A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome
Phase: PHASE3
Conditions: Dravet Syndrome, Seizure Disorder
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

16.1.1
Protocol and Protocol Amendments 
The latest global version of the protocol used during the study is provided in this section. 
Previous DQGcountry-specific versions of the protocol are available on request. 
For Study ZX008-1501: 
Protocol ZX008-1501 Amendment 3.0 dated 31-October-2016
For Study ZX008-1502: 
Protocol ZX008-1502 Amendment 2.0 dated 31-October-2016
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

Confidential 
Clinical Study Protocol 
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo- controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as an 
Adjunctive Therapy in Children and Young Adults with 
Dravet Syndrome
Study Number: 
ZX008-1501
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008
IND Number: 
125797
EudraCT Number: 
2015-004167-37 
Sponsor: 
Zogenix International Limited  
A wholly owned subsidiary of Zogenix, Inc.  
5858 Horton Street, Suite 455  
Emeryville, CA 94608 USA
Sponsor's Medical 
Contact: 
  
Date of Study  
Protocol: 
31 October 2016 (Protocol Amendment 3.0) 
18 January 2016 (Protocol Amendment 2) 
18 December 2015 (Protocol Amendment 1) 
02 November 2015 version 1.3 (Original Protocol) 
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. 
PUB
t
LIC 
A 94
A 9
BLIC
UBL
COPY 
imited 
imited 
sidia
idiary o
ry
et, Suite 
t, Suite 
4608 
608
This document 
Thi
Th
cannot
02
02
be 
Ja
18 Dec
18 Dec
used 
ber 2016
er 201
nuary 
uary 
to 
o support 
f Zo
Zo
55 5 
USA
SA
su
any 
ogenix,
genix
marketing 
08
authorization 
application 
in
and 
Novem
vem
any 
mber 201
mber 20
mber
mbe
extensions 
(Protoco
Protoc
6 (Pro
 (Pro
or variations 
, Inc.  
Inc.  
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 2 of 182
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. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 3 of 182
TABLE OF CONTENTS 
Clinical Study Protocol ................................................................................................................ 1
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT OF 
STUDY ........................................................................................................................... 2
TABLE OF CONTENTS ............................................................................................................. 3
SIGNATURE OF SPONSOR .................................................................................................... 10
SIGNATURE OF COORDINATING INVESTIGATOR ......................................................... 11
SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR ...................................................... 12
LIST OF ABBREVIATIONS .................................................................................................... 13
STUDY SYNOPSIS ................................................................................................................... 15
1.
INTRODUCTION ........................................................................................................ 25
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED ..... 25
1.1.1
Existing Treatment for Dravet Syndrome .............................................. 25
1.1.2
Other Antiepileptic Medications ............................................................ 26
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT ............. 26
1.3
PRECLINICAL DATA ......................................................................... 27
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT .... 28
1.5
RATIONALE FOR CURRENT STUDY .............................................. 28
1.6
RISK-BENEFIT ASSESSMENT .......................................................... 29
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 29
2.1
PRIMARY OBJECTIVE ....................................................................... 29
2.2
KEY SECONDARY OBJECTIVES ..................................................... 29
2.3
ADDITIONAL SECONDARY OBJECTIVES ..................................... 30
2.4
SAFETY OBJECTIVE .......................................................................... 31
2.5
PHARMACOKINETIC OBJECTIVE .................................................. 31
2.6
EXPLORATORY OBJECTIVE ............................................................ 31
2.7
STUDY ENDPOINTS ........................................................................... 31
2.7.1
Efficacy Endpoints ................................................................................. 31
2.7.2
Safety Endpoints .................................................................................... 32
2.7.3
Pharmacokinetic Endpoints ................................................................... 32
3.
INVESTIGATIONAL PLAN ....................................................................................... 32
PUBLIC 
Me
D INFO
 INFO
CAL DA
CAL DA
GROUN
GROUN
NAL
NA
COPY 
......
ATION 
ATION
Dravet Sy
Dravet S
edicat
dica
This document cannot 
RI
R
KEY
KEY
2.3
A
2.4
2.4
be 
VES A
ES 
MAR
MA
used
E FOR C
FOR 
NEFIT 
NEFIT 
AN
AN
to
A
INFOR
NFOR
support 
ndrom
drom
ons ...........
s .........
MATION
MATION
A ...........
.........
any 
.....
INDICA
INDIC
e ....
e
marketing 
.
..............
..........
...............
..........
...............
..........
...............
.........
.......
authorization 
2
.......... 3
......... 1
....... 
application 
SAFET
SAFE
5
PHA
PH
2.6
2.6
2.7
2
and
SECON
CON
DITION
DITIO
any 
END
END
OBJECT
OBJECT
DA
extens
M
sions 
ON S
ON S
............
............
ATION
ATION
URRENT
RREN
SSESSM
SESSM
PO
or
.........
.......
T
variations 
....
.............
..........
............
..........
ATION 
TION 
............
...........
thereof. 
0
.. 11
11
......... 12
...... 12
.......
......

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 4 of 182
3.1
OVERALL STUDY DESIGN AND PLAN .................................. 32
3.2
NUMBER OF SUBJECTS .................................................................... 33
3.3
STUDY DURATION ............................................................................ 33
3.4
NUMBER OF STUDY CENTERS ....................................................... 33
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS ...................................................................... 33
3.6
PREMATURE TERMINATION OF STUDY ...................................... 34
3.7
STUDY MONITORING PROCEDURES ............................................ 35
3.7.1
Independent Data and Safety Monitoring Committee ........................... 35
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) .................... 35
4.
SELECTION OF STUDY POPULATION .................................................................. 35
4.1
INCLUSION CRITERIA ...................................................................... 36
4.2
EXCLUSION CRITERIA ..................................................................... 37
4.3
RANDOMIZATION INCLUSION CRITERIA ................................... 38
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL ................................ 38
4.4.1
Sperm and Egg Donation ....................................................................... 39
4.4.2
Pregnancy............................................................................................... 40
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 40
4.6
TERMINATION OF THE CLINICAL STUDY ................................... 42
4.7
REPLACEMENT OF SUBJECTS ........................................................ 42
4.8
ELIGIBILITY FOR EXTENSION STUDY ......................................... 42
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION .......................... 42
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT ...... 43
5.1.1 Labeling and Packaging ......................................................................... 43
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO ............................................................................. 44
5.2.1 Labeling and Packaging ......................................................................... 44
5.3
SHIPMENT AND STORAGE .............................................................. 44
5.4
IMP ACCOUNTABILITY .................................................................... 44
5.5
TREATMENT ADMINISTRATION .................................................... 45
5.5.1 Randomization ....................................................................................... 45
5.5.2 Titration Period ...................................................................................... 45
5.5.3
Maintenance Period ............................................................................... 46
PUBLIC 
PR
Donatio
Donatio
..............
.............
VAL OF
VAL OF
NAT
NA
COPY 
......
............
...........
NCLUSIO
LUSIO
ODU
ODU
This document cannot 
ON
O
IDEN
IDEN
5.1.1
1.1 L
5.2
5.2
be 
GIBIL
BIL
NAL 
NAL
used
S
ION OF
ON OF
EMENT
MENT
TY
TY
to
...
UBJEC
UBJEC
support 
N CRI
CR
TIVE PO
IVE PO
................
...........
............
........
any 
.......
.............
...........
TER
TE
marketing 
.
..............
.........
................
..........
PCAB) ....
CAB) ..
...............
.........
.......
authorization 
.... 33
. 33
......... 3
....... 3
application 
DESC
DESC
AND
AN
5.2.1
5.2.1 L
5.3
5.3
and
TITY O
TY O
eling a
ling 
any 
FOR E
OR
EDICINA
DICINA
F
extensions
...........
......
.............
.............
S FROM
FROM
HE CL
HE CLI
OF SUB
F SUB
EX
or
ENTI
ENT
variations 
......
.............
.........
.............
..........
............
.........
RIA ......
IA ......
A
thereof. 
4
.. 35
35
.......... 35
......... 35
.......
......

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 5 of 182
5.5.4
Taper Period ........................................................................................... 46
5.5.5
Transition Period.................................................................................... 47
5.6
BLINDING ............................................................................................ 48
5.7
PRIOR AND CONCOMITANT MEDICATION ................................. 48
5.7.1
Vagal Nerve Stimulation ....................................................................... 49
5.7.2
Ketogenic Diet ....................................................................................... 49
5.7.3
Rescue Medication for Seizures ............................................................ 49
5.7.4
Prohibited Concomitant Medication and Food ...................................... 49
5.8
TREATMENT COMPLIANCE ............................................................ 50
6.
VISIT SCHEDULE ...................................................................................................... 50
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1) ......... 51
6.1.1
Screening, Clinic Visit 1 (Study Day -42) ............................................. 51
6.1.2
Phone Visit 2 (Study Day -21) ............................................................... 53
6.1.3
Clinic Visit 3 (Study Day -1): Randomization ...................................... 53
6.2
TITRATION AND MAINTENANCE PERIODS ................................ 55
6.2.1
Titration Period Study Day 1 ................................................................. 55
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) ................. 55
6.2.3
Clinic Visit 6 (Titration Period Study Day 15) ...................................... 55
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29) ............................... 56
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43) ............................... 56
6.2.6
Phone Visit 9 (Maintenance Period Study Day 57) ............................... 58
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71) ............................. 58
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85) ............................. 59
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination ............................................................................................ 59
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) ............. 61
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY 
DAY 197-281) ....................................................................................... 62
6.5
ESTIMATED BLOOD VOLUME COLLECTION .............................. 62
7.
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ................... 64
7.1
EFFICACY ASSESSMENTS ............................................................... 64
7.1.1
Seizure Assessments .............................................................................. 65
7.1.2
Clinical Global Impression - Improvement ........................................... 66
PUBLIC 
D MA
 M
od Study 
d Study 
its 4 and
ts 4 and
Visit 6 (
Visit 6 (
COPY 
y Day
y D
-21) ........
-21) ...
Day -1): R
ay -1): 
INT
INT
This document cannot 
Clini
Clini
.8
Pho
Pho
6.2.9
6.2.9
be
one Visi
one Vis
c V
c V
used 
Titra
tra
7 (Main
(Main
sit 8 (M
sit 8 (M
to 
5 (Ti
(Ti
ation
ation
support 
andomiz
ndomiz
ENANCE
NANC
Day 1 ........
y 1 ........
tration
trati
any 
..........
.......
.............
.......
t
marketing 
......
................
..............
...............
..........
...............
..........
STUDY 
STUDY
authorization 
. 49
49
....... 49
.... 49
.......
......
application 
Clin
Termin
Term
3
POS
PO
6.4
6.4
EF
E
and 
sit 
sit
ne Visit 1
Visit 1
ic Vi
c Vi
any
(Mainte
(Maint
10 (Ma
10 (M
extensions
.............
.........
n Period
Period
eriod Stu
iod St
enan
ance P
ce P
ntenan
tenan
or 
ERIOD
ERIO
variations 
........
......
DAY -1
DAY -1
.............
............
..............
..........
n .......
n .......
thereof. 
49
.... 49
. 49
........... 5
.......... 5

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 6 of 182
7.1.3
Quality of Life in Childhood Epilepsy Scale ......................................... 66
7.1.4
Pediatric Quality of Life Inventory (PedsQL) ....................................... 66
7.1.5
Parent/Caregiver Quality of Life ........................................................... 67
7.2
SAFETY ASSESSMENTS.................................................................... 67
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication ............................................................................................. 67
7.2.2
Physical Examinations ........................................................................... 67
7.2.3
Neurological Examinations .................................................................... 68
7.2.4
Vital Signs.............................................................................................. 68
7.2.5
Laboratory Measurements ..................................................................... 68
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s) ........................ 69
7.2.7
Electrocardiograms ................................................................................ 69
7.2.8
Doppler Echocardiography .................................................................... 70
7.2.9
Tanner Staging ....................................................................................... 70
7.2.10 Columbia-Suicide Severity Rating Scale ............................................... 70
7.2.11 Adverse Events ...................................................................................... 70
7.2.12 Behavior Rating Inventory of Executive Function (BRIEF) ................. 71
7.3
PHARMACOKINETIC ASSESSMENTS ............................................ 71
7.4
APPROPRIATENESS OF MEASUREMENTS ................................... 71
8.
ADVERSE EVENTS .................................................................................................... 71
8.1
DEFINITIONS ...................................................................................... 71
8.1.1
Adverse Events ...................................................................................... 71
8.1.2
Serious Adverse Events ......................................................................... 73
4.
Results in persistent or significant disability or incapacity. .................. 73
8.1.3
Adverse Events of Special Interest ........................................................ 73
8.1.4
Adverse Events Requiring Hospitalization ............................................ 75
8.2
SEVERITY OF ADVERSE EVENTS .................................................. 75
8.3
CAUSALITY OF ADVERSE EVENTS ............................................... 76
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING .. 77
8.5
ADVERSE EVENT REPORTING ....................................................... 77
8.5.1 Adverse Events ...................................................................................... 77
8.6
SERIOUS ADVERSE EVENTS REPORTING .................................... 77
PUBLIC 
Sev
Sev
.............
..........
ating Inv
ating Inv
MACOK
MACOK
PRI
PR
COPY 
......
..
.............
...........
..............
..............
erity R
erity 
This document cannot 
Adv
Adv
2
Serio
Serio
4.
R
8.1.3
8.1.3
be 
INITI
NITI
verse 
verse
used
ATENES
TENES
.............
..........
ON
ON
to
nt
ETIC A
ETIC 
support 
..........
.......
ating Scal
ting Sca
...............
...........
ory of E
ry of
any 
......
....
..............
............
......
marketing
...
..............
............
................
..........
................
..........
Drug(s) ..
Drug(s)
.......
authorization 
y y 
.... 67
.. 67
......... 6
....... 6
application
Adver
Adve
1.4.4
Adv
Ad
8.2
8.2
8.3
8
and
s Adve
Adve
ults in 
lts in
any 
........
.....
ents .......
nts .......
se
extensions 
..........
......
Ex
Executive
ecutive
SSESSM
SESSM
OF ME
OF ME
............
..........
or
.........
.......
variations 
......
..............
...........
.............
...........
..............
..........
............
...........
thereof. 
7
... 68
 68
.......... 68
......... 68
.......
......

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 7 of 182
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events ..... 78
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY 
INVESTIGATOR TO IEC/IRB ............................................................ 79
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR .................................. 79
8.9
FOLLOW-UP OF ADVERSE EVENTS .............................................. 79
8.9.1
Follow-up of Echocardiogram Findings ................................................ 79
8.10
PREGNANCY ....................................................................................... 82
9.
DATA HANDLING PROCEDURES .......................................................................... 82
9.1
RECORDING OF DATA ...................................................................... 82
9.2
DATA QUALITY ASSURANCE ......................................................... 82
9.3
RECORD RETENTION ........................................................................ 83
10.
STATISTICS ................................................................................................................ 83
10.1
DETERMINATION OF SAMPLE SIZE .............................................. 83
10.2
ANALYSIS POPULATIONS ............................................................... 83
10.2.1 Safety (SAF) Population ........................................................................ 83
10.2.2 Modified Intent-to-Treat (mITT) Population ......................................... 84
10.2.3 Per Protocol (PP) Population ................................................................. 84
10.3
TREATMENT GROUPS ...................................................................... 84
10.4
TREATMENT PERIODS...................................................................... 84
10.5
STATISTICAL ANALYSES AND METHODS .................................. 85
10.5.1 Efficacy Analyses .................................................................................. 85
10.5.2 Safety Analyses...................................................................................... 87
10.5.3 Pharmacokinetic Analyses ..................................................................... 87
10.6
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND 
SAFETY MONITORING COMMITTEE ............................................. 88
11.
ETHICAL & REGULATORY CONSIDERATIONS .................................................. 88
11.1
ETHICAL CONSIDERATIONS ........................................................... 88
11.2
INFORMED CONSENT ....................................................................... 88
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS
COMMITTEE/INSTITUTIONAL REVIEW BOARD......................... 90
11.4
PROTOCOL COMPLIANCE ............................................................... 90
12.
ADMINISTRATIVE ASPECTS .................................................................................. 91
PUBLIC
pulation
pulatio
ent-to-Tr
ent-to-T
ocol (PP)
col (PP)
TMEN
TM
COPY
...........
.........
SAMPL
SAMPL
ATIONS
TIONS
This document 
ETHI
ETH
cannot
2 Safety
Safet
0.5.3
5.3 Ph
Ph
10.6
10.6
be 
IST
icacy A
icacy A
used 
T GRO
GRO
ENT PE
NT PE
ICA
ICA
to
Populat
opula
U
support 
SIZ
SI
...............
.......
................
.........
at (mITT)
(mITT)
ion
any 
............
.........
ZE ......
E ...
marketing 
...........
......
...............
..........
...............
...........
................
..........
...........
.......
authorization 
9
.. 79
. 79
......... 79
....... 7
application 
ANA
ANA
SAFE
SAF
CAL & RE
L & R
11.1
11.1
1
and 
Analys
naly
rmacoki
macok
LY
LY
any 
AN
alyses .....
lyses ...
ses..
ses
extensions 
.......
...
) Populat
Populat
n ............
.........
S ..........
.........
IODS...
ODS..
ALY
ALY
or 
.....
..
.......
variations
.............
.........
.............
............
............
...........
.............
.........
thereof. 
 82
82
....... 82
.... 82
...........
.........

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 8 of 182
12.1
CLINICAL TRIAL AGREEMENT ...................................................... 91
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR ........................... 91
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE
 ............................................................................................................... 92
12.4
STUDY FILES AND MATERIALS ..................................................... 92
12.5
INITIATION OF THE STUDY ............................................................ 92
12.6
SUBJECT REIMBURSEMENT ........................................................... 93
12.7
LIABILITY AND INSURANCE .......................................................... 93
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY ............... 93
12.9
MONITORING OF THE STUDY ........................................................ 94
12.10 PROTOCOL AMENDMENTS ............................................................. 95
12.11 AUDITS AND INSPECTIONS............................................................. 95
12.12 CLINICAL STUDY REPORT .............................................................. 95
12.13 USE OF DATA AND PUBLICATIONS .............................................. 96
13.
REFERENCE LIST ...................................................................................................... 97
14.
APPENDICES .............................................................................................................. 99
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS ..................... 100
APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE ............................ 102
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION ....... 108
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE ....................... 118
APPENDIX 5 – TANNER STAGING ..................................................................................... 131
APPENDIX 6 – PEDSQL (INCLUDING FAMILY IMPACT MODULE) ............................ 133
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE ..................................................................... 144
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE ................................. 146
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES ........................ 147
APPENDIX 10 – PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES ................... 148
APPENDIX 11 – PROTOCOL AMENDMENT 2 SUMMARY OF CHANGES ................... 161
APPENDIX 12 – PROTOCOL AMENDMENT 3 SUMMARY OF CHANGES ................... 173
Table 1:
Schedule of Assessments........................................................................................................... 22
Table 2:
Investigational Medicinal Product – ZX008 .............................................................................43
Table 3:
Titration Algorithm ................................................................................................................... 46
Table 4:
Taper Algorithm........................................................................................................................ 47
Table 5:
Transition Algorithm................................................................................................................. 47
Table 6:
Time Windows for Assessments ............................................................................................... 50
PUBLIC 
.....
.............
..........
BI
BITED C
TED C
– SUIC
– SUICI
RAT
RA
COPY 
......
RT ........
RT .......
UBLICA
BLICA
........
.......
This document
DIX 10
DIX 10
PENDIX
ENDIX
APPEN
APPEN
Tab
Tab
T
cannot 
QL 
L 
Q-5D-5L 
5D-5L 
HOSPI
HOSP
9 – MA
– MA
be 
STAG
TAG
(INCL
(INC
used
NG INV
G INV
LIFE IN
IFE IN
IN
IN
to
ON
E SEVE
 SEV
support 
TION
ON
...............
..........
...............
...........
NCOMIT
COM
any 
.......
............
...........
S....
S
marketing 
.
..............
..........
LITY ......
ITY ...
...............
..........
...............
.........
.......
authorization 
92
.... 92
.. 92
......... 9
....... 9
application 
XIMUM
MUM
PROTOC
ROTO
11 – PRO
1 – PR
DIX 12 – P
X 12 –
Sche
Sche
and
QUESTI
UEST
AL ANX
L AN
any 
.......
.....
DING F
DING F
ON
extensions 
..........
......
TANT M
TANT M
RITY RA
TY RA
NTORY
NTORY
CHILDH
HILDH
or
........
.......
variations 
....
.............
..........
.............
..........
............
..........
............
..........
thereof. 
3
.. 93
93
......... 93
...... 93
.......
......

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 9 of 182
Table 7:
Schedule of Post-Treatment Cardiac Follow-up .......................................................................62
Table 8:
Estimated Blood Volume Collection*.......................................................................................63
Table 9:
Priorities for Blood Sample Collections....................................................................................64
Table 10:
Adverse Events of Special Interest...................................................................74
Table 11:
Severity Definition of Adverse Events.............................................................76
Table 12:
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings ......80
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
80
application and any extensions or variations thereof. 

This
ot be
ation 
d

03NOV2016
P
This
on 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 12 of 182
SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR
Study Number: 
ZX008-1501 
Study Title: 
A Multicenter, Randomized, Double-blind, 
Parallel Group, Placebo-controlled Trial of Two 
Fixed Doses of ZX008 (Fenfluramine 
Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with 
Dravet Syndrome 
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 & Affiliation):
Signature 
Date (Day/Month/Year) 
PUBLIC
y did
y
ecei
ceive a
ve a
col.
col.
d out by
d out by
UB
COPY 
by an 
by a
in accord
in acco
Harmoni
Harmo
regulator
egulator
rectio
rectio
This document 
Signa
Sign
um
cannot be used 
the in
e i
to 
nves
nves
o support
atio
tio
requirem
equire
will be in
will be
necessary 
ecessar
s
any 
penden
pende
nce with 
nce with
n (ICH
n (IC
mar
his study
is stud
t E
arketing 
tive
ive
with
ith
ar
authorization 
application 
ure 
re 
pl
and any 
an extensions 
instr
nstr
gator
ator
io
or
nt
ormed
orme
ucti
cti
variations 
y protoco
y protoc
Ethics
Ethics
the study
he stud
H) Guide
Guid
ts. I w
s. I w
s thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 13 of 182
LIST OF ABBREVIATIONS
ABBREVATION
DEFINITION
AE
Adverse Event
AED
antiepileptic drug
AESI
Adverse Event of Special Interest
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
AUC0-t
area under the concentration-time curve from time zero to time=t
BID
bis in die; two times per day
BMI
Body Mass Index
BRIEF
Behavior Rating Inventory for Executive Function
C-SSRS
Columbia-Suicide Severity Rating Scale
CBD
cannabidiol
CFR
Code of Federal Regulations
Cmax
Maximum observed concentration determined directly from the 
concentration-time profile
CYP
cytochrome P450
dL
Deciliter
DS
Dravet syndrome
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
electronic Case Report Form
EOS
End of study
EPAR
European Public Assessment Report
EQ-5D-5L
Standardized measure of health status
ET
Early Termination
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GH
Growth Hormone
GMP
Good Manufacturing Practices
HADS
Hospital Anxiety and Depression Scale
HR
Heart Rate
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDSMC
Independent Data and Safety Monitoring Committee
IEC
Independent Ethics Committee
IGF-1
Insulin-like Growth Factor-1
IMP
Investigational Medicinal Product
IPCAB
International Pediatric Cardiology Advisory Board
IRB
Institutional Review Board
ABBREVATION
DEFINITION
IU
International Unit
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response (System) 
KD
Ketogenic diet
kg
Kilogram
LH
Luteinizing Hormone
MCSF 
Mean Convulsive Seizure Frequency 
Y
PY
OP
CO
m
C C
ase Repor
e Repo
C
udy
udy
LIC
ean Publi
an Publi
BL
ndardized
dardized
UB
rly Term
rly T
PU
cle
cl
P
This document cannot be used to support any marketing authorization 
h
th
th
th
t
au
a
g
ting
et
ke
ar
ned directly
direc
ma
y 
any
t a
rt
po
Form
orm
pp
up
Assessmen
ssessm
su
measure of 
easure 
o
ination
ation
d to
Stimulating
mulati
d 
Clinical Pr
linical 
se
owth Horm
th Hor
us
Good Man
od M
e u
Hospita
Hospi
be
t
Hear
He
t b
ot
In
ot
ot
no
an
ca
t c
nt
CAB
AB
e
IRB
m
ABBRE
ABBR
um
o
IU
IU
oc
o
IV
o
application and any extensions or variations thereof. 
o
eo
eo
eo
ere
he
th
s
y from the 
from th
n
at
ria
a
v
or
o
ns
nt Report
Report
on
health statu
ealth st
sio
ns
g Hormone
Hormo
ten
ractice
ctice
xte
mone
n
ex
nufacturing
factur
y e
al Anxiety a
Anxiety 
ny
t Rate
Rate
a
formed Co
ormed 
d
Internatio
nternat
nd
Indepe
ndep
a
n
Inde
In
n
on
I
ion
on
ati
ca
lic
EVATION
VATIO
p
app
a

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 14 of 182
ABBREVATION
DEFINITION
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/kg/day 
milligram per kilogram per day 
min 
Minutes 
mITT 
modified Intent-to-Treat 
mL 
Milliliter 
PedsQL 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetics 
PP 
Per Protocol 
QoL 
Quality of Life 
QOLCE 
Quality of Life in Childhood Epilepsy 
QTcF 
corrected QT interval using Fredericia method 
SAE 
Serious Adverse Event 
SAF 
safety population 
SD 
Standard Deviation 
SMEI 
Severe Myoclonic Epilepsy Of Infancy 
SUDEP 
Sudden Unexpected Death in Epilepsy 
T+M 
Titration plus Maintenance Periods 
t1/2 
terminal half-life 
THC 
tetrahydrocannabinol 
Tmax 
time to maximum concentration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VNS 
Vagal Nerve Stimulator/Stimulation 
ZX008 
Fenfluramine Hydrochloride Oral Solution 
PU
nfluram
nflu
PUB
gal
gal
UBLIC
t of Norm
t of Norm
IC
c
lating H
lating 
C
IC
tates of A
ates of A
LI
d States
States P
BL
Nerve
Nerv
UB
PU
P
COPY 
Epile
Ep
Y
e Periods
e Period
Y
PY
l
OP
oncentr
ncen
CO
C
This document cannot be used
ine Hyd
Hyd
d
St
S
d
ed to 
armac
mac
mulato
mulato
to
t
supp
al
pport t
ion
on 
or
mone
one
po
pp
erica
rica
up
opei
op
s
any y
ny
an
a
marketing 
g
ng
tin
ket
rk
ar
ma
m
authorization 
h
th
uth
th
au
a
application and any extens
chloride O
hloride O
nsions s
ns
a
on
Stimulat
timulat
si
ns
te
or r
or
o variations 
ns
on
tio
iat
ri
va
v
thereof. 
o
eo
eo
e
er
the
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 15 of 182
STUDY SYNOPSIS 
Study Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled 
Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an 
Adjunctive Therapy in Children and Young Adults with Dravet Syndrome
Study Number: ZX008-1501
Study Product: Fenfluramine Hydrochloride Oral Solution, ZX008
Type of Study:
Efficacy, safety, and pharmacokinetics study
Indication Studied:
Adjunctive therapy in Dravet syndrome
Phase of Development: Phase III
Countries: North America
Sponsor: Zogenix International Limited
Coordinating Investigator: 
Joseph Sullivan, MD
University of California, San 
Francisco San Francisco, CA USA
Estimated Duration of Individual Subject Participation:
The duration of the participation in the study for an individual subject is expected to be up 
to 22 weeks, with a follow-up 3 to 6 months after the last dose of study medication for 
final safety monitoring.
Objectives: 
The primary objective of the study is: 
x
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome in children and young adults based on change in the 
frequency of convulsive seizures between baseline and the combined Titration and 
Maintenance Periods (T+M). 
The key secondary objectives of the study are: 
x
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome based on change in the frequency of convulsive seizures 
between baseline and T+M. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
x
The longest convulsive seizure-free interval.
See Statistical Methods (Section 10.5.1.3) for hierarchical testing 
procedure. Additional secondary efficacy objectives of the study are: 
x To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints:
o
The number of convulsive seizure-free days.
o
The proportion of subjects who achieve 75% reductions from baseline in 
convulsive seizure frequency.
o
The change from baseline in non-convulsive seizure frequency.
o
The change from baseline in convulsive + non-convulsive seizure frequency.
o
The incidence of rescue medication usage.
o
The incidence of hospitalization to treat seizures.
PUBLIC
mg/kg/day
g/kg/da
me in ch
me in ch
zures bet
zures bet
+M).
M)
of the s
of the s
08
08
COPY
n:
n
dividual
dividu
he last do
 last do
CO
This document
lo
istical M
tical M
dure. Ad
ure. Ad
x To de
To de
su
s
o
cannot
of subj
f subj
uency.
ncy.
ortion of 
tion of 
frequen
equen
ngest 
gest 
M
be
the ZX
ZX
on the f
on the f
used 
udy ar
y a
.2 mg/kg
mg/kg
ndrome b
drome b
M. 
M. 
0
to 
een
re:e:
support 
is superior
superio
dren and y
ren and 
baseli
bas
rtrt any 
ject is e
ect is 
of study m
of study m
marketing 
me
g
ng
tin
m
authorization 
h
th
uth
th
a
application
y.
onvulsive
onvulsiv
thods (Sec
ods (S
itional sec
ional s
monstrate t
monstrate
perior to pl
rior to
o
Th
T
o
and 
s wh
w
ubjects w
jects w
any 
0.2 and
0.2 an
owing en
owing e
ho achi
ho ac
extensions 
r to pla
o pl
young adu
ung ad
ne and th
ne and t
day is sup
ay is sup
sed on ch
ed on ch
or 
ace
variations 
pected to
pected to
medicati
medicati
on
va
thereof. 
e
re
re
er

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 16 of 182
o
The incidence of status epilepticus.
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are 
(independently) superior to placebo on the following endpoints:
o
Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator.
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver.
o
The change from baseline in the Quality of Life in Childhood Epilepsy 
(QOLCE) score to measure quality of life.
o
The change from baseline in the Pediatric Quality of Life Inventory™ (PedsQL) 
score.
o
The change from baseline in PedsQL Family Impact module score.
o
The change from baseline in the quality of life (QoL) of the parent/caregiver 
using the EQ- 5D-5L scale.
o
The change from baseline in affective symptoms of the parent/caregiver 
using the Hospital Anxiety and Depression Scale (HADS).
The safety objective of the study is: 
x
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, vital signs (blood pressure, heart rate, temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms (ECHO), and body weight. Cognitive 
Function will be assessed in subjects 5 years and older using the cognition domain score on 
the QOLCE. Cognitive function will be assessed using and age-appropriate versions of the 
BRIEF
The pharmacokinetics (PK) objective of the study is:
x
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in 
subjects ages 2-6 years and 6-18 years with Dravet syndrome.
The exploratory objectives of the study are:
x
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK 
endpoints.
Methodology:
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy, safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young adult 
subjects with Dravet syndrome. Approximately 30 study sites in North America are planned to 
participate. The 6-week Baseline Period will consist of the establishment of initial eligibility 
during a screening visit followed by an observation period where subjects will be assessed for 
baseline seizure activity based on recordings of daily seizure activity entered into a diary. Upon 
completion of the Baseline Period, subjects who qualify for the study will be randomized (1:1:1) 
in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
maximum dose: 30 mg/day) or placebo.
Randomization will be stratified by age group (< 6 years, 6 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in each age group. All subjects will be 
titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects will 
continue treatment at their randomly assigned dose over a 12-week Maintenance Period. Total 
treatment time from the beginning of the Titration Period through the end of the Maintenance 
Period is 14 weeks. At the end of the Maintenance Period (or early discontinuation), all subjects 
will undergo a 2-week taper or transition period (Post-Dosing Follow-Up) depending on whether 
they exit the study or are enrolled in the separate long-term open-label extension study. A follow-
up ECG and ECHO will be performed 3-6 months after study drug discontinuation for early 
PUBLIC
5 
ill be as
l be a
ive of the
ve of the
ZX008 0
ZX008 0
and
and 6-1
6-
f the st
f the
COPY 
0.2 an
0.2 
rameters,
ameters
eart
art rate, 
rate
ram
ams (EC
s (EC
years a
ears 
This document 
ion of
n o
ouble-bli
uble-bl
aximum d
imum d
Random
andom
treatm
treatm
titr
tit
o
cannot
K of 
of
t syndro
yndro
6-week B
week B
ning visi
ng visi
zure acti
ure acti
f the
f the
be
ble-blind
ble-blin
ZX0
ZX0
used 
ye
y
udy are:
are:
and 0.8 m
d 0.8 m
us
to 
 and 0
nd 0
ears wi
ars w
support 
mp
mp
HO), and
), and
d older usi
older u
sed using 
ed usi
udy is:
dy is:
0.8 m
8
any 
mg/kg
mg/k
ysical ex
ysical e
erature
eratu
b
marketing 
edsQ
nt/caregive
caregi
ent/caregiv
t/careg
S).
/da
authorization 
QL) 
QL) 
th
application 
fo
ity base
bas
Baseline P
Baseline
d manner 
mann
ose: 30 mg
se: 30 m
zation will 
tion wi
ent arms, a
t arms,
ed to their
d to their
ue tre
ue t
and
e. App
App
seline Pe
ine Pe
llowed
owed
d
any 
arallel-g
arallel-
when us
when 
roxi
extensions 
and
mg/kg/day
g/kg/da
h Dravet 
Dravet 
g/kg/day 
kg/day 
e
or
g the 
g the
d age-
age-
variations 
ver 
ay to pla
ay to pla
xaminatio
minatio
e, and res
and res
dy weig
y weig
co
thereof. 
er
re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 17 of 182
termination, or for those subjects who complete the study but do not enter the open-label 
extension study.
Parents/caregivers will use a diary daily to record the number/type of seizures, dosing, and use of 
rescue medication. A schedule of assessments is provided in Table 1.
External Individuals and 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. 
ECGs and Doppler ECHOs will be centrally read (Biomedical Systems, Inc.) and interpreted 
under blinded conditions using pre-specified criteria, and if necessary, with review by the IPCAB.
Number of Subjects:
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor.
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled 
into the study:
1.
Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug.
2.
Subject must have documented medical history to support a clinical diagnosis of 
Dravet syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs.
3.
Subjects must meet all of the following 5 criteria:
a.
Onset of seizures in the first year of life in an otherwise healthy infant.
b.
A history of seizures that are either generalized tonic-clonic or unilateral 
clonic or bilateral clonic, and are prolonged.
c.
Initial development is normal.
d.
History of normal brain MRI without cortical brain malformation.
e.
Lack of alternative diagnosis.
4.
Subjects must meet at least one of the following 3 criteria:
a.
Emergence of another seizure type, including myoclonic, generalized tonic-
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type.
b.
Prolonged exposure to warm temperatures induces seizures and/or seizures are 
associated with fevers due to illness or vaccines, hot baths, high levels of 
activity and sudden temperature changes and/or seizures are induced by strong 
natural and/or fluorescent lighting, as well as certain visual patterns.
c.
Genetic test results consistent with a diagnosis of Dravet syndrome 
(pathogenic, likely pathogenic, variant of unknown significance, or 
inconclusive but unlikely to support an alternative diagnosis.)
5.
Subject must have had 4 convulsive seizures (tonic, tonic-atonic, tonic-clonic, 
clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian 
report to investigator or investigator medical notes.
PUBLIC
ble f
ble
treated 
treated
nted med
nted med
e convuls
e convuls
f th
f t
COPY
female
fema
ects of ch
cts of ch
cts of chi
ts of ch
s of ch
of child
ild
forms
form
This document 
b
o
cannot
ve
y of no
of no
k of alte
of alte
must me
must me
Emerg
Emer
clon
clon
be
iz
ateral c
ral 
lopme
lopme
used 
e followi
followi
in the fir
n the fir
ures tha
res tha
to
cal 
e seizu
e seizu
support
dbear
bea
earing or
aring o
of birth co
f birth 
this study
his stud
history
histo
any 
2 to 18
2 to 1
bearing p
bearing p
ring p
ing
ma
on criteria 
n criteri
arketing 
he I
Baseline
Baseline
zed into the
d into t
m of 10 subj
of 10 su
g
ar
authorization 
ials.
ls.
ted
PCAB
PCA
th
a
application 
nce o
ce o
c, tonic, a
c, tonic,
pe.e.
Prolonged
Prolong
associa
assoc
acti
ac
n
c
and
al br
l br
native dia
tive di
t at least
at least
f an
f an
any 
e
c, and a
c, and
s normal
s normal
ain M
ain M
extensions 
y and 
and 
y to suppo
to supp
are not 
re not 
g 5 criter
5 criter
t year of l
year of 
e eithe
eithe
or
hil
hil
trol (se
rol (s
for
for
variations
to be enr
o be enr
years, inc
years, inc
potential 
tential 
otential m
ential m
d-fath
d-fa
ns 
je
ns thereof. 
e
cts
cts
re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 18 of 182
6.
All medications or interventions for epilepsy (including ketogenic diet [KD] and 
vagal nerve stimulation [VNS]) must be stable for at least 4 weeks prior to 
screening and are expected to remain stable throughout the study.
7.
Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian.
8.
Subject has provided assent in accordance with Institutional Review Board 
(IRB) requirements, if capable.
9.
Subject’s parent/caregiver is willing and able to be compliant with diary 
completion, visit schedule and study drug accountability.
Exclusion Criteria: All subjects must meet none of the following exclusion criteria to be 
enrolled into the study:
1.
Subject has a known hypersensitivity to fenfluramine or any of the excipients in 
the study medication.
2.
Subject has pulmonary arterial hypertension.
3.
Subject has current or past history of cardiovascular or cerebrovascular 
disease, such as cardiac valvulopathy, myocardial infarction or stroke. 
4.
Subject has current or recent history of Anorexia Nervosa, bulimia, or depression 
within the prior year that required medical treatment or psychological treatment for 
a duration greater than 1 month.
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s 
opinion, based on clinical interview and responses provided on the Columbia-
Suicide Severity Rating Scale (C-SSRS). Subjects must be excluded if they report 
suicidal behavior in the past 6 months as measured by the C-SSRS at Screening or 
Baseline, which includes suicidal ideation with intent and plan (Item #5). If a 
subject reports suicidal ideation on Item 4 without specific plan, and the 
investigator feels that the subject is appropriate for the study considering the 
potential risks, the investigator must document appropriateness for inclusion, and 
discuss with the parent/caregiver to be alert to mood or behavioral changes, 
especially around times of dose adjustment.
6.
Subject has a current or past history of glaucoma.
7.
Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x ULN) 
may be entered into the study after review and approval by the Medical Monitor in 
conjunction with the sponsor, in consideration of comorbidities and concomitant 
medications.
8.
Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine- oxidase inhibitors; any centrally-acting compound with clinically 
appreciable amount of serotonin agonist or antagonist properties, including serotonin 
reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; or 
cyproheptadine (see Appendix 1). (Note: Short- term medication requirements will be 
handled on a per case basis by the Medical Monitor.)
9.
Subject is currently receiving or has received stiripentol in the past 21 days 
prior to Screening.
10.
Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy.
11.
Subject is unwilling to refrain from large or daily servings of grapefruits and/or 
Seville oranges, and their juices beginning with the Baseline Period and 
PUBLIC 
SRS)
SRS)
months as
nths as
cidal idea
cidal idea
eation on
ation on
he subjec
he subjec
estigato
estig
COPY
Ner
Ne
atment o
atment 
or harm t
harm t
d respon
 respon
S
This document
no
appreci
preci
reupta
reupta
cyp
cyp
h
9.9
o
cannot
ent
d into t
into t
n with the
with th
ons.
ns.
ct is rece
is rece
amine
mine
b
be
or p
te or sev
te or se
(eleva
(elev
used
must d
ust 
giver to b
er to b
of dose ad
dose ad
ast hi
ast h
to
tem 4
m 
approp
appro
doc
support 
others
others
es provide
prov
bjects must
ects mu
measured b
asured 
on with in
n with in
4 with
4 wi
any 
ulim
lim
ycholog
ycholo
, ini
marketing 
be
ents in
nts in
scular
ular
stroke.
troke.
a, or
a
authorization 
th
au
application
ving c
ng 
oxidase i
oxidase 
e amount o
amoun
e inhibitio
inhibiti
oheptadine
oheptadin
andled on a
dled on
Subject is
ubject 
prior to
prior 
Sub
S
and
study
ud
sponsor, 
ponsor,
conc
onc
any 
ry y
hepatic
hepat
d liver en
liver en
y after
y aft
extensions
by the C
the 
ntent and 
ent and 
hout spec
ut spec
iate for th
te for t
ument ap
ment ap
alert to 
lert to
ustment.
tment.
of gl
ofgl
or 
on 
on
e exclu
e excl
C
variations 
r depressi
epress
cal treatm
al treatm
the inve
he inve
the
he
thereof. 
re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 19 of 182
throughout the study.
12.
Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole 
blood cannabidiol (CBD) at the Screening Visit.
13.
Subject has participated in another clinical trial within the past 30 days.
14.
Subject is currently receiving an investigational product.
15.
Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions.
16.
Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, 
that would negatively impact study participation, collection of study data, or pose a risk to 
the subject.
Randomization Inclusion Criteria: Subjects must meet all of the inclusion criteria above 
plus the following criteria, to be randomized:
1.
Subject has been approved for study inclusion by the Epilepsy Study Consortium.
2.
Subject does not have a cardiovascular or cardiopulmonary abnormality based on 
ECHO, ECG or physical examination, including but not limited to trace mitral or 
aortic valve regurgitation or signs of pulmonary hypertension, and is approved for 
entry by the central cardiac reader.
3.
Subject demonstrates a stable baseline with 6 convulsive seizures during the 
6-week Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the 
second 3 weeks.
4.
Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (e.g., at least 90% compliant).
Study Product, Dose, and Mode of Administration:
ZX008 is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. Subjects 
will be randomized to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
maximum dose: 30 mg/day) or placebo. Study medication will be administered twice a day 
(BID) in equally divided doses with food.
Reference Product, Dose, and Mode of Administration:
Matching ZX008 placebo is supplied as an oral solution.
Duration of Treatment:
All subjects will receive ZX008 or matching placebo for up to approximately 16 weeks (Titration 
Period=2 weeks; Maintenance Period=12 weeks; Taper/Transition Period=2 weeks). After 
completion of the Maintenance Period, eligible subjects may enroll in the open-label extension 
study, after completion of the transition. Subjects who do not enroll in the open-label extension 
study will undergo a taper off of study medication (doses will be administered in a blinded fashion
similar to the titration, i.e., doses will be decreased in 4-day increments). Follow-up 
cardiovascular safety assessments, including ECG and ECHO, will be performed 3 to 6 months 
following the last dose of study medication.
Criteria for Evaluation:
Efficacy:
x
Number of seizures by type 
x
Convulsive seizure-free interval 
x
Clinical Global Impression – Improvement as assessed by parent/caregiver 
x
Clinical Global Impression – Improvement as assessed by principal investigator 
x
QOLCE to measure changes in quality of life of the subject 
x
PedsQL to measure changes in quality of life of the subject 
x
PedsQL Family Impact module to measure changes in quality of life of the parent/caregiver 
PUBLIC 
n com
com
of the inv
f the in
Adminis
Admini
ion in co
on in co
1 of 2 dos
 of 2 dos
r place
r pla
i
LIC COPY 
hyp
y
6 conv
6 conv
m of 2 in t
of 2 in 
plia
plia
This docume
riteria fo
eria fo
Efficacy
Efficacy
cu
x
ment
the
he
ascular 
scular 
wing the
ng the
me
o
cannot
 ZX
ZX
ntenanc
enanc
Maintena
ainten
mpletion o
letion 
dergo a t
ergo a 
titrat
titrat
be 
X008 
X008
e
upp
pp
e used
o. Stud
Stud
h food.
od.
Mode of
ode of
lied a
lied a
se
to
centr
entr
of ZX0
of ZX
y
support 
e first
firs
t with diar
with di
stigator (e
igator (
ration:
ation:
ration
atio
up
any 
n, an
a
ve seizu
ve seizu
3 w
3
marketing 
se a
ria above
a above
y Consortiu
Consort
rmality bas
ality b
d to trace 
to trac
nd is a
nd is
ng authorization 
s or a
r a
pilepsy, 
ilepsy
risk 
risk 
th
applica
Evaluatio
Evalua
cation 
per of
er of
n, i.e., do
n, i.e., d
fety assess
ty asse
ast dose of
st dose 
Number o
Number 
Convul
Convu
i
ca
and 
Period
rio
nce Perio
e Perio
he tran
e tran
f o
f o
any 
matching
matchin
=12 
=1
y
n o
n o
y extensions 
y
.g., at 
, at 
s of 1.25
of 1.25
8 (0.2 mg
(0.2 m
medicatio
dicatio
ns
dminist
minist
ral s
rals
xt
or 
comple
omp
lea
l
variations 
um
sed on 
d on 
mitral or
mitral o
approved
proved
res durin
es durin
eeks and
ks and
thereof. 
o 
re
re
re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 20 of 182
x
QoL of parent/caregiver using the EQ-5D-5L scale 
x
Affective symptoms of parent/caregiver using the HADS scale 
x
Duration of prolonged seizures (seizure type that, during baseline, had duration >2 minutes) 
x
Number of episodes of status epilepticus 
x
Number of instances of rescue medication use and number of doses 
x
Number of inpatient hospital admissions due to seizures
Safety: 
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. The BRIEF will be 
administered to track cognitive function. 
Pharmacokinetics: 
Steady-state plasma fenfluramine PK parameters (maximum observed concentration determined 
directly from the concentration time profile [Cmax], area under the concentration time curve from 
time zero to time=t [AUC0-t], time to maximum concentration [Tmax], and terminal half-life 
[t1/2]) after administration of ZX008 derived using population PK methods.
Sample Size Determination:
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). 
The EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
stiripentol groups, the standard deviation (SD) of the percentage change in seizure frequency 
from baseline to month 2 was 42% in the French trial and 26% in the Italian trial. The analogous 
SDs for placebo groups were 38% and 62%. An SD of 50% was assumed for the primary analysis 
in this trial comparing ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure 
frequency. Using a two-sided test at the Į=0.05 significance level, a sample size of 35 subjects 
per treatment group affords 90% power to detect a difference in mean change from baseline of 
40 percentage points. Similar assumptions and calculations yield a requirement for an additional 
35 subjects in the 0.2 mg/kg/day ZX008 group. Thus, the total sample size is planned to be 
105 subjects (35 per arm).
Statistical Methods:
Study Populations:
Safety Population: All safety analyses will be performed on the Safety Population defined as all 
randomized subjects who receive at least one dose of study medication. Subjects will be analyzed 
according to the treatment actually received.
Modified Intent-to-Treat (mITT) Population: The mITT Population is defined as all randomized 
subjects who receive at least one dose of study medication and for whom at least 1 week of diary 
data are available. Subjects will be analyzed according to the treatment group to which they were 
randomized. The primary comparison of ZX008 0.8 mg/kg/day to placebo as well as key 
secondary efficacy assessments will be performed on the mITT Population.
Per Protocol (PP) Population: The PP Population is defined as all randomized subjects who 
receive at least one dose of ZX008 or placebo, complete the Maintenance Period, and have no 
major protocol violations that would have a significant impact on clinical outcome.
Efficacy
Primary Efficacy Analysis: The primary efficacy endpoint is the change in the mean convulsive 
seizure frequency (MCSF) per 28 days during the T+M periods compared with Baseline. The 
MCSF will be calculated from all available data collected during the Baseline and treatment 
PUBLIC
D)
French
French
62%. An
62%. An
g/kg/day
g/kg/day
t at the
t at the Į
% power
% powe
ssum
ssu
COPY
ed studie
ed studi
Report (E
Report 
udies: STI
dies: ST
of
of the 
the
f
t
This document
who r
ho 
e availab
vailab
omized. 
mized.
econdary
ondary
Per Pr
Per Pr
rece
rec
m
o
cannot
safety
afety
s who re
who re
treatmen
eatmen
ent-to-Tr
t-to-Tr
receiv
ece
be used
to d
o d
tions an
ons an
X008 gro
008 gr
u
to
0.05 si
0.05 s
detect 
etect 
support 
AR
AR
CLO Fra
O Fr
ercentage 
rcentag
al and 26%
and 2
SD of 50%
D of 50%
placebo 
laceb
gnif
any 
subjects
subject
R) for st
) for 
nc
marketing 
on determin
on determ
time curve
me cur
minal half
nal h
m
authorization 
th
application 
at (mIT
(mI
e at least o
at least 
. Subjects 
Subject
he primary
e prim
fficacy as
ficacy a
tocol (PP)
col (PP
e at least 
at least 
rotoc
rot
and
alyse
lys
eive at le
ve at le
actually 
ctually
TT)
TT)
any 
es will
s wi
y extensions
% in
% was as
was a
on the ch
on the ch
ficance le
cance l
differenc
ifferen
calalculatio
culati
up. Thus,
. Thus,
e
or
hange
hang
the I
the I
variations 
e fro
-life 
ife 
 with Dr
with Dr
iripentol
ipentol
and ST
and ST
in
io
thereof. 
ned 
ned 
om
re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 21 of 182
periods. The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with 
Baseline MCSF as a covariate. The primary analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at the alpha=0.05 level of significance. The 
primary endpoint will also be analyzed using a nonparametric method and if normality 
assumptions are not met, the results of the nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be performed to assess the sensitivity of the 
primary analysis to changes in concomitant AED medications that may occur during the course of 
the trial. Specifically, the primary analysis will be repeated with a factor added to indicate 
whether a subject had a change in concomitant AED medication during the T+M period.
Safety
All safety data will be appropriately analyzed by treatment group. The number and percentage of 
subjects with AEs will be displayed by body system and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries in terms of severity and relationship 
to study drug will also be provided. Adverse Events of Special Interest (AESI) and Serious AEs 
(SAEs) will be summarized separately in a similar manner. Laboratory tests, vital signs, physical 
examinations, neurological examinations, ECG, Doppler echocardiogram, C-SSRS, Tanner 
Staging results, etc, will be summarized appropriately, by treatment. All safety summaries will be 
based on the Safety Population.
Pharmacokinetics
A population PK model will be fit to the fenfluramine concentration-time data collected during 
the Maintenance Period. This model will be informed by all relevant data available at the time of 
data collection (both adults and pediatrics). The population mean and interindividual variability 
estimates from the fit of the population PK model will be summarized. Derived plasma PK 
parameters (Cmax, AUC0-t, Tmax, and t1/2) will be summarized descriptively by treatment 
group and compared to historical data from adults. Summary statistics for plasma concentrations 
will be provided by PK sampling time.
PUBLIC 
flu
be info
e info
ics). The
ics). The
ion PK m
ion PK m
x, and t
and t1
cal data f
cal data 
ng tim
ng t
P
COPY
ec
ech
, by trea
, by tre
ramine
ramin
This document cannot be used 
om
om
e.
ed to 
) will
wil
adu
adultlt
support 
concentrat
oncentr
d by all re
by al
opulation 
pulation
el will be
l will be
be s
be
any 
gram
gra
nt. All s
nt. All 
marketing 
d.
nd percenta
percenta
he Medica
he Medic
verity and r
rity and
AESI) and 
ESI) an
tests, vita
tests, v
m, C-S
m C
auth
rse of 
e of 
thorization 
th
application and any extensions
elev
mean a
mean a
e summa
summa
summariz
mmari
Summar
umma
te
or
on-tim
on-ti
ant da
ant d
variations
relat
Serious
erious
al signs, 
al signs, 
SSRS, T
SRS, T
afety sum
fety sum
me
there
age of 
e of 
l
tionsh
tions
reof. 
re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 22 of 182
Table 1: 
Schedule of Assessments 
Study Assessments
Baseline Perioda
Titration + Maintenance Period
EOS/
ETb
Post- 
Dosing
Cardiac 
Follow- 
up
Screening
2
(Phone)
Random- 
ization
Titration Period
Maintenance Period
Visit Number
1
3
4, 5
(Phone)
6
7
(Phone)
8
9
(Phone)
10
11
(Phone)
12
13
14
Study Day
-42
-21
-1
1
4, 8
15
29
43
57
71
85
99
113
197-281
Informed Consent (subject and parent)
X













Inclusion/Exclusion Criteria
X
X











Demographics
X













Medical/Neurological History
X













Epilepsy history
X













Collect retrospective seizure diary data
X













Prior Medication
X
X











Physical Examination, complete
X
X








X
Xc 
Physical Examination, abbreviated





X
X
X



Xc 
Neurological Examination, complete
X










X


Neurological Examination, abbreviated


X


X








Vital signs
X
X


X
X
X
X


Weight, Height, BMI
X
X


X
X
X
X


12-lead ECG
X
X




X



X
Xc 
Doppler ECHO
X





Xd 



Xd 
Xc 
Urine pregnancy test
Xe 
Xe 


Xe 
Xe 
Xe 
Xe 


Clinical laboratory evaluation
(hematology/clinical chemistry/urinalysis, etc) 
X
X


X
X
X
X


Plasma sample for ZX008 
pharmacokinetics







4Xf






Plasma sample for background AEDs


Xg 


Xg 
Xg 



Xg 


Urine THC Panel/Whole blood CBD
X
X


X
X
X
X


Tanner Staging (for subjects >7 years old) 

X








X


Subject Diary
D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh
C/R 
Epilepsy genotype panel
Xl
Study Medication


D 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh
C/R 
C-SSRS
X
X


X
X
X
X


PUBLIC 
C
IC
LIC
IC
BL
UB
UB
PUB
PU
PU
P
COPY 
Y
PY
OP
CO
CO
CO
C
This document 
D
t
n
me
me
me
m
cum
cannot 
ot
no
n
a n
an
ca
ca
ca
c
be 
e
X
be used 
d
se
us
us
us
u
to 
X
o
to
t
support 
rt
or
po
p
u p
up
su
su
su
s
any y
ny
a y
an
a
marketing 
EOS
EOS
E
g
nin
11
11
(Phone)
(Ph
et
rk
71
8
71
rk
rk
ar
m r
m
authorization 
31 Octobe
31 Octob
tho
application 
X
n
io
R
C/R
C
ioio
at
ca
c
X
pli
pp
and 
d
nd
Xg
nd
and
a
any y
ny
a y
a
extensions s
X
s
o s
on
ioioio
ns
e
X
en
te
xte
e te
ex
e
or r
o variations s
5
9
s
ns
ns
ns
on
ti n
tio
ati
ia
a a
ar
va
va
va
v
thereof. 
Tb
Post- 
Post- 
Dosin
Dosin
C
eo
eo
he
12
12
he
he
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 23 of 182
Table 1: 
Schedule of Assessments continued 
Study Assessments
Baseline Perioda
Titration + Maintenance Period
EOS/
ETb
Post- 
Dosing
Cardiac 
Follow- 
up
Screening
2
(Phone)
Random- 
ization
Titration Period
Maintenance Period
Visit Number
1
3
4, 5
(Phone)
6
7
(Phone)
8
9
(Phone)
10
11
(Phone)
12
13
14
Study Day
-43 to -42 or 
-42 to -41
-21
-1
1
4, 8
15
29
43
57
71
85
99
113
197-281
Clinical Global Impression - 
Improvement (assessed by 
parent/caregiver)





X 
X 
X
X


Clinical Global Impression - 
Improvement (assessed by principal 
investigator)





X 
X 
X
X


BRIEF


X




X 



X


QOLCE


X




X 



X


PedsQL


X




X 



X


EQ-5D-5L (QoL of parent/caregiver)


X








X


HADS (Affect of parent/caregiver)


X




X 



X


Randomize subject


X











First Day of Study Drug Administration



Xj 

Daily Diary Completion
X
Concomitant Medication



X
Adverse events
X
Adverse events of special interest
X
Xk 
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol;
D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early termination; EQ-5D- 5L=standardized measure of health status; HADS=Hospital 
Anxiety and Depression Scale; PedsQL=Pediatric Quality of Life Inventory; QoL=quality of life; QOLCE=Quality of Life in Childhood Epilepsy; 
R=Review 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The 
procedures to be completed at the Screening visit may be completed in a single day or split so that they are completed over the 2-day period (i.e., Days -43 
to -42 or Days -42 to -41). 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study 
medication over an up to 2-week period. 
c: 
Follow-up ECG, ECHO, and physical examination will be performed 3-6 months after early termination, or for those subjects who complete the study but do 
not enter the open-label extension study (see Section 6.4). 
d:  The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54. The Visit 12 ECHO must be performed any time between 
Study Day 90 and Study Day 113; if a subject discontinues early from the study, the ECHO should be scheduled as soon as practical. If the Study Day 
PUBLIC 
C
IC
IC
IC
BLI
B
Xj
X
UB
UB
PU
P
COPY 
Y
PY
O Y
OP
CO
CO
CO
C
This document 
nd th
d th
eriod. 
od. 
ysical exam
cal exa
nsion study
on study
e performe
erform
y Day 113
Day 113
cannot 
f Li
L
screening 
reening
g visit may
isit may
ose w
ose w
be
or Rat
Ra
=early ter
=early te
fefe Inve
Inv
used 
d
ed
s
u
ng I
ng
to 
to
to
t
support 
X
t
o
X
ort
po
po
po
pp
su p
sup
su
s
any 
a y
an
a
marketing 
EOS
EO
ET
ETb
in
11
11
(Phone)
Phone)
12
ing
k
in
85
85
ket
rk
X
rk
m rk
X
m
authorization 
31 Octobe
31 Octob
tho
au
au
a
application 
e c
o complete t
complet
nation will b
ation wil
see Section 
see Sectio
any time be
ny time
f a subject d
a subjec
and 
or the study
the stud
omple
mplet
any 
ntory
ntor
ation; EQ
tion; EQ
ry; QoL=q
y; QoL=q
extensions 
X
s
ns
ioio
X
si
en
te
ex
e
of
or r
or
o variations
X
s
i ns
tio
ati
ria
va
va
va
v
thereof.
ost- 
Dosing
osing
Cardi
Card
Fol
Fol
f
of
of
eof
13
13
re
he
99
99
he
he
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 24 of 182
43 ECHO was completed < 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring the 
subject to the clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing  potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration.  
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 6, 8 and 12. 
h: 
Study drug/diary dispensed for the Transition Period for subjects entering the open-label extension study and for the Taper Period for subjects exiting the 
study. 
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the morning of Study Day 1. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Mandatory one time collection any time during or after screening. 
PUBLIC COPY 
This document cannot be used to support any marketing 
administrat
ministra
er Per
Period for
iod f
authorization 
31 Octobe
31 Octob
tho
agrees to b
ees to b
application and any extensions or variations thereof. 
ng th
ng
on.
subjects e
subjects e

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 25 of 182
1.
INTRODUCTION
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment 
of patients with Dravet syndrome (DS). 
DS, 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. 
1.1.1
Existing Treatment for Dravet Syndrome
DS is a highly treatment-resistant and refractory epilepsy syndrome. Establishment of a seizure-
free condition in affected children, even with anticonvulsant drug polypharmacy, is extremely 
rare, since all seizure types in DS appear to be drug resistant, with minimal improvement on 
currently available anticonvulsant drug therapies (Dravet 2000; Dravet 2005). Moreover, classic 
anticonvulsant medications whose mechanism is via sodium channel blockade, such as 
phenytoin and carbamazepine, increase these children’s seizure frequency and severity. 
To date, only one treatment, Diacomit® (stiripentol) is approved, and only in Europe, Canada, 
Japan, and Australia, as adjunctive therapy in patients with severe myoclonic epilepsy in infancy 
(SMEI, Dravet syndrome), and must be co-administered with clobazam and valproate. 
Stiripentol has not been approved for use in the United States of America, but is available under 
compassionate use protocols at certain clinical sites. 
 fenfluramine has been used as an unlicensed medicine in Belgium at 
2 academic medical centers, currently using an approved protocol under a Belgium Royal 
Decree (government approved prospective observation trial) for the treatment of DS; the 
efficacy and safety of this therapeutic approach have been published in a peer reviewed journal 
PUBLIC
en
012) th
12) th
eral poss
eral pos
n of cere
of cere
ology re
ology re
of pati
of p
COPY
or
or
langua
langu
he degre
e de
 of seizu
of seizu
count
coun
This document
ant
an
in and c
and c
date, only
te, onl
apan, an
pan, an
(SMEI
(SMEI
Stir
Stir
cannot
nt-re
-r
ected ch
cted ch
zure typ
ure typ
able ant
ble an
t med
med
be
atmen
men
sista
sist
used
ma
ents w
nts wh
eventua
ventu
nt
to
bral
ains un
ins u
h
support 
res, and
s, an
r a higher
a high
other pop
ther p
blele etiolo
etiol
circul
circ
any
esss
hypera
hyper
of cogni
f cog
d m
marketing 
ion
s the co
the c
eizures an
izures an
affected 
affecte
ssion, ata
sion, at
begins to b
egins to
sion. D
ion
authorization 
atment
tment 
vere form
re form
n most
mos
application 
conv
onv
cations w
cations 
rbamazep
bamaze
y one treat
one tre
d Australi
Austra
Dravet s
Dravet s
ol ha
ol ha
and
t
ldren, 
dren, 
s in DS 
in DS 
vuls
vuls
any 
r Dra
r Dr
and ref
and r
eve
extensions
pula
ul
ogies, in
ies, in
lation, a
ation, a
known a
nown a
survive 
survive
ly live in
y live in
or
inincid
cid
ation
atio
variations 
axia, s
ia, 
become
ecome
Dravet c
ravet c
ctivity, a
tivity, a
nitive im
ive im
ight be
ght be
en
thereof. 
m of 
m o
ndition
tion
and statu
d statu
children
children
slee
slee

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 26 of 182
(Ceulemans 2012; Ceulemans 2016) and reported to be very favorable. There are no treatments 
specifically approved for the treatment of DS in the United States of America (USA). 
Accordingly, there remains an unmet need for an approved treatment for children with DS. 
1.1.2
Other Antiepileptic Medications
USA and European Union approved anti-epileptic drug products include valproate, topiramate, 
carbamazepine, oxcarbazepine, lamotrigine, benzodiazepines, phenobarbital, potassium 
bromide, ethosuximide, phenytoin, and vigabatrin. The treatment of DS frequently requires a 
combination of two or three of these compounds, but with continued suboptimal seizure control. 
It cannot be assumed that because a treatment has been shown to be effective in common 
seizure types, that it will be effective in DS. In fact, some commonly used anti- epileptic drugs 
with a sodium channel mechanism of action, such as carbamazepine, oxcarbazepine, phenytoin, 
and lamotrigine, make DS worse. 
A review of the treatment modalities used for DS has been published by Chiron and Dulac 
(Chiron and Dulac 2011). This review indicates that valproate is commonly used as a first-line 
agent to prevent the recurrence of febrile seizures and oral/nasal/rectal benzodiazepine is used 
for any long-lasting seizures. However, the authors comment that these agents are most often 
insufficient. These author experts state that lamotrigine, carbamazepine, and high doses of 
intravenous phenobarbital should be avoided because they may worsen seizures and that 
topiramate, levetiracetam and bromide may provide substantial efficacy as adjunctive therapy 
for some patients. The authors comment that the benefit of these compounds is mild and there 
are no trials to validate the impression of any effect. 
Given the cognitive consequences believed to be caused, at least in part, by frequent childhood 
seizure activity, there is a medical need for a new anticonvulsant treatment that can significantly 
reduce seizure activity in DS. There is the possibility that early, effective seizure control could 
be disease-modifying, leading to an improvement in longer-term outcomes with respect to 
motor impairment, behavioral issues, and cognitive function. 
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of DS. Fenfluramine is an amphetamine analogue that was first 
synthesized many years ago. It was approved in a large number of countries and widely 
prescribed as an appetite suppressant for the treatment of adult obesity. Brand names for 
fenfluramine formulations included Ponderax, Pondimin and others.  Fenfluramine was also 
PUBLIC
that 
hat lal
 avoided
avoided
omide m
omide m
comme
comme
mpressi
mpressi
COPY
has be
has b
that
that vala
t
zur
zures an
es an
auth
author
am
This document
dev
ev
ve treatm
e treatm
esized m
sized m
escribed
scribed
fenflura
nflura
cannot
ead
ad
ehavior
avior
ACKGR
CKGR
velop
elop
be
d
DS. Th
S. Th
ding t
ding
used 
on of 
of 
es believ
belie
cal ne
cal ne
to
y 
t that t
that 
any
an
support 
oral/
oral/
s commen
omm
otrigine, c
rigine,
because 
ecause 
provi
provide
d
he
any 
ublish
ublis
oate is c
oate is c
/nasa
na
marketing 
ently
ntly
timal sei
timal se
ctive in c
tive in
used anti
sed an
ne, oxcarb
, oxca
ed
authorization 
topiram
opiram
assium
ssium 
req
req
application 
O
ng a new
ng a new
ment of DS
nt of D
any years
any yea
as an app
s an ap
mine form
ine for
and
issue
ssue
UND 
UND
any 
is the p
is the
an impro
n impro
es, a
es
extensions
car
they m
hey m
e substa
e substa
benefit
enefit
effect.
effect.
ed to be
d to be
for a n
or a n
or 
t tha
th
bama
bama
variations
i  
bazepi
azepi
d by Chi
d by Ch
common
ommon
al/rectal
l/rectal
at th
t th
thereof. 
uires a
res a
zure con
ure con
ommon
mmon
epilep
epilep

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 27 of 182
used extensively in an off-label combination with phentermine (“Fen-Phen”). Fenfluramine is a 
racemic compound and the single enantiomer D-fenfluramine (dexfenfluramine) was also 
approved and marketed as Adifax, Redux, and others. 
Fenfluramine was introduced in the USA in 1973. Products containing fenfluramine and D- 
fenfluramine were withdrawn from the USA market in 1997 after reports of heart valve disease 
and pulmonary hypertension (Connolly 1997; CDC 1997; Wong 1998). While the risk/benefit 
relationship for fenfluramine is thus considered unfavorable for the treatment of obesity in adults, 
establishing seizure control in DS or any of the catastrophic childhood epilepsies might lead to a 
more acceptable risk/benefit profile for fenfluramine, especially if lower doses can be used 
successfully. 
As a result of this previous extensive use of fenfluramine, there is a large body of information in 
the public domain concerning its pharmacology, toxicology and use in the treatment of obesity 
(ZX008 IB 2016). There is also a large body of information concerning its clinical safety profile. 
1.3
PRECLINICAL DATA
The pharmacokinetics of fenfluramine, norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The pharmacokinetics in humans differs from that of other 
species, with a longer duration of exposure to both the parent and the metabolite. In vitro 
metabolism studies have shown that there are large species differences in pharmacokinetics and 
metabolism of fenfluramine after oral administration. In humans, fenfluramine is metabolized 
primarily to norfenfluramine. CYP1A2, CYP2B6, and CYP2D6 appear to be the predominant 
CYP enzymes that metabolize fenfluramine to norfenfluramine. CYP2C9, CYP2C19, and 
CYP3A4 also appear to be involved, but to a lesser degree. There is also some contribution of 
renal clearance to the elimination of dexfenfluramine (8%-16%) and nordexfenflurmaine (7%-8%) 
from the body. Because fenfluramine and its active metabolite norfenfluramine have multiple 
pathways of elimination, interference with a single pathway is unlikely to cause a significant 
change in fenfluramine’s clearance though the probability of an interaction increases if multiple 
elimination mechanisms are affected simultaneously. 
While in vitro studies showed that both fenfluramine and norfenfluramine cause weak inhibition of 
CYP2D6 and fenfluramine causes weak induction of CYP3A4 and CYP2B6, further analysis 
based on the FDA’s mechanistic static model shows that fenfluramine and its major metabolite 
norfenfluramine are unlikely to alter the pharmacokinetics of substrates of these CYP450 enzymes 
in the range of ZX008 doses that will be administered in this study. 
A Good Laboratory Practice dose-range-finding juvenile toxicology and toxicokinetic study, 
which included a 3-week repeat dose main study, and histopathology of heart valves and other 
key organs, found no effect on heart valves or other organs. 
Based on clinical signs and decreased body weight gain, the no-observed-adverse-effect-level for 
this study was 12 mg/kg/day. This is equivalent to a human dose of 1.94 mg/kg/day based on 
PUBLIC
orfe
orf
. The p
The p
xposure 
xposure
hat ther
hat ther
fter oral 
fter ora
CYP
CY
COPY
ormati
rma
enflu
enflu
This document
ro s
o 
and fen
nd fen
on the F
n the 
rfenflura
enflur
in the ra
n the ra
A G
A G
cannot
fen
fen
on, inte
n, inte
mine’s c
ine’s c
hanisms
anism
tudi
tud
be
vo
nation 
tion
nflura
nflura
used
d
A2, CY
A2, CY
nflurami
luram
lve
ved, b
d, b
to 
are 
re
minist
minis
Y
support 
amine and
mine an
armac
macokin
ok
o both the
both th
lalarge
rg
any 
u
oncern
oncer
marketing 
of obe
ob
epsies mig
psies mi
doses can
oses c
a lalarge b
rge 
use in th
se in
i
authorization 
d D-
d D-
lve dise
e dise
risk/be
risk/be
esit
esi
application 
are
s showed
 show
fluramine
urami
DA’s mec
DA’s m
mine are u
ine ar
nge of ZX
ge of Z
abor
ab
and
ferenc
enc
earance 
arance 
e affe
affe
any 
dexfen
dexfen
ne and i
ne and i
ce w
e w
extensions 
netic
eti
e parent
parent
e species
specie
ation. In
tion. In
P2B6, an
2B6, an
ne to nor
to nor
to a le
o a le
or
their 
their
cs in
s in
variations 
body of i
dy of 
the treat
he treat
ing its cl
ng its c
thereof. 
nefit 
efi
y in adul
in adu
ght lead
t lead
n be use
n be use

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 28 of 182
body surface area, and provides a safety factor of 2.4 for the highest dose of 0.8 mg/kg/day that 
will be administered clinically. 
Further details on the preclinical data of ZX008 are available in the Investigator’s Brochure 
(ZX008 IB 2016). The current version is available in the Investigator Study File. 
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT
Not applicable. 
1.5
RATIONALE FOR CURRENT STUDY
Based on several published reports of fenfluramine’s successful treatment of refractory 
childhood epilepsy in the 1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and its successful 
treatment of 11 refractory pediatric epilepsy patients in Belgium (Boel 1996), in 2002 Drs. 
Ceulemans and Lagae were granted authorization to prescribe fenfluramine to their patients with 
refractory pediatric epilepsy conditions, including DS, under an approved protocol under a 
Belgium government program (Royal Decree). To date, these pediatric neurologists have DS 
patients (infants, children, young adults, and now also adults), being successfully treated with 
fenfluramine 
 The efficacy and safety of this therapeutic approach has been 
reported to be overwhelmingly favorable. In the most recent assessment of efficacy of these 
patients reported by the investigators in 2016, the average length of treatment was over 12 years, 
with one patient being successfully treated for 26 years (Ceulemans 2016). Of the 15 DS treated 
patients, 10 (67%) were reported as seizure-free, with the average time of seizure-freedom being 6 
years (range 1-19 years). Twelve patients (87%) had a greater than 90% reduction in seizure 
frequency and 14 patients (93%) with greater than 70% reduction in seizure frequency. 
In addition, numerous publications discuss the use of fenfluramine in over 500 children with 
neurobehavioral conditions for the treatment of mostly autism and ADHD, without any reports of 
any cardiovascular adverse events (ZX008 IB 2016). 
Prior to being withdrawn from the market, fenfluramine was marketed at doses of 20 mg and 40 
mg three times daily for the management of obesity in adults. The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. Doses tested in pediatric 
studies evaluating autism and ADHD ranged from 0.65 mg/kg/day to 3.6 mg/kg/day, but a 
commonly used dose was 1.5 mg/kg/day. Occasionally, fixed doses of 30 to 80 mg were used.  
The PK exposure associated with the proposed doses in DS studies of 0.2 mg/kg/day and 
0.8 mg/kg/day administered orally (in equally divided doses BID) is expected to be lower than 
that obtained at the doses used in the past for the treatment of obesity in adults and of 
neurobehavioral conditions in children and adolescents (ZX008 IB 2016). The doses used in this 
study are based on the data from the DS patients being successfully treated in Belgium discussed 
above. 
There are no treatments specifically approved for the treatment of DS in the USA, and in fact, 
commonly used anticonvulsants with a sodium channel mode of action, such as phenytoin and 
PUBLIC 
cacy a
acy 
able. In t
able. In 
ors in 20
rs in 20
ully trea
lly trea
ted as
ted as s
e
COPY 
 pres
pr
g DS, un
g DS, u
. To dat
To da
d now a
now a
and
This document
0.12
12
evaluatin
valuatin
monly us
nly us
e PK exp
PK ex
0.8 mg
0.8 mg
that 
that 
cannot
ns
n
verse
erse e
thdrawn
drawn
s daily 
daily 
2 to 0
to
be
ication
ation
 for 
 for th
used 
eizur
zur
patients (
ients (
) with g
with g
to
ed for 
d for
re-fr
e-f
support 
, the
the
so adults
adult
safety of 
afety o
e most re
e most r
, the av
the av
26
any 
fenfl
fenf
er an
er an app
ap
ese pe
se p
marketing 
ent of ref
ent of re
di 1988) a
1988) 
(Boel 199
Boel 19
ura
authorization 
application 
or the
r th
.9 mg/kg/
.9 mg/k
g autism 
autism
d dose w
d dose 
osure ass
sure a
kg/day ad
g/day ad
ned a
ed
and 
ents (Z
ts (
from th
om th
e m
e m
any 
scuss t
scuss
treatme
treatme
ZX0
ZX
extensions
f th
ecent a
cent 
verage le
verage l
year
ears (C
s (C
ee, with 
e, with 
87%) ha
%) h
eater 
ater tha
th
or 
be
b
is the
is the
variations
and its
d it
96), in 2
6), in 2
amine to
mine to
proved p
oved p
diatric 
iatric 
eing 
eing
thereof. 
ractory
actory
s su
s

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 29 of 182
carbamazepine, worsen the condition. Accordingly, there remains a significant unmet need for an 
approved treatment for children and adults with DS. 
1.6 
RISK-BENEFIT ASSESSMENT
As described above, fenfluramine has been used successfully 
 in some DS 
patients to control seizures, without emergence of clinical valvulopathy or pulmonary 
hypertension. Fenfluramine was administered to over 500 children with neurobehavioral 
conditions, including autism and ADHD with good safety and tolerability, most often at a 
1 mg/kg dose. 
The pharmacologic and toxicological profile for the active pharmaceutical ingredient, 
fenfluramine, following oral administration is well established (see ZX008 IB 2016). 
The safety monitoring practices employed by this protocol are adequate to protect the subjects’ 
safety and should detect expected and unexpected treatment-emergent adverse events. 
The approximate volume of blood (108.7 mL) planned for collection from each subject over the 
course of the entire study (Screening to End of Study, but not including repeat or additional tests 
ordered by the investigator) presents no undue risk to the subjects. 
The ZX008 0.2 mg/kg/day and 0.8 mg/kg/day doses are believed to be therapeutic doses, which 
could provide sufficient anti-epileptic support for a sustained period of time during the study. 
The available information suggests that the present clinical study has an acceptable risk-benefit 
ratio. 
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1
PRIMARY OBJECTIVE
The primary objective of the study is: 
x
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the 
treatment of Dravet syndrome in children and young adults based on change in the 
frequency of convulsive seizures between baseline and the combined Titration and 
Maintenance Periods (T+M). 
2.2
KEY SECONDARY OBJECTIVES
The key secondary objectives of the study are: 
x
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in the 
treatment of Dravet syndrome based on change in the frequency of convulsive seizures 
between baseline and T+M. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
/kg/day
kg/day
ic suppo
ic suppo
ests that 
sts that
COPY 
atm
at
anne
anned fo
d f
f Study, 
Study
ue risk 
ue risk 
This document
uen
en
aintena
ntena
The key
he key
cannot
of the
f the
strate tha
rate th
nt of Dra
of Dr
ncy of 
y of 
be
OBJEC
OBJEC
t
used 
CTIVE
TIVE
to
he pre
he pre
support 
but n
ut n
o the sub
the su
oses ar
ses are b
t for a sus
for a su
esen
any 
merg
er
collectio
collecti
not inc
ot i
marketing 
st ofte
oft
cal ingred
cal ingre
ZX008 IB 
008 IB
equate to
quate 
gent a
gen
authorization 
DS 
DS 
y
avioral
vioral
en a
en a
application
vet s
et 
convulsiv
convuls
ce Period
e Perio
KEY SE
KEY S
secondary
econda
dem
d
and 
udy 
dy
t ZX008
ZX008
synd
synd
any 
VE
VE
is:
is:
extensions
belie
eli
ustained 
ained
nt clinica
clinic
S AND
AND
or 
ects
ec
eved
eve
variations 
B 201
20
o protec
protec
adverse 
dverse
on from 
from
cluding
uding
s.s
thereof. 
t a
dient,
dient,
16). 
16).

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 30 of 182
o
The proportion of subjects who achieve a 40% reduction from baseline in 
convulsive seizure frequency. 
o
The proportion of subjects who achieve a 50% reduction from baseline in 
convulsive seizure frequency. 
o
The longest convulsive seizure-free interval. 
See Statistical Methods (Section 10.5.1.3) for hierarchical testing procedure. 
2.3
ADDITIONAL SECONDARY OBJECTIVES
Other secondary objectives of the study are: 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The number of convulsive seizure-free days. 
o
The proportion of subjects who achieve 75% reductions from baseline in convulsive 
seizure frequency. 
o
The change from baseline in non-convulsive seizure frequency. 
o
The change from baseline in convulsive + non-convulsive seizure frequency 
o
The incidence of rescue medication usage 
o
The incidence of hospitalization to treat seizures 
o
The incidence of status epilepticus. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator. 
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver. 
o
The change from baseline in the QOLCE score. 
o
The change from baseline in the PedsQL score. 
o
The change from baseline in the PedsQL Family Impact module score. 
o
The change from baseline in the QoL of the parent/caregiver using the EQ-5D-5L 
scale. 
o
The change from baseline in the affective symptoms of the parent/caregiver using the 
HADS. 
PUBLIC
e in no
e in n
seline in
seline in
f rescue 
rescue 
of hos
of h
COPY
ree day
ree d
achieve
achiev
on
This document
pa
pa
o
cannot 
bo
al Glob
l Glob
vestigato
stigato
Clinica
Clinic
are
be
the ZX
e Z
on
on the
the
used
pitaliz
taliza
status e
tatus e
X0
X0
to
medica
edica
t
support 
75
7
convulsiv
onvuls
convulsi
onvulsiv
tion
any 
5% red
% re
marketing 
e groups a
groups
authorization 
application 
l Globa
Glob
nt/caregiv
t/careg
The chang
The cha
o
The c
The
o
T
and
l Impr
Impr
 
l
any 
8 0.2 a
8 0.2
ollowing
ollowin
ess
extensions 
ve 
ve + non
e + non
n usage
usage
on to tre
to tre
ilepticu
epticu
or 
seizu
seizu
variations
are (ind
e (ind
ductions
ctions
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 31 of 182
2.4
SAFETY OBJECTIVE
The safety objective of the study is: 
x
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to AEs, laboratory parameters, physical examination, neurological examination, vital 
signs (blood pressure, heart rate [HR], temperature, and respiratory rate), ECGs, ECHOs, 
and body weight. Cognitive Function will be assessed using the cognition domain score on 
the QOLCE and age-appropriate versions of the BRIEF.  
2.5
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective of the study is: 
x
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects ages 2-6 
years and >6-18 years with Dravet syndrome. 
2.6
EXPLORATORY OBJECTIVE
The exploratory objective of the study is: 
x
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK 
endpoints. 
2.7
STUDY ENDPOINTS
2.7.1
Efficacy Endpoints
The efficacy endpoints of the study are: 
x
Number of seizures by type 
x
Convulsive seizure-free interval 
x
Clinical Global Impression – Improvement as assessed by parent/caregiver 
x
Clinical Global Impression – Improvement as assessed by principal investigator 
x
QOLCE to measure changes in quality of life of the subject 
x
PedsQL to measure changes in quality of life of the subject 
x
PedsQL Family Impact module to measure changes in quality of life of the parent/caregiver 
x
QoL of the parent/caregiver using the EQ-5D-5L scale 
x
Affective symptoms of the parent/caregiver using the HADS scale 
x
Duration of prolonged seizures (seizure type that, during baseline, had duration 
x
>2 minutes) 
PUBLIC 
0.8 mg
.8 m
NTS
NTS
nts
nts
COPY 
g/k
g/k
This document
OLCE t
LCE 
PedsQ
PedsQ
x
Pe
P
x
cannot 
ure-f
re-
obal Imp
bal Imp
l Globa
Globa
be
by typ
by typ
ree
ree
used 
udy are
dy are
to support 
g/day do
day dose
any marketing 
t steady st
steady
authorization 
with
ith
nation, v
tion, v
Gs, ECH
s, ECH
domain s
omain s
application 
Impre
mpre
measure 
measur
L to meas
L to mea
dsQL Fam
sQL Fa
oL of 
oL of
and 
intn
ression 
ession 
ess
any 
erval
erval
extensions 
e
or 
on pr
on p
variations
state in
ate in s
thereof. 
core
co

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 32 of 182
x
Number of episodes of status epilepticus 
x
Number of instances of rescue medication use and number of doses 
x
Number of inpatient hospital admissions due to seizures 
2.7.2
Safety Endpoints
The safety endpoints of the study are: 
x
AEs 
x
Laboratory safety (hematology, chemistry, urinalysis) 
x
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
x
Physical examination 
x
Neurological examination 
x
12-lead ECGs 
x
Doppler ECHOs 
x
Body weight 
x
BRIEF to measure cognition. 
2.7.3
Pharmacokinetic Endpoints
The PK endpoints of the study are: 
x
Steady-state plasma fenfluramine PK parameters (Cmax, AUC0-t, Tmax, and t1/2) after 
administration of ZX008 derived using population PK methods 
3.
INVESTIGATIONAL PLAN
3.1
OVERALL STUDY DESIGN AND PLAN
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the efficacy, 
safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young adult subjects 
with Dravet syndrome. Approximately 30 study sites in North America are planned to participate. 
The 6-week Baseline Period will consist of the establishment of initial eligibility during a 
screening visit followed by an observation period where subjects will be assessed for baseline 
seizure activity based on recordings of daily seizure activity entered into a diary. Upon completion 
of the Baseline Period, subjects who qualify for the study will be randomized (1:1:1) in a double-
blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 
mg/day) or placebo. Randomization will be stratified by age group (<6 years, 6 years) to ensure 
balance across treatment arms, and at least 40% of subjects will be in each age group. All subjects 
will be titrated to their randomized dose over a 14-day Titration Period. Following titration 
PUBLIC 
on.
on.
ic Endp
ic Endp
are
ar
COPY 
This document
ltic
tic
nd PK o
d PK o
Dravet sy
avet sy
6-week
-week
screenin
eenin
seizur
seizur
of 
of
cannot
TIGA
TIGA
VERAL
ERAL
enter
ente
be
X008 d
08 
used 
oin
in
flurami
ram
to 
ntsts
support any marketing 
ratory rat
atory r
authorization 
application 
L
double-b
double
ZX008 w
X008 
ndrome. A
ndrome.
Baseline 
aselin
g visit foll
visit fo
activity 
tivity
li
and 
TION
IO
STU
STU
any 
ed usi
d u
NAL
NA
extensions 
PK pa
PK p
or variations 
te)
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 33 of 182
subjects will continue treatment at their randomly assigned dose over a 12-week Maintenance 
Period. Total treatment time from the beginning of the Titration Period through the end of the 
Maintenance Period is 14 weeks. Parents/caregivers will use a diary daily to record the 
number/type of seizures, dosing, and use of rescue medication. A schedule of assessments is 
provided in Table 1. 
At the end of the Maintenance Period (or early discontinuation), all subjects will undergo a 
2-week taper or transition period (Post-Dosing Follow-Up) depending on whether they exit the 
study or are enrolled in the separate long-term open-label extension study. 
A follow-up ECHO, ECG, and possibly physical examination will be performed 3-6 months 
after study drug discontinuation for early termination, or for those subjects who complete the 
study but do not enter the open-label extension study. 
3.2
NUMBER OF SUBJECTS
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor. 
3.3
STUDY DURATION
The duration of participation in the study for an individual subject is expected to be up to 22 
weeks, plus follow-up safety visit 3 to 6 months after the last dose: 
x
Baseline Period – 6 weeks 
x
T+M Period - 14 weeks 
x
Post-Dosing Visit – 2 weeks after study completion or early termination 
x
Cardiac Follow-up (ECG and ECHO)– 3-6 months after study drug discontinuation for early 
termination or for subjects who complete the study but do not enroll in the open-label 
extension study. 
3.4
NUMBER OF STUDY CENTERS
The study expects to use up to approximately 30 research centers in North America. Additional 
study centers within or outside of North America may be added if enrollment cannot be 
completed in a timely manner. 
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT 
GROUPS
It is recognized that performing clinical studies in young children or in subjects with reduced 
cognitive capacity presents particular practical and ethical issues. However, given the seriousness 
of DS, and the possible consequences of current inadequate treatments, the use of children with 
PUBLIC 
the stud
the stud
visit 3
visit 3 t
COPY
obtain 
obtain
that 105
that 1
random
random
This document
NU
NU
tudy exp
udy ex
udy cent
y cent
comple
omple
3
cannot 
t 
ow-up (E
w-up (E
n or for 
or for
on study
n study
be 
ks 
– 2 we
– 2 we
used 
6 m
6 m
to
y for an
for a
mont
mont
support 
su
ze more
mor
n ini
any 
5 subjec
subj
ubjects 
bject
e t
marketing 
ormed 3-6
rmed 3-6
ects who c
ts who
authorization 
s 
dergo a
rgo a
they ex
hey e
application 
MBER OF
BER O
ects to us
ects to u
rs within 
s withi
ed in a tim
d in a ti
and
CG and
G an
ubjects 
bjects
any 
s after st
s after s
d E
extensions 
ndividua
dividua
s after t
after t
or variations 
cts who 
s who 
 will be
will be
han a m
an a m
thereof. 
it the
the
6 month
month
complet
complet

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 34 of 182
DS in this study is considered justified. Stratifying the randomization by age group is considered 
appropriate because the frequency and severity of major seizures can be higher in younger 
subjects. The two strata in the study will be subjects aged below 6 years and subjects aged 6 -18 
years. The study design has incorporated a titration period to enable subjects randomized to the 
high dose group adequate time to acclimate to this dose. Following the Titration Period, subjects 
will enter a 12-week Maintenance Period where they will continue on their randomized dose for 
the remainder of the study. The 12-week duration of the Maintenance Period is in keeping with 
the current standard study duration for evaluating the efficacy of chronic medications. Given the 
individual variability in seizure frequency and seizure type in this patient population, the primary 
endpoint, which seeks to compare an appropriate baseline of convulsive seizure frequency to the 
convulsive seizure frequency following treatment, is an appropriate primary endpoint for efficacy 
in this population. 
Subjects will receive investigational medicinal product (IMP; ZX008 or placebo) in addition to 
their existing antiepileptic medications at their stable doses throughout the entire study. Thus, 
subjects receiving placebo will not be denied active therapy; they will continue to receive their 
existing medications at the exact same dosages. As the principal study measurement (convulsive 
seizures) might be considered subjective, a double-blind study design will prevent subjective bias. 
Upon study completion, eligible subjects will be able to receive ZX008 in an open-label extension 
study for up to 1 additional year of treatment. 
3.6
PREMATURE TERMINATION OF STUDY
The sponsor can terminate the study prematurely at any time for medical or ethical reasons at 
individual or at all study sites. The investigator will be notified in writing, outlining the reasons 
for the termination. Instructions will be provided if assessments beyond those described in the 
study protocol need to be conducted. 
If the study is terminated prematurely for any reason, the investigator should promptly inform 
the subjects participating at his or her study site and should ensure that appropriate alternative 
therapy is available and that End-of-Study procedures are conducted, as described in 
Section 6.2.9 and Section 6.3. 
All study materials including investigational medicinal product (IMP) and completed, partially 
completed, and blank documentation, except documents needed for archiving requirements, will 
be returned to the sponsor. The study monitor will ensure that any outstanding data clarification 
issues and queries are resolved, and that all study records at the study site are complete. 
In accordance with applicable regulatory requirements, the sponsor will promptly inform the 
competent regulatory authorities of the termination and its reason(s), and the investigator or 
sponsor will promptly inform the Independent Ethics Committee (IEC)/IRB. 
PUBLIC 
wil
wi
eatment.
tment
RMINA
RMINA
e study p
e study 
The
Th
COPY
e do
d
ve
ve thera
 ther
. As the
 As th
double-b
ouble-
l be
l be
This document
te
d, and b
and b
rned to t
ned to 
es and q
s and q
In accor
n accor
comp
com
sp
sp
cannot
ng at 
g at 
le and 
 and
Section
ectio
rials in
ials in
l
be 
du
premat
prema
hihi
used
rem
em
investig
nvestig
will be p
will be 
cted.
cted.
to 
TI
mature
matur
support
prin
ri
lind stud
nd stu
ble to rec
le to r
ON OF
ON O
any
ough
oug
y; they w
y; they w
ncipal 
cipa
marketing
atio
pulation
ulation
eizure fre
zure fre
mar
mary end
y en
r
X008 or p
008 or
hout
ho
authorization 
18
o the
the
subjects
ubject
ed dose 
d dose 
keeping 
eeping
ons. G
ns. 
application
cluding 
cluding
ank docum
k docu
he sponso
he spons
ueries are 
ries ar
dance with
ance wi
nt regu
t regu
l
and
s or 
or
that
hat En
 E
t
.3.3.
any 
ely for 
ely for
her st
her 
d
extensions 
F STUD
F STU
ly atat any
 any
t
tor will 
or will
rovide
ovided
or
de
d
ive Z
ive Z
variations 
plp acebo)
acebo
ut the ent
the ent
will cont
ll cont
study 
tudy m
esign
esign
thereof.
with
w
iven the
ven th
the prim
he prim
equency 
uency
point fo
point fo

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 35 of 182
3.7
STUDY MONITORING PROCEDURES
3.7.1
Independent Data and Safety Monitoring Committee
The IDSMC is an independent advisory body that monitors participant safety, data quality and 
progress of the clinical trial. The IDSMC charter will outline the roles and responsibilities of the 
committee and guide its operations and frequency of meetings. The IDSMC will consist of 
individuals external to the sponsor who have relevant clinical trial expertise and experience in 
safety assessment. 
At regularly defined intervals, the IDSMC will convene to review and monitor study progress, 
AEs and SAEs, other measures of safety such as ECGs or ECHOs, and efficacy data as dictated by 
the charter. 
The IDMSC will: 
x
Be responsible for providing recommendations to the sponsor surrounding study conduct 
matters that affect safety. 
x
Review safety data at ad hoc time points and identify if significant safety concerns arise 
during the study. 
x
Review pharmacokinetic data and any other data that may affect subject continuation. 
x
Make recommendations regarding the continuation, suspension, or termination of the study. 
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB)
The IPCAB is an advisory body to the sponsor that monitors cardiac safety of the ZX008 clinical 
trials and provides advice to the IDMSC. The IPCAB charter outlines the roles and 
responsibilities of the committee and guide its operations, and review of individual subject cases. 
The IPCAB consists of individuals external to the sponsor who have relevant experience in 
cardiology, pediatric cardiology, and echocardiography. The IPCAB will advise the sponsor and 
the IDSMC on the cardiac safety monitoring plan, including alert criteria and decision pathway 
for subject management relative to cardiac safety in the clinical studies of ZX008. 
All ECHO examinations performed throughout the trial will be sent to an experienced pediatric 
cardiologist central reader (Biomedical Systems, Inc.). If the central reader classifies a subject as 
having met a pre-defined threshold value indicative of potential cardiac valvulopathy or 
pulmonary hypertension, or any other unexpected cardiac adverse event, the case will then be sent 
for secondary adjudication by one or more members of the IPCAB according to the procedures 
outlined in the IPCAB manual. In addition, member of the IPCAB will perform audits of ECHOs 
deemed normal by the central cardiac reader. 
4.
SELECTION OF STUDY POPULATION
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Before evaluating these criteria and deciding on the eligibility of 
PUBLIC 
and any
and any
regarding
gardin
Pedia
Ped
COPY 
ons
ons to
ints and
ints and
This document
exam
xam
ogist cen
ist cen
ng met a
g met a
ulmonary
monary
for seco
or seco
outli
outl
d
cannot 
indi
nd
cardiolo
cardiol
e cardiac
cardia
nagemen
ageme
ini
be
the 
mittee a
mittee 
vidu
vidu
used
tric Ca
ic C
to the sp
o the s
IDM
IDM
to 
the 
he 
support 
identify
entify
other da
ther dat
conti
con
any 
sponso
spon
if
marketing 
nitor study
itor study
efficacy
efficacy d
or
authorization 
and 
nd 
ies of th
ies of th
nsist of 
st of 
xperienc
perien
application 
t relat
rela
ations perf
ions pe
ral reader
al reade
pre-define
re-defin
hyperten
hyperte
ndary adj
dary adj
n the
n the
and
ala
gy, and
y, an
safety m
afety m
tive
tive
any
C. 
d guide 
guide
extern
exte
e
extensions
ta that m
that 
inua
nuation
tion
diac Ad
diac Ad
onsor th
nsor th
The 
The
or variations 
r surroun
surrou
signifi
ignifi
thereof. 
e inin
dy progre
progre
data as d
data as 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 36 of 182
subjects to participate in the study, it is important that the investigator is familiar with the safety 
profile of ZX008 by referring to the Investigator’s Brochure, as supplied by the sponsor. 
4.1
INCLUSION CRITERIA
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug. 
2. Subject must have documented medical history to support a clinical diagnosis of Dravet 
syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs. 
3.
Subjects must meet all of the following 5 criteria: 
a.
Onset of seizures in the first year of life in an otherwise healthy infant. 
b. A history of seizures that are either generalized tonic-clonic or unilateral clonic 
or bilateral clonic, and are prolonged. 
c.
Initial development is normal. 
d. History of normal brain MRI without cortical brain malformation. 
e.
Lack of alternative diagnosis. 
4. Subjects must meet at least one of the following 3 criteria: 
a.
Emergence of another seizure type, including myoclonic, generalized tonic- 
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type. 
b. Prolonged exposure to warm temperatures induces seizures and/or seizures are 
associated with fevers due to illness or vaccines, hot baths, high levels of 
activity and sudden temperature changes and/or seizures are induced by strong 
natural and/or fluorescent lighting, as well as certain visual patterns. 
c.
Genetic test results consistent with a diagnosis of Dravet syndrome (pathogenic, 
likely pathogenic, variant of unknown significance, or inconclusive but unlikely 
to support an alternative diagnosis.) 
5. Subject must have had 4 convulsive seizures (tonic, tonic-atonic, tonic-clonic, clonic) 
per 4-week period for past 12 weeks prior to screening, by parent/guardian report to 
investigator or investigator medical notes. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable 
for at least 4 weeks prior to screening and are expected to remain stable throughout the 
study. 
7. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
PUBLIC
rs
hat are 
hat are
and are p
and are p
ent is no
nt is no
rmal bra
rmal bra
native
nati
COPY
or
or
not com
not co
wing 5 cr
wing 5 cr
t year 
yea
This document 
c.c.
5.5. S
cannot
nged e
ged e
ociated 
ciated
activity
ctivity
natur
natur
G
be
c, aton
ato
used
diagno
agno
ast one
st one o
se
another
nother
nici
to
mal
MRI w
MRI 
si
support 
iteria:
ria:
of life in a
life in
f
ther ge
er gener
n
rolonged. 
olonged
l
i
any
por
o
etely c
etely 
marketing 
l
l must h
must 
aththering p
ering p
see Sectio
see Secti
or 90 days
90 day
rt a c
rt a li
authorization 
nclusive
clusive
must n
must n
h
application 
an
al and/o
and/o
netic test
etic te
likely pat
kely p
to supp
to su
ubject mu
bject m
per 4-we
per 4-w
nves
nve
and 
posure
sur
with fev
th fev
d sudd
sud
any 
absenc
absen
e to w
e to
extensions 
rali
al
ithou
hout co
t c
s. 
f the fol
the fol
izure t
zure
or
n oth
n oth
zed 
zed
variations 
s aft
af
inical di
nical di
ontrolled
ntrolled
er
thereof. 
as
ot be 
be
ave a
e a
potential
otentia
on 4.4), w
n 4.4), 
ter th
ter t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 37 of 182
8. Subject has provided assent in accordance with Institutional Review Board (IRB) 
requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, 
visit schedule and study drug accountability. 
4.2
EXCLUSION CRITERIA
Subjects meeting any of the following exclusion criteria must not be enrolled into the study: 
1.
Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication. 
2.
Subject has pulmonary arterial hypertension. 
3.
Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke.  
4.
Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within 
the prior year that required medical treatment or psychological treatment for a duration 
greater than 1 month. 
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, 
based on clinical interview and/or responses provided on the C-SSRS. Subjects must be 
excluded if they report suicidal behavior in the past 6 months as measured by the C- 
SSRS at Screening or Baseline, which includes suicidal ideation with intent and plan 
(Item #5). If a subject reports suicidal ideation on Item 4 without specific plan, and the 
investigator feels that the subject is appropriate for the study considering the potential 
risks, the investigator must document appropriateness for inclusion, and discuss with the 
parent/caregiver to be alert to mood or behavioral changes, especially around times of 
dose adjustment. 
6.
Subject has a current or past history of glaucoma. 
7.
Subjects with moderate or severe hepatic impairment may not be entered. Asymptomatic 
subjects with mild hepatic impairment (elevated liver enzymes < 3xULN and/or elevated 
bilirubin <2xULN) may be entered into the study after review and approval by the 
Medical Monitor in conjunction with the sponsor, with consideration of potential cause, 
concomitant medications, and other risk factors. 
8.
Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine-oxidase inhibitors; any centrally-acting compound with clinically appreciable 
amount of serotonin agonist or antagonist properties, including serotonin reuptake 
inhibition; 
atomoxetine, 
or 
other 
centrally-acting 
noradrenergic 
agonist; 
or 
cyproheptadine (see Appendix 1). (Note: Short-term medication requirements will be 
handled on a per case basis by the Medical Monitor.) 
9.
Subject is currently receiving or has received stiripentol in the past 21 days prior to 
Screening. 
10. Subject 
is 
currently 
taking 
carbamazepine, 
oxcarbamazepine, 
eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy. 
or r
al behav
l beha
line, wh
line, wh
ports
ports su
su
t the subj
the sub
r mus
r m
COPY
orer
tmen
tment 
harm or 
arm or h
respon
espo
This document
ubject
bject
monoa
monoa
amo
amo
i
cannot
mod
mild h
mild h
<2xULN
2xULN
al Monit
Monit
mitant
mitant
be
ent or p
or 
derate 
derate 
used
ec
docum
ocum
ert 
rt to mo
to m
pa
to
cida
ct is ap
t is a
support 
arm to 
m to
ses provid
s prov
or inin the p
the
ch includ
h inclu
al idea
l id
any
vo
vo
psychol
sycho
oth
marketing 
xcipien
cipien
ebrovascu
brovasc
sa, 
sa, bu
authorization 
the stud
he stu
application 
or i
medicat
medica
s receivi
recei
mine-oxid
ine-ox
unt of s
nt of 
nhibition; 
ibition
cyprohe
cyprohe
and
an
and 
patic 
atic
) may be
may be
in conj
n con
any 
histor
histo
r se
severe 
vere 
impa
im
extensions
past 
as
des suici
s suic
ation on 
tion on
propriate
opriat
nt approp
nt appro
od or be
d or be
or
ed on
ed on
6 m
6 m
variations 
ular di
ar d
ulimia, o
limia, o
ogical tr
gical tr
ers, in 
rs, in 
t
thereof. 
y:
s in the s
n the 
ise
ise

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 38 of 182
11. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with the Baseline Period and throughout the study. 
12. Subject has positive result on urine THC Panel or whole blood CBD at the Screening 
Visit. 
13. Subject has participated in another clinical trial within the past 30 days. 
14. Subject is currently receiving an investigational product. 
15. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions. 
16. Subject has a clinically significant condition, or has had clinically relevant symptoms or 
a clinically significant illness in the 4 weeks prior to the Screening Visit, other than 
epilepsy, that would negatively impact study participation, collection of study data, or 
pose a risk to the subject. 
4.3
RANDOMIZATION INCLUSION CRITERIA
Subjects must meet all of the inclusion criteria above plus the following criteria, to be 
randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have a cardiovascular or cardiopulmonary abnormality based on ECHO, 
ECG or physical examination, including but not limited to trace mitral or aortic valve 
regurgitation or signs of pulmonary hypertension, and is approved for entry by the central 
cardiac reader. 
3. Subject demonstrates a stable baseline with ш6 convulsive seizures during the 6-week 
Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the second three 
weeks. 
4. Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (e.g., at least 90% compliant). 
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL
Male subjects who are sexually active with a partner of childbearing potential must use, with 
their partner, a condom plus an approved method of highly effective contraception from the time 
of informed consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o
oral 
o
intravaginal 
o
transdermal 
x
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
PUBLIC
ud
ovascul
vascu
on, in
on, inclu
clu
pulmon
pulmon
s a st
s a 
COPY 
RI
R
bove plu
ove plu
y incl
y inc
This document
, a a 
ed cons
d cons
followin
llowin
x
Com
Com
i
cannot 
, in
 i
ECTS O
CTS O
who are 
ho are 
cond
cond
be
aregive
giv
n the o
n the o
used
able ba
le b
minimu
minim
to 
ary h
y
support 
sion by th
ion by
or cardio
r card
ding but n
ing but
hypert
hyp
any 
he follow
he follo
marketing 
relevant s
elevant 
ng Visit, 
g Visi
ollecti
lection o
on
authorization 
g
inistratio
nistrati
application 
exua
xu
om plus a
m plus 
nt until 9
t until 
 methods
method
mbined (es
ined (
ibition o
bition
and 
F REP
REP
ally
ally
any 
as been
as be
inion of
nion of
extensions
opul
pu
not limi
ot lim
tensi
ension,
on
eline wit
line wi
m of 2 
m of 2 
or
e Epi
e Ep
lmon
mo
variations 
of
owing cr
ing cr
le
thereof. 
n n 
symptom
mptom
other th
other th
f study
study

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 39 of 182
o
oral 
o
injectable 
o
implantable intrauterine device 
o
intrauterine hormone-releasing system 
x
Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Female subjects who are not of childbearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential, unless they are at least 2 years 
post-menopausal or permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. 
Female subjects who are sexually active and are of childbearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed consent 
until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (i.e., condom for male partner): 
o
oral 
o
intravaginal 
o
transdermal 
x
Progestogen-only hormonal contraception associated with inhibition of ovulation and a 
barrier method (i.e., condom for male partner):  
o
oral 
o
injectable 
o
implantable intrauterine device 
o
intrauterine hormone-releasing system 
x
Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, they must comply with the contraceptive requirements detailed above. 
4.4.1
Sperm and Egg Donation
Male subjects should not donate sperm and female subjects should refrain from egg donation 
for the duration of the study and for at least 90 days after the last day of study medication 
administration. 
PUBLIC 
ier m
ier m
COPY 
n conta
n conta
methth
This document 
urgical 
rgical 
ernative
native
usual lif
ual lif
partne
partne
cannot 
able
ble 
mplantab
plantab
intrau
ntrau
be 
ond
used 
nal cont
al cont
dom f
dom f
to support 
ning) hor
ng) ho
od (i.e., c
d (i.e., 
any marketing 
metho
tho
are at le
are at le
include h
nclude
otential m
tential
om the t
m the
authorization 
ods o
ods
application
erine ho
rine ho
terilizatio
rilizat
y, true ab
true a
style. If a
yle. If
they mu
hey m
and 
intraut
ntraut
any 
m
extensions 
co
aception
ception
male p
ale p
or 
mon
mo
ndom 
dom
variations
must use
ust use
time of i
time of
nal c
nal
thereof. 
f 
ast 2 yea
t 2 yea
hysterec
hystere

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 40 of 182
4.4.2
Pregnancy
Subjects will be instructed that if they/their partner become pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of pregnancy 
occurring during the study but confirmed after completion of the study. In the event that a 
subject/subject’s partner is subsequently found to be pregnant after the volunteer is included 
in the study, then consent will be sought from the partner and, if granted, any pregnancy will 
be followed and the status of mother and/or child will be reported to the sponsor after 
delivery. Any subject reporting a pregnancy during the study will be withdrawn from the 
study and should complete the taper schedule. 
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the study for any reason at any time. They may be considered withdrawn if they 
fail to return for visits, or become lost to follow-up for any other reason. 
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 electronic case report form (eCRF). All subjects who withdraw from the study 
with an ongoing 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 (e.g., dates of telephone calls, registered letters). 
Subjects must be discontinued from the study for the following reasons, if deemed appropriate by 
the sponsor or investigator: 
1. Development of signs or symptoms indicative of cardiac valvulopathy or regurgitation 
(mitral, aortic, tricuspid, pulmonary valves), or pulmonary hypertension for which 
IDSMC, in consultation with the IPCAB, the central cardiac reader, and the investigator 
believe the benefit of continued participation does not outweigh the risk. 
2. Subject is found to have entered the clinical investigation in violation of the protocol. 
3. Subject requires or starts using the use of an unacceptable or contraindicated 
concomitant medication. 
4. Subject’s condition changes after entering the clinical investigation so that the subject no 
longer meets the inclusion criteria or develops any of the exclusion criteria. 
5. Subject is noncompliant with procedures set forth in the protocol in an ongoing or 
repeated manner. 
6. Subject experiences an AE that warrants withdrawal from the clinical investigation. 
7. Clinically significant worsening of seizures, judged by investigator or subject/caregiver 
form
for
until th
until th
, all data
, all dat
f premat
f premat
ollow-u
ollow-u
w
COPY
for an
for a
ththe inve
e in
prematu
premat
m (eC
m (e
This document
MC
MC
believe t
lieve t
Subje
Subje
3.3. Sub
Sub
cannot 
inu
in
gator:
tor:
ment of s
nt of s
, aortic,
aortic
C, in 
in
be 
one
ne c c
ued fr
ued fr
used 
p (i.e.
(i.e
thout sta
out sta
enting i
nting i
calls
calls
to 
ure di
e d
tht
support 
stig
ti
re wi
e withd
th
RF
RF). All 
). Al
even
vent is r
t is
to be co
o be col
iscon
sco
any 
her rea
her re
gator m
ator 
d
marketing 
wn from
from
ASSESS
ASSES
ubjects m
bjects
e consid
cons
authorization 
uded 
uded 
ancy wil
cy wil
fter 
ter 
m
application 
tricusp
icus
consultati
onsultat
he benefit 
benef
t is found
t is foun
ject requi
ect req
oncomita
ncomi
Subject
ubjec
and 
gns or s
ns or s
pid
pid
any 
egis
egi
m the stu
m the stu
extensions 
resolv
sol
llected p
ected p
ntinuatio
inuatio
ose subj
e subj
ting an
ng an in
n
the sou
he sou
ster
ster
or
ubjec
ubjec
ved
ved
variations 
M
may vol
ay vol
dered w
dered w
son. 
on. 
must mak
ust ma
wal fro
wal fro
thereof. 
he
MENT
MENT

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 41 of 182
such that treatment outside of the protocol and other than ZX008 is assumed to be in the 
subject’s best interest. Frequent or increased use of rescue medication may be considered 
indicative of worsening. 
8. An “actual suicide attempt” as classified by the Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
10. Subject is found to be pregnant while on study. 
Discontinuation decisions will be made at each participating site by the site investigator, except 
that discontinuations due to development of cardiovascular or cardiopulmonary complications are 
to be made by the IDMSC with input from the IPCAB and the investigator. 
If feasible, the process of discontinuation should be discussed with the Medical Monitor. The 
decisions regarding the discontinuation of the investigational therapy, whether the study 
medication should be stopped immediately or tapered should be discussed with the Medical 
Monitor, but final decisions about the process will remain at the discretion of the site principal 
investigator. 
Subjects who are discontinued from the clinical investigation for any reason will not be 
replaced. 
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. Subjects must be 
discontinued from receiving ZX008 and/or participating in any further study procedures under the 
following circumstances: 
x
The subject or the subject’s legally authorized representative wishes to discontinue 
participation in the study. 
x
The investigator advises that the subject’s safety or well-being could be compromised by 
further participation in the study. 
x
The sponsor requests that a subject discontinues participation in the study (e.g., due to 
suspicion of fraud, multiple enrollments in clinical studies, lack of compliance). 
The IDSMC may request that the study be terminated after review of the safety information at any 
time during the study. The IDMSC will review the data for the development of heart valve disease 
and pulmonary hypertension as they occur on a case-by-case basis and at regular meetings. 
In the event that the study is terminated prematurely then the procedure for termination should be 
followed as described in Section 3.6. 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 eCRF and in the subject’s medical records (e.g., AEs, lack of compliance, lost to 
PUBLIC 
clini
lin
en
ent to pa
t to pa
The dec
The dec
e subje
e subje
0
COPY
g
red sho
ed sh
ill rema
ill rema
cal i
cal i
This document
spo
p
spicion
picion
DSMC m
SMC 
me during
durin
and pulm
nd pulm
In th
In th
f
cannot 
he s
e 
ator adv
tor adv
rticipati
ticipat
onsor r
nsor 
be
ubject’
ubject
study
stud
used 
ct’s fu
’s f
08 and/o
and/o
to
rti
ion to
ion to
futu
utu
support 
vestigatio
estiga
cipate in
ipate
wi
any 
be
be dis
di
at the di
at the di
marketing 
investiga
investig
monary co
onary c
gator.
ator.
h ththe Med
e M
apy, w
apy, w
authorization 
Scale
cale
tinue in
inue in
application
equests t
equests
f fraud, m
fraud,
may reque
ay requ
the study
he stu
monary hy
onary h
nt th
nt
and
ses that
es that
n in the
in the
any 
gally a
gally
h
extensions 
in the stu
the st
withdraw
hdraw
e medic
medic
particip
articip
or
n for a
n for 
variations 
dical M
cal M
whether t
hether 
ussed w
ussed w
iscretion
scretion
thereof. 
ator, exc
or, ex
omplica
omplica

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 42 of 182
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. Specific procedures required are described in Section 6.2.9 and Section 6.3. 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. 
4.6
TERMINATION OF THE CLINICAL 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 continues, then the clinical 
study may be terminated. The clinical 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 clinical study include, but are not limited to: 
x
The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in the 
clinical study. 
x
Failure to enroll subjects at the required rate. 
x
A decision of the sponsor to suspend or discontinue development of ZX008. 
4.7
REPLACEMENT OF SUBJECTS
Enough subjects will be enrolled in the trial to ensure that approximately 105 subjects are 
randomized into the T+M Period.  Randomized subjects will not be replaced. 
4.8
ELIGIBILITY FOR EXTENSION STUDY
Subjects who complete the 12-week Maintenance Period of this study will be eligible to enroll in 
a planned, separate, open-label extension trial of ZX008 if they meet Inclusion/Exclusion criteria 
for that study regarding their suitability for continued participation in a trial of fenfluramine. 
Subjects must complete the entire 12-week Maintenance Period in order to be offered enrollment 
into the separate, open-label extension trial of ZX008. Those subjects who do not complete the 
12-week Maintenance Period of the study may, on a case-by-case basis, be eligible for entrance 
into the separate open-label extension study after consideration of the circumstances of the early 
termination and the potential benefit-risk of continued participation in a ZX008 trial. The 
decision whether to permit open-label extension study participation resides solely with the 
sponsor, who may consult with the site investigator, the IPCAB and/or the IDSMC. 
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION
PUBLIC 
n of th
of th
cted, re
cted, rele
cts at th
cts at th
COPY
or
o
s if the 
s if the
ay be 
y be ter
t
he c
h
This document
o c c
, separa
separa
t study r
study 
bjects m
ects m
into the
nto the
12-w
12-w
inin
cannot
en
+M Pe
M Pe
IGIBIL
GIBIL
compl
ompl
be 
NT
rolled
rolled
i
used 
e req
req
to suspe
o susp
OF
OF
to 
quire
uire
support 
min
linical stu
nical st
vant, or u
ant, or 
any 
SM
nical
ical stu
st
ated at
ated 
marketing 
will be 
ill be
further in
further in
g part
g participa
icip
C be
C b
authorization 
udy at 
udy at 
le to tha
to tha
ar as
r as
t compl
compl
application
T
te the 12
te the 1
e, open-la
open-
egarding t
egarding
ust compl
t com
separate, 
eparate,
Maint
Maint
and 
od.  R
d.  
TY FO
Y FO
any 
UB
UB
n the tria
the tria
Rand
Ran
extensions 
ud
unaccept
accep
d rate.
rate.
nd d or dis
or dis
JEC
JE
or 
y inclu
y incl
variations 
ecomes a
omes 
udy cont
dy cont
t the spo
the spo
thereof. 
andled i
ndled 
informat
format
ation in 
tion in 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 43 of 182
ZX008/matching placebo will be administered in the current study. A brief description of the 
ZX008 product is provided below (Table 2). 
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 1.25, 2.5, and 5 mg/mL
Route/Mode of Administration 
Oral
Manufacturer 
PCI Pharma Services on behalf of Zogenix
International Limited 
 
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 
and provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. The excipients selected 
have been approved for use in the formulations of currently marketed drug products and are 
considered to be safe. The solution formulations will be suitably flavored and colored, and will 
contain preservatives and a thickening agent. The product is sugar free and is intended to be 
compatible with a KD. 
The formulation will be provided in bottles with tamper-evident, child-resistant caps. The 
clinical trials material will be supplied in 1 bottle size with nominal fill volume of 120 mL. 
Matching placebo also will be provided.  Doses to be studied include 0.2 mg/kg/day and 
0.8 mg/kg/day divided into two daily (BID) doses, up to a maximum of 30 mg/day. An 
intermediate dose of 0.4 mg/kg/day will be used for titration. The concentration of ZX008 oral 
solution received by subjects (1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) will be randomized 
across the 3 available concentrations in order to ensure blinding. 
If the parent/caregiver is unable to administer the full dose due to spillage (e.g., dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. Care must be taken not to overdose. If 
the amount spilled is not known, the parent/caregiver should not give additional medication to 
avoid potential overdose. 
5.1.1 
Labeling and Packaging
The ZX008 product will be packaged and labeled according to current International Conference on 
Harmonization (ICH), Good Manufacturing Practices (GMP), and Good Clinical Practices (GCP) 
guidelines, and national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
PUBLIC 
ulatio
ulati
g agent.
g agent.
de
ded in bo
d in bo
suppl
sup
COPY 
L M
L 
of fenflu
fenflu
f
L, 2.5 m
2.5 m
ons
ons of c
of c
ons
This document
oting t
ting t
unt spill
nt spil
d potenti
potenti
5.1
5.1
The
Th
cannot 
bjects
ect
e concen
concen
egiver is
giver is
ng, sub
ng, sub
th
be
wo d
g/kg/da
g/kg/d
s (1
s (1
used
ttl
ed in 1
d in 1
ovided.  
vided.
daily
daily
to
les wit
es wi
b
support 
/mL,
mL
urrently m
rently
will be su
will be s
The produ
e produ
any 
IN
IN
amine hy
mine hy
 and 
an
marketin
ehalf of Zo
alf of Z
rk
AL P
AL
ting 
ng
tin
authorization 
riz
ho
uth
au
a
application 
un
ject spit
ect sp
extra am
extra am
ed is not k
d is not
al overdos
overd
1 
La
L
8 p
8
and
25
25
ratio
ations
n
nabl
able t
e 
any 
BID
ID
will be 
will be
mg/mL
mg/m
in
extensions
uit
uct is s
ct is s
h tamper
amper
ottle siz
ottle siz
Doses to
oses to
D)
D) do
d
or 
mark
ar
ably f
ably 
variations 
PRODU
RODU
ydrochlo
drochl
5 mg
5 mg/m
/m
keted
ete
ther
ogenix
genix
t ereof
reof. 
f
of
er

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 44 of 182
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO
Placebo solution is identical in aspect and composition to ZX008 and is composed of identical 
ingredients used in the ZX008 formulation, except that it does not contain the active ingredient, 
fenfluramine hydrochloride. 
No comparators or reference treatments will be used. 
5.2.1 
Labeling and Packaging
Placebo solution will be packaged in an identical manner to ZX008. The matching placebo product 
will be packaged and labeled according to current ICH, GMP, and GCP guidelines, and national 
legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.3
SHIPMENT AND STORAGE
IMP will be supplied to the study sites by the sponsor or its delegate. 
All IMP will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
pharmacy, the site’s standard operating procedures, and applicable regulations. IMP must be 
stored separately from normal hospital or practice inventories, in a locked facility with access 
limited to the investigator and authorized personnel. The investigator must ensure that the IMP is 
dispensed only to subjects enrolled in this study according to this study protocol. 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug. Study medication must be 
stored at 15-25°C (59-77°F) with excursions of 5-30°C (41-86°F) permitted; do not freeze. 
Storage and handling instructions of the IMP maintained at the subject’s home are described in 
the subject’s IMP handling instructions. 
All unused IMP will be saved by the site for final disposition according to the sponsor’s 
directive. 
5.4
IMP ACCOUNTABILITY
The investigator or delegate will confirm receipt of all shipments of the IMP in writing using 
the receipt form(s) provided by the sponsor or vendor. 
Assignment of ZX008 or placebo to the subject will be handled through an interactive voice 
randomization (IVR) or Interactive Web Response (IWR) platform. The investigator or delegate 
will be required to register the subject through IVR/IWR and all study medication will be assigned 
to the subject through the IVR/IWR. The IVR/IWR will also maintain a log of all received and 
PUBLIC 
th
stored, 
tored,
uctions 
uctions 
erating p
erating 
 hospita
hospit
auth
aut
COPY 
e spon
e spo
This document 
IMP 
MP 
.
4
The inv
The in
the 
the 
cannot
77°F) 
7°F) 
ing instr
ng inst
MP ha
P hand
nd
wi
wi
be 
ature
ure
nufact
nufact
used
l or 
or
orized p
ized p
led in th
d in th
an
an
to 
roced
roced
r prac
prac
support 
sor or its d
or or it
nd handle
d hand
upplied 
pplied tot
dur
ures
any marketing 
matching 
matchin
P guidelin
P guide
ng instru
ng ins
authorization 
al
dient,
ent,
application 
ing i
ng 
l be saved
be sav
IMP AC
IMP 
stigator 
tigator 
for
fo
and 
ith ex
h e
uctions o
ctions o
instr
nstr
any 
trans
tran
e up to 
e up to
xcurs
xcur
extensions
ed str
d str
o the res
the res
s, and ap
and a
ice inve
e inve
rsonnel
sonnel
s study a
study a
sp
or
elega
eleg
ict
i t
variations 
ructions 
uctions 
ate
thereof. 
g placebo
placeb
es, and
es, and

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 45 of 182
dispensed medication. 
All supplies must be accounted for throughout the study using the drug accountability form 
provided by the sponsor before the start of the study. At the end of the study, the dated and 
signed (by the investigator or delegate, e.g., pharmacist) original drug accountability form must 
be retained at the study site as verification of final drug accountability. 
Records for the delivery of the IMP to the study site, the inventory at the study site, the use by 
each subject (use by subject will be documented in the subject diary), and the destruction or 
return of the IMP to the sponsor must be maintained by the investigator (or delegate). The records 
will include dates, quantities, batch numbers, and unique code numbers assigned to the IMP and 
to the subjects. The investigator must maintain records documenting that subjects were provided 
with the doses of the IMP specified in this study protocol. Furthermore, the investigator must 
reconcile all IMPs received from the sponsor. The investigator must provide reasons for any 
discrepancies in drug accountability. Forms will be provided by the sponsor to ensure 
standardized and complete drug accountability. 
5.5
TREATMENT ADMINISTRATION
5.5.1 
Randomization
Upon completion of the Baseline Period, subjects who qualify for the study will be randomized 
(1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
30mg/day maximum) or placebo. The randomization will be stratified by age (<6 years, 6 years) 
to ensure balance across treatment arms, and at least 40% of subjects will be in each age group. 
Subjects will be assigned a randomization number by the IVR/IWR system upon confirmation that 
subject qualifies for enrollment in the Titration Period. Once a randomization number is assigned 
to a subject, the site will record the subject’s initials and identification number on the 
corresponding study drug bottles. Each bottle will contain the assigned treatment (ZX008 0.2 
mg/kg/day, ZX008 0.8 mg/kg/day, or placebo). ZX008 and placebo will be identical, thus 
rendering the study drug and placebo indistinguishable. For each IMP bottle and randomization 
number assigned, the following information will be recorded on the drug accountability form: 
subject initials, unique bottle number, date each bottle is assigned, and drug used and unused 
during the study. 
5.5.2 
Titration Period
The investigator (or delegate) will dispense IMP only to subjects included in this study 
following the procedures set out in this study protocol. 
Study medication will be administered as equal doses BID in the morning and in the evening 
approximately 12 hours apart, with food. Each dose should be separated by a minimum of 8 
hours and a maximum of 12 hours. A missed dose of study medication may be taken later up to 
8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
Administration of the IMP will be based on the randomized dose and subject’s weight (kg) at 
PUBLIC 
riod, sub
riod, su
to receiv
o receiv
bo. The 
bo. The 
ment a
men
COPY 
ATION
TION
This document
study.
tudy
2 
The inv
he inv
follow
follow
S
cannot
g b
g
8 mg/k
mg/k
drug an
drug an
d, the fol
the fo
 uniqu
uniqu
be
ord th
d th
bottles
bottles
/
used
rms, an
s, an
mization
mization
in the T
the 
n
e
to
e 1 
ndomi
ndom
d
support 
jects
ects who
wh
of 
of 2 d
2
any 
th
marketing 
estr
elegate)
legate
signed to 
gned to 
at subject
at subjec
ore, 
e, the in
the 
ust provid
st prov
he spon
he sp
authorization 
m must 
must 
, the use
he use
ructio
uctio
application 
ow
e bottle 
bottle
itration 
itration
stigator (o
tigator 
wing the p
ng the p
edi
and 
day, o
ay, 
d placeb
placeb
wing in
ing i
any 
bject’
bject
Each bot
Each bot
or
or plp
r
extensions
o qualify
qualif
doses of 
oses of
ation wi
ion w
at least 
least 
t
numbe
umbe
ration 
ation
or variations 
nvest
vest
de reaso
reaso
nsor to 
nsor to 
thereof. 
by
n or 
or 
The rec
The rec
o the IMP
he IMP
s were p
s were p
tiga
iga

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 46 of 182
Visit 3 (Study Day -1). At Visit 8 (Study Day 43), if the subject’s weight (kg) has changed 
±25% of the weight at Study Day-1, the IMP dose will be recalculated. Subjects should be 
dosed using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups (Section 5.6) and allow step titration to the 
high dose, the dose for each subject will be titrated starting with a dose of ZX008 
0.2 mg/kg/day (or placebo equivalent) BID. After 4 days at this dose level (Study Day 5), 
subjects randomized to the ZX008 0.8 mg/kg/day group will increase their dose to 
0.4 mg/kg/day (maximum 30 mg/day) while doses in the other two groups will remain 
constant. On Study Day 9, the dose for the 0.8 mg/kg/day group will increase to the target dose 
or a maximum of 30 mg/day. The titration is expected to take a total of 14 days (Table 3). A 
new bottle of IMP will be started by the subject at each level of the titration step. See 
Section 5.6 for more information about the volume of ZX008 or placebo to be administered. 
Table 3: 
Titration Algorithm 
Randomized Group
Titration Step 1
Study Day 1-4
Titration Step 2
Study Days 5-8
Titration Step 3
Study Days 9-14
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.8 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.8 mg/kg/day
Placebo
Placebo
Placebo
Placebo
Note: maximum daily dose of ZX008 is 30 mg
5.5.3
Maintenance Period
After completion of the Titration Period, subjects will enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an additional 
12 weeks. Study medication will continue to be administered BID in the morning and in the 
evening, approximately 12 hours apart, with food. Each dose should be separated by a 
minimum of 8 hours and a maximum of 12 hours. A missed dose of study medication may be 
taken later up to 8 hours before the next scheduled dose; otherwise, the missed dose should not 
be given. 
5.5.4
Taper Period
Subjects who complete of the Maintenance Period and will not be continuing into the open- 
label extension study, and subjects who discontinue from the study early, will be tapered off of 
study medication.  Study medication will be administered as equal doses BID in the morning 
and in the evening approximately 12 hours apart, with food. Each dose should be separated by a 
minimum of 8 hours and a maximum of 12 hours. A missed dose of study medication may be 
taken later up to 8 hours before the next scheduled dose; otherwise, the missed dose should not 
be given. IMP should be administered using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups, all subjects who do not continue into the 
kg/day
g/day
C
mg/kg/day
mg/kg/day
C
acebo
acebo
LI
8 is 30 m
is 30 m
BL
UB
COPY 
OP
CO
C
This document 
T
ubjects 
bjects 
label e
abel e
stud
stud
cannot 
dicatio
catio
mately 12
ately 12
hours an
ours an
p to 8 h
to 8 h
be
trati
andomi
andom
on
on
used 
od
on P
on P
to 
to support 
itration
ration
Study D
tudy 
t
ZX008 0
ZX008
po
ZX00
ZX00
pp
up
s
any 
St
a
marketing 
se 
will rem
will rem
crease to t
ease to t
of
o 14 day
14 da
f
e titration
titratio
r placebo
placeb
authorization 
on to the
to the
y Day 5
Day 5
toto
application 
urs be
rs b
aper Peri
per Pe
who comp
ho com
xtension s
ension
medica
medica
and
wil
wil
hours 
hours 
a maxi
a max
efo
efo
any 
riod
iod
d dose o
d dose
contin
cont
extensions
.2 
8 0.4 m
0.4 m
s
Place
Place
ns
on
sio
, su
su
or 
ys 5-8
s 5
mg/kg
mg/kg
or 
/
o variations 
n step
step
o to be a
to be a
p 2
p 2
8
a
thereof. 
,
ainin
the targe
e targe
s (Table
s (Tabl
p. S
p S

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 47 of 182
open-extension study will participate in a dose-tapering procedure over the course of 8 days. On 
the first day of the tapering period subjects in the ZX008 0.8 mg/kg/day group will decrease to a 
dose of ZX008 0.4 mg/kg/day BID (maximum 30 mg/day). After 4 days at this dose level 
(Study Day 5), subjects randomized to the ZX008 0.8 mg/kg/day group will decrease their dose 
to 0.2 mg/kg/day. Subjects in the ZX008 0.2 mg/kg/day group will decrease their dose to 
placebo on the first day of tapering while doses in the placebo group will remain constant 
throughout the tapering procedure. On Study Day 9, all subjects will stop taking study 
medication. The taper is expected to take a total of 8 days (Table 4). A new bottle of IMP will 
be started by the subject at each level of the taper step. 
Table 4: 
Taper Algorithm 
Randomized Group
Taper Step 1
Day 1-4 after study completion or 
early termination
Taper Step 2
Days 5-8 after study completion or 
early termination
ZX008 0.2 mg/kg/day
Placebo
Placebo
ZX008 0.8 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Placebo
Placebo
Placebo
Note:  maximum daily dose of ZX008 is 30 mg.
5.5.5
Transition Period
Subjects who complete the Maintenance Period and will be continuing into the open-label 
extension study will be transitioned from double-blind study medication to open-label ZX008 
(Table 5). Study medication will be administered as equal doses BID in the morning and in the 
evening approximately 12 hours apart, with food. Each dose should be separated by a minimum 
of 8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later 
up to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
Study medication should be administered using the oral dosing syringe provided. 
All subjects entering the open-label extension study will be transitioned from their blinded daily 
dose (placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) to the 0.2 mg/kg dose during the 
2-week interval between Visits 12 and 13, without breaking the blind. The IVR/IWR system 
will assign two bottles of IMP to the subject, one for each step in the transition. A new bottle of 
IMP will be started by the subject at each level of the transition step. See Section 5.6 for more 
information about the volume of ZX008 or placebo to be administered. 
Table 5: 
Transition Algorithm 
Dose Group in 
Double-Blind Study
Transition Step 1
Day 1-4 after Visit 12
Transition Step 2
Days 5-14 after Visit 12
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.8 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
PUBLIC 
.
C
Mainte
Mainte
tio
ti
COPY 
PY
kg/day
g/day
OP
o
CO
C
This document
interva
terva
assign tw
ign tw
MP will b
P will b
informa
form
Tab
Ta
cannot 
the n
e n
should b
hould b
ntering t
ering t
o, 0.2 m
, 0.2 
al
be
hou
um of 1
um of 1
ext
ext
used
nance
anc
ned from
d from
will be a
ll be a
urs ap
rs a
to 
e Pe
e Pe
support 
rtrtrt
or
po
any 
ys
y
ny
an marketing 
ottl
Tap
T
5-8 af
5-8 
a
authorization 
 a a
ir dose
r dose 
e to
onstant 
nstant 
study 
study 
le of 
e of
application 
he 
mg/kg/d
g/kg/d
between V
etween 
o bottles o
bottles
e started b
started
ion about
n abo
and
sch
c
e admin
admi
open-
open-
any 
rt, w
rt, 
ours. A
ours. 
eduled
edule
is
extensions 
riod and 
od and
doubl
ouble-e-
minister
minister
with
with
or r
o variations 
per Step 
er Step 
ter study
er stud
early ter
early ter
ns
P
ia
ZX0
ZX0
ar
va
v
thereof.
MP wil
MP wil

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 48 of 182
Placebo
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
Note: maximum daily dose of ZX008 is 30 mg.
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning 
on Day 1 of the transition (the day following Visit 12). Subjects who had been randomized to 
0.2 mg/kg/day will continue to receive that dose. Subjects who had been randomized to 
0.8 mg/kg/day or were receiving the maximum dose of 30 mg/day decrease to a dose of ZX008 
0.4 mg/kg/day, or a maximum of 30 mg/day. After 4 days at this dose level (Day 5), these 
subjects will decrease their dose to 0.2 mg/kg/day. Subjects will report to the clinic on Day 15 
for enrollment into the open-label extension study. 
5.6
BLINDING
At the end of the Baseline Period, subjects who qualify to enter the study will be randomized to 
receive ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day (maximum dose: 30 mg/day), or placebo 
and assigned a randomization number by the IVR/IWR system. Once a randomization number 
is assigned to a subject, the site will record the subject’s initials on the corresponding study drug 
labels. Each bottle will contain the assigned treatment (ZX008 or placebo) and the ZX008 and 
placebo solutions will be identical. 
The blinding scheme instituted for this study will ensure that the volume of study medication 
taken cannot be associated with the dose group, thus unblinding the study. This is achieved by 
random assignment of different concentrations of the ZX008 oral solution (1.25 mg/mL, 
2.5 mg/mL, and/or 5 mg/mL) by the IVR/IWR system. The IVR/IWR system will instruct site 
personnel to the volume of oral solution to be administered based on that subject’s weight. 
(Dose will be recalculated by the system once at the midpoint of the study.) During the 
Titration, Maintenance, and Taper/Transition Periods, the subjects and study personnel 
(investigators, clinical staff, personnel involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the treatment allocation and to the concentration of 
ZX008 oral solution. If an investigator feels the blind should be broken, he/she can do so when 
necessary for treatment decisions. However, the investigator should endeavor to discuss with 
the Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study medication 
versus placebo is needed to determine course of medical treatment for the event. The subject 
will be discontinued from the clinical trial upon breaking of the blind and the decision whether 
the subject can enter the separate open-label extension study will rest with the Sponsor if the 
subject exited Study 1501 prior to completion. 
5.7
PRIOR AND CONCOMITANT MEDICATION
All medications taken by a subject during the Screening and Baseline Seizure Assessment 
Periods are regarded as prior therapy and must be documented in the eCRF. Significant 
medications (e.g., antibiotics) taken within 30 days prior to the Screening visit should also be 
captured. All prior and concomitant AEDs will be collected in the CRF. 
PUBLIC 
this stu
this stu
the dos
the dos
ent conc
ent conc
L) by
L) by t
l
COPY
day
ay
VR/IWR
R/IW
he subje
he sub
ed treatm
d treat
This document 
n in t
in 
s placebo
placeb
l be disc
be dis
the subj
e subj
subje
subje
5
cannot
onsor) 
nsor) 
ion. If an
n. If a
reatmen
eatmen
Monito
Monito
he
he
be 
nd Ta
Ta
aff,
aff, per
pe
w
used 
he IVR
IVR
solution
lution
the sys
the sy
per
per
to
gr
ntrati
ntratio
R/I
R/I
support
t s s
ment (ZX
nt (ZX
y will ens
ill ens
roup, 
oup, th
ns
any 
mum
mum
ystem. O
ystem. 
initial
initia
0
marketing
Day
ay
the clinic
the clini
r the stud
the stu
m do
m d
authorization 
nning 
ning
domized 
mized 
ed to
d to
dose of
dose of
y 5), 
5), 
application 
r or Spo
r Sp
vent the k
vent the
is needed
need
ontinued 
ontinued
ct can ent
can e
t exited S
exited 
and
ll be
l b
investig
nvesti
decisio
ecisio
any
Trans
ran
onnel inv
onnel in
e blind
e bli
extensions
nsure th
ure th
hus unbl
hus unb
s of the Z
of the Z
WR syst
R syst
to be ad
be ad
m on
m once
ce
iti
iti
or 
08
08
variations 
dy will b
dy will 
ose: 30 m
e: 30 m
Once a r
nce a r
ls on the
on the
8 or p
 or p
thereof. 
ZX0
ZX
hese
se 
c on Day
on Day

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 49 of 182
All medications taken by a subject after the first administration of IMP are regarded as 
concomitant medication and must be documented in the eCRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations. Subjects are required to take at least one 
concomitant AED during the study. All subjects will continue to receive their existing AED(s) 
with the same doses throughout the study. Every effort should be made to ensure that the regimen 
of existing medications remains stable during the study; any changes must be discussed with the 
sponsor prior to implementation. If a decrease in a concomitant AED is necessary to manage an 
AE, this must be discussed with the sponsor as soon as possible after implementation if not before 
implementation. Non-study medications and therapies that are considered necessary for the 
subject’s welfare and will not interfere with the response to the study medication may be given at 
the discretion of the investigator, informing the Medical Monitor as soon as possible. 
It should be noted for any subject receiving hypoglycemic agents, the investigator should 
consider diabetic medication changes in the setting of weight loss and hypoglycemia. 
5.7.1
Vagal Nerve Stimulation
Subjects receiving treatment with a VNS may be included as long as the VNS has been in place 
for at least 6 months prior to entry into the study, the VNS battery is not due for replacement 
during the study, and stimulation parameters have been kept constant for 4 weeks prior to 
screening and must remain so throughout the study. The subject’s use of VNS will be recorded in 
the CRF. 
5.7.2
Ketogenic Diet
Adherence to the KD, or a modified version of KD, is permitted during the study if the dietary 
habits were initiated more than 4 weeks prior to Screening and remain stable throughout the 
study. The subject’s use of KD will be recorded in the CRF. 
5.7.3
Rescue Medication for Seizures
The subject's usual or prescribed regimen and frequency of rescue therapy for seizures should be 
entered into the prior and or concomitant medication sections of the eCRF. 
Use of rescue medication is permitted during the study and should be recorded on the eCRF (day, 
medication[s], dose[s]) and in the diary (day, timeframe associated with seizure episodes). 
Repeated administrations within the same episode should be recorded separately. 
5.7.4
Prohibited Concomitant Medication and Food
A list of medications/foods that are to be avoided as ongoing medications or for chronic use if 
initiated during the study from the time of signing the informed consent form (ICF) until the end-
of-study visit (or early termination) is provided in Appendix 1. If medical necessity requires 
short-term use of one or more of these medications during the course of the study, please contact 
the Medical Monitor for approval.  
The following concomitant medications are prohibited during the clinical trial: 
PUBLIC
eters h
eters 
hout the
hout the
COPY 
y be inclu
y be incl
tudy, t
udy, t
ha
This document
ue m
e m
on[s], do
[s], do
ted adm
d adm
5.7.4
.7.4
A lis
A li
inin
cannot 
edic
di
or presc
presc
prior and
rior an
medic
medic
be
KD wi
D w
atio
ati
used 
ied versi
d ver
4 week
week
llll
to support 
ded a
ed a
e VNS ba
VNS
e been ke
been k
study. Th
dy. Th
any 
as lon
s l
marketing
tati
cessary 
essary
dication m
cation m
on as poss
on as po
the invest
e inve
s and hyp
and h
authorization 
one
ne
D(s) 
s) 
e regime
egime
ed with 
d with 
to mana
o mana
ion if
on if
application 
o
ation is p
tion is p
se[s]) and 
[s]) an
nistration
nistratio
Prohi
Pro
medic
medic
and 
n 
n
ribed reg
bed reg
r conc
conc
any 
p
e recor
e rec
for Seiz
or S
extensions
ept
he subje
subj
on of 
n of KD
KD
prior to
ior t
or 
tte
ttery
r
cons
cons
variations
tigator 
gator
ypoglyce
poglyce
ng g as th
as th
y isi
thereof.
ge an
ge
not befo
ot befo
for the
r the
may be g
y be g
sible.
ible.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 50 of 182
x
AEDs: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, retigabine/ezogabine 
x
Stiripentol (STP): Subjects must be off STP for a minimum of 21 days prior to the Screening 
visit. 
x
Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to screening, has stable liver function and hematology 
laboratory tests, and the dose is expected to remain constant throughout the study. 
x
Drugs that interact with central serotonin, including but not limited to: imipramine, 
monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-
norepinephrine reuptake inhibitors, vortioxetine 
x
Drugs that increase cardiovascular risk including: atomoxetine and those with noradrenergic 
reuptake properties (NRIs, SNRIs) 
x
Drugs intended to facilitate weight loss 
x
Other:  any form of marijuana, THC and derivatives (including Epidiolex®) 
x
A list of medications/foods that are to be avoided as ongoing medications or for chronic use 
if initiated during the study from the time of signing the informed consent form (ICF) until 
the end-of-study visit (or early termination) is provided in Appendix 1. If medical necessity 
requires short-term use of one or more of these medications during the course of the study, 
please contact the Medical Monitor for approval. 
5.8
TREATMENT COMPLIANCE
Each subject or parent/caregiver will record the dose, dosing frequency and IMP consumption in 
the subject’s diary. Subjects will bring their used, partially used, and unused IMP to every study 
visit. Treatment compliance will be monitored by measuring the volume of IMP in these bottles 
and comparing to the dispensation log and diary records. 
6.
VISIT SCHEDULE
Study procedures will be conducted according to the Schedule of Assessments in Table 1. 
Time windows for all assessments are detailed in Table 6. 
Table 6: 
Time Windows for Assessments 
Visit / Procedure
Time window (relative to scheduled visit / procedure)
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41): 
Not applicable
Visit 2 (Phone; Study Day -21)
± 3 days
Visit 3 (Clinic; Study Day -1; Randomization)
+ 4 daysa
Visits 4, 5 (Phone: Study Days 4, 8)
± 3 days
Visit 6 (Clinic; Study Day 15)
± 4 days
Visit 7 (Phone: Study Day 29)
± 4 days
Visit 8 (Clinic; Study Day 43)
± 4 days
PUBLIC 
the ti
the t
y termina
ermin
one or m
ne or m
cal Moni
l Mon
COM
CO
COPY 
d derivat
d deriv
o be av
o be av
ime
ime
This document 
ows f
ws 
le 6: 
6: 
Visit
Visi
cu
do
V
do
do
d
cannot 
spen
pe
T SCH
SCH
res will
es wil
or
be
will
e will
e will b
nsati
nsat
used
PLIAN
LIA
will rec
will rec
l brin
brin
to
or for 
or for
NC
N
support 
ve
oided as o
ded as 
of signin
of signi
tion) is pr
on) is p
e of th
of thes
app
any 
s (inclu
s (inc
marketing 
imipra
mipr
rs, seroto
rs, seroto
ne and tho
e and t
authorization 
ening
ning
on n 
nd hema
d hema
e study. 
study. 
am
application 
be cond
e con
ll assessm
ll asses
Time W
Time
Procedur
rocedur
pp
Clinic
lin
ap
and 
on
EDUL
DUL
d
any
the
he
monitor
monito
log and
log a
extensions
g
rovide
ovide
se medi
se med
proval.
roval.
E
ord the d
d the d
eir us
ir us
or 
ngo
g
the in
the in
d
variations
hose w
se w
uding Ep
ding E
oing
oing
thereof. 
mine,
ne,
onin-
nin-
with
ith

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 51 of 182
Visit 9 (Phone: Study Day 57)
± 4 days
Visit 10 (Clinic; Study Day 71)
± 4 days
Visit 11 (Phone: Study Day 85)
± 4 days
Visit 12 (Clinic: Study Day 99)
± 4 days
Visit 13 (Clinic; Study Day 113; post dosing)
± 4 days
Visit 14 (ECHO clinic; 3-6 months after last dose)
+ 30 days
Blood collection for ZX008 PK
± 15 minutes
Blood collection for AED concentration
Prior to morning dose of AED medication
AED=antiepileptic drug (s); ECHO=echocardiogram; PK = pharmacokinetics 
a 
In cases where the screening period is extended beyond 42 days, the immediate 42 days before the Randomization visit will 
be used to calculate the baseline seizure frequency
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1)
The Baseline Period of the study encompasses the screening activities that will occur on Study 
Day -42 as well as the observation period where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity entered into a diary. 
6.1.1
Screening, Clinic Visit 1 (Study Day -42)
Screening is the predetermined series of procedures with which each investigator selects an 
appropriate and representative sample of subjects for enrollment into the study. Select 
screening data will be documented in the IVR/IWR and eCRF. 
Written informed parental or guardian consent and assent of minors (if the subject is capable of 
providing assent) must be obtained before a subject can start any of the screening procedures. The 
procedure(s) for obtaining written informed consent and assent of minor (if the subject is capable 
of providing assent) are described in Section 11.2. 
The Screening visit will occur on Study Day -42; however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study Day -42 or Study Day -42 and Study Day -41). 
Splitting the visit procedures across 2 nonsequential days requires the approval of the medical 
monitor. The following procedures will be performed for all subjects before the start of seizure 
activity observation: 
x
Obtain written informed consent for the study 
x
Obtain written informed consent from parent/caregiver to collect PedsQL Family 
Impact, HADS, and EQ-5D-5L ratings of parent/caregiver symptoms and quality of 
life 
x
Review inclusion and exclusion criteria 
x
Record demographic information 
x
Record medical, neurological, and epilepsy history 
x
Record current epilepsy status (number/type/duration seizures per month) 
x
Collect past 6 months (or available duration) of parent/caregiver seizure diary data if 
PUBLIC
sub
he IVR
he IVR
dian cons
dian con
ned 
ned befo
befo
itten inf
itten inf
ed
ed
COPY 
ent
en
Day -42
Day -4
ce
cedures w
dures w
bjects 
jects
This document
Obt
Ob
Im
I
x
oc
x
d
cannot
ng proc
proc
n:
Obtain w
btain w
be
udy D
y D
ures ac
ures ac
used
orme
rm
n Sectio
Sectio
on St
on S
ay
a
to
e a su
e a su
ed co
ed co
support 
with wh
h wh
for enrollm
r enrol
WR and e
R and
nt and as
t and as
bjec
bj
any 
to a
o 
ich
i
marketing 
e Rand
Rand
DAY -1)
DAY -1)
ies that w
s that 
assess
ssessed 
ed
a diar
a dia
authorization 
titi
ati
at
at
iza
ori
ho
uth
au
application 
itten i
ten 
in written
writte
mpact, HA
mpact, HA
lifefe
Rev
Rev
and 
dures
ure
inf
nf
any 
43 and
43 an
ss 2 no
ss 2 no
s will
s w
extensions 
eCR
CR
ssent of 
sent of
ct can st
t can s
nsen
ent an
t an
n 11.2.
11.2.
y Day
y Day
d
or
ment i
ment 
RF. 
F
variations
will occ
ll oc
for base
or base
ry.
each in
each i
t
thereof. 
f
zation visi
tion vis
cu

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 52 of 182
available (screen shots of cell phones are acceptable, as are photocopies of paper 
diaries or print outs) and place in source file 
x
Record prior medications 
x
Complete physical examination, including height, weight, and calculation of BMI 
x
Complete neurological examination 
x
12-lead electrocardiogram 
x
Doppler ECHO (this may be obtained any time between Study Day -42 and Study 
Day -21) 
x
Vital signs 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) 
x
Urine THC panel 
x
Whole blood CBD 
x
Obtain blood sample for epilepsy genotype panel 
x
C-SSRS Children’s Baseline/Screening Assessment (Appendix 2) 
x
Instruct parent/caregiver on use of diary 
x
Dispense diary (after above procedures have been concluded) 
x
Record AEs 
x
Record AESIs 
Only eligible subjects as specified by the inclusion and exclusion criteria with an independently 
confirmed diagnosis of DS by the Epilepsy Study Consortium will be enrolled into the study. 
After enrollment into the study, each subject will be issued a “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will be 
advised to retain this card on his person for the entire duration of the study so that the investigator 
or the sponsor can be contacted in case of emergency. 
In certain circumstances the sponsor may allow subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the screening period extended, or to be re-screened 
for eligibility. In all cases the investigator should consult with the Medical Monitor. Decisions 
whether to permit rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or rescreening can be influenced by many 
PUBLIC 
e for epi
for epi
n’s Ba
n’s Ba
COPY 
ild-b
ild-
mis
mistry, h
try
This document
s
diagn
diagn
enrollm
enrollm
ormation
rmation
advised 
dvised 
or the
or the
I
cannot 
Es
rd AESI
d AES
ubject
bject
be
y (after
afte
used 
eline
ine
egiver on
iver on
r a
to 
epsy
ps
/Sc
/Sc
support 
em
y geno
y ge
any 
g pote
po
matolog
atolo
marketing 
udy Day -4
dy Day
enti
en
authorization 
of BMI
BMI
application 
as spec
as spe
is of DS b
of DS
ent into 
ent into
about the
about t
o retain th
retain 
onsor c
nsor 
and any 
ove pr
ove p
extensions 
notype p
type p
eening A
ening A
use of d
use of d
or variations 
ialal
gy, urina
, urina
thereof. 
-42 and 
-42 and

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 53 of 182
factors individual to that subject case. Some general principles apply: 
1. If baseline seizure screening is extended or the subject is discontinued and then rescreened, the 
screening period for establishing the baseline seizure frequency will be the immediate 6 weeks 
before the randomization visit. 
2. Subjects who are found to be on a prohibited medication at the screening visit may be weaned 
off of that medication provided: 
a.
Decisions to withdraw a disallowed concomitant medication must be made with the 
agreement of the prescribing physician 
b. If the medication has antiepileptic properties, a wash out of at least 5 half-lives 
must be completed before collection of baseline seizure data.  
c.
If a decision has been made to wean off of a medication without antiepileptic 
properties and the wash-out period (at least 5 half-lives) is expected to be shorter 
than 5 weeks, then the subject may remain in screening and chart seizures using the 
seizure diary. 
6.1.2
Phone Visit 2 (Study Day -21)
Site personnel will contact the subject via telephone on Study Day -21 and record the 
following: 
x
AEs 
x
AESI 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.1.3
Clinic Visit 3 (Study Day -1): Randomization
This period is intended to ensure that subjects meet the study entry criteria and confirm they have 
experienced 6 convulsive seizures during the 6-week Baseline Period, with at least 2 seizures in 
each 3-week half of the Baseline Period. Subjects must have at least 42 days of prospective diary 
data at Visit 3. Subjects will report to the clinic in the morning on Study Day -1 to allow for 
plasma sample collection for AED pharmacokinetic evaluation prior to the morning dose of these 
medications. Subjects should not take their morning dose(s) of AED medication prior to 
reporting to the clinic. 
The following procedures will be performed on Study Day -1: 
x
Review inclusion and exclusion criteria 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
and calculate the number of convulsive seizures during the first 3 weeks, the second 3 
weeks, and over the full 6-weeks of the observation period. 
PUBLIC 
y -2
y
t vi
t via tele
a tel
COPY
at l
t 
ay rema
y rem
21)
1)
This document
it 3. S
3. S
sample c
mple 
cations. 
ations. 
porting t
orting t
The fo
The fo
cannot 
Visit 3
sit
ded to e
d to e
convulsi
onvulsi
alf of th
lf of th
ub
be 
th re
3 (S
3 (S
used 
eview
evie
to support 
phone on 
one on
any 
half
al
n screen
n scre
marketing 
must 
ust
ut of at lea
ut of at l
ure data. 
e data
dication w
ication
-lives
-liv
authorization 
d, the
the
6 weeks 
6 weeks 
ay be w
ay be w
be m
be m
application 
ve
e Basel
Base
ects will 
ects wil
ollection 
llection
Subjects s
ubjects
o the clini
the clin
owing p
wing 
and
tu
nsure
ure tha
 tha
seizur
eizu
i
any 
the 
the
dy Day
y Da
extensions
Study
Study
dia
dia
or 
D
variations 
without 
ithout 
s) is exp
 is exp
ning and
ng and
thereof. 
made wit
de wit
ast 5 ha
ast 5 ha

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 54 of 182
x
Record prior medications since previous visit 
x
Complete physical examination, including height and weight, and calculation of BMI 
x
Abbreviated neurological examination 
x
Vital signs 
x
12-lead ECG 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry, and hematology, and urinalysis) 
x
Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
x
Urine THC panel 
x
Whole blood CBD 
x
Tanner Staging for subjects >7 years of age (Appendix 5) 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
BRIEF (Appendix 3) 
x
QOLCE (Appendix 4) 
x
PedsQL (Appendix 6) 
x
PedsQL Family Impact module (Appendix 6) 
x
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
x
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
x
Record AEs 
x
Record AESI 
x
When eligibility for the Titration Period is confirmed, randomize (blinded) subject to 
treatment assignment (ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or placebo) 
x
Dispense study medication (If administration of the first dose of study medication 
occurs in the clinic, the next dose should be at least 8 hours later or the following 
s >7
>7 y
ary 
ary with 
with
’s S
’s
COPY 
yea
This document 
Par
Par
A
x
do
cannot 
p
L (Appen
(Appe
dsQL Fa
sQL F
ren
ren
be 
ix
pendix 
pendix
used 
ince Las
ce La
3)
3)
to support 
s of age (
of age
arent/car
rent/ca
any marketing 
, and urin
and ur
aluation p
uation
authorization 
BMI
MI 
application 
mil
/Caregive
Caregiv
ffective s
ffective
Record
Reco
R
and 
ndix 6)
ix 6)
ly Im
y Im
any 
)
extensions 
(A
regiver 
egiver 
Visit A
Visit A
or 
ppend
ppen
variations
prior to 
ior to 
thereof. 
alysis) 
alysis) 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 55 of 182
morning. The dose on the following morning will count as Study Day 1.) 
6.2
TITRATION AND MAINTENANCE PERIODS
6.2.1
Titration Period Study Day 1
Subjects will take their first dose of study medication on the morning of Study Day 1. Study 
Day 1 is considered the first day of dosing, even for those subjects that received an in-clinic dose 
on Study Day -1. 
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8)
Site personnel will contact the subject via telephone on Titration Period Study Days 4 and 8 
and record the following: 
x
AEs 
x
AESI 
x
Concomitant medications
In addition, site personnel will review study medication dosing procedure and the diary entries 
with the parent/caregiver. 
6.2.3
Clinic Visit 6 (Titration Period Study Day 15)
Subjects will report to the clinic in the morning on Titration Period Study Day 15. Subjects should 
not take their morning dose(s) of AED medication prior to reporting to the clinic. The following 
procedures will be performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
Record concomitant medications 
x
Abbreviated physical examination, including height and weight, and calculation of 
BMI 
x
Abbreviated neurological examination 
x
Obtain vital signs 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x
Urine THC panel 
x
Whole blood CBD 
tudy m
tudy m
tration P
ration P
nic in t
nic i
COPY 
me
This document 
Abb
Ab
x
oc
x
cannot
concom
ncom
breviate
reviate
MI
MI
be 
nt seizu
nt seiz
used
he mor
e mor
AED m
AED m
to
eriod 
eriod
support 
ication do
cation 
Stu
any marketing 
8)
od Study D
d Study
authorization 
. Study 
Study 
n in-clin
n-clin
application 
d p
reviated n
eviate
Obtain v
Obtain 
Urin
Uri
and
tant m
nt m
physic
hysic
any 
e activity
e activi
edid
extensions 
dos
udy Day
dy Day
ng on Ti
ng on T
dicatio
ication
or 
ng pr
ng pr
variations 
D
thereof. 
c do
c 
ays 4 
ays 4 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 56 of 182
x
Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
Record AEs 
x
Record AESI 
x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x
Dispense study medication 
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29)
Site personnel will contact the subject via telephone on Maintenance Period Study Day 29 and 
record the following: 
x
AEs 
x
AESI 
x
Concomitant medications 
In addition, site personnel will review the diary entries with the parent/caregiver. 
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43)
x
Subjects will report to the clinic in the morning on Maintenance Period Study Day 43. 
Subjects should not take their morning dose(s) of study medication and AED 
medication prior to reporting to the clinic. The following procedures will be 
performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
Record concomitant medications 
x
Abbreviated physical examination, including height and weight, and calculation of 
BMI (Note: if the subject’s weight is ±25% of the weight at Study Day-1, the IMP 
dose will be recalculated) 
PUBLIC 
nance P
nance P
ubject vi
ubject vi
COPY
sed stud
sed stu
This document
Sub
Sub
Su
Su
x
do
cannot 
nt 
nt 
sonnel w
onnel w
Clinic V
Clinic 
j
be 
medic
med
used to 
telep
ele
support 
eriod Stu
iod Stu
phon
pho
any 
medicati
medica
marketing 
caregiv
aregiv
vestigator
stigato
authorization 
application 
Visit 8
sit 
cts will re
ts will
bjects sho
ects sh
medicatio
medica
perform
perfo
R
and 
will revie
l revie
8 (M
8 (M
any 
ions 
ons 
extensions
udy Day
dy Da
ne on M
e on M
or variations 
ion; per
on; per
thereof. 
r)
r) 
r) 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 57 of 182
x
Obtain vital signs 
x
12-lead electrocardiogram 
x
Doppler ECHO (this must be obtained any time between Study Day 40 and Study 
Day 54) 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x
Urine THC panel 
x
Whole blood CBD 
x
Collect plasma sample for ZX008 pharmacokinetic evaluation at the following 
timepoints: within 1 hour prior to the morning dose of study medication, and 1, 2 and 
4-6 hours after the morning dose of study medication 
x
Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
BRIEF (Appendix 3) 
x
QOLCE (Appendix 4) 
x
PedsQL (Appendix 6) 
x
PedsQL Family Impact module (Appendix 6) 
x
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
Record AEs 
x
Record AESI 
x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x
Dispense study medication 
PUBLIC 
ry 
ry with p
with p
n’s S
n’s 
COPY
morni
mor
f study m
study m
D pharm
D pharm
This document 
Af
A
C
x
doc
cannot
(Appen
Appen
dsQL Fa
QL Fa
ffect
ffec
be
pendix 
pendix
used
nce Las
ce La
3)
3)
to support 
acokine
cokinet
arent/care
rent/ca
any 
ose of
ose o
dication
dication
marketing 
rinalysi
nalys
evaluat
evalu
st
authorization 
Study
tudy
application 
ve sympt
ve symp
inical Glo
ical G
Clinica
Clinic
Re
R
and 
dix 6)
x 6)
ly Imp
y Im
any extensions 
egiver 
giver 
Visit As
Visit A
or 
ev
e
variations 
tion at th
ion at t
tudy me
tudy m
evalua
valua
thereof. 
)

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 58 of 182
6.2.6
Phone Visit 9 (Maintenance Period Study Day 57)
Site personnel will contact the subject via telephone on Maintenance Period Study Day 57 and 
record the following: 
x
AEs 
x
AESI 
x
Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71)
Subjects will report to the clinic on Maintenance Period Study Day 71. The following 
procedures will be performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
Record concomitant medications 
x
Abbreviated physical examination, including height and weight, and calculation of 
BMI 
x
Obtain vital signs 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x
Urine THC panel 
x
Whole blood CBD 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
Record AEs 
x
Record AESI 
x
Collect used, partially used and unused study medication; perform drug accountability 
PUBLIC
aminatio
minati
s 
es
es
COPY 
umber/ty
umbe
ns 
ns
This document
Dis
Dis
C
x
c
x
do
cannot 
p
blood C
lood C
ollect an
ect an
spe
be 
uat
anel
anel
used 
for fem
r fem
tion (s
ion (s
to support 
pe
p
n, includi
includ
any 
/duratio
dura
marketing 
aregiver.
egiver
1)
ay 71. T
y 71. T
authorization 
application 
d rev
nse diary
se diary
-SSRS C
SSRS C
Clinic
Clini
C
and 
BD 
D 
view
view
any 
um
um
extensions
ing he
he
les of ch
s of c
m che
m ch
or 
igi
variations 
The follo
he follo
on) from
n) from
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 59 of 182
and review with parent/caregiver 
x
Dispense study medication 
At Clinic Visit 10, compliant subjects who have tolerated IMP should be presented with the ICF 
for the open-label extension study. Informed consent for the open-label extension study must be 
signed at Visit 12 or earlier in order to enter the open-label extension study. 
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85)
Site personnel will contact the subject via telephone on Maintenance Period Study Day 85 and 
record the following: 
x
AEs 
x
AESI 
x
Concomitant Medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination
The End-of-Study participation for an individual subject occurs after he/she has received IMP for 
12 weeks in the Maintenance Period. At the End-of-Study visit, the subject may enroll into the 
separate extension study if they have completed 12 weeks of treatment in the Maintenance 
Period. Other circumstances for participation in the extension study are described in Section 4.8. 
The End-of-Study visit may also occur if the subject withdraws participation from the study or the 
sponsor terminates the study. If the subject withdraws participation from the study, they may on a 
case-by-case basis, be eligible for entrance into the separate open-label extension study after 
consideration of the circumstances of the early termination and the potential benefit- risk of 
continued participation in a ZX008 trial. The decision whether to permit open-label extension 
study participation resides solely with the sponsor, who may consult with the site investigator. If 
the sponsor terminates the study early, the subject may or may not be offered enrollment into the 
open-label extension, depending on the reason for termination. 
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The sponsor terminates the study. 
3. The subject completes all study related visits and procedures. 
The following procedures will be performed: 
PUBLIC
nance
nance
for 
for an in
an in
Period. 
Period.
y ha
y h
COPY 
ary entri
ary entr
P
This document 
r term
term
bel exten
l exte
jects wil
cts wi
cannot
eligibl
ligibl
circum
ircum
pation in
ation i
tion res
on res
mina
mina
be 
also 
lso 
dy. If 
dy. If thth
e
used
At t
At 
ve comp
comp
participa
articip
occ
cc
to 
dividu
dividu
the En
he E
support 
es with 
with
eriod 
riod Stu
S
ual s
al
any 
th
marketing 
Study D
Study D
authorization 
he ICF 
e ICF
y must b
y must b
application 
des sol
es so
tes the stu
es the s
sion, depe
n, dep
visit the 
visit th
1.1. Th
Th
and
for e
or e
tances o
ances o
a ZX00
ZX00
l
any
r if th
if t
subject 
subject
entran
ntra
extensions 
udy
subject o
ubject 
d-of-Stu
of-St
eted 12 w
ed 12 
tion in
on in tht
he
h
or 
Day
Da
variations 
paren
paren
thereof. 
Day 85 an
y 85 an

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 60 of 182
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
Record concomitant medications 
x
Complete physical examination, including height and weight, and calculation of BMI 
x
Complete neurological examination 
x
Obtain vital signs 
x
12-lead electrocardiogram 
x
Doppler ECHO (must be performed any time between Study Day 90 and Study 
x
Day 113; if subject terminates early from the study, the ECHO should be scheduled as 
soon as practical). If the Study Day 43 ECHO was completed 30 days prior to early 
termination, the Visit 12 ECHO will not be performed provided the parent/guardian 
agrees to bring the subject to the clinic for the cardiac follow-up visit (see Table 7). 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x
Urine THC panel 
x
Whole blood CBD 
x
Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
x
Tanner Staging for subjects >7 years of age (Appendix 5) 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
BRIEF (Appendix 3) 
x
QOLCE (Appendix 4) 
x
PedsQL (Appendix 6) 
x
PedsQL Family Impact module (Appendix 6) 
PUBLIC
rum ch
rum ch
D 
D 
COPY 
ot be 
ot b
inic for t
nic for 
es of ch
es of ch
This document 
C
C
x
doc
cannot
and rev
d rev
pense d
ense d
-SSR
SSR
be
ng for s
ng for 
used 
ple for A
e for A
n(s)
n(s)
to support
ld-bearin
d-beari
misistry and
try a
any 
ormed
orme
e cardiac
cardiac
marketing 
udy Day 9
dy Day
the ECHO
ECH
complet
ompl
p
authorization 
n of BM
of BM
application 
a
S Childre
S Childr
inical Glo
ical G
Clinica
Clinic
BR
B
and
ew dia
dia
y
any 
jects >7
ects >
ry w
extensions 
d he
h
ED phar
D phar
or 
p
emat
ma
variations
O should
shoul
ted 
ted 30 
30
provided
provided
c follow
follow
potent
otent
thereof. 
90 and S
0 and S

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 61 of 182
x
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
x
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
x
Record AEs 
x
Record AESIs 
x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x
Dispense study medication 
Informed consent for the open-label extension study must be signed at Visit 12 (if not signed 
earlier) in order to enter the open-label extension study. 
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113)
For subjects entering the open-label extension study, the subject will visit the clinic on 
Day 113. The following will be recorded/performed and the subject will immediately be 
enrolled in that separate study: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
AEs 
x
AESIs 
x
Concomitant medications 
x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
If the subject does not enter the open-label extension study (or discontinues from the study 
early), the subject will visit the clinic on Study Day 113 (or 14 days after the day of 
discontinuation). The following will be recorded/performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
AEs 
x
AESIs 
x
Concomitant medications 
x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
PUBLIC 
e activity
e activi
COPY
IT 13; S
IT 13;
sion stu
ion st
perfo
erform
rm
This document 
atio
Re
Re
x
oc
cannot
w with
w with
es not e
s not e
ject will
ct wil
on). Th
n). T
be 
partial
partial
h p
h p
used 
cation
cation
to support
dy, th
, t
d and the
and th
(number/
numbe
any
UDY D
UDY D
he sub
he s
marketing 
dr
d at Visit 
at Visi
authorization 
rug acc
ug acc
application
vis
e follow
e follow
view curre
w cur
AEs 
AEs 
AE
AE
and 
aren
re
nter
ter the
the
it the
t the
any 
used an
used an
nt/care
nt/ca
extensions 
r/type/du
ype/du
or 
sub
su
variations
12 (if 
2 (if
AY 113
AY 113
ubject wi
ect w
bject
bjec
thereof.
ountab
untab

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 62 of 182
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY DAY 197-281)
If the subject completes the study but does not enter the open-label extension study or 
discontinues from the study early, the subject will return to the clinic for follow-up cardiac 
testing (ECHO, ECG, and in some cases physical examination). The timing and frequency of 
exams are in Table 7. Subjects on blinded medication who are found to have been on placebo are 
not required to participate in follow-up testing once the blind is broken at the end of the study. As 
the ECHO and ECG will be administered in a separate clinic than the pediatric neurology clinic, 
an asymptomatic subject receiving a second follow-up ECHO and ECG does not require a 
physical examination. 
Subjects with positive findings on ECHO, ECG and/or physical examination should continue to be 
followed until the finding is resolved or stable and unlikely to change, with reports submitted as 
AESI to the ZX008 safety database. 
Table 7: 
Schedule of Post-Treatment Cardiac Follow-up 
Parameter
Duration of Blindeda or Fenfluramine Treatment
Less than 
2 weeks
Cumulative
2 to 4 weeks
>4 and
<13 weeks
>13 weeks
Have had any cardiac 
sign or symptom 
regardless of the time 
on study drugb
ECHO
No
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment
Yes,
3 and 6 months 
post-treatment
Yes,
3 and 6 months post- 
treatment, and until 
resolved, or stable and 
unlikely to change
ECG
No
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment
Yes,
3 and 6 months 
post-treatment
Yes,
3 and 6 months post- 
treatment and until 
resolved, or stable and 
unlikely to change
Physical 
examination
No
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment only
Yes,
3 and 6 months post- 
treatment, and until 
resolved, or stable and 
unlikely to change
a If blind is broken at the end of the study and a subject revealed to have taken only placebo, no further testing is 
required.
b    Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral,
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension 
as adjudicated by the IPCAB.
6.5
ESTIMATED BLOOD VOLUME COLLECTION
The maximum total blood volume collected during the study for clinical laboratory testing, 
genotyping, and PK will be approximately 99.7 mL, as outlined in Table 8. 
PUBLIC 
eks
ks
LIC
es,
es,
onths post
nths post
treatmen
treatmen
BL
COPY
diac Fo
diac F
nded
nde
a or 
o
OP
CO
This document
 broken 
roken 
red.d.
ositive sign
tive sig
aortic; mi
rtic; m
as adju
as adju
t
cu
cannot 
ot
ot
ot
c
be 
mo
treat
trea
use
Yes,
es,
nths po
nths p
sed 
d
se
to
3 mo
3 m
t
support 
enflura
flura
t
4 and
and
<13 weeks
3 weeks
ort
ort
Yes,
Ye
nth
su
any 
w-up 
w-up 
min
a
marketing 
not req
t re
nation sho
nation sh
e, with re
, with 
authorization 
y of 
of 
lacebo a
lacebo a
f the stud
he stud
urology
rology
qui
qu
application 
on
he end of th
end of 
or symptom
or symptom
d or greater i
r great
icated by th
ated by
io
pp
and 
Yes,
Yes,
3 month
 month
tre
tre
d any y
a
ext
Y
extensions 
>
n
hs post- 
post- 
atment
ment
on
on
3 m
3 m
xt
or variations 
eport
ort
Treatm
Treatm
a
v
thereof.
y
clinic
linic
re a
ould con
uld con
ts su
s su

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 63 of 182
Table 8: 
Estimated Blood Volume Collection* 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to 
-41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical 
Chemistry 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
24mL 
LH, FSH, 
Estradiol, 
Testosterone, 
Prolactin 
 
4mL 
 
4mL 
4mL 
4mL 
16mL 
Genotyping 
5 mL 
 
5 mL 
Hematology 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
IGF-1, GH 
 
2.5mL 
 
2.5mL 
2.5mL 
2.5mL 
10 mL 
Coagulation 
 
2.7mL 
 
2.7mL 
Cannabidiol 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
ZX008 PK 
plasma 
 
4 x 2 mL 
 
8 mL 
AED plasma 
sample 
 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
 
1 x 2 mL 
8 mL 
Volume for 
flushing 
indwelling 
catheter 
 
4 x 0.5 mL 
 
2 mL 
Approximate 
total blood 
volume per 
subject 
13mL 
19.2mL 
10mL 
26.5mL 
14.5mL 
16.5mL 
99.7 mL 
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; 
PK=pharmacokinetics 
*In concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), blood 
PUBLIC 
C
7mL
7mL
C
LIC
PU
COPY 
Y
mL 
mL 
Y
CO
CO
This docum
proximate
oximat
ment
g
nt
nt 
nt
otal blood
l blood
volume
volume
subj
subj
me
d
annot t
annot
nnot
ot
ca
ca
be
be used 
mL 
us
us
to
to 
o
to
to
to
port 
uppo
po
2
rt
po
sup
supp
any y
2mL 
2mL 
y marketing 
L 
g
in
mark
mark
m
authorization 
day) 
ay) 
tio
To
To
at
ho
4mL
mL
ho
ho
a
app
r
pplication
lication
ation 
n
lic
pp
and 
d
1 x 2
1 x 2
d
a
any
any 
ny
a
extens
nsioio s
ons 
ons
io
2mL
2mL
ns
ex
e
or
5mL 
mL 
variations
tions
ons s
ns
2m
2m
tio
va
va
va
thereof. 
of
4mL 
mL 
of
eof
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 64 of 182
collection volumes for children weighing up to 15 kg will be: 
x
the maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 mL. 
On Day 43/Visit 8 the pharmacokinetic blood draw will be completed as the priority and the blood 
draw for chemistry and hematology will be skipped for those subjects who weigh less than 13.5 kg, 
unless medical concerns (for example, from previous tests or reported side effects) prioritize 
chemistry and/or hematology. 
If blood collection is restricted due to volume or due to inability to draw adequate volume, 
collection should be prioritized as shown in Table 9: 
Table 9: 
Priorities for Blood Sample Collections 
Assessment
Priority
ZX008 PK sample 
Priority 1 
Clinical chemistry 
Priority 2 
Cannabidiol 
Priority 2 
AED plasma sample 
Priority 2 
LH, FSH, estradiol, testosterone, GH, prolactin 
Priority 3 
Hematology 
Priority 3 
IGF-1 
Priority 4 
Genotyping 
One time collection any time during or after 
screening 
Coagulation 
One time collection any time before PK day 
7.
EFFICACY, SAFETY, AND 
PHARMACOKINETIC ASSESSMENTS
For an overview of the study variables and measurement times, see Schedule of Assessments 
(Table 1). 
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.8. 
7.1
EFFICACY ASSESSMENTS
Baseline is defined as the seizure frequency during the 6-week Baseline Period. 
Retrospective diary data (up to 6 months) will be collected, if available, for an exploratory 
evaluation of the duration of baseline data capture on interpretation of post-treatment effect. 
For all questionnaires and rating scales, the same evaluator (at the clinical site and 
PUBLIC 
C
actin
actin
LIC
BL
UB
PU
COPY 
on
on
PY
OP
CO
C
This document 
ie
bles used
es used
cribed in
ibed i
7.1
7.1
B
cannot
ACY
ACY
ARMA
RMA
w of th
w of th
be used 
d
se
us
to
to
to support trt
po
pp
up
su
any 
any
a
Pr
a
marketing 
ects) p
ts) p
w adequat
w adequ
authorization 
d 
y and the
nd the
less tha
ess tha
pri
pri
application
e study v
study
to measu
to meas
Section 5
ection
EF
E
and 
SAFE
AF
COKIN
OKIN
any 
ETY
ET
extensions s
ns
on
sio
ns
xt
ex
or 
Prior
Pri
Prior
Prio
or
o
P
o variations 
ria
iority 1
ority 1
ar
rity
it
v
thereof.
n 13.5
13.5
oritize
itize
te volum
e volum

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 65 of 182
parent/caregiver) will complete the assessments for the duration of the study. Substitutions at the 
clinic with another rater that has established inter-rater reliability is acceptable on an infrequent 
basis. For the in-clinic questionnaires and rating scales completed by the parent/caregiver, if the 
same parent/caregiver cannot complete the questionnaire/rating scale at a visit, the 
questionnaire/rating scale will not be completed. For the diary, the same parent/caregiver will 
complete all entries throughout the study. 
7.1.1
Seizure Assessments
Seizure frequency by type and duration (<2 minutes, 2-10 minutes, >10 minutes) will be 
recorded daily by the parent/caregiver in a diary. Seizure types include: 
A: 
Hemiclonic (note lateralization – right body, left body, or independent right and 
left) 
B: 
Focal With or Without Retained Awareness 
C: 
Secondarily Generalized Tonic Clonic (evolving to bilateral convulsive seizure 
from focal seizure) 
D: 
Generalized Tonic Clonic Convulsion 
E: 
Absence or Atypical Absence 
F: 
Myoclonic 
G: 
Tonic 
H: 
Atonic 
I: 
Clonic 
J: 
Tonic/Atonic (cannot differentiate) 
K: 
Infantile Spasms (if under 3 years of age) 
L: 
Epileptic Spasms (if 3 years of age and older) 
O: 
Other 
Efficacy endpoints that will be derived from the diary data include frequency of convulsive 
seizures and of all seizures, and the number/duration of seizure free intervals. 
Seizures that evolve into SE will be captured by type and duration (>10 minutes) as are all 
seizures. The diagnosis of SE made by a medical professional should be entered as an SAE if a 
prolonged seizure or series of seizures persists for 30 minutes or longer, regardless of 
administration of rescue medication. SE lasting for less than 30 minutes should be entered as an 
AE, unless one of the other SAE criteria (e.g. hospitalization) are met. If this incident involves 
multiple seizures close in time, the SE definition applies if the seizures are close together such that 
consciousness is not regained between ictal events. 
PUBLIC 
C
bsence
bsence
COPY 
rere
lonic
oni (ev
(e
onvuls
onvu
This document 
cy endpo
y endp
ures and
res and
Seizure
eizure
seizu
seiz
pr
pr
cannot 
e Spa
Spa
leptic Sp
eptic Sp
Other
Other
be
ic (can
ic (can
sm
sm
used to support 
on
any 
lving to 
lving to
marketing 
nutes) wil
utes) wi
y, or indep
or ind
authorization 
he
r will
will
application 
ints that w
ints that
of all seiz
f all se
that evol
hat evo
The d
The d
and 
s (i(i
asms (if
sms (if
any 
differe
diffe
f under
f und
extensions or variations 
epen
pen
o bilatera
ilatera
thereof. 
ll be
be
ndent
nden

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 66 of 182
7.1.2
Clinical Global Impression - Improvement
Both the parent/caregiver and the investigator will rate their global impression of the subject’s 
condition throughout the study according to the schedule in Table 1. 
The CGI scale measures the change in the subject’s clinical status from a specific point in time, 
i.e., the Baseline Period. The CGI rating scale permits a global evaluation of the subject’s 
improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows: 
1=very much improved 
2=much improved 
3=minimally improved  
4= no change 
5=minimally worse 
6=much worse 
7=very much worse 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how their child’s symptoms have improved or worsened relative to baseline before 
the beginning of the study (before any study drug was taken). 
The investigator will be asked to indicate the appropriate response that adequately describes 
how the subject’s symptoms have improved or worsened relative to baseline before the 
beginning of the study (before any study drug was taken). A paragraph describing symptoms 
and function at baseline will be document in the source file prior to rating. 
7.1.3
Quality of Life in Childhood Epilepsy Scale
The QOLCE (Appendix 4), a low-burden parent/caregiver completed assessment that looks at 
how epilepsy affects day-to-day functioning of their child in various life areas, including physical 
activities, well-being, cognition, social activities, behavior and general health, will be conducted 
according to the schedule in Table 1. The QOLCE has been validated in children aged 4 and 
older, and there are published data on the use of the QOLCE in children with epilepsy as young 
as 2 years of age (Sabaz 2000; Talarska 2007). 
The cognitive domain of the QOLCE consists of the following subscales: attention/concentration, 
memory, languages, and "other cognition". Each of these subscales have shown good internal 
reliability and consistency (Cronbach's alpha > 0.80) in the population aged 4 and above. The 
cognitive domain of the QOLCE will be used to assess cognition during study participation in the 
population aged 5 and older as of the subject’s age at baseline. 
7.1.4
Pediatric Quality of Life Inventory (PedsQL)
The PedsQL (Appendix 6) is a pediatric modular measure of health-related QoL completed by 
PUBLIC
indica
ndicatete
ms have
ms have
re any st
re any s
d to ind
to ind
COPY 
This document
ll
to the 
o the 
nd there
d there
years of
ears of
The cog
he cog
memo
memo
rel
rel
cannot
y of Li
of Li
endix 4)
ndix 4)
fects day
cts day
-being
being
be 
be do
e d
ife
ife
used
icate t
ate t
improve
mprov
ny stud
ny stu
ocu
ocu
to 
udy dr
udy d
the
he
support 
he approp
e appro
mpr
mproved
oved
rug w
ug
any marketing authorization 
n time,
time,
ect’s
ct’s
scale ran
ale ran
application
-to
cognitio
ognit
hedule in 
edule 
are publis
re publ
age (Saba
ge (Sa
nitive dom
tive do
 langua
langu
and 
in C
n 
a low-b
a low-b
o-day 
day 
any
ment i
ent 
Childh
Child
extensions
priate
iate
or wor
or wor
was tak
was tak
appropr
ppropri
d or 
or wor
wo
drug w
rug w
n
or 
re
variations thereof. 
ging
g

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 67 of 182
the parent/caregiver on behalf of the subject. It consists of 4 core scales that measure physical, 
emotional, social, and school functioning. The PedsQL will be conducted according to the 
schedule in Table 1. 
7.1.5
Parent/Caregiver Quality of Life
The impact on the quality of life of the parent/caregiver responsible for a patient with DS will be 
assessed according to the schedule in Table 1 using 3 scales: the EQ-5D-5L, the HADS, and the 
PedsQL Family Impact Module. Parents/caregivers who do not give consent to collect these 
ratings scales will not complete them. The same parent/caregiver should complete these ratings 
throughout the study. If that person is not available at the visit, the scales should not be completed. 
The EQ-5D-5L (Appendix 7) 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 HADS (Appendix 8) 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 PedsQL Family Impact module (Appendix 6) is designed to measure the impact of pediatric 
chronic health conditions on parents and the family by measuring parent self-reported physical, 
emotional, social, and cognitive functioning, communication, worry, and family daily activities 
relationships. 
The parent/caregiver will be asked to indicate the appropriate response that adequately describes 
how the care of their child with DS has impacted their quality of life using the scales described 
above.
7.2
SAFETY ASSESSMENTS
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication
Subject demographics (sex, age, height, weight, and BMI), all ongoing conditions and relevant 
medical history from the past 5 years (including all major hospitalizations and surgeries) as well 
as the subject’s current medical status will be recorded at the Screening visit. Significant 
medications taken during the 30 days prior to the Screening visit will be documented. 
Medication history will be updated as outlined in Table 1. 
7.2.2
Physical Examinations
Complete and abbreviated physical examinations, including height and weight, will be conducted 
by the investigator or designee during the study as outlined in Table 1. A complete standard of 
care physical examination for each subject will be performed and will cover the following body 
systems: general appearance, skin, eyes, ears, nose, throat, heart, lungs, abdomen, neurological 
PUBLIC
ppendi
pend
and the 
and the 
unctionin
unctionin
ske
sked
COPY
to dete
to de
14-item
14-ite
pression
ression
ix
This document
ogr
og
history f
tory f
subject’s
ubject’
dications
cation
Medica
Medica
7.7.
cannot 
AS
ograph
graph
edicatio
dicati
raphic
aphic
be 
SESS
SESS
used
o indic
indic
DS has im
 has 
to 
g,
support 
sca
ca
6) is 
is desig
desi
ami
mily by 
ly by 
co
commu
mm
any 
mine the 
mine th
le that
le th
marketing 
o colle
coll
mplete th
mplete th
s should n
should
tus used t
us used
s of 6 que
of 6 qu
authorization 
h DS wi
DS w
HADS, a
ADS, 
ect
ect
application
n
s (sex, ag
s (sex, a
om the pa
m the p
current m
current
taken dur
aken du
ion histor
n histo
and 
cs, Med
, Med
any 
ENTS
ENTS
extensions
gne
measu
measu
unicatio
unicatio
e the app
e the app
mpacted 
acted 
or 
ed to m
d to 
variations 
to pr
o pr
estions a
ions a
levels o
evels o
genera
genera
thereof.
nd the
d the
these
hese
hese ratin
e rat
not be co
not be c
rovi
rovi

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 68 of 182
system, lymph nodes, spine, and extremities. An abbreviated physical examination for each 
subject will cover the following body systems: heart, lungs, and follow up of other systems as 
appropriate based on last exam and reported AEs. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.3
Neurological Examinations
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1. A complete standard of care neurological 
examination for each subject will be performed and will cover the following: cranial nerves, 
muscle strength and tone, reflexes, coordination, sensory function, and gait. An abbreviated 
neurological follow-up examination for each subject will evaluate any symptoms or systems 
found to be abnormal and unstable or potentially unstable that might evolve during study 
treatment, or to investigate any reported or observed AEs. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.4
Vital Signs
Vital signs including blood pressure, heart rate, temperature, and respiratory rate will be 
documented for subjects during study as outlined in Table 1. 
7.2.5
Laboratory Measurements
Laboratory safety parameters will be analyzed using standard validated methods. 
The following parameters will be assessed by the laboratory as described in Table 1 and 
Table 8: 
x
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular 
volume, leukocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
platelets 
x
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), 
bicarbonate, blood urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride 
(Cl), creatinine, creatine kinase, gamma-glutamyl transferase (GGT), globulin, 
glucose, lactate dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), 
thyroid function (T3, T4, and thyroid stimulating hormone [TSH]), total bilirubin, 
direct bilirubin, total cholesterol, total protein, triglycerides, uric acid. 
x
Tests of growth and precocious puberty: Growth hormone (GH), insulin-like growth 
factor-1 (IGF-1, low sensitivity), prolactin, Luteinizing Hormone (LH), Follicle 
PUB
stst
UBLIC 
re, heart 
e, heart 
udy as
udy a
sur
su
COPY
d AEs
d AE
ing
ng cons
co
dy will b
y will b
This document
plat
pla
B
cannot 
tology: h
logy: 
ume, leu
me, leu
oncentr
ncentr
tel
t l
be
will be 
will be
used 
ements
ments
ill be an
ll be a
to
outlin
outlin
support 
de
e docum
docum
te, temp
e, temp
ed i
d
any 
red by t
ed by
men
marketing 
investi
nvest
are neurol
re neuro
wing: cran
wing: cr
nd gait. A
gait. A
any symp
ny sym
ght 
ght evo
ev
authorization 
allyly
E.
E.
i
application 
ko
ation, n
ion, n
ets 
lood Bioc
lood Bio
aminotr
aminot
bicar
bica
(C
(C
and
emoglob
moglo
ocytes,
cytes
any 
essed b
essed
extensions 
perature,
rature,
in Table
n Tabl
lyzed u
yzed u
or variations
An ab
n a
mptoms o
toms o
olve dur
olve dur
the inve
he inve
ted in t
ed in 
thereof. 
ator or 
or or 
ological
ogical
anial ner
nial ner
bbre
bbre

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 69 of 182
Stimulating Hormone (FSH), testosterone, estradiol 
x
Epilepsy genotype panel 
x
Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated 
partial thromboplastin time (PTT) 
x
Whole blood cannabidiol 
x
Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, urobilinogen, 
leukocyte esterase, and occult blood. Microscopic analysis will be performed for 
blood, all cell types, and casts. 
x
Urine pregnancy test: Urine pregnancy testing will be performed in female subjects of 
childbearing potential. 
x
Urine THC panel 
x
The investigator will receive the laboratory report from the central laboratory. After 
reviewing the report and evaluating any results that are outside the normal range, the 
investigator must sign and date the laboratory report. 
Tests resulting in abnormal laboratory values that have been classified by the investigator as 
abnormal, clinically significant should be repeated as soon as possible after receiving the 
laboratory report to rule out laboratory errors. 
At Screening, any laboratory values that deviate from the reference ranges and are considered by 
the investigator as clinically relevant must be documented on the medical history form of the 
eCRF. Any deviation outside of the reference range considered by the investigator as clinically 
significant (i.e., classified as an abnormal, clinically significant value) at any visit after screening 
will be documented in the eCRF as an AE (see Section 9). 
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s)
Plasma samples to ensure that concomitant antiepileptic drug(s) (AEDs) dosing is within an 
acceptable range will be conducted during the study as outlined in Table 1. Samples collected at 
Visit 6 will be analyzed after collection as a safety measure. Samples collected at other time 
points will be analyzed at study end and do not constitute safety assessments. 
7.2.7
Electrocardiograms
Twelve-lead ECGs will be conducted during study as outlined in Table 1 after the subject has 
been in the supine position resting for 5 minutes. Heart rate, PR duration, QRS duration, QT 
duration, QTcF (Fridericia's correction formula), and the investigator’s overall interpretation 
will be recorded. 
PUBLIC 
date t
date 
ry value
y value
hould be
ould be
boratory
boratory
alue
alu
COPY 
laborato
aborat
ating an
ating an
the
the
This document
ang
ll be an
be an
will be a
will be 
7.2.7
2.7
Twelv
Twel
be
be
cannot 
he e
e e
a Samp
Samp
 to ensu
o ensu
ge wil
e wil
be
of 
as an
as an ab
a
CRF
CR
used
that de
hat d
vant mu
ant mu
the re
the re
to 
rep
rrors. 
rors. 
support
ry y rere
y results 
results
aboratory
borato
that have
hat hav
eated a
eated
any 
eport f
port
marketing 
irubin, 
bin,
ll be perf
ll be perf
performe
erform
authorization 
ctivated 
vated 
u
application
re th
be cond
be con
lyzed afte
yzed af
nalyzed a
nalyzed 
Electr
Elec
lead EC
ead E
and
a
e for C
for C
hat co
at c
any
erere
rmal, c
rmal, 
 an AE
an A
ext
st 
xtensions
y
e been c
been 
as soon 
as soon
iate from
ate fro
be doc
be doc
ence 
nce
or
hat 
ha
report
epor
variations
ed in fe
d in f
from the
om th
t are
are
thereof. 
robilinog
bilinog
formed f
ormed 
em

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 70 of 182
7.2.8
Doppler Echocardiography
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1. Doppler echocardiography uses ultrasound technology to 
examine the heart or blood vessels. An ECHO uses high frequency sound waves to create an 
image of the heart while the use of Doppler technology allows determination of the speed and 
direction of blood flow by utilizing the Doppler effect. Predetermined standard guidelines on the 
proper evaluation of certain measurements, as well as abnormality thresholds, were constructed 
by the sponsor’s IPCAB prior to study initiation. These thresholds are provided in Table 10 
(Adverse Events of Special Interest). A manual of proper ECHO technique for sites is provided 
in a separate document. 
7.2.9
Tanner Staging
Tanner Staging (Appendix 5) will be assessed for subjects >7 years old during the study as 
outlined in Table 1. Conceptually, pubertal maturation can be described in terms of sequence, 
timing, and tempo. Puberty consists of a series of predictable events, and the sequence of 
changes in secondary sexual characteristics has been categorized by several groups. The staging 
system used most frequently was published by Marshall and Tanner (1969, 1970) and the 
sequence of changes are commonly referred to as ‘Tanner stages’. 
7.2.10
Columbia-Suicide Severity Rating Scale
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1. The C-SSRS is a 
validated rating scale that assesses suicidal behavior and ideation. The scale is used to assess and 
track suicide events and provides a summary measure of suicidal tendency. The C-SSRS version 
6/23/10 (Children's Baseline/Screening and Children’s Since Last Visit) will be used in this study 
as appropriate for the age and level of intellectual development. 
Subjects who are younger than 7 years chronologically, or who are judged by the investigator 
not to have the mental capacity to understand the questions as specified on the C-SSRS, will not 
complete the rating. The investigator should use his/her judgment to substitute intellectually-
appropriate questions to probe the tendency for self-harm. 
If a subject with the intellectual capacity to complete the C-SSRS has their 7th birthday during 
the study, use of the C-SSRS should be initiated at subsequent visits. 
7.2.11
Adverse Events
Adverse events will be collected from the time of signing the informed consent form/assent form 
until the end of the study, including the follow-up clinic visit. Details of the definitions and 
categorization of AEs, and procedures for the reporting of AEs, are available in Section 9. 
Severity and causality of AEs will be evaluated according to the criteria specified in Section 8.2 
and Section 8.3, respectively. The observation period for AE reporting is specified in 
Section 8.4. At the beginning of each visit at the study site, the study personnel will specifically 
PUBLIC
erred to
red t
everity 
everity
assessed
assessed
esses s
esse
COPY
ion ca
on 
f predict
predic
as been c
been 
by Ma
by Ma
o a
This document
t with 
with 
y, use of
use o
.2.11
.11
Adver
Adver
unti
unt
cannot 
ger th
r t
al capac
capac
ng. The i
. The 
estions t
stions 
thth
be
nd leleve
v
han
han
used
d
uicidal
icida
a summ
summ
reening
eenin
l
to
uring 
uring
b
support 
atego
ego
shall and 
all an
s ‘Tanner
‘Tanne
ating Sc
ting S
any 
descr
desc
ble event
le even
rize
riz
marketing 
d in T
in T
for sites i
for sites 
ars old d
rs old
ib
authorization 
an 
eed and 
ed and 
elines on
ines o
e const
cons
Tab
ab
application 
o prob
prob
e intellectu
intellec
the C-SS
he C-S
Advers
Adve
events w
events w
nd o
d
and
7 y y
ty to un
y to u
vestigat
estiga
be
be t
any 
f intell
f inte
ears ch
ars c
de
extensions 
r st
cale
cale
udy as o
udy as 
eha
ehavior 
vior 
ary meas
y meas
nd Ch
d Ch
or 
Tann
an
ages’
ages’
variations 
during t
during 
bed in te
bed in te
nts, and t
, and t
d by sev
d by sev
ner
ner
thereof. 
ructed 
cted
le 10
10
is provid
prov

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 71 of 182
inquire about any AEs that might have occurred since the last study site visit. All AEs will be 
recorded on the appropriate eCRF page. 
7.2.12
Behavior Rating Inventory of Executive Function (BRIEF)
The BRIEF is a standardized, validated rating scale to measure executive function in children ages 
2-18within the home and school environments; it will be assessed according to the schedule in 
Table 1. The BRIEF measures multiple aspects of executive functioning; scales include Inhibit 
(control impulses; stop behavior), Shift (move freely from one activity/situation to another; 
transition; problem-solving flexibility), Emotional Control (modulate emotional responses 
appropriately), Initiate (begin activity; generate ideas), Working Memory (hold information in 
mind for purpose of completing task), and Plan/Organize/Organization of Materials (anticipate 
future events; set goals; develop steps; grasp main ideas), and Monitor (check work; assess own 
performance). 
7.3
PHARMACOKINETIC ASSESSMENTS
Blood samples for PK assessments of fenfluramine and its metabolite (norfenfluramine) will be 
obtained from all subjects via an indwelling cannula or by venipuncture. 
Blood samples for PK assessment (2 mL) will be obtained at the following time points: 
x
Maintenance Period Study Day 43: within 1 hour prior to the morning dose, and 1, 2, 
and 4-6 hours after the morning dose. 
A total of 4 PK samples will be drawn for each subject for a total of approximately 8 mL of 
blood. 
When blood draws for PK coincide with other assessments, the PK draws take precedence. 
The procedure for the collection and handling of PK samples is outlined in a separate study 
manual. 
7.4
APPROPRIATENESS OF MEASUREMENTS
All of the variables assessed are standard tests or procedures that are commonly used in studies of 
this type. 
8.
ADVERSE EVENTS
8.1
DEFINITIONS
8.1.1
Adverse Events
According to ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended 
sign (including an abnormal, clinically significant laboratory finding), symptom, or disease 
PUBLIC
mL) will
L) wil
Study D
Study D
r the mo
r the mo
e dra
e d
COPY
MENTS
MENT
amine an
mine a
cannul
cannul
This document 
riai
8.1
8.1
8
cannot 
lle
PROPR
ROPR
ables a
bles a
be 
inc
ection 
ection 
used
wn for 
n for 
ide w
ide w
to
ay
ning d
ning d
support 
d its m
its 
a or by ve
r by v
e obtaine
obtain
43: wit
43: w
ose
any 
metab
met
marketing 
n to a
to 
onal resp
onal resp
y (hold inf
(hold i
n of Mate
of Ma
itor (chec
or (che
authorization 
hildren a
hildren a
chedule 
hedule
clude In
lude I
ano
ano
application
I
sessed a
essed 
ADVER
ADVER
DEF
DE
and 
ATEN
TEN
any 
h o
d handli
d handl
extensions 
ed at
d a
thin 1 
thin 1 ho
h
se. 
ch subje
ch subje
ther
the
or 
nipu
ip
t the
the
variations
eri
ck wor
k wor
bolite (n
olite (
unct
unc
thereof. 
hibit 
ib
her;
er;
ponses 
nses 
nformatio
formati
ials (an
als (a
k

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 72 of 182
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product. The period of observation for 
adverse events extends from the time the subject gives informed consent until the end of study. 
Adverse events may include: 
x
Exacerbation (i.e., an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. Exacerbation of seizures is considered an 
AE if there was an increase in frequency beyond the subject's typical pre-study 
fluctuations, or in the event that seizures lengthen in duration in a clinically 
meaningful way compared with baseline, or if a new seizure type emerges. 
x
A clinical event occurring after consent but before IMP administration. 
x
Intercurrent illnesses with an onset after administration of IMP.  
Adverse events do not include: 
x
Medical or surgical procedures (the condition that leads to the procedure is the AE, 
e.g., tonsillitis is the AE if a tonsillectomy is performed) 
x
Situations where an untoward medical occurrence has not taken place. For example: 
o
Planned hospitalizations due to pre-existing conditions, which have not 
worsened. 
o
Hospitalizations that occur for procedures not due to an AE (e.g., cosmetic 
surgery). 
o
Hospitalizations for a diagnostic procedure where the hospital stay is less than 24 
hours in duration or for normal management procedures (e.g., chemotherapy). 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as clinically 
significant must be recorded in the eCRF as AEs. In addition, at the investigator’s discretion, 
any changes or trends over time in laboratory parameters can be recorded in the eCRF as AEs if 
such changes or trends are considered to be clinically relevant, even if the absolute values are 
within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
1. Laboratory parameters are already beyond the reference range, unless a further 
increase/decrease can be considered an exacerbation of a pre-existing condition. 
2. Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (e.g., hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
3. Abnormal parameters that are obviously biologically implausible (e.g., values that 
PUBLIC
he c
he 
nsillecto
sillect
ward med
ard med
talizati
talizati
COPY
fter adm
fter ad
ondi
ond
This document
es or tr
or tr
anges or
ges or
in the re
the re
Laborato
borato
1.1
cannot 
n dura
dur
ty param
y param
s at any 
at any 
st be re
be re
ren
be
tions fo
tions f
atio
atio
used 
ns du
s d
that occ
hat occ
to 
ca
ue t
ue t
support 
on that le
n that
my is perf
y is pe
al occur
occu
any 
istration
stratio
marketing 
the f
e 
ures is c
es is c
's typical 
typica
tion in a c
ion in a
eizure typ
zure ty
MP adm
MP a
authorization 
y. 
sting con
ing con
history s
story s
frequ
frequ
application 
vis
corded i
orded 
nds over ti
s over 
trends are
rends a
ference ran
rence 
ry finding
findin
borato
orato
and 
n o o
eters, an
ers, an
it afte
t afte
any 
a diagno
diagn
r for no
for 
extensions 
forme
rme
rrence h
rence h
o pre-
pre-exi
exi
ur for pr
for pr
or
ads to
ads to
ed)
ed)
variations
pe em
em
ministra
ministr
n of IM
of IM
thereof. 
ectio
ct
ency or 
cy or 
nsidere
sidere
pre-stud
e-stu
linicall
linicall
erg

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 73 of 182
are incompatible with life). 
4. An abnormal laboratory value that cannot be confirmed after a repeated analysis, 
preferably in the same laboratory (e.g., the previous result could be marked as not 
valid and should not necessarily be reported as an AE). 
8.1.2
Serious Adverse Events
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1.
Results in death – The event must be the cause of death for the SAE to meet this serious 
criterion. 
2.
Is life-threatening – The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
3.
Requires in-patient hospitalization or prolongation of existing hospitalization – The 
sponsor considers “hospitalization or prolongation of existing hospitalization” for at least 
24 hours as the defining criterion for an SAE.  Hospital admissions for planned surgery or 
for normal disease management procedures (e.g., chemotherapy) are not considered as 
defining criteria for SAEs. 
4.
Results in persistent or significant disability or incapacity.
5.
Is a congenital anomaly or birth defect.
6.
Is medically significant – A medically significant event is defined as an event that does 
not meet any of the other 5 SAE criteria, but which is judged by a physician to potentially 
jeopardize the subject or require medical or surgical intervention to prevent one of the 
above outcomes listed as an SAE criterion. Anaphylaxis that is successfully treated by 
administration of epinephrine prior to other sequelae is an example of a potentially 
medically important event. 
For the purpose of data collection in this study, a prolonged seizure or series of seizures from 
which the subject does not regain consciousness between ictal events, that is at least 30 
minutes in duration, is termed status epilepticus (SE). A single episode of SE in a 24-hour 
period, regardless of whether rescue medication was administered, should be entered in the AE 
log as well as in the seizure diary. If two or more episodes occur within 24 hours, each lasting 
30 minutes or more, an SAE of SE should be recorded. Hospitalization to manage SE, 
regardless of the number of episodes, should be reported as an SAE. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
8.1.3
Adverse Events of Special Interest
As per ICH guidance (E2F Development Safety Update Report [2011]), the sponsor has 
identified the following AESIs for the ZX008 program (Table 10). 
PUBLIC 
nifificant
cant
f
y or birt
y or bir
ant 
ant – A 
– A
her 5
her
COPY
on
on
ongatio
ongati
SAE.
SAE H
cedures (
edures (
This document 
egard
gard
well as 
well as 
minutes
minutes
regardle
gardle
Advers
Adver
cannot 
rtan
an
f data co
data c
ect does
ct doe
uration
ration
dles
dles
be
a
pineph
pineph
t eve
t ev
used
med
me
SAE cr
AE cr
require 
equire
s an S
s an S
to 
h defe
h def
dicall
dicall
support 
.g., che
g., ch
disability
sability
fect.
ect
any
of f
f existin
f exist
pital ad
pital
em
marketing 
to mee
me
vent in wh
vent in w
to an eve
o an ev
re severe
e sever
existin
exis
authorization 
t at any
at any
application 
is term
term
of wheth
of whe
n the seiz
the se
or more, a
or more
s of the n
of the
events t
events t
and
llection
ection
ot rega
t rega
me
any
E
e prior 
e prior
extensions
y or inc
or inc
y signific
ignific
eria, but
ria, bu
medical 
edical
crite
crite
or variations 
ent th
nt th
e.
ing hosp
ng hosp
ng hospit
hospit
dmission
mission
otherap
therap
thereof. 
dose:
os
his serio
is ser
hich the
hich the
hatat

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 74 of 182
Table 10: 
Adverse Events of Special Interest 
CV/Respiratory
1. Chest pain – any pain in sternal area that is described for example as crushing, burning, sharp, 
stabbing or dull.
2. Dyspnea/shortness of breath – any signs of difficult or labored breathing unrelated to a previous 
medical condition that has not worsened.
3. Persistent cough – longer than 4 weeks without a confirmed identified pathogen (or any other 
persistent cough that the investigator feels is suspicious).
4. Increase in blood pressure >30% from Screening blood pressure or a systolic pressure 140 mmHg 
after repeated measures during one visit. Blood pressure should be repeated at appropriate times 
within the visit.
5. Jugular venous distention- visible bulging of the external jugular veins on either side of the neck
6. New onset heart murmur
7. Pulmonary rales – an abnormal respiratory sound heard during auscultation of the lungs, which is 
also described as a crackle.
8. Tachycardia – a persistent HR >30% above the screening value and unrelated to exercise, 
exertion or anxiety.  Heart rate should be repeated at appropriate times within the visit.
9.
Signs that could indicate right ventricular failure:

Peripheral edema

Ascites

Syncope

Decompensated right ventricular failure – symptoms include shortness of breath, 
frequent coughing especially when lying flat, abdominal swelling and pain, dizziness, 
fainting, and fatigue
10.  Signs on ECHO indicative of potential valvulopathy

valve regurgitation (aortic or mitral)

moderate or severe valve regurgitation (tricuspid or pulmonary)

Mean Mitral valve gradient  4 mmHg

Mean Aortic valve gradient  15 mmHg

Mean Tricuspid valve gradient  4 mmHg

Peak Pulmonary valve gradient  21 mmHg
11. Signs on ECHO indicative of pulmonary hypertension
a. Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings OR
b.
One of the following findings in the absence of being able to measure Tricuspid 
Regurgitation Jet velocity:
i.
Change in right ventricle/left ventricle basal diameter ratio > 1.0
ii.
Right ventricular acceleration time < 100 msec
iii. Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory decrease) 
and/or right atrium
iv.  Change in the geometry of the interventricular septum in systole (flattening) with left 
ventricular eccentricity index >1.1 in systole and/or in diastole
v.
Early diastolic pulmonary regurgitation velocity > 2.2 m/sec
vi. Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2
continued
PUBLIC 
ght ventr
ght ventr
ng especi
g especi
atigue
atigue
tive
tiv
P
COPY
e screen
e scree
epeated
epeated a
d
Y
ar failure
ar failure
OP
This document 
One
On
Regu
Regu
i.i
do
cannot
ort
Tricusp
ricusp
eak Pulm
k Pulm
n ECHO
ECHO
uspid R
spid R
of
of
nn
be
ve
l valve 
alve
ic valv
ic valv
used
of potent
poten
n (aortic 
(aortic
re valv
re valv
d to
cu
ly whe
y whe
t
support 
ap
ap
lar failu
ar fail
n ly
t any 
value an
value a
propriat
ropri
ny
a
marketing
c pressure
c pressur
ed at appro
d at app
g
ins on eith
s on e
ke
ark
auscu
auscultat
l
ma
authorization 
titi
ati
at
at
revious 
revious
or
r any oth
any oth
ut
application 
in
gurgitat
rgita
he followin
e follow
gitation Je
itation
Change in
Change
i.
Right v
Righ
iii.
iii. Dila
D
ivi
and 
d valv
valv
nary valv
ry valv
dicativ
icativ
i
an
any 
dient 
dient 
gradient 
radien 
e gra
e g
extensions 
re – sym
re – sym
ying fl
ng flat,
at,
al valvul
valvul
r mitral)
mitral)
gurg
urgitit
en
or variations 
er s
r s
s
tion of th
ion of th
n
nd unrela
d unrela
te time
times w
s w
at
va
thereof. 
r 
140 mm
140 mm
opriate ti
riate ti
eo
ide o
de o
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 75 of 182
Table 10: 
Adverse Events of Special Interest (continued)
Metabolic/Endocrine
1. Elevated prolactin level 2x above the upper limit of normal (ULN)
2. Galactorrhea
3. Gynecomastia
4. Increase in fasting serum blood glucose 2x ULN
5. Hypoglycemia – serum blood glucose more than 20% below the glucose level on Study Day -1 
value or more than 10% below LLN (reference range 60 – 140 mg/dL)
Neuropsychiatric
1. Serotonin syndrome (At least 3 of following symptoms must be present: Agitation, 
restlessness, confusion, both increased HR and blood pressure, dilated pupils, muscle 
twitching, muscle rigidity, hyperhidrosis, diarrhea, headache, shivering, tremors, both nausea 
and vomiting)
2. Hallucinations
3. Psychosis
4. Euphoria
5. Mood disorders: depression and anxiety if they rise to a level of a disorder
6. Suicidal thoughts, ideation or gestures
Genitourinary
1. Priapism
8.1.4
Adverse Events Requiring Hospitalization
If a subject is treated in a medical facility (hospital, emergency room, free-standing clinic) 
related to the occurrence of any AE, the following data will be collected to model health care 
utilization in patients with Dravet syndrome: AE/reason for hospitalization/clinic visit; 
duration of the visit in hours/days; admission to intensive care unit; and name/number of 
procedures performed, including but not limited to, electroencephalogram, ECG, ECHO, 
positive emission tomography (PET) scan, magnetic resonance imaging (MRI), x-ray, 
computed tomography CT) scan, surgery, and lumbar puncture/spinal tap. 
8.2
SEVERITY OF ADVERSE EVENTS
The severity of AEs (whether nonserious or serious AEs) is to be assessed by the 
investigator as follows (Table 11). 
PUBLIC 
C 
ts Requ
ts Requ
medica
med
COPY 
Y
they rise
they r
PY
OP
CO
C
This document
verity 
erity 
estigator
stigato
cannot
d,
omogr
mogr
graphy C
aphy C
SEVE
SEVE
be
ours/
rs/d
includ
includ
used
l facili
acil
y AE, th
AE, th
ravet s
avet s
ay
to
ring H
ring H
tyt
support trt
po
pp
Hos
H
any y
a level o
a leve
any
a
marketing 
Agitation,
Agitation,
pupils, m
pupils, m
ring, tremo
ng, trem
g
ma
m
authorization 
tio
tio
tio
at
iza
ori
ho
Study D
tudy D
uth
a
application 
RITY 
ITY
f AEs (wh
AEs (w
as follow
as follow
and 
hy (P
y (
T) scan,
) scan
O
any 
admi
adm
g but no
g but no
PET)
PET
extensions 
spitaliza
italiza
(hospita
(hospita
e follow
follow
dro
rome
me
or 
or
o variations 
ors
ns
io
ati
of a disor
a disor
ria
ar
v
thereof. 
y -1 
y -
uscle
uscle
, both
 both
of

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 76 of 182
Table 11: 
Severity Definition of Adverse Events 
Severity 
Definition 
Mild: 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the research participant.
Severe: 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
CDISC SDTM Severity Intensity Scale for Adverse Event Terminology 
8.3
CAUSALITY OF ADVERSE EVENTS
The causal relationship of an AE to IMP must always be assessed by the investigator. All AEs 
will be classified as either related or not related to IMP. If a causality assessment is not 
provided for an AE (including an SAE), that AE will be considered as related to IMP. 
The degree of certainty with which an AE is attributed to IMP or an alternative cause (e.g., 
natural history of the underlying disease, concomitant medication) will be determined by how 
well the event can be understood in terms of: 
x
Known pharmacology of ZX008 
x
Clinically and/or pathophysiologically plausible context 
x
Reaction of a similar nature previously observed with similar products, or reported in the 
literature for similar products as being product related (e.g., headache, facial flushing, 
pallor) 
x
Plausibility supported by the temporal relationship (e.g., the event being related by time to 
administration or termination of treatment with IMP drug withdrawal or reproduced on 
rechallenge) 
The following classifications should be used in categorization of relatedness: 
Not Related: 
Concomitant illness, accident or event with no reasonable association with 
study drug. 
PUBLIC
VERS
VERS
E to IMP
E to IMP
ated
ated or
o
ding an 
ding an 
COPY 
atutu
Advers
Adver
OP
CO
This document 
atu
atu
allor)
lor)
Plaus
Plau
ad
ad
cannot 
colo
ol
and/or pa
d/or p
on of a s
n of a s
ure for
re for
be 
ersto
rsto
ogy o
ogy 
used 
SAE
AE
hich an 
h an 
ying dis
ing di
od
od
to 
not re
t r
E), th
E), th
support 
e Eve
Ev
rt
EVENTS
VEN
must 
must alw
alw
elate
la
any 
ay r
ay
ent T
nt
a
marketing 
spec
pec
es of dai
es of da
rmanent 
manen
es of dai
s of da
requi
req
ar
authorization 
tioioio
mal
rally
ally
za
ific
ific
au
application
mila
mila
similar p
similar 
ibility sup
bility su
ministrati
nistra
rechallen
echallen
low
and
thophys
ophys
ar na
r na
any 
term
ter
ZX008
X00
extensions 
S
ways be 
ays be 
ed to IM
to IM
t AE wi
AE wi
AE is att
is att
se, con
e, con
ms
or variations 
ily livin
y livin
uire inten
re inte
s
Termino
ermino
ar
va
thereof. 
therape
erape
ily living
y livin
risk of 
risk of
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 77 of 182
Related: 
The event follows a reasonable temporal sequence from administration of 
study drug and is definitive pharmacologically; cannot to be attributed to 
concurrent disease or other factors or medications. A clinically reasonable 
response should be observed if the study drug is withdrawn or dose reduced. 
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING
The observation period for AE and SAE reporting in an individual subject will start at the time of 
giving written informed consent for participation in the current study and finish 15 days after the 
last dose of study drug or the last visit, whichever is later. For subjects who enroll in the open-
label extension study, ongoing AEs will be followed in that study. 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with IMP (irrespective of whether or 
not it is considered by the investigator to be causally related to IMP), then this must also be 
reported to the sponsor (see Section 8.6). 
8.5
ADVERSE EVENT REPORTING
8.5.1 
Adverse Events
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred. Adverse events will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the end of study visit, the AE will continue to be followed 
up until resolution or stabilization. 
If, during the study period, a subject presents with a pre-existing condition that was not noted at 
the time of study entry, the condition should be retrospectively recorded in the Medical History 
section of the eCRF. 
8.6 
SERIOUS ADVERSE EVENTS REPORTING
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [1994]). 
In the event of a SAE the investigator or delegate must:  
1. Enter all relevant information in the AE page of the eCRF 
2. Inform the Medical Monitor or the Sponsor of the SAE via email or telephone within 
24 hours of becoming aware of the SAE. 
3. Follow the initial notification with a completed SAE report form. The SAE form must be 
emailed or faxed to iHC within 24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, beginning the day Informed Consent is 
tigator (
tigator 
ecorded
ecorded
ecorded 
ecorded
must fo
must fo
ing
ing
COPY 
NG
NG
This document
wil
ents of
nts of
pedited 
edited
the eve
e eve
1
cannot 
RIOUS
IOUS
ll com
com
be
 a sub
su
he con
he con
used
low 
ow
after the
ter the
on.n.
bje
bje
to
n pr
n prefe
up o
up o
support 
r delegat
delega
n the AE
the AE
feren
any marketing 
h 1
enroll in
nroll i
observat
observ
(irrespect
rrespe
MP), the
MP), th
authorization 
able
ble
reduced
educed
rt at the 
at the
5 day
 day
application
ply with 
ply with
CH Topic
H Top
Reporting
Reportin
t of a SA
of a S
Enter a
Enter a
f
and 
ADVER
DVE
any 
prese
pre
tion sho
tion sho
extensions
te) wil
) wi
E page o
page o
ence to th
ce to t
n the cou
he co
end of st
nd of s
or 
l d
variations
tio
ctive of
ive o
en this m
en this m
thereof.
tim
after th
after th
the open
he ope
on peri
n per
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 78 of 182
signed, whether or not causally related to IMP must be reported immediately via telephone or 
email (within 24 hours of the investigator becoming aware of the event) to the sponsor or the 
Medical Monitor.
Adverse events occurring in the period between the time the subject gave written informed 
consent and the first exposure to IMP that meet one or more of the seriousness criteria for AEs 
must be reported to the sponsor and the Medical Monitor in the same manner as other SAEs and 
will be included in the clinical study database. 
Any SAE that occurs 15 days after the last dose of study drug or the last visit, whichever is later 
that is considered to be causally related to IMP must be reported immediately (i.e., within 24 
hours of the investigator becoming aware of the event) to the sponsor and the Medical 
Monitor. 
Contact details and guidance for reporting SAEs will be provided to study site before the study 
starts. 
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events
The minimum reporting requirements for immediate reporting of SAEs include: 
1. Identifiable subject 
2. Suspected drug product 
3. Event description 
4. Identifiable reporting source 
In addition, the investigator must: 
1. Report all SAEs to the relevant IRB/IEC within the timeframe specified by the 
IRB/IEC. 
2. Submit follow-up reports to the sponsor Global Clinical Safety and 
Pharmacovigilance and the Medical Monitor until the SAE has resolved, or, in the 
case of permanent impairment, until stabilized. 
3. Ensure that the AE term(s) and causality assessment for all SAEs is entered in the 
eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying the sponsor. 
When submitting SAE reports to the sponsor, subjects should be identified only by their subject 
number and study number. The investigator should not include the subject’s name and address. 
SAE Update reports can be submitted to the sponsor any time that additional relevant information 
becomes available. In cases of death, the investigator should supply the sponsor and the IEC/IRB 
(as applicable, see Section 8.7) with any additional requested information as it becomes available 
(e.g., autopsy reports and detailed medical reports). Once an SAE is reported to the sponsor’s 
Safety Group, a Safety Specialist may contact the investigator with follow-up questions. 
PUBLIC 
ct 
rting sou
rting sou
COPY 
Report
Repo
mmedia
media
This document 
eC
eC
minimum
minimu
eive add
ve add
When s
When 
num
num
cannot
ollow-
llow-
macovigi
covig
e of perm
of per
Ensure t
nsure t
RF
RF
be 
Es to t
to 
used 
c
st:t:
the
the
to 
e
support 
ng
e reporti
report
any 
of Ser
of Se
marketing 
t, which
whic
iately (i.e
ately (i.e
sor and t
sor and
d to stud
d to stu
authorization 
ed 
for AEs
for AE
er SAE
r SAE
application 
hat the A
the
m requirem
m require
tional inf
onal in
ubmitting
bmittin
and stu
and st
and
rep
rep
ance and
nce an
anent im
nent 
A
any
levan
leva
orts to
orts
extensions 
nt
or 
g of
g o
variations 
dy site b
dy site b
rious Ad
ous A
f SA
f S
thereof. 
ever is la
ver is l
e., withi
, withi
he Med
he Med

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 79 of 182
The procedure to be followed if an ongoing AE becomes an SAE after the end of the 
observation period for AEs is described in Section 8.9. 
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR TO 
IEC/IRB
The timeframe within an IEC/IRB must be notified of a death or an unexpected SAE considered 
at least possibly related to the IMP is stipulated by each individual IEC/IRB. The investigator is 
responsible for complying with the requirements for IEC/IRB notification. The investigator will 
notify the relevant IEC/IRB within the applicable timeframe by forwarding the safety report (e.g., 
MedWatch/CIOMS form) completed by the sponsor for the notifiable event. 
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE EVENTS 
BY INVESTIGATOR TO SPONSOR
Even if none of the criteria for an SAE are fulfilled, any of the following events must be 
reported by the investigator to the Medical Monitor within 72 hours from the time the 
investigator is notified. 
1. Hypersensitivity reactions 
2. Pulmonary hypertension 
3. Cardiac symptoms requiring intervention, or valvulopathy, if identified 
outside of study-related monitoring 
8.9
FOLLOW-UP OF ADVERSE EVENTS
Every effort should be made to follow-up subjects who continue to experience an AE or an SAE 
on completion of the study or until the AE resolves. All follow-up information (and attempted 
follow-up contacts) should be documented in the subject’s medical records. Details of the 
subject’s progress should also be submitted to the sponsor’s Global Clinical Safety and 
Pharmacovigilance and the Medical Monitor.  In the event of a SAE a blood sample for ZX008 
and AED PK should be collected as soon as feasible. 
Subjects who are discontinued from the study or complete the study and have been found to have 
any signs of valvulopathy or pulmonary hypertension on ECHO will be followed until the 
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication, unless it is determined after unblinding that the 
subject did not receive ZX008. 
8.9.1
Follow-up of Echocardiogram Findings
All ECHOs will be evaluated by a central reader from BioMedical Systems, Inc. (BMS), in 
consultation with the IPCAB, if warranted. Findings related to pulmonary hypertension or 
valvulopathy on any of the four valves (aortic, mitral, pulmonary, triscuspid) will be reported to 
the investigator with grades of normal, trace, mild, moderate or severe. If the ECHO result has 
PUBLIC 
uiring in
uiring 
ated mo
ted mo
OF A
OF
COPY 
d, any
d, an
tor with
tor wit
This document 
of val
f val
on has re
has re
months fr
nths f
subject d
bject d
cannot
uld a
d 
and the 
nd the 
uld be c
d be c
are disc
re disc
lvu
lvu
be
r u
d be do
d be do
also b
also 
used 
DVER
VER
follow-u
ollow-
ntil th
ntil th
to 
itor
RS
support 
terven
rvention
tio
ring 
ing
any 
he foll
he fo
72 hour
72 hou
marketing 
e inv
inv
g the safet
the safe
vent.
ent.
OUS AD
OUS A
ow
authorization 
R TO 
TO
E consid
consid
investig
nvest
vest
vest
application 
ontinue
tinu
opathy or
opathy 
olved or 
lved o
om the las
m the l
id not rec
d not re
and
Medica
edica
llected a
ected 
ed
any
AE
A
mented 
mented
submitt
ubm
l M
l M
extensions
n, or val
or va
E EVEN
EVEN
p subjec
subjec
E res
E res
or variations 
DVER
VER
wing eve
wing eve
rs from 
from 
thereof. 
gator i
ato
gator wi
or wi
ty report
report
RS

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 80 of 182
progressed in severity since the last reading then new oversight measures will be enacted as 
described below in Levels 1-3. Table 11 describes the severity of ECHO findings with the level 
of increasing oversight if the subject is to remain in the study. 
Table 12: 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings 
Severity
Valve
Aortic
Mitral
Pulmonary
Tricuspid
Normal
Level 1
Level 1
Level 1
Level 1
Trace
Level 2
Level 2
Level 1
Level 1
Mild
Level 2
Level 2
Level 1
Level 1
Moderate
Level 3
Level 3
Level 3
Level 3
Severe
Level 3
Level 3
Level 3
Level 3
Level 1:   Continue per protocol 
Level 2: 
1. If there is a desire to continue study medication: 
a.
The investigator will evaluate the efficacy to date based on study diaries and 
consult with the parent/guardian, and determine whether study treatment was 
associated with significant, meaningful benefit in number, severity and/or 
duration of seizures and/or on the impact on daily functioning. 
b. The investigator will consider whether the subject has had reasonable trials (dose 
and duration) of other available anticonvulsants (e.g. valproic acid, clobazam, or 
topiramate), alone or in combination, and not maintained the level of seizure 
control achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risk, and the parent/guardian feels strongly that the child be 
maintained on the study medication when understanding the risks, the parent/guardian 
must sign a new consent which describes the additional risk and the child should provide 
assent if appropriate. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted to 
the IDSMC for review, including consideration of effects on seizures and comorbidities. 
4. The Co-Chairs of the IPCAB are alerted to the request and prepare, after consultation 
with BMS, an evaluation of the cardiopulmonary risk and proposed monitoring plan if 
applicable, for submission to the IDSMC. 
5. IDMSC will review the submission from the Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including the possible outcomes: 
alua
alu
nt/guard
t/guar
gnificant
gnifican
ures and
res and
ator wil
ator wi
of o
of
COPY 
medicat
medicat
ate th
ate th
This document 
a.a.
3. The 
The 
thth
4
cannot
tentia
entia
on the s
on the 
n a new
a new
if appr
if appr
IfIf
be 
eve
feels c
feels c
l r
l r
used
con
co
ther ava
her av
one or in
ne or in
d wit
d w
to 
or o
r o
nside
nside
support 
on:n:
e effi
efficacy
ca
an, and d
n, and 
meaning
meaning
n the
th
any marketing 
Le
L
g
L
ng
tin
ket
ke
ke
rk
a k
authorization 
elel
dings 
dings 
uth
Tricus
ricu
au
a
application 
opriate
riate
oth of the
oth of t
reatment
atme
nvestigat
vestig
e IDSMC
IDSM
The Co-
he Co
h
and
sk, 
k,
tudy me
dy me
onsent 
nsent 
any 
stutu
nsiderati
nsiderat
and th
nd t
di
extensions 
determ
term
gful
ful bene
ben
e impact
impact
r whethe
whethe
lable an
able an
combin
ombin
udy m
dy
or
to dat
o da
min
min
variations s
ns thereof. 
id
f
el 1
of
Level 1
vel 1
re
Level 
Level 
er
Lev
Lev
the
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 81 of 182
a.
Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c.
Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
Level 3: 
1. The investigator will evaluate efficacy to date based on study diaries and consult with 
the parent/guardian, and determine whether the achieved benefit justifies the 
consideration of continuing study treatment by the IDSMC. MINIMAL efficacy 
criteria for IDSMC consideration: 
a.
Seizures must be more than 75% improved (number of convulsive seizures per 
28 days) on treatment over baseline, and improvement must be consistent. 
b. The number, type, duration, and distribution of seizures at baseline should be of a 
severity, which justifies the risks of cardiopulmonary complications, considering 
the subject’s age and overall health. 
c.
Subject has had reasonable trials (dose and duration) of other available 
anticonvulsants (e.g., valproic acid, clobazam, topiramate), alone or in 
combination, and not maintained the level of seizure control achieved with study 
medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risks, and the parent/guardian feels strongly that the child be 
maintained on the study medication when understanding the risks, the parent/guardian 
must sign a new consent, which describes the additional risks and the child should 
provide assent if possible. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted 
to the IDSMC for review, which includes effects of study medication on seizures and 
comorbidities related to Dravet syndrome. 
4. The Co-Chairs of the IPCAB are alerted to the request, and in consultation with BMS 
prepare an evaluation of the risks and proposed monitoring plan if applicable for 
submission to the IDSMC. 
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind 
the subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including these possible outcomes: 
a.
Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c.
Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
PUBLIC 
onsiderat
nsiderat
sks, and
sks, and
tudy med
tudy med
nsent,
nsent,
i
COPY 
h. 
h. 
s (dose a
s (dose 
ic acid, c
ic acid, c
ained t
ained
This document
pa
p
ubmis
bmis
5. IDSM
IDSM
thth
6
cannot
C for 
C for 
ities rela
es rel
o-Chair
-Chair
are an 
re an 
be 
prepar
prepar
used
which
hich
ble.e.
conditi
condit
to
the
cation 
ation
d
support 
lobaza
baza
he level 
e level o
on of 
n of con
con
e parent
paren
any 
on
d duratio
duratio
am,
marketing 
fie
MAL ef
MAL e
f convulsiv
convul
ent must b
nt must
izures at 
zures a
nary co
nary 
authorization 
d consul
consul
es the 
s the 
application
of
evaluatio
aluati
on to the 
n to th
MC will re
MC will 
e subject t
subject
IDSMC 
IDSMC
a.a
and
view
ew
ted to D
d to D
f the I
the I
any 
a case h
a case 
w, whi
wh
extensions
ntinued 
nued
t/guardi
/guardi
t
when und
hen und
scribes
cribes
ns are n
s are n
or
f seiz
f sei
variations 
be co
e co
base
aselin
lin
omplica
omplica
on) of o
n) of o
topiram
opiram
zur
thereof. 
wi
ficacy
cacy
ve seizu
ve seizu
onsi
nsi

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 82 of 182
8.10 
PREGNANCY
This study is open to female and male subjects. Whenever possible, a pregnancy in a female 
subjects or the female partner of a male subject exposed to IMP should be followed to term so 
as to assess any potential occurrence of congenital anomalies or birth defects. Any follow-up 
information, including premature termination and the status of the mother and child after 
delivery, should be reported by the investigator to the sponsor using a pregnancy 
reporting/outcome form. 
9.
DATA HANDLING PROCEDURES
9.1
RECORDING OF DATA
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. 
An eCRF and a subject diary will be provided by the sponsor (or delegate) for each subject 
enrolled into the study. Study site staff will enter data directly into the validated electronic data 
capture (EDC) system by completing the eCRF via a secure internet connection. The investigator 
is responsible for ensuring accurate and proper completion of the eCRF and subject diary for 
recording data according to the instructions given in the eCRF and subject diary. 
All entries in the eCRF 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 (see Section 12.8). 
Source data must be completed legibly for each subject enrolled into the study and signed by the 
investigator (or delegate). 
Data entry in the eCRF and subject diary must be completed in a timely manner so that they 
always reflect the latest observations on the subjects enrolled in the study. 
The subject’s diary will be completed by the parent/caregiver at home. Data entries will be 
reviewed by the investigator for completion and consistency. 
9.2
DATA QUALITY ASSURANCE
An initiation meeting will be held before starting the study, during which the study design, 
procedures to be followed, and measures for ensuring standardized performance will be 
explained by a delegate from the sponsor, and a common understanding of the requirements of 
the study will be reached with the investigator and other relevant personnel at the study site. 
Data generated throughout the study will be monitored and the data entered in the eCRFs will 
be checked against the subject records for completeness and accuracy. The sponsor’s study 
monitor will perform this function. 
The computer system used for study data handling will be fully FDA 21 CFR Part 11 compliant. 
All creation, modification or deletion of electronic study records will be documented through an 
automated Audit Trail. Following completion of eCRF pages and entry of the data into a 
PUBLIC
d prop
d prop
ructions
uctions
backed 
backed 
rding to
rding to
ed leg
ed l
COPY 
tute
ut
by the sp
y the sp
enter da
enter dat
CRF vi
CRF vi
er
This document
ation me
on me
dures to
ures to
plained b
ained 
the stud
e stud
Dat
Dat
b
cannot
will be c
l be c
nvestigat
vestigat
DATA
ATA
be
subj
ubj
bservati
bservat
used
all 
all
ibly for
bly fo
ect
ect
to 
up by
p by
appli
appli
support 
direc
direc
a secure
secu
completio
omplet
given in th
ven in th
the 
th
any 
e dat
e da
nsor (or d
sor (or 
ctly i
tly
marketing 
each subj
ach su
required
require
ta.
ta
authorization 
so 
so 
w-up 
up 
ter 
ter 
application 
QUALI
UAL
ting will 
ng wil
be follow
be follo
y a deleg
a dele
y will be r
will be
nerate
erate
and 
mplet
ple
or for co
for co
any 
ary m
ary
ns on the
ns on th
ted b
ed
extensions
on 
he eCR
e eCR
relevan
elevan
able reg
ble reg
each
ach subj
sub
mu
mu
or 
inter
inte
of the
of th
variations
ject. T
ect. T
d inform
d inform
delegate
elegate
nto the
nto the
rne
thereof. 
h

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 83 of 182
database, the data will be checked electronically for consistency and plausibility. Data queries 
will be generated for questionable data and response clarification will be sought from the 
investigator. These data queries must be resolved in a timely manner by the investigator (or 
delegate). 
9.3
RECORD RETENTION
A study document binder will be provided by the sponsor for the investigator at each site for all 
requisite study documents (constituting the “Investigator Study File”). 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements. 
The investigator is responsible for archiving the Investigator Study File, the subject’s records, 
and the source data according to applicable regulatory requirements. These documents have to 
be archived for at least 15 years or at least 2 years after the last approval of a marketing 
application in an ICH region, but should be retained for longer if required by regulatory 
requirements or by agreement with the sponsor. 
If the investigator can no longer maintain the archive of study records (e.g., due to retirement or 
relocation), the sponsor must be informed in writing about any change in responsibility for record 
retention, including the name of the new responsible party, contact information, and location of 
the study records. Records may not be destroyed without prior written consent from the sponsor. 
10.
STATISTICS
10.1
DETERMINATION OF SAMPLE SIZE
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). 
The EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
stiripentol groups, the SD of the percentage change in seizure frequency from baseline to month 
2 was 42% in the French trial and 26% in the Italian trial. The analogous SDs for placebo groups 
were 38% and 62%. An SD of 50% was assumed for the primary analysis in this trial comparing 
ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure frequency. Using a two-
sided test at the Į=0.05 significance level, a sample size of 35 subjects per treatment group 
affords 90% power to detect a difference in mean change from baseline of 40 percentage points. 
Similar assumptions and calculations yield a requirement for an additional 35 subjects in the 0.2 
mg/kg/day ZX008 group. Thus, the total sample size is planned to be 105 subjects (35 per arm). 
10.2
ANALYSIS POPULATIONS
10.2.1
Safety (SAF) Population
All safety analyses will be performed on the SAF Population defined as all randomized subjects 
PUBLIC 
in the
n th
rmed in
rmed in
he new r
he new 
y not be 
not be 
COPY
ry y
s after t
s after
tained fo
ained
nsor. 
sor. 
e ar
This document 
and 6
nd 6
0.8 mg/
.8 mg
d test at 
test at 
ffords 9
fords 9
Simila
Simila
mg/
mg
cannot
an
uropea
ropea
rizes the
zes th
ps, the S
s, the S
the Fre
he Fre
62%
62%
be 
TI
ndomiz
ndomiz
used 
ON O
ON 
to
estroy
estroy
support 
r lo
chive of s
hive of 
writi
riting ab
ng a
ponsible
onsible
ed
any 
men
me
last 
ast app
ap
nger if
nger
marketing 
he approv
e approv
ume
umentatio
ntat
dy File, t
dy File
nts. T
nts.
authorization 
ach site
ch sit
application 
D 
nch tria
h tri
%. An SD 
. An SD
kg/day to 
g/day t
he
he Į=0.0
=0.
% power
% powe
assumpti
ssumpt
ay ZX
y Z
and 
Publ
ubl
results 
esults 
of the 
f the
l
any 
F S
d, placeb
d, placeb
ic As
ic A
extensions
stu
bout an
out a
e party, 
e party
withou
withou
AM
AM
or 
dy rec
dy re
variations 
the subj
he subj
These do
hese d
proval of
oval of
f require
requir
thereof. 
for al
or
ved stud
ed stud
on relate
on relat

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 84 of 182
who receive at least one dose of ZX008 or placebo. Subjects will be analyzed according to the 
treatment actually received. 
10.2.2
Modified Intent-to-Treat (mITT) Population
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZDX008 0.8 mg/kg/day to placebo, as well as key secondary analyses, will be 
performed on the mITT Population. 
10.2.3
Per Protocol (PP) Population
The PP Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo, complete the entire 12 week Maintenance Period, and have no major 
protocol deviations that would have a significant impact on clinical outcome. Subjects will be 
analyzed according to the treatment they received. The primary and key secondary efficacy 
analyses will be repeated on the PP Population if there are substantial differences in the makeup 
of the mITT and PP Populations. 
10.3
TREATMENT GROUPS
Subjects will be randomly assigned to one of three treatment groups: ZX008 0.8 mg/kg/day, 
ZX008 0.2 mg/kg/day, or placebo. 
10.4
TREATMENT PERIODS
Baseline Period 
The Baseline Period covers the approximately 42-day span just prior to randomization and the 
start of treatment. The baseline frequency of convulsive seizures will be calculated from data 
collected during this period. 
Titration Period 
The Titration Period covers the first 14 days of treatment while subjects are titrated to their 
randomized dose. It begins on the first day of treatment (Study Day 1) and extends through 
Study Day 15 regardless of the exact day on which a subject reaches his or her assigned dose. 
The Titration Period applies to all subjects including placebo recipients. 
Maintenance Period 
The Maintenance Period covers the 12 weeks following the end of the titration period. It begins 
on Study Day 16 and extends through Study Day 99. 
Titration +Maintenance (T+M) Period 
The T+M period combines the Titration and Maintenance periods, beginning on Study Day 1 
and extending through Study Day 99. The T+M period is considered the treatment period. 
PUBLIC 
PS
PS
d to one
d to one
ebo.
bo.
PER
PE
COPY 
mpact
mpa
ed. The p
d. The 
on if
n if ther
the
f
This document
n
ed dos
d dos
Day 15 
Day 15 
e Titratio
Titratio
Mainten
ainten
oc
The
The
cannot
bas
ba
period.
period
Period
eriod
be
rs the 
rs the 
seline
selin
used 
IODS
ODS
to support 
are
are
f three tr
three t
any 
linica
linic
mary an
mary an
subs
sub
marketing 
nalys
aly
eive at lea
ve at l
riod, an
riod, 
l o
l
authorization 
se of 
e of 
ects will
ts wil
rimary
imary
ses
ses
application 
covers t
overs 
It begins 
begin
egardless
gardles
n Period a
Period
ance Peri
ce Pe
ap
ntena
ten
and any
roxima
roxim
requenc
requenc
extensions 
treatmen
eatmen
or variations
ast one 
t one 
nd have 
nd have 
outcome
outcome
nd key s
key s
tantial d
ntial 
thereof. 
will be
ill be

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 85 of 182
Follow-up Period 
The Follow-up Period begins immediately at the end of T+M period and extends to a final visit 2 
weeks later; i.e., from Study Day 99 through Study Day 113. Only subjects who do not roll over 
enrollment into the open-label extension will participate in the Follow-up Period. 
10.5
STATISTICAL ANALYSES AND METHODS
All efficacy, safety, and PK data will be summarized. 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. 
Efficacy and PK data will be summarized by treatment (ZX008, placebo) age cohort (<6 years 
and 6 years of age), as well as for the total subjects in the population. 
A complete description of the statistical analyses and methods will be available in a SAP, 
which will be finalized before the database is locked. 
10.5.1
Efficacy Analyses
10.5.1.1
Primary Efficacy Analysis
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) 
per 28 days between the Baseline and T+M periods. The MCSF will be calculated from all 
available data collected during the Baseline or T+M Periods. 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with baseline 
frequency as a covariate. The primary analysis will compare the ZX008 0.8 mg/kg/day group to 
the placebo group using a two-sided test at the Į=0.05 level of significance. 
Since the ANCOVA used in the primary analysis relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric method that does not require as stringent 
assumptions. A nonparametric test such as the van Elteren test, which extends the Wilcoxon rank 
sum test to include stratified data, will be used to compare the ZX008 0.8 mg/kg/day group to the 
placebo group while stratifying for age group. If normality assumptions are not met, the results of 
the nonparametric test will be used to assess the primary objective. 
An additional analysis will be performed to assess the sensitivity of the primary analysis to 
changes in dose or type of concomitant AED medications that may occur during the course of 
the trial, which are protocol violations. Specifically, the primary analysis will be repeated with a 
factor added to indicate whether a subject had a change in prescribed dose or type of 
concomitant AED medication during the T+M period. Further exploratory analyses may be 
conducted if changes in concomitant AED medication appear to have a significant impact on the 
primary outcome. 
Additional analyses will compare the percentage changes between the baseline MCSF and the 
PUBLIC 
sisis
he chang
he chan
ne and T
ne and T
ng the B
ng the B
COPY 
nd me
nd m
cked.
ked
This document
nc
group w
oup w
nparame
param
n additio
additi
change
change
the t
the
fafa
cannot
used in
sed in
be anal
be anal
A nonpar
nonpar
clude s
ude s
h
be 
he pri
pr
two-si
two-si
used 
asel
se
lyzed us
yzed us
and age 
nd age 
ima
ima
to 
+M pe
+M p
line o
ine o
support 
inin the m
the m
eriod
ri
any 
ds will
ds wi
marketing 
um
nd uppe
d upp
d percent
d percent
 as warra
 as warr
acebo) ag
cebo) 
lation.
ation.
be
b
authorization 
2 2
over 
over
mmari
mmari
application
ame
tratified 
atified
ile stratify
e strat
tric test w
tric test 
nal analys
al anal
in dose o
n dose
which
whic
d
and
the pri
e pr
yzed
ed usin
usin
d
etric t
tric t
any
anal
an
d test at 
d test a
imar
m
extensions 
mean con
ean con
ds. The 
s. The 
T+M P
T+M P
ing an
g an an
a
roup (<
oup (<
lys
l
or variations
ge coh
e coh
e availa
e availa
thereof
zed usin
d usin
quartile
uartil
tages.
ges. 
anted. 
nted. 
or

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 86 of 182
MCSF measured independently during the Titration Period alone and the Maintenance Period 
alone. 
10.5.1.2
Key Secondary Analyses
The first key secondary endpoint – the proportion of subjects who achieve a 40% reduction 
from baseline in convulsive seizure frequency – is derived directly from the primary endpoint. 
That is, the proportion of subjects in the ZX008 0.8 mg/kg/day group who have a change in 
convulsive frequency of at least -40 percentage points will be compared to the analogous 
proportion in the placebo group. The comparison will be made using a logistic regression 
model that incorporates the same factors and covariates as the ANCOVA used in the primary 
analysis. The second secondary endpoint – the proportion achieving a 50% reduction in 
convulsive seizures – will be analyzed similarly. The analyses will be performed using data 
collected over the T+M period. 
The longest interval between convulsive seizures will be calculated for each subject over the 
entire T+M period. The ZX008 0.8 mg/kg/day and placebo groups will be compared using a 
log-rank test. 
The MCSF in the ZX008 0.2 mg/kg/day group will be compared to the placebo group using the 
same methods employed for the primary analysis. Analyses of other key secondary endpoints 
involving the ZX008 0.2 mg/kg/day group will employ similar methods as those used to compare 
ZX008 0.8 mg/kg/day to placebo. Whenever feasible, secondary analyses involving either ZX008 
0.8 mg/kg/day or ZX008 0.2 mg/kg/day will be repeated using post-treatment data collected 
during the Titration Period alone and during the Maintenance Period alone. 
10.5.1.3
Multiplicity Strategy and Testing Hierarchy
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate at 
Į=0.05 across the family of analyses that support the primary and key secondary objectives. The 
strategy specifies a hierarchy of significance tests where each test acts as a gatekeeper to the tests 
below it. 
The primary and key secondary endpoints will be assessed in the following order beginning 
with comparisons of ZX008 0.8 mg/kg/day to placebo on 
x
The change in MCSF from baseline. 
x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
x
The longest convulsive seizure-free interval. 
The evaluation of key secondary endpoints continues by comparing the ZX008 0.2 mg/kg/day 
group to placebo in the following order: 
PUBLIC
gro
gr
ary anal
ry ana
y gr
y group 
oup
o. When
. When
mg/kg/d
mg/kg/
one a
one
COPY 
will b
wil
and pla
nd pla
oup w
oup w
This document 
ariso
ris
The cha
he ch
x
Th
Th
cannot
y o
y
ierarch
rarch
nd key s
d key 
ons o
ons o
be
emplo
mplo
of ana
of ana
used
ay 
ay
nd duri
duri
egy and
gy and
to 
ever 
ver 
will b
will b
support 
ill be
l be com
co
sisis. Analy
. Ana
will emplo
ill emp
feasi
fea
any 
lculat
lcula
bo grou
bo grou
marketing 
e anal
ana
stic regre
stic regr
A used in 
used i
50% re
50% 
l be perfo
e perf
ed
authorization 
ction
ion
endpoin
endpoin
change i
ange 
logo
log
application 
econd
con
f ZX008 
ZX008
nge in MC
ge in M
proportio
proport
eizure fre
zure f
he pr
he
and 
of sig
f sig
dary
dary
any 
serial 
seria
ses that s
es that 
gnific
ni
extensions 
yses 
ses 
oy simil
y simi
ible
ble, sec
, sec
e rep
repeate
eate
g the Ma
the Ma
Testing 
esting
or
pared 
pared
of o
of
variations
e
ormed u
med 
d fo
d for eac
r ea
ups will 
ps will
thereof. 
n
us 
ession
sion
n the prim
the pri
duction
uction

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 87 of 182
x
The change in MCSF from baseline. 
x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
x
The longest convulsive seizure-free interval. 
10.5.2
Safety Analyses
Summaries of safety data will be presented by treatment – ZX008 0.8 mg/kg/day, ZX008 
0.2 mg/kg/day or placebo – separately for the Titration, Maintenance and T+M periods. The 
number and percentage of subjects in each treatment group with AEs will be displayed by body 
system and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries of AEs by severity and relationship to study drug will also be presented. A separate 
summary will be provided for all serious AEs (SAEs). Selected summaries will be repeated 
broken out by age group, i.e., for ages <6 years and 6 years.
Hematology and chemistry laboratory results will be summarized using shift tables that tabulate 
the proportion of subjects who have lab results that change from baseline. Shift tables will be 
presented for each time point where lab results are collected. Mean change from baseline will also 
be calculated for continuous hematology and chemistry results at all time points available. 
Laboratory tests, vital signs, physical examinations, neurological examinations, ECG, Doppler 
echocardiogram, C-SSRS, Tanner Staging results, etc, will be summarized appropriately, by 
treatment. All safety summaries will be based on the SAF Population. 
10.5.3 
Pharmacokinetic Analyses
All data will be evaluated using population PK analysis methods and the methods will be 
described in detail in a separate PK analysis plan. In brief, the plan is to use published data to 
construct a population PK model for fenfluramine in adults. Given the age range of subjects to be 
enrolled in this study, it will be possible to use the known ontogeny of drug disposition in 
children to predict fenfluramine PK in subjects with Dravet syndrome from the population PK 
model. The robustness of the empirical model will then be confirmed by applying the model to 
PK data collected from this study. In this way, the effect of body size, age, and any other 
relevant factors can be quantified to assure that an adequate understanding of fenfluramine PK is 
obtained. 
The full methods and results of the population PK analysis of data from this study will be 
provided in a separate report. The clinical study report will contain a brief summary of the 
analysis including: the population mean and interindividual variability estimates from the fit of  
the population PK model; summary statistics of the plasma concentrations by PK sampling time 
and of the individual, derived plasma PK parameters (Cmax, AUC0-t, Tmax, and t1/2) by 
PUBLIC
sult
su
ab resul
b resu
e lab res
e lab re
matology
atology
physic
physic
ne
ne
COPY
study 
stud
SAEs). S
SAEs). S
ars and 
ars and 
ts wi
ts wi
This document
o pred
pred
The rob
he rob
data coll
ata coll
elevant f
evant f
obtain
obtain
Th
T
cannot
ated u
ted u
in a sep
n a sep
ulation P
ation P
s study
study
ici
be
inetic A
inetic 
i
used 
l exa
exa
r Staging
taging
s will be
ill be
to 
and 
and 
amin
mi
support 
6 year
year
l be
be summ
sum
 that chan
hat ch
ults are co
ts are c
chem
che
any 
g
g will
g will a
ected su
ected su
rs.
rs
marketing 
mg/kg/day
mg/kg/d
e and T+M
and T
AEs will 
Es wil
ulator
ulatory
r
l
authorization 
vulsive 
lsive
application 
K 
 it will 
it will
fenfluram
fenflura
ustness of
stness o
ected from
cted fro
actors can
ctors ca
d. 
et
and 
ng po
 po
arate
ate PK
PK
mode
mode
b
any 
alyses
alyses
opulat
pul
extensions 
nge f
ge f
ollected
llected
mistry re
istry re
atio
tions, n
ns, n
results,
esults
based o
ased o
or
arized
arize
from
from
variations
M p
M p
be displ
e disp
y Activit
Activi
so be pr
so be pr
ummarie
mmari
thereof. 
y, ZX00
y, ZX00
perio
perio

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 88 of 182
treatment group. The clinical study report will also contain a comparison of the PK of 
fenfluramine in the children enrolled in this study to historical data from adults. 
10.6 ANALYSES PROVIDED TO AN INDEPENDENT DATA AND SAFETY 
MONITORING COMMITTEE
A safety oversight monitoring plan will be in place with an IDSMC evaluating data from the 
subjects. Details will be provided in the IDSMC charter. The IDSMC’s primary responsibility is 
to ensure that study subjects are not exposed to unanticipated harm that could have been 
prevented by timely review and intervention. The IDSMC is established to review safety data at 
predefined time points, and to recommend to the sponsor whether to continue, modify, or 
terminate the study as necessary. The IDSMC is composed of expert permanent members who 
cover relevant specialties (neurology, cardiology, pediatrics, and statistics). The IDSMC 
members may request assistance from a number of additional and hoc members if needed. 
11.
ETHICAL & REGULATORY CONSIDERATIONS
11.1
ETHICAL 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 study will also be carried out according to all applicable international and national 
regulatory requirements. 
The sponsor and the investigator must inform each other (e.g., 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 study. 
11.2
INFORMED CONSENT
The investigator is responsible for obtaining a subject’s written informed consent to participate 
in the 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. 
All subjects will be informed that the study will be registered in the public database at 
ClinicalTrials.gov in accordance with the FDA Amendments Act of 2007 (Section 12.3). 
Before undergoing screening procedures for possible enrollment into the study, subjects must be 
informed, in an understandable form, about the nature, scope, and possible consequences of the 
PUBLIC
oco
oco
f the cur
the cu
s describ
s descri
fic qualit
c qualit
 the part
 the pa
t th
t the
COPY
Y CO
Y C
NS
NS
ol are 
l are
This document 
IN
IN
nvestiga
vestiga
the study
e stud
A Subj
A Subj
prov
pro
cannot
investig
vesti
l ethical
ethical
e study.
study.
FO
FO
be 
ed ou
d ou
used
icip
ci
rights, s
ghts, 
re credib
cred
ut ac
ut ac
to 
y stan
sta
pation
pation
support 
desi
esigned t
gned
ent ICH G
nt ICH
ed in
d in ICH
ICH
ndard
nda
any 
IDER
IDE
marketing 
have
ave
review s
review s
ntinue, mo
inue, m
permanen
erman
tatistics). 
tistics
d hoc me
hoc m
RA
authorization 
from th
rom th
esponsi
spons
e be
e be
application 
RMED C
RMED
or is respo
or is res
ect Inform
t Inform
ns of I
ns of
and 
tor m
or m
and lega
nd lega
any 
ordin
ord
must i
us
extensions 
GCP 
CP 
H Topic 
Topic 
d for 
for de
de
of huma
f huma
fety, and
ety, and
le.e.
ng
ng
or
o ensu
o ens
gui
gu
variations
nt
 The ID
The I
embers 
mbers
ATION
ATION
thereof. 
bility 
lit
en
afety da
fety da
odify, or
odify, o
memb
mem
D

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 89 of 182
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 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 study and to 
consider their participation in the study. If, after reading the Subject Information Sheet and the 
ICF, consent is given to participate in the 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 eCRF. 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 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. 
PUBLIC 
nd/o
nd/
ICF have
CF hav
et and IC
et and I
e rel
e r
COPY
e inform
e info
be prov
be prov
rded 
ded in t
in t
or in 
or in
This document
other w
her w
ned to th
d to th
subject’
ubject’
n the stu
the stu
should
shoul
inf
inf
cannot 
ng g 
t’s Lega
s Leg
nable to
able to
ess sh
ss sh
i
be
if 
rticipat
rticipa
all pa
all p
used
CF 
F 
vant to
ant to
RB befor
befo
new in
new in
i
to 
must 
must 
support
e subjec
subje
he Invest
e Inve
to o be app
be app
any 
mu
conse
cons
ed with 
d with 
t
marketing 
t subj
subj
thout any 
hout any
t details o
details
ect Inform
ct Info
ust be s
st be
t
authorization 
be
on on 
n on 
ted in th
d in th
med co
med co
ect
ec
application 
rea
uld be p
ld be 
ten inform
en info
e subject o
subject
legally a
egally
dy and, if 
y and, 
also sign
so sign
on i
on
and
ly Acce
y Acc
ad, or 
d, or 
any 
o
in the 
in th
es conc
es conc
extensions
proved 
roved
be revise
revise
he s
e subje
ubje
e they
hey ca
ca
rmatio
mati
or
s s
gator 
gator
variations 
of the
the
mation 
ation 
signed a
igned a
nt discus
t discus
a copy 
copy 
eCRF
eCRF
thereof. 
nsent 
en
s have th
have t
y disadva
disadv
e stu
e stu

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 90 of 182
Assent for Subjects Under the Age of Consent (Pediatric Subjects) 
All subjects are under the age of consent (i.e., 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. 
11.3
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. 
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. 
11.4
PROTOCOL COMPLIANCE
The investigator must conduct the study in compliance with this 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. 
PUBLIC
nd wil
nd wi
roval sho
oval sho
under In
under 
th th
th 
COPY
ONS A
ONS A
NAL RE
NAL R
pprop
ppropr
l a
This document 
other 
her
n notific
notific
uired by
ired by
nformat
format
regula
regul
cannot
udy. T
dy. T
rofessi
ofessio
preferab
referab
n his or 
his or
app
app
be
acco
acc
ged to o
ged to o
The
Th
used
ve
ve
e applic
applic
ure that
re that
orda
orda
to 
estig
stigatat
support 
VI
VI
ate docum
doc
wait all re
it all r
uld d menti
menti
any 
D INDE
IND
EW BO
EW B
marketing 
y and, 
and,
the legal
the lega
CF, the le
F, the 
ritten info
tten in
t, and that
nd tha
authorization 
s who 
s who 
their 
heir 
and any 
and any
the subj
he subj
egally a
gally a
ifif
application 
y
her exp
r ex
licable reg
icable r
ation of th
ion of 
the spons
he spon
on, a lette
n, a let
ory requi
y requi
and
refo
ef
nal curr
al curr
writ
written
te
pe
any 
ce w
ce w
ain ev
ain evidi
ore, th
ore, t
extensions
ele
ion the 
n the
onal New
nal New
ble regul
le regu
he i
e inve
nve
with
with
or 
ents 
ent
vant a
vant 
variations
form
t assent
assen
PENDE
PEND
OARD
ARD
s tot
thereof.
ccepta
cepta
capable o
pable 
lly accep
y acce
egally a
egally a
mation
matio

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 91 of 182
The investigator should not implement any deviation from, or changes to, the 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 study protocol. Exceptions include 
only cases of medical emergency to address immediate hazards to study subjects, or when the 
changes involve only logistic or administrative aspects of the 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: 
x
The sponsor (delegate) for agreement. 
x
The IEC/IRB for review and approval or favorable opinion (if required). 
x
The applicable competent regulatory authority (if required). 
Details of the procedure for implementing study protocol amendments are available in 
Section 12.10. 
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 study 
protocol in the eCRF and/or in the Protocol Deviation Log, if applicable. 
12.
ADMINISTRATIVE ASPECTS
12.1
CLINICAL TRIAL AGREEMENT
This study will be conducted under a Clinical Trial Agreement between the sponsor (or delegate) 
and the respective institutions representing the study sites. Any financial support given to the 
study sites will be detailed in the Clinical Trial Agreement. The Clinical Trial Agreement, which 
must be signed before the start of any study related procedures, will clearly delineate the 
responsibilities and obligations of the investigator and the sponsor (delegate), and will form the 
contractual basis upon which the study will be conducted. 
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR
Prior to study initiation, the investigator and any subinvestigator(s) to be directly involved in the 
treatment or evaluation of study subjects at each study site will disclose to the sponsor (delegate) 
any relevant financial or proprietary interests in either the study product or the sponsor company. 
The appropriate disclosure form(s) will be provided by the sponsor (delegate) for this purpose. 
Any relevant updates to the financial disclosure information that occur during the conduct of the 
study, or during one year after completion of the study, will be provided by the investigator and 
subinvestigator(s) to the sponsor (delegate). All financial disclosure information provided by the 
investigator and subinvestigator(s) will be submitted to appropriate competent authorities 
PUBLIC
igator (o
gator (
ons and 
ons and
he Proto
Proto
RAT
RA
COPY
ority (if
ority (
udy prot
udy pro
This document 
bas
ba
rior to st
or to s
treatm
treatm
any
any
T
cannot 
itutio
utio
etailed i
tailed i
efore th
fore th
s and 
and ob
o
sis up
is u
be
ted und
ted und
ons
ons
used
VE A
E A
AL AG
AL AG
to 
col D
ol D
S
support 
ocol a
ol a
delegate)
delegat
xplain an
plain an
Devia
Dev
any
quired)
quired
amen
me
marketing 
d devi
dev
ol amendm
l amendm
on (if req
on (if r
authorization 
ude
de
the
he
medical
edical
out prio
ut prio
iati
ati
application 
ligati
gati
on which
on whic
INANCI
INANC
udy initiat
dy initi
nt or eval
t or eva
vant f
vant f
and
ep
ep
n the C
e C
start of 
tart of
ons
on
any 
a Clinic
a Clin
resentin
esen
in
extensions 
e) mu
mu
ny deviat
devia
ation Lo
ion Lo
PECT
PECT
REEM
EEM
or 
ust i
st i
variations 
equired).
quired)
ndments
dments
thereof. 
on or 
n or 
ment(s)
ent(s)

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 92 of 182
according to the applicable regulatory requirements. 
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE
The sponsor will provide the relevant study protocol information in a public database 
(ClinicalTrials.gov) before or at commencement of the study, as required by the 2007 FDA 
Amendments Act. The sponsor (delegate) may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
If a potential subject contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor (delegate) may forward the relevant study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will assess 
the suitability of the subject for enrollment into the study. Results of this study will be disclosed 
according to the relevant regulatory requirements. All publications in peer-reviewed medical 
journals resulting from this study will be listed in the original study protocol registration record 
on ClinicalTrials.gov. 
12.4
STUDY FILES AND MATERIALS
Before the start of any study related procedures, all essential documents specified by ICH GCP 
and other applicable regulations must be available in the relevant files maintained by the sponsor 
(or delegate) and the investigator. An Investigator Study File prepared by the sponsor (or 
delegate), containing all applicable documents for use at the study site, will be made available to 
the investigator before the start of the study. A list of personnel and organizations responsible for 
conduct of the study as well as the list of investigators will be included in the Investigator Study 
File. The respective files will be kept and updated by the sponsor (or delegate) and the 
investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by the sponsor’s study monitor (or delegate) to determine that 
all required documentation is present and correct (see Section 12.9). 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority (see Section 12.11). 
12.5
INITIATION OF THE STUDY
Before the start of the study at each study site, the sponsor’s study monitor (or delegate) will 
visit the study site to ensure adequacy of the facilities and to discuss responsibilities regarding 
study protocol adherence with the investigator and other personnel involved in the study. 
The investigator may not enroll any subjects into the study before the sponsor has received 
written approval or a favorable opinion from the IEC/IRB for conducting the study and a formal 
meeting has been conducted by the sponsor’s study monitor (or delegate) to initiate the study 
(study initiation visit). This meeting will include an inventory of study supplies and a detailed 
review of the study protocol and procedures, the eCRF, IMP accountability, and the subject 
PUBLIC
ed
be avai
be ava
An Inves
An Inve
ble docu
le docu
rt of the
t of the
r
as the 
as th
COPY 
IALS
ALS
ures, a
ures,
This document 
IN
I
fore the 
re the
visit the 
sit the 
study
study
T
cannot 
nspec
pe
ntation 
tation 
be audit
e audit
hority
ority
be
and mat
and ma
ctio
ctio
used
st
list of i
st of 
kept and
ept an
to
ment
udy. A
udy. A
support 
ll essentia
essen
ble in the
e in th
igator Stu
ator S
ts for 
ts fo
any marketing 
y, the in
the in
contact d
contact d
investiga
investig
f this stud
his stu
ns in peer-
in pee
udy pro
dy pr
authorization 
FDA 
FDA 
nclusion
lusion
application 
d 
see Sec
ee Se
ITIATIO
TIATI
tart of the
art of th
study site 
udy sit
rotocol a
otocol
and
n b
n b
s pres
prese
or insp
or ins
any
ials mai
als ma
y the sp
y the
nt
extensions
 rel
re
udy File
dy File
use at t
use at t
list of p
st of p
vestig
estigato
ato
updated
updated
or
docu
doc
evan
eva
variations
dy w
y w
r-review
eview
otocol re
tocol re
thereof. 
estigato
tigato
details to
tails to
ator will
ator wil
will b
will b

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 93 of 182
diary. 
12.6
SUBJECT REIMBURSEMENT
Where relevant, subjects will be reimbursed for reasonable travel costs associated with 
participation in this study, after presentation of receipts for the travel in question, at a rate to be 
approved by the IEC/IRB. Subjects will not be paid for participating in the study. 
12.7
LIABILITY AND INSURANCE
The civil liability of the involved parties with respect to financial loss due to personal injury 
and other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
The sponsor will provide insurance to the investigator if required by the applicable regulatory 
and legal requirement(s).
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY
All study documents, including the study protocol and eCRFs, are the confidential property of 
the sponsor and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with the 
requirements of individual study sites. Subjects not enrolled into the study will be documented 
as such in the screening log together with the reason for not having been enrolled. 
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by 
applicable regulatory requirements. All subject names will be kept in confidence and will not be 
revealed to the sponsor. Subject names must be made unreadable on any documents made 
available to the sponsor. 
Subjects participating in the study will be identified in the eCRF by the subject number allotted 
to them during the study. 
The ICF will include a statement that all study findings, irrespective of the medium on which they 
are stored, will be handled in strictest confidence in accordance with applicable data protection 
laws (e.g., the European Data Protection Directive [95/46/EC] and the USA Health Insurance 
Portability and Accountability Act [HIPAA]), and will be evaluated by the sponsor and/or a 
competent regulatory authority in an anonymized form. The subjects are also to be informed that 
their medical records may be audited or inspected by qualified delegates from the sponsor or a 
competent regulatory authority. The subject’s written consent authorizing direct access to his 
medical records, and computer processing and publishing of his anonymous personal data, must 
PUBLIC 
TIO
TI
study pr
tudy pr
as such
as such
study w
study w
udy s
udy
COPY 
his study
his stud
pplicable
licab
ON 
ON A
This document
particip
articip
m during
during
he ICF w
ICF w
are stor
e stor
laws
laws
Po
P
cannot 
be ret
re
ry requir
y requ
ponsor. 
onsor. 
e spons
spons
be 
ain a 
n a
ticipan
ticipan
ain
ain
used
ll b
l 
tes. Sub
es. Su
ether w
her witi
per
per
to 
be doc
be do
support 
regu
eg
ND CON
D CO
tocol a
ocol and
nd
any 
will
will be in
be i
ulatory
ulato
marketing 
to person
to person
ed are gov
d are g
d by the a
by the
authorization 
rate to b
rate to b
application 
or.
ting in the
ng in t
the study
he stud
ill include
l includ
d, will be
, will b
g., the 
., the
and
ed d
ements.
ments
ubject n
bject n
any 
nal l
nal
in the st
in the 
n a co
n a c
A
extensions
d eCRF
eCRF
umen
mented
ted
ects
cts not 
no
h the rea
the rea
list
list
or
FIDE
FIDE
variations 
applicab
pplicab
nsured a
sured a
ry and le
and l
thereof. 
nal injur
al injur
verned b
verned 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 94 of 182
be obtained prior to participation in the study. 
A subject’s identity will be disclosed by the investigator only in case of emergency (i.e., to 
address any immediate health hazard). 
12.9
MONITORING OF THE STUDY
The investigator at each site will allow the sponsor’s study monitor (or delegate) reasonable 
access to the eCRFs and direct access to related source documents for monitoring purposes as 
frequently as the sponsor deems necessary. These documents include records of tests performed 
as a requirement for participating in the study as well as other medical records required to confirm 
information contained in the eCRF, such as past history and secondary diagnoses. 
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the eCRF. The investigator and other relevant personnel at 
each study site will be expected to cooperate with the sponsor’s study monitor to assist in 
providing any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of 
all documentation required for the study. The study monitor will ensure that the investigator at 
each site has been provided with adequate means for organization and filing of study 
documentation (see Section 12.4). 
The date on which the study monitor (or delegate) visits the study site will be recorded in the 
Site Visit Log. During monitoring visits, the study site’s coordinator (if applicable) and the 
investigator should be available, the source documentation should be accessible, and a suitable 
environment should be provided for the study monitor to review study related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
x
Resolution of any problems. 
x
Examination of all study documentation for completion, adherence to the study protocol, 
and possible AEs. 
x
Clarification of inconsistencies or missing data. 
x
Verification of study data against source documents. 
x
Checks that investigator obligations have been fulfilled. 
x
Review of ICFs and dates of consent. 
x
Inspection of IMP with respect to storage, labeling, and documentation. 
x
Drug accountability 
After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the eCRF correctly and in a timely manner, after which the investigator 
PUBLIC 
y. Th
. Th
quate
uate m
monitor (
monitor (
oring
orin
COPY
sti
st
the sp
the sp
e Invest
Invest
e st
e st
This document 
arifica
rifica
Verific
Verifi
x
Ch
C
x
cannot
any pr
ny pr
ion of al
n of a
ssible A
ible A
atio
atio
be
onitorin
onitori
b
used
isits, t
its, t
the sour
he sour
d for th
d for t
to
r deleg
dele
the
h
support
gator Stu
ator St
udy y monit
mon
ans for or
ns for o
t
any
d o
d 
or’s stu
or’s st
marketing 
ng
s of test
of tes
cords requ
ords requ
diagnose
diagnos
ld record 
d recor
other 
othe
authorization 
easonab
sonab
g purpo
purpo
application 
Es.
n of incon
n of inc
ation of s
ation of
ecks that 
cks tha
Review 
Review
and 
lem
em
study d
tudy d
any
visi
visits co
ts c
s.s.
extensions
rganiz
ganiz
te) vi
e) visits
sit
study si
tudy s
e docum
docum
study m
tudy m
or
dy F
y 
r will 
will
at
variations 
all data
all data
relevant
elevan
dy moni
dy moni
File
File
thereof. 
e
ses as 
es as 
perform
erform
uired to 
red to 
es. 
s. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 95 of 182
will sign the eCRF. 
12.10
PROTOCOL AMENDMENTS
A “substantial” amendment of a study protocol is any written description of change(s) to, or 
formal clarification of, a study protocol that may have a significant impact on the safety or 
physical or mental integrity of subjects, the scientific value of the study, the conduct or 
management of the study, or the quality or safety of any IMP used in the study. The IEC/IRB 
must approve all substantial protocol amendments prior to their implementation. If required by 
applicable local regulatory requirements, the local regulatory authority must also approve all 
substantial protocol amendments prior to their implementation. 
A “non-substantial” amendment of a study protocol includes minor corrections or clarifications 
that have no significant impact on the way the study is to be conducted and has no effect on the 
safety of participating subjects (e.g., change in study monitor, contact details, etc). If required by 
applicable local regulatory requirements, the IEC/IRB, and/or the local regulatory authority 
should be notified of all non-substantial protocol amendments. The substantial and non- 
substantial protocol amendments will be integrated into an updated study protocol at the 
discretion of the sponsor if the changes to the original study protocol are numerous, or if required 
by applicable regulatory requirements. 
12.11
AUDITS AND INSPECTIONS
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority. 
In the event of an audit by the sponsor, the investigator must make all study related 
documentation available to the auditor(s). Regulatory authorities may request access to all 
study related documentation, including source documents, for inspection and copying in 
keeping with applicable regulations. The sponsor will immediately notify the investigator (or 
vice versa) of an upcoming audit or inspection. 
If an audit or inspection occurs, the investigator and relevant personnel at the study site must 
allocate sufficient time to discuss the findings and any relevant issues. 
12.12
CLINICAL STUDY REPORT
After completion of the study, a clinical study report covering clinical and statistical aspects of 
the study will be prepared by the sponsor (or delegate) in consultation with the coordinating 
investigator. As required by the applicable regulatory requirements, the clinical study report will 
be signed by the sponsor’s responsible medical officer as well as the coordinating investigator (if 
applicable). 
Progress reports and/or a summary of the clinical study report will be provided to the IEC/IRB 
and competent regulatory authorities in accordance with applicable requirements. 
PUBLIC 
PECTI
PECTI
inspecte
inspecte
COPY
IRB, a
RB
l amend
amend
gr
grated in
ated i
he or
he origi
This document 
C
er comp
r comp
the study
e study
inves
inves
be 
be
cannot 
e reg
re
coming 
oming 
spection
pection
ient tim
ent tim
be
he a
on, inc
on, inc
gula
gula
used 
d b
sponsor, 
onsor,
audit
audi
to
by qua
y qua
support 
to an 
o an 
nal study
l stu
NS
any 
or the l
r the
ents. Th
ents. Th
upd
up
marketing 
on. If
n. If
st also ap
t also ap
correction
rrecti
ducted and
cted a
ontact d
ntact 
oc
authorization 
or r 
ty or 
ty or 
t or 
or 
he IEC/
he IEC
f req
f req
application 
oc
e to dis
o di
INICAL
NICA
etion of t
tion of
will be p
will be 
ator. As
tor. A
by
b
and
ioio
audit or
udit or
ccurs
curs
any 
(s).
s)
ding sou
ing so
ns. The
s. Th
in
extensions 
ifieied del
d del
he inves
e inves
. Re
Re
or 
proto
ro
variations
ns o
s o
d has no
has n
details, e
etails, 
cal regu
cal regu
he subst
subst
ated 
ated stu
stu
toco
oc
thereof. 
IRB 
RB
uired by
ired by
prove al
rove a
or cla
or cl

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 96 of 182
12.13
USE OF DATA AND PUBLICATIONS
The rights and obligations of investigators and the sponsor concerning any formal presentation 
or publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study (see Section 12.1). 
For multicenter studies, the first publication must be based upon all data obtained from all 
analyses, as stipulated in the study protocol by the biostatistician and not by the investigators. 
Investigators participating in multicenter studies must agree not to present data gathered 
individually or by a subgroup of study sites before the full, initial publication is available or 
5 years after the last clinical study visit, whichever is later, unless this has been agreed to by all 
other investigators and by the sponsor. 
The sponsor must receive a copy of any intended communications in advance of the proposed 
submission date. This is to allow the sponsor time to review the communication for accuracy 
(thus avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential and/or proprietary information is not inadvertently divulged, to provide any relevant 
supplementary information, and to allow establishment of co-authorship (as appropriate). The 
authorship of communications arising from pooled data will include investigators from study 
sites that contributed data as well as relevant personnel from the sponsor. Ownership of all data 
will remain with the sponsor. 
PUBLIC
levant 
vant
COPY
sions 
sion
ot inadv
t inadv
ablis
ablishme
hm
m pooled
pooled
pe
This document cannot be used to support 
nt of c
of c
data will
ata wi
rsonnel fr
onnel 
any 
gulato
gula
ently di
ently di
co-au
co
marketing 
ga
g
n is avai
is ava
as been ag
s been 
s in advan
in adv
commu
comm
ry
authorization 
m all
m all
nvestigat
estigat
athere
there
application and any extensions 
rom
or 
inclu
c
m th
m the
variations
ance of t
ce of 
unication
unicatio
y author
y autho
vulged,
vulged,
uthorsh
uthorsh
ude
ud
thereof. 
ors.
able or 
le or 
greed to
greed to

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 97 of 182
13.
REFERENCE LIST
Aicardi J and Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine (3 
cases). NEJM 1985; Nov 28;313(22):1419. 
Aicardi J, Gastaut H, and Misès J. Syncopal attacks compulsively self-induced by Valsalva's 
maneuver associated with typical absence seizures. A case report. Arch Neurol 1988 
Aug;45(8):923-5. 
Boel M and Casaer P. Add-On therapy of fenfluramine in intractable self-induced epilepsy. 
Neuropediatrics. 1996; 27: 171-173. 
Center for Disease Control. Cardiac valvulopathy associated with exposure to fenfluramine or 
dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health 
Recommendations, November 1997. Morbidity and Mortality Weekly Report. 1997; 
46(45):1061-1084. 
Ceulemans B, Boel M, Leyssens K, Van Rossem C, Neels P, Jorens PG, Lagae L. Successful 
use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012; 53: 1131-
1139.  
Ceulemans, B., Schoonjans, A.-S., Marchau, F., Paelinck, B. P., & Lagae, L.. Five-year 
extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. 
Epilepsia 2016 (*):1–6, 2016 http://doi.org/10.1111/epi.13407 
Chiron C and Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia 2011; 
52(Suppl. 2):72–75. 
Connolly HM, Crary JL, McGoon MD, Hensrud DD et al.  Valvular heart disease associated with 
fenfluramine-phentermine. New Engl J Med 1997;337(9):581-8. Erratum in: N Engl J Med 1997 
Dec 11;337(24):1783. 
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: 
Dravet syndrome.  Adv Neurol 2005; 95: 71-102. 
Dravet C. Les epilepsies graves de l’enfant.  Vie Med. 1978;8:543–548. 
Dravet C.  Severe myoclonic epilepsy in infants and its related syndromes.  Epilepsia 2000; 41:7. 
EMA 2007. Stiripentol SmPC and EPAR Scientific Discussion. Available at 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000664/huma 
n_med_000742.jsp&mid=WC0b01ac058001d124.  Accessed 31 July 2015. 
Hurst, DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 1990;31:397-400. 
ICH Topic E2F: Development Safety Update Report, 2011. 
ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, 1994. 
PUBLIC 
Marchau
Marchau
patients w
patients w
http://do
ttp://do
harm
har
COPY 
em
em C, N
C,
for Dra
for Dra
This document 
Les e
es 
t C.  Sev
C.  Sev
MA 2007
A 2007
http://w
ttp://w
n_m
n_m
H
cannot 
M, Ogu
M, Ogu
me.  Adv
e.  Adv
epil
epil
be 
cGoo
Go
. New 
. New
used
acologi
colog
on M
on M
to
with
org/10
org/10
support
eels
el
et syndr
t synd
F., ., Paelin
Paelin
h Drave
Drav
1
any 
W
s P, Jor
P, J
marketing 
nduced ep
nduced e
xposure to
posure
s Interim
Interim
eekly R
eekly
authorization 
ne (3
ne (3
alsalva's
lsalva's
988 8 
application 
Ne
psies grav
psies gr
ere myocl
e myoc
. Stiripen
Stiripe
ww.ema.e
w.ema
000742
00074
and 
ni H, Fuk
H, Fu
eurol 
urol 
any
D, He
D, H
ngl J Me
ngl J M
extensions
nck, B.
ck, B
et syndr
et syndr
111/epi
11/epi
trea
reatmen
tme
en
en
or 
me
m
variations 
to fen
fen
Public 
Public
Report. 
Report.
orens PG
ens PG
e. Ep
e. Ep
thereof. 
epilepsy.
ilepsy
nflu
nflu

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 98 of 182
Marshall WA, Tanner JM. Variations in the pattern of pubetal changes in boys. Arch Dis Child 
1970; 45:13. 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of Disease 
in Childhood. 1969;44(235):291-303. 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in 
epilepsy. Epilepsia 2012;53, 227–233. 
Sabaz M, Carins D, Lawson J, Nheu N et al. Validation of a New Quality of Life Measure for 
Children with Epilepsy. Epilepsia 2000; 41(6):765-774. 
Shorvon S, Tomson T.  Sudden unexpected death in epilepsy. Lancet 2011;378: 2028–38. 
Talarska D. The usefulness of Quality of Life Childhood Epilepsy (QOLCE) questionnaire in 
evaluating the quality of life of children with epilepsy. Advances Med. Sci 2007; 52 suppl 1:191- 
193. 
Wong J, Reddy SS, Klein AL. Anorectic drugs and valvular heart disease: a biological and 
clinical perspective.  Cleveland Clinical Journal of Medicine 1998; 65:35-41. 
ZX008 Investigator’s Brochure Version 3, January 5, 2016. 
PUBLIC 
3, J
,
COPY 
and 
nd valv
valv
nal of M
al of M
Janua
Janu
This document cannot be used to support 
edicin
dic
y 5, 2016
5, 201
any 
ar heart 
ar heart
ne 19
ne
marketing 
Life M
fe M
011;378: 
011;378
(QOLCE
QOLC
s Med. Sc
Med. 
authorization 
sease
sease
d death 
d death 
Mea
Mea
application and any extensions or variations
E) ques
que
ci 2007
i 2007
disease
isease
998; 65:
8; 65
thereof. 
sure for 
e for
 2028–3
2028–3
stiti

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 99 of 182
14.
APPENDICES
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 100 of 182
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
Generic Name 
Generic Name
alfentanil 
naratriptan 
almotriptan 
nefazodone 
alprenolol 
nortriptyline 
amitriptyline 
ondansetron 
amphetamine 
oxcarbazepine 
astemizole 
oxycodone 
atomoxetine 
paroxetine 
bufuralol 
perphenazine 
bupropion 
phenacetin 
buspirone 
phenobarbital 
cafergot 
phenytoin 
cannabidiol 
promethazine 
carbamazepine 
propafenone 
cerivastatin 
retigabine/ezogabine 
citalopram 
risperidone 
clomipramine 
ritonavir 
codeine 
rizatriptan 
cyproheptadine 
selegiline 
desipramine 
sertraline 
dextromethorphan 
stiripentol 
duloxetine 
sumatriptan 
eletriptan 
telaprevir 
encainide 
THC and derivatives 
ergotamine tartrate 
tramadol 
eslicarbazepine 
trazodone 
felbamate 
vortioxetine 
fentanyl 
zolmitriptan 
PUBLIC 
C
LI
UB
P
COPY 
ara
perph
erp
Y
PY
p
PY
PY
CO
C
This document
thorph
horph
xetine 
tine 
nt
eletriptan
etriptan
me
enca
enca
cu
do
do
do
cannot
ot
nn
ca
be
be used 
d
se
u
to 
o
t
support 
enace
nac
phenoba
heno
rt
p
phe
he
po
pp
up
s
any 
azine
azine
y
tin
tin
an marketing 
g
eti
rk
ma
authorization 
NS 
NS 
za
ori
th
au
application 
on
ati
lic
de
pp
a
and 
d
an
any y
any extensions
enytoin
nytoin
promet
rome
ns
i
pro
r
sio
nsi
en
xt
e
or 
bital
bital
o variations 
n
ati
ri
v
thereof. 
f
eo
he
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 101 of 182
fluoxetine 
zuclopenthixol 
fluvoxamine 
 
frovatriptan 
 
imipramine 
 
levacetylmethadol (LAAM) 
linezolid 
 
meperidine 
 
methadone 
 
metoclopramide 
 
mexiletine 
 
PUBLIC COPY 
Y
This document cannot be used to support any y marketing 
g
tin
rke
ma
m
authorization 
ioio
tio
at
ri
th
au
application and any extensions or variations 
ns
tio
thereof. 
f
eo
her
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 102 of 182
APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE
This do
uthorization 
ereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 103 of 182
COPY 
This do
nt cannot be used to support any marketing 
horization 
auth
ation and any extensions or variations 
eof. 
there

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 104 of 182
PUBLIC COPY 
This doc
ocument cannot be used to support any marketing 
horization 
auth
application and any extensions or variations 
eof. 
there

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 105 of 182
This do
horization 
eof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 106 of 182
PUBLIC COPY 
This document cannot be used to support any marketing 
horization 
autho
on
on and any extensions or variations 
eof. 
thereo

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 107 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
thorization 
auth
application and any extensions or variations 
eof. 
thereo

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 108 of 182
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE 
FUNCTION 
This do
d t
uthorization 
n
reof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 109 of 182
COPY 
This document cannot be used to support any marketing 
zation 
authoriza
ap
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 110 of 182
PUBLIC COPY 
This document t cannot be used to support any marketing 
zation 
autho
applicatioion and any extensions or variations thereo

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 111 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
ation 
authorizati
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 112 of 182
COPY 
This document cannot be used to support any marketing 
ation 
authorizati
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 113 of 182
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizatio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 114 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
on 
authorizatio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 115 of 182
PUBLIC COPY 
This docu
ocument cannot be used to support any marketing 
zation 
authoriza
ap
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 116 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
tion 
authorizatio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 117 of 182
COPY 
This document cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 118 of 182
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE
This document cannot 
rization 
application and a

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 119 of 182
PUBLIC COPY 
This docu
ent cannot be used to support any marketing 
orization 
authoriz
app
application and any extensions or variations 
f. 
thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 120 of 182
This document cannot be 
arketing 
rization 
authoriz
application and any 
s thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 121 of 182
PUBLIC COPY 
This docu
nt cannot be used to support any marketing 
rization 
authoriz
app
pplication and any extensions or variations thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 122 of 182
This document cannot be
tin
ting 
orization 
auth
application and any
ereof. 
ere

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 123 of 182
PUBLIC COPY 
This docume
ment cannot be used to support any marketing 
zation 
authori
application and any extensions or variations thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 124 of 182
PUBLIC COPY 
This document ca
cannot be used to support any marketing 
zation 
authoriz
application 
n and any extensions or variations thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 125 of 182
PUBLIC COPY 
This document 
nt cannot be used to support any marketing 
zation 
authoriz
applicatio
tion and any extensions or variations thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 126 of 182
PUBLIC CO
COPY 
This document cannot be used to suppor
ort any marketing 
orization 
authori
application and any extensions or r variations 
of. 
thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 127 of 182
PUBLIC COPY 
This document cannot be used to support any marketing 
zation 
authorizat
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 128 of 182
PUBLIC COPY 
This document cannot be used 
d to support any marketing 
ation 
authorizat
application and any exten
ensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 129 of 182
PUBLIC COPY 
This document can
annot be used to support any marketing 
orization 
autho
application and any extensions or variations 
of. 
thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 130 of 182
PUBLIC CO
COPY 
This document cannot be used to support 
rt any marketing 
zation 
authoriza
application and any extensions or va
variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 131 of 182
APPENDIX 5 – TANNER STAGING
This do
orization 
of. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 132 of 182
This do
horization 
eof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016
Confidential 
Page 133 of 182
APPENDIX 6 – PEDSQL (INCLUDING FAMILY IMPACT MODULE) 
COPY 
This doc
ocument cannot be used to support any marketing 
thorization 
E)
E)
auth
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 134 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 135 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 136 of 182
COPY 
This do
document cannot be used to support any marketing 
ation 
authorizati
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 137 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
ation 
authorizatio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 138 of 182
COPY 
This document cannot be used to support any marketing 
ation 
authorizati
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 139 of 182
PUBLIC COPY 
This doc
ocument cannot be used to support any marketing 
ation 
authorizat
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 140 of 182
PUBLIC COPY 
This doc
ocument cannot be used to support any marketing 
ation 
authorizatio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 141 of 182
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
authorizati
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 142 of 182
PUBLIC COPY 
This do
document cannot be used to support any marketing 
ation 
authorizat
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 143 of 182
COPY 
This do
document cannot be used to support any marketing 
ion 
authorizatio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 144 of 182
COPY 
This document cannot be used to support any marketing 
rization 
authoriz
application and any extensions or variations 
. 
thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 145 of 182
COPY 
This do
document cannot be used to support any marketing 
ation 
authorizatio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 146 of 182
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE 
PUBLIC COPY 
This docu
ocument cannot be used to support any marketing 
ation 
authorizat
ap
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 147 of 182
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES 
This docume
ization 
ca
 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 148 of 182
APPENDIX 10 – PROTOCOL AMENDMENT 1
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 

Sponsor name change 

Added new section of transition for subjects who will enter the open-label extension study 

Removed the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, 
testosterone, GH, prolactin, and IGF-1 

Clarified the maximum dose of ZX008 is 30 mg/day 

Clarified the collection duration of prior and concomitant AEDs 

Clarified data to be collected with the use of rescue medication 

Moved the BRIEF-P description from the efficacy section to the safety section 

Added new section of collection of data for AEs requiring hospitalization 
Additional clarifications and changes were made based on feedback received from the United 
States Food and Drug Administration, and include the following: 

Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and AESI with 
regard to valve regurgitation seen on ECHO. 

Clarified that the central cardiac reader will provide consultation to the IDSMC when a 
subject may be removed from the study due to development of signs or symptoms 
indicative of valvulopathy, regurgitation, or pulmonary hypertension 

Clarified expedited reporting of cardiac events other than SAEs 

Added section on grading of and follow-up for ECHO findings 
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
and tables of contents, etc, are not listed. 
Rationale: There has been a name change for the sponsor’s subsidiary.
Original Text
Amendment Text
PUBLIC 
ere m
ere m
on, and i
n, and i
nclusion 
clusion 
ation se
ation se
car
ca d
COPY
c
ficacy 
ficacy
for AEs r
or AE
mad
mad
This document 
ecific
cifi
ons are 
s are 
nges, su
ges, su
and table
d tabl
cannot 
n grad
gra
or each c
each c
c C
c C
be
thy
epo
eportin
rtin
ding
ding
used
n o
n o
iac read
ac read
rom the 
m the 
y, regu
 regu
to 
riteri
teri
on EC
on EC
support 
eq
based on
ased o
nclude the
ude the
ia, po
a p
any
a
tion to t
ion to
uiring h
uiring
marketing 
l ex
FSH, est
SH, es
AEDs 
EDs 
tion
ion
authorization 
xtensi
tensi
application 
hanges 
anges 
marked in
arked i
ch as the c
h as the
s of conte
of cont
and 
of
o
hange/cl
nge/c
any
gitat
of cardi
f card
and fo
and 
extensions
e follow
follow
ost-treat
t-treat
HO. 
O. 
er will pr
will p
tudy due
udy du
ation
ation
or
feedba
eedb
variations 
he safety
e safety
hospitali
ospital
thereof.
on study
n study
adiol,
diol,

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 149 of 182
Title page, Signature of Sponsor page, Synopsis, 
Table 2, and document headers
Brabant Pharma Limited
Title page, Signature of Sponsor page, Synopsis, Table 2, 
and document headers
Brabant Pharma Limited Zogenix International Limited
Rationale: A transition period for those subjects entering the open-label extension study has been 
added in order to preserve the study blind and allow all subjects to enter the follow-on study receiving
COPY 
This document cannot be used to support any marketing authoriza
een
receivin
receivin
zation 
ed
ati
za
ho
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 150 of 182
open-label study medication.
Original Text
Amendment Text
Synopsis 
Methodology: 
After completion of the Maintenance Period, 
eligible subjects will be offered enrollment in a 
separate open-label extension trial.
Duration of Treatment:
All subjects will receive ZX008 or matching 
placebo for up to approximately 14 weeks 
(Titration Period=2 weeks; Maintenance 
Period=12 weeks). After completion of the 
Maintenance Period, eligible subjects may enroll 
in the open-label extension study.
Table 1. Schedule of Assessments, Footnotes
c: Only for subjects who do not roll over into the 
open-label extension study.
k: Follow-up ECG, ECHO, and physical 
examination will be performed 3-6 months after 
early termination, or for those subjects who 
complete the study but do not enter the open-label 
extension study (see Section 6.4).
l: Only adverse events related to cardiac safety 
will be collected at this visit.
Section 3.1
After completion of the Maintenance Period, 
eligible subjects will be offered enrollment in a 
separate open-label extension trial.
Synopsis 
Methodology: 
At the end of the Maintenance Period (or early 
discontinuation), all subjects will undergo a 2-week 
taper or transition period (Post-Dosing Follow-Up) 
depending on whether they exit the study or are 
enrolled in the separate long-term open-label extension 
study.
Duration of Treatment:
All subjects will receive ZX008 or matching placebo for 
up to approximately 14 16 weeks (Titration Period=2 
weeks; Maintenance Period=12 weeks; 
Taper/Transition=2 weeks). After completion of the 
Maintenance Period, eligible subjects may enroll in the 
open-label extension study, after completion of the 
transition.
Table 1. Schedule of Assessments, Footnotes
(appropriate adjustments were made within the table 
regarding these footnotes)
c: Only for subjects who do not roll over into the open- 
label extension study. Follow-up ECG, ECHO, and 
physical examination will be performed 3-6 months 
after early termination, or for those subjects who 
complete the study but do not enter the open-label 
extension study (see Section 6.4).
k: Follow-up ECG, ECHO, and physical examination will 
be performed 3-6 months after early termination, or for 
those subjects who complete the study but do not enter the 
open-label extension study (see Section 6.4). Only 
adverse events related to cardiac safety will be 
collected at this visit.
l: Only adverse events related to cardiac safety will be 
collected at this visit.
Section 3.1
After completion of the Maintenance Period, eligible 
subjects will be offered enrollment in a separate open-label 
extension trial.   At the end of the Maintenance Period 
(or early discontinuation), all subjects will undergo a 2- 
week taper or transition period (Post-Dosing Follow-
PUBLIC 
otnotes
otnotes
l
COPY
app
ap
eeks; Ma
eeks; M
Taper/T
Tape
Maint
Main
ope
ope
CO
This document
he s
e s
on study 
study 
 Only ad
Only ad
will be 
will be
do
cannot 
ECHO, a
CHO, a
l be perfo
be perfo
ion, or fo
on, or fo
tudy 
udy
be used 
ver into t
r into t
to support 
nance 
ance 
n-label exte
abel ex
ansition
nsition
s
T
s
any 
ely 1
ely 
nance Pe
nance P
sition=2
sition
Perio
Per
marketing 
in
he study
stud
erm open-l
rm open-
eive ZX0
ive ZX
4 16 
m
authorization 
titi
ati
early
arly
rgo a 2-w
go a 2-w
g Follo
Follo
za
application 
those 
hose 
ut do not en
ut do no
ee Section 
e Sectio
erse events
se even
ollected at 
lected a
1
and 
nd physic
physic
ed 3-6 m
d 3-6 
sub
any exte
e
xtensions 
Table 1. S
ble 1. S
(appro
(appro
rega
reg
xte
or 
sion
sio
variations 
08 or ma
08 or ma
weeks (T
weeks (T
riod=12 w
od=12 w
2 weeks
weeks)
d, eligib
d, eligib
n stu
stu
thereof. 
eek 
e
w-Up)
Up)
r are
are
label ext
bel ext

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 151 of 182
None 
Up) depending on whether they exit the study or are 
enrolled in the separate long-term open-label extension 
study.
5.5.5 Transition Period
Subjects who complete the Maintenance Period and 
will be continuing into the open-label extension study 
will be transitioned from double-blind study 
medication to open-label ZX008 (Table 5). Study 
medication will be administered as equal doses BID in 
the morning and in the evening approximately 12 
hours apart, with food. Each dose should be separated 
by a minimum of 8 hours and a maximum of 12 hours. 
A missed dose of study medication may be taken later 
up to 8 hours before the next scheduled dose; 
otherwise, the missed dose should not be given. Study 
medication will be administered using the oral dosing 
syringe provided.
All subjects entering the open-label extension study 
will be transitioned from their blinded daily dose 
(placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) 
to the 0.2 mg/kg dose during the 2-week interval 
between Visits 12 and 13, without breaking the blind. 
The IVR/IWR system will assign two bottles of IMP to 
the subject, one for each step in the transition. A new 
bottle of IMP will be started by the subject at each 
level of the transition step. See Section 5.6 for more 
information about the volume of ZX008 or placebo to 
be administered.
Table 5.  Transition Algorithm
Dose Group 
in Double- 
Blind Study
Transition Step 1 
Day 1-4 after Visit 
12
Transition Step 2
Days 5-14 after
Visit 12
ZX008 0.2
mg/kg/day
ZX008 0.2
mg/kg/day
ZX008 0.2
mg/kg/day
ZX008 0.8
mg/kg/day
ZX008 0.4
mg/kg/day
ZX008 0.2
mg/kg/day
Placebo
ZX008 0.2
mg/kg/day
ZX008 0.2
mg/kg/day
Note: maximum daily dose of ZX008 is 30 mg.
Subjects who had been randomized to placebo increase 
their dose to 0.2 mg/kg/day beginning on Day 1 of the 
transition (the day following Visit 12.) Subjects who 
had been randomized to 0.2 mg/kg/day will continue to 
receive that dose. Subjects who had been randomized 
to 0.8 mg/kg/day or were receiving the maximum dose
PUBLIC COP
COPY 
to 8 ho
to 8 
otherwise
therwis
medica
medi
syri
syr
This document 
o
cannot be used to supp
s
port 
ion 
on
ge provid
e provi
All subjec
All subj
will be 
will be 
(plac
(pl
to
any 
stst
efore t
efore
he missed
he misse
will be
will b
marketing 
bel e
l e
-blind stu
blind st
08 (Table 
8 (Table 
tered as eq
ed as 
evening ap
ening a
d. Each do
Each d
hours a
hours and
udy me
udy m
h
authorization 
ati
on 
n 
ce Perio
e Perio
xtens
xten
application and any extens
xte sions
cts e
transiti
ansiti
cebo, 0.2
cebo, 0.2
o the 0.2 
he 0.2 
between
betwee
The 
The 
th
th
or 
nteri
nter
variations
pr
ose shou
e sho
d a maxi
 maxi
edi
dication
cation
e next sch
e next sc
d dose
dose sh
sh
e adminis
admini
thereof. 
and 
an
on study
study
dy y
5). Study
). Study
qual dose
ual dos
roxima
oxima
l

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 152 of 182
Section 6.2.7 
None
Section 6.2.9

Dispense study medication for taper 
subjects not enrolling in the open-label 
extension study
None
Section 6.3 
None
of 30 mg/day decrease to a dose of ZX008 0.4 
mg/kg/day, or a max of 30 mg/day. After 4 days at this 
dose level (Day 5), these subjects will decrease their 
dose to 0.2 mg/kg/day. Subjects will report to the clinic 
on Day 15 for enrollment into the open-label extension 
study.
Section 6.2.7
At Clinic Visit 10, compliant subjects who have 
tolerated IMP should be presented with the ICF for the 
open-label extension study. Informed consent for the 
open-label extension study must be signed at Visit 12 or 
earlier in order to enter the open-label extension study.
Section 6.2.9

Dispense study medication for taper subjects not 
enrolling in the open-label extension study
Informed consent for the open-label extension study 
must be signed at Visit 12 (if not signed earlier) in 
order to enter the open-label extension study.
Section 6.3
For subjects entering the open-label extension study, 
the subject will visit the clinic on Day 113. The 
following will be recorded/performed and the subject 
will immediately be enrolled in that separate study:

Review current seizure activity 
(number/type/duration) from diary since 
previous visit

AEs

AESIs

Concomitant medications

Collect used, partially used and unused study 
medication; perform drug accountability and 
review with parent/caregiver
Rationale: To remove the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, 
testosterone, GH, prolactin, and IGF-1.
Original Text
Amendment Text
Section 1.6
The approximate volume of blood (108.7 mL) 
planned for collection from each subject over the 
course of the entire study (Screening to End of
Section 1.6
The approximate volume of blood (115.7 108.7 mL) 
planned for collection from each subject over the course of 
the entire study (Screening to End of Study, but not
PUBLIC COPY 
on 6
n 
Y

D
CO
This docu
Rat
Ra
t
cument 
cu
do
cannot be used to support 
enro
enr
t
s
Informe
Inform
must
must
or
s
any 
pense stud
pense stu
olling i
olling
a
marketing 
bjects who
bjects wh
ented with
nted wi
. Informed
Inform
dy must
y must b
ter the ope
the o
authorizati
is
r
e clinic
clinic
extensio
tensio
ation 
ati
app
nale:
ale: To
To
rone
ron
pplication 
pp
and any extensions
ed conse
d cons
be signe
be sign
der to en
er to e
Sect
Sec
te
F
xte
or variations
e si
en-label
n-labe
dy medic
medic
in the ope
the op
a
thereof. 
 have 
have 
h the ICF
he IC
d consen
d consen
gned
gned

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 153 of 182
PUBLIC COPY 
This document cannot be used to support any marketing 
ti g authorization 
ati
uth
au
application and any extensions or variations thereof. 
her of.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 154 of 182
Original Text
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Hematology 
2 mL 
2 mL
2 mL
2 mL
2 mL 
2 mL
12 mL
Genotyping 
5 mL 
-- 
-- 
-- 
-- 
-- 
5 mL 
IGF-1 
3.5 mL 
3.5 mL
3.5 mL
3.5 mL
3.5mL 
3.5 mL
21 mL
Coagulation 
-- 
2.7 mL
--
--
-- 
--
2.7 mL
Cannabidiol 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
--
4 × 2 mL
-- 
--
8 mL
AED plasma sample 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
8 mL 
Volume for flushing 
indwelling catheter 
-- 
-- 
4 × 0.5 mL 
-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 mL 
19.7 mL 
17.0 mL 
27.0 mL 
15.0 mL 
17.0 mL
115.7 mL 
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
 
Amendment Text
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (studyday)
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry -- 
Included in 
Chemistry 
Included in 
Chemistry --
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Hematology 
2 mL 
2 mL
2 mL
2 mL
2 mL 
2 mL
12 mL
Genotyping 
5 mL 
--
--
--
-- 
--
5 mL
IGF-1 
3.5 mL --
3.5 mL 
3.5 mL --
3.5 mL 
3.5mL 
3.5 mL 
21 14 mL 
Coagulation 
-- 
2.7 mL
--
--
-- 
--
2.7 mL
Cannabidiol 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
--
4 × 2 mL
-- 
--
8 mL
AED plasma sample 
1 x 2 mL
1 x 2 mL
1 x 2 mL
1 x 2 mL
8 mL
Volume for flushing 
indwelling catheter 
-- 
-- 
4 × 0.5 mL 
-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 16.5 mL 
19.7 mL 
17.0 13.5
mL
27.0 mL 
15.0 mL 
17.0 mL
115.7 
108.7 mL
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
PUBLIC 
IC
ne; 
C
llection
llection
ne P
ne
P
COPY 
1 x 2 
x 
Y
OP
L 
L 
OP
COP
GF-1=i
GF-1=
C
This docu
ocum
Approx
Approx
volum
volum
ment 
K samp
amp
t
lasma sam
ma sam
nt
ume for flu
e for fl
ndwelling c
welling c
en
m
cu
cu
FS
F
can
annot
Che
Ch
t
2
ot
no
nn
nn
nn
an
ca
e
c
be 
mL
cluded in
cluded in
be
mistry
mistr
be used 
riod (study
d (study
d
41)
1)
Ran
Ran
ed
us
us
us
u
to support 
pp
.0 mL 
mL 
t
or
ulin-like grow
in-like gr
po
any 
1 x 2 m
1 x 2
y
4 × 0.5
4 × 0.5
ny
a
marketing 
d in 
emistry
emistry
g
2 mL 
2 mL 
tin
-- 
-
et
3.5m
3
ke
r
ark
ar
mL 
L 
a
2 mL
mL
m
L
m
authorization 
on
or
Day 99
Day 9
tho
a
7.5
7.
au
a
appli
ate total bloo
 total bl
per sub
 subjb ec
ect
lication 
2 m
2
n
on
titio
ati
hing
heter 
heter 
at
at
plic
pp
=follicle stim
ollicle stim
a
-- -
and 
d
mL
d
5 mL
mL ----
an
a
any 
7
Includ
Inclu
Che
y
a
extensions s
y)
en
en
mization 
zation 
Day -1
ay -1
xte
 mL
mL
e
or
or
h factor
h facto
or variations
mL
-- 
s
2 mL 
mL 
ns
----
on
tio
a
mL 
L 
at
ria
7.0 mL 
.0 mL 
ar
v
thereof. 
mL
f.
luded in
ded in
Chemistry
hemist
of.f.
2 m
2 m
er
he
th
th
th
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 155 of 182
Rationale: To clarify the maximum dose of ZX008 is 30 mg/day.
Original Text
Amendment Text
Section 5.5.2
After 4 days at this dose level (Study Day 5), 
subjects randomized to the ZX008 0.8 mg/kg/day 
group will increase their dose to 0.4 mg/kg/day 
while doses in the other two groups will remain 
constant.  On Study Day 9, the dose for the
0.8 mg/kg/day group will increase to the target 
dose.
Table 3 
None
Section 5.5.4
On the first day of the tapering period subjects in 
the ZX008 0.8 mg/kg/day group will decrease to a 
dose of ZX008 0.4 mg/kg/day BID.
Table 4 
None
Section 5.5.2
After 4 days at this dose level (Study Day 5), subjects 
randomized to the ZX008 0.8 mg/kg/day group will 
increase their dose to 0.4 mg/kg/day (maximum 30 
mg/day) while doses in the other two groups will remain 
constant. On Study Day 9, the dose for the 0.8 mg/kg/day 
group will increase to the target dose or a maximum of 30 
mg/day.
Table 3
Note: maximum daily dose of ZX008 is 30 mg.
Section 5.5.4
On the first day of the tapering period subjects in the 
ZX008 0.8 mg/kg/day group will decrease to a dose of 
ZX008 0.4 mg/kg/day BID (maximum 30 mg/day).
Table 4
Note: maximum daily dose of ZX008 is 30 mg.
Rationale: To clarify the collection duration of prior and concomitant AEDs.
Original Text
Amendment Text
Section 5.7
All medications taken by a subject during the 
Screening and Baseline Seizure Assessment 
Periods are regarded as prior therapy and must be 
documented in the eCRF. Significant medications 
(e.g., antiepileptic drugs [AEDs], antibiotics) 
taken within 30 days prior to the Screening visit 
should also be captured.
Section 5.7
All medications taken by a subject during the Screening and 
Baseline Seizure Assessment Periods are regarded as prior 
therapy and must be documented in the eCRF. Significant 
medications (e.g., antiepileptic drugs [AEDs], antibiotics) 
taken within 30 days prior to the Screening visit should also 
be captured. All prior and concomitant AEDs will be 
collected in the CRF.
Rationale: To clarify data to be collected with the use of rescue medication.
Original Text
Amendment Text
Section 5.7.3
Use of rescue medication is permitted during the 
study and should be recorded on the eCRF (day, 
time, medication[s], dose[s]) and in the diary (day, 
time). Repeated administrations within the same 
episode should be recorded separately.
Section 5.7.3
Use of rescue medication is permitted during the study and 
should be recorded on the eCRF (day, time, medication[s], 
dose[s]) and in the diary (day, timeframe associated with 
seizure episodes). Repeated administrations within the 
same episode should be recorded separately.
PUBLIC 
e to a
e to a
COPY 
n
Sectio
Sectio
CO
On
On
CO
This document
pilep
ile
ithin 30 
hin 30 
ld also be
also b
Rationa
ation
me
Orig
Orig
cu
o
Se
S
oc
do
cannot
by a sub
y a sub
eline Seiz
ne Seiz
rded as pr
ed as p
n the eCR
the eCR
ptic d
ptic
be 
be used 
ction du
tion du
se
u
to support 
5.5.4
5.
rt
he first day
first 
X008 0.8 m
008 0.8
ZX008 0
ZX008 
s
any marketing 
gr
for the 
r the
dose 
dose or a m
or a m
aily dose o
ly dos
authorization 
tio
atiti
ubjects
ubjects
oup will
p will
ximum 3
mum 3
oups w
ups w
0
za
application 
F. Sign
Sign
ugs [AEDs
ugs [AE
ays prior to
s prior t
captured.
ptured.
: To clari
To cl
ic
al Text
l Text
pp
n 5.7.3
5.7.3
a
scu
ap
and 
ct duri
dur
re Assess
Assess
therapy
herap
ifi
ifi
any
ng th
ny y
ny extensions 
.4 mg/k
mg/
Table 4
Table 4
en
Not
Not
xte
ion of p
on of
xt
e
or 
of th
of 
/kg/da
/kg/da
kg/
k /
variations 
of ZX008
of ZX008
he ta
e t
thereof.
l remain
remain
 mg/kg/d
mg/kg/
maximum
ximum

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 156 of 182
Rationale: To move the BRIEF-P description from the efficacy section to the safety section
Original Text
7.1.4 Behavior Rating Inventory of Executive 
Function – Preschool Version (BRIEF-P)
Amendment Text
7.1.4 7.2.12 Behavior Rating Inventory of Executive 
Function – Preschool Version (BRIEF-P)
Rationale: To add new section of collection of data for AEs requiring hospitalization.
Original Text
Amendment Text
None
Section 8.1.4  Adverse Events Requiring Hospitalization
If a subject is treated in a medical facility (hospital, 
emergency room, free-standing clinic) related to the 
occurrence of any AE, the following data will be 
collected to model health care utilization in patients with 
Dravet syndrome: AE/reason for hospitalization/clinic 
visit; duration of the visit in hours/days; admission to 
intensive care unit; and name/number of procedures 
performed, including but not limited to, 
electroencephalogram, ECG, ECHO, positive emission 
tomography (PET) scan, magnetic resonance imaging 
(MRI), x-ray, computed tomography CT) scan, surgery, 
and lumbar puncture/spinal tap.
Rationale: To clarify randomization inclusion criteria, post-treatment cardiac follow-up, and AESI 
with regard to valve regurgitation seen on ECHO.
Original Text
Amendment Text
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria:
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, 
ECG or physical examination, including but not 
limited to any mitral, aortic, tricuspid or 
pulmonary valve regurgitation or signs of 
pulmonary hypertension, and is approved for entry 
by the cardiac central reader.
Section 6.4, Table 6, footnote b
Positive sign or symptom includes any sign of 
valve thickening or regurgitation (mitral, aortic, 
pulmonary, tricuspid), or sign or symptom 
indicative of potential pulmonary hypertension as 
adjudicated by the IPCAB.
Section 8.1.3, Table 8
10.  Signs on ECHO indicative of potential
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria:
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, ECG or 
physical examination, including but not limited to any trace 
mitral, or aortic, tricuspid or pulmonary valve regurgitation 
or signs of pulmonary hypertension, and is approved for 
entry by the cardiac central cardiac reader.
Section 6.4, Table 7 footnote b
Positive sign or symptom includes any sign development 
of valve thickening or regurgitation (“trace” or greater in 
mitral, aortic,; mild or greater in pulmonary, tricuspid), or 
sign or symptom indicative of potential pulmonary 
hypertension as adjudicated by the IPCAB.
Section 8.1.3, Table 9
10.  Signs on ECHO indicative of potential valvulopathy
P
S
PUBLIC 
on inclus
on inclus
on seen o
seen 
LIC
U
P
COPY
du
du
ensive c
ensive
perform
perfo
electr
ectr
tom
tom
CO
This document 
y hype
hype
cardiac c
ardiac c
Section 
ection 
u
Posit
Posi
va
v
do
cannot 
e a card
a card
normality
rmality
xaminati
aminat
mitral, ao
tral, ao
lve regu
ve reg
ertet
be 
iteria:
iteria:
dio
dio
used
ction 8.1.3
on 8.1.
d to 
ECH
ECH
to
t
support 
encep
ncep
ography (P
raphy 
MRI), x-ra
RI), x-r
and lumb
and lum
n criteria
criteria
HO.
O
up
any
the
th
unit; an
unit; a
includin
nclud
halog
hal
marketing 
uiring
ring
dical facil
cal fa
ndin
nding clini
g clin
the followi
e follo
alth care u
lth car
AE/reaso
AE/reas
visit
vis
authorization 
tio
ve
tio
tio
ho
ut
Ho
H
a
application 
ic, t
gitation o
tation
sion, and i
sion, and
ntral reader
ral read
4, Table 6,
Table 
pp
ve sign or s
sign or 
hickeni
hickeni
and
asc
asc
ased on
sed on
n, includi
includ
ricusp
ricus
any 
ular or
lar o
EC
extensions 
bar pu
r pu
, po
post-tre
st-tre
s
Amend
Amend
si
e
Syn
Syn
en
xte
or
ET)
ET
comp
comp
unc
unc
variations
ng d
g
utilizatio
ilizati
n for hos
n for ho
in hours
n hour
d na
name/n
me/n
ng but no
but no
gram, EC
am, E
) sca
sca
thereof. 
spitalizat
italiza
ity (hosp
(hos
c) relate
c) relate
data w
data
of.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 157 of 182
valvulopathy
  mild valve regurgitation (aortic, mitral, 
tricuspid, or pulmonary)
 Mean Mitral valve gradient  4 mmHg
 Mean Aortic valve gradient  15 mmHg
 Mean Tricuspid valve gradient > 4 mmHg
 Mean Pulmonary valve gradient > 21 mmHg
 valve regurgitation (aortic or mitral)
  mild valve regurgitation (aortic, mitral, tricuspid, or 
pulmonary)
 Mean Mitral valve gradient  4 mmHg
 Mean Aortic valve gradient  15 mmHg
 Mean Tricuspid valve gradient >  4 mmHg
 Mean Pulmonary valve gradient >  21 mmHg
Rationale: To clarify that the central cardiac reader will provide consultation to the IDSMC when a 
subject may be removed from the study due to development of signs or symptoms indicative of 
valvulopathy, regurgitation, or pulmonary hypertension.
Original Text
Amendment Text
Section 4.5
Subjects may be discontinued from the study for 
the following reasons, if deemed appropriate by 
the sponsor or investigator:
1. Development of signs or symptoms indicative of 
cardiac valvulopathy or regurgitation (mitral, 
aortic, tricuspid, pulmonary valves), or pulmonary 
hypertension for which IDSMC, in consultation 
with the IPCAB and the investigator believe the 
benefit of continued participation does not 
outweigh the risk.
Section 4.5
Subjects may be discontinued from the study for the 
following reasons, if deemed appropriate by the sponsor or 
investigator:
1. Development of signs or symptoms indicative of cardiac 
valvulopathy or regurgitation (mitral, aortic, tricuspid, 
pulmonary valves), or pulmonary hypertension for which 
IDSMC, in consultation with the IPCAB, the central 
cardiac reader, and the investigator believe the benefit of 
continued participation does not outweigh the risk.
Rationale: To clarify expedited reporting of cardiac events other than SAEs.
Original Text
Amendment Text
Section 8.8
Even if none of the criteria for an SAE are 
fulfilled, any of the following events must be 
reported by the investigator to the Medical 
Monitor within 72 hours from the time the 
investigator is notified.
4. Hypersensitivity reactions
5. Pulmonary hypertension
6. Cardiac symptoms requiring intervention, or 
valvulopathy
Section 8.8
Even if none of the criteria for an SAE are fulfilled, any of 
the following events must be reported by the investigator to 
the Medical Monitor within 72 hours from the time the 
investigator is notified.
1.
Hypersensitivity reactions
2.
Pulmonary hypertension
3.
Cardiac symptoms requiring intervention, or 
valvulopathy, if identified outside of study-related 
monitoring
PUBLIC 
tion
on 
eve the
e the
not
not
ted repo
ted repo
U
P
COPY
ry y 
wing
in
vestigato
vestigat
1. Deve
1. De
valvu
valv
pu
p
CO
This document 
y
c symp
symp
ulopathy
opathy
en cannot
tor to
or t
urs from 
rs from 
fied.
ed.
vity react
y react
hyperte
yperte
tom
t
be 
an S
n S
g events
g event
the
the
use
AE
AE
sed 
ting 
ng
d
se
to 
of c
of c
to support 
pm
p
opathy o
athy 
monary val
onary v
DSMC, in 
SMC, i
cardiac 
cardiac
contin
contin
s
any 
s, if d
, if
ment of s
ent of
r r
marketing 
he IDS
IDS
ms indica
ms indic
ket
continued
ontinu
eem
ee
rk
authorization 
Hg
1 mmHg
mmHg
tio
M
au
application 
ns
sion
on
s requiring
requirin
ca
and
Me
he time 
ime 
any 
ust be
ust be
dical 
dical 
he
extensions 
co
reader
ader
nued part
ued part
rdiac eve
diac eve
si
Am
Am
ten
xte
xtxt
or 
es), o
es),
nsulta
nsulta
variations 
d from the
from the
med appro
appro
signs or s
ns or s
gurgitat
urgitat
r p
thereof. 
C when a
when a
ative of 
ve of 
f
the
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 158 of 182
Rationale: To add a new section on grading of, and follow-up for, ECHO findings.
Original Text
Amendment Text
None
Section 8.9.1  Follow-up of Echocardiogram Findings
All ECHOs will be evaluated by a central reader from 
BioMedical Systems, Inc. (BMS), in consultation with 
the IPCAB if warranted. Findings related to pulmonary 
hypertension or valvulopathy on any of the four valves 
(aortic, mitral, pulmonary, triscuspid) will be reported 
to the investigator with grades of normal, trace, mild, 
moderate or severe. If the ECHO result has progressed 
in severity since the last reading then new oversight 
measures will be enacted as described below in Levels 1-
3. Table 11 describes the severity of ECHO findings 
with the level of increasing oversight if the subject is to 
remain in the study.
Table 11. Clinical Measures Enacted Upon Increasing 
Severity of ECHO Findings
Level 1: 
Continue per protocol
Level 2:
1. If there is a desire to continue study medication:
a.
The investigator will evaluate the 
efficacy to date based on study diaries 
and consult with the parent/guardian, 
and determine whether study treatment 
was associated with significant, 
meaningful benefit in number, severity 
and/or duration of seizures and/or on 
the impact on daily functioning.
b.
The investigator will consider whether 
the subject has had reasonable trials 
(dose and duration) of other available 
anticonvulsants (e.g. valproic acid, 
clobazam, or topiramate), alone or in 
combination, and not maintained the 
level of seizure control achieved with 
study medication.
Severity
Valve
Aortic
Mitral
Pulmonary
Tricuspid
Normal
Level 1
Level 1
Level 1
Level 1
Trace
Level 2
Level 2
Level 1
Level 1
Mild
Level 2
Level 2
Level 1
Level 1
Moderate
Level 3
Level 3
Level 3
Level 3
Severe
Level 3
Level 3
Level 3
Level 3
PUBLIC COPY
the 
h
main in 
main in
Table
Table
CO
C
This document 
do
cannot be used to supp
s pport 
11. Cli
. Cli
Sev
S
Severit
Severity
or
Normal
Normal
pp
u
Trac
Trac
up
su
M
su
su
s
any 
incr
inc
study.
study.
nica
i
marketing 
any of t
y of 
cuspid) wi
cuspid) w
es of norm
of no
ECHO re
ECHO 
t reading t
eading
cted as
d as de
d
es the se
s the s
easin
ea
authorization 
tio
atiti
dings
ings
reader fr
eader fr
nsultation
ultation
ated to 
ed to 
th
th
za
application and any extens
xtens
Severe
Severe
nsions
A
s
Lev
Lev
s
ns
Le
Le
ns
ns
ld
on
Moderate
odera
io
ns
en
or 
rity 
ity
r
ortic
rtic
or
o variations
then 
en
scribed 
ribed 
verity of 
verity of 
ng oversi
 oversi
 Measu
Measu
of E
of
thereof.
wit
ulmona
mona
four valv
ur valv
ll be rep
be rep
mal, trace
 trac
sult has 
ult has 
new
new

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 159 of 182
2.
If the investigator feels consideration of continued 
treatment is warranted considering benefit and 
potential risks, and the parent/guardian feels 
strongly that the child be maintained on the study 
medication when understanding the risks, the 
parent/guardian must sign a new consent which 
describes the additional risks and the child should 
provide assent if appropriate.
a.
If both of these conditions are not met, 
the subject is discontinued from 
treatment.
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to the 
IDSMC for review, including consideration of 
effects on seizures and comorbidities.
4.
The Co-Chairs of the IPCAB are alerted to the 
request and prepare, after consultation with 
BMS, an evaluation of the cardiopulmonary risks 
and proposed monitoring plan, if applicable for 
submission to the IDMSC.
5.
IDMSC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted.
6.
IDSMC makes a determination of appropriate 
path, including the possible outcomes:
a.
Discontinue study medication
b.
Increase frequency of ECHO and ECG 
monitoring
c.
Add additional ECG and/or ECHO 
measures to be monitored
d.
Reduce the dose of study medication
Level 3:
1. The investigator will evaluate efficacy to date 
based on study diaries and consult with the 
parent/guardian, and determine whether the 
achieved benefit justifies the consideration of 
continuing study treatment by the IDSMC. 
MINIMAL efficacy criteria for IDSMC 
consideration:
a.
Seizures must be more than 75% 
improved (number of convulsive 
seizures per 28 days) on treatment over 
baseline, and improvement must be 
consistent.
b.
The number, type, duration, and 
distribution of seizures at baseline 
should be of a severity, which justifies 
the risk of cardiopulmonary
PUBLIC COPY
CO
4.
The
T
re
This document 
o
cannot be used to support
s
rt
BMS,
MS
and pro
and pr
subm
sub
5.5
ID
I
any 
Chairs 
Chair
est and p
st and p
an ev
an
marketing 
ondition
dition
discontinue
iscontinu
repa
epares a 
res 
ntinuation
inuati
review, inc
view, in
zures a
zures
authorization 
tio
d 
d 
ls
the study
e study
sks, the 
s, the
nsent wh
nsent wh
the chil
he chil
application and any extension
xte
ns 
MSC
MSC
Investig
nvestig
subje
subj
6.6.
ID
ID
or
ose
os
sion to
sion t
wi
variations 
ca
to be 
o be
cluding c
uding c
nd como
nd como
f the IPC
f the IPC
repare, a
epare, a
valuation
uation
ed mo
ed m
thereof. 
sh
are not m
e not m
ed from
 from
ase hist
se hist

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 160 of 182
complications, considering the subject’s 
age and overall health.
c.
Subject has had reasonable trials (dose 
and duration) of other available 
anticonvulsants (e.g., valproic acid, 
clobazam, topiramate), alone or in 
combination, and not maintained the 
level of seizure control achieved with 
study medication.
2.
If the investigator feels consideration of 
continued treatment is warranted considering 
the benefit and potential risk, and the 
parent/guardian feels strongly that the child be 
maintained on the study medication when 
understanding the risks, the parent/guardian 
must sign a new consent, which describes the 
additional risk and the child should provide 
assent if possible.
a.
If both of these conditions are not met, 
the subject is discontinued from 
treatment.
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to the 
IDSMC for review, which includes effects of 
study medication on seizures and comorbidities 
related to Dravet syndrome.
4.
The Co-Chairs of the IPCAB are alerted to the 
request, and in consultation with BMS prepare 
an evaluation of the risk and proposed 
monitoring plan if applicable for submission to 
the IDMSC.
5.
IDSMC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted.
6.
IDSMC makes a determination of appropriate 
path, including these possible outcomes:
a.
Discontinue study medication
b.
Increase frequency of ECHO and ECG 
monitoring
c.
Add additional ECG and/or ECHO 
measures to be monitored
d.
Reduce the dose of study medication
PUBLIC COPY 
CO
a
This document 
o
cannot be used to support 
s
a
3.3.
any 
gn a
gn 
tional ri
tional 
sent if p
sent i
I
marketing 
ls consider
s conside
nt is 
is warra
war
potential r
potential
ian feels st
n feels
d on the stu
on the 
nding the
ding th
new
n
authorization 
tio
(dose
(dose
c acid,
cid,
one or in
ne or in
maintaine
intaine
l achiev
achiev
application and any extensions 
xte
The in
he in
ration
ration
IDS
ID
or 
the
th
trea
tre
nve
variations
trong
n
udy med
dy med
e risks, th
risks, th
w consent
consent
sk and th
k and th
ossible.
ssible.
f both of
both of
e sub
su
thereof. 
th
d with 
with 
ration of 
tion o
anted con
ed co
sk, and 
sk, and 
gly t
ly t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 161 of 182
APPENDIX 11 – PROTOCOL AMENDMENT 2
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 

Replaced CHU9D with PedsQL 

Updated statistical analysis section to be consistent with the separate statistical analysis 
plan 

Clarified inclusion criterion #7 regarding the requirement for a whole blood sample for a 
broad epilepsy-related gene panel 
A change was made based on feedback received from the United States Food and Drug 
Administration, and include the following: 

Added the assessment of cognition for subjects 5 years of age, so that all study 
participants are now being assessed for cognition using the BRIEF. The description of the 
BRIEF was moved from the efficacy section to the safety section. 
Clarifications and changes were made based on feedback received from the European Voluntary 
Harmonization Procedure Clinical Trials Group, and include the following: 

Updated contraception requirements for the study 

Clarified when subjects must be discontinued from the study 

Clarified that the investigator may discontinue a subject from the study in the case of a 
medical emergency 

Added statistical information regarding sensitivity analyses for concomitant AED 
medication changes during the study 
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale:  To replace the CHU9D with the PedsQL for the assessment of quality of life.
Original Text
Amendment Text
PUBLIC 
cy
cy s
made bas
made ba
nical Tr
nical Tr
qu
qu
COPY 
ubjects
bjects 
r cogn
r cogniti
sectio
ectio
This document 
of Spec
f Spec
Addition
ddition
chang
chang
tab
tab
cannot 
infor
nfo
anges du
nges d
for eac
or eac
be 
tiga
g
ma
ma
used
rements 
ments
must 
st be d
be d
tor m
tor m
to
s Grou
s Gro
support 
5 y
on using
n usin
n to the sa
to the s
d on feed
on feed
any 
ears of 
ars o
g t
marketing 
stic
le blood s
blood s
d States F
States
authorization 
cal an
al an
application 
h chang
chang
fic Chang
fic Chan
are mark
are ma
, such a
such
con
and
ion
on
ring the
ng th
any 
y di
y d
n regar
rega
extensions 
dback re
dback r
p, and in
and in
for the st
r the s
scontinu
continu
isco
isco
or
fety se
ety s
variations 
Food an
Food an
f age, so
age, so
e BRI
e BRI
thereof. 
alysis
ysis 
sample f
mple f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 162 of 182
Synopsis, Section 2.3
Additional secondary efficacy objectives of the study 
are:

To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints:
Synopsis, Section 2.3
Additional secondary efficacy objectives of the study 
are:

To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) superior 
to placebo on the following endpoints:
PUBLIC COPY 
This document cannot be used to support any marketing authorizati
) superior
uperio
ho
tion 
tio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 163 of 182
o
The change from baseline in the Child Health
Utility 9D Scale (CHU9D) score.
Synopsis (Criteria for Evaluation/Efficacy), 
Section 2.7.1

CHU9D to measure changes in quality of life 
of the subject
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

CHU9D (Appendix 6)
Section 7.1.4 Child Health Utility 9D Scale
The CHU9D (Appendix 6) is a pediatric generic 
preference based measure of health-related QoL 
completed by the parent/caregiver on behalf of the 
subject. It consists of a descriptive system and a set of 
preference weights, giving utility values for each 
health state described by the descriptive system, 
allowing the calculation of quality adjusted life years 
for use in cost utility analysis. The CHU9D will be 
conducted according to the schedule in Table 1.
Section 7.1.5
The impact on the quality of life of the 
parent/caregiver responsible for a patient with DS will 
be assessed according to the schedule in Table 1 using 
2 scales: the EQ-5D-5L and the HADS. 
Parents/caregivers who do not give consent to collect 
these ratings scales will not complete them. The same 
parent/caregiver should complete these ratings 
throughout the study. If that person is not available at 
the visit, the scales should not be completed.
Appendix 6 was updated and is not presented here.
o The change from baseline in the Child Health 
Utility 9D Scale (CHU9D) Pediatric Quality 
of Life InventoryTM (PedsQL) score.
Synopsis (Criteria for Evaluation/Efficacy), 
Section 2.7.1

CHU9D PedsQL to measure changes in quality 
of life of the subject
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

CHU9D Peds QL (Appendix 6)
Section 7.1.4 Child Health Utility 9D Scale Pediatric 
Quality of Life Inventory
The PedsQL CHU9D (Appendix 6) is a pediatric 
generic preference based modular measure of health- 
related QoL completed by the parent/caregiver on behalf 
of the subject. It consists of a descriptive system and a 
set of preference weights, giving utility values for each 
health state described by the descriptive system, 
allowing the calculation of quality adjusted life years for 
use in cost utility analysis 4 core scales that measure 
physical, emotional, social, and school functioning.
The PedsQL CHU9D will be conducted according to 
the schedule in Table 1.
Section 7.1.5
The impact on the quality of life of the parent/caregiver 
responsible for a patient with DS will be assessed 
according to the schedule in Table 1 using 2 3 scales: 
the EQ-5D-5L, and the HADS, and the PedsQL 
Family Impact Module. Parents/caregivers who do not 
give consent to collect these ratings scales will not 
complete them. The same parent/caregiver should 
complete these ratings throughout the study. If that 
person is not available at the visit, the scales should not 
be completed.
The PedsQL Family Impact module (Appendix 6) is 
designed to measure the impact of pediatric chronic 
health conditions on parents and the family by 
measuring parent self-reported physical, emotional, 
social, and cognitive functioning, communication, 
worry, and family daily activities relationships.
Appendix 6 was updated and is not presented here.
each
each
ystem, 
stem,
usted life 
usted life
CHU9D w
HU9D w
dule in Ta
dule in Ta
COPY
OP
set of 
et of 
Y
ectio
ct
Y
Quality
Quali
PY
The
Th
ge
O
This document 
o
regiver
egiver
ghout the 
out the
visit, the
isit, the
cannot
sible 
ble fo
g to the s
to the
D-5L an
D-5L an
vers who 
s who 
scales w
ales w
s
be 
f life of 
f life of 
r
used to 
ll be
e 1.1.
suppo
up
ars 
rs 
port 
eric pre
ric pr
rt
elated QoL
ated Q
of the su
of the 
set of
set o
pp
he
he
p
any 
Child
Chi
y
Chih
y
Life Inv
Life In
any
sQL 
QL CH
C
efer
f
H
marketing 
ot presente
t presente
d 6.2.9
d 6.2.9
ke
dures will b
es wil
Peds QL 
eds QL (
d He
d H
authorization 
tio
ty y
changes 
hanges 
application 
o no
ll not com
not co
ould
uld compl
com
udy. If tha
dy. If th
cales shou
cales sho
and
pati
pat
hedule in
edule i
the HAD
he HAD
t give
t giv
any 
ent wit
ent w
T
extensio
en
allowin
llowin
ons
f prefer
refer
s
alth state
h state
ns
allowing
allowing
io
use in
use i
si
ph
ph
or 
com
com
ect. It c
ct. It 
en
variat
alth Uti
lth Ut
atitions 
be per
per
(Appendi
ppend
lth Utili
h Utili
tio
entory
ntory
ria
HU9D (Ap
U9D (A
ar
nce base
nce base
va
plel
thereof. 
n qu
d here.
here.
form
form

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 164 of 182
Rationale: To update the statistical sections of the protocol to be consistent with the separate statistical analysis 
plan.
Original Text
Amendment Text
Synopsis, Section 3.1, Section 5.5.1
Synopsis-Methodology
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in 
each age group.
Synopsis
Synopsis-Statistical Methods/Efficacy
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M 
periods compared with Baseline. The MCSF will be 
calculated from all available data collected during the 
Baseline and treatment periods. The primary endpoint 
will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group (three levels) 
and age group (< 6 years, 6 to 18 years) as factors, 
and with Baseline MCSF as a covariate. The primary 
analysis will compare the ZX008 0.8 mg/kg/day  
group to the placebo group using a two-sided test at 
the alpha=0.05 level of significance.
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint also will be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
van Elteren test will be used to assess the primary 
objective.
Section 10.5.1.1
The primary efficacy endpoint is the change in the
Synopsis, Section 3.1, Section 5.5.1
Synopsis-Methodology
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across treatment 
arms, and at least 40% of subjects will be in each age 
group.
Synopsis
Synopsis-Statistical Methods/Efficacy
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M periods 
compared with Baseline. The MCSF will be calculated 
from all available data collected during the Baseline and 
treatment periods. The primary endpoint will be 
analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group 
(< 6 years, 6 to 18 years) as factors, and with Baseline 
MCSF as a covariate.  The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group using a two-sided test at the alpha=0.05 level of 
significance. The primary endpoint will also be 
analyzed using a nonparametric method and if 
normality assumptions are not met, the results of the 
nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be 
performed to assess the sensitivity of the primary 
analysis to changes in concomitant AED medications 
that may occur during the course of the trial.
Specifically, the primary analysis will be repeated 
with a factor added to indicate whether a subject had 
a change in concomitant AED medication during the 
T+M period.
Since the ANCOVA used in the primary analysis relies 
on assumptions of normality, the primary endpoint also 
will be analyzed using a nonparametric method that 
does not require as stringent assumptions. Specifically, 
the van Elteren test, which extends the Wilcoxon rank 
sum test to include stratified data, will be used to 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group while stratifying for age group. If normality 
assumptions are not met, the results of the van Elteren 
test will be used to assess the primary objective.
Section 10.5.1.1
The primary efficacy endpoint is the change in the mean
PUBLIC 
factor
actor
he prima
e prim
mg/kg/day
mg/kg/day
wo-side
wo-sided
ce.
ce.
primary
primary
y t
y
COP
evels)
vels)
s
OPY
omp
m
from al
from a
treatm
tre
an
OP
This document 
do
cannot 
ZX008
X008
while str
hile str
tions are 
ons are
will be u
will be u
be
est, wh
t, wh
ncl
nclude s
ude s
0
used 
analy
naly
e primary
primary
g a nonpa
a nonpa
ingent 
ngent 
i
to 
st a
sisis
sup
y
t
upport 
lyzed u
zed u
model with
del w
(< 6 year
(< 6 ye
MCSF
MCS
com
co
up
any 
h Ba
h B
ailable d
ailable 
t periods
perio
sing
i
marketing 
hods/Effica
hods/Eff
alysis: The
ysis: Th
ange in the
nge in th
F) per 28
F) per 
selin
se
authoriza
group (< 6
oup (< 6
e across 
across 
ll be in 
be in 
ization 
tio
at
iza
application 
ed 
and
mg
m
ifying fo
ying f
ot met, th
met, t
to ass
o ass
any 
xtends 
xtend
tified data
tified dat
g/kg/day
/kg/d
r a
exten
ametric
metric
mption
mption
ensions 
F as a c
as a 
mpare the
are the
group us
group us
signif
signi
ana
ana
en
or 
reatm
ea
6 to 
6 to 
or
cov
variations
 prim
prim
mean co
mean co
da
days dur
ys dur
e. The M
 The M
ata collec
a collec
s. The pri
The pr
an analy
an analy
men
men
thereof. 
eatm
ach age
ch age
cy
cy
mary
ary

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 165 of 182
mean convulsive seizure frequency (MCSF) per 28 
days between the Baseline and T+M periods. The 
MCSF will be calculated from all available data 
collected during the Baseline or T+M Periods.
The primary endpoint will be analyzed using an 
analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group
(< 6 years, 6 to 18 years) as factors, and with 
baseline frequency as a covariate. The primary 
analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at 
the Į=0.05 level of significance.
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
van Elteren test will be used to assess the primary 
objective.
Additional analyses will compare the percentage 
changes between the baseline MCSF and the MCSF 
measured independently during the Titration Period 
alone and the Maintenance Period alone.
Section 10.5.1.2
The longest interval between convulsive seizures will 
be calculated for each subject over the entire T+M 
period. Subjects whose longest interval extends to the 
end of treatment or end of study will be considered 
right-censored. The ZX008 0.8 mg/kg/day and 
placebo groups will be compared using a log-rank
PUBLIC
y gro
y gr
age group
ge grou
results of
results o
s the prim
s the prim
the
th
COPY 
OP
e
, will
will
up 
up
This document 
o
cannot be 
riod a
od a
used
percentag
rcentag
F and the
and the
e Titrat
Titrat
on
to 
ary
support 
up
If 
he
any marketing authorization 
tio
application and any extensions 
en
MCSF 
CSF 
Period
eriod
or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 166 of 182
convulsive seizure frequency (MCSF) per 28 days 
between the Baseline and T+M periods. The MCSF 
will be calculated from all available data collected 
during the Baseline or T+M Periods.
The primary endpoint will be analyzed using an 
analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 
years, 6 to 18 years) as factors, and with baseline 
frequency as a covariate.
The primary analysis will compare the ZX008
0.8 mg/kg/day group to the placebo group using a 
two- sided test at the Į=0.05 level of significance.
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint will also be analyzed using a 
nonparametric method that does not require as 
stringent assumptions. Specifically, A 
nonparametric test such as the van Elteren test, 
which extends the Wilcoxon rank sum test to 
include stratified data, will be used to compare the 
ZX008 0.8 mg/kg/day group to the placebo group 
while stratifying for age group. If normality 
assumptions are not met, the results of the van 
Elteren nonparametric test will be used to assess 
the primary objective.
An additional analysis will be performed to 
assess the sensitivity of the primary analysis to 
changes in dose or type of concomitant AED 
medications that may occur during the course of 
the trial, which are protocol violations. 
Specifically, the primary analysis will be 
repeated with a factor added to indicate whether 
a subject had a change in prescribed dose or type 
of concomitant AED medication during the T+M 
period. Further exploratory analyses may be 
conducted if changes in concomitant AED 
medication appear to have a significant impact 
on the primary outcome.
Additional analyses will compare the 
percentage changes between the baseline 
MCSF and the MCSF measured independently 
during the Titration Period alone and the 
Maintenance Period alone.
Section 10.5.1.2
The longest interval between convulsive seizures 
will be calculated for each subject over the entire 
T+M period. Subjects whose longest interval 
extends to the end of treatment or end of study will 
be considered right- censored. The ZX008 0.8 
mg/kg/day and placebo groups will be compared 
using a log-rank test. The median
PUBLIC 
s s 
med to
med to
y analysis
y analysi
itant A
itan
he
h
COPY 
This document 
analys
aly
ge change
change
F and the 
and the
ring the T
ng the T
Maintena
aintena
Sec
Sec
o
T
cannot
atio
atio
tory ana
ry ana
in concom
concom
to have a
o have a
outcome.
tcome
es w
es
be 
indica
dica
cribed d
cribed d
n dur
n du
used 
o 
D 
ourse of 
rse of 
s. 
ll be
be
e w
e w
to support any marketing authorization 
application 
ll compare t
l compar
between the
etween 
CSF measu
SF mea
ration Period
tion Per
e Period alo
Period a
10.5.1.2
0.5.1.2
ap
est in
st
and 
es may
ma
tant AED
nt AED
gnificant
nifican
any 
ther
her
or type
or type
the T+M
he T+
 be
be
extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 167 of 182
test. The median length of the longest seizure-free 
interval will be presented for each treatment group.
Section 10.5.1.3
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as 
a gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance.
Section 10.5.2
Selected summaries will be repeated broken out by 
age group, i.e., for ages <6 years and 6 to 18 
length of the longest seizure-free interval will be 
presented for each treatment group.
Section 10.5.1.3
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as a 
gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance.
Section 10.5.2
Selected summaries will be repeated broken out by age 
group, i.e., for ages <6 years and 6 to 18 years.
Rationale: To clarify inclusion criterion #7 regarding the requirement for a whole blood sample for a broad 
epilepsy-related gene panel.
Original Text
Amendment Text
Synopsis, Section 4.1
Subject agrees to provide whole blood sample for a 
Dravet syndrome genetic testing panel, if genetic 
screening results from an acceptable commercial 
laboratory or medical center are not available for 
SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, 
GABRD, GABRG2, and PCDH19.
Synopsis, Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel Dravet 
syndrome genetic testing panel, if genetic screening 
results from an acceptable commercial laboratory or 
medical center are not available for SCN1A, SCN1B, 
SCN2A, SCN8A, SCN9A, GABRD, GABRG2, and 
PCDH19.
Rationale: To add the assessment of cognition for subjects 5 years of age, so that all study participants are now 
being assessed for cognition using the BRIEF, and to move the description of the BRIEF from the efficacy 
section to the safety section.
Original Text
Amendment Text
Synopsis, Section 2.4
The safety objective of the study is:
o
To compare the safety and tolerability of ZX008
0.2 and 0.8 mg/kg/day to placebo with regard to 
adverse events (AEs), laboratory parameters, 
physical examination, neurological examination, 
vital signs (blood pressure, heart rate, 
temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms 
(ECHO), and body weight. Cognitive Function 
will be assessed in subjects 5 years and older 
using the cognition domain score on the QOLCE. 
Cognitive function in subjects <5 years at 
baseline will be assessed using the Brief Rating 
Inventory of Executive Function-Preschool 
version (BRIEF-P).
Synopsis, Section 2.4
The safety objective of the study is:
o
To compare the safety and tolerability of ZX008 0.2
and 0.8 mg/kg/day to placebo with regard to adverse 
events (AEs), laboratory parameters, physical 
examination, neurological examination, vital signs 
(blood pressure, heart rate, temperature, and 
respiratory rate), electrocardiograms (ECG), 
echocardiograms (ECHO), and body weight. 
Cognitive Function will be assessed in subjects 5 
years and older using the cognition domain score on 
the QOLCE.  Cognitive function in subjects <5 
years at baseline will be assessed using age- 
appropriate versions of the Brief Rating Inventory 
of Executive Function-Preschool version (BRIEF- 
P).
PUBLIC 
mple for a
ple for 
if geneti
if genet
e commer
commer
not availa
not availa
N8A, SC
N8A, SC
9
COPY
lec
e
group, 
group
g the requ
g the re
PY
CO
C
This document
0
rse eve
e eve
hysical ex
sical e
vital sig
vital sig
temp
temp
elel
do
cannot
4
ive of the
 of the
re the saf
the sa
8 mg/k
mg/k
t
ot t
ot be
nt
using th
ng t
b
used 
N9A, 
A, 
of cog
of cog
us
to 
al
e for
for 
suppo
Synopsi
Synop
pp
Subje
Subj
br
br
port 
Amendmen
mendm
rt
po
up
any 
mari
ar
for ages 
for age
ment
ent for a
fo
any marketing 
here ea
re e
it. If any te
t. If any t
ng
Į=0.05 lev
=0.05 l
tin
an achieve 
an achiev
ke
s wi
s
authorization 
atekeeper
keepe
atat Į=0.0
=0.0
ort the pr
t the pr
rategy s
ategy s
ch
ch
tio
application
ty and
an
/day to pl
day to p
(AEs), 
AEs), lab
l
amination, 
nation
s (blood pr
s (blood 
rature, and 
ture, a
ctrocardiog
ocardi
ECHO), an
CHO), 
be a
be
and 
tudy is:
udy is
d tol
to
d any 
on
o
RIEF, an
RIEF, 
an extensions
s,
ect agre
agre
oad epile
ad epile
syndrom
yndrom
io
result
resul
si
me
me
n
en
n for s
for s
ex
or 
Section
ectio
o
es
or
Te
T
or variations 
l be
be repe
repe
<6 years 
6 years 
a whole b
whole 
ria
xt
v
thereof.
ma
ecifies a
ifies 
est acts a
st acts a
st fails to
fails t
re
vel, then n
then 
her
statistica
tatistica
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 168 of 182
Synopsis (Criteria for Evaluation/Safety)

The cognition domain of the QOLCE will 
also be used to track cognitive function 
relative to baseline in children 5 years and 
older. The BRIEF-P will be administered to 
children younger than 5 years to track 
cognitive function.
Table 1 was updated and is not presented here. 
Section 2.7.2
The safety endpoints of the study are:

Behavior Rating Inventory of Executive Function, 
Preschool Version ( BRIEF-P) to measure 
cognition in subjects aged 2 to < 5 years at 
baseline

Cognition subscale of QOLCE will be used to 
assess cognitive function for children aged 5 
years and older at baseline
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

BRIEF-P for subjects < 5 years (Appendix 3)
Section 7.1.12
The BRIEF-P is a standardized, validated rating scale 
to measure executive function in preschool aged 
children within the home and school environments 
that will be assessed according to the schedule in 
Table 1. The BRIEF-P measures multiple aspects of 
executive functioning; scales include Inhibit, Shift, 
Emotional Control, Working Memory, and 
Plan/Organize.
Appendix 3 was updated and is not presented here.
Synopsis (Criteria for Evaluation/Safety), Section 2.7.2

The cognition domain of the QOLCE will also 
be used to track cognitive function relative to 
baseline in children 5 years and older. The 
BRIEF-P will be administered to children 
younger than 5 years to track cognitive 
function.
Table 1 was updated and is not presented here. 
Section 2.7.2
The safety endpoints of the study are:

Behavior Rating Inventory of Executive Function, 
Preschool Version ( BRIEF-P) to measure cognition 
in subjects aged 2 to < 5 years at baseline

Cognition subscale of QOLCE will be used to 
assess cognitive function for children aged 5 years 
and older at baseline
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

BRIEF-P for subjects < 5 years (Appendix 3)
Section 7.2.12
The BRIEF-P is a standardized, validated rating scale to 
measure executive function in preschool aged children 
ages 2-18 years within the home and school 
environments; that it will be assessed according to the 
schedule in Table 1. The BRIEF-P measures multiple 
aspects of executive functioning; scales include Inhibit, 
(control impulses; stop behavior), Shift (move freely 
from one activity/situation to another; transition; 
problem-solving flexibility), Emotional Control 
(modulate emotional responses appropriately), 
Initiate (begin activity; generate ideas), Working 
Memory (hold information in mind for purpose of 
completing task), Plan/Organize/Organization of 
Materials (anticipate future events; set goals;  
develop steps; grasp main ideas), and Monitor (check 
work; assess own performance).
Appendix 3 was updated and is not presented here.
Rationale:  To update contraception requirements for the study.
Original Text
Amendment Text
Section 4.4
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until
Section 4.4
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until
PUBLIC 
ed:
d:
rs (Appen
rs (Appe
validat
validat
rere
COPY
C
Y
ass
as
Y
OP
This document 
A
do
cannot
rking M
king M
be
o 
res mu
s mu
s includ
includ
M
used 
d rating
atin
chool age
ool age
l environ
nviron
he sch
he sch
i
to 
g s
sup
ix 3)
x 3)
upport 
Sections
Section
pp
The f
The 
up
any 
n subs
n sub
y
cognitive
cognitiv
ny
older at b
lder a
a
marketing 
resente
sent
the study a
the stud
Inventory 
nventor
rk
rsion ( BRI
ion ( BR
ma
ged 2 to <
ged 2 t
m
cale
authorizati
lso o 
at
ve to
ve to
za
The
he
hildren
dren
hor
gnitive
nitive
ed
tion 
tio
application 
ix 3 w
x 3
and 
mory
ory
any 
ulel
aspect
aspec
nhibit, Sh
nhibit, S
, and 
and
exten
ale
ments
nts
e inin
ensions
ollowin
owi

BR
BR
Sectio
Secti
ns
Th
Th
en
or 
1.3, 6.
1.3, 6
o
ng
variations 
of Ex
f Ex
s
IEF-
F-P) to
P) to
ns
< 5 years
< 5 year
on
e of QOL
of QOL
ati
e function
functio
ia
baseline
seline
ar
thereof. 
ere.
re:e:
ecu
ecu
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 169 of 182
90 days after the last dose of study medication.
Two or more of the following methods are acceptable 
and must include at least 1 barrier method:

Surgical sterilization (i.e., bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects 
or partners)

Placement of an intrauterine device or 
intrauterine system

Hormonal contraception (implantable, patch, oral, 
injectable)

Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm 
or cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository)
Male subjects who have been sterilized or have 
partners of non-childbearing potential (including 
homosexual men) are required to use one barrier 
method of contraception (condom). This is to prevent 
unintended exposure of the partner to the study drug 
via seminal fluid.
Male subjects who have pregnant partners are 
required to use one barrier method of contraception 
(condom).
Alternatively, true abstinence is acceptable when it is 
in line with the subject’s preferred and usual lifestyle. 
If a subject is usually not sexually active but becomes 
active, they, with their partner, must comply with the 
contraceptive requirements detailed above.
Female subjects of non-childbearing potential, i.e., 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 
6 months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
(e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study.
90 days after the last dose of study medication.
Two or more of the following methods are acceptable 
and must include at least 1 barrier method:

Surgical sterilization (i.e., bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects or 
partners)

Placement of an intrauterine device or intrauterine 
system

Hormonal contraception (implantable, patch, oral, 
injectable)

Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository)
Male subjects who have been sterilized or have partners 
of non-childbearing potential (including homosexual 
men) are required to use one barrier method of 
contraception (condom). This is to prevent unintended 
exposure of the partner to the study drug via seminal 
fluid.
Male subjects who have pregnant partners are required 
to use one barrier method of contraception (condom).
Alternatively, true abstinence is acceptable when it is in 
line with the subject’s preferred and usual lifestyle. If a 
subject is usually not sexually active but becomes 
active, they, with their partner, must comply with the 
contraceptive requirements detailed above.
Female subjects of non-childbearing potential, i.e., 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 6 
months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
(e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study.
Male subjects who are sexually active with a partner 
of child-bearing potential must use, with their
PUBLIC 
ave
ve
cluding
uding 
ne barrie
ne barrie
This is to
This is to
er to the 
er to the 
COPY
OP
su
Y
the
th
Y
This document 
o
e subject
subjec
men who
en who
spontaneo
ontaneo
anothe
anothe
6 m
6 m
[
cannot
nence 
ence 
ect’s pref
t’s pre
ally not
ly not s
ith their p
their p
require
equire
be 
od
s
used 
partners a
rtners a
of con
of con
to
preve
ev
dy drug
dy dru
support 
up
ent
ent
t
erv
foam/g
foam/
rt
Male su
Male s
p
of no
of no
pp
me
m
any 
eithe
eith
y
bject’s us
bject’s u
ny
ical/vau
cal/va
a
gel/
marketing 
devic
evic
g
on (implan
n (impl
eti
s (for male 
for mal
ark
heir partner
r partn
ma
or cervic
or cerv
m
r the
t
authorization 
tio
able
able
za
al
h
y for fem
for fem
th
or male su
male su
ut
e o
application 
rtne
ments deta
nts det
of non-chil
non-ch
re post-me
re post-m
us amenorrh
amenor
cause or sp
ause or
ths confir
hs confir
esult 
esu
and
ccep
cep
red and 
ed and 
xually act
ually ac
r, mu
r, mu
any 
ce
table w
table
extensio
en
eption
ption
ons
bj
n-child
child
s
en) are re
n) are re
ns
contrace
ontrace
io
expos
expo
s
flu
flu
n
or 
cts wh
cts wh
o
b
variations 
subjec
ubje
s
’s use of 
use of
ns
cal/vault c
al/vault 
io
eir part
r partne
ne
ati
se of an o
of an o
ia
lt caps] w
caps] w
ar
ilm/c
lm/crea
rea
va
thereof. 
bjec
j
intrauter
trauter
eo
ntable, pa
ntable, pa
he
ctst
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 170 of 182
partner, a condom plus an approved method of 
highly effective contraception from the time of 
informed consent until 90 days after study discharge.
The following methods are acceptable:

Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception 
associated with inhibition of ovulation:

oral

injectable

implantable intrauterine device

intrauterine hormone-releasing 
system

Surgical sterilization (vasectomy or bilateral 
tubal occlusion)
Female subjects who are not of child-bearing 
potential do not need to use any methods of 
contraception. A woman is considered of 
childbearing potential, unless they are at least 2 
years post-menopausal or permanently sterile. 
Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy.
Female subjects who are sexually active and are of 
child-bearing potential must use, with their partner, 
an approved method of highly effective 
contraception from the time of informed consent 
until 30 days following the last follow up visit.
The following methods are acceptable:

Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception 
associated with inhibition of ovulation

oral

injectable

implantable intrauterine device
PUBLIC COPY 
OP

This document 
o
cannot be used to support 
up
rt
Surgic
Surgi
tubal
tub
Fem
Fem
p
any 

im
i

in
in
marketing 
al
malal
hormonal
hormon
inhibition
nhibit
oralal
injectab
injec
pl
authorization 
tio
harge.
harge.
gen 
en 
ption ass
on ass
application and any extensio
en ions
male sub
le sub
otential 
otential 
contrac
contra
child
chil
y
or
cclusi
cclus
variations 
n of ov
of o
ble
ble
lantable 
lantable
ntrauteri
rauteri
system
system
teriliza
eriliza
thereof. 
ciat
contrac
ontrac
ul

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 171 of 182

intrauterine hormone-releasing
system

Surgical sterilization (vasectomy or bilateral 
tubal occlusion)
Alternatively, true abstinence is acceptable when it is 
in line with the subject’s preferred and usual 
lifestyle. If a subject is usually not sexually active but 
becomes active, they, with their partner, they must 
comply with the contraceptive requirements detailed 
above.
Rationale:  To clarify when subjects must be discontinued from the study.
Original Text
Amendment Text
Section 4.5
Subjects may be discontinued from the study for the 
following reasons, if deemed appropriate by the 
sponsor or investigator: (list of reasons is unchanged).
Section 4.5
Subjects may must be discontinued from the study for 
the following reasons, if deemed appropriate by the 
sponsor or investigator:  (list of reasons is unchanged).
Rationale: To clarify that the investigator may discontinue a subject from the study in the case of a medical 
emergency.
Original Text
Amendment Text
Section 5.6
The blinding scheme instituted for this study will 
ensure that the volume of study medication taken 
cannot be associated with the dose group, thus 
unblinding the study. This is achieved by random 
assignment of different concentrations of the ZX008 
oral solution (1.25 mg/mL, 2.5 mg/mL, and/or
5 mg/mL) by the IVR/IWR system. The IVR/IWR 
system will instruct site personnel to the volume of 
oral solution to be administered based on that 
subject’s weight. (Dose will be recalculated by the 
system once at the midpoint of the study.) During the 
Titration, Maintenance, Taper/Transition Periods, the 
subjects and study personnel (investigators, clinical 
staff, personnel involved in data collection and 
analysis, the Medical Monitor, and the sponsor) will 
be blinded to the treatment allocation and to the 
concentration of ZX008 oral solution. The Medical 
Monitor will have the ability to unblind subjects in the 
case of an emergency.
Section 5.6
The blinding scheme instituted for this study will ensure 
that the volume of study medication taken cannot be 
associated with the dose group, thus unblinding the 
study. This is achieved by random assignment of 
different concentrations of the ZX008 oral solution 
(1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) by the 
IVR/IWR system. The IVR/IWR system will instruct 
site personnel to the volume of oral solution to be 
administered based on that subject’s weight. (Dose will 
be recalculated by the system once at the midpoint of 
the study.) During the Titration, Maintenance, 
Taper/Transition Periods, the subjects and study 
personnel (investigators, clinical staff, personnel 
involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the 
treatment allocation and to the concentration of ZX008 
oral solution. The Medical Monitor will have the ability 
to unblind subjects in the case of an emergency. If an 
investigator feels the blind should be broken, he/she 
can do so when necessary for treatment
decisions. However, the investigator should 
endeavor to discuss with the Medical Monitor or 
Sponsor’s Medical Representative, if available. The 
blind should only be broken in the event the 
knowledge of whether the subject is on active study 
medication versus placebo is needed to determine 
course of medical treatment for the event. The 
subject will be discontinued from the clinical trial
PUBLIC 
udy will
udy will
ation take
ation tak
group, thu
roup, th
hieved by 
ieved by
rations
ratio
/
C COPY
he fol
f
sponsor
spons
P
ntinue a 
ntinue 
PY
CO
C
This document
e M
d to the
to the
ntration o
ration 
onitor wil
itor wi
case of a
ase of a
do
cannot
ill 
point of
oint of
nce, Ta
e, Tape
pe
a
y personn
personn
el involve
involv
Medica
edica
be
nel 
ed base
bas
be rec
be re
used
an
f the ZX
he Z
L, and/or
and/or
m. The IV
The IV
o the 
o the
to 
dom
dom
X0
suppo
Section
Secti
port 
bj
Amendme
mendm
ort
pp
The b
The 
th
po
up
any 
reaso
reas
investiga
investig
ct from
ct fro
an marketing 
t 
r partn
partn
ive require
ve requir
et
ke
ust 
st be dis
be d
ns
ar
authorization 
al
table whe
ble wh
and usua
d usua
sexuall
xuall
e
tio
application
in da
n d
Monitor, a
Monitor,
eatment all
atment 
ZX008 or
X008 
have the ab
have the 
emergency
mergen
and
e stud
stu
Transitio
ransitio
(investi
investi
ta c
a c
any 
lum
um
that 
that 
ulated by
ulated by
dy.) D
y )
exten
08 
IWR 
WR 
me of
me of
ensions
5.
s
blinding
indin
at the vo
t the vo
associat
ssocia
study
study
didi
en
or 
t Tex
T
or variations 
scontinue
scontinu
if deeme
deeme
ator: 
or: (list
(lis
s
the study
he study
ria
t
v
thereof.
active b
ctive b
they mu
hey mu
ements d
ents d
he
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 172 of 182
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
o
ori
tio
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 173 of 182
APPENDIX 12 – PROTOCOL AMENDMENT 3 
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 
x
Removed atonic seizures and added tonic-atonic from the types of convulsive seizures in 
Inclusion Criterion #5. 
x
Removal of Inclusion Criterion #7 to clarify that participation in the epilepsy-related genetic 
testing is not required for participation. 
x
Updated the preclinical data information and, based on this information, revised the list of 
prohibited concomitant medications. 
x
Clarified that the number of convulsive seizures during the 6-week baseline period is  6. 
x
Added PedsQL Family Impact module to the efficacy measures. 
x
Clarify study days of Screening during the Baseline Period and the timing of assessments in 
that period. 
x
Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening. 
x
Added the list of countries in which Diacomit® (stiripentol) is approved. 
x
Added supporting references to existing citations of data. 
x
Clarified the safety objective. 
x
Specify that the number of study centers is approximate. 
x
Clarified the duration of use of contraception after the last dose of study drug. 
x
Removal of social media policy from the reason or removing a subject from therapy or 
assessment. 
  
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale:  To clarify the types of seizures that satisfy the requirement for the 12 weeks before screening.
Original Text
Amendment Text
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures 
(tonic-clonic, tonic, atonic, clonic) per 4-week 
period for past 12 weeks prior to screening, by 
parent/guardian report to investigator or 
investigator medical notes. 
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures 
(tonic-clonic, tonic, tonic-atonic, clonic) per 4-week 
period for past 12 weeks prior to screening, by 
parent/guardian report to investigator or investigator 
medical notes. 
Rationale:  Remove the requirement for participation in epilepsy-related gene testing from the inclusion 
PUBLIC
which 
which D
es to 
es to ex
ex
ective.
ctive.
ber of st
ber of s
f u
f
COPY
e efe
e Base
e Basel
epsy gen
psy gen
This document
such a
uch a
of conte
conte
Ratio
Ratio
um
Or
Or
oc
do
do
do
cannot
h chang
chang
Change
hange
marke
marke
s t
be used 
udy c
dy 
se of con
of co
a policy
a policy
to 
cent
cent
support 
otyp
ype pa
e p
iacomit® 
comit®
ting citat
ng citat
any 
mea
me
Period 
Period
marketing 
epilepsy
pileps
ormation,
ormation
he 6-week
e 6-we
asures
asur
authorization 
ive seizu
e seiz
application 
in bold
bol
he correct
e correc
ts, and lis
s, and 
ale: 
le: To c
To
p
nal Text
al Te
app
n C
a
and 
/clari
lari
any 
ficat
fic
extensions
® (stiri
stiri
tions of 
ons of 
ers is app
s is app
traceptio
aceptio
from th
om th
or 
pe
variations 
k baseli
baseli
k
es. 
and the 
nd the 
is ma
is ma
thereof. 
re
-related 
elated
revised
revised

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 174 of 182
criteria.
Original Text
Amendment Text
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Rationale:  Revised the list of prohibited concomitant medications.
Original Text
Amendment Text
Exclusion Criterion 8, Synopsis and Section 4.2
Subject is receiving concomitant therapy with: 
centrally-acting anorectic agents; monoamine- 
oxidase inhibitors; any centrally-acting compound 
with clinically appreciable amount of serotonin 
agonist or antagonist properties, including serotonin 
reuptake inhibition; atomoxetine, or other centrally-
acting noradrenergic agonist; cyproheptadine, 
and/or cytochrome P450 (CYP) 2D6/3A4/2B6 
inhibitors/substrates (see Appendix 1). (Note: Short-
term medication requirements will be handled on a 
per case basis by the Medical Monitor.)
Exclusion Criterion 8, Synopsis and Section 4.2
Subject is receiving concomitant therapy with: 
centrally-acting anorectic agents; monoamine- 
oxidase inhibitors; any centrally-acting compound 
with clinically appreciable amount of serotonin 
agonist or antagonist properties, including serotonin 
reuptake inhibition; atomoxetine, or other centrally-
acting noradrenergic agonist; or cyproheptadine, 
and/or cytochrome P450 (CYP) 2D6/3A4/2B6 
inhibitors/substrates (see Appendix 1). (Note: Short- 
term medication requirements will be handled on a 
per case basis by the Medical Monitor.)
Rationale:  Clarified that the number of convulsive seizures during the 6-week baseline period is ш 6.
Original Text
Amendment Text
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with 
>6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks and
2 in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet the 
study entry criteria and confirm they have experienced 
>6 convulsive seizures during the 6-week Baseline 
Period, with at least 2 seizures in each 3-week half of 
the Baseline Period. 
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with > 
ш6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks and 
2 in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet the 
study entry criteria and confirm they have experienced 
6 >6 convulsive seizures during the 6-week Baseline 
Period, with at least 2 seizures in each 3-week half of 
the Baseline Period. 
Rationale:  Added PedsQL Family Impact module to the efficacy measures.
Original Text
Amendment Text
Synopsis, Criteria for Evaluation: Efficacy
Not applicable 
Section 2.3, Additional Secondary Objectives 
Not applicable 
Section 2.7.1, Efficacy Endpoints 
Not applicable 
Section 6.1.3, 6.2.9 
Not applicable 
Synopsis, Criteria for Evaluation: Efficacy
PedsQL Family Impact module to measure changes 
in quality of life of the parent/caregiver 
Section 2.3, Additional Secondary Objectives 
The change from baseline in the PedsQL Family 
Impact module score. 
Section 2.7.1, Efficacy Endpoints 
PedsQL Family Impact module to measure changes in 
quality of life of the parent/caregiver 
Section 6.1.3, 6.2.9
PedsQL Family Impact module (Appendix 6) 
Rationale:  Clarify study days of Screening during the Baseline Period.
Original Text
Amendment Text
Table 1: Schedule of Assessments 
a: 
The Baseline Period is comprised of the initial screening for the study
Table 1: Schedule of Assessments 
a:
The Baseline Period is comprised of the initial screening for the study and
PUBLIC
nopsis a
nopsis
C
ine with
ine with
e 6-week
e 6-week
n the firs
n the fir
C COPY
nhibi
hi
Y
term m
term 
per 
p
OP
lsive seiz
lsive se
OP
CO
C
This document 
cable
abl
ion 2.3, A
 2.3, 
me
Not applic
t applic
Secti
Sect
oc
N
do
can
iteria for
eria fo
cannot 
zur
zur
d PedsQL
PedsQL
o
nn
an
be
m the
ng the 6-
ng the 6
es in 
es in
used 
3 3
that subje
at sub
ey ha
ey ha
to 
Baselin
seli
weeks 
weeks
support 
ase
ures duri
s dur
t
Amendm
mend
ort
ne
ne
Rando
Ran
pp
Sect
Sec
p
S
po
up
any 
ubstrat
bstr
y
ication re
ication 
basis b
basis
ng
a
marketing 
th
nts; mon
; mo
trally-actin
rally-actin
le amount
amou
prop
roperties,
erti
; atomoxe
atomox
ergic agoni
gic ago
ome P450
me P4
m
es
authorization 
tio
for a
for a
zatio
tio
ori
ho
d Section
Section
au
herapy 
erapy 
th
application
Evalua
valu
n
dditional S
ditional 
ca
ble 
le
n 2.7.1, E
2.7.1, Ef
ap
pplicable
plicabl
a
atio
ti
and 
Family I
amily I
d
an
a
any
exp
xp
ek Basel
ek Base
h 3-week
h 3-week
extensions 
nd
s meet th
meet t
erie
erie
mi
s
ion 4.3
on 4.3
ns
Subject de
bject d
ш6 conv
con
Peri
Peri
2
en
or 
nt Te
nt T
zation
ation
or variations 
tine, o
ne, o
ist; or
or cy
cy
0 (CYP) 
0 (CYP)
io
(see A
ee App
pp
equireme
quirem
by the Me
the Me
the 6-w
he 6-w
a
x
v
thereof. 
.2.
f
with:
th:
amine-
mine-
ng compo
comp
of serot
f serot
includin
ncludi
r o
r o

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 175 of 182
and the assessment of baseline seizure activity recorded daily in the diary. 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -42 to -41):
the assessment of baseline seizure activity recorded daily in the diary. The 
procedures to be completed at the Screening visit may be completed in a 
single day or split so that they are completed over the 2-day period (i.e., 
Days -43 to -42 or Days -42 to -41). 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41):
Rationale:  Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening.
Original Text 
Amendment Text 
Table 1: Schedule of Assessments 
Table 1: Schedule of Assessments 
     l.  Mandatory one time collection any time during or after screening. 
Rationale:  Added the list of countries in which Diacomit® (stiripentol) is approved.
Original Text
Amendment Text
Section 1.1.1, Existing Treatment for Dravet 
Syndrome 
To date, only one treatment, Diacomit® (stiripentol) is 
approved, and only in Europe as adjunctive therapy in 
patients with severe myoclonic epilepsy in infancy 
(SMEI, Dravet syndrome), and must be 
co-administered with clobazam and valproate. 
Stiripentol has not been approved for use in the United 
States of America, but is available under 
compassionate use protocols at certain clinical sites. 
Section 1.1.1, Existing Treatment for Dravet Syndrome 
To date, only one treatment, Diacomit® (stiripentol) is 
approved, and only in Europe, Canada, Japan, and 
Australia, as adjunctive therapy in patients with severe 
myoclonic epilepsy in infancy (SMEI, Dravet syndrome), 
and must be co-administered with clobazam and 
valproate. Stiripentol has not been approved for use in 
the United States of America, but is available under 
compassionate use protocols at certain clinical sites. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Existing Treatment for Dravet Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved 
prospective observation trial) for the treatment of DS; 
the efficacy and safety of this therapeutic approach 
have been published in a peer reviewed journal and 
reported to be very favorable. There are no treatments 
specifically approved for the treatment of DS in the 
United States of America (USA). Accordingly, there 
remains an unmet need for an approved treatment for 
children with DS. 
Section 1.1.1, Existing Treatment for Dravet Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved 
prospective observation trial) for the treatment of DS; the 
efficacy and safety of this therapeutic approach have 
been published in a peer reviewed journal 
(Ceulemans 2012; Ceulemans 2016) and reported to be 
very favorable. There are no treatments specifically 
approved for the treatment of DS in the United States of 
America (USA). Accordingly, there remains an unmet 
need for an approved treatment for children with DS. 
Rationale:  Revised the preclinical data section.
Original Text
Amendment Text
Section 1.3, Preclinical Data 
The pharmacokinetics of fenfluramine, 
norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The 
pharmacokinetics in humans differs from that of other 
species, with a longer duration of exposure to both the 
parent and the metabolite. In vitro metabolism studies 
have shown that there are large species differences in 
Section 1.3, Preclinical Data 
The pharmacokinetics of fenfluramine, norfenfluramine 
and their respective isomers has been studied in mice, 
rats, dogs and humans. The pharmacokinetics in humans 
differs from that of other species, with a longer duration 
of exposure to both the parent and the metabolite. In vitro 
metabolism studies have shown that there are large 
species differences in pharmacokinetics and metabolism 
PUBLIC
. 
n the Un
n the U
r r 
in clinica
n clinica
referenc
referenc
B
U
for D
for
P
COPY
o d
approv
appr
Austr
Austr
my
m
OP
This docu
Sect
Sect
ocument
ates o
es
s an unm
an unm
dren with
n with
Rationale
tiona
me
Origin
Origin
um
T
cu
do
cannot
trial)
ria
y of this 
of this 
ed in a pe
d in a pe
ery favor
ry favor
pproved
proved
of A
of A
be
prove
ove
vernment
vernmen
 for 
 for
used
avet Syn
vet Syn
ed
been use
een us
at 2 acad
2 acad
d pr
d pr
d to
to an e
to an 
to
t
support 
d 
es. 
s. 
clon
lon
d must b
must 
valproate
valproa
the Un
the U
com
com
up
xist
i
s
any 
one
n
nd only
nd on
a, as adju
, as adju
ic epile
ic ep
marketing 
ny time
time durin
du
pproved.
proved
ket
rk
xisting Tre
sting T
m
e treatm
e trea
i
a
authorization 
-41):
1):
tio
d at 
at 
riz
th
ut
app
on 1.3, Prec
1.3, Pre
application 
bl
or ththe t
e 
merica (U
erica (USA
t need for a
need for
DS. 
S. 
Revised 
Revise
ica
al Text
Text
pli
harmac
armac
pp
and
he
herapeu
apeu
r reviewe
eviewe
e. Ther
 Ther
any 
col u
col 
proved 
proved 
treatmen
reatm
tic a
ti
extensions
nited
mpassion
assion
ting citat
ng citat
io
Am
Am
si
en
rome 
ome
te
as an
s an 
ic medi
c med
nd
S
en
en
or
o
Stiripe
Stirip
State
Stat
variations s
eatment fo
tment fo
on
ment, Dia
ent, Dia
n Europe
n Europe
unctive th
tive th
epsy in in
sy in i
-admin
-admin
ns thereo
g or after sc
 after s
the
t
of. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 176 of 182
pharmacokinetics and metabolism of fenfluramine 
after oral administration. In humans, fenfluramine is 
metabolized to norfenfluramine. CYP2C19 and 
CYP2D6 appear to be the predominant CYP enzymes 
that metabolize fenfluramine to norfenfluramine. 
CYP1A2, CYP2B6 and CYP3A4/5 also appear to be 
involved, but to a lesser degree. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s 
mechanistic static model, ZX008 is predicted to 
potentially cause clinically significant inhibition of 
CYP2D6 in the range of doses that will be 
administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s 
mechanistic static model, ZX008 is predicted to 
potentially cause clinically significant inhibition of 
CYP2D6 in the range of doses that will be 
administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
of fenfluramine after oral administration. In humans, 
fenfluramine is metabolized to primarily 
norfenfluramine. CYP2C19CYP1A2, CYP2B6, and 
CYP2D6 appear to be the predominant CYP enzymes 
that metabolize fenfluramine to norfenfluramine. 
CYP2C9, CYP2C19, and CYP3A4 also appear to be 
involved, but to a lesser degree. There is also some 
contribution of renal clearance to the elimination of 
dexfenfluramine (8%-16%) and nordexfenflurmaine 
(7%-8%) from the body. Because fenfluramine and its 
active metabolite norfenfluramine have multiple 
pathways of elimination, interference with a single 
pathway is unlikely to cause a significant change in 
fenfluramine’s clearance though the probability of an 
interaction increases if multiple elimination mechanisms 
are affected simultaneously. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s mechanistic 
static model, ZX008 is predicted to potentially cause 
clinically significant inhibition of CYP2D6 in the range 
of doses that will be administered (ZX008 IB 2016). 
ZX008 is also predicted to cause a clinically significant 
induction of CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
While in vitro studies showed that both fenfluramine 
and norfenfluramine cause weak inhibition of 
CYP2D6 and fenfluramine causes weak induction of 
CYP3A4 and CYP2B6, further analysis based on the 
FDA’s mechanistic static model shows that 
fenfluramine and its major metabolite 
norfenfluramine are unlikely to alter the 
pharmacokinetics of substrates of these CYP450 
enzymes in the range of ZX008 doses that will be 
administered in this study. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy 
in the 1980s (Aicardi and Gaustaut 1985; Aicardi 
1988) and its successful treatment of 11 refractory 
pediatric epilepsy patients in Belgium (Boel 1996), in 
2002 Drs. Ceulemans and Lagae were granted 
authorization to prescribe fenfluramine to their patients 
with refractory pediatric epilepsy conditions, including 
DS, under an approved protocol under a Belgium 
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy in 
the 1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and 
its successful treatment of 11 refractory pediatric 
epilepsy patients in Belgium (Boel 1996), in 2002 Drs. 
Ceulemans and Lagae were granted authorization to 
prescribe fenfluramine to their patients with refractory 
pediatric epilepsy conditions, including DS, under an 
approved protocol under a Belgium government program 
PUBLIC 
bitio
biti
ction of 
tion of
DA’s 
DA
predicted
predicted
ficant inh
ficant inh
that will
that will
ZX0
ZX
COP
nt 
at both 
at both 
n of 
n of
OPY
viv
Y
fenflur
fenfl
PY
CYP
C
OP
CY
C
OP
This docume
Section 1
ection 
um
Based
Based
suc
suc
i
ent 
nale: 
ale: A
nt
iginal T
inal T
en
me
do
cannot 
of CY
CY
be 
abolite
olite
cause c
cause c
P2B
P2B
used 
be
08 is also
is also
ificant ind
cant in
t will be
will be
no
to
o
tion of 
tion of
support 
P3A4
3A4
t
tatic mode
tic mod
or
clinically
clinica
po
of do
of d
pp
ZX
Z
p
up
any 
tion
o
y
ne and n
ne and 
ny
6, while f
, whi
an
and 
an
a
marketing 
e fenfl
fenf
mine have 
mine have
nterference
erferen
cause a sign
ause a si
ance though
ce thou
ses if multi
s if mu
ultaneous
ltaneou
and 
an
m
authorizati
ymes
ymes
e.
pear to be
r to be
also som
also som
liminatio
minatio
dexfenfl
xfenfl
lur
ur
tion 
tio
appl
,
lic
5, Rationa
Ration
pl
on several p
severa
ssful treat
sful treat
980s 
980
lication 
ded a supp
d a su
tio
xt
xt
at
lic
and 
6, 2
6, 
any 
enflura
nflur
ically sign
ically sig
D6 or 3
D6 or
exten
uction of 
tion of 
ensions 
y
ses tha
s tha
s
X008 is al
08 is a
ns
induction
nductio
ion
admin
admin
si
how
how
ns
en
or
ZX
Z
r
signific
ignifi
or
at w
t
o variations
h the
th
ple elimi
le elim
ly. 
ly. 
induction
duction
tio
rfenflura
fenflura
ia
fenfluram
nfluram
ari
CYP2B6
YP2B6
va
X008
X00
v
thereof. 
o
rmaine
maine
mine and 
ine and
multiple
ultipl
e with a s
ith a 
nificant c
ificant c
prob
pro

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 177 of 182
government program (Royal Decree). To date, these 
pediatric neurologists have DS patients (infants, 
children, young adults, and now also adults), being 
successfully treated with fenfluramine for over 
27 years. The efficacy and safety of this therapeutic 
approach has been reported to be overwhelmingly 
favorable. In the most recent assessment of efficacy of 
these patients reported by the investigators in, the 
average length of treatment was over 12 years, with 
one patient being successfully treated for 26 years. Of 
the 15 DS treated patients, 10 (67%) were reported as 
seizure-free, with the average time of seizure-freedom 
being 6 years (range 1-19 years). Twelve patients 
(87%) had a greater than 90% reduction in seizure 
frequency and 14 patients (93%) with greater than 70% 
reduction in seizure frequency. 
(Royal Decree). To date, these pediatric neurologists 
have DS patients (infants, children, young adults, and 
now also adults), being successfully treated with 
fenfluramine for over 27 years. The efficacy and safety 
of this therapeutic approach has been reported to be 
overwhelmingly favorable. In the most recent assessment 
of efficacy of these patients reported by the investigators 
in, the average length of treatment was over 12 years, 
with one patient being successfully treated for 26 years 
(Ceulemans 2016). Of the 15 DS treated patients, 
10 (67%) were reported as seizure-free, with the average 
time of seizure-freedom being 6 years (range 1-19 years). 
Twelve patients (87%) had a greater than 90% reduction 
in seizure frequency and 14 patients (93%) with greater 
than 70% reduction in seizure frequency.
Rationale:  Clarified the safety objective.
Original Text
Amendment Text
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 
0.2 and 0.8 mg/kg/day to placebo with regard to 
AEs, laboratory parameters, physical examination, 
neurological examination, vital signs (blood 
pressure, heart rate [HR], temperature, and 
respiratory rate), ECGs, ECHOs, and body weight. 
Cognitive Function will be assessed in subjects 5 
years and older using the cognition domain score 
on the QOLCE. Cognitive function will be 
assessed using age-appropriate versions of the 
BRIEF. 
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 0.2 
and 0.8 mg/kg/day to placebo with regard to AEs, 
laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, 
heart rate [HR], temperature, and respiratory rate), 
ECGs, ECHOs, and body weight. Cognitive Function 
will be assessed using the cognition domain score on 
the QOLCE and age-appropriate versions of the 
BRIEF. Cognitive Function will be assessed in subjects 
5 years and older using the cognition domain score on 
the QOLCE. Cognitive function will be assessed using 
age-appropriate versions of the BRIEF. 
Rationale:  Clarify that the number of participating study centers is approximately 30.
Original Text
Amendment Text
Section 3.4, Number of Study Centers 
The study expects to use up to 30 research centers 
in North America. Additional study centers within 
or outside of North America may be added if 
enrollment cannot be completed in a timely 
manner. 
Section 3.4, Number of Study Centers 
The study expects to use up to approximately
30 research centers in North America. Additional study 
centers within or outside of North America may be 
added if enrollment cannot be completed in a timely 
manner. 
Rationale:  Clarified the duration of use of contraception after the last dose of study drug and added barrier 
method to the list of acceptable methods of birth control.
Original Text
Amendment Text
Section 4.4 
Male subjects who are sexually active with a 
partner of child-bearing potential must use, with 
their partner, a condom plus an approved method 
of highly effective contraception from the time of 
informed consent until 90 days after study 
discharge. 
Female subjects who are sexually active and are of 
Section 4.4 
Male subjects who are sexually active with a partner of 
childbearing potential must use, with their partner, a 
condom plus an approved method of highly effective 
contraception from the time of informed consent until 
90 days after the last dose of study drug after study 
discharge. 
Female subjects who are sexually active and are of 
PUBLIC 
nation
nation
ood d
, and 
, and 
nd body w
d body w
ssed in su
sed in su
tion dom
tion dom
on
on
COP
OPY
Syno
S
OP
T
PY
Amen
Ame
Y
PY
OP
This document
of 
ent cann
t cann
er. 
ationale:
ionale
method 
method
e
Orig
Orig
um
o
Se
Se
oc
do
cannot
r of Stud
of Stud
no
s to use u
to use u
rica. Add
ca. Ad
North A
North A
ot 
t
t
ot be 
e numb
e numb
be
b
used 
ain sco
n sc
will be 
be
rsions of t
ons of 
to 
eight
g
cts 5
cts 5
ore
ore
sup
upport 
p
t
compar
ompa
and 0.8 mg
d 0.8 
laborato
labora
neuro
neur
he
h
up
any
s and Se
s and 
a
re th
any 
ent Text
ent Tex
y
any marketing 
S treat
trea
izure-free,
izure-free
eing 6 year
ng 6 ye
had a great
had a gre
and 14
d 14 pat
p
on in seizur
in seiz
m
authorization 
safety
safety
to be
be
nt assessm
asses
the invest
he invest
s over 12
over 12
reated f
eated f
ed
ed
tio
ap
on 4.4 
n 4.4 
a
bjec
bj
application
ional
ona
merica m
erica m
be complet
e comp
Clarified t
Clarified
o the list of
the list
ca
nal Text
 Text
p
app
and 
Centers 
enters
nd
to 30 res
o 30 re
l stud
stu
d any 
of partic
of partic
ny
an exten
e
ensions
ory
ologica
gica
eart rate [
rt rate [
ECGs, E
ECGs, E
will b
will 
th
th
en
or 
kg/da
g/
param
param
l e
varia
ection
tion 2.4
2.
ar
e safety
safety
ay t
riations
ients
nt
re freque
freque
io
at
ria
thereof.
yea
r 26 yea
26 yea
patients,
tients,
with the 
ith th
s (range 
range
er than 9
r than 9
 (93
(93

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 178 of 182
child-bearing potential must use, with their 
partner, an approved method of highly effective 
contraception from the time of informed consent 
until 30 days following the last follow up visit. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition 
of ovulation: 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation 
childbearing potential must use, with their partner, an 
approved method of highly effective contraception 
from the time of informed consent until 30 days 
following the last follow up visit 90 days after the last 
dose of study drug. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation and a barrier method (i.e., condom for 
male partner): 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation and a barrier method 
(i.e., condom for male partner): 
Rationale:  Removal of social media policy.
Original Text
Amendment Text
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can 
influence the expectations of potential new study 
subjects and investigators. Throughout their 
participation in this trial, subjects, their 
parent/caregivers and immediate family members, 
including grandparents, can acknowledge participation 
in the study on social media; however, they will be 
required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it 
can negatively affect the sponsor’s ability to interpret 
study results and possibly to use the study for 
registration. Individuals with serious and/or repeated 
violations of this policy may be required to exit the 
study at the discretion of the sponsor in consultation 
with the principal investigator, without the possibility 
of entering the separate open-label extension study. 
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can influence 
the expectations of potential new study subjects and 
investigators. Throughout their participation in this trial, 
subjects, their parent/caregivers and immediate family 
members, including grandparents, can acknowledge 
participation in the study on social media; however, they 
will be required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it 
can negatively affect the sponsor’s ability to interpret 
study results and possibly to use the study for 
registration. Individuals with serious and/or repeated 
violations of this policy may be required to exit the study 
at the discretion of the sponsor in consultation with the 
principal investigator, without the possibility of entering 
the separate open-label extension study. 
Rationale:  Revised the prohibited concomitant medication and foods list, including Appendix 1.
Original Text
Amendment Text
Section 5.7.4 
Drugs/foods that potentially interact with ZX008 via 
the CYP2D6, CYP3A4, and/or CYP2B6 pathways: A 
list of medications/foods that are to be avoided as 
ongoing medications or for chronic use if initiated 
during the study from the time of signing the informed 
consent form (ICF) until the end-of-study visit (or 
early termination) is provided in Appendix 1. If 
medical necessity requires short-term use of one or 
more of these medications during the course of the 
study, please contact the Medical Monitor for 
approval. 
Section 5.7.4 
Drugs/foods that potentially interact with ZX008 via the 
CYP2D6, CYP3A4, and/or CYP2B6 pathways: A list of 
medications/foods that are to be avoided as ongoing 
medications or for chronic use if initiated during the 
study from the time of signing the informed consent form 
(ICF) until the end-of-study visit (or early termination) is 
provided in Appendix 1. If medical necessity requires 
short-term use of one or more of these medications 
during the course of the study, please contact the Medical 
Monitor for approval. 
Appendix 1: replaced, edits not shown herein. 
PUBLIC 
study 
tudy
heir 
ir
ir 
ir 
mily mem
mily mem
nowledge
nowledge
owever,
owev
or
COP
he
he
OPY
famil
m
Y
Media
Medi
PY
Sect
S
OP
R
OP
This document
on 5.7.4 
 5.7.4 
e
rugs/food
gs/food
the CYP
he CYP
nt 
 
al Text
Text
t
list o
list o
on
on
nt
do
cannot
wit
y may b
may b
on of the 
n of the
l investig
nvestig
e separate
separat
Revise
evise
ca
c
be
or
use the
se the
h serio
h serio
used 
p
hey wi
y w
actual IM
ual IM
y, or toler
or toler
s abilit
abili
to
bers, 
ers,
rticipat
rticipa
ll b
l b
support 
n
t
velation
elation
rt
effect(s) of
fect(s)
or
the expe
the ex
p
inves
inve
pp
su
su
up
any 
uding
din
y
licy as de
cy as d
ny
4.9 
4.9 
a
ns a
mar
members
membe
m
gra
g
arketing 
tracept
acep
nd a barr
nd a barr
rtner)
ner):
et
ke
ar
authorization 
he last
he last
ining)
ng) 
nhibition
nhibition
 condom
ondom
tion
ion
tio
applicati
that poten
that pote
2D6, CYP3
6, CYP
ation
open-
pen
the proh
the proh
n
io
medication
dicatio
ng medic
g med
he s
h
ati
and
equir
qui
ponsor in
onsor in
or, witho
r, with
-labe
labe
any 
o i
o 
dy for 
y for 
and/or rep
and/or rep
red to 
red t
exten
n 
bility as i
lity as i
nterp
nterp
ensio
membe
memb
ons
ec
stigator
gator
s
ubjects, th
jects, th
n
member
member
io
partic
parti
s
w
n
en
or 
unapp
na
r
ations 
ations
o variations 
s of the su
of the 
on
andpare
dparent
ati
escri
cribed 
bed
ia
out clin
out clin
va
pro
v
s thereof. 
for
associate
ssociate
er meth
r met
he
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 179 of 182
Appendix 1: replaced, edits not shown herein. 
Rationale:  Clarify the timing of procedures during the baseline period and screening period.
Original Text
Amendment Text
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 
and Study Day -41 as well as the observation period 
where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity 
entered into a diary. With the exception of the Doppler 
ECHO, which may be completed any time during the 
Baseline Period up to Study Day -21, all screening 
assessments will be completed on Study Day -42 and 
Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study 
Day -42 and Study Day -41 for all subjects before the 
start of seizure activity observation: 
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 and 
Study Day -41 as well as the observation period where 
subjects will be assessed for baseline seizure activity 
based on recordings of daily seizure activity entered into 
a diary. With the exception of the Doppler ECHO, which 
may be completed any time during the Baseline Period 
up to Study Day -21, all screening assessments will be 
completed on Study Day -42 and Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study Day -42 
and Study Day -41 for all subjects before the start of 
seizure activity observation:
The Screening visit will occur on Study Day -42; 
however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study Day
-42 or Study Day -42 and Study Day -41). Splitting 
the visit procedures across 2 nonsequential days 
requires the approval of the medical monitor. The 
following procedures will be performed for all 
subjects before the start of seizure activity 
observation: 
Rationale:  Added text clarifying procedures for rescreening.
Original Text
Amendment Text
Section 6.1.1 
None. 
Section 6.1.1 
In certain circumstances the sponsor may allow subjects 
who did not meet all inclusion/exclusion criteria at the 
time of the Screening Visit to have the screening period 
extended, or to be re-screened for eligibility. In all cases 
the investigator should consult with the Medical Monitor. 
Decisions whether to permit rescreening resides solely 
with the sponsor.  
The decision whether to permit extended screening or 
rescreening can be influenced by many factors individual 
to that subject case. Some general principles apply: 
1.
If baseline seizure screening is extended or the 
subject is discontinued and then rescreened, the 
screening period for establishing the baseline seizure 
frequency will be the immediate 6 weeks before the 
randomization visit. 
2.
Subjects who are found to be on a prohibited 
medication at the screening visit may be weaned off 
of that medication provided: 
a.
Decisions to withdraw a disallowed concomitant
medication must be made with the agreement of 
the prescribing physician 
PUBLIC 
ying pr
ying
PU
P
COPY
eizur
z
Y
The Sc
The S
how
h
2
OP
This document 
do
cannot be used
cedure
dure
d
ed
se
to 
s f
to support 
ve
onsecut
nsecu
-42 or Stu
2 or S
the visi
the vi
requ
requ
fo
fo
up
any 
ity ob
ty o
y
ening visi
ening vi
r, the pr
, the 
tive
marketing 
re
he Dopp
Dop
g
during the B
during the 
ing
creening as
eening 
eti
ay -42 and 
y -42 an
ke
edures will 
ures wi
rk
which will o
ich wil
ma
41 for al
41 for 
m
serv
se
authorization 
tio
tio
tio
 the
he
y Day -42
Day -4
n period w
period w
seizure a
izure a
activity
ctivity
l
at
application and any extensions
t p
uires th
res th
ollowing 
lowing 
subject
subject
obse
obse
n
r rescree
rescree
ns
ten
e
xt
or 
y Da
y D
roced
roced
variations 
be pe
e pe
s
occur bet
cur bet
ns
l subjects
subject
ion
vation:
tion:
ati
it will o
will oc
rocedure
cedure
days (e
days (e
y -
thereof.
tivit
entered 
ntered 
r ECHO, 
ECHO, 
eo
Baseline 
seline
re
ssessmen
ssessmen
he
Study Da
tudy D
th
rfor
fo
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 180 of 182
b.
If the medication has antiepileptic properties, a 
wash out of at least 5 half-lives must be 
completed before collection of baseline seizure 
data.  
c.
If a decision has been made to wean off of a 
medication without antiepileptic properties and 
the wash-out period (at least 5 half-lives) is 
expected to be shorter than 5 weeks, then the 
subject may remain in screening and chart 
seizures using the seizure diary. 
Rationale:  Clarify timing of dosing on Day -1 and Day 1.
Original Text
Amendment Text
Section 6.1.3 
x
Dispense study medication 
Section 6.2.1 
Subjects will begin dosing with IMP in the 
morning of Titration Period Study Day 1. 
Section 6.1.3 
Dispense study medication (If administration of the first 
dose of study medication occurs in the clinic, the next 
dose should be at least 8 hours later or the following 
morning. The dose on the following morning will count 
as Study Day 1.) 
Section 6.2.1 
Subjects will take their first dose of study medication on 
the morning of Study Day 1. Study Day 1 is considered 
the first day of dosing, even for those subjects that 
received an in-clinic dose on Study Day -1. Subjects will 
begin dosing with IMP in the morning of Titration Period 
Study Day 1. 
Rationale:  Revised estimated blood volume collection in Table 8 and text describing volumes for 
collection.
Original Text
Amendment Text
Section 6.5 
The original Table 8 was replaced; edits to this 
table are not shown herein. 
The maximum total blood volume collected during 
the study for clinical laboratory testing, 
genotyping, and PK will be approximately 
108.7 mL, as outlined in Table 8 
Section 6.5 
The original Table 8 was replaced; edits not shown 
herein. A new table, Table 9, showing the priorities for 
blood collection was added.  
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and PK 
will be approximately 108.7 99.7 mL, as outlined in 
Table 8. 
*In concordance with The Seattle Children’s Research 
Foundation Guidance (Appendix 9), blood collection 
volumes for children weighing up to 15 kg will be: 
x
the maximum allowable volume of blood in 
one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 mL.
On Day 43/Visit 8 the pharmacokinetic blood draw will 
be completed as the priority and the blood draw for 
chemistry and hematology will be skipped for those 
subjects who weigh less than 13.5 kg, unless medical 
PUBLIC 
blood v
blood v
UB
P
COPY
morni
mor
as Stud
as Stu
Sect
S
OP
S
OP
This document 
do
cannot
ood 
od vol
vol
al laborat
laborat
PK will b
K will
outlined 
utlined
be 
ced
use
edits
edit
sed 
u
ed
se
to 
me
me col
col
to support 
n
t
bjects w
ects w
the mornin
he morn
the first
the fir
recei
rece
b
up
any 
e dose
dos
Day 1.) 
Day 1.) 
6.2.1 
.2.1 
a
ill
market
dication (If 
cation (I
dication oc
cation o
at least 8 
t least 
on
eting 
ure diar
 dia
g
tin
ket
authorization 
zure
ure 
ff of a 
f of a
roperties 
erties
half-lives)
alf-lives)
weeks, t
weeks, t
ening an
ning an
y
tio
application 
n Tabl
Tab
and 
me coll
col
ry testing
testing
approxi
pproxi
e 8
e 8
any 
thih
lected
ect
extxtensions
t d
ved an 
d an
egin dosi
gin dosi
on
Study D
Study D
io
ction in 
ion in 
sio
te
xt
or 
g of S
g of 
ay of d
y of d
variations 
admin
dmin
ccurs in th
urs in th
hours lat
hours la
n the follo
he follo
ake thei
ke thei
tud
the
nist
ist
hereof. 
en 
d chart 
har
eo
ere
he

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 181 of 182
concerns (for example, from previous tests or reported 
side effects) prioritize chemistry and/or hematology. 
If blood collection is restricted due to volume or due to 
inability to draw adequate volume, collection should be 
prioritized as shown in Table 9:
Rationale:  Clarification of SE as an AE or SAE.
Original Text
Amendment Text
Section 7.1.1 
Seizures that evolve into SE will be captured by 
type and duration (>10 min) as are all seizures. 
The diagnosis of SE should be entered as an AE or 
SAE if a prolonged seizure or series of seizures 
persists for 30 minutes or longer, regardless of 
administration of rescue medication. If this 
incident involves multiple seizures close in time, 
the SE definition applies if the seizures are close 
together such that consciousness is not regained 
between ictal events 
Section 7.1.1 
Seizures that evolve into SE will be captured by type and 
duration (>10 minutes) as are all seizures. The diagnosis 
of SE made by a medical professional should be entered 
as an SAE if a prolonged seizure or series of seizures 
persists for 30 minutes or longer, regardless of 
administration of rescue medication. SE lasting for less 
than 30 minutes should be entered as an AE, unless one 
of the other SAE criteria (e.g. hospitalization) are met. If 
this incident involves multiple seizures close in time, the 
SE definition applies if the seizures are close together 
such that consciousness is not regained between ictal 
events. 
Rationale:  Clarify SAE reporting.
Original Text
Amendment Text
PUBLIC 
C
LI
COPY
of the
th
this inc
this in
SE d
S
su
OP
C
This document cannot be used to supp
Ame
Am
pport 
fin
ch that c
that c
events.
ents.
po
pp
up
up
up
any 
SAE c
AE
ent involv
nt invol
ition ap
tion a
on
marketing 
ll be cap
be ca
e all seizure
all seizur
professiona
rofessio
ed seiz
d seizure o
u
tes or longe
s or lon
f rescue me
escue m
should b
should
rite
i
au
t
authorization 
ue to
to
hould be
ould be
tio
ho
th
au
application and any extensions
endmen
dme
s
ns or 
or 
o variations 
er, reg
, reg
dication. 
cation.
e entered
entere
ria (e.g. h
a (e.g. h
ves multip
s multi
plies if th
ies if th
ciousnes
iousne
thereof. 
red by typ
d by typ
es. The d
The d
al should 
al should
r series 
r series
gard
ard
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 182 of 182
Section 8.6 
For SAEs occurring during the study, the 
investigator or delegate will enter all relevant 
information in the AE page of the eCRF. An 
electronic document containing the AE page and 
other applicable pages of the eCRF must be sent 
(via facsimile or email) to the sponsor together 
with a Notification of Serious Adverse Event at 
Investigator Site cover page, which has been 
signed and dated by the investigator. If an 
electronic document is not able to be generated 
(eg, internet access problem), a handwritten paper 
SAE report must be completed, which must be 
signed and dated by the investigator. 
All SAEs that occur during the course of the study, 
whether or not causally related to IMP must be 
reported immediately via telephone and either 
facsimile or email (within 24 hours of the 
investigator becoming aware of the event) to the 
sponsor and the Medical Monitor. 
Section 8.6 
For SAEs occurring during the study, the 
investigator or delegate will enter all relevant 
information in the AE page of the eCRF. An 
electronic document containing the AE page and 
other applicable pages of the eCRF must be sent (via 
facsimile or email) to the sponsor together with a 
Notification of Serious Adverse Event at 
Investigator Site cover page, which has been signed 
and dated by the investigator. If an electronic 
document is not able to be generated (eg, internet 
access problem), a handwritten paper SAE report 
must be completed, which must be signed and dated 
by the investigator. 
In the event of a SAE the investigator or delegate must:  
1.
Enter all relevant information in the AE page 
of the eCRF. 
2.
Inform the Medical Monitor or the Sponsor of 
the SAE via email or telephone within 
24 hours of becoming aware of the SAE. 
3.
Follow the initial notification with a 
completed SAE report form. The SAE form 
must be emailed or faxed to iHC within 
24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, 
beginning the day Informed Consent is signed, whether 
or not causally related to IMP must be reported 
immediately via telephone or email (within 24 hours of 
the investigator becoming aware of the event) to the 
sponsor or the Medical Monitor 
Rationale: To evaluate a correlation between study drug and SAE. 
Original Text 
Amendment Text 
Section 8.9 
None. 
Section 8.9  In the event of a SAE a blood sample for 
ZX008 and AED PK should be collected as soon as 
feasible.
PUBLIC COPY 
OP
This document
ale:e: To 
To 
t
ginal Tex
nal Te
en
ection 8
ction 8
um
None.
None.
me
do
doc
cannot 
c
be used to support 
2.
tht
2
3
up
any 
r all 
r al
f the eCR
the eC
Inform
Infor
marketing 
an ele
n ele
g
nerated (eg
nerated (e
ng
ritten paper
ten pap
tin
ich must be
ch must 
ke
AE the inv
AE the in
relev
re
authorizati
nd 
ri
sent (via
nt (vi
or
er with a 
r with a
tho
nt at 
at 
ut
has bee
has bee
au
ctr
ctr
tion 
tio
application 
aluate a co
uate a c
tio
at
ica
ap
and any extensions 
.
Fo
Fo
co
co
All
All
en
or
4 hour
4 hou
llo
ll
variations 
vestigator
stigator
vant infor
nt infor
F. 
m the Med
he Me
AE via 
AE via 
thereof.
n signed
igned
f
nic
o
g, interne
intern
re
r SAE rep
AE re
er
signed a
signed a
the

Confidential 
Clinical Study Protocol
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo- 
controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine 
Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and 
Young Adults with Dravet Syndrome 
Study Number: 
ZX008-1502 
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number: 
125797 
EudraCT Number: 
2015-004167-37 
Sponsor: 
Zogenix International Limited  
A wholly owned subsidiary of Zogenix, Inc. 
5858 Horton Street, Suite 455 
Emeryville, CA 94608 USA 
Sponsor's Medical 
Contact 
Date of Study 
Protocol: 
31 October 2016 (Protocol Amendment 2.0) 
11 January 2016 (Protocol Amendment 1) 
30 October 2015 version 1.0 (Original Protocol) 
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. 
PUBLIC 
94608
9460
BLI
PUBL
COPY 
mited 
mited
idia
idiary of
ry o
Suite 4
Suite 4
8 U
8 U
This document cannot 
30 O
30 
be
Januar
nua
Octo
Oct
used 
ber 201
ber 201
to support 
Zogen
oge
55 
SA 
A 
sup
any 
nix, 
nix
marketing 
8 
authorization 
dren and
dren and
application and 
be
be
any 
016 (Pr
016 (P
r 2015 v
201
extensio
(Protoc
Protoc
ons 
ions or variations 
Inc. 
nc.
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 2 of 175
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. 
PUBLIC COPY 
This document cannot be used to support any marketing 
spons
ons
authorization 
16
io
supplie
suppli
or
or
application and any extensions or variations thereof. 
d toto
or the
the

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 3 of 175
TABLE OF CONTENTS 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT OF 
STUDY .............................................................................................................................. 2
TABLE OF CONTENTS ......................................................................................................... 3
SIGNATURE OF SPONSOR ................................................................................................ 11
SIGNATURE OF COORDINATING INVESTIGATOR ..................................................... 12
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) ..................................................... 13
Principal Investigator............................................................................................................................... 13
LIST OF ABBREVIATIONS ................................................................................................ 14
Table 1:Schedule of Assessments (continued)........................................................................................ 25
1.
INTRODUCTION ........................................................................................................... 26
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED ......................................... 26
1.1.1
Existing Treatment for Dravet Syndrome .................................................................................. 26
1.1.2
Other Antiepileptic Medications ................................................................................................ 27
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT .................................................. 27
1.3
PRECLINICAL DATA ............................................................................................................. 28
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT ........................................ 28
1.5
RATIONALE FOR CURRENT STUDY .................................................................................. 29
1.6
RISK-BENEFIT ASSESSMENT .............................................................................................. 29
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 30
2.1
PRIMARY OBJECTIVE ........................................................................................................... 30
2.2
KEY SECONDARY OBJECTIVES ......................................................................................... 30
2.3
ADDITIONAL SECONDARY OBJECTIVES ......................................................................... 30
2.4
SAFETY OBJECTIVE .............................................................................................................. 31
PUBLIC
..........
........
ts (contin
ts (conti
..........
..........
COPY 
GA
IG
IGATO
AT
............
...........
This document 
RAT
RAT
RI
RI
STU
STU
2
cannot
OUND
UND
LINICA
NICA
ACKGRO
CKGR
IO
IO
be 
t fo
ptic Me
ptic Me
used 
.....
...
ORM
RMAT
AT
or Dra
r Dra
to 
ue
......
support
R
..............
..........
.............
.........
d).........
d)......
any 
....
S) ......
S) ...
marketing 
........
.....
.............
.........
.............
........
.......
authorization 
ber 2016
2016
za
CONDU
ONDU
application 
UND
ND
NALE FO
NALE 
K-BENEF
-BEN
DY OBJE
Y OBJ
PRI
PR
and 
NFO
FOR
DATA 
DATA 
IN
IN
any 
t S
cations ..
cations 
RMA
M
extensions 
.......
.....
.............
............
...........
........
ON ON 
N ON 
Syndr
yndr
or 
.....
..
variations
.........
......
...........
........
............
........
.......
thereof. 
CT O
CT
...........
........
...........
..........

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 4 of 175
2.5
PHARMACOKINETIC OBJECTIVE ....................................................................................... 31
2.6
EXPLORATORY OBJECTIVE ................................................................................................ 32
2.7
STUDY ENDPOINTS ............................................................................................................... 32
2.7.1
Efficacy Endpoints ..................................................................................................................... 32
2.7.2
Safety Endpoints ........................................................................................................................ 32
2.7.3
Pharmacokinetic Endpoints........................................................................................................ 33
3.
INVESTIGATIONAL PLAN .......................................................................................... 33
3.1
OVERALL STUDY DESIGN AND PLAN .............................................................................. 33
3.2
NUMBER OF SUBJECTS ........................................................................................................ 33
3.3
STUDY DURATION ................................................................................................................ 33
3.4
NUMBER OF STUDY CENTERS ........................................................................................... 34
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT GROUPS ............ 34
3.6
PREMATURE TERMINATION OF STUDY .......................................................................... 34
3.7
STUDY MONITORING PROCEDURES ................................................................................. 35
3.7.1
Independent Data and Safety Monitoring Committee ............................................................... 35
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) ......................................................... 35
4.
SELECTION OF STUDY POPULATION ..................................................................... 36
4.1
INCLUSION CRITERIA ........................................................................................................... 36
4.2
EXCLUSION CRITERIA ......................................................................................................... 37
4.3
RANDOMIZATION INCLUSION CRITERIA ........................................................................ 38
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL .................................................................... 39
4.4.1
Sperm and Egg Donation ........................................................................................................... 40
4.4.2
Pregnancy................................................................................................................................... 40
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT ..................................... 40
4.6
TERMINATION OF THE CLINICAL STUDY ....................................................................... 42
4.7
REPLACEMENT OF SUBJECTS ............................................................................................ 42
4.8
ELIGIBILITY FOR EXTENSION STUDY .............................................................................. 42
PUBLIC
R
Y DE
DESIG
SIG
NATION
NATION
RING PR
RING PR
nd S
nd 
COPY
.
...........
.........
............
.........
S ........
 ......
This document 
SUB
SUB
1
Sp
Sp
4.4.2
4.2
4.5
4.5
cannot
N CRI
N CR
USION C
SION C
NDOM
NDOM
JE
JE
be
UD
UDY P
Y 
T
used
fety Mo
ty Mo
c Cardia
Cardia
to
CEDU
CEDU
support 
.......
...
..............
.......
N AND CH
AND C
OF STUD
F STU
any 
.
............
.........
........
marketing 
........
................
..............
...............
.............
.............
......
..........
.......
authorization 
ber 2016
2016
za
............ 3
.......... 3
............
............
............
.........
........
......
application 
ZATI
AT
CTS OF R
TS OF 
rm and Eg
rm and E
Pregnancy
regnan
REM
REM
T
and 
ERIA
RI
RITERI
TERI
ON
ON
any
PULA
PULA
A ........
A.....
extensions 
HOIC
OIC
DY ........
Y .......
ES ........
S .......
itoring C
oring C
Advisor
Adviso
or 
.......
.....
E
variations
..........
.......
.............
............
............
.........
.............
........
thereof.
..
........
..........
....
.............
........
.............
............

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 5 of 175
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION ............................. 43
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT ........................................... 43
5.1.1
Labeling and Packaging ............................................................................................................. 44
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, AND/OR PLACEBO 44
5.2.1
Labeling and Packaging ............................................................................................................. 44
5.3
SHIPMENT AND STORAGE................................................................................................... 44
5.4
IMP ACCOUNTABILITY ........................................................................................................ 45
5.5
TREATMENT ADMINISTRATION ........................................................................................ 45
5.5.1
Randomization ........................................................................................................................... 45
5.5.2
Titration Period .......................................................................................................................... 46
Table 3 Titration Algorithm .................................................................................................................... 46
5.5.3
Maintenance Period ................................................................................................................... 46
5.5.4
Taper Period ............................................................................................................................... 47
Table 4:Taper Algorithm ........................................................................................................................ 47
5.5.5
Transition Period ........................................................................................................................ 47
Table 5:Transition Algorithm ................................................................................................................. 48
5.6
BLINDING ................................................................................................................................ 48
5.7
PRIOR AND CONCOMITANT MEDICATION ..................................................................... 49
5.7.1
Vagal Nerve Stimulation ............................................................................................................ 49
5.7.2
Ketogenic Diet ........................................................................................................................... 49
5.7.3
Rescue Medication for Seizures ................................................................................................. 49
5.7.4
Prohibited Concomitant Medication and Food .......................................................................... 49
5.8
TREATMENT COMPLIANCE ................................................................................................ 50
6.
VISIT SCHEDULE ......................................................................................................... 50
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1) ............................................. 51
6.1.1
Screening, Clinic Visit 1 (Study Day -42) ................................................................................. 51
6.1.2
Phone Visit 2 (Study Day -21) ................................................................................................... 53
6.1.3
Clinic Visit 3 (Study Day -1): Randomization ........................................................................... 53
PUBLIC
..........
.......
..............
.............
.............
............
...........
.....
COPY
.........
......
.............
.........
............
...........
This document
Proh
Proh
8
T
.
VIS
VIS
cannot
rve Stim
Stim
genic Die
nic Die
scue M
cue M
be 
....
ONCO
ONCO
used 
.........
.....
.............
.........
......
......
to
..........
........
support 
...
..............
..........
...............
.........
...............
............
any 
..........
........
...........
.......
marketing 
AND/
ND
................
..............
..............
..........
...............
..........
.............
.........
authorization 
ber 2016
2016
za
.......... 4
....... 4
............
...........
.............
..........
/OR
OR
application 
dication
catio
ted Conco
d Con
EATMEN
EATME
T SCHE
SCH
BA
BA
and
lation .
ion .
............
.........
any 
.....
ITANT M
ITANT
......
extensions 
....
.............
...........
.............
..........
.............
.........
.............
.........
.....
or 
.....
..
........
.....
variations
..........
.....
............
............
............
............
.............
..........
.......
thereof. 
.....
PLACEB
ACEB
..............
..........
............
...........

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 6 of 175
6.2
TITRATION AND MAINTENANCE PERIODS ..................................................................... 54
6.2.1
Titration Period Study Day 1 ..................................................................................................... 54
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) ..................................................... 54
6.2.3
Clinic Visit 6 (Titration Period Study Day 15) .......................................................................... 54
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29) ................................................................... 55
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43) ................................................................... 55
6.2.6
Phone Visit 9 (Maintenance Period Study Day 57) ................................................................... 56
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71) ................................................................. 56
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85) ................................................................. 57
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early Termination ........... 57
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) .................................................. 59
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY DAY 197-281) ...................... 59
6.5
ESTIMATED BLOOD VOLUME COLLECTION .................................................................. 60
7.
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ..................... 62
7.1
EFFICACY ASSESSMENTS ................................................................................................... 62
7.1.1
Seizure Assessments .................................................................................................................. 63
7.1.2
Clinical Global Impression - Improvement ............................................................................... 64
7.1.3
Quality of Life in Childhood Epilepsy Scale ............................................................................. 64
7.1.4
PedsQL Quality of Life Inventory (PedsQL) ............................................................................. 64
7.1.5
Parent/Caregiver Quality of Life ............................................................................................... 64
7.2
SAFETY ASSESSMENTS ........................................................................................................ 65
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study Medication ............... 65
7.2.2
Physical Examinations ............................................................................................................... 65
7.2.3
Neurological Examinations ........................................................................................................ 65
7.2.4
Vital Signs .................................................................................................................................. 66
7.2.5
Laboratory Measurements ......................................................................................................... 66
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s) ............................................................. 67
7.2.7
Electrocardiograms .................................................................................................................... 68
PUBLIC
SIT (C
IT (C
OLUME
OLUM
AND PH
AND PH
SME
SM
COPY
y Day 
y Da
tudy Da
tudy D
SIT 13; S
IT 13; 
L
This document 
SA
Dem
Dem
.2.2.2
P
7.2.3
7.2.3
7
cannot 
fe i
fe 
Quality 
Quality
nt/Careg
t/Careg
AFETY
FETY
be
mpres
pres
n Ch
n Ch
used
NTS ...
TS ...
............
.........
sioi
to
ARM
ARM
support
9
TUDY D
UDY D
NIC VISIT
C VIS
COLLEC
OLLEC
AC
any 
..........
........
9): End 
): En
marketing 
........
................
..............
...............
.............
................
...........
..............
...........
authorization 
ber 2016
2016
za
............ 5
.......... 5
.............
.............
..............
..........
........
......
application
ve
ASSESS
SSES
ographics, 
raphic
hysical Ex
ysical 
Neurolo
Neur
Vit
Vit
and
f Life
Life In
In
r Qual
Qua
any 
- Impr
- Imp
hood Ep
ood 
extensions 
T 
TION ...
ION ..
COKIN
OKIN
.............
...........
............
.........
or 
Y 
Y
4; ST
4; ST
variations
..........
.....
..............
............
.............
............
of Study
f Stud
 113)
113)
thereof.
....
.............
.........
.............
........
.............
............

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 7 of 175
7.2.8
Doppler Echocardiography ........................................................................................................ 68
7.2.9
Tanner Staging ........................................................................................................................... 68
7.2.10
Columbia-Suicide Severity Rating Scale ................................................................................... 68
7.2.11
Adverse Events .......................................................................................................................... 69
7.2.12
Behavior Rating Inventory of Executive Function (BRIEF) ..................................................... 69
7.3
PHARMACOKINETIC ASSESSMENTS ................................................................................ 69
7.4
APPROPRIATENESS OF MEASUREMENTS ....................................................................... 70
8.
ADVERSE EVENTS ....................................................................................................... 70
8.1
DEFINITIONS .......................................................................................................................... 70
8.1.1
Adverse Events .......................................................................................................................... 70
8.1.2
Serious Adverse Events ............................................................................................................. 71
4.
Results in persistent or significant disability or incapacity. ....................................................... 71
8.1.3
Adverse Events of Special Interest ............................................................................................ 72
8.1.4
Adverse Events Requiring Hospitalization ................................................................................ 74
8.2
SEVERITY OF ADVERSE EVENTS ...................................................................................... 74
8.3
CAUSALITY OF ADVERSE EVENTS ................................................................................... 75
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING ...................................... 76
8.5
ADVERSE EVENT REPORTING ............................................................................................ 76
8.5.1
Adverse Events .......................................................................................................................... 76
8.6
SERIOUS ADVERSE EVENTS REPORTING ........................................................................ 76
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events ......................................... 77
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR TO IEC/IRB ....... 77
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE EVENTS BY 
INVESTIGATOR TO SPONSOR ............................................................................................. 78
8.9
FOLLOW-UP OF ADVERSE EVENTS ................................................................................... 78
8.9.1
Follow-up of Echocardiogram Findings .................................................................................... 78
8.10
PREGNANCY ........................................................................................................................... 80
9.
DATA HANDLING PROCEDURES ............................................................................. 80
PUBLIC
..
ificant d
icant d
ial Intere
al Intere
quiring H
quiring H
VER
VE
COPY
...........
.........
............
.........
..........
.......
This document 
Req
Re
REP
REP
.8
R
8.8
cannot 
EVE
VE
Events .
vents 
IOUS A
OUS A
quirem
uirem
be 
N PER
PER
ENT 
ENT
used
SE EVE
E EVE
DVERSE
VERSE
IO
IO
to
pitaliz
pitaliz
support 
......
...
..............
.......
ability or 
bility o
.............
........
any 
.
............
.........
........
marketing 
.....
................
..............
...............
.........
...............
.........
..........
.......
authorization 
ber 2016
2016
za
..........
........ 6
........
.............
....
..............
..........
........
......
application
V
ents for I
ents for 
RTING O
RTING
EPORTIN
EPORT
INVEST
NVES
FOL
FO
and
...........
.........
VERSE
ERSE
any 
FOR 
FOR
PORTIN
PORT
extensions 
incapa
cap
.............
............
tion .......
on ......
TS .......
TS ......
EVENT
VENT
A
or 
.......
.....
aci
variations 
........
.....
...........
..........
............
.........
.............
........
thereof.
....
.......
..........
.....
.............
........
.............
...........

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 8 of 175
9.1
RECORDING OF DATA .......................................................................................................... 80
9.2
DATA QUALITY ASSURANCE ............................................................................................. 81
9.3
RECORD RETENTION ............................................................................................................ 81
10. STATISTICS ................................................................................................................... 82
10.1
DETERMINATION OF SAMPLE SIZE .................................................................................. 82
10.2
ANALYSIS POPULATIONS ................................................................................................... 82
10.2.1
Safety (SAF) Population ............................................................................................................ 82
10.2.2
Modified Intent-to-Treat (mITT) Population ............................................................................. 82
10.2.3
Per Protocol (PP) Population ..................................................................................................... 82
10.3
TREATMENT GROUPS ........................................................................................................... 83
10.4
TREATMENT PERIODS .......................................................................................................... 83
10.5
STATISTICAL ANALYSES AND METHODS ...................................................................... 83
10.5.1
Efficacy Analyses ...................................................................................................................... 84
10.5.1.1
Primary Efficacy Analysis .............................................................................. 84
10.5.1.2
Key Secondary Analyses ................................................................................ 84
10.5.1.3
Multiplicity Strategy and Testing Hierarchy .................................................. 85
10.5.2
Safety Analyses .......................................................................................................................... 85
10.5.3
Pharmacokinetic Analyses ......................................................................................................... 86
10.6
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND SAFETY MONITORING 
COMMITTEE ............................................................................................................................ 86
11. ETHICAL & REGULATORY CONSIDERATIONS..................................................... 86
11.1
ETHICAL CONSIDERATIONS ............................................................................................... 86
11.2
INFORMED CONSENT ........................................................................................................... 87
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD ............................................................. 88
11.4
PROTOCOL COMPLIANCE.................................................................................................... 89
12. ADMINISTRATIVE ASPECTS ..................................................................................... 89
12.1
CLINICAL TRIAL AGREEMENT .......................................................................................... 89
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR ................................................................ 90
PUBLIC
..
S AND 
 AND
..............
............
mary Effi
mary Effi
ey Seco
ey Seco
ltip
lti
COPY
....
............
..........
............
.........
..........
.......
This document 
ETH
ET
INF
INF
11.3.3
1
cannot
PR
PR
TEE ....
EE ....
& REG
& REG
HICA
HIC
be
c Analy
naly
OVI
OV
used
ndary
dar
icity Str
ity Str
............
.........
to
acy An
acy A
y An
y An
support 
.......
...
..............
.......
ETHODS
ETHOD
.............
........
naly
any 
....
.............
...........
........
marketing 
........
.....
...............
..........
..............
..........
................
.........
..........
.......
authorization 
ber 2016
2016
za
............ 8
.......... 8
.............
.............
............
.........
application 
UL
L CONSI
L CON
ORMED C
MED
REGULAT
EGULA
COMM
COMM
PRO
PR
and
D
..........
.....
LATO
ATO
any 
..........
........
D TO A
D TO
extensions 
S ......
....
.............
............
ysis .......
is .......
lyses .....
ses ....
egy and 
gy and
...........
.........
or 
.......
.....
variations
.............
.........
.............
............
.............
.........
.............
........
thereof. 
..
...........
........
.............
.........
..........
........

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 9 of 175
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE ............................... 90
12.4
STUDY FILES AND MATERIALS ......................................................................................... 90
12.5
INITIATION OF THE STUDY ................................................................................................. 90
12.6
SUBJECT REIMBURSEMENT ............................................................................................... 91
12.7
LIABILITY AND INSURANCE .............................................................................................. 91
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY ................................................... 91
12.9
MONITORING OF THE STUDY ............................................................................................. 92
12.10
PROTOCOL AMENDMENTS ................................................................................................. 93
12.11
AUDITS AND INSPECTIONS ................................................................................................. 93
12.12
CLINICAL STUDY REPORT .................................................................................................. 93
12.13
USE OF DATA AND PUBLICATIONS .................................................................................. 94
13. REFERENCE LIST ......................................................................................................... 95
14. APPENDICES ................................................................................................................. 97
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS .................. 98
APPENDIX 2 – COLUMBIA – SUICIDE SEVERTY RATING SCALE ......................... 100
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION ... 106
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE .................. 116
APPENDIX 5 – TANNER STAGING ................................................................................ 129
APPENDIX 6 – PEDsQL (INCLUDING FAMILY IMPACT MODULE) ........................ 131
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE ................................................................ 142
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE ............................ 144
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES .................... 146
APPENDIX 10 – PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES .............. 147
PUBLIC
..........
........
...........
..........
ROH
RO
COPY 
.........
.....
............
........
TIONS ..
IONS .
This document
DIX 6 –
IX 6 –
PENDI
ENDI
APPE
APPE
cannot 
UALIT
UALIT
 – TA
– TAN
be 
VIOR R
VIOR R
used
BIT
ITE
A – SU
– SU
to 
........
D
support 
.
............
.........
.............
.........
........
any 
.........
.......
............
.......
marketing 
.....
...............
.............
...............
.........
...............
.........
..............
.........
authorization 
ber 2016
2016
za
............ 9
.......... 9
............
............
.............
.........
........
......
application 
NER
NER
PEDsQL
EDsQ
X 7 – EQ
7 – EQ
DIX 8 –
DIX 8
and
Y OF L
OF L
R S
any 
ATING 
ATING
F
extensions 
.......
....
...........
.........
CONC
ONC
CIDE S
DE S
or 
.
variations 
........
.....
.............
.........
............
.........
............
.........
........
.......
thereof.
..
............
.........
............
........
.............
...........

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 10 of 175
APPENDIX 11 – PROTOCOL AMENDMENT 2 SUMMARY OF CHANGES .............. 166
Table 1:
Schedule of Assessments........................................................................................................................ 24
Table 2:
Investigational Medicinal Product – ZX008 .......................................................................................... 43
Table 3
Titration Algorithm................................................................................................................................. 46
Table 4:
Taper Algorithm...................................................................................................................................... 47
Table 5:
Transition Algorithm............................................................................................................................... 48
Table 6:
Time Windows for Assessments ............................................................................................................ 51
Table 7:
Schedule of Post-Treatment Cardiac Follow-up .................................................................................... 60
Table 8:
Estimated Blood Volume Collection*.................................................................................................... 61
Table 9:
Priorities for Blood Sample Collections................................................................................................. 62
Table 10:
Adverse Events of Special Interest............................................................................................. 73
Table 11:
Severity Definition of Adverse Events....................................................................................... 75
Table 12:
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings................................. 78
PUBLIC COPY 
....
...........
....
ents
ents......
.
n Increas
n Increas
This document cannot be used to support 
ng Sev
g Sev
any 
.....
...........
.........
...........
.......
erity
eri
marketing 
.
...........
......
..............
..........
..............
........
.............
........
.............
........
.............
........
....
..
authorization 
ber 2016
2016
za
........ 16
..... 16
...........
......
.......
......
application and any extensions or variations 
.
...........
......
...........
......
...........
.........
...........
..........
..........
......
of ECH
of ECH
thereof. 
...
...........
.....
...........
.........
...........
..
...........
...........
......
......

annot be
and any

ument canno
plication and 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 13 of 175
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) 
Study Number: ZX008-1502 
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled 
Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral 
Solution as an Adjunctive Therapy in Children and Young Adults with Dravet 
Syndrome 
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 (Day/Month/Year) 
PUB
filled ou
filled ou
BLIC
ent
en
accordin
ccordi
B
COPY
Inde
nd
dance w
dance w
CH) Guid
CH) Gu
sure tha
sure tha
s of
s of tht
f
This document cannot 
n:
be used 
t by th
by t
to 
he i
he
support 
elin
lin
all pers
all pers
is study p
study 
to the stu
o the s
s
any
nt Et
nt E
the stud
the stu
ne for G
e for
ma
ng this st
ng this 
thics
th
marketing
laceb
ce
chloride)
chloride
ung Adults
g Adu
ma
authorization 
bo-c
bo-c
application and any extensio
nvestigat
vestigat
ions 
udy pr
y p
ion or
otocol
otoco
roto
rot
variations
tudy pro
udy pro
s Comm
Comm
dy protoc
y proto
Good 
ood Cl
Cl
nel inv
el inv
ns 
ns thereof. 
ontrolled 
rolled
Oral 
Oral 
ts with D
with 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 14 of 175
LIST OF ABBREVIATIONS 
ABBREVATION
DEFINITION
AE
Adverse Event
AED
antiepileptic drug
AESI
Adverse Event of Special Interest
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
AUC0-t
area under the concentration-time curve from time zero to time=t
BID
bis in die; two times per day
BMI
Body Mass Index
BRIEF
Behavior Rating Inventory for Executive Function
C-SSRS
Columbia-Suicide Severity Rating Scale
CBD
cannabidiol
CFR
Code of Federal Regulations
Cmax 
Maximum observed concentration determined directly from the 
concentration-time profile
CYP
cytochrome P450
dL
Deciliter
DS
Dravet syndrome
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
electronic Case Report Form
EOS
End of study
EPAR
European Public Assessment Report
EQ-5D-5L
Standardized measure of health status
ET
Early Termination
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GH
Growth Hormone
GMP
Good Manufacturing Practices
HADS
Hospital Anxiety and Depression Scale
HR
Heart Rate
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDSMC
Independent Data and Safety Monitoring Committee
IEC
Independent Ethics Committee
IGF-1
Insulin-like Growth Factor-1
IMP
Investigational Medicinal Product
IPCAB
International Pediatric Cardiology Advisory Board
IRB
Institutional Review Board
ABBREVATION 
DEFINITION 
IU 
International Unit 
PUBLIC 
450
450
C
syndrome
syndrom
LIC
trocardio
ocardio
BL
chocardio
chocardio
UB
ectron
ectr
PU
P
COPY 
Ra
R
Y
lations
ation
PY
d concent
concen
me profile
e profile
OP
C
This documen
H
ent t
nt
en
IDSMC
SMC
m
IEC
IEC
um
o
IG
IG
oc
do
do
do
cannot t
ot
no
nn
a
c
be
Stan
an
Early 
Early
e
b
Fol
Fo
be used
gr
g
c Case 
Case 
d
f study
study
ed
opean Pu
pean P
se
dard
dard
us
to 
ram
am
am
am
to
R
t
support 
ation 
ion
po
pp
up
su
any y
ny
deter
det
a
marketing 
ng
zero to tim
ero to t
tin
ket
rk
Function
unction
a
m
authorization 
riz
riz
ri
ho
th
au
a
application 
H
n
on
tio
ca
lic
p
ap
a
and
ic
ood Cl
d C
d
Growth
Growth
nd
Goo
Goo
an
a
any 
d m
rminatio
minati
y
e Stimul
Stim
any
nic
a
extensions 
ns
on
sio
port Form
port Form
ns
te
lic Asse
c Asse
xt
eas
eas
e
or 
or
o variations 
ns
on
tio
ia
mined d
mined d
ar
thereof. 
f.
of
eo
me=t
me=t
er
the
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 15 of 175
ABBREVATION
DEFINITION
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response (System) 
KD 
Ketogenic diet 
kg 
Kilogram 
LH 
Luteinizing Hormone 
MCSF 
Mean Convulsive Seizure Frequency 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/kg/day 
milligram per kilogram per day 
min 
Minutes 
mITT 
modified Intent-to-Treat 
mL 
Milliliter 
PedsQL 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetics 
PP 
Per Protocol 
QoL 
Quality of Life 
QOLCE 
Quality of Life in Childhood Epilepsy 
QTcF 
corrected QT interval using Fredericia method 
SAE 
Serious Adverse Event 
SAF 
safety population 
SD 
Standard Deviation 
SMEI 
Severe Myoclonic Epilepsy Of Infancy 
SUDEP 
Sudden Unexpected Death in Epilepsy 
T+M 
Titration plus Maintenance Periods 
t1/2 
terminal half-life 
THC 
tetrahydrocannabinol 
Tmax 
time to maximum concentration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VNS 
Vagal Nerve Stimulator/Stimulation 
ZX008 
Fenfluramine Hydrochloride Oral Solution 
PUBLIC 
interv
inter
dverse Ev
erse E
C
populatio
opulatio
LIC
dard 
ard Dev
De
BL
evere My
evere M
UB
udden
udd
PU
P
COPY 
ven
e
Y
PY
OP
 Childh
Childh
CO
val
C
This document t
nt cannot t
ot
no
nn
ca
c
be 
tetrah
tra
time t
time 
e
b
Th
Th
b
used
ocl
Unexpe
expe
d
ion plus M
n plus M
ed
minal
nal ha
ha
se
hydr
hydr
us
to 
ation
on
onic E
onic E
to
t
t
support t
od Epileps
Epil
rt 
sing Frede
ng Fred
po
nt
pp
up
s
any y
ny
a
marketing 
g
ng
tin
ke
rk
a
m
authorization 
iziz
riz
oriri
ho
th
au
a
application 
V
n
on
tion and
ro
ro
Upper L
er L
d
United
United
nd
Unit
Uni
an
a
any 
anna
ann
maximum
aximu
y 
d Stimu
d Stim
any
mi
a
extensions 
er
ns
on
ilepsy O
epsy O
sio
d Death 
d Death 
ns
Maintenan
intenan
te
ifefe
xt
bin
bi
e
or 
y
cia me
ia me
or
o variations s
ns
on
ati
ria
ar
va
thereof. 
f.
of
e
er
the
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 16 of 175
STUDY SYNOPSIS 
Study Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled 
Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an 
Adjunctive Therapy in Children and Young Adults with Dravet Syndrome
Study Number: ZX008-1501
Study Product: Fenfluramine Hydrochloride Oral Solution, ZX008
Type of Study:
Efficacy, safety, and pharmacokinetics study
Indication Studied:
Adjunctive therapy in Dravet syndrome
Phase of Development: Phase III
Countries: Europe, Australia, South Korea
Sponsor: Zogenix International Limited
Coordinating Investigator: 
Lieven Lagae, MD, PhD 
Leuven University, Department of Development and 
Regeneration, Section Pediatric Neurology 
Leuven, Belgium 
Estimated Duration of Individual Subject Participation:
The duration of the participation in the study for an individual subject is expected to be up 
to 22 weeks, with a follow-up 3 to 6 months after the last dose of study medication for 
final safety monitoring.
Objectives: 
The primary objective of the study is: 
x
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome in children and young adults based on change in the 
frequency of convulsive seizures between baseline and the combined Titration and 
Maintenance Periods (T+M). 
The key secondary objectives of the study are: 
x
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome based on change in the frequency of convulsive seizures 
between baseline and T+M. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
x
The longest convulsive seizure-free interval.
See Statistical Methods (Section 10.5.1.3) for hierarchical testing 
procedure. Additional secondary efficacy objectives of the study are: 
x To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints:
o
The number of convulsive seizure-free days.
o
The proportion of subjects who achieve 75% reductions from baseline in 
convulsive seizure frequency.
o
The change from baseline in non-convulsive seizure frequency.
PUBLIC 
is: 
is: 
008 0.8 m
08 0.8 m
et syndro
et syndro
ve seiz
ve s
C COPY 
n P
n 
ticipatio
cipatio
for an ind
r an in
after th
after th
PY
This document
zur
The pro
he pro
seizur
seizur
x
The
The
See Sta
See St
proc
proc
do
cannot 
ne an
an
rate that 
te that 
o placeb
placeb
oportion
portio
e frequ
frequ
be 
ZX00
X00
avet sy
avet sy
d T
d T
used
me 
me
ures be
es be
M).).
of the st
f the s
8 0
8 0
to 
g/kg/d
kg/d
in chi
in chi
supp
day i
ay
pport 
vidua
du
last dose
ast dos
pp
any 
Neu
Ne
l sub
l su
ny marketing 
et syndrom
et syndrom
tralia, Sou
alia, So
tin
ket
Developm
Develop
urology
urolo
rk
authorization 
an 
ri
th
u
a
application 
of su
f su
ency.
ency.
rtion of su
ion of 
frequency
requenc
longest co
ongest 
stical Met
tical M
dure. Add
ure. Add
o dem
o dem
and
M
he ZX0
e ZX0
on the f
on the 
ubjec
bjec
any 
mg/k
mg
rome bas
rome b
8
extensions 
s superio
superi
dren and
en and
een
een base
base
y are:
are:
kg
k
or 
of st
f 
o variations 
ment and 
ent and 
y
s
ject is e
ect is e
tudy
ud
ia
thereof. 
f
me
of
uth Kore
uth Kore
er
the
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 17 of 175
o
The change from baseline in convulsive + non-convulsive seizure frequency.
o
The incidence of rescue medication usage.
o
The incidence of hospitalization to treat seizures.
o
The incidence of status epilepticus.
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are 
(independently) superior to placebo on the following endpoints:
o
Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator.
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver.
o
The change from baseline in the Quality of Life in Childhood Epilepsy 
(QOLCE) score to measure quality of life.
o
The change from baseline in the Pediatric Quality of Life Inventory™ (PedsQL) 
score.
o
The change from baseline in PedsQL Family Impact module score.
o
The change from baseline in the quality of life (QoL) of the parent/caregiver 
using the EQ- 5D-5L scale.
o
The change from baseline in affective symptoms of the parent/caregiver 
using the Hospital Anxiety and Depression Scale (HADS).
The safety objective of the study is: 
x
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, vital signs (blood pressure, heart rate, temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms (ECHO), and body weight. Cognitive 
Function will be assessed in subjects 5 years and older using the cognition domain score on 
the QOLCE. Cognitive function will be assessed using and age-appropriate versions of the 
BRIEF
The pharmacokinetics (PK) objective of the study is:
x
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in 
subjects ages 2-6 years and 6-18 years with Dravet syndrome.
The exploratory objectives of the study are:
x
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK 
endpoints.
Methodology:
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy, safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young adult 
subjects with Dravet syndrome. Approximately 30 study sites in Europe, Australia, and South 
Korea are planned to participate. The 6-week Baseline Period will consist of the establishment of 
initial eligibility during a screening visit followed by an observation period where subjects will 
be assessed for baseline seizure activity based on recordings of daily seizure activity entered into 
a diary. Upon completion of the Baseline Period, subjects who qualify for the study will be 
randomized (1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 
0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo.
Randomization will be stratified by age group (< 6 years, 6 years) to ensure balance across 
PUBLIC 
y and 
y and
olerabili
olerabili
(AEs), la
(AEs), l
ns (blood
ns (bloo
CG), 
CG
COPY
L Family
L Fami
quality of
quality
affectiv
ffect
De
D
This document
dology:
ology:
is a mu
 a mu
t
po
p
fficacy, 
icacy, 
subject
subject
Kor
Kor
in
t
do
cannot 
e the P
he 
s 2-6 yea
2-6 yea
y objecti
object
mpare the
are the
ints.
nts.
c
be 
PK) obj
PK) obj
PK
PK
used
pre
pr
chocard
hocar
in subjec
n subje
function
unction
to 
borato
borato
essure
ssure
i
support 
lif
symptom
ympto
pression S
ression 
of ZX00
f ZX00
ry p
ry
any 
mpact m
pact m
e (QoL)
(Qo
marketing 
e prin
pri
by the
y the
hood Epile
od Epi
Life Inve
Life In
authorization 
ncipa
ncip
ri
application
center
nter,r
on 
ZX0
do
afety, and 
fety, an
with Drav
with Dr
a are plan
are plan
eligib
eligib
ion and
f Z
f Z
s and
and 
es of the
s of th
008 0
008 0
any 
ive of th
ive of t
X008 0
X008
6
extensions 
Sca
8 0.2 an
0.2 an
aramete
ramete
heart
eart rat
rat
gram
grams (E
s (E
s 5 years
5 years
ill be a
l be a
or 
of th
of 
le (HA
e (HA
variations 
epsy
p
entory™
entory™
odule sc
dule sc
) of the p
of the p
he
thereof. 
y
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 18 of 175
treatment arms, and at least 40% of subjects will be in each age group. All subjects will be 
titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects will 
continue treatment at their randomly assigned dose over a 12-week Maintenance Period. Total 
treatment time from the beginning of the Titration Period through the end of the Maintenance 
Period is 14 weeks. At the end of the Maintenance Period (or early discontinuation), all subjects 
will undergo a 2-week taper or transition period (Post-Dosing Follow-Up) depending on whether 
they exit the study or are enrolled in the separate long-term open-label extension study. A follow-
up ECG and ECHO will be performed 3-6 months after study drug discontinuation for early 
termination, or for those subjects who complete the study but do not enter the open-label 
extension study.
Parents/caregivers will use a diary daily to record the number/type of seizures, dosing, and use of 
rescue medication. A schedule of assessments is provided in Table 1.
External Individuals and 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. 
ECGs and Doppler ECHOs will be centrally read (Biomedical Systems, Inc.) and interpreted 
under blinded conditions using pre-specified criteria, and if necessary, with review by the IPCAB.
Number of Subjects:
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor.
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled 
into the study:
1.
Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug.
2.
Subject must have documented medical history to support a clinical diagnosis of 
Dravet syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs.
3.
Subjects must meet all of the following 5 criteria:
a.
Onset of seizures in the first year of life in an otherwise healthy infant.
b.
A history of seizures that are either generalized tonic-clonic or unilateral 
clonic or bilateral clonic, and are prolonged.
c.
Initial development is normal.
d.
History of normal brain MRI without cortical brain malformation.
e.
Lack of alternative diagnosis.
4.
Subjects must meet at least one of the following 3 criteria:
P
cts m
cts
PUBLIC 
ied
screened
screened
s estimat
s estimat
site will 
ite will 
he spons
he spons
C
P
COPY
dent 
en
ght
ght. . A s
A
itor th
tor the c
read
read (Bi
(B
d criter
crite
C
This document 
Subjec
bje
Dravet
Dravet
anti
ant
3.3.
S
do
cannot
ast
ast
ne pregn
pregn
g to use m
o use m
es abstin
abstin
udy dru
dy dru
ct m
ct m
be
n
eening V
ning 
-feedi
-feed
used
ust mee
st mee
pregna
pregna
d
r.
d to
d 
otot rand
 ran
support 
rdi
rd
medical
medica
a, and if n
and if 
to obtain 
obtain 
that 105
hat 10
om
po
any 
and S
nd 
arate Inte
arate Int
ac safe
ac saf
S
marketing
tudy
d
tion for e
on for 
e open-lab
open-lab
eizures, do
zures,
1.
afet
f
ma
authorization 
ll
nce
subjects
ubject
on whet
on whet
y. A f
. A 
ri
application 
nc
ust have d
ust have
syndrome
ndrom
pileptic dr
pileptic 
ubjects mu
bjects m
a.a.
O
b.b
and 
ncy te
cy t
edically 
dically 
ce, whi
, wh
any 
, n
t. Fema
t. Fem
. Female
Female
est. S
st
exten
all of the
l of the
non-la
on-la
ensions
115 subj
15 sub
5 subject
 subject
mize mor
ze mor
en
or
cessa
cessa
or variations 
osing
sin
ty Monit
y Monit
ernationa
nation
ety of the
y of the
stems, 
tems,
n thereof. 
herer
ollow-
ow-
arlyly
bel
g, an
g an
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 19 of 175
a.
Emergence of another seizure type, including myoclonic, generalized tonic-
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type.
b.
Prolonged exposure to warm temperatures induces seizures and/or seizures are 
associated with fevers due to illness or vaccines, hot baths, high levels of 
activity and sudden temperature changes and/or seizures are induced by strong 
natural and/or fluorescent lighting, as well as certain visual patterns.
c.
Genetic test results consistent with a diagnosis of Dravet syndrome 
(pathogenic, likely pathogenic, variant of unknown significance, or 
inconclusive but unlikely to support an alternative diagnosis.)
5.
Subject must have had 4 convulsive seizures (tonic, tonic-atonic, tonic-clonic, 
clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian 
report to investigator or investigator medical notes.
6.
All medications or interventions for epilepsy (including ketogenic diet [KD] and 
vagal nerve stimulation [VNS]) must be stable for at least 4 weeks prior to 
screening and are expected to remain stable throughout the study.
7.
Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian.
8.
Subject has provided assent in accordance with Institutional Review Board 
(IRB) requirements, if capable.
9.
Subject’s parent/caregiver is willing and able to be compliant with diary 
completion, visit schedule and study drug accountability.
Exclusion Criteria: All subjects must meet none of the following exclusion criteria to be 
enrolled into the study:
1.
Subject has a known hypersensitivity to fenfluramine or any of the excipients in 
the study medication.
2.
Subject has pulmonary arterial hypertension.
3.
Subject has current or past history of cardiovascular or cerebrovascular 
disease, such as cardiac valvulopathy, myocardial infarction or stroke. 
4.
Subject has current or recent history of Anorexia Nervosa, bulimia, or depression 
within the prior year that required medical treatment or psychological treatment for 
a duration greater than 1 month.
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s 
opinion, based on clinical interview and responses provided on the Columbia-
Suicide Severity Rating Scale (C-SSRS). Subjects must be excluded if they report 
suicidal behavior in the past 6 months as measured by the C-SSRS at Screening or 
Baseline, which includes suicidal ideation with intent and plan (Item #5). If a 
subject reports suicidal ideation on Item 4 without specific plan, and the 
investigator feels that the subject is appropriate for the study considering the 
potential risks, the investigator must document appropriateness for inclusion, and 
discuss with the parent/caregiver to be alert to mood or behavioral changes, 
especially around times of dose adjustment.
6.
Subject has a current or past history of glaucoma.
PU
ects m
ects
PUBLIC
sible
ibl
ccordanc
cordan
le.e.
er is willi
r is will
dule and
dule and
PU
COPY 
(inclu
(in
table for
able for
table thro
able th
ure of th
ure of th
pare
pare
This document
ur
Subjec
ubjec
opinio
opinio
Su
Su
do
cannot 
rrent 
ent
h as card
as card
has curre
as curre
n the prio
he prio
ation g
tion g
i
be 
n.
onary ar
onary ar
or p
or p
used
st mee
mee
persens
persen
d to
t n
to
ng g an
udy dr
udy dr
to support
ugho
gh
e study an
study a
t/guardian
guardi
with Insti
with Ins
nd abl
nd a
any 
ketog
keto
least 4 w
least 4 w
out the
out t
marketing 
me
ce, or 
e, or 
is.)
is.)
nic, tonic-
c, toni
ng, by par
g, by p
en
authorization 
are
by strong
y strong
ri
application
yea
y
reater tha
ater th
 at immin
at imm
n, based o
based 
cide Sever
de Sev
uicidal be
icidal b
Baseline
Baselin
subje
subje
and
ast
as
ac valv
c valv
t or rece
or rec
ar tha
r tha
any 
ial hyper
al hyp
history
histo
ulo
extens
one of th
e of th
vity to f
ity to f
nsions 
tution
tion
e to be c
to be c
g accoun
accoun
ns
or 
inin
nal
nal
variations 
-clon
clo
rent/guar
nt/gua
ic diet [K
ic diet [
weeks pr
eks pr
e study.
tudy.
nform
form
thereof. 
nic,
nic
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 20 of 175
7.
Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x ULN) 
may be entered into the study after review and approval by the Medical Monitor in 
conjunction with the sponsor, in consideration of comorbidities and concomitant 
medications.
8.
Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine- oxidase inhibitors; any centrally-acting compound with clinically 
appreciable amount of serotonin agonist or antagonist properties, including serotonin 
reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; or 
cyproheptadine (see Appendix 1). (Note: Short- term medication requirements will be 
handled on a per case basis by the Medical Monitor.)
9.
Subject is currently receiving or has received stiripentol in the past 21 days 
prior to Screening.
10.
Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy.
11.
Subject is unwilling to refrain from large or daily servings of grapefruits and/or 
Seville oranges, and their juices beginning with the Baseline Period and 
throughout the study.
12.
Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole 
blood cannabidiol (CBD) at the Screening Visit.
13.
Subject has participated in another clinical trial within the past 30 days.
14.
Subject is currently receiving an investigational product.
15.
Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions.
16.
Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, 
that would negatively impact study participation, collection of study data, or pose a risk to 
the subject.
Randomization Inclusion Criteria: Subjects must meet all of the inclusion criteria above 
plus the following criteria, to be randomized:
1.
Subject has been approved for study inclusion by the Epilepsy Study Consortium.
2.
Subject does not have a cardiovascular or cardiopulmonary abnormality based on 
ECHO, ECG or physical examination, including but not limited to trace mitral or 
aortic valve regurgitation or signs of pulmonary hypertension, and is approved for 
entry by the central cardiac reader.
3.
Subject demonstrates a stable baseline with 6 convulsive seizures during the 
6-week Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the 
second 3 weeks.
4.
Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (e.g., at least 90% compliant).
Study Product, Dose, and Mode of Administration:
ZX008 is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. Subjects 
PUBLIC 
urine te
urine tet
at the Scr
at the Scr
in anoth
in anoth
eceiving
eceiving
r una
r un
COPY
arb
ar
y of the
y of th
ge or dai
ge or da
nning w
nning w
This document
ubje
bj
ECHO
ECHO
aorti
aort
en
e
3.3.
do
cannot
nclusion
lusion
ng criter
g criter
ect has b
ct has b
ect do
ct do
ot 
ot be
y
nt illne
llne
vely im
vely im
used
an i
n 
le to co
e to co
her study
r study
signifi
signifi
ss
to 
r clini
r clin
nvest
nvest
support 
y serv
serv
ith the Ba
the 
ahydrocan
hydrocan
ning Vis
ning Vis
cal 
any
ne
ne
within th
within 
ings
ing
marketing 
lly
ng serot
sero
gic agonist
ic agonis
quirement
uiremen
past 21 da
ast 21 
, eslic
, esl
authorization 
) )
s; 
y
ri
application 
en ap
n ap
s not hav
s not hav
ECG or ph
CG or p
valve reg
valve r
ry by the 
y by th
Subject de
ubject 
6-week
6-week
seco
se
and
Criteria
riteria
, to be r
to be r
pro
pro
d any 
the 4 w
the 4
ct study 
ct study
a
extensions
nnabino
nabino
it.
trial wit
rial wit
gational p
tional
ply with
ply with
procedur
ocedur
t cond
cond
or 
eline
lin
l
variations 
ays
ys
arbazepi
rbazep
e past 30
e past 30
of grap
of grap
e P
thereof. 
nin 
t; or
or 
ts will be
s will be
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 21 of 175
will be randomized to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
maximum dose: 30 mg/day) or placebo. Study medication will be administered twice a day 
(BID) in equally divided doses with food.
Reference Product, Dose, and Mode of Administration:
Matching ZX008 placebo is supplied as an oral solution.
Duration of Treatment:
All subjects will receive ZX008 or matching placebo for up to approximately 16 weeks (Titration 
Period=2 weeks; Maintenance Period=12 weeks; Taper/Transition Period=2 weeks). After 
completion of the Maintenance Period, eligible subjects may enroll in the open-label extension 
study, after completion of the transition. Subjects who do not enroll in the open-label extension 
study will undergo a taper off of study medication (doses will be administered in a blinded fashion
similar to the titration, i.e., doses will be decreased in 4-day increments). Follow-up 
cardiovascular safety assessments, including ECG and ECHO, will be performed 3 to 6 months 
following the last dose of study medication.
Criteria for Evaluation:
Efficacy:
x
Number of seizures by type 
x
Convulsive seizure-free interval 
x
Clinical Global Impression – Improvement as assessed by parent/caregiver 
x
Clinical Global Impression – Improvement as assessed by principal investigator 
x
QOLCE to measure changes in quality of life of the subject 
x
PedsQL to measure changes in quality of life of the subject 
x
PedsQL Family Impact module to measure changes in quality of life of the parent/caregiver 
x
QoL of parent/caregiver using the EQ-5D-5L scale 
x
Affective symptoms of parent/caregiver using the HADS scale 
x
Duration of prolonged seizures (seizure type that, during baseline, had duration >2 minutes) 
x
Number of episodes of status epilepticus 
x
Number of instances of rescue medication use and number of doses 
x
Number of inpatient hospital admissions due to seizures
Safety: 
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. The BRIEF will be 
administered to track cognitive function. 
Pharmacokinetics: 
Steady-state plasma fenfluramine PK parameters (maximum observed concentration determined 
directly from the concentration time profile [Cmax], area under the concentration time curve from 
time zero to time=t [AUC0-t], time to maximum concentration [Tmax], and terminal half-life 
[t1/2]) after administration of ZX008 derived using population PK methods.
Sample Size Determination:
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). 
The EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
PUBLIC
rovemen
roveme
mprovem
mprovem
s in quali
s in quali
ges in qu
ges in qu
module
module
usi
us
COPY 
Y
This document
tion, 1
on, 1
nistered t
stered 
armacok
macok
m
Steady-s
teady-s
direct
direct
tim
tim
do
cannot
nces
ce
patient h
ient h
y safety 
safety 
rt rate, 
t rate,
2
be
seiz
 of statu
 of stat
of re
of r
used 
to me
o m
g the EQ
the EQ
arent/care
nt/care
zures 
zures
to
y o
ity of l
ity of 
easu
asu
support 
as assessed
assess
nt as asses
as asses
f life of 
life o
fe
any y marketing 
eeks
ek
eks). Aft
ks). Aft
en-label ex
n-label ex
open-labe
pen-lab
stered in a
ered in
nts). Follo
). Fo
be perfo
be perf
authorization 
ri
or
s (Tit
(Ti
ut
application 
ar
emperat
mpera
ead ECGs
ad ECG
 track cog
ack co
netics:
netics:
lic
ate plasma 
 plasm
y from the 
rom th
ero to tim
ro to t
er a
and
spital a
ital a
amete
mete
any
eizu
z
pilepticu
pileptic
ue medic
e med
dm
d
extensions
d by
ssed by p
ed by 
f the subj
the subj
of the su
f the su
e chang
change
5D-5L sc
D-5L sc
iver usin
ver usin
ure ty
re t
or 
pare
par
variations 
a b
ow-up 
w-up 
ormed 3 t
ormed 3 
ati
thereof. 
ation
ion
r
xtension
ension
el extens
l extens
linded
inde
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 22 of 175
stiripentol groups, the standard deviation (SD) of the percentage change in seizure frequency 
from baseline to month 2 was 42% in the French trial and 26% in the Italian trial. The analogous 
SDs for placebo groups were 38% and 62%. An SD of 50% was assumed for the primary analysis 
in this trial comparing ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure 
frequency. Using a two-sided test at the Į=0.05 significance level, a sample size of 35 subjects 
per treatment group affords 90% power to detect a difference in mean change from baseline of 
40 percentage points. Similar assumptions and calculations yield a requirement for an additional 
35 subjects in the 0.2 mg/kg/day ZX008 group. Thus, the total sample size is planned to be 
105 subjects (35 per arm).
Statistical Methods:
Study Populations:
Safety Population: All safety analyses will be performed on the Safety Population defined as all 
randomized subjects who receive at least one dose of study medication. Subjects will be analyzed 
according to the treatment actually received.
Modified Intent-to-Treat (mITT) Population: The mITT Population is defined as all randomized 
subjects who receive at least one dose of study medication and for whom at least 1 week of diary 
data are available. Subjects will be analyzed according to the treatment group to which they were 
randomized. The primary comparison of ZX008 0.8 mg/kg/day to placebo as well as key 
secondary efficacy assessments will be performed on the mITT Population.
Per Protocol (PP) Population: The PP Population is defined as all randomized subjects who 
receive at least one dose of ZX008 or placebo, complete the Maintenance Period, and have no 
major protocol violations that would have a significant impact on clinical outcome.
Efficacy
Primary Efficacy Analysis: The primary efficacy endpoint is the change in the mean convulsive 
seizure frequency (MCSF) per 28 days during the T+M periods compared with Baseline. The 
MCSF will be calculated from all available data collected during the Baseline and treatment 
periods. The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with 
Baseline MCSF as a covariate. The primary analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at the alpha=0.05 level of significance. The 
primary endpoint will also be analyzed using a nonparametric method and if normality 
assumptions are not met, the results of the nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be performed to assess the sensitivity of the 
primary analysis to changes in concomitant AED medications that may occur during the course of 
the trial. Specifically, the primary analysis will be repeated with a factor added to indicate 
whether a subject had a change in concomitant AED medication during the T+M period.
Safety
All safety data will be appropriately analyzed by treatment group. The number and percentage of 
subjects with AEs will be displayed by body system and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries in terms of severity and relationship 
to study drug will also be provided. Adverse Events of Special Interest (AESI) and Serious AEs 
(SAEs) will be summarized separately in a similar manner. Laboratory tests, vital signs, physical 
PUBLIC 
f ZX00
ZX0
be perfor
perfor
e PP Pop
e PP Pop
008 or pl
08 or pl
t would 
t would 
COPY 
 mITT P
mITT P
y medi
medicat
ca
accord
accord
08
08
This document
ions ar
ns ar
imary en
mary e
mary an
mary an
the trial.
he trial
wheth
wheth
Sa
S
o
do
cannot
ndp
dp
nt group
group
as a cova
a cova
acebo gr
cebo g
point w
oint w
e
be
er 2
from all
om al
oint w
oint
used 
have 
ave
 primary
rimary
28 day
8 da
to
cebo, 
cebo, c
a sig
a sig
support 
on and
n and
ng to the t
to the
8 mg/kg/
8 mg/kg
med on the
d on the
ation is d
tion i
om
any 
ulation i
ulation i
d for
d f
marketi
ety Popula
y Popu
ion. Sub
on. Su
eting
an a
n 
anned to 
ned to
eti
authorization 
ysis 
is 
ure
ubjects 
jects
seline of
eline of
addit
ddit
ri
application 
oup
l also be
also b
ot met, the
t met, t
dpoint. An
oint. A
lysis to ch
ysis to c
Specifical
ecific
er a subjec
a subje
and
three le
ee l
iate. The
te. The
p using
using
any 
dur
du
ailable d
ilable
l be anal
be an
evel
extensions
d
 mITT
mITT
defined 
defined 
mplete th
lete th
nificant i
icant i
efficacy 
fficacy 
ring
ing
or 
eatm
at
y to p
y to p
P
variations 
ation def
on def
bjects wi
bjects w
is define
define
whom a
whom 
ment
en
thereof. 
onalal
be
f
he

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 23 of 175
examinations, neurological examinations, ECG, Doppler echocardiogram, C-SSRS, Tanner 
Staging results, etc, will be summarized appropriately, by treatment. All safety summaries will be 
based on the Safety Population.
Pharmacokinetics
A population PK model will be fit to the fenfluramine concentration-time data collected during 
the Maintenance Period. This model will be informed by all relevant data available at the time of 
data collection (both adults and pediatrics). The population mean and interindividual variability 
estimates from the fit of the population PK model will be summarized. Derived plasma PK 
parameters (Cmax, AUC0-t, Tmax, and t1/2) will be summarized descriptively by treatment 
group and compared to historical data from adults. Summary statistics for plasma concentrations 
will be provided by PK sampling time.
PUBLIC COPY 
This document cannot be used to support any marketing
ual va
al v
plasma P
plasma 
ely by trea
y by tre
plasma c
plasma 
ar
authori
during 
uring
the time
he tim
ariab
aria
rization 
ri
application and any extensions or variations s thereof
of 
of 
ility 
PK 
atment
ment
oncentra
ncentra
f. 
f

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 24 of 175
Table 1: 
Schedule of Assessments 
Study Assessments 
Baseline Perioda
Titration + Maintenance Period
EOS/ 
ETb
Post- 
Dosing 
Cardiac 
Follow- 
up 
Screening 
2 
(Phone) 
Random- 
ization 
Titration Period 
Maintenance Period 
Visit Number 
1 
3 
4, 5 
(Phone) 
6 
7 
(Phone) 
8 
9 
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-42 
-21 
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197-281 
Informed Consent (subject and parent) 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X
X
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect retrospective seizure diary data 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication 
X
X
 
 
 
 
 
 
 
 
 
 
 
Physical Examination, complete 
X
X
 
 
 
 
 
 
 
 
X
Xc 
Physical Examination, abbreviated 
 
 
 
 
 
X
X
X
 
 
 
Xc 
Neurological Examination, complete 
X
 
 
 
 
 
 
 
 
 
 
X
 
 
Neurological Examination, abbreviated 
 
 
X
 
 
X
 
 
 
 
 
 
 
 
Vital signs 
X
X
 
 
X
X
X
X
 
 
Weight, Height, BMI 
X
X
 
 
X
X
X
X
 
 
12-lead ECG 
X
X
 
 
 
 
X
 
 
 
X
Xc 
Doppler ECHO 
X
 
 
 
 
 
Xd 
 
 
 
Xd 
Xc 
Urine pregnancy test 
Xe 
Xe 
 
 
Xe 
Xe 
Xe 
Xe 
 
 
Clinical laboratory evaluation 
(hematology/clinical chemistry/urinalysis, etc) 
X
X
 
 
X
X
X
X
 
 
Plasma sample for ZX008 pharmacokinetics  
 
 
 
 
 
 
4Xf
 
 
 
 
 
 
Plasma sample for background AEDs 
 
 
Xg 
 
 
Xg 
Xg 
 
 
 
Xg 
 
 
Urine THC Panel/Whole blood CBD 
X
X
 
 
X
X
X
X
 
 
Tanner Staging (for subjects >7 years old) 
 
 
X
 
 
 
 
 
 
 
 
X
 
 
Subject Diary 
D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh
C/R 
Epilepsy genotype panel 
Xl
 
 
 
Study Medication 
 
 
D 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh
C/R 
C-SSRS 
X
X
 
 
X
X
X
X
 
 
continued
PUBLIC 
C
LIC
BL C
BL
BL
UB
X
PU
P
COPY 
Y
PY
OP
OP
OP
CO
C
This document 
)
t
en
me
m
cu
oc
cannot t
not
no
no
nn
X
an
ca
be 
be
be
be
b
used 
d
ed
X
ed
se
X
us
u
to 
o
to
to
to support trtrt
ort
o
p o
pp
up
up
up
su
su
s
any y
ny
ny
ny
a
marketing 
d
ting
enance Peri
nance Pe
eti
9 9 
(Phone
(Pho
rk
ma
43 
5
43 
ma
ma
m
authorization 
ho
application 
n
o
D 
tio
at
ica
pl
X
pli
pp
ppl
pp
ap
and 
d 
an
an
an
a
any y
ny
ny
any
an
an extensions s
on
X
on
on
io
n
X
ns
en
en
en
xte
ex
e
or r
or
o variations 
od
10 
10 
n
57 
7
57 
7
n
on
io
ati
riria
ari
ar
ar
va
thereof. 
re
he
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 25 of 175
Table 1: Schedule of Assessments (continued) 
Study Assessments 
Baseline Perioda
Titration + Maintenance Period 
EOS/ 
ETb
Follow 
-upc
Cardiac 
Follow- 
up 
Screening 
2 
(Phone) 
Random- 
ization 
Titration Period 
Maintenance Period 
Visit Number 
1 
3 
4, 5 
(Phone) 
6 
7 
(Phone) 
8 
9 
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-42
-21
-1
1
4, 8
15
29 
43
57
71
85
99
113
197-281 
Clinical Global Impression - Improvement 
(assessed by parent/caregiver) 
 
 
 
 
 
X
X
X
X
 
 
Clinical Global Impression - Improvement 
(assessed by principal investigator) 
 
 
 
 
 
X
X
X
X
 
 
BRIEF 
X
X
X
QOLCE 
X
X
X
PedsQL 
X
X
X
EQ-5D-5L (QoL of parent/caregiver) 
X
X
HADS (Affect of parent/caregiver) 
X
X
X
Randomize subject 
X
First Day of Study Drug Administration 
Xj 
Daily Diary Completion 
X
Concomitant Medication 
X
Adverse events 
X
Adverse events of special interest 
X
Xk 
AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early termination; EQ-5D-5L=standardized measure of health status; HADS=Hospital Anxiety 
and Depression Scale; QoL=quality of life; BRIEF-P=Behavior Rating Inventory of Executive Function, Preschool version; QOLCE=Quality of Life in Childhood Epilepsy; R=Review 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The procedures to be completed at the Screening visit may be completed in a single day 
or split so that they are completed over the 2-day period (i.e., Days -43 to -42 or Days -42 to -41). 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week period. 
c: 
Follow-up ECG, ECHO, and physical examination will be performed 3-6 months after early termination, or for those subjects who complete the study but do not enter the open-label extension study (see Section 6.4). 
d:  
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54. The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a subject discontinues early from the study, the 
ECHO should be scheduled as soon as practical. If the Study Day 43 ECHO was completed 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring the subject to the 
clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration.
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 6, 8 and 12. 
h: 
Study drug/diary dispensed for the transition for subjects entering the open-label extension study and for tapering for subjects exiting the study.
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the morning of Study Day 1. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Mandatory one time collection any time during or after screening. 
PUBLIC 
C
Xj
X
IC
L C
LI
BL
BL
UB
PU
P
ense; E
ense
COPY 
X
Y
PY
P
OPY
OP
OP
OP
CO
C
This document 
or a
or a
cannot 
d prior to the 
or to the 
cond
nducted pri
ucted pri
d
tering the op
ing the op
edure (titratio
ure (titratio
tudy Day 1.
y Day 1. 
collected at
ollected a
c
er scree
r scre
be
hs after
after
Study Day 5
y Day 
O was comp
O was comp
used
=electrocard
trocard
unction, Presc
ction, Presc
nt of baseline 
f baseline
o -41).
1).
t to enroll 
to enroll
arly
arly
to 
o
to support trt
ort
ort
o
p
pp
up
s
any 
ny
X
ny
ny
an
a
marketing 
g
ce Period
Period
ng
9
(Phone)
(Phone)
1
eti
et
57
57
rk
a
X
ar
ma
X
m
authorization 
ho
a
application 
s visit.
it.
g. 
g
and
e at Visit 8 
Visit 8
o the dose of A
e dose of 
abel extensio
el extensio
h parent/ca
parent/ca
any 
ation, 
ation
Visit 12 ECH
Visit 12 E
30 days prio
30 days pri
nd 1
extensions s
X
ns
on
sio
ns
en
m; EOS=end
m; EOS=en
ol version; QO
ersion; QO
ure activity re
activity r
parate op
arate op
fo
f
or r
or
or
o variations 
71
71
s
X
ns
on
tio
i
o
ia
ari
X
ari
ari
X
va
v
thereof. 
E
of
eo
eo
eo
eo
0
11
11
(Ph
(
he
th
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 26 of 175
1.
INTRODUCTION 
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED 
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment of 
patients with Dravet syndrome (DS). 
DS, 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. 
1.1.1
Existing Treatment for Dravet Syndrome 
DS is a highly treatment-resistant and refractory epilepsy syndrome. Establishment of a seizure-
free condition in affected children, even with anticonvulsant drug polypharmacy, is extremely 
rare, since all seizure types in DS appear to be drug resistant, with minimal improvement on 
currently available anticonvulsant drug therapies (Dravet 2000; Dravet 2005). Moreover, classic 
anticonvulsant medications whose mechanism is via sodium channel blockade, such as phenytoin 
and carbamazepine, increase these children’s seizure frequency and severity. 
To date, only one treatment, Diacomit® (stiripentol) is approved, and only in Europe, Canada, 
Japan, and Australia, as adjunctive therapy in patients with severe myoclonic epilepsy in infancy 
(SMEI, Dravet syndrome), and must be co-administered with clobazam and valproate. Stiripentol 
has not been approved for use in the United States of America, but is available under 
compassionate use protocols at certain clinical sites. 
 fenfluramine has been used as an unlicensed medicine in Belgium at 
2 academic medical centers, currently using an approved protocol under a Belgium Royal Decree 
(government approved prospective observation trial) for the treatment of DS; the efficacy and 
safety of this therapeutic approach have been published in peer reviewed journal 
PUBLIC
t in 
t in
en with 
n with
UDEP; N
UDEP; 
several 
several 
ation of 
ation of 
rema
rem
COPY
sturb
ur
age
ge 2 yea
2 ye
k of coor
k of co
hers 
ers (Dra
(Dra
part,
part
This document
y
nvulsa
vulsa
d carbam
arbam
To date
To date
Japa
Japa
(S
(
cannot
atment-
ment-
in affect
n affect
all seizur
seizu
availab
vailab
be 
reatme
reatm
used
er
ns unkn
s unk
urvive to
vive to
in inst
in ins
to
possib
ssi
rebral c
ebral 
support
dinin
vet 1978
t 1978
with the fr
ith the
S also en
also e
ashef 201
shef 20
ble
ble et
any
and c
and 
due to la
due to 
atio
tion, p
n
H
marketing 
and sever
and sever
condition
conditi
e conditio
condit
d status ep
status
velop sev
velop s
ogn
o
authorization 
16
io
tive trea
ve trea
application 
e ty
e antic
anticon
o
medicatio
medica
azepine, in
zepine, 
 only one
only on
n, and Aus
and A
MEI, Dra
EI, Dr
t b
and
esistan
stan
d childr
childr
ypes in
pes in
any 
t for Dra
t for Dr
nt an
t a
extensions 
coun
oun
12) than 
than 
tiologies
ologies
irculatio
culatio
wn and o
wn and 
adulthoo
dulthoo
tional 
onal
or
Hu
equenc
quen
ter
ter
variations
on p
pileptic
ileptic
ve
v ral co
ral co
nitive im
tive im
ack of in
ck of i
poor dev
oor de
urst 19
rst 19
thereof. 
ment 
me
re form o
 form 
n most c
n most 
progr
prog

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 27 of 175
(Ceulemans 2012; Ceulemans 2016) and reported to be very favorable. There are no treatments 
specifically approved for the treatment of DS in the United States of America (USA). 
Accordingly, there remains an unmet need for an approved treatment for children with DS. 
1.1.2
Other Antiepileptic Medications 
USA and European Union approved anti-epileptic drug products include valproate, topiramate, 
carbamazepine, oxcarbazepine, lamotrigine, benzodiazepines, phenobarbital, potassium bromide, 
ethosuximide, phenytoin, and vigabatrin. The treatment of DS frequently requires a combination 
of two or three of these compounds, but with continued suboptimal seizure control. It cannot be 
assumed that because a treatment has been shown to be effective in common seizure types, that it 
will be effective in DS. In fact, some commonly used anti- epileptic drugs with a sodium channel 
mechanism of action, such as carbamazepine, oxcarbazepine, phenytoin, and lamotrigine, make 
DS worse. 
A review of the treatment modalities used for DS has been published by Chiron and Dulac 
(Chiron and Dulac 2011). This review indicates that valproate is commonly used as a first-line 
agent to prevent the recurrence of febrile seizures and oral/nasal/rectal benzodiazepine is used for 
any long-lasting seizures. However, the authors comment that these agents are most often 
insufficient. These author experts state that lamotrigine, carbamazepine, and high doses of 
intravenous phenobarbital should be avoided because they may worsen seizures and that 
topiramate, levetiracetam and bromide may provide substantial efficacy as adjunctive therapy for 
some patients. The authors comment that the benefit of these compounds is mild and there are no 
trials to validate the impression of any effect. 
Given the cognitive consequences believed to be caused, at least in part, by frequent childhood 
seizure activity, there is a medical need for a new anticonvulsant treatment that can significantly 
reduce seizure activity in DS. There is the possibility that early, effective seizure control could 
be disease-modifying, leading to an improvement in longer-term outcomes with respect to motor 
impairment, behavioral issues, and cognitive function. 
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT 
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of DS. Fenfluramine is an amphetamine analogue that was first 
synthesized many years ago. It was approved in a large number of countries and widely 
prescribed as an appetite suppressant for the treatment of adult obesity. Brand names for 
fenfluramine formulations included Ponderax, Pondimin and others. Fenfluramine was also 
used extensively in an off-label combination with phentermine (“Fen-Phen”). Fenfluramine is 
a racemic compound and the single enantiomer D-fenfluramine (dexfenfluramine) was also 
approved and marketed as Adifax, Redux, and others. 
Fenfluramine was introduced in the USA in 1973. Products containing fenfluramine and D- 
fenfluramine were withdrawn from the USA market in 1997 after reports of heart valve disease 
and pulmonary hypertension (Connolly 1997; CDC 1997; Wong 1998). While the risk/benefit 
PUBLIC 
the au
he au
state tha
state tha
uld be
ld be av
av
d bromid
d bromi
s comm
s comm
sion
sio
COPY 
DS has 
DS has 
cates tha
ates th
seizure
seizure
tho
th
This document 
ix is d
x is d
unctive t
ctive 
ynthesiz
nthesiz
prescr
prescr
fen
fen
cannot 
ng, lea
g, lea
avioral i
vioral
BACK
ACK
dev
dev
be 
a me
me
in DS. 
in DS.
adi
adi
used
nt th
nt t
of any e
f any 
ences b
ences 
dica
dica
to
e may 
e may
hat th
hat th
support 
valpr
valp
and oral
nd ora
s comme
comm
lamotrigi
amotrig
ded beca
ed beca
pro
any 
en publi
en publi
roate
roa
marketing 
, potas
otas
requires a
requires 
zure contr
ure con
common 
ommo
ptic drugs 
c drug
phenytoin
henyto
authorization 
16
io
s 
DS.
te, topi
e, top
si
application 
GRO
RO
loping a n
oping a
eatment o
tment 
ed many y
d many
bed as an 
d as a
luramine 
uramine
exten
exten
and
ng t
g 
ssues, an
ues, a
OUN
UN
any 
eed
eed
here is th
here is t
o an im
an 
d
extensions
ent
ine, car
ne, ca
ause they
ause the
ovide
vide su
su
e bene
benefit
fi
ffect.
ect.
ieved to
eved to
fo
f
or 
nasa
as
that th
that t
b
variations
se
s with a
with a
n, and la
n, and la
ished by
hed by
e is com
is com
al/re
al/r
thereof.
ramate,
mate
um brom
m brom
a combin
combi
trol. It ca
rol. It ca
eizure 
izure 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 28 of 175
relationship for fenfluramine is thus considered unfavorable for the treatment of obesity in adults, 
establishing seizure control in DS or any of the catastrophic childhood epilepsies might lead to a 
more acceptable risk/benefit profile for fenfluramine, especially if lower doses can be used 
successfully. 
As a result of this previous extensive use of fenfluramine, there is a large body of information 
in the public domain concerning its pharmacology, toxicology and use in the treatment of 
obesity (ZX008 IB 2016). There is also a large body of information concerning its clinical 
safety profile. 
1.3
PRECLINICAL DATA 
The pharmacokinetics of fenfluramine, norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The pharmacokinetics in humans differs from that of 
other species, with a longer duration of exposure to both the parent and the metabolite. In vitro 
metabolism studies have shown that there are large species differences in pharmacokinetics and 
metabolism of fenfluramine after oral administration. In humans, fenfluramine is metabolized 
primarily to norfenfluramine. CYP1A2, CYP2B6 and CYP2D6 appear to be the predominant 
CYP enzymes that metabolize fenfluramine to norfenfluramine.  CYP2C9, CYP2C19, and 
CYP3A4 also appear to be involved, but to a lesser degree.  There is also some contribution of 
renal clearance to the elimination of dexfenfluramine (8%-16%) and nordexfenflurmaine 
(7%-8%) from the body.  Because fenfluramine and its major metabolite norfenfluramine have 
multiple pathways of elimination, interference with a single pathway is unlikely to cause a 
significant change in fenfluramine’s clearance though the probability of an interaction increases 
if multiple elimination mechanisms are affected simultaneously. 
While in vitro studies showed that both fenfluramine and norfenfluramine cause weak inhibition 
of CYP2D6 and fenfluramine causes weak induction of CYP3A4 and CYP2B6, further analysis 
based on the FDA’s mechanistic static model shows that fenfluramine and its major metabolite 
norfenfluramine are unlikely to alter the pharmacokinetics of substrates of these CYP450 
enzymes in the range of ZX008 doses that will be administeredin this study.  
A Good Laboratory Practice dose-range-finding juvenile toxicology and toxicokinetic study, 
which included a 3-week repeat dose main study, and histopathology of heart valves and other 
key organs, found no effect on heart valves or other organs. 
Based on clinical signs and decreased body weight gain, the no-observed-adverse-effect-level 
for this study was 12 mg/kg/day. This is equivalent to a human dose of 1.94 mg/kg/day based 
on body surface area, and provides a safety factor of 2.4 for the highest dose of 0.8 mg/kg/day 
that will be administered clinically.
Further details on the preclinical data of ZX008 are available in the Investigator’s Brochure 
(ZX008 IB 2016). The current version is available in the Investigator Study File. 
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT 
Not applicable. 
PUBLIC 
ramin
amin
ed, but to
, but t
on of dex
on of de
ecause fe
cause fe
ination,
ination
ram
ram
COPY
e to bo
to b
large sp
rge sp
nist
nistratio
rati
CYP2B
CYP2B
e t
This document
includ
nclud
y organs,
rgans
Based o
Based 
for th
for t
on
o
cannot 
s mec
me
are unli
are un
he range
range
aborato
borato
de
d
be 
owed
wed
ramine 
ramine
ha
ha
used
inter
nte
ine’s cle
e’s cle
anisms a
nisms a
thth
to
nfluram
fluram
rfere
rfere
support 
n. In h
In 
and CYP
nd CY
norfenflu
norfenf
a lesser d
a lesser d
enfluram
nfluram
mine
i
any 
e pare
e par n
ies diffe
es diffe
huma
hum
marketing 
rea
ning its c
ng its 
eir respect
r respe
in huma
n hum
t
authorization 
16
io
ults,
ts,
d to a 
d to a 
ed 
f informa
nforma
atment
ment
application 
ry Practi
Prac
a 3-week
a 3-wee
found no 
ound no
n clinical 
clinica
is study w
study
body surf
ody su
ill b
ill
and
istst
kely to a
ly to a
f ZX00
ZX00
any 
both
both
uses we
ses w
c static
c stat
t
extensions
ur
degree.
egree
mine (8%
mine (8%
e and its
and its
nce with 
e with
rance th
ance th
re affecte
affecte
fef
or 
2D6
2D
amine
mine
variations 
tive isom
ve isom
ans diffe
ans diff
and the
and the
erences i
ences i
ans, fen
ns, fen
6 ap
ap
thereof. 
tion
of 
inical
ical

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 29 of 175
1.5
RATIONALE FOR CURRENT STUDY 
Based on several published reports of fenfluramine’s successful treatment of refractory childhood 
epilepsy in the 1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and its successful treatment of 
11 refractory pediatric epilepsy patients in Belgium (Boel 1996), in 2002 Drs. 
Ceulemans and Lagae were granted authorization to prescribe fenfluramine to their patients with 
refractory pediatric epilepsy conditions, including DS, under an approved protocol under a 
Belgium government program (Royal Decree). To date, these pediatric neurologists have DS 
patients (infants, children, young adults, and now also adults), being successfully treated with 
fenfluramine 
 The efficacy and safety of this therapeutic approach has been 
reported to be overwhelmingly favorable. In the most recent assessment of efficacy of these 
patients reported by the investigators in 2016, the average length of treatment was over 12 years, 
with one patient being successfully treated for 26 years (Ceulemans 2016). Of the 15 DS treated 
patients, 10 (67%) were reported as seizure-free, with the average time of seizure-freedom being 
6 years (range 1-19 years). Twelve patients (87%) had a greater than 90% reduction in seizure 
frequency and 14 patients (93%) with greater than 70% reduction in seizure frequency. 
In addition, numerous publications discuss the use of fenfluramine in over 500 children with 
neurobehavioral conditions for the treatment of mostly autism and ADHD, without any reports 
of any cardiovascular adverse events (ZX008 IB 2016). 
Prior to being withdrawn from the market, fenfluramine was marketed at doses of 20 mg and 40 
mg three times daily for the management of obesity in adults. The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. Doses tested in 
pediatric studies evaluating autism and ADHD ranged from 0.65 mg/kg/day to 3.6 mg/kg/day, 
but a commonly used dose was 1.5 mg/kg/day. Occasionally, fixed doses of 30 to 80 mg were 
used. The PK exposure associated with the proposed doses in DS studies of 0.2 mg/kg/day and 
0.8 mg/kg/day administered orally (in equally divided doses BID) is expected to be lower than 
that obtained at the doses used in the past for the treatment of obesity in adults and of 
neurobehavioral conditions in children and adolescents (ZX008 IB 2016). The doses used in this 
study are based on the data from the DS patients being successfully treated in Belgium discussed 
above. 
There are no treatments specifically approved for the treatment of DS in the USA, and in fact, 
commonly used anticonvulsants with a sodium channel mode of action, such as phenytoin and 
carbamazepine, worsen the condition. Accordingly, there remains a significant unmet need for an 
approved treatment for children and adults with DS. 
1.6 
RISK-BENEFIT ASSESSMENT 
As described above, fenfluramine has been used successfully for up to 27 years in some DS 
patients to control seizures, without emergence of clinical valvulopathy or pulmonary 
hypertension. Fenfluramine was administered to over 500 children with neurobehavioral 
PUBLIC 
h grea
grea
ns
ns discu
 discu
r r the trea
the trea
rse even
rse even
rom 
rom
COPY
e aver
e av
r 26 year
26 yea
e-free, w
free, w
nts (87%
ts (87%
ater
t
This document
hav
ha
y are ba
re ba
ove.
ve.
There 
There
com
com
cannot
d d 
osure a
ure a
y admini
admin
ed at the
d at th
vioral
ioral
be
mg
ating au
ing a
dose w
dose 
used
the mar
e mar
manage
manag
g/kg/da
/kg/da
to
tme
(ZX00
(ZX0
support 
th the
th
) had a gr
had a g
than 70% 
han 70%
the use o
he use
ent of m
nt of
8
any 
ength 
ength
(Ceulem
Ceulem
e ave
av
marketing 
e to their
o thei
d protoco
protoco
ic neurolo
ic neuro
ng success
g succe
herapeutic
erapeu
sessmen
sessm
of
authorization 
16
io
ry childh
ry child
l treatme
treatme
application 
doses
ose
condition
conditio
d on the d
on the
are no trea
e no tr
monly use
monly u
amazep
amaze
and 
ociate
ciat
tered or
ered or
s us
s us
any 
m and 
m and
s 1.5 mg
s 1.5 m
ed w
d
extensions
r
of fenflu
f fenfl
mostly a
mostly 
IB 2016
B 201
et, fenflu
, fenfl
ment of 
ent of 
n sub
sub
or 
eater
at
ductio
ducti
variations 
sfully
full
c approa
appro
nt of eff
nt of ef
treatme
treatm
f
mans 201
ns 201
rage
age tim
tim
er th
r th
thereof. 
patients w
atients 
ol under 
under 
ogists ha
gists ha
y tre
y tre

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 30 of 175
conditions, including autism and ADHD with good safety and tolerability, most often at a 
1 mg/kg dose. 
The pharmacologic and toxicological profile for the active pharmaceutical ingredient, 
fenfluramine, following oral administration is well established (see ZX008 IB 2016). 
The safety monitoring practices employed by this protocol are adequate to protect the subjects’ 
safety and should detect expected and unexpected treatment-emergent adverse events. 
The approximate volume of blood (108.7 mL) planned for collection from each subject over the 
course of the entire study (Screening to End of Study, but not including repeat or additional tests 
ordered by the investigator) presents no undue risk to the subjects. 
The ZX008 0.2 mg/kg/day and 0.8 mg/kg/day doses are believed to be therapeutic doses, which 
could provide sufficient anti-epileptic support for a sustained period of time during the study. 
The available information suggests that the present clinical study has an acceptable risk-benefit 
ratio. 
2.
STUDY OBJECTIVES AND ENDPOINTS 
2.1
PRIMARY OBJECTIVE 
The primary objective of the study is: 
• 
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive 
therapy in the treatment of Dravet syndrome in children and young adults based 
on change in the frequency of convulsive seizures between baseline and the 
combined Titration and Maintenance Periods (T+M). 
2.2
KEY SECONDARY OBJECTIVES 
The key secondary objectives of the study are: 
• To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy 
in the treatment of Dravet syndrome based on change in the frequency of convulsive 
seizures between baseline and T+M. 
• 
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The proportion of subjects who achieve a 40% reduction from baseline in 
convulsive seizure frequency. 
o
The proportion of subjects who achieve a 50% reduction from baseline in 
convulsive seizure frequency. 
o
The longest convulsive seizure-free interval. 
See Statistical Methods (Section 10.5.1.3) for hierarchical testing procedure. 
2.3
ADDITIONAL SECONDARY OBJECTIVES 
PUBLIC 
IVE 
VE 
tudy is:
tudy is:
at ZX00
at ZX0
men
me
COPY
sen
sent clin
t cl
AND 
AND 
This document
sei
se
To d
To d
su
cannot
ry objec
y objec
emonstr
monstr
the trea
he trea
zure
zure
be 
ONDA
ONDA
used
8 0
of Drav
f Dra
uency of
ncy o
and Ma
nd M
to 
.8 mg
8 mg
support 
ENDPO
NDPO
any 
p
al study 
l study
marketing 
e eve
ev
m each sub
m each sub
g repeat o
repeat 
ed to be th
to be t
eriod o
riod 
authorization 
16
io
ct the su
the su
ents
ents
application 
ment o
ent 
between 
betwee
emonstrat
monstra
perior to p
perior to
o
and
ves of 
s of
e that Z
that Z
of
of
any 
Y OBJE
Y OBJE
the
th
extensions 
kg/day is
g/day is
t syndrom
yndro
convulsi
nvulsi
tenanc
nanc
or 
NT
N
variations 
herapeut
rapeut
of time d
f time d
has an
as an a
TS
TS
thereof. 
bjects
ec
bject ov
ject ov
or additio
r additio

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 31 of 175
Other secondary objectives of the study are: 
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The number of convulsive seizure-free days. 
o
The proportion of subjects who achieve 75% reduction from baseline in 
convulsive seizure frequency. 
o
The change from baseline in non-convulsive seizure frequency.
o
The change from baseline in convulsive + non-convulsive seizure 
frequency 
o
The incidence of rescue medication usage 
o
The incidence of hospitalization to treat seizures 
o
The incidence of status epilepticus. 
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
Clinical Global Impression – Improvement rating, as assessed by the 
principal investigator. 
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver. 
o
The change from baseline in the QOLCE score. 
o
The change from baseline in the PedsQL score. 
o
The change from baseline in the PedsQL Family Impact module score. 
o
The change from baseline in the QoL of the parent/caregiver using the 
EQ-5D-5L scale. 
o
The change from baseline in the affective symptoms of the 
parent/caregiver using the HADS. 
2.4
SAFETY OBJECTIVE 
The safety objective of the study is: 
• To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to AEs, laboratory parameters, physical examination, neurological examination, 
vital signs (blood pressure, heart rate [HR], temperature, and respiratory rate), ECGs, 
ECHOs, and body weight Cognitive Function will be assessed using the cognition 
domain score on the QOLCE and age-appropriate versions of the BRIEF. 
2.5
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective of the study is: 
• To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects ages 
2-6 years and >6-18 years with Dravet syndrome. 
PUBLIC 
igato
gato
bal Impr
bal Impr
regiver.
egiver.
hange fro
hange fro
change
change
COPY 
pticu
ic
nd 0.8 m
d 0.8 m
ng endpo
g endp
pression
ression
r
This document 
ety 
ty
•
To c
To c
r
cannot
Th
T
par
par
SAFETY
AFETY
objec
objec
be
Q-5D-5
5D-
he ch
he c
used
from b
om 
nge from
ge from
ange fr
ange f
5L
5L
to
m base
m base
ba
b
support
nts:
ts:
– Improv
Impro
ession – Im
sion – Im
in
any 
kg/day d
kg/day d
marketing 
equency
quency
vulsive se
lsive s
izures
zures 
authorization 
16
io
ntly)
tly)
m baselin
baselin
application
O
ive of the
ive of th
ompare th
mpare 
gard to A
gard to 
vital sign
vital si
ECHO
ECH
dom
do
and 
nt/care
care
OBJEC
BJE
any 
cale.
cale.
ge from 
e from 
egive
gi
extensions
mprove
mprov
ne in the 
in the 
eline in 
ine in 
baseline
aseline
m basel
base
or 
me
m
variations 
dose grou
se grou
ent ra
ent r
thereof. 
e in
e
izure
ure

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 32 of 175
2.6
EXPLORATORY OBJECTIVE 
The exploratory objective of the study is: 
• To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and 
PK endpoints. 
2.7
STUDY ENDPOINTS 
2.7.1
Efficacy Endpoints 
The efficacy endpoints of the study are: 
• 
Number of seizures by type 
• 
Convulsive seizure-free interval 
• 
Clinical Global Impression – Improvement as assessed by parent/caregiver 
• 
Clinical Global Impression – Improvement as assessed by principal investigator 
• 
QOLCE to measure changes in quality of life of the subject 
• 
PedsQL to measure changes in quality of life of the subject 
• 
PedsQL Family Impact module to measure changes in quality of life of the 
parent/caregiver 
• 
QoL of the parent/caregiver using the EQ-5D-5L scale 
• 
Affective symptoms of the parent/caregiver using the HADS scale 
• 
Duration of prolonged seizures (seizure type that, during baseline, had duration 
>2 minutes) 
• 
Number of episodes of status epilepticus 
• 
Number of instances of rescue medication use and number of doses 
• 
Number of inpatient hospital admissions due to seizures 
2.7.2
Safety Endpoints 
The safety endpoints of the study are: 
• 
AEs 
• 
Laboratory safety (hematology, chemistry, urinalysis) 
• 
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• 
Physical examination 
• 
Neurological examination 
• 
12-lead ECGs 
• 
Doppler ECHOs 
• 
Body weight 
• 
BRIEF to measure cognition 
PUBLIC
change
hang
mpact mo
mpact mo
er r 
parent/ca
parent/ca
sympto
sympto
COPY 
Improvem
mprove
– Impro
– Impr
ges in q
ges in q
s i
This document 
•
•
cannot 
mber
be
Number 
umber 
afety En
ety En
endpoi
endpo
be
)
r of epi
r of ep
of i
of i
used 
ms of 
s of
olonged s
onged s
to
egiver
egiver
the
the
support 
vemen
me
uality of l
lity of
n quality o
quality
dule to m
ule to m
us
any 
ent as ass
nt as as
nt as 
t a
marketing authorization 
16
io
y, safety
safety
application 
nts of th
s of t
AEs 
AEs 
Labor
Lab
Vi
V
•
•
•
and
s
f inpati
inpat
dpoints 
points
h
any
des of
es of st
f
ances o
nces
en
extensions
of 
meas
asure 
ure
sing the E
g the E
paren
arent/c
t/c
eizures (
zures 
or 
fe of
e 
ife of
ife o
variations 
sessed b
essed b
assesse
assesse
f th
f th
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 33 of 175
2.7.3
Pharmacokinetic Endpoints 
The PK endpoints of the study are: 
• 
Steady-state plasma fenfluramine PK parameters (Cmax, AUC0-t, Tmax, and t1/2) 
after administration of ZX008 derived using population PK methods 
3.
INVESTIGATIONAL PLAN 
3.1
OVERALL STUDY DESIGN AND PLAN 
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy, safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young 
adult subjects with Dravet syndrome. Approximately 30 study sites in Europe, Australia, and 
South Korea are planned to participate. The 6-week Baseline Period will consist of the 
establishment of initial eligibility during a screening visit followed by an observation period 
where subjects will be assessed for baseline seizure activity based on recordings of daily 
seizure activity entered into a diary. Upon completion of the Baseline Period, subjects who 
qualify for the study will be randomized (1:1:1) in a double-blind manner to receive 1 of 2 
doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. 
Randomization will be stratified by age group (<6 years, 6 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in each age group. All subjects will be 
titrated to their randomized dose over a 14-day Titration Period. Following titration subjects 
will continue treatment at their randomly assigned dose over a 12-week Maintenance Period. 
Total treatment time from the beginning of the Titration Period through the end of the 
Maintenance Period is 14 weeks. Parents/caregivers will use a diary daily to record the 
number/type of seizures, dosing, and use of rescue medication. A schedule of assessments is 
provided in Table 1. 
At the end of the Maintenance Period (or early discontinuation), all subjects will undergo a 
2-week taper or transition period (Post-Dosing Follow-Up) depending on whether they exit the 
study or are enrolled in the separate long-term open-label extension study. 
A follow-up ECHO, ECG, and possibly physical examination will be performed 3-6 months 
after study drug discontinuation for early termination, or for those subjects who complete the 
study but do not enter the open-label extension study. 
3.2
NUMBER OF SUBJECTS 
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor. 
3.3
STUDY DURATION 
The duration of participation in the study for an individual subject is expected to be up to 
PUBLIC 
mg/k
mg/k
by age g
y age g
% of sub
% of sub
dose ov
dose ov
their ra
their ra
he
he
COPY 
ning v
ning
eizure ac
izure a
completi
omple
(1:1:1
1:1:1)
g/da
g/da
This document
w u
study d
udy d
udy but d
y but d
3.2
3.2
A
cannot
Mainten
ainten
r transitio
ransiti
enrolled
nrolled
up ECH
p ECH
be 
dosi
used 
ndom
dom
beginnin
ginnin
eeks. Par
ks. Par
ing,
ing,
to
ec
a 14-d
a 14-
mly a
ly
support
n of
o
n a doubl
a doub
y; maximu
maxim
oup (<6 y
up (<6 y
ctsts will 
wil
ay
any 
ollowe
ollow
vity based
ity base
f the B
the
marketing 
d, study to
d, study t
y in pediat
n pedi
ites in Eur
es in E
eriod w
eriod 
ed b
d
authorization 
16
io
application
HO, ECG
HO, ECG
g disconti
discon
o not enter
not ent
NUM
NU
proximat
oxim
O
and
nce P
ce P
n period
period
the sep
he se
any 
d u
Period
Perio
extensions
years,
ars, 6
be in ea
be in ea
y Titratio
Titratio
ssigned d
signed d
of the T
the 
f
nts/care
ts/care
se o
se o
or
bli
bl
m dose
m dos
variations
atric 
ric
urope, A
ope, A
ill consi
ll cons
by an ob
by an ob
d on rec
on rec
Baseline 
seline
ind m
ind
thereof. 
o assess t
assess 
and 
and

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 34 of 175
22 weeks, plus follow-up safety visit 3 to 6 months after the last dose: 
• Baseline Period – 6 weeks 
• T+M Period - 14 weeks 
• Post-Dosing Visit – 2 weeks after study completion or early termination 
• Cardiac Follow-up (ECG and ECHO)– 3-6 months after study drug discontinuation for 
early termination or for subjects who complete the study but do not enroll in the 
open-label extension study. 
3.4
NUMBER OF STUDY CENTERS 
The study expects to use up to approximately 30 research centers in Europe, Australia, and South 
Korea. Additional study centers within or outside of Europe, Australia, and South Korea may be 
added if enrollment cannot be completed in a timely manner. 
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT 
GROUPS 
It is recognized that performing clinical studies in young children or in subjects with reduced 
cognitive capacity presents particular practical and ethical issues. However, given the 
seriousness of DS, and the possible consequences of current inadequate treatments, the use of 
children with DS in this study is considered justified. Stratifying the randomization by age group 
is considered appropriate because the frequency and severity of major seizures can be higher in 
younger subjects. The two strata in the study will be subjects aged below 6 years and subjects 
aged 6 -18 years. The study design has incorporated a titration period to enable subjects 
randomized to the high dose group adequate time to acclimate to this dose. Following the 
Titration Period, subjects will enter a 12-week Maintenance Period where they will continue on 
their randomized dose for the remainder of the study. The 12-week duration of the Maintenance 
Period is in keeping with the current standard study duration for evaluating the efficacy of 
chronic medications. Given the individual variability in seizure frequency and seizure type in this 
patient population, the primary endpoint, which seeks to compare an appropriate baseline of 
convulsive seizure frequency to the convulsive seizure frequency following treatment, is an 
appropriate primary endpoint for efficacy in this population. 
Subjects will receive investigational medicinal product (IMP; ZX008 or placebo) in addition to 
their existing antiepileptic medications at their stable doses throughout the entire study. Thus, 
subjects receiving placebo will not be denied active therapy; they will continue to receive their 
existing medications at the exact same dosages. As the principal study measurement (convulsive 
seizures) might be considered subjective, a double-blind study design will prevent subjective 
bias. Upon study completion, eligible subjects will be able to receive ZX008 in an open-label 
extension study for up to 1 additional year of treatment. 
3.6
PREMATURE TERMINATION OF STUDY 
The sponsor can terminate the study prematurely at any time for medical or ethical reasons at 
individual or at all study sites. The investigator will be notified in writing, outlining the reasons 
PUBLIC
l s
ar prac
ar pract
ble conse
e conse
is consid
is consid
ecause th
ecause th
 strata 
 strata 
de
d
COPY 
y
SIGN 
SIGN A
studi
tudies
e
This document 
iate
ate
jects wil
ects wi
heir exis
eir exis
subjec
subjec
exi
exi
cannot 
g with
wit
ons. Giv
ns. Giv
ation, the
ion, th
seizure 
seizure
e prim
prim
be
will
wil
for the 
for the
h th
h th
used 
n the 
the
sign has 
n has 
group a
roup a
l ent
l ent
to
ere
freque
frequ
stu
stu
support 
in young c
n young
al and ethi
and e
quences
ences of
ed ju
d justif
t
nc
any 
D CHO
D CHO
marketing 
ol
in Europe,
Europ
ustralia, an
stralia, 
authorization 
16
io
ntinuatio
nuatio
l in the
in the
application 
frequ
equ
ary endpo
ary endp
receive in
eceive
ing antiep
ng antie
s receivin
receiv
ting medic
ng med
ures) m
res) m
and
cu
c
en the i
n the i
primary
rimary
enc
enc
any 
a 12
a 1
mainder 
mainde
urrent s
rrent
nd
extensions
ical
f curren
curren
fied. Str
fied. Str
cy a
y and s
nd s
dy will b
y will b
ncorp
corpora
or
equate t
quate 
2-w
2 w
or
hildre
hildr
 issu
issu
variations 
, Aus
Aus
and South
d Sout
ICE OF
CE OF
en
thereof. 
n fo
stra
tra

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 35 of 175
for the termination. Instructions will be provided if assessments beyond those described in the 
study protocol need to be conducted. 
If the study is terminated prematurely for any reason, the investigator should promptly inform 
the subjects participating at his or her study site and should ensure that appropriate alternative 
therapy is available and that End-of-Study procedures are conducted, as described in 
Section 6.2.9 and Section 6.3. 
All study materials including investigational medicinal product (IMP) and completed, partially 
completed, and blank documentation, except documents needed for archiving requirements, will 
be returned to the sponsor. The study monitor will ensure that any outstanding data clarification 
issues and queries are resolved, and that all study records at the study site are complete. 
In accordance with applicable regulatory requirements, the sponsor will promptly inform the 
competent regulatory authorities of the termination and its reason(s), and the investigator or 
sponsor will promptly inform the Independent Ethics Committee (IEC)/IRB. 
3.7
STUDY MONITORING PROCEDURES 
3.7.1
Independent Data and Safety Monitoring Committee 
The IDSMC is an independent advisory body that monitors participant safety, data quality and 
progress of the clinical trial. The IDSMC charter will outline the roles and responsibilities of the 
committee and guide its operations and frequency of meetings. The IDSMC will consist of 
individuals external to the sponsor who have relevant clinical trial expertise and experience in 
safety assessment. 
At regularly defined intervals, the IDSMC will convene to review and monitor study progress, 
AEs and SAEs, other measures of safety such as ECGs or ECHOs, and efficacy data as dictated 
by the charter. 
The IDMSC will: 
• 
Be responsible for providing recommendations to the sponsor surrounding 
study conduct matters that affect safety. 
• 
Review safety data at ad hoc time points and identify if significant safety 
concerns arise during the study. 
• 
Review pharmacokinetic data and any other data that may affect subject 
continuation. 
• 
Make recommendations regarding the continuation, suspension, or termination 
of the study. 
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) 
The IPCAB is an advisory body to the sponsor that monitors cardiac safety of the ZX008 clinical 
trials and provides advice to the IDMSC. The IPCAB charter outlines the roles and 
responsibilities of the committee and guides its operations, and review of individual subject 
PUBLIC
d Safe
d Safe
advisory 
advisory
The IDS
he IDS
perations
peration
spon
spo
COPY
n an
a
Ethics C
Ethics 
OCEDU
OCED
This document 
•
cannot 
l:
Be r
Be r
s
be
vals
measure
measure
used
an
an
or who
who
r
s, the
s, the
to 
MC ch
C c
nd freq
d freq
h
support 
RES
ES 
Monitori
Monito
ody that 
dy that 
harte
har
any 
eason
easo
mmittee 
mmittee
marketing
complete
complet
hiving req
ving re
utstan
tstanding
din
udy site ar
dy site 
nsor will
nsor wi
n(s),
n(
authorization 
16
io
y inform
inform
e alterna
alterna
describ
describ
application
espo
p
udy cond
dy con
Review s
Review
conce
conc
Re
R
•
and 
onsib
nsib
any
DSM
S
f safety
f safet
extensions 
ing g
monitor
monitor
r will ou
will ou
uency of
ency of
ave relev
ve relev
MC 
MC
or 
Com
Com
variations 
are com
com
l promp
l promp
, and the
nd the
(IEC)/IR
IEC)/I
thereof. 
ed 
ed, partia
, partia
quiremen
reme
data cla
data cla
mp
mp

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 36 of 175
cases. The IPCAB consists of individuals external to the sponsor who have relevant experience in 
cardiology, pediatric cardiology, and echocardiography. The IPCAB will advise the sponsor and 
the IDSMC on the cardiac safety monitoring plan, including alert criteria and decision pathway 
for subject management relative to cardiac safety in the clinical studies of ZX008. 
All ECHO examinations performed throughout the trial will be sent to an experienced pediatric 
cardiologist central reader (Biomedical Systems, Inc.). If the central reader classifies a subject as 
having met a pre-defined threshold value indicative of potential cardiac valvulopathy or 
pulmonary hypertension, or any other unexpected cardiac adverse event, the case will then be 
sent for secondary adjudication by one or more members of the IPCAB according to the 
procedures outlined in the IPCAB manual. In addition, member of the IPCAB will perform audits 
of ECHOs deemed normal by the central cardiac reader. 
4.
SELECTION OF STUDY POPULATION 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Before evaluating these criteria and deciding on the eligibility 
of subjects to participate in the study, it is important that the investigator is familiar with the 
safety profile of ZX008 by referring to the Investigator’s Brochure, as supplied by the sponsor. 
4.1
INCLUSION CRITERIA 
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug. 
2. Subject must have documented medical history to support a clinical diagnosis of Dravet 
syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs. 
3.
Subjects must meet all of the following 5 criteria: 
a.
Onset of seizures in the first year of life in an otherwise healthy infant. 
b. A history of seizures that are either generalized tonic-clonic or unilateral clonic 
or bilateral clonic, and are prolonged. 
c.
Initial development is normal. 
d. History of normal brain MRI without cortical brain malformation. 
e.
Lack of alternative diagnosis. 
4. Subjects must meet at least one of the following 3 criteria: 
a.
Emergence of another seizure type, including myoclonic, generalized tonic- 
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type. 
PUBLIC
to the 
o the
TERIA 
TERIA
followin
followin
non-p
non
COPY 
U
basi
basis of 
s of 
aluating
aluating
s impo
impo
In
This document
yn
y
antie
antie
3.
Su
Su
cannot
use
us
bstinen
tinen
y drug. 
drug. 
ject mus
ct mus
ndrome
drom
be
fe
regnan
egnan
e med
e med
used
g
regnant
egnant
ng Visit
g Visi
eding.
eding.
to
inclus
inclus
support 
hese c
ese c
tant that th
t tha
vestigator
stigato
any 
ON
inclusio
inclusio
crite
crit
marketing 
ss
vulopath
ulopat
the case w
he case w
B accordin
accord
the IPCAB
e IPCA
N
authorization 
16
io
e inin
r and 
r and 
athway
hway
nced ped
ed ped
ifies a 
fies a 
h
application
hav
, where c
, where 
leptic drug
ptic dr
bjects mus
ects mu
a.a.
Ons
O
b.b
A
and 
, whil
whi
ve do
ve do
any 
e
est. Su
est. S
ally acce
lly acce
le be
e b
extensions 
s 
n criteri
criter
non-lacta
on-lact
Female 
emale
male s
male 
or 
e inv
e in
Broc
Broch
variations 
B w
on and e
n and e
ria and 
ia and 
ves
thereof.
iatr
subject 
bject 
y or r 
will then
ill then
ing to the
ng to th
will p
will p

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 37 of 175
b. Prolonged exposure to warm temperatures induces seizures and/or seizures are 
associated with fevers due to illness or vaccines, hot baths, high levels of 
activity and sudden temperature changes and/or seizures are induced by strong 
natural and/or fluorescent lighting, as well as certain visual patterns. 
c.
Genetic test results consistent with a diagnosis of Dravet syndrome (pathogenic, 
likely pathogenic, variant of unknown significance, or inconclusive but unlikely 
to support an alternative diagnosis.) 
5. Subject must have had 4 convulsive seizures (tonic, tonic-atonic, tonic-clonic, clonic) 
per 4-week period for past 12 weeks prior to screening, by parent/guardian report to 
investigator or investigator medical notes. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable for 
at least 4 weeks prior to screening and are expected to remain stable throughout the 
study. 
7. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
8. Subject has provided assent in accordance with Institutional Review Board (IRB) 
requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, 
visit schedule and study drug accountability. 
4.2
EXCLUSION CRITERIA 
Subjects meeting any of the following exclusion criteria must not be enrolled into the study: 
1.
Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication.
2.
Subject has pulmonary arterial hypertension. 
3.
Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke. 
4.
Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within 
the prior year that required medical treatment or psychological treatment for a duration 
greater than 1 month. 
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, 
based on clinical interview and/or responses provided on the C-SSRS. Subjects must be 
excluded if they report suicidal behavior in the past 6 months as measured by the C- SSRS 
at Screening or Baseline, which includes suicidal ideation with intent and plan (Item #5). 
If a subject reports suicidal ideation on Item 4 without a specific plan, and the investigator 
feels that the subject is appropriate for the study considering the potential risks, the 
investigator must document appropriateness for inclusion, and discuss with the 
parent/caregiver to be alert to mood or behavioral changes, especially around times of 
dose adjustment. 
6.
Subject has a current or past history of glaucoma. 
7.
Subjects with moderate or severe hepatic impairment may not be entered. Asymptomatic 
subjects with mild hepatic impairment (elevated liver enzymes < 3xULN and/or elevated 
PUBLIC
willing
willin
rug acco
rug acco
CRITER
CRITER
he foll
he fo
COPY
of the 
of the
parent/g
paren
ordan
ordance 
ce 
This document
grere
Subje
Subj
bas
ba
cannot 
curre
urr
alvulopa
lvulopa
ct has cu
has cu
prior ye
prior ye
ater th
ter th
be
monary
monary
ent o
ent
used
wing e
ng e
hypersen
ypersen
to 
IA 
A
support 
with Ins
th In
nd able to
d able
untability.
tability.
any
dy and i
y and
rdian.
dian
stitu
t
marketing 
tonic-clo
tonic-clo
nt/guardia
/guard
t
KD and VN
D and V
emain sta
main s
authorization 
16
io
trong
ong
me (patho
(patho
sive but
ive bu
application
ar thth
an 1 mon
an 1 mo
t is at imm
is at im
d on clini
on cl
xcluded i
cluded
at Scree
at Scre
If a s
If a s
fef
and
r p
r p
hy, my
y, my
rent or r
ent or 
hat r
at r
any 
terial hy
erial h
ast hi
ast hist
oc
extensions 
o be
lusion cr
lusion c
sitivity t
tivity t
or 
com
com
variations
NS) mu
) m
able thro
ble thro
nformed 
formed
utional R
ional R
thereof. 
unlike
unlik
nic, clon
c, clon
an report
an repor
us

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 38 of 175
bilirubin <2xULN) may be entered into the study after review and approval by the 
Medical Monitor in conjunction with the sponsor, with consideration of potential cause, 
concomitant medications, and other risk factors. 
8.
Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine-oxidase inhibitors; any centrally-acting compound with clinically appreciable 
amount of serotonin agonist or antagonist properties, including serotonin reuptake 
inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; or cyproheptadine 
(see Appendix 1). (Note: Short-term medication requirements will be handled on a per 
case basis by the Medical Monitor.) 
9.
Subject is currently receiving or has received stiripentol in the past 21 days prior to 
Screening. 
10. Subject 
is 
currently 
taking 
carbamazepine, 
oxcarbamazepine, 
eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy. 
11. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with the Baseline Period and throughout the study. 
12. Subject has positive result on urine THC Panel or whole blood CBD at the Screening 
Visit. 
13. Subject has participated in another clinical trial within the past 30 days. 
14. Subject is currently receiving an investigational product. 
15. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions. 
16. Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than 
epilepsy, that would negatively impact study participation, collection of study data, or 
pose a risk to the subject. 
4.3
RANDOMIZATION INCLUSION CRITERIA 
Subjects must meet all of the inclusion criteria above plus the following criteria, to be 
randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have a cardiovascular or cardiopulmonary abnormality based on ECHO, 
ECG or physical examination, including but not limited to trace mitral or aortic, valve 
regurgitation or signs of pulmonary hypertension, and is approved for entry by the central 
cardiac reader. 
3. Subject demonstrates a stable baseline with 6 convulsive seizures during the 6-week 
Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the second three 
weeks. 
4. Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (eg, at least 90% compliant). 
rin
n another
another
eiving
eiving a
or unab
or unab
sts, oth
sts, oth
COPY 
en n
arge or 
arge o d
g with th
g with th
ne THC
e TH
This document
Subje
Subj
2. Sub
Su
cannot 
NDOMI
DOM
st meet 
t meet 
d:
be 
uld ne
d n
he subje
he subje
used 
r stud
stud
y signifi
signifi
illness 
llness
ega
ega
to
in
to com
to co
dy
dy
support 
Baseli
Basel
Panel or 
Panel o
clinical tr
inical tr
nvestiga
vestig
mp
any 
thth
y servin
serv
ine
i
marketing 
st; or
t; o
ill be ha
ill be ha
e past 21 
 past 2
xcarbama
carbam
ese w
ese 
authorization 
16
io
use, 
use,
ctic ag
ctic ag
ally appr
y app
erotonin
otonin
r cy
cy
application 
ll 
t has been
has bee
ject does n
ject doe
ECG or ph
CG or p
regurgit
regurg
cardi
cardi
Su
S
and
ATION
ATIO
of the 
f the
any 
vely i
ely
N
extensions
rial with
al wit
ational p
ational p
ply with 
with 
rocedure
ocedure
ant cond
t cond
the 4 w
he 4 w
m
or
whole
whol
variations 
azepine, 
zepine, 
within th
ithin 
ngs of gr
s of gr
Period 
eriod 
e b
thereof. 
reupt
reup
prohepta
hepta
ndled on
dled on
days pri
ays pr

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 39 of 175
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL 
Male subjects who are sexually active with a partner of childbearing potential must use, with their 
partner, a condom plus an approved method of highly effective contraception from the time of 
informed consent until 90 days after the last dose of study drug.
The following methods are acceptable: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (ie, condom for male partner): 
í
oral 
í
intravaginal 
í
transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation and a barrier 
method (ie, condom for male partner): 
í
oral 
í
injectable 
í
implantable intrauterine device 
í
intrauterine hormone-releasing system 
• Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Female subjects who are not of child-bearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential, unless they are at least 2 years 
post-menopausal or permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. 
Female subjects who are sexually active and are of child-bearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed 
consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (i.e., condom for male partner): 
í
oral 
í
intravaginal 
í
transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation and a barrier 
method (i.e., condom for male partner): 
í
oral 
í
injectable 
í
implantable intrauterine device 
í
intrauterine hormone-releasing system 
• Surgical sterilization (vasectomy or bilateral tubal occlusion) 
PUBLIC 
eleasi
leas
my or bi
my or bi
t of chil
t of chil
s consi
s consi
en
en
COPY 
vice
vice
ng
This document 
biti
iti
í
•
cannot
m
ays afte
ys afte
method
method
ned (est
ed (est
on o
on o
be
e sexua
exu
ethod 
ethod 
used 
dered 
ed 
ly sterile
sterile
bilateral
lateral
allll
to
bearin
bearin
of c
of
support 
system
ystem
ateral tuba
eral tub
any marketing 
on assoc
asso
tner):
ner):
inhibitio
nhibit
authorization 
16
io
h their 
their 
me of 
e of 
ci
application 
ogen a
gen 
ovulation
ovulati
oral
ral
í
intrav
intra
í
tra
t
Progestog
rogesto
method
method
and 
the la
e l
are acce
are acce
an
an
any 
active 
activ
highly e
highly 
ast do
ast d
extensions
al occlu
 occl
potentia
tentia
hildbear
ildbear
Perman
erman
oophore
ophore
or variations 
n of 
n of ovu
ov
thereof. 
ated with
ed with

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 40 of 175
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, they must comply with the contraceptive requirements detailed above. 
4.4.1
Sperm and Egg Donation 
Male subjects should not donate sperm and female subjects should refrain from egg donation 
for the duration of the study and for at least 90 days after the last day of study medication 
administration. 
4.4.2
Pregnancy 
Subjects will be instructed that if they/their partner become pregnant during the study this should 
be reported to the investigator. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject/subject’s 
partner is subsequently found to be pregnant after the volunteer is included in the study, then 
consent will be sought from the partner and, if granted, any pregnancy will be followed and the 
status of mother and/or child will be reported to the sponsor after delivery. 
Any subject reporting a pregnancy during the study will be withdrawn from the study and should 
complete the taper schedule. 
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the study for any reason at any time. They may be considered withdrawn if they 
fail to return for visits, or become lost to follow-up for any other reason. 
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 electronic case report form (eCRF). All subjects who withdraw from the study 
with an ongoing 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 (ie, 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). 
Subjects must be discontinued from the study for the following reasons, if deemed appropriate by 
the sponsor or investigator: 
1. Development of signs or symptoms indicative of cardiac valvulopathy or regurgitation 
(mitral, aortic, tricuspid, pulmonary valves), or pulmonary hypertension for which 
IDSMC, in consultation with the IPCAB, the central cardiac reader, and the investigator 
believe the benefit of continued participation does not outweigh the risk. 
PUBLIC
during t
during 
F SUBJ
F SUBJ
ged 
ge
COPY
of the
of th
after the 
fter the
d, if gr
if gran
a
orted to 
rted to 
This document 
uldld
subjects
ubjects
ailed to a
led to 
should
shoul
the 
the 
cannot 
ary re
y r
he electr
e electr
ng AE m
g AE m
prematu
rematu
be co
be co
be
al occur
al occu
easo
easo
used
o comp
comp
any reaso
y reas
come l
come l
to
CTS F
CTS 
support 
ed, an
d, a
he spons
 spons
e stud
study wi
y w
d
R
any 
y. In th
y. In 
lunteer 
lunteer i
ny pr
ny
marketing 
dy medi
med
gnant duri
nant du
notified
notifi
he
authorization 
16
io
heir 
heir 
egg don
gg do
i
application
ely a
ly 
lected at
lected a
who are lo
ho are
ppear for 
ppear fo
show "du
how "d
ubject (eg
bject (e
ects m
cts
and
n f
nic cas
ic cas
ust be fo
st be f
after
after
any 
or any r
or any
or a
r a sub
s
e r
extensions 
ill be
l b
ROM TH
M TH
te all stu
all stu
n at any 
at any 
to fol
o fo
or 
r aft
a
e wi
e w
variations 
ing the s
g the 
d of preg
d of pre
e event t
e event t
is includ
s includ
regnanc
egnanc
ter d
er
thereof. 
ation
ion
ation
on 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 41 of 175
2. Subject is found to have entered the clinical investigation in violation of the protocol. 
3. Subject requires or starts using the use of an unacceptable or contraindicated 
concomitant medication. 
4. Subject’s condition changes after entering the clinical investigation so that the subject no 
longer meets the inclusion criteria or develops any of the exclusion criteria. 
5. Subject is noncompliant with procedures set forth in the protocol in an ongoing or 
repeated manner. 
6. Subject experiences an AE that warrants withdrawal from the clinical investigation. 
7. Clinically significant worsening of seizures, judged by investigator or subject/caregiver 
such that treatment outside of the protocol and other than ZX008 is assumed to be in the 
subject’s best interest. Frequent or increased use of rescue medication may be considered 
indicative of worsening. 
8. An “actual suicide attempt” as classified by the Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
10. Subject is found to be pregnant while on study. 
Discontinuation decisions will be made at each participating site by the site investigator, except 
that discontinuations due to development of cardiovascular or cardiopulmonary complications are 
to be made by the IDMSC with input from the IPCAB and the investigator. 
If feasible, the process of discontinuation should be discussed with the Medical Monitor. The 
decisions regarding the discontinuation of the investigational therapy, whether the study 
medication should be stopped immediately or tapered should be discussed with the Medical 
Monitor, but final decisions about the process will remain at the discretion of the site principal 
investigator. 
Subjects who are discontinued from the clinical investigation for any reason will not be 
replaced. 
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. Subjects must be 
discontinued from receiving ZX008 and/or participating in any further study procedures under 
the following circumstances: 
• The subject or the subject’s legally authorized representative wishes to discontinue 
participation in the study. 
• The investigator advises that the subject’s safety or well-being could be 
compromised by further participation in the study. 
• The sponsor requests that a subject discontinues participation in the study (eg, due 
to suspicion of fraud, multiple enrollments in clinical studies, lack of compliance, 
etc). 
PUBLIC 
t w
t w
made at 
made at
velopmen
velopmen
with input
ith inpu
discon
discon
COPY 
y the
th
is not in 
s not i
hile o
hile o
This document
he r
e 
tudy wi
dy wi
scontinu
continu
the follo
he foll
cannot
discont
scont
ay withd
y withd
reason
eason
be 
ons a
ns a
used
inuatio
uatio
tinuation
nuation
d im
d imme
me
bou
bou
to
from t
from 
on
support 
he 
he 
n study. 
study.
ach part
ch partici
of car
f cardio
dio
the I
h
any 
mbia
mbi
subject
ubje
marketing 
al investi
al invest
ator or sub
or or su
008 is ass
08 is a
medicatio
edicat
-Sui
-S
authorization 
16
io
subject n
subject n
going or
oing o
application
raw t
w 
for doin
for doin
not prejud
ot preju
d from re
d from 
wing circu
wing cir
•
Th
T
and 
ued fr
ed f
their
their
any 
he pr
he p
rom 
om
extensions
cipatin
patin
ovascula
vascula
IPCAB 
PCAB
hould
ould be
be
d
of ththe in
e in
ately or
tely o
roc
roc
or variations
sum
on may
n may
icide Sev
ide Sev
t’s be
s best i
st i
thereof. 
gation.
ation.
bject/car
bject/car
med to
med to

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 42 of 175
The IDSMC may request that the study be terminated after review of the safety information at 
any time during the study. The IDMSC will review the data for the development of heart valve 
disease and pulmonary hypertension as they occur on a case-by-case basis and at regular 
meetings. 
In the event that the study is terminated prematurely then the procedure for termination should 
be followed as described in Section 3.6. 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 eCRF 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. Specific procedures required are described in Section 6.2.9 and Section 6.3. 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. 
4.6
TERMINATION OF THE CLINICAL 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 continues, then the clinical 
study may be terminated. The clinical 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 clinical 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. 
4.7
REPLACEMENT OF SUBJECTS 
Enough subjects will be enrolled in the trial to ensure that approximately 105 subjects are 
randomized into the T+M Period.  Randomized subjects will not be replaced. 
4.8
ELIGIBILITY FOR EXTENSION STUDY 
Subjects who complete the 12-week Maintenance Period of this study will be eligible to enroll 
in a planned, separate, open-label extension trial of ZX008 if they meet Inclusion/Exclusion 
criteria for that study regarding their suitability for continued participation in a trial of 
PUBLIC 
col.
col
bject dis
bject di
ubjects c
ubjects c
s are exp
are exp
COPY
edur
du
the study
he stud
described
escrib
ust be
ust be pe
p
This document
The
Th
the c
the c
•
Fai
Fa
•
4.7
4.7
cannot 
nated
ated
absence 
sence 
hat may 
at may
e disco
disco
be
onso
nso
a possib
a possib
T
used 
N OF T
OF T
or, th
or th
to
erience
rienc
support 
in n 
rformed
formed
continue
ontinues
mpleti
pleting
ng
ed b
d
any 
ally
ally
 discont
 discon
Secti
Section
marketing 
t w
dy must b
y must 
k of comp
of com
ve should
e shoul
requ
re
authorization 
16
io
alve
alve
nation sh
tion sh
will alw
ill alw
application
wa
very of a
very of 
nical study
cal stud
ure to enr
ure to en
A decision
decisio
RE
R
ugh su
gh su
and
e c
e 
f such 
such 
arrant t
rrant 
any 
Med
Me
hazard t
azard
linical 
linica
fi
extensions
partici
partic
g the stu
g the stu
by a subj
y a sub
HE CLI
E CLI
dica
dica
or variations 
d conf
conf
uired at t
ired at 
tinued or
nued o
n 6.2.9 a
6.2.9 a
all sub
all sub
thereof. 
oul
ways
ys 
be record
recor
liance, l
iance, l
firm
irm

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 43 of 175
fenfluramine. 
Subjects must complete the entire 12-week Maintenance Period in order to be offered 
enrollment into the separate, open-label extension trial of ZX008. Those subjects who do not 
complete the 12-week Maintenance Period of the study may, on a case-by-case basis, be eligible 
for entrance into the separate open-label extension study after consideration of the 
circumstances of the early termination and the potential benefit-risk of continued participation 
in a ZX008 trial. The decision whether to permit open-label extension study participation 
resides solely with the sponsor, who may consult with the site investigator, the IPCAB and/or 
the IDSMC. 
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION 
ZX008/matching placebo will be administered in the current study. A brief description of the 
ZX008 product is provided below (Table 2). 
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 1.25, 2.5, and 5 mg/mL 
Route/Mode of Administration 
Oral
Manufacturer
PCI Pharma Services on behalf of Zogenix 
International Limited 
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 
and provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. The excipients selected 
have been approved for use in the formulations of currently marketed drug products and are 
considered to be safe. The solution formulations will be suitably flavored and colored, and will 
contain preservatives and a thickening agent. The product is sugar free and is intended to be 
compatible with a KD. 
The formulation will be provided in bottles with tamper-evident, child-resistant caps. The clinical 
trials material will be supplied in 1 bottle size with nominal fill volume of 120 mL. Matching 
placebo also will be provided. Doses to be studied include 0.2 mg/kg/day and 
0.8 mg/kg/day divided into two daily (BID) doses, up to a maximum of 30 mg/day. An 
intermediate dose of 0.4 mg/kg/day will be used for titration. The concentration of ZX008 oral 
solution received by subjects (1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) will be randomized 
across the 3 available concentrations in order to ensure blinding. 
PUBLIC 
C
LIC
BL
UB
ge form 
ge form 
PU
n
P
COPY
inin the c
the 
Produc
Produc
This document
n
dered t
red t
ntain pre
in pre
compati
ompati
The
The
trtr
cannot 
TITY 
ITY 
roduct is
oduct is
d in con
in con
approv
ppro
be 
O
used 
nd str
d st
d
ed
u
to 
o
rengt
eng
to support 
– ZX00
– ZX0
Stud
Stu
p
ZX
Z
up
su
s
any 
ent stud
nt stu
marketing 
ed
y particip
partic
or, the IPC
r, the IPC
ODUCT
ODUC
authorization 
16
io
do not 
not 
s, be elig
be elig
d partic
partic
application
cent
ed for us
d for u
e safe. Th
safe. 
ervatives 
rvative
le with a 
e with 
formulatio
rmulat
s materi
mate
o a
and 
 IN
IN
an oral a
n oral a
tratio
ratio
any y
VEST
VES
extensions 
y Pro
Pr
008
08
s
Fenfluram
Fenflura
on
Not ap
ot ap
io
)
Sol
So
ns
en
xte
e
or 
du
du
o variations 
T INFO
T INF
y. A brie
A brie
thereof. 
ipation
ation
ation
on 
CAB and
AB and

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 44 of 175
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. Care must be taken not to overdose. 
If the amount spilled is not known, the parent/caregiver should not give additional medication to 
avoid potential overdose. 
5.1.1 
Labeling and Packaging 
The ZX008 product will be packaged and labeled according to current International Conference 
on Harmonization (ICH), Good Manufacturing Practices (GMP), and Good Clinical Practices 
(GCP) guidelines, and national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO 
Placebo solution is identical in aspect and composition to ZX008 and is composed of identical 
ingredients used in the ZX008 formulation, except that it does not contain the active ingredient, 
fenfluramine hydrochloride. 
No comparators or reference treatments will be used. 
5.2.1 
Labeling and Packaging 
Placebo solution will be packaged in an identical manner to ZX008. The matching placebo 
product will be packaged and labeled according to current ICH, GMP, and GCP guidelines, and 
national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.3
SHIPMENT AND STORAGE 
IMP will be supplied to the study sites by the sponsor or its delegate. 
All IMP will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
pharmacy, the site’s standard operating procedures, and applicable regulations. IMP must be 
stored separately from normal hospital or practice inventories, in a locked facility with access 
limited to the investigator and authorized personnel. The investigator must ensure that the IMP is 
dispensed only to subjects enrolled in this study according to this study protocol. 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug. Study medication must be 
stored at 15-25°C (59-77°F) with excursions of 5-30°C (41-86°F) permitted; do not freeze. 
Storage and handling instructions of the IMP maintained at the subject’s home are described in 
PUBLIC 
lation
ation
reatment
reatment
nd Pack
d Pack
COPY
E TRE
E TRE
d compo
d compo
n, ex
n ex
This document 
ll be
b
IMP wil
MP wi
container
ntaine
pharm
pharm
sto
sto
cannot
r thth
he inves
e inves
SHIPM
SHIPM
e sup
e sup
be 
nts. 
s. 
e pro
e pr
used 
aging
ging
aged in a
ged in a
d labele
d label
to 
w
g
support
sition to Z
tion to
cept that i
pt that
will be u
ll be 
any 
MENT
MENT
marketing 
ternationa
ernationa
Good Clin
ood Cl
ling instru
ng inst
authorization 
16
io
d 
ve the 
ve the 
erdose. 
dose. 
dication
dication
application 
EN
plied to th
lied to t
be transp
e trans
or produc
or produ
acy, the si
y, the 
ed separat
d separa
ed to t
ed to 
and
igator.
ator.
NT AN
T AN
any 
ct can b
t can
extensions 
used.
sed.
identic
identic
accord
ccor
or
X0
does n
does 
variations 
uctions f
tions 
, COMP
COMP
008 a
008
thereof. 
al Confe
Confe
nical Pra
nical Pra

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 45 of 175
the subject’s IMP handling instructions. 
All unused IMP will be saved by the site for final disposition according to the sponsor’s 
directive. 
5.4
IMP ACCOUNTABILITY 
The investigator or delegate will confirm receipt of all shipments of the IMP in writing using 
the receipt form(s) provided by the sponsor or vendor. 
Assignment of ZX008 or placebo to the subject will be handled through an interactive voice 
randomization (IVR) or Interactive Web Response (IWR) platform. The investigator or delegate 
will be required to register the subject through IVR/IWR and all study medication will be 
assigned to the subject through the IVR/IWR. The IVR/IWR will also maintain a log of all 
received and dispensed medication. 
All supplies must be accounted for throughout the study using the drug accountability form 
provided by the sponsor before the start of the study. At the end of the study, the dated and 
signed (by the investigator or delegate, eg, pharmacist) original drug accountability form must 
be retained at the study site as verification of final drug accountability. 
Records for the delivery of the IMP to the study site, the inventory at the study site, the use by 
each subject (use by subject will be documented in the subject diary), and the destruction or 
return of the IMP to the sponsor must be maintained by the investigator (or delegate). The 
records will include dates, quantities, batch numbers, and unique code numbers assigned to the 
IMP and to the subjects. The investigator must maintain records documenting that subjects were 
provided with the doses of the IMP specified in this study protocol. Furthermore, the investigator 
must reconcile all IMPs received from the sponsor. The investigator must provide reasons for 
any discrepancies in drug accountability. Forms will be provided by the sponsor to ensure 
standardized and complete drug accountability. 
5.5
TREATMENT ADMINISTRATION 
5.5.1
Randomization 
Upon completion of the Baseline Period, subjects who qualify for the study will be randomized 
(1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 
0.8 mg/kg/day; 30mg/day maximum) or placebo. The randomization will be stratified by age (<6 
years, 6 years) to ensure balance across treatment arms, and at least 40% of subjects will be in 
each age group. Subjects will be assigned a randomization number by the IVR/IWR system upon 
confirmation that subject qualifies for enrollment in the Titration Period. Once a randomization 
number is assigned to a subject, the site will record the subject’s initials and identification 
number on the corresponding study drug bottles. Each bottle will contain the assigned treatment 
(ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or placebo). ZX008 and placebo will be identical, 
thus rendering the study drug and placebo indistinguishable. For each IMP bottle and 
randomization number assigned, the following information will be recorded on the drug 
PUBLIC 
ation 
ation
MP to the
MP to the
ill be do
ill be do
onsor mu
onsor mu
quant
quant
i
COPY 
t the stud
the stu
the
he study
stud
g, pha
g, pharm
rm
of
of
This document
n compl
compl
1:1:1) in 
1:1) in 
0.8 mg
0.8 mg
yea
yea
e
cannot 
omple
mpl
REATM
EATM
Rand
Ran
be
ecei
ce
ug acco
ug acc
ete
ete
used 
ties, ba
s, b
nvestigat
vestigat
he IM
e IMP 
P 
ved
ved
to
um
be ma
be m
atc
atc
support 
. At t
At 
acist) ori
cist) or
inal drug 
nal drug
study 
udy site
si
mented 
ented
any 
using th
using th
the en
the
marketing 
n w
h an inter
an inte
The inves
The inv
study med
udy m
will also m
ll also
authorization 
16
io
writin
ritin
application 
omizatio
mizat
tion of the
on of t
a double-b
a double
kg/day; 30
g/day; 
s, 6 years
6 yea
h age gr
age g
ma
and 
rug
ru
ENT AD
NT A
any 
om t
om 
ntability
ntability
g accou
acco
extensions
e, the in
the in
in the su
in the su
tained b
ained b
h number
number
or must 
must m
ecified 
cified
the
the
or
inal
na
ccount
coun
variations
st
dication
icatio
maintain
intain
he drug a
drug a
nd of th
of th
al dru
l dr
thereof. 
g using
sing
ractive v
active v
igator 
gator 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 46 of 175
accountability form: subject initials, unique bottle number, date each bottle is assigned, and drug 
used and unused during the study. 
5.5.2
Titration Period 
The investigator (or delegate) will dispense IMP only to subjects included in this study 
following the procedures set out in this study protocol. 
Study medication will be administered as equal doses BID in the morning and in the evening 
approximately 12 hours apart, with food. Each dose should be separated by a minimum of 8 
hours and a maximum of 12 hours. A missed dose of study medication may be taken later up to 
8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
Administration of the IMP will be based on the randomized dose and subject’s weight (kg) at 
Visit 3 (Study Day -1). At Visit 8 (Study Day 43), if the subject’s weight (kg) has changed 
±25% of the weight at Study Day-1, the IMP dose will be recalculated. Subjects should be 
dosed using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups (Section 5.6) and allow step titration to the 
high dose, the dose for each subject will be titrated starting with a dose of ZX008 
0.2 mg/kg/day (or placebo equivalent) BID. After 4 days at this dose level (Study Day 5), 
subjects randomized to the ZX008 0.8 mg/kg/day group will increase their dose to 0.4 
mg/kg/day (maximum 30 mg/day) while doses in the other two groups will remain constant. On 
Study Day 9, the dose for the 0.8 mg/kg/day group will increase to the target dose or a 
maximum of 30 mg/day. The titration is expected to take a total of 14 days (Table 3). A new 
bottle of IMP will be started by the subject at each level of the titration step. See Section 5.6 for 
more information about the volume of ZX008 or placebo to be administered. 
Table 3 
Titration Algorithm 
Randomized Group 
Titration Step 1
Study Day 1-4 
Titration Step 2
Study Days 5-8 
Titration Step 3
Study Days 9-14 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.8 mg/kg/day 
Placebo 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg 
5.5.3
Maintenance Period 
After completion of the Titration Period, subjects will enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an additional 
12 weeks. Study medication will continue to be administered BID in the morning and in the 
evening, approximately 12 hours apart, with food. Each dose should be separated by a 
minimum of 8 hours and a maximum of 12 hours. A missed dose of study medication may be 
taken later up to 8 hours before the next scheduled dose; otherwise, the missed dose should not 
be given. 
PUBLIC
all 
t will b
t will b
valent) B
valent) B
X008 0.
X008 0.
mg/day)
mg/day)
r the 0.
r the
COPY
3), if t
3), if
P dos
dose wi
e w
ded. 
ded
dose g
dose 
This document
o 
t
.8 m
8 m
t
te: maxim
maxim
nt
me
5.5
5.5
cannot 
tion A
on 
d Group
Group
ot
mg/kg/day
g/kg/da
an
mg/kg/
mg/kg/
ca
c
be 
the v
he 
Alg
Alg
used
8 mg/k
mg/k
titration
tration
d by the
by th
volu
volu
to
mg
hile do
hile d
kg/
support 
roups (Sec
ups (S
titrated sta
rated 
D. Afte
D. After 4
r
g/kg/da
/kg
any 
ubject’
ubject
be recalc
be recalc
marketing 
ng and in t
g and in t
ted by a m
d by a
tion may 
on may
ose should
e shou
ose and 
se an
authorization 
16
io
ug
s study 
study
applicatioion 
n
ay 
ay 
n
io
um daily do
m daily d
ati
ca
3
M
com
and 
orit
ri
Titra
Titra
S
d
a
ZX
ZX
a
any 
e of 
e o
hm 
hm 
extensions
artin
rti
4 days a
days a
ay group
y grou
es in
s in the
th
day group
y grou
is expect
expec
ubject a
bject a
ZX
ZX
or
tion 5
ion 5
ng w
g w
variations
be
d not b
not b
d subject
subject
weight (
weight 
culated. 
ulated.
6
thereof. 
the even
he even
minimum
minimum
e taken
taken

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 47 of 175
5.5.4
Taper Period 
Subjects who complete the Maintenance Period and will not be continuing into the open-label 
extension study, and subjects who discontinue from the study early, will be tapered off of study 
medication. Study medication will be administered as equal doses BID in the morning and in the 
evening approximately 12 hours apart, with food. Each dose should be separated by a minimum 
of 8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later 
up to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
IMP should be administered using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups, all subjects who do not continue into the 
open-extension study will participate in a dose-tapering procedure over the course of 8 days. On 
the first day of the tapering period subjects in the ZX008 0.8 mg/kg/day group will decrease to a 
dose of ZX008 0.4 mg/kg/day BID (maximum 30 mg/day). After 4 days at this dose level (Study 
Day 5), subjects randomized to the ZX008 0.8 mg/kg/day group will decrease their dose to 0.2 
mg/kg/day. Subjects in the ZX008 0.2 mg/kg/day group will decrease their dose to placebo on 
the first day of tapering while doses in the placebo group will remain constant throughout the 
tapering procedure. On Study Day 9, all subjects will stop taking study medication. The taper is 
expected to take a total of 8 days (Table 4). A new bottle of IMP will be started by the subject at 
each level of the taper step. 
Table 4: 
Taper Algorithm 
Randomized Group 
Taper Step 1
Day 1-4 after study completion or 
early termination 
Taper Step 2 
Days 5-8 after study completion or 
early termination 
ZX008 0.2 mg/kg/day 
Placebo
Placebo 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day 
Placebo 
Placebo
Placebo 
Note:  maximum daily dose of ZX008 is 30 mg.
5.5.5
Transition Period 
Subjects who complete the Maintenance Period and will be continuing into the open-label 
extension study will be transitioned from double-blind study medication to open-label ZX008 
(Table 5). Study medication will be administered as equal doses BID in the morning and in the 
evening approximately 12 hours apart, with food. Each dose should be separated by a minimum 
of 8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later 
up to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
Study medication should be administered using the oral dosing syringe provided. 
All subjects entering the open-label extension study will be transitioned from their blinded daily 
dose (placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) to the 0.2 mg/kg dose during the 2-
week interval between Visits 12 and 13, without breaking the blind. The IVR/IWR system will 
assign two bottles of IMP to the subject, one for each step in the transition. A new bottle of IMP 
will be started by the subject at each level of the transition step. See Section 5.6 for more 
able 4
ble 4
hm 
hm 
y
PU
COPY
m
mg/
mg/kg/
k
g/day gro
g/day gro
e placebo
e placeb
subjec
subjec
)
This document 
cts wh
ts wh
tension s
nsion 
(Table 5
Table 5
eveni
even
of 
of
cannot 
y dose o
dose o
t
ot
Trans
Tran
ho
h
be 
be
b
of
of
b
u
Z
used 
Tape
Tape
4 after st
after st
early
early
us
u
to 
r S
to support 
group
roup
s will stop
will s
A new bot
new bo
any 
Af
Af
group 
group
p will de
will de
p wil
w
marketing 
ay
hould no
ould n
ho do not c
o do not
e over the
over th
mg/g/kg/day
kg/da
fter 4 d
ter 4
authorization 
16
io
label
bel
f of study
of study
ng and i
ng and i
by a mi
y a mi
y be tak
be tak
application 
tion 
on
complete t
omplete
udy will b
y will
. Study m
 Study 
ng approxi
appro
 hours an
hours a
o 8 ho
o 8 ho
and 
X00
X0
d
Per
Per
any 
008 0.4
008 0
y
Pla
Pla
ny
8 is 30 
8 is 3
an
a
extensions 
ttle
ep 1
p 1
dy comp
y comp
terminat
rminat
ns
lacebo
acebo
ex
e
or 
takin
tak
of IM
of IM
variations 
e cour
cour
y group w
group w
days at 
ays at thth
will decr
will decr
ecrea
crease t
se t
l remai
remai
ng
thereof.
nim
en later
n later
be given
e give
ontinue
ontinue
se
se

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 48 of 175
information about the volume of ZX008 or placebo to be administered. 
Table 5: 
Transition Algorithm 
Dose Group in 
Double-Blind 
Transition Step 1
Day 1-4 after Visit 12 
Transition Step 2 
Days 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day 
Note:  maximum daily dose of ZX008 is 30 mg.
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning on 
day 1 of the transition (the day following Visit 12; Study Day 100.) Subjects who had been 
randomized to 0.2 mg/kg/day will continue to receive that dose. Subjects who had been 
randomized to 0.8 mg/kg/day or were receiving the maximum dose of 30 mg/day decrease to a 
dose of ZX008 0.4 mg/kg/day. After 4 days at this dose level (day 5; Study Day 104), these 
subjects will decrease their dose to 0.2 mg/kg/day. Subjects will report to the clinic on day 15 
(Study Day 113) for enrollment into the open-label extension study. 
5.6
BLINDING 
At the end of the Baseline Period, subjects who qualify to enter the study will be randomized to 
receive ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day (maximum dose: 30 mg/day), or placebo 
and assigned a randomization number by the IVR/IWR system. Once a randomization number is 
assigned to a subject, the site will record the subject’s initials on the corresponding study drug 
labels. Each bottle will contain the assigned treatment (ZX008 or placebo) and the ZX008 and 
placebo solutions will be identical. 
The blinding scheme instituted for this study will ensure that the volume of study medication 
taken cannot be associated with the dose group, thus unblinding the study. This is achieved by 
random assignment of different concentrations of the ZX008 oral solution (1.25 mg/mL, 
2.5 mg/mL, and/or 5 mg/mL) by the IVR/IWR system. The IVR/IWR system will instruct site 
personnel to the volume of oral solution to be administered based on that subject’s weight. 
(Dose will be recalculated by the system once at the midpoint of the study.) During the 
Titration, Maintenance, Taper/Transition Periods, the subjects and study personnel 
(investigators, clinical staff, personnel involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the treatment allocation and to the concentration of 
ZX008 oral solution. If an investigator feels the blind should be broken, he/she can do so when 
necessary for treatment decisions. However, the investigator should endeavor to discuss with 
the Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study medication 
versus placebo is needed to determine course of medical treatment for the event. The subject 
will be discontinued from the clinical trial upon breaking of the blind and the decision whether 
the subject can enter the separate open-label extension study will rest with the Sponsor if the 
subject exited Study 1502 prior to completion. 
PUBLIC 
he 
eriod, su
eriod, s
g/day, ZX
g/day, Z
tion n
tion
COPY
o
ng 
ng the m
the
ays at th
ays at 
mg/kg/d
mg/kg/
open-
open
This document
nel 
el
se will b
will b
itration, 
ration
(invest
(inves
Mon
Mo
Z
cannot 
me in
e in
associat
ssociat
nment o
ment o
L, and/or
and/or
to the
to the
be
be iden
ide
stitu
stit
used
00
00
umber 
mber 
 will rec
will re
tain
ain the
the
ti
to 
bjects
ects
08 0.8 
8 0.8
support 
s d
s d
ay. Subj
y. Sub
abel exten
bel ext
who
wh
any 
tha
th
ximum d
ximum
dose lev
ose l
ec
marketing 
g/kg/
kg
mg/kg/da
mg/kg/d
g
ng
tin
se to 0.2 m
to 0.2
Day 100
Day 10
t do
t d
authorization 
16
io
t 12 
hor
g/day 
day 
ut
day 
day 
au
application
5 mg
m
volume o
volume
recalcula
ecalcu
Maintenan
Maintena
gators, cli
ators, c
itor, and t
or, and
008 oral
08 oral
ssary
ssa
and
te
ed with
with
differen
differe
g/mL
g/mL
any 
l.l.
d for thi
for t
the
extensions 
o qua
qualify
lify
mg/kg/da
g/kg/da
y the IVR
the IVR
ord the s
d the s
signed
igne
or
sion s
sion 
variations
mg/kg/
mg/kg
0.) Subje
0.) Subj
ose. Sub
e. Sub
dose of 
ose of 
vel (day
el (day
s will
will
t
thereof. 
f.
o
re
her
d

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 49 of 175
5.7
PRIOR AND CONCOMITANT MEDICATION 
All medications taken by a subject during the Screening and Baseline Seizure Assessment 
Periods are regarded as prior therapy and must be documented in the eCRF. Significant 
medications (eg, antibiotics) taken within 30 days prior to the Screening visit should also be 
captured. All prior and concomitant AEDs will be collected in the CRF. 
All medications taken by a subject after the first administration of IMP are regarded as 
concomitant medication and must be documented in the eCRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations. Subjects are required to take at least one 
concomitant AED during the study. All subjects will continue to receive their existing AED(s) 
with the same doses throughout the study. Every effort should be made to ensure that the regimen 
of existing medications remains stable during the study; any changes must be discussed with the 
sponsor prior to implementation. If a decrease in a concomitant AED is necessary to manage an 
AE, this must be discussed with the sponsor as soon as possible after implementation if not 
before implementation. Non-study medications and therapies that are considered necessary for 
the subject’s welfare and will not interfere with the response to the study medication may be 
given at the discretion of the investigator, informing the Medical Monitor as soon as possible. 
It should be noted for any subject receiving hypoglycemic agents, the investigator should 
consider diabetic medication changes in the setting of weight loss and hypoglycemia. 
5.7.1
Vagal Nerve Stimulation 
Subjects receiving treatment with a VNS may be included as long as the VNS has been in place 
for at least 6 months prior to entry into the study, the VNS battery is not due for replacement 
during the study, and stimulation parameters have been kept constant for 4 weeks prior to 
screening and must remain so throughout the study. The subject’s use of VNS will be recorded in 
the CRF. 
5.7.2
Ketogenic Diet 
Adherence to the KD, or a modified version of KD, is permitted during the study if the dietary 
habits were initiated more than 4 weeks prior to Screening and remain stable throughout the 
study. The subject’s use of KD will be recorded in the CRF. 
5.7.3
Rescue Medication for Seizures 
The subject's usual or prescribed regimen and frequency of rescue therapy for seizures should 
be entered into the prior and or concomitant medication sections of the eCRF. 
Use of rescue medication is permitted during the study and should be recorded on the eCRF (day, 
medication[s], dose[s]) and in the diary (day, timeframe associated with seizure episodes). 
Repeated administrations within the same episode should be recorded separately. 
5.7.4
Prohibited Concomitant Medication and Food 
A list of medications/foods that are to be avoided as ongoing medications or for chronic use if 
PUBLIC
eceiving
ceivin
anges in 
anges in
timulati
timulati
nt wi
nt w
COPY
c
soon as
oon 
ns and 
ns an th
with the
with th
, inform
inform
This document
ere
er
. The su
The s
7.3
The s
The 
be
b
cannot 
togenic D
genic 
to the K
the K
e initia
initi
be
ul
main so 
in so
used
h a VN
a VN
entry int
try in
ation p
tion p
h
to 
n
support 
respon
espon
ming the M
g the
hypoglyce
ypogly
he setting 
e setting
any 
ntn
sible a
sible 
apies tha
apies tha
nse
ns
marketing
gard
ard
over-the-c
over-the-
equired 
quired to
eive their e
ive thei
made to e
made to 
anges mu
nges m
AE
AED 
f
authorization 
16
io
also be
also be
ded a
ed a
application
D, or
o
ted more
ted mor
ject’s use
ect’s us
Rescue 
Rescu
ubject's us
bject's u
ntered in
tered in
f re
and 
Dietet
r a m
r a m
any 
oughou
ugho
extensions 
emic 
mic 
g of weig
f weig
may be 
may be
o the stud
the stu
meter
meter
or 
edica
edi
age
age
variations 
ensure
sure
ust be dis
t be dis
is neces
s neces
ter imple
er imple
at are co
t are co
to the st
o the s
al M
thereof. 
counter 
unter 
take at 
ake a
existing
xisting
e thth

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 50 of 175
initiated during the study from the time of signing the informed consent form (ICF) until the end-
of-study visit (or early termination) is provided in Appendix 1. If medical necessity requires 
short-term use of one or more of these medications during the course of the study, please contact 
the Medical Monitor for approval. 
The following concomitant medications are prohibited during the clinical trial: 
• AEDs: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, 
retigabine/ezogabine 
• Stiripentol (STP): Subjects must be off STP for a minimum of 21 days prior to the 
Screening visit. 
• Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to screening, has stable liver function and 
hematology laboratory tests, and the dose is expected to remain constant throughout the 
study. 
• Drugs that interact with central serotonin, including, but not limited to: imipramine, 
monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-
norepinephrine reuptake inhibitors, vortioxetine 
• Drugs that increase cardiovascular risk including: atomoxetine and those with noradrenergic 
reuptake properties (NRIs, SNRIs) 
• Drugs intended to facilitate weight loss 
• Other:  any form of marijuana, THC and derivatives (including Epidiolex®) 
5.8
TREATMENT COMPLIANCE 
Each subject or parent/caregiver will record the dose, dosing frequency and IMP consumption in 
the subject’s diary. Subjects will bring their used, partially used, and unused IMP to every study 
visit. Treatment compliance will be monitored by measuring the volume of IMP in these bottles 
and comparing to the dispensation log and diary records. 
6.
VISIT SCHEDULE 
Study procedures will be conducted according to the Schedule of Assessments in Table 1. 
Time windows for all assessments are detailed in Table 6. 
PUBLIC
scular 
cular
, SNRIs)
SNRIs)
itate wei
tate wei
marijuan
marijuan
C
COPY 
nin, incl
nin, incl
ective
ective se
se
rs, vorti
s, vort
risi
This document
roc
oc
window
windo
cannot
pli
p
the disp
e dis
ISIT S
SIT S
edure
edure
be
eg
jects w
ts w
iance w
iance w
used 
OMPLI
MPLI
iver
ver w
r
il
to
, THC
 THC
support 
otonin
tonin
oxetine
etine
k includ
includini
t loss
loss 
an
any 
toto
ing, but 
ng, but 
n reu
n re
marketing 
 days prio
days pr
s the subj
the sub
stable
table live
li
remai
rem
authorization 
16
io
nd-
d-
s 
e contact
contact
application
s will be c
will be
for all as
or all 
and 
nsatio
sati
CHEDU
HED
any 
ring th
ring 
ll be mon
be mo
on lo
on
extensions 
ng: 
nd deriva
deriva
ANCE 
NCE 
record
cord
or 
atomo
atom
variations 
ject ha
ct h
er functi
functi
in consta
n consta
not limi
not limi
ptake i
ptake i
thereof. 
or to the
to th
as
as

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 51 of 175
Table 6: 
Time Windows for Assessments 
Visit / Procedure
Time window (relative to scheduled visit / procedure)
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41): 
Not applicable
Visit 2 (Phone; Study Day -21)
± 3 days
Visit 3 (Clinic; Study Day -1; Randomization)
+ 4 daysa
Visits 4, 5 (Phone: Study Days 4, 8)
± 3 days
Visit 6 (Clinic; Study Day 15)
± 4 days
Visit 7 (Phone: Study Day 29)
± 4 days
Visit 8 (Clinic; Study Day 43)
± 4 days
Visit 9 (Phone: Study Day 57)
± 4 days
Visit 10 (Clinic; Study Day 71)
± 4 days
Visit 11 (Phone: Study Day 85)
± 4 days
Visit 12 (Clinic: Study Day 99)
± 4 days
Visit 13 (Clinic; Study Day 113; post dosing)
± 4 days
Visit 14 (ECHO clinic; 3-6 months after last dose)
+ 30 days
Blood collection for ZX008 PK
± 15 minutes
Blood collection for AED concentration
Prior to morning dose of AED medication
AED=antiepileptic drug (s); ECHO=echocardiogram; PK = pharmacokinetics 
a 
In cases where the screening period is extended beyond 42 days, the immediate 42 days before the Randomization visit will 
be used to calculate the baseline seizure frequency
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1) 
The Baseline Period of the study encompasses the screening activities that will occur on Study 
Day -42 as well as the observation period where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity entered into a diary. 
6.1.1
Screening, Clinic Visit 1 (Study Day -42) 
Screening is the predetermined series of procedures with which each investigator selects an 
appropriate and representative sample of subjects for enrollment into the study. Select 
screening data will be documented in the IVR/IWR and eCRF. 
Written informed parental or guardian consent and assent of minors (if the subject is capable of 
providing assent) must be obtained before a subject can start any of the screening procedures. 
The procedure(s) for obtaining written informed consent and assent of minor (if the subject is 
capable of providing assent) are described in Section 11.2. 
The Screening visit will occur on Study Day -42; however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study Day -42 or Study Day -42 and Study Day -41). 
Splitting the visit procedures across 2 nonsequential days requires the approval of the medical 
monitor. The following procedures will be performed for all subjects before the start of seizure 
activity observation: 
• Obtain written informed consent for the study 
• Obtain written informed consent from parent/caregiver to collect PedsQL Family 
Impact, HADS, and EQ-5D-5L ratings of parent/caregiver symptoms and quality of life 
PUBLIC 
ed b
ed b
equency
equency
RIOD (S
IOD (S
e study 
e study 
rva
rv
COPY 
days
ay
30 days
30 day
Y
± 15 min
± 15 
PY
O
Prior
rior
OP
CO
CO
CO
PK = phar
phar
K
eyond
yond
This document
ng a
g 
procedu
rocedu
apable of
able o
The S
The S
2 c
2 c
cannot
dete
et
epresen
resen
will be 
will be 
formed p
ormed 
assen
ssen
be 
, Clin
Clin
ermin
ermi
used 
ncom
com
ion perio
n peri
of daily 
f daily
icic
to 
TUDY
UD
mpa
mpa
support 
o morn
morn
trt 
acokinetics
okinetic
2 days
days, the i
, th
Y DA
Y D
any y
s
any
ing d
ing
a
marketing 
g 
ting
et
ke
ark
ma
m
authorization 
16
io
ure)
re)
iza
ri
ho
th
au
a
application 
arenta
rent
) must be 
must b
e(s) for ob
s) for o
providing
providin
creening v
eening
nsecutive
secutiv
ting th
ting t
and
tive sa
ve sa
ocume
cumen
al o
l o
any 
sit
sit 1 (
1
series o
series o
amp
extensions 
AY -42 
Y -42 
ses th
es the s
e s
d where
where
eizure a
izure a
(S
(S
or
mediate
mediat
variations s
ns
io
ati
ria
ose of A
e of A
ar
va
thereof. 
f
of.
eo
ere
he
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 52 of 175
• Review inclusion and exclusion criteria 
• Record demographic information 
• Record medical, neurological, and epilepsy history 
• Record current epilepsy status (number/type/duration seizures per month) 
• Collect past 6 months (or available duration) of parent/caregiver seizure diary data if 
available (screen shots of cell phones are acceptable, as are photocopies of paper diaries 
or print outs) and place in source file 
• Record prior medications 
• Complete physical examination, including height, weight, and calculation of BMI 
• Complete neurological examination 
• 12-lead electrocardiogram 
• Doppler ECHO (this may be obtained any time between Study Day -42 and Study 
Day -21) 
• Vital signs 
• Urine pregnancy test for females of child-bearing potential 
• Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) 
• Urine THC panel 
• Whole blood CBD 
• Obtain blood sample for epilepsy genotype panel 
• C-SSRS Children’s Baseline/Screening Assessment (Appendix 2) 
• Instruct parent/caregiver on use of diary 
• Dispense diary (after above procedures have been concluded)
• Record AEs 
• Record AESIs 
Only eligible subjects as specified by the inclusion and exclusion criteria with an independently 
confirmed diagnosis of DS by the Epilepsy Study Consortium will be enrolled into the study. 
After enrollment into the study, each subject will be issued a “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will be 
advised to retain this card on his person for the entire duration of the study so that the investigator 
or the sponsor can be contacted in case of emergency. 
In certain circumstances the sponsor may allow subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the screening period extended, or to be re-screened 
for eligibility. In all cases the investigator should consult with the Medical Monitor. Decisions 
whether to permit rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or rescreening can be influenced by many factors 
individual to that subject case. Some general principles apply: 
1. If baseline seizure screening is extended or the subject is discontinued and then rescreened, the 
screening period for establishing the baseline seizure frequency will be the immediate 6 weeks 
PUBLIC 
or epilep
or epilep
Baseline
Baseline
eg
egiver 
iver 
COPY 
f child-be
child-b
emis
mi try
try
This document
ation
io
ed to re
d to re
r the spon
he spo
In certa
n certa
crite
crite
fo
f
cannot
ects as 
ts as 
gnosis of
nosis of
ollment 
lment 
n abo
abo
be used 
n use 
use
bove pr
ove pro
to
y g
Scr
Screen
een
of
of
support 
aring
ing
hematolo
matol
genotyp
enoty
ng
any 
pote
pot
marketing 
calculatio
lculat
n Study 
Stud
authorization 
16
io
ary data
ry data
of pape
f pape
application 
nto t
to 
ut the sub
t the su
ain this ca
n this c
sor can be
sor can 
n circums
circum
ia at the ti
at the t
gibility
gibilit
and
pecifie
cifie
DS by th
S by th
the
he
any 
ed by
d
extensions 
pe panel
pe panel
g Assess
Assess
diary
ary
edures h
dures 
or 
y, u
y, 
variations 
Day -42
Day -4
ntial
ial
urin
rin
thereof.
if 
diaries
iarie
on of BM
n of BM

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 53 of 175
before the randomization visit. 
2. Subjects who are found to be on a prohibited medication at the screening visit may be weaned 
off of that medication provided: 
a.
Decisions to withdraw a disallowed concomitant medication must be made with the 
agreement of the prescribing physician 
b. If the medication has antiepileptic properties, a wash out of at least 5 half-lives must 
be completed before collection of baseline seizure data.  
c.
If a decision has been made to wean off of a medication without antiepileptic 
properties and the wash-out period (at least 5 half-lives) is expected to be shorter 
than 5 weeks, then the subject may remain in screening and chart seizures using 
the seizure diary. 
6.1.2
Phone Visit 2 (Study Day -21) 
Site personnel will contact the subject via telephone on Study Day -21 and record the 
following: 
• AEs 
• AESI 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.1.3
Clinic Visit 3 (Study Day -1): Randomization 
This period is intended to ensure that subjects meet the study entry criteria and confirm they 
have experienced 6 convulsive seizures during the 6-week Baseline Period, with at least 2 
seizures in each 3-week half of the Baseline Period. Subjects must have at least 42 days of 
prospective diary data at Visit 3. Subjects will report to the clinic in the morning on Study Day -
1 to allow for plasma sample collection for AED pharmacokinetic evaluation prior to the 
morning dose of these medications. Subjects should not take their morning dose(s) of AED 
medication prior to reporting to the clinic. 
The following procedures will be performed on Study Day -1: 
• Review inclusion and exclusion criteria 
• Review current seizure activity (number/type/duration) from diary since previous visit 
and calculate the number of convulsive seizures during the first 3 weeks, the second 3 
weeks, and over the full 6-weeks of the observation period. 
• Record prior medications since previous visit 
• Complete physical examination, including height and weight, and calculation of BMI 
• Abbreviated neurological examination 
• Vital signs 
• 12-lead ECG 
• Urine pregnancy test for females of child-bearing potential 
PUBLIC 
with revie
ith revi
(S
(S
COPY 
telephon
telephon
This document
ollowin
lowin
•
Re
Re
•
cannot
data at 
ta at 
asma sa
sma sa
e of thes
of the
n prior to
prior t
be 
nvulsiv
ulsi
k half 
k half 
V
used 
udy Day
dy Day
nsu
sure th
re th
ve
ve
to
w the d
w the d
support 
e on Stu
on St
iar
any 
udy
marketing 
t least 
east 
ication w
ication 
-lives) is 
ives) i
screening 
reenin
authorization 
16
io
weaned 
weaned 
e made w
made 
5
application 
report
epor
procedure
rocedu
iew inclu
iew inc
Review cu
eview 
and cal
and c
week
we
R
and
sit 
it 3
mple col
ple col
medicat
medica
tin
tin
any 
izures
zur
the Base
the Bas
3. Subj
. Su
extensions 
ry entrie
entrie
-1): Ran
1): Ran
subject
ubject
s d
or variations 
expe
xpe
g and ch
nd ch
Day -2
Day -2
thereof. 
half-lives
lf-lives
without a
ithout a
ecte
cte

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 54 of 175
• Laboratory evaluation (serum chemistry, and hematology, and urinalysis) 
• Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
• Urine THC panel 
• Whole blood CBD 
• Tanner Staging for subjects >7 years of age (Appendix 5) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• BRIEF (Appendix 3) 
• QOLCE (Appendix 4) 
• PedsQL (Appendix 6) 
• PedsQL Family Impact module (Appendix 6) 
• Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
• Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
• Record AEs 
• Record AESI 
• When eligibility for the Titration Period is confirmed, randomize (blinded) subject to 
treatment assignment (ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or placebo) 
• Dispense study medication (If administration of the first dose of study medication occurs in 
the clinic, the next dose should be at least 8 hours later or the following morning. The dose 
on the following morning will count as Study Day 1.) 
6.2
TITRATION AND MAINTENANCE PERIODS 
6.2.1
Titration Period Study Day 1 
Subjects will take their first dose of study medication on the morning of Study Day 1. Study Day 1 is 
considered the first day of dosing, even for those subjects that received an in-clinic dose on Study 
Day -1.
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) 
Site personnel will contact the subject via telephone on Titration Period Study Days 4 and 8 
and record the following: 
• AEs 
• AESI 
• Concomitant medications
In addition, site personnel will review study medication dosing procedure and the diary entries 
with the parent/caregiver. 
6.2.3
Clinic Visit 6 (Titration Period Study Day 15) 
PUBLIC 
itration P
tration P
ZX008 0
ZX008 0
dication (
ication (
dose s
dose s
rn
rn
COPY 
ix 6) 
x 6)
D-5L sc
D-5L sc
giv
giver usi
er us
This document
P
Site perso
te pers
and re
and re
cannot 
ion 
on
their fir
heir f
first day
rst day
be 
A
Peri
Per
used 
oululd d
ng will c
will c
ND M
ND 
to
2 
f admin
admi
be
be
support 
ng the 
g the
eriod is
iod is co
co
mg/kg/
mg/kg d
is
any 
 (Appen
(Appen
HA
H
marketing authorization 
16
io
ose
se 
application 
hone Visit
one Vis
nnel will 
nnel wil
ord the fo
rd the 
•
AEs 
AEs 
A
and
st dose o
dose o
of dosin
f dosin
any 
AIN
I
Study D
Study
f
extensions
onfirme
nfirm
day, ZX
day, ZX
stration o
ation o
t least 8
least 8
ount as S
nt as 
NTE
NTE
or variations 
ndix 7) 
dix 7) 
DS scal
DS scal
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 55 of 175
Subjects will report to the clinic in the morning on Titration Period Study Day 15. Subjects 
should not take their morning dose(s) of AED medication prior to reporting to the clinic. The 
following procedures will be performed: 
• Review current seizure activity (number/type/duration) from diary since previous visit 
• Record concomitant medications 
• Abbreviated physical examination, including height and weight, and calculation of BMI 
• Abbreviated neurological examination 
• Obtain vital signs 
• Urine pregnancy test for females of child-bearing potential 
• Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
• Urine THC panel 
• Whole blood CBD 
• Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• Record AEs 
• Record AESI 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication 
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 29 and 
record the following: 
• AEs 
• AESI 
• Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43) 
Subjects will report to the clinic in the morning on Maintenance Period Study Day 43. Subjects 
should not take their morning dose(s) of study medication and AED medication prior to reporting 
to the clinic.  The following procedures will be performed: 
• Review current seizure activity (number/type/duration) from diary since previous visit 
• Record concomitant medications 
PUBLIC
ast 
ast Visi
Vis
on – Imp
on – Im
ssion – I
sion – I
COPY
cokine
cokin t
nt/careg
nt/careg
This document 
AEs 
AEs 
•
AE
AE
•
In 
In 
cannot 
ne Visit
e Visi
nel will c
l will c
follow
ollow
be
medica
dic
used 
used an
sed an
nt/care
nt/care
ti
to 
mpro
p
support 
ver r 
Assessmen
ssessm
ovement (
ement
oveme
ovem
any
valuati
valuat
marketing 
alcu
and urinaly
nd urina
authorization 
16
io
he
vious visi
ous vis
ulation
lation
application 
ont
ng:g:
SI 
S
Concomit
oncom
ddition, s
dition, s
and
7 (Main
(Main
tact 
act thth
any extensions
nt (A
t (
(assesse
ssesse
ent (asse
nt (asse
d unused 
nused 
ver 
er 
or 
Appe
App
variations 
lysis) 
sis)
on prior t
n prior t
thereof.
of BMI
of BM

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 56 of 175
• Abbreviated physical examination, including height and weight, and calculation of BMI 
(Note: if the subject’s weight is ±25% of the weight at Study Day-1, the IMP dose 
will be recalculated) 
• Obtain vital signs 
• 12-lead electrocardiogram 
• Doppler ECHO (this must be obtained any time between Study Day 40 and Study 
Day 54) 
• Urine pregnancy test for females of child-bearing potential 
• Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
• Urine THC panel 
• Whole blood CBD 
• Collect plasma sample for ZX008 pharmacokinetic evaluation at the following timepoints: 
within 1 hour prior to the morning dose of study medication, and 1, 2 and 4-6 hours after 
the morning dose of study medication 
• Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose of 
study medication(s) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• BRIEF (Appendix 3) 
• QOLCE (Appendix 4) 
• PedsQL (Appendix 6) 
• Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• Record AEs 
• Record AESI 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication 
6.2.6
Phone Visit 9 (Maintenance Period Study Day 57) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 57 and 
record the following: 
• AEs 
• AESI 
• Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71) 
PUBLIC 
paren
pare
ce Last 
ce Last V
)
x 4)
x 4)
6)
6)
COPY 
study
stu
rmacokin
macok
nt/c
nt/c
This document 
Disp
Dis
.2.6
2.6
Site 
Site 
rere
cannot 
AESI
ESI
ct used, 
t used
d review
review
pens
pen
be
mpre
p e
Impres
Impre
used 
of paren
f paren
ssio
ssio
to support 
etitic c
aregiver 
giver 
sit Asses
t Asses
any 
icatio
cati
evalu
eval
marketing 
urinalysis)
nalysi
uation at
ation 
n
authorization 
16
io
MI 
ose
se 
nd Stud
d Stud
application 
p
with p
ith p
e study me
study m
Phone 
Phone
ersonnel w
rsonne
ord the fo
d the fo
A
and 
artially 
tially 
parar
any 
– Im
– Im
on – Imp
on – Im
extensions 
ssment (
ssment (
/caregiv
aregiv
mpro
mpro
or variations 
t the fol
t the fol
and 1, 2
nd 1, 2
uation pr
ion pr
thereof. 
y 
)

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 57 of 175
Subjects will report to the clinic on Maintenance Period Study Day 71. The following 
procedures will be performed: 
• Review current seizure activity (number/type/duration) from diary since previous visit 
• Record concomitant medications 
• Abbreviated physical examination, including height and weight, and calculation of BMI 
• Obtain vital signs 
• Urine pregnancy test for females of child-bearing potential 
• Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
• Urine THC panel 
• Whole blood CBD 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• Record AEs 
• Record AESI 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication 
At Clinic Visit 10, compliant subjects who have tolerated IMP should be presented with the 
ICF for the open-label extension study. Informed consent for the open-label extension study 
must be signed at Visit 12 or earlier in order to enter the open-label extension study. 
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 85 and 
record the following: 
• AEs 
• AESI 
• Concomitant Medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination 
The End-of-Study participation for an individual subject occurs after he/she has received IMP 
for 12 weeks in the Maintenance Period. At the End-of-Study visit, the subject may enroll into 
the separate extension study if they have completed 12 weeks of treatment in the Maintenance 
Period. Other circumstances for participation in the extension study are described in Section 4.8. 
The End-of-Study visit may also occur if the subject withdraws participation from the study or 
PUBLIC 
ed and u
ed and 
nt/caregiv
/caregiv
dication
dication
nt s
nt
COPY
sessmen
sessme
ement (a
ement
rovemen
roveme
This document
AE
AE
Conc
Conc
In additi
n additi
6.2
6.2
cannot
ll conta
conta
owing:
wing:
s 
SI
SI
be 
2 or
it 11 (M
it 11 (M
used
ubjects w
ects w
sion stud
on stud
earli
earl
to 
er 
support 
sse
(assess
asses
nused stud
used stu
any
Append
Appen
ssed by
ssed 
ed
marketing 
inalysis) 
alysis)
authorization 
16
io
us visit 
visit 
ulation o
ation o
application 
mitant M
mitant M
on, site per
n, site p
9
and
the su
he su
any 
in
intenan
intenan
ubje
bj
extensions 
dy medic
medi
ho have
o have
y. Inform
Inform
orde
ord
or variations 
ix 2) 
x 2) 
y parent/
parent
by inve
y inve
thereof. 
f BM
f B

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 58 of 175
the sponsor terminates the study.  If the subject withdraws participation from the study, they may 
on a case-by-case basis, be eligible for entrance into the separate open-label extension study after 
consideration of the circumstances of the early termination and the potential benefit- risk of 
continued participation in a ZX008 trial. The decision whether to permit open-label extension 
study participation resides solely with the sponsor, who may consult with the site investigator. If 
the sponsor terminates the study early, the subject may or may not be offered enrollment into the 
open-label extension, depending on the reason for termination. 
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The sponsor terminates the study. 
3. The subject completes all study related visits and procedures. 
The following procedures will be performed: 
• Review current seizure activity (number/type/duration) from diary since previous visit 
• Record concomitant medications 
• Complete physical examination, including height and weight, and calculation of BMI 
• Complete neurological examination 
• Obtain vital signs 
• 12-lead electrocardiogram 
• Doppler ECHO (must be performed any time between Study Day 90 and Study Day 
113; if subject terminates early from the study, the ECHO should be scheduled as soon 
as practical. If the Study Day 43 ECHO was completed 30 days prior to early 
termination, the Visit 12 ECHO will not be performed provided the parent/guardian 
agrees to bring the subject to the clinic for the cardiac follow-up visit (see Table 7). 
• Urine pregnancy test for females of child-bearing potential 
• Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
• Urine THC panel 
• Whole blood CBD 
• Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
• Tanner Staging for subjects >7 years of age (Appendix 5) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• BRIEF (Appendix 3) 
• QOLCE (Appendix 4) 
• PedsQL (Appendix 6) 
on, inc
n, in
aminatio
aminatio
iogram
iogram
must be
must 
COPY 
mber/typ
mber/ty
clul
This document
Colle
Colle
of st
of s
•
T
•
cannot
g
nancy 
ancy 
ory evalu
y eval
e THC p
THC p
hole blo
ole blo
ect
be 
Visit 
sit 
the sub
the sub
t
used
perform
rfor
tes early
s early
udy
udy Da
Da
12
12
to 
m
support 
e/dura
dur
ding heig
ng heigh
any 
ation
atio
marketing 
ng events o
g events 
n in the stu
in the st
ocedures. 
cedure
authorization 
16
io
may
ay
y after 
y after 
of f 
xtension
xtension
nvestiga
vestiga
rollment
ollmen
application 
n
d CBD
CBD
plasma sa
lasma s
udy medic
dy med
anner Stag
nner Sta
Collect a
Collect
•
Dispe
Dispe
C-
C
and
t for
fo
ation (se
tion (s
el
D
any 
CHO 
HO
ct to
ct to the 
the
r fema
fem
extensions 
ht 
d any 
d any tim
ti
from the
om the
43 ECH
3 ECH
w
or 
and w
nd w
variations 
n) from
from d
m
thereof. 
into th
nto t
occur:
ccur:
dy.
dy.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 59 of 175
• PedsQL Family Impact module (Appendix 6) 
• Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
• Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
• Record AEs 
• Record AESIs 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication for taper for subjects not enrolling in the open-label 
extension study 
Informed consent for the open-label extension study must be signed at Visit 12 (if not signed 
earlier) in order to enter the open-label extension study. 
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) 
For subjects entering the open-label extension study, the subject will visit the clinic on Study 
Day 113. The following will be recorded/performed and the subject will immediately be enrolled 
in that separate study: 
• Review current seizure activity (number/type/duration) from diary since previous visit AEs 
• AESIs 
• Concomitant medications 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
If the subject does not enter the open-label extension study (or discontinues from the study 
early), the subject will visit the clinic on Study Day 113 (or 14 days after the day of 
discontinuation). The following will be recorded/performed: 
• Review current seizure activity (number/type/duration) from diary since previous visit 
• AEs 
• AESIs 
• Concomitant medications 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY DAY 197-281) 
If the subject completes the study but does not enter the open-label extension study or 
discontinues from the study early, the subject will return to the clinic for follow-up cardiac 
testing (ECHO, ECG, and in some cases physical examination). The timing and frequency of 
exams are in Table 7. Subjects on blinded medication who are found to have been on placebo are 
not required to participate in follow-up testing once the blind is broken at the end of the study. As 
PUBLIC
ivity
ity (nu
(nu
cations
ations
ly u
ly
COPY 
IT 13;
T 1
sion stu
sion s
perform
perform
This document 
AES
AES
•
Co
Co
•
cannot
The fol
he fol
w current
current
s 
IsI
be 
enter
nter
vis
visit th
it th
lol
used
sed and 
d and 
nt/careg
/careg
th
th
to support 
dy
d and th
and t
mber/type/
er/type
any 
UDY D
UDY
the sub
the s
he
marketing 
the open-l
he open-l
ed at Visit
d at Vis
DA
authorization 
16
io
account
coun
application 
comitant 
omitan
Collect u
ollect
and re
and r
and 
wing
ing
seizure a
eizure a
any 
open-
pen
clinic on
clinic on
g will b
wil
extensions
/durati
urat
unused st
used st
ver 
er 
lal
or 
on
variations 
t 12 (i
12 (
AY 113) 
AY 113)
bject wil
ect wi
ubject 
ubject
thereof. 
ability
ility
label
bel
if n
if n

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 60 of 175
the ECHO and ECG will be administered in a separate clinic than the pediatric neurology clinic, 
an asymptomatic subject receiving a second follow-up ECHO and ECG does not require a 
physical examination. 
Subjects with positive findings on ECHO, ECG and/or physical examination should continue to 
be followed until the finding is resolved or stable and unlikely to change, with reports submitted 
as AESI to the ZX008 safety database. 
Table 7: 
Schedule of Post-Treatment Cardiac Follow-up 
Parameter
Duration of Blindeda or Fenfluramine Treatment
Less than 
2 weeks
Cumulative
2 to 4 weeks
>4 and
<13 weeks
>13 weeks
Have had any cardiac 
sign or symptom 
regardless of the time 
on study drugb
ECHO
No
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment
Yes,
3 and 6 months 
post-treatment
Yes,
3 and 6 months post- 
treatment, and until 
resolved, or stable and 
unlikely to change
ECG
No
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment
Yes,
3 and 6 months 
post-treatment
Yes,
3 and 6 months post- 
treatment and until 
resolved, or stable and 
unlikely to change
Physical 
examination
No
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment
Yes,
3 months post- 
treatment only
Yes,
3 and 6 months post- 
treatment, and until 
resolved, or stable and 
unlikely to change
a If blind is broken at the end of the study and a subject revealed to have taken only placebo, no further testing is 
required.
b    Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral,
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension 
as adjudicated by the IPCAB.
6.5
ESTIMATED BLOOD VOLUME COLLECTION 
The maximum total blood volume collected during the study for clinical laboratory testing, 
genotyping, and PK will be approximately 99.7 mL, as outlined in Table 8. 
PUBLIC 
C
 post- 
post- 
tment
tment
C
Y
mo
m
PU
COPY 
eeks
ks
Yes,
Yes,
months post
months p
treatmen
treatme
Y
C
This document 
maximu
axim
genotypin
notyp
cannot 
om incl
m incl
ter in pulm
r in pulm
y the IPCA
the IPC
nn
ES
ES
be
of the stud
of the stu
d
e used 
,
ths post-
s post- 
eatment
atment
to 
to
to
to support 
rt
Yes,
Yes,
months pos
months pos
treatme
treatm
po
any 
13 wee
13 w
Yes
Ye
3 and 6
3 and
post
ny marketing 
ment
ent
ke
ks
H
ark
rk
authorization 
16
io
ic,
continue
continu
ports sub
rts sub
application 
TIMATE
IMAT
m total bl
total 
g, and PK
, and P
and
any
an
nary, tric
ary, tric
B.
an
any 
d a subjec
d a subj
develop
deve
sp
y extensions
t-
nt
ns
3 a
3 
ns
Yes,
Yes,
3 months
3 months
trea
tre
ns
e
or 
o variations
Have had 
ve had
sign o
sign 
regar
rega
s
at
months
onths
treatment
reatmen
iat
at
thereof. 
mit
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 61 of 175
Table 8: 
Estimated Blood Volume Collection* 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to 
-41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical 
Chemistry 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
24mL 
LH, FSH, 
Estradiol, 
Testosterone, 
Prolactin 
 
4mL 
 
4mL 
4mL 
4mL 
16mL 
Genotyping 
5 mL 
 
5 mL 
Hematology 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
IGF-1, GH 
 
2.5mL 
 
2.5mL 
2.5mL 
2.5mL 
10 mL 
Coagulation 
 
2.7mL 
 
2.7mL 
Cannabidiol 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
ZX008 PK 
plasma 
 
4 x 2 mL 
 
8 mL 
AED plasma 
sample 
 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
 
1 x 2 mL 
8 mL 
Volume for 
flushing 
indwelling 
catheter 
 
4 x 0.5 mL 
 
2 mL 
Approximate 
total blood 
volume per 
subject 
13mL 
19.2mL 
10mL 
26.5mL 
14.5mL 
16.5mL 
99.7 mL 
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; 
PK=pharmacokinetics 
*In concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), blood 
collection volumes for children weighing up to 15 kg will be: 
PUBLIC
L
C 
C
2.7mL
2.7mL
BL
P
COPY
PY 
Y
2mL
2mL
PY
C
Y
C
This document 
elling
ng 
heter 
ter 
Approxi
Approxi
total b
total b
vol
vol
m
do
ca
cannot
ann
c
ot t
ot
ca
ca
c
be
be 
be
b
used 
2mL
2mL
d
u
to 
o
pport 
ort
suppor
ppor
or
su
su
any
ny y
2mL
2m
ny marketing 
in
4mL 
4mL 
ing
m
in
ma
ma
m
authorization 
16
io
tudy day)
dy day)
iza
99 
99 
ori
ho
4mL
m
u
application 
n
lication 
ation
li
ate
ood d
e per 
per 
plic
pli
an
and 
a d
a
any
any 
any extensions 
n
2
n
ension
sion
on
en
ex
e
or 
5mL
5mL
r variations 
ns
iations
ations
ns
ns
ia
va
v
thereof. 
2
f
eo
4mL
4mL
re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 62 of 175
x
the maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 mL. 
On Day 43/Visit 8 the pharmacokinetic blood draw will be completed as the priority and the blood 
draw for chemistry and hematology will be skipped for those subjects who weigh less than 13.5 kg, 
unless medical concerns (for example, from previous tests or reported side effects) prioritize 
chemistry and/or hematology. 
If blood collection is restricted due to volume or due to inability to draw adequate volume, collection 
should be prioritized as shown in Table 9: 
Table 9: 
Priorities for Blood Sample Collections 
Assessment
Priority
ZX008 PK sample 
Priority 1 
Clinical chemistry 
Priority 2 
Cannabidiol 
Priority 2 
AED plasma sample 
Priority 2 
LH, FSH, estradiol, testosterone, GH, prolactin 
Priority 3 
Hematology 
Priority 3 
IGF-1 
Priority 4 
Genotyping 
One time collection any time during or after screening 
Coagulation 
One time collection any time before PK day 
7.
EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS 
For an overview of the study variables and measurement times, see Schedule of Assessments 
(Table 1). 
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.8. 
7.1
EFFICACY ASSESSMENTS 
Baseline is defined as the seizure frequency during the 6-week Baseline Period. 
Retrospective diary data (up to 6 months) will be collected, if available, for an exploratory 
evaluation of the duration of baseline data capture on interpretation of post-treatment effect. 
PUBLIC 
C
actin
actin
IC
LI
BL
UB
PU
P
COPY 
PY 
Y
OPY
O
CO
C
This document
s 
bed in 
ed in
7.1
Base
Base
cannot 
S
w of the 
of the 
used to
sed to
S
be 
CY, SA
Y, S
MEN
MEN
used 
d
ed
AF
AF
to 
to 
t
support 
Pr
Pr
Prior
Prio
t
o
Prio
Pr
or
po
P
po
po
pp
up
s
any 
ny
ority 1
ority
an
t
a
marketing 
ects) p
ts) 
w adequate
adequa
authorization 
16
io
d 
and the
nd the
less tha
ess tha
prio
prio
application
measure
measur
ction 5.8
tion 5
EFFIC
EFFI
line is def
ne is d
ospect
ospect
and
tudy va
dy var
any 
ETY,
ETY
S 
S 
extensions
Prio
Priorit
Priori
s
Prio
Prio
ns
o
P
ion
o
si
ns
te
A
or 
tyty 2
r
rity 2
ity 2
or
o variations 
iat
ari
2
va
v
thereof. 
n 13.5 
13.5
ritize
ze
e volum
e volum

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 63 of 175
For all questionnaires and rating scales, the same evaluator (at the clinical site and 
parent/caregiver) will complete the assessments for the duration of the study. Substitutions at 
the clinic with another rater that has established inter-rater reliability is acceptable on an 
infrequent basis. For the in-clinic questionnaires and rating scales completed by the 
parent/caregiver, if the same parent/caregiver cannot complete the questionnaire/rating scale at 
a visit, the questionnaire/rating scale will not be completed. For the diary, the same 
parent/caregiver will complete all entries throughout the study. 
7.1.1
Seizure Assessments 
Seizure frequency by type and duration (<2 minutes, 2-10 minutes, >10 minutes) will be 
recorded daily by the parent/caregiver in a diary. Seizure types include: 
A: 
Hemiclonic (note lateralization – right body, left body, or independent right and 
left) 
B: 
Focal With or Without Retained Awareness 
C: 
Secondarily Generalized Tonic Clonic (evolving to bilateral convulsive seizure 
from focal seizure)   ͒
D: 
Generalized Tonic Clonic Convulsion 
E: 
Absence or Atypical Absence 
F: 
Myoclonic 
G: 
Tonic 
H: 
Atonic 
I: 
Clonic 
J: 
Tonic/Atonic (cannot differentiate)  ͒
K: 
Infantile Spasms (if under 3 years of age) 
L: 
Epileptic Spasms (if 3 years of age and older)
O: 
Other 
Efficacy endpoints that will be derived from the diary data include frequency of convulsive 
seizures and of all seizures, and the number/duration of seizure free intervals. 
Seizures that evolve into SE will be captured by type and duration (>10 minutes) as are all 
seizures. The diagnosis of SE made by a medical professional should be entered as an SAE if a 
prolonged seizure or series of seizures persists for 30 minutes or longer, regardless of 
administration of rescue medication. SE lasting for less than 30 minutes should be entered as an 
AE, unless one of the other SAE criteria (e.g. hospitalization) are met. If this incident involves 
multiple seizures close in time, the SE definition applies if the seizures are close together such 
that consciousness is not regained between ictal events. 
PUBLIC
zed Ton
ed To
  
onic Clon
nic Clo
Atypica
Atypica
COPY
– righ
right bo
t b
ained A
ained A
i
This document
L: 
L: 
O: 
O:
Effica
Effica
seiz
seiz
cannot 
ic
Tonic/At
onic/At
Infan
Infa
E
be used 
Ab
Ab
to 
c Co
Co
bsence
sence
support 
wareness 
areness
Clonic
Clonic (e
nvul
nv
any 
y, left bo
y, left b
marketing 
 >10 minu
10 mi
nclude:
clude:
authorization 
at 
at 
ating sca
ing sc
me
me
application 
tile Sp
le S
pileptic S
pileptic 
Other 
Othe
y endpoin
endpo
ures and o
res and 
res t
res
and 
onic (can
nic (can
pas
pas
any extensions 
evol
vo
sion 
ion
or 
lving
vin
variations 
utes
te
ody, or in
dy, or in
thereof. 
e 
s) wi
s) w

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 64 of 175
7.1.2
Clinical Global Impression - Improvement 
Both the parent/caregiver and the investigator will rate their global impression of the subject’s 
condition throughout the study according to the schedule in Table 1. 
The CGI scale measures the change in the subject’s clinical status from a specific point in time, 
ie, the Baseline Period. The CGI rating scale permits a global evaluation of the subject’s 
improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows: 
1=very much improved 
2=much improved 
3=minimally improved 
4= no change 
5=minimally worse 
6=much worse 
7=very much worse 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how their child’s symptoms have improved or worsened relative to baseline before 
the beginning of the study (before any study drug was taken). 
The investigator will be asked to indicate the appropriate response that adequately describes 
how the subject’s symptoms have improved or worsened relative to baseline before the 
beginning of the study (before any study drug was taken). A paragraph describing symptoms 
and function at baseline will be document in the source file prior to rating. 
7.1.3
Quality of Life in Childhood Epilepsy Scale 
The QOLCE (Appendix 4), a low-burden parent/caregiver completed assessment that looks at 
how epilepsy affects day-to-day functioning of their child in various life areas, including 
physical activities, well-being, cognition, social activities, behavior and general health, will be 
conducted according to the schedule in Table 1. The QOLCE has been validated in children 
aged 4 and older, and there are published data on the use of the QOLCE in children with 
epilepsy as young as 2 years of age (Sabaz 2000; Talarska 2007). 
7.1.4
PedsQL Quality of Life Inventory (PedsQL) 
The PedsQL (Appendix 6) is a pediatric modular measure of health-related QoL completed by 
the parent/caregiver on behalf of the subject. It consists of 4 core scales that measure physical, 
emotional, social, and school functioning. The PedsQL will be conducted according to the 
schedule in Table 1. 
7.1.5
Parent/Caregiver Quality of Life 
The impact on the quality of life of the parent/caregiver responsible for a patient with DS will 
be assessed according to the schedule in Table 1 using 3 scales: the EQ-5D-5L, the HADS, and 
PUBLIC 
s have
hav
any stud
any stu
to indic
to indic
ms have i
ms have i
fore an
fore a
b
COPY 
ica
cate th
te th
e im
i
This document 
sy as y
y as y
7.1.4
1.4
The P
The 
the
th
cannot
di
cts day
s day
ies, well
s, well
ccording
cording
d older, 
older,
you
you
be 
Life
ife
x 4), a
x 4), a
used
y stud
stud
e docum
docum
in C
in C
to
ate t
proved
roved
y d
support 
e appropri
pprop
proved or
oved o
y drug wa
drug wa
the app
he a
any marketing 
point
int
authorization 
ect’s
ct’s
oint in t
int in t
ubject’s
bject’s
sca
sca
application 
to
and ther
d the
ng as 2 ye
g as 2 y
PedsQ
Peds
edsQL (A
dsQL (
parent/ca
arent/ca
ional
ional
and 
o-day
day
being, c
eing, c
the sc
the sc
any 
ildh
ild
ow-burde
w-burde
func
fun
extensions
r 
as taken
 take
propr
ropriate
iat
or worsen
worse
rug wa
ug was
nt in the
t in the
hoo
hoo
or 
te re
e 
worsen
orse
)
variations 
resp
esp
thereof. 
e ranging
anging

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 65 of 175
the PedsQL Family Impact Module. Parents/caregivers who do not give consent to collect these 
ratings scales will not complete them. The same parent/caregiver should complete these ratings 
throughout the study. If that person is not available at the visit, the scales should not be 
completed. 
The EQ-5D-5L (Appendix 7) 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 HADS (Appendix 8) 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 PedsQL Family Impact module (Appendix 6) is designed to measure the impact of 
pediatric chronic health conditions on parents and the family by measuring parent self-reported 
physical, emotional, social, and cognitive functioning, communication, worry, and family daily 
activities relationships. This module will not be used in Norway, Sweden, and Denmark. 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how the care of their child with DS has impacted their quality of life using the scales 
described above. 
7.2
SAFETY ASSESSMENTS 
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication 
Subject demographics (sex, age, height, weight, and BMI), all ongoing conditions and relevant 
medical history from the past 5 years (including all major hospitalizations and surgeries) as 
well as the subject’s current medical status will be recorded at the Screening visit. Significant 
medications taken during the 30 days prior to the Screening visit will be documented. 
Medication history will be updated as outlined in Table 1. 
7.2.2
Physical Examinations 
Complete and abbreviated physical examinations, including height and weight, will be 
conducted by the investigator or designee during the study as outlined in Table 1. A complete 
standard of care physical examination for each subject will be performed and will cover the 
following body systems: general appearance, skin, eyes, ears, nose, throat, heart, lungs, 
abdomen, neurological system, lymph nodes, spine, and extremities. An abbreviated physical 
examination for each subject will cover the following body systems: heart, lungs, and follow 
up of other systems as appropriate based on last exam and reported AEs. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.3
Neurological Examinations 
PUBLIC 
with 
with 
SSMEN
SMEN
cs, M
cs, 
COPY
d the
h
tioning, 
tioning
t be used
be us
ica
cate th
te th
DS
DS
This document 
mplete a
plete a
conducte
onducte
standa
standa
fol
fol
cannot
s cur
cu
n during
during
history w
story w
Phy
Ph
be
x, a
,
he past 
he past 
rent
ren
used
edical/N
dical/
age, h
age, 
to 
TS 
support 
in n 
e appropri
pprop
has s impac
impa
any 
y by 
by
mmunic
mmuni
Norwa
Norw
marketing 
q
els of anxi
s of anx
nerates ord
erates o
to measu
o meas
mea
m
authorization 
se 
ings 
ings
rovide a
vide a
uestion
estion
application 
sical Exam
sical Ex
nd abbrevi
abbrev
d by the in
by the 
rd of care 
d of car
owing bod
wing bo
men, 
men,
and
m
the 30 
he 30 
 be upd
be upd
any
ghth
ears (in
ears (i
didical st
cal
day
d
extensions 
cte
eurologi
urologi
t, we
w
or 
te re
e 
d thei
d thei
variations 
ure the im
ure the im
asuring p
uring p
cation, w
tion, w
ay, Swed
y, Swed
resp
esp
thereof. 
s and 
and 
iety and 
y and
dinal da
inal da

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 66 of 175
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1. A complete standard of care neurological 
examination for each subject will be performed and will cover the following: cranial nerves, 
muscle strength and tone, reflexes, coordination, sensory function, and gait. An abbreviated 
neurological follow-up examination for each subject will evaluate any symptoms or systems 
found to be abnormal and unstable or potentially unstable that might evolve during study 
treatment, or to investigate any reported or observed AEs. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.4
Vital Signs 
Vital signs including blood pressure, heart rate, temperature, and respiratory rate will be 
documented for subjects during study as outlined in Table 1. 
7.2.5
Laboratory Measurements 
Laboratory safety parameters will be analyzed using standard validated methods. 
The following parameters will be assessed by the laboratory as described in Table 1: 
• Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean 
corpuscular volume, leukocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils and platelets 
• Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), 
bicarbonate, blood urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), 
chloride (Cl), creatinine, creatine kinase, gamma-glutamyl transferase (GGT), 
globulin, glucose, lactate dehydrogenase (LDH), phosphorus, potassium (K), 
sodium (Na), thyroid function (T3, T4, and thyroid stimulating hormone [TSH]), 
PUBLIC 
na
assessed
assessed
globin, h
globin, h
e, leuk
e, le
b
COPY
p
d in Ta
d in 
lyzed u
yzed
This document cannot 
, bloo
bloo
(Cl), cre
Cl), cr
lin, gluc
n, gluc
dium (Na
um (N
be 
stry: a
y: a
se (ALT
se (AL
d u
d u
used
ocytes
ytes
n concen
concen
ls and p
s and p
albu
albu
to
matocr
matocr
m
support 
sing stand
ing sta
by the lab
y the lab
any 
1. 
1. 
marketing 
estigator a
stigator a
he eCRF 
e eCR
nd respi
d resp
authorization 
ves,
es,
viated 
viated 
r system
system
ng study
g stud
application 
), thyr
thy
and
rea 
ea
atinine, 
inine, 
se, lacta
e, lacta
roid
oi
any
in (A
in (
SGPT), 
SGPT)
nitrog
nitro
extensions
borator
orator
, erythro
erythro
ean corp
an corp
tration, 
ation, 
telets
lets
AL
AL
or
ard v
ard v
variations 
iratory r
ratory r
ali
thereof. 
as clinica
clinica
as an A
as an A

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 67 of 175
total bilirubin, direct bilirubin, total cholesterol, total protein, triglycerides, uric 
acid. 
• Tests of growth and precocious puberty: Growth hormone (GH), insulin-like 
growth factor-1 (IGF-1, low sensitivity), prolactin, Luteinizing Hormone (LH), 
Follicle Stimulating Hormone (FSH), testosterone, estradiol 
• Epilepsy genotype panel 
• Coagulation: Prothrombin time (PT)/International normalized ratio (INR), 
activated partial thromboplastin time (PTT) 
• Whole blood cannabidiol 
• Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, 
urobilinogen, leukocyte esterase, and occult blood. Microscopic analysis will be 
performed for blood, all cell types, and casts. 
• Urine pregnancy test: Urine pregnancy testing will be performed in female 
subjects of childbearing potential. 
• Urine THC panel 
The investigator will receive the laboratory report from the central laboratory. After reviewing 
the report and evaluating any results that are outside the normal range, the investigator must 
sign and date the laboratory report. 
Tests resulting in abnormal laboratory values that have been classified by the investigator as 
abnormal, clinically significant should be repeated as soon as possible after receiving the 
laboratory report to rule out laboratory errors. 
At Screening any laboratory values that deviate from the reference ranges and are considered  
by the investigator as clinically relevant must be documented on the medical history form of  
the eCRF. Any deviation outside of the reference range considered by the investigator as 
clinically significant (ie, classified as an abnormal, clinically significant value) at any visit after 
screening will be documented in the eCRF as an AE (see Section 9). 
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s) 
Plasma samples to ensure that concomitant antiepileptic drug(s) (AEDs) dosing is within an 
acceptable range will be conducted during the study as outlined in Table 1. Samples collected 
PUBLIC
orator
rato
sults tha
ults tha
port. 
port. 
al labora
al labora
ificant
ifica
COPY 
sts. 
sts
testing w
testing
y
This document
ma samp
samp
ceptable
eptable
cannot
viat
iat
ant (ie, 
t (ie, 
be docu
e docu
Plasm
Plasm
be
ory
clinical
clinica
ion o
ion 
used
to
should
houl
boratory
oratory
y valu
valu
to
ry valu
y val
d
support 
epo
port from
rt fro
arere outsi
outsi
any 
ll be per
ll be pe
marketing 
io (INR),
o (INR), 
tein, biliru
in, bil
roscopic
roscop
authorization 
LH),
H),
application 
a Samp
Sam
es to ensu
s to ens
range wil
range w
and
lassifie
ssifi
mented in
ented in
any
thth
relevan
releva
side of 
ide of 
ed a
d
extensions
m 
de the 
e the
es that
that h
t
be repe
be repea
errors. 
rrors. 
hat de
at de
or 
he ce
he ce
variations 
ubin, 
bin, 
c analys
c analys
rformed 
ormed 
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 68 of 175
at Visit 6 will be analyzed after collection as a safety measure. Samples collected at other time 
points will be analyzed at study end and do not constitute safety assessments. 
7.2.7
Electrocardiograms 
Twelve-lead ECGs will be conducted during study as outlined in Table 1 after the subject has 
been in the supine position resting for 5 minutes. Heart rate, PR duration, QRS duration, QT 
duration, QTcF (Fridericia's correction formula), and the investigator’s overall interpretation 
will be recorded. 
7.2.8
Doppler Echocardiography 
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1. Doppler echocardiography uses ultrasound technology to 
examine the heart or blood vessels. An ECHO uses high frequency sound waves to create an 
image of the heart while the use of Doppler technology allows determination of the speed and 
direction of blood flow by utilizing the Doppler effect. Predetermined standard guidelines on 
the proper evaluation of certain measurements, as well as abnormality thresholds, were 
constructed by the sponsor’s IPCAB prior to study initiation. These thresholds are provided in 
Table 9 (Adverse Events of Special Interest). A manual of proper ECHO technique for sites is 
provided in a separate document. 
7.2.9
Tanner Staging 
Tanner Staging (Appendix 5) will be assessed for subjects >7 years old during the study as 
outlined in Table 1. Conceptually, pubertal maturation can be described in terms of sequence, 
timing, and tempo. Puberty consists of a series of predictable events, and the sequence of 
changes in secondary sexual characteristics has been categorized by several groups. The 
staging system used most frequently was published by Marshall and Tanner (1969, 1970) and 
the sequence of changes are commonly referred to as ‘Tanner stages’. 
7.2.10
Columbia-Suicide Severity Rating Scale 
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1. The C-SSRS is a 
validated rating scale that assesses suicidal behavior and ideation. The scale is used to assess 
and track suicide events and provides a summary measure of suicidal tendency. The C-SSRS 
version 6/23/10 (Children's Baseline/Screening and Children’s Since Last Visit) will be used in 
this study as appropriate for the age and level of intellectual development. 
Subjects who are younger than 7 years chronologically, or who are judged by the investigator 
not to have the mental capacity to understand the questions as specified on the C-SSRS, will 
urem
urem
B prior 
B prior
ecial Inte
ecial Inte
ment.
ment.
ng
ng
COPY 
ocar
ocardi
us
uses hig
es hi
r technol
echno
Doppler 
oppler 
ent
ent
This document
SRS (Ap
RS (Ap
alidated 
dated 
and tra
nd tra
vers
vers
thth
cannot
ry se
se
sed mos
ed mos
of chang
f chang
Colu
Colu
be
eptu
p
berty co
berty co
xua
xua
used 
) will
will be
 be
ually
ually
to support 
ogy a
gy 
ffect. Pre
ect. Pr
, as well a
as well
o study in
study in
st).
t). A m
A m
any 
phy us
phy u
frequen
frequen
allows
llow
marketing 
, QRS 
QRS
s overall i
overall 
experien
xperi
es
authorization 
me
me
the su
he su
d
application
mbia-Su
bia-Su
pendix 2) 
ndix 2
ating scal
ating sca
k suicide 
suicid
on 6/23/1
n 6/23/
study a
tudy 
and
ch
freque
eque
s are com
are co
any 
ube
ub
sts of a 
sts of 
aracteri
aract
ntly
extensions
nitiatio
tiatio
manual of
nual of
assessed
ssessed
ertal
erta
or
etete
abnor
abno
variations 
nce
nce for t
for 
s ultraso
s ultraso
ncy soun
y soun
s determ
determ
ermin
erm
thereof.
bject ha
ect ha
uration, Q
ation, Q
interpre
nterpre

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 69 of 175
not complete the rating. The investigator should use his/her judgment to substitute 
intellectually-appropriate questions to probe the tendency for self-harm. 
If a subject with the intellectual capacity to complete the C-SSRS has their 7th birthday during 
the study, use of the C-SSRS should be initiated at subsequent visits. 
7.2.11
Adverse Events 
Adverse events will be collected from the time of signing the informed consent form/assent form 
until the end of the study, including the follow-up clinic visit.  Details of the definitions and 
categorization of AEs, and procedures for the reporting of AEs, are available in Section 9. 
Severity and causality of AEs will be evaluated according to the criteria specified in Section 8.2 
and Section 8.3, respectively. The observation period for AE reporting is specified in 
Section 8.4. At the beginning of each visit at the study site, the study personnel will specifically 
inquire about any AEs that might have occurred since the last study site visit. All AEs will be 
recorded on the appropriate eCRF page. 
7.2.12
Behavior Rating Inventory of Executive Function (BRIEF) 
The BRIEF is a standardized, validated rating scale to measure executive function in children 
ages 2-18 years within the home and school environments; it will be assessed according to the 
schedule in Table 1. The BRIEF measures multiple aspects of executive functioning; scales 
include Inhibit (control impulses; stop behavior), Shift (move freely from one activity/situation 
to another; transition; problem-solving flexibility), Emotional Control (modulate emotional 
responses appropriately), Initiate (begin activity; generate ideas), Working Memory (hold 
information in mind for purpose of completing task), Plan/Organize/Organization of Materials 
(anticipate future events; set goals; develop steps; grasp main ideas), and Monitor (check work; 
assess own performance). 
7.3
PHARMACOKINETIC ASSESSMENTS 
Blood samples for PK assessments of fenfluramine and its metabolite (norfenfluramine) will be 
obtained from all subjects via an indwelling cannula or by venipuncture. 
Blood samples for PK assessment (2 mL) will be obtained at the following time points: 
• Maintenance Period Study Day 43: within 1 hour prior to the morning dose, and 1, 2, 
and 4-6 hours after the morning dose. 
A total of 4 PK samples will be drawn for each subject for a total of approximately 8 mL of 
blood. 
When blood draws for PK coincide with other assessments, the PK draws take precedence. 
The procedure for the collection and handling of PK samples is outlined in a separate study 
manual. 
ory of
ry of
idated ra
dated ra
me and sc
e and sc
RIEF me
RIEF me
pulses;
pulses
COPY
study s
study
ed 
ed since 
since 
Ex
E
This document 
d from
from
ood samp
d sam
•
A
cannot 
ance).
nce).
HARMA
ARMA
ples for
es for
m a
m a
be 
urpos
rpo
s; set go
; set g
used
stop b
op b
solving 
olving 
iate (be
ate (b
se o
se o
to
hoo
ures m
ures m
eh
support 
ecutive F
cutive 
ing scale t
ng scale
l envir
env
l
any 
the stu
the st
e last stu
last stu
marketing 
sent form
sent form
f the defin
the def
vailable in
ailable
criteria sp
riteria 
porting i
orting
d
authorization 
6
i
during 
uring
application 
PK asse
K ass
l subjects 
subject
es for PK
es for PK
Maintenan
ainten
and 4-6
and 4-
l of 4
l of 4
and 
COKIN
OKIN
any
comp
om
s; develo
s; deve
extensions
Fu
to measu
 meas
ronment
nmen
ltiple
iple asp
as
avior), Sh
ior), S
lexib
xibility
ility
n activi
activi
plel
or 
nction
ction
variations
pecified 
cified
is specif
s specif
dy person
y person
udy site
dy site
thereof. 
m/assent 
assent 
nitions a
nitions a
Section
Sectio

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 70 of 175
7.4
APPROPRIATENESS OF MEASUREMENTS 
All of the variables assessed are standard tests or procedures that are commonly used in studies 
of this type. 
8.
ADVERSE EVENTS 
8.1
DEFINITIONS 
8.1.1
Adverse Events 
According to ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. The period of observation for 
adverse events extends from the time the subject gives informed consent until the end of study. 
Adverse events may include: 
• 
Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. Exacerbation of seizures is considered an 
AE if there was an increase in frequency beyond the subject's typical pre-study 
fluctuations, or in the event that seizures lengthen in duration in a clinically 
meaningful way compared with baseline, or if a new seizure type emerges. 
• 
A clinical event occurring after consent but before IMP administration. 
• 
Intercurrent illnesses with an onset after administration of IMP. 
Adverse events do not include: 
• 
Medical or surgical procedures (the condition that leads to the procedure is the AE, 
eg, tonsillitis is the AE if a tonsillectomy is performed) 
• 
Situations where an untoward medical occurrence has not taken place.  For example: 
o
Planned hospitalizations due to pre-existing conditions, which have not 
worsened. 
o
Hospitalizations that occur for procedures not due to an AE (eg, cosmetic 
surgery). 
o
Hospitalizations for a diagnostic procedure where the hospital stay is less than 24 
hours in duration or for normal management procedures (eg, chemotherapy). 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must be recorded in the eCRF as AEs. In addition, at the investigator’s 
PUBLIC 
ease in t
ease in t
study en
study en
be repo
be repo
ndition
ndition
COPY
sigi
medicin
medici
stigation
stigatio
subject
ubject g
t
This document
M
eg, t
eg, 
S
cannot 
t illn
illn
nts do no
s do n
edical
dical
be
com
om
nt occur
nt occu
ess
ess
used 
during
urin
rease in 
ase in
he event
event
mpare
mpar
to
ry 
ed as a
d as a
g th
g t
support 
l) )
ves info
es info
e frequen
freque
should
shoul
A
any 
lab
lab
investig
nvesti
produc
rodu t
rm
marketing 
ence in a 
nce in 
which doe
ich do
be any un
be any 
orato
ora
authorization 
6
i
udies
ies
application
or surgic
or surgi
nsillitis is 
sillitis i
tuations w
uations 
o
Plan
Pla
w
o
and 
s w
s 
include
nclude
any 
with
wit
ng after 
ng after
with an 
ith a
extensions
ncy or se
y or s
d be
be reco
reco
AE if 
AE if thth
e study. 
study. 
requenc
quenc
hat seizu
at seiz
h b
h b
or variations
pa
es not n
not n
nfavorab
nfavora
ory 
ry find
find
gational) 
tional)
t. The pe
The p
ed con
d con
thereof. 
atient o
atient 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 71 of 175
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
1. Laboratory parameters are already beyond the reference range, unless a further 
increase/decrease can be considered an exacerbation of a pre-existing condition. 
2. Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, hemolysis) and flagged as such by the laboratory in the laboratory 
report. 
3. Abnormal parameters that are obviously biologically implausible (eg, values that 
are incompatible with life). 
4. An abnormal laboratory value that cannot be confirmed after a repeated analysis, 
preferably in the same laboratory (eg, the previous result could be marked as not 
valid and should not necessarily be reported as an AE). 
8.1.2
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1.
Results in death – The event must be the cause of death for the SAE to meet this serious 
criterion. 
2.
Is life-threatening – The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
3.
Requires in-patient hospitalization or prolongation of existing hospitalization – The 
sponsor considers “hospitalization or prolongation of existing hospitalization” for at least 
24 hours as the defining criterion for an SAE.  Hospital admissions for planned surgery or 
for normal disease management procedures (eg, chemotherapy) are not considered as 
defining criteria for SAEs. 
4.
Results in persistent or significant disability or incapacity. 
5.
Is a congenital anomaly or birth defect. 
6.
Is medically significant – A medically significant event is defined as an event that does 
not meet any of the other 5 SAE criteria, but which is judged by a physician to potentially 
jeopardize the subject or require medical or surgical intervention to prevent one of the 
above outcomes listed as an SAE criterion. Anaphylaxis that is successfully treated by 
administration of epinephrine prior to other sequelae is an example of a potentially 
medically important event. 
For the purpose of data collection in this study, a prolonged seizure or series of seizures from 
which the subject does not regain consciousness between ictal events, that is at least 30 minutes 
in duration, is termed status epilepticus (SE). A single episode of SE in a 24-hour period, 
PUBLIC
fined as
fined a
vent mus
ent mus
– The t
– The t
thth
COPY
co
previou
previ
rted as a
rted as a
This document 
esu
su
Is a co
Is a co
6.
Is 
Is
cannot
er
the def
e def
al diseas
diseas
ng criteri
g criter
ults in
ts in
be
ent hos
ho
s “hosp
s “hosp
used 
rm “li
m “l
time of
me of
ave cau
ve cau
to 
ife-
fe
support 
ny untow
unto
be the ca
e the ca
any 
afa
esult
esult co
c
t
AE). 
E). 
marketing
nditi
dit
luences o
luences 
y in the lab
in the l
ble (eg, v
le (eg, 
fter a r
fter a
authorization 
6
i
her r 
on.
on.
application
a f
persisten
persiste
ngenital a
enita
medically
edical
not meet a
ot mee
jeopard
jeopard
abov
abov
and 
ng cr
g c
manage
manage
for SAE
r SA
any 
alizatio
alizat
aliza
alization
tion
riterio
riter
extensions 
ward m
rd
use of d
se of d
hreateni
reateni
he even
even
d death
d death
or 
med
med
variations 
values 
ues
repeated
epeated
ld be m
ld be m
thereof. 
n the
the
aboratory
rator
tha
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 72 of 175
regardless of whether rescue medication was administered, should be entered in the AE log as 
well as in the seizure diary. If two or more episodes occur within 24 hours, each lasting 30 
minutes or more, an SAE of SE should be recorded. Hospitalization to manage SE, regardless 
of the number of episodes, should be reported as an SAE. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
8.1.3
Adverse Events of Special Interest 
As per ICH guidance (E2F Development Safety Update Report [2011]), the sponsor has 
identified the following AESIs for the ZX008 program (Table 10). 
PUBLIC COPY 
This document cannot be used to support any marketing 
the sponso
e sponso
authorization 
6
i
rdless
less
AEs. 
AEs. 
application and any extensions or variations thereof. 
or has 
has 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 73 of 175
Table 10: 
Adverse Events of Special Interest 
CV/Respiratory
1. Chest pain – any pain in sternal area that is described for example as crushing, burning, sharp, 
stabbing or dull.
2. Dyspnea/shortness of breath – any signs of difficult or labored breathing unrelated to a previous 
medical condition that has not worsened.
3. Persistent cough – longer than 4 weeks without a confirmed identified pathogen (or any other 
persistent cough that the investigator feels is suspicious).
4. Increase in blood pressure >30% from Screening blood pressure or a systolic pressure 140 mmHg 
after repeated measures during one visit. Blood pressure should be repeated at appropriate times 
within the visit.
5. Jugular venous distention- visible bulging of the external jugular veins on either side of theneck
6. New onset heart murmur
7. Pulmonary rales – an abnormal respiratory sound heard during auscultation of the lungs, which is 
also described as a crackle.
8. Tachycardia – a persistent HR >30% above the screening value and unrelated to exercise, 
exertion or anxiety.  Heart rate should be repeated at appropriate times within the visit.
9.
Signs that could indicate right ventricular failure:

Peripheral edema

Ascites

Syncope

Decompensated right ventricular failure – symptoms include shortness of breath, 
frequent coughing especially when lying flat, abdominal swelling and pain, dizziness, 
fainting, and fatigue
10.  Signs on ECHO indicative of potential valvulopathy

Valve regurgitation (aortic or mitral)

Moderate or severe valve regurgitation (tricuspid or pulmonary)

Mean Mitral valve gradient  4 mmHg

Mean Aortic valve gradient  15 mmHg

Mean Tricuspid valve gradient  4 mmHg

Peak Pulmonary valve gradient  21 mmHg
11. Signs on ECHO indicative of pulmonary hypertension
a.  Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings OR
b.
One of the following findings in the absence of being able to measure Tricuspid 
Regurgitation Jet velocity:
i.
Change in right ventricle/left ventricle basal diameter ratio > 1.0
ii.
 Right ventricular acceleration time < 100 msec
iii.
Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory decrease) 
and/or right atrium
iv.  Change in the geometry of the interventricular septum in systole (flattening) with left 
ventricular eccentricity index >1.1 in systole and/or in diastole
v. 
Early diastolic pulmonary regurgitation velocity > 2.2 m/sec
vi.
Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2
PUBLIC 
icul
icu
d right ve
right ve
hing esp
hing esp
titigu
COPY
nd heard
nd hea
Y
ve th
e the scr
e sc
be re
e repeat
eat
OP
ar fail
ar fai
C
This document
T
b.
One
On
R
i
oc
cannot 
alve g
lve g
uspid valv
pid va
lmonary 
monary
s on ECH
on EC
ricusp
icusp
an
be 
valve r
lve 
gradien
gradien
rad
rad
used 
ciall
iall
ve of pote
of pot
ic or mi
c or mi
eg
ed to
tricu
ricular
la
y wh
y wh
support 
ening
ning
at a
at app
pp
a
ro
r p
re:
fa
or any
ing ausc
ing au
y
value
val
a
marketing 
en (or any
en (or any
g
stolic press
stolic pre
peated at a
ated a
eti
r veins on 
veins o
ma
m
authorization 
016
io
ri
sharp, 
harp, 
ho
o a previ
a prev
u
application
O ind
ind
d Regurgit
d Regurg
f the follow
he foll
gurgitation 
rgitatio
Change
Chang
ii.
 Righ
 Ri
iii.
iii.
D
iv
and
ent 
nt
gradien
gradien
alve grad
ve grad
dica
ica
a
any 
itation
tatio
4 mmHg
4 mmH
 15 mm
 15 

extensions 
ailure – s
ure – s
n lying fl
ying fl
tial valv
al valv
)
te
or 
atat
r variations 
appro
p
either sid
ther si
ns
ion
ltation o
ltation o
ati
e and unr
nd unr
e tim
e tim
ar
v
thereof. 
us 
f
other 
ther 
eo
ure
ure 140
140
opria
opria
he

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 74 of 175
Table 10: 
Adverse Events of Special Interest (continued) 
Metabolic/Endocrine
1. 
Elevated prolactin level 2x above the upper limit of normal (ULN)
2. 
Galactorrhea
3. 
Gynecomastia
4. 
Increase in fasting serum blood glucose 2x ULN
5. 
Hypoglycemia – serum blood glucose more than 20% below the glucose level on Study Day -1 value or
more than 10% below LLN (reference range 60 – 140 mg/dL)
Neuropsychiatric
1. 
Serotonin syndrome (At least 3 of following symptoms must be present: Agitation, restlessness,
confusion, both increased HR and blood pressure, dilated pupils, muscle twitching, muscle rigidity, 
hyperhidrosis, diarrhea, headache, shivering, tremors, both nausea and vomiting)
2. 
Hallucinations
3. 
Psychosis
4. 
Euphoria
5. 
Mood disorders: depression and anxiety if they rise to a level of a disorder
6. 
Suicidal thoughts, ideation or gestures
Genitourinary
1. 
Priapism
8.1.4
Adverse Events Requiring Hospitalization 
If a subject is treated in a medical facility (hospital, emergency room, free-standing clinic) related 
to the occurrence of any AE, the following data will be collected to model health care utilization 
in patients with Dravet syndrome: AE/reason for hospitalization/clinic visit; duration of the visit in 
hours/days; admission to intensive care unit; and name/number of procedures performed, 
including but not limited to, electroencephalogram, ECG, ECHO, positive emission tomography 
(PET) scan, magnetic resonance imaging (MRI), x-ray, computed tomography CT) scan, surgery, 
and lumbar puncture/spinal tap. 
8.2
SEVERITY OF ADVERSE EVENTS 
The severity of AEs (whether nonserious or serious AEs) is to be assessed by the investigator as 
follows (Table 11). 
C
Requiri
Requiri
medi
medical f
cal 
E, the
E, th
COPY 
Y
ey rise to 
ey rise 
PY
OP
CO
C
This document 
(Tab
Tab
cannot
re
re/spin
/spin
EVERIT
VERI
y of AE
of AE
ble 1
le
be
to, ele
, el
esonan
esonan
l
used
cil
ci
followi
ollowi
me: AE/
e: AE
ns
nsive c
ive c
ct
to 
g H
lity (ho
ity (h
support 
lev
lev
t
ort
po
pp
Hospita
Hospi
any y
ny
el of a d
el of a
an
a
marketing 
Study Day
udy Da
g
Agitation, re
gitation,
e twit
twitching
ch
nd vomiting
vomiti
tin
ma
m
authorization 
016
io
za
za
za
riz
or
tho
ut
au
a
application 
 (whet
whe
1).).
and 
tap.p. 
Y OF A
OF A
the
th
any 
encep
ence
imaging
imaging
extensions s
alization
alization
spital, em
pital, em
g data wi
data wi
eason fo
son fo
e unit; 
unit;
h
or 
or
o variations 
g, musc
musc
g)
on
tio
at
isorder
order
ria
va
v
thereof. 
f
1 value o
value o
of
lessnes
essnes
le
er

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 75 of 175
Table 11: 
Severity Definition of Adverse Events 
Severity 
Definition 
Mild: 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the research participant.
Severe: 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
CDISC SDTM Severity Intensity Scale for Adverse Event Terminology 
8.3
CAUSALITY OF ADVERSE EVENTS 
The causal relationship of an AE to IMP must always be assessed by the investigator. All AEs will 
be classified as either related or not related to IMP. If a causality assessment is not provided for 
an AE (including an SAE), that AE will be considered as related to IMP. 
The degree of certainty with which an AE is attributed to IMP or an alternative cause (eg, natural 
history of the underlying disease, concomitant medication) will be determined by how well the 
event can be understood in terms of: 
• Known pharmacology of ZX008 
• Clinically and/or pathophysiologically plausible context 
• Reaction of a similar nature previously observed with similar products, or reported in 
the literature for similar products as being product related (eg, headache, facial 
flushing, pallor) 
• Plausibility supported by the temporal relationship (eg, the event being related by 
time to administration or termination of treatment with IMP drug withdrawal or 
reproduced on rechallenge) 
The following classifications should be used in categorization of relatedness: 
1. Not Related: 
Concomitant illness, accident or event with no reasonable association 
with study drug. 
2. Related: 
The event follows a reasonable temporal sequence from administration of 
study drug and is definitive pharmacologically; cannot to be attributed to 
concurrent disease or other factors or medications. A clinically reasonable 
response should be observed if the study drug is withdrawn or dose 
reduced. 
PUBLIC 
DVERS
DVERS
AE to IM
E to IM
d 
d or 
or no
no
that A
tha
COPY
ual 
a
status, o
status,
r Adve
r Adve
CO
C
This document
f
•
Pl
Pl
The f
The 
1
cannot 
pharm
harm
cally and
lly an
action o
tion o
he litera
e liter
flush
lush
be
ise
in term
term
ac
ac
used
E will 
will
which an
hich an
as
ase, c
e, c
to
P mu
elated
elated
b
support 
se Event 
Even
rt
o
EVENT
EVENT
ust al
ust a
any 
ies o
ies 
may req
may re
marketing 
l specific
l specific
ties of da
es of d
ermanent
rmane
g
of da
of d
ma
authorization 
016
io
iza
imal
mal
erally
ally
ori
application 
ure f
re 
ng, pallor)
g, pallo
usibility s
sibility
ime to ad
ime to a
reprodu
reprod
ollowing c
lowing
Rela
Re
and
log
og
or patho
r path
a simila
simila
or s
or
any 
co
co
f:f:
y of ZX
y of Z
extensions 
S 
ways be 
ays be
o IMP. I
IMP. 
conside
conside
AE is att
E is at
omita
mita
or 
Term
er
or variations 
t r
aily livin
ly livi
uire inte
ire inte
on
mino
min
va
thereof. 
c therape
therap
aily livin
ily livin
risk of
isk of
eo

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 76 of 175
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING 
The observation period for AE and SAE reporting in an individual subject will start at the time of 
giving written informed consent for participation in the current study and finish 15 days after the 
last dose of study drug or the last visit, whichever is later. For subjects who enroll in the open-label 
extension study, ongoing AEs will be followed in that study. 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with IMP (irrespective of whether or not 
it is considered by the investigator to be causally related to IMP), then this must also be reported 
to the sponsor (see Section 8.6). 
8.5
ADVERSE EVENT REPORTING 
8.5.1 
Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred. Adverse events will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or stabilization. 
If an AE is ongoing after the end of study visit, the AE will continue to be followed up until 
resolution or stabilization. 
If, during the study period, a subject presents with a pre-existing condition that was not noted at the 
time of study entry, the condition should be retrospectively recorded in the Medical History section 
of the eCRF. 
8.6
SERIOUS ADVERSE EVENTS REPORTING 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting [1994]). 
In the event of a SAE the investigator or delegate must:  
1.
Enter all relevant information in the AE page of the eCRF 
2.
Inform the Medical Monitor or the Sponsor of the SAE via email or telephone within 
24 hours of becoming aware of the SAE. 
3.
Follow the initial notification with a completed SAE report form. The SAE form 
must be emailed or faxed to iHC within 24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, beginning the day Informed Consent is signed, 
whether or not causally related to IMP must be reported immediately via telephone or email (within 
24 hours of the investigator becoming aware of the event) to the sponsor or the Medical Monitor.
Adverse events occurring in the period between the time the subject gave written informed consent 
and the first exposure to IMP that meet one or more of the seriousness criteria for AEs must be 
PUBLIC
n p
ow up 
ow up
f study v
f study v
a subjec
a subjec
dition
diti
COPY 
r delegat
r dele
n n the AE
the AE
prefere
efer
This document 
1.1.
cannot
wit
wi
Topic E
Topic 
ing [199
ng [199
f a SAE
a SAE
E
be 
DVER
VER
h all
h al
used
pr
pr
should
ould
RSE
RS
to 
esents
esent
b
support 
)
page o
age o
nce to the 
e to th
the cour
he cou s
sit,t, the AE
the AE
any 
will det
will d
f th
f
marketing
on p
n p
ive of wh
ive of w
s must als
must a
authorization 
016
io
me of 
me of 
after the
ter the
he open-
e open-
perio
erio
application 
he in
e in
nter all rel
ter all r
Inform 
Inform
24 h
24 
3.3.
F
and
p
2A (Cl
A (C
4]).)
ve
ve
any 
EVEN
EVE
plicable
plicab
linic
li
extensions
e o
E will c
will c
with a
with a p
e retrosp
retrosp
N
or
isting
istin
f an A
f an
variations 
termine w
rmine
e eCRF
 eCRF
thereof. 
d has 
as 
hether or
ther or
so be rep
be re

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 77 of 175
reported to the sponsor and the Medical Monitor in the same manner as other SAEs and will be 
included in the clinical study database. 
Any SAE that occurs 15 days after the last dose of study drug or the last visit, whichever is later that is 
considered to be causally related to IMP must be reported immediately (i.e., within 24 hours of the 
investigator becoming aware of the event) to the sponsor and the Medical Monitor. 
Contact details and guidance for reporting SAEs will be provided to study site before the study starts.
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events 
The minimum reporting requirements for immediate reporting of SAEs include: 
1. Identifiable subject 
2. Suspected drug product 
3. Event description 
4. Identifiable reporting source In 
addition, the investigator must: 
1. Report all SAEs to the relevant IRB/IEC within the timeframe specified by the 
IRB/IEC. 
2. Submit follow-up reports to the sponsor Global Clinical Safety and 
Pharmacovigilance and the Medical Monitor until the SAE has resolved, or, in the 
case of permanent impairment, until stabilized. 
3. Ensure that the AE term(s) and causality assessment for all SAEs is entered in the 
eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying the sponsor. 
When submitting SAE reports to the sponsor, subjects should be identified only by their subject 
number and study number. The investigator should not include the subject’s name and address. 
SAE Update reports can be submitted to the sponsor any time that additional relevant information 
becomes available. In cases of death, the investigator should supply the sponsor and the IEC/IRB 
(as applicable, see Section 8.7) with any additional requested information as it becomes available 
(eg, autopsy reports and detailed medical reports). Once an SAE is reported to the sponsor’s Safety 
Group, a Safety Specialist may contact the investigator with follow-up questions. 
The procedure to be followed if an ongoing AE becomes an SAE after the end of the 
observation period for AEs is described in Section 8.9. 
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR TO 
IEC/IRB 
The timeframe within an IEC/IRB must be notified of a death or an unexpected SAE considered at 
least possibly related to the IMP is stipulated by each individual IEC/IRB. The investigator is 
PUBLIC
levant IR
evant I
reports to
eports t
nce and t
nce and 
t im
t im
COPY 
This document
ate
ate
es avail
avail
applicab
pplicab
eg, autop
g, auto
Group
Group
Th
Th
cannot 
forma
rm
g SAE re
AE re
udy num
dy num
e repor
repor
be
ments fo
ments fo
atio
atio
used
he M
e M
airment
irmen
term(s) a
erm(s) 
to 
the sp
the sp
Medic
Medic
support 
B/IEC wit
/IEC w
pons
on
any marketing 
efore
for
rse Event
e Even
Es include
includ
authorization 
016
io
later th
ater th
4 hours 
hours 
tor.
e the
e the
application
be
ts can be 
ts can be
ble. In cas
e. In ca
e, see Sect
e, see Se
sy reports
y repor
a Safety S
Safety
rocedur
ocedu
i
and 
toto
ports to t
rts to t
er. The
. The
any 
eporting
eportin
fully d
fully
extensions 
thin th
in t
sor Glob
or Glob
al Monit
Moni
until stab
ntil sta
nd causa
d caus
or 
he
he
variations 
e:
thereof. 
study sta
udy sta
ts 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 78 of 175
responsible for complying with the requirements for IEC/IRB notification. The investigator will 
notify the relevant IEC/IRB within the applicable timeframe by forwarding the safety report (eg, 
MedWatch/CIOMS form) completed by the sponsor for the notifiable event. 
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE EVENTS BY 
INVESTIGATOR TO SPONSOR 
Even if none of the criteria for an SAE are fulfilled, any of the following events must be 
reported by the investigator to the Medical Monitor within 72 hours from the time the 
investigator is notified. 
1. Hypersensitivity reactions 
2. Pulmonary hypertension 
3. Cardiac symptoms requiring intervention, or valvulopathy, if identified 
outside of study-related monitoring 
8.9
FOLLOW-UP OF ADVERSE EVENTS 
Every effort should be made to follow-up subjects who continue to experience an AE or an SAE 
on completion of the study or until the AE resolves. All follow-up information (and attempted 
follow-up contacts) should be documented in the subject’s medical records. Details of the subject’s 
progress should also be submitted to the sponsor’s Global Clinical Safety and Pharmacovigilance 
and the Medical Monitor. In the event of a SAE a blood sample for ZX008 and AED PK should be 
collected as soon as feasible. 
Subjects who are discontinued from the study or complete the study and have been found to have 
any signs of valvulopathy or pulmonary hypertension on ECHO will be followed until the 
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication, unless it is determined after unblinding that the 
subject did not receive ZX008. 
8.9.1
Follow-up of Echocardiogram Findings 
All ECHOs will be evaluated by a central reader from BioMedical Systems, Inc. (BMS), in 
consultation with the IPCAB, if warranted. Findings related to pulmonary hypertension or 
valvulopathy on any of the four valves (aortic, mitral, pulmonary, triscuspid) will be reported to the 
investigator with grades of normal, trace, mild, moderate or severe. If the ECHO result has 
progressed in severity since the last reading then new oversight measures will be enacted as 
described below in Levels 1-3. Table 12 describes the severity of ECHO findings with the level of 
increasing oversight if the subject is to remain in the study. 
Table 12: 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings 
Severity
Valve
Aortic
Mitral
Pulmonary
Tricuspid
PUBLIC
-up s
-up
the AE r
he AE 
cumente
cument
tted to th
ed to th
n th
n the eve
e ev
e
COPY 
on, or 
on, 
E EVEN
E EVEN
subje
subj
This document
HOs w
HOs w
sultation
ltation
alvulopa
lvulopa
investi
nvesti
prog
prog
d
cannot
last do
st do
eceive Z
eive Z
Follo
Follo
wilil
be
or p
or stabil
or stabi
used 
nt 
nt
d from
from t
m
pulmo
pulm
to 
e spo
spo
of a S
of a S
support 
TS 
S 
cts who co
who 
solves. A
lves. A
in the su
n the su
onsor
onso
any 
ulopat
ulopa
marketing 
nts mus
mus
he time th
he time th
hy
h
authorization 
016
io
(eg, 
(eg, 
EVENT
VENT
t
application 
w-up o
up 
be evalua
be evalu
with the IP
ith the 
thy on any
hy on an
gator with 
tor wit
ressed in 
essed in
ibed b
bed b
and 
of st
f s
X008.
008.
of E
of E
any
ary
ry
d where
d whe
tudy m
udy
extensions 
All foll
foll
ubject’s m
ect’s m
r’s Globa
Globa
AE a blo
E a blo
e study 
study 
y hyp
hy
or
ntinue
tinue
ow
variations 
y, if iden
y, if iden
thereof. 
e
e

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 79 of 175
Normal
Level 1
Level 1
Level 1
Level 1
Trace
Level 2
Level 2
Level 1
Level 1
Mild
Level 2
Level 2
Level 1
Level 1
Moderate
Level 3
Level 3
Level 3
Level 3
Severe
Level 3
Level 3
Level 3
Level 3
Level 1:   Continue per protocol 
Level 2: 
1. If there is a desire to continue study medication: 
a.
The investigator will evaluate the efficacy to date based on study diaries and 
consult with the parent/guardian, and determine whether study treatment was 
associated with significant, meaningful benefit in number, severity and/or 
duration of seizures and/or on the impact on daily functioning. 
b. The investigator will consider whether the subject has had reasonable trials (dose and 
duration) of other available anticonvulsants (e.g. valproic acid, clobazam, or 
topiramate), alone or in combination, and not maintained the level of seizure control 
achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering benefit 
and potential risks, and the parent/guardian feels strongly that the child be maintained on the 
study medication when understanding the risks, the parent/guardian must sign a new consent 
which describes the additional risks and the child should provide assent if appropriate. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted to the 
IDSMC for review, including consideration of effects on seizures and comorbidities. 
4. The Co-Chairs of the IPCAB are alerted to the request and prepare, after consultation with 
BMS, an evaluation of the cardiopulmonary risks and proposed monitoring plan if 
applicable, for submission to the IDSMC. 
5. IDMSC will review the submissions from the Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including the possible outcomes: 
a.
Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c.
Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
Level 3: 
1. The investigator will evaluate efficacy to date based on study diaries and consult with the 
parent/guardian, and determine whether the achieved benefit justifies the consideration of 
continuing study treatment by the IDSMC. MINIMAL efficacy criteria for IDSMC 
PUBLIC 
comb
mb
medicatio
dicatio
nsideratio
siderati
the paren
he paren
n under
n under
ditio
diti
COPY
fulul b
impact 
impac
whether 
whethe
anticonv
nticonv
inat
inat
This document 
MSC 
MSC 
subject 
ubject
6. IDS
IDS
cannot
p
view, i
ew, i
airs of th
rs of th
n evaluat
evalua
able, fo
ble, fo
be 
epares 
epares
nc
nc
used
tand
and
nal risks
l risks
conditio
nditio
to
/guard
/guar
ding 
ding
support
he su
s
ulsants (e
sants (
on, and no
n, and 
n. 
of con
f contin
ian
i
any
in nu
in n
da
daily fu
ily f
ubject
ubje
marketing 
ased on st
sed on 
whether s
hether
umb
um
authorization 
016
io
ririri
3
ho
th
application 
on
submis
ubmi
l review t
review
reatment 
eatmen
MC makes
C mak
a.a.
Dis
D
b.b.
c
and 
udin
udi
e IPCAB
IPCAB
n of the
of th
any 
case hist
case his
ng con
ng co
extensions 
nued tre
ued tre
n feel
feels st
s st
he risks,
e risks,
and the
nd the
s are no
are no
or
g. v
. v
maint
main
variations
tudy di
udy d
study tre
study tre
ber, seve
er, seve
unctionin
nctioni
t has ha
has ha
valp
valpr
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 80 of 175
consideration: 
a.
Seizures must be more than 75% improved (number of convulsive seizures per 28 
days) on treatment over baseline, and improvement must be consistent. 
b. The number, type, duration, and distribution of seizures at baseline should be of a 
severity, which justifies the risks of cardiopulmonary complications, considering the 
subject’s age and overall health. 
c.
Subject has had reasonable trials (dose and duration) of other available 
anticonvulsants (eg, valproic acid, clobazam, topiramate), alone or in combination, 
and not maintained the level of seizure control achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risks, and the parent/guardian feels strongly that the child be 
maintained on the study medication when understanding the risks, the parent/guardian must 
sign a new consent which describes the additional risks and the child should provide assent 
if possible. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted to 
the IDSMC for review, which includes effects of study medication on seizures and 
comorbidities related to Dravet syndrome. 
4. The Co-Chairs of the IPCAB are alerted to the request, and in consultation with BMS 
prepare an evaluation of the risks and proposed monitoring plan if applicable for 
submission to the IDSMC. 
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including these possible outcomes: 
a.
Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c.
Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
8.10 
PREGNANCY 
This study is open to female and male subjects. Whenever possible, a pregnancy in a female 
subjects or the female partner of a male subject exposed to IMP should be followed to term so as 
to assess any potential occurrence of congenital anomalies or birth defects. Any follow-up 
information, including premature termination and the status of the mother and child after delivery, 
should be reported by the investigator to the sponsor using a pregnancy reporting/outcome form. 
9.
DATA HANDLING PROCEDURES 
9.1
RECORDING OF DATA 
The investigator (or delegate) will maintain individual records for each subject. These records 
PUBLIC
his
h includ
includ
ravet syn
ravet sy
PCAB ar
CAB ar
n of the 
n of the
SMC
SM
COPY 
ditio
ti
ot me
ot met, t
story a
tory 
This document
PR
PR
s study i
study i
subjects 
bjects 
to ass
to ass
inf
inf
cannot
tinue
nu
ease freq
ase freq
dd addit
d addi
Reduce
Reduce
RE
be
wa
determ
determ
e stu
e stu
used 
isk
sk
submis
ubmis
arrante
rrante
to 
aler
aler
ks and 
s and
support 
he s
e 
nd rationa
d ration
effects of
ffects 
drome.
ome.
ted to
ted
any 
ks an
ks a
ubject 
ubjec
marketing 
ailabl
lab
ne or in c
ne or in c
ith study m
h study
is warran
warra
trongly th
ngly t
g the risk
the ris
nd th
nd
authorization 
016
io
28 
28 
d be of a
d be of a
onsideri
nsideri
le
application 
the e
GNANC
GNAN
s open to f
s open to
or the fem
the fem
ss any pot
any p
mation, i
ation
be r
and
dy
uency o
ncy o
onal EC
nal EC
dose
dose
any
tion of 
ion of
medicat
medic
f E
f
extensions 
f stu
stu
o the req
the req
proposed
oposed
on from
n from
or
e for c
e for
dy m
dy
variations
nte
hat the c
t the 
ks, the pa
ks, the p
he child 
e child 
is disco
s disco
thereof. 
ombinat
mbinat
medicati
medicat
d cons
d cons
h

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 81 of 175
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. 
An eCRF and a subject diary will be provided by the sponsor (or delegate) for each subject enrolled 
into the study. Study site staff will enter data directly into the validated electronic data capture 
(EDC) system by completing the eCRF via a secure internet connection. The investigator is 
responsible for ensuring accurate and proper completion of the eCRF and subject diary for 
recording data according to the instructions given in the eCRF and subject diary. 
All entries in the eCRF 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 (see Section 12.8). Source 
data must be completed legibly for each subject enrolled into the study and signed by the 
investigator (or delegate). 
Data entry in the eCRF and subject diary must be completed in a timely manner so that they 
always reflect the latest observations on the subjects enrolled in the study. 
The subject’s diary will be completed by the parent/caregiver at home. Data entries will be 
reviewed by the investigator for completion and consistency. 
9.2
DATA QUALITY ASSURANCE 
An initiation meeting will be held before starting the study, during which the study design, 
procedures to be followed, and measures for ensuring standardized performance will be explained 
by a delegate from the sponsor, and a common understanding of the requirements of the study will 
be reached with the investigator and other relevant personnel at the study site. 
Data generated throughout the study will be monitored and the data entered in the eCRFs will be 
checked against the subject records for completeness and accuracy. The sponsor’s study monitor 
will perform this function. 
The computer system used for study data handling will be fully FDA 21 CFR Part 11 compliant. 
All creation, modification or deletion of electronic study records will be documented through an 
automated Audit Trail. Following completion of eCRF pages and entry of the data into a database, 
the data will be checked electronically for consistency and plausibility. Data queries will be 
generated for questionable data and response clarification will be sought from the investigator. 
These data queries must be resolved in a timely manner by the investigator (or delegate). 
9.3
RECORD RETENTION 
A study document binder will be provided by the sponsor for the investigator at each site for all 
requisite study documents (constituting the “Investigator Study File”). 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements. 
The investigator is responsible for archiving the Investigator Study File, the subject’s records, and 
PUBLIC 
URANC
URAN
ld before
ld before
nd measu
nd measu
sor, an
sor, an
or
COPY
omp
m
ects
ects enr
en
 parent/c
parent/
n and c
n and c
This document
will
ill
ted for 
d for 
se data q
e data 
9.3.3
A s
A s
cannot
io
em used
m used
odificatio
dificati
udit Tra
it Tra
be ch
be ch
be
ct reco
rec
n.n.
used 
d a com
co
and othe
d othe
e study
study
d
to
sta
es for e
s for 
mm
mm
support 
aregiv
egiv
nsistency
sistenc
E 
arting th
rting 
ns
any 
n a t
n a 
ed in the
ed in th
ver a
ver
marketing 
t d
ary.y. 
the study 
he study
see Section
ee Secti
udy and si
dy and 
imel
im
authorization 
016
io
and 
nd 
ct enroll
enroll
a capture
capture
tigator is
ator is
diary f
iary f
application
l. Fo
ecked ele
ecked el
uestionable
stionab
ueries mus
ueries mu
RECO
RE
dy docu
y doc
e st
and
for stud
or stu
n or dele
or dele
ollow
llow
any 
for com
for c
dy d
extensions 
he study
he study
suring st
uring st
on under
n under
r relevan
elevan
ll be m
be m
or variations 
igned 
ned
ly mann
y mann
e study.
study. 
t home. 
home.
thereof. 
or 
site. All
e. A
n 12.8). 
12.8). 
by
by

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 82 of 175
the source data according to applicable regulatory requirements. These documents have to be 
archived for at least 15 years or at least 2 years after the last approval of a marketing application in 
an ICH region, but should be retained for longer if required by regulatory requirements or by 
agreement with the sponsor. 
If the investigator can no longer maintain the archive of study records (eg, due to retirement or 
relocation), the sponsor must be informed in writing about any change in responsibility for record 
retention, including the name of the new responsible party, contact information, and location of the 
study records. Records may not be destroyed without prior written consent from the sponsor. 
10.
STATISTICS 
10.1
DETERMINATION OF SAMPLE SIZE 
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). The 
EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
stiripentol groups, the SD of the percentage change in seizure frequency from baseline to month 2 
was 42% in the French trial and 26% in the Italian trial. The analogous SDs for placebo groups 
were 38% and 62%. An SD of 50% was assumed for the primary analysis in this trial comparing 
ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure frequency. Using a two-
sided test at the Į=0.05 significance level, a sample size of 35 subjects per treatment group affords 
90% power to detect a difference in mean change from baseline of 40 percentage points. Similar 
assumptions and calculations yield a requirement for an additional 35 subjects in the 0.2 mg/kg/day 
ZX008 group. Thus, the total sample size is planned to be 105 subjects (35 per arm). 
10.2
ANALYSIS POPULATIONS 
10.2.1
Safety (SAF) Population 
All safety analyses will be performed on the SAF Population defined as all randomized subjects 
who receive at least one dose of ZX008 or placebo. Subjects will be analyzed according to the 
treatment actually received. 
10.2.2
Modified Intent-to-Treat (mITT) Population 
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZDX008 0.8 mg/kg/day to placebo, as well as key secondary analyses, will be 
performed on the mITT Population. 
10.2.3
Per Protocol (PP) Population 
The PP Population is defined as all randomized subjects who receive at least one dose of ZX008 
or placebo, complete the entire 12 week Maintenance Period, and have no major protocol 
PUBLIC
the
th
was assu
as ass
on the ch
on the c
ance lev
ance lev
rence in 
rence in 
ns yiel
ns y
COPY
lled 
e
t Report
t Repor
es: STIC
es: STI
e change
e chang
e Itali
Ital
This document 
M
he mITT
e mITT
ZX008
ZX00
anal
ana
c
cannot 
(SAF
SAF
es will b
will b
least on
east o
tually r
ually r
be 
OPU
PU
) P
) P
used
me
a requ
requ
ample siz
mple siz
ULA
ULA
to
el, a 
 a 
an cha
an ch
i
support 
LO 
O
in seizur
n seizu
n trial. Th
trial. T
med for 
d for tht
ange from
nge from
samp
sam
any
s in s
s in
EPAR) fo
EPAR) f
France
Franc
marketing 
si
on, and 
, and
from the 
from the 
subje
su
authorization 
016
io
ion in
ion in
by y 
tiremen
remen
bility f
ility f
l
application 
e 
eceived.
eived
odified In
ified 
Populatio
opulat
or placebo
r place
zed accor
ed acco
rison
iso
and 
opu
p
e perform
perform
dose o
ose o
any 
ION
ION
ulation
latio
extensions 
he prim
pri
m baselin
baselin
m
le size o
e size o
nge from
from
ement fo
ment fo
e is pl
is plann
ann
S
or
e analo
anal
mar
mar
variations 
ects wit
cts wit
or stiripe
r stirip
e and ST
and ST
equen
equen
thereof.
or
or recor
recor
cation o
ation o
 sponsor
ponsor

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 83 of 175
deviations that would have a significant impact on clinical outcome. Subjects will be analyzed 
according to the treatment they received. The primary and key secondary efficacy analyses will be 
repeated on the PP Population if there are substantial differences in the makeup of the mITT and 
PP Populations. 
10.3
TREATMENT GROUPS 
Subjects will be randomly assigned to one of three treatment groups: ZX008 0.8 mg/kg/day, 
ZX008 0.2 mg/kg/day, or placebo. 
10.4
TREATMENT PERIODS 
Baseline Period 
The Baseline Period covers the approximately 42-day span just prior to randomization and the 
start of treatment. The baseline frequency of convulsive seizures will be calculated from data 
collected during this period. 
Titration Period 
The Titration Period covers the first 14 days of treatment while subjects are titrated to their 
randomized dose. It begins on the first day of treatment (Study Day 1) and extends through Study 
Day 15 regardless of the exact day on which a subject reaches his or her assigned dose. The 
Titration Period applies to all subjects including placebo recipients. 
Maintenance Period 
The Maintenance Period covers the 12 weeks following the end of the titration period. It begins on 
Study Day 16 and extends through Study Day 99. 
Titration +Maintenance (T+M) Period 
The T+M period combines the Titration and Maintenance periods, beginning on Study Day 1 and 
extending through Study Day 99. The T+M period is considered the treatment period. 
Follow-up Period 
The Follow-up Period begins immediately at the end of T+M period and extends to a final visit 2 
weeks later; ie, from Study Day 99 through Study Day 113. Only subjects who do not roll over 
enrollment into the open-label extension will participate in the Follow-up Period. 
10.5
STATISTICAL ANALYSES AND METHODS 
All efficacy, safety, and PK data will be summarized. 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. 
Efficacy and PK data will be summarized by treatment (ZX008, placebo) age cohort (<6 years and 
6 years of age), as well as for the total subjects in the population. 
PUBLIC
4 days 
4 days
first day 
irst day 
ay on wh
ay on wh
subj
subjects
ects
COPY
da
d
onvulsi
onvul
o
This document 
low-up
w-up
s later; i
later; 
rollment
ollmen
10.5
10.5
A
cannot
ombines
bines
gh Study
h Study
eriod 
riod 
ca
p P
be 
hro
(T+M) 
(T+M)
b
used 
s the 12
he 12
ough S
ugh S
to
ic
ncludi
nclud
support 
treatment
reatmen
f treatmen
treatmen
h a subj
sub
ng
any
jus
us
seizure
seizur
marketing 
0.8 mg/
mg
t prio
t pr
authorization 
016
io
will be
ill be
TT and 
T and 
/k/k
application 
eriod begi
riod be
, from Stu
rom S
into the op
nto the 
STA
ST
cacy
cac
and 
he Tit
 Tit
Day 99. 
ay 99. 
any 
udy
d
eriod 
eriod 
an
ratio
rat
extensions
t w
nt (Stud
t (Stu
ect reac
ect reac
g placebo
lacebo
weeks fo
eeks fo
y Da
y Da
or 
hile
hile
variations 
or to ran
to ra
will be
will b
thereof. 
g/day,
day,

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 84 of 175
A complete description of the statistical analyses and methods will be available in a SAP, 
which will be finalized before the database is locked. 
10.5.1
Efficacy Analyses 
10.5.1.1
Primary Efficacy Analysis 
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 
28 days between the Baseline and T+M periods. The MCSF will be calculated from all available 
data collected during the Baseline or T+M Periods. 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with baseline 
frequency as a covariate.  The primary analysis will compare the ZX008 0.8 mg/kg/day group to the 
placebo group using a two-sided test at the Į=0.05 level of significance. 
Since the ANCOVA used in the primary analysis relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric method that does not require as stringent 
assumptions. A test such as the van Elteren test, which extends the Wilcoxon rank sum test to 
include stratified data, will be used to compare the ZX008 0.8 mg/kg/day group to the placebo 
group while stratifying for age group. If normality assumptions are not met, the results of the van 
Elteren test will be used to assess the primary objective. 
An additional analysis will be performed to assess the sensitivity of the primary analysis to 
changes in dose or type of concomitant AED medications that may occur during the course of the 
trial, which are protocol violations. Specifically, the primary analysis will be repeated with a factor 
added to indicate whether a subject had a change in prescribed dose or type of concomitant AED 
medication during the T+M period. Further exploratory analyses may be conducted if changes in 
concomitant AED medication appear to have a significant impact on the primary outcome. 
Additional analyses will compare the changes between the baseline MCSF and the MCSF measured 
independently during the Titration Period alone and the Maintenance Period alone. 
10.5.1.2
Key Secondary Analyses 
The first key secondary endpoint – the proportion of subjects who achieve a 40% reduction from 
baseline in convulsive seizure frequency – is derived directly from the primary endpoint. That is, 
the proportion of subjects in the ZX008 0.8 mg/kg/day group who have a change in convulsive 
frequency of at least -40 percentage points will be compared to the analogous proportion in the 
placebo group. The comparison will be made using a logistic regression model that incorporates 
the same factors and covariates as the ANCOVA used in the primary analysis. The second 
secondary endpoint – the proportion achieving a 50% reduction in convulsive seizures – will be 
analyzed similarly. The analyses will be performed using data collected over the T+M period. 
The longest interval between convulsive seizures will be calculated for each subject over the 
entire T+M period. The ZX008 0.8 mg/kg/day and placebo groups will be compared using a log-
rank test. 
PUBLIC
teren t
eren 
to co
to comp
mp
roup. If 
roup. If 
sess the p
ess the 
be per
be p
COPY 
l com
l co
05 level 
05 leve
alysis rel
alysis re
parame
parame
e
This document 
K
first key 
st key
aseline in
eline in
the prop
he prop
frequ
frequ
plp
cannot
medicat
dicat
yses will
es will
y during
during
Key S
Key S
be 
a subj
sub
+M per
+M per
i
used
ormed 
med
omitant 
mitant 
tions. S
ons. S
jec
jec
to
o
rimary
imary
t
support 
es on 
s on 
tric metho
c met
 which ex
which 
are the ZX
e the ZX
rmality a
mality
ob
any 
the Z
he 
f signific
signifi
assu
as
marketing 
frequenc
frequenc
lated from
ated fr
iance
nce (AN
(A
s) as fact
) as fa
X0
X
authorization 
016
io
application 
the 
econdary 
condary
econdary 
condar
convulsiv
convulsi
ortion of s
rtion of
ency of at
ncy of a
o grou
o grou
and 
n app
ap
compare
ompare
Titra
Titra
any 
had a 
had a
d. Furthe
d. Furth
pear to
pear
extensions
xte
X008 0.
008 0
assumpt
sump
bjective.
ective.
assess th
assess t
AED med
ED med
cificall
ificall
ch
or 
d tha
d th
nds th
nds th
variations
NCOVA
COVA
tors,
ors, and
and
008 0.8 m
08 0.8 m
cance.
nce.
mption
mption
at d
t
thereof. 
y (MCS
(MCS
m all ava
all av

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 85 of 175
The MCSF in the ZX008 0.2 mg/kg/day group will be compared to the placebo group using the 
same methods employed for the primary analysis. Analyses of other key secondary endpoints 
involving the ZX008 0.2 mg/kg/day group will employ similar methods as those used to compare 
ZX008 0.8 mg/kg/day to placebo. Whenever feasible, secondary analyses involving either ZX008 
0.8 mg/kg/day or ZX008 0.2 mg/kg/day will be repeated using post-treatment data collected during 
the Titration Period alone and during the Maintenance Period alone. 
10.5.1.3
Multiplicity Strategy and Testing Hierarchy 
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate at 
Į=0.05 across the family of analyses that support the primary and key secondary objectives. The 
strategy specifies a hierarchy of significance tests where each test acts as a gatekeeper to the tests 
below it. 
The primary and key secondary endpoints will be assessed in the following order beginning 
with comparisons of ZX008 0.8 mg/kg/day to placebo on 
• The change in MCSF from baseline. 
• The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
• The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
• The longest convulsive seizure-free interval. 
The evaluation of key secondary endpoints continues by comparing the ZX008 0.2 mg/kg/day 
group to placebo in the following order: 
• The change in MCSF from baseline. 
• The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
• The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
• The longest convulsive seizure-free interval. 
10.5.2
Safety Analyses 
Summaries of safety data will be presented by treatment – ZX008 0.8 mg/kg/day, ZX008 
0.2 mg/kg/day or placebo – separately for the Titration, Maintenance and T+M periods. The 
number and percentage of subjects in each treatment group with AEs will be displayed by body 
system and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries of AEs by severity and relationship to study drug will also be presented. A separate 
summary will be provided for all serious AEs (SAEs). Selected summaries will be repeated broken 
out by age group, ie, for ages <6 years and 6 years. 
Hematology and chemistry laboratory results will be summarized using shift tables that tabulate the 
PUBLIC 
hie
who achi
who achi
e se
e seizu
i
COPY
sses
se
acebo on
acebo o
ve a
ve a 
This document
ure
The long
he long
.5.2.2
Summ
Summ
0.2
0.2
cannot
of sub
of sub
uency.
ncy.
portion o
ortion 
frequ
frequ
be
SF from
SF from
j
used 
e-free
fre
ry endpo
endpo
ing ord
ng or
to 
inin
support 
0% reduc
% redu
ve a
e a 50%
50%
any 
the f
the 
marketing 
n the Type
the Typ
secondary
seconda
cts as a ga
ts as a g
follo
fol
authorization 
016
io
ompare
mpare
her ZX0
her ZX0
ollected 
lected 
application 
f su
ncy.
cy.
st convuls
convu
Safety A
Safety 
aries of sa
ies of 
g/kg/day
/kg/d
an
and 
cts w
ts w
ubject
bject
any 
aseline.
seline
who ac
who
extensions 
% reduct
reduct
rval.
val.
nts conti
s conti
or
ion fr
ion 
variations 
atekee
ekee
owing or
wing or
thereof. 
e 1 error
 erro
objecti
objecti
epe
pe

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 86 of 175
proportion of subjects who have lab results that change from baseline. Shift tables will be presented 
for each time point where lab results are collected. Mean change from baseline will also be 
calculated for continuous hematology and chemistry results at all time points available. 
Laboratory tests, vital signs, physical examinations, neurological examinations, ECG, Doppler 
echocardiogram, C-SSRS, Tanner Staging results, etc, will be summarized appropriately, by 
treatment. All safety summaries will be based on the SAF Population. 
10.5.3 
Pharmacokinetic Analyses 
All data will be evaluated using population PK analysis methods and the methods will be 
described in detail in a separate PK analysis plan. In brief, the plan is to use published data to 
construct a population PK model for fenfluramine in adults. Given the age range of subjects to be 
enrolled in this study, it will be possible to use the known ontogeny of drug disposition in children 
to predict fenfluramine PK in subjects with Dravet syndrome from the population PK model. The 
robustness of the empirical model will then be confirmed by applying the model to PK data 
collected from this study. In this way, the effect of body size, age, and any other relevant factors 
can be quantified to assure that an adequate understanding of fenfluramine PK is obtained. 
The full methods and results of the population PK analysis of data from this study will be provided 
in a separate report. The clinical study report will contain a brief summary of the analysis 
including: the population mean and interindividual variability estimates from the fit of the 
population PK model; summary statistics of the plasma concentrations by PK sampling time and of 
the individual, derived plasma PK parameters (Cmax, AUC0-t, Tmax, and t1/2) by treatment group. 
The clinical study report will also contain a comparison of the PK of fenfluramine in the children 
enrolled in this study to historical data from adults.
10.6 
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND SAFETY
MONITORING COMMITTEE 
A safety oversight monitoring plan will be in place with an IDSMC evaluating data from the 
subjects. Details will be provided in the IDMC charter. The IDSMC’s primary responsibility is to 
ensure that study subjects are not exposed to unanticipated harm that could have been prevented by 
timely review and intervention. The IDMC is established to review safety data at predefined time 
points, and to recommend to the sponsor whether to continue, modify, or terminate the study as 
necessary. The IDMC is composed of expert permanent members who cover relevant specialties 
(neurology, cardiology, pediatrics, and statistics). The IDSMC members may request assistance 
from a number of additional and hoc members if needed. 
11.
ETHICAL & REGULATORY CONSIDERATIONS 
11.1
ETHICAL 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 
PUBLIC
opulatio
pulati
udy repo
udy repo
and inte
nd inte
ary stati
ary stati
ma
ma PK
 PK
l
COPY
t syndr
syn
confirme
onfirm
fectct of b
of b
t
e under
e under
This document 
eview
view
s, and to
and to
cessary. 
essary.
(neurolo
neurol
from
from
1
cannot 
ORIN
RI
ht monit
monit
ils will b
s will b
study su
udy su
an
an
be
S PROV
S PRO
NG
NG
used
param
ram
so contai
contai
ical dat
al da
to
indi
cs of t
cs of 
etet
support 
dy siz
y siz
tanding o
nding 
PK anal
K ana y
rt will con
will co
ividual
vid
any 
g
e fr
e from 
om
by apply
by apply
ze, a
ze
marketing 
he method
he metho
s to use p
to use 
n ththe age 
e ag
eny of d
ny of
th
authorization 
016
io
nted 
ed 
Doppler
Doppler
iately, by
tely, b
application 
e p
bjects ar
ects a
d interven
interve
recommen
comm
The IDMC
The IDM
gy, cardio
y, card
 number 
umbe
and 
CO
C
ring plan
ng plan
provide
rovid
any 
DED TO
DED T
OMMIT
MM
extensions
ysis o
is 
ntain a b
ain a b
l variabi
variab
e plas
plasma
m
rs (Cmax
(Cma
n a comp
a comp
from ad
om ad
or 
fen
fe
of da
of d
variations 
publis
blis
range o
ange o
drug disp
drug dis
he popul
he popu
ying the 
ing the
ge, and 
e, and 
nflur
flu
thereof. 
ds will b
s will b
shed
hed

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 87 of 175
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 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 study. 
11.2
INFORMED CONSENT 
The investigator is responsible for obtaining a subject’s written informed consent to participate in 
the 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. 
All subjects will be informed that the study will be registered in the public database at 
ClinicalTrials.gov in accordance with the FDA Amendments Act of 2007 (Section 12.3). 
Before undergoing screening procedures for possible enrollment into the 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 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 study and to 
consider their participation in the study. If, after reading the Subject Information Sheet and the 
ICF, consent is given to participate in the 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 eCRF. 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. 
PUBLIC
study w
study 
with the
th the F
rocedure
ocedure
ble form
ble form
t be g
t be
COPY 
ct s
ct
CF w
F will b
ill b
uiremen
uiremen
This document
ithth
ir subse
subse
bjects m
ects m
consider
onside
ICF, 
ICF, 
by
by
cannot 
d t
ICH GC
CH GC
ust emp
t emp
draw 
draw 
be 
ormati
matio
o the s
o the s
used
ab
a
iven or
ven or
 regulato
gula
nces of
ces of
to 
s for p
for 
bout th
bout t
l
support 
prep
pre
ts.
l be regist
be reg
DA Amen
A Amen
poss
pos
any 
n in
n in
pared 
pare
marketing
initiation
initiatio
first subj
first sub
form
form
authorization 
016
io
dard 
dard
ected, an
ted, an
onalal
application
asiz
s
hei
heir cons
r con
uent care.
ent care
ust be give
st be giv
their parti
heir pa
onsent is 
nsent i
e subjec
subje
if
and 
P Section
Section
ze tha
e th
any 
heet. T
eet.
bject, and
ject, and
extensions
tere
ndments
dments
iblble enro
e enro
e na
nature,
ture
y to
y to subj
subj
ry requir
requir
e study
stud
T
or 
ed in 
d in
variations 
med cons
d cons
by the s
y the 
thereof. 
n visit, vi
visit, vi
ject is en
t is e

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 88 of 175
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 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. 
11.3
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. 
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 
gally a
gally 
e of Con
of Co
of conse
of cons
ly accep
y accep
and
an
COPY
d 
dated th
dated
e w
e witnes
itnes
y y explain
explai
represe
eprese
ac
This document 
pa
p
R
The sp
The sp
reg
reg
cannot
to t
to 
and per
d per
persona
ersona
e inform
inform
rently 
ently 
be
to 
entative
entativ
the s
the s
used
able
bl
pos
ossibl
sibl
assent d
assent d
subjec
subjec
to
nt (ie, p
nt (ie, 
e rep
e rep
support 
ed to, 
d to, 
ntative, an
tive, 
eptable re
ptable r
sent (Ped
ent (Ped
ped
any 
bje
bj
CF, the
CF, th
ttests tha
tests tha
and
an
marketing 
nable to re
able to 
n. After th
n. After
n has been
has bee
afafter the 
ter th
f
ec
ect’s p
t’s
authorization 
016
io
ments
ments
t to their
t to their
ation sh
ion sh
d ICF. 
ICF. 
application 
tio
understoo
dersto
GULAT
ULA
COMMI
COMM
onsor (or d
nsor (or
atory aut
ory aut
s int
i
and
onally 
ally 
y date th
date th
n in
n in t
any
ha
h
nd after
nd aft
ect’s pa
ect’s pa
date
d
extensions 
epr
diatric S
tric S
diatric su
atric su
esen
entativ
tativ
consequ
onsequ
ocument
cument
as be
as be
or 
d ththat
esenta
esent
variations 
n read
read
subject 
ubject 
participat
articipat
witness 
witness 
at the in
the in
appa
apparen
re
t ini
thereof. 
ead, an i
d, an
he ICF a
e ICF a
d an
an

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 89 of 175
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. 
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. 
11.4
PROTOCOL COMPLIANCE 
The investigator must conduct the study in compliance with this 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 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 study protocol. Exceptions include only cases of 
medical emergency to address immediate hazards to study subjects, or when the changes involve 
only logistic or administrative aspects of the 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). 
Details of the procedure for implementing study protocol amendments are available in 
Section 12.10. 
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 study 
protocol in the eCRF and/or in the Protocol Deviation Log, if applicable. 
12.
ADMINISTRATIVE ASPECTS 
12.1
CLINICAL TRIAL AGREEMENT 
This study will be conducted under a Clinical Trial Agreement between the sponsor (or delegate) 
and the respective institutions representing the study sites. Any financial support given to the study 
sites will be detailed in the Clinical Trial Agreement. The Clinical Trial Agreement, which must be 
signed before the start of any study related procedures, will clearly delineate the responsibilities 
and obligations of the investigator and the sponsor (delegate), and will form the contractual basis 
upon which the study will be conducted. 
PUBLIC
e h
s of the
of the
ncy, the 
ncy, the 
e to addr
to add
able opin
ble opin
and, 
and
COPY
ation fro
tion fr
review 
review
nt to th
nt to the
hazard
azar
This document
lieie
any nota
y nota
ocol in t
col in 
12.2.
12
12
cannot 
cable
able
ocedure f
edure 
st opp
t opp
be
elega
ega
for rev
for rev
co
co
used
on.
on
f approp
appro
ate) 
ate)
to 
ss an
s an
. As s
As s
support 
nd
tudy pro
udy pr
to study 
o study
udy. 
dy. 
ves
estigato
tigato
imm
im
any 
or cha
or chan
docum
docu
oto
marketing 
re
dy protoco
y proto
and which
d whic
authorization 
016
io
nical
nical
also
so
s inform
nform
egulato
gulato
application
ortunity, 
ortunity
le protoco
 protoc
he eCRF a
he eCRF 
ADM
ADM
C
and 
mpe
mp
or imple
imple
any 
r agr
r ag
w and ap
w and a
etent re
tent r
extensions 
or at each
at each
mediate 
ediate
oon n as po
as p
iate, the 
te, the
reem
reem
or
ubjec
ubjec
variations 
ol as 
l as
h has bee
has be
ges to, th
es to, th
mented ap
nted a
col. Ex
ol. Ex
t
thereof. 
atio
ry
agr
agr

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 90 of 175
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR 
Prior to study initiation, the investigator and any subinvestigator(s) to be directly involved in the 
treatment or evaluation of study subjects at each study site will disclose to the sponsor (delegate) 
any relevant financial or proprietary interests in either the study product or the sponsor company. 
The appropriate disclosure form(s) will be provided by the sponsor (delegate) for this purpose. 
Any relevant updates to the financial disclosure information that occur during the conduct of the 
study, or during one year after completion of the study, will be provided by the investigator and 
subinvestigator(s) to the sponsor (delegate). All financial disclosure information provided by the 
investigator and subinvestigator(s) will be submitted to appropriate competent authorities 
according to the applicable regulatory requirements. 
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE 
The sponsor will provide the relevant study protocol information in a public database 
(ClinicalTrials.gov) before or at commencement of the study, as required by the 2007 FDA 
Amendments Act. The sponsor (delegate) may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
If a potential subject contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor (delegate) may forward the relevant study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will assess the 
suitability of the subject for enrollment into the study. Results of this study will be disclosed 
according to the relevant regulatory requirements. All publications in peer-reviewed medical 
journals resulting from this study will be listed in the original study protocol registration record on 
ClinicalTrials.gov. 
12.4
STUDY FILES AND MATERIALS 
Before the start of any study related procedures, all essential documents specified by ICH GCP and 
other applicable regulations must be available in the relevant files maintained by the sponsor (or 
delegate) and the investigator. An Investigator Study File prepared by the sponsor (or delegate), 
containing all applicable documents for use at the study site, will be made available to the 
investigator before the start of the study. A list of personnel and organizations responsible for 
conduct of the study as well as the list of investigators will be included in the Investigator Study 
File. The respective files will be kept and updated by the sponsor (or delegate) and the investigator, 
as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by the sponsor’s study monitor (or delegate) to determine that all 
required documentation is present and correct (see Section 12.9). 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority (see Section 12.11). 
12.5
INITIATION OF THE STUDY 
PUBLIC
nsor reg
nsor re
may forw
may forw
and excl
and excl
en
enrollme
rollme
gulator
gulator
d
COPY
col info
ol in
t of the 
of the 
ay also p
y also 
atory re
tory re
This document
tor b
or 
ct of the
of the
. The res
The re
as applic
applic
All s
All s
m
cannot 
y stud
stu
egulation
ulation
he invest
inves
ll applic
applic
befor
befor
be
ES AN
 AN
dy
dy
used
y requi
equ
y will be
ill be
D
to
usio
into th
into t
ire
support 
rovide
vide
quirement
remen
rding part
ing pa
ard the re
rd the r
on crite
n cr
any 
ation in
tion i
udy, as re
dy, as r
e stu
e st
marketing 
e
he inves
inve
mation pro
ation pro
mpetent au
etent a
SULTS D
ULTS
authorization 
016
io
n the
the
elegate)
egate)
r compa
compa
his purpo
 purpo
conduc
ondu
t
application 
ble d
le d
the start
the star
tudy as w
udy as w
pective fil
pective 
ble.
le.
udy docum
dy docu
be avai
e ava
d
and
ela
ela
s must 
must b
gator. A
ator. A
docu
docu
any 
MATE
MAT
ted pro
ed pr
e
extensions
ticip
cip
elevant s
evant s
ria for t
ria for 
e study. R
study. 
ment
ents. A
s. A
listed in
sted in
or 
ati
ation
o
variations 
DISCLO
DISCLO
a public 
a public
equired 
quired 
dy infor
dy infor
thereof.
se.
of the
f the
gator and
ator an
ovided by
vided b
uthorities
thoritie

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 91 of 175
Before the start of the study at each study site, the sponsor’s study monitor (or delegate) will visit 
the study site to ensure adequacy of the facilities and to discuss responsibilities regarding study 
protocol adherence with the investigator and other personnel involved in the study. 
The investigator may not enroll any subjects into the study before the sponsor has received written 
approval or a favorable opinion from the IEC/IRB for conducting the study and a formal meeting 
has been conducted by the sponsor’s study monitor (or delegate) to initiate the study (study 
initiation visit). This meeting will include an inventory of study supplies and a detailed review of 
the study protocol and procedures, the eCRF, IMP accountability, and the subject diary. 
12.6
SUBJECT REIMBURSEMENT 
Where relevant, subjects will be reimbursed for reasonable travel costs associated with 
participation in this study, after presentation of receipts for the travel in question, at a rate to be 
approved by the IEC/IRB. Subjects will not be paid for participating in the study. 
12.7
LIABILITY AND INSURANCE 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
The sponsor will provide insurance to the investigator if required by the applicable regulatory and 
legal requirement(s). 
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY 
All study documents, including the study protocol and eCRFs, are the confidential property of the 
sponsor and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with the 
requirements of individual study sites. Subjects not enrolled into the study will be documented as 
such in the screening log together with the reason for not having been enrolled. 
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by applicable 
regulatory requirements. All subject names will be kept in confidence and will not be revealed to 
the sponsor. Subject names must be made unreadable on any documents made available to the 
sponsor. 
Subjects participating in the study will be identified in the eCRF by the subject number allotted to 
them during the study. 
The ICF will include a statement that all study findings, irrespective of the medium on which they 
are stored, will be handled in strictest confidence in accordance with applicable data protection laws 
PUBLIC
w
lt of
lt of thi
th
f
ance to t
nce to t
ec
ect
COPY
p
id for p
d fo
E
with res
ith re
This document
the scr
he scr
 investig
nvesti
dentifica
entific
These
These
reg
reg
cannot
, inclu
inclu
ld be tre
d be tre
creened 
reened 
s of ind
of ind
ee
be
DENT
ENT
udi
udi
used 
taking p
king p
ance with
ce with
to 
he inv
inv
support 
pect to fin
ct to f
study bein
udy be
vestig
vest
any 
cipatin
cipati
marketing 
tu
a detail
etai
subject di
ubject di
costs ass
osts as
av
avel in 
el i
authorization 
016
io
it 
dy
dy
eived wr
ived wr
ormal me
mal m
dy (stu
y (stu
application 
for 
ividual s
vidual
ning log to
ing log
ator will m
ator will
tion List) 
on List
ecords sh
cords 
atory req
ory re
nsor
and
ng th
g t
ted as su
d as s
the st
he st
any 
CATIO
CATI
he stud
he stu
extensions 
ng c
g
gatator if r
or if r
art in thi
t in thi
the app
he app
or
ncia
ncial
ondu
ond
variations 
ociated 
ciated 
question
questio
in the st
in the s
lo
thereof. 
etin
dy y
review 
eview
iary.
ry. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 92 of 175
(eg, the European Data Protection Directive [95/46/EC] and the USA Health Insurance Portability 
and Accountability Act [HIPAA]), and will be evaluated by the sponsor and/or a competent 
regulatory authority in an anonymized form. The subjects are also to be informed that their medical 
records may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority. The subject’s written consent authorizing direct access to his medical records, 
and computer processing and publishing of his anonymous personal data, must be obtained prior to 
participation in the study. 
A subject’s identity will be disclosed by the investigator only in case of emergency (ie, to 
address any immediate health hazard). 
12.9
MONITORING OF THE STUDY 
The investigator at each site will allow the sponsor’s study monitor (or delegate) reasonable access 
to the eCRFs and direct access to related source documents for monitoring purposes as frequently as 
the sponsor deems necessary. These documents include records of tests performed as a requirement 
for participating in the study as well as other medical records required to confirm information 
contained in the eCRF, such as past history and secondary diagnoses. 
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the eCRF. The investigator and other relevant personnel at 
each study site will be expected to cooperate with the sponsor’s study monitor to assist in 
providing any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of all 
documentation required for the study. The study monitor will ensure that the investigator at each 
site has been provided with adequate means for organization and filing of study documentation 
(see Section 12.4). 
The date on which the study monitor (or delegate) visits the study site will be recorded in the Site 
Visit Log. During monitoring visits, the study site’s coordinator (if applicable) and the investigator 
should be available, the source documentation should be accessible, and a suitable environment 
should be provided for the study monitor to review study related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
• Resolution of any problems. 
• Examination of all study documentation for completion, adherence to the study 
protocol, and possible AEs. 
• Clarification of inconsistencies or missing data. 
• Verification of study data against source documents. 
• Checks that investigator obligations have been fulfilled. 
• Review of ICFs and dates of consent. 
• Inspection of IMP with respect to storage, labeling, and documentation. 
• Drug accountability 
PUBLIC 
investiga
investig
n the eC
the eC
cted 
cted to c
to 
matio
mat
COPY
ocume
ocum
s include
include
medica
medica
y and s
and s
This document 
e pro
pro
main obj
ain obj
•
cannot 
h the stu
the stu
ing mon
ng mo
vailable,
ailable,
ovid
vid
be
the
ith adeq
ith ade
used 
op
op
n. 
access 
access 
e stud
e stu
to 
RF. T
F. T
perate 
erate
support 
recor
ecor
condary d
ndary 
or r (or del
(or de
Th
The in
e
any 
for mon
or mo
cords of
cords of
rds re
ds
marketing 
mergency (
ergency (
tor (or d
or (or
it
authorization 
016
io
ity
r medica
medica
etent 
etent 
edical re
dical r
obtaine
obtaine
application 
the sou
e so
d for the s
d for th
ectives of 
ctives o
Resoluti
Resolu
•
Exam
Exa
pr
p
and
dy monit
y moni
oring vi
ring vi
urc
any
Th
T
te mean
te mea
extensions 
legate) s
egate) s
nvestigat
vestiga
with the s
th the 
o the Inv
the Inv
he st
he st
or 
agno
gn
variations 
dele
delegate
gate
toring pu
toring p
f tests pe
tests pe
equired 
quired 
ose
ose
thereof. 
d prior
prio
(ie, to 
e, to 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 93 of 175
After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the eCRF correctly and in a timely manner, after which the investigator will 
sign the eCRF. 
12.10
PROTOCOL AMENDMENTS 
A “substantial” amendment of a study protocol is any written description of change(s) to, or formal 
clarification of, a study protocol that may have a significant impact on the safety or physical or 
mental integrity of subjects, the scientific value of the study, the conduct or management of the 
study, or the quality or safety of any IMP used in the study. The IEC/IRB must approve all 
substantial protocol amendments prior to their implementation. If required by applicable local 
regulatory requirements, the local regulatory authority must also approve all substantial protocol 
amendments prior to their implementation. 
A “non-substantial” amendment of a study protocol includes minor corrections or clarifications that 
have no significant impact on the way the study is to be conducted and has no effect on the safety of 
participating subjects (eg, change in study monitor, contact details, etc). If required by applicable 
local regulatory requirements, the IEC/IRB, and/or the local regulatory authority should be notified 
of all non-substantial protocol amendments. The substantial and non- substantial protocol 
amendments will be integrated into an updated study protocol at the discretion of the sponsor if the 
changes to the original study protocol are numerous, or if required by applicable regulatory 
requirements. 
12.11
AUDITS AND INSPECTIONS 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority. 
In the event of an audit by the sponsor, the investigator must make all study related 
documentation available to the auditor(s). Regulatory authorities may request access to all study 
related documentation, including source documents, for inspection and copying in keeping with 
applicable regulations. The sponsor will immediately notify the investigator (or vice versa) of an 
upcoming audit or inspection. 
If an audit or inspection occurs, the investigator and relevant personnel at the study site must 
allocate sufficient time to discuss the findings and any relevant issues. 
12.12
CLINICAL STUDY REPORT 
After completion of the study, a clinical study report covering clinical and statistical aspects of the 
study will be prepared by the sponsor (or delegate) in consultation with the coordinating 
investigator. As required by the applicable regulatory requirements, the clinical study report will be 
signed by the sponsor’s responsible medical officer as well as the coordinating investigator (if 
applicable). 
Progress reports and/or a summary of the clinical study report will be provided to the IEC/IRB and 
competent regulatory authorities in accordance with applicable requirements. 
PUBLIC
ents
ent
n updat
n upda
ocol are n
ocol are
INSPE
INS
COPY
l inc
in
is to be 
is to be
onitor,
nitor, co
B, and/or
, and/or
s. Th
. Th
This document 
dit or i
t or i
te suffic
e suffic
12.12
.12
Afte
Aft
sts
cannot 
ble t
le 
tion, inc
on, inc
lations. 
tions. 
udit or in
dit or i
ins
ins
be
by the sp
by the s
o th
o th
used 
CTIO
TIO
nspected 
ected
to 
ON
support 
ntac
ta
the local
e loca
substantia
ubstant
d study pr
study p
umerous, 
merous
any 
mino
min
nducted 
nducted
ct detai
t det
marketing
ty or
or
managem
managem
 must app
must ap
ired by ap
red by a
prove all s
rove al
r co
r
authorization 
016
io
or will
or will
e(s) to, 
(s) to, 
r phy
phy
application 
specti
ect
pection oc
ection o
ent time t
nt time
CLINI
CLI
completi
omplet
will b
will b
and
a
uding s
ding s
he spon
e spon
ion.
ion
any 
nsor, th
nsor, the
uditor(s
ditor
ou
extensions 
rotoco
toc
or if req
r if req
by qualif
y quali
or
g
and n
and 
ol a
ol a
variations 
substa
ubst
orrerection
ction
and has 
nd has
ils, etc).
s, etc).
gulator
ulator
thereof. 
r form
f
sical or 
al or
ment of th
nt of th
prove all
ve a
plicable
plicable
ant
ant

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 94 of 175
12.13
USE OF DATA AND PUBLICATIONS 
The rights and obligations of investigators and the sponsor concerning any formal presentation or 
publication of data collected as a direct or indirect result of this study will be addressed specifically 
in the Clinical Trial Agreement for the study (see Section 12.1). 
For multicenter studies, the first publication must be based upon all data obtained from all 
analyses, as stipulated in the study protocol by the biostatistician and not by the investigators. 
Investigators participating in multicenter studies must agree not to present data gathered 
individually or by a subgroup of study sites before the full, initial publication is available or 5 
years after the last clinical study visit, whichever is later, unless this has been agreed to by all 
other investigators and by the sponsor. 
The sponsor must receive a copy of any intended communications in advance of the proposed 
submission date. This is to allow the sponsor time to review the communication for accuracy (thus 
avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential and/or proprietary information is not inadvertently divulged, to provide any relevant 
supplementary information, and to allow establishment of co-authorship (as appropriate). The 
authorship of communications arising from pooled data will include investigators from study sites 
that contributed data as well as relevant personnel from the sponsor. Ownership of all data will 
remain with the sponsor. 
PUBLIC
rom
rom
ant pers
nt per
COPY
o rer
ns to reg
ns to re
not inad
not in
stablis
tablishm
h
m pool
poo
This document cannot be used to support 
vert
er
ent of co
nt of c
ed data wi
d data w
nnel from 
nel from
any 
e co
e c
atory 
atory aut
au
ently d
ently
marketing
e inv
inv
ata gathe
ata gathe
tion is ava
on is a
s been ag
s been a
ns in adv
in ad
omm
om
authorization 
016
io
ion or 
on or 
pecifical
ecifica
from all
rom all
vestig
estig
application and any extensions 
the s
he s
or
l ininclu
cl
spon
spo
variations 
vance of 
vance of
municatio
unicatio
thorities
horities
divulged
vulged
uthors
thors
d
thereof. 
ators.
ors.
red d 
ailable o
able 
reed to 
eed to 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 95 of 175
13.
REFERENCE LIST 
Aicardi J and Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine (3 
cases). NEJM 1985; Nov 28;313(22):1419. 
Aicardi J, Gastaut H, and Misès J. Syncopal attacks compulsively self-induced by Valsalva's 
maneuver associated with typical absence seizures. A case report. Arch Neurol 1988 
Aug;45(8):923-5. 
Boel M and Casaer P. Add-On therapy of fenfluramine in intractable self-induced epilepsy. 
Neuropediatrics. 1996; 27: 171-173. 
Center for Disease Control. Cardiac valvulopathy associated with exposure to fenfluramine or 
dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health 
Recommendations, November 1997. Morbidity and Mortality Weekly Report. 1997; 
46(45):1061-1084. 
Ceulemans B, Boel M, Leyssens K, Van Rossem C, Neels P, Jorens PG, Lagae L. Successful 
use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012; 53: 1131-
1139.  
Ceulemans, B., Schoonjans, A.-S., Marchau, F., Paelinck, B. P., & Lagae, L.. Five-year 
extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. 
Epilepsia 2016 (*):1–6, 2016 http://doi.org/10.1111/epi.13407 
Chiron C and Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia 2011; 
52(Suppl. 2):72–75. 
Connolly HM, Crary JL, McGoon MD, Hensrud DD et al.  Valvular heart disease associated with 
fenfluramine-phentermine. New Engl J Med 1997;337(9):581-8. Erratum in: N Engl J Med 1997 
Dec 11;337(24):1783. 
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: 
Dravet syndrome.  Adv Neurol 2005; 95: 71-102. 
Dravet C. Les epilepsies graves de l’enfant.  Vie Med. 1978;8:543–548. 
Dravet C.  Severe myoclonic epilepsy in infants and its related syndromes.  Epilepsia 2000; 41:7. 
EMA 2007. Stiripentol SmPC and EPAR Scientific Discussion. Available at 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000664/huma 
n_med_000742.jsp&mid=WC0b01ac058001d124.  Accessed 31 July 2015. 
Hurst, DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 1990;31:397-400. 
ICH Topic E2F: Development Safety Update Report, 2011. 
ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, 1994. 
PUBLIC 
ment
ment f
t
-S., Mar
S., Mar
f 10 patie
f 10 patie
6 h
6 http
COPY
um
and Mor
and Mo
Rossem 
ossem 
for
f
This document
t C. Les
C. Les
ravet C. 
vet C. 
EMA 
EMA 
http
htt
cannot 
rmine
mine
783.
83.
reau M, 
au M, 
rome. 
ome. 
be 
McGo
McGo
N
used
//doi.o
oi.o
harmacol
rmaco
to
hau
s with
s with
rg
support 
C, Neels P
Neels
Dravet syn
ravet s
u, F., 
, F. P
any 
ices
ice
lity Wee
lity We
marketing 
by
ol 1988
1988
elf-induce
elf-indu
h exposu
h expos
Inte
In
authorization 
6
i
ramine (
ramine (
Valsal
Valsa
application 
Ogu
Adv 
dv Neu
Ne
pilepsies 
ilepsie
Severe my
Severe m
007. Stiri
07. Sti
/www.em
www.em
000
0
and 
ew 
w
uni H,
ni H
any 
n MD, H
n MD, H
Engl J
Engl
extensions 
nd
Paelinck,
aelinck
Dravet sy
ravet s
10.1111
10.1111
ogic trea
gic trea
or 
Jor
Jo
rome.
rome
variations 
ure to fe
ure to fe
erim Pub
im Pub
ekly Rep
ly Rep
rens
en
thereof. 
va's 
a's 
d epilep
d epilep

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 96 of 175
Marshall WA, Tanner JM. Variations in the pattern of pubetal changes in boys. Arch Dis Child 
1970; 45:13. 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of Disease 
in Childhood. 1969;44(235):291-303. 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in 
epilepsy. Epilepsia 2012;53, 227–233. 
Sabaz M, Carins D, Lawson J, Nheu N et al. Validation of a New Quality of Life Measure for 
Children with Epilepsy. Epilepsia 2000; 41(6):765-774. 
Shorvon S, Tomson T.  Sudden unexpected death in epilepsy. Lancet 2011;378: 2028–38. 
Talarska D. The usefulness of Quality of Life Childhood Epilepsy (QOLCE) questionnaire in 
evaluating the quality of life of children with epilepsy. Advances Med. Sci 2007; 52 suppl 1:191- 
193. 
Wong J, Reddy SS, Klein AL. Anorectic drugs and valvular heart disease: a biological and 
clinical perspective.  Cleveland Clinical Journal of Medicine 1998; 65:35-41. 
ZX008 Investigator’s Brochure Version 3, January 5, 2016. 
PUBLIC
on 3, J
on 3, J
COPY 
sy.y
gs and 
s and v
ournal of
urnal o
This document cannot be used to support
lvul
vu
Medicin
Medicin
uary 5, 20
ry 5, 
any 
ces 
es
lar hea
ar h
marketing 
f Life Me
f Life M
et 2011;37
2011;
sy (
y (QOLC
QOL
Med.
Me
authorization 
6
i
Disease
isease
cted dea
ted dea
application and any extensions 
016
or 
19
19
variations 
78: 2
8: 
CE) ques
E) ques
. Sci 200
Sci 20
art disea
t disea
998; 6
98;
thereof. 
h in
h i
easure fo
sure f
2028
2028

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 97 of 175
14.
APPENDICES 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 98 of 175
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
Generic Name 
Generic Name
alfentanil 
naratriptan 
almotriptan 
nefazodone 
alprenolol 
nortriptyline 
amitriptyline 
ondansetron 
amphetamine 
oxcarbazepine 
astemizole 
oxycodone 
atomoxetine 
paroxetine 
bufuralol 
perphenazine 
bupropion 
phenacetin 
buspirone 
phenobarbital 
cafergot 
phenytoin 
cannabidiol 
promethazine 
carbamazepine 
propafenone 
cerivastatin 
retigabine/ezogabine 
citalopram 
risperidone 
clomipramine 
ritonavir 
codeine 
rizatriptan 
cyproheptadine 
selegiline 
desipramine 
sertraline 
dextromethorphan 
stiripentol 
duloxetine 
sumatriptan 
eletriptan 
telaprevir 
encainide 
THC and derivatives 
ergotamine tartrate 
tramadol 
eslicarbazepine 
trazodone 
felbamate 
vortioxetine 
fentanyl 
zolmitriptan 
fluoxetine 
zuclopenthixol 
PUBLIC 
IC
BL
U
P
COPY 
parox
a
PY
per
PY
PY
OP
C
This document
methorp
ethorp
loxetine 
xetine 
nt
eletript
eletrip
me
c
en
en
cu
oc
o
cannot
no
 
n
h
ca
be 
e
b
used 
d
se
to 
to support
phe
phenacet
henace
t
pheno
h
o
pp
p
pp
pp
su
any 
nazine
nazin
ny
a
marketing 
g
tin
ke
ar
m
authorization 
IONS 
ONS 
riz
tho
au
app
inide
nide
pplication 
an 
on
ati
an 
lic
pp
i
ap
and 
d
a
any y
an extensions 
oba
phenytoin
enytoin
s
prom
rom
on
si
p
sisi
ten
ex
or 
rbital
bital
r
o variations 
ns
tio
ia
va
thereof. 
f
eo
er
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 99 of 175
fluvoxamine 
 
frovatriptan 
 
imipramine 
 
levacetylmethadol (LAAM) 
linezolid 
 
meperidine 
 
methadone 
 
metoclopramide 
 
mexiletine 
 
COPY 
This document cannot be used to support any marketing 
g
tin
ke
a
m
authorization 
titi
ati
za
ori
th
au
application and any extensions or variations 
ns
tio
thereof. 
f
eo
er
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 100 of 175
APPENDIX 2 – COLUMBIA – SUICIDE SEVERTY RATING SCALE 
PUBLIC COPY 
This doc
ocument cannot be used to support any marketing authorization 
application and any extensions or variations 
eof. 
thereo

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 101 of 175
COPY 
This document cannot be used to support any marketing 
rization 
authoriz
application and any extensions or variations 
. 
thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 102 of 175
COPY 
This docu
cument cannot be used to support any marketing 
orization 
authori
application and any extensions or variations 
of. 
thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 103 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
thorization 
au
application and any extensions or variations 
of. 
thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 104 of 175
COPY 
This document cannot be used to support any marketing 
ization 
authorizat
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 105 of 175
PUBLIC COPY 
This do
document cannot be used to support any marketing 
rization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 106 of 175
PUBLIC COPY 
This do
document cannot be used to support any marketing 
ization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 107 of 175
COPY 
This docu
cument cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 108 of 175
COPY 
This docu
ocument cannot be used to support any marketing 
ization 
authoriz
ap
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 109 of 175
PUBLIC COPY 
This do
document cannot be used to support any marketing 
ization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 110 of 175
PUBLIC COPY 
This doc
ocument cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 111 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
ization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 112 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 113 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
rization 
authori
application and any extensions or variations 
. 
thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 114 of 175
PUBLIC COPY 
This do
document cannot be used to support any marketing 
ation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 115 of 175
PUBLIC COPY 
This doc
ocument cannot be used to support any marketing 
ation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 116 of 175
PUBLIC COPY 
This document cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 117 of 175
PUBLIC COPY 
This document cannot be used to support any marketing 
ization 
authoriz
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 118 of 175
PUBLIC COPY 
This docum
ument cannot be used to support any marketing 
horization 
31 Octob
1 Octob
riz
aut
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 119 of 175
PUBLIC COPY 
This docum
ument cannot be used to support any marketing 
horization 
31 Octob
1 Octob
riz
auth
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 120 of 175
PUBLIC COPY 
This docume
ment cannot be used to support any marketing 
rization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 121 of 175
PUBLIC COPY 
This document cannot be used to support any marketing 
ization 
authoriz
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 122 of 175
PUBLIC COPY 
This document cannot be used to support any marketing 
rization 
authoriz
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 123 of 175
PUBLIC COPY 
This docume
ment cannot be used to support any marketing 
horization 
31 Octob
1 Octob
riz
aut
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 124 of 175
COPY 
This docu
se
sed to support any marketing 
rization 
authoriz
xtxtensions or variations 
 
thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 125 of 175
PUBLIC COPY 
This document cannot be used to support any marketing 
rization 
authori
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 126 of 175
PUBLIC COPY 
This docu
t be used to support any marketing 
orization 
authoriz
an
any extensions or variations 
f. 
thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 127 of 175
PUBLIC COPY 
This docum
ument cannot be used to support any marketing 
rization 
authoriz
application and any extensions or variations 
 
thereof.

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 128 of 175
COPY 
This documen
ent cannot be used to support any marketing 
orization 
authori
ap
application and any extensions or variations 
of. 
thereof

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 129 of 175
APPENDIX 5 – TANNER STAGING 
This docu
ed
uthorization 
xte
reof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 130 of 175
This docu
thorization 
reof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 
APPENDIX 6 – PEDsQL (INCLUDING FAMILY IMPACT MODULE) 
PUBLIC COPY 
This document cannot be used to support any marketing 
horization 
)
autho
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 132 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
ization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 133 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 134 of 175
COPY 
This document cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 135 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 136 of 175
COPY 
This document cannot be used to support any marketing 
ization 
authoriz
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 137 of 175
PUBLIC COPY 
This do
document cannot be used to support any marketing 
zation 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 138 of 175
COPY 
This document cannot be used to support any marketing 
ization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 139 of 175
PUBLIC COPY 
This doc
ocument cannot be used to support any marketing 
rization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 140 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
ization 
authoriza
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 141 of 175
COPY 
This doc
ocument cannot be used to support any marketing 
rization 
authoriz
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 142 of 175
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE 
This docu
g authorization 
thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 143 of 175
This docu
ng authorization 
s thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 144 of 175
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE 
PUBLIC COPY 
This document cannot be used to support any marketing 
thorization 
auth
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 145 of 175
PUBLIC COPY 
This docume
ment cannot be used to support any marketing 
orization 
authori
applplication and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 146 of 175
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES 
This docume
rization 
lic

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 147 of 175
APPENDIX 10 – PROTOCOL AMENDMENT 1 
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 
• Sponsor name change 
• Removed the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, 
testosterone, GH, prolactin, and IGF-1 
• Clarified the maximum dose of ZX008 is 30 mg/day 
• Clarified the collection duration of prior and concomitant AEDs 
• Clarified data to be collected with the use of rescue medication 
• Added new section of collection of data for AEs requiring hospitalization 
• Replaced CHU9D with PedsQL 
• Updated statistical analysis section to be consistent with the separate statistical analysis 
plan 
• Clarified study duration for participants 
• Clarified inclusion criterion #7 regarding the requirement for a whole blood sample for a 
broad epilepsy-related gene panel 
• Added requirement that subjects who may qualify for and plan to enroll into the separate 
open-label extension study at the end of this study should be consented prior to Visit 12 
• Clarified for all questionnaires and rating scales when rater substitution is acceptable for the 
clinic staff and the parent/caregiver 
Clarifications and changes were made based on feedback received from the United States Food 
and Drug Administration, and include the following: 
• Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and AESI with 
regard to valve regurgitation seen on ECHO. 
• Clarified that the central cardiac reader will provide consultation to the IDSMC when a 
subject may be removed from the study due to development of signs or symptoms 
indicative of valvulopathy, regurgitation, or pulmonary hypertension 
• Clarified expedited reporting of cardiac events other than SAEs 
• Added section on grading of and follow-up for ECHO findings 
• Added the assessment of cognition for subjects 5 years of age, so that all study 
participants are now being assessed for cognition using the BRIEF. The description of the 
BRIEF was moved from the efficacy section to the safety section. 
Clarifications and changes were made based on feedback received from the European Voluntary 
Harmonization Procedure Clinical Trials Group, and include the following: 
• Updated contraception requirements for the study 
PUBLIC
pan
p
regardin
egardi
panel
pane
ubjects w
bjects w
tudy at th
udy at th
onnair
onn
COPY 
Es s
consiste
consi
nts 
ts
This document
ject m
ect
ndicativ
dicativ
Clarif
Clari
•
Ad
A
•
cannot 
atio
tio
ndomizat
domiza
valve re
alve re
ed that t
d that t
may
may
be
ges we
ges we
n, an
n, a
used
e
es and r
and 
caregive
aregive
to
ho m
o m
end of
end of
support 
t
the requi
he req
may qu
may
any 
g ho
h
with the
with t
marketing
FSH, estr
H, est
Ds 
ion
on
ospita
ospi
authorization 
6
i
application 
e cen
cen
be remov
be remo
of valvul
of valv
ed expedi
ed expe
ded sectio
d sect
Added the
dded th
particip
articip
I
and
on inclu
n inclu
urgitatio
rgitatio
tra
tra
any
made ba
made b
nclude t
nclude
i
extensions 
ireme
em
ualify fo
alify fo
hisis study
stud
ing scal
ng scal
or 
ent
ent
variations 
alization
ization
e separat
separa
thereof. 
adiol,
iol,

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 148 of 175
• Clarified when subjects must be discontinued from the study 
Clarified that the investigator may discontinue a subject from the study in the case of a medical 
emergency 
• Added statistical information regarding sensitivity analyses for concomitant AED 
medication changes during the study 
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale: There has been a name change for the sponsor’s subsidiary.
Original Text 
Amendment Text
Title page, Signature of Sponsor page, Synopsis, 
Table 2, and document headers 
Brabant Pharma Limited 
Title page, Signature of Sponsor page, Synopsis, Table 
2, and document headers 
Brabant Pharma Limited Zogenix International 
Limited
Rationale: To replace the CHU9D with the PedsQL for the assessment of quality of life. 
Original Text 
Amendment Text
Synopsis, Section 2.3 
Additional secondary efficacy objectives of the study 
are: 
• 
To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The change from baseline in the Child Health
Utility 9D Scale (CHU9D) score. 
Synopsis (Criteria for Evaluation/Efficacy), Section 
2.7.1 
• 
CHU9D to measure changes in quality of life 
of the subject 
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, 6.2.9, and 7.1.4 
The following procedures will be performed: 
• 
CHU9D (Appendix 6) 
Appendix 6 was updated and is not presented here. 
Section 7.1.5 
The impact on the quality of life of the 
parent/caregiver responsible for a patient with DS will 
be assessed according to the schedule in Table 1 using 
Synopsis, Section 2.3
Additional secondary efficacy objectives of the study 
are: 
• 
To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) superior 
to placebo on the following endpoints: 
o
The change from baseline in the Child Health
Utility 9D Scale (CHU9D) PedsQL score. 
Synopsis (Criteria for Evaluation/Efficacy), Section 
2.7.1 
• 
CHU9D PedsQL to measure changes in quality 
of life of the subject 
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, 6.2.9, and 7.1.4 
The following procedures will be performed: 
• 
CHU9D Peds QL (Appendix 6) 
Appendix 6 was updated and is not presented here. 
Section 7.1.5 
The impact on the quality of life of the parent/caregiver 
responsible for a patient with DS will be assessed 
according to the schedule in Table 1 using 2 3 scales: 
PUBLIC 
psis,
psis
C
D with th
D with th
B
U
PU
COPY 
ponsor’s 
onsor’
OP
CO
C
This document
CHU
CHU
of th
of t
Table 1
Table 1
S
c
cannot
on
on
from ba
om ba
D Scale (C
Scale (
riteria for
ria fo
ca
9
be
X0
s are (ind
s are (in
the fo
the f
used 
ctives of t
ives of t
8 0.2
8 0.2
d to 
PedsQL
PedsQ
to
t
suppor
Title page
Title p
po
2, and 
2, an
pp
Bra
B
p ort 
ubsid
si
mendme
mendme
rt
L
or
up
L for
f
s
any 
iary.
iary.
a
marketing 
rough. Mi
ough. M
rk
updating
dating h
authorization 
6
i
dical
ical
AED 
D 
application 
n
Evalu
alu
n
to measure
o measu
e subject 
ubject 
was updated
as updat
tions 6.1.3
ons 6.1.3
ap
ollow
llo
and
ine in
e in
HU9D) sc
U9D) sc
ation
ation
any
d 0
d 0
ndently)
ndently
wing endp
ing endp
the C
the
exten
e study 
study 
8
nsions
docu
oc
s
bant Pha
nt Pha
ns
Limited
mited
r the asse
the asse
io
Am
Am
si
n
S
n
en
or
Signat
Signa
or
umen
men
or
T
r variations 
inor e
or e
headers a
aders a
ar
ext
ext
va
v
thereof. 
edit
edit

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 149 of 175
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
6
it
application and any extensions or variations thereof. 

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 150 of 175
2 scales: the EQ-5D-5L and the HADS. 
Parents/caregivers who do not give consent to collect 
these ratings scales will not complete them. The same 
parent/caregiver should complete these ratings 
throughout the study. If that person is not available at 
the visit, the scales should not be completed. 
the EQ-5D-5L, and the HADS, and the PedsQL 
Family Impact Module. Parents/caregivers who do not 
give consent to collect these ratings scales will not 
complete them. The same parent/caregiver should 
complete these ratings throughout the study. If that 
person is not available at the visit, the scales should not 
be completed. 
The PedsQL Family Impact module (Appendix 6) is 
designed to measure the impact of pediatric chronic 
health conditions on parents and the family by 
measuring parent self-reported physical, emotional, 
social, and cognitive functioning, communication, 
worry. and family daily activities relationships. This 
module will not be used in Norway, Sweden, and 
Denmark.
Rationale: To update the statistical sections of the protocol to be consistent with the separate statistical analysis 
plan. 
Original Text 
Amendment Text 
Synopsis, Section 3.1, Section 5.5.1 
Synopsis-Methodology 
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in 
each age group. 
Synopsis 
Synopsis-Statistical Methods/Efficacy 
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M 
periods compared with Baseline. The MCSF will be 
calculated from all available data collected during the 
Baseline and treatment periods. The primary endpoint 
will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group (three levels) 
and age group (< 6 years, 6 to 18 years) as factors, 
and with Baseline MCSF as a covariate. The primary 
analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at 
the alpha=0.05 level of significance. 
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint also will be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
Synopsis, Section 3.1, Section 5.5.1 
Synopsis-Methodology 
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across treatment 
arms, and at least 40% of subjects will be in each age 
group. 
Synopsis 
Synopsis-Statistical Methods/Efficacy 
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M periods 
compared with Baseline. The MCSF will be calculated 
from all available data collected during the Baseline and 
treatment periods. The primary endpoint will be 
analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group 
(< 6 years, 6 to 18 years) as factors, and with Baseline 
MCSF as a covariate.  The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group using a two-sided test at the alpha=0.05 level of 
significance. The primary endpoint will also be 
analyzed using a nonparametric method and if 
normality assumptions are not met, the results of the 
nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be 
performed to assess the sensitivity of the primary 
analysis to changes in concomitant AED medications 
that may occur during the course of the trial. 
Specifically, the primary analysis will be repeated 
with a factor added to indicate whether a subject had 
PUBLIC 
e group (<
group (<
nce acros
nce acros
of subject
of subjec
COPY
od
od
Denma
Den
otocol to
tocol to 
PY
CO
C
This document 
e group
grou
with Base
h Base
nalysis w
alysis w
group to
group t
the a
the a
Si
Si
cu
cannot
28
h Base
Base
available
vailab
eatment p
tment p
zed using
d using
) model
mode
p (<
(<
be
he p
he mean 
mean
days du
days du
i
used 
icacy
acy 
rimary
rimar
to 
will be
will b
sup
e ini
upport 
mendme
mendme
rt
Synopsis,
Synops
po
Synops
Syno
Ran
Ran
y
or
up
any 
ot b
t 
consistent
onsistent
ny marketing 
he
module (A
module (A
mpact of p
pact of
arents and 
rents an
lf-repor
reported
t
ive func
e functio
t
ily daily a
ly daily
e use
e us
authorization 
6
i
ho do not 
do not 
ill not 
ill not 
r should 
should 
study. If th
dy. If t
scales s
cales s
a
application 
an a
with treatm
th trea
6 years,
 years, 6
ne MCSF 
e MCS
l compare t
compare
the placebo
e placeb
pha=0.05 le
a=0.05 
ce the ANC
the ANC
s on ass
s on as
nt
and
. The
Th
data colle
ata coll
iods. The
ods. Th
nalysi
nalys
any 
ffic
fi
vulsive s
vulsive
g the T+M
g the T+M
e MCS
 MC
t
exten
acy
acy
nsions
sis-M
ndomizat
omizat
years, 
years, 6 t
6
arms, a
arms, a
grou
gro
en
or
T
Section
ection
or
Metho
Metho
r variations
d phy
ph
ning, com
ng, co
ctivities 
ctivities 
d in Norw
in Nor
t with the 
with the 
ia
ext 
ext
va
v
thereof.
at 
hould not
uld no
Appendix 
pendix
ediatric c
atric 
the famil
he famil
ysica
sica

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 151 of 175
van Elteren test will be used to assess the primary 
objective. 
Section 10.5.1.1 
The primary efficacy endpoint is the change in the 
mean convulsive seizure frequency (MCSF) per 28 
days between the Baseline and T+M periods. The 
MCSF will be calculated from all available data 
collected during the Baseline or T+M Periods. 
The primary endpoint will be analyzed using an 
analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 
years, 6 to 18 years) as factors, and with baseline 
frequency as a covariate. The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the 
placebo group using a two-sided test at the Į=0.05 
level of significance. 
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
van Elteren test will be used to assess the primary 
objective. 
Additional analyses will compare the percentage 
changes between the baseline MCSF and the MCSF 
measured independently during the Titration Period 
alone and the Maintenance Period alone. 
a change in concomitant AED medication during the 
T+M period. 
Since the ANCOVA used in the primary analysis relies 
on assumptions of normality, the primary endpoint also 
will be analyzed using a nonparametric method that 
does not require as stringent assumptions. Specifically, 
the van Elteren test, which extends the Wilcoxon rank 
sum test to include stratified data, will be used to 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group while stratifying for age group. If normality 
assumptions are not met, the results of the van Elteren 
test will be used to assess the primary objective. 
Section 10.5.1.1 
The primary efficacy endpoint is the change in the mean 
convulsive seizure frequency (MCSF) per 28 days 
between the Baseline and T+M periods. The MCSF will 
be calculated from all available data collected during the 
Baseline or T+M Periods. 
The primary endpoint will be analyzed using an analysis 
of covariance (ANCOVA) model with treatment group 
(three levels) and age group (< 6 years, 6 to 18 years) 
as factors, and with baseline frequency as a covariate. 
The primary analysis will compare the ZX008 
0.8 mg/kg/day group to the placebo group using a two- 
sided test at the Į=0.05 level of significance. 
Since the ANCOVA used in the primary analysis relies 
on assumptions of normality, the primary endpoint will 
also be analyzed using a nonparametric method that 
does not require as stringent assumptions. Specifically, 
A test such as the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will be 
used to compare the ZX008 0.8 mg/kg/day group to the 
placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the van 
Elteren test will be used to assess the primary objective. 
An additional analysis will be performed to assess 
the sensitivity of the primary analysis to changes in 
dose or type of concomitant AED medications that 
may occur during the course of the trial, which are 
protocol violations. Specifically, the primary analysis 
will be repeated with a factor added to indicate 
whether a subject had a change in prescribed dose or 
type of concomitant AED medication during the 
T+M period. Further exploratory analyses may be 
conducted if changes in concomitant AED 
medication appear to have a significant impact on 
PUBLIC 
sing an
ng an
odel with
odel with
age group
age group
and with
and with
primary 
primary 
day 
day
COPY
The p
e
convul
convu
betw
b
be
b
OP
This document
o c
placebo
lacebo
rmality as
ality as
van Eltere
n Elter
objecti
objecti
A
cu
cannot
f no
f n
e analyze
nalyze
not requi
ot requi
he van Elt
van E
ank sum t
k sum 
compar
ompar
be
inin the pr
 the pr
rmali
rmal
used
nalys
aly
roup to th
up to th
st at the
at the
to 
< 6
aseline
aseline
is wi
is wi
support 
calculat
lcula
Baseline or
seline
The p
The
of 
o
up
any 
efficac
ffic
seizure f
seizure
the Base
the Ba
ted f
t d
marketing 
the
a, will be
will b
g
kg/day grou
g/day grou
ting
r age group
ge grou
et
t, the result
the res
ke
ssess the pr
ess the
ark
cy e
c
authorization 
6
i
the
he
ysis relies
s relies
or
ndpoint al
ndpoint a
ho
method th
thod th
th
ons. Spec
ns. Spe
au
Wilc
Wilc
a
at
at
application
st to in
to i
the ZX00
the ZX0
oup while s
up whil
umptions ar
ptions 
test will b
test will 
e.
ditional an
tional an
ges be
es
and 
using a
ing 
 as string
s string
en test, w
n test, w
nclu
clu
any 
ry analys
y analy
he prima
he pri
a non
a no
exten
0.05
05
nsions 
rimary
mary
covarianc
varian
(three lev
(three le
as fact
as fact
The
The
0
en
or 
+M
+M
y en
en
variations 
rimary 
mary
s
ndpoint 
dpoint isi
frequency
quency
eline and 
ne and 
rom all a
om all a
M Per
Pe
thereof. 
fically
ca
f
xon rank 
n rank 
of
sed to
d to
eo
up to the p
to the p
ere
. If norma
If norma
he
of the v
of the v
th
ob

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 152 of 175
Section 10.5.1.2 
The longest interval between convulsive seizures will 
be calculated for each subject over the entire T+M 
period. Subjects whose longest interval extends to the 
end of treatment or end of study will be considered 
right-censored. The ZX008 0.8 mg/kg/day and 
placebo groups will be compared using a log-rank 
test. The median length of the longest seizure-free 
interval will be presented for each treatment group. 
Section 10.5.1.3 
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as 
a gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance. 
Section 10.5.2 
Selected summaries will be repeated broken out by 
age group, ie, for ages <6 years and 6 to 18 years. 
the primary outcome.
Additional analyses will compare the percentage 
changes between the baseline MCSF and the MCSF 
measured independently during the Titration Period 
alone and the Maintenance Period alone. 
Section 10.5.1.2 
The longest interval between convulsive seizures will be 
calculated for each subject over the entire T+M period. 
Subjects whose longest interval extends to the end of 
treatment or end of study will be considered right- 
censored. The ZX008 0.8 mg/kg/day and placebo groups 
will be compared using a log-rank test. The median 
length of the longest seizure-free interval will be 
presented for each treatment group. 
Section 10.5.1.3 
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as a 
gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance. 
Section 10.5.2 
Selected summaries will be repeated broken out by age 
group, ie, for ages <6 years and 6 to 18 years. 
Rationale: To clarify inclusion criterion #7 regarding the requirement for a whole blood sample for a broad 
epilepsy-related gene panel. 
Original Text 
Amendment Text
Synopsis, Section 4.1 
Subject agrees to provide whole blood sample for a 
Dravet syndrome genetic testing panel, if genetic 
screening results from an acceptable commercial 
laboratory or medical center are not available for 
SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, 
GABRD, GABRG2, and PCDH19. 
Synopsis, Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel Dravet 
syndrome genetic testing panel, if genetic screening 
results from an acceptable commercial laboratory or 
medical center are not available for SCN1A, SCN1B, 
SCN2A, SCN8A, SCN9A, GABRD, GABRG2, and 
PCDH19. 
Rationale:  To clarify the study duration for participants.
Original Text 
Amendment Text
Synopsis 
Duration of Treatment: All subjects will receive 
ZX008 or matching placebo for up to approximately 
14 weeks (Titration Period=2 weeks; Maintenance 
Period=12 weeks). After completion of the 
Synopsis
Duration of Treatment: All subjects will receive ZX008 
or matching placebo for up to approximately 14 16 
weeks (Titration Period=2 weeks; Maintenance 
Period=12 weeks; Taper/Transition=2 weeks). After 
PUBLIC
Į=0.
=0
t the prim
the prim
ategy spec
tegy spe
re each tes
e each tes
t. If any te
If any te
0.05 leve
0.05 leve
eve s
eve
COPY
keeper 
eeper 
05
05
ill 
ll
length 
lengt
Y
presen
presen
PY
OP
This document 
t agree
agree
vet syndro
et syndro
creening r
eening 
laborato
laborat
SCN
SCN
G
cu
ca
ection 4
ction 
c
s tot
annot 
<6 y
6 y
rify inclus
fy inclu
gene pan
gene pa
ot
xt 
nn
ca
be
e repeate
e repeat
ears a
ears
used 
then
he
tistical 
stical 
to
ac
fails to
fails t
n no t
n no t
support 
y 
fies a
es a
ts as
 as
ction 10.
ion 10
or
The effica
The effi
strategy
strat
acro
acro
a
up
any 
ed 
ed
e longes
e longe
ny
d for each 
for each
an marketing 
n convulsiv
convu
ct over the 
ct over th
st interv
interval e
a
rk
f study will 
udy w
ar
X008 0.8 m
008 0.8
using 
usin
authorization 
6
i
tage
tage
ho
the MCSF
e MCS
ration Per
ion Per
ne.e.
a
application 
1
o
provide wh
provide w
me genetic 
e genet
sults from a
sults from
y or medica
or medi
n
A, SCN1B,
, SCN1
BRD, GAB
RD, GA
n
a
and
on criteri
n criter
l.
d
an
a
any 
roken out
oken o
6 to 18 y
6 to 1
a
extensions
t 
y to
oss the fa
s the fa
nd key se
d key s
hierarch
hierarc
gatek
gatek
ac
a
n
en
or
y analy
y ana
main
main
variations
xten
be consi
e cons
ns
mg/kg/day
mg/kg/day
a log-rank
log-ran
seizure-fr
eizure-fr
at
treatmen
reatmen
ria
3
thereof. 
od
ve seizure
seizur
entire T+
entire T+
nds to
nds to
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 153 of 175
Maintenance Period, eligible subjects may enroll in 
the open-label extension study. 
completion of the Maintenance Period, eligible subjects 
may enroll in the open-label extension study, after 
completion of the transition. 
Rationale: To add the requirement that subjects who may qualify for and plan to enroll into the separate open- 
label extension study at the end of this study be consented prior to Visit 12.
Original Text 
Amendment Text 
Section 6.2.7 
None 
Section 6.2.9 
None 
Section 6.2.7 
At Clinic Visit 10, compliant subjects who have 
tolerated IMP should be presented with the ICF for 
the open-label extension study. Informed consent for 
the open-label extension study must be signed at 
Visit 12 or earlier in order to enter the open-label 
extension study. 
Section 6.2.9 
Informed consent for the open-label extension study 
must be signed at Visit 12 (if not signed earlier) in 
order to enter the open-label extension study. 
Rationale: To clarify for all questionnaires and rating scales when rater substitution is acceptable for the clinic 
staff and the parent/caregiver. 
Original Text 
Amendment Text
Section 7.1 
For all questionnaires and rating scales, the same 
evaluator (at the clinical site and parent/caregiver) 
will complete the assessments for the duration of the 
study. If that evaluator cannot complete the 
questionnaire/rating scale at a visit, the 
questionnaire/rating scale will not be completed. For 
the diary, the same parent/caregiver will complete all 
entries throughout the study. 
Section 7.1
For all questionnaires and rating scales, the same 
evaluator (at the clinical site and parent/caregiver) will 
complete the assessments for the duration of the study. 
Substitutions at the clinic with another rater that has 
established inter-rater reliability is acceptable on an 
infrequent basis. For the in-clinic questionnaires and 
rating scales completed by the parent/caregiver, if 
the same parent/caregiver cannot complete the 
questionnaire/rating scale at a visit, the 
questionnaire/rating scale will not be completed. For 
the diary, the same parent/caregiver will complete all 
entries throughout the study. If that evaluator cannot 
complete the questionnaire/rating scale at a visit, the 
questionnaire/rating scale will not be completed.  For 
the diary, the same parent/caregiver will complete all 
entries throughout the study. 
Rationale: To add the assessment of cognition for subjects 5 years of age, so that all study participants are now 
being assessed for cognition using the BRIEF, and to move the description of the BRIEF from the efficacy 
section to the safety section. 
Original Text 
Amendment Text
Synopsis, Section 2.4 
The safety objective of the study is: 
o
To compare the safety and tolerability of ZX008 
0.2 and 0.8 mg/kg/day to placebo with regard to 
adverse events (AEs), laboratory parameters, 
physical examination, neurological examination,
vital signs (blood pressure, heart rate,
Synopsis, Section 2.4
The safety objective of the study is: 
o
To compare the safety and tolerability of ZX008 0.2
and 0.8 mg/kg/day to placebo with regard to adverse 
events (AEs), laboratory parameters, physical 
examination, neurological examination, vital signs 
(blood pressure, heart rate, temperature, and 
PUBL
scales, the
scales, th
nd parent/
nd paren
LIC 
and 
IC
for the
for 
BLI
COPY 
Section
Sect
PY
Infor
Infor
mu
m
OP
rating 
rating
CO
This docume
Ration
Ration
bein
bein
ment 
se
s
me
cu
c
cannot 
ud
be
l no
caregive
regive
dy.
dy.
used
are
ar
duration
ation
plete the 
ete the 
sit, the
the 
t be co
t be c
to 
same
same
egiver) 
giver)
support 
t be 
be
rder to en
der to e
cales when 
les wh
or
Am
Am
pp
up
S
sup
up
any 
9
n
d consent
d consent
signed
signe
marketing 
subjects w
subjects 
presented w
esented
n st
n study. In
udy. I
sion study 
n stud
in orde
order t
authorization 
6
i
bjects
jects
ter
at
at
at
parate ope
rate ope
ho
au
a
applic
e: To add t
To add
assessed fo
ssessed 
ication 
tion to the 
on to the 
ic
inal T
inal T
ap
i
and any 
plet
le
l comple
l comp
extensions
endmen
ndmen
s
the 
the 
ted. F
ed. F
ection 7.
ction 7
ion
For all 
For all
eval
eval
co
ns
en
or
r t
ater sub
ater su
r variations
mus
u
o enter t
enter 
t for the o
for the 
d at Visit 
t Visit 
the op
he op
v
thereof. 
f
who have 
o hav
with the I
h the 
formed c
ormed c
t be 
t be
of

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 154 of 175
temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms 
(ECHO), and body weight. Cognitive Function 
will be assessed in subjects 5 years and older 
using the cognition domain score on the QOLCE. 
Cognitive function in subjects <5 years at 
baseline will be assessed using the Brief Rating 
Inventory of Executive Function-Preschool 
version (BRIEF-P). 
Synopsis (Criteria for Evaluation/Safety) 
• 
The cognition domain of the QOLCE will 
also be used to track cognitive function 
relative to baseline in children 5 years and 
older. The BRIEF-P will be administered to 
children younger than 5 years to track 
cognitive function. 
Table 1 was updated and is not presented here. 
Section 2.7.2 
The safety endpoints of the study are: 
• 
Behavior Rating Inventory of Executive Function, 
Preschool Version (BRIEF-P) to measure 
cognition in subjects aged 2 to < 5 years at 
baseline 
Sections 6.1.3, 6.2.5, and 6.2.9, 
The following procedures will be performed: 
• 
BRIEF-P for subjects < 5 years (Appendix 3) 
Section 7.1.4 
The BRIEF-P is a standardized, validated rating scale 
to measure executive function in preschool aged 
children within the home and school environments 
that will be assessed according to the schedule in 
Table 1. The BRIEF-P measures multiple aspects of 
executive functioning; scales include Inhibit, Shift, 
Emotional Control, Working Memory, and 
Plan/Organize. 
Appendix 3 was updated and is not presented here. 
respiratory rate), electrocardiograms (ECG), 
echocardiograms (ECHO), and body weight. 
Cognitive Function will be assessed in subjects 5 
years and older using the cognition domain score on 
the QOLCE.  Cognitive function in subjects <5 
years at baseline will be assessed using age- 
appropriate versions of the Brief Rating Inventory 
of Executive Function-Preschool version (BRIEF- 
P). 
Synopsis (Criteria for Evaluation/Safety), Section 2.7.2 
• 
The cognition domain of the QOLCE will also 
be used to track cognitive function relative to 
baseline in children 5 years and older. The 
BRIEF will be administered to children 
younger than 5 years to track cognitive 
function. 
Table 1 was updated and is not presented here. 
Section 2.7.2 
The safety endpoints of the study are: 
• 
Behavior Rating Inventory of Executive Function, 
Preschool Version (BRIEF-P) to measure cognition 
in subjects aged 2 to < 5 years at baseline 
Sections 6.1.3, 6.2.5, and 6.2.9 
The following procedures will be performed: 
• 
BRIEF-P for subjects < 5 years (Appendix 3) 
Section 7.2.12 
The BRIEF-P is a standardized, validated rating scale to 
measure executive function in preschool aged children 
ages 2-18 years within the home and school 
environments; that it will be assessed according to the 
schedule in Table 1. The BRIEF-P measures multiple 
aspects of executive functioning; scales include Inhibit, 
(control impulses; stop behavior), Shift (move freely 
from one activity/situation to another; transition; 
problem-solving flexibility), Emotional Control 
(modulate emotional responses appropriately), 
Initiate (begin activity; generate ideas), Working 
Memory (hold information in mind for purpose of 
completing task), Plan/Organize/Organization of 
Materials (anticipate future events; set goals; 
develop steps; grasp main ideas), and Monitor (check 
work; assess own performance). 
Appendix 3 was updated and is not presented here. 
Rationale:  To update contraception requirements for the study.
PUBLIC 
cutive Fun
utive Fun
o measure
o measure
o < 5 yea
o < 5 yea
COPY 
Ta
T
OP
This document
ve fu
 fu
ional Co
nal Co
an/Organ
Organ
cu
cannot
dardi
ard
ve functio
unctio
he home a
home a
sessed ac
essed ac
e BRIEF
BRIEF
nctio
nctio
be 
zed,
zed,
used 
performe
erforme
5 years
5 years
to 
at t 
sup
ion,n, 
upport 
le 1 w
1 w
Section 2
Section
po
The sa
The 
• • 
up
any 
nger th
ger 
y
nction.
nction.
as up
as u
marketing 
ol v
luation/Safe
ation/Sa
et
domain of 
omain o
ke
rack cognit
ck cog
ark
in children 
childre
ma
will be ad
will be
han 5
ha
authorizat
cts 5
s 5 
iz
n score on
score on
or
jects <5
ects <5
ho
ng age-
age-
f Rating I
Rating I
version
ersio
a
ation 
6
i
at
application 
P measu
meas
ng; scales
ng; scale
rol, Workin
l, Work
e.
and
al
in presc
pres
d school 
school 
ding to 
ng to
ure
any 
p
dated rat
dated 
hoo
h
exten
pendix
pendix
nsions
afety 
ety
Behavio
Behavi
ns
Presc
Presc
on
in 
in 
io
en
or 
.2 2 
o
endp
endp
variations 
ive fun
e fun
s
5 years a
years a
ns
dministere
minister
5 years to
years to
ati
dated and
ted and
thereof. 
ventor
en
(BRIEF- 
RIEF-
ety), Sect
ety), Sect
he
he QOLC
e QOL
th
nctiti
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 155 of 175
Original Text 
Amendment Text
Section 4.4 
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until 
90 days after the last dose of study medication. 
Two or more of the following methods are acceptable 
and must include at least 1 barrier method: 
• 
Surgical sterilization (ie, bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects 
or partners) 
• 
Placement of an intrauterine device or 
intrauterine system 
• 
Hormonal contraception (implantable, patch, oral, 
injectable) 
• 
Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm 
or cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository) 
Male subjects who have been sterilized or have 
partners of non-childbearing potential (including 
homosexual men) are required to use one barrier 
method of contraception (condom). This is to prevent 
unintended exposure of the partner to the study drug 
via seminal fluid. 
Male subjects who have pregnant partners are 
required to use one barrier method of contraception 
(condom). 
Alternatively, true abstinence is acceptable when it is 
in line with the subject’s preferred and usual 
lifestyle. If a subject is usually not sexually active but 
becomes active, they, with their partner, must comply 
with the contraceptive requirements detailed above. 
Female subjects of non-childbearing potential, ie, 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 
6 months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
Section 4.4
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until 
90 days after the last dose of study medication. 
Two or more of the following methods are acceptable 
and must include at least 1 barrier method: 
•
Surgical sterilization (ie, bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects or 
partners) 
•
Placement of an intrauterine device or intrauterine 
system 
•
Hormonal contraception (implantable, patch, oral, 
injectable) 
•
Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository) 
Male subjects who have been sterilized or have partners 
of non-childbearing potential (including homosexual 
men) are required to use one barrier method of 
contraception (condom). This is to prevent unintended 
exposure of the partner to the study drug via seminal 
fluid. 
Male subjects who have pregnant partners are required 
to use one barrier method of contraception (condom). 
Alternatively, true abstinence is acceptable when it is in 
line with the subject’s preferred and usual lifestyle. If a 
subject is usually not sexually active but becomes 
active, they, with their partner, must comply with the 
contraceptive requirements detailed above. 
Female subjects of non-childbearing potential, ie, 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 6 
months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
(eg, tubal occlusion, hysterectomy, bilateral 
PUBLIC 
condom
condo
p [diaphra
diaphra
micidal
micidal
ory)
ry) 
sterilized
sterilized
tent
ten
COP
e a 
e a 
e cap
e cap
ale 
le
m o
OPY
H
Y
H
Y
inj
in
Y
•
OP
OP
This document
ivel
ve
ne with
e with
estyle. If 
yle. If 
becomes 
ecomes
with th
with t
F
cu
cannot
have preg
ve preg
ne barrier
barrier
y, true
y, tru
be 
partner
rtne
used
or hav
r ha
l (includi
(includ
use one ba
e one b
m). This
m). This
toto
to 
ve
ve
sup
m 
upport 
Bar
condom
condo
rt
[diaph
[dia
or
subj
po
t
up
any
al cont
l co
y
con
co
y
able)
able)
ny
ier meth
er me
a
m o
a
marketing 
hods
er metho
metho
g 
bilateral tu
bilateral tu
ting
y, hysterect
hystere
et
s; vasectom
vasecto
ke
an intraute
n intrau
ma
rac
authorization 
6
i
at
heir 
eir 
iz
e
o
nsent unti
sent unt
ho
cation. 
ion. 
th
 are a
are a
a
at
at
application 
abstin
abstinence
enc
the subjec
e subje
subject is u
ubject is
ctive, they,
tive, they
e contracept
ontrace
male subje
ale sub
en wh
n w
and
ant part
t par
method of
thod of
any 
study
stud
ners
exten
g
rier r 
o preve
preve
y d
nsions
je
he subj
sub
s
cervica
cervica
ns
foam
foam
o
Ma
Ma
ns
en
or 
agm o
gm
r
ts, eith
s, eith
o
ec
variat
eption (i
ption (
tions 
y
rine devi
ne devi
ns
ption (im
ion (im
ati
hods (for m
ds (for 
ar
their pa
their pa
va
or c
v
thereof. 
ceptable
ptable
of
ubalal
er
tomy for f
omy for 
he
for mal
for ma
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 156 of 175
(eg, tubal occlusion, hysterectomy, bilateral 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study. 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study. 
Male subjects who are sexually active with a partner 
of child-bearing potential must use, with their 
partner, a condom plus an approved method of 
highly effective contraception from the time of 
informed consent until 90 days after study discharge. 
The following methods are acceptable: 
• 
Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation: 
í
oral 
í
intravaginal 
í
transdermal 
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation: 
í
oral 
í
injectable 
í
implantable intrauterine device 
í
intrauterine hormone-releasing 
system 
• 
Surgical sterilization (vasectomy or bilateral 
tubal occlusion) 
Female subjects who are not of child-bearing 
potential do not need to use any methods of 
contraception. A woman is considered of 
childbearing potential, unless they are at least 2 
years post-menopausal or permanently sterile. 
Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
Female subjects who are sexually active and are of 
child-bearing potential must use, with their partner, 
an approved method of highly effective 
contraception from the time of informed consent 
until 30 days following the last follow up visit. 
The following methods are acceptable: 
• 
Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation: 
í
oral 
í
intravaginal 
í
transdermal 
PUBLIC COPY 
• •
OP
This document 
cu
cannot be used to support 
Pro
ro
associ
assoc
up
any 
int
i
í
tra
tr
gestogen
estog
ate
marketing 
m t
s after st
after s
re acceptab
accept
en and pro
n and p
rmonal con
monal c
on of ovula
n of ovu
oral
oral
rav
authorizat
h a partn
h a part
th their
their
d method
metho
he tim
he tim
ation 
6
i
at
application and any extensions 
• •
en
or 
í
o
í
variations 
g
ntracep
acep
tion:
on: 
vaginal 
aginal
nsderma
sderm
n-only ho
only ho
with in
with in
ora
thereof. 
of f 
e of 
of 
dy discha
discha
ble:
ble:
gestogen
estogen
ptio
ti

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 157 of 175
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation 
í
oral 
í
injectable 
í
implantable intrauterine device 
í
intrauterine hormone-releasing 
system 
• 
Surgical sterilization (vasectomy or bilateral 
tubal occlusion) 
Alternatively, true abstinence is acceptable when it is 
in line with the subject’s preferred and usual 
lifestyle. If a subject is usually not sexually active but 
becomes active, they, with their partner, they must 
comply with the contraceptive requirements detailed 
above. 
Rationale:  To clarify when subjects must be discontinued from the study.
Original Text 
Amendment Text
Section 4.5 
Subjects may be discontinued from the study for the 
following reasons, if deemed appropriate by the 
sponsor or investigator: (list of reasons is unchanged). 
Section 4.5
Subjects may must be discontinued from the study for 
the following reasons, if deemed appropriate by the 
sponsor or investigator:  (list of reasons is unchanged). 
Rationale: To clarify that the investigator may discontinue a subject from the study in the case of a medical 
emergency. 
Original Text 
Amendment Text
Section 5.6 
The blinding scheme instituted for this study will 
ensure that the volume of study medication taken 
cannot be associated with the dose group, thus 
unblinding the study. This is achieved by random 
assignment of different concentrations of the ZX008 
oral solution (1.25 mg/mL, 2.5 mg/mL, and/or 
5 mg/mL) by the IVR/IWR system. The IVR/IWR 
system will instruct site personnel to the volume of 
oral solution to be administered based on that 
subject’s weight. (Dose will be recalculated by the 
system once at the midpoint of the study.) During the 
Titration, Maintenance, Taper/Transition Periods, the 
subjects and study personnel (investigators, clinical 
staff, personnel involved in data collection and 
analysis, the Medical Monitor, and the sponsor) will 
be blinded to the treatment allocation and to the 
concentration of ZX008 oral solution. The Medical 
Monitor will have the ability to unblind subjects in the 
case of an emergency. 
Section 5.6 
The blinding scheme instituted for this study will ensure 
that the volume of study medication taken cannot be 
associated with the dose group, thus unblinding the 
study. This is achieved by random assignment of 
different concentrations of the ZX008 oral solution 
(1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) by the 
IVR/IWR system. The IVR/IWR system will instruct 
site personnel to the volume of oral solution to be 
administered based on that subject’s weight. (Dose will 
be recalculated by the system once at the midpoint of 
the study.) During the Titration, Maintenance, 
Taper/Transition Periods, the subjects and study 
personnel (investigators, clinical staff, personnel 
involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the 
treatment allocation and to the concentration of ZX008 
oral solution. The Medical Monitor will have the ability 
to unblind subjects in the case of an emergency. If an 
investigator feels the blind should be broken, he/she 
can do so when necessary for treatment decisions. 
However, the investigator should endeavor to discuss 
with the Medical Monitor or Sponsor’s Medical 
Representative, if available. The blind should only be 
PUBLIC
tudy for t
udy for 
ate by the
ate by th
sons is un
sons is un
nvestigato
vestigato
UB
P
COPY
becom
co
comply
comp
abov
ab
OP
continued
continued
OP
CO
C
This document
tioio
ct’s weig
’s weig
stem once
m once
Titration
itration
subjec
subje
staf
staf
cu
cannot
This i
his 
rent conc
t conc
5 mg/mL
mg/mL
the IVR/I
e IVR/I
instruct 
nstruct 
n to be
to b
be 
udy me
y m
the dose 
the dose
s ach
s ach
used
or this st
r this s
dic
dic
ed 
d
ed to
han
may disc
may dis
o sup
ged).
ged).
uppo
Section 
Section
pp
Subje
Subj
the
th
port 
rom the
m the
t
Amendme
mendm
rt
po
up
s
any 
ve, th
ve, t
th the co
h the c
stut
a
marketing 
mon
asectomy o
asectomy o
abstinence
bstinen
ubject
bject’s pr
’s p
bject is us
ject is
ey,
ey
authorization 
6
i
erine dev
ine dev
ne-rele
e-rel
a
application 
te perso
pers
dministere
dministe
. (Dose wil
Dose w
at the midpo
the mid
Maintenanc
Maintenan
s and study 
nd stud
personnel 
ersonne
lysis, the 
ysis, th
nded
nd
and
ev
trations
ation
2.5 mg/m
5 mg/m
R system
system
onn
onn
any 
on tak
on ta
up, thus 
up, thus
ed by ran
d by r
of
exte
y will
will
en
tensions 
cts ma
s ma
s
e followin
ollowin
sponsor o
sponsor 
ntinue
ue a su
a su
io
en
en
xte
or 
5
y
or
Te
T
or variations 
is acc
acc
referred a
erred 
sually no
ually no
with thei
ith thei
ntracepti
tracept
dy.y
ar
xt
v
thereof. 
e
sing 
ng 
or bilater
r bilater
ept
pt

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 158 of 175
broken in the event the knowledge of whether the 
subject is on active study medication versus placebo 
is needed to determine course of medical treatment 
for the event. The subject will be discontinued from 
the clinical trial upon breaking of the blind and the 
decision whether the subject can enter the separate 
open-label extension study will rest with the Sponsor 
if the subject exited Study 1502 prior to completion. 
Rationale: To remove the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, testosterone, 
GH, prolactin, and IGF-1. 
Original Text 
Amendment Text
Section 1.6 
The approximate volume of blood (108.7 mL) 
planned for collection from each subject over the 
course of the entire study (Screening to End of Study, 
but not including repeat or additional tests ordered by 
the investigator) presents no undue risk to the 
subjects. 
Section 6.5 
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and 
PK will be approximately 115.7 mL. 
Section 1.6
The approximate volume of blood (115.7 108.7 mL) 
planned for collection from each subject over the course 
of the entire study (Screening to End of Study, but not 
including repeat or additional tests ordered by the 
investigator) presents no undue risk to the subjects. 
Section 6.5 
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and PK 
will be approximately 115.7 108.7 mL. 
PUBLIC 
ected duri
cted duri
genotypin
genotypi
mL.
mL.
U
COP
y
OPY
ann
an
of the e
of the
includ
includ
inv
in
OP
This document cannot be used to 
g,
to sup
g the
he
and 
nd 
upport 
stigat
iga
Section
Sect
pp
The
The
up
any
llec
ec
e study (
e study 
g repeat o
repeat o
or) pr
or)
marketing 
en
rest wi
st w
502 prior to
02 prior t
SH, estradi
H, estra
ting
ke
volume o
volume
ion fr
ion
ar
authorization 
6
i
he
he
placebo
acebo
reatment
atmen
ntinued fr
nued f
e blind an
lind a
ter the 
r the 
th
th
a
application and any extensions
n 6.5
s
maximu
maximu
tudy for c
tudy for 
will be 
will be
si
or variations 
of blood (
of blood (
rom each
m each
creening 
reening 
r addition
addition
esents no
ents no
s thereof. 
d th
d
eparate
arate
he Spons
e Spons
o comple
compl
iol, testos
testo
ere
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 159 of 175
Original Text 
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
Genotyping 
5 mL 
-- 
-- 
-- 
-- 
-- 
5 mL 
IGF-1 
3.5 mL 
3.5 mL 
3.5 mL 
3.5 mL 
3.5mL 
3.5 mL 
21 mL 
Coagulation 
-- 
2.7 mL 
-- 
-- 
-- 
-- 
2.7 mL 
Cannabidiol 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
-- 
4 × 2 mL 
-- 
-- 
8 mL 
AED plasma sample 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
8 mL 
Volume for flushing 
indwelling catheter 
-- 
-- 
4 × 0.5 mL 
-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 mL 
19.7 mL 
17.0 mL 
27.0 mL 
15.0 mL 
17.0 mL
115.7 mL 
 FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
 
Amendment Text 
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry -- 
Included in 
Chemistry 
Included in 
Chemistry --
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
Genotyping 
5 mL 
-- 
-- 
-- 
-- 
-- 
5 mL 
IGF-1 
3.5 mL -- 
3.5 mL
3.5 mL --
3.5 mL
3.5mL 
3.5 mL
21 14 mL
Coagulation 
-- 
2.7 mL 
-- 
-- 
-- 
-- 
2.7 mL 
Cannabidiol 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
-- 
4 × 2 mL 
-- 
-- 
8 mL 
AED plasma sample 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
8 mL 
Volume for flushing 
indwelling catheter 
-- 
-- 
4 × 0.5 mL 
-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 16.5 mL 
19.7 mL 
17.0 13.5
mL
27.0 mL 
15.0 mL 
17.0 mL
115.7 
108.7 mL
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
PUB
UBLIC
---
19.7 
19.7 
C 
BL
owth
owth horm
 horm
B
COPY 
3.5 m
.5
Y
-- 
--
Y
P
2 
PY
OP
OP
OP
mL 
mL 
CO
CO
This docume
cument 
in
matology
ology
nt
Genotyping
otypin
en
IGF-1 
GF-1 
e
m
Coagu
Coagu
m
um
Can
Ca
um
um
u
cannot t
o
Sc
S
(D
(D
ot 
no
ry
nn
radiol, 
iol,
, GH, 
GH, 
an
be
me Collec
Colle
Ba
B
b
used to 
o
e; 
support t
x 2 mL 
 mL 
rt
or
p
 
17
pp
sup
u
GF-1=insu
GF-1=in
s
any 
3.5 m
3.5 m
y
--
ny
2 m
any
a
4
a
marketing 
d (study d
tudy d
g
Day 71 
ay 71 
ng
7.5 mL 
7.5 mL
eti
ry 
Include
Inclu
Che
C
ke
a
mL 
L 
ma
m
authorization 
r 2016
2016
io
iz
a
a
me fo
ap
ED plasma
D plasm
application 
Inc
In
n
Chem
Che
on
io
tioio
at
ca
tion 
lic
bidiol
iol
pl
X008 PK samp
08 PK sam
pp
ap
a
and 
line 
ine
ening
ng
-42 to -41)
2 to -41
d
7.5 mL
7.5 mL
an
ud
a
any 
Period (s
eriod
an
a
extensioioions
0 mL 
mL 
s
ons
lin-like
lin-like gro
gr
io
or
4 × 0.
4 × 0
r
o variations 
d in
mistry
ry 
2 mL 
2 mL 
ns
-- 
-- 
on
3.5
3.5
tio
at
ria
mL 
ria
ria
× 2 mL 
mL 
ar
x 2 mL
2 mL
va
v
thereof. 
of
of
Day 99 
Day 99 
eo
7.5 
7.5 
he
th
In
I
the
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 160 of 175
Rationale: To clarify the maximum dose of ZX008 is 30 mg/day.
Original Text 
Amendment Text
Section 5.5.2 
After 4 days at this dose level (Study Day 5), subjects 
randomized to the ZX008 0.8 mg/kg/day group will 
increase their dose to 0.4 mg/kg/day while doses in 
the other two groups will remain constant. On Study 
Day 9, the dose for the 0.8 mg/kg/day group will 
increase to the target dose. 
Table 3 
None 
Section 5.5.4 
On the first day of the tapering period subjects in the 
ZX008 0.8 mg/kg/day group will decrease to a dose of 
ZX008 0.4 mg/kg/day BID. 
Table 4 and Table 5 
None 
Section 5.5.2
After 4 days at this dose level (Study Day 5), subjects 
randomized to the ZX008 0.8 mg/kg/day group will 
increase their dose to 0.4 mg/kg/day (maximum 30 
mg/day) while doses in the other two groups will 
remain constant. On Study Day 9, the dose for the 0.8 
mg/kg/day group will increase to the target dose or a 
maximum of 30 mg/day. 
Table 3 
Note: maximum daily dose of ZX008 is 30 mg. 
Section 5.5.4 
On the first day of the tapering period subjects in the 
ZX008 0.8 mg/kg/day group will decrease to a dose of 
ZX008 0.4 mg/kg/day BID (maximum 30 mg/day). 
Table 4 and Table 5 
Note: maximum daily dose of ZX008 is 30 mg. 
Rationale: To clarify the collection duration of prior and concomitant AEDs.
Original Text 
Amendment Text
Section 5.7 
All medications taken by a subject during the 
Screening and Baseline Seizure Assessment Periods 
are regarded as prior therapy and must be documented 
in the eCRF. Significant medications (eg, antiepileptic 
drugs [AEDs], antibiotics) taken within 30 days prior 
to the Screening visit should also be captured. 
Section 5.7
All medications taken by a subject during the Screening 
and Baseline Seizure Assessment Periods are regarded 
as prior therapy and must be documented in the eCRF. 
Significant medications (eg, antiepileptic drugs [AEDs], 
antibiotics) taken within 30 days prior to the Screening 
visit should also be captured. All prior and 
concomitant AEDs will be collected in the CRF. 
Rationale: To clarify data to be collected with the use of rescue medication.
Original Text 
Amendment Text
Section 5.7.3 
Use of rescue medication is permitted during the 
study and should be recorded on the eCRF (day, time, 
medication[s], dose[s]) and in the diary (day, time). 
Repeated administrations within the same episode 
should be recorded separately. 
Section 5.7.3
Use of rescue medication is permitted during the study 
and should be recorded on the eCRF (day, time, 
medication[s], dose[s]) and in the diary (day, timeframe 
associated with seizure episodes). Repeated 
administrations within the same episode should be 
recorded separately. 
PU
ect d
ect
PUBLIC 
n duration
n duration
BL
UB
PU
COPY
e of 
of 
Section
Secti
PY
On th
O
ZX
Z
OP
This document
escu
sc
and sho
nd sho
dication[
cation[
Repeated
epeated
should
shoul
cu
c
can
3
c
ue med
e med
annot 
houl
ou
arify data 
fy data
o
nn
an
be
icati
c
taken w
taken w
d also
d als
used 
ring the
ng the
sessment
essmen
d must be
must b
ons (
ons (
to 
f p
o
to support 
008 0.
8 0
ZX008 0.4 
X008 0.4
Table 
Tabl
pp
No
N
up
prior and 
ior an
su
s
any 
4
n
rst day of
rst day
8 mg/
8 m
marketing 
y (
two gro
wo gr
y 9, the dos
y 9, the do
ase to the ta
se to th
y.y.
m daily do
daily 
authorization 
6
i
a
iz
5), subje
), subj
ay group 
group 
maxim
maxim
o
or
application 
cation is pe
cation is p
d be recorde
e recor
, dose[s]) a
dose[s])
dministrati
dministra
be recorded
record
app
and 
o be colle
be colle
d
n
a
any 
anti
ant
n 30 days
n 30 day
captured
captu
extensions
4 and
an
s
te: maxim
: maxi
concomit
concomit
n
Amen
Amen
io
eriods 
riods 
ocument
ument
epil
epil
Sec
Sec
n
A
s
en
or 
g/k
g/k
d Tab
Ta
variations 
ose of ZX
se of ZX
f the tape
the tape
kg/day g
g/day g
kg/day
g/da
thereof. 
ill
il
m 30
30
s will 
will
se for the 
for the
arget dose
et dos

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 161 of 175
Rationale: To add new section of collection of data for AEs requiring hospitalization.
Original Text 
Amendment Text
None 
Section 8.1.4 Adverse Events Requiring 
Hospitalization 
If a subject is treated in a medical facility (hospital, 
emergency room, free-standing clinic) related to the 
occurrence of any AE, the following data will be 
collected to model health care utilization in patients 
with Dravet syndrome: AE/reason for 
hospitalization/clinic visit; duration of the visit in 
hours/days; admission to intensive care unit; and 
name/number of procedures performed, including 
but not limited to, electroencephalogram, ECG, 
ECHO, positive emission tomography (PET) scan, 
magnetic resonance imaging (MRI), x-ray, computed 
tomography CT) scan, surgery, and lumbar 
puncture/spinal tap.
Rationale: To clarify randomization inclusion criteria, post-treatment cardiac follow-up, and AESI with regard to 
valve regurgitation seen on ECHO. 
Original Text 
Amendment Text
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria: 
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, ECG 
or physical examination, including but not limited to 
any mitral, aortic, tricuspid or pulmonary valve 
regurgitation or signs of pulmonary hypertension, and 
is approved for entry by the cardiac central reader. 
Section 6.4, Table 6, footnote b 
Positive sign or symptom includes any sign of valve 
thickening or regurgitation (mitral, aortic, pulmonary, 
tricuspid), or sign or symptom indicative of potential 
pulmonary hypertension as adjudicated by the IPCAB. 
Section 8.1.3, Table 8 
10. Signs on ECHO indicative of potential 
valvulopathy 
•  mild valve regurgitation (aortic, mitral, tricuspid, 
or pulmonary) 
• Mean Mitral valve gradient  4 mmHg 
• Mean Aortic valve gradient  15 mmHg 
• Mean Tricuspid valve gradient > 4 mmHg 
• Mean Pulmonary valve gradient > 21 mmHg 
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria: 
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, ECG or 
physical examination, including but not limited to any 
trace mitral, or aortic, tricuspid or pulmonary valve 
regurgitation or signs of pulmonary hypertension, and is 
approved for entry by the cardiac central cardiac reader. 
Section 6.4, Table 7 footnote b 
Positive sign or symptom includes any sign 
development of valve thickening or regurgitation 
(“trace” or greater in mitral, aortic,; mild or greater 
in pulmonary, tricuspid), or sign or symptom indicative 
of potential pulmonary hypertension as adjudicated by 
the IPCAB. 
Section 8.1.3, Table 9 
10.  Signs on ECHO indicative of potential valvulopathy 
• valve regurgitation (aortic or mitral) 
•  mild valve regurgitation (aortic, mitral, tricuspid, or 
pulmonary) 
• Mean Mitral valve gradient  4 mmHg 
• Mean Aortic valve gradient  15 mmHg 
• Mean Tricuspid valve gradient >  4 mmHg 
• Mean Pulmonary valve gradient >  21 mmHg 
PUBL
Section 8.
ection 8.
ria:
ria
BLIC 
on c
on 
IC
BL
COPY
ut n
t
ECHO
ECH
magn
magn
tom
to
OP
riteria
riteria
C
This document 
g
id), or 
d), or 
monary hy
onary hy
Se
S
cu
cannot 
f pu
p
by th
y the e 
ble 6, foo
e 6, foo
nn
n or symp
r symp
or regur
r regur
sigi
be
udin
d or pulm
d or pulm
ulmona
ulmona
used 
scular or 
cular or 
sed on EC
d on E
g but 
g but
to 
3
su
S
support 
ograp
gra
uncture/s
ncture/
post-tr
ost-treatm
ea
or
Am
A
pp
up
sup
u
any
d to
t
sitive em
sitive e
c resonan
 resonan
phy C
hy
marketing 
l fa
g clinic) 
inic)
ollowing da
llowing d
care utiliza
are util
: AE/reaso
AE/rea
c visi
isit; dur
t; du
ssion to int
sion to 
f procedu
proced
, elec
, ele
authorization 
6
i
a
iz
acility (
cility (
or
application 
m in
itation (m
ation (m
or symptom
or sympt
pertension a
tension
tion 8.1.3, T
on 8.1.3,
ap
Signs on
igns o
opa
and 
iac 
ac
ote b 
te b 
an
nclude
clud
any 
lim
lim
ry valve
ry valv
hypertens
hypertens
central
entr
exten
HO, ECG
O, ECG
mited
mited
nsions
Synopsis,
Synopsis,
Syn
Syn
ns ns
endmen
ndmen
s
R
ns
en
or
na
na
nt card
nt card
r variations
ation
tio
tensive c
nsive c
res perfo
res perfo
troencep
oencep
ission tom
ssion tom
nce imagi
ce imagi
T) scan, 
scan, 
l ta
l tap
v
thereof. 
ospital, 
spital,
ated to th
ted to th
ata will b
will b
ation in p
ion in p
n for
for
n of t
of t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 162 of 175
Normal Values for Children 2-18 years 
• 
No regurgitation 
• 
Mean Mitral valve gradient  < 4 mmHg 
• 
Mean Aortic valve gradient < 15 mmHg 
• 
Mean Tricuspid valve gradient < 4mmHg 
• 
Mean Pulmonary valve gradient < 21mmHg 
Normal Values for Children 2-18 years 
•
No regurgitation 
•
Mean Mitral valve gradient  < 4 mmHg 
•
Mean Aortic valve gradient < 15 mmHg 
•
Mean Tricuspid valve gradient < 4mmHg 
•
Mean Pulmonary valve gradient < 21mmHg 
Rationale: To clarify that the central cardiac reader will provide consultation to the IDSMC when a subject may 
be removed from the study due to development of signs or symptoms indicative of valvulopathy, regurgitation, or 
pulmonary hypertension.
Original Text 
Amendment Text
Section 4.5 
Subjects may be discontinued from the study for the 
following reasons, if deemed appropriate by the 
sponsor or investigator: 
1. Development of signs or symptoms indicative of 
cardiac valvulopathy or regurgitation (mitral, aortic, 
tricuspid, pulmonary valves), or pulmonary 
hypertension for which IDSMC, in consultation with 
the IPCAB and the investigator believe the benefit of 
continued participation does not outweigh the risk. 
Section 4.5
Subjects may be discontinued from the study for the 
following reasons, if deemed appropriate by the sponsor 
or investigator: 
1. Development of signs or symptoms indicative of 
cardiac valvulopathy or regurgitation (mitral, aortic, 
tricuspid, pulmonary valves), or pulmonary 
hypertension for which IDSMC, in consultation with the 
IPCAB, the central cardiac reader, and the 
investigator believe the benefit of continued 
participation does not outweigh the risk. 
Rationale: To clarify expedited reporting of cardiac events other than SAEs.
Original Text 
Amendment Text
Section 8.8 
Even if none of the criteria for an SAE are fulfilled, 
any of the following events must be reported by the 
investigator to the Medical Monitor within 72 hours 
from the time the investigator is notified. 
1.
Hypersensitivity reactions 
2.
Pulmonary hypertension 
3.
Cardiac symptoms requiring intervention, or 
valvulopathy 
Section 8.8
Even if none of the criteria for an SAE are fulfilled, any 
of the following events must be reported by the 
investigator to the Medical Monitor within 72 hours 
from the time the investigator is notified. 
1.
Hypersensitivity reactions 
2.
Pulmonary hypertension 
3.
Cardiac symptoms requiring intervention, or 
valvulopathy, if identified outside of study-related 
monitoring 
PUBLIC
ultation w
tation w
e the bene
e the ben
tweigh th
tweigh th
ed report
ed report
PU
P
COP
of 
ortic,
rti
OPY
Subje
bj
followi
follow
or in
or
1
OP
This document t cannot
tigat
ga
y reaction
eaction
ypertensi
ertensi
ymptoms 
mptoms
opathy 
athy 
c
be
must b
ust 
l Monito
l Monito
or is 
or is
used
n SAE a
SAE a
be r
be r
ed 
g of
of
d
ed to 
risk
card
card
to sup
it of 
of 
k
upport 
Develop
evelop
cardiac valv
diac v
tricuspid
tricusp
hyper
hype
IPC
IP
up
any 
be di
be d
reasons, i
easons,
igator:
gator
pmen
ma
scon
sc
marketing 
5 m
ent < 4mm
< 4m
ng
radient < 21
radient < 2
ing
IDSMC wh
DSMC 
of valvulop
f valvul
tin
t
ar
ma
authorization 
6
i
mHg 
Hg 
ut
mmHg 
mHg 
a
a
application 
io
and 
uiring in
iring 
any 
rted b
rted
ithin
thin 72 h
72
fied. 
fied. 
exte
fulfilled
lfilled
by
b
tensions 
tension
nsio
CAB,
AB, the
the
investiga
nvestig
partici
partici
c events o
vents o
ns
en
en
te
or
ulopa
lop
pulmon
ulmon
n fo
n fo
variation
ntinued fr
inued fr
f deemed 
deemed
ons s
t of sign
of sign
athy
thy
on thereof. 
Hg 
e
1mmHg
mmHg
re
hen a sub
hen a sub
thy, regu
hy, reg
er

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 163 of 175
Rationale: To add a new section on grading of, and follow-up for, ECHO findings.
Original Text 
Amendment Text
None 
Section 8.9.1 Follow-up of Echocardiogram Findings 
All ECHOs will be evaluated by a central reader 
from BioMedical Systems, Inc. (BMS), in 
consultation with the IPCAB if warranted. Findings 
related to pulmonary hypertension or valvulopathy 
on any of the four valves (aortic, mitral, pulmonary, 
triscuspid) will be reported to the investigator with 
grades of normal, trace, mild, moderate or severe. If 
the ECHO result has progressed in severity since the 
last reading then new oversight measures will be 
enacted as described below in Levels 1-3. Table 11 
describes the severity of ECHO findings with the 
level of increasing oversight if the subject is to 
remain in the study. 
Table 11. Clinical Measures Enacted Upon 
Increasing Severity of ECHO Findings 
Level 1: 
Continue per protocol
Level 2: 
1. If there is a desire to continue study 
medication: 
a.
The investigator will evaluate the 
efficacy to date based on study 
diaries and consult with the 
parent/guardian, and determine 
whether study treatment was 
associated with significant, 
meaningful benefit in number, 
severity and/or duration of seizures 
and/or on the impact on daily 
functioning. 
b.
The investigator will consider 
whether the subject has had 
reasonable trials (dose and duration) 
of other available anticonvulsants 
(e.g. valproic acid, clobazam, or 
topiramate), alone or in combination, 
and not maintained the level of 
seizure control achieved with study 
medication. 
2.
If the investigator feels consideration of 
Severity 
Valve 
Aortic
Mitral
Pulmonary 
Tricuspid
Normal
Level 1
Level 1
Level 1 
Level 1
Trace
Level 2
Level 2
Level 1 
Level 1
Mild
Level 2
Level 2
Level 1 
Level 1
Moderate 
Level 3 
Level 3 
Level 3 
Level 3 
Severe
Level 3
Level 3
Level 3 
Level 3
PUBLIC COPY
escr
sc
level o
level 
rema
rema
Ta
T
OP
This document 
cu
cannot be used to support 
le 11
 11
up
Severity
Severi
ort
p
Norm
No
pp
pp
Tr
pp
pp
p
any
seve
ev
reasing 
reasing
n the stu
n the stu
Clin
Cl
marketing 
ar
sion or 
n or
rtic, mitra
rtic, mitra
ed to the in
to the 
e, mild, mo
, mild, 
s progresse
rogre
new oversi
ew ove
ribed belo
bed be
rity o
rity
authorization 
6
i
a
iz
m Findin
m Findin
ral reade
l reade
S), in 
, in
ranted
anted
or
application and any extension
en ons
al
ace
s
Mild
ld
ns
Modera
Modera
on
s
Seve
Sev
sio
ns
ns
or 
cre
cr
Aortic
Aort
or
o
Lev
Lev
o variations
ed in
d in
ight mea
ht mea
w in Lev
in Lev
of ECHO
ECHO
versight
versight
dy. 
y
ical Mea
l Mea
easing
easin
v
thereof.
Findings
ndings
vulopath
ulopath
l, pulmon
pulmo
nvestigato
estigat
derate or
erate o
seve
seve

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 164 of 175
continued treatment is warranted considering 
benefit and potential risks, and the 
parent/guardian feels strongly that the child be 
maintained on the study medication when 
understanding the risks, the parent/guardian 
must sign a new consent which describes the 
additional risks and the child should provide 
assent if appropriate. 
a. If both of these conditions are not
met, the subject is discontinued from 
treatment. 
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to 
the IDSMC for review, including consideration 
of effects on seizures and comorbidities. 
4.
The Co-Chairs of the IPCAB are alerted to the 
request and prepare, after consultation with 
BMS, an evaluation of the cardiopulmonary 
risks and proposed monitoring plan, if 
applicable for submission to the IDMSC. 
5.
IDMSC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6.
IDSMC makes a determination of appropriate 
path, including the possible outcomes: 
a.
Discontinue study medication 
b.
Increase frequency of ECHO and 
ECG monitoring 
c.
Add additional ECG and/or ECHO 
measures to be monitored 
d.
Reduce the dose of study medication 
Level 3: 
1. The investigator will evaluate efficacy to date 
based on study diaries and consult with the 
parent/guardian, and determine whether the 
achieved benefit justifies the consideration of 
continuing study treatment by the IDSMC. 
MINIMAL efficacy criteria for IDSMC 
consideration: 
a.
Seizures must be more than 75% 
improved (number of convulsive 
seizures per 28 days) on treatment 
over baseline, and improvement 
must be consistent. 
b.
The number, type, duration, and 
distribution of seizures at baseline 
should be of a severity, which 
justifies the risk of cardiopulmonary 
complications, considering the 
subject’s age and overall health. 
COPY 
OP
4.4
This document 
cu
cannot be used to support 
up
r
BM
BM
risk
r
5.5
any 
cts on
cts o
e Co-Cha
e Co-Ch
equest a
quest
S
marketing 
hild s
ld 
hese condi
ese condi
subject is 
ubject 
ment.
ent.
ator prepa
or prep
for continu
r conti
C for re
C for
se
authorization 
6
i
at
at
ring
ring
he child b
child b
on when 
n when 
rent/gua
ent/gua
h descri
descri
hou
hou
application and any extensions 
n
s
ap
IDM
DM
Inve
Inve
su
s
6.6
or 
and p
and
licabl
licabl
SC
variations
ares a ca
es a c
uation to
ion to
eview, in
view, in
izures an
ures a
airs of th
rs of th
and prepa
d prep
n evalu
evalu
pr
thereof. 
dia
es the
s the 
d provide
rovid
tions are
ons are
discontin
disconti

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 165 of 175
c.
Subject has had reasonable trials 
(dose and duration) of other 
available anticonvulsants (eg, 
valproic acid, clobazam, topiramate), 
alone or in combination, and not 
maintained the level of seizure 
control achieved with study 
medication. 
2.
If the investigator feels consideration of 
continued treatment is warranted considering 
the benefit and potential risk, and the 
parent/guardian feels strongly that the child 
be maintained on the study medication when 
understanding the risks, the parent/guardian 
must sign a new consent, which describes the 
additional risk and the child should provide 
assent if possible. 
a.
If both of these conditions are not 
met, the subject is discontinued from 
treatment. 
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to 
the IDSMC for review, which includes effects 
of study medication on seizures and 
comorbidities related to Dravet syndrome. 
4.
The Co-Chairs of the IPCAB are alerted to 
the request, and in consultation with BMS 
prepare an evaluation of the risk and 
proposed monitoring plan if applicable for 
submission to the IDMSC. 
5.
IDSMC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6.
IDSMC makes a determination of 
appropriate path, including these possible 
outcomes: 
a.
Discontinue study medication 
b.
Increase frequency of ECHO and 
ECG monitoring 
c.
Add additional ECG and/or ECHO 
measures to be monitored 
d.
Reduce the dose of study medication 
PUBLIC COPY 
OP
This document 
cu
cannot be used to support 
up
3
any 
t sign a
t sign
dditional 
dditional
ssent if
ssent 
a
marketing 
d with
with
eels consid
els consid
ment is war
nt is wa
d potential
potenti
rdian feels 
ian fee
ained on t
ned on
nding th
ndin
ne
authorization 
6
i
a
s 
eg,
topiram
topiram
on, and n
n, and n
l of seizu
of seizu
stu
stu
application 
a
and any extensions
n
.
The 
The
rati
rati
t
or 
i
variations
 ri
strongl
rong
he study 
study 
he risks, 
he risks, 
ew conse
ew conse
risk and 
sk and 
f possible
ossible
If bot
If bot
me
thereof. 
t 
e
y 
deration o
ration o
rranted co
ranted c
sk, and
sk, an

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 166 of 175
APPENDIX 11 – PROTOCOL AMENDMENT 2 
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 
x
Removed atonic seizures and added tonic-atonic from the types of convulsive seizures in 
Inclusion Criterion #5. 
x
Removal of Inclusion Criterion #7 to clarify that participation in the epilepsy-related genetic 
testing is not required for participation. 
x
Updated the preclinical data information and, based on this information, revised the list of 
prohibited concomitant medications. 
x
Clarified that the number of convulsive seizures during the 6-week baseline period is  6. 
x
Added PedsQL Family Impact module to the efficacy measures. 
x
Clarify study days of Screening during the Baseline Period and the timing of assessments in 
that period. 
x
Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening. 
x
Added the list of countries in which Diacomit® (stiripentol) is approved. 
x
Added supporting references to existing citations of data. 
x
Clarified the safety objective. 
x
Specify that the number of study centers is approximate. 
x
Clarified the duration of use of contraception after the last dose of study drug. 
x
Removal of social media policy from the reason or removing a subject from therapy or 
assessment. 
  
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale:  To clarify the types of seizures that satisfy the requirement for the 12 weeks before screening.
Original Text
Amendment Text
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures (tonic-
clonic, tonic, atonic, clonic) per 4-week period for past 
12 weeks prior to screening, by parent/guardian report 
to investigator or investigator medical notes. 
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures 
(tonic-clonic, tonic, tonic-atonic, atonic, clonic) per 
4-week period for past 12 weeks prior to screening, 
by parent/guardian report to investigator or 
investigator medical notes. 
Rationale:  Remove the requirement for participation in epilepsy-related gene testing from the inclusion 
criteria.
Original Text
Amendment Text
PUBLIC
which 
which D
ces to 
ces to ex
ex
ective.
ctive.
mber of s
mber of 
n of u
n o
COPY
e e
e Base
e Basel
epsy gen
epsy ge
This document
suc
uc
of conte
f conte
Ratio
Rati
m
u
Or
Or
um
cu
c
cannot 
h cha
ch
Change
hange
e marked
marked
ch as t
h as t
be 
nge
ng
used
udy
ud
e of co
of co
ia policy
polic
to 
y cent
y cent
support 
otyp
ype pa
e p
acomit® 
comit®
sting citat
ing cita
any 
mea
me
Period 
Period
ne
marketing
epilepsy
epilepsy
ormation,
ormatio
he 6-week
e 6-we
asures
asur
authorization 
6
i
ive seizu
e seizu
application
in b
he correct
he correc
ts, and list
, and l
ale: 
e: To cl
To
lic
ginal Text
nal Tex
p
lusion Cr
usion C
ap
ect m
ct
app
and 
/clcl
bold 
old
any 
aririficati
fica
extensions 
(stir
stir
tions of d
ns of 
rs is app
s is app
raceptio
acepti
from the
rom th
or 
ipen
ipen
variations 
k baselin
baselin
k
s. 
and the t
nd the t
is man
is man
thereof. 
res i
e
related g
elated g
revised
revised

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 167 of 175
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Rationale:  Revised the list of prohibited concomitant medications.
Original Text
Amendment Text
Exclusion Criterion 8, Synopsis and Section 4.2
Subject is receiving concomitant therapy with: 
centrally-acting anorectic agents; monoamine- oxidase 
inhibitors; any centrally-acting compound with 
clinically appreciable amount of serotonin agonist or 
antagonist properties, including serotonin reuptake 
inhibition; atomoxetine, or other centrally-acting 
noradrenergic agonist; cyproheptadine, and/or 
cytochrome P450 (CYP) 2D6/3A4/2B6 
inhibitors/substrates (see Appendix 1). (Note: Short- 
term medication requirements will be handled on a per 
case basis by the Medical Monitor.)
Exclusion Criterion 8, Synopsis and Section 4.2
Subject is receiving concomitant therapy with: 
centrally-acting anorectic agents; monoamine- 
oxidase inhibitors; any centrally-acting compound 
with clinically appreciable amount of serotonin 
agonist or antagonist properties, including 
serotonin reuptake inhibition; atomoxetine, or 
other centrally-acting noradrenergic agonist; or
cyproheptadine, and/or cytochrome P450 (CYP) 
2D6/3A4/2B6 inhibitors/substrates (see Appendix 
1). (Note: Short- term medication requirements 
will be handled on a per case basis by the Medical 
Monitor.)
Rationale:  Clarified that the number of convulsive seizures during the 6-week baseline period is  6.
Original Text
Amendment Text
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with 
>6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks and 2 
in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet the 
study entry criteria and confirm they have experienced >6 
convulsive seizures during the 6-week Baseline Period, 
with at least 2 seizures in each 3-week half of the Baseline 
Period. 
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with > 
ш6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks 
and 2 in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet 
the study entry criteria and confirm they have 
experienced 6 >6 convulsive seizures during the 6-
week Baseline Period, with at least 2 seizures in each 
3-week half of the Baseline Period. 
Rationale:  Added PedsQL Family Impact module to the efficacy measures.
Original Text
Amendment Text
Synopsis, Criteria for Evaluation: Efficacy
Not applicable 
Section 2.3, Additional Secondary Objectives 
Not applicable 
Section 2.7.1, Efficacy Endpoints 
Not applicable 
Section 6.1.3, 6.2.9 
Not applicable 
Synopsis, Criteria for Evaluation: Efficacy
PedsQL Family Impact module to measure 
changes in quality of life of the parent/caregiver 
Section 2.3, Additional Secondary Objectives 
The change from baseline in the PedsQL Family 
Impact module score. 
Section 2.7.1, Efficacy Endpoints 
PedsQL Family Impact module to measure changes 
in quality of life of the parent/caregiver 
Section 6.1.3, 6.2.9
PedsQL Family Impact module (Appendix 6) 
nopsis
nopsi
C
line with
ine with
he 6-week
e 6-week
in the firs
in the firs
C C
an
COPY 
1)
wi
w
PY
ulsive sei
ulsive se
OP
CO
C
This document
tion 2.3, A
n 2.3, A
en
Not applic
t applic
Secti
Secti
cu
N
cu
cann
riteria for
teria fo
an
able 
ble
nnot 
d PedsQL
PedsQL
ot
no
nn
be 
the 6-w
e 6-w
each 3-w
each 3-w
used 
that subje
at subje
they hav
hey ha
wee
to
Base
weeks
weeks
suppo
pport 
Mo
ures dur
es dur
t
Amen
Am
ort
po
line
line
Ran
R
po
ppo
any 
e: Sho
: Sh
be handle
be handl
nitor.)
itor.)
ing
a
marketing 
ents;
nts
ntrally-ac
rally-a
able amoun
le amoun
properties
ropert
e inhibi
inhibition
ti
-acting nor
cting n
dine, and/or
ne, and/
ma
B6 inhib
B6 inh
m
rt-
authorization 
6
i
e for a
for a
atiti
ati
riz
ho
nd Sectio
d Secti
ut
t therapy
therap
mon
mon
th
application 
Ev
dditional Se
itional S
at
ble 
b e
n 2.7.1, E
.7.1, Eff
pp
t applicable
applicabl
n 6
an
aluatio
luatio
and
Family
mily
d
nd
an
any 
Baselin
asel
k half of t
half of
Im
a
extensions 
nd 2
ts meet th
meet th
xperien
perien
nd
Section
ction
ns
Subjec
Subjec
ш6 c
6 
P
sio
or 
men
me
omizat
miza
o
4
or variations
n;
radrene
rene
r cytochr
cytochr
ns
itors/sub
tors/sub
io
term med
erm me
d on a pe
on a pe
the 6-w
he 6-w
va
t T
v
thereof. 
with:
with
oamine-
mine-
ing comp
g comp
t of sero
of sero
s, includi
, includ
atomox
atomox

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 168 of 175
Rationale:  Clarify study days of Screening during the Baseline Period.
Original Text
Amendment Text
Table 1: Schedule of Assessments 
a: 
The Baseline Period is comprised of the initial screening for the study and 
the assessment of baseline seizure activity recorded daily in the diary. 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -42 to -41):
Table 1: Schedule of Assessments 
a: 
The Baseline Period is comprised of the initial screening for the study 
and the assessment of baseline seizure activity recorded daily in the diary. 
The procedures to be completed at the Screening visit may be 
completed in a single day or split so that they are completed over the 2-
day period (i.e., Days -43 to -42 or Days -42 to -41). 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41):
Rationale:  Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening.
Original Text 
Amendment Text 
Table 1: Schedule of Assessments 
Table 1: Schedule of Assessments 
     
     l.   Mandatory one time collection any time during or after      
screening. 
Rationale:  Added the list of countries in which Diacomit® (stiripentol) is approved.
Original Text
Amendment Text
Section 1.1.1, Existing Treatment for Dravet Syndrome 
To date, only one treatment, Diacomit® (stiripentol) is 
approved, and only in Europe as adjunctive therapy in 
patients with severe myoclonic epilepsy in infancy (SMEI, 
Dravet syndrome), and must be co-administered with 
clobazam and valproate. Stiripentol has not been approved 
for use in the United States of America, but is available 
under compassionate use protocols at certain clinical sites.
Section 1.1.1, Existing Treatment for Dravet 
Syndrome 
To date, only one treatment, Diacomit® (stiripentol) is 
approved, and only in Europe, Canada, Japan, and 
Australia, as adjunctive therapy in patients with 
severe myoclonic epilepsy in infancy (SMEI, Dravet 
syndrome), and must be co-administered with 
clobazam and valproate. Stiripentol has not been 
approved for use in the United States of America, but 
is available under compassionate use protocols at 
certain clinical sites. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Existing Treatment for Dravet Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved prospective 
observation trial) for the treatment of DS; the efficacy and 
safety of this therapeutic approach have been published in 
a peer reviewed journal and reported to be very favorable. 
There are no treatments specifically approved for the 
treatment of DS in the United States of America (USA). 
Accordingly, there remains an unmet need for an approved 
treatment for children with DS. 
Section 1.1.1, Existing Treatment for Dravet 
Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved 
prospective observation trial) for the treatment of DS; 
the efficacy and safety of this therapeutic approach 
have been published in a peer reviewed journal 
(Ceulemans 2012; Ceulemans 2016) and reported to 
be very favorable. There are no treatments specifically 
approved for the treatment of DS in the United States 
of America (USA). Accordingly, there remains an 
unmet need for an approved treatment for children 
with DS. 
Rationale:  Revised the preclinical data section.
Original Text
Amendment Text
Section 1.3, Preclinical Data 
The pharmacokinetics of fenfluramine, norfenfluramine 
Section 1.3, Preclinical Data 
The pharmacokinetics of fenfluramine, 
iripen
rip
ive therap
ve thera
psy in infa
sy in inf
-administ
-administ
ntol has n
tol has n
f America
Americ
f
cols 
col
COPY 
Y
Diacomit®
Diacom
PY
OP
yndrome
ndrome
C
tol)
tol)
CO
This document
m R
rvation t
ation t
fety of th
y of th
a peer re
peer re
There
Ther
tre
tre
cu
cannot
g Treatm
Treatm
o
s, fenflur
fenflur
edicine in
icine in
rrently us
ently us
oyal D
yal D
t be
porting 
porting
e
be used
but 
but
t certain 
ertain 
to
ed 
been ap
been a
is ava
is ava
support 
(
Ame
Am
t
in
cy (SMEI,
y (SMEI
with
with
pr
Section
Sec
o
Syn
Sy
p
T
rt
ppo
any 
reenin
reen
y
tiripento
iripen
any
ndm
d
a
ma
atory one 
atory o
arketing 
s
3 to -4
to -4
but not requ
ut not req
g
ext
ext
et
edule of A
ule of 
ke
authorization 
6
ititi
ati
at
at
ning for the 
ng for the 
daily in the 
ily in the 
visit may be
isit may be
re complete
complet
to -41). 
41)
ssments
sments
a
2 o
2
za
application 
ng an
an a
cree (gove
cree (gov
) for the tre
for the 
therapeutic
herapeu
iewed journ
ewed jou
re no treatm
e no tre
ment of DS
ent of D
cordingly
ording
ment 
men
and 
nt for D
for D
d
mine has b
ne has b
elgium a
gium 
ppr
ppr
d a
rave
any 
erence to
rence t
y
any
a
extensions 
oved
ed
lable
ble
nical sites
ical site
To date
date
approve
approv
Aust
Aus
se
se
sio
or 
1.1.1
.1
r
ome
ome
o
on
on
variations
ime collectio
me collect
at
l) is appr
is app
ria
ent Text
t Tex
ar
1, E
va
s 
ssess
es
thereof. 
-42 to -4
42 to -4
uired at 
ed at 
eo
he
men
men
th

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 169 of 175
and their respective isomers has been studied in mice, rats, 
dogs and humans. The pharmacokinetics in humans differs 
from that of other species, with a longer duration of 
exposure to both the parent and the metabolite. In vitro 
metabolism studies have shown that there are large species 
differences in pharmacokinetics and metabolism of 
fenfluramine after oral administration. In humans, 
fenfluramine is metabolized to norfenfluramine. CYP2C19 
and CYP2D6 appear to be the predominant CYP enzymes 
that metabolize fenfluramine to norfenfluramine. CYP1A2, 
CYP2B6 and CYP3A4/5 also appear to be involved, but to 
a lesser degree. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of CYP3A4 
and CYP2B6. Based on the FDA’s mechanistic static 
model, ZX008 is predicted to potentially cause clinically 
significant inhibition of CYP2D6 in the range of doses that 
will be administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be administered. 
The major metabolite norfenfluramine, however, is not 
expected to cause clinically significant inhibition or 
induction of CYP2B6, 2D6 or 3A4. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of CYP3A4 
and CYP2B6. Based on the FDA’s mechanistic static 
model, ZX008 is predicted to potentially cause clinically 
significant inhibition of CYP2D6 in the range of doses that 
will be administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be administered. 
The major metabolite norfenfluramine, however, is not 
expected to cause clinically significant inhibition or 
induction of CYP2B6, 2D6 or 3A4. 
norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The 
pharmacokinetics in humans differs from that of other 
species, with a longer duration of exposure to both the 
parent and the metabolite. In vitro metabolism studies 
have shown that there are large species differences in 
pharmacokinetics and metabolism of fenfluramine 
after oral administration. In humans, fenfluramine is 
metabolized to primarily norfenfluramine. CYP2C19 
CYP1A2, CYP2B6 and CYP2D6 appear to be the 
predominant CYP enzymes that metabolize 
fenfluramine to norfenfluramine. CYP1A2, CYP2B6 
and CYP3A4/5  CYP2C9, CYP2C19, and CYP3A4 
also appear to be involved, but to a lesser degree.  
There is also some contribution of renal clearance to 
the elimination of dexfenfluramine (8%-16%) and 
nordexfenflurmaine (7%-8%) from the body. Because 
fenfluramine and its active metabolite norfenfluramine 
have multiple pathways of elimination, interference 
with a single pathway is unlikely to cause a significant 
change in fenfluramine’s clearance though the 
probability of an interaction increases if multiple 
elimination mechanisms are affected simultaneously. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s 
mechanistic static model, ZX008 is predicted to 
potentially cause clinically significant inhibition of 
CYP2D6 in the range of doses that will be 
administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
While in vitro studies showed that both 
fenfluramine and norfenfluramine cause weak 
inhibition of CYP2D6 and fenfluramine causes 
weak induction of CYP3A4 and CYP2B6, further 
analysis based on the FDA’s mechanistic static 
model shows that fenfluramine and its major 
metabolite norfenfluramine are unlikely to alter the 
pharmacokinetics of substrates of these CYP450 
enzymes in the range of ZX008 doses that will be 
administered in this study. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy in the 
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy 
PUBLIC
dmin
dm
however, 
owever
nt inhibiti
nt inhibit
4.
studies s
studies s
mine cau
mine cau
cause
cau
COPY
lyly
ses that 
ses tha
 also
 also
tion of 
ion of 
ster
ster
PY
th
no
n
PY
This document 
cu
cannot
nica
nic
the dose
he dos
olite norf
ite norf
use clinic
e clini
f CYP2B
CYP2B
be
P2D6
D6
008 IB 20
008 IB 2
lly si
lly s
used
inh
inh
inductio
nductio
 mechan
mechan
tentially
entially
in th
in th
to
ow that 
w that
ibitio
ibitio
suppo
d. 
not 
ot 
n or 
ot
pport 
have m
have m
with a 
with
chan
ch
p
ppo
any 
nation
natio
xfenflurm
fenflur
luramine
urami
mult
marketing 
uman
ma
orfenflura
fenflura
CYP2D6 a
CYP2D6 a
zymes that m
mes th
rfenflurami
fenflura
CYP2C9, 
CYP2C
o be involv
be invo
o some co
some 
of
authorization 
6
i
been
en
at of other
of other
re to both 
to both
abolism st
abolism s
cies differ
s differ
m of fenfl
of fenf
ns, fen
s, fen
titi
ati
application 
 2D6 
D6
and 
hat w
at w
nfluramin
luramin
y signifi
signifi
or 3
or 3
any 
ange
ang
). ZX008
. ZX00
ficant ind
cant i
ll be
ll b
extensio
h 
of 
of CYP3A
f CYP3A
ic static
static
use clin
se clin
of
of
sions 
probabi
bab
elimina
elimina
In vi
In v
on
fef
o
sio
or 
ngle
ng
e in fen
 in fe
lity
lit
variations 
CYP2
YP2
ed, but to
, but to
ntributio
ntributio
dexfenflu
exfenflu
maine (7%
ine (7%
and its a
nd its a
ple pathw
ple path
e pat
pa
thereof. 
ramine
am
fluramine 
ramine
mine. CYP
ne. CYP
eo
appear to 
ppear to 
metaboliz
metaboliz
e. CYP1
. CYP
th
C1
C1

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 170 of 175
1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and its 
successful treatment of 11 refractory pediatric epilepsy 
patients in Belgium (Boel 1996), in 2002 Drs. Ceulemans 
and Lagae were granted authorization to prescribe 
fenfluramine to their patients with refractory pediatric 
epilepsy conditions, including DS, under an approved 
protocol under a Belgium government program (Royal 
Decree). To date, these pediatric neurologists have DS 
patients (infants, children, young adults, and now also 
adults), being successfully treated with fenfluramine for 
over 27 years. The efficacy and safety of this therapeutic 
approach has been reported to be overwhelmingly 
favorable. In the most recent assessment of efficacy of 
these patients reported by the investigators in, the average 
length of treatment was over 12 years, with one patient 
being successfully treated for 26 years. Of the 15 DS 
treated patients, 10 (67%) were reported as seizure-free, 
with the average time of seizure-freedom being 6 years 
(range 1-19 years). Twelve patients (87%) had a greater 
than 90% reduction in seizure frequency and 14 patients 
(93%) with greater than 70% reduction in seizure 
frequency. 
in the 1980s (Aicardi and Gaustaut 1985; Aicardi 
1988) and its successful treatment of 11 refractory 
pediatric epilepsy patients in Belgium (Boel 1996), in 
2002 Drs. Ceulemans and Lagae were granted 
authorization to prescribe fenfluramine to their patients 
with refractory pediatric epilepsy conditions, including 
DS, under an approved protocol under a Belgium 
government program (Royal Decree). To date, these 
pediatric neurologists have DS patients (infants, 
children, young adults, and now also adults), being 
successfully treated with fenfluramine for over 
27 years. The efficacy and safety of this therapeutic 
approach has been reported to be overwhelmingly 
favorable. In the most recent assessment of efficacy of 
these patients reported by the investigators in, the 
average length of treatment was over 12 years, with 
one patient being successfully treated for 26 years 
(Ceulemans 2016). Of the 15 DS treated patients, 
10 (67%) were reported as seizure-free, with the 
average time of seizure-freedom being 6 years (range 
1-19 years). Twelve patients (87%) had a greater than 
90% reduction in seizure frequency and 14 patients 
(93%) with greater than 70% reduction in seizure 
frequency.
Rationale:  Clarified the safety objective.
Original Text
Amendment Text
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 0.2 
and 0.8 mg/kg/day to placebo with regard to AEs, 
laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, 
heart rate [HR], temperature, and respiratory rate), 
ECGs, ECHOs, and body weight. Cognitive Function 
will be assessed in subjects 5 years and older using the 
cognition domain score on the QOLCE. Cognitive 
function will be assessed using age-appropriate 
versions of the BRIEF. 
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 0.2 
and 0.8 mg/kg/day to placebo with regard to AEs, 
laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, 
heart rate [HR], temperature, and respiratory rate), 
ECGs, ECHOs, and body weight. Cognitive 
Function will be assessed using the cognition 
domain score on the QOLCE and age-appropriate 
versions of the BRIEF. Cognitive Function will be 
assessed in subjects 5 years and older using the 
cognition domain score on the QOLCE. Cognitive 
function will be assessed using age-appropriate 
versions of the BRIEF. 
Rationale:  Clarify that the number of participating study centers is approximately 30.
Original Text
Amendment Text
Section 3.4, Number of Study Centers 
The study expects to use up to 30 research centers in 
Europe, Australia, and South Korea. Additional study 
centers within or outside of Europe, Australia, and 
South Korea may be added if enrollment cannot be 
completed in a timely manner. 
Section 3.4, Number of Study Centers 
The study expects to use up to approximately
30 research centers in Europe, Australia, and South 
Korea. Additional study centers within or outside of 
Europe, Australia, and South Korea may be added if 
enrollment cannot be completed in a timely manner. 
Rationale:  Clarified the duration of use of contraception after the last dose of study drug and added barrier 
method to the list of acceptable methods of birth control.
Original Text
Amendment Text
P
ety
ety
PUBLIC 
eizure
eizur
ty objecti
y objecti
UB
PU
P
COPY
e,e,
ears 
ears 
greater 
greater 
4 patient
patient
PY
av
on
o
PY
This document 
of
o
Ratio
Rati
m
u
Or
Or
um
cu
c
cannot
ratur
atu
d body w
ody w
in subject
subjec
main score
ain scor
ill be asse
l be asse
the B
he B
be 
ical ex
al e
 vital sig
vital si
e, an
e, an
used 
Objective
jective
ed
bility of Z
ty of Z
ith regar
th rega
am
am
d to 
.
o
to support 
C
10 (67
10 (67
averag
ave
1-19
1
9
ppo
s
any 
ength
engt
atient bein
tient be
ulemans
lema
7%)
7%
marketing 
Decrcr
DS patien
DS patie
and now als
nd now als
with h fenflura
fenflu
acy and saf
cy and s
een report
n repor ed
the most re
e most
ts reporte
s repor
of t
authorization 
6
i
ory y 
1996), in
996), in
nted 
ed 
 to their p
to their 
nditions, 
itions, 
under a B
der a B
ee). T
e). T
titi
ati
ap
ction 3.4, 
ion 3.4
app
ginal Text
nal Tex
plication 
sed usi
d us
EF.
EF.
ale: 
e: Clari
Cla
lic
p
tudy
t
app
and 
ght. Co
t. Co
5 years a
years a
n the QO
the Q
ng
ng
any 
tion,
tion
(blood pr
blood p
spiratory
pirato
gniti
exten
008 0.2 
8 0.2 
o AEs,
AEs, 
ensions 
90% red
% re
(93%) w
(93%) 
frequ
freq
ioio
ns
en
or 
time
im
years). T
ears).
duc
d
variations 
d to be 
o be 
ecent asse
nt asse
d by the i
d by the 
treatment
eatment
ng succes
succes
2016
016). O
). O
were rep
were rep
e of
of
thereof. 
gium 
giu
date, thes
ate, the
s (infants
(infants
o adults),
adults),
amine for
amine for
ty of thi
y of th
ov

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 171 of 175
Section 4.4 
Male subjects who are sexually active with a partner of 
child-bearing potential must use, with their partner, a 
condom plus an approved method of highly effective 
contraception from the time of informed consent until 
90 days after study discharge. 
Female subjects who are sexually active and are of 
child-bearing potential must use, with their partner, an 
approved method of highly effective contraception 
from the time of informed consent until 30 days 
following the last follow up visit. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation: 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation 
Section 4.4 
Male subjects who are sexually active with a partner 
of childbearing potential must use, with their partner, 
a condom plus an approved method of highly 
effective contraception from the time of informed 
consent until 90 days after the last dose of study 
drug after study discharge. 
Female subjects who are sexually active and are of 
childbearing potential must use, with their partner, an 
approved method of highly effective contraception 
from the time of informed consent until 30 days 
following the last follow up visit 90 days after the 
last dose of study drug. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation and a barrier method (i.e., condom for 
male partner): 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation and a barrier method 
(i.e., condom for male partner): 
Rationale:  Removal of social media policy.
Original Text
Amendment Text
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can influence 
the expectations of potential new study subjects and 
investigators. Throughout their participation in this trial, 
subjects, their parent/caregivers and immediate family 
members, including grandparents, can acknowledge 
participation in the study on social media; however, they 
will be required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it can 
negatively affect the sponsor’s ability to interpret study 
results and possibly to use the study for registration. 
Individuals with serious and/or repeated violations of this 
policy may be required to exit the study at the discretion of 
the sponsor in consultation with the principal investigator, 
without the possibility of entering the separate open-label 
extension study. 
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can 
influence the expectations of potential new study 
subjects and investigators. Throughout their 
participation in this trial, subjects, their 
parent/caregivers and immediate family members, 
including grandparents, can acknowledge participation 
in the study on social media; however, they will be 
required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it 
can negatively affect the sponsor’s ability to interpret 
study results and possibly to use the study for 
registration. Individuals with serious and/or repeated 
violations of this policy may be required to exit the 
study at the discretion of the sponsor in consultation 
with the principal investigator, without the possibility 
of entering the separate open-label extension study. 
Rationale:  Revised the prohibited concomitant medication and foods list, including Appendix 1.
Original Text
Amendment Text
Section 5.7.4 
Drugs/foods that potentially interact with ZX008 via the 
CYP2D6, CYP3A4, and/or CYP2B6 pathways: A list of 
medications/foods that are to be avoided as ongoing 
medications or for chronic use if initiated during the study 
Section 5.7.4 
Drugs/foods that potentially interact with ZX008 via 
the CYP2D6, CYP3A4, and/or CYP2B6 pathways: A 
list of medications/foods that are to be avoided as 
ongoing medications or for chronic use if initiated 
PUBLIC
ubject’s im
bject’s i
ts) violate
s) violate
n Section
n Section
LIC 
icy.
icy.
C
LIC COPY
o
m
PY
C
This document
ely a
ly 
ts and po
and po
ndividuals
vidual
policy m
olicy m
the sp
the sp
wi
wi
cu
cannot
careg
reg
g grandp
randpa
he study 
e study 
ed not to 
d not to
placebo)
lacebo)
affect
ffec
be 
l new 
new 
their par
their pa
vers
ver
used 
4.9.9.
rticipation
cipatio
edicatio
dicatio
stud
stud
to
med
he Soci
e Soc
sup
diate
diate
upport 
with i
with
(i.e., co
(i.e.
o
po
A
pp
pp
up
any 
and 
and
partner)
artner
gestogen
estog
nhib
h
marketing 
ally y
use, with
se, wit
hly effectiv
ly effectiv
rmed consen
ed con
follow up v
llow up
ke
dy drug
y drug.
strogen and
rogen a
ontracepti
ntracep
a ba
authorization 
6
i
artner 
ner 
r partner, 
partner,
ghly 
ly 
f informe
f inform
dose of st
se of s
active
activ
titi
ati
application 
dose, ef
se, e
he sponsor’
he sponso
ibly to use 
bly to us
with serious
th seriou
y be requir
y be requ
nsor in con
or in c
hout the pos
ut the p
ension stu
nsion s
and
an
ents, can
s, ca
n social m
ocial m
ulge sus
lge su
ffi
ffi
any 
ubjec
ubje
ipation in
pation i
immedi
imme
n ack
extensio
and the 
d the 
an influ
n infl
ts
sions
Section
Section
on
The
The
o
faf
s 
Amend
men
s
sio
or 
ndom
do
or
m
o variations 
d progesto
rogesto
on associ
on assoc
arrier me
rrier m
-only hor
nly hor
ition of o
ion of o
m fo
fo
thereof. 
and are of
d are o
heir partn
eir partn
e contrac
contrac
nt until 30
nt until 30
e
it 90 da
90 da
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 172 of 175
from the time of signing the informed consent form (ICF) 
until the end-of-study visit (or early termination) is 
provided in Appendix 1. If medical necessity requires 
short-term use of one or more of these medications during 
the course of the study, please contact the Medical Monitor 
for approval. 
Appendix 1: replaced, edits not shown herein. 
during the study from the time of signing the informed 
consent form (ICF) until the end-of-study visit (or 
early termination) is provided in Appendix 1. If 
medical necessity requires short-term use of one or 
more of these medications during the course of the 
study, please contact the Medical Monitor for 
approval. 
Appendix 1: replaced, edits not shown herein. 
Rationale:  Clarify the window for assessments (Table 6).
Original Text
Amendment Text
Section 6, Table 6 
Visit 3 (Clinic; Study Day ± 4 daysa
Section 6, Table 6 
Visit 3 (Clinic; Study Day -
± + 4 daysa
Rationale:  Clarify the timing of procedures during the baseline period and screening period.
Original Text
Amendment Text
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 and 
Study Day -41 as well as the observation period where 
subjects will be assessed for baseline seizure activity based 
on recordings of daily seizure activity entered into a diary. 
With the exception of the Doppler ECHO, which may be 
completed any time during the Baseline Period up to Study 
Day -21, all screening assessments will be completed on 
Study Day -42 and Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study Day -42 
and Study Day -41 for all subjects before the start of 
seizure activity observation: 
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 
and Study Day -41 as well as the observation period 
where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity 
entered into a diary. With the exception of the Doppler 
ECHO, which may be completed any time during the 
Baseline Period up to Study Day -21, all screening 
assessments will be completed on Study Day -42 and 
Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study 
Day -42 and Study Day -41 for all subjects before the 
start of seizure activity observation:
The Screening visit will occur on Study Day -42; 
however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study 
Day -42 or Study Day -42 and Study Day -41). 
Splitting the visit procedures across 2 
nonsequential days requires the approval of the 
medical monitor. The following procedures will be 
performed for all subjects before the start of 
seizure activity observation: 
Rationale:  Added text clarifying procedures for rescreening.
Original Text
Amendment Text
Section 6.1.1 
None. 
Section 6.1.1 
In certain circumstances the sponsor may allow 
subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the 
screening period extended, or to be re-screened for 
eligibility. In all cases the investigator should consult 
with the Medical Monitor. Decisions whether to permit 
rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or 
rescreening can be influenced by many factors 
PUBLIC
d i
, which 
, which
e Period u
e Period u
will be com
will be co
1.
be perfor
be perfo
cur bet
cur b
t
COPY 
and 
nd 
here
ere
tivity base
ivity bas
nto a d
nto a d
Th
sc
s
PY
This documen
Rationale
ational
ent 
en
Origin
Origin
me
u
Sect
Sec
cu
N
um
cu
cannot be used
e
een Stu
n Stu
before the
ore the
to 
d during
d durin
dy
d
support 
ry. 
y. 
y be 
be
to Study 
o Study
leted on
eted on
and 
nd
t
where 
where
activi
acti
en
ppo
any y
eline P
eline 
ening activ
ning acti
Study D
Study
a
marketing 
ot sh
sh
g
ng
tudy Day -
dy Day
ke
rk tin
and screeni
d screen
rk
nt Text
Text
a
m
authorization 
6
i
med
med
(or r 
. If 
If 
of one or
f one or
ourse of t
ourse of 
onitor for
itor fo
own h
own 
titi
ati
appl
n 6.1.1
6.1.1
pp
ne.e.
plication 
Added te
Added 
at
l Text
Text
ic
pli
and any extensions
the
Day -42 
ay -42 
tart of 
rt of 
tere
ECHO, 
CHO
s 
Baseli
Basel
on
ass
as
o
sio
or
j
y based
y base
d into
d int
variations
±
s
ng perio
g peri
s
ns
iod of th
iod of th
vities that
ies tha
Day -41 a
ay -41 a
a
ects wi
ects wi
d
on thereof. 
erein.
in.
o
re
± + 4 d
4 d
th
ther
t

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 173 of 175
individual to that subject case. Some general principles 
apply: 
1.
If baseline seizure screening is extended or the 
subject is discontinued and then rescreened, the 
screening period for establishing the baseline 
seizure frequency will be the immediate 6 weeks 
before the randomization visit. 
2.
Subjects who are found to be on a prohibited 
medication at the screening visit may be weaned 
off of that medication provided: 
a.
Decisions to withdraw a disallowed 
concomitant medication must be made with 
the agreement of the prescribing physician 
b.
If the medication has antiepileptic properties, 
a wash out of at least 5 half-lives must be 
completed before collection of baseline 
seizure data.  
c.
If a decision has been made to wean off of a 
medication without antiepileptic properties 
and the wash-out period (at least 5 half-lives) 
is expected to be shorter than 5 weeks, then 
the subject may remain in screening and chart 
seizures using the seizure diary. 
Rationale:  Clarify timing of dosing on Day -1 and Day 1.
Original Text
Amendment Text
Section 6.1.3 
x
Dispense study medication 
Section 6.2.1 
Subjects will begin dosing with IMP in the morning of 
Titration Period Study Day 1. 
Section 6.1.3 
Dispense study medication (If administration of the 
first dose of study medication occurs in the clinic, the 
next dose should be at least 8 hours later or the 
following morning. The dose on the following 
morning will count as Study Day 1.) 
Section 6.2.1 
Subjects will take their first dose of study medication 
on the morning of Study Day 1. Study Day 1 is 
considered the first day of dosing, even for those 
subjects that received an in-clinic dose on Study Day -
1. Subjects will begin dosing with IMP in the morning 
of Titration Period Study Day 1. 
Rationale:  Revised estimated blood volume collection in Table 8 and text describing volumes for collection.
Original Text
Amendment Text
Section 6.5 
The original Table 8 was replaced; edits to this table 
are not shown herein. 
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and 
PK will be approximately 108.7 mL, as outlined in 
Table 8. 
Section 6.5 
The original Table 8 was replaced; edits not shown 
herein. A new table, Table 9, showing the priorities for 
blood collection was added.  
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and 
PK will be approximately 108.7 99.7 mL, as outlined 
in Table 8. 
*In concordance with The Seattle Children’s 
PUBLIC 
sing on D
ing on D
BL
UB
tio
tio
PU
COPY 
PY
This docum
Sect
Sec
ment 
ationale
onale
en
Origin
Origin
me
cu
T
m
cu
cannot be 
h
1.
be used 
IMP in 
MP in 
u
to 
ay -1
o
to support 
ppo
and D
and
su
any 
compl
com
seizur
seizu
c.c.
If a
If
marketing 
o be 
be
ening visit
ing visi
on provided
n provided
withdraw a
ithdraw
ant medicat
nt medic
reement of t
ement o
he medicati
medica
ash out o
ash ou
ete
authorization 
6
i
iples
les
d or the
r the
reened, th
ened, th
he baselin
he baselin
mmediate 
ediate
it.
on a p
on a 
titi
ati
appli
n 6.5.5
plication 
Revised e
Revised
at
l Text
Text
ica
pp
e original T
original T
not show
not sho
pli
and any y extensio
A
sions 
o
Day 1.
ay 1.
on
sio
sio
mornin
mornin
e
ns
or 
and 
an
is e
is e
t
variations
i
the pres
pre
on has an
n has an
of at least
f at least
ed before 
before
e data. 
data.  
decision
ecision
medicatio
edicatio
the
h
thereof. 
rohibited 
hibited 
may be w
ay be w
d:
a disallow
a disallo
on must
n must
cr

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 174 of 175
Research Foundation Guidance (Appendix 9), blood 
collection volumes for children weighing up to 15 kg 
will be: 
x
the maximum allowable volume of blood in 
one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 
mL. 
On Day 43/Visit 8 the pharmacokinetic blood draw 
will be completed as the priority and the blood draw 
for chemistry and hematology will be skipped for 
those subjects who weigh less than 13.5 kg, unless 
medical concerns (for example, from previous tests 
or reported side effects) prioritize chemistry and/or 
hematology. 
If blood collection is restricted due to volume or due 
to inability to draw adequate volume, collection 
should be prioritized as shown in Table 9:
Rationale:  Clarification of SE as an AE or SAE.
Original Text
Amendment Text
Section 7.1.1 
Seizures that evolve into SE will be captured by type 
and duration (>10 min) as are all seizures. The 
diagnosis of SE should be entered as an AE or SAE if 
a prolonged seizure or series of seizures persists for 30 
minutes or longer, regardless of administration of 
rescue medication. If this incident involves multiple 
seizures close in time, the SE definition applies if the 
seizures are close together such that consciousness is 
not regained between ictal events 
Section 7.1.1 
Seizures that evolve into SE will be captured by type 
and duration (>10 minutes) as are all seizures. The 
diagnosis of SE made by a medical professional should 
be entered as an SAE if a prolonged seizure or series 
of seizures persists for 30 minutes or longer, regardless 
of administration of rescue medication. SE lasting for 
less than 30 minutes should be entered as an AE, 
unless one of the other SAE criteria (e.g. 
hospitalization) are met. If this incident involves 
multiple seizures close in time, the SE definition 
applies if the seizures are close together such that 
consciousness is not regained between ictal events. 
Rationale:  Clarify SAE reporting.
Original Text
Amendment Text
Section 8.6 
For SAEs occurring during the study, the investigator 
or delegate will enter all relevant information in the 
AE page of the eCRF. An electronic document 
containing the AE page and other applicable pages of 
the eCRF must be sent (via facsimile or email) to the 
sponsor together with a Notification of Serious 
Adverse Event at Investigator Site cover page, 
which has been signed and dated by the investigator. If 
an electronic document is not able to be generated (eg, 
internet access problem), a handwritten paper SAE 
report must be completed, which must be signed and 
dated by the investigator. 
Section 8.6 
For SAEs occurring during the study, the 
investigator or delegate will enter all relevant 
information in the AE page of the eCRF. An 
electronic document containing the AE page and 
other applicable pages of the eCRF must be sent 
(via facsimile or email) to the sponsor together 
with a Notification of Serious Adverse Event at 
Investigator Site cover page, which has been 
signed and dated by the investigator. If an 
electronic document is not able to be generated 
(eg, internet access problem), a handwritten paper 
SAE report must be completed, which must be 
PUBL
l be captu
be captu
all seizu
all seizu
red a
red
BLIC
AE or S
AE or 
C
LIC
BL
COPY
or
o
hem
he
I
PY
C
This document
ction 8.6
ion 8.6
e
For SAE
or SAE
or del
or de
AE
AE
t
alele
inal Te
nal Te
t
nt
cu
cannot
her
her
n ictal e
ictal e
:  Clar
Clar
ca
c
be
iden
SE defin
SE defi
such 
such
used
s. T
s. T
an AE o
n AE o
zures per
ures per
administ
dminis
t invo
t inv
to
ed by ty
d by ty
The
he
su
pe
support 
blo
b
to inabi
inab
should 
shoul
po
E.
po
pp
pp
su
any 
d sid
si
ogy. 
ogy. 
od colle
od col
lity
marketing 
30-da
-da
pharmacok
harmac
the priori
the pri
d hematolo
hemato
who weigh
ho weig
erns (for 
rns (fo
e effe
e e
authorization 
6
i
ood 
od 
15 kg 
5 kg 
me of blo
e of blo
% of tota
of tot
y pe
y pe
titi
ati
applicati
occurring d
occurring
gate will en
te will 
page of the 
ge of th
ntaining th
aining 
CRF 
CR
ation 
fy SAE re
fy SAE r
n
io
ati
and 
nts 
any
es m
s m
n applies
n appli
consciou
consciou
extensio
AE if 
AE if 
sts for 30
s for 30
ion of 
on of 
sions
Amend
Amend
s
multi
ulti
Secti
Secti
o
Se
Se
ns
sio
or 
e prio
e pr
o variations
gy wi
y w
less than
ess tha
example,
example,
ects) pr
ts) prioio
ction is r
ion is r
to draw
o draw
ori
thereof. 
iod is 44-
d is 44-
kinetic bl
netic bl
y and th
y and th
ill b
ll b

Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 175 of 175
All SAEs that occur during the course of the study, 
whether or not causally related to IMP must be 
reported immediately via telephone and either 
facsimile or email (within 24 hours of the investigator 
becoming aware of the event) to the sponsor and the 
Medical Monitor. 
signed and dated by the investigator. 
In the event of a SAE the investigator or delegate 
must:  
1.
Enter all relevant information in the AE 
page of the eCRF. 
2.
Inform the Medical Monitor or the Sponsor 
of the SAE via email or telephone within 
24 hours of becoming aware of the SAE. 
3.
Follow the initial notification with a 
completed SAE report form. The SAE form 
must be emailed or faxed to iHC within 
24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, 
beginning the day Informed Consent is signed, 
whether or not causally related to IMP must be 
reported immediately via telephone or email (within 
24 hours of the investigator becoming aware of the 
event) to the sponsor or the Medical Monitor. Any 
SAE that occurs 15 days after the last dose of study 
drug or the last visit, whichever is later that is 
considered to be causally related to IMP must be 
reported immediately (i.e., within 24 hours of the 
investigator becoming aware of the event) to the 
sponsor and the Medical Monitor. 
Rationale:  To evaluate a correlation between study drug and SAE. 
Original Text 
Amendment Text 
Section 8.9 
None. 
Section 8.9  In the event of a SAE a blood sample 
for ZX008 and AED PK should be collected as soon 
as feasible.
PUBLIC COPY
A
begi
be
wh
PY
This document cannot 
ot be used 
tion betw
n betw
ed
s
u
to support
eporte
ort
24 hours
24 hour
event) 
even
SAE
S
d
ppo
any
hat o
at 
g the day
g the d
er or not c
er or not c
ed imm
d im
marketing 
on
il or tel
or te
ming awar
ming awar
nitial notifi
ial not
d SAE repo
SAE re
e emailed o
emaile
hours of bec
urs of b
ccur d
ccu
authorization 
6
i
te
in the AE
n the A
nitor or 
tor or 
ep
titi
ati
application and 
d any 
a
extensions
E tha
drug or th
ug or th
conside
conside
repo
repo
inin
sio
en study d
study d
te
ex
e
or
f th
f t
o the sp
the s
t occ
t occ
variations 
ort
r faxed
faxe
coming aw
ming aw
during
uring the
th
Informed
Informed
causally r
ausally r
mediately 
diately
he inv
he in
thereof.
he Spons
Spons
one withi
ne withi
e of the S
of the 
cation wi
cation w
form. T
form. T
d t