Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics 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

1.
TITLE PAGE
CLINICAL STUDY PROTOCOL 
Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Assess the Efficacy, Safety, Tolerability, and 
Pharmacokinetics of NBI-827104 in Pediatric Subjects with Epileptic 
Encephalopathy with Continuous Spike-and-Wave During Sleep 
Study No.:  NBI-827104-CSWS2010 
IND 142876 
EudraCT# 2020-003141-11 
Amendment 3.0 (05 August 2021) 
Amendment 2.0 (03 May 2021) 
Amendment 1 (19 June 2020) 
Original Protocol (30 September 2019) 
Development Phase:  2 
Study Sponsor: 
Neurocrine Biosciences, Inc. 
 
 
Telephone:  
 
Facsimile:  
 
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 #: NCT04625101

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SIGNATURES: 
I agree to conduct this study in accordance with the requirements of this Clinical Study Protocol 
and in accordance with the following: 
• Established principles of International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) 
• All applicable laws and regulations 
 
CLINICAL STUDY TITLE:  Phase 2 Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Assess the Efficacy, Safety, Tolerability, and 
Pharmacokinetics of NBI-827104 in Pediatric Subjects with Epileptic Encephalopathy with 
Continuous Spike-and-Wave During Sleep 
 
PROTOCOL No.: 
NBI-827104-CSWS2010 
 
 
As Agreed: 
 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
CENTER:  
 
 
________________________________________________________ 
(Print Study Center Name) 

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Accepted for the Study Sponsor: 
STUDY SPONSOR: Neurocrine Biosciences, Inc. 
 
 
 
 
 
 
 
Telephone:  
 
 
Facsimile: 
 
 
__________________________________ 
 
 
 
 

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LIST OF PERSONNEL 
Neurocrine Biosciences, Inc. 
 
 
 
 
Telephone: 
 
Cell Phone: 
 
 
 
Telephone: 
 
 
Serious Adverse Event Reporting: 
Telephone: 
 
Facsimile: 
 
Email: 
 

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2. 
SYNOPSIS 
Title of study:  Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of NBI-827104 in Pediatric Subjects with 
Epileptic Encephalopathy with Continuous Spike-and-Wave During Sleep 
Protocol number:  NBI-827104-CSWS2010 
Phase of development:  2 
Study center(s):  Approximately 24 study centers in regions including, but not limited to, the United States, 
Europe, and Canada 
Primary Objective:  
• 
To assess the effect of NBI-827104 on the overnight epileptiform video-electroencephalogram 
(video-EEG) activity in pediatric subjects with epileptic encephalopathy with continuous spike-and-wave 
during sleep (EECSWS) 
Secondary Objective:  
• 
To evaluate the safety and tolerability of multiple doses of NBI-827104 in pediatric subjects with 
EECSWS 
Other Objectives: 
• 
 
 
 
 
 
 
 
Methodology:  This is a Phase 2, multicenter, double-blind, placebo-controlled, parallel-group study designed to 
assess the efficacy, safety, tolerability, and PK of NBI-827104 in pediatric subjects with EECSWS.  
Approximately 24 male and female subjects, 4 to 12 years of age (inclusive), will be enrolled for study 
participation.  Treatment will be administered for up to 
 including titration and taper periods. 
After providing parental or legal guardian informed consent with pediatric assent from developmentally capable 
pediatric subjects, subjects will be screened to determine eligibility (Days -28 to -1) before the start of study 
treatment dosing on Day 1.  Caregiver(s) will be given a seizure diary at screening, Day 1, and 
 
 and caregiver(s) will return the seizure diary at the next scheduled visit.  At least 4 days of 
baseline seizure diary data should be obtained prior to randomization.  On Day 1, eligible subjects who have a 
diagnosis confirmed by an external Diagnosis Confirmation Panel (DCP) will return to the study center for 
collection of baseline safety and efficacy assessments.  Subjects who are confirmed as eligible will then be 
randomized to NBI-827104 or placebo.  The first 6 subjects (randomized 2:1; ie, 4 subjects randomized to 
NBI-827104 and 2 subjects randomized to placebo) will be enrolled into a sentinel cohort for the analysis of 
safety, tolerability, and PK data through the end of 
 followed by the remaining 18 subjects in the main 
cohort (randomized 2:1 [NBI-827104:placebo]).  Study treatment will last for up to 
 
 
 
 
 
 
 
 
 
 
 
If an open-label extension (OLE) study is open for enrollment, eligible subjects may enter the OLE study 
following the completion of the 
 study visit at the end of the maintenance period.  For subjects who 
enroll directly in the OLE study, the 
 visit will be the final study visit of the current study.  For all other 
subjects, the end of the posttreatment safety period constitutes the end of the study. 

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The starting dose of study treatment for the sentinel cohort (dose level 1) will be based on body weight categories 
(based on subjects’ body weight on Day 1), as detailed in the table below. 
 
 
 
  Based on the exposure data obtained from the sentinel cohort, the doses may be adjusted if 
required to achieve the targeted exposure in the main cohort.  
 
 
 
 
 
Subjects who cannot tolerate the lowest allowable dose (ie, dose level 1) should 
remain in the study, but study treatment dosing will be discontinued. 
At the 
 visit, subjects will receive study treatment to administer at home during the taper period.  
 
 
  
 
 
  
During the posttreatment safety period, subjects/caregivers will be instructed to: 
• 
Contact the investigator (or designee) if symptoms worsen and require medical attention 
• 
Report any adverse events (AEs) or serious adverse events (SAEs) 
 
 
Safety and tolerability assessments including AE monitoring, clinical laboratory tests (including hematology, 
serum chemistry, and urinalysis), vital signs measurements, physical and neurological examinations, 12-lead 
electrocardiograms (ECGs), and ophthalmic examinations will be conducted throughout the study. 
Ongoing review of safety and tolerability data and the unblinded analysis of sentinel cohort data (including safety 
and tolerability) will be conducted by the Independent Data Monitoring Committee (IDMC); sentinel cohort data 
(including PK data) will be evaluated before proceeding to the main cohort.  The IDMC has the overall 
responsibility of safeguarding the interests of the subjects by monitoring data obtained in the study and making 
appropriate recommendations based on the reported data, thus ensuring that the study is being conducted with 
high scientific and ethical standards.  Study site personnel and the Sponsor (except for supply chain personnel not 
involved in decisions regarding subject treatment) will remain blinded. 
Available PK and safety data for the sentinel cohort will be reviewed by the IDMC to determine if a dose 
adjustment should be instituted prior to enrolling the main cohort.  Dose reductions or alterations in the escalation 
paradigm may be recommended by the IDMC to the Sponsor after the sentinel cohort if the drug is not 
sufficiently tolerated.  In addition, dose reductions or escalations may be instituted if the median exposure values 
for the sentinel cohort lie outside the 5th to 95th percentiles of the simulated reference range across the PK 
sampling intervals. 
 

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Study population:  A total of approximately 24 male and female pediatric subjects, 4 to 12 years of age, 
inclusive, with EECSWS will be enrolled.  Diagnosis of EECSWS must be confirmed by the DCP. It is estimated 
that 24 subjects should be randomized in order to have 21 evaluable subjects at the end of 
 and 
18 evaluable subjects at the end of 
 
Duration of treatment and study participation:  The expected duration of study participation for subjects who 
do not enroll directly into an OLE study is up to 
, including up to 
 of screening, up to 
 
of study treatment, and a posttreatment safety period of 
. The expected duration of study participation for 
subjects who enroll directly into an OLE study is up to 
, including up to 
 of screening and up to 
 of study treatment.  
Investigational product, dosage and mode of administration:  NBI-827104 will be provided as minitablets of 
 
 
 
 
 
 
 
Reference therapy, dose and mode of administration, batch number:  Matching NBI-827104 placebo 
minitablets will be provided. 
Criteria for evaluation: 
Efficacy: 
• 
Overnight video-EEG  
o 
SWI 
o 
 
o 
 
• 
Clinical Global Impression of Change 
• 
Caregiver Global Impression of Change 
• 
Clinical Global Impression of Severity 
• 
 
o 
 
o 
 
o 
 
o 
 
• 
 
 
 
  
 
 
 
 
 
 

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o 
 
 
 
 
 
 
 
 
 
   
 
Safety:   
Safety and tolerability will be monitored throughout the study and will include the following assessments: 
• 
AEs 
• 
Clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
• 
Vital signs (including blood pressure, pulse rate, and body temperature) 
• 
Physical examinations, including neurological examinations 
• 
12-lead ECG 
• 
Columbia-Suicide Severity Rating Scale, Children’s Version 
• 
Ophthalmic examinations 
Statistical methods: 
 
 
 
 
 
Safety data will be summarized using descriptive statistics. 
 

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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
4. 
ETHICS ......................................................................................................................17 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Background .................................................................................................................17 
5.2. 
NBI-827104 ................................................................................................................18 
5.3. 
Study and Dose Rationale ...........................................................................................18 
5.4. 
Benefit-Risk Assessment ............................................................................................19 
6. 
STUDY OBJECTIVES ..............................................................................................20 
7. 
STUDY DESIGN .......................................................................................................21 
8. 
STUDY POPULATION .............................................................................................25 
8.1. 
Inclusion Criteria ........................................................................................................25 
8.2. 
Exclusion Criteria .......................................................................................................26 
8.3. 
Subject Identification and Replacement of Subjects ..................................................28 
8.4. 
Randomization ............................................................................................................28 
9. 
STUDY EVALUATIONS ..........................................................................................28 
9.1. 
Schedule of Assessments ............................................................................................28 
9.2. 
Efficacy Assessments .................................................................................................32 
9.2.1. 
Overnight Video-Electroencephalogram ....................................................................32 
9.2.2. 
 .....................................................................................................32 
9.2.3. 
 .........................................................................32 
9.2.4. 
Clinical Global Impression of Change .......................................................................33 
9.2.5. 
Caregiver Global Impression of Change ....................................................................33 
9.2.6. 
Clinical Global Impression of Severity ......................................................................33 
9.2.7. 
 ..................................................33 
9.2.7.1. 
 
..........................................33 
9.2.7.2. 
 
 ...........................................34 
9.2.7.3. 
 
.......................................34 

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9.2.7.4. 
 
........................................34 
9.2.7.5. 
 .................................................................................35 
9.2.8. 
 .................................................................................................35 
9.2.8.1. 
 ....................35 
9.2.8.2. 
.........36 
9.2.8.3. 
 ............................................................................................36 
9.2.8.4. 
 
......................................................................................................................37 
9.3. 
Pharmacokinetic Assessments ....................................................................................37 
9.4. 
Safety Assessments .....................................................................................................38 
9.4.1. 
Independent Data Monitoring Committee ..................................................................38 
9.4.2. 
Vital Sign Measurements ............................................................................................38 
9.4.3. 
Medical History ..........................................................................................................39 
9.4.4. 
Physical and Neurological Examination Including Height/Length and 
Weight .........................................................................................................................39 
9.4.5. 
Electrocardiogram .......................................................................................................39 
9.4.6. 
Clinical Laboratory Assessments ...............................................................................39 
9.4.7. 
Estimated Total Blood Sample Volume .....................................................................40 
9.4.8. 
Columbia-Suicide Severity Rating Scale Children’s Versions ..................................41 
9.4.9. 
Ophthalmic Examination ............................................................................................41 
9.5. 
Specific Study Period Information .............................................................................41 
9.5.1. 
Screening (Days -28 to -1) ..........................................................................................42 
9.5.1.1. 
Diagnosis Confirmation Panel ....................................................................................43 
9.5.2. 
Titration Period ...........................................................................................................43 
9.5.2.1. 
 ...........................................................................................................................43 
9.5.2.2. 
 ............................................................................................44 
9.5.3. 
Maintenance Period ....................................................................................................45 
9.5.3.1. 
 ............................................................................................45 
9.5.3.2. 
 ..........................................................................................45 
9.5.3.3. 
 ......................................47 
9.5.4. 
Taper Period -
 ..............................................................................47 

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9.5.5. 
Posttreatment End of Study – 
 ..............48 
9.6. 
Study Duration ............................................................................................................49 
9.7. 
Prohibitions and Restrictions ......................................................................................49 
9.7.1. 
Prior and Concomitant Medications ...........................................................................49 
9.7.2. 
Dietary Restrictions ....................................................................................................50 
9.7.3. 
Other Restrictions .......................................................................................................50 
9.8. 
Discontinuation of Study Treatment and Subject Withdrawal ...................................50 
9.8.1. 
Discontinuation of Study Treatment Dosing ..............................................................50 
9.8.2. 
Withdrawal from Study ..............................................................................................51 
9.8.3. 
Sponsor’s Termination or Pause of Study ..................................................................52 
10. 
STUDY TREATMENT ..............................................................................................52 
10.1. 
Study Treatment Supplies ...........................................................................................52 
10.1.1. 
NBI-827104 ................................................................................................................52 
10.1.2. 
Placebo/Reference Drug .............................................................................................52 
10.2. 
Study Treatment Storage ............................................................................................52 
10.3. 
Study Treatment Packaging and Labeling ..................................................................52 
10.4. 
Direct-to-Subject Shipments of Study Treatment .......................................................52 
10.5. 
Blinding ......................................................................................................................53 
10.6. 
Study Treatment Preparation and Administration ......................................................53 
10.7. 
Study Treatment Compliance and Accountability ......................................................53 
10.8. 
Study Treatment Return ..............................................................................................54 
11. 
ADVERSE EVENTS..................................................................................................54 
11.1. 
Definition ....................................................................................................................54 
11.1.1. 
Intensity of Adverse Events ........................................................................................55 
11.1.2. 
Relationship to Study treatment ..................................................................................55 
11.2. 
Recording Adverse Events .........................................................................................56 
11.3. 
Poststudy Follow-Up of Adverse Events ....................................................................56 
11.4. 
Serious Adverse Events ..............................................................................................57 
11.4.1. 
Definition of a Serious Adverse Event .......................................................................57 
11.4.2. 
Managing Serious Adverse Events .............................................................................58 
11.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................58 
11.4.4. 
Expedited Safety Reports ...........................................................................................58 

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11.5. 
Pregnancy ...................................................................................................................59 
12. 
DOCUMENTATION OF DATA ...............................................................................59 
12.1. 
Case Report Forms .....................................................................................................59 
12.2. 
Data Capture, Review, and Validation .......................................................................60 
12.3. 
Coding Dictionaries ....................................................................................................60 
13. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................60 
13.1. 
Overview .....................................................................................................................60 
13.2. 
Analysis Sets ...............................................................................................................60 
13.3. 
Sample Size Determination ........................................................................................61 
13.4. 
Handling of Missing Data ...........................................................................................62 
13.5. 
Disposition of Subjects ...............................................................................................62 
13.6. 
Important Protocol Deviations ....................................................................................62 
13.7. 
Demographics and Baseline Subject Characteristics ..................................................62 
13.8. 
Study Treatment Dosing and Compliance ..................................................................62 
13.9. 
Pharmacokinetic Parameters .......................................................................................63 
13.10. 
Efficacy Data ..............................................................................................................63 
13.11. 
Safety Data ..................................................................................................................64 
13.12. 
Sentinel Cohort Analysis ............................................................................................65 
14. 
REGULATORY AND ETHICAL ISSUES ...............................................................65 
14.1. 
General Legal References ...........................................................................................65 
14.2. 
Institutional Review Board/Independent Ethics Committee ......................................65 
14.3. 
Protocol Adherence – Amendments ...........................................................................66 
14.4. 
Required Documents ..................................................................................................66 
14.5. 
Informed Consent .......................................................................................................66 
14.6. 
Study Monitoring ........................................................................................................66 
14.7. 
Quality Assurance .......................................................................................................67 
14.8. 
Record Retention ........................................................................................................67 
14.9. 
Confidentiality ............................................................................................................67 
14.10. 
Publication Policy .......................................................................................................67 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................68 
16. 
REFERENCES ...........................................................................................................69 
 
 

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LIST OF TABLES 
Table 1: 
 .....................................................................................................22 
Table 2: 
Schedule of Assessments ............................................................................................29 
Table 3: 
 .....................................................................40 
Table 4: 
Intensity of Adverse Events ........................................................................................55 
Table 5: 
Relationship of Adverse Events to Study treatment ...................................................56 
Table 6: 
Contact Information for Drug Safety and Pharmacovigilance ...................................58 
Table 7: 
 ..................................................................62 
 
LIST OF FIGURES 
Figure 1: 
 .............................................................................................24 
 
  

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ASM 
antiseizure medication  
ANCOVA 
analysis of covariance 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
 
 
β-hCG 
beta-human chorionic gonadotropin 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CI 
confidence interval 
  
 
COVID-19 
Coronavirus Disease 2019 
 
 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSWS 
continuous spike-and-wave during sleep 
 
 
 
 
 
 
 
 
 
 
 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DCP 
Diagnosis Confirmation Panel 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
electrocardiogram 

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eCRF 
electronic case report form 
EDC 
electronic data capture 
EECSWS 
epileptic encephalopathy with continuous spike-and-wave during sleep 
EEG 
electroencephalogram 
EOS 
end of study 
 
 
ESES 
electrical status epilepticus during sleep 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEC 
Global Executive Composite 
GGT 
gamma-glutamyl transferase 
GI-C 
Global Impression of Change 
GMR 
geometric mean ratio 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C antibody 
HIV-Ab 
human immunodeficiency virus antibody or antigen 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IGE 
idiopathic generalized epilepsy 
IRB 
Institutional Review Board 
IVIG 
intravenous immunoglobulin 
max. 
maximum 
min. 
minimum 
MMRM 
mixed model for repeated measurements 
NOAEL 
no observed adverse effect level 
NREM 
nonrapid eye movement 
OLE 
open-label extension 
PK 
pharmacokinetics 
QTcF 
corrected QT interval using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 

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SBP 
systolic blood pressure 
SD 
standard deviation 
 
 
SWI 
spike-wave index 
τ 
dosing interval 
T3 
triiodothyronine 
T4 
thyroxine 
  
 
 
 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
 
 
VNS 
Vagal nerve stimulator 
 
 
 

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4. 
ETHICS 
The sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and with the 
laws and regulations of the country in which the study is conducted. 
The investigator and/or sponsor/Contract Research Organization (CRO) will submit this protocol 
and any related document(s) provided to the parent(s) / legally designated representative and the 
subject to an Independent Ethics Committee (IEC) / Institutional Review Board (IRB) and to the 
national competent (health) authority (as applicable).  Approval documentation (as applicable) 
from both the IEC/IRB and the national competent (health) authority must be obtained before 
starting the study. 
5. 
INTRODUCTION 
5.1. 
Background 
Calcium is an important signal transduction element in neurons and its entry into the cell is 
tightly regulated by two 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:  Cav3.1, 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 et al., 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 et al., 2006; 
Zamponi et al., 2010; Cheong et al., 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 et al., 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). 

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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 et al., 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 cortico-thalamocortical circuitry involved in 
absence seizures are considered to contribute also to sleep-potentiated continuous spike-wave 
discharges observed in epileptic encephalopathy with continuous spike-wave discharges during 
sleep (EECSWS) (Sánchez Fernández et al., 2012; Singhal et al., 2014).  EECSWS is a spectrum 
of epileptic conditions (International League Against Epilepsy, 2018) 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 et al., 2014).  The sleep 
potentiation of epileptiform activity leads to an electroencephalographic 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 et al., 2014; 
Tassinari et al., 2000; Nickels et al., 2008).  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). 
5.2. 
NBI-827104  
NBI-827104 is a novel selective and orally available triple T-type calcium channel blocker. 
NBI-827104 effectively crosses the blood-brain barrier and shows dose-dependent efficacy in 
3 rodent models of generalized epilepsy, including synergistic effects when combined with 
established antiseizure medications (ASMs).  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 will be developed for the treatment of EECSWS.   
5.3. 
Study and Dose Rationale 
 
 
 
 
 
 
 
 

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  Based on a population pharmacokinetic (PK) model, weight-based dose regimens 
were developed across weight categories to determine the actual daily mg doses to be 
administered based on individual subject body weight. 
The maximum exposure level for all subjects will be the target exposure level 
 
  The doses for the sentinel cohort (Table 1) were calculated based on a population 
PK model.  After 
 PK data are assessed in the sentinel cohort, doses for the main cohort 
may be adjusted to achieve the target exposure level.  Dose reductions or alterations in the 
escalation paradigm may be implemented after the sentinel cohort if the drug is not sufficiently 
tolerated. 
5.4. 
Benefit-Risk Assessment 
EECSWS is a spectrum of epileptic conditions (International League Against Epilepsy, 2018) 
with onset in early childhood and include sleep potentiation of epileptiform activity. The 
potentiation of epileptiform activity during sleep leads to an electroencephalogram (EEG) pattern 
of electrical status epilepticus during sleep (ESES), which consists of continuous spike-waves 
during non-REM 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 et al., 2014; Tassinari et al., 2000; Nickels et al., 2008). 
Abnormal T-type calcium channel oscillations have been implicated in the pathophysiology of 
IGE and spike-wave discharges, in particular. As a novel selective and orally available triple 
T‑-type calcium channel blocker which effectively crosses the blood-brain barrier, NBI-827104 
may be effective in the treatment of EECSWS. NBI-827104 has demonstrated efficacy in 
3 rodent models of generalized epilepsy, including synergistic effects when combined with 
established ASMs. The current study will be the first clinical study to evaluate efficacy of 
NBI‑827104 in pediatric subjects with EECSWS. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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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 
pediatric subjects with EECSWS. This is a randomized, placebo-controlled study that includes a 
sentinel cohort of 6 subjects that allows the analysis of safety, tolerability, and PK data through 
 of the study before enrolling additional subjects. The randomization scheme of 2:1 
(NBI‑827104:placebo) enables a higher proportion of subjects to receive active treatment while 
still allowing for assessment of efficacy, safety, and tolerability in a randomized, placebo-
controlled study design. 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 and ophthalmic examinations as noted above.  
6. 
STUDY OBJECTIVES 
Primary Objective:  
• To assess the effect of NBI-827104 on the overnight epileptiform 
video-electroencephalogram (video-EEG) activity in pediatric subjects with 
EECSWS 
Secondary Objective: 
• To evaluate the safety and tolerability of multiple doses of NBI-827104 in pediatric 
subjects with EECSWS 
Other Objectives: 
• 
 

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• 
 
 
 
 
 
7. 
STUDY DESIGN 
This is a Phase 2, multicenter, double-blind, placebo-controlled, parallel-group study designed to 
assess the efficacy, safety, tolerability, and PK of NBI-827104 in pediatric subjects with 
EECSWS.  Approximately 24 male and female subjects, aged 4 to 12 years (inclusive), will be 
enrolled for study participation.  Treatment will be administered for up to
 including 
titration and taper periods. 
After providing parental or legal guardian informed consent with pediatric assent from 
developmentally capable pediatric subjects, subjects will be screened to determine eligibility 
(Days -28 to -1) before the start of study treatment dosing on Day 1.  Caregiver(s) will be given a 
seizure diary 
, and caregiver(s) 
will return the seizure diary at the next scheduled visit.  At least 4 days of baseline seizure diary 
data should be obtained prior to randomization. On Day 1, eligible subjects who have a diagnosis 
confirmed by an external Diagnosis Confirmation Panel (DCP) will return to the study center for 
collection of baseline safety and efficacy assessments.  Subjects who are confirmed as eligible 
for the study will then be randomized to NBI-827104 or placebo.  The first 6 subjects 
(randomized 2:1; ie, 4 subjects randomized to NBI-827104 and 2 subjects randomized to 
placebo) will be enrolled into a sentinel cohort for the analysis of safety, tolerability, and PK data 
through the end of 
 followed by the remaining 18 subjects in the main cohort 
(randomized 2:1 [NBI-827104:placebo]).  Study treatment will last for up to 
, 
 
 
 
 
 
 
 
 
 
 
If an open-label extension (OLE) study is open for enrollment, eligible subjects may enter the 
OLE study following the completion of the 
 study visit at the end of the maintenance 
period.  For subjects who enroll directly in the OLE study, the 
 visit will be the final 
study visit of the current study.  For all other subjects, the end of the posttreatment safety period 
constitutes the end of the study. 
The starting dose of study treatment for the sentinel cohort (dose level 1) will be based on body 
weight categories (based on subjects’ body weight on Day 1), as detailed in Table 1.  This study 
intends to target exposures equivalent to those observed 
 
 in adults 
  Based on the exposure 

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data obtained from the sentinel cohort, the doses may be adjusted if required to achieve the 
targeted exposure in the main cohort. 
Table 1: 
 
 
 
 
 
Subjects who cannot tolerate the lowest allowable study dose (ie, dose level 1) should remain in 
the study but study treatment dosing will be discontinued. 
At the 
 visit, subjects will receive study treatment to administer at home during the taper 
period. 
 
 
 
 
  During the posttreatment 
safety period, subjects/caregivers will be instructed to: 
• Contact the investigator (or designee) if symptoms worsen and require medical 
attention 
• Report any adverse events (AEs) or serious adverse events (SAEs) 
 
 
 
Safety and tolerability assessments including AE monitoring, clinical laboratory tests (including 
hematology, serum chemistry, and urinalysis), vital signs measurements, physical and 
neurological examinations, 12-lead electrocardiogram (ECG), and ophthalmic examinations will 
be conducted throughout the study. 
Ongoing review of unblinded safety and tolerability data and the analysis of sentinel cohort data 
(including safety, tolerability) will be conducted by the Independent Data Monitoring Committee 

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(IDMC); sentinel cohort data (including PK data) will be evaluated before proceeding to the 
main cohort.  The IDMC has the overall responsibility of safeguarding the interests of the 
subjects by monitoring data obtained in the study and making appropriate recommendations 
based on the reported data, thus ensuring that the study is being conducted with high scientific 
and ethical standards.  Study site personnel and the Sponsor (except for supply chain personnel 
not involved in decisions regarding subject treatment) will remain blinded. 
Available PK and safety data for the sentinel cohort will be reviewed by the IDMC to determine 
if a dose adjustment should be instituted prior to enrolling the main cohort.  Dose reductions or 
alterations in the escalation paradigm may be recommended to the Sponsor by the IDMC after 
the sentinel cohort if the drug is not sufficiently tolerated.  In addition, dose reductions or 
escalations may be instituted if the median exposure values for the sentinel cohort lie outside the 
5th to 95th percentiles of the simulated reference range across the PK sampling intervals. 
 
 
 
 
 
 
The schematic of the study design is presented in Figure 1. 

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Figure 1: 
 

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8. 
STUDY POPULATION 
8.1. 
Inclusion Criteria 
To participate in this study, subjects must meet the following criteria:  
1. Signed informed consent by the parent(s) or legal representative(s) and, if applicable, 
assent from developmentally capable pediatric subjects. Consent/assent may be done 
remotely, if allowed per the site’s institutional policy and remote consenting procedures 
are in place. 
2. Diagnosis of EECSWS described by the following criteria: 
• Male and female pediatric subjects aged between 4 and 12 years (inclusive) at 
screening. 
• Genetic, structural, or unknown origin of EECSWS.  Determination of potential 
genetic origin of EECSWS should be based on prior genetic testing results, if 
available; however, no genetic testing is required for the determination of study 
eligibility. 
• SWI >50% during the first hour of overnight NREM sleep based on centralized 
reading.  
• Focal, multifocal, or generalized spike-and-wave complexes with sleep activation 
based on investigator assessment and confirmed by central EEG reader. 
• Cognitive stagnation or regression associated with continuous spike-and-wave during 
sleep (CSWS) as assessed by clinical evaluation. 
Subjects with Landau Kleffner Syndrome are eligible to participate in the study if they 
meet the above specified diagnostic criteria.  
3. Have diagnosis of EECSWS confirmed by the DCP. 
4. Subjects of childbearing potential must agree to use highly effective birth control 
methods consistently while participating in the study until 90 days after the last dose of 
the study treatment.  A female subject of childbearing potential is defined as a subject 
who has had her first menstrual cycle (ie, menarche).  A male subject of childbearing 
potential is defined as a subject who has reached spermarche. 
Acceptable methods of birth control for female subjects of childbearing potential are: 
• Combined (estrogen and progestogen containing) hormonal contraception or 
progestogen-only hormonal contraception associated with the inhibition of ovulation 
used with an effective nonhormonal method of contraception (eg, barrier 
contraception used with spermicide)  
• Intrauterine hormone-releasing system (IUS) used with an effective nonhormonal 
method of contraception (eg, barrier contraception used with spermicide) 
• Intrauterine device (IUD) 
• Bilateral tubal occlusion 

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• Vasectomized partner 
• True abstinence from sexual intercourse as the preferred and usual lifestyle.  Note that 
periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
 
Female subjects of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test result at screening and a negative urine pregnancy 
test at Day 1. 
 
The acceptable method of contraception for male subjects of childbearing potential is 
condom with spermicide (cream, spray, foam, gel, suppository, or polymer film). 
5. Stable dosage and stable time of intake of at least 1 and up to 3 ASMs, excluding pulse 
therapies such as systemic corticosteroids and intravenous immunoglobulin (IVIG), from 
4 weeks prior to screening and anticipated to be stable from screening until end of study 
(EOS).  Vagal nerve stimulator (VNS) and ketogenic diet are not counted as ASMs. 
6. Treatment other than ASMs (excluding pulse therapies such as systemic corticosteroids 
and IVIG) must be at a stable dosage from 2 weeks prior to screening and anticipated to 
be stable from screening until EOS. 
7. The subject, if using a VNS, must have had the VNS placed at least 3 months prior to 
screening with stable settings for ≥1 month; settings must remain stable throughout the 
duration of the study. 
8.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they: 
1. Are females who are pregnant or currently breastfeeding. 
2. Lennox-Gastaut syndrome, Doose syndrome (epilepsy with myoclonic-atonic seizures), 
or Dravet syndrome. 
3. Have a history of neurodegenerative disorders. 
4. Presence of a relevant psychiatric disease interfering with cognitive or behavioral 
functioning (eg, depression, schizophrenia, autism spectrum disorders) unless associated 
with the EECSWS diagnosis as assessed by the investigator. 
5. Presence of relevant neurological disorders other than EECSWS and its underlying 
conditions as judged by the investigator.  Symptomatic conditions underlying EECSWS 
(eg, neonatal strokes) have to be stable for at least 1 year prior to screening.  
6. Life expectancy <12 months due to any concomitant disease. 
7. Body weight <10 kg at randomization. 
8. Had a medically significant illness within 30 days before Day 1. 
9. Have a medically significant abnormality, physical or neurological examination finding, 
or any other measurements, other than those associated with EECSWS and its underlying 
conditions, observed during screening or Day 1. 

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10. Clinically relevant findings in systolic blood pressure (SBP), diastolic blood pressure 
(DBP), or pulse rate at screening or Day 1 as determined by the investigator. 
11. Have an average triplicate ECG corrected QT interval using Fridericia’s formula (QTcF) 
>450 msec or presence of any significant cardiac abnormality at screening. 
12. Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry 
including thyroid function parameters, and urinalysis) at screening as determined by the 
investigator. 
13. Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-
glutamyl transferase (GGT) levels >2 × the upper limit of normal (ULN) at screening. 
14. Have mild to severe renal impairment as determined by the investigator. 
15. Have a history of tonic seizures during sleep. 
16. Significant eye disease at screening, which in the opinion of the investigator would affect 
the subject's ability to safely participate in the study, or findings that would preclude 
ophthalmic safety examinations. 
17. Have received any prohibited medication within 30 days before screening (Section 9.7.1). 
18. Have taken cannabinoids, excluding Epidiolex®/Epidyolex®, within 30 days of screening. 
19. Pulse therapy such as systemic corticosteroids and IVIG are prohibited for at least 
8 weeks prior to screening. 
20. 
 
21. Have a known or suspected diagnosis of Acquired Immune Deficiency Syndrome 
(AIDS), or have tested seropositive for human immunodeficiency virus antibody 
(HIV-Ab) or antigen at screening. 
22. Tested positive at screening for hepatitis B surface antigen (HBsAg) or hepatitis C virus 
antibody (HCV-Ab) with confirmatory positive nucleic acid amplification reflex test. 
23. Planned surgical intervention related to structural abnormalities of the brain from 
screening through the duration of the study. 
24. Have a significant risk of suicidal or violent behavior.  Subjects will be excluded if they 
have: 
• Any lifetime history of suicidal behavior or 
• Any lifetime history of 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 Columbia-Suicide Severity Rating Scale (C-SSRS), or 
based on clinical impression for younger subjects. 
25. Known intolerance or hypersensitivity to NBI-827104, selective T-type calcium channel 
blockers, or to any of the excipients of the minitablet. 

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26. Have received any other investigational drug within 30 days or 5 half-lives (if known), 
whichever is longer, of Day 1 or plan to use an investigational drug (other than the study 
treatment) during the study. 
27. Any circumstances or conditions, which, in the opinion of the investigator, may affect 
participation in the study or compliance with the protocol. 
8.3. 
Subject Identification and Replacement of Subjects 
Subjects will be identified by their unique Subject identification (ID) number.  The subject ID 
will be noted on electronic case report forms (eCRFs), all source documentation, laboratory 
documents, and ECG tracings.  Subjects who discontinue from the study will not be replaced. 
8.4. 
Randomization 
On Day 1, eligible subjects will return to the study center for collection of baseline safety and 
efficacy assessments.  Subjects who continue to be eligible for the study will then be randomized 
to NBI-827104 or placebo.  The first 6 subjects (randomized 2:1; ie, 4 subjects randomized to 
NBI-827104 and 2 subjects randomized to placebo) will be enrolled into a sentinel cohort for the 
analysis and review of safety, tolerability, and PK data through 
 by an IDMC, before 
proceeding with enrollment of the remaining 18 subjects in the main cohort (randomized 2:1 
[NBI-827104:placebo]). 
9. 
STUDY EVALUATIONS 
9.1. 
Schedule of Assessments 
A schedule of assessments is shown in Table 2.  All study visits after Day 1 will have a visit 
window of ±3 days.  Visits will be the beginning of the week for 
 and the end 
of the week for 
.  Informed consent by the parent(s) or legal representative(s) 
and, if applicable, pediatric assent from developmentally capable pediatric subjects must be 
collected before any study-related procedures are performed.  Consent/assent may be done 
remotely, if allowed per the site’s institutional policy 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. 

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Table 2: 
Schedule of Assessments 

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9.2. 
Efficacy Assessments 
9.2.1. 
Overnight Video-Electroencephalogram 
Inpatient overnight video-EEG using a standard international 10/20 EEG recording setup and 
concurrent video will be conducted at screening and the end of 
, or early 
termination for subjects who discontinue before the end of 
  
The overnight video-EEG recording will be centrally read and used to compute the endpoints on 
epileptic activity (eg,
 
 
  As an outcome measure of this study to 
quantify electrographic CSWS activity, the SWI is defined as the percentage of seconds with 
≥1 spike-wave complex(es) during defined periods of overnight NREM sleep (Aeby et al., 2005; 
Scheltens-de Boer, 2009). 
Detailed information on the conduct and analysis of the video-EEG will be provided in the EEG 
Charter. 
9.2.2. 
 
 
 
 
 
 
 
 
 
 
9.2.3. 
 
 
  
 
 
   
 

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9.2.4. 
Clinical Global Impression of Change 
The Clinical Global Impression of Change (CGI-C), which is based on a 7-point scale (range:  
1=very much improved to 7=very much worse), will be used to rate the overall global 
improvement since the initiation of study treatment dosing.  This scale is a modification of a 
scale developed by the Psychopharmacology Research Branch of the National Institute of Mental 
Health to rate the subject’s overall improvement in clinical disorder and provides a global 
evaluation of improvement over time from the clinician’s perspective (Guy, 1976). 
The investigator (or qualified designee) will rate the scale at the scheduled timepoints; if 
possible, the same person should rate the CGI-C at all timepoints.  
 
9.2.5. 
Caregiver Global Impression of Change 
The Caregiver Global Impression of Change (Caregiver GI-C), which is based on a 7-point scale 
(range:  1=very much improved to 7=very much worse), will be used to rate the overall global 
condition since the initiation of study treatment dosing.  This scale is a modification of a scale 
developed by the Psychopharmacology Research Branch of the National Institute of Mental 
Health to rate the subject’s overall improvement in clinical disorder and provides a global 
evaluation of improvement over time from the caregiver’s perspective (Guy, 1976). 
A caregiver will rate the scale at the scheduled timepoints; if possible, the same person should 
rate the Caregiver GI-C at all timepoints.  
 
9.2.6. 
Clinical Global Impression of Severity 
The Clinical Global Impression of Severity (CGI-S) scale will be used to assess overall severity 
on a 7-point scale (range:  1=normal, not at all ill to 7=among the most extremely ill patients).  
 
 
9.2.7. 
 
 
  
9.2.7.1. 
 
 
 
 
 
 
 
 
 
 

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9.2.7.2. 
 
 
 
 
 
 
 
9.2.7.3. 
 
 
 
 
 
   
 
9.2.7.4. 
 
 
 
 
 
 
 
 

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9.2.7.5. 
 
 
 
 
 
 
   
9.2.8. 
 
 
  
9.2.8.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 

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9.2.8.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
9.2.8.3. 
 
 
 
   
 
 

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9.2.8.4. 
 
 
  
 
 
9.3. 
Pharmacokinetic Assessments 
Blood samples for determination of plasma concentrations of NBI-827104 and metabolites will 
be collected 
 
 
 
 
 
 
 
 
 
 
 
 The blood samples will be processed and stored 

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according to the procedure as specified in the laboratory manual.  Samples will be shipped 
 
 to the central laboratory for analysis. 
9.4. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 9.7.1 and Section 11, respectively.  Additional safety assessments are described in the 
following sections. 
For any abnormal safety assessment deemed clinically significant, the investigator will perform 
appropriate follow-up assessments (eg, repeat analysis), until the cause of the abnormality is 
determined and/or until the value returns to baseline (or within normal limits), or the investigator 
deems the abnormality to be of no clinical significance. 
Appropriate psychiatric evaluation and intervention will be provided for any treatment-emergent 
suicidal behavior or clinically significant suicidal ideation.  
9.4.1. 
Independent Data Monitoring Committee 
Ongoing review of safety and tolerability data and the unblinded analysis of sentinel cohort data 
(including safety, tolerability, and PK data [PK data will only be assessed at 
 will be 
conducted by the IDMC.  The IDMC has the overall responsibility of safeguarding the interests 
of the subjects by monitoring data obtained in the study and making appropriate 
recommendations based on the reported data, thus ensuring that the study is being conducted 
with high scientific and ethical standards.  Provisions will be in place to maintain the blinding of 
Sponsor study personnel.  The IDMC charter will describe the responsibilities, meeting 
frequency and data review procedures for the members to follow. 
The first 6 subjects (randomized 2:1; ie, 4 subjects randomized to NBI-827104 and 2 subjects 
randomized to placebo) will be enrolled into a sentinel cohort for the analysis and review of 
safety, tolerability, and review of PK data through 
 by an IDMC, before proceeding with 
enrollment of the  remaining 18 subjects in the main cohort (randomized 2:1 
[NBI-827104:placebo]). 
9.4.2. 
Vital Sign Measurements 
Vital sign measurements, including SBP and DBP, pulse rate, and body temperature will be 
measured.  Orthostatic blood pressures may be considered optional if the subject is unable to 
stand (eg, subject is in a wheelchair). If the investigator is unable to obtain orthostatic blood 
pressures, the reason for non-collection must be documented.  Blood pressure and pulse rate will 
be measured using a calibrated 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 before any scheduled blood sample collection at 
screening, Day 1 (prior to study treatment administration), and beginning of 
 (prior to 
study treatment administration),  (prior to study treatment administration),  (prior to study 
treatment administration), end of 
 (prior to study treatment administration and 3 hours 
post study treatment administration),  (prior to study treatment administration), 
 (prior to 
study treatment administration), 
 (prior to study treatment administration), 
 and 
 (or 
early termination). 

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9.4.3. 
Medical History 
A medical history will be taken at the screening visit and updated on Day 1 and as needed 
throughout the study.  
9.4.4. 
Physical and Neurological Examination Including Height/Length and Weight 
The complete physical and neurological examination will consist of an assessment of general 
appearance, skin and mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph 
nodes, chest/lungs, cardiovascular, abdomen, extremities, musculoskeletal, and neurological 
system, including assessment of level of consciousness, mental status, motor activity (including 
strength, tone, coordination, and reflexes), sensory testing, and gait.   
A complete physical and neurological examination including weight will be performed at 
screening, Day 1 and end of 
 (or early termination).  Height/length 
will be measured at screening only.  Height/length may be optional if the participant is unable to 
stand. If the investigator is unable to obtain height, the reason for non-collection must be 
captured in the eCRF. Height and weight will be measured with subjects not wearing shoes. 
9.4.5. 
Electrocardiogram 
A standard 12-lead ECG will be recorded in triplicate (at least 1 minute apart and within 
15 minutes) after the subject has rested supine for at least 5 minutes.  The ECG will be centrally 
read and the parameters that will be assessed include pulse, 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 or designee will provide a description of the abnormality recorded on the AE 
eCRF.  
The 12-lead ECG will be conducted at screening, Day 1 (prior to study treatment administration), 
and beginning of 
 (prior to study treatment administration),  (prior to study treatment 
administration),  (prior to study treatment administration), end of 
 (prior to study 
treatment administration and 3 hours post study treatment administration), 
 (prior to study 
treatment administration), 
 and 
 (or early termination). 
9.4.6. 
Clinical Laboratory Assessments 
All clinical laboratory assessments will be performed by a central laboratory.  In addition, a urine 
pregnancy test will be performed by the study site on Day 1 to confirm subject eligibility.  The 
central laboratory will provide instructions and supplies to the study staff before study initiation 
and instructions will be included in a laboratory manual.  The laboratory test battery will include 
routine and screening laboratory tests. 
The following clinical safety laboratory assays will be performed:   
Hematology:  complete blood count including white blood cell (WBC) count with differential, 
red blood cell (RBC) count, hemoglobin, hematocrit, and platelet count, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular 
volume (MCV), red cell distribution width (RDW), mean platelet volume (MPV). 

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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 cholesterol, triglycerides, 
total protein, glucose, TSH, T3 (free fraction), and T4 (free fraction). 
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, 
participant is in a diaper). 
The following additional laboratory tests will be performed: 
Serology:  Blood will be collected for HIV-Ab, HBsAg, and HCV-Ab and reflex nucleic acid 
amplification testing (if applicable) at screening. 
Drug screen: Blood will be collected at screening for a cannabinoid drug testing. A urine 
cannabinoid drug test may be performed if blood test results are not available prior to 
randomization at Day 1. 
Pregnancy Test:  Pregnancy tests will be performed for female subjects of childbearing potential.  
A serum (β-hCG) pregnancy test will be performed at screening and a urine pregnancy test will 
be performed on Day 1 and end of 
 using a urine pregnancy kit provided 
by the central laboratory. A serum pregnancy test may be performed if it is not possible to obtain 
urine. 
9.4.7. 
Estimated Total Blood Sample Volume 
The estimated total blood sample volume for each subject is presented in Table 3.  These 
estimates include samples to be collected during screening, the treatment periods, and the final 
visit (or upon early termination). 
Table 3: 
 

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9.4.8. 
Columbia-Suicide Severity Rating Scale Children’s Versions 
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 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 at screening. 
Younger subjects or subjects with developmental impairment for whom the C-SSRS would be 
inappropriate will be monitored for suicidality based on clinical impression. 
Subjects with any lifetime suicidal behavior or lifetime suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with 
specific plan and intent) based on the C-SSRS should be excluded (see exclusion criterion #24). 
The C-SSRS will be administered and scored by the investigator or qualified study center 
personnel at screening, Day 1, beginning of 
 and end of 
 
(or early termination). 
9.4.9. 
Ophthalmic Examination 
An age-appropriate ophthalmic examination will be performed consisting of visual acuity, 
pupillary light reflex, retinoscopy, as well as slit lamp microscopy testing (following pupillary 
dilation, and if cooperation can be achieved).  
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. 
Ophthalmic examinations will be performed at screening, and end of weeks 
 
 (or early termination) and may be performed within 7 days of the scheduled visit. 
9.5. 
Specific Study Period Information 
Study visits during the maintenance 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 
(Section 10.4).  If any study visits during the maintenance 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, overnight video-EEG) may be 
rescheduled.  Any visit assessments that are missed or conducted outside the visit window will 
be recorded as COVID-19 related protocol deviations. 
Assessments for each study visit are not required to be conducted in the order listed in the 
following sections but should be scheduled to minimize subject fatigue and interference with the 
subject's ability to sleep during the video-EEG, for study visits with an overnight video-EEG. 

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9.5.1. 
Screening (Days -28 to -1) 
After signed informed consent by the parent(s) or legal representative(s) and, if applicable, 
pediatric assent from developmentally capable pediatric subjects is/are obtained, subjects will 
undergo screening procedures between Day -28 and Day -1. 
During screening, the following study evaluations and tasks will be performed at the study 
center: 

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9.5.1.1. 
Diagnosis Confirmation Panel 
An external DCP will review and confirm that the subject meets the clinical diagnosis of 
EECSWS to determine study eligibility prior to randomization on Day 1. Medical history 
information, as well as any further medical information supporting the diagnosis if available 
(including the screening overnight video-EEG), will be provided to the DCP to review to 
confirm the diagnosis. A DCP charter will describe the responsibilities and data review 
procedures. 
9.5.2. 
Titration Period 
9.5.2.1. 
 

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9.5.2.2. 
 

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9.5.3. 
Maintenance Period 
9.5.3.1. 
 
9.5.3.2. 
 

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9.5.3.3. 
 
9.5.4. 
Taper Period - 
 

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9.5.5. 
Posttreatment End of Study – 
 

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9.6. 
Study Duration 
The expected duration of study participation for subjects who do not enroll directly into an OLE 
study is up to 
, including up to 
 of screening, up to 
 of study treatment, 
and a posttreatment safety period of 
.  The expected duration of study participation for 
subjects who enroll directly into an OLE study is up to 
, including up to 
 of 
screening and up to
 of study treatment. 
9.7. 
Prohibitions and Restrictions 
9.7.1. 
Prior and Concomitant Medications 
All prescription and over-the-counter medications, dietary supplements (including vitamins), and 
herbal supplements taken by the subject within 30 days before screening will be recorded on the 
Prior and Concomitant Medications page of the eCRF.   
The following medications are allowed: 
•
Stable background treatment (ie, no dose changes from 
 prior to screening
and no changes anticipated during the study) with at least 1 and up to 3 concomitant
ASMs and/or ketogenic diet/modified Atkins diet.  Epidiolex/Epidyolex is allowed
and will be considered an ASM.  Felbamate is allowed if the subject has been
receiving the drug for at least 1 year prior to screening with no safety concerns.
During the study duration, subjects will receive the ASMs according to their regular
administration schedule.  Vagal nerve stimulator (VNS) and ketogenic diet are not
counted as ASMs.
•
Supportive non-ASM specific therapies (eg, methylphenidate) on stable dose from
2 weeks prior to screening and no changes anticipated during the study.
•
Standard of care medication or medication to treat AEs not mentioned as a prohibited
concomitant medication.
The following medications are prohibited beginning 30 days before screening until the final 
study visit (or early termination): 
•
•
Cannabinoids except Epidiolex/Epidyolex.
Pulse therapies such as systemic corticosteroids and IVIG are prohibited for at least 8 weeks 
prior to screening until the final study visit (or early termination). Other chronic use of steroids, 
with the exception of steroid replacement therapy, must be approved by the Sponsor. 

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9.7.2. 
Dietary Restrictions 
 
 
9.7.3. 
Other Restrictions 
Subjects will be confined to the study center for 3 overnight stays (screening, 
 visit 
[approximately 24 hours], and 
 visit).  Subjects will be discharged from the study center 
after completion of study assessments in the morning after overnight stays. 
Participation in another investigational drug study is prohibited for at least 30 days after the last 
dose of study treatment or 30 days after study completion, whichever is longer. 
9.8. 
Discontinuation of Study Treatment and Subject Withdrawal 
Subjects/caregivers can discontinue study treatment or withdraw their consent to participate in 
the study at any time.  The investigator must discontinue study treatment dosing or withdraw any 
subject from the study if a subject/caregiver requests study treatment dosing to be discontinued 
or to be withdrawn from the study, respectively.  All subjects prematurely discontinuing study 
treatment dosing should continue study participation to be followed for safety and efficacy 
outcomes. 
9.8.1. 
Discontinuation of Study Treatment Dosing 
If a subject prematurely discontinues study treatment dosing, the investigator will record the 
reason for discontinuation on the relevant eCRF.  Such subjects will not be automatically 
withdrawn from the study and should continue participation in the study.  The investigator, 
subject’s parent/legal guardian, and subject should discuss a plan for continued participation.  
Data for any outcome measures, particularly the primary endpoint, as well as safety follow-up, 
are important to collect.  For any subsequent study visits after study treatment is prematurely 
discontinued, subjects will not be required to undergo PK sampling.  Additional study visits and 
assessments for participants who discontinue study treatment but agree to remain in the study 
may be conducted remotely.  If medically indicated, treatment with medication listed under 
Section 9.7.1 is no longer prohibited after study treatment discontinuation. 
Reasons for discontinuation from study treatment include but are not limited to: 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Site termination by the Sponsor 
• Study termination by the Sponsor 
• AE 
• Pregnancy 
• Lack of efficacy 

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• Protocol deviation 
The investigator must discontinue study treatment dosing if the subject experiences any of the 
following: 
• If the type, frequency, or severity of any AE becomes unacceptable/intolerable, 
despite attempts to decrease the dose. 
• If the subject is unable to tolerate the lowest allowable study dose (ie, dose level 1).   
• QTcF value >500 msec (cardiologist verified) on any ECG tracing.  
• If the subject exhibits suicidal behavior, or suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal 
ideation with specific plan and intent) based on the C-SSRS, or in the opinion of the 
investigator. 
• Subject is confirmed to be pregnant. 
• Subject has any clinically significant treatment-emergent ophthalmic finding. 
• Subject has any clinically significant treatment-emergent thyroid function test 
abnormality (TSH, T3 [free fraction], and T4 [free fraction]). 
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 times 
ULN) or ECG abnormality. 
• Subject requires a medication that is prohibited by the protocol. 
It is crucial to obtain follow-up data for any subject who discontinues study treatment dosing 
because of an AE, abnormal laboratory test, vital sign measurement, physical and neurological 
examination, ECG finding, or ophthalmic evaluation.  In any case, every effort must be made to 
undertake safety follow-up procedures. 
9.8.2. 
Withdrawal from Study 
If a subject prematurely withdraws from the study, the investigator will record the reason for 
withdrawal on the relevant eCRF.  All subjects who withdraw from the study prematurely will be 
asked to have all early termination assessments performed. 
Reasons for withdrawal from study include, but are not limited to: 
• Withdrawal by the subject 
• Adverse Event 
• Death 
• Lost to follow-up 
• Site terminated by Sponsor 
• Study terminated by Sponsor 

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• Protocol deviation 
• Investigator decision 
9.8.3. 
Sponsor’s Termination or Pause of Study 
The Sponsor reserves the right to discontinue or pause the study overall or at the level of 
individual sites at any time for clinical or administrative reasons.  Study termination must be 
implemented by the investigator, if instructed to do so by the Sponsor in a time frame that is 
compatible with the subjects’ well-being. 
10. 
STUDY TREATMENT 
10.1. 
Study Treatment Supplies 
10.1.1. 
NBI-827104 
The Sponsor or its designee will provide the study center with a supply of NBI-827104 
minitablets sufficient for the completion of the treatment period of the study.  
10.1.2. 
Placebo/Reference Drug 
The Study Sponsor or its designee will provide the study center with a supply of matching 
placebo minitablets sufficient for the completion of the treatment period of the study. 
10.2. 
Study Treatment Storage 
Formulated NBI-827104 and placebo minitablets 
 
   
The investigator should refer to the label of the study treatment for information on the storage 
conditions. 
Study treatment should be stored and inventoried according to applicable local and federal 
regulations and study procedures. 
10.3. 
Study Treatment Packaging and Labeling 
Each bottle of NBI-827104 or matching placebo will be supplied with a minitablet dispensing 
device.  Instructions on use of the device for dosing will be provided in the Pharmacy Manual. 
Study treatment will be labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
10.4. 
Direct-to-Subject Shipments of Study Treatment 
To ensure continued access to study treatment, if a subject is unable to go to the site when study 
treatment is to be dispensed, study treatment may be delivered from the site’s pharmacy to the 
subject’s residence by a distributor independent from the Sponsor. The subject’s name, address, 
and other contact details will not be accessible to the Sponsor, and the distributor will not have 
access to the subject’s health information. 

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10.5. 
Blinding 
This study includes up to 
 of double-blind, placebo-controlled treatment during which 
the subject, investigator, and all study center personnel will be blinded to the subject’s treatment.  
The Sponsor will be blinded except for supply chain personnel who are not involved in decisions 
regarding subject treatment.  During this treatment period, all subjects will receive NBI-827104 
or placebo to be self-administered once daily. 
The randomization code will be broken for an individual subject only if the subject is pregnant, 
experiences an SAE that the investigator feels cannot be adequately treated without knowing the 
subject’s treatment assignment, or for regulatory reporting requirements.  In the case of a 
medical emergency in which knowledge of the identity of the study treatment is important for 
subject management, the investigator has the responsibility for unblinding the randomized 
treatment assignment using an Interactive Web Response System.  It is recommended that the 
investigator contact the Study Medical Monitor (or designee) before unblinding if it would not 
result in unnecessary delay to the immediate medical management of the subject.  
Documentation of the unblinding must be maintained. 
Members of the IDMC and individuals who generate the IDMC reports and the independent 
vendor providing the PK analysis will be unblinded throughout the study. 
10.6. 
Study Treatment Preparation and Administration 
NBI-827104 will be provided as minitablets 
 
 
 
 
 
 
 
 
 
  
 
 
 
10.7. 
Study Treatment Compliance and Accountability 
Subjects/caregivers will bring all unused study treatment and empty drug packaging material to 
the center at specified study visits for drug accountability and reconciliation by study center 
personnel.  A compliance check will be performed by 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 

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responsible for maintaining accurate records of the quantity and dates of all study treatment 
supplies received, dispensed, and returned. 
10.8. 
Study Treatment Return 
Returns will be shipped to NBI or its designee at the completion of the study according to 
instructions provided by NBI or its designee according to applicable state and federal regulations 
and study procedures.  
11. 
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 ICF has been signed 
until the subject’s final study visit (or upon early termination). 
11.1. 
Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
conditions present at the start of the study; (2) subject deterioration beyond what would be 
expected due to primary illness; (3) intercurrent illness; and (4) drug interaction. 
All suicidal behaviors and clinically significant suicidal ideations will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  The investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.  Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
treatment, must be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
study treatment.  
The following are not considered AEs: 
• Continuous persistent disease/symptom present before drug administration, unless it 
unexpectedly progresses, or increases in severity following drug administration 
• Seizures will not be considered AEs unless there is a significant increase in seizure 
frequency, there is a new seizure type, occurrence of status epilepticus, and/or in the 
investigator’s opinion it should be captured as an AE. 
• Treatment failure or lack of efficacy 

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• Pregnancy 
• Overdose of either study treatment or concomitant medication without any clinical 
signs or symptoms. 
11.1.1. 
Intensity of Adverse Events 
AEs must be graded for intensity.  An intensity category of mild, moderate, or severe, as defined 
in Table 4, 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 4: 
Intensity of Adverse Events 
Grade  
Intensity 
Mild 
An adverse event that is usually transient and may require only minimal treatment 
or therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living. 
Moderate An adverse event that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
subject. 
Severe 
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
11.1.2. 
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 5.  An AE is deemed associated with the use 
of the study treatment “if there is a reasonable possibility that the drug caused the AE” 
(otherwise referred to as a suspected adverse reaction).  Reasonable possibility means there is 
evidence to suggest a causal relationship between the drug and the AE (Title 21 Code of Federal 
Regulations [CFR] 312.32 [a]). 

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Table 5: 
Relationship of Adverse Events to Study treatment 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration 
of the drug or in which the drug level has been established in body fluids or 
tissue; that follows a known or expected response pattern to the suspected 
drug; and that is confirmed by improvement on stopping or reducing the 
dosage of the drug, and reappearance of the reaction on repeated exposure. 
Possible 
An adverse event in which there is reasonable possibility that the drug caused 
the event.  Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the adverse event. 
Unlikely 
A reaction that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or suspected response pattern to the 
suspected drug; but that could reasonably be explained by known 
characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
11.2. 
Recording Adverse Events 
For randomized subjects, each AE will be listed as a separate entry on an AE eCRF.  Screen 
failure subjects will have AE information noted only in the source document.  The investigator 
(or designee) will provide information on dates of onset and resolution, intensity, seriousness, 
frequency, action(s) taken, changes in study treatment usage, relationship to study treatment, and 
outcome.   
The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours to the Sponsor or its designee: 
• SAE, including death 
• Pregnancy 
• Treatment unblinding for any reason 
• Events of suicidal behavior or suicidal ideation type 4 (active suicidal ideation with 
some intent to act, without specific plan) or type 5 (active suicidal ideation with 
specific plan and intent) based on the C-SSRS. 
11.3. 
Poststudy Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical and neurological 
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.   

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AEs ongoing at the final visit or at early termination will be followed for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes or resolves or until 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. 
11.4. 
Serious Adverse Events 
All SAEs will be recorded from the time the ICF has been signed 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 11.4.3. 
11.4.1. 
Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcome: 
• Death. 
• A life-threatening AE.  Life-threatening means that the subject was, in the view of the 
investigator or Sponsor, at immediate risk of death from the reaction as it occurred.  It 
does not mean that hypothetically the event might have caused death if it occurred in 
a more serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization.  Hospitalization 
for elective treatment or a pre-existing condition that did not worsen during the 
clinical investigation is not considered an AE.  Hospitalization or nursing home 
admission for the purpose of caregiver respite is not considered an AE.  
Complications 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. 

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11.4.2. 
Managing Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible.  The physician in attendance will do whatever is medically needed for the 
safety and well-being of the subject.  The subject will remain under observation as long as 
medically indicated.  Appropriate laboratory studies will be conducted until all parameters return 
to normal or are otherwise explained or stable.  The subject will be followed until the SAE 
resolves or until the subject is medically stabilized.  The investigator (or designee) will notify the 
study Medical Monitor or designee (and the IRB/IEC, if necessary) immediately (within 
24 hours) of the SAE and the outcome of the SAE. 
11.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events 
SAEs and other immediately reportable events (defined in Section 11.2) must be reported within 
24 hours of first knowledge of the event by study personnel to the Sponsor (contact information 
provided on the respective forms).  Reports of SAEs and pregnancies must be followed by a fax 
or email of the SAE or Pregnancy Form.  It is important that the investigator provides his or her 
assessment of relationship to study treatment at the time of the initial SAE report. 
For SAEs and pregnancies, contact Drug Safety and Pharmacovigilance (DSPV) (Table 6).  
Treatment unblinding and events of suicidal behavior or suicidal ideation type 4 or 5 based on 
the C-SSRS (or based on clinical impression for subjects under 6 years) should be reported to the 
Study Medical Monitor. 
Table 6: 
Contact Information for Drug Safety and Pharmacovigilance 
Telephone: 
Facsimile: 
e-mail
 
Study Medical Monitor: 
 
Email:  
 
Telephone:  
 
11.4.4. 
Expedited Safety Reports 
The Sponsor or its representatives will submit an Expedited Safety Report for any suspected 
adverse reaction (as defined in Section 11.1.2) 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. 

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11.5. 
Pregnancy 
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met.  However, all 
pregnancies in female subjects who received NBI-827104 will be followed to assess for 
congenital anomaly.  Subjects of childbearing potential must be counseled at all visits to 
continue using birth control (see inclusion criterion #4 in Section 8.1) until 90 days after the last 
dose of study treatment.  If at any time between the time the ICF is signed and the last study 
visit, a subject (or the subject’s parent/legal guardian) believes she is pregnant, the subject will 
be instructed to return to the study center within 24 hours and undergo a serum pregnancy test to 
confirm pregnancy.  
All confirmed pregnancies in subjects who received study treatment must be immediately 
reported to the Sponsor, followed by fax or email of the pregnancy form.  A first 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). 
12. 
DOCUMENTATION OF DATA 
12.1. 
Case Report Forms 
The eCRF data for this study are being collected with an electronic data capture (EDC) system.  
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 EDC 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 eCRF for each subject 
must be reviewed by the investigator and electronically signed on the appropriate eCRF page(s).  
This should be done as soon as possible after the subject completes 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. 
The EDC vendor will provide access to the Sponsor 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 provided via a secure transfer mechanism) 

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and provided to the investigator at that time as a durable record of the center’s eCRF data.  
Although not required, the investigator may make paper printouts of the data. 
All clinical work conducted under this protocol is subject to 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 online by authorized study center personnel.  
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 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).  Prior and concomitant medications will be coded using the 
chosen version of the World Health Organization Drug Dictionary (WHO Drug).  
13. 
STATISTICAL AND ANALYTICAL PLAN 
13.1. 
Overview 
The analysis plan provided in this protocol represents a brief description of the planned analyses.  
The comprehensive statistical analysis plan (SAP) will be generated prior to final study database 
lock.  The SAP may include a number of additional analyses and data summaries not described 
in this protocol. 
 
. 
13.2. 
Analysis Sets 
Four analysis sets are defined: 
• Full Analysis Set (FAS) 
This analysis set includes all randomized subjects who took at least one dose of study 
treatment and have at least one efficacy video-EEG assessment. Subjects will be analyzed 
according to their randomized treatment group. 

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• Per-protocol set 
This analysis set includes all randomized subjects who completed at least 6 weeks of 
treatment without protocol deviations that may affect the evaluation of the primary 
endpoint. Subjects will be analyzed according to their randomized treatment group. 
Details regarding the specific protocol deviations or criteria that will exclude subjects 
from the per-protocol set will be defined in the SAP. 
• Safety set 
All subjects who received at least one dose of study treatment in the study will be 
included in the Safety set.  The Safety set is the primary analysis population for safety 
assessments. Subjects will be analyzed according to the study treatment they received. 
• Pharmacokinetic set 
This analysis set comprises all subjects included in the Safety set who had at least one 
evaluable plasma concentration after initiation of NBI-827104 and did not deviate from 
the protocol in a way that might affect the evaluation of the PK endpoint. The PK set will 
be employed in the analysis of the PK parameters. 
13.3. 
Sample Size Determination 
The sample size is based on the primary endpoint, expressed as a ratio of SWI at the end of 
 to baseline.  A ratio to baseline was preferred over an absolute or relative change from 
baseline, because of the better statistical properties of the former.   
The associated summary statistic on a treatment group level is the geometric mean ratio (GMR) 
to baseline (obtained by exponentiating the mean of the log-transformed ratios).  A GMR <1 
indicates an improvement from baseline in the treatment group. 
The treatment effect is expressed as a ratio of ratios: the GMR in the NBI-827104 group divided 
by the GMR in the placebo group.  
 
 
 
 
 
 
These numbers will provide the following power to detect a difference in the primary endpoint 
between NBI-827104 and placebo at 
 (at a two-sided α=0.10) as presented in Table 7.   

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Table 7: 
 
13.4. 
Handling of Missing Data 
All available study data will be included in relevant summaries and data displays, including any 
available data for subjects with incomplete or missing data.  Missing data for the primary 
efficacy endpoint (ratio of SWI at the end of 
 to baseline) will be imputed using last 
observation carried forward. Any methods of handling missing data in the secondary and other 
endpoints will be specified in the SAP. 
13.5. 
Disposition of Subjects 
A summary of subject disposition will be prepared that displays the number of subjects who 
were randomized, received study treatment, and completed the study.  The number of subjects 
who did not complete the study will be displayed both overall and by reason for discontinuation. 
13.6. 
Important Protocol Deviations 
A summary of the number and percentage of subjects with important protocol deviations by 
deviation category and by treatment group will be provided for all randomized subjects. 
13.7. 
Demographics and Baseline Subject Characteristics 
Age, height/length, weight, body mass index, gender, race, and ethnicity will be summarized 
with descriptive statistics or frequency tables as appropriate. 
13.8. 
Study Treatment Dosing and Compliance 
The average daily dose of study treatment will be summarized using descriptive statistics over 
the periods corresponding to each dose level (ie, 
) for 
each body weight category.  The cumulative dose of study treatment taken over the entire study 
period will also be summarized. 

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The number and percentage of subjects who are dose compliant (at least 80% of expected dose 
taken) will be summarized with descriptive statistics by visit and for the full treatment period. 
13.9. 
Pharmacokinetic Parameters 
PK analyses will be performed using the pharmacokinetic analysis set.  PK parameters will be 
calculated using non-compartmental methods. 
 
 
 
 
 
 
 
 
 
 
 
13.10. 
Efficacy Data 
Primary efficacy endpoint: 
• Ratio of SWI at the end of 
 to baseline during the first hour (60 minutes) of 
NREM sleep based on centralized video-EEG reading, where baseline is defined as 
the last value measured prior to intake of study treatment on Day 1. 
The primary endpoint was selected based on the observation of highest SWI during the first 
NREM sleep phases compared with the last (Bölsterli Heinzle et al., 2014), as well as 
demonstrated sensitivity and responsiveness in a retrospective review of video-EEG data 
collected in a patient population of children with EECSWS (Aeby et al., 2005). 
Secondary efficacy endpoints: 
• Ratio of SWI at the end of 
 to baseline during the first hour (60 minutes) of 
NREM sleep, based on centralized evaluation. 
• Caregiver GI-C and CGI-C scores at the end of 
 
• Change from baseline to the end of 
 in CGI-S scores.  
Exploratory efficacy endpoints: 

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The primary efficacy analyses will be performed using the FAS.  The Per-protocol analysis set 
will be used for supportive analyses. 
 
 
 
 
 
13.11. 
Safety Data 
Safety analyses will be performed using the Safety set. 
AEs will be summarized (frequency counts and percentages) by system organ class and/or 
preferred term, and maximum intensity. 
Descriptive summary statistics of the observed values and changes from baseline to each 
scheduled visit in clinical laboratory parameters will be provided.  The number (%) of subjects 
with marked laboratory abnormalities will be tabulated. 

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Observed values and changes from baseline to each scheduled visit in vital signs (SBP and DBP, 
pulse rate), ECG parameters (QTcF, HR, PR interval, QRS duration), and C-SSRS will be 
summarized.  The number (%) of subjects with marked ECG abnormalities will be tabulated. 
13.12. 
Sentinel Cohort Analysis 
The first 6 subjects (randomized 2:1; ie, 4 subjects randomized to NBI-827104 and 2 subjects 
randomized to placebo) will be enrolled into a sentinel cohort for the analysis of safety, 
tolerability, and PK data through 
  Efficacy analyses will not be performed as part of this 
analysis,
 
The unblinded analysis of safety and tolerability data for the sentinel cohort will be conducted by 
the IDMC.  The analysis of the PK data through 
 in the sentinel cohort will be conducted 
by an independent, unblinded vendor; this vendor will provide reports to the Sponsor and the 
IDMC.  Based on the tolerability and exposure data obtained from the sentinel cohort, the IDMC 
may recommend that doses and/or the escalation paradigm be adjusted to achieve the targeted 
exposure or improve tolerability.  Provisions will be made to ensure all Sponsor personnel 
remain blinded throughout the study. 
14. 
REGULATORY AND ETHICAL ISSUES 
14.1. 
General Legal References 
The study will be carried out according to provisions of the US CFR, the US Food and Drug 
Administration (FDA), the laws and regulations of the country in which the study is conducted, 
and the ICH Guidelines for GCP.  All clinical work conducted under this protocol is subject to 
GCP regulations.  This includes an inspection by the Sponsor or its representative, health 
authority, or IRB/IEC representatives at any time.  The investigator must agree to the inspection 
of study-related records by health authority representatives and/or the Sponsor or its designee. 
14.2. 
Institutional Review Board/Independent Ethics Committee 
The final approved protocol and the ICF will be reviewed by the IRB/IEC at the study center.  
The committee’s decision concerning conduct of the study will be sent in writing to the 
investigator and a copy will be forwarded to the Sponsor.  The investigator must agree to make 
any required progress reports to the IRB/IEC, as well as reports of SAEs, life-threatening 
problems, or death. 
A list of members participating in the IEC/IRB meetings must be provided, including the names, 
qualifications, and functions of these members.  If that is not possible, the attempts made to 
obtain this information along with an explanation as to why it cannot be obtained or disclosed 
must be documented in the study documentation.  
If a member of the site study personnel was present during an IEC/IRB meeting, it must be clear 
that this person did not vote. 

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14.3. 
Protocol Adherence – Amendments 
The protocol must be read thoroughly, and the instructions must be followed exactly.  Any 
changes in the protocol will require a formal amendment.  Such amendments will be agreed upon 
and approved in writing by the investigator and the Sponsor.  The IRB/IEC and local health 
authorities will be notified of all amendments to the protocol in accordance with local 
regulations. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator and/or sponsor/CRO to the IEC/IRB and to the 
national competent (health) authority in accordance with local procedures and regulations. 
14.4. 
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 both protocol and consent form. 
• Copy of the IRB/IEC approved written ICF to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided 
by a central laboratory. 
14.5. 
Informed Consent 
Parent(s) or legal guardian(s) will provide informed consent with pediatric assent (if 
developmentally capable of providing assent) before the performance of any study-related 
procedures.  Consent/assent may be done remotely, if allowed per the site’s institutional policy 
and remote consenting procedures are in place. 
Each subject’s chart will include the signed ICF with pediatric assent for study participation.  
When the study treatment is completed and the eCRF has been monitored, the ICF and pediatric 
assent will be kept in the investigator’s central study file.  Regulatory authorities may check the 
existence of the signed ICF and the pediatric assent in this central study folder. 
14.6. 
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 

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monitor will also perform drug accountability checks and may periodically request review of the 
investigator study file to ensure completeness of documentation in all respects of clinical study 
conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period.  The investigator or 
appointed delegate will receive the study monitor during these on-site visits, will cooperate in 
providing the documents for inspection, and will respond to inquiries.  In addition, the 
investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
14.7. 
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 FDA Guidelines, and 
according to all local and federal regulations.  Quality assurance audits may be performed at the 
discretion of the Sponsor. 
14.8. 
Record Retention 
Study records should be retained in compliance with all local and federal 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. 
14.9. 
Confidentiality 
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. 
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 to 
current federal regulations, the investigator is obliged to furnish the Sponsor with the complete 
test results and all data compiled in this study. 
14.10. 
Publication Policy 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. Authorship will be 

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determined by mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements. 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION 
The Sponsor reserves the right to terminate the study at any time globally or locally.  
Investigators can terminate the participation of their site in the study at any time. 
If a study is suspended or prematurely terminated, the sponsor will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons for 
the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator — in 
agreement with the sponsor — must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up.  The sponsor may inform the investigator of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the subjects’ interests. 

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