Long-Term, Open-Label Extension Study to Evaluate the Safety and Tolerability of NBI-827104 in Pediatric Subjects With Epileptic Encephalopathy With Continuous Spike-and-Wave During Sleep
Phase: PHASE2
Conditions: Epileptic Encephalopathy, Continuous Spike and Wave During Sleep
Sponsor: Neurocrine Biosciences

Neurocrine Biosciences, Inc. 
Study No. NBI-827104-CSWS2025 Clinical Protocol Amendment 2.0 
30 March 2023 
Confidential 
1 
Protocol Title: 
Long-Term, Open-Label Extension Study to Evaluate the 
Safety and Tolerability of NBI-827104 in Pediatric 
Subjects with Epileptic Encephalopathy with Continuous 
Spike-and-Wave During Sleep 
Protocol Identifier: 
NBI-827104-CSWS2025 
EudraCT:  
2021-006788-11 
Phase: 
Phase 2 
Sponsor: 
Neurocrine Biosciences, Inc. 
 
San Diego, CA 
 
United States 
Study Medical Director: 
 
Telephone: 
Cell Phone: 
Serious Adverse Event 
Reporting: 
Facsimile: 
Email: 
 
Protocol Amendment 
2.0 – 30 March 2023 
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. 
NCT #: NCT05301894

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Study No. NBI-827104-CSWS2025 Clinical Protocol Amendment 2.0 
30 March 2023 
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PROTOCOL AMENDMENTS  
Protocol/Amendments 
Date 
Original Protocol 
26 August 2021 
Amendment 1.0 
29 November 2021 
Amendment 1.1 
19 April 2022 
Amendment 1.2 
19 August 2022 
Amendment 2.0 
30 March 2023 
 
 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENTS .......................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................9 
1. 
SYNOPSIS .................................................................................................................12 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Background .................................................................................................................18 
2.1.1. 
Epileptic Encephalopathy with Continuous Spike-Wave Discharges During 
Sleep and Idiopathic Generalized Epilepsy ................................................................18 
2.1.2. 
NBI-827104 Clinical Experience ...............................................................................19 
2.2. 
Benefit/Risk Assessment for NBI-827104 and EECSWS ..........................................20 
3. 
OBJECTIVES .............................................................................................................22 
3.1. 
Primary .......................................................................................................................22 
3.2. 
 ...........................................................................................................................22 
4. 
STUDY DESIGN .......................................................................................................22 
4.1. 
Overall Study Design ..................................................................................................22 
4.1.1. 
Screening Period .........................................................................................................23 
4.1.2. 
Dose Titration Period (Dose Level 1 through Dose Level 3) .....................................24 
4.1.3. 
Long-Term Treatment Periods (A, B, and C) .............................................................24 
4.1.4. 
Dose Taper Period ......................................................................................................25 
4.1.5. 
Study Treatment Discontinuation ...............................................................................26 
4.1.6. 
Safety Follow-Up Period ............................................................................................26 
4.2. 
Interim Analysis ..........................................................................................................26 
4.3. 
Rationale for Dose Selection ......................................................................................27 
4.4. 
End of Study Definition ..............................................................................................27 
5. 
 .............................................................................................29 
5.1. 
 
 ............................................................................................29 
5.1.1. 
 ........................................................................................................29 
5.1.2. 
 .......................................................................................................30 
5.2. 
 
 .........................................31 
5.2.1. 
 ........................................................................................................31 
5.2.2. 
 .......................................................................................................32 

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6. 
STUDY TREATMENT ..............................................................................................34 
6.1. 
General Information ....................................................................................................34 
6.2. 
Study Treatment Administration ................................................................................35 
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. 
Procedures for Overdose .............................................................................................35 
7. 
SUBJECT RESTRICTIONS ......................................................................................36 
7.1. 
Prior and Concomitant Medications ...........................................................................36 
7.2. 
Dietary and Other Restrictions ...................................................................................37 
8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL ........................................................................................................38 
8.1. 
Discontinuation of Study Treatment ...........................................................................38 
8.2. 
Withdrawal from Study ..............................................................................................39 
8.3. 
Sponsor’s Termination or Suspension of Study or Study Site ...................................40 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
9.1. 
 .................................................................................................40 
9.1.1. 
 ....................................................................40 
9.1.2. 
 ....................................................................................................41 
9.1.3. 
 ......................................................................41 
9.1.4. 
 .......................................................................41 
9.1.5. 
 ....................................................................41 
9.1.6. 
 ..................................................42 
9.1.6.1. 
 
 ....................................................................42 
9.1.6.2. 
 
.....................................................................42 
9.1.6.3. 
 
 ...................................................................42 
9.1.6.4. 
 
 ....................................................................43 
9.1.6.5. 
 ....................................................................................................43 
9.1.7. 
 .................................................................................................43 

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9.1.7.1. 
 
 
 .....................................................................................................................43 
9.1.7.2. 
 .............................................................45 
9.1.7.3. 
 ....................................................45 
9.1.8. 
 .........................................................................45 
9.2. 
 ....................................................................................46 
9.3. 
Safety Assessments .....................................................................................................46 
9.3.1. 
Medical History ..........................................................................................................46 
9.3.2. 
Body Weight ...............................................................................................................47 
9.3.3. 
Physical and Neurological Examination Including Height/Length and Tanner 
Staging ........................................................................................................................47 
9.3.4. 
 ............................................................................................47 
9.3.5. 
Vital Sign Measurements ............................................................................................47 
9.3.6. 
Electrocardiogram .......................................................................................................48 
9.3.7. 
Clinical Laboratory Assessments ...............................................................................48 
9.3.8. 
Estimated Maximum Total Blood Sample Volume ....................................................49 
9.3.9. 
Columbia-Suicide Severity Rating Scale ....................................................................49 
9.4. 
Specific Study Period Information .............................................................................50 
9.4.1. 
Screening Period 
 ..............................................................................50 
9.4.1.1. 
Diagnosis Confirmation Panel ....................................................................................51 
9.4.2. 
Treatment Period 
 
 ............................................................................................................................51 
9.4.2.1. 
Dose Titration Period 
 .........................................................................51 
9.4.2.2. 
Long-Term Treatment Periods A, B, and C 
 
 .............................................................................51 
9.4.3. 
Dose Taper Period 
 
 ............................................................................................................................52 
9.4.4. 
Safety Follow-Up Period 
 
 .................................................................................................................53 
9.4.4.1. 
Safety Follow-Up Call 
 ......................................53 
9.4.4.2. 
End of Study 
 .....................................................53 
10. 
ADVERSE EVENTS ..................................................................................................54 
10.1. 
Definition ....................................................................................................................54 

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10.1.1. 
Intensity of Adverse Events ........................................................................................55 
10.1.2. 
Relationship to Study Treatment ................................................................................55 
10.2. 
Recording Adverse Events .........................................................................................56 
10.3. 
Poststudy Follow-Up of Adverse Events ....................................................................56 
10.4. 
Serious Adverse Events ..............................................................................................56 
10.4.1. 
Definition of a Serious Adverse Event .......................................................................57 
10.4.2. 
Managing Serious Adverse Events .............................................................................57 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................57 
10.4.4. 
Expedited Safety Reports ...........................................................................................58 
10.5. 
Urgent Safety Measures ..............................................................................................58 
10.6. 
Pregnancy ...................................................................................................................58 
11. 
STATISTICAL METHODS .......................................................................................60 
11.1. 
Statistical Hypothesis ..................................................................................................60 
11.2. 
Sample Size Determination ........................................................................................60 
11.3. 
Analysis Sets ...............................................................................................................60 
11.4. 
Endpoints ....................................................................................................................60 
11.4.1. 
Primary (Safety) ..........................................................................................................61 
11.4.2. 
 ...........................................................................................................................61 
11.4.2.1. 
 .............................................................................................................61 
11.4.2.2. 
 ..........................................................................................................61 
11.4.2.3. 
 ...........................................................................................61 
11.5. 
Statistical Analyses .....................................................................................................61 
11.5.1. 
 .......................................................................................................62 
11.5.2. 
Safety Analyses ..........................................................................................................62 
11.5.3. 
 ..........................................................................................62 
11.6. 
Interim Analyses .........................................................................................................62 
11.6.1. 
Data Monitoring Committee .......................................................................................62 
11.6.2. 
Interim Analysis ..........................................................................................................63 
12. 
SUPPORTING DOCUMENTATION........................................................................64 
12.1. 
Case Report Forms .....................................................................................................64 
12.2. 
Data Capture, Review, and Validation .......................................................................64 

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12.3. 
Coding Dictionaries ....................................................................................................65 
12.4. 
Ethics ..........................................................................................................................65 
12.5. 
General Legal References ...........................................................................................65 
12.6. 
Institutional Review Board/Independent Ethics Committee ......................................65 
12.7. 
Protocol Adherence – Amendments ...........................................................................66 
12.8. 
Required Documents ..................................................................................................66 
12.9. 
Informed Consent/Assent ...........................................................................................66 
12.10. 
Study Monitoring ........................................................................................................66 
12.11. 
Quality Assurance .......................................................................................................67 
12.12. 
Record Retention ........................................................................................................67 
12.13. 
Confidentiality and Data Protection ...........................................................................67 
12.14. 
Publication and Disclosure Policy ..............................................................................68 
13. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................69 
14. 
REFERENCES ...........................................................................................................70 
APPENDIX A. SCHEDULES OF ASSESSMENTS .................................................................74 
APPENDIX B. INVESTIGATOR SIGNATURE ......................................................................85 
APPENDIX C. SPONSOR APPROVAL SIGNATURE ............................................................86 
 
LIST OF TABLES  
Table 1: 
 ..........................................................25 
Table 2: 
Study Treatment ..........................................................................................................34 
Table 3: 
Concomitant Medication Restrictions ........................................................................36 
Table 4: 
 ....................................................49 
Table 5: 
Dose Taper Procedure .................................................................................................52 
Table 6: 
Intensity of Adverse Events ........................................................................................55 
Table 7: 
Relationship of Adverse Events to Study Treatment ..................................................55 
Table 8: 
Contact Information for Drug Safety and Pharmacovigilance ...................................58 
Table 9: 
Analysis Sets ...............................................................................................................60 
Table 10: 
 
 ................................................................................................................75 
Table 11: 
 
.................................................................................81 

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LIST OF FIGURES  
Figure 1: 
 .............................................................................................28 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
β-hCG 
β-human chorionic gonadotropin 
 
 
AE 
Adverse event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine aminotransferase 
ASM 
Antiseizure medication 
AST 
Aspartate aminotransferase 
 
 
 
 
 
 
 
 
 
 
 
 
CaV 
Voltage-gated calcium channel subtype 
CFR 
Code of Federal Regulations 
 
 
 
 
CI 
Confidence interval 
 
 
CRO 
Contract research organization 
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSWS
Continuous spike-and-wave during sleep 
 
 
 
 
 
 
 
DCP 
Diagnosis Confirmation Panel 
DL 
Dose level 
DMC 
Data Monitoring Committee 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 

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DSPV 
Drug Safety and Pharmacovigilance 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EECSWS 
Epileptic encephalopathy with continuous spike-and-wave during sleep 
EEG 
Electroencephalogram 
 
 
ESES 
Electrical status epilepticus during sleep 
ET 
Early termination 
FOS 
Focal onset seizures 
GAERS 
Genetic absence epilepsy in rats from Strasbourg 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GTCS 
Generalized tonic clonic seizure 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus 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 
IGE 
Idiopathic generalized epilepsy 
IRB 
Institutional Review Board 
IVIG 
Intravenous immunoglobulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
NOAEL 
No observed adverse effect level 
NREM 
Nonrapid eye movement 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
QTcF 
Corrected QT interval using Fridericia’s formula 
qd 
Once a day 
REM 
Rapid eye movement 
SAE 
Serious adverse event 

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SAP 
Statistical analysis plan 
 
 
 
 
 
 
 
 
TEAE 
Treatment-emergent adverse event 
 
 
 
 
US 
United States 
 
 
VNS 
Vagus nerve stimulator 
WAG/Rij 
Wistar Albino Glaxo from Rijswijk 
 
 
 
 
 

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1. 
SYNOPSIS  
Title of study: Long-Term, Open-Label Extension Study to Evaluate the Safety and Tolerability of 
NBI-827104 in Pediatric Subjects with Epileptic Encephalopathy with Continuous Spike-and-Wave 
During Sleep 
Protocol number: NBI-827104-CSWS2025 
Phase of development: 2 
Study center(s): This study will be conducted at approximately 24 study centers in the United States 
and Europe. 
Objectives 
Primary: 
• 
To evaluate the long-term safety and tolerability of NBI-827104 in pediatric subjects with 
epileptic encephalopathy with continuous spike-and-wave during sleep (EECSWS). 
 
 
 
 
 
 
 
Study design: 
This is a Phase 2, multicenter, open-label extension, interventional study to evaluate the long-term 
safety, tolerability, 
 effectiveness of NBI-827104 in pediatric subjects with EECSWS. This 
study will enroll approximately 24 male and female subjects, who were 4 to 12 years of age (inclusive) 
at the time of enrollment in the Phase 2, multicenter, randomized, double-blind, placebo controlled, 
parallel-group Study NBI 827104 CSWS2010. These subjects may enroll directly or indirectly into this 
study, as described below. 
• 
Complete Week 12 of Study NBI-827104-CSWS2010 and enroll directly into the current 
study. The Week 12 End of Maintenance Visit for Study NBI-827104-CSWS2010 and the 
Day 1 Visit for the current study will occur at the same visit. 
• 
Complete Week 12, a 1-week dose taper if applicable, and the posttreatment safety period of 
Study NBI-827104-CSWS2010. A gap between the final visit of Study NBI-827104-
CSWS2010 and the current study is allowed. These subjects are required to undergo screening 
procedures in the current study. 
Subjects who did not participate in Study-NBI 827104-CSWS2010 may enroll if 
 
; these subjects will be 
aged 4 to 12 years (inclusive) at the time of enrollment in Study NBI-827104-CSWS2025. Subjects 
may be eligible to enter the current study if they meet the specified inclusion criteria and none of the 
exclusion criteria. Subjects who did not participate in Study NBI-827104-CSWS2010 will have their 
diagnosis confirmed by an external Diagnosis Confirmation Panel (DCP). 
Parental or legal guardian informed consent with pediatric assent from developmentally capable 
subjects must be provided for all subjects. Enrollment of eligible subjects will not be limited based on 
body weight category or age group.  
The study will consist of the following periods: 

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• 
Screening Period 
: Applicable only for subjects who do not 
enroll directly from or did not participate in Study NBI-827104-CSWS2010 
• 
Dose Titration Period 
: Titration from DL 1 to DL 3 
• 
Long-Term Treatment Period 
: Treatment at the highest tolerated dose of the 
Dose Titration Period, with the potential for up to 2 additional, sequential dose escalations as 
follows: 
− 
Long-Term Treatment Period A 
: For subjects who 
titrate to a maximum of DL 3 
− 
Long-Term Treatment Period B 
: For subjects 
who exit Long-Term Treatment Period A to escalate to DL 4 
− 
Long-Term Treatment Period C 
, if applicable: 
For subjects who exit Long-Term Treatment Period B to escalate to DL 5. Dose 
escalation to DL 5 will depend on evaluation of safety, tolerability, 
 of subjects 
who escalate to DL 4. 
• 
Dose Taper Period 
 
• 
Safety Follow-Up Period 
 
The maximum duration of an individual subject’s study participation is up to 242 weeks.  
NBI-827104 will be administered orally, once a day (qd), during the Dose Titration, Long-Term 
Treatment, and Dose Taper Periods, for a maximum treatment duration of 234 weeks. Study visits will 
occur approximately every 
 during the first 
 of the study and the first 
 
after dose escalation to DL 4 and DL 5. Thereafter, study visits will occur every 
, with 
phone calls approximately 
 after each study visit. At the end of their final Long-Term 
Treatment Period (A, B, or C), subjects will begin the Taper Period, followed by the Safety Follow-Up 
Period. 
Screening Period:  
For subjects who enroll directly from Study NBI-827104-CSWS2010, informed consent/assent may be 
provided within 28 days prior to Day 1, or on Day 1 (the same visit as the Week 12 End of 
Maintenance Visit for Study NBI-827104-CSWS2010). For subjects who do not enroll directly or who 
did not participate in Study NBI-827104-CSWS2010, informed consent/assent must be provided before 
screening assessments start. After providing parental or legal guardian informed consent with pediatric 
assent from developmentally capable subjects, subjects who do not enroll directly from Study 
NBI-827104-CSWS2010 will be screened to determine eligibility 
 before the start of 
study treatment dosing on Day 1. 
Subjects who did not previously participate in Study NBI-827104-CSWS2010 may be permitted to 
enroll in this study if
 
. 
Dose Titration Period (Dose Level 1 through Dose Level 3):  
During the Dose Titration Period, all subjects will start at DL 1 based on body weight category as 
shown in the table below. The initial weight group assignment will be based on the subject’s weight on 
Day 1. Subjects will receive the initial dose at 
 and may increase to
 and 
. Investigator discretion may be used to determine the dose titration schedule based on 
tolerability, but dose titration should be no faster than once every 
, excepting situations where 
breakthrough seizures or other safety issues are observed. Exceptions to the titration schedule for safety 
purposes should be discussed with the Medical Monitor. Titration to DLs that a subject did not tolerate 
in Study NBI-827104-CSWS2010 is permitted but not required. The site will contact the subject’s 
parent(s)/caregiver(s) at the end of each week during the Dose Titration Period to assess tolerability. If 

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a subject cannot tolerate a dose after dose titration, they can receive the previously tolerated DL and 
remain at that DL for up to 
 in Long-Term Treatment Period A. Subjects who cannot tolerate 
the lowest allowable dose (ie, DL 1) will discontinue study treatment and be withdrawn from the study. 
 
 
Long-Term Treatment Periods (A, B, and C): 
Subjects who tolerate DL 3 for at least 
 will return to the study site as soon as feasible on 
 to increase their dose to DL 4 and initiate Long-Term Treatment Period B 
 
). Subjects who do not tolerate DL 3 or who are otherwise not candidates for dose escalation to 
DL 4 will continue in Long-Term Treatment Period A 
 at their highest tolerated DL 
(DL 1 to 3) until the 
 End of Long-Term Treatment Visit or early termination (ET). 
 
 
 If the data support an increase to DL 5, the maximum DL for the study will be 
increased to DL 5 
. Thereafter, subjects who 
have tolerated DL 4 for at least 1 week will return to the study site to escalate to DL 5 and initiate 
Long-Term Treatment Period C 
. Subjects who did not tolerate DL 4 or who are 
otherwise not candidates for dose escalation to DL 5 will continue in Long-Term Treatment Period B at 
their highest tolerated DL (DL 1 to 4) until the 
 End of Long-Term Treatment Visit or ET. If 
the maximum DL for the study is not increased to DL 5, subjects who escalated to DL 4 will continue 
with Long-Term Treatment Period B at their highest tolerated DL (DL 1 to 4) until the 
 End 
of Long-Term Treatment Visit or ET.  
Throughout the Long-Term Treatment Period (A, B, or C), subjects will maintain their highest 
tolerated dose until the end of study treatment. During Long-Term Treatment Period A, study treatment 
dose may be increased or decreased by 1 DL 
 within the subject’s body weight category as 
needed based on investigator assessment of safety, tolerability, or efficacy, up to DL 3. During 
Long-Term Treatment Period B or C, if a subject cannot tolerate the dose escalation to DL 4 and 5, 
respectively, the subject may receive the next lower tolerated DL and should remain at that dose until 
. After 
, the dose may be increased or decreased by 1 DL 
 within the 
subject’s body weight category as needed based on safety, tolerability, or efficacy, up to the maximum 
approved DL. A subject's dose may not exceed the allowable maximum dose for their body weight 
category (see table).  
Initiation or adjustments of concomitant ASMs, vagus nerve stimulator (VNS) settings, and/or a 
ketogenic diet are not allowed for 
 of study 
treatment. Usage of steroids and/or intravenous immunoglobulin (IVIG) are not allowed for 
 
prior to screening (or Day 1 for subjects who enrolled directly from Study NBI-827104-CSWS2010) 
and through the first 
 of study treatment. After the first 
 of study treatment and through 

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 (A, B, or C), initiation or adjustment of concomitant ASMs, VNS settings, ketogenic diet, 
steroids, and/or IVIG will require prior consultation with the Medical Monitor. After 
 (A, B, or 
C), these treatments may be increased, decreased, stopped, or started based on investigator assessment 
with parent/caregiver input and additional consultation with the Medical Monitor is not required.  
Dose Taper Period: 
At the end of their final Long-Term Treatment Period (A, B, or C), subjects will enter an up to 
 
Dose Taper Period to avoid potential withdrawal seizures due to abrupt treatment discontinuation 
(Marciani et al., 1985). The dose of study treatment will be reduced by 1 DL every 
. 
Subjects receiving DL 1 or DL 2 at the end of their final Long-Term Treatment Period will not require 
dose tapering and will enter the Safety Follow-Up Period after completing the Long-Term Treatment 
Period. 
Study Treatment Discontinuation: 
Subjects receiving DL 3 or higher who discontinue study treatment at any time before the end of their 
final Long-Term Treatment Period (A, B, or C) should undergo dose de-escalation if appropriate to 
avoid potential withdrawal seizures due to abrupt treatment discontinuation. The subject’s current dose 
would be reduced, based on the investigator’s judgment and medical urgency, in a stepwise manner 
over a period of up to 
. Guidance for implementing a more rapid de-escalation will be provided 
as needed to the investigator by the Medical Monitor on an individual basis based on clinical judgment. 
Subjects who prematurely discontinue study treatment should complete ET assessments as soon as 
feasible, undergo dose de-escalation if appropriate, and have a safety follow-up phone call and visit 
approximately 
 after the last dose of study treatment, respectively (if a subject’s last 
dose of study treatment was 
 before the ET Visit, no additional phone call is needed; if a 
subject’s last dose of study treatment was 
 before the ET Visit, no additional visit is needed). 
Subjects who discontinue study treatment will be withdrawn from the study.  
Safety Follow-Up Period: 
After the last dose of study treatment, subjects will enter a 
 Safety Follow-Up Period, which 
includes a follow-up telephone call approximately
 after the last dose of study treatment and a 
study visit approximately 
 after the last dose of study treatment. 
Study population: Up to approximately 24 male and female subjects who meet all of the inclusion and 
none of the exclusion criteria may participate in this study. Eligible subjects who participated in Study 
NBI-827104-CSWS2010 aged 4 to 12 years (inclusive) at the time of enrollment in 
Study NBI-827104-CSWS2010 may enroll directly or indirectly into this study.  
Subjects who did not participate in Study-NBI 827104-CSWS2010 may enroll if 
 
; these new subjects 
will be aged 4 to 12 years (inclusive) at the time of enrollment in Study NBI-827104-CSWS2025. 
Duration of study treatment and study participation: The maximum duration of study participation 
for each subject is up to approximately 242 weeks, including up to 234 weeks of study treatment. 
Investigational product, dosage, and mode of administration: NBI-827104 oral granules for 
sprinkle will be provided as 
 for oral administration to be taken qd
 
. 
Reference therapy, dose, and mode of administration: Not applicable 

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Endpoints 
Primary (Safety): 
• 
The occurrence of serious treatment-emergent adverse events (TEAEs). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical methods: 
Summary of safety analyses 
Subject incidence of TEAEs, serious TEAEs, TEAEs leading to discontinuation of study treatment, and 
fatal TEAEs will be summarized by system organ class and preferred term. 
Descriptive statistics will be generated for additional safety data, including clinical laboratory analytes 
(hematology and clinical chemistry, including thyroid function studies), vital signs, body weight, 
electrocardiogram parameters, and Children’s C-SSRS. 
 
 
 
 

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Plasma NBI-827104 concentrations will be summarized by DL and timepoint overall and by body 
weight category using arithmetic mean, minimum (min), median, maximum (max), SD, standard error 
(SE), and two-sided 95% CI of the mean. 
 
 
 
 
 

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2. 
INTRODUCTION  
2.1. 
Background  
2.1.1. 
Epileptic Encephalopathy with Continuous Spike-Wave Discharges During 
Sleep and Idiopathic Generalized Epilepsy  
Calcium is an important signal transduction element in neurons and its entry into the cell is 
tightly regulated by 2 major classes of voltage-gated calcium channels: the high-voltage 
activated (L-, N-, P/Q- and R-types) and the low-voltage activated (T-type) calcium channels 
(Catterall et al., 2005). Three T-type calcium channel subtypes with different 
electrophysiological properties have been described: voltage-gated calcium channel subtype 
(CaV)3.1, CaV3.2 and CaV3.3 (Lee et al., 1999; Perez-Reyes, 2003) and are widely expressed in 
the brain (Talley et al., 1999). Under physiological conditions, T-type calcium channels promote 
cellular rebound bursting by de-inactivating during hyperpolarization and opening at low-voltage 
thresholds. With their high expression levels in both cortex and thalamus (Talley et al., 1999), 
these channels are positioned to regulate synchronized oscillations within the thalamocortical 
circuit (Cheong and Shin, 2013, Lambert et al., 2014). 
Abnormal T-type calcium channel-mediated oscillations can be observed during idiopathic 
generalized epilepsy (IGE) seizures, in particular absence seizures that are characterized by 
spike-wave discharges, in both humans and animals (Khosravani and Zamponi, 2006; 
Zamponi et al., 2010; Cheong and Shin, 2013). The role of T-type calcium channels in 
generating spike-wave discharges in the cortico-thalamocortical network in absence seizures is 
well described. Mutations were identified in the gene expressing the CaV3.2 subtype in patients 
with childhood absence epilepsy and other forms of IGE (Khosravani and Zamponi, 2006; 
Heron et al., 2007; Zamponi et al., 2010; Eckle et al., 2014). Several of these mutations increase 
the intrinsic activity of the channels, whereas others increase the intracellular trafficking of the 
channels to the plasma membrane; most mutations enhance calcium currents. A direct 
consequence of this is increased excitability in neurons that exhibit enhanced bursting activity, 
thereby contributing to the generation of epileptiform discharges. Several rodent models confirm 
the importance of the CaV3.2 channel subtype. In genetic rat models of spontaneous absence-like 
epilepsy (genetic absence epilepsy in rats from Strasbourg [GAERS]; Wistar Albino Glaxo from 
Rijswijk [WAG/Rij]), a gain-of-function mutation of the CaV3.2 gene has been reported 
(Powell et al., 2009), as well as elevated levels of CaV3.2 mRNA, and increased T-type calcium 
currents (Tsakiridou et al., 1995; Talley et al., 2000; Broicher et al., 2008; Powell et al., 2009). 
Several lines of evidence also link mutations in the CaV3.1 subtype with epilepsy in humans and 
in rodent animal models. Genetic variants have been detected in patients with juvenile myoclonic 
epilepsy, another form of IGE (Lory and Mezghrani, 2010). Overexpression of CaV3.1 channels 
in mice leads to frequent bilateral cortical seizures (Ernst et al., 2009) and CaV3.1 knockout mice 
are protected from absence seizures (Kim et al., 2001; Song et al., 2004). No association has 
been made so far between CaV3.3 subtype mutations and human epilepsy. 
Disruptions in the neurotransmission of the same corticothalamocortical circuitry involved in 
absence seizures are considered to contribute also to sleep-potentiated continuous spike-wave 
discharges observed in epileptic encephalopathy with continuous spike-and-wave during sleep 

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(EECSWS) (Sánchez Fernández et al., 2012; Singhal and Sullivan, 2014). EECSWS is a 
spectrum of epileptic conditions (ILAE, 2020) sharing the following characteristics: 
(1) electroclinical seizures, (2) sleep potentiation of epileptiform activity, (3) neurocognitive 
regression/stagnation, and (4) an age-related evolution of the condition, with onset in early 
childhood and spontaneous improvement before puberty (Sánchez Fernández et al., 2012; 
De Giorgis et al., 2017; Singhal and Sullivan, 2014). The sleep potentiation of epileptiform 
activity leads to an electroencephalogram (EEG) pattern of electrical status epilepticus during 
sleep (ESES), which consists of continuous spike-waves during nonrapid eye movement 
(NREM) sleep. This phenomenon has been suggested to interfere with normal recuperation 
functions of sleep, thereby adversely affecting learning abilities, language, memory, and other 
cognitive domains (Bölsterli et al., 2011; Bölsterli Heinzle et al., 2014; Bölsterli et al., 2017). 
Although the clinical seizures and ESES disappear with age (around puberty) 
(Morikawa et al., 1989; Saltik et al., 2005; Kobayashi et al., 2006; Loddenkemper et al., 2011), 
neurocognitive regression can remain (Singhal and Sullivan, 2014; Tassinari et al., 2000; 
Nickels and Wirrell, 2008). Some have suggested that neuronal loss may occur in EECSWS, 
explaining both the resolution of seizures and ESES in adolescence but the persistence of 
cognitive disability (Kessi et al., 2019). This has been supported by magnetic resonance imaging 
volumetric analysis of neocortical regions and subcortical substructures in patients with 
Landau-Kleffner syndrome. Such analysis has revealed volumetric reductions in bilateral 
superior temporal areas, particularly the planum temporale and superior temporal gyrus 
(Takeoka et al., 2004). The extent of the neurocognitive regression seems to correlate with the 
duration a child had been affected by ESES (Seegmüller et al., 2012; Maltoni et al., 2016; 
van den Munckhof et al., 2018). 
2.1.2. 
NBI-827104 Clinical Experience  
NBI-827104 (formerly ACT-709478) is a novel selective and orally available triple T-type 
calcium channel blocker. 
 
 
 Considering the role of T-type calcium channels in 
the pathophysiology of IGE and spike-wave discharges in particular, the nonclinical data, and the 
unmet medical need, NBI-827104 is being developed for the treatment of EECSWS. 
Study NBI-827104-CSWS2010 was a Phase 2, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the efficacy, safety, tolerability, and PK of 
NBI-827104 in pediatric subjects with EECSWS reviewed and approved by an external 
Diagnosis Confirmation Panel (DCP).
 
 
 For subjects who enroll directly 
from Study NBI-827104-CSWS2010 to the current Study NBI-827104-CSWS2025, subjects will 
have completed 12 weeks of either placebo or NBI-827104 study treatment 
 
 in Study NBI-827104-CSWS2010. For subjects who do not enroll 
directly, with a gap between the 2 studies, subjects will have completed 12 or 13 weeks of either 

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placebo or NBI-827104 study treatment 
 
 and a 
 posttreatment safety period in 
Study NBI-827104-CSWS2010. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A complete summary of the available clinical and nonclinical data for NBI-827104 is provided in 
the Investigator’s Brochure. 
2.2. 
Benefit/Risk Assessment for NBI-827104 and EECSWS  
EECSWS is a spectrum of epileptic conditions (ILAE, 2020) with onset in early childhood and 
include sleep potentiation of epileptiform activity. The potentiation of epileptiform activity 
during sleep leads to an EEG pattern of ESES, which consists of continuous spike-waves during 
NREM sleep and has been suggested to interfere with normal recuperation functions of sleep, 
thereby adversely affecting learning abilities, language, memory, and other cognitive domains 
(Bölsterli et al., 2011; Bölsterli Heinzle et al., 2014; Bölsterli et al., 2017). Although spontaneous 
improvement before puberty is observed with EECSWS, neurocognitive regression can remain 
(Singhal and Sullivan, 2014; Tassinari et al., 2000; Nickels and Wirrell, 2008). This has been 
postulated by some to be secondary to neuronal loss (as suggested by volumetric analysis in 
certain patients with Landau-Kleffner syndrome) (Kessi et al., 2019; Takeoka et al., 2004). 
However, the definitive mechanisms underlying the continued neurocognitive regression have 
not been fully elucidated. 
Abnormal T-type calcium channel oscillations have been implicated in the pathophysiology of 
IGE and spike-wave discharges, in particular.
 
 
Study NBI-827104-CSWS2010 is the first clinical study to evaluate efficacy 
of NBI‑827104 in pediatric subjects with EECSWS, and the current study is an open-label 
extension of Study NBI-827104-CSWS2010. 

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 Overall, the nonclinical and clinical data, including safety, PK, 
and PD data available to date support the doses, dose titration paradigm, and duration of 
treatment in the current study. Further descriptions of nonclinical and clinical safety findings and 
the reference safety information for NBI-827104 are provided in the current version of the 
Investigator’s Brochure. 
ASMs can be associated with potential risks, including cardiovascular effects, central nervous 
system effects, an increased risk of suicidal thoughts or behavior, and hypersensitivity reactions. 
The current study includes vital sign assessments and centrally read 12-lead electrocardiograms 
(ECGs) throughout the study to monitor for cardiovascular abnormalities. 
There are no approved treatments for pediatric patients with EECSWS. Considering the role of 
T-type calcium channels in the pathophysiology of spike-wave discharges, the nonclinical and 
clinical data, and the unmet medical need, NBI-827104 is being developed for the treatment of 

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pediatric subjects with EECSWS. The study includes appropriate safety monitoring throughout 
the study, including assessment of suicidal behavior and ideation using the Children’s 
Columbia-Suicide Severity Rating Scale (C-SSRS) as appropriate 
 
 as noted above. An external, independent Data Monitoring Committee (DMC) will 
review safety and tolerability data in accordance with the DMC charter throughout the study. 
3. 
OBJECTIVES  
3.1. 
Primary  
The primary objective for this study is to evaluate the long-term safety and tolerability of 
NBI-827104 in pediatric subjects with EECSWS. 
3.2. 
  
 
 
 
 
 
 
 
 
 
4. 
STUDY DESIGN  
4.1. 
Overall Study Design  
This is a Phase 2, multicenter, open-label extension, interventional study to evaluate the 
long-term safety, tolerability, 
 effectiveness of NBI-827104 in pediatric subjects with 
EECSWS. This study will enroll approximately 24 male and female subjects, who were 4 to 
12 years of age (inclusive) at the time of enrollment in the Phase 2, multicenter, randomized, 
double-blind, placebo controlled, parallel-group Study NBI 827104 CSWS2010. These subjects 
may enroll directly or indirectly into this study, as described below. 
• Complete Week 12 of Study NBI-827104-CSWS2010 and enroll directly into the 
current study. The Week 12 End of Maintenance Visit for Study NBI-827104-
CSWS2010 and the Day 1 Visit for the current study will occur at the same visit. 
• Complete Week 12, a 1-week dose taper if applicable, and the posttreatment safety 
period of Study NBI-827104-CSWS2010. A gap between the final visit of Study 
NBI-827104-CSWS2010 and the current study is allowed. These subjects are 
required to undergo screening procedures in the current study. 
Subjects who did not participate in Study-NBI 827104-CSWS2010 may enroll if 
 
; these subjects 

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will be aged 4 to 12 years (inclusive) at the time of enrollment in Study 
NBI-827104-CSWS2025. Subjects may be eligible to enter the current study if they meet the 
specified inclusion and none of the exclusion criteria. Subjects who did not participate in Study 
NBI-827104-CSWS2010 will have their diagnosis confirmed by an external DCP. 
Parental or legal guardian informed consent with pediatric assent from developmentally capable 
subjects must be provided for all subjects. Enrollment of eligible subjects will not be limited 
based on body weight category or age group.  
The study will consist of the following periods: 
• Screening Period 
: Applicable only for subjects who do 
not enroll directly from or did not participate in Study NBI-827104-CSWS2010 
• Dose Titration Period 
: Titration from DL 1 to DL 3 
• Long-Term Treatment Period 
): Treatment at the highest tolerated 
dose of the Dose Titration Period, with the potential for up to 2 additional, sequential 
dose escalations as follows: 
− Long-Term Treatment Period A 
: For subjects 
who titrate to a maximum of DL 3 
− Long-Term Treatment Period B 
: For 
subjects who exit Long-Term Treatment Period A to escalate to DL 4 
− Long-Term Treatment Period C 
, if 
applicable: For subjects who exit Long-Term Treatment Period B to escalate to 
DL 5. Dose escalation to DL 5 will depend on evaluation of safety, tolerability, 
 of subjects who escalate to DL 4. 
• Dose Taper Period 
 
• Safety Follow-Up Period 
 
The maximum duration of an individual subject’s study participation is up to 242 weeks.  
NBI-827104 will be administered orally qd during the Dose Titration, Long-Term Treatment, 
and Dose Taper Periods, for a maximum treatment duration of 234 weeks. Study visits will occur 
approximately every 
 during the first 
 of the study and the first 
 
after dose escalation to DL 4 and DL 5. Thereafter, study visits will occur every 
, 
with phone calls approximately 
 after each study visit. At the end of their final 
Long-Term Treatment Period (A, B, or C), subjects will begin the Taper Period, followed by the 
Safety Follow-Up Period. Study visits are shown Figure 1 and in the Schedules of Assessments 
in Table 10 and Table 11.  
4.1.1. 
Screening Period  
For subjects who enroll directly from Study NBI-827104-CSWS2010, informed consent/assent 
may be provided within 28 days prior to Day 1, or on Day 1 (the same visit as the Week 12 End 
of Maintenance Visit for Study NBI-827104-CSWS2010). For subjects who do not enroll 
directly or who did not participate in Study NBI-827104-CSWS2010, informed consent/assent 

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must be provided before screening assessments start. After providing parental or legal guardian 
informed consent with pediatric assent from developmentally capable subjects, subjects who do 
not enroll directly from Study NBI-827104-CSWS2010 will be screened to determine eligibility 
 before the start of study treatment dosing on Day 1. 
Subjects who did not previously participate in Study NBI-827104-CSWS2010 may be permitted 
to enroll in this study if 
 
.  
4.1.2. 
Dose Titration Period (Dose Level 1 through Dose Level 3)  
During the Dose Titration Period, all subjects will start at DL 1 based on body weight category 
shown in Table 1. The initial weight group assignment will be based on the subject’s weight on 
Day 1. Subjects will receive the initial dose at 
 and may increase to 
 
 and 
. Investigator discretion may be used to determine the dose titration 
schedule based on tolerability, but dose titration should be no faster than once every 
, 
excepting situations where breakthrough seizures or other safety issues are observed. Exceptions 
to the titration schedule for safety purposes should be discussed with the Medical Monitor. 
Titration to DLs that a subject did not tolerate in Study NBI-827104-CSWS2010 is permitted but 
not required. The site will contact the subject’s parent(s)/caregiver(s) at the end of each week 
during the Dose Titration Period to assess tolerability. If a subject cannot tolerate a dose after 
dose titration, they can receive the previously tolerated DL and remain at that DL for up to 
 in Long-Term Treatment Period A. Subjects who cannot tolerate the lowest allowable 
dose (ie, DL 1) will discontinue study treatment and be withdrawn from the study. 
4.1.3. 
Long-Term Treatment Periods (A, B, and C)  
Subjects who tolerate DL 3 for at least 
 will return to the study site as soon as feasible on 
 to increase their dose to DL 4 and initiate Long-Term Treatment Period B 
 
 (Table 11). Subjects who do not tolerate DL 3 or who are otherwise not candidates for 
dose escalation to DL 4 will continue in Long-Term Treatment Period A 
 at 
their highest tolerated DL (DL 1 to 3) until the 
 End of Long-Term Treatment Visit or 
early termination (ET) (Table 10). 
 
 
If the data support an increase to DL 5, the maximum 
DL for the study will be increased to DL 5 
 
 Thereafter, subjects who have tolerated DL 4 for at least 1 week will return to the 
study site to escalate to DL 5 and initiate Long-Term Treatment Period C 
 
. Subjects who did not tolerate DL 4 or who are otherwise not candidates for dose escalation 
to DL 5 will continue in Long-Term Treatment Period B at their highest tolerated DL (DL 1 to 4) 
until the 
 End of Long-Term Treatment Visit or ET. If the maximum DL for the study 
is not increased to DL 5, subjects who escalated to DL 4 will continue with Long-Term 
Treatment Period B at their highest tolerated DL (DL 1 to 4) until the 
 End of Long-
Term Treatment Visit or ET.  

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Throughout the Long-Term Treatment Period (A, B, or C), subjects will maintain their highest 
tolerated dose until the end of study treatment. During Long-Term Treatment Period A, study 
treatment dose may be increased or decreased by 1 DL 
 within the subject’s body weight 
category as needed based on investigator assessment of safety, tolerability, or efficacy, up to 
DL 3. During Long-Term Treatment Period B or C, if a subject cannot tolerate the dose 
escalation to DL 4 and 5, respectively, the subject may receive the next lower tolerated DL and 
should remain at that dose until 
. After 
, study treatment dose may be 
increased or decreased by 1 DL 
 within the subject’s body weight category as needed 
based on investigator assessment of safety, tolerability, or efficacy, up to DL 4 (Long-Term 
Treatment Period B) or DL 5 (Long-Term Treatment Period C). A subject's dose may not exceed 
the allowable maximum dose for their body weight category (Table 1).  
It is anticipated that during the course of the study, subjects may change weight groups. Subjects 
will begin each DL based on their body weight category as shown in the table above; however, 
once a subject is on a stable dose, an increase in body weight will not automatically trigger a 
change in dose if a subject changes weight groups. If the investigator determines a dose change 
is indicated based on safety, tolerability, or efficacy considerations, a subject’s dose may be 
adjusted to an approved DL based on the new weight group. 
Table 1: 
  
 
Initiation or adjustments of concomitant ASMs, vagus nerve stimulator (VNS) settings, and/or a 
ketogenic diet are not allowed for 
 of study 
treatment. Usage of steroids and/or intravenous immunoglobulin (IVIG) are not allowed for 
 prior to screening (or Day 1 for subjects who enrolled directly from Study 
NBI-827104-CSWS2010) and through the first 
 of study treatment. After the first 
 of study treatment and through 
 (A, B, or C), initiation of adjustment of 
concomitant ASMs, VNS settings, ketogenic diet, steroids, and/or IVIG will require prior 
consultation with the Medical Monitor. After 
 (A, B, or C), these treatments may be 
increased, decreased, stopped, or started based on investigator assessment with parent/caregiver 
input and additional consultation with the Medical Monitor is not required. 
4.1.4. 
Dose Taper Period  
At the end of their final Long-Term Treatment Period (A, B, or C), subjects will enter an up to 
 Dose Taper Period to avoid potential withdrawal seizures due to abrupt treatment 
discontinuation (Marciani et al., 1985). The dose of study treatment will be reduced by 1 DL 

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every 
. Subjects receiving DL 1 or DL 2 at the end of their final Long-Term 
Treatment Period will not require dose tapering and will enter the Safety Follow-Up Period after 
completing the Long-Term Treatment Period. The dose taper procedure is described in 
Section 9.4.3. 
4.1.5. 
Study Treatment Discontinuation  
Subjects receiving DL 3 or higher who discontinue study treatment at any time before the end of 
their final Long-Term Treatment Period (A, B, or C) should undergo dose de-escalation if 
appropriate to avoid potential withdrawal seizures due to abrupt treatment discontinuation. The 
subject’s current dose would be reduced, based on the investigator’s judgment and medical 
urgency, in a stepwise manner over a period of up to 
. Guidance for implementing a 
more rapid de-escalation will be provided as needed to the investigator by the Medical Monitor 
on an individual basis based on clinical judgment.  
Subjects who prematurely discontinue study treatment should complete ET assessments as soon 
as feasible, and a safety follow-up phone call and visit approximately 
 after 
the last dose of study treatment, respectively (if a subject’s last dose of study treatment was 
  
 before the ET Visit, no additional phone call is needed; if a subject’s last dose of study 
treatment was 
 before the ET Visit, no additional visit is needed). Subjects who 
discontinue study treatment will be withdrawn from the study.  
4.1.6. 
Safety Follow-Up Period  
After the last dose of study treatment, subjects will enter a 
k Safety Follow-Up Period, 
which includes a follow-up telephone call approximately 
 after the last dose of study 
treatment and a study visit approximately 
 after the last dose of study treatment. 
A schematic of the study design is shown in Figure 1. Study assessments and procedures are 
described in Section 9 and will be performed according to the Schedules of Assessments 
(Table 10 and Table 11). 
4.2. 
Interim Analysis  
The Sponsor will review the safety, tolerability, 
 of NBI-827104 DL 4 to determine if the 
study will continue, with the possibility to increase the maximum dose level to DL 5. Safety, 
tolerability,
 data will be evaluated as follows:  
1. 
 
  
2. 
 
 
 
 
 
 

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An independent DMC (Section 11.6.1) will also review the safety and tolerability 
 
 and make a recommendation to the Sponsor for whether the 
study may continue per the protocol. 
4.3. 
Rationale for Dose Selection  
The available clinical data of NBI-827104 include 
 
 
The doses were considered generally well tolerated. The dose 
titration design was based on Phase 1 clinical experience that an up-titration regimen improves 
tolerability of NBI-827104.  
In Study NBI-827104-CSWS2010, the targeted exposure range (mean area under the plasma 
concentration versus time curve during a dosing interval [AUC0-τ]) of 
 was 
determined by
 
The mean AUC0-τ in pediatric 
subjects in Study CSWS2010 
 was below the targeted exposure range and was 
 
   
Therefore, DL 4, and the potential for DL 5, have been added to the current study, 
 
 
 
 
 
 
The DL 4 doses for the current study (Table 1) were calculated based on
 
(see Section 11.6.2). 
4.4. 
End of Study Definition  
Primary Completion: The primary completion date is defined as the date when the last subject 
is assessed or receives an intervention for the final collection of data used for the primary 
endpoint(s), whether the study concluded as planned or was terminated early. The planned 
primary completion date for this study is the date when the last subject has completed their 
Safety Follow-Up Visit assessments. If the study is terminated early, then the primary 
completion date will be the date of the last visit for the last subject in the study. 
End of Study: The end of study is defined as the date of the last visit of the last subject or last 
scheduled procedure shown in the Schedule of Assessments for the last subject in the study 
globally.

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Figure 1: 
  

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5. 
  
 
5.1. 
 
 
 
 
5.1.1. 
  

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5.1.2. 
  

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5.2. 
 
  
 
 
5.2.1. 
  

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5.2.2. 
  

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6. 
STUDY TREATMENT  
6.1. 
General Information  
The study treatment is summarized in Table 2. 
Table 2: 
Study Treatment  
Treatment 
Active (NBI-827104) 
Treatment administration 
Subjects will receive the initial dose at 
 and may 
increase to 
 based on 
tolerability. Subjects who tolerate DL 3 will increase to DL 4 
 If the maximum dose 
for the study is increased to DL5, subjects who tolerate DL 4 
will increase to DL 5 
  
The highest tolerated DL will be maintained through the end of 
the Long-Term Treatment Period (A, B, or C). Doses should 
not be adjusted from 
 unless 
the subject is unable to tolerate their current dose. During LT 
Treatment Period A and after 
 in LT Treatment 
Periods B and C, the dose may be increased or decreased by 
1 DL 
 within the subject’s weight group as needed based 
on safety, tolerability, or efficacy, up to the maximum 
approved DL. Subjects will undergo an 
 dose taper 
at the end of their final Long-Term Treatment Period. 
Unit dose strength 
 
Dose level 
Study treatment doses for each DL are provided for each 
weight group in Table 1. 
Dose formulation 
Oral granules for sprinkle (minitablets) for oral administration 
Route of administration 
Oral 
Sourcing 
Provided centrally by Sponsor 
Packaging and labeling 
Study treatment will be provided in
 
 
. Instructions on 
use of the device for dosing will be provided in the Pharmacy 
Manual. Each bottle will be labeled in accordance with 
applicable regulatory requirements. 
DL=dose level, LT=Long-Term. 

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6.2. 
Study Treatment Administration  
NBI-827104 will be provided as 
 to be taken
 
 
 Further 
instruction will be provided in the Pharmacy Manual. 
Information on dose titration, dose adjustments, dose de-escalation, and dose tapering is 
provided in Section 4.1. 
If a subject forgets or is unable to take the study treatment, the dose should still be taken as long 
as it is within 
 of the usual dosing time; otherwise, the study treatment should be taken at 
the next dosing time. 
6.3. 
Study Treatment Storage and Compliance  
The designated personnel are 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  
Parent(s)/caregiver(s) will bring all unused study treatment and empty packaging material to the 
center at specified study visits for study treatment accountability and reconciliation by study 
center personnel. A compliance check will be performed by weighing the container with the 
minitablets 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. 
If unused study treatment is not returned to the Sponsor or designee, alternative disposition of 
study treatment must be documented and follow local laws and regulations. 
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 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. 
Procedures for Overdose  
Any dose of NBI-827104 greater than the subject’s assigned dose within a 24-hour time period 
will be considered an overdose. 

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In the event of a suspected overdose, the investigator and/or treating physician should: 
1. Closely monitor the subject for any adverse event (AE)/serious adverse event (SAE) and 
laboratory abnormalities and follow the AE reporting process. The Study Medical 
Monitor should be contacted for AEs related to an overdose. 
2. Document the total quantity and duration of the excess dose in the electronic Case Report 
Form (eCRF). 
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 (for subjects who do not 
enroll directly from or did not participate in Study NBI-827104-CSWS2010) or Day 1 (for 
subjects who enroll directly from Study NBI-827104-CSWS2010) will be recorded on the Prior 
and Concomitant Medications page of the eCRF. 
The medications listed in Table 3 are prohibited for the duration indicated. 
Table 3: 
  

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Duration 
Prohibited/Restricted Concomitant Medication 
Within 30 days prior to screeninga 
and during the entire study 
 
 
 
Investigational treatments other than NBI-827104 received in the 
context of a clinical study, unless approved by the Sponsor. 
ACTH=adrenocorticotropic hormone; ASM=antiseizure medication; CYP=cytochrome P450; IVIG=intravenous 
immunoglobulin; VNS=vagus nerve stimulator. 
a Durations prior to screening are applicable only to subjects who do not enroll directly from Study 
NBI-827104-CSWS2010 to the current study or who did not participate in Study NBI-827104-CSWS2010. For 
subjects who enroll directly from Study NBI-827104-CSWS2010, the start of the duration of the restriction is the 
start of the subject's participation in this study (ie, Day 1) 
Rescue Medicine  
Subjects can have a 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 will be documented separately from concomitant ASMs. 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 
 and must be documented in the 
eCRF. 
ASMs  
Concomitant ASMs must be stable within 
 prior to Day 1 in the Dose Titration Period 
and through the first 
 of study treatment. After the first 
 of study treatment and 
through 
 (A, B, or C), initiation or adjustment of concomitant ASMs will require prior 
consultation with the Medical Monitor. After 
 (A, B, or C), concomitant ASMs may be 
increased, decreased, stopped, or started based on investigator assessment with parent/caregiver 
input and additional consultation with the Medical Monitor is not required. If ASMs need to be 
adjusted prior to the first 
 of study treatment for safety reasons, these exceptions must be 
discussed with the Medical Monitor.  
7.2. 
Dietary and Other Restrictions  
VNS settings and/or a ketogenic diet must be stable from 
 prior to Day 1 (for subjects 
who do not enroll directly from or participate in Study NBI-827104-CSWS2010) or Day 1 (for 
subjects who enroll directly from Study NBI-827104-CSWS2010) and through the first 
 
of study treatment (adjustments are not allowed). After the first 
 of study treatment and 
for the remainder of the study, a ketogenic diet may be started or adjusted and a VNS may be 
implanted or adjusted. 
 are prohibited from within 
 prior to 
screening (for subjects who do not enroll directly from or participate in Study NBI-827104-
CSWS2010) or Day 1 (for subjects who enroll directly from Study NBI-827104-CSWS2010) 
and until the end of the subject's participation in the study. 

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 is prohibited from within 
 prior to screening (for subjects 
who do not enroll directly from or participate in Study NBI-827104-CSWS2010) or Day 1 (for 
subjects who enroll directly from Study NBI-827104-CSWS2010) and until the end of the 
subject's participation in the study. 
Male subjects of childbearing potential must agree to refrain from donating sperm during the 
study and for 90 days after the last dose of the study treatment. 
8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL  
At any time during the study subjects or their parent(s)/legal guardian(s) can discontinue study 
treatment or withdraw their consent/assent to participate in the study. The investigator must 
discontinue study treatment or withdraw any subject from the study at their or their 
parent(s’)/legal guardian(s’) request. 
8.1. 
Discontinuation of Study Treatment  
If a subject prematurely discontinues study treatment, the investigator will record the reason for 
discontinuation on the relevant eCRF. Data for any outcome measures, particularly the primary 
and secondary endpoints, as well as safety follow-up, are important to collect as described in 
Section 8.2. Subjects receiving DL 3 or higher who discontinue study treatment at any time 
before the end of long-term treatment should undergo dose de-escalation, if appropriate, as 
described in Section 9.4.3 .  
After a Safety Follow-Up Visit, subjects will be withdrawn from the study. 
Reasons for discontinuation from study treatment include but are not limited to: 
• Withdrawal by subject or parent(s)/legal guardian(s) 
• Death 
• Lost to follow-up 
• Site termination by the Sponsor 
• Study termination by the Sponsor 
• AE 
• Pregnancy 
• Lack of efficacy 
• Protocol deviation 
• Investigator decision 
• Sponsor decision 
The investigator must discontinue study treatment if the subject experiences any of the 
following: 

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• The type, frequency, or severity of any AE becomes unacceptable/intolerable, despite 
attempts to decrease the DL. This includes AEs of seizures. Criteria for evaluating 
whether seizures should be considered AEs are provided in Section 10.1. 
• The subject is unable to tolerate the lowest allowable dose of study treatment 
(ie, DL 1). 
• QTcF of >500 msec (cardiologist verified) on any ECG tracing. 
• The subject is confirmed to be pregnant. 
• Withdrawal of consent/assent for study treatment administration by parent(s)/legal 
guardian(s) or the subject. 
• 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 Children’s C-SSRS or clinical 
impression. 
 
 
 
 
 
The investigator or the Sponsor may discontinue study treatment dosing for other reasons 
including those described below: 
• Subject develops a clinically significant laboratory (eg, ALT or AST ≥2.5 × the upper 
limit of normal) or ECG abnormality. 
• Subject requires a medication that is prohibited by the protocol. 
Every effort should be taken to obtain follow-up data for any subject who discontinues study 
treatment because of an AE, abnormal laboratory test, vital sign measurement, physical 
examination, or ECG finding. 
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 ET assessments performed as soon as feasible and, unless consent has been 
withdrawn, will be asked to have a Safety Follow-Up phone call and visit approximately 1 week 
and 4 weeks after the last dose of study treatment, respectively. If a subject’s last dose of study 
treatment was >1 week before the ET Visit, no additional phone call is needed; if a subject’s last 
dose of study treatment was >4 weeks before the ET Visit, no additional visit is needed. 
Reasons for withdrawal from the study include, but are not limited to: 
• Withdrawal by the subject or parent(s)/legal guardian(s) 
• AE 
• Death 

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• Lost to follow-up 
• Site terminated by Sponsor 
• Study terminated by Sponsor 
• Protocol deviation 
• Investigator decision 
• Sponsor 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 or suspend the entire 
study, or terminate or suspend the study at individual sites, at any time for any reason. If the 
study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRBs/IECs, 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 therapy and/or follow-up. 
9. 
STUDY ASSESSMENTS AND PROCEDURES  
A schedule of assessments is provided in Table 10 and Table 11 (Appendix A). No study 
procedures should be performed until after signed inform consent is obtained from the 
parent(s)/legal guardian(s) and pediatric assent from the subject, if applicable (which may be 
done remotely, if allowed and remote consenting 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. 
9.1. 
  
9.1.1. 
  
 
 
 
 
 
 
 
 
 
 

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9.1.2. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.3. 
  
 
 
9.1.4. 
  
 
 
 
 
 
9.1.5. 
  
 
 
 
 
 

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9.1.6. 
  
 
 
 
 
 
 
9.1.6.1. 
 
  
 
 
 
 
 
 
 
9.1.6.2. 
 
  
 
 
 
 
 
 
 
 
9.1.6.3. 
 
 
 
 
 
 

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9.1.6.4. 
 
  
 
 
 
 
 
 
 
 
9.1.6.5. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
9.1.7. 
  
 
9.1.7.1. 
 
 
  
 
 
 
 
 
 
 
 

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9.1.7.2. 
  
 
  
 
 
 
9.1.7.3. 
  
 
 
 
 
 
 
 
 
 
 
 
9.1.8. 
  
 

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9.2. 
  
 
 
  
 
 
 
 
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 described in the 
following sections will be completed at the timepoints specified in the Schedule of Assessments 
(Table 10 and Table 11). 
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. 
Clinically relevant findings occurring after informed consent and meeting the definition of an AE 
(new AE or worsening of a previously existing condition) must be recorded on an AE page of the 
eCRF. 
Appropriate psychiatric evaluation and intervention will be provided for any treatment-emergent 
suicidal behavior or clinically significant suicidal ideation. 
9.3.1. 
Medical History  
For subjects who do not enroll directly from or participate in Study NBI-827104-CSWS2010, a 
medical history will be taken at the screening visit and updated on Day 1 and as needed 
throughout the study. 
For subjects who enroll directly, a medical history will be taken to update the relevant history 
from Study NBI-827104-CSWS2010 on Day 1 and as needed throughout the study. 

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9.3.2. 
Body Weight  
Body weight will be measured at the study visits indicated in the Schedules of Assessments 
(Table 10 and Table 11). The initial weight group assignment will be based on the subject’s 
weight on Day 1. 
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, 
extremities, skin and mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph 
nodes, chest, lungs, cardiovascular, abdomen, genito-urinary, musculoskeletal, and neurological 
system, including assessment of level of consciousness, mental status, muscle strength and tone, 
coordination and gait,
 
 
. 
Height/length will be measured with subjects not wearing shoes. Height 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 physical examination schedule is provided in 
Table 10 and Table 11. 
Physical signs of puberty will be assessed using Tanner staging as appropriate based on subject 
age and stage of puberty as part of the physical examination. 
9.3.4. 
  
 
 
 
 
 
 
 
 
 
9.3.5. 
Vital Sign Measurements  
Vital signs will be measured for the following: orthostatic systolic and diastolic blood pressure, 
orthostatic pulse rate, respiratory rate, and body temperature. 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 using a calibrated 

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automatic blood pressure cuff after the subject has been supine for at least 5 minutes and after 
approximately 2 minutes standing, if possible. 
Vital sign measurements will be obtained prior to study treatment administration on Day 1 or any 
scheduled blood sample collection, where applicable, at the timepoints specified in the Schedules 
of Assessments (Table 10 and Table 11). 
9.3.6. 
Electrocardiogram  
A standard 12-lead ECG will be recorded after the subject has rested supine for at least 
5 minutes. The ECG should be performed in triplicate (at least 1 minute apart and within 
15 minutes), if possible. The ECG will be centrally read and parameters that will be assessed 
include heart rate, PR interval, QRS duration, QT interval, and QTcF (machine readings or 
calculated). 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 will provide a 
description of the abnormality recorded on the AE eCRF. 
The ECG assessment should be performed prior to study treatment administration on Day 1, and 
prior to any blood sample collection at the timepoints specified in the Schedules of Assessments. 
9.3.7. 
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 following clinical safety laboratory 
assays will be performed: 
Hematology: complete blood count including white blood cell count with differential, red blood 
cell count, hemoglobin, hematocrit, and platelet count, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, red cell distribution width, 
and mean platelet volume. 
Clinical chemistry: sodium, potassium, calcium, magnesium, phosphorus, chloride, blood urea 
nitrogen, bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate 
dehydrogenase, AST, ALT, GGT, creatine kinase, total bilirubin, total protein, glucose, 
 
. 
Urinalysis: specific gravity, nitrite, ketones, protein, urobilinogen, glucose, bilirubin, leukocyte 
esterase, occult blood, and pH; microscopic examination of sediment will be performed only if 
the results of the urinalysis dipstick evaluation are positive for nitrite, protein, leukocyte esterase, 
or blood. Urine samples may be considered optional if the subject is unable to provide urine 
(eg, subject is in a diaper). 
The following additional laboratory test will be performed at screening for subjects who do not 
enroll directly from or did not participate in Study NBI-827104-CSWS2010: 
Serology: Blood will be collected for HIV-Ab, HBsAg, and HCV-Ab and reflex nucleic acid 
amplification testing (if applicable) at screening. 
Drug screen: Urine will be collected at screening for cannabinoid drug testing. 

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Pregnancy test: Pregnancy tests will be performed throughout the study for female subjects of 
childbearing potential. A serum β-hCG pregnancy test will be performed at screening for 
subjects who do not enroll directly. A urine pregnancy test (using a urine pregnancy kit provided 
by the central laboratory) will be performed at the postscreening timepoints indicated in the 
Schedules of Assessments (Table 10 and Table 11). Female subjects who become of childbearing 
potential during the study will be required to undergo pregnancy testing at the timepoints 
indicated in the Schedule of Assessments (Table 10). Serum pregnancy tests should be 
performed if urine cannot be collected. Any positive urine pregnancy test should be confirmed 
by a serum pregnancy test. 
9.3.8. 
Estimated Maximum Total Blood Sample Volume  
The estimated maximum total blood volume for each subject collected during the study from 
screening (if applicable) to last visit (Safety Follow-Up Visit) is provided in Table 4.  
Based on the blood volumes to be collected at the scheduled study visits, the blood volume 
collected will not exceed 3% of the total blood volume during a period of 4 weeks and will not 
exceed 1% at any single time. 
Table 4: 
  
 
9.3.9. 
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 (Children’s Baseline version) and at baseline and visits throughout the study 
(Children’s Since Last Contact version). All versions of the C-SSRS include a series of screening 

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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 Children’s Version will be administered to subjects ≥6 years of age on Day 1. 
Younger subjects or subjects with developmental impairment for whom the C-SSRS would be 
inappropriate will be monitored for suicidality based on clinical impression. If the investigator is 
unable to conduct the C-SSRS screening, for example due to developmental disability, the reason 
for noncollection must be captured in the eCRF. 
The C-SSRS will be administered and scored by the investigator or qualified personnel 
throughout the study as indicated in the Schedules of Assessments (Table 10 and Table 11). 
9.4. 
Specific Study Period Information  
A complete list of study assessments to be performed at the study center during the study periods 
by visit is provided in the Schedules of Assessments (Table 10 and Table 11). 
Study visits during the Long-Term Treatment Period may be conducted remotely if individual in-
person study visits at the study site are not possible due to Corona Virus Disease 2019 (COVID 
19) related reasons (eg, subject is not able to travel to the site for safety reasons or as part of 
public health measures). In this situation, study treatment may be shipped directly to a subject. If 
any study visits during the Long-Term Treatment Period required to be conducted at the site are 
conducted via telephone or a tele-health platform, this will be documented in the source. 
Assessments at these visits that must be conducted at the site (eg, 
) may be 
rescheduled. Any visit assessments that are missed or conducted outside the visit window will be 
recorded as COVID-19 related protocol deviations. 
9.4.1. 
Screening Period 
  
After providing parental or legal guardian informed consent with pediatric assent from 
developmentally capable subjects, subjects who do not enroll directly from or participate in 
Study NBI-827104-CSWS2010 will be screened to determine eligibility between 
 
 that may be completed in 1 or more visits. 
At least 4 days of baseline 
 data should be collected during the Screening Period. 
During screening, parent(s)/caregiver(s) of subjects who do not enroll directly from or participate 
in Study NBI-827104-CSWS2010 will be instructed or retrained by site personnel on how to 
self-administer the
 at study visits. 
All screening procedures must be completed, and results must be evaluated by the investigator 
before the procedures are performed on Day 1. 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 did not participate in Study NBI-827104-CSWS2010 and who do not meet 
inclusion criterion #2 and #3 (Section 5.2.1) at their initial screening in Study NBI-827104-
CSWS2025 will not be eligible for rescreening. 

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9.4.1.1. 
Diagnosis Confirmation Panel  
For subjects who did not participate in Study NBI-827104-CSWS2010, an external DCP will 
review and confirm that the subject meets the clinical diagnosis of EECSWS to determine study 
eligibility prior to Day 1. Medical history information, as well as any further medical information 
supporting the diagnosis if available (including the screening 
), will be 
provided to the DCP to review to confirm the diagnosis. A DCP charter will describe the 
responsibilities and data review procedures. 
9.4.2. 
Treatment Period 
  
9.4.2.1. 
Dose Titration Period 
  
Subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible to be 
enrolled into the study on Day 1. 
For subjects who enroll directly from Study NBI-827104-CSWS2010, informed consent/assent 
will be provided on Day 1 or within 28 days prior to Day 1 before any assessments are 
performed for the current study. Medical history from Study NBI-827104-CSWS2010 will be 
updated. Parent(s)/caregiver(s) will be instructed on how to self-administer the 
 on Day 1 only if they were not trained during screening in 
Study NBI-827104-CSWS2010. 
For subjects who do not enroll directly from or participate in Study NBI-827104-CSWS2010, 
medical history will be updated from screening on Day 1 and 
 may be 
performed up to 4 days prior to Day 1. 
Vital signs, ECG, and clinical laboratory assessments should be performed before the first dose 
of study treatment is administered on Day 1. The first dose of study treatment will be taken at the 
study site. 
Subjects will begin study treatment at DL 1 based on weight group on Day 1 (Table 1). Study 
treatment dose may be increased to DL 2 and DL 3 during the Dose Titration Period based on 
investigator judgment. 
 the study site will call the 
parent(s)/caregiver(s) to assess for any AEs and determine dose titration or adjustment. 
9.4.2.2. 
Long-Term Treatment Periods A, B, and C 
 
  
Subjects may enter Long-Term Treatment Period B after completing the
 Dose Titration 
Period. Subjects who do not tolerate DL 3 or who are otherwise not candidates for dose 
escalation will continue in Long-Term Treatment Period A at their highest tolerated DL (DL 1 to 
3) until the 
 End of Long-Term Treatment Visit or ET. Dose escalation to DL 4 (and 
DL 5, if applicable) and treatment during Long-Term Treatment Periods B and C will be 
performed as described in Section 4.1.3.  
Tolerability of the subject’s currently assigned DL will be assessed at each study visit. 
Investigator assessment of tolerability will include a review of AEs and 
 data as well 
as discussion with parent(s)/caregiver(s). Confirmation that these activities have been performed 
will be indicated in the eCRF. 

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Study Site Visits  
Study assessments may be performed before or after the administration of study treatment, 
except on study visits in which dose is being changed (
) and 
 
. Subjects should withhold their study treatment on days of dose changes and 
 
 until after completion of predose assessments. Additionally, vital sign measurements 
and ECG assessments should be performed prior to any blood sample collection. 
Phone Calls  
At certain timepoints in the study, phone calls with the study site will be used to perform 
assessments as indicated in the Schedule of Assessments (Table 10 and Table 11).  
Discontinuation  
Subjects receiving DL 3 or higher who discontinue study treatment at any time before the end of 
long-term treatment should undergo dose de-escalation if appropriate to avoid potential 
withdrawal seizures due to abrupt treatment discontinuation. The subject’s current dose would be 
reduced, based on the investigator’s judgment and medical urgency, in a stepwise manner over a 
period of up to 
. Guidance for implementing a more rapid de-escalation will be provided 
as needed to the investigator by the Medical Monitor on an individual basis based on clinical 
judgment. Subjects receiving DL 1 who discontinue study treatment do not require dose de-
escalation. Subjects who discontinue study treatment will be withdrawn from the study.  
9.4.3. 
Dose Taper Period 
  
At the end of their final Long-Term Treatment Period (A, B, or C), subjects will begin the Dose 
Taper Period.  
During the Dose Taper Period, the study treatment is tapered to avoid potential withdrawal 
seizures due to abrupt treatment discontinuation and ensure all subjects have discontinued 
NBI-827104 
 as shown in Table 5. Subjects who are receiving DL 1 or 2 at 
the end of their final Long-Term Treatment Period do not need to undergo dose tapering and can 
immediately enter the Safety Follow-Up Period.  
Table 5: 
Dose Taper Procedure  
Dose Level at End of 
Long-Term 
Treatment Period 
Dose Level During Taper Period 
 
 
 
Dose Level 1 or 2 
Off treatment (start 
Safety Follow-Up)  
Not applicable (Safety Follow-Up) 
Dose Level 3 
Dose Level 2 
Off treatment (start 
Safety Follow-Up) 
Not applicable 
(Safety Follow-Up) 
Dose Level 4 
Dose Level 3 
Dose Level 2 
Off treatment (start 
Safety Follow-Up) 
Dose Level 5 
Dose Level 4 
Dose Level 3 
Dose Level 2 
 

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9.4.4. 
Safety Follow-Up Period 
 
  
9.4.4.1. 
Safety Follow-Up Call 
  
During the Safety Follow-Up Period, approximately 
 after the last dose of study treatment, 
the study site will call the parent(s)/caregiver(s) to collect AE information. 
9.4.4.2. 
End of Study 
  
The Safety Follow-Up Visit is the final study visit. 

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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 
informed consent form (ICF) (for subjects who do not enroll directly from or participate in 
Study NBI-827104-CSWS2010) or Day 1 (for subjects who enroll directly) until the subject’s 
final study visit (or upon ET). 
10.1. 
Definition  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that occurs after enrollment into the study and which does 
not necessarily have a causal relationship with the study treatment. An AE can therefore be any 
unfavorable and unintended sign (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. 
A treatment-emergent adverse event (TEAE) is an AE that started or worsened in severity 
following the first dose of study treatment. 
Adverse events 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 or parent(s)/caregiver(s) 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: 
• 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. 
• Continuous persistent disease/symptom present before study treatment administration, 
unless it unexpectedly progresses, or increases in severity following study treatment 
administration 

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• Study treatment failure or lack of efficacy 
• Pregnancy 
• Overdose of either study treatment or concomitant medication without any clinical signs 
or symptoms 
10.1.1. 
Intensity of Adverse Events  
Adverse events must be graded for intensity. An intensity category of mild, moderate, or severe, 
as defined in Table 6, 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.” 
Table 6: 
Intensity of Adverse Events  
Grade 
Intensity 
Mild 
An AE 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 AE 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 AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
AE=adverse event. 
10.1.2. 
Relationship to Study Treatment  
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study treatment using the criteria outlined in Table 7. An AE is deemed associated with the use 
of the study treatment “if there is a reasonable possibility that the treatment caused the AE” 
(otherwise referred to as a suspected adverse reaction). Reasonable possibility means there is 
evidence to suggest a causal relationship between the study treatment and the AE (Title 21 Code 
of Federal Regulations [CFR] 312.32 [a]). 
Table 7: 
Relationship of Adverse Events to Study Treatment  
Relationship 
Description 
Definite 
The AE follows a reasonable temporal sequence from administration of the study 
treatment, abates upon discontinuation of the study treatment, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears when the study 
treatment is reintroduced. 
Possible 
The AE follows a reasonable temporal sequence from administration of the study 
treatment 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 study treatment and the AE. 

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Relationship 
Description 
Unlikely 
The temporal sequence between the AE and the study treatment is such that the 
study treatment 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 
study treatment, may not abate upon discontinuation of the study treatment, does not 
follow a known or hypothesized cause-effect relationship, and (if applicable) may 
not reappear when the treatment is reintroduced, furthermore, there may exist a clear 
alternative medical explanation (eg, underlying disease state) or association with 
study procedure or study conduct. 
AE=adverse event. 
10.2. 
Recording Adverse Events  
For enrolled 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. 
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. 
Adverse events ongoing at the final visit or at ET 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 (for subjects who do not 
enroll directly from Study NBI-827104-CSWS2010) or Day 1 (for subjects who enroll directly) 
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. 

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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 preexisting 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 
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. 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events  
SAEs and pregnancies must be reported within 24 hours of first knowledge of the event by study 
personnel to Neurocrine Biosciences, Inc. (NBI) Drug Safety and Pharmacovigilance (DSPV). 
Reports of SAEs and pregnancies must be followed by a fax or email of the SAE or Pregnancy 
Form (Table 8). It is important that the investigator provides his or her assessment of relationship 
to study treatment at the time of the initial SAE report. The investigator (or designee) will also 

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notify the IRB/IEC, if necessary) of the SAE and the outcome of the SAE, as required by the 
IRB/IEC. 
Additionally, the following category of medical events that could occur during participation in a 
clinical study must be reported within 24 hours to the study Medical Monitor: 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 or clinical impression. Contact information for the study Medical Monitor will be 
provided to the study sites. 
Table 8: 
Contact Information for Drug Safety and Pharmacovigilance  
Facsimile 
 
Email 
 
10.4.4. 
Expedited Safety Reports  
The Sponsor or its representatives will submit an Expedited Safety Report for any suspected 
adverse reaction (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. 
The Sponsor 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. 
Urgent Safety Measures  
If an event occurs that is related to the conduct of the study or the development of the study 
treatment, and this new event is likely to affect the safety of subjects, the Sponsor and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard. The Sponsor will work with the investigator to ensure the IRB/IEC and local 
regulatory authority are notified within 3 days or in accordance with applicable local laws and 
regulations. 
10.6. 
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-827104 will be followed to assess for pregnancy 
outcome. Subjects of childbearing potential must be counseled at all visits to continue using 
contraception (inclusion criterion #3, Section 5.1) until 90 days after the last dose of study 
treatment. If a female subject believes she is pregnant at any time between signing the ICF and 
the last study visit, she should return to the study center within 24 hours and undergo a serum 
pregnancy test. Female subjects confirmed to be pregnant will be discontinued from the study 
treatment and withdrawn from the study. 
All confirmed pregnancies in female subjects or in female partners of male subjects who 
received study treatment must be immediately reported to NBI (contact information is provided 
in Section 10.4.3), followed by fax or email of the pregnancy form to NBI DSPV. A first 

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trimester ultrasound may be requested for all confirmed pregnancies. Pregnancies in subjects 
who received NBI-827104 will be followed until resolution (ie, termination [voluntary or 
spontaneous] or birth). 
Male subjects with female partners who become pregnant during the study must notify the study 
center as soon as possible. The study center will ask to follow the subject’s partner’s pregnancy. 

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11. 
STATISTICAL METHODS  
This section represents a brief description of the planned primary analysis of the primary and 
secondary endpoints. A comprehensive and detailed statistical analysis plan (SAP) will be 
generated and finalized prior to study database lock. The SAP will provide additional details 
regarding the methods of analysis summarized in this protocol, describe analysis methods for 
other endpoints, describe analyses to characterize the study conduct and population, and may 
describe sensitivity and supplementary analyses for selected endpoints. 
11.1. 
Statistical Hypothesis  
There will be no formal hypothesis testing of the primary endpoint. 
11.2. 
Sample Size Determination  
A total sample size of up to approximately 24 male and female subjects is based on the sample 
size of Study NBI-827104-CSWS2010. At least 12 subjects are targeted to complete Week 12 at 
the highest DL evaluated in the study. 
11.3. 
Analysis Sets  
Statistical analysis sets used in this study are defined in Table 9. Additional analysis sets may be 
specified in the SAP.  
Table 9: 
Analysis Sets  
Population 
Description 
Full analysis set  
The full analysis set will include all enrolled subjects who receive at least 
1 dose of study treatment and have any efficacy data collected after the 
Day 1 Visit. 
Safety analysis set 
The safety analysis set will include all enrolled subjects who take at least 
1 dose of study treatment. 
 
 
11.4. 
Endpoints  
For the endpoints below, 
 
. The Treatment Period includes a 
 Dose Titration 
Period. Additional endpoints may be described in the SAP. 

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11.4.1. 
Primary (Safety)  
• The occurrence of serious TEAEs.  
11.4.2. 
  
11.4.2.1. 
  
 
 
 
 
 
 
 
 
 
 
 
11.4.2.2. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4.2.3. 
  
 
 
11.5. 
Statistical Analyses  
Descriptive statistical methods will be used to summarize the data from this study. Descriptive 
statistics typically include the number of subjects (n), mean, standard deviation or standard error, 
median, first and third quartile, minimum, maximum, and CIs for continuous variables; and 
refers to the number and percentage of subjects for categorical variables. 

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Unless otherwise specified, the assessments collected at the Day 1 Visit will be used as baseline. 
 
 
 Additional 
definitions of baseline may be specified in the SAP. 
11.5.1. 
  
 
11.5.2. 
Safety Analyses  
The subject incidence of serious TEAEs, TEAEs leading to discontinuation of study treatment, 
and fatal TEAEs will be summarized using descriptive statistics. 
Additional summaries of TEAEs, including summaries by system organ class and preferred term, 
will be provided. 
Descriptive statistics will be generated for additional safety data, including selected laboratory 
analytes, vital signs, body weight, ECG parameters, and C-SSRS, which will be further described 
in the SAP. 
11.5.3. 
  
 
 
 
 
 
 
 
 
 
 
  
11.6. 
Interim Analyses  
11.6.1. 
Data Monitoring Committee  
An independent DMC will periodically review accumulating study data to avoid exposing 
subjects to excessive risk as a result of the study procedures and treatment. The DMC will 
consist of at least 3 members, including physicians and a statistician with expertise in the areas 
of clinical trials, epileptology, and biostatistics. The data review may result in recommendation 
for early termination of the study or changes to the protocol and informed consent. A DMC 
charter will describe the responsibilities, timing of meetings, and data review procedures. 

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11.6.2. 
Interim Analysis  
The Sponsor will review the safety, tolerability, 
 of NBI-827104 DL 4 to determine if the 
study will continue, with the possibility to increase the maximum dose level for the study to DL 
5
 
  
This review will guide the selection of doses for DL 5, if applicable. 
 
 
 
 
 
 
 
 
 
 
An independent DMC (Section 11.6.1) will also review the safety and tolerability data 
 
 and make a recommendation to the Sponsor for whether the 
study may continue per the protocol. 

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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 
, New York, United States (US). The EDC 
system and the study-specific eCRFs will comply with Title 21 CFR Part 11. The documentation 
related to the validation of the EDC system is available through the vendor, 
, while the 
validation of the study-specific eCRFs will be conducted by the Sponsor 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 electronically sign 
the eCRFs as soon as possible after the subject completes or discontinues from the study. 
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 the Sponsor (or designee). The Sponsor 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. 
 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 Good Clinical Practice (GCP) 
regulations. This includes an inspection by the Sponsor 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 the Sponsor. 
12.2. 
Data Capture, Review, and Validation  
Data entered in the EDC system will be verified against the source data by the Sponsor (or 
designee). Any discrepancies will be corrected on-line by authorized study center personnel. 
After data is entered into 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 the Sponsor 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 

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eCRF. Once entered and saved in an eCRF, data immediately become part of the study database 
and are available to the Sponsor. 
12.3. 
Coding Dictionaries  
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA), per the Sponsor. Prior and concomitant medications will be 
coded using the chosen version of the World Health Organization Drug Dictionary, per the 
Sponsor. 
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) 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 IRB/IEC and to the national competent (health) authority (as 
applicable). Approval documentation (as applicable) from both the IRB/IEC and the national 
competent (health) authority must be obtained before starting the study. 
12.5. 
General Legal References  
The study will be carried out according to provisions of the US CFR, the US Food and Drug 
Administration, 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 IRB/IEC 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 IRB/IEC meeting, it must be clear 
that this person did not vote. 

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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 IRB/IEC and to the 
national competent (health) authority in accordance with local procedures and regulations. 
12.8. 
Required Documents  
The investigator must provide the Sponsor 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 
• 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 ICF 
• 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 determined by the investigator to be capable of providing 
assent according to national laws and regulations before the performance of any study related 
procedures. Informed consent/assent may be done remotely, if allowed per site 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 treatment accountability checks and may periodically request review 

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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 the Sponsor’s standard operating procedures 
designed to ensure that all procedures are in compliance with GCP and the laws and regulations 
of the country in which the study is conducted. Quality assurance audits may be performed at the 
discretion of the Sponsor. 
12.12. 
Record Retention  
Study records should be retained in compliance with federal, national, and/or local regulations of 
the clinical site. 
The Sponsor 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, the Sponsor must be 
informed of the individual who will be assuming this responsibility. 
12.13. 
Confidentiality and Data Protection 
The Sponsor 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. Information technology systems used to collect, process, and 
store study-related data are secured by technical and organizational security measures designed 
to protect such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
All information concerning this study and which was not previously published is considered 
confidential information. This confidential information shall remain the sole property of the 
Sponsor; it shall not be disclosed to others without written consent of the Sponsor; 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 the Sponsor as deemed necessary. To 
allow the use of the information derived from this clinical study and to ensure compliance with 
the laws and regulations of the country in which the study is conducted, the investigator is 
obliged to provide the Sponsor with the complete test results and all data compiled in this study. 

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12.14. 
Publication and Disclosure 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. 
The Sponsor will submit study results for posting on public registry(ies) as required for 
compliance with applicable laws and/or regulations in the region(s) where the study is being 
conducted. For the purposes of study results disclosure, study completion is defined as the date 
of the last visit or procedure for the last subject in the study globally. 

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13. 
STUDY COMMENCEMENT AND DISCONTINUATION  
Upon satisfactory receipt of all required regulatory documents, the Sponsor (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 treatment 
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. 
SCHEDULES OF ASSESSMENTS  
 

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Table 10: 
 

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Table 11: 
 

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APPENDIX B. INVESTIGATOR SIGNATURE  
CLINICAL STUDY TITLE: Long-Term, Open-Label Extension Study to Evaluate the Safety 
and Tolerability of NBI-827104 in Pediatric Subjects with Epileptic Encephalopathy with 
Continuous Spike-and-Wave During Sleep 
 
PROTOCOL No.: 
NBI-827104-CSWS2025 
 
 
As Agreed: 
 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
 
 
Date 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
_________________________________________________________ 
(Print Principal Investigator Name) 
 
 
STUDY CENTER: 
 
 
________________________________________________________ 
(Print Study Center Name) 
 

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APPENDIX C. SPONSOR APPROVAL SIGNATURE  
The undersigned has reviewed and approves the content of this document. 
 
 
 
  
Electronically signed and dated 
 
 
_________________________ 
 
________________________ 
________ 
  
 
Signature 
 
 
 
Date 
Neurocrine Biosciences, Inc. 
 
San Diego, CA 
 
United States 

Signature Page for VV-CLIN-002592 v2.0
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07-Apr-2023 19:10:33 GMT+0000