Clinical trial NCT03299842
Conditions: Dravet Syndrome
Keywords: seizure tonic clonic epilepsy myoclonic encephalopathy
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Start date: 2017-07-12; Completion date: 2018-07-05
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an exploratory sub-study to ZX008-1503 \[NCT02823145\]. Subjects will be fitted with an Embrace seizure detection watch and seizures detected by the watch will be compared to those entered into an electronic seizure diary.

Detailed description:
This sub study will include up to 20 participants who meet the entry criteria for the main Study ZX008-1503 and who are willing to wear the Embrace watch and use the Embrace Alert app for 12 consecutive weeks. Those invited to participate will undergo all procedures included in the main study during their participation in this sub-study,

Arms: arm 1: ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated to an effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day).
Interventions: intervention 1: ZX008 (Fenfluramine Hydrochloride)
Intervention descriptions: intervention 1: ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated to an effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day).

Protocol documents:
Prot_SAP_003.pdf: 
This protocol includes information and data that contain trade secrets and privileged or confidential information, which is the property of the sponsor. 
This information must not be made public without written permission from the sponsor. These restrictions on disclosure will apply equally to all future 
information supplied to you. This material may be disclosed to and used by your personnel and associates as may be necessary to conduct the clinical 
study. 
Confidential 
 
 
Sub-study Protocol 
 
Study Title: 
 
An Exploratory, Pilot Study to Assess the Usability of the Embrace 
Seizure Detection Watch in Children and Young Adults with Dravet 
Syndrome: A Sub-study to the ZX008-1503 Open-Label Extension Trial 
Study Number: 
ZX008-1503-SS01 
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number: 
125797 
Sponsor: 
Zogenix International Limited 
A wholly owned subsidiary of Zogenix, Inc.  
5858 Horton Street, Suite 455 
Emeryville, CA 94608 USA 
Sponsor's Medical 
Contact 
 
 
Zogenix, Inc. 
 
Date/Version of 
Study Protocol: 
 
 
28 August 2017 (Protocol Amendment 2.0) 
14 June 2017 (Protocol Amendment 1.0) 
13 January 2017 version 1.0 (Original Protocol) 
 
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Page 2 of 48  
 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR 
CONDUCT OF STUDY 
A list of personnel and organizations responsible for the conduct of the study will be supplied to 
study sites as part of the Investigator Study File. This list will be updated by the sponsor or the 
sponsor's agent and provided to study sites as needed. 
 
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TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................... 6 
SIGNATURE OF SPONSOR ................................................................................. 7 
SIGNATURE OF COORDINATING INVESTIGATOR ................................... 8 
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) .................................... 9 
LIST OF ABBREVIATIONS ............................................................................... 10 
STUDY SYNOPSIS ............................................................................................... 11 
1. 
BACKGROUND AND RATIONALE ............................................ 16 
1.1 
BACKGROUND ................................................................................................. 16 
1.2 
RATIONALE FOR CURRENT SUB-STUDY, ZX008-1503-SS01 ................ 16 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................. 18 
2.1 
PRIMARY OBJECTIVE ................................................................................... 18 
2.2 
SECONDARY OBJECTIVES ........................................................................... 18 
3. 
INVESTIGATIONAL PLAN .......................................................... 19 
3.1 
OVERALL STUDY DESIGN AND PLAN ...................................................... 19 
3.2 
NUMBER OF SUBJECTS ................................................................................. 20 
3.3 
STUDY DURATION .......................................................................................... 20 
3.4 
NUMBER OF STUDY CENTERS .................................................................... 20 
3.5 
STUDY MONITORING PROCEDURES ........................................................ 21 
4. 
SELECTION OF STUDY POPULATION .................................... 21 
4.1 
INCLUSION CRITERIA ................................................................................... 21 
4.2 
EXCLUSION CRITERIA .................................................................................. 22 
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4.3 
SUBJECTS OF REPRODUCTIVE POTENTIAL .......................................... 22 
4.4 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .......... 22 
4.5 
TERMINATION OF THE SUB-STUDY ......................................................... 23 
4.6 
REPLACEMENT OF SUBJECTS .................................................................... 23 
5. 
STUDY VISITS AND PROCEDURES .......................................... 24 
6. 
INVESTIGATIONAL PRODUCT INFORMATION .................. 24 
6.1 
ZX008 (FENFLURAMINE HYDROCHLORIDE ORAL SOLUTION) ...... 24 
6.2 
EMPATICA EMBRACE SYSTEM .................................................................. 25 
6.2.1 
Hardware ............................................................................................................. 25 
6.2.2 
Software ............................................................................................................... 26 
6.2.3 
Usability of the Empatica Embrace Watch System (Embrace) ...................... 27 
6.2.4 
Device Risks ......................................................................................................... 27 
6.3 
BLINDING .......................................................................................................... 28 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE ............................ 28 
8. 
STATISTICS ..................................................................................... 29 
8.1 
SAMPLE SIZE .................................................................................................... 29 
8.2 
ANALYSIS POPULATIONS ............................................................................ 29 
8.2.1 
Safety (SAF) Population ..................................................................................... 29 
8.2.2 
Embrace Treatment (EmB) Population ............................................................ 29 
8.3 
DATA ANALYSIS .............................................................................................. 29 
8.3.1 
Safety Analysis .................................................................................................... 29 
8.3.2 
Efficacy Analysis ................................................................................................. 29 
8.4 
STATISTICAL METHODS .............................................................................. 30 
9. 
DATA HANDLING PROCEDURES ............................................. 31 
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10. 
ETHICAL & REGULATORY CONSIDERATIONS .................. 32 
10.1 
INFORMED CONSENT .................................................................................... 32 
10.2 
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD .................................. 34 
10.3 
PROTOCOL COMPLIANCE ........................................................................... 35 
11. 
ADMINISTRATIVE ASPECTS ..................................................... 35 
12. 
REFERENCE LIST .......................................................................... 36 
13. 
APPENDICES ................................................................................... 37 
APPENDIX 1 – LIKERT EASE OF USE QUESTIONNAIRE ........................ 38 
APPENDIX 2 – PERCEIVED STRESS SCALE (PSS) ..................................... 39 
APPENDIX 3 – SUMMARY OF CHANGES ..................................................... 40 
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LIST OF TABLES 
TABLE 1: SCHEDULE OF ADDITIONAL ASSESSMENTS FOR SUBJECTS ENROLLED IN 
THE SUB-STUDY ....................................................................................................................... 20 
TABLE 2: INVESTIGATIONAL MEDICINAL PRODUCT – ZX008 ............................................. 25 
 
 
LIST OF FIGURES 
FIGURE 1:  EMBRACE WRIST-WORN MONITORING DEVICE (EMBRACE WATCH) .......... 25 
FIGURE 2:  EMBRACE SYSTEM ARCHITECTURE ...................................................................... 26 
FIGURE 3:  EMPATICA ALERT APP ONBOARDING SCREENS ................................................ 27 
 
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SIGNATURE OF COORDINATING INVESTIGATOR
Study Number: ZX008-1503-SS01
Study Title: An Exploratory, Pilot Study to Assess the Usability of the Embrace Seizure
Detection Watch in Children and Young Adults with Dravet Syndrome: A
Sub-study to the ZX008-1503 Open-Label Extension Trial
Coordinating Investigator: 
Institute of Neurology and Neurosurgery at St. Barnabas
Research Department
Livingston, NJ USA
cy)l?pl zon 
(Date [DD/MMMWYYY])
Confidential
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SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) 
Study Number: ZX008-1503-SS01 
Study Title: 
An Exploratory, Pilot Study to Assess the Usability of the Embrace Seizure 
Detection Watch in Children and Young Adults with Dravet Syndrome: A 
Sub-study to the ZX008-1503 Open-Label Extension Trial 
___________________________________________________________________________ 
I have read this study protocol, including all appendices. By signing this study protocol, I agree 
to conduct the clinical study, following approval by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), in accordance with the study protocol, the current 
International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP), 
and applicable regulatory requirements. I will ensure that all personnel involved in the study 
under my direction will be informed about the contents of this study protocol and will receive 
all necessary instructions for performing the study according to the study protocol. 
___________________________________________________________________________ 
Name and affiliation to be filled out by the investigator 
 
 
Principal Investigator  
Name and affiliation: 
____________________________________________ 
 
____________________________________________ 
 
__________________________________________ 
___________________________ 
 (Signature)  
(Date [DD/MMM/YYYY])  
 
 
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LIST OF ABBREVIATIONS 
ABBREVATION 
DEFINITION 
AE 
adverse event 
BID 
bis in die; two times per day 
BRIEF 
Behavior Rating Inventory of Executive Function 
CBD 
whole blood cannabidiol 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DS 
Dravet syndrome 
ECG 
electrocardiogram 
EDA 
electrodermal activity 
EmB 
Embrace treatment population 
EMBRACE 
Empatica Embrace watch system 
EOS 
end of study 
EQ-5D-5L 
standardized measure of health status 
ERT 
Seizure Diary custom built by ERT 
ET 
Early Termination 
EU-REACH 
European Union Registration, Evaluation, Authorisation and Restriction 
of Chemicals 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
ICH 
International Conference on Harmonization 
IDSMC 
Independent Data and Safety Monitoring Committee 
IEC 
Independent Ethics Committee 
IPCAB 
International Pediatric Cardiology Advisory Board 
IRB 
Institutional Review Board 
LED 
light-emitting diode 
MMRE 
mixed model repeated measures 
OLE 
open-label extension 
PSS 
Perceived Stress Scale 
QoL 
Quality of Life 
SAF 
safety analysis population 
SMEI 
Severe Myoclonic Epilepsy Of Infancy 
SUDEP 
Sudden Unexpected Death in Epilepsy 
THC 
tetrahydrocannabinol 
ULN 
upper limit of normal 
USA 
United States of America 
ZX008 
Fenfluramine Hydrochloride Oral Solution 
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STUDY SYNOPSIS 
Study Title: An Exploratory, Pilot Study to Assess the Usability of the Embrace Seizure Detection 
Watch in Children and Young Adults with Dravet Syndrome: A Sub-study to the ZX008-1503 
Open-Label Extension Trial 
Study Number: ZX008-1503-SS01 
Study Product: Fenfluramine Hydrochloride, ZX008 
Type of Study: 
Exploratory 
Indication Studied: Dravet syndrome 
 
Phase of Development: III 
Countries: North America 
Sponsor: Zogenix International Limited  
Coordinating Investigator: 
 
Institute of Neurology and Neurosurgery at St. Barnabas 
Research Department 
Livingston, New Jersey USA 
Estimated Duration of Individual Subject Participation: 
The duration of the study for an individual subject is expected to be approximately 12 weeks with the 
option to extend to 24 weeks. 
Objectives: 
The primary objective of the study is:  
 
To assess the overall usability and performance (correct use and ease of use) of the Empatica 
Embrace Seizure Detection watch system (Embrace) in outpatients with Dravet syndrome. 
The secondary exploratory objectives of the study are: 
 To compare objective convulsive seizure count, as captured by the Embrace, to convulsive 
seizure count captured manually in the seizure diary. 
 To compare objective convulsive seizure count during periods of sleep, as captured by the 
Embrace, to convulsive seizure count during periods of sleep captured manually in the 
electronic seizure diary. 
 To examine if the size of the electrodermal activity (EDA) response during and after a 
convulsive seizure is reduced over time with the ZX008 treatment. 
 To examine if skin-surface temperature changes with ZX008 treatment. 
 To examine if skin-surface temperature levels are different during periods of time preceding 
convulsive seizures than during times that are seizure-free. 
 To examine correlation of study drug dose and fever-induced convulsive seizure frequency, 
severity, and duration. 
 To examine the timing of diary-reported events vs. automatically detected events.  
 To assess quality of life while using the Embrace system with the following measures: 
- Quality of Life (QoL) of the parent/caregiver using the EQ-5D-5L scale. 
- Affective symptoms of the parent/caregiver using the Hospital Anxiety and Depression 
Scale (HADS). 
 To assess caregiver stress using the Perceived Stress Scale (PSS). 
 
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Methodology: This is a sub-study to the ZX008-1503 OLE study. All participants in this sub-study 
will have participated in Study ZX008-1501 or ZX008-1504 Cohort 2 and then continued in 
Study ZX008-1503, which is a multicenter, open-label, long-term safety study of ZX008 
(fenfluramine hydrochloride) in pediatric and young adult subjects with Dravet syndrome. The main 
Study ZX008-1503 consists of a 12-month OLE Treatment Period and a 2-week Post-Dosing Period. 
Details of dose and dose-adjustments are described in the main Study ZX008-1503.   
This sub-study will include up to 20 participants who meet the entry criteria for the main 
Study ZX008-1503 and who are willing to wear the Embrace watch and use the Embrace system per 
the user instructions for 12 consecutive weeks. Those invited to participate will undergo all 
procedures included in the main Study ZX008-1503 during their participation in this sub-study, plus 
any additional procedures specific for the sub-study. At the conclusion of the sub-study, participants 
will revert to only using the ERT seizure diary for the remainder of their participation in the main 
Study ZX008-1503. Efficacy analyses for sub-study participants that rely on the ERT seizure diary or 
that are specific to the Embrace watch will not be included in the main ZX008-1503 analyses.  
At the time of consent for the main Study ZX008-1503, subjects will also be presented with the 
consent for this sub-study. Subjects who consent for the sub-study will be fitted with an Embrace 
watch at Study Visit 1. Subjects (and/or parents/caregivers) will also be given instructions on how to 
use the Embrace system. The Alert app must be running on the provided iPod touch and remain in 
close proximity of the patient. However, parents/caregivers will continue to use the ERT seizure 
diary to record the number/type of seizures, rescue medications, and study drug administration.  
At pre-determined assessment times, parents/caregivers will complete questionnaires specific for the 
sub-study, including the Ease of Use Questionnaire and the Perceived Stress Scale (PSS), to measure 
user experience. 
External Committees: The ZX008 clinical program will employ an Independent Data and Safety 
Monitoring Committee (IDSMC) that will be responsible for safety oversight. A separate 
International Pediatric Cardiology Advisory Board (IPCAB) will monitor the cardiac safety of the 
ZX008 clinical trials.  
Number of Subjects: Up to 20 subjects will be enrolled from the main Study ZX008-1503. 
Inclusion Criteria: Subject must meet all of the entry criteria for the main Study ZX008-1503 to be 
eligible for the sub-study. In addition to meeting the above listed criteria, subjects in the sub-study 
must also be willing to wear and use the Embrace watch and parents/caregivers must be willing to 
use the Alert app per the user instructions. This includes: 
 
1. Subject is willing to wear the Embrace watch on the wrist (alternatively ankle, if needed for 
younger children). Subjects are asked to wear the watch for as many hours of the day as 
possible, and for the entire night, if possible, for the 12-week duration of the sub-study.  
2. Subject’s parent/caregiver is willing to use the Alert App and receive voice and SMS 
notifications on their personal smart-phone, and ensure the smart-phone has internet 
connectivity; iOS 8.2 or higher is required for iPhone users. 
3. Subject/subject’s caregiver is willing to ensure that the Embrace watch remains within close 
proximity of the paired iPod Touch running the Empatica Alert app. 
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4. Subject/subject’s caregiver is willing to ensure that the Embrace system is properly stored when 
not in use, and is not left exposed to direct sunlight, moisture, humidity or rain while in storage. 
The Embrace watch is water resistant but should never be submerged in water. Bathing and/or 
showering with the watch is acceptable, however. 
5. Subject/subject’s caregiver is willing to regularly clean the Embrace watch, routinely inspect the 
watch for sharp edges and damage, and ensure the watch is never worn over damaged or broken 
skin. 
6. Subject/subject’s caregiver is willing to ensure that the Embrace system is properly charged 
daily during a time when the subject is being observed so any seizures that occur during times 
that the device is not being worn are able to be added to the record manually. 
 
Exclusion Criteria: Subjects meeting any of the exclusion criteria for main Study ZX008-1503 are 
not eligible for the sub-study.  In addition, subject must not be enrolled into the sub-study if: 
1. Subject has a known hypersensitivity to any of the Embrace device materials. 
2. Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to Visit 1, other than epilepsy, that would 
negatively impact study participation, collection of study data, or pose a risk to the subject. 
 
Study Product, Dose, and Mode of Administration: 
ZX008: supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated to an 
effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day). Study medication will be 
administered twice a day (BID) in equally divided doses with food. 
 
Empatica Embrace watch system (Embrace)/Embrace Alert app: The noninvasive Embrace 
wrist-worn monitoring device, reads physiological data (EDA, skin temperature, and motion) from 
the surface of the skin and can transmit it wirelessly to a receiver. The watch is used in conjunction 
with the Embrace Alert app. The Alert app detects events from user physiology, such as convulsive 
seizures, and sends an alert to a caregiver via a phone call or text message. The Alert app runs on 
an iPod Touch and must remain in close proximity of the patient.  
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Duration of Treatment: Subjects will be permitted to participate in the sub-study for the initial 12 
weeks of participation in the main OLE study (ZX008-1503).  Subjects may have the opportunity to 
extend participation in the sub-study for up to 24 weeks. 
Criteria for Evaluation: 
Safety:  
Safety criteria are identical to those in the main Study ZX008-1503 and include AEs, laboratory 
safety parameters (hematology, chemistry, urinalysis), vital signs (blood pressure, heart rate, 
temperature, and respiratory rate), physical examination, neurological examination, 12-lead ECGs, 
Doppler ECHOs, and body weight.  
Efficacy: 
The primary criteria for evaluation in the sub-study is the change over time in the 5-point Likert Ease 
of Use Questionnaire to measure user experience.  
Secondary exploratory efficacy criteria for evaluation include change over time in the following: 
 
Perceived Stress Scale (PSS) to measure caregiver burden. 
 
Correlation of monthly (28-day) convulsive seizure count between the Embrace watch and 
seizure diary. 
 
Size of EDA response during and in the post-ictal hour of convulsive seizures. 
 
Skin-surface temperature (measured on wrist). 
 
Frequency of fever-related convulsive seizures. 
 
Comparison of convulsive seizure count during periods of sleep, and during the combined 
titration and maintenance periods, between the Embrace watch and seizure diary. 
 
Correlation of convulsive seizure time and classification as determined by Embrace watch 
and seizure diary. 
 
EQ-5D-5L to measure quality of life of the parent/caregiver while using the Embrace. 
 
HADS to measure affective symptoms of the parent/caregiver while using the Embrace. 
All other efficacy criteria are identical to those in the main Study ZX008-1503. 
Sample Size Determination: This sub-study is designed as a pilot exploratory study to provide 
preliminary information on the ease of use of the Embrace watch to detect seizures in outpatients 
with Dravet syndrome, therefore, the sample size is based more on feasibility than on power to detect 
differences. 
Statistical Methods: 
All safety data will be summarized as described in the ZX008-1503 protocol and associated 
Statistical Analysis Plan. Efficacy analyses for sub-study participants that rely on the ERT seizure 
diary or that are specific to the Embrace watch will not be included in the main ZX008-1503 
analyses. Exploratory data for the Embrace watch system data will be processed as follows: 
 Embrace’s automated convulsive seizure detection results will be manually compared to the 
diary counts of convulsive seizures. Cohen’s Kappa values will be computed for agreement. 
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 The above will be repeated separately for events during periods of sleep vs. events while 
awake, based on Embrace’s determination of sleep/wake (periods of sleep will be based on 
actigraphy and EDA as measured by the Embrace watch). 
 For each seizure detected by the Embrace watch, the peri-ictal EDA recording will be 
segmented from 60 minutes before detected seizure onset to 120 minutes afterward. 
A“significant EDA response” is declared when an increase in skin conductance level of more 
than 2 times the standard deviation of the pre-ictal baseline occurs. Significant EDA responses 
will be analyzed in terms of the amplitude of their EDA_peak, the response duration, defined as 
the difference between “EDA_end” and “EDA_start,” and the natural logarithm of the area 
under the curve (AUC) of the rising phase (from “EDA_start” to “EDA_peak”) and of the total 
response (from “EDA_start”to “EDA_end”), ie, LogAUCrise and LogAUCtot. These measures 
will be examined to see if they vary over time with the treatment.  
 Skin-surface temperature changes will be averaged daily and compared over time, with separate 
comparisons made for “seizure-free” periods and for “pre-seizure periods.” The duration of 
these periods will be based on average 60-minute intervals, but may also be examined with 
shorter intervals. 
 Each episode of fever, defined as any body temperature above 98.6°F (37°C), and number, 
severity, and duration of each seizure detected by Embrace will be correlated to dose of study 
drug. 
 
 
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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND 
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment 
of patients with Dravet syndrome (DS). 
Dravet syndrome, also known as severe myoclonic epilepsy of infancy (SMEI), is a rare and 
severe form of epilepsy first described by Charlotte Dravet in 1978 (Dravet 1978). The 
condition most commonly appears during the first year of life as frequent febrile seizures. As 
the condition progresses, other types of seizures typically occur, including myoclonic seizures 
and status epilepticus (Dravet 1978). Following the appearance of these seizures, affected 
children develop several co-morbid conditions including psychomotor regression, ataxia, sleep 
disturbance, and cognitive impairment. Intellectual impairment begins to become apparent 
around age 2 years due to lack of intellectual/behavioral progression. Dravet children often 
have a lack of coordination, poor development of language, hyperactivity, and difficulty 
relating to others (Dravet 1978; Hurst 1990). The degree of cognitive impairment appears to 
correlate, at least in part, with the frequency of seizures, and might be a result of repeated 
cerebral hypoxia. Children with DS also encounter a higher incidence of Sudden Unexpected 
Death in Epilepsy (SUDEP; Nashef 2012) than other populations with epilepsy. Indirect 
evidence has linked SUDEP to several possible etiologies, including seizure-induced apnea, 
pulmonary edema, dysregulation of cerebral circulation, and cardiac arrhythmias (Shorvon 
2011), although the actual etiology remains unknown and other mechanisms have not been 
ruled out. The vast majority of patients who survive to adulthood are wholly dependent on 
around-the-clock caregivers and eventually live in institutional care homes.  
Zogenix is conducting an international, multicenter, open-label, long-term safety study of 
ZX008 in pediatric and young adult subjects with Dravet syndrome who have successfully 
completed 14 weeks of treatment in core study ZX008-1501, ZX008-1502, and ZX008-1504 
Cohort 2, or successfully completed core study ZX008-1504 Cohort 1, and are candidates for 
continuous treatment for an extended period of time. The ZX008-1503 trial will consist of a 
12-month open-label extension (OLE) Treatment Period and a 2-week Post-Dosing Period. 
Thus, subjects who complete this trial will have been treated with ZX008 for a minimum of up 
to 1 year (including their participation in both the core study and this study). 
1.2 
RATIONALE FOR CURRENT SUB-STUDY, ZX008-1503-SS01 
This is a sub-study to the ZX008-1503 OLE trial, which will include up to 20 participants who 
are enrolled in Study ZX008-1503. This is an exploratory sub-study to provide preliminary 
information on the overall usability and performance of the Empatica Embrace watch system 
(Embrace) in outpatients with Dravet syndrome.  
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Seizure frequency is the primary outcome measure for individual treatment and for clinical 
trials. The current gold standard for demonstrating efficacy of new anti-epileptic drugs is a 50% 
reduction in seizure frequency. This efficacy standard is based on patients or their caregivers 
maintaining seizure diaries.  
Use of sensitive seizure detection technology may allow greater accuracy in seizure counting. 
Seizure detection technology may also provide means to address specific clinical questions, 
such as the occurrence of unwitnessed seizures during periods of sleep. 
The Embrace has been designed for automated convulsive seizure detection and 
characterization. The Embrace watch monitors electrodermal activity (EDA) and 
accelerometer-sensed changes in motion to analyze the information and detect patterns that are 
typically observed in convulsive seizures in real-time. The data can then be used to compare 
seizure detections, false alarms, and seizures that are not detected, to e-diary seizure report 
information.  
This sub-study for patients enrolled in the open-label extension study may provide insights into 
seizure triggers, such as temperature, or facilitate seizure counts during sleep and allow for 
comparison of various endpoints captured by the Embrace to the same endpoints captured in an 
electronic hand-held seizure diary. 
 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is: 
 
To assess the overall usability and performance (correct use and ease of use) of 
the Empatica Embrace Seizure Detection watch system (Embrace) in outpatients 
with Dravet syndrome. 
2.2 
SECONDARY OBJECTIVES 
The secondary exploratory objectives of the study are: 
 
To compare objective convulsive seizure count, as captured by the Embrace, to 
convulsive seizure count captured manually in the electronic seizure diary. 
 
To compare objective convulsive seizure count during periods of sleep, as captured by 
the Embrace, to convulsive seizure count during periods of sleep captured manually in 
the electronic seizure diary. 
 
To examine if the size of the electrodermal activity (EDA) response during and after a 
convulsive seizure is reduced over time with ZX008 treatment.  
 
To examine if skin-surface temperature changes with ZX008 treatment. 
 
To examine if skin-surface temperature levels are different during periods of time 
preceding convulsive seizures than during times that are seizure-free. 
 
To examine correlation of study drug dose and fever-induced convulsive seizure 
frequency, severity, and duration. 
 
To examine the timing of diary-reported events vs. automatically detected events. 
 
To assess quality of life while using the Embrace system with the following measures: 
o 
Quality of Life (QoL) of the parent/caregiver using the EQ-5D-5L scale. 
o 
Affective symptoms of the parent/caregiver using the Hospital Anxiety and 
Depression Scale (HADS). 
 
To assess caregiver stress using the Perceived Stress Scale (PSS). 
 
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3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN 
This is a sub-study to the ZX008-1503 OLE study. All participants in this sub-study will have 
participated in Study ZX008-1501 or ZX008-1504 Cohort 2 in the United States or Canada and 
then continued in Study ZX008-1503, which is a multicenter, open-label, long-term safety 
study of ZX008 (fenfluramine hydrochloride) in pediatric and young adult subjects with Dravet 
syndrome. The main Study ZX008-1503 consists of a 12-month OLE Treatment Period and a 
2-week Post-Dosing Period in which all subjects will receive ZX008 starting at 0.2 mg/kg, 
titrating to an effective dose, up to 0.8 mg/kg/day (not to exceed 30 mg/day). Thus, subjects 
who complete the main study will have been treated with ZX008 for a minimum of up to 
1 year. This sub-study will include up to 20 participants who meet the entry criteria for the 
main Study ZX008-1503 and who are willing to wear the Embrace watch and their 
parent/caregiver who is willing to use the Embrace Alert app per the user instructions for 
12 consecutive weeks.  Those invited to participate will undergo all procedures included in the 
main Study ZX008-1503, plus any additional procedures for the sub-study. At the conclusion 
of the sub-study, participants will only use the ERT seizure diary for the remainder of their 
participation in the main Study ZX008-1503.  Efficacy analyses for sub-study participants that 
rely on the ERT seizure diary or that are specific to the Embrace watch will not be included in 
the main ZX008-1503 analyses.  
At the time of consent for the main Study ZX008-1503 subjects will also be presented with the 
consent for this sub-study. Subjects who consent to participate in the sub-study will be fitted 
with an Embrace watch at Study Visit 1. Subjects (and/or parents/caregivers) will also be given 
instructions on how to use the Embrace system. The Alert app must be running on the provided 
iPod touch and remain in close proximity of the patient. However, parents/caregivers will 
continue to use the ERT seizure diary to record the number/type of seizures, use of rescue 
medication, and study drug administration.  
At pre-determined assessment times, parents/caregivers will complete questionnaires specific 
for the sub-study, including: 
1. Ease of Use Questionnaire, which comprises a 5-point Likert scale (1- Very easy, to 
5- Very difficult). 
2. Perceived Stress Scale (PSS), which consists of 10 items. 
3. Parents/caregivers will also complete the EQ-5D-5L and HADS in order to assess 
quality of life while using the Embrace. 
A schedule of sub-study assessments is provided in Table 1.  
 
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Table 1: Schedule of Additional Assessments for Subjects Enrolled in the Sub-study 
Study Assessments 
 
OLE Treatment Period 
Visit Number 
Visit 1a 
Visit 2 
Visits 3-4 
(Months 1-2) b 
Visit 5 (EOS/ET) 
Month 12 c 
Study Day 
1a 
15 
30, 60 
90 
Clinic 
Phone 
Informed Consent 
X 
 
 
 
 
Entry Criteria 
X 
 
 
 
 
Issue/fit Embrace watch system and 
provide instructions on its use 
 
X 
 
 
 
 
Perceived Stress Scale (PSS) 
X 
 
 
X 
X 
Ease of Use Questionnaire 
 
X 
 
X 
X 
EQ-5D-5L (QoL of parent/caregiver) 
X 
 
 
X 
X 
HADS (Affect of parent/caregiver) 
X 
 
 
X 
X 
Abbreviations: EOS/ET=End of Study/Early Termination; HADS=Hospital Anxiety and Depression Scale; 
OLE=open-label extension; PSS=Perceived Stress Scale; QoL=Quality of Life 
Note: All other Study ZX008-1503 procedures must be completed as described in the main study protocol. 
a Visit 1/Day 1 for sub-study ZX008-1503-SS01 corresponds to Visit 1/Day 1 for the main Study ZX008-1503. 
b Subjects who continue for an additional 3 months will repeat Study Day 30 and 60 procedures on Study Days 90 
and 120, and the end of study visit will be Study Day 150. 
c At EOS/ET, subjects will be required to return the Embrace watch and study iPod. 
3.2 
NUMBER OF SUBJECTS 
Up to 20 subjects from the main Study ZX008-1503 will have the option to participate in 
sub-study ZX008-1503-SS01 upon separate consent and fulfillment of entry criteria as detailed 
in Sections 4.1 and 4.2.  Subjects will be approached sequentially until the target number of 
participants is reached. 
3.3 
STUDY DURATION 
The duration of the main Study ZX008-1503 for an individual who enters from 
Study ZX008-1501 or ZX008-1504 Cohort 2 is up to approximately 54 weeks. All subjects will 
receive ZX008 for up to approximately 52 weeks in Study ZX008-1503 and all subjects, 
including those who prematurely discontinue from the study, will undergo an up to 2-week 
taper of study medication, at the conclusion of the study. Subjects will be permitted to 
participate in the sub-study for the initial 12 weeks of participation in the main OLE study 
(ZX008-1503).  Subjects may have the opportunity to extend participation in the sub-study for 
up to 24 weeks. 
3.4 
NUMBER OF STUDY CENTERS 
It is anticipated that sub-study subjects will be enrolled from approximately 5 to 10 study sites 
participating in both Study ZX008-1501 or ZX008-1504 and Study ZX008-1503. 
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3.5 
STUDY MONITORING PROCEDURES 
As in the main Study ZX008-1503, an Independent Data and Safety Monitoring Committee 
(IDSMC) will be responsible for safety oversight, and a separate International Pediatric 
Cardiology Advisory Board (IPCAB) will monitor the cardiac safety of the ZX008 clinical 
trials and provide advice to the IDMSC. 
4. 
SELECTION OF STUDY POPULATION 
Patients must fulfill all the entry criteria for Study ZX008-1503 and none of the exclusion 
criteria, as shown in Sections 4.1 and 4.2, respectively, to qualify for randomization into this 
sub-study.  
4.1 
INCLUSION CRITERIA 
In addition to meeting all of the main Study ZX008-1503 inclusion criteria subjects in the sub-
study must also be willing to wear and use the Embrace watch and parents/caregivers must be 
willing to use the Alert app. This includes: 
1. Subject is willing to wear the Embrace watch on the wrist (alternatively ankle, if needed 
for younger children). Subjects are asked to wear the watch for as many hours of the 
day as possible and for the entire night, if possible, for the duration of the sub-study. 
2. Subject’s parent/caregiver is willing to use the Alert App and receive voice and SMS 
notifications on their personal smart-phone, and ensure the smart-phone has internet 
connectivity; iOS 8.2 or higher is required for iPhone users. 
3. Subject/subject’s caregiver is willing to ensure that the Embrace watch remains within 
close proximity of the paired iPod Touch running the Empatica Alert app. 
4. Subject/subject’s caregiver is willing to ensure that the Embrace system is properly 
stored when not in use, and is not left exposed to direct sunlight, moisture, humidity or 
rain while in storage. The Embrace watch is water resistant but should never be 
submerged in water. Bathing and/or showering with the watch is acceptable, however.  
5. Subject/subject’s caregiver is willing to regularly clean the Embrace watch, routinely 
inspect the watch for sharp edges and damage, and ensure the watch is never worn over 
damaged or broken skin. 
6. Subject/subject’s caregiver is willing to ensure that the Embrace system is properly 
charged daily during a time when the subject is being observed so any seizures that 
occur during times that the device is not being worn are able to be added to the record 
manually. 
 
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4.2 
EXCLUSION CRITERIA 
Subjects meeting any of main Study ZX008-1503 exclusion criteria must not be enrolled into 
the sub-study. In addition, subject must not be enrolled into the sub-study if: 
1. Subject has a known hypersensitivity to any of the Embrace device materials. 
2. Subject has a clinically significant condition, or has had clinically relevant symptoms or 
a clinically significant illness in the 4 weeks prior to Visit 1, other than epilepsy, that 
would negatively impact study participation, collection of study data, or pose a risk to 
the subject. 
4.3 
SUBJECTS OF REPRODUCTIVE POTENTIAL 
Female subjects who are sexually active and are of child-bearing potential and male subjects 
who are sexually active with a partner of child-bearing potential must adhere to the 
contraception requirements as outlined in the main protocol ZX008-1503. 
4.4 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the sub-study for any reason at any time. Subjects who withdraw from the 
sub-study may still remain in the main study ZX008-1503. These subjects will then use only 
the ERT seizure diary. Subjects who are withdrawn from the main Study ZX008-1503 (either 
voluntarily or by the sponsor or investigator) must also be withdrawn from the sub-study. 
Subjects may be considered withdrawn or withdrawn by the investigator if they fail to return 
for visits, refuse to follow instructions regarding use of the Embrace watch or associated apps, 
lose or damage the Embrace in circumstances that do not support replacement, or become lost 
to follow-up for any other reason. All subjects who withdraw from the study early are required 
to return the Embrace watch and study iPod. 
If premature withdrawal occurs for any reason, the investigator must make a genuine effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the case report form (CRF). All subjects who withdraw from the study with 
an ongoing adverse event (AE) must be followed until the event is resolved or deemed stable. If 
a subject withdraws prematurely after dosing, all data to be collected prior to discharge from 
the clinical site should be collected at the time of premature discontinuation or at the scheduled 
discharge.   
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because they 
failed to appear for study visits without stating an intention to withdraw), the investigator 
should show "due diligence" by documenting in the source documents the steps taken to 
contact the subject (eg, dates of telephone calls, registered letters).  
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Subjects may withdraw their consent to participate in the study at any time without having to 
justify the reason for doing so. The decision to withdraw consent and discontinue participation 
in the study will not prejudice the subject’s future medical treatment in any way.  
In the event that the study is terminated prematurely then the procedure for termination should 
be followed as described in the main Study ZX008-1503 protocol. Concern for the interests of 
the subject will always prevail over the interests of the study. 
The reason for, and date of discontinuation from participation in the study must be recorded in 
detail in the CRF and in the subject’s medical records (eg, AEs, lack of compliance, lost to 
follow-up, etc.). If possible, the subject/subject’s legal representative should confirm his 
decision in writing. 
The investigator will attempt to complete all procedures usually required at the end of the study 
at the time when the subject’s participation in the study is discontinued or as close as possible 
to that time, as described in the ZX008-1503 protocol. As far as possible, a complete final 
examination must be performed on all subjects who do not complete the study according to the 
study protocol.  
Data collected until the time a subject discontinues participation in the study will be handled in 
the same manner as data for subjects completing the study. Where possible, further information 
will be collected if any AEs are experienced by a subject after discontinuing participation in the 
study. 
4.5 
TERMINATION OF THE SUB-STUDY 
If the investigator, the sponsor, the Medical Monitor, or the IDSMC becomes aware of 
conditions or events that suggest a possible hazard to subjects if the clinical study or sub-study 
continues, then the sub-study may be terminated. The sub-study may be terminated at the 
sponsor’s discretion at any time also in the absence of such a finding. 
Conditions that may warrant termination of the sub-study include, but are not limited to: 
 The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in 
the clinical study. 
 Failure to enroll subjects at the required rate. 
 A decision of the sponsor to suspend or discontinue development of ZX008.  
 Lack of availability of the Embrace detection device. 
4.6 
REPLACEMENT OF SUBJECTS 
Enrolled subjects will not be replaced. 
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5. 
STUDY VISITS AND PROCEDURES 
Subjects participating in the sub-study will undergo all clinic visits and procedures included in 
the main Study ZX008-1503, plus additional procedures for the sub-study, as described in 
Table 1. The following questionnaires/scales will be completed at the specified time points: 
 To assess user experience with the Embrace watch system, a 5-point Likert Ease of Use 
Questionnaire (Appendix 1) will be completed at Clinic Visit 2 (Day 15), monthly at 
Clinic Visits 3-7, and at the end of study participation (Clinic Visit 8).  
 The Perceived Stress Scale (PSS) (Appendix 2) is the most widely used psychological 
instrument for measuring the perception of stress. It is a measure of the degree to which 
situations in one’s life are appraised as stressful. It is a 10-item scale that asks about 
feelings and thoughts during the last month. In each case, respondents are asked how 
often they felt a certain way. The PSS will be used to evaluate whether objective seizure 
detection and automated seizure alerts have any impact on perceived stress of the 
parent/caregiver. This scale will be completed at Clinic Visit 1 (Day 1), monthly at 
Clinic Visits 3-7, and at the end of study participation (Clinic Visit 8). 
 The EQ-5D-5L (see main StudyZX008-1503) is a standardized measure of health status 
used to provide a simple, generic assessment for clinical and economic appraisal. It 
consists of 6 questions and can be completed in less than 10 minutes. The EQ-5D-5L is 
included in the main study ZX008-1503, but for the sub-study the assessment should be 
as it relates to use of the Embrace watch. This questionnaire will be completed at Clinic 
Visit 1 (Day 1), monthly at Clinic Visits 3-7, and at the end of study participation 
(Clinic Visit 8). 
 The Hospital Anxiety and Depression Scale (HADS) (see main StudyZX008-1503) is a 
tool commonly used to determine the levels of anxiety and depression that a person is 
experiencing. It is a 14-item scale that generates ordinal data. Seven of the items relate 
to anxiety and 7 relate to depression. The HADS is included in the main study 
ZX008-1503, but for the sub-study the assessment should be as it relates to use of the 
Embrace watch. This scale will be completed at Clinic Visit 1 (Day 1) monthly at Clinic 
Visits 3-7, and at the end of study participation (Clinic Visit 8). 
6. 
INVESTIGATIONAL PRODUCT INFORMATION 
6.1 
ZX008 (FENFLURAMINE HYDROCHLORIDE ORAL SOLUTION) 
Sub-study subjects will receive ZX008 as part of their treatment in main Study ZX008-1503. A 
brief description of the ZX008 product is provided in Table 2. 
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Table 2: Investigational Medicinal Product – ZX008 
 
Study Product 
Substance Code 
ZX008  
Active Substance (INN) 
Fenfluramine Hydrochloride 
Trade Name 
Not applicable 
Formulation (including dosage form and strength) 
Solution 2.5 mg/mL 
Route/Mode of Administration  
Oral 
Manufacturer 
PCI Pharma Services on behalf of Zogenix 
International Limited 
 
ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated 
to an effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day). Study medication 
will be administered twice a day (BID) in equally divided doses with food. Please refer to the 
ZX008-1503 protocol for a detailed description of the ZX008 drug product and its 
administration. 
6.2 
EMPATICA EMBRACE SYSTEM 
6.2.1 
Hardware 
The Embrace wrist-worn monitoring device (Embrace watch; Figure 1) reads physiological 
data from the surface of the skin and can transmit it wirelessly to a receiver. More specifically 
the electronic device measures: EDA, skin temperature, and motion (3-axis acceleration and 3D 
orientation with a gyroscope). Designed to be non-stigmatising for patients, the device also 
displays time in an analog-like display. User interactions are via a 12- full-color light-emitting 
diode (LED) circular display, vibration motor for haptic feedback and capacitive touch button. 
Figure 1:  Embrace Wrist-worn Monitoring Device (Embrace Watch) 
 
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6.2.2 
Software 
Figure 2:  Embrace System Architecture 
 
 
6.2.2.1 
Embrace Alert App 
The Embrace Alert app detects events from user physiology, such as a convulsive seizure, and 
sends an alert to a caregiver through a phone call or text message. Real-time seizure detection 
and alerting is still experimental and is for investigational use only. It also collects raw data 
from Embrace hardware and sends is to a receiver (smart phone memory) and consequently to a 
cloud storage system for later retrieval. The Alert app runs on an iPod Touch and must remain 
in close proximity of the patient. The Alert app is also used for device configuration (eg, setting 
the clock and activating/deactivating night-mode which suppresses interactions) and firmware 
management. 
6.2.2.2 
MyEmbrace 
MyEmbrace is a secure web portal used to configure an Empatica account for patients. The 
MyEmbrace includes profile configuration and user guides. There is no user-data visualization 
in the MyEmbrace portal. 
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The study coordinator will configure the Embrace watch and paired phone on behalf of the 
patient and/or parent/caregiver. Custom documentation is to be prepared so patients and their 
parents/caregiver need not be exposed to the MyEmbrace interface at any time. 
6.2.3 
Usability of the Empatica Embrace Watch System (Embrace) 
In the context of investigational use, the experimental seizure detection and alert components 
can be activated for patients and caregivers with their informed consent about the experimental 
nature of the functionality. Usability testing to support patient home-use has been underway 
since March 2016 with eight iterations introduced prior to August 2016 (revision history on 
hand as per the Embrace Change-log). In-app getting started guides, quick-start documentation 
and troubleshooting guides are sufficient to support the vast majority of patient caregiver 
groups in current trials. Due to the fact that patients/caregivers will be enrolled by study staff, 
those who might otherwise be unable to get set-up independently should be able to be enrolled 
and on-boarded without issue. The Empatica Alert app Onboarding screens are shown in Figure 
3, and also provided in Appendix 3. 
Figure 3:  Empatica Alert App Onboarding Screens 
 
6.2.4 
Device Risks 
The Embrace watch system is currently marketed in the United States for consumer use in sleep 
and activity tracking without the seizure detection and alerting components. It does not 
currently have FDA 510(k) clearance but was designed in compliance with IEC 
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60601-1-2:2014 standards. Empatica, the maker of the Embrace system, is a medical device 
company in compliance with EN ISO 13485 standards (cert No. 9124.EPTC). 
6.3 
BLINDING 
This is an open-label sub-study to OLE Study ZX008-5103.  
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
The Embrace is similar to other smartwatches that have been worn by patients over multiple 
days, and is believed to present minimal risk. The device passes a small current across the skin 
surface (similar to capacitive sensors in nature). It is non-invasive composed of well-
established materials used in wearable devices and designed with ISO 10993-5 standards. The 
only notable risk so far has been that some wearers of similar devices occasionally develop 
contact dermatitis. Risk of contact dermatitis has been mitigated by restricting the use of 
common allergens – including nickel and cobalt, which affect 11.8% and 2.3% of the 
population, respectively (Mortz, et al 2013) – in the device materials and selecting grades of 
stainless steel that have nickel levels well below those required by EU REACH regulations. 
Occasionally skin reactions in similar devices may be caused by bacterial build-up on a watch 
or watch band as opposed to the material of the device itself so users will be reminded to clean 
the devices regularly.  
To date, there have been two reports of allergic reaction related to wearing the Embrace watch. 
Subjects will be instructed to use the sensor only on the surface of healthy skin, to clean 
the sensor regularly, and to stop wearing it if the skin becomes red, itchy, or broken in 
any way. 
The Embrace system does not transmit radio signals that may interfere with hospital equipment 
or life-sustaining medical equipment. While the device has the capability of wireless 
transmission, it uses the Bluetooth standard, which is a reserved 2.4 GHz frequency band used 
in consumer electronics and within transmission power requirements. The device is compliant 
with IEC 60601-1-2:2014, EN 300 301 328 489 standards on electromagnetic emissions and 
interference. The rechargeable LiPol battery has an integrated protection circuit and the power 
system meets IEC 62133 standards. 
Any unanticipated adverse device events (regardless of seriousness or severity) and 
unanticipated problems related to study participation should be reported as in the main 
Study ZX008-1503. 
The physiological signals recorded using this device will not be used to make diagnostic or 
treatment decisions. 
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Safety monitoring will be done as per the main Study ZX008-1503 protocol.  
8. 
STATISTICS 
8.1 
SAMPLE SIZE 
This sub-study is designed as a pilot exploratory study to provide preliminary information on 
the ease of use of the Embrace watch to detect seizures in outpatients with Dravet syndrome, 
therefore, the sample size is based on feasibility.  
8.2 
ANALYSIS POPULATIONS 
8.2.1 
Safety (SAF) Population  
Participants in the sub-study will be included in the main Study 1503 safety analyses, which 
will be performed on the SAF Population defined as all subjects who receive at least one dose 
of ZX008 during the open label extension. 
8.2.2 
Embrace Treatment (EmB) Population  
The EmB Population for the sub-study is defined as all subjects who receive at least one dose 
of ZX008 and have valid Embrace seizure data for at least one week during the open label 
extension. Effectiveness analyses for the sub-study will be performed on the EmB Population. 
8.3 
DATA ANALYSIS 
8.3.1 
Safety Analysis 
Safety criteria will be identical to that in the main study ZX008-1503, and include AEs, 
laboratory safety parameters (hematology, chemistry, and urinalysis), vital signs (blood 
pressure, heart rate, temperature, and respiratory rate), physical examination, neurological 
examination, 12-lead electrocardiograms (ECGs), Doppler ECHOs, and body weight. The 
BRIEF will be administered to track cognitive function. Adverse events considered to be 
related to the Embrace watch will be analyzed separately for participants in the sub-study. 
8.3.2 
Efficacy Analysis 
The primary criteria for evaluation in the sub-study is the change over time in the 5-point Likert 
Ease of Use Questionnaire to measure user experience. 
Secondary exploratory efficacy criteria for evaluation include change over time in the 
following: 
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 Perceived Stress Scale (PSS) to measure caregiver burden. 
 Correlation of monthly (28-day) convulsive seizure count between the Embrace watch 
and seizure diary. 
 Size of EDA response during and in the post-ictal hour of convulsive seizures. 
 Skin-surface temperature (measured on wrist). 
 Frequency of fever-related convulsive seizures. 
 Comparison of convulsive seizure count during periods of sleep, and during the 
combined titration and maintenance periods between the Embrace watch and seizure 
diary. 
 Correlation of convulsive seizure time and classification as determined by Embrace 
watch and seizure diary. 
 EQ-5D-5L to measure quality of life of the parent/caregiver quality of life while using 
the Embrace. 
 HADS to measure affective symptoms of the parent/caregiver while using the Embrace. 
 
All other efficacy criteria are identical to those in the main Study ZX008-1503. 
8.4 
STATISTICAL METHODS 
All safety data will be summarized as described in the main Study ZX008-1503 protocol and 
associated Statistical Analysis Plan. Efficacy analyses for sub-study participants that rely on the 
ERT seizure diary or are specific to the Embrace will not be included in the main Study 
ZX008-1503 analyses. Exploratory data for the Embrace watch system data will be processed 
as follows: 
Continuous data will be summarized using descriptive statistics including means, standard 
deviations, medians, lower and upper quartiles, and ranges. Categorical variables will be 
summarized with frequencies and percentages. Confidence intervals will be calculated for key 
parameters or estimates as warranted. 
A complete description of the statistical analyses and methods will be available in the 
Statistical Analysis Plan, which will be finalized before the database is locked.  
The primary analysis will rely on descriptive statistics to summarize responses to the Ease of 
Use Questionnaire from each time point where the questionnaire is administered. In particular, 
the modal, ie, most frequent, response to each item on the questionnaire will be reported at each 
time point. Responses across all items on the questionnaire will be summed to create an overall 
index that will also be reported at each time point. 
Exploratory data for the Embrace watch system data will be processed as follows: 
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 Embrace’s automated convulsive seizure detection results will be manually compared to 
the diary counts of convulsive seizures. Spearman rank correlation will be used to 
quantify agreement. 
 The Spearman rank correlation described above will be repeated separately for events 
during periods of sleep and for events while awake, based on Embrace’s determination 
of sleep/wake (periods of sleep will be based on actigraphy and EDA as measured by 
the Embrace watch). 
 For each seizure, the peri-ictal EDA recording will be segmented from 60 minutes 
before detected seizure onset to 120 minutes afterward. A“significant EDA response” is 
declared when an increase in skin conductance level of more than 2 times the standard 
deviation of the pre-ictal baseline occurs. The time of the beginning of such an EDA 
response is defined as “EDA_start,” the time of the maximum peak of the EDA 
response is defined as “EDA_peak,” and the point in time following this peak, when the 
EDA falls below 10% of the peak amplitude is defined as “EDA_end.” Significant EDA 
responses will be analyzed in terms of the amplitude of their EDA_peak, the response 
duration, defined as the difference between “EDA_end” and “EDA_start,” and the 
natural logarithm of the area under the curve (AUC) of the rising phase (from 
“EDA_start” to “EDA_peak”) and of the total response (from “EDA_start”to 
“EDA_end”), ie, LogAUCrise and LogAUCtot. These measures will be examined to see 
if they vary over time with the treatment. Each of the measures will be evaluated for 
changes over time using a mixed model repeated measures (MMRE) that allows for a 
different intercepts for each subject (ie, a random effect) but a common slope over time 
(ie, a fixed effect).   
 
Skin-surface temperature changes will be averaged daily and compared over time, with 
separate comparisons made for “seizure-free” periods and for “pre-seizure periods.” 
The duration of these periods will be based on average 60-minute intervals, but may 
also be examined more with shorter intervals. Changes in skin-surface temperature 
over time will be evaluated using similar MMREs as described above for EDA 
endpoints. 
9. 
DATA HANDLING PROCEDURES 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, study-required information and data, 
and other notes as appropriate. These records constitute source data.  
A CRF will be provided by the sponsor (or delegate) for each subject enrolled into the 
sub-study. Study site staff will enter data directly into the validated electronic data capture 
(EDC) system by completing the CRF via a secure internet connection. The investigator is 
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responsible for ensuring accurate and proper completion of the CRF for recording data 
according to the instructions given in the CRF.  
All entries in the CRF must be backed up by the relevant source data at the study site. All 
source data will be kept according to all applicable regulatory requirements. Source data must 
be completed legibly for each subject enrolled into the sub-study and signed by the investigator 
(or delegate).  
Data entry in the CRF must be completed in a timely manner so that they always reflect the 
latest observations on the subjects enrolled in the sub-study.  
All Embrace data will be automatically captured and stored in a de-identified manner on a 
secure MySQL database and/or secured Amazon S3 buckets as part of the Empatica production 
server and analytics backend. Individual subjects will be tracked by the de-identified subject id 
assigned to each subject at the consent. No personally identifiable information will be directly 
linked to BPT data. 
10. 
ETHICAL & REGULATORY CONSIDERATIONS 
The procedures set out in this study protocol are designed to ensure that the sponsor and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 
evaluation and documentation of this study, as described in ICH Topic E6 Guideline. ICH GCP 
is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve the participation of human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
protected, and that the clinical study data are credible. 
The sub-study will also be carried out according to all applicable international and national 
regulatory requirements. 
The sponsor and the investigator must inform each other (eg, during a study initiation visit, via 
e-mail, etc.) that all ethical and legal requirements have been met before the first subject is 
enrolled into the sub-study. 
10.1 
INFORMED CONSENT 
The investigator is responsible for obtaining a subject’s written informed consent to participate 
in the sub-study. 
A Subject Information Sheet and a master ICF will be prepared by the sponsor according to the 
provisions of ICH GCP and local legal requirements. 
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Before undergoing screening for possible enrollment into the sub-study, subjects must be 
informed, in an understandable form, about the nature, scope, and possible consequences of the 
study. This information must be given orally to subjects by a physician or medically qualified 
person (according to applicable regulatory requirements) who is well informed about the 
nature, scope, and possible consequences of the study. Written information about the study will 
also be provided in a Subject Information Sheet. The date on which this oral and written 
information on the study was provided to the subject, and by whom it was provided, must be 
documented in the ICF. 
As specified in ICH GCP Section 4.8 and the US 21CFR Section 50.25, the informed consent 
discussion must emphasize that participation in the sub-study is voluntary and that subjects 
have the right to withdraw their consent at any time without giving a reason and without any 
disadvantage for their subsequent care. 
Subjects must be given ample time and opportunity to inquire about details of the sub-study 
and to consider their participation in the sub-study. If, after reading the Subject Information 
Sheet and the ICF, consent is given to participate in the sub-study, then the ICF must be signed 
and personally dated by the subject and the person conducting the informed consent discussion 
(and an impartial witness, if required). The subject will be provided with a copy of the signed 
ICF.  
Verification of the signed ICF will be recorded in the subject’s CRF. The original signed ICF 
will be filed with the subject’s records and/or in the Investigator Study File. 
The Subject Information Sheet and ICF have to be approved by the IEC/IRB before they can be 
used in the study. 
The Subject Information Sheet and ICF must be revised whenever important new information 
becomes available that may be relevant to the subject’s consent. Any revision of these 
documents must be approved by the IEC/IRB before they can be used in the study. Subjects 
must be informed in a timely manner if new information becomes available that may be 
relevant to their willingness to continue participation in the study. The communication of this 
information should be documented by having all parties concerned sign and personally date the 
revised ICF. 
Subject or Subject’s Legally Acceptable Representative Unable to Read 
If a subject is unable to read, or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. After the 
ICF and any other written information provided to the subject, parent or guardian has been read 
and explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
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participation in the study and, if capable of doing so, has signed and personally dated the ICF, 
the witness should also sign and personally date the ICF. By signing the ICF, the witness attests 
that the information in the ICF and any other written information was accurately explained to, 
and apparently understood by, the subject or the subject’s legally acceptable representative, and 
that informed consent was freely given by the subject or the subject’s legally acceptable 
representative. 
Assent for Subjects Under the Age of Consent (Pediatric Subjects) 
All subjects are under the age of consent (ie, pediatric subjects under 18 years of age); the 
written informed consent of a legally acceptable representative is required. Pediatric subjects 
who can understand the nature, scope, and possible consequences of the study must also give 
their assent, orally and/or in writing via the assent document, as appropriate. After the ICF and 
any other written information to be provided to subjects has been read and explained to the 
subject and the subject’s legally acceptable representative, and after the subject and the legally 
acceptable representative have orally consented to the subject’s participation in the study and, if 
capable of doing so, the subject has signed and personally dated the assent document, the 
legally acceptable representative should sign and personally date the ICF. By signing the ICF, 
the legally acceptable representative attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that assent was freely given by the subject. 
10.2 
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD 
The sponsor (or delegate) will submit the appropriate documents to all applicable competent 
regulatory authorities and IEC/IRBs, and will await all relevant approval before enrolling any 
subjects into the study. Written approval should mention the study protocol by study title, study 
number, and version date. 
This study will be conducted under Investigational New Drug (IND) Application and 
documented in accordance with the applicable regulatory guidelines and requirements. 
The sponsor (delegate) will ensure that the investigators conduct the study as stipulated in this 
study protocol and in accordance with all applicable regulatory requirements. The sponsor 
(delegate) is obliged to obtain evidence of the investigator’s qualification to perform the 
clinical study. Therefore, the investigator has to provide a signed and dated copy of his or her 
professional curriculum vitae (prepared no more than 2 years beforehand and preferably written 
in English) before the start of the study, including information on his or her experience in 
conducting clinical studies according to ICH GCP and other applicable regulatory 
requirements. 
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Written notification of the identity and occupation of the members of the IEC/IRB is also 
required by the sponsor (delegate). Should the IEC/IRB be unwilling to provide this 
information, a letter stating that the committee was constituted in accordance with applicable 
regulatory requirements should be provided. 
10.3 
PROTOCOL COMPLIANCE  
The investigator must conduct the study in compliance with this sub-study protocol as agreed to 
by the sponsor and, if required, by any competent regulatory authority, and which has been 
approved by, or given a favorable opinion by, the IEC/IRB. 
The investigator should not implement any deviation from, or changes to, the sub-study 
protocol without agreement by the sponsor (delegate) and prior review and documented 
approval or favorable opinion from the IEC/IRB of an amendment to the sub-study protocol. 
Exceptions include only cases of medical emergency to address immediate hazards to sub-study 
subjects, or when the changes involve only logistic or administrative aspects of the sub-study. 
In the event of a medical emergency, the investigator at each site may institute any medical 
procedures deemed appropriate to address an immediate hazard to a subject without prior 
IEC/IRB approval or favorable opinion. As soon as possible, the implemented deviation or 
change, the reason(s) for it, and, if appropriate, the proposed study protocol amendment(s) 
should be submitted to: 
 The sponsor (delegate) for agreement. 
 The IEC/IRB for review and approval or favorable opinion (if required). 
 The applicable competent regulatory authority (if required). 
At the earliest opportunity, the investigator (or delegate) must inform the sponsor (delegate) 
about any notable protocol deviations and explain any deviation from the approved sub-study 
protocol in the CRF and/or in the Protocol Deviation Log, if applicable. 
11. 
ADMINISTRATIVE ASPECTS 
The administrative aspects of this sub-study are described in the main Study ZX008-1503 
protocol. 
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12. 
REFERENCE LIST 
Dravet C. Les epilepsies graves de l’enfant.  Vie Med. 1978;8:543–548. 
Hurst, DL.  Epidemiology of severe myoclonic epilepsy of infancy.  Epilepsia 1990;31:397-400. 
Mortz, C. G., Bindslev‐Jensen, C., & Andersen, K. E. (2013). Prevalence, incidence rates and 
persistence of contact allergy and allergic contact dermatitis in the Odense Adolescence Cohort 
Study: a 15‐year follow‐up.British Journal of Dermatology, 168(2), 318-325. 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in 
epilepsy. Epilepsia 2012;53, 227–233. 
Shorvon S, Tomson T.  Sudden unexpected death in epilepsy. Lancet 2011;378: 2028–38. 
 
 
 
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13. 
APPENDICES 
 
 
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APPENDIX 1 – LIKERT EASE OF USE QUESTIONNAIRE 
 
 
 
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APPENDIX 2 – PERCEIVED STRESS SCALE (PSS) 
 
 
 
 
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APPENDIX 3 – SUMMARY OF CHANGES 
Clarifications and changes were made to the protocol amendment 2.0, including removal of the 
Empatica Mate app (Empatica Mate Onboarding for iOS Devices) to collect and summarize 
seizure activity data, and inclusion of subjects who have successfully completed 14 weeks of 
treatment with ZX008 in Cohort 2 of study ZX008-1504. Parents/caregivers will use the ERT 
seizure diary to record the number/type of seizures.  
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial and 
non-substantive changes, such as the correction of typing or formatting errors, updated use of 
abbreviations, updating headers and footers, tables of contents, list of abbreviations, signature 
pages, etc, are not listed. Note that the list of specific changes below is presented in the order in 
which they appear in the protocol. 
Rationale:  Remove the Empatica Mate app for collecting and summarizing seizure activity data and 
clarify use of Embrace system for assessing quality of life.  
Original Text 
Amendment Text 
Synopsis Objectives and Section 2.2 Secondary 
Objectives: 
The secondary exploratory objectives of the 
study are: 
 To compare objective convulsive seizure 
count, as captured by the Embrace, to 
convulsive seizure count captured manually 
in the Embrace electronic seizure diary 
(Empatica’s Mate app, hand-held diary 
software running on an Apple iPod Touch 
or Apple/Android smartphone). 
Synopsis Objectives and Section 2.2 Secondary 
Objectives:  
The secondary exploratory objectives of the 
study are: 
 To compare objective convulsive seizure 
count, as captured by the Embrace, to 
convulsive seizure count captured manually 
in the Embrace electronic seizure diary 
(Empatica’s Mate app, hand-held diary 
software running on an Apple iPod Touch 
or Apple/Android smartphone). 
 To compare objective convulsive seizure 
count during periods of sleep, as captured by 
the Embrace, to convulsive seizure count 
during periods of sleep captured manually in 
the Embrace electronic seizure diary. 
 To compare objective convulsive seizure 
count during periods of sleep, as captured by 
the Embrace, to convulsive seizure count 
during periods of sleep captured manually in 
the Embrace electronic seizure diary. 
 To assess quality of life while using the 
Embrace and Alert app with the following 
measures: 
 To assess quality of life while using the 
Embrace and Alert app system with the 
following measures: 
Rationale: Update study plan to include subjects who have successfully completed 14 weeks of 
treatment with ZX008 in Cohort 2 of study ZX008-1504  
Original Text 
Amendment Text 
Synopsis Methodology: 
This is a sub-study to the ZX008-1503 OLE 
study. All participants in this sub-study will have 
Synopsis Methodology: 
This is a sub-study to the ZX008-1503 OLE 
study. All participants in this sub-study will have 
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participated in Study ZX008-1501 and then 
continued in Study ZX008-1503, which is a 
multicenter, open-label, long-term safety study of 
ZX008 (fenfluramine hydrochloride) in pediatric 
and young adult subjects with Dravet syndrome. 
The main Study ZX008-1503 consists of a 
12-month OLE Treatment Period and a 2-week 
Post-Dosing Period. Details of dose and dose-
adjustments are described in the main Study 
ZX008-1503.   
participated in Study ZX008-1501 or 
ZX008-1504 Cohort 2 and then continued in 
Study ZX008-1503, which is a multicenter, 
open-label, long-term safety study of ZX008 
(fenfluramine hydrochloride) in pediatric and 
young adult subjects with Dravet syndrome. The 
main Study ZX008-1503 consists of a 12-month 
OLE Treatment Period and a 2-week Post-Dosing 
Period. Details of dose and dose-adjustments are 
described in the main Study ZX008-1503.  
Rationale:  Remove the Empatica Mate app for collecting and summarizing seizure activity data and 
clarify use of ERT seizure diary at conclusion of sub-study. 
Original Text 
Amendment Text 
Synopsis Methodology: 
This sub-study will include up to 20 participants 
who meet the entry criteria for the main 
Study ZX008-1503 and who are willing to wear 
the Embrace watch and use the Embrace Alert 
app and Mate app per the user instructions for 
12 consecutive weeks. Those invited to 
participate will undergo all procedures included 
in the main Study ZX008-1503 during their 
participation in this sub-study, except recording 
seizures in the ERT seizure diary, plus any 
additional procedures specific for the sub-study. 
At the conclusion of the sub-study, participants 
will revert to using the ERT seizure diary for the 
remainder of their participation in the main Study 
ZX008-1503.  The sub-study participants will be 
included in the safety analyses for the main Study 
ZX008-1503, but will not be included in any 
efficacy analyses that require the ERT seizure 
diary, or are specific to the Embrace. 
At the time of consent for the main Study 
ZX008-1503 subjects will also be presented with 
the consent for this sub-study. Subjects who 
consent for the sub-study will be fitted with an 
Embrace watch at Study Visit 1. Subjects (and/or 
parents/caregivers) will also be given instructions 
on how to use the Embrace, the Embrace Alert 
app, and the Embrace Mate app. 
Parents/caregivers will use the Embrace Mate 
app instead of the ERT seizure diary to record the 
Synopsis Methodology: 
This sub-study will include up to 20 participants 
who meet the entry criteria for the main 
Study ZX008-1503 and who are willing to wear 
the Embrace watch and use the Embrace Alert 
app and Mate appsystem per the user instructions 
for 12 consecutive weeks. Those invited to 
participate will undergo all procedures included 
in the main Study ZX008-1503 during their 
participation in this sub-study, except recording 
seizures in the ERT seizure diary, plus any 
additional procedures specific for the sub-study. 
At the conclusion of the sub-study, participants 
will revert to only using the ERT seizure diary 
for the remainder of their participation in the 
main Study ZX008-1503. Efficacy analyses for 
sub-study participants that rely on the ERT 
seizure diary or that are specific to the 
Embrace watch will not be included in the 
main ZX008-1503 analyses.  The sub-study 
participants will be included in the safety 
analyses for the main Study ZX008-1503, but 
will not be included in any efficacy analyses that 
require the ERT seizure diary, or are specific to 
the Embrace. 
 
At the time of consent for the main Study 
ZX008-1503 subjects will also be presented with 
the consent for this sub-study. Subjects who 
consent for the sub-study will be fitted with an 
Embrace watch at Study Visit 1. Subjects (and/or 
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number/type of seizures. The Mate app has the 
option to be installed on a parent’s smartphone 
(iOS or Android). When installed on a 
smartphone the Mate app can be accessed from 
more than one device simultaneously (eg, two 
parents can both have it installed). The Alert app 
must be running on the provided iPod touch and 
remain in close proximity of the patient. 
parents/caregivers) will also be given instructions 
on how to use the Embrace, the Embrace Alert 
app, and the Embrace Mate app system. The 
Alert app must be running on the provided 
iPod touch and remain in close proximity of 
the patient.  However, Pparents/caregivers will 
continue to use the Embrace Mate app instead of 
the ERT seizure diary to record the number/type 
of seizures, rescue medications, and study drug 
administration. The Mate app has the option to 
be installed on a parent’s smartphone (iOS or 
Android). When installed on a smartphone the 
Mate app can be accessed from more than one 
device simultaneously (eg, two parents can both 
have it installed). The Alert app must be running 
on the provided iPod touch and remain in close 
proximity of the patient. 
Rationale:  Remove inclusion criteria for using the Empatica Mate app for collecting and 
summarizing seizure activity data. 
Original Text 
Amendment Text 
Synopsis Inclusion Criteria and Section 4.1: 
Subject must meet all of the entry criteria for the 
main Study ZX008-1503 to be eligible for the 
sub-study. In addition to meeting the above listed 
criteria, subjects in the sub-study must also be 
willing to wear and use the Embrace watch and 
parents/caregivers must be willing to use the 
Alert app and Mate app per the user instructions. 
 
Inclusion Criteria 4: Subject/subject’s caregiver 
is willing to ensure that the Embrace system is 
properly stored when not in use, and is not left 
exposed to direct sunlight, moisture, humidity or 
rain while in storage. The Embrace watch is 
water resistant but should never be submerged in 
water.   
Synopsis Inclusion Criteria and Section 4.1: 
Subject must meet all of the entry criteria for the 
main Study ZX008-1503 to be eligible for the 
sub-study. In addition to meeting the above listed 
criteria, subjects in the sub-study must also be 
willing to wear and use the Embrace watch and 
parents/caregivers must be willing to use the 
Alert app and Mate app per the user instructions. 
 
Inclusion Criteria 4: Subject/subject’s caregiver 
is willing to ensure that the Embrace system is 
properly stored when not in use, and is not left 
exposed to direct sunlight, moisture, humidity or 
rain while in storage. The Embrace watch is 
water resistant but should never be submerged in 
water. Bathing and/or showering with the 
watch is acceptable, however. 
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Rationale:  Remove description of the Empatica Mate app for collecting and summarizing seizure 
activity data. 
Original Text 
Amendment Text 
Synopsis:  Study Product, Dose, and Mode of 
Administration: 
Empatica Embrace watch system 
(Embrace)/Embrace Alert app/ Embrace Mate 
app: The noninvasive Embrace wrist-worn 
monitoring device, reads physiological data 
(EDA, skin temperature, and motion) from the 
surface of the skin and can transmit it wirelessly 
to a receiver. The watch is used in conjunction 
with the Embrace Alert app and Embrace Mate 
app. The Alert app detects events from user 
physiology, such as convulsive seizure, and sends 
an alert to a caregiver via a phone call or text 
message. The Alert app runs on an iPod Touch 
and must remain in close proximity of the 
patient. The Mate app is a diary-based interface 
running on an iPod Touch (or optionally on the 
parent/caregiver personal smartphone) for 
displaying summarized data pertaining to the 
user’s behavior. The Mate app can be used to log 
and characterize seizures that are detected by the 
Alert app in a semi-automated fashion; all seizure 
data reported by the Alert app will be visualized 
in the Mate app unless it is characterized as a 
False-Alarm. Seizures that are not detected can 
be manually entered into the record by 
patient/caregiver. 
Synopsis:  Study Product, Dose, and Mode of 
Administration: 
Empatica Embrace watch system 
(Embrace)/Embrace Alert app/ Embrace Mate 
app: The noninvasive Embrace wrist-worn 
monitoring device, reads physiological data 
(EDA, skin temperature, and motion) from the 
surface of the skin and can transmit it wirelessly 
to a receiver. The watch is used in conjunction 
with the Embrace Alert appand Embrace Mate 
app. The Alert app detects events from user 
physiology, such as convulsive seizures, and 
sends an alert to a caregiver via a phone call or 
text message. The Alert app runs on an iPod 
Touch and must remain in close proximity of the 
patient. The Mate app is a diary-based interface 
running on an iPod Touch (or optionally on the 
parent/caregiver personal smartphone) for 
displaying summarized data pertaining to the 
user’s behavior. The Mate app can be used to log 
and characterize seizures that are detected by the 
Alert app in a semi-automated fashion; all seizure 
data reported by the Alert app will be visualized 
in the Mate app unless it is characterized as a 
False-Alarm. Seizures that are not detected can 
be manually entered into the record by 
patient/caregiver. 
Rationale:  Clarify study objectives 
Original Text 
Amendment Text 
Synopsis Sample Size Determination and 
Section 8.1  
This sub-study is designed as a pilot exploratory 
study to provide preliminary information on the 
Embrace watch in outpatients with Dravet 
syndrome, therefore, the sample size is based 
more on feasibility than on power to detect 
differences. 
Synopsis Sample Size Determination and 
Section 8.1  
This sub-study is designed as a pilot exploratory 
study to provide preliminary information on the 
ease of use of the Embrace watch to detect 
seizures in outpatients with Dravet syndrome, 
therefore, the sample size is based more on 
feasibility than on power to detect differences. 
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Rationale:  Clarify evaluation criteria 
Original Text 
Amendment Text 
Synopsis Criteria for Evaluation and 
Section 8.3.2 
Secondary exploratory efficacy criteria for 
evaluation include change over time in the 
following: 
 
Perceived Stress Scale (PSS) to measure 
caregiver burden. 
 
Correlation of monthly (28-day) 
convulsive seizure count between the 
Embrace watch and seizure diary. 
 
Size of EDA response during and in the 
post-ictal hour following convulsive 
seizures. 
 
Skin-surface temperature (measured on 
wrist). 
 
Frequency of fever-related convulsive 
seizures. 
 
Comparison of convulsive seizure count 
during periods of sleep, during titration 
and maintenance, between the Embrace 
watch and seizure diary. 
 
Correlation of convulsive seizure time 
and classification as determined by 
Embrace watch and seizure diary. 
 
EQ-5D-5L to measure quality of life of 
the parent/caregiver while using the 
Embrace. 
 
HADS to measure affective symptoms of 
the parent/caregiver while using the 
Embrace. 
All other efficacy criteria are identical to those in 
the main Study ZX008-1503. 
Synopsis Criteria for Evaluation and 
Section 8.3.2 
Secondary exploratory efficacy criteria for 
evaluation include change over time in the 
following: 
 
Perceived Stress Scale (PSS) to measure 
caregiver burden. 
 
Correlation of monthly (28-day) 
convulsive seizure count between the 
Embrace watch and seizure diary. 
 
Size of EDA response during and in the 
post-ictal hour following of convulsive 
seizures. 
 
Skin-surface temperature (measured on 
wrist). 
 
Frequency of fever-related convulsive 
seizures. 
 
Comparison of convulsive seizure count 
during periods of sleep, and during the 
combined titration and maintenance 
periods, between the Embrace watch and 
seizure diary. 
 
Correlation of convulsive seizure time 
and classification as determined by 
Embrace watch and seizure diary. 
 
EQ-5D-5L to measure quality of life of 
the parent/caregiver while using the 
Embrace. 
 
HADS to measure affective symptoms of 
the parent/caregiver while using the 
Embrace. 
All other efficacy criteria are identical to those in 
the main Study ZX008-1503. 
Rationale: Update study plan to include subjects who have successfully completed 14 weeks of 
treatment with ZX008 in Cohort 2 of study ZX008-1504 
Original Text 
Amendment Text 
Section 3.1 Overall Study Design and Plan  
This is a sub-study to the ZX008-1503 OLE 
study. All participants in this sub-study will have 
participated in Study ZX008-1501 in the United 
Section 3.1 Overall Study Design and Plan 
This is a sub-study to the ZX008-1503 OLE 
study. All participants in this sub-study will have 
participated in Study ZX008-1501 or 
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Page 45 of 48 
States or Canada and then continued in 
Study ZX008-1503, which is a multicenter, 
open-label, long-term safety study of ZX008 
(fenfluramine hydrochloride) in pediatric and 
young adult subjects with Dravet syndrome. 
ZX008-1504 Cohort 2 in the United States or 
Canada and then continued in Study ZX008-
1503, which is a multicenter, open-label, long-
term safety study of ZX008 (fenfluramine 
hydrochloride) in pediatric and young adult 
subjects with Dravet syndrome. 
Rationale:  Remove the Empatica Mate app for collecting and summarizing seizure activity data, and 
clarify use of ERT seizure diary at conclusion of sub-study and at time of consent for main study. 
Original Text 
Amendment Text 
Section 3.1 Overall Study Design and Plan  
This sub-study will include up to 20 participants 
who meet the entry criteria for the main 
Study ZX008-1503 and who are willing to wear 
the Embrace watch and their parent/caregiver 
who is willing to use the Embrace Alert app and 
Embrace Mate app per the user instructions for 
12 consecutive weeks.  Those invited to 
participate will undergo all procedures included 
in the main Study ZX008-1503, plus any 
additional procedures for the sub-study. At the 
conclusion of the sub-study, participants will 
revert to using the ERT seizure diary for the 
remainder of their participation in the main Study 
ZX008-1503.  The sub-study participants will be 
included in the safety analyses for the main Study 
ZX008-1503, but will not be included in any 
efficacy analyses that require the ERT seizure 
diary, or are specific to the Embrace. 
 
At the time of consent for the main Study 
ZX008-1503 subjects will also be presented with 
the consent for this sub-study. Subjects who 
consent to participate in the sub-study will be 
fitted with an Embrace watch at Study Visit 1. 
Subjects (and/or parents/caregivers) will also be 
given instructions on how to use the Embrace, 
the Embrace Alert app, and the Embrace Mate 
app. Parents/caregivers will use the Embrace 
Mate app instead of the ERT seizure diary to 
record the number/type of seizures. The Mate app 
has the option to be installed on a parent’s 
smartphone (iOS or Android). When installed on 
a smartphone the Mate app can be accessed from 
more than one device simultaneously (eg, two 
parents can both have it installed). The Alert app 
Section 3.1 Overall Study Design and Plan 
This sub-study will include up to 20 participants 
who meet the entry criteria for the main 
Study ZX008-1503 and who are willing to wear 
the Embrace watch and their parent/caregiver 
who is willing to use the Embrace Alert app and 
Embrace Mate app per the user instructions for 
12 consecutive weeks.  Those invited to 
participate will undergo all procedures included 
in the main Study ZX008-1503, plus any 
additional procedures for the sub-study. At the 
conclusion of the sub-study, participants will 
revert to using only use the ERT seizure diary for 
the remainder of their participation in the main 
Study ZX008-1503.  Efficacy analyses for sub-
study participants that rely on the ERT 
seizure diary or that are specific to the 
Embrace watch will not be included in the 
main ZX008-1503 analyses.  The sub-study 
participants will be included in the safety 
analyses for the main Study ZX008-1503, but 
will not be included in any efficacy analyses that 
require the ERT seizure diary, or are specific to 
the Embrace. 
 
At the time of consent for the main Study 
ZX008-1503 subjects will also be presented with 
the consent for this sub-study. Subjects who 
consent to participate in the sub-study will be 
fitted with an Embrace watch at Study Visit 1. 
Subjects (and/or parents/caregivers) will also be 
given instructions on how to use the Embrace 
system,the Embrace Alert app, and the Embrace 
Mate app. The Alert app must be running on 
provided iPod touch and remain in close 
proximity of the patient. However, 
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Zogenix International Limited 
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Page 46 of 48 
must be running on provided iPod touch and 
remain in close proximity of the patient. 
Pparents/caregivers will continue to use the 
Embrace Mate app instead of the ERT seizure 
diary to record the number/type of seizures, use 
of rescue medication, and study drug 
administration. The Mate app has the option to 
be installed on a parent’s smartphone (iOS or 
Android). When installed on a smartphone the 
Mate app can be accessed from more than one 
device simultaneously (eg, two parents can both 
have it installed). The Alert app must be running 
on provided iPod touch and remain in close 
proximity of the patient. 
Rationale: Update study duration to include subjects who enter the study from ZX008-1504, Cohort 2 
Original Text 
Amendment Text 
Section 3.3 Study Duration  
The duration of the main Study ZX008-1503 for 
an individual who enters from 
Study ZX008-1501 is up to approximately 54 
weeks. All subjects will receive ZX008 for up to 
approximately 52 weeks in Study ZX008-1503 
and all subjects, including those who prematurely 
discontinue from the study, will undergo an up to 
2-week taper of study medication, at the 
conclusion of the study.  
Section 3.3 Study Duration The duration of the 
main Study ZX008-1503 for an individual who 
enters from Study ZX008-1501 or ZX008-1504 
Cohort 2 is up to approximately 54 weeks. All 
subjects will receive ZX008 for up to 
approximately 52 weeks in Study ZX008-1503 
and all subjects, including those who prematurely 
discontinue from the study, will undergo an up to 
2-week taper of study medication, at the 
conclusion of the study. 
Rationale: Increase the number of study centers and clarify that subjects from ZX008-1504, Cohort 2 
can participate in the study. 
Original Text 
Amendment Text 
Section 3.4 Number of Study Centers 
It is anticipated that sub-study subjects will be 
enrolled from approximately 3 to 5 study sites 
participating in both Study ZX008-1501 and 
Study ZX008-1503. 
Section 3.4 Number of Study Centers 
It is anticipated that sub-study subjects will be 
enrolled from approximately 3 to 5 5 to 10 study 
sites participating in both Study ZX008-1501 or 
ZX008-1504 and Study ZX008-1503. 
Rationale:  Remove the Empatica Mate app for collecting and summarizing seizure activity data. 
Original Text 
Amendment Text 
Section 4.1 Inclusion Criteria 
In addition to meeting all of the main Study 
ZX008-1503 inclusion criteria subjects in the 
sub-study must also be willing to wear and use 
the Embrace watch and parents/caregivers must 
be willing to use the Alert app and Mate app. 
Section 4.1 Inclusion Criteria  
In addition to meeting all of the main Study 
ZX008-1503 inclusion criteria subjects in the 
sub-study must also be willing to wear and use 
the Embrace watch and parents/caregivers must 
be willing to use the Alert app and Mate app. 
Rationale:  Clarify use of ERT seizure diary for subjects who withdraw early from sub-study. 
Original Text 
Amendment Text 
Section 4.4 Removal of Subjects from Therapy or 
Assessment 
Section 4.4 Removal of Subjects from Therapy or 
Assessment 
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Page 47 of 48 
While subjects are encouraged to complete all 
study evaluations, subjects may voluntarily 
withdraw from the sub-study for any reason at 
any time. Subjects who withdraw from the 
sub-study may still remain in the main study 
ZX008-1503. These subjects will then use the 
ERT seizure diary. Subjects who are withdrawn 
from the main Study ZX008-1503 (either 
voluntarily or by the sponsor or investigator) 
must also be withdrawn from the sub-study. 
While subjects are encouraged to complete all 
study evaluations, subjects may voluntarily 
withdraw from the sub-study for any reason at 
any time. Subjects who withdraw from the 
sub-study may still remain in the main study 
ZX008-1503. These subjects will then use only 
the ERT seizure diary. Subjects who are 
withdrawn from the main Study ZX008-1503 
(either voluntarily or by the sponsor or 
investigator) must also be withdrawn from the 
sub-study. 
Rationale:  Remove description of the Empatica Mate app for collecting and summarizing seizure 
activity data. 
Original Text 
Amendment Text 
Section 6.2.2.1 Embrace Alert App 
The Embrace Alert app detects events from user 
physiology, such as a convulsive seizure, and 
sends an alert to a caregiver through a phone call 
or text message. Real-time seizure detection and 
alerting is still experimental and is for 
investigational use only. It also collects raw data 
from Embrace hardware and sends is to a 
receiver (smart phone memory) and consequently 
to a cloud storage system for later retrieval. The 
Alert app runs on an iPod Touch and must 
remain in close proximity of the patient. The 
Mate app is a diary-based interface for displaying 
summarized data pertaining to the user’s 
behavior. The Alert app is also used for device 
configuration (eg, setting the clock and 
activating/deactivating night-mode which 
suppresses interactions) and firmware 
management. 
Section 6.2.2.1 Embrace Alert App 
The Embrace Alert app detects events from user 
physiology, such as a convulsive seizure, and 
sends an alert to a caregiver through a phone call 
or text message. Real-time seizure detection and 
alerting is still experimental and is for 
investigational use only. It also collects raw data 
from Embrace hardware and sends is to a 
receiver (smart phone memory) and consequently 
to a cloud storage system for later retrieval. The 
Alert app runs on an iPod Touch and must 
remain in close proximity of the patient. The 
Mate app is a diary-based interface for displaying 
summarized data pertaining to the user’s 
behavior. The Alert app is also used for device 
configuration (eg, setting the clock and 
activating/deactivating night-mode which 
suppresses interactions) and firmware 
management. 
Rationale:  Remove description of the Empatica Mate app for collecting and summarizing seizure 
activity data. 
Original Text 
Amendment Text 
Section 6.2.2.2 Embrace Mate App 
The Embrace Mate app is a diary-based interface 
running on an iPod Touch (or optionally on the 
parent/caregiver personal smartphone) for 
displaying summarized data pertaining to user’s 
behaviour. Among these, there is detailed 
information about sleep behaviour, physical 
activity summarization, and the display of 
seizures detected by Embrace. The Mate app can 
Section 6.2.2.2 
The Embrace Mate app is a diary-based interface 
running on an iPod Touch (or optionally on the 
parent/caregiver personal smartphone) for 
displaying summarized data pertaining to user’s 
behaviour. Among these, there is detailed 
information about sleep behaviour, physical 
activity summarization, and the display of 
seizures detected by Embrace. The Mate app can 
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Page 48 of 48 
be used to log and characterize seizures that are 
detected by the Alert app in a semi-automated 
fashion; all seizure data reported by the Alert app 
will be visualized in the Mate app unless it is 
characterized as a False-Alarm. Seizures that are 
not detected can be manually entered into the 
record by the patient/caregiver. The Mate app 
retrieves information from Empatica’s cloud, not 
the Embrace directly, so it can be optimally 
installed on a parent’s/caregiver’s smartphone 
that is not in continuous proximity to the 
Embrace watch. Mate can be used to characterize 
seizures detected with the Alert app, report 
missed seizures, and report false alarms. The 
Empatica Mate App Seizure Logging screens are 
shown in Figure 3. 
Figure 3: Empatica Mate App Seizure Logging 
Screens [figure not shown] 
be used to log and characterize seizures that are 
detected by the Alert app in a semi-automated 
fashion; all seizure data reported by the Alert app 
will be visualized in the Mate app unless it is 
characterized as a False-Alarm. Seizures that are 
not detected can be manually entered into the 
record by the patient/caregiver. The Mate app 
retrieves information from Empatica’s cloud, not 
the Embrace directly, so it can be optimally 
installed on a parent’s/caregiver’s smartphone 
that is not in continuous proximity to the 
Embrace watch. Mate can be used to characterize 
seizures detected with the Alert app, report 
missed seizures, and report false alarms. The 
Empatica Mate App Seizure Logging screens are 
shown in Figure 3. 
Figure 3: Empatica Mate App Seizure Logging 
Screens [figure not shown] 
Rationale:  Remove the appendix describing the Empatica Mate app for collecting and summarizing 
seizure activity data. 
Original Text 
Amendment Text 
Appendix 3 Empatica Mate Onboarding 
[Appendix 3 text and graphics not shown] 
Appendix 3 Empatica Mate Onboarding 
[Appendix 3 text and graphics not shown] 
 
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