qualifications, and functions of these members. If that is not possible, the attempts made to 
obtain this information along with an explanation as to why it cannot be obtained or disclosed 
must be documented in the study documentation.  
If a member of the site study personnel was present during an IEC/IRB meeting, it must be clear 
that this person did not vote. 
12.7. 
Protocol Adherence – Amendments 
The protocol must be read thoroughly, and the instructions must be followed exactly. Any 
changes in the protocol will require a formal amendment. Such amendments will be agreed upon 
and approved in writing by the investigator and the Sponsor. The IRB/IEC and local health 
authorities will be notified of all amendments to the protocol in accordance with local 
regulations. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator and/or Sponsor/CRO to the IEC/IRB and to the 
national competent (health) authority and approved prior to implementation, as applicable, in 
accordance with local procedures and regulations. 
12.8. 
Required Documents 
The investigator must provide NBI or its designee with the following documents before the 
enrollment of any subject (originals should be kept by the investigator in the investigator’s study 
regulatory document binder): 
• Signed copy of the protocol signature page. 
• Investigator’s Brochure acknowledgement page. 
• Completed and signed statement of investigator qualifications, as applicable.  
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• Financial disclosure documentation as required. 
• Curriculum vitae and current medical license of the investigator and subinvestigators. 
• Letter of approval from the IRB/IEC for protocol and consent form. 
• Copy of the IRB/IEC approved written ICF to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory. 
12.9. 
Informed Consent/Assent 
The subject’s parent(s) or legal guardian(s) will provide informed consent with signed and 
witnessed pediatric assent for subjects <18 years of age determined by the investigator to be 
capable of providing assent and for subjects ≥18 years of age who are not capable of providing 
consent according to national laws and regulations before the performance of any study related 
procedures. Subjects who are ≥18 years of age and capable of providing consent will provide 
informed consent. Informed consent/assent may be done remotely by the investigator or 
designee, only if allowed by national laws and regulations and institutional guidelines and 
remote consenting procedures are in place. 
Each subject’s chart will include the signed ICF for study participation. When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file. Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the study. 
12.10. 
Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator. This will include telephone calls and on-site visits. During the on-site visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol. As part of the data 
audit, source documents will be made available for review by the study monitor. The study 
monitor will also perform drug accountability checks and may periodically request review of the 
investigator study file to ensure completeness of documentation in all respects of clinical study 
conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period. The investigator or 
appointed delegate will receive the study monitor during these on-site visits, will cooperate in 
providing the documents for inspection, and will respond to inquiries. In addition, the 
investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
12.11. 
Quality Assurance 
The study will be conducted in accordance with NBI’s standard operating procedures designed to 
ensure that all procedures are in compliance with GCP and FDA Guidelines, and the laws and 
regulations of the country in which the study is conducted. Quality assurance audits may be 
performed at the discretion of NBI. 
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12.12. 
Record Retention 
Study records should be retained in compliance with the federal regulations of the clinical site. 
NBI may request these records to be retained for a longer period if required by applicable 
regulatory requirements or Sponsor contractual obligations. If the investigator is unable to retain 
the study documents for the required amount of time, NBI must be informed of the individual 
who will be assuming this responsibility. 
12.13. 
Confidentiality 
NBI or its designee, and the study center affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, all data will be identified only by 
an identification number. 
All information concerning this study and which was not previously published is considered 
confidential information. This confidential information shall remain the sole property of NBI; it 
shall not be disclosed to others without written consent of NBI; and shall not be used except in 
the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by NBI as deemed necessary. To allow the 
use of the information derived from this clinical study and to ensure compliance the laws and 
regulations of the country in which the study is conducted, the investigator is obliged to furnish 
NBI with the complete test results and all data compiled in this study. 
12.14. 
Publication Policy 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. Authorship will be 
determined by mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements. 
13. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Upon satisfactory receipt of all required regulatory documents, NBI (or designee) will arrange 
that all study materials be delivered to the study site. Subject entry should not begin until after 
the required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred. All personnel expected to be involved in the conduct of 
the study will undergo orientation to include review of the study protocol, instructions for eCRF 
completion, AE reporting, and overall responsibilities including those for drug accountability 
and study file maintenance. 
If the study is discontinued, all subjects should undergo a complete follow-up examination. Any 
clinically relevant finding, including laboratory values of potential clinical concern, and adverse 
experiences will be followed until they resolve or return to a clinically acceptable level. 
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14. 
 
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APPENDIX A. SCHEDULE OF ASSESSMENTS 
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Table 10: 
 
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APPENDIX B. INVESTIGATORS SIGNATURE 
CLINICAL STUDY TITLE:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of NBI-921352 as 
Adjunctive Therapy in Subjects with SCN8A Developmental and Epileptic Encephalopathy 
Syndrome (SCN8A-DEE) 
 
PROTOCOL No.: 
NBI-921352-DEE2012 
 
 
As Agreed: 
 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
 
 
Date 
 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
 
STUDY CENTER:   
 
________________________________________________________ 
(Print Study Center Name) 
 
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APPENDIX C. SPONSORS APPROVAL SIGNATURE 
Accepted for the Sponsor: 
SPONSOR: 
Neurocrine Biosciences, Inc. 
 
 
 
 
 
 
 
 
Telephone:  
 
 
 
Facsimile: 
 
 
 
________________________ 
Neurocrine Biosciences, Inc.