Clinical trial NCT02823145
Conditions: Dravet Syndrome
Keywords: seizure tonic clonic epilepsy myoclonic encephalopathy
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Start date: 2016-06-08; Completion date: 2023-01-27
Enrollment: 375 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an international, multicenter, open-label, long-term safety study of ZX008 in subjects with Dravet syndrome.

Detailed description:
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with Dravet syndrome who participated in one of the core studies (ZX008-1501 and ZX008-1502) and are candidates for continuous treatment for an extended period of time. This trial will consist of a 36-month Open-Label Extension (OLE) Treatment Period and a 2-week Post-Dosing Period.

Arms: arm 1: ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated to an effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day).
Interventions: intervention 1: ZX008 (Fenfluramine Hydrochloride)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
This protocol includes information and data that contain trade secrets and privileged or confidential information, which is the property of the 
Sponsor. This information must not be made public without written permission from the Sponsor. These restrictions on disclosure will apply 
equally to all future information supplied to you. This material may be disclosed to and used by your personnel and associates as may be 
necessary to conduct the clinical study. 
Confidential
Clinical Study Protocol
Study Title:
An Open-Label Extension Trial to Assess the Long-Term Safety of 
ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome 
Study Number:
ZX008-1503 
Study Product:
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number:
125797 
EudraCT:
2016-002804-14 
Sponsor:
Zogenix International Limited
A wholly owned subsidiary of Zogenix, Inc.  
5959 Horton Street, 
 
Emeryville, CA 94608 USA 
Sponsor's Medical 
Contact 
Zogenix, Inc.
Date/Version of 
Study Protocol: 
03 August 2020 (amendment 5.0: ROW)
02 February 2018 (amendment 4.0: ROW) 
05 May 2017 (amendment 3.0: ROW) 
01 November 2016 (amendment 2.0: ROW) 
13 September 2016 (amendment 1.2.1: ROW) 
31 May 2016 (amendment 1.2: ROW) 
07 March 2016 (original)
PUBLIC
x, Inc
UBL
x, Inc.
B
.
ugus
P
ugus
LIC 
BLIC
Y
te
Y
te
ary of 
PY 
ary of 
CO
4608 US
CO
4608 US
OPY
C
This document cannot 
01 
ot
01 
13
o
13
be
 May 
be 
 May 
No
b
No
used
2020 (
ed 
2020 (
ruary
use
ruary 2
se
2
20
u
20
to 
t
support 
A
o
A
su
any
genix, I
any 
genix, I
marketing authorization 
ctive
iza
ctive
application 
31 M
n
31 M
07
o
07
and 
vem
d
vem
Septem
and
Septem
Ma
a
Ma
any 
7 (am
ny 
7 (am
mber 2
an
mber 2
extensions 
mendme
ten
mendme
18 (ame
ext
18 (ame
e
or variations 
nc. 
ria
nc. 
thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 2 of 194  
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 
lied to 
zati
lied to 
or 
r
or or 
riz
or the
za
the
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 3 of 194  
TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................ 3
LIST OF TABLES................................................................................................. 10
SIGNATURE OF SPONSOR ...............................................................................11
SIGNATURES OF CO-COORDINATING INVESTIGATORS .....................12
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S)..................................15
LIST OF ABBREVIATIONS ...............................................................................16
STUDY SYNOPSIS ...............................................................................................18
1.
INTRODUCTION ............................................................................30
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED ............... 30
1.1.1
Existing Treatment for Dravet Syndrome ........................................................ 31
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT ........................ 33
1.3
CLINICAL DATA .............................................................................................. 33
1.4
PRECLINICAL DATA ...................................................................................... 35
1.5
PHARMACOKINETICS ................................................................................... 36
1.6
CLINICAL PHARMACOLOGY ...................................................................... 37
1.7
BACKGROUND INFORMATION ON REFERENCE PRODUCT ............. 38
1.8
RATIONALE FOR CURRENT STUDY .......................................................... 38
1.9
RATIONALE FOR INCLUDING DE NOVO SUBJECTS ............................ 38
1.10
RISK-BENEFIT ASSESSMENT ...................................................................... 39
2.
STUDY OBJECTIVES AND ENDPOINTS ..................................41
2.1
PRIMARY OBJECTIVE ................................................................................... 41
2.2
SECONDARY OBJECTIVES ........................................................................... 41
2.3
EXPLORATORY OBJECTIVES ..................................................................... 42
2.4
STUDY ENDPOINTS ......................................................................................... 42
PUBLIC 
OR
C
OR
nt for Dr
BLIC
nt for Dr
ND INF
UBL
ND INF
DATA
PU
DATA
COPY 
.......
Y
.......
.........
CO
.........
MAT
C
MAT
This document 
2.
c
2.
2.1
doc
2.1
cannot 
CA
t
CA
CKGR
not
CKGR
RATIO
an
RATIO
RA
c
RA
be 
COK
e
COK
AL PH
be
AL PH
used 
.......
d
.......
L DAT
se
L DAT
KIN
u
KIN
to 
ORM
o
ORM
to support 
.......
rt
.......
ION ON
po
ION ON
avet Syn
supp
avet Syn
MATI
s
MATI
any 
.......
ny
.......
..
marketing 
RS
g
RS .
g
.
..........
ket
..........
..........
ma
..........
authorization 
....
ti
.... 3
tio
 3
.........
riz
......... 1
a
1
.........
uth
.........
application 
NA
n
NA
TIONAL
tion
TIONAL
RISK
cat
RISK-B
t
B
ST
pl
ST
and
OUND 
nd 
OUND 
ALE 
an
ALE 
any 
TIC
y
TIC
ARMAC
any
ARMAC
N
extensions
ndrome
ns 
ndrome
ION O
sion
ION O
............
ens
............
A
e
A ..........
exte
..........
CS
e
CS
e
or
INDI
or 
INDI
variations 
........
ns
........
........
at
........
........
va
.......
thereof. 
........
eo
........
........
he
........


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 4 of 194  
2.4.1
Effectiveness Endpoints ...................................................................................... 42
2.4.2
Safety Endpoints ................................................................................................. 42
2.4.3
Exploratory Endpoints ....................................................................................... 43
3.
INVESTIGATIONAL PLAN..........................................................44
3.1
OVERALL STUDY DESIGN AND PLAN ...................................................... 44
3.2
NUMBER OF SUBJECTS ................................................................................. 46
3.3
STUDY DURATION .......................................................................................... 46
3.4
NUMBER OF STUDY CENTERS .................................................................... 46
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS ................................................................................... 46
3.6
PREMATURE TERMINATION OF STUDY ................................................. 46
3.7
STUDY MONITORING PROCEDURES ........................................................ 47
3.7.1
Independent Data and Safety Monitoring Committee (IDSMC) ................... 47
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) ............................ 48
4.
SELECTION OF STUDY POPULATION....................................49
4.1
INCLUSION CRITERIA ................................................................................... 49
4.2
EXCLUSION CRITERIA .................................................................................. 50
4.3
SUBJECTS OF REPRODUCTIVE POTENTIAL .......................................... 52
4.3.1
Sperm and Egg Donation ................................................................................... 53
4.3.2
Pregnancy ............................................................................................................ 53
4.4
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .......... 53
4.5
TERMINATION OF THE CLINICAL STUDY ............................................. 56
4.6
REPLACEMENT OF SUBJECTS .................................................................... 56
5.
INVESTIGATIONAL MEDICINAL PRODUCT 
INFORMATION...............................................................................57
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT ............... 57
5.1.1
Labeling and Packaging ..................................................................................... 57
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO .......................................................................................... 58
PUBLIC
tric Car
LIC 
tric Car
N OF S
UBL
N OF S
P
N CRI
PU
N CRI
COPY 
N OF 
PY 
N OF 
ROCED
OP
ROCED
afety M
CO
afety M
This document 
5.
c
5.
5
d
5
nnot 
and
t
and
egnancy
no
egnancy
ca
REMO
an
REMO
TE
c
TE
be 
S OF
e
S OF
d Eg
be
d Eg
used 
TERI
d
TERI
CRITE
se
CRITE
R
u
R
to 
TUD
to
TUD
IA
t
IA
support 
UR
t
UR
Monitorin
port
Monitorin
diac Adv
upp
diac Adv
DY 
s
DY
any 
UDY
ny
UDY .
y 
 .
ES
an
ES....
an
....
marketing 
..
..............
ing
..............
..............
ket
..............
HOICE O
ark
HOICE O
.............
ma
............
authorization 
42
o
42
...... 43
atio
...... 43
........
or
........
...........
uth
...........
.........
au
.........
application 
VA
n
VA
RMINAT
tion
RMINAT
REPLA
cat
REPLA
IN
pl
IN
and
g
d
g
............
nd 
............
a
AL O
a
AL O
any 
PRO
y
PRO
Donatio
any
Donatio
nsions 
visory
s 
visory
POPU
sion
POPU
exten
...........
ens
...........
RIA
ext
RIA ......
exte
 ......
OD
e
OD
or
g Co
or 
g Co
y B
o
y B
variations 
OF 
ns
OF 
............
ons
............
...........
iati
...........
............
ari
............
om
v
om
thereof.
...........
of. 
...........
............
reo
............
............
the
............


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 5 of 194  
5.3
IMP ACCOUNTABILITY ................................................................................. 58
5.4
TREATMENT ADMINISTRATION ............................................................... 58
5.4.1
OLE Treatment Period ....................................................................................... 58
5.4.2
Taper Period ........................................................................................................ 60
5.4.2.1
Taper Period for Subjects not Receiving Concomitant STP .............................. 60
5.4.2.2
Taper Period for Subjects from Core Study ZX008-1504 Cohort 1 
Regimen 3 and Cohort 2 Receiving Concomitant STP ...................................... 60
5.5
BLINDING .......................................................................................................... 61
5.6
PRIOR AND CONCOMITANT MEDICATION ............................................ 61
5.6.1
Vagal Nerve Stimulation .................................................................................... 62
5.6.2
Ketogenic Diet ..................................................................................................... 62
5.6.3
Rescue Medication for Seizures ......................................................................... 62
5.6.4
Prohibited Concomitant Medication and Food ................................................ 62
5.7
TREATMENT COMPLIANCE ........................................................................ 63
6.
VISIT SCHEDULE ..........................................................................64
6.1
OLE TREATMENT PERIOD ........................................................................... 64
6.1.1
Screening Visit for de novo Subjects ................................................................. 65
6.1.2
Clinic Visit 1 (Study Day 1; Transition from Core Study) .............................. 66
6.1.2.1
Clinic Visit 1 for Subjects from Core Studies ZX008-1501 or ZX008-
1502 ....................................................................................................................... 66
6.1.2.2
Clinic Visit 1 for Subjects from Core Study ZX008-1504 ................................... 68
6.1.3
Clinic/Phone Visit 2 (Study Day 15) .................................................................. 69
6.1.4
Clinic Visits 3-15 (Months, 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33) ............. 70
6.1.5
Clinic Visit 16 (Month 36): End of Study/Early Termination ........................ 71
6.2
POST-DOSE VISIT (CLINIC VISIT 17; STUDY DAY 1099) ...................... 72
6.3
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 18, 19; 3 AND 6 
MONTHS) AFTER LAST DOSE OF IMP ...................................................... 73
6.4
ESTIMATED BLOOD VOLUME COLLECTION ........................................ 74
6.5
STUDY CONDUCT DURING COVD-19 ........................................................ 74
UBLIC 
PLIA
C
PLIA
DULE
BL
DULE
PU
TMENT
PU
TMENT
it
P
it
COPY 
...
Y
...
es
OP
es........
OPY
........
Medicat
CO
Medicat
AN
C
AN
This document 
C
.2
c
.2
6.3
doc
6.3
annot 
........
ot
........
linic Vis
nno
linic Vis
can
Clinic
can
Clinic
C
c
C
be 
1 (
it 1 for
be
it 1 for
b
used 
P
d
P
for de n
sed
for de n
(Study
us
Study
to 
.
PERIO
to
PERIO
support 
on and
ort 
on and
CE
p
CE..........
ppo
..........
s
.......
s
.......
any 
....
y
....
............
any
............
d F
d F
marketing 
.......
g
.......
.............
ting
.............
..............
ke
..............
..............
mar
..............
........
m
........
authorization 
58
o
58
...... 58
atio
...... 58
............
riza
............
............
tho
............
rt 1 
au
rt 1 
.....
a
.....
application 
/Phon
on 
/Phon
inic Visi
tio
inic Visi
Clinic V
lica
Clinic V
PO
pl
PO
and 
....
d
....
it 1 for S
and
t 1 for S
ne
a
ne
any 
a
y
a
Subjects
any
Subjects
.........
an
.........
ons 
.
extensio
........
ion
........
D
n
D........
nsi
........
ovo Sub
xte
ovo Sub
ay 1;
ex
ay 1;
or 
........
or
........
variations
............
ons 
............
............
tio
............
...........
aria
...........
ood ....
va
ood ....
thereof. 
.............
eof.
.............
............
ere
............
..........
the
..........


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 6 of 194  
7.
EFFECTIVENESS, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS................................................................................75
7.1
EFFECTIVENESS ASSESSMENTS ................................................................ 75
7.1.1
Seizure Assessments ............................................................................................ 75
7.1.2
Clinical Global Impression - Improvement ...................................................... 76
7.1.3
Quality of Life in Childhood Epilepsy Scale ..................................................... 76
7.1.4
Pediatric Quality of Life Inventory (PedsQL) .................................................. 77
7.1.5
Parent/Caregiver Quality of Life ....................................................................... 77
7.1.6
Study Medication Palatability Assessment ....................................................... 77
7.2
EXPLORATORY ASSESSMENTS .................................................................. 78
7.2.1
Sleep Quality and Meal Time Behavior Questions .......................................... 78
7.2.2
Karolinska Sleepiness Scale ............................................................................... 79
7.2.3
Healthcare Utilization Questions ....................................................................... 79
7.3
SAFETY ASSESSMENTS ................................................................................. 79
7.3.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-
Study Medication ................................................................................................ 79
7.3.2
Physical Examinations ........................................................................................ 79
7.3.3
Neurological Examinations ................................................................................ 80
7.3.4
Vital Signs ............................................................................................................ 80
7.3.5
Laboratory Measurements ................................................................................. 80
7.3.6
Plasma Sample for Concomitant Antiepileptic Drug(s) .................................. 81
7.3.7
Electrocardiograms ............................................................................................. 81
7.3.8
Doppler Echocardiography ................................................................................ 81
7.3.9
Tanner Staging .................................................................................................... 82
7.3.10
Columbia-Suicide Severity Rating Scale .......................................................... 82
7.3.11
Adverse Events .................................................................................................... 82
7.3.12
Behavior Rating Inventory of Executive Function (BRIEF) .......................... 83
7.4
APPROPRIATENESS OF MEASUREMENTS .............................................. 83
8.
ADVERSE EVENTS ........................................................................84
PUBLIC 
ENTS
IC 
ENTS
Medical/
BLI
Medical/
tion
PUB
tion .....
UB
.....
amina
PU
amina
COPY 
ehavi
Y
ehavi
............
OPY
............
uestion
CO
uestion
C
This document 
3.10
cum
3.10
7.3.1
doc
7.3.1
7
d
7
cannot 
atory
ot
atory
asma Sa
nno
asma Sa
Electr
can
Electr
Do
c
Do
be 
b
.......
be
.......
y M
b
y M
used
tions ..
ed 
tions ..
Examina
use
Examina
u
to 
.........
to 
.........
t
support
.............
ort 
............
.............
pp
.............
eurolog
sup
eurolog
.....
s
any 
uestio
ny 
uestio
..........
an
..........
marketing 
.........
g 
.........
...............
eting
...............
..............
rke
..............
..............
ma
..............
on
m
on
authorization 
5
o
5
..... 75
atio
..... 75
............
riza
............
...........
tho
...........
............
aut
............
a
application 
ocard
n
ocard
ppler Ec
tion
ppler Ec
Tanner
icat
Tanner
Col
pli
Col
and 
ea
d
ea
mple fo
and
mple fo
diog
a
diog
any 
........
ny 
........
surem
an
surem
extensions 
.....
s
.....
gical/Ep
ions
gical/Ep
...........
sio
...........
.............
ten
.............
tions ...
ext
tions ...
e
or 
...
r
...
.......
o
.......
variations 
.....
s
.....
............
ons
............
ns
ia
ns .........
atio
.........
............
aria
............
.......
va
.......
thereof. 
.....
f
.....
............
eof
............
............
here
............
........
th
........


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 7 of 194  
8.1
DEFINITIONS .................................................................................................... 84
8.1.1
Adverse Events .................................................................................................... 84
8.1.2
Serious Adverse Events ...................................................................................... 85
8.1.3
Adverse Events of Special Interest .................................................................... 86
8.1.4
Adverse Events Requiring Hospitalization ....................................................... 87
8.2
SEVERITY OF ADVERSE EVENTS .............................................................. 87
8.3
CAUSALITY OF ADVERSE EVENTS ........................................................... 88
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING ........... 88
8.5
ADVERSE EVENT REPORTING ................................................................... 89
8.5.1
Adverse Events .................................................................................................... 89
8.6
SERIOUS ADVERSE EVENTS REPORTING ............................................... 89
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events ............. 90
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY 
INVESTIGATOR TO IEC/IRB ........................................................................ 91
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR ............................................. 91
8.9
FOLLOW-UP OF ADVERSE EVENTS .......................................................... 91
8.9.1
Follow-up of Echocardiogram Findings ........................................................... 92
8.10
PREGNANCY ..................................................................................................... 94
9.
DATA HANDLING PROCEDURES .............................................95
9.1
RECORDING OF DATA ................................................................................... 95
9.2
DATA QUALITY ASSURANCE ...................................................................... 95
9.3
RECORD RETENTION .................................................................................... 96
10.
STATISTICS.....................................................................................97
10.1
DETERMINATION OF SAMPLE SIZE ......................................................... 97
10.2
ANALYSIS POPULATIONS ............................................................................ 97
10.2.1
Safety (SAF) Population ..................................................................................... 97
10.2.2
Modified Intent-to-Treat (mITT) Population................................................... 97
10.2.3
Per Protocol (PP) Population ............................................................................. 97
BLIC 
O IEC
C
O IEC
EVEN
BLIC
EVEN
PUB
NVEST
UBL
NVEST
UP OF
PU
UP OF
COPY 
REP
Y
REP
e Repor
OPY
e Repor
OUS AD
CO
OUS AD
C/I
C
C/I
This document
R
t 
R
10.1
ocu
10.1
10
do
10
cannot 
A HA
ot
A HA
ECORD
nno
ECORD
DATA
can
DATA
R
c
R
be 
CY
e
CY
AN
b
AN
used 
ADV
d
ADV
chocard
sed
chocard
......
u
......
to 
GA
o
GA
VER
to
VER
support 
tin
t
tin
VERSE
ort
VERSE
RB
p
RB ..........
ppo
..........
TS OTHE
sup
TS OTHE
ATOR
s
ATOR
any 
TING
ny 
TING
g of Se
an
g of Se
marketing 
..........
ng 
..........
T REPO
etin
T REPO
..............
rke
..............
..............
ma
.............
G
m
G
m
authorization 
84
o
84
...... 85
atio
...... 85
............
riza
............
............
tho
............
...........
aut
...........
a
ion 
A QUA
on 
A QUA
applicati
ECORD 
tio
ECORD 
STA
plic
STA
D
p
D
and 
ND
d
ND
ING O
and
ING O
AL
a
AL
any 
....
y
....
LING
an
LING
ons 
.
ER TH
ns
ER TH
extensio
R TO S
sion
R TO S
SE EVE
ens
SE EVE
iogram 
exte
iogram 
.....
e
.....
or 
EV
r
EV
........
or
........
variations 
....
s
....
............
ons
............
............
atio
............
erious A
varia
erious A
VEN
v
VEN
thereof. 
.......
f
.......
...........
eof
...........
ORTING
her
ORTING
.......
th
.......


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 8 of 194  
10.3
TREATMENT GROUPS ................................................................................... 97
10.4
TREATMENT PERIODS .................................................................................. 97
10.5
STATISTICAL ANALYSES AND METHODS .............................................. 99
10.5.1
Safety Analyses .................................................................................................... 99
10.5.2
Effectiveness Analyses ........................................................................................ 99
10.5.2.1
Key Effectiveness Analysis ................................................................................... 99
10.5.2.2
Other Secondary Analyses ................................................................................. 100
10.6
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND 
SAFETY MONITORING COMMITTEE ..................................................... 101
11.
ETHICAL & REGULATORY CONSIDERATIONS................102
11.1
ETHICAL CONSIDERATIONS ..................................................................... 102
11.2
INFORMED CONSENT .................................................................................. 102
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT 
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD ................ 104
11.4
PROTOCOL COMPLIANCE ......................................................................... 104
12.
ADMINISTRATIVE ASPECTS ...................................................106
12.1
CLINICAL TRIAL AGREEMENT ................................................................ 106
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR .................................... 106
12.3
CLINICAL STUDY REGISTRATION AND RESULTS 
DISCLOSURE ................................................................................................... 106
12.4
STUDY FILES AND MATERIALS ................................................................ 106
12.5
INITIATION OF THE STUDY ....................................................................... 107
12.6
SUBJECT REIMBURSEMENT ..................................................................... 107
12.7
LIABILITY AND INSURANCE ..................................................................... 107
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY ...................... 108
12.9
MONITORING OF THE STUDY .................................................................. 108
12.10
PROTOCOL AMENDMENTS ....................................................................... 109
12.11
AUDITS AND INSPECTIONS ........................................................................ 110
12.12
CLINICAL STUDY REPORT ........................................................................ 110
UBLIC
EE/IN
C 
EE/IN
MPLIA
BLI
MPLIA
PU
TRAT
PU
TRAT
R
P
R
COPY 
S
PY
S.......
PY 
.......
...........
OP
...........
DERA
CO
DERA
NS
C
NS
This document 
12.8
cu
12.8
12.9
do
12.9
cannot
LOSU
ot 
LOSU
TUDY 
nno
TUDY 
INIT
ca
INIT
be 
L 
L 
AL ST
be
AL ST
UR
b
UR
used 
IV
d
IV
IAL AG
sed
IAL AG
DISC
us
DISC
to 
VE A
to
VE A
support 
....
t
....
TIONS A
port
TIONS A
TITUTI
ppo
TITUTI
NCE
su
NCE.....
up
.....
any 
.........
ny 
.........
.........
an
.........
marketing 
..........
ng 
..........
DATA A
etin
DATA A
..............
ke
..............
IDERA
ma
IDERA
authorization 
97
o
97
...... 99
atio
...... 99
.............
oriza
.............
............
tho
............
............
aut
...........
a
tion 
ATIO
on 
ATIO
applicati
UBJECT
atio
UBJECT
L
lic
LIABI
ica
IABI
SU
p
SU
and 
E
d
E...
d
...
ILES A
and
ILES A
N
a
N
any 
O
y
O
DY REG
any
DY REG
........
a
........
sions 
O
s
O
............
ons
............
exten
SPECT
nsi
SPECT
REEM
xte
REEM
SUR
ex
SUR
or 
ND
or
ND
NAL
or
NAL
variations 
ATION
ons
ATION
...........
iati
...........
............
ari
............
IN
v
IN
thereof. 
.......
f
.......
............
eof
............
AND 
her
AND 
..........
the
..........


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 9 of 194  
12.13
USE OF DATA AND PUBLICATIONS ......................................................... 111
13.
REFERENCE LIST........................................................................112
14.
APPENDICES.................................................................................117
14.1
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT 
MEDICATIONS ............................................................................................... 117
14.2
APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING 
SCALE ............................................................................................................... 118
14.3
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF 
EXECUTIVE FUNCTION – PRESCHOOL VERSION .............................. 124
14.4
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY 
SCALE ............................................................................................................... 134
14.5
APPENDIX 5 – TANNER STAGING ............................................................. 147
14.6
APPENDIX 6 – PEDSQL ................................................................................. 149
14.7
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE ............................................ 160
14.8
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE ...... 162
14.9
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW 
VOLUMES ........................................................................................................ 163
14.10
APPENDIX 10 – KAROLINSKA SLEEPINESS SCALE ............................ 165
14.11
APPENDIX 11 - STUDY CONDUCT DURING COVID-19 ........................ 166
SUMMARY OF PROTOCOL AMENDMENT 5.0 ............................................................... 170
LIC 
D-
C
D-5L
C
5L
PUBL
OSPIT
BLIC
OSPIT
–
U
– MAX
UB
MAX
...........
PU
...........
COPY 
...
Y
...
AGING
PY
AGING
............
CO
............
L Q
C
L Q
This document cannot 
T
t
T
be 
11
e
11
b
OCOL
be
OCOL
used 
.....
d
.....
–
s
– KAR
sed
KAR
1
u
1 -
u
- ST
us
ST
to 
MUM
to 
MUM
......
to
......
upport 
..........
ort 
..........
UESTIO
ppo
UESTIO
su
AL ANXI
sup
AL ANXI
M A
s
M A
any 
...
y
...
...........
any
...........
a
marketing 
ATI
g
ATI
............
ng 
............
RY OF
keti
RY OF
RSION
rke
RSION
e
ILDHOO
ma
ILDHOO
........
m
........
authorization 
112
tio
112
.......
riz
.......11
za
11
...........
uth
...........
ING 
au
ING 
application and any 
UD
y
UD
AMEND
any
AMEND
s
ON
extensions
IETY A
ns 
IETY A
ALLOW
sio
ALLOW
............
ens
............
OLINSK
xte
OLINSK
Y C
e
Y C
or 
NAIR
or 
NAIR
variations 
....
s
....
OD EP
ons
OD EP
...........
tio
...........
............
ria
............
..........
va
.........
thereof. 
............
reo
............
........
th
........


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 10 of 194  
LIST OF TABLES
TABLE 1.
SCHEDULE OF ASSESSMENTS FOR SUBJECTS FROM CORE STUDIES 
ZX008-1501 AND ZX008-1502, AND DE NOVO SUBJECTS** ............................ 26
TABLE 2.
SCHEDULE OF ASSESSMENTS FOR SUBJECTS FROM CORE STUDY 
ZX008-1504 ................................................................................................................. 28
TABLE 3
POST HOC ESTIMATES OF FENFLURAMINE AND 
NORFENFLURAMINE STEADY-STATE PHARMACOKINETIC 
PARAMETERS IN SUBJECTS WITH DRAVET SYNDROME IN STUDY 1 
(GEOMETRIC MEAN [CV%]) ................................................................................... 37
TABLE 4.
INVESTIGATIONAL MEDICINAL PRODUCT – ZX008 ....................................... 57
TABLE 5. 
TAPER ALGORITHM FOR SUBJECTS FROM CORE STUDIES ZX008-
1501, ZX008-1502, AND ZX008-1504 COHORT 1/REGIMENS 1&2NOT 
RECEIVING CONCOMITANT STP .......................................................................... 60
TABLE 6. 
TAPER ALGORITHM FOR SUBJECTS RECEIVING CONCOMITANT STP....... 61
TABLE 7.
TIME WINDOWS FOR ASSESSMENTS .................................................................. 64
TABLE 8.
SCHEDULE OF POST-TREATMENT CARDIAC FOLLOW-UP ............................ 73
TABLE 9.
ESTIMATED BLOOD VOLUME COLLECTIONA................................................... 74
TABLE 10.
ADVERSE EVENTS OF SPECIAL INTEREST ........................................................ 87
TABLE 11. 
SEVERITY DEFINITION OF ADVERSE EVENTSA ............................................... 87
TABLE 12.
CLINICAL MEASURES ENACTED UPON INCREASING SEVERITY OF 
ECHO FINDINGS........................................................................................................ 92
PUBLIC 
FOR
C
FOR
S FOR A
BL
S FOR A
OF PO
PU
OF PO
COPY 
JECT
Y
JECT
08-1504
OPY
08-1504
ANT STP
COP
ANT STP
R S
C
R S
This document cannot
ERITY
not 
ERITY
CLINIC
an
CLINIC
c
ECH
ca
ECH
be
E EVE
be 
E EVE
sed 
ST
d
ST
us
-
d
-
BLOOD
use
BLOOD
to 
TRE
to
TRE
support 
......
rt
......
UBJECTS
ppo
UBJECTS
SSESSM
sup
SESSM
any 
ROM 
ny 
ROM 
OHORT
any
OHORT
......
a
marketing 
KINET
ng 
KINET
DROME 
ting
DROME 
..............
keti
..............
T 
m
T – ZX00
mar
– ZX00
CO
m
CO
authorization 
...........
atio
...........
TUDY
oriz
TUDY
............
tho
............
IC
a
IC
n
AL
n
AL
application
O FIND
on 
O FIND
and
DEFIN
d 
DEFIN
L ME
a
L ME
any 
S OF S
ny 
S OF S
NIT
a
NIT
nsions 
S
MENTS
ons
MENTS
exten
ATMEN
ens
ATMEN
VOLUM
ext
VOLUM
or 
RECE
or
RECE
variations
08 .......
ns 
08 .......
ORE ST
atio
ORE ST
T 1/RE
aria
T 1/RE
............
var
...........
thereof. 
IN STU
ere
IN STU
............
the
............


PUBLIC COPY
COPY 
PY
COP
This 
me
docume
ment annot 
can
be used 
us
to 
ort
support
ort any 
an marketing authorization 
ic
application
ication and 
a
any extensions 
ex
or variations 
var
thereof. 


PUBLIC COPY 
Y
This document ca
cannot e
be used 
u
to support any marketing 
a
authorization 
application
on and ny 
any extensions or variations thereof. 


PUBLIC 
Y
COPY 
Y
This 
nt
document
nt 
ot
cannot be 
ed 
used to support 
y
any y marketing 
ma
thorization 
auth
tio
applicatio
tion 
d
and any 
a
tensions 
exte
or variations thereof. 


PUBLIC 
P
Y
COPY 
Y
This 
n
document 
not 
canno be 
ed 
used to support 
y
any y
arketing 
ma
authorization 
at
applicat
ation nd 
and any 
tensions 
exte
or 
ons 
tio
variatio
tion thereof. 


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 15 of 194  
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S)
Study Number: ZX008-1503 
Study Title: An Open-Label Extension Trial to Assess the Long-Term Safety 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 [DD/MMM/YYYY]) 
  
PUBLIC
the inv
IC 
the inv
PY
t
Y
t
ntents o
PY 
ntents o
COP
accordi
OPY
accordi
______
CO
______
C
This document 
_____
nt
_____
ature) (D
men
ature) (D
cannot
_____
ot 
_____
c
be 
b
used to support 
g
t
g
______
ort
______
stigator 
ppo
stigator 
any
ers
y
ers
his stud
ny 
his stud
a
to the 
any
to the 
marketing 
___
g
___
study pro
ting
study pro
thics Com
ket
thics Com
dy protoc
arke
dy protoc
Good Cl
mar
Good Cl
sonnel
m
sonnel
authorization 
d Young
horiz
d Young
___
a
___
application 
_______
tio
_______
ate [DD/M
lica
ate [DD/M
and 
____
d
____
any 
_____
an
_____
extensions or 
riations 
col, t
s
col, t
linical P
ons
linical P
l involv
tion
l involv
y protoc
riati
y protoc
va
study p
aria
study p
___
v
___
thereof. 
______
of
______
otocol, I
here
otocol, I
mmittee
the
mmittee
the
th
the


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 16 of 194  
LIST OF ABBREVIATIONS
ABBREVATION
DEFINITION
ADHD
attention deficit hyperactivity disorder
AE
adverse event
AED
antiepileptic drug
AESI
adverse event of special interest
ANCOVA
analysis of covariance
BID
bis in die; two times per day
BMI
body mass index
BRIEF
Behavior Rating Inventory for Executive Function
CBD
cannabidiol
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impression - Improvement
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
dL
deciliter
DS
Dravet syndrome
ECG
electrocardiogram
ECHO
echocardiogram
EOS
end of study
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
GP
general practitioner
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
PUBLIC 
0
C
0
C
yndrome
BLIC
yndrome
LIC
ocardiog
UB
ocardiog
BL
hocardio
PU
hocardio
U
of
P
of
P
COPY 
Impro
Y
Impro
Y
Severity 
COP
Severity 
OP
CO
C
This s
ent 
nt
docume
CF
c
CF
m
ICH
doc
ICH
cu
d
ID
do
ID
do
d
nnot
G
ot 
G
t
ot
canno
no
n
ca
be 
arly te
be 
arly te
follicl
be
follicl
be
b
used 
gram
d
gram
tudy
sed
tudy
d
ardized
use
ardized
se
erm
u
erm
u
to 
am
to
am
m
t
m
to support 
Rating
rt
Rating
rt
po
upp
su
any 
nt
ny
nt
ny
Sca
a
Sca
a
marketing 
g
ng
ction
ke
ction
et
rk
ma
m
authorization 
titi
ati
ati
za
ori
tho
u
a
cation 
G
n
G
n
gen
n
ge
n
on
on
tio
applica o
ca
pli
pp
a
nd 
od Cli
d
od Cli
and
growth h
and
growth h
and
Good
a
Good
an
any 
nation
ny 
nation
stimulati
any
stimulati
ny
nica
a
nica
a
extensions s
on
si
en
measure 
ex
easure 
xt
e
or 
or variations 
ns
tio
iat
le
v
e
ar
v
thereof. 
of
re
he
t


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 17 of 194  
ABBREVATION
DEFINITION
IRB
Institutional Review Board
IVR
interactive voice response (system)
IWR
interactive web response (system)
KD
ketogenic diet
kg
kilogram
LH
luteinizing hormone
LLN
lower limit of normal
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
OLE
open-label extension
PedsQL
Pediatric Quality of Life Inventory
PDN
Postnatal day
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
SE
status epilepticus
SMEI
severe myoclonic epilepsy of infancy
STP
stiripentol
SUDEP
sudden unexpected death in epilepsy
THC
tetrahydrocannabinol
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 
ty o
C
ty o
ay
LI
ay
C
ocol
BL
ocol
LIC
ity
PU
ity of 
PUB
of life
UB
life
B
ality o
PU
ality o
PU
P
COPY 
PY
on
C
on
OP
of Lif
C
of Lif
CO
This s
ment t
nt
docume
H
u
H
me
ULN
cu
ULN
um
USA
doc
USA
oc
d
U
d
U
do
d
not 
s
t
s
ot
s
ot
s
ot
ot
ot
ot
canno
no
an
c
be
safety p
be 
safety p
tand
b
tand
be used
Life i
d 
Life i
ed QT in
sed
ed QT in
ed
us adve
us
us adve
se
u
to 
n C
t
n C
to support t
Inventory
po
Inventory
or
pp
up
s
any y
ny
a
marketing 
g
ing
ket
rk
ma
m
authorization 
ati
ati
ati
at
iza
or
th
au
a
ication 
s
n
stir
n 
ti
on
su
su
on
on
on
on
ati
applica
ica
pl
ap
a
nd
r
tus
nd
tus epi
nd 
epi
d
and
severe 
an
severe 
nd
i
a
i
a
any 
ulation
ny 
ulation
y
d deviati
an
d deviati
ny
a
extensions 
ns
io
hildhood
tens
hildhood
ns
terval us
xte
terval us
te
e event
ex
event
ex
e
or r
o variations s
ns
tio
ia
ar
v
thereof. 
f
of
re
he
t


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 18 of 194  
STUDY SYNOPSIS
Study Title: An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine 
Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet 
Syndrome
Study Number: ZX008-1503
Study Product: Fenfluramine Hydrochloride, ZX008
Type of Study:
Safety and effectiveness study
Indication Studied: 
Adjunct therapy in Dravet syndrome
Phase of Development: Phase III 
Countries: North America, Europe, Australia
Sponsor: Zogenix International Limited
Co-Coordinating Investigators:
 Pediatric Epilepsy Center
University of California, San Francisco
San Francisco, CA USA
Leuven University, Department of 
Development and Regeneration,
Section Pediatric Neurology
  Leuven, Belgium
Service de Neuromètabolisme
CHU Paris - Hȏpital Necker-Enfants 
Malades
  Paris, France
Estimated Duration of Individual Subject Participation:
The duration of the study for an individual subject is expected to be up to approximately 36 months. 
Objectives:
The primary objective of the study is:  
•
To assess the long-term safety and tolerability of ZX008. 
The secondary objectives of the study are: 
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following effectiveness 
measures:
- The change in the frequency of convulsive seizures from Visit 3 to Visit 8 (ie, Day 31 to 
Day 365) and for the entire Year 1 treatment period (ie, Visit 1/Day 1 to Visit 8/Day 365) 
- The proportion of subjects who achieve a ≥40%, ≥50%, and ≥75% reduction in convulsive 
seizure frequency 
- The longest convulsive seizure-free interval
- The percentage of convulsive seizure-free days
- The non-convulsive seizure frequency
- The convulsive + non-convulsive seizure frequency. 
• To estimate the incidence of the following on subjects receiving ZX008: 
- Use of rescue medication
- Hospitalization to treat seizures 
- Status epilepticus (SE)
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following quality of life 
(QoL) measures:
- Quality of Life in Childhood Epilepsy (QOLCE) score 
- Pediatric Quality of Life Inventory™ (PedsQL) score 
- PedsQL Family Impact module score  
- QoL of the parent/caregiver using the standardized measure of health status (EQ-5D-5L) scale
- Affective symptoms of the parent/caregiver using the Hospital Anxiety and Depression Scale 
(HADS)
PUBLIC 
and toler
LIC
and toler
y are:
BLI
y are:
8
U
8 relativ
UB
relativ
uenc
P
uenc
COPY 
Y
ipation:
OPY
ipation:
ct is exp
COP
ct is exp
Y
CO
CO
This s
t
document 
e of r
nt
e of r
Hospita
ent
Hospita
-
m
- Statu
me
Statu
• To as
um
To as
(Q
cu
(Q
d
cannot
vul
t
vul
e of 
ot
e of co
ot 
co
onvulsive
nno
onvulsive
vulsive +
ann
vulsive +
ate the i
ca
te the i
esc
c
esc
be 
ec
sive se
be
sive se
used
of conv
ed 
of conv
re Year 
se
re Year 
cts who
us
ts who
to
e to th
to 
e to th
rt
cted
rt
cted
support 
bility of
upp
bility of Z
p
Z
e pr
s
e pr
rt any 
to be
a
to be
ny
keting 
ustralia
ng 
ustralia
ng
tin
mark
Service de
ark
Service de
CHU P
ma
CHU P
Mal
m
Mal
P
m rke
authorization 
e 
t
e 
ati
riz
hor
th
a
on 
n
ncidence
on 
ncidence
applicatio
ue medica
tion
ue medica
ization to 
cati
ization to 
e
li
epileptic
lica
pileptic
ess the ef
pli
ess the ef
oL) measu
app
L) measu
Quality
ap
Quality
d
and 
ulsiv
d
ulsiv
seizure f
and
seizure f
on
a
on-con
an
-con
a
any y
ure-
an
ure-free 
ny
free 
e sei
a
e sei
extensions 
ZX008
s 
ZX008
re
s
re-ZX00
sio
-ZX00
ulsive sei
ten
ulsive sei
treatmen
exte
treatmen
hieve 
ex
hieve 
or variations
e Neurom
ns 
e Neurom
aris
on
aris -
on
- Hȏp
ns
Hȏp
ades
tio
ades
aris, Fran
atio
aris, Fran
up to
var
up to ap
r
ap
iat
va
va
s thereof. 
of
eo
er
th


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 19 of 194  
• To assess the effect of ZX008 on the following QoL measures:
- Clinical Global Impression – Improvement (CGI-I) rating, as assessed by the principal 
investigator 
- CGI-I rating, as assessed by the parent/caregiver
The exploratory objectives of the study are: 
• To assess the effect of ZX008 on the following QoL measures for subjects who participated in the 
core study ZX008-1504: 
- Sleep quality and mealtime behavior, as assessed by the parent/caregiver
- Karolinska Sleep Scale
- Health and social care resource use (These measures include planned and unplanned hospital 
visits, use of ambulances, general practitioner [GP] visits, speech and language therapy 
utilization, occupational and physical therapy utilization).
Methodology: This is an international, multicenter, open-label, long-term safety study of ZX008 in 
pediatric and young adult subjects with Dravet syndrome (DS).  Subjects eligible for participation are 
those who have successfully completed 14 weeks of treatment in 1 of the 3 core studies ZX008-1501, 
ZX008-1502, or ZX008-1504 Cohort 2, or successfully completed core study ZX008-1504 Cohort 1 
and are candidates for continuous treatment for an extended period of time. In addition, subjects who 
are >18 to ≤35 years of age at the time of screening, and who meet all other eligibility criteria may be 
eligible for participation after discussion with the Medical Monitor and sponsor about the potential 
risks and benefits for receiving ZX008.  Participation for these subjects will be at the discretion of the 
sponsor. 
This trial will consist of an up to 36-month Open-Label Extension (OLE) Treatment Period and a 
2-week Post-Dosing Period. Thus, subjects who complete this trial will have been treated with ZX008 
for a minimum of up to 3 years (including their participation in both the core study and this study). 
Subjects who did not participate in one of the core studies will undergo a screening period up to 28 
days to confirm eligibility prior to receiving their first dose in the OLE Treatment Period.
During the OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day for 1 month 
to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 0.2 mg/kg/day, the 
investigator may adjust the dose of each subject based on effectiveness and tolerability. For subjects
who are not receiving concomitant stiripentol (STP), including de novo subjects and those who 
participated in core studies ZX008-1501, Z008-1502, and dose regimen 1 or 2 from Cohort 1 of 
ZX008-1504, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 
0.8 mg/kg/day but not to exceed total dose of 30 mg/day. For subjects who are receiving concomitant 
STP, including de novo subjects and those who participated in core study ZX008-1504 Cohort 1, dose 
regimen 3 and Cohort 2, the first dose change will be to 0.4 mg/kg/day and the final dose change will 
be to 0.5 mg/kg/day, but not to exceed 20 mg/day. Dose increases should not occur earlier than every 
14 days at each dose level. Dose increases may only occur after a review of the diary and reported 
adverse events (AEs), and if, in the investigator’s opinion, seizure frequency, severity, or duration 
indicates a change in medication regimen is warranted. Dose decreases for tolerability can occur at the 
investigator’s discretion, in dose amounts and frequency appropriate for the situation. ZX008 dose 
adjustments outside of these parameters should be discussed with the Medical Monitor prior to 
initiation.
PUBLIC 
tic
C
tic
month
BL
month O
L
O
s, subjec
PUB
s, subjec
(includ
PU
(includ
n
P
n
COPY
co
Y
co
xtended 
PY 
xtended 
ng, and w
OPY
ng, and w
he Medi
COP
he Medi
ipation
CO
ipation
This s
t
d
t
d
document
/day bu
nt 
/day bu
cluding d
men
cluding d
men 3 an
me
men 3 an
e to 0.5 m
cum
e to 0.5 m
14 days
docu
14 days
adve
do
adve
in
d
in
d
cannot
f this
ot
f this
st the do
not 
st the do
ng conco
nno
ng conco
ore studi
can
ore studi
c
ose ch
ca
ose ch
c
be
Period, 
be 
Period, 
dos
b
dos
used 
ing th
d
ing th
one of th
sed
one of th
o receivi
use
receivi
to
Ope
o
p
 who c
to 
 who c
heir
to
heir
support 
ho
t
ho
al Moni
ort 
al Mon
for these 
por
for these 
en
s
n-Labe
su
-Labe
om
any 
cor
y
cor
iod of 
any
iod of ti
y
ti
meet al
an
meet al
ito
a
it
keting 
unpla
g 
unpla
language t
ting
language t
market
m safety
rke
m safety stu
e
stu
cts eligible
ark
cts eligible
f the 3 
ma
f the 3 co
a
co
re stu
m
re stu
ket
authorization 
ated in th
oriz
ated in th
ann
a
ann
ati
n
es Z
n
es Z
application
anges sho
on 
anges sh
not to exce
atio
not to exce
e novo su
cat
e novo su
d Cohort 2
plica
d Cohort 2
g/kg/day, 
ppl
g/kg/day, 
at each do
app
t each do
vents 
ap
vents 
and
e i
d
e of ea
nd 
e of ea
mitant
and
mitant st
d
st
X008
a
X008
any
subject
any 
subject
n all stu
an
n all stu
ch s
a
ch s
extensions 
el Extens
ion
el Extens
mplete th
nsio
mplete th
participa
ens
participa
core stu
xte
core stu
g their f
ext
g their f
or
ubjec
or 
ubjec
variations
ud
e for pa
ns 
e for pa
ore stud
ons
ore studi
s
i
udy ZX0
atio
udy ZX0
me.
ia
me. In a
riat
In a
ll other e
aria
ll other e
and sp
va
and sp
cts
v
cts
hereof. 
ed hospit
eof
ed hospit
therapy 
ereo
therapy 
the
dy of Z
th
dy of Z
the


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 20 of 194  
In addition, if a subject has been stable on the same dose of ZX008 for 6 months or longer, 
investigators may adjust the doses of one or more of the other concomitant anti-epileptic drugs (AEDs) 
as per typical clinical practice. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs or anti-epileptic 
treatments may be introduced while in this study. All medication dose changes must be documented 
with a clinical explanation and justification. Concomitant AED dose adjustments outside of these 
parameters should be discussed with the Medical Monitor prior to initiation if possible.  
If after approximately the midway point of the first 30 days on ZX008 0.2 mg/kg/day there is a 
clinically meaningful worsening in seizure type, frequency, and/or duration, compared with the recent 
treatment in the core study, the investigator, in consultation with the medical monitor, may increase the 
dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not receiving concomitant STP; 
20 mg/day for subjects who are receiving concomitant STP). A clinically meaningful worsening would 
be an increase in frequency, severity or duration of existing seizures, or emergence of a new seizure 
type. The description of clinical worsening must be documented in the source notes and case report 
form (CRF). Further increase to 0.8 mg/kg/day (maximum 30 mg/day) for subjects who are not 
receiving concomitant STP, and to 0.5 mg/kg/day (maximum 20 mg/day) for subjects who are 
receiving concomitant STP could also be undertaken for the same conditions after a minimum of 4 
days on 0.4 mg/kg/day, if the condition has not stabilized on the 0.4 mg/kg/day dose. Dosing outside of 
the specified range (ie, 0.2 to 0.8 mg/kg/day) may be considered after consultation between the 
investigator and Medical Monitor. 
A follow-up electrocardiogram (ECG) and echocardiogram (ECHO) will be performed at 3 and 
6 months after study drug discontinuation for early termination and for those subjects who complete the 
study. 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 for subjects from core studies 
ZX008-1501 and ZX008-1502 and those who did not participate in one of the core studies (de novo 
subjects), and in Table 2 for subjects from core study ZX008-1504.  
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core studies will 
transition to a separate extension study (Study 1900) once that study is approved and the study site is 
initiated. Continuation in a separate extension protocol will be based on benefit/risk and continued 
eligibility criteria being met. De novo subjects must have participated in this trial for at least 3 months 
with at least 1 ECHO completed and continue to meet eligibility requirements to be eligible to 
transition to a separate extension protocol. Alternatively, subjects will transition to commercial product 
once it is available. For subjects who are entering the separate extension trial or who transition to 
commercially available drug, post-dosing and cardiac safety follow-up visits are not required in this 
trial. Subjects who transition to commercially available drug must have an ECHO within 3-6 months 
before starting commercial drug and will have follow-up ECHOs within the required timeframe while 
on commercial drug.
External Committees:  The ZX008 clinical program will employ an Independent Data and Safety 
Monitoring Committee (IDSMC) that will be responsible for safety oversight. A separate International 
Pediatric Cardiology Advisory Board (IPCAB) will monitor the cardiac safety of the ZX008 clinical 
trials. 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. 
PUBLIC 
ay) ma
C 
ay) ma
CG
UB
CG) and
UB
) and
ontinuati
PU
ontinuati
y da
P
y da
COPY
u
Y
u
mum 3
PY 
mum 3
(maximu
OPY
(maximu
aken for
COP
aken for
t stabil
CO
t stabil
ay
C
ay
This s document
t 1 EC
nt 
t 1 EC
n to a se
ent
n to a se
t is avai
me
t is avai
mmercia
cum
mmercia
trial
oc
trial.
oc
. Su
cu
Su
befo
doc
befo
o
d
o
d
not
treatme
ot 
treatme
cann
ate exten
nno
ate exten
uation in
ann
uation in
ia bein
ca
ia bein
CH
c
CH
be
an
r subjec
be 
r subjec
used
on fo
d
on fo
ly to rec
ed 
ly to rec
ments is p
use
ments is p
d thos
us
d thos
to
echoc
to 
echoc
for ea
to
for ea
support 
he sa
rt
he sa
zed on the
port
zed on th
be conside
ppo
be conside
ardi
s
ardi
any 
th
y
th
g/day)
ny 
g/day)
20 
an
20 mg/d
any
mg/d
me c
a
me c
marketing 
ay th
g
ay th
mpared w
ing
mpared w
monitor, m
etin
monitor, m
iving conc
ket
iving conc
ly meanin
ark
ly meanin
or emerg
ma
or emerg
he
m
he sour
m
sour
f
authorization 
ust 
at
ust 
ileptic 
izat
ileptic 
mented 
oriz
mented 
f these 
thor
f these 
here
a
here
ati
application 
a s
n
g met
on
g met. D
n 
. D
O complet
tion
O complet
arate exte
cati
arate exte
able. 
lic
able. For s
ca
For s
ly availab
ppli
ly availab
jects who
app
jects who
arting 
ap
arting 
nd 
t in St
d
t in St
an
sion stud
and
sion stud
eparat
an
eparat
any
wh
y
wh
rom co
ny 
rom co
tudy 
a
tudy
extensions 
ere
iogram (
sio
iogram (
ly termin
ens
ly termin
rd the nu
ten
rd the nu
rovided i
exte
rovided i
ho did
ex
ho did
or 
0.4 m
or
0.4 m
d afte
or
d afte
variations
ngful w
s 
ngful w
gence of 
ons
gence of 
ce notes
tion
ce notes
or 
i
or subjec
iati
subjec
day) for 
aria
day) for 
conditio
var
onditio
mg
v
mg
thereof. 
s a 
eo
s a 
ith the re
reo
ith the re
may incr
here
may incr
omitan
the
omitan
wor
t
wor


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 21 of 194  
Number of Subjects: Up to approximately 340 subjects from the core studies and up to 50 subjects 
who did not participate in the core studies may be enrolled. 
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled into the 
study: 
1.
Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit.  
2.
Subject has satisfactorily completed the core study in the opinion of the investigator and the 
Sponsor. NOTE: Those subjects who do not complete the 12-week Maintenance Period of the 
core study may, on a case-by-case basis, be eligible for entrance 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 OLE study participation resides solely with 
the Sponsor, who may consult with the site investigator, the IPCAB and/or the IDSMC. 
3.
Subject is male or non-pregnant, non-lactating female. 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, which includes abstinence, 
while being treated on this study and for 90 days after the last dose of study drug. 
4.
Subject has documented medical history to support a clinical diagnosis of DS, where 
convulsive seizures are not completely controlled by current antiepileptic drugs. 
5.
Subject has been informed of the nature of the study and informed consent has been obtained 
from the legally responsible parent/guardian. 
6.
Subject has provided assent in accordance with Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) requirements, if capable.
7.
Subject’s caregiver is willing and able to be compliant with diary completion, visit schedule 
and study drug accountability. 
8.
Subject’s parent/caregiver has been compliant with diary completion during the core study, in 
the opinion of the investigator (eg, at least 90% compliant).
9.
Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant and 
stable dose of clobazam (CLB) and/or valproic acid (VPA), and STP (Cohort 1 dose regimen 3 
and Cohort 2 only) for at least 4 weeks prior to screening and are expected to remain stable 
throughout the study. 
10. Subjects who are >18 to ≤35 years of age at the time of screening and did not participate in one 
of the core studies must meet criteria 3 to 7 above and the following criteria below in order to 
be considered for participation. Participation is at the discretion of the Sponsor: 
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 brainmalformation.
e.
Lack of alternative diagnosis.
f.
Meets one of the following 3 confirmatory diagnostic criteria:
i. Emergence of another seizure type, including myoclonic, generalized
tonic-clonic, tonic, atonic, absence and/or focal has developed after the
first seizure type.
ii.
Prolonged exposure to warm temperatures induces seizures and/or 
seizures are associated with fevers due to illness or vaccines, hot baths,
PUBLIC
g
C
g
cordan
IC 
cordan
rements, 
LIC
rements, 
ng and ab
UBL
ng and ab
bility. 
PUB
bility. 
ver has 
PU
ver has 
ga
P
ga
COPY
s a
Y
s a
upport 
PY 
upport 
ntrolled b
OPY
ntrolled b
e of the s
COP
e of the s
ardian.
CO
ardian.
ce
C
ce
This s document
b.
nt
b.
A
t 
A
d
ot
udy
t
udy
canno
are >18 
not 
are >18 
studies m
nno
studies m
dered fo
an
dered fo
Onse
ca
Onse
be
m (C
e
(C
for at le
be 
for at le
b
used 
been 
d
been 
or (eg, at
ed
or (eg, at
udy ZX0
use
udy ZX0
CLB
us
CLB)
s
)
to 
e 
com
to
com
support 
y
t
y
udy an
rt 
udy an
with Instit
ppo
with Instit
f capable.
upp
f capable.
to be co
su
o be co
any
last
y
last
inical d
ny 
inical d
current a
any
current a
nd in
a
nd in
marketing 
reside
g
reside
d/or the ID
ting
d/or the ID
cts of child
etin
cts of child
of childbe
rket
of childbe
aring or ch
ark
aring or ch
ontrol, wh
ma
ontrol, wh
t dose
m
t dose
authorization 
nd the
oriz
nd the
riod of t
hor
riod of t
ion of th
uth
ion of th
ued part
au
ed part
s s
a
s s
ati
application 
par
n
par
of
o
of seizu
on 
seizu
history
atio
history of
o
of
or bilatera
cat
or bilatera
Initial 
plic
Initial 
d.
p
d.
Hist
ppl
Hist
e.
ap
e.
L
pp
L
f.
a
f
and
o ≤35 y
nd 
o ≤35 y
ust mee
and
ust mee
rticip
an
rticip
any
nd/
y
nd/
4 week
ny 
4 week
year
a
year
extensions 
tut
s
tut
ompliant
ion
ompliant
pliant wi
ens
pliant wi
least 90%
xten
least 90%
8
e
8-1504 
ext
-1504 
/or 
e
/or v
e
v
or 
ional 
or
ional 
variations
hild-
ns
hild-fa
s 
fa
hich inc
ons
hich incl
s
l
e of study
tio
e of study
agnosis o
riat
agnosis o
antiepile
aria
antiepile
formed
va
formed
thereof.
cipatio
of. 
cipatio
lely with
eof
lely with
DSMC.
ereo
DSMC.
ldbearing
her
ldbearing
aring po
the
aring po
th
t
th


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 22 of 194  
high levels of activity and sudden temperature changes and/or seizures 
are induced by strong naturaland/or fluorescent lighting, as well as 
certain visualpatterns.
iii.
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.)
g.
Subject has been approved for study inclusion by the Epilepsy Study Consortium.
h.
Subject does not have an exclusionary cardiovascular or cardiopulmonary abnormality 
based on ECHO, ECG or physical examination and is approved for entry by the central 
cardiac reader.  Exclusionary abnormalities include, but are not limited to:
i.
Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of age 
ii.
Possible signs of pulmonary hypertension with abnormal or greater than upper 
limit of normal values 
iii.
Evidence of diastolic dysfunction
i.
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.
j.
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.
11. 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 current or past history of cardiovascular or cerebrovascular disease, myocardial 
infarction or stroke.
3.
Subject from one of the core studies with current cardiac valvulopathy or pulmonary 
hypertension that the investigator, parent, IPCAB, IDSMC, or Sponsor deems clinically 
significant and warrants discontinuation of study medication.
4.
For de novo subjects: possible signs of pulmonary hypertension with abnormal or greater than 
upper limit of normal values. 
5.
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.
6.
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 as measured by the 
C-SSRS Since Last Visit, 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.
7.
Subject has a current or past history of glaucoma.
PUBLIC
d to
C
d to
illing a
LIC 
illing a
ountabil
BLIC
ountabil
must mee
UBL
must mee
ypersen
PU
ypersen
COPY
we
Y
we
or medi
PY 
or medi
s for epi
OPY
s for epi
S]) must
CO
S]) must
o rem
C
o rem
This s document
ect 
t
ect 
rior year
ent 
rior year
than 1 m
men
than 1 m
6.6.
Subj
me
Subj
o
um
o
d
cannot 
at the 
ot
at the 
d warran
not
d warran
vo subjec
nn
vo subjec
mit
ca
mit of n
can
of n
has c
ca
has c
be
f the cor
be 
f the cor
inv
b
inv
used
sitivity
d 
sitivity
st histor
use
t histor
to 
non
o
non
y to
t
y to
support 
eps
t
eps
be stabl
ort 
be stab
in stable 
por
in stable 
d able to b
pp
d able to b
ty.
s
y.
ne of th
su
ne of th
any 
or to
y
or to
notes.
any
notes.
y (incl
an
y (incl
e
marketing 
mited 
g
mited 
ubjects >1
ting
ubjects >1
ormal or gr
ketin
ormal or gr
nic, tonic
ma
nic, tonic
o scr
m
o scr
authorization 
onsortiu
tho
onsortiu
ry abnor
uth
ry abnor
try by t
au
try by t
to:
a
to:
ati
application 
rmal
n
rmal
urrent or r
ion
urrent or 
hat requir
atio
hat requir
onth.
cat
onth.
ect is at im
plic
ect is at im
clinical in
ppl
clinical in
C
a
C-
a
-SSRS
app
SSRS
SSR
a
SSR
and
esti
d
esti
ts disco
nd 
ts disco
s:
a
: possib
and
possib
val
a
val
any 
studies w
any
studies w
gator, p
an
gator, p
nti
extensions 
be co
s
be co
he follow
ion
he follow
fenflura
tens
fenflura
of cardi
ext
of cardi
or
hroug
or 
hroug
omp
o
omp
variations 
c
i
c-
o
-atonic
ions
atonic
reening,
atio
reening,
luding k
vari
luding k
or at le
va
or at le
h
v
h
thereof.
m
he cent
of. 
he cent
18 yrs of
ereo
18 yrs of
greater th
her
greater th


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 23 of 194  
8.
Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic 
impairment (elevated liver enzymes < 3x upper limit of normal [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.
9.
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 (Appendix 1). (Note: Short-term 
medication requirements will be handled on a per case basis by the Medical Monitor.)
10. Subject is currently taking carbamazepine, oxcarbazepine, eslicarbazepine, phenobarbital, or 
phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
11. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504 
(Cohort 1/dose regimens 1 &2): Subject is currently receiving or has received stiripentol in the 
past 21 days prior to core study Visit 1.
12. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with the Visit 1 and throughout the study.
13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood 
cannabidiol (CBD) at Visit 1.
14. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions. 
15. Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness at Visit 1, other than epilepsy, that would negatively impact study 
participation, collection of study data, or pose a risk to the subject, including chronic obstructive 
pulmonary disease, interstitial lung disease, or portal hypertension.
16. Subject has participated in another clinical trial within the past 30 days (ie, the last visit of the 
previous study was in the past 30 days), with the exception of one of the core studies.
Study Product, Dose, and Mode of Administration:
•
ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated 
to an effective dose beginning with 0.2 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; maximum 20 mg/day for subjects who are receiving concomitant STP). 
Study medication will be administered twice a day (BID) in equally divided doses with food.
Reference Product, Dose, and Mode of Administration:
Not applicable. 
Duration of Treatment:
All subjects will receive ZX008 for up to approximately 36 months. All subjects, including those who 
prematurely discontinue from the study, will undergo an up to 2-week taper of study medication, at the 
conclusion of the study. 
Criteria for Evaluation:
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 Behavior Rating Inventory for Executive Function 
(BRIEF) will be administered to track cognitive function.
PUBLIC
comply
IC 
comply
ocedures
BLIC
ocedures
gnificant
UBL
gnificant
ess 
PU
ess at V
UB
at V
n
P
n of stud
PU
of stud
stit
P
stit
COPY
daily se
PY 
daily se
he 
O
he Visit 1
OPY
Visit 1
ahydroca
COP
ahydroca
C
This s
nt 
rod
t
rod
cable
nt
cable.
nt
.
men
on of Tr
men
on of Tr
docum
subjects 
ume
subjects 
remature
cum
remature
conclu
doc
conclu
en
do
Cri
do
Cri
S
d
S
do
d
cannot 
s an o
ot
s an o
eginning
not
eginning
tant STP
nno
tant STP
n will be
can
n will be
duct, 
ca
duct, 
ca
be
the 
e
the 
Mode o
be 
Mode o
oral
b
oral
e used 
y dat
d
y dat
al lung d
sed
al lung d
n anothe
use
n anothe
past 
us
past 
to
co
o
it 1
to
it 1, ot
to 
, ot
a, o
to
a, o
support 
nnabino
ort 
nnabin
with schedu
ppo
with schedu
and study
supp
and study
ondition
su
ndition
he
s
h
any
ngs of g
ny 
ngs of g
nd 
a
nd throu
an
throu
ol (
a
ol (
marketing 
. (Not
g
. (Not
dical Mon
ting
dical Mon
zepine, ph
ketin
zepine, ph
aintenanc
rke
aintenanc
502, or ZX
ark
502, or ZX
ng or has r
ma
g or has r
authorization 
oamine
oriz
oamine
unt of 
tho
unt of 
on; 
u
on; 
and/or 
au
and/or 
te:
a
te:
ati
ation
adm
n
adm
Dose, and
ion 
Dose, and
n
icat
atment:
cat
atment:
appli
will receiv
plic
will receiv
y disconti
ppl
y disconti
on of the 
app
n of the 
at
ap
or E
a
or E
ap
and
so
d
so
with 0.
nd 
with 0.
maximu
and
maximu
minis
a
minis
any 
da
y
da
Adminis
any
Adminis
ution in
an
ution in
2 m
a
2
y extensions
dule
s
dule
y restric
ns 
y restric
n, or has
ion
n, or has
er than e
nsio
er than e
pose a r
ens
pose a r
sease, or
xten
sease, or
clinical
ext
clinical
ays)
e
ays)
e
or 
d vis
or
d vis
variations
ce
X008-
ns 
X008-
received
ons
received
rapefruit
riat
rapefruit
ughout th
aria
ughout th
THC) P
va
THC) P
thereof. 
Short-
eof
Short-ter
of
ter
nitor.)
ere
nitor.)
henobarb
her
henobarb
t
t
therap
the
herap
15
t
15


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 24 of 194  
Effectiveness:
•
Number of seizures by type 
•
Convulsive seizure-free interval
•
CGI-I as assessed by parent/caregiver
•
CGI-I 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 parent/caregiver using the EQ-5D-5L scale
•
Affective symptoms of parent/caregiver using the Hospital Anxiety and Depression Scale 
(HADS) (in parents/caregivers from core studies ZX008-1501 and ZX008-1502 only) 
•
Duration of prolonged seizures (seizure type that, during pre-ZX008 baseline, had duration 
> 2 minutes)
•
Number of episodes of SE
•
Number of instances of rescue medication use and number of doses
•
Number of inpatient hospital admissions due to seizures
Exploratory (in subjects who participated in core study ZX008-1504 only): 
•
Health and social care resource use, including GP visits, speech and language, occupational 
and physical therapy, in addition to acute hospital and institutional length of stay, loss of work, 
etc.  
•
Sleep quality
•
Mealtime behavior
•
Karolinska Sleepiness Scale to measure the effect of study medication on sleepiness
Sample Size Determination:
The sample size will be determined by the number of subjects who participate in 1 of the 3 core studies 
– Study ZX008-1501, Study ZX008-1502, or ZX008-1504 - and who volunteer for the extension study 
and meet the necessary criteria for enrollment. Approximately 100-120 subjects are expected to 
participate in each of the core trials; thus, if all participants also enroll in the extension, the total sample 
size of the extension trial would be up to approximately 340.  In addition, up to 50 additional subjects, 
who otherwise would have qualified for participation in one of the core studies, but are >18 to ≤35 
years of age may participate.
Statistical Methods:
Study Populations 
Safety Population: Safety analyses will be performed on the Safety Population defined as all subjects 
who receive at least one dose of ZX008 during the open label extension. 
Modified Intent-to-Treat (mITT) Population: The mITT Population is defined as all subjects who 
receive at least one dose of ZX008 and have valid seizure data during the open label extension. 
Safety 
The number and percentage of subjects who experience treatment emergent 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. Serious AEs 
PUBLIC 
e, incl
C 
e, incl
on to acu
LIC
on to acu
cale
P
cale
COPY 
and n
Y
and n
ue to 
OPY
ue to seiz
PY
seiz
ore stud
CO
ore stud
lud
C
lud
This s
t
ma
t
ma
ment
Metho
nt 
Metho
Populatio
men
Populatio
me
docum
ty Popul
me
ty Popul
ho receiv
cum
ho receiv
Mod
do
Mod
re
d
re
t
d
ot
riter
t
riter
canno
the core 
not 
the core 
n trial w
nno
n trial w
would ha
can
would ha
ay part
ca
y part
c
d
c
d
c
be
mine
e
mine
ZX008
be 
ZX008
ia fo
b
ia fo
ed 
to meas
ed
to meas
use
d by 
us
d by 
se
to support 
y ZX008
port
y ZX008-
t
-
ng GP vis
ppo
ng GP vis
e hospital 
upp
e hospital 
any 
er of d
ny 
er of d
es
a
es
marketing 
par
p
nd Depress
ting
nd Depress
ZX008-15
keti
ZX008-15
X008 basel
arke
X008 basel
os
authorization 
rent/ca
au
ent/ca
ati
on 
ve qu
n
ve qu
cipate.
on
cipate.
plication
s:s:
ns
c
ns
c
app
tion
pli
tion: Safe
plica
: Safe
e at least o
ppl
e at least o
Inten
ap
Inten
ion
d
e
d
and
rials; th
nd 
rials; th
ould be u
and
uld be u
ualifi
a
ualifi
any
e nu
y
e nu
502, or 
ny 
502, or 
nrollme
an
nrollme
hus
a
hus
xtensions
sit
and in
ns 
and in
re the ef
xten
re the ef
exte
umb
e
umb
xte
or 
504 
or
504 
s, spee
or
s, spee
o variations 
line,
s
line,
ses
a
ses
onl
v
onl
thereof. 
regiver 
of.
regiver 
sion Sca
here
sion Sca
502 only
the
502 only
, had
th
, had


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 25 of 194  
(SAEs) will be summarized separately in a similar manner. Laboratory tests, vital signs, physical 
examinations, neurological examinations, ECG, ECHO, cognition and body weight will be summarized 
using appropriate methods.
Effectiveness
The frequency of convulsive seizures during a given treatment period will be derived from the number 
and type of events recorded in subject diaries. The seizure frequency per 28 days will be calculated as 
the number of seizures recorded divided by the number of days in the period and multiplied by 28. The 
convulsive seizure frequency during the OLE Treatment Period will be compared to the pre-ZX008 
baseline frequency measured prior to first treatment with ZX008. Both the mean and median change 
from baseline will be presented and the statistical significance of the change will be assessed using an 
analysis of covariance (ANCOVA) with baseline frequency as a covariate and age group (< 6 or ≥ 6 
years old) as a factor. Other factors may be included in the model if they are found to be informative 
during analyses of the core trials. Similar methods will be used to assess the change in frequency of 
non-convulsive seizures and the composite endpoint of non-convulsive plus convulsive seizures. The 
percentage of subjects who achieve a ≥40%, ≥50%, and ≥75% reduction in seizures will be presented 
along 95% confidence intervals for each percentage. Quality of life measures, such as the QOLCE 
assessed during the OLE Treatment Period, will be compared to the analogous baseline measure 
assessed prior to first treatment with ZX008.  Subjects who did not participate in one of the core 
studies will be excluded from analyses of effectiveness and the change over time will be described.
PUBLIC 
C
OPY
d ≥
Y
d ≥
Quality
PY 
Quality
e compar
OPY
e compar
CO
ubjects w
COP
ubjects w
ctivene
CO
ctivene
C
This document cannot be used to 
t
port
ho did 
ort 
ho did
s
p
s and the 
por
and the 
suppo
po
any
du
y
du
life me
ny 
life me
to the a
any
to the a
not
a
not
marketing 
nd me
g
nd me
l be asses
ting
l be asses
d age grou
ketin
d age grou
are found t
rke
are found t
ss the chan
ark
ss the chan
ve plus co
ma
ve plus co
ction 
m
ction 
authorization 
number
oriz
number
lculated 
thor
lculated 
ied by 2
uth
ied by 2
he pre-Z
aut
e pre-Z
edia
a
edia
ati
application and any extensions or
hang
or 
hang
or
or variations
nge in 
ns 
nge in 
onvulsiv
ons
onvulsiv
in seizu
atio
in seizu
asures
riat
asures, su
at
, su
analogou
aria
analogou
v
particip
va
particip
ge
v
ge
thereof. 
X008
f
X008
n change
eof
n change
ssed usin
ereo
ssed usin
oup (<
her
oup (< 6 
er
6 
o be inf
the
o be inf
fr
t
fr


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 26 of 194  
Table 1. 
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects** 
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, and 33)
Visit 16d
(EOS/ET) 
Month 36
Visit 17o
Visit 18, 19o
Study Day
-28 to 1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
Clinic
Phone
Informed Consent
X
Entry Criteria
X
Demographics
X
Medical/Neurological History
Xa
Epilepsy History
Xa,b
Physical Examination, complete
Xa
X
Xe
Physical Examination, abbreviated
X
X
Xe
Neurological Examination, complete
Xf
X
Neurological Examination, abbreviated
X
X
Vital signs
X
X
X
X
Weight, Height, BMI
Xa
X
X
X
12-lead ECG
Xa
X
X
Xe
Doppler ECHO
Xa
Xg,h
X
Xe
Urine Pregnancy Testh
X
X
X
Clinical laboratory evaluation 
(hematology/clinical chemistry/urinalysis, etc)
Xj
Xj
X
X
Urine THC Panel/Whole blood CBD
Xa
X
X
Plasma sample for background AEDs
X
X
X
Tanner Staging (for subjects >7 to ≤ 18 years)
Xa
Xk
X
Xk
C-SSRS
Xa
X
X
CGI-I (assessed by parent/caregiver)
Xa
X
X
CGI-I (assessed by principal investigator)
Xa
X
X
QOLCE
Xa
X
X
EQ-5D-5L (QoL of parent/caregiver)
Xa
X
X
HADS (Affect of parent/caregiver)
Xa
X
X
BRIEF
Xa
X
X
continued 
PUBLIC 
C
LIC
BL
B
X
U
X
UB
UB
UB
UB
X
PU
X
U
X
P
X
PU
P
COPY 
35
Y
35, 
Y
, 
Y
PY
OP
CO
C
This 
T
nt 
or)
nt
or)
t
ment
nt
iver)
me
iver)
en
cume
giver)
um
giver)
me
um
docu
cu
cannot 
X
o
Xa
o
a
t 
ot
X
nn
Xa
n
a
no
X
n
X
n
ca
ca
ca
ca
ca
c
be 
X
e
Xj
e
j
Xj
X
e
Xj
X
e
b
used 
d
ed
se
s
us
to 
to
to
to
to
to
t
support 
rt
or
po
pp
su
s
any 
905
y
905
y
ny
a
marketing 
ZX008-
ng 
ZX008-
ting
18, 
ar
18, 
m
)
m
)
Visit
ket
Visit
(EO
k
(EO
M
et
rk
5, 455, 
ma
5, 455, 
995
m
995
ma
authorization 
ut
tion 
X
o
Xa
o
a
n
X
tio
Xa
tio
a
on
plication
X
ati
Xa
ti
a
tio
c
X
a
X
ca
ic
pplic
licicicic
pl
appl
pp
and 
X
nd
X
d
nd
a
any y
a
extensions 
X
ns
X
s
ns
io
si
n
te
xt
ex
e
or r
o variations
OS/ET
s
OS/ET
Month 
ns
Month 36
s 
36
1085
on
1085
ns
i
ati
ati
ati
ati
ati
ria
ar
va
v
thereof. 
502
eo
502, an
eo
, an
Post
er
Post
ere
h
6
t
6d
th
d
T)
th
T)
he
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 27 of 194  
Table 1. 
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects** 
(continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 
18, 21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET) 
Month 36
Visit 17o
Visit 18, 19o
Study Day
-28 to 1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
Clinic
Phone
PedsQL n
Xa
X
X
Study medication palatability assessment
Xl
Subject Diary
D
C/R/D
R
C/R/D
C/R
C/R
Study Medication
Db
C/R/D
R
C/R/D
C/R/D
C/R
Daily Diary Completion
------------------------------------------------------ X -----------------------------------------------------
Concomitant Medication
Xa
----------------------------------------------X--------------------------------------------------
Adverse Events
Xa
----------------------------------------------X--------------------------------------------------
Adverse events of special interest
Xa
----------------------------------------------X--------------------------------------------------
Xm
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CGI-I=Clinical Global Impression-Improvement; 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
NOTE:  If a subject has a birthday during the study that makes a previously unrequired assessment now required (eg, Tanner staging in a male subject who turns 8 years old during the study), this assessment(s) should be 
initiated at visits subsequent to the birthday.
** de Novo subjects are subjects who did not participate in one of the core studies and may or may not be currently taking STP.
a:
For subjects enrolling from one of the core studies use data collected at Visit 12 and Visit 13 of Study ZX008-1501 or ZX008-1502. 
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures.  All results to determine eligibility must be reviewed prior to receiving the first 
dose of study study medication at Visit 1.  
For all subjects, clinical laboratory results and all ECHO/ECG results must be available and meet eligibility criteria prior to receiving the first dose of study medication at Visit 1.
b:
De Novo subjects must meet entry criteria 3 to 7, and 10, including having 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.
c:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
d:
Or early termination.
e;
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination (see Section 6.3).
f:
For subjects enrolling from one of the core studies, use core study Visit 12 information unless complete neurological examination is warranted based on significant changes in subject status.
g:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
h:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 ECHO may be performed any time within 3 weeks prior to the study visit. If a subject discontinues early from the study, the ECHO should be scheduled as soon as practical (see 
Table 7).
i:
Females of child-bearing potential
j:
For subjects enrolling from one of the core studies, use data collected at Visit 12 of ZX008-1501 or ZX008-1502 for Visit 1 unless clinical laboratory evaluation is warranted based on significant changes in subject status. Visit 2 
clinical laboratory evaluation is optional based on subject status for all cohorts.
k:
Visits 6, 15, and 27 only.
l:
Visits 3 and 4 (Months 1 and 2) only.
m:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
n:
o:
Not to be completed for de novo subjects >18 years old.
For subjects who are entering the separate extension trial or who transition to commercially available drug, post-dosing and cardiac safety follow-up visits are not required in this trial.
C
--
C
--
PUBLIC 
----------
C 
----------
C
---------
LIC
---------
IC
----------
BL
----------
BLI
Executive Fun
UB
Executive Fun
S=Hospital A
PUB
S=Hospital A
B
required
P
required
COPY 
, 7
Y
, 7
Y
PY
OP
CO
C
-----
C
-----
CO
C
This 
T
ent 
core studies,
ent
core studies,
ume
onal based o
en
onal based o
2) only.
m
2) only.
to cardiac s
um
to cardiac s
docu
de novo subj
cu
de novo subj
entering the 
ocu
entering the 
not
as a phone
ot 
as a phone
cann
be performed
nno
be performed
e core study
ann
e core study
15, 18, 21
an
15, 18, 21
n
d 33
c
d 33 ECHO
ca
ECHO
be
must be ava
be 
must be ava
ving had ≥
be
ving had ≥
used
sessment 
d 
sessment 
d may or ma
se
d may or ma
and Visit 1
use
and Visit 1
period, inf
us
eriod, inf
to
on; C=C
o
on; C=C
ty and Dep
to 
ty and Dep
t
ort 
C/R/
t
C/R/
C/R/D
ort 
C/R/D
rt
por
------
po
------ X
po
X
suppo
-
or
------------
pp
------------
po
-----------
up
-----------
pp
---------
su
---------
sup
ollect;
s
ollect;
s
any 
05, 
y
05, 
y
ny
D
a
D
a
marketing 
X008
g
X008
ting
3
m
3)
m
)
Visit
ket
Visit 16
t
16c
(EOS/E
rke
(EOS/E
Mo
r
Mo
et
ar
, 455, 
ma
, 455, 
995
m
995
ma
authorization 
ut
8-15
a
8-15
plication 
27, 3
n
27, 3
ay be perfo
n 
ay be perfo
data collected
atio
data collected
pp
ubject status
cat
ubject status fo
t
fo
y will be collec
pli
y will be collec
app
s >18 years old
pp
s >18 years old
arate extension
app
rate extension
nd 
t.
d
t.
an
and 6 month
and
and 6 month
t 12 inform
an
12 inform
, and 3
a
, and 3
any y
and meet el
ny
and meet el
nvulsive seizu
any
nvulsive seizu
extensions 
---
s
---X
s
X
-------
ns
-------X
s
X
s
---------
on
---------
ns
CBD=canna
sio
CBD=canna
sion Scale; P
nsio
sion Scale; P
io
required
ten
required (eg
n
(eg
not be curre
xte
not be curre
Study ZX0
ex
Study ZX0
consent 
ex
consent 
or 
-------
or
-------
r
X
o
X----
o
----
or variations 
ET)
s
ET)
nth 
n
nth 36
ns
36
s
1085
on
1085
ns
ati
iaiaiaia
ria
ar
va
v
thereof. 
02, and 
eof.
02, and 
Post
her
Post-
er
-Do
er
Do
ere
Vis
he
Vis
he
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 28 of 194  
Table 2. 
Schedule of Assessments for Subjects from Core Study ZX008-1504 
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET) 
Month 36
Visit 17m
Visit 18, 19m
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
Clinic
Phone
Informed Consent
X
Entry Criteria
X
Demographics
X
Medical/Neurological History
Xa
Epilepsy History
Xa
Physical Examination, complete
Xa
X
Xd
Physical Examination, abbreviated
X
X
Xd
Neurological Examination, complete
Xe
X
Neurological Examination, abbreviated
X
X
Vital signs
X
X
X
X
Weight, Height, BMI
Xa
X
X
X
12-lead ECG
Xa
X
X
Xd
Doppler ECHO
Xa
Xf,g
X
Xd
Urine Pregnancy Testh
X
X
X
Clinical laboratory evaluation 
(hematology/clinical chemistry/urinalysis, etc)
Xi
Xi
X
X
Urine THC Panel/Whole blood CBD
Xa
X
X
Plasma sample for background AEDs
X
X
X
Tanner Staging (for subjects > 7 years old)
Xa
Xj
X
Xj
C-SSRS
Xa
X
X
CGI-I (assessed by parent/caregiver)
Xa
X
X
CGI-I (assessed by principal investigator)
Xa
X
X
QOLCE
Xa
X
X
EQ-5D-5L (QoL of parent/caregiver)
Xa
X
X
BRIEF
Xa
X
X
Healthcare utilization questions
Xa
X
X
continued 
PUBLIC 
C
LIC
BL
B
X
U
X
UB
X
PU
X
PU
P
COPY 
Y
PY
OP
CO
C
This 
T
nt 
)
t
)
t
ment
er)
e
er)
nt
e
um
ns
u
ns
docum
um
not t
X
no
Xa
no
a
ot
cann
X
nn
Xa
n
a
n
an
ca
ca
ca
ca
ca
c
be 
be
b
used 
d
ed
se
se
se
se
se
X
u
Xi
u
i
u
to 
o
to support trt
o
pp
up
su
s
any y
any
a
marketing 
ng
8, 
k
8, 
Visit
etin
Visit 16
n
16
(EOS/
ke
(EOS/
Mo
k
Mo
tin
rk
5, 455, 
mar
5, 455, 
05, 995
ma
5, 995
ar
m
authorization 
ut
ion 
X
o
Xa
o
a
n
atio
X
tio
Xa
io
a
application
X
t
Xa
ati
c
X
ca
icic
licicic
plic
and 
X
d
X
d
and
a
any 
ny
an
a
extensions 
X
s
X
s
X
n
X
on
io
s
en
te
xt
ex
ex
ex
ex
e
or r
o variations 
nth 
s
nth 3
s
3
1085
ns
1085
s
titititio
ati
at
at
at
at
ria
ar
va
thereof. 
Post
ere
Post-
e
-D
e
D
eo
ET)
th
ET)
6
t
6
V
er
V
er
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 29 of 194  
Table 2. 
Schedule of Assessments for Subjects from Core Study ZX008-1504 (continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 
18, 21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET) 
Month 36
Visit 17m
Visit 18, 19m
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
Clinic
Phone
Karolinska Sleep Scale
Xa
X
X
Sleep quality/mealtime behavior questions
Xa
X
X
PedsQL
Xa
X
X
Study medication palatability assessment
Xk
Subject Diary
D
C/R/D
R
C/R/D
C/R
C/R
Study Medication
Db
C/R/D
R
C/R/D
C/R/D
C/R
Daily Diary Completion
------------------------------------------------------ X -----------------------------------------------------
Concomitant Medications
Xa
----------------------------------------------X--------------------------------------------------
Adverse Events
Xa
----------------------------------------------X--------------------------------------------------
Adverse events of special interest
Xa
----------------------------------------------X--------------------------------------------------
Xl
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CGI-I=Clinical Global Impression-Improvement; 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
NOTE:  If a subject has a birthday during the study that makes a previously unrequired assessment now required (eg, Tanner staging in a male subject who turns 8 years old during the study), this assessment(s) should be initiated 
at visits subsequent to the birthday.
a:
For subjects from the core Study ZX008-1504 Cohort 1, use data collected at the last visit of the transition period; for subjects from core Study ZX008-1504 Cohort 2 use data collected at the Visit 12 and Visit 13.
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures.  All results to determine eligibility must be reviewed prior to 
receiving the first dose of study drug at Visit 1.  
For subjects from ZX008-1504 Cohort 2 and de novo subjects, clinical laboratory, ECHO, and ECG results must be available and meet eligibility criteria prior to receiving the first dose of study drug at Visit 1.
b:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
c:
Or early termination.
d:
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination (see Section 6.3).
e;
Unless complete neurological examination is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1 and for subjects from Study 
ZX008-1504 Cohort 2, use data collected at the Visit 12.
f:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
g:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 ECHO may be performed any time within 3 weeks prior to the study visit. If a subject discontinues early from the study, the ECHO should be scheduled as soon as 
practical (see Table 7).
h:
Females of child-bearing potential
i:
Unless clinical laboratory evaluation is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1; for subjects from Study ZX008-
1504 Cohort 2, use data collected at the Visit 12. For Visit 2, clinical laboratory evaluation is optional based on subject status.
j:
Visits 6, 15, and 27.
k:
Visits 3 and 4 (Months 1 and 2) only.
l:
m:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
For subjects who are entering the separate extension trial or who transition to commercially available drug, post-dosing and cardiac safety follow-up visits are not required in this trial. 
UBLIC 
-------
C
-------
C
---------
LIC
---------
C
----------
BL
----------
LI
---------
UB
---------
BL
PUB
ory of Execu
PUB
ory of Execu
P
health statu
PU
health statu
UB
P
COPY 
Y
PY 
PY
O
CO
C
This 
T
ent 
is warrante
ent
is warrante
ume
a
m
at the Visit 
men
t the Visit 
d 2) only.
um
d 2) only.
docu
ed to cardia
cum
ed to cardia
entering the
ocu
entering the
cannot 
as a p
t
as a p
e 
n
e performed
not
performed
d based on 
nno
d based on 
it 12.
n
it 12.
2, 15, 18
can
2, 15, 18, 2
n
, 2
and 33
ca
nd 33 EC
ca
EC
be 
ng th
e
ng th
ical labora
be
ical labora
hone 
b
hone 
used 
HAD
d
HAD
assessment 
sed
assessment 
at the
us
t the last 
us
last 
s peri
u
s peri
o
----
o
----
to
Function
to 
Function
t
S=Hos
to
S=Hos
o support 
C/R/D
ort 
C/R/
t
C/R/
or
C/R/
ort
----------
pp
---------- X
o
X
po
-----------
up
-----------
pp
-----------
su
----------
up
----
s
----
s
any y
ny
X
a
Xk
a
k
an
D
a
marketing 
ued)
g
ued)
g
Visit
tin
Visit 16
ing
16c
ng
c
(EOS/ET
keti
(EOS/ET
Mont
rke
Mont
ing
rk
g
455, 
ar
455, 
5, 995
ma
5, 995
1
rk
rk
rk
ark
a
m
authorization 
ut
cation 
24, 27
n
24, 27
O may be
on
O may be pe
n 
p
ased on signif
ati
ased on signif
plica
For Visit 2, c
ica
For Visit 2, c
app
afety will be c
pp
afety will be c
parate extensio
app
parate extensio
and
and 6
nd
and 6 mon
nd 
mon
nificant cha
and
nificant cha
30, a
a
30, a
any 
form
y
form
ECHO
any
ECHO, and
ny
, and
sions
-
--------
s
--------X
s 
X
s
---------
on
---------
ns
---------
io
---------
on
nsio
=Collect; CB
nsi
=Collect; CB
exten
al Anxiety 
ens
al Anxiety 
sio
w required (
xte
w required (
of the tran
ex
f the tran
ed c
e
ed c
or r
------
o
------
or
o variations 
h 3
1085
ns
1085
s
X
on
X
on
tio
at
iat
at
at
a
ari
va
v
thereof. 
ost
re
ost-
re
-Dosin
reo
Dosin
eo
T)
th
T)
6
t
6
Visit 
ere
Visit 
re
th
t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 30 of 194  
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) and Lennox-Gastaut syndrome. Fenfluramine 
(Fintepla®) is authorized for sale in the United States for the treatment of seizures associated 
with Dravet syndrome in patients 2 years of age and older 
Dravet syndrome, previously 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 
International League Against Epilepsy (ILAE) considers Dravet syndrome a developmental and 
epileptic encephalopathy, “a condition in which the epileptic activity itself may directly 
contribute additional cognitive and behavioral impairments over those expected from the 
underlying etiology alone and that suppression of epileptic activity might minimize this 
additional impairment” (Scheffer 2017). 
Dravet syndrome is estimated to affect 1 out of every 15,700 live births in the US and less than 
1 in 20,000 persons in the European Union (Wu 2015; EMA 2014). Dravet syndrome is 
responsible for 7% of the severe epilepsies starting before the age of 3 years (Ceulemans 2004). 
The diagnosis of Dravet syndrome is based on clinical signs and symptoms, though the 
presence of a mutation in the SCN1A gene is considered a likely, though not definitive, marker 
for the disorder (Dravet 2011; Fujiwara 2006). Dravet syndrome is usually not diagnosed until 
at least 1 year of age (Cooper 2016) and is characterized by medically intractable seizures along 
with motor and neurodevelopmental comorbidities. Onset of the first seizure typically occurs in 
the first year of life (usually at 5 to 8 months of age) in otherwise healthy infants and most 
often consists of prolonged, unilateral or generalized, clonic seizures provoked by fever 
(Orphanet 2014; Ceulemans 2004; Dravet 2011). These patients will have poor response or 
worsening seizures to standard antiepileptic drugs, in particular, sodium channel antagonist 
medications (Dravet 2011).  
After the first year, other types of seizures often begin to occur with high frequency and include 
(1) convulsive seizures consisting of generalized clonic seizures, generalized tonic-clonic 
(GTC) seizures or alternating unilateral clonic seizures (in the youngest patients, they often 
evolve into status epilepticus [SE]); (2) myoclonic seizures (appearing between the ages of 1 
and 5 years); (3) atypical absences (appearing at different ages between 4 months and 6 years 
or later); (4) focal seizures with or without secondary generalization (appearing between the 
ages 4 months and 4 years); or (5) rarely, tonic seizures (TS) (Dravet 2011). Individuals with 
Dravet syndrome are at higher risk for SE that often results in injury and hospitalization 
(Ceulemans 2004). A high incidence for SUDEP (sudden expected death in epilepsy) exists in 
PUBLIC
ion
C
ion
epsies s
IC 
epsies s
me is ba
UBL
me is ba
SCN1A
PUB
SCN1A
1
P
1;
P
; Fuj
PU
Fuj
COPY 
pi
Y
pi
ut of eve
COP
ut of eve
n (
C
n (Wu
CO
Wu
C
This ocument
first y
nt 
first y
nvulsive
men
nvulsive
TC) seizu
ume
TC) seizu
evolve in
cum
evolve in
doc
and 5
doc
and 5
or 
do
or 
nnot
ge
t
ge
leman
ot 
leman
ca
es to 
nn
es to sta
no
sta
ravet 20
an
ravet 20
c
be
p
ly at 5
be 
ly at 5
d, uni
be
d, uni
used
wara 2
ed 
wara 2
016
se
016) and
sed
) and
mental 
us
mental 
t
u
t
to
ed
o
gene is
to 
gene is
20
t
20
support 
ry 15,7
ort 
ry 15,7
2015
po
2015;
or
; EM
or
EM
arting bef
ppo
arting bef
d on clin
su
on clin
any 
ctiv
y
ctiv
700
a
700
marketing 
ncy (SM
ng 
ncy (SM
(
et
(Dravet 
ting
Dravet 
drome a d
ket
drome a d
vity itself
ark
vity itself
er those e
ma
er those e
vity m
m
vity m
authorization 
eatment
iza
eatment
h
 associa
tho
 associa
a
application 
11
n
11)
n
)
r, other ty
atio
r, other ty
seizures c
cat
seizures c
ures or alt
plic
ures or alt
to status 
ppl
to status 
a
ears); (3
ap
ars); (3
4)
a
4)
a
nd 
2004
d
2004; 
d 
; 
an
ndard an
and
dard an
a
any 
8 mon
ny 
8 mon
teral or g
any
teral or g
Dra
a
Dra
extensions 
fore 
s
fore 
nical sig
ion
nical sig
consider
nsio
consider
06
te
06). Dra
tens
). Dra
is chara
xte
is chara
morbi
ex
morbi
e
or 
A 20
or
A 20
the 
o
the 
variations 
f may
s
f may
expecte
ons
expecte
might m
atio
might m
live bi
va
live bi
01
v
01
thereof. 
EI), is a 
reo
EI), is a 
1978
ere
1978). 
re
). 
develop
the
develop
y di
th
y di


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 31 of 194  
Dravet syndrome with the major risk factor being the frequency of generalized tonic-clonic 
seizures (Harden 2017).  
Dravet syndrome is highly treatment-resistant and affects infants, children, adolescents, and 
adults. In general, convulsive seizure semiology is similar in patients across ages, although 
seizures tend to become less frequent and less severe in patients with Dravet syndrome as they 
enter adulthood (Lagae 2018). Generalized convulsive seizures, mostly reported as generalized 
tonic-clonic seizures persist into adulthood, often with a focal onset. These seizures are less 
frequent than in childhood and are mostly nocturnal. Some of these major convulsive seizures 
may have less typical aspects, for example, bilateral or asymmetric tonic posturing, followed in 
some cases by a tonic vibratory state or clonic movements (Oguni, 2001; Akiyama 2009). 
Throughout the lives of patients with Dravet syndrome, frequent and disabling seizures are 
associated with significant neurobehavioral, cognitive, developmental, and motor 
comorbidities,
1.1.1
Existing Treatment for Dravet Syndrome 
Currently no treatment algorithm exists for Dravet syndrome as recommended by the ILAE 
(International League Against Epilepsy) or any other similar medical entity. The main 
treatment goal in Dravet syndrome aims to reduce the frequency, duration, and severity of 
seizures with the ultimate goal of complete or near-complete seizure-freedom (Wirrell 2017). 
Attaining seizure-freedom or near seizure-freedom may be particularly important during the 
early developmental years. However, even with currently available AED polypharmacy, 
seizure-freedom or near seizure-freedom is rarely achieved (Dravet 2000; Dravet 2005, 
Dravet 2011, Chiron 2011). Commonly prescribed anticonvulsant medications, the sodium 
channel antagonists such as phenytoin and carbamazepine, exacerbate seizures in Dravet 
syndrome and are thus not useful (Wirrell 2016). Treatment for Dravet syndrome involves 
finding the best combination of medicines to treat seizures with tolerable side effects, 
preventing SE, and reducing comorbidity and mortality risk. Elimination or significant 
reduction of prolonged convulsive seizures and SE should represent the highest priority in 
treatment (Wirrell 2017).
Stiripentol and cannabidiol are the only 2 treatments approved for seizures associated with 
Dravet syndrome. 
Other therapies, topiramate (TPM), levetiracetam (LEV), and bromide may provide efficacy as 
adjunctive therapy for some patients (Chiron 2011). Published uncontrolled studies with LEV 
(Striano 2007), verapamil (Iannetti 2009), ketogenic diet (KD) (Caraballo 2011a; Caraballo 
2011b), deep brain stimulation (Andrade 2010), and vagal nerve stimulation (VNS) (Zamponi 
2011) show infrequent clinically meaningful improvement. Carbamazepine, oxcarbazepine, 
lamotrigine, phenytoin, vigabatrin, and high doses of intravenous (IV) phenobarbital should be 
avoided because they often exacerbate seizures (Sazgar 2005; Wirrell 2016; de Lange 2018). 
PUBLIC
) or
C
) or
ims to r
LIC 
ims to r
complet
BLIC
complet
ear seizu
UBL
ear seizu
Howeve
PU
Howeve
ure
P
ure
P
f
P
f
COPY
ndrom
PY 
ndrom
r Dravet
COP
r Dravet
r any 
CO
r any 
This document
ol and 
nt 
ol and 
t syndro
men
t syndro
ther ther
cum
ther ther
adjunc
ocu
adjunc
(
do
(Str
do
Str
2
d
2
annot 
natio
ot
natio
reducin
not
reducin
longed c
ann
longed c
ca
rrell 20
can
rrell 20
c
be
phe
e
phe
t usefu
be 
t usefu
on o
b
on o
used
, ev
d
, ev
reedom
ed 
reedom
ommonl
use
ommonl
enyto
us
enyto
to 
re
o
re-fre
to
-fre
ven w
to
ven w
support 
syndrom
ort 
syndro
other sim
por
other sim
duce the 
upp
duce the 
or near
sup
or near
p
eedo
s
eedo
any 
me
a
marketing
nvu
g
nvu
posturin
ng 
posturin
1
e
1;
et
; Akiyam
eting
Akiyam
d disablin
ket
d disablin
ental, and
ark
ental, and
authorization 
d
gh 
iz
gh 
me as the
horiz
me as the
s genera
tho
s genera
ures are
auth
ures are
vulsiv
au
ulsiv
application 
7).
on
).
nnabidiol
atio
nnabidiol
me.
ica
me.
apies, top
pplic
apies, top
ve therap
app
ve therap
2007
ap
2007
and
f m
d
f m
g como
nd 
g como
nvulsiv
an
nvulsiv
any
n an
y
n an
Wirrell
ny 
Wirrell
medicin
an
medicin
b
extensions 
frequ
s
frequ
-compl
ons
-comple
s
e
om may
sion
om may
ith curre
nsi
ith curre
s rarely 
xten
s rarely 
y prescri
exte
prescri
nd c
e
nd c
or
lar m
or 
lar m
uen
o
uen
variations
d mot
ns 
d mot
as rec
va
as rec
d
v
d
thereof.
less
f
less
 seizure
of. 
 seizure
g, follow
reo
g, follow
ama 200
here
ama 200
g seizu
the
g seizu
tor
t
tor


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 32 of 194  
Rescue medications (clonazepam, diazepam, lorazepam, and midazolam, etc) are often used to 
stop prolonged seizures that may evolve to SE and require emergency intervention.  
Due to the severe and refractory nature of seizures associated with Dravet syndrome and given 
the risks of premature death from SUDEP, cognitive deficits, and other neurological 
consequences, there remains an urgent unmet medical need for the treatment of convulsive 
seizures associated with Dravet syndrome. The frequent and disabling seizures of different 
types, and the associated significant neurobehavioral, cognitive, developmental, and motor 
comorbidities that characterize Dravet syndrome, have a major negative impact on the patient's 
quality of life, as well as on their families. The neurobehavioral, cognitive, developmental, and 
motor comorbidities are at least partly caused by the poor control of seizures resulting in 
ongoing damage to the brain (Wolff 2006; Ragona 2011; Nabbout 2013; Wirrell 2016). A high 
incidence for SUDEP exists in Dravet syndrome with the major risk factor being the frequency 
of generalized tonic-clonic GTC seizures. 
Dravet syndrome drains a family emotionally, physically, and financially. Parents/caregivers 
suffer emotional exhaustion and anxiety related to the “fear of the next seizure” and “will this 
be the seizure that kills my child” (Campbell 2018). Patients with the highest seizure frequency 
tend to have more comorbidities and a lower quality of life (Lagae 2017). A 2006 study 
identified the challenges faced by parents caring for children with Dravet syndrome, reporting 
that the combination of persistent, severe seizures, together with developmental, behavioral, 
and sleep issues result in a high caregiver stress load with little ability to find respite and relief 
(Nolan 2006). The comorbid conditions, high mortality, disorder management requirements, 
and difficulties with family adaptation result in constant distress (Skluzacek 2011). In addition, 
Dravet syndrome is associated with extensive healthcare costs due to increased medical care 
use and intensive caregiver supervision as well as indirect burdens such as losses of 
productivity, family time, and leisure (Whittington 2018). The unremitting seizure episodes 
account for a high degree of healthcare resource utilization including hospitalizations, 
emergency room visits, and emergency transport services (Strzelczyk 2014). Aras and 
coworkers report 4 or more emergency room admissions in > 10% of children and up to 30 
admissions per year for some (Aras 2015). The impacts of Dravet syndrome typically not 
considered by healthcare professionals when making treatment decisions include the child’s 
expressive and receptive communications with family members, disruption of daily activities, 
and caregivers’ social interactions (Villas 2017; Nabbout 2013). 
A more effective treatment for Dravet syndrome that will abolish or significantly reduce 
seizure activity in a higher proportion of patients and provide periods of seizure freedom is 
urgently needed. Moreover, such outcomes could also lessen chronic brain injury and 
neuroinflammation due to unremitting seizures and thus potentially also improve Dravet 
syndromes’ associated comorbidities. 
PUBLIC 
nts ca
C
nts ca
evere se
LIC
evere se
caregive
UBL
caregive
conditio
PUB
conditio
adapta
PU
adapta
P
COPY
ysica
Y
ysica
d to the “
PY 
d to the “
l 2018
COP
l 2018)
P
)
wer qual
CO
wer qual
arin
C
arin
This document
by
t
by
ve and r
nt 
ve and r
aregivers
men
aregivers
more ef
cum
more ef
seizure
ocu
seizure
urge
do
urge
n
d
n
cannot
ee
t
ee
its, and
ot 
its, and
4 or mo
nno
4 or mo
year fo
ann
year fo
c
hea
ca
health
ca
lth
c
be
and le
be 
and le
of hea
be
of hea
b
used 
ion re
d 
ion re
with exte
sed
with exte
pervisio
use
pervisio
eisu
u
eisu
to
r s
s, high
to 
s, high
esu
to
esu
support
Patie
rt
Patie
ity of life
ort 
ity of lif
g for chil
ppo
g for chil
izures, to
upp
izures, to
tress lo
su
tress lo
h m
s
h
any
nd fin
y 
nd fin
ear of th
any
ear of th
ents w
a
ents w
marketing 
 develo
ng 
 develo
zures resu
ting
zures resu
13
ke
13; 
ket
; Wirr
eti
Wirr
sk facto
arke
sk factor
e
r
nan
m
nan
authorization 
ven 
at
ven 
lsive 
oriz
lsive 
ifferent 
thor
ifferent 
and mo
uth
and mo
t on th
au
on th
a
n
so
n
so
application
hcare pro
on 
hcare pr
ceptive co
atio
ceptive co
’ social in
icat
’ social in
fective tre
ppli
fective tre
activity i
app
activity i
need
ap
need
and 
merg
d
merg
e emerg
and
e emerg
ome (
an
me (A
n
A
any 
e (
ny
e (Wh
ny 
Wh
hcare re
any
hcare re
gency
a
gency
extensions
ld
ogether
ns 
ogether
oad with
ions
oad with
mortality
nsio
mortality
t in con
tens
t in con
nsive he
xte
nsive he
as we
ex
as we
hi
e
hi
or 
(
r
(La
r
La
ren w
or 
ren w
o variations 
r bein
s
r bein
ncially. P
atio
ncially. P
he next s
riat
he next s
with the
var
with the
agae
va
agae
thereof.
or
e patien
of. 
e patien
pmental,
eof
pmental,
ulting in
here
ulting in
rell 201
the
rell 201
ng t
th
ng t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 33 of 194  
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of DS. Fenfluramine 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 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). There is also a large body of information concerning its clinical safety 
profile.
1.3
CLINICAL DATA
Zogenix has conducted 2 positive, adequate and well-controlled, multi-national, randomized, 
double-blind, placebo-controlled trials of ZX008 in subjects with Dravet syndrome aged 2 to 18 
years, Study 1 and Study 1504 Cohort 2. Study 1 compared 2 doses of ZX008, 0.8 mg/kg/day
and 0.2 mg/kg/day, to placebo in subjects receiving standard of care anti-epileptic treatments
excluding stiripentol (STP). Study 1504 Cohort 2 compared a dose of ZX008 0.5 mg/kg/day to
placebo in subjects who were receiving stable standard of care anti-epileptic treatments where
administration of STP (in combination with clobazam [CLB] and/or valproate [VPA]; ie, the
STP regimen) was mandatory. These subjects were randomized to receive ZX008 or placebo in 
addition to their current standard of care treatments. The dose of 0.5 mg/kg/day was selected to 
account for the anticipated drug interaction when ZX008 was administered in combination with 
STP.  
The primary efficacy measure in both studies was the change from baseline in the frequency of 
convulsive seizures (per 28 days) during the combined 14-week (Study 1) or 15-week 
(Study 1504 Cohort 2) Treatment period. Key secondary objectives in both studies included a 
comparison of subjects who experienced at least a 50% reduction in monthly convulsive 
seizure frequency (also known as the ≥ 50% Responder Rate), and the median longest seizure 
free interval between convulsive seizures.  
PUBLIC
harmac
IC 
harmac
a large b
BLIC
a large b
TA
PU
TA
COPY
enefit 
PY 
enefit 
of fenf
CO
of fenf
C
This document
men) w
nt 
men) w
n to the
en
n to the
ount for 
me
ount for 
TP
cu
TP. 
cu
. 
The 
doc
The 
co
d
co
cannot
y
t
y
o place
ot 
o place
tol (STP
nno
tol (STP
ects who
ann
ects who
n of ST
ca
n of ST
wa
c
wa
be 
rolled
be
rolled
1504 C
be
1504 C
b
b
b
used 
ive, ade
use
ive, ade
d tr
u
d tr
to support 
uramine, 
port
uramine,
ogy, toxi
ppo
ogy, toxi
s
dy of inf
supp
dy of inf
any y
file for
ny 
file for
marketing 
fenfluram
ting
fenfluram
reports of
keti
reports of
Wong 19
arke
Wong 19
avorable 
mar
avorable 
he cata
m
he cata
f
authorization 
ames for
riza
ames for
as also 
horiz
as also 
fluramin
tho
fluramin
e) was a
aut
e) was a
application 
w
P (in co
on 
P (in co
s mandato
tion
s mandato
r current 
cat
r current 
the anticip
plica
the anticip
mary ef
ap
mary ef
and
o in 
d
o in 
). Study
and 
). Study
were re
an
were re
a
any
ls of 
ny 
ls of 
ohort 2. S
any
ohort 2. S
subje
a
subje
extensions
ico
s
ico
formati
ns 
formati
quate an
ext
uate an
f Z
e
f Z
or
here
or 
here
logy 
or
logy 
variations
998
s
998)
s
)
for the
ns 
for the
astrophic
tion
astrophic
fenflura
iati
fenflura
e is
v
e is
thereof. 
so 
f
so 
mine and
ere
mine and
f heart v
the
f heart v
)
th
) W
th
W


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 34 of 194  
Both Study 1 and Study 1504 Cohort 2 met the primary efficacy endpoint and all key secondary 
efficacy endpoints. In Study 1, subjects randomized to ZX008 0.8 mg/kg/day achieved a 
reduction in mean monthly (28 days) baseline-adjusted CSF of 62.3% compared to placebo 
(P < 0.001) and subjects randomized to ZX008 0.2 mg/kg/day achieved a 32.4% reduction 
compared to placebo (P = 0.021). In Study 1504 Cohort 2, in which all subjects were taking 
STP, subjects randomized to ZX008 0.5 mg/kg/day achieved a 54.0% reduction compared to 
placebo (P < 0.001).  
Controlling for multiplicity with a hierarchical testing procedure, all key secondary endpoints 
were met in both studies, for ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups (Study 1) and 
ZX008 0.5 mg/kg/day (Study 1504 Cohort 2). In Study 1, the proportion of subjects achieving a 
≥ 50% reduction from Baseline in CSF was 67.5% for the ZX008 0.8 mg/kg/day group, and 
38.5% for the 0.2 mg/kg/day group, with both groups being statistically significantly different 
from placebo (12.5%; P < 0.001 and P = 0.009, respectively). In Study 1504 Cohort 2, 53.5% 
of subjects randomized to ZX008 0.5 mg/kg/day compared to 4.5% of subjects randomized to 
placebo achieved a ≥ 50% reduction from Baseline in CSF (P <0.001).  
ZX008 was generally well tolerated in both Study 1 and Study 1504 Cohort 2. Though more 
subjects randomized to ZX008 than to placebo reported TEAEs during the double-blind 
studies, the percent of subjects with serious TEAEs was similar. Additionally, the adverse 
events observed in the program were either already known to be associated with fenfluramine, 
are common to many other antiepileptic drugs being prescribed to these patients, and/or are 
common to the age group and population studied. Specifically, the most common adverse 
events seen were diarrhea, fatigue, pyrexia, upper respiratory tract infection, blood glucose 
decreased, weight decreased, decreased appetite, lethargy and tremor. No valvular heart 
disease, pulmonary arterial hypertension or abnormal valve structure was observed in any 
subject at any time during the entire program.  
In an integrated analysis of safety of the double-blind studies, 117 (95.9%) subjects in any 
ZX008 treatment group and 68 (81.0%) subjects in the combined placebo group reported at 
least 1 TEAE. The most common (≥ 10%) TEAEs reported in subjects receiving any dose of 
ZX008 were: blood glucose decreased, constipation, decreased appetite, diarrhea, 
echocardiogram abnormal, fall, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, 
somnolence, status epilepticus, tremor, upper respiratory tract infection, vomiting, and weight 
decreased. All of the echocardiogram abnormal TEAEs were trace mitral or trace aortic valve 
regurgitation, which are normal physiological findings seen in healthy children (Webb 2015).  
Fifteen (12.3%) subjects in any ZX008 treatment group and 11 (13.1%) subjects in the 
combined placebo group reported at least 1 serious TEAE. The most frequently reported (≥5%) 
serious AEs (SAEs) were status epilepticus and seizure. A total of 3 (2.5%) subjects in any
ZX008 treatment group and 1 (1.2%) subject in the combined placebo group reported a serious 
TEAE determined by Investigators to be related to the study drug. In Study 1, two subjects, 
both of whom were in the ZX008 0.8 mg/kg/day group, reported SAEs that were considered by 
the Investigator to be related to study drug: SAEs of lethargy, and diarrhea leading to 
PUBLIC 
rious
C
rious
e eit
LIC
e either 
IC
her 
pileptic 
BLI
pileptic 
populat
PUB
populat
atigue, 
PU
atigue, 
de
P
de
COPY
ne in C
PY 
ne in C
Stu
O
Study 1
OP
dy 1
P
cebo rep
CO
cebo rep
s TE
C
s TE
This 
ment
gram
t
gram
ence, sta
ent 
ence, sta
ased
me
ased
docu
.
me
. A
e
A
gurgitati
um
gurgitati
Fifteen
ocu
Fifteen
com
doc
com
se
d
se
cannot
is o
t
is o
oup and
not 
oup and
he most 
nno
he most 
blood g
can
blood g
m ab
ca
m ab
be 
the en
be
the en
f saf
be
f saf
used 
pyrex
d
pyrex
creased a
sed
creased a
pertens
use
pertens
ntir
u
ntir
to
on stu
to 
on stu
xia,
to
xia,
support
and 
t
and 
orted TE
ort 
orted T
AEs was 
ppo
AEs was 
already kn
upp
already kn
ugs bein
sup
ugs bein
die
s
die
any
(P <0
ny 
(P <0
Study
an
Study
marketing 
ups (St
ng 
ups (St
n of subje
ting
n of subje
8 mg/kg/d
keti
8 mg/kg/d
ically sig
arke
ically sig
n Study 1
mar
n Study 1
4.5% o
m
4.5% o
0
authorization 
king 
riz
king 
pared to
hori
pared to
dary en
au
dary en
tu
a
tu
cation 
ucose
n
ucose
normal, f
tion
normal, 
us epilep
atio
us epilep
pplic
l of the ec
lica
l of the ec
on, which
pplic
on, which
ap
(12.3%) s
app
(12.3%) s
d plac
ap
d plac
and
68 (81
nd 
68 (81
ommon
and
ommon
e de
a
e de
any
progr
ny 
progr
y
a
y of the 
any
of the 
0%
a
0%
extensions
known 
ns 
known 
ng presc
ions
ng presc
ed. Spec
sio
ed. Spec
upper re
ens
upper re
ppetite, 
xte
ppetite, 
n or ab
ext
n or ab
ra
e
ra
or
AE
r
AE
imilar
or 
imilar
t
o
t
variations
gnifi
s
gnifi
1504 Co
ons 
1504 Co
of subjec
tion
of subjec
001).
iati
001).
a
y 1504 C
vari
y 1504 C
Es du
va
Es du
thereof.
dpoint
of. 
dpoint
dy 1) an
eof
dy 1) an
ects ach
ere
ects ach
day grou
the
day grou
ficant
th
ficant


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 35 of 194  
hospitalization in a 
 who was discontinued from the study; SAEs of seizure 
leading to hospitalization, drowsiness, reduced appetite, and weight loss in a 
who was discontinued from the study (The recorded weight loss was less than 1 kg.) In Study 
1504 Cohort 2, two subjects reported SAEs that were considered by the Investigator to be 
related to study drug: 2 episodes of seizure cluster, and seizure leading to hospitalization in a 
 in the placebo group; lethargy in a 
 in the ZX008 0.5 mg/kg/day 
group who was discontinued from the study. During the double-blind treatment periods, 7 
(5.7%) subjects in any ZX008 treatment group and 1 (1.2%) subject in the combined placebo 
group reported a TEAE that lead to discontinuation from study participation. There were no 
deaths during the double-blind treatment periods.
Subjects in Study 1 and Study 1504 if eligible could participate in this study, Study 1503, an 
open-label long-term, safety extension study. In a safety update of Study 1503 (cut-off date 14-
Oct 2019, n=330 enrolled), the median percent change in CSF compared to baseline (core 
study) for the overall open-label Treatment period (Day 1 to End of Study [EOS]) was -66.8% 
(P <0.001). The reduction from baseline in monthly CSF observed at Month 1 of the open-label 
Treatment period was maintained through Month 24, the longest treatment duration included in 
the analysis. A total of 317/330 subjects reported at least 1 TEAE during the open-label 
Treatment period. The most common (≥ 10%) TEAEs reported during the open-label Study 
1503 at the time of the cut-off date were blood glucose decreased, decreased appetite, diarrhea, 
ear infection, echocardiogram abnormal, influenza, nasopharyngitis, pyrexia, seizure, and upper 
respiratory tract infection. As in the double-blind studies, all of the echocardiogram abnormal 
TEAEs in Study 1503 were trace mitral or trace aortic valve regurgitation, which are not 
considered pathologic as stated in current guidelines on the use of ECHO for the assessment of 
valve function (Zoghbi 2017, Lancellotti 2010a, Lancellotti 2010b) . At least 1 treatment-
emergent SAE was reported by 80/330 (24.2%) subjects. The most frequently reported (≥ 5%) 
SAE was seizure, occurring in 24/330 (7.3%) of subjects. A total of 176/330 subjects (53.3%) 
experienced at least 1 TEAE that was considered to be related to study treatment and 8/330 
subjects (2.4%) reported at least 1 SAE that was considered to be related to study treatment. 
A total of 11/330 (3.3%) subjects discontinued due to a TEAE. 
Please reference the ZX008 IB for more detailed information on the safety and efficacy of 
ZX008. 
1.4
PRECLINICAL DATA
The pharmacokinetics (PK) of fenfluramine, norfenfluramine and their respective isomers has 
been studied in mice, rats, dogs and humans. The PK 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 PK and metabolism 
of fenfluramine after oral administration. A 10-week GLP juvenile toxicology and toxicokinetic 
study in rats, which included fenfluramine hydrochloride doses of 3.5, 9 and 20 mg/kg/day by 
PUBLIC
≥ 10
C
≥ 10
were blo
LIC 
were blo
normal, i
BLIC
normal, i
n the do
UBL
n the do
trace mi
PU
trace mi
ed in
P
ed in
COPY
(D
Y
(D
thly CS
PY 
thly CS
onth 24, 
OPY
onth 24, 
ported a
CO
ported a
0%) T
C
0%) T
This document 
en
t
en
The ph
docu
The ph
bee
do
bee
cannot 
TEA
ot
TEA
orted at
not
orted at
0 (3.3%
ann
0 (3.3%
nce the
ca
ce the
be
d by
e
d by
ng in 2
be 
ng in 2
AE t
b
AE t
used
tral
d
tral
curren
ed 
curren
Lancello
use
Lancello
y 8
u
y 80/3
us
0/3
to 
uble-b
to
uble-b
l or tr
to
l or tr
support t
t least 1
ort 
t least 
EAEs rep
por
EAEs rep
d glucose
upp
d glucose
nfluenza, 
sup
fluenza, 
blind
s
blind
any
En
y
En
observe
ny 
observe
e longes
any
e longes
1 T
a
1 T
marketing 
n. Th
g
n. Th
is study, S
keti
is study, S
f Study 15
arke
f Study 15
compared
mar
compared
nd of S
m
nd of S
d
authorization 
y
n in a 
riza
n in a 
mg/kg/
hori
mg/kg/
eriods, 7
utho
eriods, 7
bined p
aut
bined p
here
a
here
za
application 
ZX008 
on 
ZX008
RECLIN
plic
RECLIN
armacok
app
rmacok
ied
a
ied
and
hat
d
hat
least 1 
nd 
least 1 
subject
an
ubject
any 
0 (
y
0 (
330 (7.3
any
330 (7.3
was co
an
was co
SA
extensions 
e dec
s
e dec
 nasoph
ons
 nasoph
d studie
sion
d studie
ace aorti
ensi
ace aorti
guidelin
xten
guidelin
ti 2010a
exte
ti 2010a
(24.2
e
(24.2
or
orted
or 
orted
crea
o
crea
variations 
503 
s
503 
d to bas
ons
d to bas
Study [E
tion
Study [E
d at Mon
riati
d at Mon
est treatm
aria
est treatm
EAE d
va
EAE d
d
v
d
thereof. 
aceb
f
aceb
were no 
eof.
were no 
Study 1
the
Study 1
(
th
(cu
th
cu


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 36 of 194  
oral gavage for 10 weeks (Days 7 to 76 postpartum).  The data from the juvenile toxicology 
studies suggest that the effects of fenfluramine in juvenile animals (CNS-related clinical signs, 
effects on body weight and food consumption, and neurobehavioral deficits) are similar to 
effects previously reported in neonatal and adult rats (ZX008 IB). There was no evidence of 
CNS-related histopathology findings.; Importantly, there were also no histopathologic findings 
in aortic or mitral cardiac valves, and no adverse effects on any other tissues at necropsy.  
The NOAEL for the juvenile rats was determined to be 9 mg/kg/day. A NOAEL of 9 
mg/kg/day corresponds to PND 76 AUC0-t of 3480 hr*ng/mL for males and 4680 hr*ng/mL 
for females for fenfluramine, and 4470 hr*ng/mL for males and 6210 hr*ng/mL for females for 
norfenfluramine. The AUC(0-t) at the NOAEL in this study, 9 mg/kg/day, provided a safety 
factor (both sexes combined) of approximately 3-fold or higher for fenfluramine and 
approximately 6-fold or higher for norfenfluramine. 
Further preclinical data on ZX008 are available in the Investigator’s Brochure (ZX008 IB). 
1.5
PHARMACOKINETICS 
Fenfluramine is metabolized to norfenfluramine. CYP1A2, CYP2B6 and CYP2D6 appear to be 
the predominant CYP (cytochrome P450) 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 Food and Drug Administration’s (FDA’s) mechanistic static 
model shows that fenfluramine and its major metabolite norfenfluramine are unlikely to alter 
the PK of substrates of these CYP450 enzymes in the range of ZX008 doses that will be 
administered in this study. 
Study 1 and Study 1504 Cohort 2 
Pharmacokinetic parameters of fenfluramine and norfenfluramine for patients with Dravet 
syndrome were determined using a population pharmacokinetic (PopPK) model developed 
using PK data from both healthy volunteers and patients with Dravet syndrome and are 
provided in the Table 3 below. 
PUBLIC
50) en
C 
50) en
C19 and 
LIC
C19 and 
ibution 
UBL
ibution 
rmaine (
PUB
rmaine (
P
amine 
PU
amine 
P
COPY 
amine. 
CO
amine. 
nzy
C
nzy
This 
t
document
substr
nt 
substr
stered in
men
stered in
tudy 1 a
cum
tudy 1 a
Pha
do
Pha
s
d
s
cannot 
show
ot 
show
2D6 and
nno
2D6 and
based o
ann
based o
that fen
ca
that fen
ra
c
ra
be 
d
b
d
used
have m
d 
have m
use a sig
sed
use a sig
creases
use
creases
to
f r
o
% - 
to
% - 8
o 
8
mu
to
mu
support 
CYP1A2
port
CYP1A2
mes that
ppo
mes that
CYP3A4 
upp
CYP3A4 
renal cl
su
renal cl
%)
s
%)
any 
g
y
g
marketing 
g/mL f
ng 
g/mL f
ay, provid
ting
ay, provid
enflurami
keti
enflurami
ator’s B
m
ator’s B
authorization 
of 
z
of 
findings 
riza
findings 
opsy.  
hori
opsy.  
of 9 
uth
of 9 
680 hr
au
680 hr
f
a
f
on 
n 
nfluram
on 
nfluram
applicati
es of thes
tion
es of thes
this stud
cati
this stud
nd Study 
ppli
nd Study 
okine
ap
okine
and
tha
d
tha
fenflura
nd 
fenflura
the Fo
an
he Fo
i
a
i
any 
at both
a
at both
ions
m
also ap
ns 
also ap
learance
ion
learance
nsio
)
n
)
exten
from t
nsio
from t
tiple pa
tens
tiple pa
nificant 
xte
nificant 
f multi
ex
f multi
or 
CY
or
CY
etabo
or
etabo
variations 
Brochur
tion
Brochur
YP2
v
YP2
thereof.
*ng/mL
of. 
*ng/mL
r female
eof
r female
ded a sa
here
ded a sa
ine and 
the
ine and 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 37 of 194  
Table 3 
Post Hoc Estimates of Fenfluramine and Norfenfluramine Steady-State 
Pharmacokinetic Parameters in Subjects with Dravet Syndrome in Study 1 
(Geometric Mean [CV%])
Analyte:
Fenfluramine
Norfenfluramine
ZX008 Dose
0.2 mg/kg/day
0.8 mg/kg/day
0.2 mg/kg/day
0.8 mg/kg/day
Cmax (ng/mL)
18.5 (29.1)
68.0 (40.7)
9.60 (52.8)
37.8 (49.9)
AUC0-24 (ng.hr/mL)
375 (32.9)
1390 (43.5)
220 (55.5)
872 (52.1)
Tmax (hr) Median 
(Min, Max)
3.00 (3.00 to 3.50)
3.00 (3.00 to 3.50)
4.00 (3.50 to 5.00)
4.50 (3.50 to 5.00)
Source: ICPD Report 00445-3, Table 5.
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours; BID = twice daily; 
Cmax = peak plasma drug concentration; CV= coefficient of variation; Max = maximum; Min = minimum; Tmax = time of peak 
plasma drug concentration. 
Study 1504 Cohort 2 required STP as a concomitant medication. Although the dose of ZX008 
in Study 1504 Cohort 2 was lower than the high dose in Study 1, fenfluramine AUC0-24 values 
were approximately 130% higher in Study 1504 Cohort 2, than the high dose in Study 1, and 
norfenfluramine AUC0-24 values were approximately 60% lower than in Study 1. However, the 
clinical results indicated that the efficacy and AE profile were similar between Study 1 and 
Study 1504, indicating that the dose adjustment studied for the concomitant use of the STP 
regimen met the intended clinical outcome.
1.6
CLINICAL PHARMACOLOGY 
Please see the ZX008 IB for details on clinical pharmacology. Below are the clinical 
pharmacology conclusions.  
•
Coadministration of ZX008 with the STP regimen (STP with CLB and/or VPA) resulted in 
an increased fenfluramine and decreased norfenfluramine concentrations, and therefore a 
dose adjustment is used in the clinical trials.
•
STP is the predominant perpetrator of the interaction; while VPA and CLB do not have a 
significant independent impact on the PK of fenfluramine or norfenfluramine, whether 
administered with or without STP.
•
Coadministration of ZX008 with CBD at steady state resulted in increased fenfluramine 
concentrations but this increase was within the range of 
 dosing used in Study 1504 
Cohort 2; thus, no dose adjustment is recommended when fenfluramine is coadministered 
with CBD. 
PUBLIC
pp
C
pp
acy an
IC 
acy an
se adjust
BLIC
se adjust
al outco
UBL
al outco
ARM
PU
ARM
COPY
ant m
PY 
ant m
gh dose 
OPY
gh dose 
1504 Co
COP
1504 Co
roxima
CO
roxima
d
C
d
This document
s the p
nt 
s the p
nificant 
ent
nificant 
dminist
me
dminist
•
o
•
Co
cu
Co
cannot
of ZX
ot 
of ZX
nfluram
no
nfluram
ment
an
ment is
nn
is
n
pre
c
pre
be 
. 
b
. 
0
b
0
used
ACOL
d 
ACOL
etails o
use
etails o
to 
me.
o
me.
O
t
O
support 
hort 2
rt 
hort 2
tely 60%
port
tely 60%
AE profil
ppo
AE profil
ment stud
sup
ment stud
any 
ation. 
ny 
ation. 
Study 1
any
Study 1
, tha
a
tha
marketing 
4
g
4
ting
ng
ng
4 hours; BID
ket
4 hours; BID
Min = mini
rke
Min = mini
A
authorization 
ati
g/kg/day
oriz
g/kg/day
iz
37.8 (49.9
tho
37.8 (49.9
ho
872 (
aut
872 (
50 (
a
50 (
pplication 
s
dominant 
tion
dominant 
ndepende
cati
ndepende
red with
lica
red with
ap
dministra
app
dministra
entra
ap
entra
and 
08 w
d
08 w
ne and 
nd
ne and 
ed in th
an
d in th
any 
with th
a
with th
extensions
le w
s
le w
died for
ns 
died for
GY 
te
GY 
clinica
ex
clinica
or
lowe
or 
lowe
were 
or
were 
variations 
mum
s
mum
Although
iatio
Although
1, fenflu
aria
1, fenflu
an the h
va
n the h
er t
v
er t
thereof. 
2.1)
f
2.1)
3.50 to 5.
eof.
3.50 to 5.
ere
D = twice 
the
D = twice 
m; T
th
m; T


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 38 of 194  
•
In the population PK analysis, intrinsic patient factors (age, gender, race/ethnicity, and 
BMI) demonstrated no substantial impact on the clearance or exposure to fenfluramine or 
norfenfluramine when dosed on a mg/kg basis to a maximum of 30 mg/day. 
•
ZX008 had no effect on QTc intervals at either the therapeutic or supratherapeutic dose, 
and no relationship was observed between fenfluramine or norfenfluramine exposure and 
QTcF.
•
ZX008 exhibited approximately dose proportional PK over a 4-fold range of doses (15 to 
120 mg/day). 
•
CYP450 metabolizer genotype for CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 
had no impact on the PK of fenfluramine or norfenfluramine. 
1.7
BACKGROUND INFORMATION ON REFERENCE PRODUCT
Not applicable.
1.8
RATIONALE FOR CURRENT STUDY
The rationale for conducting this open-label extension study is primarily to evaluate the long-
term safety of ZX008 in DS. This protocol also provides the opportunity for continued 
treatment for subjects responding to treatment from the Phase 3 double-blind studies, and an 
opportunity for initial treatment with ZX008 for subjects randomized to placebo in those 
studies. 
1.9
RATIONALE FOR INCLUDING DE NOVO SUBJECTS
Subjects who are >18 to ≤35 years of age at the time of screening, and who meet all other 
eligibility criteria may be eligible for participation after discussion with the Medical Monitor 
and sponsor about the potential risks and benefits for receiving ZX008.  Participation for these 
subjects will be at the discretion of the sponsor.   
Epileptic seizures tend to become less frequent and less severe after childhood; however, the 
mortality rate remains high.  One study on the long-term outcome of 24 adult patients with DS 
reported 5 (20.8%) deaths, at a mean age of 24.8 years, one by status epilepticus, three by 
sudden unexpected death in epilepsy (SUDEP), and one of unknown cause (Genton 2011). 
Fever sensitivity (temperature variations) persists throughout the clinical course of DS, but its 
impact on seizure frequency and severity is milder than in infancy. Generalized convulsive 
seizures, mostly reported as generalized tonic-clonic seizures persist, often with a focal onset 
but are less frequent than in childhood and mostly nocturnal. Some of these major convulsive 
seizures have less typical aspects, for example, bilateral or asymmetric tonic posturing, 
followed in some cases by a tonic vibratory state or clonic movements (Oguni 2001; 
PUBLIC 
pen-
LIC
pen-labe
LIC
labe
s protoc
BL
s protoc
ding to tr
PUB
ding to tr
ment
PU
ment wi
PU
wi
COPY 
NT ST
CO
NT ST
This document 
c seizur
ent
c seizur
ality rat
me
ality rat
ported 5
cum
ported 5
sudden
ocu
sudden
Feve
do
Feve
im
d
im
ot 
to ≤3
ot 
to ≤3
cann
may be e
not
may be e
ut the p
ann
ut the p
be at the
can
e at the
be 
FOR
e
FOR
35 y
b
35 y
used 
h ZX
d
h ZX
R IN
u
R IN
to
eatmen
to 
eatmen
X00
to
X00
support 
UDY
ort
UDY
extension
upp
extension
also pro
sup
also pro
t f
s
t f
any marketing 
e o
g
9, CYP2D
keti
9, CYP2D
ENCE 
m
ENCE 
authorization 
ose, 
riz
ose, 
sure and
horiz
sure and
of dos
au
f dos
application 
discre
on 
discre
es tend to
atio
es tend to
remains 
lica
remains 
(20.8%) 
pplic
(20.8%) 
unexpect
app
unexpect
nsitiv
ap
nsitiv
d
year
d
year
and
ligible f
nd 
ligible f
ential r
an
ential r
eti
a
eti
any 
LU
y
LU
r
a
rs of ag
an
s of ag
extensions
n stud
ns 
n stud
rovides t
ions
rovides t
from 
nsio
from the
sio
the
8 for sub
ens
8 for sub
UDI
e
UDI
or 
o variations 
PROD
tion
PROD
thereof.
s (15 to
of. 
s (15 to
D6, or C
the
D6, or C


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 39 of 194  
Akiyama 2010). Other seizures like myoclonic seizures, atypical absences, and complex partial 
seizures are less common in adulthood.  Motor abnormalities are also common in adulthood, as 
is intellectual disability. Dependency in adulthood is nearly constant. 
Including subjects >18 to ≤35 years of age provides the opportunity to investigate the impact of 
ZX008 on DS outcomes as subjects transition to adulthood.
1.10
RISK-BENEFIT ASSESSMENT
Fenfluramine has been used successfully for up to 30 years in Belgium in refractory pediatric 
epilepsy patients, including those with DS (Boel 1996, Ceulemans 2012, Ceulemans 2016, 
Schoonjans 2016, Schoonjans 2017). The efficacy and safety of this therapeutic approach has 
been reported to be overwhelmingly favorable. 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. No patients experienced 
emergence of clinical valvulopathy or pulmonary hypertension. 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. Fenfluramine has 
also been administered to over 500 children with neurobehavioral conditions, including autism 
and ADHD with good safety and tolerability. Doses tested in these pediatric studies 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. 
In addition, ZX008 demonstrated a statistically significant and clinically meaningful reduction 
in monthly convulsive seizure frequency in Study 1 and Study 1504 Cohort 2 and was 
generally well tolerated.  There was no clinical or echocardiographic evidence of cardiac 
valvulopathy or pulmonary hypertension and no patient discontinued participation or required a 
change in monitoring in the study due to cardiac factors. The PK exposure associated with the 
doses of ZX008 in the DS studies of 0.2 mg/kg/day to 0.8 mg/kg/day administered orally [in 
equally divided doses twice per day (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). The doses used in this study are based on the data 
from the DS patients being successfully treated in Belgium discussed above and supported by 
results from Study 1 and Study 1504 Cohort 2. 
Interim results from this open-label study show that the effects observed during the double-
blind studies were durable and long-lasting; the reduction in convulsive seizures for subjects in 
Study 1503 was maintained throughout study participation of up to 3 years at the time of the 
interim analysis, with no evidence for developing tolerance. The pharmacologic and 
toxicological profile for the active pharmaceutical ingredient, fenfluramine, following oral 
administration is well established (ZX008 IB).
BLIC
dre
C
dre
erability
LIC 
erability
g/day, bu
BLIC
g/day, bu
PUB
 to 80 m
UBL
 to 80 m
rated 
PU
rated 
COPY
%
Y
%
in seizu
PY 
in seizu
nary hyp
OPY
nary hyp
cts over 
COP
cts over 
en wit
CO
en wit
This 
ument
and
t
and
DS pat
ent 
DS pat
s from S
men
s from S
docu
nterim 
cum
nterim 
blind
doc
blind
Stu
do
Stu
nnot
n th
t
n th
he DS s
ot 
he DS s
oses tw
nno
oses tw
ca
the past 
can
the past 
d ado
ca
d ado
be
e
y hype
be 
y hype
he stu
be
he stu
used
a statis
ed 
a statis
frequenc
sed
frequenc
e was 
us
e was 
u
to 
g we
o
g we
ti
t
ti
support t
 year o
ort 
 year o
h neurobe
por
h neurobe
Doses tes
pp
Doses tes
t a comm
sup
a comm
ere us
s
ere us
any
on
y
on
freque
ny 
freque
ension.
any
ension.
of a
a
of a
marketing 
refracto
ng 
refracto
,
t
, Ceulem
ting
Ceulem
therapeut
keti
therapeut
ed patien
arke
ed patien
om being
mar
om being
n in se
m
n in se
authorization 
mpact of
riza
mpact of
a
plication
for th
n
for th
escents (
ion 
escents 
ents being
atio
ents being
tudy 1 an
icat
tudy 1 an
app
esults fro
pp
esults fro
udies w
ap
udies w
3
a
3
and 
udies 
d
udies 
ce per d
and
ce per d
the tr
a
the tr
any y
nsion a
ny 
nsion a
y due to
any
y due to
of 0
a
of 0
nsions 
ested
s
ested
monly us
ons
monly us
exte
sed. 
sio
sed. 
cally sig
ten
cally sig
y in Stud
exte
y in Stud
clinic
ex
clinic
or
havio
or 
havio
d in t
o
d in t
variations 
nts, 1
s
nts, 1
g 6 year
ons
g 6 year
eizure fr
tion
eizure fr
ncy. No 
iati
ncy. No 
n. The do
aria
n. The do
ge to a
va
ge to a
v
thereof. 
y pediat
eof
y pediat
mans 20
ere
mans 20
tic appr
the
tic appr
10 (
th
10 (


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 40 of 194  
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. Subjects 
will be enrolled into this study from the core studies where they had been transitioned to the 
lowest dose of ZX008 (0.2 mg/kg/day; maximum 30 mg/day or 20 mg/day for subjects from 
ZX008-1504 Cohort 1 dose regimen 3 or Cohort 2) and will remain on this dose for the first 
month of this study. After this time, the dose of ZX008 may be adjusted based on effectiveness 
and tolerability. For subjects that participated in core studies ZX008-1501, ZX008-1502, and 
dose regimen 1 or 2 from Cohort 1 of ZX008-1504 dose increases may be made in increments 
of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day (maximum dose 30 mg/day), and these 
increases should not occur earlier than every 14 days at each dose level. For subjects that 
participated in core study ZX008-1504 Cohort 1 dose regimen 3 and Cohort 2 and are receiving 
concomitant STP the first dose change will be to 0.4 mg/kg/day and the final dose change will 
be to 0.5 mg/kg/day, but not to exceed 20 mg/day. Dose increases may only occur after a 
review of the diary and reported adverse events (AEs), and if, in the investigator’s opinion, 
seizure frequency, severity, and/or duration indicates a change in medication regimen is 
warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. Dose adjustments outside of these 
parameters must be discussed with the Medical Monitor prior to initiation.  
It is acknowledged that the initial dose of ZX008 in this study, 0.2 mg/kg/day, may or may not 
be effective or may be less effective than 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking 
concomitant STP) for some subjects and some subjects may experience a worsening of their 
seizure condition after transitioning to the lower dose. However, there is benefit in identifying a 
minimally effective dose for all subjects in the study since the cardiotoxicity of fenfluramine 
appears to be dose-related in adults. The dosing instructions of this protocol permit dose 
adjustment during the first month of fixed dosing at 0.2 mg/kg/day if a clinically meaningful 
worsening occurs, such as an increase in frequency, severity or duration of existing seizures, or 
emergence of a new seizure type. 
The approximate volume of blood (240 mL) planned for collection from each subject over the 
course of the entire study (approximately 3 years, 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, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day, and 0.5 mg/kg/day 
(in subjects taking concomitant STP) 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.
PUBLIC
ose of ZX
LIC 
ose of ZX
ive than 
BLI
ive than 
bjects an
UB
bjects an
tioning
PU
tioning
all
P
all
P
COPY
tes 
Y
tes 
occur at 
PY 
occur at 
ituation.
OP
ituation.
edical M
CO
edical M
This 
ment 
the 
nt
the 
ZX008 0
men
ZX008 0
docu
n subject
um
n subject
provide
ocu
provide
Th
d
Th
cannot 
eizure
ot
eizure
e volum
ann
e volum
entire st
can
entire st
inv
c
inv
be
mon
e
mon
s an inc
be 
s an inc
e ty
b
e ty
used
to th
d
to th
ubjects 
ed 
ubjects 
dults
use
dults. Th
se
. Th
nth o
us
nth o
to
d som
to 
d som
the lo
to
the lo
support
Dos
t
Dos
onitor pr
ort 
onitor p
X008 in th
upp
X008 in th
.8 mg/kg
sup
8 mg/kg
me su
s
me su
any 
ge in
y
ge in
e invest
any
e invest
se adju
an
se adju
i
marketing
day),
g
day),
For subje
ing 
For subje
Cohort 2 a
etin
Cohort 2 a
d the final
rket
d the final
es may on
ark
es may on
in the inv
ma
n the inv
n me
m
n me
authorization 
m
za
m
first 
riz
first 
fectivene
hori
fectivene
-1502, 
tho
-1502, 
e in incr
aut
e in incr
, and
a
, and
lication 
udy (a
n 
udy (a
stigator
tion
stigator)
n
)
2 mg/kg/
lica
2 mg/kg/
app
s taking c
plic
s taking c
sufficien
app
sufficien
b
and 
pe
d
pe
of bloo
and
of bloo
app
a
app
any 
fixe
y
fixe
ase in f
any
ase in f
extensions
his stu
ns 
his stu
g/day (o
ons
g/day (o
subjects 
sio
subjects 
wer dos
ens
wer dos
n the stu
xten
n the stu
e dosing
ext
e dosing
ed d
e
ed d
or 
or 
r
or 
udy
o
udy
variations
nly occ
ns 
nly occ
nvestigat
ions
nvestigat
medicatio
atio
medicatio
tigator’s
riat
tigator’s
ustment
vari
ustment
to in
va
to in
thereof. 
emen
f
emen
these 
eof
these 
ects that
reo
ects that
and are 
here
and are 
dose c
the
dose c
t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 41 of 194  
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1
PRIMARY OBJECTIVE
The primary objective of the study is: 
•
To assess the long-term safety and tolerability of ZX008. 
2.2
SECONDARY OBJECTIVES 
The secondary objectives of the study are: 
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following 
effectiveness measures:
- The change in the frequency of convulsive seizures from Visit 3 to Visit 8 (ie, Day 31 
to Day 365) and for the entire Year 1 treatment period (ie, Visit 1/Day 1 to Visit 8/ 
Day 365) 
- The proportion of subjects who achieve a ≥ 40%, ≥ 50%, and ≥ 75% reduction in 
convulsive seizure frequency 
- The longest convulsive seizure-free interval
- The percentage of convulsive seizure-free days
- The non-convulsive seizure frequency 
- The convulsive + non-convulsive seizure frequency
• To estimate the incidence of the following on subjects receiving ZX008: 
- Use of rescue medication
- Hospitalization to treat seizures
- Status epilepticus (SE)
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following QoL 
measures:
- Quality of Life in Childhood Epilepsy (QOLCE) score 
- Pediatric Quality of Life Inventory™ (PedsQL score) 
- PedsQL Family Impact module score 
- QoL of the parent/caregiver using the standardized measure of health status 
(EQ-5D-5L scale
- Affective symptoms of the parent/caregiver using the Hospital Anxiety and Depression 
Scale (HADS)
• To assess the effect of ZX008 on the following QoL measures: 
- Clinical Global Impression – Improvement (CGI-I) rating, as assessed by the principal 
investigator 
- CGI-I rating, as assessed by the parent/caregiver 
PUBLIC
fre
C
fre
ve seizur
LIC 
ve seizur
ure frequ
BLI
ure frequ
convuls
UB
convuls
nce of th
PU
nce of th
tio
P
tio
COPY 
me
Y
me
eve a ≥ 4
OPY
eve a ≥ 4
e int
C
e int
This document
oL of
nt 
oL of
(EQ
ent
(EQ-5D
nt
-5D
-
m
- Affe
me
Affe
S
m
S
•
oc
• T
cu
T
cannot 
Life in 
not
Life in 
c Qualit
ann
c Qualit
QL Fam
can
QL Fam
f th
c
f th
be
SE)
e
SE)
of ZX0
be 
of ZX0
used 
e fo
d
e fo
t seizure
use
t seizure
to
ve sei
to 
ve sei
ollow
to
ollow
support 
0%
t
0%
rval
po
rval
-free day
upp
free day
ncy
su
ncy
izur
s
izur
any 
od (
y
od (
%, ≥ 50
an
%, ≥ 50
marketing 
ne on the 
ket
ne on the 
om Visit 
ma
m Visit 
(ie, V
m
(ie, V
authorization 
cation 
y
ily Imp
on 
ily Imp
e parent/c
tion
e parent/c
-
c
-5L scale
cati
5L scale
pplic
ctive sym
plica
ctive sym
cale (HAD
ppli
cale (HAD
ap
assess t
app
assess t
Clini
a
Clini
and
Childho
nd 
Childho
of Life
an
of Life
a
any 
8
a
8 relativ
any
relativ
d
extensions 
ys
ns
ys
re frequ
sio
re frequ
ing on s
ens
ing on s
s
or variations 
3 to Vi
ons
3 to Vi
Visit 1/D
atio
Visit 1/D
0%, and 
vari
0%, and 
thereof. 
follow
the
follow


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 42 of 194  
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for subjects who participated in core study ZX008-1504 are: 
• To assess the effect of ZX008 on the following QoL measures: 
- Sleep quality and mealtime behavior, as assessed by the parent/caregiver 
- Karolinska Sleep Scale
- Health and social care resource use (These measures include planned and unplanned 
hospital visits, use of ambulances, General Practitioner (GP) visits, speech and 
language therapy utilization, occupational and physical therapy utilization) 
2.4
STUDY ENDPOINTS
2.4.1
Effectiveness Endpoints
The effectiveness endpoints of the study are: 
•
Number of seizures by type 
•
Convulsive seizure-free interval
•
CGI-I as assessed by parent/caregiver
•
CGI-I 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 parent/caregiver using the EQ-5D-5L scale
•
Affective symptoms of parent/caregiver using the HADS (in parents/caregivers from 
core studies ZX008-1501 and ZX008-1502 only) 
•
Duration of prolonged seizures (seizure type that, during pre-Z008 baseline, had 
duration > 2 minutes) 
•
Number of episodes of SE
•
Number of instances of rescue medication use and number of doses 
•
Number of inpatient hospital admissions due to seizures 
2.4.2
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
PUBLIC
gi
C
gi
al inves
LIC 
al inves
es in qu
BLIC
es in qu
anges in 
UB
anges in 
act mod
PU
act mod
COPY 
ver
CO
ver
This 
cument
umber
nt 
umber
2
doc
The sa
docu
The sa
cannot
rolong
ot 
rolong
2 minut
no
2 minut
of epis
ann
of epis
er of in
ca
er of in
c
be
s of p
e
s of p
08-1501
be 
08-1501
ed
b
ed
used 
ule t
d
ule t
er using 
use
r using 
pare
u
pare
to 
qualit
to
qualit
to m
to
to m
support 
gator 
upp
gator 
lity of lif
sup
ity of lif
ty of
s
ty of
any marketing 
pe
g
p
tilization
ng 
tilization
authorization 
nd unpla
auth
nd unpla
eech a
au
ech a
ion 
od
stances
on 
stances
pplicati
f inpatien
atio
f inpatien
Safety
plica
Safety En
ca
En
ap
ety endp
app
ty endp
and 
sei
d
sei
es) 
n
es) 
es of 
an
es of S
n
S
any 
t/car
y
t/car
and ZX0
any
and ZX0
zures 
an
zures 
extensions 
fe of the
ons
fe of the
f life of 
sion
f life of 
easure ch
ens
easure ch
he EQ-5
ext
he EQ-5
reg
e
reg
or variations thereof. 
nne
f
nne
nd 
o
nd 
) ) 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 43 of 194  
•
12-lead electrocardiogram (ECGs) 
•
Doppler echocardiogram (ECHOs) 
•
Body weight 
•
Behavior Rating Inventory for Executive Function (BRIEF) to measure 
cognition 
2.4.3
Exploratory Endpoints 
For subjects who participated in core study ZX008-1504 only, the exploratory endpoints of this 
study are: 
•
Health and social care resource use, including GP visits, speech and language, 
occupational and physical therapy, in addition to acute hospital and institutional length 
of stay, loss of work, etc. 
•
Sleep quality
•
Mealtime behavior
•
Karolinska Sleepiness Scale to measure the effect of study medication on sleepiness 
PUBLIC COPY 
e the effe
OPY
e the effe
This document cannot be used to support any 
t of
an
t of stud
any
 stud
f f
an
f f
marketing 
ry e
g
ry e
h and lang
etin
h and lang
ital and in
rke
ital and in
authorization 
endpo
a
endpo
application and any extensions or 
iations 
in
var
dy medi
aria
dy medi
thereof.
oints of t
of. 
oints of t
nguage, 
her
nguage, 
stitutio
the
stitutio


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 44 of 194  
3.
INVESTIGATIONAL PLAN
3.1
OVERALL STUDY DESIGN AND PLAN
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric 
and young adult subjects with DS. Subjects eligible for participation are those who have 
successfully completed 14 weeks of treatment in core studies ZX008-1501 or ZX008-1502, and 
15 weeks of treatment in core study ZX008-1504 Cohort 2, or successfully completed core 
study ZX008-1504 Cohort 1, and are candidates for continuous treatment for an extended 
period of time. In addition, subjects who are >18 to ≤35 years of age at the time of screening, 
and who meet all other eligibility criteria may be eligible for participation after discussion with 
the Medical Monitor and sponsor about the potential risks and benefits for receiving ZX008.  
Participation for these subjects will be at the discretion of the sponsor.  
This trial will consist of an up to 36-month open-label extension (OLE) Treatment Period and a 
2-week Post-Dosing Period. Thus, subjects who complete this trial will have been treated with 
ZX008 for a minimum of up to 3 years (including their participation in both the core study and 
this study). Subjects who did not participate in one of the core studies will undergo a screening 
period up to 28 days to confirm eligibility prior to receiving their first dose in the OLE 
Treatment Period
During the OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day for 
1 month to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 
0.2 mg/kg/day, the investigator may adjust the dose of each subject based on effectiveness and 
tolerability. For subjects who are not receiving concomitant STP, including de novo subjects 
and those who participated in core studies ZX008-1501, ZX008-1502, and dose regimen 1 or 2 
from Cohort 1 of ZX008-1504, dose changes should be made in increments of 0.2 mg/kg/day, 
to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day. For subjects who
are receiving concomitant STP, including de novo subjects and those who participated in core 
study ZX008-1504 Cohort 1 dose regimen 3 and Cohort 2, and the first dose change will be to 
0.4 mg/kg/day and the final dose change will be to 0.5 mg/kg/day, but not to exceed 20 mg/day.  
Dose increases should not occur earlier than every 14 days at each dose level. Dose increases 
may only occur after a review of the diary and reported AEs, and if, in the investigator’s 
opinion, seizure frequency, severity, and/or duration indicates a change in medication regimen 
is warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these 
parameters should be discussed with the Medical Monitor prior to initiation.  
In addition, if a subject has been stable on the same dose of ZX008 for 6 months or longer, 
investigators may adjust the doses of one or more of the other concomitant AEDs as per typical 
clinical practice. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs or 
PUBLIC 
ity p
C
ity p
riod, all 
UBL
riod, all 
ess 
PU
ess of th
PU
of th
or m
P
or m
COPY
abe
Y
abe
o compl
PY 
o compl
uding th
OPY
uding th
te in on
CO
te in on
prior
C
prior
This 
ent 
ases 
nt
ases 
ly occur
ent
ly occur
docum
ion, seiz
me
ion, seiz
warrant
cum
warrant
amoun
ocu
amoun
para
do
para
cannot 
mg/k
ot
mg/k
mitant S
not
mitant S
04 Coho
ann
04 Coho
y and th
can
y and th
sho
c
sho
be
in c
e
in c
1504, d
be 
1504, d
g/d
b
g/d
used
is d
d
is d
ay adju
ed 
ay adju
are not r
use
re not r
core s
us
ore s
to 
ubjec
to
ubjec
dose 
to
dose 
support
ir p
t
ir p
of the c
ort 
of the 
to receiv
ppo
to receiv
cts w
s
cts w
any 
sion
y
sion
 this tri
any
 this tri
particip
an
particip
marketing
r an
g
r an
e time o
ing 
e time o
ion after 
eting
ion after 
fits for re
rket
fits for re
onsor.  
ark
onsor.  
n (
m
n (OL
m
OL
authorization 
diatric 
riza
diatric 
ave 
ho
ave 
008-1502
tho
008-1502
mpleted c
auth
mpleted c
n exte
au
n exte
cation 
e final
n 
e final
uld not oc
tion
uld not o
after a rev
catio
after a rev
applic
ure freque
lica
ure freque
ed. Dose d
pplic
ed. Dose d
s and freq
app
 and freq
ers sh
ap
ers sh
and
ay 
d
ay 
TP,
nd
TP, inc
d 
inc
t 1 dos
and
t 1 dos
l do
a
l do
any
udie
y
udie
se chan
any 
se chan
but not
an
but not
lul
extensions 
will be t
sion
will be t
n all stu
ens
n all stu
t the dos
xten
t the dos
ceiving 
exte
ceiving 
es Z
e
es Z
or
re
r
re
ng the
or 
ng the
variations 
LE
ti
LE)
ati
) Tre
tio
Tre
al will h
riat
al will h
pation i
vari
pation i
e stud
va
e stud
thereof. 
ore
f
ore
nded 
of
nded 
f screeni
reo
f screeni
discuss
here
discuss
ceiving
the
ceiving


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 45 of 194  
antiepileptic treatments may be introduced while in this study. All medication dose changes 
must be documented with a clinical explanation and justification. Concomitant AED dose 
adjustments outside of these parameters should be discussed with the Medical Monitor prior to 
initiation.  
If after approximately the midway point of the first 30 days on ZX008 0.2 mg/kg/day there is a 
clinically meaningful worsening in seizure type, frequency, and/or duration compared with the 
recent treatment in the core study, the investigator, in consultation with the Medical Monitor, 
may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; 20 mg/day for subjects who are receiving concomitant STP). A 
clinically meaningful worsening would be an increase in frequency, severity or duration of 
existing seizures, or emergence of a new seizure type. The description of the clinical worsening 
must be documented in the source notes and case report form (CRF). Further increase to 0.8 
mg/kg/day (maximum 30 mg/day for subjects who are not receiving concomitant STP and to 
0.5 m/kg/day (maximum 20 mg/day) for subjects who are receiving concomitant STP) could 
also be undertaken for the same conditions after a minimum of 4 days on 0.4 mg/kg/day, if the 
condition has not stabilized on the 0.4 mg/kg/day dose. Dosing outside of the specified range 
(ie, 0.2 to 0.8 mg/kg/day or 0.5 mg/kg/day for subjects who are receiving concomitant STP) 
may be considered after consultation between the investigator and Medical Monitor. 
A follow-up ECG and ECHO will be performed 3 and 6 months after study drug 
discontinuation for early termination and for those subjects who complete the study. 
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 and Table 2. 
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core 
studies will transition to a separate extension study (Study 1900) once that study is approved 
and the study site is initiated. Continuation in a separate extension protocol will be based on 
benefit/risk and continued eligibility criteria being met. De novo subjects must have 
participated in this trial for at least 3 months with at least 1 ECHO completed and continue to 
meet eligibility requirements to be eligible to transition to a separate extension protocol. 
Alternatively, subjects will transition to commercial product once it is available. For subjects 
who are entering the separate extension trial or who transition to commercially available drug, 
post-dosing and cardiac safety follow-up visits are not required in this trial. Subjects who 
transition to commercially available drug must have an ECHO within 3-6 months before
starting commercial drug and will have follow-up ECHOs within the required timeframe while 
on commercial drug.  
PUBLIC 
etwe
C
etwe
l be perf
BLIC
l be perf
nation an
UBL
nation an
aily t
P
aily t
COPY
who
Y
who
r a mini
PY 
r a mini
/day do
OPY
/day do
y for 
CO
y for sub
CO
sub
een t
C
een t
This 
ument
ility
t
ility
ively, su
ent 
ively, su
are enter
men
are enter
st-dosin
um
st-dosin
doc
transitio
ocu
transitio
starti
doc
starti
on
d
on
ot
o a
t
o a
canno
initiate
not 
initiate
ontinue
nno
ontinue
this tria
can
this tria
y requ
ca
y requ
be
atment
be 
atment
sepa
be
sepa
used
o recor
ed 
o recor
of asses
used
of asses
i
u
i
to 
d for
to
d for
d
support
e
t
e. D
t
. D
ects wh
ort 
ects wh
he investi
po
he investi
rm
su
rmed 3
sup
ed 3 a
p
a
r tho
s
r tho
any 
ceiv
y
ceiv
um of 4 
any
um of 4 
Dosing
an
Dosing
marketing
who
g
who
ncomitan
ing 
ncomitan
verity or 
eting
verity or 
on of the 
ket
on of the 
RF
a
RF). 
ark
). Furth
ark
Furth
eiving 
ma
iving co
a
co
ving 
m
ving
authorization 
o 
ti
o 
y there is
horiz
y there is
ared with
tho
ared with
dical M
auth
dical M
h
o are n
au
o are n
pplication
l for
n
l for
uirement
ion 
uirement
bjects wil
atio
bjects wil
ng the se
icat
ng the se
g and card
plic
g and card
ap
n to comm
app
n to comm
comme
ap
comme
d
and
. Cont
nd 
. Cont
d eligibil
and
eligibil
r at l
a
r at l
any 
Study 
ny 
Study 
t
a
te exten
any
e exten
tinu
a
tinu
extensions 
and 6 m
ons
and 6 m
ose subje
sion
ose subje
the num
ten
the num
ments i
exte
ments i
or
a
r
a
ator a
or 
ator a
variations 
her in
s
her in
ncomit
ons
ncomit
concom
atio
concom
days on
riat
days on
g outsid
vari
g outsid
re rec
va
re rec
thereof. 
nito
f
nito
not 
o
not 
nt STP). 
reo
nt STP). 
duratio
here
duratio
clinical
the
clinical
ncr
t
ncr


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 46 of 194  
3.2
NUMBER OF SUBJECTS
Up to approximately 340 subjects from the core studies and up to 50 subjects who did not 
participate in the core studies may be enrolled. 
3.3
STUDY DURATION
The duration of participation in the study for an individual subject is expected to be up to 158 
weeks, plus follow-up safety visit 3 and 6 months after the last dose: 
•
OLE Treatment Period - 36 months (156 weeks)
•
Post-Dosing Visit - 2 weeks after study completion or early termination
•
Cardiac Follow-up (ECG and ECHO) - 3 and 6 months after study drug discontinuation 
for early termination and for those subjects who complete the study; not applicable to 
subjects who transition to commercial product. 
3.4
NUMBER OF STUDY CENTERS
The study expects to use up to approximately 75 research centers in North America, Europe, 
Australia and Japan.  
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. The study design has incorporated an 
initial 1-month of treatment at the lowest dose (ZX008 0.2 mg/kg/day) after which time the 
investigator may adjust the dose based on effectiveness and tolerability. After the first month, 
dose increases will be made incrementally every 14 days to ensure adequate time to acclimate
to the new dose. Dose decreases for tolerability can occur at the investigator’s discretion, in 
dose amounts and frequency appropriate for the situation. The duration of the study, up to 36 
months, will allow for collection of appropriate data to characterize the safety profile of 
ZX008. 
3.6
PREMATURE TERMINATION OF STUDY
The Sponsor can terminate the study prematurely at any time for medical or ethical reasons at 
individual study sites or at all study sites. The investigator will be notified in writing, outlining 
PUBLIC 
oximate
LIC
oximate
OR ST
PU
OR ST
COPY
ts who
PY 
ts who
product
OPY
product
TERS
CO
TERS
This 
nt 
ases w
nt
ases w
cumen
ew dose
ent
ew dose
amount
me
amount
months, w
cum
months, w
doc
ZX008
ocu
ZX008
3
d
3
cannot 
d the 
ot
d the 
n this stu
not
n this stu
of treatm
ann
of treatm
may adju
can
ay adju
wil
c
wil
be
ming
e
ming
ts parti
be 
ts parti
po
b
po
used 
UDY
d
UDY
g clin
us
g clin
to 
Y D
to
Y D
support 
y 75 
up
y 75 rese
pp
rese
any 
mplete
ny 
mplete
marketing 
y termina
arke
y termina
 after st
ma
after st
e th
authorization 
o be up t
uth
o be up t
tion 
st the d
on 
st the 
be made
tion
be made
applicat
Dose de
cati
Dose de
s and freq
lica
s and freq
will allow 
ppli
will allow 
and
sib
d
sib
dy is co
nd 
dy is co
nt at th
an
nt at th
do
a
do
any 
cal s
y
cal s
lar prac
any
lar prac
le con
an
le con
extensions
arch c
ns 
arch c
ESIGN 
ens
ESIGN 
stud
e
stud
or 
o variations 
ation
s
ation
study dru
tion
study dru
the stud
iatio
the stud
thereof. 
o 1
n
th
n


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 47 of 194  
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 6.1.5 and Section 6.2. 
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)/Institutional Review 
Board (IRB). 
3.7
STUDY MONITORING PROCEDURES
3.7.1
Independent Data and Safety Monitoring Committee (IDSMC)
The Independent Data and Safety Monitoring Committee (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 PK data and any other data that may affect subject continuation
•
Make recommendations regarding the continuation, suspension, or termination of the 
study 
PUBLIC
PROC
IC 
PROC
and Saf
UBL
and Saf
afety M
PU
afety M
P
COPY
on and
PY 
on and
nt Ethics
OPY
nt Ethics
C
C
C
This document t
M
e
MSC
ent
SC w
nt
w
•
u
•
B
m
B
cannot 
a
t
a
ed interv
nno
ed interv
other m
ann
other m
. 
c
be 
e ID
be
e IDS
e
S
l expe
be
l expe
sed
Monito
d 
Monito
afety, da
sed
afety, da
u
nd resp
use
nd resp
M
u
M
to 
ety 
o
ety 
ori
to
ori
support t
EDURES
ppo
EDURES
Monit
su
Monit
any
po
y
po
reason
ny 
reason
ommitte
any
ommitte
marketing 
om
g
ving req
ng 
ving req
outstandi
eting
outstandi
ds at the s
ket
ds at the s
onsor 
m
onsor w
(
authorization 
orm
at
orm
native 
riza
native 
mpleted
au
pleted
plication 
ea
l:
c
l:
app
responsi
ppli
responsi
conduct m
app
conduct m
evie
a
evie
and
als, the 
nd 
als, the 
asures 
an
sures 
any 
will 
y 
will 
se and e
any
se and e
extensions 
S
s
S
itoring 
ion
itoring C
n
C
ng Comm
tens
ng Comm
ta qualit
xte
ta qualit
e
nsibiliti
ex
sibiliti
co
e
co
or variations 
will pro
tion
will pro
(s), and 
iati
(s), and 
tee (
ari
tee (IEC
aria
IEC
thereof.
, partia
of. 
, partia
uirement
reo
uirement
ding data
here
ding data
study si
the
study si


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 48 of 194  
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) 
The International Pediatric Cardiac Advisory Board (IPCAB) is an advisory body to the 
Sponsor that monitors cardiac safety of the ZX008 clinical trials and provides advice to the 
IDSMC. 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. 
PUBLIC OPY
car
Y
car
membe
PY 
membe
additio
OPY
additio
CO
entral ca
CO
entral ca
This document cannot be used to 
t
n, m
t
n, m
suppor
diac rea
ort 
diac re
any
ver
y
ver
of the I
any 
of the I
member
an
member
ad
a
d
arketing 
anag
g
anag
to an exp
ket
to an exp
ral reader
ark
ral reader
m
ntial cardi
ma
tial cardi
rse ev
m
rse ev
authorization 
guide 
riza
guide 
uals 
hor
uals 
iology, 
tho
iology, 
cardiac s
auth
cardiac s
geme
au
geme
application and any extensions or r
ns 
r clas
s
r clas
variation
diac valv
ons
diac valv
vent, the
tion
vent, the
PCAB a
riat
PCAB a
er of the
aria
er of the
r
v
r.
v
.
thereof.
afet
f
afet
nt relati
of. 
nt relati
erience
the
erience
ssif
th
ssif


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 49 of 194  
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.  
4.1
INCLUSION CRITERIA
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit.  
2. Subject has satisfactorily completed the core study in the opinion of the investigator and 
the Sponsor. 
NOTE: Those subjects who do not complete the 12-week Maintenance Period of the 
core study may, on a case-by-case basis, be eligible for entrance 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. 
3. Subject is male or non-pregnant, non-lactating female. 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, 
which includes abstinence, while being treated on this study and for 90 days after the 
last dose of study drug. 
4. Subject has documented medical history to support a clinical diagnosis of DS, where 
convulsive seizures are not completely controlled by current antiepileptic drugs. 
5. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
6. Subject has provided assent in accordance with IRB/IEC requirements, if capable.
7. Subject’s caregiver is willing and able to be compliant with diary completion, visit 
schedule and study drug accountability. 
8. Subject’s parent/caregiver has been compliant with diary completion during the core 
study, in the opinion of the investigator (eg, at least 90% compliant). 
9. Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant 
and stable dose of CLB and/or VPA, and STP (Cohort 1 dose regimen 3 and Cohort 2 
only) for at least 4 weeks prior to screening and are expected to remain stable 
throughout the study. 
10. Subjects who are >18 to ≤35 years of age at the time of screening and did not 
participate in one of the core studies must meet criteria 3 to 7 above and the following 
criteria below in order to be considered for participation. Participation is at the 
discretion of the Sponsor: 
a. Onset of seizures in the first year of life in an otherwise healthy infant.
PUBLIC
 no
C
 no
nt or 
LIC
nt or bre
C 
bre
tive urin
BLIC
tive urin
t be will
UBL
t be will
nence, w
PU
nence, w
g.
P
g.
COPY
nd
Y
nd
on whe
PY 
on whe
the Spo
OPY
the Spo
IDSMC
COP
IDSMC
on-
CO
on-lac
CO
lac
This document
bject
t
bject
study, in
ent 
study, in
Subje
men
Subje
and
m
and
cannot
the l
ot
the l
provide
not 
provide
caregiv
nno
caregiv
ule and s
can
le and s
t’s p
ca
t’s p
be
are
e
nforme
be 
nforme
lega
b
lega
used 
hil
d
hil
d medica
use
d medica
 not c
us
not c
to 
ng to
to
ng to
le bein
to
le bein
support t
tating fem
por
tating fem
stst-feeding
upp
-feeding
e pregnan
sup
e pregnan
o use 
s
o use 
any
en
y
en
er to pe
ny 
er to pe
or, who
any
or, who
marketing 
udy Scre
ng 
udy Scre
n of the i
ting
n of the i
Maintena
arke
Maintena
entrance 
mar
entrance 
ntial be
m
ntial be
authorization 
study: 
auth
study: 
a
lication 
tudy 
n
tudy 
arent/care
tion
arent/care
the opini
atio
the opini
cts enterin
lica
cts enterin
appl
stable do
plic
stable do
only)
app
only) for 
pp
for 
hroug
ap
hroug
and
y
d
y
d assen
nd 
d assen
r is wil
and
r is wil
dru
a
dru
any
mp
y
mp
of the n
ny 
of the n
respon
any
respon
t in
a
t i
extensions 
ng. Fe
s
ng. Fe
ncy test
ons
ncy test
e medica
sion
e medica
g treate
nsi
g treate
l history
exte
l history
plete
ex
plete
or
male
or
male.
or
. F
r 
F
ema
o
ema
variations 
ance
s
ance
e after co
ons
e after co
benefit-
tion
benefit-r
on
r
rmit ope
riati
rmit ope
o may c
aria
o may c
F
v
F
thereof. 
ening Vi
reof
ening Vi
investig
here
investig
Per
th
Per


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 50 of 194  
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 brainmalformation.
e. Lack of alternative diagnosis.
f.
Meets one of the following 3 confirmatory diagnostic criteria:
i. Emergence of another seizure type, including myoclonic,
generalized tonic-clonic, tonic, atonic, absence and/or focal has
developed after the first seizure type.
ii. 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 naturaland/or fluorescent 
lighting, as well as certain visualpatterns.
iii. 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.)
g. Subject has been approved for study inclusion by the Epilepsy Study 
Consortium.
h. Subject does not have an exclusionary cardiovascular or cardiopulmonary 
abnormality based on ECHO, ECG or physical examination and is approved for 
entry by the central cardiac reader.  Exclusionary abnormalities include, but are 
not limited to:
i. Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of 
age
ii. Possible signs of pulmonary hypertension with abnormal or greater than 
upper limit of normal values 
iii. Evidence of diastolic dysfunction
i.
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.
j.
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.
11. 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:
PUBLIC 
ve
C
ve
ave an ex
BLIC
ave an ex
ed on EC
UBL
ed on EC
entral c
PUB
entral c
COPY 
Y
tent
PY
tent w
Y 
w
hogenic
OPY
hogenic
likely
COP
likely to
OP
to
d for s
CO
d for s
This document
j.
ent
j.
A
t 
A
11.
cu
11.
not
upp
t
upp
can
Evid
not 
Evid
ubject m
nno
ubject m
clonic
can
clonic
par
ca
par
be
ssible s
be 
ssible s
er 
b
er lim
be
lim
used 
rd
d
rd
greater m
sed
greater m
to
CHO
o
CHO
diac re
to 
diac re
support t
suppo
ort 
suppo
tudy incl
por
tudy incl
clusionar
sup
clusionar
O, ECG
s
O, ECG
any y
a 
ny
a diag
ny 
diag
variant
any
variant
y
ort
a
ort
marketing 
ces seizu
ting
ces seizu
ess
ket
ess or
eti
or va
va
emperatu
arke
emperatu
natural
mar
naturalan
r
an
rns.
m
rns.
authorization 
c,
u
c,
focal
aut
focal h
t
h
tion 
clon
n
clon
nt/guard
tion
nt/guard
pplicat
All medic
atio
All medic
and vag
lica
and vag
to sc
plic
to sc
ap
Subject’s
app
Subject’s
ompl
ap
ompl
and
nce of
nd 
nce of
ust hav
and
ust hav
nic)
a
nic)
any
ns of pu
ny 
ns of pu
t
a
t
a
of nor
any
of nor
dia
a
dia
extensions
ry cardi
ons 
ry cardi
G or ph
sion
G or ph
ader.  Ex
nsi
ader.  Ex
mitral or 
exte
mitral or 
or
usion
or 
usion
variations
ure 
s
ure 
d/or flu
ns 
d/or flu
nosis
iati
nosis of
ti
of
of
a
of unkn
aria
unkn
an alter
va
n alter
n b
v
n b
thereof. 
as
f
as
ures and
ere
ures and
accines
ther
accines
chan
th
chan


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 51 of 194  
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the 
study medication. 
2. Subject has current or past history of cardiovascular or cerebrovascular disease, 
myocardial infarction or stroke.
3. Subject from one of the core studies with current cardiac valvulopathy or pulmonary 
hypertension that the investigator, parent, IPCAB, IDSMC, or Sponsor deems clinically 
significant and warrants discontinuation of study medication. 
4. For de novo subjects: possible signs of pulmonary hypertension with abnormal or 
greater than upper limit of normal values 
5. 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. 
6. 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 as 
measured by the C-SSRS Since Last Visit, 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. 
7. Subject has a current or past history of glaucoma. 
8. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x upper limited of normal [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.
9. 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 
(Appendix 1). (Note: Short-term medication requirements will be handled on a per case 
basis by the Medical Monitor.) 
10. Subject is currently taking carbamazepine, oxcarbazepine, eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy.
11. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504 
(Cohort 1/dose regimens 1 &2):  Subject is currently receiving or has received STP in 
the past 21 days prior to core study Visit 1. 
PUBLIC 
mus
C
mus
giver to b
LIC
giver to b
ustment. 
BLI
ustment. 
r past hi
PUB
r past hi
e or sev
PU
e or sev
ev
P
ev
COPY
excl
Y
excl
it
P
it, whic
PY 
, whic
ts suicid
OP
ts suicid
ubject i
CO
ubject i
t do
C
t do
This document
prohe
nt 
prohe
(Appen
ent
Appen
basis
me
basis
10.
cum
10. Su
m
Su
cannot
eiving
ot 
eiving
e-oxidas
not
e-oxidas
ble amo
ann
ble amo
ke inhi
ca
ke inhi
pt
c
pt
be 
nitor 
e
nitor 
conco
be
conco
co
b
co
used 
ere h
d
ere h
ated live
sed
ated live
ULN) m
use
ULN) m
in c
u
in c
to
story o
to 
story o
hepa
to
hepa
support
al id
t
al id
s approp
ort 
s approp
cument ap
ppo
cument ap
e alert to
upp
e alert to
of g
s
of g
any 
f the
y
f the
include
any
include
deation
an
deation
i
marketing
, or depr
ing 
, or depr
treatmen
etin
treatmen
s, in the in
ark
s, in the in
the Colu
ma
he Colu
ey re
m
ey re
authorization 
nary
riz
nary
s clinica
hori
s clinica
bnormal 
aut
normal 
cation 
bition; a
on 
bition; 
dine, and
tion
dine, and
dix 1
cat
dix 1
ppli
). (N
ati
). (N
by the M
plica
by the M
ubject is c
ppli
ubject is c
ap
phenoba
app
phenoba
aint
a
aint
and
nco
d
nco
e inhibi
nd 
e inhibi
nt of se
an
nt of se
t
a
t
any 
njun
y
njun
tant me
any
tant me
omitan
an
omitan
extensions
p
o mood
ns 
o mood
glaucom
sio
glaucom
tic impa
ens
tic impa
r enzym
xten
r enzym
ay be e
ext
ay be e
ncti
e
ncti
or
ate
r
ate
propri
or 
propri
d
o
d
variations
nvesti
ns 
nvesti
umb
ion
umbia
ons
ia-
n
-S
ns
S
eport su
atio
eport su
s suicid
riat
s suicid
n on Ite
vari
n on Ite
e for 
va
e for 
thereof. 
or 
f
or 
ession w
reo
ession w
nt for a d
here
nt for a d
t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 52 of 194  
12. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with Visit 1 and throughout the study. 
13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood 
cannabidiol (CBD) at Visit 1.
14. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions. 
15.  Subject has a clinically significant condition, or has had clinically relevant symptoms 
or a clinically significant illness in the 4 weeks prior to Visit 1, other than epilepsy, that 
would negatively impact study participation, collection of study data, or pose a risk to 
the subject, including chronic obstructive pulmonary disease, interstitial lung disease, or portal 
hypertension. 
16. Subject has participated in another clinical trial within the past 30 days (ie, the last visit 
of the previous study was in the past 30 days), with the exception of the core studies. 
4.3
SUBJECTS OF REPRODUCTIVE POTENTIAL
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 the last dose of study drug. 
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 90 days following the last dose of study drug. 
PUBLIC 
afte
C
afte
able:
BLIC
able:
progest
PUB
progest
COPY 
O
Y
O
partner 
OPY
partner 
method o
CO
method o
er
C
er the
C
the
This document 
−
in
t
in
rgical st
men
rgical st
emale su
cum
emale su
contra
docu
contra
pos
do
pos
b
d
b
cannot 
horm
ot
horm
jectable
ann
jectable
implan
can
implan
ntr
c
ntr
be 
l 
b
l 
mon
b
mon
used 
og
d
og
to
en con
to 
en con
support 
of 
t
of 
f highly
ort 
f highl
last dose 
por
last dose 
any 
AL
y
AL
child-b
an
child-b
y e
a
marketing
, or 
g
, or 
al lung di
ing 
al lung di
ast 30 day
rket
ast 30 day
xception o
ark
xception o
L
m
L
authorization 
t
on
riz
on
t sympt
tho
t sympt
an epile
aut
an epile
pos
a
pos
application 
table in
on 
table in
uterine h
tion
uterine h
rilization
cat
rilization
ubjects wh
ppli
ubjects wh
eption. A
app
ption. A
opau
a
opau
and 
al c
d
al c
t
a
t
any 
ontrac
an
ontrac
extensions 
taining) 
nsio
taining) 
or
of stu
or 
of stu
variations
y
of the
ns 
of the
bearing p
aria
bearing p
ffectiv
va
fectiv
d
v
d
thereof.
psy, 
f
psy, 
 a risk t
eof. 
 a risk t
sease, or
reo
sease, or
s (ie, t
the
s (ie, t
t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 53 of 194  
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): 
−
oral 
−
intravaginal  
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulation and a 
barrier method (ie, condom for male partner):  
−
oral 
−
injectable 
−
implantable intrauterine device
−
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.
4.3.1
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.
4.3.2
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 subject 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. 
4.4
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.  
PUBLIC 
C
tion
LIC
tion
ate sperm
PUB
ate sperm
and fo
PU
and fo
COPY 
Y
hen it is 
OPY
hen it is 
xually ac
COP
xually ac
ceptive
CO
ceptive
This document 
then c
nt 
then c
ed and th
ent
ed and th
subject
me
subject
hould co
cum
hould co
4.4
do
4.4
cannot 
ucted 
ot 
ucted 
to the in
not
to the in
g the stu
ann
g the stu
ct’s part
can
t’s part
con
c
con
be 
tha
b
tha
used 
r at le
d
r at le
to
and f
to 
and f
east
to
east
support 
tive b
rt 
tive b
requirem
port
requirem
em
s
any y
line wit
any
line wit
but b
a
but b
marketing 
n)
m
n)
authorization 
ulation 
aut
lation 
t
on 
ner is s
on 
ner is s
applicatio
nsent will 
tion
nsent will 
e status o
cati
e status o
reporting
plica
reporting
mplete th
ppli
mplete th
RE
ap
RE
and
t if
d
t if
vestiga
nd 
vestiga
y but c
an
y but c
su
a
su
any 
they/t
an
they/t
extensions 
male sub
nsio
male sub
90 
e
90 days
ens
days
or
ents 
or 
ents 
variations 
th the 
aria
th the su
a
su
become
var
ecome
de
v
de
thereof. 
nd a 
f
nd a 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 54 of 194  
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 CRF. 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. 
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 C-SSRS. 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
PUBLIC 
ar
C
ar
ered the
BLIC
ered the
rts using
PUB
rts using
on
P
on.
P
.
COPY
ative of
PY 
ative of
lves), 
OPY
lves), o
PY
o
CAB
CO
CAB, th
OP
, th
ticipa
CO
ticipa
This document 
Clinicall
ent
Clinicall
such t
me
such t
sub
um
sub
cannot
compl
ot 
compl
anner
nno
anner.
no
.
t experi
can
experi
be
lusion
be 
lusion
b
sed 
u
nges af
use
nges af
n c
u
n c
to
he use
to 
he use
support 
p
t
p
centra
ort 
centra
ion does n
por
ion does n
clinical in
sup
clinical in
any
rdiac v
ny 
rdiac v
ulmonar
any
ulmonar
al c
a
al c
marketing
e in
g
e in
e steps ta
ing 
e steps ta
easons, if 
ark
easons, if 
authorization 
e should 
riza
e should 
r becaus
auth
r becaus
nvesti
au
vesti
plication 
ences a
on 
ences a
y significa
catio
y significa
hat treatm
lica
hat treatm
app
ject’s bes
ppli
ject’s bes
ndicative
app
ndicative
and 
nt wi
d
nt wi
a
any 
teria o
ny 
teria o
ith pro
a
ith pro
extensions
nvestig
ns 
nvestig
of an un
nsio
of an un
e
r enteri
ex
enteri
or
e
or
or
not ou
or 
not ou
variations 
f deem
s
f deem
alvulopa
iati
alvulopa
ary hype
aria
ary hype
ardiac 
va
rdiac 
t
v
t
thereof. 
e th
f
e th
gator 
of
gator 
ken to 
reo
ken to 
med
th
med


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 55 of 194  
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 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)
The IDSMC may request that the study be terminated after review of the safety information at
any time during the study. The IDSMC 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 CRF and in the subject’s medical records (eg, AEs, lack of compliance, lost to 
follow-up, etc). If possible, the subject/subject’s legal representative should confirm his 
decision in writing. 
The investigator will attempt to complete all procedures usually required at the end of the study 
at the time when the subject’s participation in the study is discontinued or as close as possible 
PUBLIC 
lly
C
lly
that the 
BLI
that the 
n in the s
PUB
n in the s
s that 
P
s that 
COPY
articipa
PY 
articipa
C
autho
CO
autho
This 
cument
th
t
th
ed as d
nt 
ed as d
l over th
men
l over th
The reas
cum
The reas
doc
detail 
doc
detail 
fol
do
fol
cannot
dy
t
dy
ary hyp
not 
ary hyp
c
hat the
ca
at the
d
c
d
be
that th
be 
that th
b
The 
be
The 
used
a subje
ed 
a subje
iple
se
iple enro
sed
enro
u
to 
tudy
to
tudy
t
support 
rized repr
por
rized repr
bject’s s
sup
bject’s s
any
at
y
at
g in any
ny 
g in any
marketing 
ith
g
n of the 
ng 
n of the 
any time 
arke
any time 
nt and dis
mar
nt and dis
tment 
m
tment 
authorization 
pt
ti
pt
ons 
at
ons 
onitor. T
tho
onitor. T
he study
auth
he study
h the M
au
the M
application
study is
on 
study is
scribed in
tio
scribed in
e interest
icat
e interest
on for, and
ppl
on for, and
a
n the CR
app
the CR
et
a
et
and
rtensio
d 
rtensio
any 
udy be
ny 
udy be
D
a
DSM
any
SMC w
ny
C w
on a
a
on a
xtensions 
safety o
ions
safety o
discont
ten
discont
ext
llments
xte
llments
e
or
esent
or 
esent
variations 
e with
s
e with
iscontin
ons
iscontin
in any w
tion
in any w
y further
iati
y further
tat
v
tat
thereof. 
Medical 
of.
Medical 
ite princ
reo
ite princ
thou
th
thou


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 56 of 194  
to that time. Specific procedures required are described in Section 6.1.5 and Section 6.2. As far 
as possible, a complete final examination must be performed on all subjects who do not 
complete the study according to the study protocol.  
Data collected until the time a subject discontinues participation in the study will be handled in 
the same manner as data for subjects completing the study. Where possible, further information 
will be collected if any AEs are experienced by a subject after discontinuing participation in the 
study. 
4.5
TERMINATION OF THE 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  
4.6
REPLACEMENT OF SUBJECTS
Enrolled subjects will not be replaced. 
PUBLIC 
C
at the
BLI
at the re
LI
re
nsor to 
PUB
nsor to 
P
COPY 
e clinica
OPY
e clinica
elevant
CO
elevant
This document cannot be 
be rep
be
be rep
used 
d
OF SUB
sed
OF SUB
plac
u
plac
to
spend
to 
spend
support 
 or unacc
port
 or unacc
uired rate
sup
ired rate
any 
f
y
f
study in
any
study in
marketing 
becomes
keti
becomes
he clinica
arke
he clinica
ay be term
mar
ay be term
finding
m
inding
authorization 
ndled in 
riza
ndled in 
nformati
horiz
nformati
cipation 
tho
cipation 
application and any 
d
ny
d.
y
.
extensions 
te
o
te
or discon
nsio
or discon
JECTS
xte
JECTS
or
eptab
or 
eptab
variations 
al stu
s
al stu
rminated
ons
rminated
g.
t
g.
nclude, b
aria
nclude, b
ble
v
ble
thereof. 
s aware 
the
s aware 
udy
th
udy


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 57 of 194  
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION
ZX008 will be administered in the current study. A brief description of the ZX008 product is 
provided below (Table 4).
Table 4. 
Investigational Medicinal Product – ZX008
Study Product
Substance Code
ZX008
Active Substance (INN)
Fenfluramine Hydrochloride
Trade Name
Not applicable
Formulation (including dosage form and strength)
Solution 2.5 mg/mL
Route/Mode of Administration 
Oral
Manufacturer
PCI Pharma Services on behalf of Zogenix 
International Limited
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 a concentration of 2.5 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 formulation will be suitably flavored, and will contain preservatives and a thickening 
agent. The product is sugar free and is intended to be compatible with a ketogenic diet (KD). 
The formulation will be provided in bottles with tamper-evident, child-resistant caps. 
Doses to be studied include 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, and 0.8 mg/kg/day 
divided into two daily doses, up to a maximum of 30 mg/day. 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 fulfil 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 ICH, Good 
Manufacturing Practices (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. 
PUBLIC 
mg/m
C 
mg/m
markete
LIC
markete
ably flav
UBL
ably flav
ee and i
PUB
ee and i
vided i
PU
vided i
COPY 
NAL M
OPY
NAL M
lution o
CO
lution o
mL
C
mL
This 
cument 
Lab
ent
Lab
he ZX00
cum
he ZX00
doc
Manuf
ocu
Manuf
D
d
D
nnot
nistrat
ot 
nistrat
fil
n
fil the d
no
 the d
can
parent/
ann
parent/
n
be 
s, up
be
s, up
e due to
be
e due to
io
b
io
used 
bottl
d 
bottl
2 2 mg/kg
use
mg/kg
p to
u
p to
to
or
intend
to 
intend
les
to
les
support 
f fenflur
port
f fenflur
The exci
ppo
The exci
d d drug pr
upp
drug pr
red,
su
ed, and
su
and
ed
s
d
any 
DICIN
any
DICIN
marketing 
g
ing
eti
s
a
s on behalf
arke
on behalf
ited
ma
ited
ke
ma
authorization 
tho
ut
a
pplication 
ar
beling an
cati
beling an
8 product
ppli
8 product
ap
cturing P
app
cturing P
and
n), h
d
n), h
ose.
nd
ose. Car
nd 
Car
a
egiver
an
egiver
any
max
y 
max
spil
an
spillage 
ny
lage 
he/she
a
he/she
extensions
ip
s
p
roduct
ns 
roduct
d will co
ion
d will co
d to be c
nsio
d to be c
with tam
tens
with tam
day, 0.4
ext
day, 0.4
xim
e
xim
or 
min
or
min
ents s
or
ents s
o variations 
f of 
s
f of Z
s
Z
on
NAL PR
aria
NAL PR
ne h
v
ne h
thereof. 
f. 
eo
re
he
Zoge
th
Zoge
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 58 of 194  
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO
No comparators, reference treatments, or placebo will be used in this study. 
5.3
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 bottles to the subject will be handled through an interactive voice 
response (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.
5.4
TREATMENT ADMINISTRATION
5.4.1
OLE Treatment 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 initial IMP will be based on the 0.2 mg/kg/day (maximum 30 mg/day or 
PUBLIC
g
C
g
ation o
IC 
ation o
MP
B
MP to th
BL
to th
will be d
PUB
will be d
nsor m
PU
nsor m
P
COPY 
the stud
OPY
the stud
the stud
COP
the stud
, pharm
CO
, pharm
f
C
f
This 
cument 
OL
ent
OL
he inves
cum
he inves
doc
follow
ocu
follow
S
d
S
cannot
c
t
c
epanci
ot 
epanci
ed and c
nno
ed and c
REATM
ca
REATM
be 
es of
be
es of
le all
be
le all I
e
I
b
used
ust be
d 
ust be
ities, ba
sed
ities, ba
nvestig
use
nvestig
f
u
f th
u
th
to
e s
o
cumen
to 
cumen
e m
to
e m
support 
y. At t
rt
y. At t
acist) ori
port
acist) or
inal drug 
ppo
inal drug 
study si
su
tudy si
te
s
any 
using th
any
using th
the e
a
the e
marketing 
interactiv
ting
interactiv
vestigato
keti
vestigato
medicatio
arke
medicatio
aintain a 
mar
aintain a 
authorization 
writing u
uth
writing u
pplication 
MENT 
on 
MENT 
E Treatm
cati
E Treatm
igator (or
ppli
igator (or
ap
ng the pro
app
ng the pro
and 
in 
d
in d
d
d
omplete
and
omplete
d
A
a
A
any 
MP
y
MP
Ps
an
Ps recei
any
recei
drug a
a
drug a
extensions 
g ac
s
g ac
ite, the 
ion
ite, the 
ed in 
nsi
ed in the
sio
the
aintaine
tens
aintaine
ch numb
xte
ch numb
or mus
ex
or mus
sp
e
sp
or 
ginal
or
ginal
coun
or
coun
variations
ion w
s
ion w
log of a
ons 
log of a
he drug 
aria
he drug 
end of t
var
nd of t
l dr
v
l dr
thereof. 
usi
ve voice
ere
ve voice
or or del
the
or or del
will 
th
will 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 59 of 194  
20 mg/day for subjects taking concomitant STP) dose and subject’s weight at Visit 1 (Study 
Day 1). At Visits 5 to 15 (Months 3 to 33), if the subject’s weight has changed ± 25% of the 
weight from the previous dose calculation, the IMP dose will be recalculated. Subjects will be 
dosed using the oral dosing syringe provided. 
During the OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day for 
1 month to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 
ZX008 0.2 mg/kg/day, the investigator may adjust the dose of each subject based on 
effectiveness and tolerability.  
Dose changes should be made in increments of 0.2 mg/kg/day, as follows: 
•
Subjects who are not receiving concomitant STP: may increase to a maximum of 
0.8 mg/kg/day but not to exceed total dose of 30 mg/day 
•
Subjects who are receiving concomitant STP: the first dose change will be to 
0.4 mg/kg/day and the final dose change will be to 0.5 mg/kg/day, but not to exceed 
20 mg/day  
Dose increases should not occur earlier than every 14 days at each dose level. Dose increases 
may only occur after a review of the diary and reported AEs, and if, in the investigator’s 
opinion, seizure frequency, severity, and/or duration indicates a change in medication regimen 
is warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these 
parameters should be discussed with the Medical Monitor prior to initiation.  
If after approximately the midway point of the first 30 days on ZX008 0.2 mg/kg/day there is a 
clinically meaningful worsening in seizure type, frequency, and/or duration compared with the 
recent treatment in the core study, the investigator, in consultation with the Medical Monitor, 
may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; 20 mg/day for subjects who are receiving concomitant STP). A 
clinically meaningful worsening would be an increase in frequency, severity or duration of 
existing seizures, or emergence of a new seizure type. The description of clinical worsening 
must be documented in the source notes and case report form (CRF). Further increase to 
0.8 mg/kg/day (maximum 30 mg/day) for subjects who are not receiving concomitant STP, and 
to 0.5 mg/kg/day (maximum: 20 mg/day) for subjects who are receiving concomitant STP 
could also be undertaken for the same conditions after a minimum of 4 days on 0.4 mg/kg/day, 
if the condition has not stabilized on the 0.4 mg/kg/day dose; however, the maximal dose 
determined for subjects on concomitant STP must not be exceeded. Dosing outside of the 
specified range (ie, 0.2 to 0.8 mg/kg/day or 0.5 mg/kg/day for subjects taking concomitant 
STP) may be considered after consultation between the investigator and Medical Monitor. 
PUBLIC
tha
C
tha
diary a
LIC 
diary a
ty, and/o
BLIC
ty, and/o
r 
U
r tolerab
UBL
tolerab
opriate f
PUB
opriate f
ed w
P
ed w
COPY
P:
Y
P:
will be
PY 
will be
an eve
CO
an eve
This 
ument
zur
t
zur
docume
ent 
docume
g/kg/day
men
g/kg/day
0.5 mg/k
um
0.5 mg/k
doc
could al
ocu
could al
if the
doc
if the
de
d
de
cannot
cor
t
cor
se to 0.
not 
se to 0.
mitant 
nn
mitant ST
no
ST
ningful w
can
ningful w
c
res, o
ca
res, o
be
sening
be 
sening
re stu
be
re stu
used
or 
d
or 
ith the 
ed 
ith the 
way po
us
way po
i
u
i
to 
ility
o
ility
the si
to
the si
t
support 
ry 14 day
por
ry 14 day
d reported
pp
d reported
r duration
sup
duration
y can 
s
y can 
any
d
y
d
0.5 mg
any 
0.5 mg
marketing 
ws:
ti
ws:
ease 
rk
ease to a m
ke
to a m
dose
m
dose ch
m
ch
authorization 
t
g/day fo
horiz
g/day fo
a dose o
tho
a dose o
ed on 
auth
ed on 
n
wors
n
wors
pplicatio
emergen
ion 
emerge
nted in the
atio
nted in the
y (maximu
icat
y (maximu
g/day (m
plic
g/day (m
ap
so be und
app
so be und
ondition
ap
ndition
d
and
mg/kg
nd 
mg/kg
P
a
P; 20 m
and
; 20 m
senin
a
senin
any y
seizure
ny 
seizure
, the inv
any
, the inv
g/da
a
g/da
extensions 
d AE
s
d AE
n indica
ons
n indica
occur a
sion
occur a
uation. Z
nsi
uation. Z
Medical M
ten
Medical M
t of th
ex
t of th
or
s at 
or
s at ea
r 
ea
Es, a
o
Es, a
variations 
m
change 
tion
change w
on
w
g/kg/day
riat
g/kg/day
v
thereof. 
maximu
th
maximu


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 60 of 194  
5.4.2
Taper Period
All subjects (those who complete the OLE Treatment Period or those who discontinue from the 
study early and are not transitioning to another ZX008 extension study or treatment with
commercial drug) will be tapered off of study medication.  
5.4.2.1
Taper Period for Subjects not Receiving Concomitant STP
The tapering scheme is a 2-step process for subjects who are not receiving concomitant STP, 
including subjects from core studies ZX008-1501 and ZX008-1502, and from study ZX008-
1504 Cohort 1/Regimens 1&2. This is described in 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. IMP 
will be administered using the oral dosing syringe provided.  
Table 5.  
Taper Algorithm for Subjects from Core Studies ZX008-1501, ZX008-1502, 
and ZX008-1504 Cohort 1/Regimens 1&2Not Receiving Concomitant STP 
Current Dose
Taper Step 1 
Days 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
Not applicable
Not applicable
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
ZX008 0.6 mg/kg/day
ZX008 0.4 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
Note:  maximum daily dose of ZX008 is 30 mg.
5.4.2.2
Taper Period for Subjects from Core Study ZX008-1504 Cohort 1 Regimen 3 and 
Cohort 2 Receiving Concomitant STP
The tapering scheme is a 3-step process for subjects receiving concomitant STP, including 
subjects from core study ZX008-1504 Cohort 1 Regimen 3 and Cohort 2, and is described in 
Table 6.  
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 
will be administered using the oral dosing syringe provided. 
PUBLIC
ort 1/R
IC 
ort 1/R
Taper
BLI
Taper
1
U
1-4
UB
-4 after
UBL
after
ear
UB
ear
LIC
PU
COPY
wise, th
PY 
wise, th
inge pro
OPY
inge pro
jects fr
CO
jects fr
R
C
R
This document
ering sch
ent 
ering sch
cts 
m
cts from
me
from
ble 6
um
ble 6. 
m
. 
Stud
doc
Stud
ap
d
ap
ot 
ose of 
ot
ose of 
cannot
ot
er Perio
ann
er Perio
ohort 2
can
ohort 2
be 
e
b
ZX
b
ZX
b
used
y
d
y
Not ap
ed 
Not ap
d
ZX008
se
ZX008
ed
ZX
us
ZX
us
u
to
study
o
study
termin
to 
termin
t
support 
om Core
port
om Core
gimens 1
ppo
gimens 1
Step 1
sup
tep 1
y com
s
y com
up
any y
missed 
ny 
missed 
ded.  
any
ded.  
marketing 
n
rom stu
ng 
rom stu
morning a
arke
morning a
separated 
mar
separated 
medicat
m
medicat
d
authorization 
e
ti
e
comita
au
comita
d
a
d
application 
Receiv
on 
Receiv
eme is a 
atio
eme is a 
core stud
lica
core stud
a
medicat
ap
edicat
d
008
d
008
and 
d
for Su
an
for Su
vin
a
vin
any 
 0
y
 0
X008 0.4
any
X008 0.4
y
an
is 30 m
an
is 30 m
any
a
extensions
1&
s
1&
mpletion o
sion
mpletion o
tion
ns
tion
s 
icable
ten
icable
ns
.
e
.2
e
2 mg/kg
exte
mg/kg
te
.4
e
.4 m
e
m
ex
or 
Stud
or
Stud
2Not
or
2Not
variations
and 
s
and 
d by a m
ons 
d by a m
tion may
tion
tion may
dose sho
iatio
dose sho
die
v
die
thereof.
nt STP
of. 
nt STP
y ZX00
eof
y ZX00
in th
th
in th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 61 of 194  
Table 6.  
Taper Algorithm for Subjects Receiving Concomitant STP
Current Dose
Taper Step 1 
Days 1-4 after study 
completion or early 
termination
Taper Step 2
Days 5-8 after study 
completion or early 
termination
Taper Step 3
Days 9-14 after study 
completion or early 
termination
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
Not applicable
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
ZX008 0.5 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Note:  maximum daily dose of ZX008 is 20 mg.
5.5
BLINDING
This is an open-label study.  
5.6
PRIOR AND CONCOMITANT MEDICATION
All prior and concomitant medication 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 CRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations.  
Subjects are required to take at least one concomitant AED throughout the study. During at 
least the first 6 months of the study, subjects will continue to receive their existing AEDs at the 
same dose as prior to initiating this study. However, once the subject has been stable on a 
ZX008 dose for at least 6 months with good seizure control, investigators will be allowed as 
per typical clinical practice to alter one or more other concomitant AED doses as deemed 
clinically appropriate. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs may be 
introduced while in this study. All medication dose changes must be documented with a clinical 
explanation and justification. Concomitant AED dose adjustments outside of these parameters 
should be discussed with the Medical Monitor prior to initiation.  
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.  
PUBLIC
th
C
th
docum
LIC 
docum
upplemen
BLIC
upplemen
at least 
PUB
at least 
e stud
P
e stud
COPY 
DIC
Y
DIC
collecte
OPY
collecte
e
C
e firs
C
firs
This 
ment 
discu
t
discu
study me
men
study me
docum
d will no
um
d will no
of the in
ocu
of the in
It 
do
It 
cannot
Con
t
Con
um of 1 
not 
um of 1 
in this s
nno
in this s
nd justif
can
nd justif
ussed
ca
ussed
be
on
e
ce to al
be 
ce to al
ncom
be
ncom
used
on
d
on
y, subj
ed 
y, subj
this stud
sed
this stud
ths wi
us
ths wi
to
ne con
to 
ne con
t
support 
d 
t
d 
administ
por
administ
nted in th
upp
nted in th
t prepara
sup
prepara
any 
ON
y
ON
n the C
an
n the C
marketing 
g authorization 
dy
t
dy
arly
za
arly
on
i
on
ati
plicable
hori
plicable
riz
applicab
utho
applicab
ho
Not appl
aut
Not appl
ut
a
lication 
catio
n
catio
d with the
tion
d with th
dications
icat
dications
appl
t interfere
plic
t interfere
vestigator
app
vestigator
be
a
b
and
oncom
nd 
oncom
tudy. 
and
udy. Al
nd
Al
on. C
a
on. C
any 
h g
y
h g
one or
ny 
one or
ant AED
any
ant AED
mita
a
mita
extensions 
he CR
s
he CR
ations.  
ons
ations.  
omitant
nsi
omitant
ts will c
ten
ts will c
y
e
y. Howe
exte
. Howe
good 
ex
good 
or
ation
or 
ation
RF
o
RF
variations 
CRF.
ari
CRF.
v
thereof. 
cable
f
cable
f.
eo


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 62 of 194  
5.6.1
Vagal Nerve Stimulation
Subjects receiving treatment with vagal nerve stimulation (VNS) may be included as long as 
the VNS has been in place for at least 6 months prior to entry into the core study, or for de novo 
subjects prior to first dose in the OLE, and stimulation parameters have been kept constant for 
4 weeks prior to core study Visit 1. During at least the first 6 months of the study, VNS 
stimulation parameters will be kept constant. However, once the subject has been stable on a 
ZX008 dose for at least 6 months with good seizure control, investigators will be allowed as 
per typical clinical practice to alter VNS stimulation parameters as deemed clinically 
appropriate. All VNS stimulation parameter changes must be documented with a clinical 
explanation and justification. VNS stimulation parameter adjustments outside of these 
boundaries should be discussed with the Medical Monitor prior to initiation. The subject’s use 
of VNS will be recorded in the CRF. 
5.6.2
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 entry into the core study, or for de novo 
subjects 4 weeks prior to first dose in the OLE. During at least the first 6 months of the study, 
the KD will be adhered to. However, once the subject has been stable on a ZX008 dose for at 
least 6 months with good seizure control, investigators will be allowed as per typical clinical 
practice to alter the KD as deemed clinically appropriate. All KD changes must be documented 
with a clinical explanation and justification. KD adjustments outside of these parameters should 
be discussed with the Medical Monitor prior to initiation. The subject’s use of KD will be 
recorded in the CRF.
5.6.3
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 CRF.   
Use of rescue medication is permitted during the study and should be recorded on the CRF
(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.
5.6.4
Prohibited Concomitant Medication and Food 
Alcohol in all forms (wine, beer, liquors) and amounts is prohibited during the study. The 
following concomitant medications/foods are prohibited during the clinical trial:
•
AEDs: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, retigabine/ezogabine 
PUBLIC
e O
C
e O
once th
LIC 
once th
control, 
BLIC
control, 
med clin
UBL
med clin
nd justif
PU
nd justif
al Mo
P
al Mo
COPY 
f KD, is
OPY
f KD, is
ior to en
COP
ior to en
OLE. 
CO
OLE. 
This document
dicatio
nt 
dicatio
ted adm
men
ted adm
6.4
cu
6.4
Alc
do
Alc
f
d
f
cannot
r presc
ot 
r presc
e
n
e prior a
nno
prior a
medic
ca
medic
c
be
cation
be 
cation
used
ca
d
ca
nitor p
ed 
nitor p
f
u
f
to 
cally
o
cally
ation
to
ation
support 
p
t
p
ry into
ort 
ry into
During at 
por
During at 
e subject h
pp
e subject h
nvestigato
sup
nvestigato
y appr
s
y appr
any 
ermitted
any
ermitted
th
a
th
marketing
clin
g
clin
d with a 
ing 
d with a 
outside of
eting
outside of
nitiation. 
ket
nitiation. 
authorization 
novo
ati
novo
ant for 
riza
ant for 
NS 
ho
NS 
stable on
tho
stable on
be allow
auth
be allow
nically
au
ically
application 
ation is 
on 
ation is
s], dose[s
atio
s], dose[s
nistration
cat
nistration
Prohib
ppl
Prohib
n all
a
n all
and 
bed r
d
bed r
nd/
an
nd/or co
and
or co
any 
Seizu
ny 
Seizu
egim
a
egim
extensions 
has b
s
has b
tors will
ons
tors will
propriate
sion
propriate
KD
n
KD adju
nsi
adju
or to ini
ten
or to ini
or
least 
or 
least 
bee
o
bee
variations 
d during
aria
d during
e core s
va
core s
th
v
th
thereof. 
ed a
f
ed a
clinical 
reo
clinical 
of these 
here
of these 
The sub
the
The sub


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 63 of 194  
• STP: Subjects who are not receiving concomitant STP, including de novo subjects and 
those from core studies ZX008-1501, ZX008-1502, and ZX008-1504 Cohort 1/Dose 
Regimens 1&2 only, must be off STP for a minimum of 21 days prior to the core study 
or OLE Screening visit. 
•
Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to the core study or OLE Screening visit, 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: imipramine, monoamine oxidase inhibitors, 
selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, 
vortioxetine 
•
Drugs that increase cardiovascular risk: atomoxetine
•
Drugs intended to facilitate weight loss
•
Other: any form of marijuana, THC and derivatives (including Epidiolex®) 
•
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. 
5.7
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.  
PUBLIC 
HC
C
HC
ly intera
BLIC
ly intera
st of
UBL
st of me
BL
me
f
BL
f
hronic u
PU
hronic u
m (
P
m (IC
P
IC
COPY 
m
Y
m
ss
O
ss
C and
C
C and
This 
ent
ct
t
ct
docume
it. 
en
it. Trea
ent 
Trea
s and co
men
s and co
cannot
MENT
ot 
MENT
c
parent
can
parent
s
c
s diar
ca
diar
be 
urin
e used
e i
d
e i
F
e
F) unti
ed 
) unti
If med
use
If med
ng the
us
ng the
to 
dica
o
dica
if initi
to
if initi
support 
deri
po
derivativ
por
vativ
t with ZX
sup
t with ZX
tions
s
tions
any marketing 
mine oxid
eting
mine oxid
hrine reup
rket
hrine reup
authorization 
y
een on
hori
een on
visit
th
visit, 
th
, ha
ho
ha
pected t
aut
pected t
n
care
n
care
tion
y
i
y. . 
applicat
Subjec
ion 
Subje
ment com
atio
ment com
mparing t
icat
mparing t
and 
COMP
d 
COMP
egive
an
egive
any 
ou
y
ou
PLI
a
PLI
extensions 
X008 vi
ons
X008 vi
/foods 
sion
/foods 
n
ated duri
nsi
ated duri
the end-
ten
the end-
ical nece
exte
cal nece
urse o
ex
urse o
or
s (inc
or 
s (inc
variations 
p
l
v
l
thereof. 
o rem
f
o rem
dase inhi
here
dase inhi
take in
the
take in


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 64 of 194  
6.
VISIT SCHEDULE
Study procedures will be conducted according to the Schedule of Assessments in Table 1 and 
Table 2. Time windows for all assessments are detailed in Table 7. For details on alternative 
procedures and allowances regarding study conduct during COVD-19 refer to Appendix 11. 
Table 7. 
Time Windows for Assessments
Visit / Procedure
Time window (relative to scheduled visit / procedure)
Visit 1 (Clinic; Study Day 1) 
Not applicable (this is the same visit as Visit 13 from the 
core study)
Visits 2 (Clinic/Phone; Study Day 15)
± 3 days
Visits 3-15 (Clinic: Study Days 30, 60, 90, 180, 
270, 365, 455, 545, 635, 725, 815, 905, 995)
± 4 days
Visit 16 (Clinic; Study Day 1085)
± 4 days
Visit 17 (Clinic; Study Day 1099; post dosing)
± 4 days
Visit 18, 19 (ECHO clinic; 3 and 6 months after 
last dose)
+ 30 days
Blood collection for AED concentration
Prior to morning dose of AED medication
AED=antiepileptic drug (s); ECHO=echocardiogram
6.1
OLE TREATMENT PERIOD
Review of inclusion and exclusion criteria and written informed parental or guardian consent 
and assent of minors (if the subject is capable of providing assent) for this study, including 
collection of HADs, EQ-5D-5L, and PedQL Family Impact Module ratings of parent/caregiver 
symptoms and quality of life, must be obtained before a subject can start any of the Visit 1
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. For subjects from the core studies it 
is assumed that consent for this study will have been obtained prior to completion of 
procedures at
•
ZX008-1501 and ZX008-1502 Visit 12/End of Study 
•
The last visit of the transition period of ZX008-1504 Cohort 1 
•
ZX008-1504 Cohort 2 Visit 12/End of Study 
For de novo subjects, consent for this study must be obtained prior to any study-related 
procedures. 
PUBLIC 
C
am
C
am
PERIO
BL
PERIO
lusion 
PU
lusion 
bj
P
bj
COPY 
4 days
PY
4 days
+ 30 day
OPY
+ 30 day
PY
CO
P
CO
P
CO
CO
CO
CO
C
This document 
s at
nt
s at
ZX00
me
ZX00
•
cu
•
T
m
T
nnot 
or obtain
not
or obtain
can
ding ass
ann
ding ass
at conse
can
at conse
be 
fe, m
e
fe, m
used 
criter
d
criter
ct is cap
sed
ct is cap
L, and P
use
L, and P
must
u
must
to 
D
ria a
to
ria a
support 
or to morn
por
or to morn
rt
po
D
any y
ny marketing 
sit as V
g 
sit as V
tin
ke
ma
m
authorization 
ve 
ve 
x 11
riz
x 11. 
iz
. 
visit / p
au
visit / p
ut
Vis
a
Vis
a
application 
nt for 
on 
nt for 
8-1501 an
lica
8-1501 an
he last vi
pp
he last vi
ZX008
ap
ZX008
nd
ing wri
nd 
ing wri
a
nt) are 
an
nt) are 
th
a
th
any 
e ob
y
e ob
t
extensions 
nd writt
ens
nd writt
able of p
xten
able of p
edQL F
ext
dQL F
btai
e
btai
or 
ng do
or 
ng do
or variations 
ns
tio
ia
se
v
se
v
thereof.
ocedur
of. 
ocedur
t 13 from
eof
t 13 from
of.
er
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 65 of 194  
Only eligible subjects as specified by the inclusion and exclusion criteria who have 
successfully completed the core study, or who are >18 to ≤35 years of age at the time of 
screening and who meet all other eligibility criteria, will be enrolled into study ZX008-1503. 
6.1.1
Screening Visit for de novo Subjects
For de novo subjects a screening period up to 28 days is required to determine eligibility prior 
to dosing. Clinical laboratory results and all ECHO/ECG results must be available and meet 
eligibility criteria prior to receiving the first dose of study medication at Visit 1. The following 
procedures will be performed during this screening period for all de novo subjects before the 
first dose of study medication: 
•
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 
•
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 3 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 must be obtained and results provided prior to starting ZX008) 
•
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 Baseline/Screening Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
•
Instruct parent/caregiver on use of diary 
PUBLIC
lable d
IC 
lable d
ell phon
BLIC
ell phon
n source
UBL
n source
ions
PU
ions
xamin
P
xamin
COPY 
pilepsy 
COP
pilepsy 
mber/ty
CO
mber/ty
C
This document 
hole b
nt
hole b
Obtain 
men
Obtain 
C-
me
C-S
me
S
•
cu
•
C
m
C
•
c
•
cannot 
nancy te
not
nancy te
ory evalu
ann
ory evalu
THC p
can
THC p
blo
c
blo
be
ogr
e
g
his mu
be 
his mu
used
ation, i
ed 
ation, i
examina
sed
examina
ram
us
am
to 
file
o
file
t
support 
histor
rt
histor
pe/durati
port
pe/durat
ation) of 
ppo
ation) of 
es are acc
supp
es are acc
e
s
e
any 
ry
a
ry
marketing 
1
o subjec
ng 
subjec
o collect P
ark
o collect P
ver sym
ma
ver sym
authorization 
gibility p
tho
gibility p
lable an
auth
lable an
The 
au
The 
application 
anel
on
anel
od CBD
tion
od CBD
blood sam
cati
blood sam
SRS Base
plica
SRS Base
GI
p
GI-
p
-I (asse
ppl
I (asse
CGI
ap
CGI-I (a
ap
-I (a
RIE
a
RIE
and
t for fe
nd 
t for fe
tion (s
an
tion (s
any
be obta
ny 
be obta
extensions
f pa
s
f pa
ceptable
ns 
ceptable
cluding 
ten
cluding 
tion 
ext
tion 
or 
on se
or
on se
rent/
or
rent/
variations
PedsQ
ns 
PedsQ
mptoms a
ions
mptoms a
eizu
v
eizu
thereof.
d m
f
d
followi
of. 
followi
ts before
reo
ts before
L
t
L


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 66 of 194  
•
Dispense diary (after above procedures have been concluded) 
•
Record AEs
Review inclusion/exclusion criteria, including echocardiogram, ECG, clinical laboratory 
results, and approval from the Epilepsy Study Consortium.  Only eligible subjects as specified 
by the inclusion and exclusion criteria with an independently confirmed diagnosis of DS by the 
Epilepsy Study Consortium, and approved by the sponsor, will be enrolled into the study and 
receive study medication. 
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 during the Screening period 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. 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. 
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
Clinic Visit 1 (Study Day 1; Transition from Core Study) 
6.1.2.1
Clinic Visit 1 for Subjects from Core Studies ZX008-1501 or ZX008-1502 
The following procedures will be performed during Visit 1 (Visit 13 of ZX008-1501 and 
ZX008-1502): 
•
Record demographic information
•
Vital signs
PUBLIC
nded scr
LIC 
nded scr
ase. Som
BLIC
ase. Som
o be on 
PUB
o be on 
ication
PU
ication
COPY
bje
Y
bje
g period
PY 
g period
s the inv
OPY
s the inv
reening 
CO
reening 
This document 
n in 
nt
n in 
C
en
C
6.1.2.1
cu
6.1.2.1
Th
do
Th
cannot 
ed bef
ot 
ed bef
been m
ann
been m
od (at le
can
od (at le
scre
c
scre
be
on has 
be 
on has 
for
b
for
used 
prov
d
prov
w a disa
sed
w a disa
u
escribi
us
scribi
to
a prohi
to 
a prohi
vide
to
vide
support 
es
t
es
resides 
ort 
resides 
ening or r
pp
ening or r
e general
sup
e general
bit
s
bit
any
 di
y
 di
have t
any 
have t
igator 
an
igator 
so
a
marketing
rd” cont
ing 
rd” cont
or parent/
eting
or parent/
f the study
ket
f the study
y. 
a
y. 
id not
m
id not
authorization 
ecified 
riza
ecified 
f DS by t
hori
f DS by t
e study 
tho
e study 
application 
ast 5 h
n 
ast 5 h
ening and
tion
ening an
linic Visi
lica
linic Visi
Clinic
app
Clinic
win
a
i
and 
e co
d
e co
de to w
and
de to w
ha
a
ha
any 
g
y
g
tiepilep
any
tiepilep
ollectio
an
ollectio
extensions 
resc
s
resc
l princip
ons
l princip
ted med
sio
ted med
d: 
e
d: 
owed c
xte
owed c
e
physi
ex
physi
or r
creen
o
creen
variations 
t meet a
tion
t meet a
he scree
riat
he scree
should 
aria
should 
ely wi
va
ely wi
thereof. 
aining 
reo
aining 
/caregiv
here
/caregiv
y so tha
the
y so tha


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 67 of 194  
•
Record prior and concomitant medications (use core study Visit 13 information)  
•
Urine pregnancy test for females of child-bearing potential 
•
Tanner Staging for subjects >7 to ≤18 years of age (Appendix 5) 
•
Instruct parent/caregiver on use of diary 
•
Record ongoing AEs as medical history (use core study Visit 13 information) 
•
Record ongoing adverse events of special interest (AESIs) as medical history (use core 
study Visit 13 information) 
•
Dispense diary (after above procedures have been concluded) 
•
Dispense study medication
Data collected from Visit 12/End of Study for the core study may be used for the following 
procedures unless otherwise indicated: 
•
Record medical, neurological, and epilepsy history 
•
Complete physical examination, including height, weight, and calculation of body mass 
index (BMI) 
•
Complete neurological examination (use data collected at core study Visit 12, unless 
there was a significant change in subject status warranting a new complete examination)
•
12-lead ECG 
•
Doppler ECHO  
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (use core study 
Visit 12 information, unless investigator determines new laboratory evaluation is 
warranted due to change in subject status) 
•
Urine THC panel  
•
Whole blood CBD  
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2)  
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8). After enrollment 
into the study, each subject will be issued a new “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.
PUBLIC 
n su
C
n su
(serum c
UB
(serum c
 unless
PU
 unless
ge
P
ge
COPY
g heig
PY 
g heig
n (use 
CO
n (use da
O
da
ubject
C
ubject
This 
ent
EF
t
EF
QOLCE
ent 
QOLCE
docume
PedsQ
men
PedsQ
•
u
•
Par
m
Par
Affec
doc
Affec
int
do
int
not t
dren’s 
ot 
dren’s 
cann
essed by
nno
essed by
assessed
ann
assessed
F (
c
F (App
ca
App
be 
r subj
be
r subj
e
S
b
S
used
inve
d
inve
n subjec
ed 
n subjec
to
hemis
to 
hemis
estig
to
estig
support 
a colle
ort 
a colle
status wa
por
status wa
stry
s
stry
any
weight
ny 
weight
ect
a
t
marketing 
used for t
keti
used for t
authorization 
y (use c
hor
y (use c
lication 
by
n
y
endix 3
on 
endix 3)
Appendix
atio
Appendix
app
L (
ic
L (Appen
icat
Appen
ent/Careg
plic
ent/Careg
a
ve symp
ap
e symp
ud
a
d
and 
nce
d
nce
parent/
and
parent/
y inve
an
y inve
any 
s > 7
any
s > 7 to 
y
to 
a
Last 
a
Last 
extensions 
, hemato
sio
, hemato
ator dete
ens
ator dete
t status)
xten
t status)
or
rranti
or 
rranti
variations 
and cal
iati
and cal
d at 
va
d at co
a
co
v
thereof. 
the foll
the
the foll


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 68 of 194  
6.1.2.2
Clinic Visit 1 for Subjects from Core Study ZX008-1504 
The following procedures will be performed during Visit 1(the last transition period of 
ZX008 1504 Cohort 1 and Visit 12 of ZX008-1504 Cohort 2): 
•
Record demographic information 
•
Vital signs
•
Urine pregnancy test for females of child-bearing potential 
Data collected from the last transition period of Cohort 1 and Visit 12/End of Study for 
Cohort 2 procedures may be used unless otherwise indicated: 
•
Record medical, neurological, and epilepsy history 
•
Record prior and concomitant medications  
•
Complete physical examination, including height, weight, and calculation of BMI  
•
Complete neurological examination (use core study Visit 12 information for subjects 
who participated in Cohort 2, and use core study information from the last transition 
period visit for subjects who participated in Cohort 1, unless there was a significant 
change in subject status warranting a new complete examination) 
•
12-lead ECG 
•
Doppler ECHO 
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (use data collected 
at core study Visit 12 for subjects who participated in Cohort 2, and use core study 
information from the last transition period visit for subjects who participated in 
Cohort 1, unless investigator determines new laboratory evaluation is warranted due to 
change in subject status)
•
Urine THC panel 
•
Whole blood CBD  
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver) 
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Healthcare utilization questions 
•
Karolinska Sleepiness Scale (Appendix 10) 
•
Sleep quality and meal time behavior questions  
•
Instruct parent/caregiver on use of diary 
PUBLIC 
nting a
C 
nting a
n (serum
PUB
n (serum
2 for s
PU
2 for s
COPY 
heig
Y
heig
e core s
OPY
e core s
e core st
COP
e core st
cipated 
CO
cipated 
a n
C
a n
This document 
I-I
t
-I (
t
(
CGI
en
CGI-I (a
ent
-I (a
BRIE
me
BRIE
•
u
•
Q
m
Q
•
c
•
annot 
el 
t
el 
CBD  
ot
CBD  
aging fo
nno
aging fo
ca
RS Child
can
RS Child
(asse
ca
(asse
be 
status)
be
status)
used
ubjects
ed 
ubjects
t transit
sed
t transit
igator 
us
gator 
to
hemis
to 
hemis
s w
t
s w
support 
udy 
rt
udy 
n Cohort
ort
n Cohor
ew compl
ppo
ew compl
any
eight
ny 
eight
dy Visit
any
dy Visit
inform
a
inform
marketing
d of Stud
ing 
d of Stud
t, an
m
t an
authorization 
pplication 
ren’s
n
ren s
ssed by p
tion
ssed by p
ssessed by
atio
ssessed by
F (
li
F (Appen
lica
Appen
pp
OLCE (
ppli
OLCE (Ap
i
Ap
ap
PedsQL 
app
PedsQL 
aren
a
aren
and 
r subjec
and
r subjec
s Sin
a
s Sin
any extensions 
le
ry, hema
nsio
ry, hema
who parti
tens
who parti
on perio
xte
on perio
termin
ex
termin
or 
or
, u
or
, u
e exa
or
e exa
variations 
nd calcu
atio
nd calcu
t 12 info
aria
t 12 info
mation 
var
mation 
unle
v
unle
thereof. 
dy for 
reo
dy for 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 69 of 194  
•
Record ongoing AEs as medical history 
•
Record ongoing AESIs as medical history 
•
Dispense diary (after above procedures have been concluded) 
•
Dispense study medication 
After enrollment into the study, each subject will be issued a new “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.
6.1.3
Clinic/Phone Visit 2 (Study Day 15) 
Visit 2 is to be performed in the clinic. At the discretion of the investigator, this visit may be
performed via phone. 
If Visit 2 is performed in the clinic, subjects will report to the clinic in the morning of that day. 
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 since previous visit 
•
Abbreviated physical examination, including height and weight, and calculation of BMI 
•
Abbreviated neurological examination
•
Vital signs
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (only if 
investigator determines new laboratory evaluation is warranted due to change in subject 
status since Visit 1)
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Collect and review diary with parent/caregiver
•
Dispense diary
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication 
If the visit is performed as a phone visit, site personnel will contact the subject on Study 
Day 15 and record/review the following: 
•
Concomitant medications
PUBLIC
ty (num
LIC 
ty (num
cations s
BLIC
cations s
xaminat
UB
xaminat
gical ex
PU
gical ex
COPY
l report
PY 
l report
s) of AE
OPY
s) of AE
erformed
CO
erformed
This document
ecord A
nt 
ecord A
Record
men
Record
•
Col
me
Col
m
•
c
•
nnot
a sam
ot 
a sam
can
(s)
n
(s)
and revi
ann
and revi
nse dia
ca
nse dia
A
c
A
be 
ines 
e
ines 
1)
b
1)
pl
b
pl
used 
ami
d
ami
(serum 
use
serum 
new
u
new
to 
on, in
to
on, in
inatio
to
inatio
support 
D 
t
D 
o
ber/type/d
upp
ber/type/d
nce previ
sup
nce previ
nclud
s
nclud
any
the clin
ny 
the clin
medicat
an
medicat
marketing 
vestigator
ark
vestigator
authorization 
ntaining
hori
ntaining
aregiver
utho
aregiver
o that th
aut
o that th
application 
ew
ry
o
ry
Es
t
Es
AESI
cat
AESI
ect used, 
plic
ect used, 
nd review
pp
nd review
a
Dispen
ap
Dispen
and 
e for
d
e for
a
w diary
an
 diary
any 
abor
y
abor
r AED
an
r AED
extensions 
durat
s
durat
vious vis
ons
vious vis
uding he
sion
uding he
n
e
n
hemistr
ext
hemistr
rato
e
rato
or 
tion
o
tion
variations
or, 
n
or, this
ns 
this
nic in th
riat
nic in th
ation pri
aria
ation pri
thereof. 
he 
f
he 
s v
t
s v


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 70 of 194  
•
AEs
•
AESI
•
Study medication use 
•
Diary entries
6.1.4
Clinic Visits 3-15 (Months, 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33)  
Subjects will report to the clinic in the morning of Clinic Visits 3 through 15. Subjects should 
not take their morning dose(s) of AED 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
•
12-lead ECG
•
Doppler ECHO (at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33) 
•
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 PK evaluation prior to the morning dose of study 
medication(s)
•
Tanner Staging for subjects > 7 to ≤18 years of age (Visits 6, 15, and 27 only) 
(Appendix 5) 
•
Collect and review diary with parent/caregiver
•
Dispense diary
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator) 
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) (for 
subjects from core studies ZX008-1501 and ZX008-1502 only) 
•
Healthcare utilization questions (for subjects from core study ZX008-1504 only)
•
Karolinska Sleepiness Scale (Appendix 10) (for subjects from core study ZX008-1504 
only) 
PUBLIC
les of 
IC 
les of 
um chem
BLIC
um chem
e for
P
e for
COPY 
9, 12, 
CO
9, 12, 
ch
C
ch
This document
GI
n
GI-I (a
nt 
-I (a
BRIEF
ent
BRIEF
QOL
me
QOL
•
cu
•
P
m
P
•
c
•
cannot 
view 
ot
view 
ary
no
ary
Childre
ann
Childre
(assess
can
(assess
ass
c
ass
be 
ubj
e
j
dia
b
dia
used
AED 
ed
AED P
d 
P
jects >
us
ects >
to support 
15, 18, 2
port
15, 18, 2
ld
p
ld-bearin
ppo
-bearin
istry and 
supp
istry and 
any marketing 
ollow
g
ollow
diary
rket
diary sin
et
sin
d weight
ma
d weight
authorization 
Subjects 
aut
ubjects 
wing
a
wing
application 
ed by p
on 
ed by p
essed by i
tion
essed by i
(Appendi
cati
Appendi
LCE (
plic
LCE (App
ica
App
edsQL (
ppl
edsQL (A
a
Parent/C
ap
Parent/C
ffec
a
ff
and 
ry
d
ry
s Since
an
s Since
pa
a
pa
any 
7
y
7
with 
an
with pa
n
pa
extensions
ng 
s
ng 
hemato
ns 
hemato
evalua
ten
evalua
to ≤1
ex
to ≤1
or 
, 24
or
, 24
poten
or
poten
variations 
ht, and c
ions
ht, and c
4 27
v
4 27
thereof.
shou
f
shou
procedu
of. 
procedu
ce prev
the
ce prev


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 71 of 194  
•
Sleep quality and mealtime behavior questions (for subjects from core study ZX008-
1504 only) 
•
Study medication palatability assessment (Visits 3 and 4 only) 
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication 
6.1.5
Clinic Visit 16 (Month 36): End of Study/Early Termination 
The End-of-Study participation for an individual subject occurs after he/she has received IMP
for 3 years in the OLE Treatment Period or if the subject is transitioning to receive ZX008 in a 
separate extension protocol when available or until ZX008 is approved in a subject’s country of 
residence and listed on a patient’s health plan formulary, whichever occurs first.. The End-of-
Study visit may also occur if the subject withdraws participation from the study or the Sponsor 
terminates the study.  
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. 
4. The subject is being transitioned to another extension study or transitioning to 
commercially available drug. 
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 ECG
•
Doppler ECHO (must be performed any time between Study Day 1064 and Study 
Day 1085; if subject terminates early from the study, the ECHO should be scheduled as 
soon as practical). If the Month 3, 6, 9, 12,1 5, 18, 21, 24, 27, 30, or 33 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 (Table 8).
•
Urine pregnancy test for females of child-bearing potential 
PUBLIC 
d-
C
d-of
C
of
C
s or is w
BLI
s or is w
nates the
UB
nates the
pletes a
PU
pletes a
ng t
P
ng t
COPY
mula
Y
mula
raws par
PY 
raws par
-Stu
C
-Stu
This document 
mple
nt
mple
Obtain v
ent
Obtain v
12-
me
12-le
e
le
•
cu
•
D
m
D
cannot
ent seiz
not 
ent seiz
oncomit
nn
oncomit
lete
ca
ete phy
can
 phy
ete n
c
ete n
be
s will b
be 
s will b
used
l stu
d
l stu
ansition
ed 
ansition
able
us
able dru
se
dru
to
study
to 
study
udy r
to
udy r
support 
dy v
pp
dy visit if
po
isit if
hdrawn 
sup
hdrawn 
p
y
s
y
any
hiche
ny 
hiche
cipation 
any
cipation 
marketing 
ion 
tin
ion 
er he/she
rke
er he/she
itioning t
mark
itioning t
approved
ma
pproved
ever
m
ever
authorization 
ountabili
hor
ountabili
application 
sical e
n 
sical e
eurologic
tion
eurologic
vital signs
cati
vital signs
ad 
li
ad ECG
lica
ECG
oppler 
ppl
oppler EC
pl
EC
Day
ap
Day 108
app
108
oon
a
oon
and
ure acti
nd 
ure acti
nt med
and
nt med
exa
a
exa
any
perform
any 
perform
vit
a
it
extensions 
from 
ons
from pa
ns
pa
elated vi
ens
elated vi
ed to ano
xten
ed to ano
g. 
e
. 
or
one th
or 
one th
variations
h
to
n
to rece
ns 
rece
d in a su
ions
d in a su
r occurs
atio
r occurs
n from th
ariat
n from th
thereof. 
has rec
the
has rec
i
t
i


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 72 of 194  
•
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
•
Urine THC panel
•
Whole blood CBD 
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
Collect and review diary with parent/caregiver
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator) 
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) (for 
subjects from core studies ZX008-1501 and ZX008-1502 only) 
•
Healthcare utilization questions (for subjects from core study ZX008-1504 only)
•
Karolinska Sleepiness Scale (Appendix 10) (for subjects from core study ZX008-1504 
only) 
•
Sleep quality and mealtime behavior questions (for subjects from core study ZX008-
1504 only) 
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication (not applicable for subjects transitioning to another 
extension protocol or to commercial drug) 
6.2
POST-DOSE VISIT (CLINIC VISIT 17; STUDY DAY 1099) 
If the subject completes the study (or discontinues from the study early), and is not 
transitioning to another extension protocol or switching to commercially available drug, the 
subject will visit the clinic on Study Day 1099 (or 14 days after the day of discontinuation) 
The following procedures will be performed: 
•
Record AEs
•
Record AESI
•
Record concomitant medications
PUBLIC 
ppen
C
ppen
me
B
me behav
BLI
behav
COPY
sc
Y
sc
using t
PY 
using t
01 and Z
OPY
01 and Z
or subjec
CO
or subjec
ndix
C
ndix
This 
ment
ect co
nt 
ect co
oning to
ent
oning to
docum
ect will 
me
ect will 
The fo
docu
The fo
t
m
t
m
canno
otocol o
ot 
otocol o
ST
a
ST-
an
-DOS
ann
DOS
om
c
om
be
rent/c
be 
rent/c
edicat
be
edicat
used 
used an
use
used an
ar
u
ar
to support
X0
t
X0
ts from 
ort 
ts from
10
pp
10)
pp
) (for s
ppo
(for s
or questi
sup
r questi
any 
pen
y
pen
HADS 
any
HADS 
08-150
an
08-150
marketing 
studies)
ma
studies)
ndix 
m
ndix 
authorization 
ication 
E
pletes the
tion
pletes the
another e
cati
another e
appli
visit the c
plica
visit the c
owing pr
app
owing pr
and 
to co
d
to co
VISI
an
VISI
any 
giver
ny
giver
n (not ap
any
n (not ap
omm
a
omm
extensions 
ions (fo
ions
ions (fo
unused
ex
unused
or
ore
r
ore
ubject
or 
ubject
variations 
7
at
7)
ati
)
scale (
riat
scale (A
t
A
502 only
vari
502 only
re stud
va
e stud
thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 73 of 194  
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
6.3
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 18, 19; 3 AND 6 MONTHS) 
AFTER LAST DOSE OF IMP
If the subject completes the 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 8. 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. 
Cardiac follow-up visits are not required for subjects who have entered another ZX008 
extension study or have transitioned to commercial drug. 
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.  
If the subject is switching to commercially available drug, (subjects must have an ECHO within 
3-6 months before starting commercial drug) the subject will complete the EOS visit and follow 
the drug administration process outlined for commercial product as advised by the subject’s 
physician. The post dosing and cardiac follow-up visits are not required. 
Table 8. 
Schedule of Post-Treatment Cardiac Follow-up
Duration of Fenfluramine Treatment
Parameter
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 druga
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 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.
PUBLIC
dru
C
dru
ned for
IC 
ned for
diac fol
BLIC
diac fol
ost
PU
ost-
PU
-Tre
UB
Tre
P
COPY
d/
Y
d/
e and u
PY 
e and u
availabl
COP
availabl
ug
C
ug)
CO
) the
CO
the
C
This 
ument 
ent
docum
Physical
cum
Physical
examin
ocu
examin
um
do
cannot
3
t 
3
ot
No
ca
No
ca
be 
to
be
be used
Du
d 
Du
d
4 week
us
4 week
ed to
tment
to 
tment
support 
e drug
ort 
e drug,
subject w
por
subject w
ommercia
ppo
ommercia
ow
su
ow-up vi
sup
-up vi
C
any
ca
y
ca
kely to
ny 
kely to
(su
a
(su
marketing 
HO
asympt
ng 
asympt
a physic
eting
a physic
g
red anoth
ket
red anoth
l exam
m
l exam
authorization 
HS
a
HS)
at
)
will 
tho
will ret
ho
ret
cal
a
cal
O and 
au
O and 
application 
n
3
n
appl
on
tion
a
ion
N
pl
ap
and 
onths p
d
onths p
treatme
nd
treatme
any y
,
a
,
post
a
post
any extensions
al p
s
al p
isits are
ons 
isits are
Cardiac
nsio
Cardiac
ation of F
ten
ation of F
en
xte
or
will co
or 
will co
rodu
o
rodu
variations 
m
t
mination
tion
ination
change
riati
change
ubjects 
va
bjects 
om
v
om
thereof.
ECG wi
of. 
ECG wi
omatic
reo
omatic
h
al exam
here
al exam
er ZX0
the
er ZX0


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 74 of 194  
6.4
ESTIMATED BLOOD VOLUME COLLECTION
The maximum total blood volume collected during the study for clinical laboratory testing, 
genotyping, and PK will be approximately 240.0 mL, as outlined in Table 9. 
Table 9. 
Estimated Blood Volume Collectiona
OLE Treatment Period (study day)
Assessment/ 
(Study Day)
15
30, 60, 90. 180, 270. 365, 455, 545, 635, 725, 815, 905, 995, 1085
Total 
Clinical chemistry 
--
7.5 mL at each visit
105 mL
LH, FSH, estradiol, 
testosterone, GH, prolactin
--
Included
in Chemistry
Hematology 
--
2 mL at each visit
28 mL
IGF-1 
-- 
3.5 mL at each visit
49 mL
Cannabidiol
--
2 mL at each visit
28 mL
AED plasma sample
1 x 2 mL
1 x 2 mL at each visit
30 mL
Approximate total blood 
volume per subject 
2.0 mL
17.0 mL at each visit
240.0 mL
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone
aIn concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), 
blood collection volumes for children weighing up to 15 kg will be:
•
The maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
•
The maximum in a 30-day period is 44-60 mL 
6.5
STUDY CONDUCT DURING COVD-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness 
caused by a novel coronavirus known as COVID-19. Alternative procedures and allowances 
are permitted due to restrictions related to COVID-19, including delays to in-person visits and 
specific assessments, performing remote phone or video visits if in-person visits cannot be 
conducted, and arranging shipments of investigational product directly to subjects. These 
allowances are detailed in Appendix 11. Though every attempt should be made to conduct 
study visits as described in this protocol, any implementation of alternative processes should be 
properly documented, including what was done differently, which assessments or visits were 
missed or performed via phone or video. 
BLIC 
ormone;
C
ormone;
PUB
e Childre
UBL
e Childre
children
PUB
children
ble
P
ble
COPY 
2 mL
Y
2 mL
1 x 2 
OPY
1 x 2 
PY
OP
C
IG
C
IG
C
This 
ument
n
t
n
itted du
nt 
itted du
ic assess
men
ic assess
nducted, 
ume
nducted, 
docu
llowanc
cum
llowanc
study
doc
study
pro
do
pro
cannot
COND
ot 
COND
, the Wo
ann
, the Wo
c
ovel c
ca
ovel c
c
be
a 30
be
a 30-da
be 
-da
used 
volume
sed
volume
u
to
n
weighi
to 
weighi
port 
.0 mL at 
ort 
.0 mL at
t
suppo
-
p
-1=insulin
ppo
1=insulin
s
po
s Resea
su
s Resea
ng
s
any 
h visit
ny 
h visit
y
at each v
any
at each v
ny
a
arketing 
,
g
ing
ke
mar
sit
m
sit
ar
m
authorization 
ho
1085
au
1085
ut
ut
ut
ut
ut
n
rld
n
rld
plication
oronavir
on 
oronavir
to restric
atio
to restric
ments, pe
icat
ments, pe
and arran
plic
and arran
app
es are det
pp
es are det
sits as d
ap
sits as d
doc
a
d
and 
UCT D
d
UCT D
d Heal
an
Heal
any
period 
ny 
period 
DUR
a
DUR
ns 
lik
extensio
arch Fo
ions
arch Fo
g up to 1
nsio
g up to 1
of blood
xte
of blood
or 
e grow
or
e grow
or variations s
tio
sit
a
sit
ia
h visit
va
visit
ar
thereof.
Total
of. 
Total
o
re
re
ere
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 75 of 194  
7.
EFFECTIVENESS, SAFETY, AND PHARMACOKINETIC
ASSESSMENTS 
For an overview of the study variables and measurement times, see Schedule of Assessments 
(Table 1 and Table 2).
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.7. 
7.1
EFFECTIVENESS ASSESSMENTS
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) 
B1: Focal With or Without Clear, Observable Motor Signs 
B2: Focal Without Clear, Observable Motor Signs 
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; also known as ‘drop attack’) 
K:  Infantile Spasms (if under 3 years of age) 
L:  
Epileptic Spasms (if 3 years of age and older) 
O: 
Other
Effectiveness 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. 
PUBLIC 
duration
UBL
duration
P
caregive
PUB
caregive
COPY
nd 
Y
nd 
nnot
PY
nnot co
Y 
co
be com
OPY
be com
hrougho
CO
hrougho
This 
ment 
yoc
t
yoc
Tonic 
nt
Tonic 
Aton
men
Aton
docum
: 
u
: 
Cl
um
Cl
J: 
cu
J: 
K
oc
K
cannot
ene
t
ene
seizure)
not 
seizure)
ed Ton
nno
ed Ton
nce or A
can
nce or A
clonic
ca
lonic
be
ear, 
be
ear, Ob
e 
Ob
eraliz
be
eraliz
used 
r i
d
r i
alization
sed
alization
t Clear
us
t Clear
b
u
b
to
(< 2
o
(< 2
in a
to
in a di
o 
di
support 
ple
t
ple
ut the st
ort 
ut the s
2 minu
su
2 minu
any
cal
y
cal
plete th
any 
plete th
ted
an
ted. Fo
an
. Fo
t
marketing 
linical site
ket
linical site
of the stud
ark
of the stud
ability
ma
ability is 
a
is 
es co
m
es co
authorization 
nts 
za
nts 
f the 
uth
f the IMP
tho
IMP
plication 
ypic
n
ypic
c 
i
c 
app
nic 
pli
nic 
Tonic/At
pp
Tonic/At
a
Infanti
ap
Infanti
i
and 
c Clonic
and
c Clonic
cal A
an
cal A
any y
rvable 
ny 
rvable 
Tonic C
any
Tonic C
extensions 
utes, 2-
sion
utes, 2-
ary
n
ary. 
n
. Seiz
nsi
Seiz
– right b
exte
– right b
Observ
ex
Observ
e
or 
y
r
y
variations 
udy
ns
udy. S
s
. S
 accepta
ons
 accepta
omplete
atio
omplete
e questi
riat
e questi
or the di
vari
or the di
y.
v
y.
thereof. 
e and 
the
e and 
ub
t
ub


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 76 of 194  
Seizures that evolve into SE will be captured by type and duration (> 10 minutes) 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. 
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 and Table 2.   
The Clinical Global Impression (CGI) scale measures the change in the subject’s clinical status 
from a specific point in time. 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 core 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 core study (before any study drug was taken). 
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 and Table 2. 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).  
PUBLIC COPY 
This document
Qua
nt 
Qua
QOLCE
me
QOLCE
ow epile
cum
ow epile
physic
docu
physic
con
do
con
d
cannot
be ask
ot 
be ask
symptom
nno
symptom
e core
an
core s
n
s
ali
c
ali
be
y
study (
be 
study (
b
used 
ked to
sed
ked to in
ed
in
mptom
us
mptom
b
u
b
to support any 
ow
y
ow
marketing 
n 
g
able
ng
able 2.
g 
2.
the subjec
keti
the subjec
al evaluat
arke
al evaluat
s rated on
mar
 rated on
ws:
m
ws:
m
authorization 
ies if 
zati
ies if 
nts
ri
nts.
riz
.
of the
au
of the
application 
ud
n
ty of Life
tion
ty of Life
(
l
(Append
lica
Append
psy affec
ppli
psy affec
l activitie
app
activitie
d ac
a
d ac
and 
d to
d
d to
d
ms have 
and
ms have 
dy (be
an
y (be
any 
ore an
ny 
ore an
indic
a
indic
extensions 
dicate th
xte
dicate th
have im
ex
ave im
e
or variations 
ation 
s
ation 
n a 7-po
ons
n a 7-po
thereof.
subject
of. 
subject
ct’s 
th
ct’s clin
he
clin
of t
th
of t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 77 of 194  
7.1.4
Pediatric 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 and Table 2. The PedsQL will only be conducted in subjects who enter 
from the core studies (ie, PedQL will not be performed on de novo subjects >18 years of age). 
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 and Table 2 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 PedsQL Family Impact module will not be assessed in the 
Netherlands.
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.
7.1.6
Study Medication Palatability Assessment 
The palatability and overall acceptability of the IMP will be assessed indirectly by the 
parent/caregiver responsible for the patient according to the schedule in Table 1 and Table 2
using 3 questions: 
PUBLIC 
nd
C
nd
utes.
IC
utes.
ol comm
UBL
ol comm
xperienci
PUB
xperienci
 and 7
PU
 and 7
COPY 
Y
zed mea
COP
zed mea
d econ
CO
d econ
This document
how t
nt 
how t
ed abov
en
ed abov
1.6
cu
1.6
The
do
The
p
d
p
cannot
c a
t
c a
ps
o
ps. The
ot 
. The
regiver
ca
regiver
he
c
he
be
nditio
be 
nditio
al, and
be
al, and
P
b
P
used
relate
ed 
relate
odule (
use
odule (
ons
u
ons
to
on
o
on
g. It is
to 
g. It is
to
t
to
support 
sure of
rt 
sure o
omic appr
por
omic appr
nly used
su
ly used
any 
bl
y
bl
f he
a
f he
marketing 
a patient 
ting
a patient 
sca
ket
scales: th
keti
les: th
rs who do
arke
rs who do
arent/care
mar
arent/care
le at th
m
e at th
authorization 
y
t
y
cal,
at
cal,
he 
ri
he 
o enter 
horiz
o enter 
ears of a
tho
ears of a
plication 
will be
on 
will be
care of th
tion
care of th
e.
c
e.
appl
Study M
ppli
Study M
tabili
ap
tabili
and 
edsQ
d
edsQ
a
any 
n par
ny 
n par
ognitive
any
ognitive
QL F
a
QL F
extensions 
d to det
ion
d to det
a 14-
nsi
a 14-item
sio
item
depress
tens
depress
ppendi
ex
ppendi
re
e
re
or 
aisal
or
aisal
r variations 
o not
s
o not
regiver s
ons
regiver s
he visit, 
tion
he visit, 
alth sta
va
alth sta
It
v
It
thereof. 
t with D
here
t with D
he EQ
the
he EQ 5
e
5
t giv
th
t giv


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 78 of 194  
QUESTION 1: Over the past month, on the basis of the reaction ⁄ facial expression of your 
child, do you think that the medicine’s taste and texture are: 
•
Acceptable to your child 
•
Not acceptable to your child 
QUESTION 2: Over the past month, please rate how much your child likes/dislikes the 
medicine’s taste using the following grading scale: 
•
5 (likes it very much) 
•
4 (likes it) 
•
3 (neither likes it or dislikes)
•
2 (dislikes it) 
•
1 (dislikes it very much)
QUESTION 3: Over the past month, do you sometimes have problems giving the medicine to 
your child due to its taste or texture? 
•
No
•
Yes 
o
How often?  

Every day in the past month 

Once to several times every week in the past month

Once or several times in the past month
7.2
EXPLORATORY ASSESSMENTS
The following exploratory assessments will be conducted for subjects who participated in core 
study ZX008-1504 only. 
7.2.1
Sleep Quality and Meal Time Behavior Questions
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes their child’s sleep quality and eating behavior since starting IMP based on the 
following questions: 
1. Since your child has started taking the study medication in this study, have you noticed that 
s/he has been waking in the middle of the night or very early in the morning more than usual? 
o
My child’s sleep is more disturbed than it was before s/he started the study medication 
o
My child’s sleep patterns are the same as they were before starting the study medication
o
My child sleeps better than s/he did before starting the study medication
PUBLIC 
ay in the
UB
ay in the
to seve
PU
to seve
r se
P
r se
COPY
metimes
PY 
metimes
This 
ment
nt/care
ent 
nt/care
bes thei
men
bes thei
docum
lowing q
ume
lowing q
1. Sin
doc
1. Sin
s/h
do
s/h
annot 
tory
ot
tory
ca
only.
not
only.
eep Qua
can
eep Qua
be 
RY
e
RY
ass
b
ass
used
al ti
d
al ti
veral tim
ed 
veral tim
ASS
us
ASS
to
past m
to 
past m
imes
to
imes
support 
mon
s
mon
any 
ave pro
any
ave pro
marketing authorization 
es the 
tho
es the 
lication 
lity 
n
lity 
ver will b
atio
ver will b
child’s s
icat
child’s s
appl
uestions:
plic
uestions:
your c
ap
your c
ee
a
and 
s
d
and
a
and
any 
SS
y
SS
ments w
any
ments w
extensions 
nth 
si
nth 
every w
ens
every w
mes in th
xten
mes in th
SME
e
SME
or variations 
blems g
riat
blems g
thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 79 of 194  
2. Since your child has started taking the study medication in this study, have you noticed that 
s/he has had a change in their mealtime behavior? 
o
My child has worse meal time behavior since starting the study medication
o
My child’s meal time behavior has not changed since starting the study medication 
o
My child has improved his/her meal time behavior since starting the study medication 
7.2.2
Karolinska Sleepiness Scale
The Karolinska Sleepiness Scale (Appendix 10) will be administered according to the schedule 
in Table 2. The Karolinska Sleepiness scale is a self-report scale that measures the subject’s 
drowsiness. It is a 9-point verbally anchored scale, which ranges from ‘extremely alert’ at one 
end of the scale to ‘extremely sleepy – fighting sleep’ at the other end of the scale. Within this 
study, the scale will be completed by the observer in an exploratory manner.
7.2.3
Healthcare Utilization Questions
In order to better understand the healthcare resource burden associated with the management of 
DS, caregivers will be asked which of the following hospital and community-based healthcare 
services they had interactions with over the preceding month: emergency room services, 
ambulance, planned and unplanned hospitalization, family physician services, speech and 
language therapy, occupational therapy, and physical therapy. This information will be 
captured in the CRF. 
7.3
SAFETY ASSESSMENTS
7.3.1
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 and current medications will be carried over from 
the core study. 
7.3.2
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 and Table 2. 
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.  
PUBLIC
th
C
th
ospital
IC 
ospital
erapy, an
BLIC
erapy, an
SSME
PU
SSME
COPY 
ource b
OPY
ource b
followin
COP
followin
he prec
CO
he prec
C
This document 
y
Ph
ent
Ph
omplete
cum
omplete
conduc
ocu
conduc
A
do
A co
o
co
c
d
c
cannot
s (sex
ot 
s (sex
om the p
nno
om the p
ect’s cu
ann
ect’s cu
.
c
.
be 
b
used 
NTS
d
NTS
Medical
use
edical
to support 
 hospi
rt 
 hospi
eding mon
por
eding mo
ation, fam
ppo
ation, fam
d physica
sup
d physica
any 
d
a
den asso
any
en asso
ital
a
ital
marketing 
ng
g
g
sures th
ng 
sures th
extremel
eting
extremel
nd of the s
ket
nd of the s
ry manne
ark
ry manne
authorization 
cation 
riza
cation 
g to th
au
to th
application 
re
ysical Exa
cati
ysical Exa
and abbre
ppli
and abbre
ed by the
app
ed by the
ete
ap
ete st
p
st
and
ge, h
d
ge, h
ast 5 ye
nd 
ast 5 ye
nt me
an
nt me
any 
height
a
height
extensions
mily
s
mily
al therap
ns 
al therap
Neurolo
ex
eurolo
or
nth: e
or 
nth: e
y phy
o
y phy
variations 
er.
s
er.
sociated 
aria
sociated 
and com
va
and com
em
v
em
thereof.
e schedu
of. 
e schedu
subject
reo
subject
ly alert’
here
ly alert’
scale. W
the
scale. W


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 80 of 194  
Any unfavorable findings not present at Visit 12 of the core study considered by the 
investigator as clinically significant, occurring at any point in the study will be documented in 
the CRF as an AE. 
7.3.3
Neurological Examinations 
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1 and Table 2. 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.  
7.3.4
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 and Table 2. 
7.3.5
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 2, and Table 9: 
•
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), 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.  
•
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 
PUBLIC 
nts
IC
nts
ll be ana
UBL
ll be ana
ill be 
PU
ill be a
U
a
COPY 
e, tempe
OPY
e, tempe
utlined in
COP
utlined in
This document 
minotra
nt 
minotra
bicarbo
ent
bicarbo
creat
me
creat
de
m
de
cannot
emogl
ot 
emogl
, basoph
no
, basoph
Bioche
can
Bioche
an
c
an
be 
globi
e
globi
b
me, leuk
be
me, leuk
ob
b
ob
used 
ssesse
d
ssesse
in, h
u
in, h
to 
ly
o
y
ed b
to
ed b
support 
Table
rt
Table
zed usin
su
zed usin
any 
ture, an
any
ture, an
e 1
a
e 1 a
a
a
marketing 
he
g
unction,
ng 
unction,
valuate an
eting
valuate an
e that mig
ket
e that mig
authorization 
stigator 
tho
stigator 
ard of ca
auth
ard of ca
follo
au
follo
plication 
mistry
on 
mistry
ferase (A
tion
ferase (A
nate, bloo
cati
nate, bloo
ne kinase
lica
ne kinase
app
hydrogen
ppli
hydrogen
function 
app
function 
ilirub
a
ilirub
and
in c
d
in c
hils and 
nd 
hils and 
:
a
:
any
mato
y 
mato
an
cytes,
any
cytes, m
y
m
oncen
an
oncen
extensions 
ing stan
ion
ing stan
y the lab
ens
y the lab
ocr
e
ocr
or variations 
nd respir
aria
nd respir
and 
va
nd Tab
va
Tab
thereof. 
re 
f
e
wing:
of
wing:
and gait
reo
and gait
any sym
here
any sym
ght evol
the
ght evol


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 81 of 194  
•
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.
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 will be 
documented in the CRF as an AE (Section 9).
7.3.6
Plasma Sample for Concomitant Antiepileptic Drug(s)
Plasma samples to ensure that concomitant AEDs dosing is within an acceptable range will be 
conducted during the study as outlined in Table 1 and Table 2. All samples will be analyzed at 
study end and do not constitute safety assessments. 
7.3.7
Electrocardiograms
Twelve-lead ECGs will be conducted during study as outlined in Table 1 and Table 2 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. 
7.3.8
Doppler Echocardiography 
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1 and Table 2. 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 
PUBLIC
e range
IC 
e range
ormal, c
BLIC
ormal, c
AE (
UB
AE (Secti
UBL
Secti
for C
PU
for C
COPY
at have
PY 
at have
eated as 
OPY
eated as 
ors.
CO
ors.
C
This document 
s been
nt 
s been
n, QT du
ent
n, QT du
rpretatio
me
rpretatio
7.3.8
ocu
7.3.8
D
d
D
cannot t
ocardio
nno
ocardio
ECGs w
can
ECGs w
n in
c
n in
be 
y as ou
be 
y as ou
b
stitute 
be
stitute 
used
oncom
ed 
oncom
concom
use
concom
utl
u
utl
to 
on 
o
on 
mit
t
mit
support t
onsidered
ppo
onsidered
inically s
sup
inically s
9
s
9).
s
).
any
en clas
ny 
en clas
on as p
any
on as p
marketing 
aboratory
ket
aboratory
ange, the 
ark
ange, the 
i
authorization 
application 
ll be
n
ll be c
 
c
n the supin
tion
n the supin
uration, Q
cati
uration, Q
n will be r
lica
n will be r
Dop
app
Dop
and 
grams
nd
grams
co
a
co
ny 
ed in 
ny 
ed in 
an
afety ass
any
afety ass
extensions
ed b
s
ed b
signific
ns 
signific
ant Ant
tens
ant Ant
tant AE
ex
ant AE
T
e
T
or 
y the
or
y the
variations 
 inve
s
 inve
ified by
iati
ified by
possible 
aria
possible 
thereof. 
. 
t
. After 
the
After 
esti
th
esti


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 82 of 194  
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. 
7.3.9
Tanner Staging
Tanner Staging (Appendix 5) will be assessed for subjects >7 years old during the study as 
outlined in Table 1 and Table 2. 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’.  
7.3.10
Columbia-Suicide Severity Rating Scale
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1 and Table 2. 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 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. 
7.3.11
Adverse Events
For de novo subjects, 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. For 
subjects who participated in one of the core studies, adverse events that occur after signing 
informed consent for this study, but before Visit 1 will be recorded as adverse events in the 
core study and medical history in ZX008-1503. 
Details of the definitions and categorization of AEs, and procedures for the reporting of AEs, 
are available in Section 8. 
PUBLIC
and
C
and
ren’s Si
LIC 
ren’s Si
of intelle
BLIC
of intelle
an 7 yea
PU
an 7 yea
ty to
P
ty to
COPY 
cal
Y
cal
g study 
OPY
g study 
esses 
CO
esses su
O
su
d
C
d prov
C
prov
This document
ovo sub
nt 
ovo sub
nt form/a
men
nt form/a
jects wh
ume
jects wh
nformed
cum
nformed
core s
doc
core s
cannot
elle
t
elle
C-SSR
not 
C-SSR
verse E
an
verse E
j
c
j
be 
es
e
ectua
be
ectua
used
rs 
d
rs 
unders
ed 
unders
vestigato
use
vestigato
tions 
us
tions 
to 
chron
to
chron
support 
s o
t
s o
cidal 
ort
cidal be
t 
b
ides a sum
por
ides a sum
ce Last V
upp
ce Last V
tual deve
sup
tual deve
any 
outlined
an
outlined
eh
a
h
marketing
escr
g
escr
vents, an
ing 
vents, an
gorized by
eting
gorized by
Marshall 
ket
Marshall 
Tanner st
ark
Tanner st
authorization 
he
au
he study
auth
study
ribed
au
ribed
application 
ven
n
ven
cts, a
atio
cts, adve
o
dve
ssent form
icat
ssent form
o particip
plic
o particip
consent 
ppl
consent 
dy and 
ap
dy and 
and
S shou
nd 
S shou
nts
a
nts
any 
p
y
p
apacity
any
apacity
ld b
a
ld b
extensions 
Visit)
s
Visit)
velopme
ons
velopme
ological
nsi
ological
and the q
ten
and the q
r should
exte
r should
robe 
ex
robe 
or
mmary
or 
mmary
wi
o
wi
variations
stages
ns 
stages
d in
ar
d in Tab
aria
Tab
vior an
va
vior an
v
thereof.
y as 
f
y as 
in terms
of. 
in terms
d the 
reo
d the 
y severa
here
y severa
and Ta
the
and Ta
’
t
’


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 83 of 194  
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 CRF page.  
7.3.12
Behavior Rating Inventory of Executive Function (BRIEF) 
The BRIEF is a standardized, validated rating scale to measure executive function. Age-
appropriate versions of the BRIEF (BRIEF-P: 2 to 5 year olds; BRIEF: 6 to 18 year olds; 
BRIEF-A: 19 to 35 year olds) will be assessed according to the schedule in Table 1 and 
Table 2. 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). 
7.4
APPROPRIATENESS OF MEASUREMENTS
All of the variables assessed are standard tests or procedures that are commonly used in studies 
of this type. 
PUBLIC
OF ME
IC 
OF ME
e standar
UBL
e standar
PY
as
Y
as
anize
PY
anize/O
Y 
/O
COP
main ide
OPY
main ide
This document cannot be used to 
d te
o
d te
support 
as
t
as
SUREM
pp
SUREM
sts or 
su
sts or 
any
ing
y
ing
anizatio
any 
anizatio
a
), and M
an
), and M
marketing 
nct
g
to 18 ye
ng 
to 18 ye
le in 
etin
le in Tabl
ing
Tabl
ning; scal
ket
ning; scal
tivity/situ
ark
tivity/situ
odulate em
ma
odulate em
g Mem
m
g Mem
authorization 
lly 
ti
lly 
be 
a
be 
ion
au
on. A
au
. A
application and any extensions 
MEN
s
MEN
r proced
sion
r proced
n
d
n
d
or 
NTS
o
NTS
riations 
uation
s
uation
motiona
ons
motiona
mory
tio
mory (h
on
(h
n of Ma
riat
n of Ma
va
Monitor
aria
Monitor
thereof. 
ge-
of
ge-
ar olds;
reo
ar olds;
le 1
e
le 1 and
ere
and
es inclu
the
es inclu
n to
th
n to


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 84 of 194  
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. For de novo subjects, the 
period of observation for adverse events extends from the time the subject gives informed 
consent until the end of study. For subjects who participated in one of the core studies, the 
period of observation for adverse events extends from Visit 1 of ZX008-1503 until the end of 
study. Adverse events that occur after signing informed consent for this study, but before 
Visit 1 will be recorded as adverse events in the core study and medical history in ZX008-1503. 
Adverse events may include: 
•
Illness present before core study entry should be recorded in the medical history 
section of the CRF along with any ongoing AEs that were present at Visit 13 of the 
core study. These events should only be reported as an AE if there is an increase in 
the frequency or severity of the condition from the core study  
•
Exacerbation of seizures is considered an AE if there was an increase in frequency 
beyond the subject's typical pre-core study fluctuations, or in the event that seizures 
lengthen in duration in a clinically meaningful way compared with core study 
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 
PUBLIC 
e
B
e study 
BLIC
study 
ong with
UBL
ong with
vents sh
PUB
vents sh
verity
P
verity
COPY
om
Y
om
nformed
PY 
nformed
the core 
OPY
the core 
This 
ment
Int
nt
Intercu
nt 
ercu
docum
verse ev
me
verse ev
•
oc
•
cannot
urat
t
urat
r if a ne
not 
r if a ne
nical ev
can
nical ev
be
zu
ect's ty
be 
ect's ty
tion i
be
tion i
d
ou
d
ou
used
of the
ed 
of the
ures is
us
res is
u
to
any 
o
any 
uld onl
to 
uld onl
t
support 
stu
t
stu
entry shou
sup
ntry shou
ongo
s
ongo
any
o
y
o
onsent f
any 
onsent f
dy and
an
dy and
marketing 
unf
g
finding)
ng 
finding)
nal) produ
eting
nal) produ
r de novo
ket
r de novo
e subject 
ark
e subject 
n one of th
ma
one of th
f ZX0
m
f ZX0
authorization 
ent or cl
tho
ent or cl
t necess
auth
t necess
favora
au
favora
ication 
ent o
n
ent o
rent
ati
rent
appli
illne
tio
illne
nts do no
plic
nts do no
Medic
app
Medic
g
a
g
and
w seizu
nd 
w seizu
occu
a
occu
any y
al pre-
ny 
al pre-
a clinica
any
a clinica
ure
a
ure
ensions
ould be r
ons 
ould be r
oing AE
sion
oing AE
y be rep
nsi
y be rep
exte
ondition
ten
ondition
nsider
ex
nsider
or variations
t give
s 
t give
the core 
ons
the core 
008-150
tio
008-150
for this s
riat
for this s
d medic
varia
d medic
thereof.
arily
f
arily
ble and
of. 
ble and
symptom
reo
symptom
uct, whe
here
uct, whe
subjec
the
subjec
es i
t
es i


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 85 of 194  
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 CRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
CRF 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 
PUBLIC
nd flag
IC 
nd flag
at are ob
PUB
at are ob
life).
PU
life).
COPY
he refe
PY 
he refe
exacerba
OPY
exacerba
sed by 
CO
sed by 
ge
C
ge
This document
esults i
ent 
esults i
criterio
me
criterio
2.
oc
2.
I
u
I
cannot t
s Adver
not
s Adver
erse eve
can
erse eve
be 
e lab
be
e lab
t neces
be
t neces
used 
alue tha
use
alue tha
ora
u
ora
to
iously
to 
iously
support 
mechanic
port
mechanic
d as such
ppo
d as such
bi
s
bi
any 
ce rang
ny 
ce rang
on of a p
any
on of a p
marketing 
in
g
e record
ng 
e record
levant, ev
eting
levant, ev
ollowing c
mar
ollowing c
authorization 
an 
an 
rapy) 
riza
rapy) 
e referen
tho
e referen
ator as 
auth
ator as 
vestig
au
vestig
application 
nt (SA
on 
nt (SA
death
atio
death –
o
–
n.
li
n.
a
life
ap
life-
pp
-thre
pp
thre
was at r
ap
as at r
and
se Even
nd 
se Even
AE
a
AE
any
ry (e
ny 
ry (e
arily be r
any
arily be r
extensions 
h by
s
h by
iologica
nsio
iologica
cannot
ext
cannot
eg
e
eg
or 
l or 
or
l or 
y the 
or
y the 
variations 
cases: 
ons
cases: 
e, unless
iatio
e, unless
pre
ar
pre-exis
aria
-exis
ph
v
ph
thereof. 
ator’s 
of
ator’s 
ed in the
reo
ed in the
ven if th
here
ven if th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 86 of 194  
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.
•
The most important term should be selected as the criteria for the SAE.  Medically 
significant should be used when none of the other terms apply, for cases in which, had 
there not been intervention, one of the other SAE outcomes would have likely 
occurred. For example, anaphylaxis successfully treated with an epinephrine injection 
would be a 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 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 non-serious 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 
e
C
e
llection 
BLIC
llection 
e subjec
UBL
e subjec
n
P
nutes
PUB
utes in 
UB
in 
ess of
PU
ess of
COPY
f the ot
PY 
f the ot
e other S
OPY
e other S
is succes
COP
is succes
vent.
CO
vent.
This 
ment 
ICH gu
men
ICH gu
docum
ntified th
me
ntified th
cannot 
SA
t
SA
at do no
nno
at do no
dverse
ca
dverse
be
o mana
be 
o mana
AE.
be
AE.
ed
du
d
wheth
ed 
wheth
use
s well a
sed
s well a
lasting
us
lasting
u
to
doe
o
doe
uration
to 
uration
t
support t
sfully t
ort 
sfully 
n this stu
sup
n this stu
es not 
su
es not 
any y
terms 
ny 
terms 
E outco
any
E outco
trea
a
trea
marketing 
sic
rventio
ng 
rventio
xis that is 
ting
xis that is 
e is an ex
keti
e is an ex
eria for
m
eria for
authorization 
event th
uth
event th
cian to
au
ian to
a
ication 
Events
on 
Event
dance (
cati
dance (
appli
E2
i
E2
e followin
plica
e followin
and 
t fall int
and
t fall int
any y
SE, reg
ny 
SE, reg
tensions
udy, a p
ns 
udy, a p
t regain 
sion
t regain 
is term
nsio
is term
rescue m
ten
rescue m
ex
in the s
exte
in the s
0 min
ex
0 min
or variations 
or the SA
tion
or the SA
apply, fo
iati
apply, fo
omes wo
aria
omes wo
ted wit
va
ted wit
thereof. 
t 
to preve
eof
to preve
s success
here
s success
xample 
the
xample 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 87 of 194  
Table 10. 
Adverse Events of Special Interest
Metabolic/Endocrine
1.
Elevated prolactin level ≥2x above the upper limit of normal (ULN)
2.
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.
Suicidal thoughts, ideation or gestures
LLN = lower limit of normal; ULN = upper limit of normal
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 DS: 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 non-serious or serious AEs) is to be assessed by the investigator 
as follows (Table 11 ).
Table 11.  
Severity Definition of Adverse Eventsa
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.
a
Clinical Data Interchange Standards Consortium Study Data Tabulation Model Severity Intensity Scale for 
Adverse Event Terminology
PUBLIC 
C
ERSE E
LIC
ERSE E
non-
PUB
non-ser
UB
ser
COPY
name
PY 
name
gram, EC
OPY
gram, EC
ce imagi
COP
ce imagi
pinal t
CO
pinal t
This document 
nt
Clin
cum
Clin
A
c
A
um
cannot 
of AE
ot
of AE
rvention.
no
rvention.
A type o
an
A type o
event
ca
event
sig
c
sig
nn
be 
n
b
n
h
b
h
b
used 
ition of
use
tion of
u
to
ous
to
ous or
o 
or
support 
ng (MR
rt 
ng (MR
ap
p
ap. 
po
. 
VENTS
upp
VENTS
se
s
any y
mber o
ny 
mber o
G, ECHO
any
G, ECHO
RI),
a
RI)
marketing 
om, free
arke
om, free-s
e
-s
collected 
mar
collected 
linic vi
ma
linic vi
f p
f
authorization 
i
ati
or
iz
or
at
at
at
or
th
au
tion 
AE
n
nterferes
on 
nterfere
ificant or p
tion
ificant or p
pplicati
A type of 
cat
A type of 
ap
status, 
plica
status, 
ti
al
p
al Data In
ppl
Data In
verse Eve
app
verse Eve
plplpli
and
t is u
d
t is u
The even
nd 
The even
E
a
E that 
an
that 
an
any y
usually
a
usually
an extensions 
erious A
nsio
erious A
Advers
ext
Advers
e
or variations
stan
s
stan
d to mod
ns 
d to mod
isit; dur
tion
isit; dur
procedu
iatio
procedu
O, posit
aria
O, posit
x-ray, 
var
x-ray, 
thereof. 
f
nding
th
nding


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 88 of 194  
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. 
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING
The observation period for AE and SAE reporting for de novo subjects 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 participated in 
one of the core studies, the observation period for adverse events will start at Visit 1 of 1503 
and finish 15 days after the last dose of study drug or the last visit, whichever is later. Ongoing 
AEs from the core studies will be considered medical history unless there is an increase in the 
frequency or severity of the condition from the core study. 
PUBLIC 
should 
BL
should 
tant illn
PU
tant illn
COPY 
ro
Y
ro
al relatio
COP
al relatio
f treatm
CO
f treatm
This document
rvation
nt 
rvation
written
men
written
last dos
ume
last dos
one of th
cum
one of th
and fi
doc
and fi
AE
do
AE
nnot
onc
t
onc
esponse
not 
esponse
ca
SERVA
an
SERVA
c
be
f
drug an
be 
drug an
urren
be
urren
used 
ess, a
d
ess, a
ollows
us
ollows
d
u
d
to 
acc
to
acc
support 
nshi
rt
nshi
nt with
ort
nt with I
used 
sup
used in
up
in
any 
ate
y
ate
ip (eg
a
ip (eg
marketing 
imilar pro
mar
imilar pro
ed (eg
m
ed (eg
authorization 
use (eg,
tho
use (eg,
mined b
auth
mined b
application 
TI
n
TI
period for
atio
period for
informed
icat
informed
e of study
plic
e of study
e core stu
ppl
e core stu
sh 15 da
ap
sh 15 da
th
a
th
and
should
nd 
should
a
ON P
an
ON P
any y
s defin
ny 
s defin
disease 
any
disease 
d be
a
d be
extensions 
n catego
ions
n catego
dent or 
ens
dent or 
reason
ex
reason
or 
MP
r
MP
r variations 
roducts, 
ons
roducts, 
g, heada
tion
g, heada
g, the ev
var
, the ev
dru
va
dru
thereof. 
y h
f
y


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 89 of 194  
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 CRF. 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 CRF. 
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 Inventive Health Care 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 for de novo subjects and at Visit 1 for subjects from the core studies, 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.  
PUBLIC 
EVENT
LIC
EVENT
all applic
PUB
all applic
E2A (
PU
E2A (C
U
C
]
P
]
COPY 
with a p
OPY
with a p
d be retr
COP
d be retr
This ocument
llo
t
llo
must b
nt 
must b
awar
men
awar
All SAE
cum
All SAE
doc
is sig
doc
is sig
no
do
no
cannot 
vant
t
vant
e Medic
not
e Medic
rs of be
ann
rs of be
ow the
ca
w the
be 
nvest
be
nvest
t info
be
t info
used 
linica
d
linica
tiga
u
tiga
to
able re
to 
able re
al
to
al S
to
S
support 
ospect
rt 
ospect
S 
S REPO
upp
REPO
gu
s
any 
existing
any
existing
tive
a
tive
marketing 
hether 
ng 
hether 
f known,
ting
f known,
individua
keti
individua
E until re
arke
E until re
he AE wil
mar
he AE wil
authorization 
a
application
initial n
ion 
initial n
emailed o
atio
emailed o
of the S
cat
of the S
th
p
that occ
ppl
at occ
a
d for de
ap
d for de
lly
a
ll
and
al Moni
nd 
al Moni
ming a
an
ming a
any
r or 
ny 
r or 
a
mation in
any
mation in
extensions
ORTIN
ns 
ORTIN
ulatory r
nsio
ulatory r
afety Da
tens
afety Da
de
e
de
or variations 
esolu
s
esolu
ll contin
ons
ll contin
g condit
aria
g condit
ly recor
va
y recor
thereof. 
ny AEs h
eof
ny AEs h
, the me
ere
, the me
al signs
the
al signs
utio
th
utio


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 90 of 194  
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 (ie, 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 
CRF.
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.
PUBLIC 
rting so
PU
rting so
COPY
iate re
PY 
iate re
This document 
cas
t
cas
3.
me
3. En
en
En
If the
doc
If the
rec
do
rec
cannot 
t follow
nno
t follow
armacov
can
armacov
se of 
ca
e of 
be
Es to th
be 
Es to th
used 
urce 
d
urce 
ust:
us
ust:
to support any 
ting of
ny 
ting of
marketing 
udy site b
eting
udy site b
ous Adve
mar
us Adve
S
authorization 
ver is
oriz
ver is
ly (ie, w
tho
ly (ie, w
nd
a
nd the M
auth
the M
application 
igila
n
igila
permanen
tion
permanen
ure that t
icat
ure that t
a
CRF.
plic
CRF.
inimum
ap
inimum
di
a
di
and 
-up rep
and
-up rep
ance
a
ance
any 
elevan
ny 
elevan
extensions or variations 
erse Eve
ons
erse Eve
SAEs in
iatio
SAEs in
thereof. 
Med
f
Med
before th
here
before th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 91 of 194  
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 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 
PUBLIC
TS O
IC 
TS O
TO SP
BLIC
TO SP
or an SA
PUB
or an SA
to the 
PU
to the 
COPY
p
Y
p
e requ
PY 
e requ
within th
OPY
within th
) compl
COP
) compl
T
C
T
This 
cument 
effort sh
ent
effort sh
E on com
me
E on com
ttempted
cum
ttempted
doc
of the 
docu
of the 
Pha
do
Pha
d
cannot
y
t
y
ymptom
ot 
ymptom
e of stud
nno
e of stud
OLLOW
ca
OLLOW
be 
y reac
be 
y reac
perten
be
perten
b
used
Medic
ed 
Medic
ctio
u
ctio
to
are fu
to 
are fu
al
t
al
support t
ted by 
ort 
ted by
HER TH
ppo
HER TH
ONSOR
sup
ONSOR
f
any
y e
y
y e
ments f
ny 
ments f
applica
any
applica
th
a
th
marketing 
NVESTI
ting
NVESTI
or an unex
mar
or an unex
each in
m
each in
authorization 
s it 
ti
s it 
orted 
zat
orted 
low-up 
riza
low-up 
of the 
auth
of the 
ation 
W
o
W-UP O
on 
UP O
pplica
ould be m
cati
ould be m
pletion of
lica
pletion of
follow
ppli
follow-u
i
-u
ap
ubject’s p
app
ubject’s p
ovig
a
ovig
and 
s requ
d
s requ
y-
a
y-related
and
related
O
a
O
any 
s
ny
s
on
an
on
uirin
a
uirin
extensions 
AN
s
AN
filled, an
nsio
filled, an
Monitor
tens
Monitor
or 
N SE
o
N SE
variations 
xpected
ons
xpected
ndividu
tion
ndividu
or IEC/IR
iati
or IEC/IR
able tim
aria
able tim
e Spons
va
Spons
thereof. 
IGATO
ere
IGATO


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 92 of 194  
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication. 
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, tricuspid) 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
Trace 
Level 1
Level 1
Level 1
Level 1
Mild (≤18 years)
Level 2
Level 1
Level 1
Level 1
Mild (>18 years)
Level 2
Level 1
Level 1
Level 1
Moderate
Level 3
Level 2
Level 2
Level 2
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 (eg, VPA, CLB, 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 subject 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 subject should 
provide assent if appropriate. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment.
PUBLIC 
C
IC
3
B
3
LIC
IC
IC
BLI
ocol
PU
ocol
COPY 
tral
PY
tral
Y
Level
OP
Level 1
P
1
PY
Leve
CO
Leve
O
L
C
L
C
This 
ument
an
nt 
an
n
docu
2. If t
cum
2. If t
cannot 
with 
ot
with 
ciated w
not
ciated w
uration o
ann
uration o
The in
ca
The in
nd
c
nd
be
on
e
gator w
be 
gator w
the
b
the
used 
tinue 
us
tinue 
to support 
1
t
vel
p
vel 1
p
1
or
Level
upp
Level 2
pp
2
pp
Level
sup
Level
up
s
any 
ve
y
ve
Pul
ny
Pul
y 
an
a
marketing 
 E
will be
ng 
will be
O finding
eting
O finding
Severity 
mar
Severity 
m
authorization 
MS), in 
oriz
MS), in 
nsion or 
tho
nsion or 
l be repo
auth
l be repo
ECHO
au
ECHO
ication 
vestigat
on 
vestiga
duration)
tion
duration)
lone or in
cati
lone or in
applic
with stu
plica
with stu
he investi
pp
he investi
nefit an
ap
nefit an
nta
a
t
and
pa
d
pa
th sign
nd 
th sign
seizure
an
seizure
a
any 
ud
y
ud
l evalua
any
l evalua
rent/gu
an
rent/gu
fi
extensions 
ns
3
ns
ns
ns
ons
dy me
ex
dy me
or r
o variations 
of ECH
ons
of ECH
io
monary
ria
monary
at
Level
var
Level 1
r
1
ria
Lev
va
Lev
va
v
thereof.
orte
f
o e
result h
of. 
result h
enacted 
reo
enacted 
gs with t
here
gs with t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 93 of 194  
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. IDSMC will review the submission from the Investigator and the IPCAB and unblind the 
subject’s core study 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 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, VPA, CLB, 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 subject 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 subject 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 DS. 
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.
PUBLIC
n
C
n
than 7
LIC 
than 7
nt over b
BLIC
nt over b
e, durati
UBL
e, durati
h justifie
PU
h justifie
ge an
P
ge an
COPY
o date 
PY 
o date 
whether t
OPY
whether t
treatmen
COP
treatmen
This document
ovid
t
ovid
a.
en
a.
If
ent 
If
3. Th
um
3. Th
cannot
ator 
ot
ator 
potenti
not 
potenti
ned on th
nno
ned on th
sign a n
can
sign a n
de as
ca
de as
be
ts (
e
(
the lev
be 
the lev
feel
b
feel
used
s t
d
s t
d overa
ed 
d overa
easonab
use
easonab
(eg, 
us
eg, V
s
V
to 
on, an
to
on, an
the ris
to
the ris
support t
t by the
ort 
t by th
% improv
upp
% improv
aseline, a
sup
aseline, a
nd di
s
nd di
any
ed on s
ny 
ed on s
achieve
any
achieve
e I
a
I
marketing 
ble
nitored 
ket
nitored 
authorization 
if 
z
if 
unblind
thor
unblind
e outco
au
e outco
application 
ew co
n
ew co
sent if po
tion
sent if po
both of th
atio
both of th
treatmen
ica
treatmen
e investig
pplic
e investig
to the IDS
app
o the IDS
comorb
ap
comorb
and
s 
d
al risk
nd
al risks
d 
s
e study 
and
 study 
ons
a
ons
any
A
y
A
of seizu
ny 
of seizu
onsider
any
onsider
an
a
extensions 
ved (
s
ved (
and imp
ons
and imp
istributi
sion
istributi
s of car
nsi
s of car
health. 
ten
health. 
le trials 
exte
le trials 
CLB
ex
CLB
or 
(num
o
(num
variations 
tudy dia
riati
tudy dia
ved bene
aria
ved bene
DSMC
va
DSMC
thereof. 
omes:
of
omes:


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 94 of 194  
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind 
the subject’s core study 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 
subject 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.  
PUBLIC COPY 
the
Y
the
This document cannot be used to support any 
or u
y
or u
marketing 
pregnancy
eting
pregnancy
ld be foll
ket
ld be foll
th defects
ark
th defects
the moth
ma
the moth
using
m
using
authorization 
s: 
t
s: 
application and any extensions or variations
s. Any
ns 
s. Any
ther and
ions
ther and
g a p
atio
g a preg
tio
reg
thereof. 
cy in a fe
here
cy in a fe
owed t
the
owed t
y f
t
y f


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 95 of 194  
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.  
A CRF 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 CRF via a secure internet connection. The 
investigator is responsible for ensuring accurate and proper completion of the CRF and subject 
diary for recording data according to the instructions given in the CRF and subject diary.  
All entries in the CRF must be backed up by the relevant source data at the study site. All 
source data will be kept according to all applicable regulatory requirements (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 CRF 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 CRFs 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 21 Code of Federal Regulations 
(CFR) Part 11 compliant. All creation, modification or deletion of electronic study records will 
be documented through an automated Audit Trail. Following completion of CRF 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).
PUBLIC
ary
IC
ary mu
IC 
mu
ns on th
BLIC
ns on th
ompleted
PUB
ompleted
for co
PU
for co
COPY
e
Y
e
ble regu
PY 
ble regu
ch subje
OPY
ch subje
C
This document
rated 
nt 
rated 
d agains
ent
d agains
nitor wil
me
nitor wil
The co
docu
The co
(
do
(CF
do
CF
b
d
b
cannot
owed, 
ot 
owed, 
egate fr
nno
egate fr
e reache
ann
e reache
th
c
th
be 
l be he
be
l be he
b
used
mplet
ed 
mplet
Y ASSU
use
ASSU
to 
by the 
to
by the 
io
t
io
support t
be compl
ppo
be compl
e subjects
sup
 subjects
any
c
y
c
ory req
ny 
ory req
enrolled
any
enrolled
marketing 
eac
g
idated e
ng 
idated e
nection
ting
nection T
g
T
ion of the
ket
ion of the
CRF
ark
CRF and
k
and
e data
m
e data
authorization 
ecords 
riza
ecords 
n and dat
horiz
n and dat
ch sub
au
ch sub
application 
d 
oughout t
tion
oughout t
t the subje
cati
t the subje
perform 
plica
perform 
mputer sy
app
mputer sy
art 11
ap
art 11
and
d me
d
d me
om the 
and
om the S
d 
S
with th
an
with th
any 
before 
any
before 
easur
a
easur
extensions
lete
s
lete
s enrolle
ons 
s enrolle
arent/ca
nsio
arent/ca
n and co
tens
n and co
ANCE
ex
ANCE
or 
d in 
o
d in 
variations
d subj
s 
subj
at the s
tion
at the s
uiremen
riati
uiremen
d into th
aria
d into th
thereof. 
ject 
of
ject 
ectronic
reo
ectronic
The
her
The
CRF a
the
CRF a
jec
t
jec


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 96 of 194  
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 (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. 
PUBLIC 
may
C
may
OPY
hive o
PY 
hive o
writing a
OPY
writing a
CO
new res
COP
new res
y not b
CO
y not b
This document cannot be used to support 
ponsib
rt 
ponsib
e destroye
por
e destroy
any 
udy rec
ny 
udy rec
out any 
any
out any 
ble p
a
ble p
marketing 
he subje
ng 
he subje
hese docu
ting
hese docu
oval of a m
keti
oval of a m
required b
arke
required b
authorization 
study 
oriz
study 
related t
tho
related t
a
application and any extensions or
d wi
or 
d wi
ariations 
by re
s
by re
ords (eg
iatio
ords (eg
change
aria
change
v
arty, co
va
arty, co
th
v
th
thereof. 
t’s recor
eof
t’s recor
uments h
here
uments h
marketi
the
marketi
egu
th
egu


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 97 of 194  
10.
STATISTICS
10.1
DETERMINATION OF SAMPLE SIZE
The sample size will be determined by the number of subjects who participate in 1 of 3 core 
studies (Study ZX008-1501, Study ZX008-1502, or Study ZX008-1504) and who volunteer for 
the extension study and meet the necessary criteria for enrollment. Approximately 100-120 
subjects are expected to participate in each of the core studies; thus, if all participants also 
enroll in the extension, the total sample size of the extension study would be approximately 340. 
10.2
ANALYSIS POPULATIONS
10.2.1
Safety (SAF) Population 
Safety analyses will be performed on the Safety (SAF) Population defined as all subjects who 
receive at least one dose of ZX008 during the open label extension. 
10.2.2
Modified Intent-to-Treat (mITT) Population 
The modified Intent-to-Treat (mITT) Population is defined as all subjects who receive at least 
one dose of ZX008 and have valid seizure data during the open label extension. Effectiveness 
analyses, such as evaluating the change in the frequency of convulsive seizures, will be 
performed on the mITT Population. 
10.2.3
Per Protocol (PP) Population  
The Per Protocol (PP) Population is defined as all subjects who receive at least one dose of 
ZX008, complete the entire OLE Treatment Period of the open label extension, and have no 
major protocol deviations that would have a significant impact on clinical outcome. Key 
effectiveness analyses will be repeated on the PP Population in addition to the mITT 
Population. 
10.3
TREATMENT GROUPS
All subjects will receive ZX008 and will be considered a single treatment group.
10.4
TREATMENT PERIODS
Pre-ZX008 Baseline Period 
For subjects who receive ZX008 in Study ZX008-1501, Study ZX008-1502, or Study 
ZX008-1504 Cohort 2, the pre-ZX008 baseline period is equivalent to the core study pre-
PUBLIC
Popula
C 
Popula
seizure d
LIC
seizure d
change 
UBL
change 
lation.
PUB
lation.
P
P
P
COPY
en lab
PY 
en lab
TT) Pop
COP
TT) Pop
ati
C
ati
This document 
TR
t
TR
ubjects w
me
ubjects w
10.4
ocu
10.4
Pr
d
Pr
cannot
ions t
ot 
ions t
yses will
not
yses will
EA
c
EA
be 
ulatio
e
ulatio
re
b
re OLE
be
OLE
ha
b
ha
used 
opulati
sed
opulati
on i
u
on i
to 
n t
o support 
ulatio
rt 
ulatio
on is defin
ppo
on is defin
ata durin
supp
ata durin
the freq
su
he freq
any y
xtensio
ny 
xtensio
on
a
on
marketing 
ppr
g
ppr
tion def
m
ion def
authorization 
core 
iz
core 
lunteer f
horiz
lunteer f
100-12
tho
100-12
ipants a
auth
ipants a
roxim
au
roxim
application 
TMENT 
tion
TMENT 
will receiv
lica
will receiv
TREA
app
TREA
8
and
wo
d
wo
be repe
nd 
be repe
ny 
defin
y
defin
any
Treatme
any
Treatme
ould ha
an
ould ha
extensions
ne
s
ng the o
ns 
ng the o
quency 
ion
quency 
on  
xt
on  
ned
e
ned
or 
d as a
or
d as a
variations 
efined as
tion
efined as
n. 
i
n. 
thereof.
so 
f
so 
ately 
of
ately 34
f. 
34


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 98 of 194  
randomization baseline period, ie, the approximately 42-day span just prior to randomization 
and start of treatment in the core study.  
For subjects who receive placebo in Study ZX008-1501, Study ZX008-1502, or Study 
ZX008-1504 Cohort 2, the pre-ZX008 baseline period begins with the core study pre-
randomization baseline period and extends through the entire span of the core study up to the 
transition period. The pre-ZX008 baseline period for a subject ends when that subject receives 
their first treatment with ZX008.
Study ZX008-1504 Cohort 1 have a shortened (exploratory) baseline period of approximately 
12 days (after the single-dose PK assessment) and this will be used in an exploratory manner. 
For de novo subjects, the pre-ZX008 baseline period is the screening period of up to 28 days 
prior to receiving the first dose. 
The baseline frequency of convulsive seizures will be calculated from data collected during the 
entire length of the pre-ZX008 baseline period. 
Open-Label Extension Treatment Period 
The OLE Treatment Period covers the 36 months during which subjects will receive open label 
treatment with ZX008.
Post-dosing Period 
The Post-dosing Period begins immediately at the end of OLE Treatment Period and extends 
for 2 weeks.
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core 
studies will transition to a separate extension study (Study 1900) once that study is approved 
and the study site is initiated. Continuation in a separate extension protocol will be based on 
benefit/risk and continued eligibility criteria being met. De novo subjects must have 
participated in this trial for at least 3 months with at least 1 ECHO completed and continue to 
meet eligibility requirements to be eligible to transition to a separate extension protocol. 
Alternatively, subjects will transition to commercial product once it is available if they have 
had an ECHO within 3-6 months before starting commercial drug. For subjects who are 
entering the separate extension trial or who transition to commercially available drug, post-
dosing and cardiac safety follow-up visits are not required in this trial. Subjects who transition 
to commercially available drug will have follow-up ECHOs within the required timeframe 
while on commercial drug.  
PUBLIC 
the 36 m
LIC
the 36 m
COPY
ill be c
PY 
ill be c
d.
O
d.
This 
nt 
d 
n
d 
documen
in t
nt
in t
igibility
ent
igibility
rnatively
me
rnatively
d d an EC
um
an EC
enterin
ocu
enterin
dosi
do
dosi
to
d
to
cannot 
f treat
ot
f treat
on to a s
not
on to a s
e is initi
ann
e is initi
nd conti
can
d conti
this
c
this
be 
tme
b
tme
used 
 immed
use
immed
to support 
onths dur
upp
onths dur
any 
ulated 
ny 
ulated 
marketing 
od of ap
ng 
od of ap
an explora
eting
an explora
ing period
arke
ing period
f
authorization 
up to the
horiz
up to the
ect rece
tho
ect rece
on 
nued e
on 
nued e
applicatio
trial for a
tion
trial for a
requireme
catio
requireme
, subjects
lica
, subjects
HO withi
ppli
HO withi
g the sepa
app
the sepa
nd ca
ap
nd ca
and
nt 
d
nt 
eparate
nd 
eparate
ted. Co
an
ed. Co
elig
a
elig
any 
in Stud
an
in Stud
extensions
uring w
ns 
uring w
ately at 
ext
ately at 
or variations 
od of 
s
od of 
rom dat
iatio
rom dat
thereof. 
proximat
reo
proximat
atory
here
atory m
re
m
f up
th
f up


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 99 of 194  
10.5
STATISTICAL ANALYSES AND METHODS
All safety, effectiveness and exploratory 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.
A complete description of the statistical analyses and methods will be available in a statistical 
analysis plan (SAP), which will be finalized before the database is locked.
10.5.1
Safety Analyses 
Adverse events will be monitored throughout each core study and the open label extension. 
Adverse events will be considered to be treatment emergent (TEAE) if they begin between the 
first day of treatment with ZX008 and the last day of the Post-dosing period or occur prior to 
first ZX008 treatment but increase in severity after ZX008 treatment begins.
The number and percentage of subjects in each treatment group with TEAEs will be displayed 
by body system and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). A table will enumerate the TEAEs that occur in at least 5% of subjects. 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 proportion of subjects who have lab results that change from pre-ZX008 baseline, where 
pre-ZX008 baseline values will be determined from lab results obtained prior to first treatment 
with ZX008. The shift tables will be presented for each time point where lab results are 
collected. Mean change from pre-ZX008 baseline will also be calculated for continuous 
hematology and chemistry results at all time points available.
Physical examinations, vital signs, ECG, ECHO and body weight will be summarized 
appropriately. All safety summaries will be based on the SAF Population.  
10.5.2
Effectiveness Analyses 
10.5.2.1
Key Effectiveness Analysis
The key effectiveness endpoint is the change in the convulsive seizure frequency per 28 days 
between the pre-ZX008 Baseline and OLE Treatment Period. The frequency of convulsive 
seizures during a given period will be derived from the number and type of events recorded in 
subject diaries. The seizure frequency per 28 days will be calculated as the number of seizures 
recorded divided by the number of days in the period and multiplied by 28. The convulsive 
PUBLIC
ing the
IC 
ing the
e the TE
BLIC
e the TE
ll seriou
UBL
ll seriou
for ages 
PUB
for ages 
P
COPY
y of th
PY 
y of th
after ZX
OPY
after ZX
each t
CO
each t
e M
C
e M
This 
cument
tely. A
nt 
tely. A
doc
2
m
2
10.5.2.
ocu
10.5.2.
T
d
T
cannot
ab
t
ab
nge fro
ot 
nge fro
hemistry
nno
hemistry
minatio
ca
minatio
All
c
All
be
s will 
be 
s will 
bles w
be
bles w
b
ed 
use
ratory re
sed
ratory re
have l
use
have l
be
u
be
to
AE
o
AE
6 yea
to 
6 yea
support 
eatment g
port
eatment 
Medical D
ppo
Medical D
AEs that o
supp
AEs that o
Es (SA
su
Es (SA
any y
ost-do
ny 
ost-do
08 treatm
any
08 treatm
marketing 
ble
g
nd the op
mar
nd the op
TEAE) i
m
EAE) i
i
authorization 
wer 
a
wer 
cies and 
riza
cies and 
as 
ho
as 
e in a s
au
in a s
cation 
ns, vital
on 
ns, vital
safety su
tion
safety su
applic
ffectiven
lica
ffectiven
Key E
app
Key E
and 
pre-Z
d
pre-Z
results 
and
results 
a
any 
eterm
ny 
eterm
be prese
any
be prese
ZX0
a
ZX0
tensions
Dic
s
Dic
occur i
ns 
occur i
AEs). Se
ion
AEs). Se
s and ≥
nsio
s and ≥6
io
6
ext
sults wil
xte
sults wil
 result
ex
result
mi
e
mi
or 
roup
or
roup
tiona
or
tiona
variations
pen labe
ons 
pen labe
if they b
tion
if they b
ing perio
iatio
ing perio
tment be
aria
tment be
p w
v
p w
thereof.
tatistica
of. 
tatistica


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 100 of 194  
seizure frequency will be calculated from all available data collected during either the 
pre-ZX008 Baseline or OLE Treatment Periods.  
Both the mean and median frequency of convulsive seizures will be presented for the 
pre-ZX008 Baseline Period and the OLE Treatment Period. The significance of the change 
between periods will be assessed using an analysis of covariance (ANCOVA) model with age 
group (< 6 years, ≥ 6 years) as a factor and with pre-ZX008 baseline frequency as a covariate. 
Other factors may be included in the model if they are found to be informative during analyses 
of the core studies. 
Since the ANCOVA relies on assumptions of normality, the key effectiveness endpoint will 
also be analyzed using a nonparametric method that does not require as stringent assumptions. 
A test such as the stratified Wilcoxon signed rank test will be used to assess the change from 
baseline while stratifying by age group. 
An additional analysis will be performed to assess the sensitivity of the key effectiveness 
analysis to changes in dose or type of concomitant AED medications that may occur during the 
course of the trial. Specifically, the analysis will be repeated with a factor added to the model to 
indicate whether a subject had a change in prescribed dose or type of concomitant AED 
medication during the OLE Treatment Period. Further exploratory analyses may be conducted 
if changes in concomitant AED medication appear to have a significant impact on the 
effectiveness of ZX008. 
Only subjects from Studies ZX008-1501, ZX008-1502, and Cohort 2 of ZX008-1504 will be 
included in change from baseline analyses of effectiveness. Subjects from Study ZX008-1504 
Cohort 1 will be excluded from such analyses since they will enter the OLE Treatment Period 
without first participating in a baseline period that includes a formal assessment of pre-ZX008 
seizure frequency.
10.5.2.2
Other Secondary Analyses
Methods similar to those used for the key effectiveness analysis will also be used to assess the 
change in frequency of non-convulsive seizures and the composite endpoint of non-convulsive 
plus convulsive seizures. The proportion of subjects who achieve a ≥40% reduction from 
baseline in convulsive seizure frequency, along with its 95% CI, will be reported. A similar 
summary will be reported for the proportion of subjects who achieve a ≥50% reduction from 
baseline. The analyses will be performed using data collected over the open label OLE 
Treatment Period. 
The longest interval between convulsive seizures will be calculated for each subject over the 
entire OLE Treatment Period. The median interval will be presented. 
PUBLIC
in
C
in
t P
IC
t Perio
IC 
erio
edicatio
BLIC
edicatio
ZX00
PU
ZX00
COPY
ss the s
PY 
ss the s
mitant AE
OPY
mitant AE
s will be
COP
s will be
n presc
CO
n presc
This 
ument
n frequ
nt 
n frequ
onvulsiv
men
onvulsiv
eline in 
ume
eline in 
docu
summary
cum
summary
baseli
doc
baseli
Tre
do
Tre
cannot 
Second
nno
Second
lar to t
ca
ar to t
c
be
o
in a ba
be 
in a ba
ed
8-1501
ed 
8-1501
use
ne analy
sed
ne analy
m such
us
m such
u
to 
Z
t
Z
support t
repeat
ort 
repeat
ribed dos
por
ribed dos
. Further 
pp
. Further 
n appear t
sup
appear t
any
sitivity
ny 
sitivity
medica
any
medica
ed
a
ed
marketing 
veness 
ting
veness en
g
en
e as string
ket
e as string
d to asses
ark
d to asses
authorization 
nge 
riz
nge 
with ag
horiz
with ag
a covari
tho
a covari
during a
auth
during a
plication 
hose use
on 
hose us
cy of non
atio
cy of non
e seizures
cat
e seizures
convulsiv
plic
convulsiv
app
will be r
ppl
will be r
e. The an
ap
. The an
a
Pe
a
Pe
and 
ary Ana
and
ary Ana
any y
ine pe
ny 
ine pe
tensions 
exp
s
exp
to have 
ons
to have 
ZX008-1
ten
ZX008-1
ex
es of eff
exte
es of eff
nalyse
ex
alyse
or
e or ty
or 
e or ty
plora
o
plora
variations 
ss the
s
ss the
of the ke
iati
of the ke
ations th
aria
ations th
with a 
va
with a 
v
thereof. 
naly
f
naly
ndpoint
here
ndpoint
gent ass
the
gent ass
e ch
th
e ch


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 101 of 194  
Palatability will be assessed through descriptive statistical methods. For example, the 
percentage of parents or caregivers who consider the medicine’s taste and texture to be 
acceptable to the subject will be presented along with a 95% CI at each time point data are 
available.
QoL measures will be summarized by descriptive statistic for each time point where they are 
obtained. Where appropriate, the significance of the change from baseline will be assessed 
using mixed effects models for repeated measures.
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.
C
ard
C
ard
PUBLIC
m a num
LIC 
m a num
OPY
e ID
PY
e IDS
Y
SM
Y 
M
O
he
OP
he
CO
Spon
OPY
Spon
MC is co
COP
MC is co
diolog
CO
diolog
This document cannot be used to 
port t
mposed
ort 
mpose
y, pediatri
por
y, pediatri
supp
ber of add
pp
ber of add
any 
ed
y
ed
is esta
ny 
is esta
a
r wheth
any
r wheth
d o
a
d o
marketing 
AND S
ng 
AND S
C evalua
arke
C evalua
D
m
DSMC’s 
mar
SMC’s 
d
m
d harm
m
harm
d
m
d
b
authorization 
they are
horiz
they are
asse
th
assessed
tho
ssed
application and any extensions 
ditio
s
ditio
or
cs
o
cs, an
or 
, an
onal
o
onal
riations 
ating 
s
ating 
primary
ons
primary
m that co
tion
m that co
li
i
lished t
iati
shed t
var
ther to c
aria
ther to c
f exper
va
f exper
d
v
d
thereof. 
AFETY
eo
AFETY
g dat
th
g dat


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 102 of 194  
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 (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 a public database at (eg, 
ClinicalTrials.gov) in accordance with the local country requirements. 
Before undergoing screening 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. 
PUBLIC 
for obtai
UBL
for obtai
P
COPY
ach oth
PY 
ach oth
ents hav
OPY
ents hav
This document
matio
nt 
matio
ding to a
ent
ding to a
possible
me
possible
rovided 
cum
rovided 
on the
docu
on the
the 
do
the 
t
cannot
accor
ot 
accor
ing scre
ann
ing scre
ndable
can
ndable
n m
c
n m
be 
med th
be
med th
d
b
d
used 
d a mast
sed
d a mast
cal leg
use
cal leg
to 
ning
o
ning
support t
g a sub
su
g a sub
any
eg, dur
ny 
eg, dur
been me
any
been me
marketing
lian
g
lian
of study
ing 
of study
rnational 
ark
rnational 
i
authorization 
d the 
riz
d the 
,
h
,
ne
th
ne. ICH
tho
. ICH
ing, reco
auth
ing, reco
nce w
au
nce w
application 
form, a
on 
form, a
must be gi
tion
must be gi
pplicable 
cati
pplicable 
conseque
plica
conseque
in a Subje
ppli
in a Subje
tudy was
app
tudy was
and 
nce
d
nce
ing for
an
ing for
b
a
b
any 
the stud
any
the stud
a
with 
a
with 
extensions 
bject’
ion
bject’s w
on
s w
er ICF w
xte
er ICF w
require
ex
require
or variations
and n
s 
and n
ing a stu
riati
ing a stu
met befor
aria
met befor
thereof. 
rdin
f
rdin
with this 
of.
with this 
subjects
reo
subjects
nat
t
nat


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 103 of 194  
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 CRF. The original signed ICF 
will be filed with the subject’s records and/or in the Investigator Study File. 
The Subject Information Sheet and ICF have to be approved by the IEC/IRB before they can be 
used in the study. 
The Subject Information Sheet and ICF must be revised whenever important new information 
becomes available that may be relevant to the subject’s consent. Any revision of these 
documents must be approved by the IEC/IRB before they can be used in the study. Subjects 
must be informed in a timely manner if new information becomes available that may be 
relevant to their willingness to continue participation in the study. The communication of this 
information should be documented by having all parties concerned sign and personally date the 
revised ICF.
Subject or Subject’s Legally Acceptable Representative Unable to Read
If a subject is unable to read, or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. After the 
ICF and any other written information provided to the subject, parent or guardian has been read 
and explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
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 
PUBLIC 
eptable
BLIC
eptable
or if a l
PUB
or if a l
presen
PU
presen
COPY
rmatio
PY 
rmatio
cipation 
OPY
cipation 
ng all p
COP
ng all p
This document 
ed 
t
ed 
tative.
nt
tative.
ent for 
ume
ent for 
All
doc
All su
c
su
wri
do
wri
d
cannot
dy 
t
dy 
lso sign
ot 
lso sign
on in the
nno
on in the
underst
can
underst
conse
ca
conse
be
gally a
be 
gally a
b
and, i
be
and, i
used
g
t durin
ed 
t durin
mation p
sed
mation p
r the su
us
the su
cc
u
cc
to
ally a
to 
ally a
ng
t
ng
support t
rties co
ort 
rties c
Represen
sup
Represen
any
n b
y
n b
ecome
ny 
ecome
the stud
any
the stud
onc
a
onc
marketing 
RB befo
ng 
RB befo
r importan
arke
r importan
t. Any
mar
t. Any rev
ar
rev
be used
m
be used
authorization 
CF. 
riz
CF. 
signed I
tho
signed I
application
ood
n
ood
nt was fr
ion 
nt was f
Subjects 
plic
Subjects 
ap
ects are
app
ects are
p
form
a
form
and 
and pe
d 
and pe
ICF and
and
ICF and
d by, 
an
d by, 
ny 
ptable 
ny 
ptable 
a
capable 
any
capable 
erso
a
erso
extensions
ntative
ns 
ntative
ceptable
nsio
ceptable
the entir
tens
the entir
rovided 
xte
rovided 
ect’s l
ex
ect’s l
e
or variations 
ant ne
s
ant ne
vision o
ns
vision o
d in the 
tion
d in the 
 availab
iati
 availab
dy. The
aria
dy. The
erned 
va
erned 
thereof. 
re they c
reo
re they c
ew
th
ew


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 104 of 194  
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. 
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 
PUBLIC
h
h all ap
IC 
h all ap
dence
BLIC
dence of 
IC
of 
vestigato
UBL
vestigato
e (prepar
PUB
e (prepar
P
f the 
PU
f the 
COPY
nal New
PY 
nal New
e regulat
OPY
e regulat
e i
C
e inve
CO
nve
C
This 
cument
PRO
nt 
PRO
investig
me
nvestig
he 
c
he 
doc
Spon
cum
Spon
approv
docu
approv
T
d
T
cannot
the
t
the
nsor 
ot
nsor (de
ot 
(de
ter statin
nno
ter statin
uirement
can
uirement
OT
c
OT
be 
e iden
be
e iden
d
ed
d
used
tudy, i
ed 
tudy, i
rding to
sed
rding to
to
r ha
o
r ha
d no m
to 
d no m
t
support t
tigators c
por
tigators c
icable reg
ppo
icable reg
he i
su
he invest
sup
nvest
as to p
su
as to p
any
rug (IN
ny 
rug (IN
y guide
any
y guide
marketing 
applicabl
eting
applicabl
roval befo
ket
roval befo
y protoco
ark
y protoco
ND
authorization 
,
t
,
ect, and
riza
ect, and
THICS
auth
THICS
ion 
s sh
n
s sh
plicatio
OCOL C
tio
OCOL C
ator must
plica
ator must
app
or and, if
ppl
or and, if
d by, or
app
d by, or
and 
egate)
d 
egate)
g that th
and
g that th
hould
an
hould
any 
y and oc
any
y and oc
)
a
). Sh
a
Sh
nsions
gul
s
gul
tigator’
ns 
tigator’
provide 
sion
provide 
ore than 
nsio
ore than 
exte
cluding i
ten
cluding i
ICH GC
exte
ICH GC
or
ondu
or 
ondu
atory
o
atory
variations 
ol by 
s
ol by 
ND) App
iati
ND) App
elines an
aria
elines an
uct
v
uct
thereof. 
ble comp
here
ble comp
ore enro
the
ore enro
stu
th
stu


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 105 of 194  
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 CRF and/or in the Protocol Deviation Log, if applicable. 
C
PUBLIC
and ex
IC 
and ex
Protocol 
BLIC
Protocol 
COPY
protoc
PY 
protoc
r (or d
CO
r (or d
C
This document cannot be used to 
port 
elegate) m
port
elegate) m
supp
lain any d
ppo
lain any d
Deviation
supp
Deviation
any 
amendm
ny 
amendm
marketing 
on (if requ
ket
on (if requ
equired) 
mar
quired) 
authorization 
or 
ri
or 
ion or 
horiz
ion or 
dment(s)
tho
dment(s)
application and any extensions
dev
s
dev
n Log, i
ns 
n Log, i
or
ust i
or 
ust i
o
viatio
or
viatio
variations 
ments are
iati
ments are
inf
v
inf
thereof. 
uired) 
the
uired) 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 106 of 194  
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 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 (eg, 
ClinicalTrials.gov) before or at commencement of the study, as required by local country 
requirements. 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 public databases (eg, 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 
PUBLIC
r d
C
r d
investig
LIC 
investig
y the inv
BLIC
y the inv
ies accor
UBL
ies accor
UDY 
P
UDY 
COPY
h 
Y
h 
nterest
PY 
nterest
e form(s
OPY
e form(s
pdates to
COP
pdates to
during
CO
during
This document
he
t
he
Based o
nt 
Based o
itability 
men
itability 
closed a
ume
closed a
medical 
cum
medical 
regist
doc
regist
cannot
nso
t
nso
cordin
not 
cordin
ubject co
ann
ubject co
e Spon
ca
Spon
c
be
or at c
be 
or at c
or
b
or (de
be
(de
used
REGIS
ed 
REGIS
relevan
us
elevan
u
to 
ding 
to
ding 
T
t
T
support t
the fin
ort 
the fin
one year 
por
one year 
tor(s) to t
upp
tor(s) to t
estigator 
sup
estigator 
g to th
s
g to th
any
e w
y
e w
either 
ny 
either 
ill be p
any
ill be p
nan
a
nan
marketing 
nsor
g
nsor
or(s) to be
mar
or(s) to be
will di
m
will di
h
authorization 
pport 
hori
pport 
cal Trial
tho
cal Trial
res, will
auth
res, will
r
a
r (del
au
(del
application
nta
n
sor 
o
sor (dele
on 
(del
the inclu
atio
the inclu
of the sub
icat
of the sub
cording t
plic
cording t
ournals r
ppl
ournals r
tion reco
ap
ion reco
and
to loc
d 
to loc
acts th
an
acts th
any 
mence
ny 
mence
gate)
any
gate) ma
ny
ma
cal r
a
cal r
extensions 
the S
s
the S
r and sub
ons
r and sub
he appli
sion
he appli
RATIO
ten
RATIO
tudy p
ex
tudy p
e
or
after c
or 
after c
Spo
o
Spo
variations 
e direct
ons
e direct
isclose t
tion
isclose t
the study
riati
the study
provided
aria
provided
cial dis
va
ial dis
v
thereof.
clea
f
clea
egate)
of
egate), a
f. 
, a


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 107 of 194  
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 CRF, 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).
PUBLIC 
tig
C
tig
y subjec
BLIC
y subjec
opinion 
UBL
opinion 
ducted b
PUB
ducted b
This 
PU
This 
COPY 
 the Spo
OPY
 the Spo
e facilit
COP
e facilit
gator a
CO
gator a
This 
cument t
LIA
ent
LIA
he civil 
cum
he civil 
doc
and oth
ocu
and oth
appl
do
appl
cannot t
ubjects w
nno
ubjects w
this
an
this stu
ann
stu
he IEC
ca
he IEC
be 
EIMB
be
EIMB
ed
y
meetin
ed 
meetin
use
tocol an
sed
tocol an
to
from
o
from
the Sp
to 
the Sp
g
t
g
support 
es and
rt 
es and
nd other p
por
nd other p
s into the
supp
s into the
m the I
su
m the I
any 
sor
an
sor’s stu
any
’s stu
d to
a
d to
marketing 
gat
g
gat
he Sponso
ket
he Sponso
authorization 
t
he
za
he
e at the 
auth
e at the 
te) to 
au
e) to 
pplication 
dy
/IRB. S
on 
/IRB. S
BILITY 
cati
BILITY 
iability o
ppli
iability o
ap
er damag
app
er damag
le leg
ap
le leg
and
will be re
nd 
will be re
, after 
an
after 
a
any 
RSEME
any
RSEME
tensions
e study 
ns 
e study 
IEC/IRB
ion
IEC/IRB
onsor
nsi
onsor’s s
sio
’s s
will incl
tens
will incl
ext
d proced
xte
d proced
or
erson
or 
erson
variations 
udy mon
aria
udy mon
discuss
va
discuss
nn
v
nn
thereof.
tud
f
tud
determi
of. 
determi
or 
th
or or a 
the
or a 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 108 of 194  
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 CRFs, 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 CRF 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 (eg, the European Data Protection Directive [95/46/EC] and the USA Health 
Insurance Portability and Accountability Act), 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 CRFs 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 CRF, such as past history and secondary 
diagnoses. 
PUBLIC
l be id
IC 
l be id
ent that
PUB
ent that
led in 
PU
led in 
P
COPY
ames 
PY 
ames 
st be ma
OPY
st be ma
en
C
en
This document
’s iden
nt 
’s iden
s any im
men
s any im
2.9
cu
2.9
The
do
The
a
d
a
cannot
ds
t
ds
atory a
ot 
atory a
ds, and c
nno
ds, and c
ed prior 
ann
ed prior 
c
ti
c
ti
be
ority i
be 
ority i
b
may b
be
may b
b
used
stricte
d 
stricte
n Data P
sed
n Data P
ountabi
use
untabi
in
u
in
to
ll stud
to 
ll stud
est
to
est
support 
tified in t
ppo
tified in t
y
s
any y
be kep
ny 
be kep
e unread
any
e unread
marketing 
co
udy wil
ng 
udy wil
ot having 
ting
ot having 
d subject n
arke
d subject n
s to be id
mar
s to be id
the dura
m
he dura
t
authorization 
perty of 
oriz
perty of 
mplian
au
mplian
ll
a
ll
plication 
to p
n
p
y will be 
tion
y will be 
mediate h
cati
mediate h
app
MONIT
ppli
MONIT
stiga
ap
stiga
and 
horit
d
horit
omputer
and
omputer
partic
an
partic
ny 
anon
ny 
anon
an
audited
any
audited
ty. Th
a
ty. Th
extensions 
the
s
the
finding
nsio
finding
confiden
tens
confiden
rotectio
xte
rotectio
y Act)
ex
y Act)
ny
e
ny
or 
CRF
or
CRF
variations
num
s
num
dentifie
ns 
dentifie
ration st
tion
ration st
t in conf
iatio
t in conf
dable on
aria
dable on
thereof.
ce with
of. 
ce with
be 
e
be 
been en
here
been en
mber
th
mber


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 109 of 194  
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the CRF. 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 
After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the CRF correctly and in a timely manner, after which the investigator 
will sign the CRF.
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 
PUBLIC
docume
IC 
docume
AEs
BLI
AEs
nconsiste
PUB
nconsiste
COPY
ted by 
PY 
ted by 
C
This document
Drug
nt 
Drug
r each s
me
r each s
ave been
cum
ave been
will si
docu
will si
1
d
1
cannot
f ICFs
ot 
f ICFs
ection o
ann
ection o
g a
c
g a
be
vestiga
be 
vestiga
b
used 
d
data ag
sed
data ag
ato
u
ato
to
cies or
to 
cies or
support 
tation for 
ppo
tation for 
any
study 
ny 
study 
marketing 
will be rec
ting
will be rec
r (if applic
ket
r (if applic
d be acces
ark
d be acces
w study r
ma
w study r
authorization 
ng 
ti
ng 
teness o
horiz
teness o
vestigat
tho
vestigat
study 
auth
study 
on 
f 
applicatio
ccountab
tion
ccountab
ubject’
lica
ubject’s v
ca
s v
entered i
ppli
entered i
n the CR
app
n the CR
and 
nd da
d
nd da
MP
an
MP w
an
w
any 
obliga
ny 
obliga
ates o
a
ates o
extensions 
r co
s
r co
missing 
nsio
missing 
ainst sou
xte
ainst sou
t
e
t
or 
mple
or
mple
variations 
ssible
s
ssible
related d
ons
related d
monitor 
iati
monitor 
thereof. 
corded 
ere
corded 
cable) a
the
cable) a
e a
th
e a


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 110 of 194  
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
or, the 
IC 
or, the 
ditor(s). 
BLIC
ditor(s). 
cluding 
UBL
cluding 
ulations. 
PUB
ulations. 
P
audit o
PU
audit o
COPY 
alified de
OPY
alified de
C
This 
ment
or. As
nt 
or. As
signed 
men
signed 
docum
estigator
me
estigator
Progre
docu
Progre
and
do
and
cannot
AL ST
ot 
AL ST
on of the
ann
on of the
be pre
ca
be pre
r
c
r
be
discus
be 
discus
U
b
U
d
Th
d
used
or inspe
ed 
or inspe
s, the in
us
, the in
s
u
s
to
sour
o
sour
he
t
he Spo
to 
Spo
t
support t
vestigator
ppo
vestigator
Regulator
sup
Regulator
rce do
su
rce do
any 
gates fr
any
gates fr
marketing
gul
g
gul
antial an
ing 
antial an
dy protoc
eting
dy protoc
ol are num
ket
ol are num
authorization 
rificatio
horiz
rificatio
effect o
tho
effect o
.
a
.). If req
auth
). If req
latory
au
latory
ication 
st
pared by
on 
pared b
quired by
tion
quired by
by the Spo
cati
by the Spo
appli
(if applic
plica
(if applic
s reports
app
s reports
peten
a
peten
and 
DY 
d
DY 
udy, a
an
udy, a
a
any 
e find
ny 
e find
REP
a
REP
extensions
r m
s
r m
ry autho
ns 
ry autho
ocument
sion
ocument
nsor 
ns
nsor wil
nsio
wil
e
tion.
ten
tion.
estigat
ex
estigat
i
e
i
or 
must m
o
must m
variations 
rom the
aria
rom the
thereof.
uire
f
uire
authori
of. 
authori
d non-
reo
d non-
col at th
here
col at th
merous,
the
merous,


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 111 of 194  
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
nic
C
nic
ntribute
LIC 
ntribute
ll remai
BLIC
ll remai
COPY
mission
PY 
mission
not inad
OPY
not inad
o allow e
COP
o allow e
cations
CO
cations
This document cannot be used to support t
stablish
ort 
stablis
arising fr
por
arising fr
data as w
pp
data as w
with the
sup
with the
any
h
y
h
regula
ny 
regula
rtently 
any
rtently 
hm
a
hm
marketing 
ata 
g
ion is av
ng 
ion is av
e
as been a
eting
as been a
ions in ad
mar
ons in ad
e comm
m
e comm
authorization 
n 
ti
n 
from all 
tho
from all 
investig
auth
investig
gathe
au
gathe
application and any 
s 
well 
s
well 
extensions
o
Sponso
ons
Sponso
or
om p
or 
om p
as r
o
as r
variations 
dvance o
ons
dvance o
munica
tion
munica
tory auth
iati
tory auth
y divulge
aria
y divulge
ent 
v
nt of c
va
of c
v
thereof. 
ato
f
o
red 
of
red 
ailable
reo
ailable
agreed t
here
agreed t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 112 of 194  
13.
REFERENCE LIST
Andrade DM, Hamani C, Lozano AM, Wennberg RA. Dravet syndrome and deep brain 
stimulation: seizure control after 10 years of treatment. Epilepsia. 2010; 51:1314–
1316.  
Akiyama M, Kobayashi K, Yoshinaga H, Yoko Ohtsuka Y. A long-term follow-up study of 
Dravet syndrome up to adulthood. Epilepsia 2010; 51:1043–1052.  
Aras LM, Isla, J, Mingorance-LeMeur, A. The European patient with Dravet syndrome:  
Results from a parent-reported survey on antiepileptic drug use in the European 
population with Dravet syndrome. Epilepsy & Behavior 2015; 44:104-109. 
Boel M and Casaer P. Add-On therapy of fenfluramine in intractable self-induced epilepsy. 
Neuropediatrics. 1996; 27: 171-173. 
Campbell JD, Whittington MD, Kim CH, et al. Assessing the impact of caring for a child 
with Dravet syndrome: Results of a caregiver survey. Epilepsy & Behav. 
2018;80:152-156. 
Caraballo RH. Nonpharmacologic treatments of Dravet syndrome: focus on the ketogenic 
diet. Epilepsia 2011a;52 (Suppl. 2):79–82. 
Caraballo R, Vaccarezza M, Cersósimo R, et al. Long-term follow-up of the ketogenic diet 
for refractory epilepsy: multicenter Argentinean experience in 216 pediatric patients. 
Seizure. 2011b;20(8):640-645. 
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, Claes L. Severe myoclonic epilepsy in infancy: toward an optimal 
treatment. J Child Neurol. 2004;19(7):516–521. 
Ceulemans B, Boel M, Leyssens K, et al. Successful use of fenfluramine as an add-on 
treatment for Dravet syndrome. Epilepsia. 2012;53:1131-1139. 
Ceulemans B, Schoonjans A, Marchau F, Paelinck B, Lagae L. Five-year extended follow-up 
status of 10 patients with Dravet syndrome treated with fenfluramine. Epilepsia. 
2016;57(7):129-34.  
Chiron C and Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia 2011; 
52(Suppl. 2):72–75. 
PUBLIC 
atme
C
atme
Suppl. 2
LIC
Suppl. 2
Cersósim
UBL
Cersósim
psy: mu
PUB
psy: mu
8):64
P
8):64
COPY
Asses
PY 
Asses
caregive
OPY
caregive
ents
C
ents
This 
ument 
mans B, 
ent
mans B, 
docu
trea
me
trea
Ceulem
cum
Ceulem
cannot
mm
t
mm
97; 46(
not 
97; 46(
Boel M,
ann
Boel M,
ment. J
can
ment. J
be
ine: U.
be 
ine: U.
endat
be
endat
d
tic
d
tic
used 
0-645. 
ed
0-645. 
Cardiac
us
ardiac
S
u
S
to
o R, 
o
o R, 
cente
to
center
o 
r
support t
of Dravet
ppo
of Dravet
:79–82.
upp
:79–82.
et al.
su
et al.
any
g the im
ny 
g the im
urvey. 
any
urvey. 
marketing 
vet sy
g 
vet sy
e in the Eu
ting
e in the Eu
5; 44:104
ketin
5; 44:104
ctable sel
mark
ctable sel
authorization 
4–
iz
4–
up study
tho
up study
ynd
a
ynd
cation 
Child 
on 
Child 
Boel M, L
catio
Boel M, L
applic
tment for
lica
tment for
ans B, Sc
ppl
ans B, Sc
status 
ap
status 
201
a
201
and
5):106
d 
5):106
Claes L
an
laes L
N
a
N
any y
Depart
ny 
Depart
ns, Nov
any
ns, Nov
61-1
a
61-1
extensions 
et
. Long
sion
. Long
n
Argentin
nsi
Argentin
e
alvulo
ex
alvulo
or
syndro
or 
syndro
variations
lf
n
lf-indu
ns 
-indu
f-f
n
f-f
mpact of 
riati
mpact of 
Epileps
aria
Epileps
thereof. 
rome: 
eof
rome: 
European
ereo
European
04-109. 
ther
04-109. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 113 of 194  
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. 
Cooper MS, Mcintosh A, Crompton DE, et al. Mortality in Dravet syndrome. Epilepsy Res. 
2016;128:43-47. doi: 10.1016/j.eplepsyres.2016.10.006. Epub 2016 Oct 26. 
de Lange IM, Gunning B, Sonsma ACM, et al. Influence of contraindicated medication use 
on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a 
clinical predictor in SCN1A-related seizure phenotypes. Epilepsia. 2018;59:1154-
1165.  
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. 
Dravet C. Dravet syndrome history. Dev Med Child Neurol. 2011;53 Suppl 2:1-6.  
European Medicines Agency (EMA) “Guideline on Clinical Investigations of Medicinal 
Products in the Treatment of Epileptic Disorders (July 2010) European Medicines 
Agency (EMA). 2014. http://www.ema.europa.eu/docs/ 
en_GB/document_library/Orphan_designation/2014/01/WC500159909.pdf. 
Fujiwara T. Clinical spectrum of mutations in SCN1A gene: severe myoclonic epilepsy in 
infancy and related epilepsies. Epilepsy Res. 2006;70:S223–S230. 
Genton, P., Velizarova, R., & Dravet, C. (2011). Dravet syndrome: The long-term outcome. 
Epilepsia 2011; 52(s2), 44–49. 
Harden C, Tomson T, Gloss D, et al. Practice guideline summary: Sudden unexpected death 
in epilepsy incidence rates and risk factors: Report of the Guideline Development, 
Dissemination, and Implementation Subcommittee of the American Academy of 
Neurology and the American Epilepsy Society. Neurology. 2017;88(17):1674-1680. 
Iannetti P, Parisi P, Spalice A, Ruggieri M, Zara F. Addition of verapamil in the treatment of 
severe myoclonic epilepsy in infancy. Epilepsy Res. 2009;85(1):89-95. 
ICH Topic E2F: Development Safety Update Report, 2011. 
PUBLIC
Dev M
IC 
Dev M
EMA) “G
UBL
EMA) “G
tment o
PUB
tment o
014. ht
PU
014. ht
P
COPY 
Med
Y
Med
ants and
OPY
ants and
M
C
M
This document
To
t
To
in epil
ent 
in epil
Diss
men
Diss
N
me
N
Ianne
ocu
Ianne
ot t
cann
arova, R
not
arova, R
sia 2011
ann
sia 2011
omson
ca
omson
be 
trum 
be
trum 
ted epi
be
ted epi
used
p://ww
d 
p://ww
ary/Orph
sed
ary/Orph
of
u
of
to
Gu
o
Epilep
to 
Epilep
ww
to
ww
support 
its 
t
its 
d Child N
ppo
d Child N
ideline 
su
deline 
tic
s
i
any 
8;8:5
y
8;8:5
related
an
related
marketing 
a. 201
g 
a. 201
yoclonic e
rke
yoclonic e
02.
ma
02.
543–
m
543–
authorization 
Res. 
riza
Res. 
dication
utho
dication
zure as 
aut
zure as 
8;5
a
8;5
application
;
T, Glos
ion 
T, Glo
psy incide
atio
psy incide
emination
icat
emination
eurology 
plic
eurology 
ti P, Paris
app
i P, Paris
seve
ap
seve
and
., & Dra
nd 
., & Dra
52(s2)
an
52(s2)
any
utatio
ny 
utatio
psies. E
any
psies. E
extensions 
Neu
s
Neu
 on Clin
ion
 on Clin
c Disord
nsio
c Disord
w.ema.eu
tens
w.ema.eu
an_desi
xte
an_desi
on
e
on
or 
rol. 2
or
rol. 2
variations 
ep
s
p
–548 
atio
–548 
d syndro
vari
d syndro
thereof. 
a a 
9:1154-
eof
9:1154-
pilepsy
th
pilepsy


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 114 of 194  
ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, 1994. 
Lagae L, Brambilla I, Mingorance A, Gibson E, Battersby A. Quality of life and 
comorbidities associated with Dravet syndrome severity: a multinational cohort 
survey. Develop Med Child Neurol. 2017;60(1):63–72. 
http://doi.org/10.1111/dmcn.13591.  
Lagae L, Schoonjans AS, Gammaitoni A, Galer B, Ceulemans B. A pilot, open-label study of 
the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-
Gastaut syndrome. Epilepsia. 2018;59:1881-1888. 
Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, et al.
European Association of Echocardiography recommendations for the assessment of 
valvular regurgitation. Part 1: aortic and pulmonary regurgitation (native valve 
disease). Eur J Echocardiogr. 2010;11(3):223-244. 
Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, et al. European 
Association of Echocardiography recommendations for the assessment of valvular 
regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease). Eur J 
Echocardiogr. 2010;11(4):307-332. 
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. 
Nabbout R, Chemaly N, Chipaux M, et al. Encephalopathy in children with Dravet syndrome 
is not a pure consequence of epilepsy. Orphanet J Rare Dis. 2013;8:176. 
Nolan KJ, Camfield CS, Camfield PR. Coping with Dravet syndrome: parental experiences 
with a catastrophic epilepsy. Dev Med Child Neurol. 2006;48(9):761-765. 
Oguni H, Hayashi K, Awaya Y, Fukuyama Y, Osawa M. Severe myoclonic epilepsy in 
infants – a review based on the Tokyo Long-Term Outcome Women’s Medical 
University series of 84 cases. Brain Dev 2001; 23:736– 748 
Orphanet. INSERM (French National Institute for Health and Medical Research). European 
website for rare diseases and orphan drugs. 2014. https://www.orpha.net/consor/cgi-
bin/index.php.
Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in children with 
Dravet syndrome. Epilepsia. 2011; 52(2):386-392.  
PUBLIC 
nd tri
C
nd tri
307-332
LIC
307-332
ariations
UB
ariations
COPY 
):223
Y
):223
ola E, Po
OP
ola E, Po
y recom
CO
y recom
icus
C
icus
This document t
H,
e
H, Hay
ent
Hay
inf
me
inf
Orp
doc
Orp
nnot
N,
t
N,
e conse
ot 
e conse
can
mfield C
ann
mfield C
a cata
ca
a cata
be 
ood
e
ood
Chipa
be
Chipa
b
used 
ariations
use
ariations
d. 196
us
. 196
to
in the
to 
in the
support
pesc
rt
pesc
mendatio
ort 
mendati
pid regur
ppo
pid regur
e pa
s
e pa
any 
n
cu BA
a
cu BA
marketing 
ne HC
g 
ne HC
A, Agrico
rke
A, Agrico
dations fo
mark
dations fo
egurgita
ma
egurgita
authorization 
rt 
r
rt 
n-label
aut
n-label
Cl)
a
Cl)
plication 
S,
trophic
on 
trophic
ashi
cat
ashi K,
ati
K, A
i
A
nts – 
lica
nts – 
app
a re
ca
a re
University
ppli
University
net. INS
ap
net. INS
and 
uenc
d
uenc
a
Camf
an
Camf
a
any 
44
y
44
x M, et a
any
x M, et a
ce of 
a
ce of
extensions 
g
attern of
sio
attern of
in patter
exte
in patter
4(235
e
4(235
or
ns f
r
ns f
itation
or 
itation
variations
ola
s
for the 
ns 
for the 
ation (n
tion
ation (n
A, Tribo
var
A, Tribo
for th
va
for th
thereof.
study
f. 
study
n Lenno
eof
n Lenno
a E, et
th
a E, et
t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 115 of 194  
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. 
Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol. 
2005;33(4):227-234.  
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position 
paper of the ILAE Commission for Classification and Terminology First publish 
online: 08 March 2017. https://doi.org/10.1111/epi.13709. 
Schoonjans A, Paelinck BP, Marchau F, et al. Low-dose fenfluramine significantly reduces 
seizure frequency in Dravet syndrome: a prospective study of a new cohort of 
patients. Eur J Neurol. Epub 2016 Oct 28. 
Schoonjans A, Paelinck BP, Marchau F, et al. Low-dose fenfluramine significantly reduces 
seizure frequency in Dravet syndrome: a prospective study of a new cohort of 
patients. Eur J Neurol. 2017;24(2):309-314. doi: 10.1111/ene.13195. Epub 2016 Oct 
28. 
Skluzacek JV, Watts KP, Parsy O, et al. Dravet syndrome and parent associations: the IDEA 
League experience with comorbid conditions, mortality, management, adaptation, 
and grief. Epilepsia. 2011;52 Suppl 2:95-101. 
Striano P, Coppola A, Pezzella M, et al. An open-label trial of levetiracetam in severe 
myoclonic epilepsy of infancy. Neurology. 2007;69:250–254. 
Strzelczyk A, Schubert-Bast S, Reese JP, et al. Evaluation of health-care utilization in 
patients with Dravet syndrome and on adjunctive treatment with stiripentol and 
clobazam. Epilepsy Behav. 2014;34:86-91. doi: 10.1016/j.yebeh.2014.03.014. Epub 
2014 Apr 13. 
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. 
Villas N, Meskis MA, Goodlife S. Dravet syndrome: Characteristics comorbidities, and 
caregiver concerns. Epilepsy Behav. 2017;74:81-86.  
Webb RH, Gentles TL, Stirling JW, et al. Valvular regurgitation using portable 
echocardiography in a healthy student population: implications for rheumatic heart 
disease screening. J Am Soc Echocardiogr. 2015;28:981 988. 
Whittington MD, Knupp KG, Vanderveen G, et al. The direct and indirect costs of Dravet 
Syndrome. Epilepsy Behav. 2018;80:109-113. doi: 10.1016/j.yebeh.2017.12.034. 
Epub 2018 Feb 2. 
Wirrell EC. Treatment of Dravet Syndrome. Can J Neurol Sci. 2016;43 Suppl 3:S13-S18. 
PUBLIC
2 Supp
C 
2 Supp
M,
B
M, et al. 
BLIC
et al. 
f infancy
UBL
f infancy
st S, R
PU
st S, R
s
P
s
COPY 
14.
Y
14.
ravet syn
COP
ravet syn
d cond
CO
d cond
pl 2
C
pl 2
This document
Me
t
Me
caregi
ent 
caregi
bb RH, 
me
bb RH, 
W
do
W
cannot
fulnes
ot 
fulnes
g the qu
not
g the qu
1:191-19
ann
1:191-19
eskis M
ca
skis M
be 
s
b
s
ed 
ese J
d
ese J
use
ndrome 
sed
ndrome 
Behav. 2
use
Behav. 2
to 
. Neu
to
. Neu
JP
to
JP
support 
drom
rt
drom
tions, mo
port
tions, m
:95-101. 
ppo
:95-101. 
An open-
sup
An open-l
p
l
urolo
s
urolo
any 
.11
y
.11
me an
a
me an
marketing 
nifican
g 
nifican
a new coh
ting
a new coh
amine sig
ark
amine sig
study of 
ma
study of 
111/en
m
111/en
authorization 
osition 
horiz
osition 
publish
tho
publish
ntl
a
ntl
plication
MA, Goo
ion 
MA, Goo
er concern
atio
er concern
Gentles T
lica
Gentles T
app
echocardi
ppli
echocardi
disease
app
disease
to
a
t
and
of Q
d
of Q
ality of 
nd 
ality of 
any 
Quality
an
Quality
f
tensions 
label tri
ons
label tri
ogy. 200
sion
ogy. 200
t al. Eva
ens
t al. Eva
ext
and on a
xte
and on a
014;34:
ext
14;34:
or 
rtali
or
rtali
variations
gnific
ns 
gnific
f a new c
ons
f a new c
ene.1319
atio
ene.1319
nd paren
var
nd paren
ity,
v
ity,
thereof. 
y reduce
eof
y reduce
hort of 
ere
hort of 
can
t
can


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 116 of 194  
Wirrell EC, Laux L, Donner E, et al. Optimizing the Diagnosis and Management of Dravet 
Syndrome: Recommendations From a North American Consensus Panel. Pediatr 
Neurol. 2017;68:18-34.e3. doi: 10.1016/j.pediatrneurol.2017.01.025. Epub 2017 Feb 
4. 
Wolff M, Casse-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet 
syndrome): natural history and neuropsychological findings. Epilepsia. 
2006;47(Suppl 2):45-48. 
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. 
Wu, YW; Sullivan, J; McDaniel, SS; et al. Incidence of Dravet Syndrome in a US 
Population. Pediatrics. 2015;5(136):e1310-1315. 
Zamponi N, Passamonti C, Cappanera S, Petrelli C. Clinical course of young patients with 
Dravet syndrome after vagal nerve stimulation. Eur J Paediatr Neurol. 
2011;15(1):8-14.  
Zoghbi WA, Adams D, Bonow RO, Enriquez-Sarano M, Foster E, Grayburn PA, et al.
Recommendations for noninvasive evaluation of native valvular regurgitation: a 
report from the American Society of Echocardiography developed in collaboration 
with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 
2017;30(4):303-71. 
ZX008 Investigator’s Brochure Version 8. 
C
PUBLIC
ociety 
C 
ociety 
iovascul
BLIC
iovascul
P
hure V
PU
hure V
COPY 
ati
Y
ati
uez-Sara
COP
uez-Sara
ve eval
CO
ve eval
of
C
of
This document cannot be used 
ersion
d
ersion
to 
n 8
to
n 8
port 
no M
rt
no M
uation of 
port
uation of
supp
Echocard
ppo
Echocard
ar Magnet
supp
ar Magnet
any 
r J P
y
r J P
M, Fo
a
M, Fo
marketing
a bi
g
a bi
98; 65:35
ing 
98; 65:35
drome in 
keti
drome in 
course of
ma
course of
Paedi
m
Paedi
authorization 
b
t
b
iolog
au
iolog
application and any extensions
dio
s
etic Res
ns 
etic Res
or 
nativ
or
nativ
o
graph
or
graph
variations 
f young 
ons
f young 
iatr Neu
atio
iatr Neu
ster E, 
var
ster E, 
ve v
v
ve v
thereof. 
cal and 
of.
cal and 
-41. 
re
-41. 
a US 
the
a US 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 117 of 194  
14.
APPENDICES
14.1
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
alfentanil
mexiletine
almotriptan
naratriptan
alprenolol
nefazodone
amitriptyline
nortriptyline
amphetamine
ondansetron
astemizole
oxcarbazepine
atomoxetine
oxycodone
bufuralol
paroxetine
bupropion
perphenazine
buspirone
phenacetin
cafergot
phenobarbital
cannabidiol
phenytoin
carbamazepine
promethazine
cerivastatin
propafenone
citalopram
retigabine/ezogabine
clomipramine
risperidone
codeine
ritonavir
cyproheptadine
rizatriptan
desipramine
selegiline
dextromethorphan
sertraline
duloxetine
sumatriptan
eletriptan
telaprevir
encainide
thc and derivatives
ergotamine tartrate
tramadol
eslicarbazepine
trazodone
felbamate
vortioxetine
fentanyl
zolmitriptan
fluoxetine
zuclopenthixol
fluvoxamine
frovatriptan
imipramine
levacetylmethadol (laam)
linezolid
meperidine
methadone
metoclopramide
PUBLIC 
an
LI
an
C
line
BL
line
LIC
traline
UBL
traline
BL
sumatrip
PUB
sumatrip
UB
telapr
PU
telapr
PU
P
thc
P
thc
P
COPY 
Y
ine
O
ine
PY
O
CO
C
This 
ent 
ethad
nt
ethad
nt
men
ridine
me
ridine
umen
thadone
um
thadone
me
cum
metoclop
cum
metoclop
docum
cu
cannot t
o
nn
an
ca
ol (l
c
ol (l
ca
be
vo
e 
vo
e
be
be
be
be
be
b
used 
vir
d
vir
and deriv
ed
and deriv
d
amadol
use
amadol
se
razodo
us
razodo
us
u
to 
n
t
n
o
to support t
or
po
pp
su
s
any 
ny
an
a
marketing 
e
ke
ke
ke
ke
ar
ma
m
authorization 
t
on 
ation
am)
tio
am)
on
tio
plicat
at
lic
ppl
ramide
pp
ramide
appl
pp
and 
zuclo
d
zuclo
d
an
an
an
an
an
a
ny 
etine
ny
etine
y
any
mitriptan
any
mitriptan
any
opent
a
opent
a
extensions s
n
io
ns
tives
xte
tives
en
xte
ex
or r
o variations 
o
tio
tio
tio
tio
iat
ari
va
v
thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 118 of 194  
14.2
 APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE
PUBLIC COPY 
This document cannot be used to support any marketing 
thorization 
auth
application and any extensions or variations 
eof. 
there


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 119 of 194  
PUBLIC COPY 
This document t cannot be used to support any marketing 
orization 
ori
autho
applicatio
tio
tion and any extensions or variations 
of. 
of
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 120 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
orization 
ori
autho
application and any extensions or variations 
of. 
of
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 121 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
orization 
authori
application and any extensions or variations 
of. 
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 122 of 194  
PUBLIC COPY 
This document ca
ca
cannot be used to support any marketing 
orization 
ori
autho
application 
n and any extensions or variations 
of. 
of
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 123 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
orization 
hori
autho
application and any extensions or variations 
of. 
eof
thereo


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 124 of 194  
14.3
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE 
FUNCTION – PRESCHOOL VERSION
PUBLIC COPY 
This do
do
document cannot be used to support any 
g 
marketing
horization 
autho
a
application and any extensions or variatio
tions 
eof. 
thereo
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 125 of 194  
PUBLIC COPY 
This docume
me
ment cannot be used to support any marketing 
ation 
authorizati
appli
pli
plication and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 126 of 194  
PUBLIC COPY 
This docu
docu
ocument cannot be used to support any marketing 
ization 
thoriza
autho
app
app
application and any extensions or variations 
eof. 
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 127 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
ation 
zati
authoriza
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 128 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
ation 
ati
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 129 of 194  
PUBLIC COPY 
This docum
document cannot be used to support any 
ket
ke
marke
keting 
ation 
izati
authoriz
application and any extensions or variations 
 
the
the
th
thereof.


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 130 of 194  
PUBLIC COPY 
This docu
cu
cument cannot be used to support any marketing 
ation 
zati
authoriza
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 131 of 194  
PUBLIC COPY 
This doc
doc
ocument cannot be used to support any marketing 
ation 
orizati
autho
application and any extensions or variations 
of. 
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 132 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
ati
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 133 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 134 of 194  
14.4
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE
PUBLIC COPY 
This document cannot be used
ed
ed to support any 
g 
marketing
zation 
authorizat
application and any exte
te
tensions or 
s 
variations thereof. 
t


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 135 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
zation 
authorizat
a
applica
ica
ication and any extensions or variations hereof. 
the


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 136 of 194  
PUBLIC COPY 
This document cannot be used to support any y marketing 
tion 
orizatio
author
application and any extensions or variatio
tio
tions 
of. 
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 137 of 194  
PUBLIC COPY 
This document ca
ca
cannot be used to support any marketing 
tion 
uthorizatio
auth
applic
plicication and any extensions or variations 
ereof. 
ther


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 138 of 194  
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
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 139 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
zation 
authorizat
a
appli
pli
plication and any extensions or variations hereof. 
th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 140 of 194  
PUBLIC COPY 
This document cannot
ot
ot be used to support any marketing 
ation 
uthorizati
auth
application and 
d any extensions or variations 
ereof. 
ther


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 141 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
uthorizatio
aut
applicatio
tio
tion and any extensions or variations 
ereof. 
ther


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 142 of 194  
PUBLIC COPY
PY
PY 
This document cannot be used to support any
ny
ny 
ing 
marketin
rization 
authoriz
application and any extensions or variations 
ria
riations
. 
thereof.


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 143 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
zation 
authoriza
au
appli
pli
plication and any extensions or variations hereof. 
the


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 144 of 194  
PUB
UB
UBLIC COPY 
This document cannot be used to 
o support any marketing 
ation 
uthorizati
auth
application and any extensio
sio
sions or variations 
ereof. 
there


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 145 of 194  
PUBLIC COPY 
This document can
an
annot be used to support any marketing 
zation 
authorizat
aut
application and any extensions or variations 
ereof. 
the


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 146 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
marketin
orization 
authori
application and any extensions or variations 
tio
tion
of. 
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 147 of 194  
14.5
APPENDIX 5 – TANNER STAGING
PUBLIC COPY 
This docum
um
ument cannot be used to support any marketing 
orization 
ori
authori
application and any extensions or variations 
f. 
of
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 148 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
orization 
ori
authori
application and any extensions or variations 
f. 
of
thereof


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 149 of 194  
14.6
APPENDIX 6 – PEDSQL
PUBLIC COPY 
This docu
cu
cument cannot be used to support any marketing 
ion 
i
authorizatio
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 150 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
ation 
ati
authorizat
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 151 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
ati
authorizat
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 152 of 194  
PUBLIC COPY 
This do
do
document cannot be used to support any marketing 
ation 
zati
authoriza
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 153 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
ati
authorizat
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 154 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
ati
authorizat
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 155 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
zati
authoriz
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 156 of 194  
PUBLIC COPY 
This do
document cannot be used to support any marketing 
ation 
ati
authorizat
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 157 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 158 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
ati
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 159 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
ati
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 160 of 194  
14.7
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE
PUBLIC COPY 
This docu
cu
cument cannot be used to support any 
eting 
marketi
authorization 
au
application and any extensions or 
ons 
variation
hereof. 
the


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 161 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
au
app
pp
pplication and any extensions or variations 
ereof. 
the


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 162 of 194  
14.8
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE
PUBLIC COPY 
This document
ument cannot 
c
be used to support any market
eting authorization 
t
ut
ut
au
au
on 
application and any extensions or variations thereof. 
r
he


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 163 of 194  
14.9
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
authorizat
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 164 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
ation 
authorizat
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 165 of 194  
14.10
APPENDIX 10 – KAROLINSKA SLEEPINESS SCALE
PUBLIC COP
OPY 
This document cannot be used to support t any marketing 
ation 
authorizati
application and any extensions or var
ariations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 166 of 194  
14.11
APPENDIX 11 - STUDY CONDUCT DURING COVID-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness caused 
by a novel coronavirus known as COVID-19.  As a result, public health initiatives, such as laws, 
regulations and policies were enacted at country and institutional levels to protect the health of the 
general public. These initiatives and policies have affected the ability of study sites to conduct the trial 
per protocol and the ability of the sponsor and/or delegate to conduct trial oversight and monitoring 
visits. 
In an effort to support the rights, safety and welfare of subjects and ensure as little impact on the 
integrity of the research as possible the following alternative processes have been implemented due to 
restrictions related to COVID-19. Though every attempt should be made to conduct study visits per 
protocol, any implementation of alternative processes should be properly documented.  
1. Allowance of Delays to In-person Study Visits
If sites are unable to conduct study visits, or subjects are unable to travel to the study site due to 
COVID-19 circumstances, an in-person visit may be delayed up to 6 weeks from the protocol-
defined visit due date. Data will need to be entered per normal procedures in the EDC, with a 
description indicating COVID-19 as the cause for delay in response to queries. If a subject is unable 
to travel to the study site within this expanded 6-week window, a telephone or video telemedicine 
visit should be attempted, as described below. If a telephone or video telemedicine visit cannot be 
conducted in the 6-week window, the visit should be considered missed and the next scheduled visit 
conducted.   
2. Allowance of Remote Telemedicine/Telephone/Video Visits:
Visit 1 should be conducted in person. For Visits 2 through 15, remote visits via telephone or video 
are acceptable when subjects are unable to travel to the site for in-person visits due to COVID-19 
circumstances. The following information should be collected and recorded in the source 
documentation and in the EDC where applicable. Log pages (e.g. AEs, concomitant medication 
changes) will be entered normally as they are not associated with specific visits; assessment forms 
located within a particular visit page will also be entered normally, however, queries will be fired to 
capture specific information explaining the basis for missing or alternatively collected (ie. remote) 
data. Detailed instruction for EDC entry may be found in the CRF Completion Guidelines (CCGs). 
•
Date and time of the telephone/video visit
•
Any changes in health status 
•
AEs/SAE assessment
•
Concomitant medication query
•
Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity
•
Scales and Questionnaires, when applicable and if feasible
o
C-SSRS
o
CGI-I (by Investigator)
PUBLIC
xpand
C 
xpand
ibed belo
LIC
ibed belo
w, the vi
BL
w, the vi
lem
P
lem
COPY
ects are
PY 
ects are
may be d
OPY
may be d
entered 
COP
entered 
ause fo
CO
ause fo
ed
C
ed
This document
p
t
p
Detaile
nt 
Detaile
•
m
•
D
e
D
•
m
•
cannot
ollo
t
ollo
d in the 
not 
d in the 
e entered
nno
e entered
in a part
ann
in a part
ecific in
ca
cific in
d i
c
d i
be
d i
e
bjects ar
be 
bjects ar
owing
be
owing
used
medicine
ed 
medicine
ed
n pers
us
n pers
to support 
er nor
rt 
er nor
delay in r
port
delay in 
6-
p
6-week w
ppo
week w
w. 
u
w. If a tele
upp
If a tele
should b
sup
should b
any
able
ny
able to 
y 
to 
yed up t
any
yed up t
mal
a
mal
marketing 
impa
g
impa
en implem
ing
en implem
onduct stu
etin
onduct stu
document
rket
document
authorization 
t
he 
i
he 
t the tria
oriz
t the tria
onitoring
thor
onitoring
act o
a
act o
cation 
cul
n
formatio
on 
formatio
nstruction 
tion
nstruction 
applic
ate and tim
lica
ate and tim
Any cha
ppli
Any cha
•
AEs/S
app
AEs/S
Co
ap
Co
and
DC w
d 
DC w
normall
and
normall
lar vis
an
ar vis
any
n. F
y
n. F
nable t
ny 
nable t
formatio
any
formatio
here
a
here
extensions
win
s
ephone
ns 
ephone
be consi
ions
be consi
Telepho
xten
Telepho
xte
For V
ex
For V
or 
espon
or
espon
dow, a
or
dow, a
o variations 
ravel to 
iati
ravel to 
to 6 wee
aria
to 6 wee
procedu
va
procedu
nse
v
nse
thereof. 
n the 
eof
n the 
mented d
reo
mented d
udy visit
her
udy visit
d.  
th
d.  


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 167 of 194  
o
Tanner Staging 
3. End-of-Study/Early Termination (EOS/ET) and Follow-up Visits:  
Cardiac follow-up visits must be conducted in-person. 
EOS/ET for subjects tapering off ZX008: 
For the EOS/ET visit (Visit 16) and Post-Dosing Follow-up visit (Visits 17-19), every attempt 
should be made to conduct these visits in-person. For subjects tapering off study-drug that are 
unable to come to the study site, the EOS/ET and Post-Dosing Follow-up visits may be conducted 
via telephone or video. However, subjects should return to the study site in person, as soon as 
feasible to conduct any safety assessments that were unable to be evaluated remotely.  If an in-
person visit cannot be scheduled within 6 months of the EOS/ET and/or Post-Dosing Follow-up 
visit windows, these visits will be considered as missed.
EOS/ET for subjects transitioning to Commercial drug: 
For the EOS/ET visit (Visit 16) and Post-Dosing Follow-up visit (Visit 17), every attempt should be 
made to conduct these visits in-person. For subjects tapering off study-drug that are unable to come 
to the study site, the EOS/ET and Post-Dosing Follow-up visits may be conducted via telephone or 
video. However, subjects should return to the study site in person, as soon as feasible to conduct any 
safety assessments that were unable to be evaluated remotely. Subjects who transition to 
commercially available drug must have an ECHO within 3-6 months before starting commercial 
drug and will have follow-up ECHOs within the required timeframe while on commercial drug.
EOS/ET for subjects transitioning to another extension study: 
For subjects transitioning into another ZX008 extension study that are unable to attend the EOS/ET 
visit due to restrictions to traveling to the study site, delays in the start-up of the extension study, or 
other COVID-related delays, the EOS/ET visit may be delayed until an in-person visit is conducted. 
Therefore, subjects may remain on study for longer than the planned duration of participation. If the 
delay is over 6 weeks, medical monitor review and approval is required. If approval to extend 
beyond 6 weeks ins granted, telephone or video visits should be conducted at least every 12 weeks 
until the in-person EOS/ET transitional visit to the other extension study is performed. The 
telephone or video visits will collect the following data, at minimum:
•
Date and time of the telephone/video visit
•
Any changes in health status  
•
AEs/SAE assessment
•
Concomitant medication query
•
Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity
PUBLIC 
t-Dos
C
t-Dos
turn to th
LIC
turn to th
able to b
BLI
able to b
must hav
UB
must hav
up ECH
PU
up ECH
COPY 
l drug:
PY
l drug:
osing Fo
COP
osing Fo
or subje
CO
or subje
ing
C
ing
This document 
e in
t
e in-p
nt
-p
phone or 
ent
phone or 
•
m
•
cannot
s 
t
s 
ed dela
ot 
ed dela
ects may
nno
ects may
6 weeks
ann
6 weeks
weeks in
can
weeks in
pers
c
pers
be
g into a
be 
g into a
to trav
be
to trav
b
used 
Os w
d
Os w
ning to a
se
ning to a
u
to 
 an E
to
 an E
within
to
within
support 
ow-u
rt
ow-u
ts taperin
ort
ts taperin
Follow-up
ppo
Follow-up
e study sit
upp
e study sit
evaluated
sup
valuated
CHO
s
CHO
any 
up vis
a
up vis
marketing 
dy-
g
dy-dr
g
dr
sits may 
ing
sits may 
in person,
etin
in person,
uated rem
ket
uated rem
nd/or Post
ark
nd/or Post
authorization 
very att
aut
very att
ug t
a
ug t
application 
 grante
on 
 grante
on EOS/ET
tion
on EOS/E
video visit
atio
video visit
Date and
plic
Date and
•
Any c
app
Any c
•
a
•
AE
ap
AE
and 
s, the 
d
s, the 
remain o
nd
remain o
me
a
medical
an
dical
d
a
d
any 
her ZX
ny 
her ZX
ng to the
any
ng to the
EOS
a
EOS
extensions
p 
te in p
ns 
te in p
d remote
ons
d remote
O within
sio
O within
the requ
ens
the requ
other ex
exte
other ex
X
e
X
or 
off 
or
off 
visits m
or
visits m
o variations
-Dosi
s 
-Dosi
sit (Visit
var
it (Visit
f stu
v
f stu
thereof. 
mpt 
f
mpt 
hat are
eof
hat are
be condu
reo
be condu
, as soon
here
, as soon
otely. 
the
otely. I
e
I
ing
t
ing


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 168 of 194  
4. Allowance of delays to ECHO, ECG, Chest X-Ray, EEG and clinical lab assessments 
when in-person study visits are missed or delayed
If it is not possible to obtain the assessments as described below, a documented risk/benefit 
discussion with the medical monitor is required to determine a course of action, which may 
include approval to delay further for a pre-specified duration, subject withdrawal, or other 
actions. The risk/benefit analysis will take into account report of drug effectiveness, AEs, 
previous assessment findings, duration of delay, clinical improvement while on study drug 
(seizure and non-seizure outcomes), and region-specific risk of attending in-person visits to 
complete the assessments. 
Doppler ECHO:   
If subjects are unable to travel to the study site due to COVID-19 circumstances, ECHOs may be 
delayed up to an additional 3 months from the protocol-designated ECHO due date (for a total of 6 
months from the time of the last ECHO) for subjects that exhibited the following on their previous, 
most recent ECHO: absent aortic regurgitation, absent or trace mitral regurgitation, and PASP <30 
mmHg.
All subjects with regurgitation ≥ trace aortic regurgitation, ≥mild mitral regurgitation, or PASP ≥30 
mmHg may have ECHO delayed from the protocol-designated ECHO due date by up to 6 weeks 
only In those cases where an ECHO cannot be performed in the specified time period at the study-
authorized facility by a certified sonographer, the Sponsor may approve administration of the 
ECHO at an alternative facility to minimize subject’s need for travel. If the ECHO cannot be 
performed, a risk/benefit analysis must be conducted as described above.
If a delayed ECHO was conducted within 30 days of a scheduled Cardiac Follow-up Visit, this 
assessment does not need to be repeated at the Cardiac Follow-up Visit provided there were no 
findings meeting Level 2 criteria (see Protocol Table 12) that require additional follow-up. 
ECG, Chest X-ray and EEG:  
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately 
in the source documentation. If not conducted at the study site, ECG, chest X-ray and EEG can be 
performed at any qualified local facility. If not conducted at the study site, results should be sent to 
the Principal Investigator for safety overread and documentation. If Level 2 or greater findings were 
observed, then the Cardiac Follow-up Visit should be re-scheduled from the date of the delayed 
ECHO.
If the ECG (or in the case of certain country-specific regulations: Chest X-ray or EEG) was 
conducted within 30 days of a scheduled Cardiac Follow-up Visit, these assessments do not need to 
PUBLIC
e aortic
IC 
e aortic
from the 
BLIC
from the 
CHO can
UBL
CHO can
fied sono
PUB
fied sono
cility to 
PU
cility to 
ly
P
ly
COPY
oco
Y
oco
ects tha
PY 
ects tha
n, absent
OPY
n, absent
C
This document
invest
nt 
invest
ssment v
ent
ssment v
n the sou
me
n the sou
perfor
cum
perfor
the 
cu
the 
c
cannot 
vel 2
t
vel 2
ray and 
nno
ray and 
nn
y indica
ca
indica
ig
c
ig
be
ondu
e
ondu
ed to be
be 
ed to be
2 crit
b
2 crit
used 
minim
d
minim
is must b
sed
is must b
ucted
us
ucted
to
no
grapher
to 
grapher
mize
to
mize
support t
egurgitatio
ppo
egurgitatio
protocol-
supp
protocol-d
pp
d
t be per
su
t be per
th
s
th
any
nate
y
nate
xhibited
any 
xhibited
trace m
an
trace m
marketing 
p
9 circums
ma
9 circums
d EC
m
d EC
authorization 
it 
it 
may
iza
may
r other
oriz
r other
ss, AEs,
tho
ss, AEs,
study d
uth
study d
erson v
au
erson v
application 
ted and w
on 
ted and 
tors’ clini
tion
tors’ clini
ersus the r
cati
ersus the r
rce docum
lica
rce docum
med at any
ppli
med at any
Principal I
app
rincipal I
rved, th
ap
rved, th
and 
d
EEG:
and
EEG:
n
an
any
ith
y
ith
peated a
ny 
peated a
a (
a
a (see Pr
any
see Pr
extensions
on, 
s
on, 
designat
ns 
designat
rformed 
ion
rformed 
he Spon
nsio
he Spon
subject’
ens
subject’
e conduc
xten
e conduc
in 30
e
in 30
or 
≥mil
or
≥mil
variations 
stances, 
ons
stances, 
CHO due
atio
CHO due
the follo
riat
the follo
mitral reg
aria
mitral reg
thereof.
u
isits to
of. 
isits to


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 169 of 194  
be repeated at the Cardiac Follow-up Visit provided there were no significant findings that require 
additional follow-up. 
Clinical Laboratory Assessments:
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately 
in the source documentation. If not conducted at the study site, clinical laboratory assessments can 
be performed at any qualified local facility with results sent to the Principal Investigator for safety 
overread and documentation.  
5. Alternative Dispensation for Study Drug 
Shipments of investigational product may be sent by courier from site pharmacy to the subject’s 
home via Sponsor-approved processes if the subject cannot or will not attend the dispensation 
visit(s). This shipment of drug should be arranged for patients who are due in the clinic for a drug 
dispensation visit. Other alternative dispensation, such as curbside pickup, may be implemented 
provided they are approved by the Sponsor and appropriate safeguards are taken to ensure 
compliance with existing regulatory requirements for maintaining investigational product 
accountability. Detailed instructions for drug handling, storage, accountability, etc. are described in 
the Pharmacy Manual.  
BLIC
pen
C
pen
ponsor 
LIC 
ponsor 
ory 
BL
ory requi
BLIC
requi
PUB
ctions fo
UBL
ctions fo
COPY
nt by co
PY 
nt by co
subject c
OPY
subject c
arranged 
CO
arranged 
C
nsatio
C
nsatio
This document cannot be used to 
dru
o
dru
ort 
ann
t
ann
for patien
ort 
for patie
suppo
, such as c
por
, such as c
nd appropr
pp
nd appropr
ements fo
sup
ements fo
ug hand
su
ug hand
any 
er from 
any
er from 
ot or w
an
ot or w
t
marketing 
nvestig
g 
nvestig
authorization 
nted base
oriz
nted base
ity of the
thor
ity of the
d appropr
uth
d appropr
assessm
au
assessm
gat
a
gat
application and any 
ons 
riate 
s
riate 
or mainta
ons
or mainta
extensio
dling, st
sion
dling, st
r
o
urbsid
or 
urbsid
safe
o
safe
variations 
site phar
riat
site phar
will not a
vari
will not a
who ar
va
who ar
v
thereof.
ments ca
of. 
ments ca
or for saf
eof
or for saf


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 170 of 194  
SUMMARY OF PROTOCOL AMENDMENT 5.0 
Clarifications and changes were made to the protocol amendment 5.0 to include study conduct 
information for the COVID-19 pandemic, updated background information related to existing 
treatments for Dravet and additional clinical and pre-clinical study data made available in the 
updated ZX008 IB. 
List of Specific Changes
Additions are marked by underlined font and deletions are marked in strikethrough. Minor 
editorial and non-substantive changes, such as the correction of typing or formatting errors, 
updated use of abbreviations, updating headers and footers, tables of contents, list of 
abbreviations, signature pages, etc, are not listed. Note that the list of specific changes below is 
presented in the order in which they appear in the protocol. 
1. Zogenix Address Change: 
Title Page and Signature Page: 
2.  Addition of the following text regarding transition of subjects to a separate ZX008 
extension protocol or to commercial drug.  
Study Synopsis: 
Table 1: Schedule of Assessments for Subjects from Core Studies ZX008-1501 and 
ZX008-1502, and de Novo Subjects and Table 2: Schedule of Assessments for Subjects in 
Core Study ZX008-1504 
PUBLIC 
ng
P
ng
PUBLIC COPY 
This docum
ument 
ot 
cannot be used 
text rega
sed
text rega
commer
use
ommer
d to support 
supp
s
any marketing 
ethroug
ng 
ethroug
g
or formatt
ting
or formatt
f contents
keti
f contents
t of speci
arke
t of speci
authorization 
t 
t
t 
ing 
at
ing 
n
i
n the
iza
the
h
a
h
application 
d
and any 
a
s
ions 
extensi
rding tra
xten
rding tra
ial drug
ext
ial drug
ensisio
or 
o variations 
ific c
s
ific c
thereof. 
 Minor
eof
 Minor
tting err
here
tting err
, list of 
the
, list of 
chan
th
chan


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 171 of 194  
LIC 
C
PUBLI
COPY 
This document cannot be used to upp
pport 
sup
any marketing 
tion 
authorizati
application and any 
ns 
extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 172 of 194  
C
PUBLIC COPY 
This document cannot be used to 
pport 
supp
any marketing 
tion 
authorizati
application and any extensions or r
o variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 173 of 194  
Section 3.1: Overall Study Design and Plan 
PUBLIC COP
OPY 
CO
This doc
document cann
nnot 
ca
be used to 
ort t
support any marketing 
tion 
authorizati
application
application an
and 
a
any extensions or variations 
v
thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 174 of 194  
PUBLIC COP
OPY 
CO
This document cannot be used to 
rt
support any marketing 
tion 
authorizati
applica
cation and any extensions or var
ariations 
va
thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 175 of 194  
Section 10.4: Treatment Periods 
3. Update to include Japan in list of participating centers
LIC 
PUBLIC COPY 
This docu
3
o
3
cument cannot be used to upport t
sup
any marketing 
rization 
authoriz
app
date
a
date
pplication and any 
s
extensions or va
variations 
. 
thereof.


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 176 of 194  
4.  Updated background information related to existing treatments for Dravet and additional 
clinical and pre-clinical study data made available in the updated ZX008 IB. 
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
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 177 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 178 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 179 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 180 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 181 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 182 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 183 of 194  
PUBLIC COPY 
This do
document 
do
cannot be used to support any marketing 
tion 
authorizati
application 
atio
atio
and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 184 of 194  
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
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 185 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 186 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 187 of 194  
PU
PUBLIC COPY 
This document cannot be used to
to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 188 of 194  
5.
Updates to the data available for Risk-Benefit Section 1.8 
6.  Reference to ZX008 IB 2016 updated to ZX008 IB. 
PUBLIC COPY 
This document 
ot
cannot be used to support any marketing 
tion 
authorizati
application 
d
and an
any 
a
extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 189 of 194  
7.  Provides study conduct information during the COVID-19 Pandemic 
PUBLIC
LIC COPY 
This document cannot be used to sup
upport any marketing authorization 
authorization
au
application and any extensions s or variations 
f
thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 190 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 191 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 192 of 194  
PUBLIC COPY 
This document cannot be used to support any marketing 
tion 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 193 of 194  
PUBLIC COPY 
This docum
ument cannot be used to support any marketing 
ation 
authorizati
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 194 of 194  
8. Table 11 updated to Table 12. Table was amended to reflect the latest safety database, 
contained in the NDA and MAA and updated in the 120-day Safety update, the lack of 
appearance of valvular heart disease or PAH in any subject supports the removal of 
IDSMC oversight of mild mitral regurgitation in children. It further supports utilization of 
the Level 2 review for moderate mitral, pulmonic and tricuspid regurgitation in the 
absence of any indicators of PAH. 
PUBLIC COPY 
Y
This document cannot be used to support any
ny marketing 
thorization 
on of 
zati
on of 
e e 
auth
application and any extensions or variat
iations thereof. 

SAP_001.pdf: 
DocuSign Envelope ID:
STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
Zogenix International Limited
A subsidiary of Zogenix, Inc. 
5959 Horton Street, 
 
Emeryville, CA 94608 USA
An Open-Label Extension Trial to Assess the Long-Term Safety of 
ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome
Protocol No: ZX008-1503 
Dated: 2 February 2018
Prepared by:
Syneos Health Clinical
This document contains confidential information of Zogenix International Limited. Any viewing or disclosure 
of such information that is not authorized in writing by Zogenix International Limited is strictly prohibited.
Such information may be used solely for the purpose of reviewing or performing this study.
STATISTICAL ANALYSIS PLAN
PUBLIC COPY 
l
C
l No:
COP
No: Z
P
Z
ed: 2 F
C CO
ed: 2 F
This document cannot be used to support any marketing authorization 
me
03
n
03
ng
k
ng-
ke
-Term
keti
Term
ution
ark
ution a
k
a
h Drave
ma
Drave
X008
rt a
X008-
a
-15
a
15
ebruary 2
por
ebruary 2
This
oc
This docu
cu
docu
of such
doc
of such
application and any extensions or variations thereof. 
ica
m
th
m Safet
the
Safet
s
n
s an
ns t
an Ad
t
Ad
et
tio
et Synd
on
Synd
503 
va
503 
2018
or v
2018
a
Prep
ex
Prep
e
Syn
ny
Syn
ment
app
ment con
pp
con
nforma
ap
nforma
h
y e


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 2 of 76
v3.0
04Aug2020
SIGNATURE PAGE
Zogenix International Limited
A subsidiary of Zogenix, Inc. 
5959 Horton Street, 
 
Emeryville, CA 94608 USA
An Open-Label Extension Trial to Assess the Long-Term Safety of 
ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome
Protocol No: ZX008-1503
STATISTICAL ANALYSIS PLAN
LIC COPY
to
PY
to As
PY 
As
chlorid
COP
chlorid
d
C
d Youn
C CO
Youn
PUBL
Protoc
BLI
Protoc
This document cannot be used to support any marketing authorization 
sess
any
sess the
ny
the
e)
ort
e) Oral
rt a
Oral
ng
pp
ng Adu
por
Adu
ol
s
ol No:
sup
No: Z
p
Z
ns or variations thereof. 
he
r
he Long
ariat
Long
l Soluti
var
Soluti
application and any extension
ults
or
ults wit
r v
wit
ZX008
ons
ZX008


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 3 of 76
v3.0
04Aug2020
AM PDT
PM PDT
Approvals
Syneos Health Approval
Electronically signed by:
Reason: I am the author
Date: Aug 12, 2020 14:04 EDT
Name, Title
Signature
Date (DD-Mmm-YYYY)
Electronically signed by: 
Reason: I am the approver
Date: Aug 12, 2020 11:13 EDT
Name, Title
Signature
Date (DD-Mmm-YYYY)
Zogenix International Limited Approval
06-Aug-2020 | 8:43:01
Name, Title
Signature
Date (DD-Mmm-YYYY)
on Behalf
05-Aug-2020 | 9:10:56
of Zogenix International Limited
Name, Title
Signature
Date (DD-Mmm-YYYY)
PUBLIC COPY 
UB
PUBL
upport any marketing authorization 
on
on
on
on
y signed
ng
signed by:
ng
by:
m the author
ting
m the author
g 12, 2020 14:04
ting
g 12, 2020 14:04
za
e
ma
cannot be used to sup
Si
o
Si
t
genix
sed
genix Inte
ed
Inte
d
ument 
Title
me
Title
This docu
cu
s d
g
supp
t c
ent 
nsions or variations thereof. 
EDT
e
EDT
Date
s th
Date (DD
th
(DD
th
on
on
on
tion and any extens
gnature
nsi
gnature
ernation
xte
ernation
en
applicat
pp
reo
io
tion
atio


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 4 of 76
v3.0
04Aug2020
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 5 of 76
v3.0
04Aug2020
REVISION HISTORY
Date
Revision
Initials
January 16, 2017
V0.1 based on 13 September 2016 version (Protocol 
Amendment 1.2.1 (ROW)
RS/GAS
February 21, 2018
V1.0 Based on Amendment 3
GAS
April 6, 2018
V1.1; signatures; prior to database lock for interim
GAS
July 15, 2018
V1.2; updated to include data cutoff dates, TOC for interim;
other edits
GAS
February 11, 2019
V2.0 Based on Amendment 4
GAS
April 1, 2019
V2.1 Updated TOC for TFLs to correct items missed in
previous version; updated Tables 7a-7d
GAS
July 14, 2020
V2.2: Updated to include TOC for Japan sites
MLW
July 30, 2020
Version 3.0 Signed for Japan Interim Analysis
MLW
August 4, 2020
Signoff
MLW
PY
F
Y
F
dated
PY
dated T
Y 
T
OPY
nclude
OPY
nclude T
Y
T
PY
COP
ned
CO
ned for
COP
for J
P
J
PUBLIC COP
CO
C C
marketing authorization 
Init
or
Init
ori
o
th
g
erim
eti
erim
ing
TOC
ke
TOC for
et
for i
et
ar
ny m
rrect
y m
rrect item
m
item
es
n
es 7a
ny
7a-
y
-7d
y 
7d
t any m
OC
a
OC for
an
for Jap
ny
Jap
ny
ort a
pan
rt
pan Interi
rt a
Interi
This document cannot be used to support a
ort
po
ons thereof. 
R
of
G
o
G
eo
re
interim;
the
interim;
he
ns
riation
ms
t
ms missed
tio
missed
aria on
pan
a
pan sites
aria
sites
ria
va
m
v
m Analys
va
Analys
application and any extensions or var
v
or


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 6 of 76
v3.0
04Aug2020
TABLE OF CONTENTS
Page
Approvals....................................................................................................................................... iii
1.
INTRODUCTION...........................................................................................................................11
2.
STUDY OBJECTIVES....................................................................................................................12
2.1
Primary Objective ..........................................................................................................................12
2.2
Secondary Objectives.....................................................................................................................12
2.3
Exploratory Objectives...................................................................................................................13
3.
STUDY DESIGN ............................................................................................................................14
3.1
Overall Study Design and Plan.......................................................................................................14
3.2
Treatments......................................................................................................................................14
3.3
Treatment Periods ..........................................................................................................................16
3.3.1
OLE Treatment Period .......................................................................................................16
3.3.2
Taper Period.......................................................................................................................16
3.4
Randomization and Blinding..........................................................................................................18
4.
SCHEDULE OF ASSESSMENTS..................................................................................................19
5.
ANALYSIS POPULATIONS..........................................................................................................23
5.1
Enrolled Population........................................................................................................................23
5.2
Safety (SAF) Population.................................................................................................................23
5.3
Modified Intent-To-Treat (mITT) Population ................................................................................23
6.
STATISTICAL METHODOLOGY ................................................................................................23
6.1
Statistical and Analytical Issues .....................................................................................................23
6.1.1
Statistical Methods.............................................................................................................23
6.1.2
Multiplicity Issues..............................................................................................................24
6.1.3
Subgroups...........................................................................................................................24
6.1.4
Definitions..........................................................................................................................24
6.1.5
Other Definitions................................................................................................................25
6.1.6
Visit Windows and Period Start/Stop Dates.......................................................................25
6.1.7
Handling of Dropouts and Missing Data ............................................................................30
PUBLIC COPY 
.........
Y
.........
......
OP
..........
P
....
..........
CO
..........
..........
C
..........
..........
LI
..........
...........
UB
...........
MENTS
PU
MENTS
This document cannot be used to support any marketing authorization 
iza
Page
iza
Page
....
h
.... iii
ho
iii
............
ut
............11
h
11
.............
g a
.............
.............
ing
.............
...........
ke
...............
.............
ar
.............
.............
m
.............
.............
ny
.............
.............
a
.............
.........
ort
.............
rt
....
...
p
.............
pp
..........
.............
up
.............
.............
o s
.............
.............
d t
.............
.............
se
.............
..............
u
..............
on
b
on...........
be
...........
o
o
o-
o
-Treat
ot b
Treat (m
b
(m
L
n
L METHO
nno
METHO
l
c
l and
can
and Anal
an
Anal
Statistic
t c
Statistic
1.2
e
1.2
Mu
n
Mu
6.1.3
um
6.1.3
6.1
u
6.1
n
application and any extensions or variations thereof. 
....12
of
12
.........
re
.........12
e
12
.............
the
.............
....
s
.............
s
.........
...............
on
...........
.............
at
.............
......
ar
.............
ar
.......
.............
v
.............
.............
o
.............
..........
ns
.............
s
...
..............
sio
..............
.............
en
..............
............
xte
..............
e
..
.....
..............
e
.........
..............
ny
..............
mITT)
d a
mITT) Popu
a
Popu
DOLOGY
nd
DOLOGY
lytical
n a
lytical Issu
a
Issu
cal
ti
cal Method
tion
Method
ultiplicity
cat
ultiplicity I
Subgroup
plic
Subgroup
.4
a
.4
Defin
pp
Defin
5
a
5


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 7 of 76
v3.0
04Aug2020
6.1.8
Conversion of time interval ................................................................................................31
6.1.9
Pooling of Investigative Sites.............................................................................................32
6.1.10
Determination of Sample Size........................................................................................32
6.2
Subject Characteristics ...................................................................................................................32
6.2.1
Subject Disposition.............................................................................................................32
6.2.2
Protocol Deviations............................................................................................................32
6.2.3
Background and Demographic Characteristics...................................................................33
6.2.4
Treatment Exposure and Compliance.................................................................................33
6.2.5
Prior and Concomitant Medications and/or Therapies (Non-medications).........................34
6.2.6
Prior and Concomitant Antiepileptic Treatment.................................................................35
6.2.7
Medical History..................................................................................................................36
6.3
Effectiveness Analyses...................................................................................................................36
6.3.1
Convulsive Seizure Frequency ...........................................................................................36
6.3.2
Other Effectiveness Analyses – Seizure Related ................................................................40
6.3.3
Other Effectiveness Analyses.............................................................................................44
6.3.4
Exploratory Analysis (in subjects from core study ZX008-1504 only) ..............................50
6.4
Safety Analysis...............................................................................................................................51
6.4.1
Adverse Events...................................................................................................................51
6.4.2
Adverse Events of Special Interest (AESI).........................................................................53
6.4.3
Physical Examination.........................................................................................................53
6.4.4
Neurological Examination..................................................................................................54
6.4.5
Vital Signs, Weight, and BMI ............................................................................................54
6.4.6
Electrocardiogram ..............................................................................................................54
6.4.7
Doppler Echocardiography.................................................................................................54
6.4.8
Tanner Staging ...................................................................................................................55
6.4.9
Laboratory Parameters........................................................................................................55
6.4.10
Columbia-Suicide Severity Rating Scale........................................................................56
6.4.11
Brief Rating Inventory of Executive Function (BRIEF, BRIEF-P, BRIEF-A)...............57
6.5
PK/PD Analysis .............................................................................................................................58
6.6
Analysis of Other Assessments ......................................................................................................58
PUBLIC COPY 
.....
Y
.....
...........
PY
...........
ure
CO
ure Rel
COP
Relat
OP
at
..........
C C
..........
bjects
LIC
bjects fro
C
fro
.......
UB
...........
B
....
...........
PU
...........
pec
P
pec
e used to support any marketing authorization 
...
h
...32
ho
32
..........
uth
..........32
h
32
..............
a
..............
......
ng
.............
ng
.......
ons)
ket
ons)........
et
........
....
rk
.............
rk
.........
.............
ma
.............
.............
y
.............
.............
an
.............
d ............
rt
............
...........
po
.............
o
..
m core
up
core stud
pp
stud
.............
s
.............
..........
d to
.............
o
...
al
e
al Interest
ed
Interest
This document cannot be
n............
us
............
amination
be u
amination
Weight,
t b
Weight, a
cardiogram
no
cardiogram
oppler
an
oppler Echo
nn
Echo
Tanner
t ca
Tanner S
a
S
.9
e
.9
Labo
nt
Labo
6.4.10
me
6.4.10
6.4.
um
6.4.
6.5
doc
6.5
6
d
6
on
extensions or variations thereof. 
.3
o
33
of
3
.......
re
.......33
eo
33
.............
he
............. 3
.............
s t
.............
..........
on
................
.............
ati
.............
.............
ria
.............
.............
va
.............
.............
or
.............
dy
n
dy ZX008
ns o
ZX008
.......
io
..............
o
.......
..............
ns
..............
(AESI)
xten
(AESI)...
e
...
application and any ex
..............
ex
..............
..............
ny
..............
nd
a
nd BMI
an
BMI .
m ............
nd
............
ocardiograp
an
ocardiograp
Staging
ion
Staging ...
n
...
oratory
atio
oratory Par
io
Par
Columb
lica
Columb
11
p
11
Bri
p
Bri
K/PD
ap
K/PD A
p
A


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 8 of 76
v3.0
04Aug2020
6.7
Interim Analysis.............................................................................................................................58
6.8
Independent Data and Safety Monitoring Committee ....................................................................59
6.9
International Pediatric Cardiac Advisory Board (IPCAB)..............................................................59
6.10
Changes to Methods Planned in the Protocol .............................................................................59
7.
REFERENCES................................................................................................................................59
8.
APPENDICES.................................................................................................................................61
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
...
h
...59
ho
59
.........
uth
..........
th
.61
h
61
on
application and any extensions or variations thereof. 


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 9 of 76
v3.0
04Aug2020
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ABBREVATION
DEFINITION
AE
Adverse Event
AED
Antiepileptic Drug
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical
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
CDISC
Clinical Data Interchange Standards Consortium
CGI
Clinical Global Impression
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
FAS
Full Analysis Set
HADS
Hospital Anxiety and Depression Scale
HR
Heart Rate
IDSMC
Independent Data and Safety Monitoring Committee
IMP
Investigational Medicinal Product
IPCAB
International Pediatric Cardiology Advisory Board
IR
Incidence rate
IVR
Interactive Voice Randomization
IWR
Interactive Web Response (System)
Kg
Kilogram
Kg/ m2
Kilogram per meter square
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
PUBLIC COPY 
Stan
Y
Stan
sion
PY
sion
Y
OPY
m
C
m
CO
am
C
am
C
Case
LIC
Case Rep
C 
Rep
C
study
BL
study
LIC
pean
UB
pean Pub
B
Pub
BL
andardiz
PU
andardiz
U
ly
P
ly T
P
T
P
t cannot be used to support any marketing authorization 
at
iz
or
th
ut
a
ng
tin
nction
rke
nction
ke
rk
ma
Consorti
y m
Consorti
m
ny
an
rt
or
ort
u
ort Form
upp
Form
pp
up
ic
o
ic Assessm
o s
Assessm
s
d
d
d measur
d to
measur
to
rmination
ed 
rmination
d t
Analysis
se
Analysis S
ed
ospital
us
ospital An
us
An
us
Heart
be
Heart Rat
e 
Rat
e u
Indepe
t be
Indepe
be
t
Inv
t 
Inv
t
ot
I
no
nn
ca
This document c
t c
n
m2
m2
m2
m
me
CSF
cu
CSF
um
MedDRA
oc
MedDRA
cu
do
mg
do
mg
s do
d
mg
d
mg
d
s d
s
n
ion and any extensions or variations thereof. 
of
eo
er
th
s t
ns
um
ati
um
tio
at
ari
va
r
o
ns
ment
sio
ment Rep
o
Rep
on
e of
ns
of health
ns
health
si
en
et
e
et
xte
nxiety
y e
nxiety and
ex
and
ex
te
n
te
y e
endent
any
endent Da
ny
Da
ny
vestigation
d a
vestigation
d a
Internatio
and
Internatio
nd
Inciden
an
Inciden
an
n
on 
Inte
n 
Inte
application
on
I
ion
on
on
o
ati
ica
pli
A
pp
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 10 of 76
v3.0
04Aug2020
ABBREVATION
DEFINITION
mL
Milliliter
MMRM
Mixed Effects Model for Repeated Measures
msec
Millisecond
OLE
Open Label Extension
OLED1
Open label Extension Day 1
PA
Protocol Amendment
PedsQL
Pediatric Quality of Life Inventory
PD
Pharmacodynamics
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
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SMEI
Severe Myoclonic Epilepsy Of Infancy
SOC
System Organ Class
T+M
Titration plus Maintenance Periods
TEAE
Treatment Emergent Adverse Event
THC
Tetrahydrocannabinol
TSH
Thyroid Stimulating Hormone
WHO-DD
World Health Organization Drug Dictionary
ZX008
Fenfluramine Hydrochloride Oral Solution
PUBLIC COPY
d
Y
d
ing
PY
ing Fre
PY 
Fre
Y
nt
O
nt
PY
OP
ysis
C C
ysis Plan
CO
Plan
CO
viation
IC C
viation
C C
ta
L
ta Tabul
LIC
Tabul
LIC
Myoclo
UBL
Myoclo
BL
tem
PU
tem Org
UB
Org
UB
tration
PU
tration
PU
P
This document cannot be used to support any marketing authorization 
on
ati
za
ori
ho
ut
au
g
ing
et
rke
ar
y
y
y
m
ricia
ny
ricia meth
ny 
meth
y
any
t a
ort
po
ion
u
ion Mode
up
Mode
pp
nic
o
nic Epilep
o su
Epilep
su
n Class
to
Class
o s
plus
d
plus Main
d t
Main
d to
ent
se
ent Emer
sed
Emer
ed
rahydrocan
use
rahydrocan
se
Thyroid
be u
Thyroid St
u
St
u
World
be
World H
be 
t
Fenf
t b
Fenf
t b
ot
ot
ot
ot
n
d any extensions or variations thereof. 
f
eo
re
he
th
ns
on
hod
ia
hod
ati
ria
a
v
or
elel
s
psy
io
psy Of
ion
Of Infa
n
Infa
on
sio
tenance
ens
tenance P
s
P
ns
rgent
xte
rgent Adve
xte
Adve
te
nnabinol
ex
nnabinol
xt
timulating
ny e
timulating
e
Health
any
Health Or
y
Or
ny
fluramine
d a
fluramine
an
application and 
d


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 11 of 76
v3.0
04Aug2020
1. INTRODUCTION
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). DS is a highly treatment-resistant and refractory epilepsy 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.
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the adjunctive treatment 
of DS. Studies ZX008-1501 and 1502 are two randomized controlled trials of two fixed doses of ZX008 
(Fenfluramine HCl) as an adjunctive therapy in children and young adults with DS. Study 1501 is conducted in 
North America (Canada and the USA), and 1502 is being conducted in Europe and Australia (Australia, 
Belgium, Denmark, France, Germany, Italy, Spain, Sweden, and the United Kingdom). The objective of each 
study is to demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the treatment 
of DS 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). Study ZX008-1504 is a multicenter, 2-Cohort 
trial to first assess the pharmacokinetic and safety profile of a single dose of ZX008 (Fenfluramine 
Hydrochloride) oral solution when added to standard of care (Cohort 1), followed by a randomized, double-
blind, placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as 
adjunctive antiepileptic therapy to stiripentol treatment in children and young adults with DS (Cohort 2).
The purpose of this Statistical Analysis Plan (SAP) is to outline the planned analyses and presentation of the 
clinical data from protocol ZX008-1503, dated 08 February2018 (amendment 4.0), an international, 
multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with DS who 
have successfully completed 14 weeks of treatment in core study ZX008-1501, ZX008-1502, and ZX008-1504 
Cohort 2, or successfully completed core study ZX008-1504 Cohort 1, and are candidates for continuous 
treatment for an extended period of time. In addition, subjects who are >18 to ≤35 years of age at the time of 
screening, and who meet all other eligibility criteria may be eligible for participation after discussion with the 
Medical Monitor and sponsor about the potential risks and benefits for receiving ZX008. Participation for
these subjects will be at the discretion of the sponsor.
Amendment 3 of this clinical trial extended the initial 12-month study period to 24 months, and Amendment 4 
extended the duration to 36 months. Thus, with the implementation of Amendment 4, this clinical trial will 
consist of an up to 36-month Open-Label Extension (OLE) Treatment Period and a 2-week Post-Dosing
PUBLIC COPY 
ndrom
Y
ndrom
uramine
COP
uramine
randomi
CO
randomi
y
C
y in
C
in child
C C
child
nd 1502
LIC
nd 1502
, Italy, S
BLI
, Italy, S
 0.8 mg/
UB
 0.8 mg/
lts based
PU
lts based
Maint
P
Maint
t cannot be used to support any marketing authorization 
f patients 
riza
f patients 
is a rare a
horiz
is a rare a
dition mos
tho
dition mos
on progre
auth
on progre
Dravet
au
Dravet 19
u
19
itions incl
ng a
itions incl
elle
tin
ellectual
ting
ctual i
g
i
ogression. 
keti
ogression. 
and diffic
rke
and diffic
ctory epile
mark
ctory epile
pe, as adju
ma
pe, as adju
and must b
y m
and must b
hydrochlo
rt a
hydrochlo
ed contro
ort
ed contro
ren
pp
ren and
ppo
and y
o
y
s being co
upp
s being co
pain, Swed
sup
pain, Swed
kg/day
to s
kg/day is s
s
is s
on chang
d to
on chang
enance Per
ed 
enance Per
etic and sa
use
etic and sa
en added t
us
en added t
lle
be
llel group
be u
l group
rapy to sti
t be
rapy to sti
atistical An
not
atistical An
rotocol ZX
nn
rotocol ZX
-label, lon
can
label, lon
cumen
ully
t
ully compl
t ca
compl
r successf
ent 
r successf
nt for an ex
men
nt for an ex
ning, and w
ume
ning, and w
edical Mo
cum
edical Mo
This do
these subj
doc
these subj
Am
s 
Am
n
tion and any extensions or variations thereof. 
ess
f
978).
of
978). Fo
f. 
Fo
luding 
eof
luding 
impairmen
ere
impairmen
Dravet ch
the
Dravet ch
culty relati
s th
culty relati
epsy syndr
ns 
epsy syndr
unctive th
ion
unctive th
be co
atio
be co-
tio
-adm
io
adm
oride, ZX0
var
oride, ZX0
lled trials
r v
lled trials
oung
o
oung adul
or
adul
onducted 
ns o
onducted 
den, and th
ons
den, and th
superior to
sio
superior to
ge in the fr
ens
ge in the fr
eriods (T+
ten
eriods (T+
afety prof
exte
afety prof
to standar
y ex
to standar
p evaluatio
ny 
p evaluatio
iripentol t
any
iripentol t
Analysis Pl
nd 
Analysis Pl
X008
an
X008-
an
-150
nd
150
ng
n
ng-
n
-
pplicat
term s
n a
term s
pleted
ion
pleted 14
n
14 w
fully comp
atio
fully comp
xtended p
icat
xtended p
who meet
plic
who meet
onitor and 
ppl
onitor and 
ap
ects will 
app
ects will 


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 12 of 76
v3.0
04Aug2020
Period. Subjects who complete this trial will have been treated with ZX008 for a minimum of up to 3 years 
(including their participation in both the core study and this study). Subjects who did not participate in one of 
the core studies will undergo a screening period up to 28 days to confirm eligibility prior to receiving their first 
dose in the OLE Treatment Period. A follow-up electrocardiogram (ECG) and echocardiogram (ECHO) will
be performed at 3 and 6 months after study drug discontinuation for early termination and for those subjects 
who complete the study.
An earlier version of this Statistical Analysis Plan detailed statistical analyses performed as an interim analysis 
to support the filing of a New Drug Application (NDA) with the US Food and Drug Administration (FDA) and 
a Marketing Authorisation Application (MAA) with the European Medicines Agency (EMA), based on 
Amendment 3 of the Study Protocol. The purpose of this updated Statistical Analysis Plan is to provide details 
of the statistical presentation of the data from this study based on Amendment 4 of the protocol, for the 120-
day safety update report following filing of the New Drug Application with the US Food and Drug 
Administration.
It is planned to perform an analysis of key safety data obtained up to February 15, 2019, for all subjects who 
entered Study ZX008-1503 by December 31, 2018.The planned interim analysis will present data without 
revealing the individual treatment groups from the Core studies. The specific list of TFLs that will be 
presented in the interim analysis will be delineated in the Table of Contents for the TFL shells.
An analysis of Study ZX008-1503 to include only those subjects who entered Study ZX008-1503 from sites in 
Japan (i.e., Japanese subjects) is planned when all Japanese subjects have reached at least the Month 3 visit.. 
Selected analyses, described in the SAP for the rest of the world, will be performed for this population.
A final analysis and report of all data obtained from this study will be provided within 6 months of completion 
of the last subject’s final study visit.
The planned analyses identified in this SAP will be included in regulatory submissions and/or future 
manuscripts. Exploratory analyses not identified or defined in the SAP may be performed to support the 
clinical development program. Any post-hoc or unplanned analyses performed and not identified in this SAP 
will be documented in the CSR or final report.
2. STUDY OBJECTIVES
2.1 PRIMARY OBJECTIVE
The primary objective of the study is to assess the long-term safety and tolerability of ZX008.
2.2 SECONDARY OBJECTIVES
The secondary objectives of the study are:
•
To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following effectiveness 
measures:
-
The change in the frequency of convulsive seizures.
PUBLIC COPY 
a
O
a obtain
OPY
obtain
18.The p
COP
18.The p
m the
C C
m the Cor
CO
Cor
lineated 
IC C
lineated 
nclude
BLIC
nclude on
IC
on
nned wh
UBL
nned wh
he SAP f
PUB
he SAP f
ata
P
ata
ot be used to support any marketing authorization 
years
atio
years
in one of 
zat
in one of 
ving
riz
ving their
riza
their
m (ECHO)
hori
m (ECHO)
for those s
tho
for those s
ormed
ng
ormed as
g 
as
Drug
tin
Drug Admi
ting
Admi
s Agency (
keti
s Agency (
al Analys
arke
al Analys
ndment 4 
mar
ndment 4 
on with th
ma
on with th
ed up
t a
ed up to
an
to Fe
ny
Fe
anned inte
rt a
anned inte
e studies. T
port
e studies. T
n the Tabl
ppo
n the Tabl
ly
s
ly those
sup
those su
p
su
en all Japa
o s
en all Japa
r the rest 
d to 
r the rest 
btained
ed 
btained frfr
t.
u
t.
d in this S
be u
d in this S
alys
b
alyses not
be
es not
gram.
ot b
gram. Any
b
Any
This document canno
the CSR 
not
the CSR 
JECTIVE
can
JECTIVE
ARY
nt
ARY OBJ
t 
OBJ
mary
me
mary obje
e
obje
2 SECON
cu
SECON
The
do
The sec
oc
sec
n
d any extensions or variations thereof. 
an
e
an interim
eo
interim
inistration
ere
inistration
(EMA), b
the
(EMA), b
sis Plan
s th
sis Plan is
h
is
of the pro
ns 
of the pro
he US Foo
tion
he US Foo
ebruary
aria
ebruary 15
a
15
erim analy
va
erim analy
The speci
or v
The speci
le of Cont
s or
le of Cont
ubjects wh
ons
ubjects wh
anese subj
sion
anese subj
of the wo
nsi
of the wo
rom
te
rom this
ten
this
SAP will b
ny e
SAP will b
t identifie
any
t identifie
y
d
y
pplication and
post
d a
post-
a
-hoc
an
hoc
or final re
nd 
or final re
ES
n
ES
JEC
atio
JECTIVE
tio
TIVE
ective
lica
ective of
ca
of
app
thth
NDARY
pp
NDARY
dary
ap
dary ob
p
ob


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 13 of 76
v3.0
04Aug2020
-
The proportion of subjects who achieve a ≥25%, ≥50%, and ≥75% reduction in convulsive 
seizure frequency.
-
The duration of the longest interval between convulsive seizures.
-
The percentage of convulsive seizure-free days.
-
The change in the frequency of non-convulsive seizures.
-
The change in the frequency of convulsive + non-convulsive seizures.
•
To estimate the incidence of the following on subjects receiving ZX008:
-
Use of rescue medication
-
Hospitalization to treat seizures
-
Status epilepticus
•
To assess the effect of ZX0008 relative to the pre-ZX0008 baseline on the following measures:
-
Quality of Life in Childhood Epilepsy (QOLCE) score
-
The Pediatric Quality of Life Inventory (PedsQL) (Version 4.0) – Parent Report
-
PedsQL Family Impact Module (Version 2.0) – Parent Report – mITT Population
-
QoL of the parent/care giver using the EQ-5D-5L scale
-
Affective symptoms of the parent/caregiver using the HADS.
•
To assess the effect of ZX0008 on the following global ratings
-
Clinical Global Impression – Improvement rating, as assessed by the principal investigator
-
Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver
2.3 EXPLORATORY OBJECTIVES
Exploratory objectives of the study are the following measures that were assessed only in subjects who had 
participated in Study ZX008-1504, Cohort 2 as their feeder study. Additional exploratory analyses may be 
undertaken if warranted, as mentioned above.
•
To assess the effect of ZX008 on the following measures:
-
Sleep quality and mealtime behavior, as assessed by the parent/caregiver
-
Karolinska Sleep Scale
-
Health and social care resource use (These measures include planned and unplanned hospital 
visits, use of ambulances, GP visits, speech and language therapy utilization, occupational and 
physical therapy utilization)
PUBLIC COPY 
OLCE)
PY
OLCE)
y
O
y (PedsQ
OPY
(PedsQ
ersion
CO
ersion 2.
O
2.
ing
C
ing the
C C
the E
C
E
parent/ca
LIC
parent/ca
08
UB
08 on
UBL
on th
BL
th
ession
PUB
ession –
U
–
essio
P
essio
to support any marketing authorization 
e
t
e
baseline
m
baseline o
ore
n
ore
L)
t
L) (Versio
t an
(Versio
0)
0) –
o
– Parent
ort 
Parent
Q
p
Q-5D
ppo
5D-
po
-5L
po
5L
egiver
up
egiver usi
pp
usi
following
o su
following
t cannot be used t
Improvem
d to
Improvem
–
ed
– Improv
ed 
Improv
TIVES
us
TIVES
study
be
study are
e 
are
08
t
08-
t
-1504, C
t b
1504, C
d, as menti
not 
d, as menti
he
a
he effect
ann
effect
This document
ep
c
ep quality
ca
quality
Karolinsk
nt c
Karolinsk
-
Health
men
Health
vis
me
vis
m
n
any extensions or variations thereof. 
n
t
n the
tio
the follo
on
follo
on
v
on 4.0)
vari
4.0) –
r
– P
t Report
r va
Report
scale
o
scale
ing
n
ing the
ns
the HA
HA
g global
ion
global rara
ation and a
ment
ns
ment rating
nsi
rating
vement
ten
vement ra
n
ra
the
n
the follow
ny 
follow
Cohort 2 a
d any
Cohort 2 a
ioned abo
d a
ioned abo
of
of
plica
ZX008
an
ZX008
y
o
y and
on
and meal
n a
meal
ka
t
ka Sleep
atio
Sleep S
h and soci
icat
h and soci
app
sits,
pli
sits, use
plic
use of
c
of
physical t
ppl
physical t


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 14 of 76
v3.0
04Aug2020
3. STUDY DESIGN
3.1 OVERALL STUDY DESIGN AND PLAN
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult 
subjects with Dravet syndrome who have successfully completed 14 weeks of treatment in core study ZX008-
1501, ZX008-1502, and ZX008-1504 Cohort 2, or successfully completed core study ZX008-1504 Cohort 1, 
and are candidates for continuous treatment for an extended period of time. This trial will consist of a 24-
month OLE Treatment Period and a 2-week Post-Dosing Period. Thus, subjects who complete this trial will 
have been treated with ZX0008 for at least 1 year (including their participation in both the core study and this 
study).
3.2 TREATMENTS
Subjects in the double-blind studies Z008-1501, -1502, and cohort 2 of 1504 who enter Study ZX008-1503 
would have transitioned to 0.2 mg/kg during the transition period (between Visits 12 and 13), as described in 
the 1501 and 1502 Clinical Study Protocols Section 5.5.5, and 1504 Sections 5.5.6 and 5.5.7. Subjects entering 
from Cohort 1 in Study ZX008-1504 will enter a transition period at a fixed dose of ZX008 0.2 mg/kg/day for 
up to 24 additional weeks.
In Study ZX008-1503, during the OLE Treatment Period, all subjects will be treated initially with 0.2 
mg/kg/day for 1 month to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 0.2 
mg/kg/day, the investigator may adjust the dose of each subject based on effectiveness and tolerability.
Subjects whose conditioned worsened relative to their status at the end of the double-blind feeder study could 
request permission to increase to 0.4 mg/kg/day (max 30mg) after approximately 2 weeks on the 0.2 mg/kg 
dose, Dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not 
to exceed total dose of 30 mg/day. Dose increases should not occur earlier than every 14 days at each dose 
level. For subjects in Study ZX008-1504 Cohort 2, the dose titration schedule is 0.2 mg/kg/day, to 0.4, to 0.5 
not to exceed 20 mg/day. Dose increases may only occur after a review of the diary and reported AEs, and if, 
in the investigator’s opinion, seizure frequency, severity, and/or duration indicates a change in medication 
regimen is warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these parameters 
should be discussed with the Medical Monitor prior to initiation.
Effectiveness and safety data will be provided for all subjects treated with ZX008. Data will be summarized by 
subjects’ treatment group in their previous study.
The treatment groups that may be used to summarize the results of the final analysis are presented in Table 1. 
Groups 1 to 5 are the basic treatment groups.
PUBLIC COPY
nd 
Y
nd 
tion per
PY 
tion per
5.5.5,
OPY
5.5.5, an
PY
an
transitio
COP
transitio
reatment
LIC 
reatment
veness
BLIC
veness
C
ust the d
UBL
ust the d
ened
PU
ened rel
U
rel
0.4 m
P
0.4 m
be used to support any marketing authorization 
and
ho
and youn
or
youn
core
uth
core stud
ho
stud
X008
aut
X008-
u
-150
ut
150
l will cons
g a
l will cons
who compl
ing 
who compl
in
et
in both
eting
both th
g
th
2 of 1504
y m
2 of 1504
od (betwee
ny 
od (betwee
d 1504
an
1504 Se
ny
Se
n period a
ort a
n period a
Period,
upp
Period, all
p
all
f this
su
this dose
up
dose
ose of each
o s
ose of each
tive
d t
tive to
to
to the
o
the
g/kg/day (
ed t
g/kg/day (
in increm
sed
in increm
. Dose in
us
. Dose in
X008
be
X008-
e
-1504
e u
1504
ument cannot b
ose increa
t be
ose increa
ion, seizur
ot b
ion, seizur
Dose decr
no
Dose decr
ency appro
ann
ency appro
sed with t
can
sed with t
s and
nt c
and safe
t c
safe
treatment
en
treatment
treatment 
um
treatment 
This doc
roups 1 to
cu
roups 1 to
n
any extensions or variations thereof. 
04 Co
f
04 Co
sist of a 2
eof.
sist of a 2
lete this tr
reo
lete this tr
he core stu
here
he core stu
4 who ente
atio
4 who ente
en Visits 1
riat
en Visits 1
ctions
aria
ctions 5.5
a
5.5
at a fixed d
va
at a fixed d
l subjects 
s o
l subjects 
e
o
e in
on
in all
ons
all stu
s
stu
h subject 
sion
h subject 
eir
n
eir status
nsi
status
(max 30m
ten
(max 30m
ents of
xte
ents of 0.
e
0.
creases sh
ex
creases sh
4 Cohort 2
ny e
4 Cohort 2
plication and an
ases may
any
ases may
y
ure frequen
d a
ure frequen
creases for
nd 
creases for
opriate fo
an
opriate fo
the Medic
n a
the Medic
fety
ati
fety data
tio
data w
t group in 
cat
t group in 
groups
plic
groups th
c
th
app
o 5 are the
app
o 5 are the


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 15 of 76
v3.0
04Aug2020
Table 1.
Treatment Groups in Study ZX008-1503 According to Treatment in Feeder Study
Name of Treatment 
Group
Treatment 
Group Code
AED Treatment from Feeder 
study
Feeder Study(s)
Approximate Total 
Number of subjects 
at Final Analysis
PBO-ZX008 OL
1
Placebo in feeder study along 
with any protocol-
approved background AED 
combination; no active ZX008
1501, 1502, 1504
Cohort 2
120
ZX 0.2 – ZX008 OL
2
Any protocol-approved 
background AED combination; 
plus, ZX008 0.2 mg/kg/day max 
30 mg
1501, 1502
80
ZX 0.8 – ZX008 OL
3
Any protocol-approved 
background AED combination; 
plus, ZX008 0.8 mg/kg/day max 
30 mg
1501, 1502
80
ZX 0.5 – ZX008 OL
4
Protocol-approved background 
regimen including STP + VPA 
and/or CBZ; plus ZX008 0.5 
mg/kg/day max 20 mg
1504 Cohort 2
40
PK - ZX008 OL
5
Protocol-approved background 
regimen including STP + VPA 
and/or CBZ; plus ZX008 0.5 
mg/kg/day max 20 mg
1504 Cohort 1
18
ZX DBA – ZX008 
OL
6 (Groups 2-4)
Any protocol-approved 
background regimen, plus 
ZX008 at any protocol-approved 
dose – DB Studies only
200
ZX DB – ZX008 OL
7 (Groups 1-4)
Any protocol-approved 
background regimen at any 
protocol-approved dose – DB 
Studies only
320
ZX – ZX008 OL
8 (Groups 2-5)
Any protocol-approved 
background regimen, plus 
ZX008 at any protocol-approved 
dose – All studies
218
ZX008 OL
9 (Groups 1-5)
Any protocol-approved 
background regimen at any 
protocol-approved dose – All 
studies
338
De Novo Subjects
10
N/A
N/A
TBD
PUBLIC COPY
ombi
Y
ombi
mg/kg/da
PY 
mg/kg/da
approved
CO
approved b
O
b
n
C
n includin
C CO
includin
/or CBZ; p
C C
/or CBZ; p
mg/kg/day
LIC
mg/kg/day
OP
Protoc
BL
Protoc
reg
UB
reg
UBL
UB
ument cannot be used to support any marketing authorization 
te
i
te Total 
iza
Total 
of
of subjects
oriz
subjects
nal Analysi
hor
nal Analysi
at
120
h
120
tho
ng
ing
ng
ng
ng
max
n
max
1501,
ma
1501, 150
ma
150
ma
ny
ackground 
ort 
ackground 
STP
po
STP +
por
+ VPA
or
VPA
us ZX008 0
ppo
us ZX008 0
max 20 mg
upp
max 20 mg
t a
-approved
su
approved b
men
to
men includin
to s
includin
nd/or CBZ; p
d to
nd/or CBZ; p
mg/kg/day
ed t
mg/kg/day
su
)
Any
se
Any p
bac
s
bac
ed
us
(Groups
ot b
(Groups 1
b
1
t b
an
OL
t
OL
This document ca
ca
ZX008
cum
ZX008 OL
um
OL
um
d
n
n and any extensions or variations thereof. 
80
e
80
re
s
2
i
2
on
A
o
A
.5.5
1504
va
1504 C
a
C
va
or
background
ion
background
ng
s
ng STP
sio
STP +
o
+ VP
o
VP
plus ZX008
ns
plus ZX008
y max 20 mg
ten
y max 20 mg
ns
protocol
ext
protocol-
xt
-app
t
app
ckground re
ex
ckground re
ZX008
y e
ZX008 at
y e
at a
dose
any
dose –
y
– D
y
D
xte
a
4)
d
4)
Any
a
Any
b
a
cation
8
io
8 (Groups
tion
(Groups
applica
n
ca
pl


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 16 of 76
v3.0
04Aug2020
3.3 TREATMENT PERIODS
The duration of participation in the study for an individual subject is expected to be up to 158 weeks, plus a 
follow-up safety visit 3 and 6 months after the last dose.
•
OLE Treatment Period – 36 months (156 weeks)
•
Post-Dosing Visit – 2 weeks after study completion or early termination.
•
Cardiac Follow-up (ECG and ECHO) – 3 and 6 months after study drug discontinuation for early 
termination and for those subjects who complete the study.
3.3.1 OLE Treatment Period
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 initial IMP will be based on the 0.2 mg/kg/day (maximum 30 mg/day or 20 mg/day for 
subjects taking concomitant STP) dose and subject’s weight at Visit 1 (Study Day 1). At Visits 5 to 15 
(Months 3 to 33), if the subject’s weight has changed ± 25% of the weight from the previous dose calculation, 
the IMP dose will be recalculated. Subjects will be dosed using the oral dosing syringe provided.
During the OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day for 1 month to 
assess effectiveness of this dose in all study subjects. After 1 month at a dose of ZX008 0.2 mg/kg/day, the 
investigator may adjust the dose of each subject based on effectiveness and tolerability.
Dose changes should be made in increments of 0.2 mg/kg/day, as follows:
•
Subjects who are not receiving concomitant STP: may increase to a maximum of 0.8 mg/kg/day but 
not to exceed total dose of 30 mg/day
•
Subjects who are receiving concomitant STP: the first dose change will be to 0.4 mg/kg/day and the 
final dose change will be to 0.5 mg/kg/day, but not to exceed 20 mg/day
Additional details on dosing are provided in the clinical study Protocol.
3.3.2 Taper Period
All subjects (those who complete the OLE Treatment Period and those who discontinue from the study early) 
will be tapered off study medication.
3.3.2.1 Taper Period for Subjects from Core Studies ZX008-1501, ZX008-1502, and ZX008-1504
Cohort 1/Regimens 1&2
The tapering scheme is a 2-step process for subjects who are not receiving concomitant STP, including 
subjects from core studies ZX008-1501 and ZX008-1502, and from study ZX008-1504 Cohort 1/Regimens 
1&2. This is described in Table 2.
PUBLIC COPY 
he
O
he 0.2 m
OPY
0.2 m
ct’s weig
COP
ct’s weig
ha
C
hanged ±
C CO
nged ±
will be 
C C
will be 
subjects 
BLIC
subjects 
l
U
l study
UBL
study
L
of each s
PUB
of each s
ncre
P
ncre
e used to support any marketing authorization 
ks,
i
ks, plus
iza
plus a 
a
a 
tinuation
au
tinuation
and
rk
and in
rke
in the
ke
the
f 8 hours a
mar
f 8 hours a
before
ma
before the
ma
the
/kg/day (m
any
/kg/day (m
ht at Visit
rt a
ht at Visit
25%
or
25% of
ort
of th
t
th
osed using
ppo
osed using
will be trea
sup
will be trea
ubjects.
o s
ubjects. A
ubject base
d to 
ubject base
ments
ed
ments of
d 
of 0
eiving
e us
eiving con
s
con
This document cannot be
se of 30 m
be 
se of 30 m
eceiving
t be
eceiving
e
ge will be 
not 
ge will be 
n dosing
ann
dosing
Period
t ca
Period
ts
e
ts (those
ent
(those
tapered o
me
tapered o
.2.1
cu
.2.1 Tap
um
Tap
Cohort 1
doc
Cohort 1
The t
s d
The t
su
s 
su
n
any extensions or variations thereof. 
for
of
for ear
f. 
ear
e evening
s th
evening
and a max
ns 
and a max
next
ion
next sche
n
sche
maximum
aria
maximum
t 1 (Study 
va
t 1 (Study 
he
o
he weight 
or v
weight 
ng the oral
s or
ng the oral
ated initia
ons
ated initia
fter
io
fter 1
on
1 mon
on
mon
ed on effe
nsio
ed on effe
0.2
t
0.2 mg/kg
xten
mg/kg
ncomitant
y ex
ncomitant
application and a
mg/day
ny
mg/day
concomita
any
concomita
e to 0.5 mg
d a
e to 0.5 mg
are
a
are provid
an
provid
who
at
who comp
atio
comp
off study m
lica
off study m
aper
pp
aper Perio
ppl
Perio
/Regime
app
/Regime


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 17 of 76
v3.0
04Aug2020
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 will be administered using the oral dosing syringe 
provided.
Table 2.
Taper Algorithm for Subjects from Core Studies ZX008-1501, ZX008-1502, and ZX008-1504 
Cohort 1/Regimens 1&2 Not Receiving Concomitant STP
Current Dose
Taper Step 1
Days 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
Not applicable
Not applicable
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
ZX008 0.6 mg/kg/day
ZX008 0.4 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
Note: maximum daily dose of ZX008 is 30 mg.
Regimen 1 = CLB + VPA + ZX008 0.2 mg/kg; Regimen 2 = CLB + VPA + ZX008 0.4 mg/kg
3.3.2.2 Taper Period for Subjects from Core Study ZX008-1504 Cohort 1 Regimen 3 and Cohort 2
The tapering scheme is a 3-step process for subjects receiving concomitant STP, including subjects from core 
study ZX008-1504 Cohort 1 Regimen 3 and Cohort 2, and is described in Table 3.
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 will be administered using the oral dosing syringe 
provided.
Table 3.
Taper Algorithm for Subjects Receiving Concomitant STP
Current Dose
Taper Step 1 
Days 1-4 after study 
completion or early
termination
Taper Step 2 
Days 5-8 after study 
completion or early
termination
Taper Step 3 
Days 9-14 after study 
completion or early
termination
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
Not applicable
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
ZX008 0.5 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Note: maximum daily dose of ZX008 is 20 mg.
Regimen 3 = CLB + VPA + STP + ZX008 0.2 mg/kg
Seizure data from the Taper period will not be included in the planned effectiveness endpoints except where 
specified. However, all safety data obtained including data obtained through the taper period, will be included 
in the safety analyses.
PUBLIC COPY 
y
Y
y
/day
PY
/day
Y
PY
OP
+
O
+ VPA
OP
VPA +
OP
+ Z
P
Z
Core
C C
Core Stu
C
Stu
or
LI
or subje
LIC
subje
n 3 and C
BLI
n 3 and C
ered
PUB
ered as
UB
as
P
dose sh
PU
dose sh
i
P
i
d to support any marketing authorization 
mately
atio
mately
of 12 
zat
of 12 
uled dose;
riza
uled dose;
g syringe 
hori
g syringe 
1502,
g au
1502, an
au
an
Taper
etin
Taper S
after
ket
after stud
et
stud
te
e
te
ting
ark
ma
m
y
ny
a
008
t
008 0.4
t a
0.4 mg/k
a
mg/k
udy
p
udy ZX00
por
ZX00
ts
u
ts receivin
upp
receivin
ohort 2, an
sup
ohort 2, an
qual
to
qual doses
to 
doses
ent cannot be used
ould be sep
d t
ould be sep
ation may 
sed
ation may 
n
u
not be giv
use
ot be giv
ithm
ot b
ithm for
t b
for S
ent
c
ent Dose
ca
Dose
ot
mg/kg/day
nt c
mg/kg/day
t c
4
e
4 mg/kg/da
ent
mg/kg/da
nt
men
0.5
me
0.5 mg/kg
me
mg/kg
This documen
e:
u
e: maximu
um
maximu
me
um
imen
cu
imen 3
cu
3 =
u
= CL
m
CL
Seizu
s do
Seizu
spe
s 
spe
n
nsions or variations thereof. 
d
o
d ZX00
of. 
ZX00
Step
he
Step 2
he
2
y
t
y completio
the
completio
rmination
s th
rmination
ere
Not
n
Not applicab
ns 
applicab
s
Not
on
Not appl
ns
appl
ns
ZX008
tio
ZX008 0
io
ZX008
ati
ZX008
ati
ia
ar
kg
v
kg
8
o
8-
o
-1504
or v
1504 C
v
C
ng
n
ng concom
ns o
concom
nd is descr
ons
nd is descr
s
n
s BID
nsio
BID in
io
in t
o
t
cation and any exten
eparated by
tens
eparated by
y be taken 
xte
y be taken 
ven. IMP 
ext
ven. IMP 
Subjects
d an
Subjects R
T
Da
n
Da
d
a
on
y
tio
lica
/day
lic
/day
applica
m
p
m daily
plic
daily dos
c
dos
lic
pl
B
p
B +
p
+ VPA
pp
VPA +
p
+
frf


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 18 of 76
v3.0
04Aug2020
3.4 RANDOMIZATION AND BLINDING
This is an open-label study and the doses to be administered are ZX008 0.2 mg/kg to 0.8 mg/kg up to a 
maximum of 30 mg/day. Subjects taking concomitant STP, including subjects from Study ZX008-1504, 
should not exceed 0.5 mg/kg/day; with a daily maximum of 20 mg. Assignment of subject to treatment is not 
randomized. All subjects begin the OLE treatment period with 0.2 mg/kg for one month, after which the dose 
may be adjusted in increments of 0.2 mg/kg to achieve appropriate level of effectiveness/tolerability.
PUBLIC COPY 
horization 
p to a 
iza
p to a 
08
o
08-1504, 
oriz
1504, 
utho
treatmen
ho
treatmen
fter
ut
fter which
uth
which
This document cannot be used to support any marketing a
ss/tolerabi
au
ss/tolerabi
n
application and any extensions or variations thereof. 
ility.
of
ility.


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 19 of 76
v3.0:
04Aug2020
4. SCHEDULE OF ASSESSMENTS
Table 4.
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects**
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 18,
21, 24, 27, 30, and 33)
Visit 16d
(EOS/ET)
Month 36
Visit 17
Visit 18, 19
Study Day
-28 to 1a
15
30, 60, 90, 180, 270, 365, 455,
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last
dose
Clinic
Phone
Informed Consent
X
Entry Criteria
X
Demographics
X
Medical/Neurological History
Xa
Epilepsy History
Xa,b
Physical Examination, complete
Xa
X
Xe
Physical Examination, abbreviated
X
X
Xe
Neurological Examination, complete
Xf
X
Neurological Examination, abbreviated
X
X
Vital signs
X
X
X
X
Weight, Height, BMI
Xa
X
X
X
12-lead ECG
Xa
X
X
Xe
Doppler ECHO
Xa
Xg,h
X
Xe
Urine Pregnancy Testh
X
X
X
Clinical laboratory evaluation
(hematology/clinical chemistry/urinalysis, etc)
Xj
Xj
X
X
Urine THC Panel/Whole blood CBD
Xa
X
X
Plasma sample for background AEDs
X
X
X
Tanner Staging (for subjects >7 to ≤18 
years)
Xa
Xk
X
Xk
C-SSRS
Xa
X
X
CGI-I (assessed by parent/caregiver)
Xa
X
X
CGI-I (assessed by principal investigator)
Xa
X
X
QOLCE
Xa
X
X
EQ-5D-5L (QoL of parent/caregiver)
Xa
X
X
HADS (Affect of parent/caregiver)
Xa
X
X
BRIEF
Xa
X
X
continued
PUBLIC COPY 
35,
Y
35, 7
Y
7
Y
PY
OP
CO
C C
C C
C C
C C
C C
C 
C
LIC
BL
UB
X
PU
X
UB
UB
UB
UB
X
PU
X
PU
X
P
X
P
not be used to support any marketing authorization 
th
CAL
on
CAL AN
n 
AN
ogenix
atio
ogenix Int
o
Int
-
t
-1502,
ting
1502, an
g
an
ti
, 18,
ar
18,
33)
m
33)
Visit 
ke
Visit 
(EO
rk
(EO
M
ke
ark
365,
m
365, 455,
m
455,
5,
n
5, 905,
ny m
905, 995
y m
995
m
ny
an
t a
ort
po
pp
up
su
o
to
d
e
se
us
u
b
X
e
Xj
Xj
Xj
X
be
b
t cannot 
X
o
Xa
ot
a
ot
no
Xa
nn
a
ca
nt 
r)r)
ument c
estigator)
en
estigator)
n
me
/caregiver)
um
/caregiver)
m
ocu
t/caregiver)
ocu
t/caregiver)
docu
oc
This do
is 
TIAL
Thi
TIAL
do
d any extensions or variations thereof. 
nd
e
nd de
ere
de Nov
re
Nov
Post
he
Post-D
her
th
16
16d
t
d
OS/ET)
ns t
OS/ET)
Month
ons
Month 36
ns
36
V
th
th
th
th
1085
on
1085
on
t
at
iat
at
at
at
ria
va
v
or 
o
X
ns
X
ns
on
sio
ns
en
xte
ex
ex
ex
ex
ex
y e
ny
a
ion and a
d a
X
nd
X
nd
an
a
X
io
Xa
on
a
n
pplicatio
X
tio
Xa
o
a
tio
a
X
t
Xa
at
ca
ca
ca
ca
ca
lic
app
pp
ap
a


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 20 of 76
v3.0:
04Aug2020
Table 4.
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects** (continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15,
18, 21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET)
Month 36
Visit 17
Visit 18, 19
Study Day
-28 to 1a
15
30, 60, 90, 180, 270, 365, 455,
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last
dose
Clinic
Phone
PedsQL n
Xa
X
X
Study medication palatability assessment
Xl
Subject Diary
D
C/R/D
R
C/R/D
C/R
C/R
Study Medication
Db
C/R/D
R
C/R/D
C/R/D
C/R
Daily Diary Completion
X
Concomitant Medication
Xa
X
Adverse Events
Xa
X
Adverse events of special interest
Xa
----------------------------------------------X--------------------------------------------------
Xm
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CGI-I=Clinical Global Impression-Improvement; 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
NOTE: If a subject has a birthday during the study that makes a previously unrequired assessment now required (eg, Tanner staging in a male subject who turns 8 years old during the study), this assessment(s)
should be initiated at visits subsequent to the birthday.
** de Novo subjects are subjects who did not participate in one of the core studies and may or may not be currently taking STP.
a:
For subjects enrolling from one of the core studies use data collected at Visit 12 and Visit 13 of Study ZX008-1501 or ZX008-1502.
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures. All results to determine eligibility must be reviewed prior to
receiving the first dose of study medication at Visit 1.
For all subjects, clinical laboratory results and all ECHO/ECG results must be available and meet eligibility criteria prior to receiving the first dose of study medication at Visit 1.
b:
De Novo subjects must meet entry criteria 3 to 7, and 10, including having 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.
c:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
d:
Or early termination.
e;
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination.
f:
For subjects enrolling from one of the core studies, use core study Visit 12 information unless complete neurological examination is warranted based on significant changes in subject status.
g:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
h:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 ECHO may be performed any time within 3 weeks prior to the study visit. If a subject discontinues early from the study, the ECHO should be scheduled as soon as
practical (see Table 7).
i:
Females of child-bearing potential
j:
For subjects enrolling from one of the core studies, use data collected at Visit 12 of ZX008-1501 or ZX008-1502 for Visit 1 unless clinical laboratory evaluation is warranted based on significant changes in subject
status. Visit 2 clinical laboratory evaluation is optional based on subject status for all cohorts.
k:
Months 6, 15, and 27 only.
l:
Visits 3 and 4 (Months 1 and 2) only.
m:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
n:
Not to be completed for de novo subjects >18 years old.
COPY 
CO
C CO
C
IC C
C
PUBLIC
Y
PY
OP
O
CO
C C
----------
LIC
----------
IC
LI
of Executiv
BLI
of Executiv
andardized m
UBL
andardized m
w
U
w
usly unrequ
PU
usly unrequ
stud
P
stud
marketing authorization 
th
CAL
on
CAL AN
n 
AN
ogenix
atio
ogenix Int
o
Int
502,
g
502, and
g a
and d
P
g
Visit 16
ting
Visit 16c
n
c
(EOS/ET
ket
(EOS/ET
Mont
ke
Mont
ing
rk
455,
a
455,
5,
m
5, 995
ma
995
rk
rk
rk
ark
a
ort any m
rt
por
po
ppo
pp
nnot be used to supp
m
y
R/D
an
R/D
ny
C/R/D
t a
C/R/D
an
X
ort
X
t a
or
po
------------
up
------------
pp
up
unction; C=Co
sup
unction; C=Co
sure
o
sure of
o s
of health
s
health
ed
d
ed assessment
d to
assessment
and
ed
and may
ed
may or
d
or
t 12
s
12 and
sed
and Visit
ed
Visit
ng
u
ng this
us
this period,
use
period,
lts must
e u
lts must be
u
be av
u
av
ing having ha
be 
ing having ha
l notes.
t b
l notes.
cted
ot
cted
cument can
as
ot b
as a
t b
a phon
b
phon
will
n
will be
no
be perform
no
perform
s, use
nn
s, use core stu
nn
core stu
, 12, 15, 18, 2
an
, 12, 15, 18, 2
0, and
ca
0, and 33 ECH
can
33 ECH
he
he core
nt
core studie
nt
studie
y evaluation is
en
y evaluation is
nd
nd 2)
um
2) only.
um
only.
ated
u
ated to
um
to cardiac
um
cardiac
This doc
is 
TIAL
Thi
TIAL
for de novo su
cu
for de novo su
ons thereof. 
de
e
de Novo
eof
Novo S
Post
re
Post-
re
-Dosing
reo
Dosing
eo
T)
t
T)
h 36
t
36
Visit
ere
Visit 1
e
1
re
th
1085
ns
1085
s t
r variation
v
or v
or
s or
o
and any extensions o
X
o
X
on
tio
at
ia
ari
va
X
o
X
o
X
r v
X
o
X
o
X
or
-------
s
-------X
s 
X---
---
s o
ns
ollect; CBD=ca
ons
ollect; CBD=ca
status;
io
status; HADS
on
HADS
now
n
now required
ns
required
may
t
may not
te
not be
en
be cu
n
cu
13
x
13 of
xt
of Study
xte
Study ZX
e
ZX
nformed
ext
nformed cons
xt
cons
ilable
y
ilable and
y e
and me
e
me
≥4
n
≥4 convulsiv
ny
convulsiv
pplication a d
visit.
d a
visit.
ed
n
ed 3
n
3 and
nd
and 6
d
6 mo
d
mo
dy
a
dy Visit
an
Visit 12 inf
n
12 inf
1, 24, 27, 30, a
an
1, 24, 27, 30, a
HO may
n a
HO may be
n a
be per
a
per
s, use
ati
s, use data
atio
data col
o
col
optional based
cat
optional based
safety
ppl
safety will
pl
will be
be
app
ubjects >18 ye
pp
ubjects >18 ye


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 21 of 76
v3.0:
04Aug2020
Table 5.
Schedule of Assessments for Subjects from Core Study ZX008-1504
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15,
18, 21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET)
Month 36
Visit 17
Visit 18, 19
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455,
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last
dose
Clinic
Phone
Informed Consent
X
Entry Criteria
X
Demographics
X
Medical/Neurological History
Xa
Epilepsy History
Xa
Physical Examination, complete
Xa
X
Xd
Physical Examination, abbreviated
X
X
Xd
Neurological Examination, complete
Xe
X
Neurological Examination, abbreviated
X
X
Vital signs
X
X
X
X
Weight, Height, BMI
Xa
X
X
X
12-lead ECG
Xa
X
X
Xd
Doppler ECHO
Xa
Xf,g
X
Xd
Urine Pregnancy Testh
X
X
X
Clinical laboratory evaluation
(hematology/clinical chemistry/urinalysis, etc)
Xi
Xi
X
X
Urine THC Panel/Whole blood CBD
Xa
X
X
Plasma sample for background AEDs
X
X
X
Tanner Staging (for subjects > 7 years old)
Xa
Xj
X
Xj
C-SSRS
Xa
X
X
CGI-I (assessed by parent/caregiver)
Xa
X
X
CGI-I (assessed by principal investigator)
Xa
X
X
QOLCE
Xa
X
X
EQ-5D-5L (QoL of parent/caregiver)
Xa
X
X
BRIEF
Xa
X
X
Healthcare utilization questions
Xa
X
X
continued
PUBLIC COPY 
Y
PY
OP
CO
C C
C C
C C
C C
C
LIC
BL
X
U
X
BL
BL
BL
BL
UB
PU
P
thorization 
CAL
on
CAL AN
n 
AN
ogenix
atio
ogenix Int
o
Int
ot be used to support any marketing auth
Pos
a
Pos
a
g a
sit 16
ng
sit 16c
ng
c
EOS/ET)
ting
EOS/ET)
Month
keti
Month 36
36
g
k
g
5,5,
95
a
95
108
e
108
ke
rk
rk
ark
a
m
y m
ny
an
t a
X
r
X
ort
po
pp
up
su
o
to
d
e
Xi
s
i
se
se
se
se
u
be
X
e
X
be
be
be
be
X
t
Xa
t
a
b
cannot b
X
ot
Xa
ot
a
ot
X
no
Xa
o
a
no
X
n
X
nn
an
ent ca
ca
t
This documen
is 
TIAL
Thi
TIAL
en
me
th
d any extensions or variations thereof. 
t-Dosing
eof.
Dosing
of.
6
Visit
reo
Visit 17
eo
17
eo
th
5
th
th
th
th
t
ns
on
tio
at
iat
at
at
at
ri
va
v
or
X
s
X
s o
X
ns
X
ns
X
n
X
on
sio
ns
en
xtxtxtxte
ext
y e
n e
ny
an
an
an
on and an
an
an
d a
nd
an
a
X
n
Xa
n
a
a
application a
X
ion
Xa
on
a
on
X
tio
Xa
o
a
tio
a
X
t
X
at
ica
ca
ca
ca


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 22 of 76
v3.0:
04Aug2020
Table 5.
Schedule of Assessments for Subjects from Core Study ZX008-1504 (continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
Visit 16c
Visit 17
Visit 18, 19
(Months 1, 2, 3, 6, 9, 12, 15,
(EOS/ET)
18, 21, 24, 27, 30, and 33)
Month 36
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455,
1085
1099
3 and 6 months post last
Clinic
Phone
545, 635, 725. 815, 905, 995
dose
Karolinska Sleep Scale
Xa
X
X
Sleep quality/mealtime behavior questions
Xa
X
X
PedsQL
Xa
X
X
Study medication palatability assessment
Xk
Subject Diary
D
C/R/D
R
C/R/D
C/R
C/R
Study Medication
Db
C/R/D
R
C/R/D
C/R/D
C/R
Daily Diary Completion
X
Concomitant Medications
Xa
X
Adverse Events
Xa
X
Adverse events of special interest
Xa
----------------------------------------------X--------------------------------------------------
Xl
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CGI-I=Clinical Global Impression-Improvement; 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
NOTE: If a subject has a birthday during the study that makes a previously unrequired assessment now required (e.g., Tanner staging in a male subject who turns 8 years old during the study), this assessment(s) should be
initiated at visits subsequent to the birthday.
a:
For subjects from the core Study ZX008-1504 Cohort 1, use data collected at the last visit of the transition period; for subjects from core Study ZX008-1504 Cohort 2 use data collected at the Visit 12 and Visit 13.
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures. All results to determine eligibility must be reviewed prior to
receiving the first dose of study drug at Visit 1.
For subjects from ZX008-1504 Cohort 2 and de novo subjects, clinical laboratory, ECHO, and ECG results must be available and meet eligibility criteria prior to receiving the first dose of study drug at Visit 1.
b:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
c:
Or early termination.
d:
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination.
e;
Unless complete neurological examination is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1 and for subjects from
Study ZX008-1504 Cohort 2, use data collected at the Visit 12.
f:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
g:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 ECHO may be performed any time within 3 weeks prior to the study visit. If a subject discontinues early from the study, the ECHO should be scheduled as soon as
practical (see Table 7).
h:
Females of child-bearing potential
i:
Unless clinical laboratory evaluation is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1; for subjects from Study
ZX008-1504 Cohort 2, use data collected at the Visit 12. For Visit 2, clinical laboratory evaluation is optional based on subject status.
j:
Months 6, 15, and 27.
k:
Visits 3 and 4 (Months 1 and 2) only.
l:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
C COPY 
C
C CO
C
LIC
LIC
PUBLI
Y
PY
OP
CO
C C
C
----------
BL
----------
LIC
BL
ory of Execu
UBL
ory of Execu
=standardiz
UB
=standardiz
view
PU
view
unrequire
PU
unrequire
thorization 
CAL
on
CAL AN
n 
AN
ogenix
atio
ogenix Int
o
Int
marketing auth
Post
a
Post
a
g a
sit
n
sit 16
ng
16c
ng
c
g
EOS/ET)
ting
EOS/ET)
g
Month
keti
Month 3
k
5,5,
108
e
108
ke
rk
95
a
95
rk
ark
port any ma
o
ppo
pp
upp
up
nt cannot be used to sup
a
m
y m
X
a
Xk
Xk
Xk
X
ny
C/R/D
t an
C/R/D
an
C/R/D
rt a
C/R/D
t a
X
or
X
ort
po
pp
------------
su
------------
up
su
e Function; C
o s
e Function; C
measure
to
measure of
o 
of he
he
ssessment now
d t
ssessment now
at the last vis
se
at the last vis
ng this
us
ng this period,
use
period,
nical
be
nical laborator
e u
laborator
as a phone vis
be
as a phone vis
performed
ot b
performed 3
b
3
d based
ot
based on
ot
on sig
t
sig
he Visit 12.
no
he Visit 12.
2,2,
This document c
is 
TIAL
Thi
TIAL
15, 18,
nn
15, 18, 21, 2
n
21, 2
and
a
and 33 ECHO
an
33 ECHO
s
n
s warranted
nt c
warranted b
c
b
ollected at the 
ent
ollected at the 
2)
m
2) only.
me
only.
d
u
d to
um
to cardiac
um
cardiac s
th
ns thereof. 
Dosing
eof
Dosing
of.
Visit
reo
Visit 17
eo
17
eo
h
6
h
6
h
th
5
th
th
th
th
t
or variations
r
s or
o
ns o
s
tion and any extensions
t
X
ons
X
ns
X
on
X
on
t
X
o
X
tio
at
iat
at
at
at
ri
va
v
X
o
X
o
X
or
X
s o
X
s o
----------
n
----------X
s
X
ns
on
=Collect; CBD
ion
=Collect; CBD
lth
s
lth status;
sio
status; HA
o
HA
required
en
required (e.g
n
(e.g
t of
x
t of the transit
xte
the transit
nformed
ex
nformed cons
x
cons
y, ECHO, and
ny e
y, ECHO, and
t.t.
nd
d
nd 6
d
6 months
d a
months
nificant
d
nificant change
d a
change
applicat
4,
a
4, 27, 30,
an
27, 30, and
n
and
may
a
may be
a
be perfor
a
perfor
ased
ti
ased on
tio
on signifi
o
signifi
Visit 12. For V
atio
Visit 12. For V
afety
pl
afety wil
plic
will
plic
l be
ic
be co
c
co


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 23 of 76
v3.0:
04Aug2020
5. ANALYSIS POPULATIONS
5.1 ENROLLED POPULATION
The enrolled population includes all subjects who gave informed consent or assent for entry into Study 
ZX008-1503.
5.2 SAFETY (SAF) POPULATION
The SAF population is the set of all enrolled subjects who received at least one dose of ZX008 during the open 
label extension. Safety analyses will be performed on the SAF Population.
5.3 MODIFIED INTENT-TO-TREAT (MITT) POPULATION
The mITT Population is defined as all enrolled subjects who receive at least one dose of ZX008 and have at 
least one month (30 days) of valid seizure data during the open label extension. Effectiveness analyses, such as 
evaluating the change in the frequency of convulsive seizures, will be performed on the mITT Population.
6. STATISTICAL METHODOLOGY
6.1 STATISTICAL AND ANALYTICAL ISSUES
6.1.1 Statistical Methods
All data on safety, effectiveness and exploratory endpoints will be summarized. Continuous data will be 
summarized using descriptive statistics including number of subjects, means, standard deviations, medians, 
lower and upper quartiles, and ranges. Categorical variables will be summarized with frequencies and 
percentages.
Effectiveness and safety data may be summarized by treatment group in previous study as described in Section
3.2 in this SAP. The effectiveness and safety data will also be summarized by age group as described in 
Section 6.1.3, and overall.
Point and interval estimates (95% confidence intervals) will be calculated for within treatment changes from 
baseline for key parameters as warranted. These within-treatment changes from baseline comparisons should 
be interpreted with caution, as any effect of treatment may be confounded with the time-course of disease or 
other factors. The primary evidence for efficacy and safety of ZX008 is based on the treatment comparisons 
from the double-blind studies, while the data from this OLE study provides evidence of long-term safety and 
effectiveness.
Confidence intervals and/or p-values, where provided for between treatment group differences, should be 
regarded as descriptive and not for formal inferential purposes.
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.3, unless 
otherwise noted). Adverse events will be coded using the most recent MedDRA version available at the time 
of analysis. Concomitant medications will be coded using the most recent version of World Health 
Organization (WHO) Drug.
PUBLIC COPY
e
Y
e ope
Y
ope
seizures
PY 
seizures
AL
IC
AL ISSU
IC 
ISSU
and expl
PUB
and expl
atistics
PU
atistics
not be used to support any marketing authorization 
nto
h
nto Study
hor
Study
ose
tin
ose of ZX
ing
of ZX
at least on
ma
at least on
bel
y
bel extens
y m
extens
will be pe
any
will be pe
ES
p
ES
ratory end
d to 
ratory end
including
ed t
including
s. Categor
sed
s. Categor
may
be
may
ument can
be
e 
be su
su
veness
t be
veness an
e
an
all.
no
all.
stimates (
ann
stimates (
parameter
can
parameter
with caut
t ca
with caut
rs. The pri
ent 
rs. The pri
double
men
double
This docum
-b
n
b
iveness.
um
iveness.
Confidenc
ocu
Confidenc
regarded
doc
regarded
All 
s d
All 
s
n
y extensions or variations thereof. 
X008
ere
X008 durin
re
durin
ne dose o
ion
ne dose o
ion.
ati
ion. Effec
atio
Effec
erformed o
riat
erformed o
dpoints wi
nsi
dpoints wi
g
t
g number
ten
number
rical varia
xte
rical varia
pplication and any
ummarize
ny 
ummarize
nd
nd safety
any
safety d
y
d
(95% conf
an
(95% conf
rsrs as
n
as warra
n a
warra
tion,
tio
tion, as an
on
as an
rimary evi
atio
rimary evi
app
blind
ica
blind studi
cat
studi
e
a
e interval
app
interval
s descr
ap
s descr


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 24 of 76
v3.0:
04Aug2020
6.1.2 Multiplicity Issues
This is an open-label extension study with no formal comparisons to be made between treatment groups 
defined by subjects’ initial regimen in the previous study. Comparisons will be made within each treatment 
group comparing measurements observed during different time points in the OLE to the measurements 
obtained during the baseline period in the double-blind or PK study completed prior to this OLE.
Confidence intervals presented for descriptive purposes only will each have nominal 95% coverage 
probability.
No formal adjustment for multiplicity is made.
6.1.3 Subgroups
Effectiveness and select safety data may be further broken down by the following subgroups:
•
Age strata (based on age at informed consent at core study entry or entry de novo): 2 to <6 years, ≥6 –
18 years.
•
Region: Countries may be grouped into two regions: North America (US/Canada), Rest-of-World 
(ROW).
•
Japan: Subjects enrolled from Japan are considered as a separate subgroup.
6.1.4 Definitions
6.1.4.1 Baseline (Core)
For de novo subjects, the baseline (core) is undefined. For other subjects, the baseline (core) is defined as 
follows.
For effectiveness endpoints (excluding seizure), the baseline (core) will be defined dependent on their core 
study. For subjects from ZX008-1501, ZX008-1502, or ZX008-1504 Cohort 2, baseline (core) is the last value 
prior to randomization in the preceding double-blind study. For subjects from ZX008-1504 Cohort 1, baseline 
(core) is the last value prior to the start of PK dosing and assessments. For De Novo subjects, the baseline is 
the last value prior to dosing in ZX008-1503.
For all subjects in Study ZX008-1501, Study ZX008-1502, or Study ZX008-1504 Cohort 2, the baseline (core) 
period is equivalent to the core study pre-randomization period, i.e., the approximately 42-day span just prior 
to randomization and start of treatment in the core study. The baseline (core) seizure frequency will be based 
on the information collected from their daily diaries during the baseline period (lasting approximately 42
days).
For subjects from Study ZX008-1504 Cohort 1 the baseline (core) for efficacy rating scales (e.g. 
questionnaires) will be the last rating prior to start of dosing in the Core Study. Baseline seizure frequency for 
Study ZX008-1504 Cohort 1 will not be calculated.
PUBLIC COPY 
t
O
t at
OP
at cor
PY
cor
nto
C
nto two
C C
two r
C
r
Japan
BLI
Japan a
L
a
nnot be used to support any marketing authorization 
oups 
zat
oups 
tr
r
treatmen
riz
eatmen
urements
hor
urements
OLE.
utho
OLE.
5%
a
5% cover
au
cover
y the
y m
the follow
y m
follow
study
t an
study entr
any
entr
gions:
por
gions: No
or
No
considere
sup
considere
(core)
us
(core) is
s
is
s (excludi
t be
s (excludi
ZX008
ot 
ZX008-1
on in
nn
on in the p
no
the p
This document ca
alue prior
an
alue prior
rior to dos
t ca
rior to dos
jects
ent
jects in
nt
in St
St
s equivale
men
s equivale
ndomizatio
um
ndomizatio
n the inform
cum
n the inform
days).
doc
days).
For s
s d
For s
qu
s
qu
n
and any extensions or variations thereof. 
age
of
age
wing
tio
wing subg
on
subg
ry
a
ry or
ari
or entry
ria
entry
rth
o
rth Amer
or v
Amer
ed
o
ed as
on
as a
ns
a se
s
se
undefined
ex
undefined
ing seizur
any
ing seizur
1501,
d a
1501, ZX0
a
ZX0
preceding
and
preceding
application a
r to the sta
n an
r to the sta
sing in ZX
on 
sing in ZX
tudy
ati
tudy ZX00
atio
ZX00
ent to the c
ica
ent to the c
ion and sta
plic
ion and sta
rmation co
pp
rmation co


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 25 of 76
v3.0:
04Aug2020
6.1.4.2 Baseline (OLE)
Baseline (OLE) value for the Open-label treatment period is defined as the last assessment on or before the 
start of the OLE period. In most cases, (though not seizure frequency) this will be the value obtained at Visit 1 
(Study Day 1) of Study ZX008-1503.
Thus, Baseline (OLE) lab, vital signs, ECG, ECHO, assessments refer to the assessments obtained on this day, 
as does Baseline (OLE) value for effectiveness endpoints with the exception of seizures.
For de novo subjects, the baseline (OLE) seizure frequency will be based on the information collected from 
their daily diaries during the baseline period (lasting approximately 28 days) prior to first dose in ZX008-1503.
6.1.4.3 Open-Label Extension (OLE) Treatment Period
The OLE Treatment Period covers the 36 months during which subjects will receive open label treatment with 
ZX008.
For each subject, OLE day 1 (OLED1) is the subject’s first day of dosing in the OLE period. Study day for 
1503 begins with OLED1.
6.1.4.4 Post-dosing Period
The Post-dosing Period begins immediately at the end of OLE Treatment Period and extends for 2 weeks.
6.1.4.5 Follow-up Period
Subjects are to return for an ECHO and ECG assessment 3 and 6 months after the end of the study. The 
follow-up period begins the day after Visit13 and ends with Visit15.
6.1.5 Other Definitions
6.1.5.1 Phase and Study Day Definitions
The analyses will require definition of 3 Phases: Pre-OLE, OLE, and Post-OLE.
•
The pre-OLE Phase comprises (1) the baseline (Core) period, (2) the Core Study (CS) period 
(including the transition period in the core study)
•
The OLE Phase starts from dosing on OLED1 and comprises (1) the OLE Treatment Period, and (2) 
the Taper Period. The last day of the OLE phase is the date of Visit 17.
•
The post-OLE phase begins one day after the date of Visit 17 in 1503 and ends with the date of Visit 
19.
Study Day 1 is the date of first dose in the OLE Study. In most cases, this will be the date of Visit 1 or the day 
after that date.
6.1.6 Visit Windows and Period Start/Stop Dates
The following definitions of phase and period will be used:
PUBLIC COPY 
wh
Y
wh
ect’s
COP
ect’s firs
OP
firs
iately
BLI
iately at
LI
at
O
P
O an
P
an
This document cannot be used to support any marketing authorization 
fore the 
izat
fore the 
ned at
riz
ned at Vi
z
Vi
obtained
uth
obtained
s.s.
nformation
ing 
nformation
ior
et
ior to
tin
to first
ing
first
bjects
y m
bjects will
y m
will
day
rt
day of
t a
of do
a
do
he
s
he end
sup
end of
up
of
d ECG
ed
ECG ass
d 
ass
er Visit13 
se
er Visit13 
dy
ot
dy Day
ot b
Day De
b
De
uire
n
uire defini
no
defini
LE
a
LE Phase
ann
Phase
ing the tra
t ca
ing the tra
OLE
nt
OLE Pha
t 
Pha
the Taper 
men
the Taper 
The
um
The po
m
po
19.
u
19.
Study
doc
Study D
c
D
after 
s d
after 
n
application and any extensions or variations thereof. 
o
n collecte
reo
n collecte
dose
here
dose in
re
in Z
e
Z
l
a
l receive
atio
receive
osing
va
osing in
ar
in th
r
th
OLE
on
OLE Trea
ns
Trea
sessment
ten
sessment 3
 and ends 
exte
 and ends 
Definitions
d an
Definitions
tion
nd
tion of
nd
of 3
d 
3 P
comprise
n an
comprise
ansition p
on 
ansition p
ase
ati
ase starts
atio
starts
Period. T
icat
Period. T
ost
p
ost-
pl
-OLE
plic
OLE p
1
a
1 is
ap
is th
p
th


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 26 of 76
v3.0:
04Aug2020
Table 6.
Definition of Phase/Period
Phase
Period
Description
Pre-OLE Phase
Baseline (Core) 
Period
This description here applies to all subjects except the de novo subjects. This period 
refers to the period prior to the beginning of the double-blind period in the Core study. 
The Baseline (Core) period start date is the date of Visit 1 in the Core study. The 
Baseline (Core) period end date is the date of Visit 3/randomization in the Core study.
For subjects in Study ZX008-1504 (Cohort 1), the baseline period starts and ends on 
the date of Visit 1.
Pre-OLE Phase
Core Study 
Period
This description here applies to all subjects except the de novo subjects. The start date 
of this period is the date of randomization or first dose in the Core (double-blind) 
study, whichever occurs first. The end date of this period is the last date the subject 
was on study treatment.
For subjects entering Study ZX008-1503 who completed Core studies ZX008-1501, 
ZX008-1502 or ZX008-1504 Cohort 2, this will be the date of Visit 13 in the core 
study. For subjects who discontinue early from the Core study, the Core study period 
end date is the latest assessment date for that study.
For subjects entering ZX008-1503 who were in ZX008-1504 Cohort 1, this will be the 
date of the Visit 17 assessment in Study 1504 Cohort 1 (for those who completed), or 
the date of the latest assessment date (for those who discontinued ZX008-1504 Cohort 
1 prematurely but were allowed entry into 1503, if any).
Pre-OLE Phase
Baseline (OLE) 
Period – de novo 
subjects
This description here applies to the de novo subjects. This start date of this period be 
the date of screening. The end date of the period will be the last date prior to the first 
dose of study drug in Study ZX008-1503.
OLE Phase
OLE Treatment 
Period
The OLE Treatment Period consists of the 36-month period from Visit 1 of the OLE 
study through Visit 16 of the OLE study
The OLE Treatment Period start date is the date of first dose in Study ZX008-1503. 
The OLE Treatment Period end date is the date of end of study visit, Visit 16/ET. For 
subjects who discontinue early from the study, the OLE Treatment Period end date 
will be the date of the ET visit - safety measures collected at the last clinic visit will 
be used even in the event that study drug was discontinued prior to the date of the 
visit.
Note: Adverse events occurring up to Visit 17 are regarded as occurring during 
treatment. In addition, AEs occurring up to 30 days after the last dose date will be 
regarding as treatment emergent.
OLE Phase
Taper Period
The Taper period consists of 2 weeks starting from end of study/early termination 
visit (Visit 16) + 1 day.
The end date of this period is the date recorded for Visit 17.
Post-OLE 
Phase
Post-OLE Period
The start date of the post-OLE period is the date of Visit 17, + 1 day for subjects who 
complete the OLE Treatment period, or the day after the date of end of taper, for 
subjects who discontinue early.
[There is not explicit end date for the post-OLE Phase. However, if needed, this may 
be set to be 45 days after the date of Visit 19, or V17 date + 210.]]
For the purpose of statistical analysis, visit windows around the target visit dates will be implemented to 
capture effectiveness and/or safety data within similar periods. These windows are distinct from the
C COPY
scon
Y
scon
sessment
PY 
sessment
ng
O
ng ZX008
OPY
ZX008
17 assess
COP
17 assess
latest
CO
latest as
CO
as
rely but w
C C
rely but w
UBLIC 
escription
LIC
escription
date
BL
date of
BLI
of sc
LI
sc
dose of stu
UBL
dose of stu
C
PUB
The
PU
The O
U
O
stud
P
stud
PUB
P
ng authorization 
ati
his period 
oriz
his period 
he
h
he Core
hor
Core stu
r
stu
re study.
tho
re study. Th
o
Th
on
on in the
uth
in the Co
h
Co
riod
a
riod starts
au
starts a
u
a
iza
pport any marketing
e
t
e novo
ting
novo sub
ng
sub
ose in the Co
ketin
ose in the Co
s period is t
rke
s period is t
who
m
who comple
ma
comple
this will be 
m
this will be 
early
y
early from
y m
from th
m
th
ate for that 
any
ate for that 
503
t a
503 who
t an
who w
ent in Study
rt a
ent in Study
sment
ort
sment date
rt
date
e allowed e
ppo
e allowed e
to supp
ng
ere
u
ere applies
upp
applies
ening.
su
ening. The
up
The
y drug in St
o s
y drug in St
pp
be used to 
E Treatmen
d to
E Treatmen
 through Vi
ed t
 through Vi
he OLE Tre
sed
he OLE Tre
The
us
The OLE T
use
OLE T
subjects
e u
subjects
will 
e 
will 
be
e
be
ment cannot be
to
be
Taper
ca
Taper
ca
nt
This docume
OLE
m
OLE
hase
cu
hase
me
d
n
eof. 
ore
nd
of
nd ends
of.
ends o
 
o
or variations thereo
jects. The
ere
jects. The s
ore (double
her
ore (double
the last date
the
the last date
eted
on
eted Core
ns
Core stu
s
stu
the date of 
tion
the date of 
he
a
he Core
atio
Core stud
o
stud
study.
riat
study.
ere
a
ere in
ar
in ZX00
ari
ZX00
y 1504 Coh
va
1504 Coh
(for
or
(for those
r v
those
ntry into 15
or 
ntry into 15
sions o
eo
to
n
to the
ns
the de
s 
de n
end
on
end date
ons
date of
s
of
tudy ZX008
sion
tudy ZX008
o
and any extensio
t Period
ns
Period con
s
con
isit 16 of th
ten
isit 16 of th
eatment Peri
xte
eatment Peri
Treatment
ex
Treatment P
s who disco
y e
s who disco
be the date 
ny 
be the date 
e used even
any
e used even
visit.
d a
visit.
Note: A
nd 
Note: A
trea
n
trea
r
ication an
sio
and
Period
ion
Period
n
pplica
Post
plic
Post-
c
-O
c
O
ica
appl
ppl


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 27 of 76
v3.0:
04Aug2020
permissible visit scheduling windows specified in the Visit Schedule in the protocol that are used for the 
conduct of the study.
The following rules will be used to window data into treatment periods for tabulations that are generated by 
time during the OLE Treatment period.
Table 7a. Time Intervals for Analysis Visits for Seizure Analysis*
Analysis 
Phase/Period
Scheduled Visit
Number in 
ZX008-1503
Analysis 
Visit**
Time Interval 
(label on output)
Time Interval 
(Day)
Pre-OLE
N/A
-99
Baseline (Core)*
Core Study Day -42 to Day-1 of Core Study
Pre-OLE
N/A
-9
Core Study (T+M)*
Day1 of Core Study to End of T+M in Core 
Study
Pre-OLE
N/A
-1
Core Study Final *
Week
End of T+M in Core Study – 6 days, to End of
T+M in Core Study
Pre-OLE de
novo
N/A
-99
Baseline (OLE)*
Day -28 to Day -1 of Study ZX008-1503
OLE
3
1
Month 1 (OLE)
1-30
OLE
4
2
Month 2 (OLE)
31-60
OLE
5
3
Month 3 (OLE)
61-90
OLE
6
Month 4-6 (OLE)
91-180
OLE
7
5
Month 7-9 (OLE)
181-270
OLE
8
6
Month 10-12 (OLE)
271-360
OLE
9
7
Month 13-15 (OLE)
361-450
OLE
10
8
Month 16-18 (OLE)
451-540
OLE
11
9
Month 19-21 (OLE)
541-630
OLE
12
10
Month 22-24 (OLE)
631-730
OLE
13
11
Month 25-27 (OLE)
731-820
OLE
14
12
Month 28-30 (OLE)
821-910
OLE
15
13
Month 31-33 (OLE)
911-1000
OLE
16
14
Month 34-36 (OLE)
1001-1095
OLE
NA
99
Month 01-EOS
(ENDPT1)
1 to min(Last Dose date, Visit 16 date)
OLE
NA
98
Month 02-EOS
(ENDPT2)
31 to min(Last Dose date, Visit 16 date)
Note: EOS/ET date = Visit16 date. Per protocol, Visit 17 is end of the OLE Phase. 
T+M=Titration + Maintenance in Core Study.
*Subjects in Study ZX008-1504 Cohort 1 will not have a baseline(core), For those subjects, the Core Study(T+M) represents all their 
seizure data during the transition period in the core study. Their core study final week will be the last 7 days of seizure data prior to the 
first visit in ZX008-1503. De novo subjects start Study ZX008-1503 treatment after a screening period.
**Analysis visit numbers are not the same as nominal visit numbers.
PUBLIC COPY
Wee
Y
Wee
eline
PY
eline (O
Y 
(O
Y
Month
COP
Month
OP
Mo
CO
Mo
CO
C
C
5
LIC
6
B
6
BL
7
UB
7
UB
PU
8
U
8
PU
P
d to support any marketing authorization 
generated
oriz
generated
Time
ng
Time Int
g 
Int
(D
g
(D
g a
Study
ke
Study Day
e
Day
ket
Day1
ar
Day1 of
ark
of Cor
k
Cor
rke
End
ma
End of
ma
of T
ma
y
E)*
a
E)*
y
(OLE)
rt a
(OLE)
t a
h 2
o
2 (OLE)
ort
(OLE)
rt
onth
p
onth 3
po
3 (OL
po
(OL
o
Month
pp
Month 4
pp
4-
p
-6
p
6
pp
Month
sup
Month 7
p
7
up
Month
su
Month
su
o
Mon
s
Mon
o s
to
to
M
t cannot be used to
to
to
to
9
e
9
d t
10
se
10
ed
11
use
11
se
12
u
12
u
e
be
b
A
t
NA
nn
NA
nn
ca
This document
e
t
e =
t
= Visit16
t ca
Visit16
n + Mainten
nt c
n + Mainten
n Study ZX0
en
n Study ZX0
ata
m
ata during
me
during t
sit in ZX00
um
sit in ZX00
Analysis
cum
Analysis vis
m
vis
n
sions or variations thereof. 
erval
eo
erval
Day)
er
Day)
of
y -
t
-42 to Day
the
42 to Day
he
e Study
s t
Study to
t
to E
St
St
th
T+M
io
T+M in Cor
on
in Cor
T+
o
T+
on
Day
ria
Day -
a
-28 to
at
28 to
at
ar
va
r v
E)
E)
r
(OLE)
s o
(OLE)
o
9
n
9 (OLE)
ns
(OLE)
s
10
io
10-
o
-12
ion
12 (OL
n
(OL
n
nth
s
nth 13
sio
13-
sio
-15
io
15 (O
(O
io
ens
Month
ns
Month 16
s
16-
s
-1
tion and any extens
Month
ten
Month 19
19
en
Month
xte
Month
te
x
Mo
x
Mo
ex
ex
ex
e
13
n
13
y
14
an
14
any
99
a
99
a
n
n a
applicati
date.
on
date. Per
n
Per
nance in Cor
atio
nance in Cor
008
ca
008-
a
-1504 C
cati
1504 C
he
li
he transition
lica
transition
8
p
8-
p
-1503. De
plic
1503. De
itit numbers
pp
numbers


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 28 of 76
v3.0:
04Aug2020
Table 7b. Time Intervals for Questionnaires*
Analysis 
Phase/Period
Scheduled Visit 
Number in ZX008-
1503
Analysis 
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
N/A
-99
Baseline (Core)
<1
Core Study Day -
42 to Day-1 of 
Core Study
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
OLE Last Visit**
99
Last Value
Day 2 to Visit 17
date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
Table 7c. Time Intervals for Analysis Visits for Laboratory Data and Vital Signs*
Analysis 
Phase/Period
Scheduled Visit 
Number in ZX008-
1503
Analysis 
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
2
2
Week 2 (OLE)
2 to 20
15
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
PUBLIC COPY
Mon
Y
Mon
Month
PY 
Month
Y
Mon
OPY
Mon
PY
O
M
OP
M
OP
CO
CO
CO
CO
CO
14
C
14
C C
15
LIC
15
IC
16
L
16
LI
B
PU
PU
PU
PU
me
P
me win
P
win
ot be used to support any marketing authorization 
et
z
et Time
zat
Time
int
ri
int (Day)
riza
(Day)
ati
Core
ho
Core Stud
o
Stud
42 to D
th
42 to D
C
hor
au
au
au
au
au
o
n
o 44
ng
44
g a
5 to
tin
5 to 74
ting
74
ng
75 to
keti
75 to 134
ti
134
ti
135 to
rke
135 to
ke
225
r
225
ark
ma
)
ma
ma
ma
ma
LE)
y
LE)
m
(OLE)
ny
(OLE)
y
21
a
21 (OLE)
an
(OLE)
any
nth
rt
nth 24
rt a
24 (OL
a
(OL
t a
Month
por
Month 27
r
27 (
ort
Month
ppo
Month
po
Mon
pp
Mon
pp
u
M
up
su
9
t
9
s
d t
s
ow,
ed
ow, please
ed t
please
a new phas
sed
a new phas
ar
u
are assigned
use
e assigned
ow
ow will
us
will be
us
be
s
or
t b
or Analy
t be
Analy
annot 
duled Visi
not
duled Visi
mber
nn
mber in
no
in ZX
o
ZX
1503
n
1503
ment can ot
an
c
nt
nt
nt
nt
nt
LE
m
LE
en
This docum
OLE
um
OLE
m
OLE
cu
OLE
um
OL
c
OL
oc
do
do
d
n
and any extensions or variations thereof. 
Core S
f
Core S
1
f
1
f
30
o
30
of
re
he
he
he
he
he
224
t
224
th
to
n
to 314
ns
314
s t
315 to
on
315 to 409
n
409
ns
410 to
tio
410 to 4
io
500 
at
500 
at
r
5
ria
ar
LE)
v
LE)
a
(OLE)
or v
(OLE)
v
30
30 (OLE)
s or
(OLE)
or
nth
n
nth 33
ns
33 (OLE
s 
(OLE
s o
Month
on
Month 36
ns
36 (O
s
(O
ns
Last
sio
Last V
io
ns
se
te
se the
ten
the close
n
close
e/period are
xte
e/period are
d as Baselin
ext
d as Baselin
used.
y e
used. [This
y e
[This
ysis
a
ysis Visits
any
Visits
t
n
t
X008
an
X008-
an
-
3
lication and a
A
d a
d
1
n a
2
tio
2
on
3
tio
3
tio
4
ca
applic
lic
pl
pp
E
app
pp
pp
app
a


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 29 of 76
v3.0:
04Aug2020
Analysis 
Phase/Period
Scheduled Visit
Number in ZX008-
1503
Analysis
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
OLE last Visit**
99
Last Value
Day 2 to Visit 17
date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
Table 7d. Time Intervals for Analysis Visits for Tanner Staging*
Analysis 
Phase/Period
Scheduled Visit
Number in ZX008-
1503
Analysis
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
2
2
Week 2 (OLE)
2 to 20
15
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
17/OLE Last Visit**
99
Last Value
Day 2 to Visit 17 
date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE). Visits where the Tanner Stage is not scheduled for collection 
are included due to early termination visits occurring between scheduled visits.
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
PUBLIC COPY 
abel
Y
abel o
Y
o
Base
OP
Base
PY
O
CO
C
4
I
4
C C
5
LI
5
LIC
6
BL
6
BL
UB
PU
PU
PU
PU
PU
P
be used to support any marketing authorization 
me
ti
me
Day)
ati
Day)
on
on
on
910
riz
910
iza
1000
or
1000
ori
10
o
10
ho
7
uth
au
a
that
g
that measu
g a
measu
se/period.
ing
se/period. F
g
F
the
ke
the precedi
ket
precedi
tput)
ny
tput)
T
m
ne
t
ne (OLE)
t an
(OLE)
an
eek
ort
eek 2
ort
2 (OLE
rt 
(OLE
t a
Month
por
Month 1
or
1 (O
r
(O
or
Month
pp
Month
po
Mon
p
Mon
pp
s
M
su
s
o s
8
d
8
to
9
ed
9
d
10
e
10
e
us
e u
ment cannot be u
e u
e u
e u
e u
be
14
o
14
t b
15
no
15
o
16
nn
16
nn
an
17/OLE
t ca
17/OLE
ca
nt
n
This docum n
ple
m
ple measure
en
measure
date of a ph
me
date of a ph
urements
um
urements ta
m
ta
e included d
cu
e included d
**The
doc
**The last
c
last
n
y extensions or variations thereof. 
of
rements
eof
rements oc
f
oc
For example
reo
For example
ng
th
ng note.]
the
note.]
Time
tio
Time Interv
io
Interv
(Day
ti
(Day
on
ri
va
E)
r
E)
va
va
va
va
OLE)
or
OLE)
r v
2
s
2 (OLE)
s o
(OLE)
or
nth
n
nth 3 
ns
3 (OLE)
ns 
(OLE)
s
Month
ion
Month 6
on
6 (O
n
(O
n
Month
sio
Month 9
o
9
io
Month
ns
Month
ns
Mo
n
Mo
en
xtxtxtxte
xt
11
y
11
ex
ation and any x
12
ny
12
y e
13
ny
13
ny
1
a
d
nd
an
a
E
i
E Last
ion
Last Visit
on
Visit
n
applicat
at
ments
cat
ments with
at
with
ase/period o
lica
ase/period o
ken on OLE
pli
ken on OLE
due to early 
pp
due to early 
bservation
ap
bservation


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 30 of 76
v3.0:
04Aug2020
Table 7e. Time Intervals for ECGs and ECHO*
Analysis 
Phase/Period
Scheduled Visit 
Number in 
ZX008-1503
Analysis Visit*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
1
1
Baseline (OLE)
<1
1
OLE
3
3
Month 1 (OLE)
2 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
17/Final Visit**
99
Last Value
2 to Visit 17 date
Post-OLE
18
999
Cardiac FU 1
Visit 17 date + 1,
to Visit 18 date
Post-OLE
19
9999
Cardiac FU 2
Visit 18 date +1, to
Visit 19 date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
** The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
6.1.7 Handling of Dropouts and Missing Data
6.1.7.1 Missing Data
There will be no explicit imputation of missing data for effectiveness endpoints.
6.1.7.2 Seizure Diaries
Seizures are recorded in the Daily Seizure Diary, while the End of Day Diary provides Yes/No confirmation 
that that seizures were experienced for a specific date, or that the date was seizure free.
•
If no seizures are entered in the DSD and the EDD confirms seizure freedom, the number of seizures 
for that date is zero.
•
If seizures are entered in the DSD and the EDD states seizures freedom, the seizures recorded for that 
date supersede the EDD stating seizure freedom.
•
If no seizures are entered in the DSD and there is no response in the EDD, that day will be considered 
to have missing diary data.
•
If no seizures are entered in the DSD and there is a Yes response in the EDD, that day will be 
considered to have missing diary data.
C COPY 
Mont
Y
Mont
Month
PY
Month
Y
Mo
OP
Mo
PY
O
CO
CO
CO
CO
CO
LIC C
99
C
99
PUBLIC C
9999
BL
9999
LI
UB
me
P
me window
PU
window
ate of a 
PU
ate of a 
P
port any marketing authorization 
et
z
et Time
zat
Time
int
ri
int (Day)
riza
(Day)
ati
1
hor
tho
ut
ut
ut
ut
aut
34
34
au
au
au
au
o
n
o 224
ng
224
g a
25 to
tin
25 to 314
ing
314
ng
315 to
eti
315 to 409
i
409
tin
410 to
ke
410 to
ket
500 
rk
500 
rk
a
5
ar
ma
E)
E)
ma
ma
ma
ma
OLE)
ny
OLE)
m
0
a
0 (OLE)
any
(OLE)
ny
h
t
h 33
t a
33 (OLE)
a
(OLE)
an
onth
ort
onth 36
rt
36 (O
(O
t a
Last
por
Last V
r
V
or
annot be used to suppo
Card
pp
Card
po
up
to su
please
d to
please use
o
use
ew phase/pe
d t
ew phase/pe
assigned as 
sed
assigned as 
t ca
will
us
will be
use
be use
e
use
and
be
and Mis
e 
Mis
icit
nn
icit imput
nno
imput
e Diaries
can
Diaries
This document
recorded
nt c
recorded
seizures w
en
seizures w
If
um
If no
m
no s
for 
u
for 
•
oc
•
I
n
or variations thereof. 
60
f
60
90
of.
90
f
180
o
180
of
re
er
e
499
th
499
the
to
s
to 589
s t
589
t
90 to
ns
90 to 679
ns
679
ns
680 to
tion
680 to 77
n
77
on
775 to
atio
775 to
tio
865
a
865
iat
r
)
v
)
ar
ar
ari
ar
LE)
r v
LE)
va
alue
o
alue
r v
ation and any extensions or
ac
s
ac FU
s o
FU 1
o
1
or
Cardiac
ons
Cardiac FU
s
FU
ns
sio
he
n
he closest
nsi
closest t
eriod are as
ten
eriod are as
Baseline (O
xte
Baseline (O
d.
e
d. [This
ext
[This is
t
is
ssing
ny
ssing Data
ny 
Data
tation
and
tation of
nd
of m
applica
in
ti
in the
tio
the Da
o
Da
were exper
cati
were exper
eizures
plic
eizures a
c
a
that date 
pp
that date 
ap
seizures
ap
seizures
su
a


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 31 of 76
v3.0:
04Aug2020
Handling of missing date information for AEs:
•
The term missing date refers to a completely missing date or to an incomplete date/partial date where parts 
are not available, e.g. missing month/day/year.
•
Missing start and end date will be imputed conservatively, i.e. missing values will be imputed in such a 
way that the duration of the AE is considered with the longest possible duration and such that, whenever 
the AE may potentially start after first IMP, the AE will be handled as a TEAE.
•
The missing start date and end date of AE will be imputed for the purpose of calculating treatment 
emergent status and assigning events to treatment periods using definitions given in the following table.
Table 8 Data Conventions for Missing Adverse Event Start or Stop Dates
Start or End 
Date Missing
Data Convention
Partial
/Missing 
Start date
Missing day – If Adverse event day is missing but month and year are present then Impute the 
1st of the month unless month is same as month of first dose of study drug then impute first dose 
date.
Missing day and month – If adverse event day and month are both missing but year is present 
then impute 1st January unless year is the same as first dose date then impute first dose date. 
Completely missing – impute first dose date unless the end date suggests it could have started 
prior to this in which case impute the 1st January of the same year as the end date.
When imputing a start date, ensure that the new imputed date is sensible i.e. is prior to the end 
date of the AE.
Partial /Missing 
End date
If the AE is “ongoing”, do not impute an end date.
The following applies to a missing end date where the AE is not “ongoing”:
Missing day – If AE end day is missing but month and year are present then Impute the last day 
of the month unless month is same as month of last dose of study drug then impute last dose 
date.
Missing day and month – If AE has missing day and month but year is present then impute 31st 
December unless year is the same as the last dose date then impute last dose date.
Completely Missing – need to look at whether the AE is still ongoing before imputing a date and 
when it started in relation to study drug. If the ongoing flag is missing then assume that AE is 
still present (i.e. do not impute a date). If the AE has stopped and start date is prior to first dose 
date then impute the 1st dose date, if it started on or after first dose date then impute a date that is 
after the last dose date.
6.1.8 Conversion of Time Interval
In case a time interval was calculated in days and needs to be converted into weeks, months or years the 
following conversion factors need to be used:
1 week
= 7 days
1 month = 30.4 days
PUBLIC COPY 
missin
Y
missin
e
P
e as
PY
as mon
PY
mon
verse
CO
verse eve
O
eve
ess year is
C C
ess year is
mpute
IC
mpute first
C C
first
case impu
LIC
case impu
art
B
art date,
BL
date,
PU
ongoing
PU
ongoing
PU
to support any marketing authorization 
where
zat
where par
at
par
mputed in s
tho
mputed in s
uch that,
uth
uch that,
alculating 
ng a
alculating 
given
tin
given in
ng
in th
g
th
s
k
s
rk
t month an
ny m
t month an
h
a
h of
an
of first
any
first do
y
do
t
o
t day
ort
day and m
rt 
and m
the same a
por
the same a
ose
p
ose date
ppo
date u
o
u
e the 1st Ja
supp
e the 1st Ja
nsure
s
nsure that
su
that
y m
cannot be used to
, do
d
do not
d t
not im
t
im
plies
se
plies to
se
to a
e
a m
d
m
If
e
If AE
e us
AE end
us
end
nth unless m
be 
nth unless m
ing
o
ing day
ot
day an
an
ecember un
nno
ecember un
Complete
ann
Complete
when i
can
when i
still
ca
still
d
This document c
d to
m
c
6.1.8
doc
6.1.8 Co
c
Co
In
s d
In ca
d
ca
fo
s
fo
n
nsions or variations thereof. 
w
 treatment
eof
 treatment
e
e
e followin
ere
followin
s t
nd year are 
iatio
nd year are 
ose
ri
ose of
ria
of stud
a
stud
month are
va
month are b
as first dose
or v
as first dose
nless
s o
nless the
o
the e
anuary of t
ns 
anuary of t
the new
on
the new im
im
tio
application and any extens
mpute
ten
mpute an
n
an en
s
en
missing
exte
missing end
te
end
d day
y e
day is
y e
is mi
e
mi
month is sa
ny 
month is sa
d month
d a
d month –
a
–
unless year 
nd
unless year 
ely
ely Missing
an
Missing
it started in
n a
it started in
l present (i
tion
l present (i
date
at
date then
atio
then im
o
im
after the
cat
after the
a
ns
lilililic
nversion
ap
nversion


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 32 of 76
v3.0:
04Aug2020
1 year
= 365.25 days
6.1.9 Pooling of Investigative Sites
Sites participating in this study are from Australia, Europe and North America. Due to the small numbers of 
subjects at each site, there is no plan to use site as a stratifying factor in the analyses; the primary analysis will 
use data pooled across site. The effectiveness and safety analyses may be presented by region.
6.1.10 Determination of Sample Size
The sample size justification as indicated in the study protocol is as follows: The sample size will be 
determined by the number of subjects in the three core studies (Study ZX008-1501, Study ZX008-1502, or 
Study ZX008-1504) who volunteer for the extension study and meet the necessary criteria for enrollment. 
Approximately 100-120 subjects are expected to participate in each of the core studies. Thus, if all of those 
participants also enrolled in the extension, the total sample size of the extension study would be between 300 
and 360.
It is expected that this sample size will provide adequate exposure information for this orphan drug, to inform 
the label at time of marketing authorization, and would allow detection of at least one, two or three rare events 
with reasonable likelihood. As an example, if a slightly conservative estimate of the number of subjects 
enrolled in Study ZX008-1503 is set at n=270, the table below provides probability calculations for detecting 
at least one, 2, or 3 events, assuming various values for an underlying event rate of 1, 2, 3, 4, 5, or 10%:
Table 9: Probability calculations for specified adverse event occurrence rates
Probability of detecting an adverse event in trial with n=270, with specified 
true event rate of:
Probability of observing
10%
5%
4%
3%
2%
1%
≥1 event
100.0
100.0
99.998
99.97
99.6
93.4
≥2 events
100.0
99.999
99.98
99.7
97.2
75.3
≥3 events
100.0
99.989
99.88
98.8
90.7
50.7
6.2 SUBJECT CHARACTERISTICS
Individual subject data will be listed for all subjects in the SAF population. Unless otherwise specified, all data 
summaries will be overall and by Core study treatment group as described in Section 3.2 of this SAP.
6.2.1 Subject Disposition
Subject disposition will be presented for all subjects overall, and by treatment group in Core study for the 
Enrolled and SAF populations. Disposition information that will be summarized includes number of subjects 
who started treatment in the OLE study, number who withdrew prematurely, and reasons for withdrawal.
6.2.2 Protocol Deviations
Protocol deviations will be reviewed, and those deviations that are regarded as major will be summarized. 
Major protocol deviations affecting effectiveness or safety assessment may include:
PUBLIC COPY 
Y
quate ex
OPY
quate ex
would
CO
would a
O
a
f a slightl
C CO
f a slightl
270, the 
IC C
270, the 
rious va
BLIC
rious va
for
UB
for spec
UB
spec
Proba
PU
Proba
PU
annot be used to support any marketing authorization 
all number
hori
all number
mary
tho
mary anal
ho
anal
egion.
auth
egion.
he sample 
eting
he sample 
8
k
8-
k
-1501, St
ket
1501, St
necessary 
arke
necessary 
th
m
the core s
mar
e core s
e extensio
m
extensio
posure info
t an
posure info
ow
rt
ow detect
rt a
detect
y conserva
por
y conserva
able below
pp
able below
ues for an 
sup
ues for an 
fied
to
fied adver
o s
adver
bility
d t
bility of
d t
of de
t
de
to
0%
u
0%
se
100.0
e u
100.0
us
b
100.0
be
100.0
be
b
1
b
1
t b
ot b
cument ca
CHARAC
can
CHARAC
ubject
nt c
ubject data
c
data
es will be o
ent
es will be o
Subjec
um
Subjec
This do
Subject di
docu
Subject di
Enrolle
do
Enrolle
who
s d
who
n
d any extensions or variations thereof. 
 size will 
here
 size will 
tudy ZX0
the
tudy ZX0
criteria fo
s th
criteria fo
studies. Th
ons
studies. Th
on
ti
on study
tion
study
ormation f
ari
ormation f
tion
v
tion of
va
of at
a
at
ative estim
or v
ative estim
w provide
s o
w provide
underlyin
ns 
underlyin
rse
si
rse event
sio
event
etecting
ens
etecting an
an
ns
5%
ext
5%
xt
100
y e
100
e
y
0
a
0
9
y
9
ny
00.0
d a
00.0
an
pplication and 
d
CTERIST
n a
CTERIST
a
t
a will
tio
will be
on
be l
n
l
overall an
cati
overall an
ctct Disposit
plic
Disposit
ap
sposition
app
sposition
d
a
d SA
a
SA


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 33 of 76
v3.0:
04Aug2020
•
Non-compliance regarding intake of IMP
•
Inappropriate intake of concomitant medication or background AEDs
•
Other non-compliance
Multiple deviations can occur in the same subject and thus a subject can be counted in more than one deviation 
category.
All protocol deviations will be presented in a subject data listing for the SAF population sorted by subject 
within study site.
6.2.3 Background and Demographic Characteristics
Subject demographics and baseline characteristics will be summarized for the SAF and mITT.
6.2.3.1 Subject Demographics/Baseline Characteristics
The following demographic characteristics will be summarized for the data at entry into 1503:
•
Age at Core Study entry [Years] / for de novo subjects, this will be the age at entry into 1503
•
Age Category( <6 years or ≥6 years)
•
Sex
•
Race
•
Ethnicity
•
Height [m]
•
Weight [kg]
•
BMI [kg/m2]
All subject demographics data will be listed for the SAF populations.
6.2.3.2 Other Baseline Characteristics
Epilepsy/seizure history will be descriptively summarized as per data type (continuous or categorical). 
All subject baseline characteristics will be listed for the SAF population.
6.2.4 Treatment Exposure and Compliance
6.2.4.1 Treatment Exposure
Treatment exposure data will be summarized for subjects’ time on treatment in Study ZX008-1503 only and 
analyzed for the SAF population.
Duration of total exposure to fenfluramine hydrochloride (i.e., time on treatment (in days)) will be calculated 
per subject as the number of days with IMP intake during the trial, as follows:
Duration of exposure = Date of last IMP intake – Date of first IMP intake + 1
PUBLIC COPY 
marize
PY 
marize
ovo
OP
ovo subj
OP
subj
This document cannot be used to support any marketing authorization 
han one
tho
han one d
on
g
on sorted
au
sorted
r the
ark
the SAF
rk
SAF
or
n
or the
ny
the data
y 
data
cts,
t
cts, this
t an
this w
n
w
data
ot b
data will
t b
will
eline
nno
eline Ch
no
Ch
history
can
history w
n
w
baseline c
nt c
baseline c
Treatmen
me
Treatmen
2.4.1
cu
2.4.1 Tr
u
Tr
Treatme
do
Treatme
analy
s d
analy
D
s
D
n
application and any extensions or variations thereof.
by
of
by subje
of. 
subj
and
s t
and mITT
s t
mITT
a
i
a at
iat
at entry
ati
entry
will
a
will be
ari
be the
ri
the
l
d
l be
d
be listed
d a
listed
aracteris
and
aracteris
will
n
will be
n a
be des
a
des
characteris
atio
characteris
nt
li
nt Exposu
lica
Exposu
reatment
pp
reatment
expos
a
expos


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 34 of 76
v3.0:
04Aug2020
The number of days exposed to fenfluramine hydrochloride will be summarized overall and by treatment 
group using n, mean, standard error, median, minimum, Q1, Q3 and maximum.
The actual dose of medication consumed will be calculated and summarized overall and by treatment group 
using n, mean, standard error, median, minimum, Q1, Q3 and maximum.
The shift in dosage of ZX008 will be presented at each scheduled visit starting from Visit 3 – OLE Month 1 
and going to Visit 16 – OLE Month 36 or End of Study. At the visit, the number of subjects who attended the 
visit will be provided with the dosage of ZX008 assigned to the subject at the last study drug dispense prior to 
the visit and the dosage of ZX008 assigned at the conclusion of the visit.
The duration of exposure to fenfluramine hydrochloride will be summarized in monthly periods based on the 
mean daily dosage in mg/kg/day and in mg/day. In addition, the duration of time in days based on the assigned 
dosage in mg/kg/day will be summarized. For the actual dosage summary, the periods where a subject has had 
a particular dosage assigned may not be concurrent.
6.2.4.2 Compliance to IMP Intake
Study medication is to be administered twice daily, and compliance is recorded in the eDiary as full (both 
doses), partial (less than full daily dose) or missed (both doses) each day. From this, compliance to IMP intake 
will be calculated by assuming that a missed dose=0% of dose consumed, partial=50% of dose consumed, and 
full=100% of dose consumed. For each subject, a daily compliance score will be thus obtained.
Compliance will be summarized for the SAF and mITT populations.
6.2.5 Prior and Concomitant Medications and/or Therapies (Non-medications)
Data are collected on the following CRFs:
•
Prior AEDs (Prior AED)
•
Concomitant AEDs (Con AED)
•
Prior and concomitant medications (MEDS)
•
Prior Non-medications (Prior Non-Meds)
•
Concomitant non-medications (Con Non-Med)
Rescue medications are recorded in subjects’ diary, however the CRF obtains a code list of a subject’s planned 
rescue medications. This section does not discuss details of rescue medication use.
Medication (collected on the prior/concomitant medication eCRF page) will be coded using the World Health 
Organization Drug Dictionary (WHO-DD).
The following algorithm will be used to define prior/baseline and concomitant medications/therapies:
Medications/therapies can be prior/baseline only, concomitant only, or prior/baseline and concomitant, 
depending on the start and stop dates.
PUBLIC COPY 
aily, and
CO
aily, and
missed
C C
missed (b
C
(b
sed
LIC
sed dose
LIC
dose
h subject
BLI
h subject
or
PU
or the
PUB
the SA
UB
SA
edi
P
edi
not be used to support any marketing authorization 
t 
t
t 
ment
riz
ment grou
riz
grou
t 3 
u
t 3 –
ut
– OLE 
uth
OLE 
bjects who
au
bjects who
tudy
ng
tudy drug
g 
drug
zed in mon
arke
zed in mon
n
m
n of
ma
of time
ar
time
mmary, the
m
mmary, the
complianc
ort 
complianc
oth
pp
oth doses)
ppo
doses)
0%
up
0% of do
upp
of do
a daily co
sup
a daily co
F
t
F and
to
and mIT
o 
mIT
ations
ed
ations an
d 
an
g CRFs:
use
CRFs:
ent cann
ED)
be
ED)
Ds
ot
Ds (Con
ot b
(Con A
b
A
ncomitant
nno
ncomitant
n
c
n-
c
-medica
can
medica
comitant
nt c
comitant
me
medicatio
men
medicatio
docum
e medicat
um
e medicat
Medication
ocu
Medication
This do
Organiz
do
Organiz
The
s 
The
n
nd any extensions or variations thereof. 
o attend
of. 
o attend
g dispense
reo
dispense
nthly perio
s th
nthly perio
in
n
in days
ons 
days b
e periods w
tion
e periods w
ce is recor
r va
ce is recor
) each
or
each day
or 
day
ose consum
ns o
ose consum
ompliance
ons
ompliance
TT
s
TT popula
nsio
popula
nd/or
te
nd/or The
en
The
lication an
AED)
d a
AED)
medicatio
and
medicatio
tions
n a
tions (Pri
a
(Pri
non
tio
non-
tio
-medi
tio
medi
ons
ic
ons are
ica
are rec
a
rec
appl
tions. Thi
plic
tions. Thi
n
a
n (collect
app
(collect
on Dru
ap
on Dru


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 35 of 76
v3.0:
04Aug2020
•
Any medication/therapy whose start and stop dates were before the start of study medication in Study 
ZX008-1503 will be considered as a prior/baseline medication.
•
Any medication initiated after commencement of study drug in Study ZX008-1503 will be regarded as 
being only concomitant.
•
Medications that were initiated before study drug was started in Study ZX008-1503 and ended during 
or after the study will be considered as prior/baseline and concomitant.
The medication will be assumed to be prior/baseline medication if it cannot be definitively shown that the 
medication did not start or continue during the OLE treatment period.
If the start date or stop date of a medication/therapy is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug. The following approach will be taken:
•
If the start date of medication/therapy is complete and occurs on or after the day of the first dose in 
1503, the medication will be assumed concomitant only. If the start date occurs prior to the first dose 
date but the end date is on or after the first dose date or the medication is recorded as ongoing, the 
medication will be considered concomitant.
•
If the start day is missing but the start month and year are complete, a medication/therapy will only be 
excluded as being concomitant (i.e. regarded as prior only) if the start month/year is before the 
month/year of study drug administration and if the stop date (either full date, month and year if 
missing day, or year if missing month and day) is before study drug administration.
•
If the start day and month are missing but the start year is complete, a medication/therapy will only be 
excluded as concomitant (i.e., will be regarded as prior/baseline only) if the start year is before the 
year of study drug administration and if the stop date (either full date, month and year if missing day, 
or year if missing month and day) is before study drug administration.
•
If the start date is completely missing and the stop date is prior to first dose or completely missing, the 
medication/therapy will be assumed a prior/baseline medication only.
Prior/baseline and concomitant medications/therapies will be summarized and sorted alphabetically, 
separately, by Anatomical Therapeutic Chemical (ATC) categories (Level 2: pharmacological or therapeutic 
subgroup and Level 3: chemical or therapeutic or pharmacological subgroup) and WHO-DD drug code. For 
each medication/therapy, the number and percentage of subjects will be displayed.
Summary tables will be presented on the SAF population.
All prior/baseline and concomitant medications/therapies will be listed for the safety population.
6.2.6 Prior and Concomitant Antiepileptic Treatment
Treatments (collected on the prior/concomitant antiepileptic treatment eCRF page) will be coded using the 
World Health Organization Drug Dictionary (WHO-DD).
Prior and concomitant antiepileptic treatments will be defined and analyzed for the SAF population similar to 
concomitant medications as described in section 6.2.5.
PUBLIC COPY
tant on
PY 
tant on
dose date
OPY
dose date
nt.
CO
nt.
month
C C
month
e. regard
LIC 
e. regard
nistration
BLIC
nistration
ng mont
UBL
ng mont
h
P
h are
PU
are mi
U
mi
(i.e.
P
(i.e.
ment cannot be used to support any marketing authorization 
Study
tion
Study
be
r
be regarde
oriz
regarde
03
u
03 and
uth
and en
h
en
finitively
ing
finitively
e date
rke
date wil
ke
wil
ollowing a
mark
ollowing a
urs on or a
y m
urs on or a
If
n
If the
ny
the sta
y 
sta
or the med
any
or the med
nd
p
nd year
po
year a
d as prior
pp
d as prior
and if the
sup
and if the
h and day) 
o su
h and day) 
sing
d t
sing but
to
but thth
will be reg
ed 
will be reg
ration and
se
ration and
and day) 
us
and day) 
mpletely
be 
mpletely
py will be 
ot b
py will be 
ncomitant 
nno
ncomitant 
omical
ann
omical Th
n
Th
evel 3: ch
ca
evel 3: ch
tion/therap
nt c
tion/therap
This docum
y
m
y tables
men
tables w
n
w
prior/basel
um
prior/basel
6.2.6
doc
6.2.6 Pr
c
Pr
Trea
s d
Trea
W
s
W
n
application and any extensions or variations thereof. 
nde
nde
shown
reo
shown tha
o
tha
l be
t
be comp
th
comp
approach 
ns 
approach 
after the da
tion
after the da
rt
i
rt date
iati
date oc
t
oc
dication is
aria
dication is
re
o
re comple
or v
comple
r only) if t
s o
r only) if t
e stop date
ons 
e stop date
) is before
ion
) is before
he
n
he start
ns
start y
egarded as
ten
egarded as
d if the sto
exte
d if the sto
is before
y ex
is before
missing
any
missing an
y
an
assumed 
d an
assumed 
t medicati
and
t medicati
Therapeuti
an
Therapeuti
emical or
n a
emical or
py, the nu
tion
py, the nu
ill
c
ill be
cat
be pres
at
pres
line
pl
line and
plic
and c
c
c
or
a
or and
ap
and


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 36 of 76
v3.0:
04Aug2020
All prior and concomitant antiepileptic treatments will be listed for the SAF population.
6.2.7 Medical History
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 and current medications will be carried over from 
the core study. AEs starting during the core study will be counted as medical history if they conclude prior to 
start of 1503. Ongoing AEs will be included as such in 1503.
Medical history will be summarized and sorted alphabetically, by primary System Organ Class and Preferred 
Term coded via the most recent version of Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of subjects will be displayed for each System Organ Class and Preferred Term within 
treatment group.
Medical history will be presented for the SAF population.
6.3 EFFECTIVENESS ANALYSES
All effectiveness and exploratory data will be summarized overall and by treatment group in Core study as 
described in Section 3.2 of this SAP. 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. Point estimates and 95% confidence intervals will be calculated 
for key parameters as warranted. No formal comparison of treatment groups is planned.
Analyses of the key effectiveness endpoints will be performed on the mITT population, except where noted.
6.3.1 Convulsive Seizure Frequency
The key effectiveness endpoint is the change in the convulsive seizure frequency per 28 days between the pre-
ZX008 Baseline and OLE Treatment Period. To aid in assessing the effect of OL treatment after treatment 
with blinded fixed doses, CSF per 28 days will also be presented for each pre-OLE cohort for the last weekly 
measure in double-blind treatment (T+M) for the entire OLE treatment period, and separately for the first, 
second and third months of the OLE. In addition, CSF over the remainder of the OLE treatment period will be 
presented, for 3-month intervals. The next section defines variables associated with these endpoints.
6.3.1.1 Variables (Estimands)
Two key CSF-related variables will be defined:
•
(1) the difference in convulsive seizure frequency per 28 days (CSF) for the open-label Treatment 
Period (Day1 to EOS) compared to the Baseline (Core Study);
•
(2) the difference in CSF for the Month2 to EOS (Day 31 to EOS) time point compared to the Baseline 
(Core).
Additional variables associated with the assessment of CSF are:
•
Baseline (Core), Core Study (T+M), Core Study Final Week [Note: The Core Study Final Week is a 
subset of the Core Study (T+M) period.]
PUBLIC COPY 
mmarized
COP
mmarized
us
C
us data
CO
data
O
and upp
C C
and upp
tages.
LIC
tages. Po
C
Po
formal co
BLI
formal co
endpoin
PUB
endpoin
n
P
n
This document cannot be used to support any marketing authorization 
hospitaliz
hori
hospitaliz
carried
tho
carried o
hey conclu
auth
hey conclu
ti
Organ
ting
Organ C
g
C
Activities
etin
Activities
Class
ket
Class and
et
and
overall an
rt a
overall an
ill
o
ill be
ort
be sum
rt
sum
er quartile
ppo
er quartile
nt
u
nt estimat
upp
estimat
mparison o
sup
mparison o
will
to
will be
o 
be p
y
s
y
s the
u
the chan
us
chan
eatment Pe
be 
eatment Pe
CSF per 28
t be
CSF per 28
d treatmen
not 
d treatmen
ths
nn
ths of
nno
of the
o
the
month inter
ann
month inter
riables
nt c
riables (E
c
(E
y
m
y CSF
men
CSF-
e
-rela
en
rela
•
(1)
um
(1) th
m
th
Per
u
Per
•
o
•
n
on and any extensions or variations thereof. 
ude
f
ude
lass and
reo
lass and P
o
P
s (MedDR
her
s (MedDR
d Preferre
the
Preferre
nd by trea
var
nd by trea
mmarized
r v
mmarized
es, and ran
or
es, and ran
tes
ns
tes and
ns o
and 95
o
95
of treatme
ions
of treatme
performed
nsio
performed
nge
y
nge in
y e
in the
ex
the
eriod. To 
ny 
eriod. To 
8 days wil
any
8 days wil
nt (T+M) f
d a
nt (T+M) f
OLE.
and
OLE. In
d
In
rvals. The
n an
rvals. The
applicatio
Estimand
tion
Estimand
ated
ca
ated variab
cat
variab
e differen
plic
differen
eriod (Day
app
riod (Day
the
a
the d


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 37 of 76
v3.0:
04Aug2020
•
CSF during the following time intervals: Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 
10-12, Month 13-15, Month 15-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month
31-33 and Month 34-36.
The frequency of convulsive seizures during a given interval will be derived from the number and type of 
events recorded in subject diaries. For each subject, the seizure frequency per 28 days will be calculated as the 
number of seizures recorded during the period, divided by the number of days in the period and multiplied by
28. The convulsive seizure frequency will be calculated from all available data collected during the relevant 
interval.
The Baseline (Core) convulsive seizure frequency, or CSFBC, is calculated as in the Core Study using the CSF 
from the 42 days immediately preceding the Randomization visit in the Core Study. For any individual subject, 
the convulsive seizure frequency per 28 days during the baseline period (CSFBC) will be derived as follows:
ʹͺ ൈ          
CSF ൌ             
For each treatment group, the mean is obtained by averaging over the subjects in the treatment group.
The convulsive seizure frequency per 28 days for the Core Study T+M period (CSFCTM) is defined below:
ʹͺ ൈ          ൅ 
CSF ൌ         ൅    
The convulsive seizure frequency per 28 days for the Core Study Final Week of T+M (CSFCSFW) is defined 
below:
ʹͺ ൈ          
CSF	 ൌ             
Additionally for the other intervals (Month 1 through Month 36) defined in Table 7a, the convulsive seizure 
frequency per 28 days for that interval, CSFOLE, i, i=1, 2, 3, … , 14, is defined as follows:
ʹͺ ൈ       𝑡ℎ
CSFǡ  ൌ      𝑡ℎ    
The two key effectiveness measures, CSFE1 and CSFE2, will be calculated as follows:
ʹͺ ൈ       ͳ  
CSFͳ ൌ      ͳ      
ʹͺ ൈ       ͵ͳ  
CSFʹ ൌ      ͵ͳ      
For each analysis group, the mean is obtained by averaging over the subjects in the analysis group.
PUBLIC COPY
BL

Y


PY
 
PY 

by averag
COP
by averag
ys
C
ys for
C C
for th
C
th

BL
 
BLIC
 
LIC


U
 
UB
 
y
P
y per
P
per 2
U
2
This document cannot be used to support any marketing authorization 
ny
s
e
Month
tion
Month
, Month
atio
, Month
r and type 
hor
r and type 
be
t
be calcula
tho
calcula
riod
au
riod and m
aut
and m
ted during
g a
ted during
 in the Co
keti
 in the Co
re
r
re Study.
arke
Study.
d (CSF
mar
d (CSFBC
a
BC)

y
 
y m
 
m


 
any

ing over th
ort a
ing over th
Core
ppo
Core Stu
po
Stu

sup
 
p


o
 
o s

days
ed t
days for
t
for

 
us


be
 
e 
 
erer interval
not 
interval
ys for that 
nno
ys for that 
CSF
t c
CSFǡ
c
ǡ
wo
m
wo key
me
key effe
e
effe
n
ication and any extensions or variations thereof. 
at
on
y
on
multip
f
multip
g the
of
the rele
of.
rele
ore Study 
the
ore Study 
For
s th
For any
th
any i
) will be d
ns 
) will be d
 
atio
 
o


ria
 
at

he subject
va
he subject
udy
udy T+M
or
T+M

ns
 
s


sio
 
o
 ൅
the Core
ens
the Core

y
 
y e
 
y e


an
 
ny

als (Month
d a
als (Month
interval, C
and
interval, C
ʹͺ
n a
ʹͺ ൈ
a
ൈ
ൌ
o
ൌ
io

applic
ectivenes
lica
ectivenes


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 38 of 76
v3.0:
04Aug2020
6.3.1.2 Changes from Baseline
In all seizure analyses, the Baseline (Core) value will be the baseline used. These analyses exclude the subjects 
from Study ZX008-1504 Cohort 1. For any of the variables defined in the previous section, the change from 
baseline for any individual subject will be calculated as
CCSF = Post-baseline value – CSFBC
The percentage change from baseline for any individual subject will be calculated as 
PCCSF = (Post-baseline value – CSFBC) *100 / CSFBC
The key effectiveness measures are CSFE1 and CSFE2. Summary statistics for the changes from baseline and 
the percentage changes from baseline will also be presented. A Wilcoxon signed rank test will be used to 
assess the significance of the change from baseline. Given that baseline refers to the period prior to initiation 
of double-blind treatment in the Core study, it is expected that long-term treatment with ZX008 will lead to a 
reduction in convulsive seizure frequency. If we designate the mean baseline (core) CSF by µBC, and the mean 
for CSFE1 and CSFE2 by µE1 and µE2, respectively, the key effectiveness objective is to test the null hypothesis
Ͳǣ 𝜇ͳ −𝜇 ൌͲ,
Against the alternative
ǣ 𝜇ͳ −𝜇 ≠Ͳ,
Rejection of the null hypothesis in favor of the alternative, in the presence of a statistically significantly 
smaller mean convulsive seizure frequency during OLE Treatment (two-sided p-value < 0.05) will be regarded 
as evidence of a treatment benefit.
In a similar manner, each of the changes over time will be summarized and assessed for statistical significance. 
The summary statistics and statistical testing will also be presented by age group.
A graph of the CSF for baseline (Core), Core Study (T+M), and during OLE Month 1 …36 will be generated, 
and another graph of the percentage changes from baseline may be plotted.
6.3.1.3 Treatment Group Estimates – Endpoint Analyses
The analysis of covariance (ANCOVA) analyses described in this section exclude de novo subjects. The 
convulsive seizure frequency per 28 days during the entire OLE Treatment period and the convulsive seizure 
frequency per 28 days during Month 2 to EOS, CSFE1 and CSFE2, respectively, will each be analyzed using an 
ANCOVA model with age group (<6 years, ≥6 years) and treatment group (4 levels) as factors, and CSFBC and 
CSFCTM as continuous covariates. The goal of this analysis is to estimate the seizure frequency during (1) the 
entire OLE treatment, and (2) during Month 2 to EOS, for each of the treatment groups included in the OLE, 
after adjusting for the other factors in the model. To avoid taking the logarithm of 0, a value of 1 will be added
PUBLIC COPY
m
Y
m
ented. A
PY 
ented. A
Given th
OPY
Given th
expected
COP
expected
we
C
we design
C CO
design
ctively, t
IC C
ctively, t
ent cannot be used to support any marketing authorization 
ude
o
ude the
oriz
the su
z
su
the change
tho
the change
ted
et
ted as
eti
as
atistics for
y m
atistics for
Wilcoxon 
ny 
Wilcoxon 
at baseline
t any
at baseline
that long
rt a
that long
ate
po
ate the
port
the m
r
m
e key
ppo
e key effe
po
effe
is in favor
be u
is in favor
izure
t be
izure freq
be
freq
nt benefit.
ot 
nt benefit.
each
nn
each of
no
of th
o
th
tatistics an
can
tatistics an
he
n
he CSF
nt 
CSF
This docume
fo
c
fo
her graph 
men
her graph 
1.3
u
1.3 Trea
um
Trea
The analy
docu
The analy
convul
do
convul
freq
s d
freq
A
s
A
n
ation and any extensions or variations thereof. 
or the chan
tio
or the chan
n signed ra
riati
n signed ra
e refers to
aria
e refers to
term trea
va
term trea
ean
or
ean baseli
or v
baseli
ectiveness
s or
ectiveness
r of the al
ny 
r of the al
quency
any
quency du
ny
du
he
a
he change
and
change
nd statistic
on a
nd statistic
applica
or
t
or baselin
tio
baselin
of the per
cat
of the per
atment
plic
atment G
c
G
sis of cov
app
is of cov
seizu
a
seizu


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 39 of 76
v3.0:
04Aug2020
to a covariate and/or response prior to taking logs. From the general linear model, least squares estimates of 
treatment means and the corresponding 95% confidence intervals, will be exponentiated and a value of 1 
subtracted from the result, (to offset the addition of 1 prior to taking logs), in order to provide estimates and 
associated 95% confidence intervals on the original scale for the response variable.
Since the ANCOVA relies on assumptions of normality, the analysis will be repeated using a nonparametric 
method that does not require as stringent assumptions. A nonparametric ANCOVA will be used to analyze the 
data, with ranks of the CSFBC, and ranks of the CSFCTM as covariates and ranks of the response (CSFE1 or 
CSFE2); other terms/factors in the model will be the same as for the parametric ANCOVA.
Due to certain portions of the core studies remaining blinded, the ANCOVA analyses described in this section 
will not be submitted with the Japanese interim analysis.
6.3.1.4 Treatment Group Estimates – CSF Over Time
The general linear mixed effects model with repeated measures (i.e. MMRM) described in this section exclude 
de novo subjects. Analyses will be performed for the convulsive seizure frequency per 28 days, over time. In 
these analyses, the CSFCSFW will not be included in the model. A MMRM will be employed to estimate the 
mean convulsive seizure frequency per 28 days, over time, for each treatment group. The model will include 
CSFBC and CSFCTM as fixed covariates; time (14 levels for Month1, Month2, Month3, Month 4-6, Month 7-9, 
Month 10-12, Month 12-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month
31-33, and Month 34-36) as a fixed effect; age stratum (2 levels) as a fixed effect; treatment group (4 levels) as 
a fixed effect; and subject as a random effect.
CSF will be log transformed prior to analysis, and a value of 1 may be added to avoid taking the logarithm of 
0.
The purpose of this modeling is to obtain least-squares adjusted means over time for the frequency of 
convulsive seizures per 28 days along with 95% confidence intervals.
While we seek to estimate the means over time, the variances and covariances are nuisance parameters and 
need to be estimated to provide associated standard errors for the treatment estimates. For the MMRM, an 
unstructured covariance matrix will be used. [If the model experiences convergence issues, a different 
covariance structure may be explored from the available choices in SAS PROC MIXED, and the covariance 
structure with the smallest AIC will be chosen.]
The model adjusted means and associated confidence limits will be plotted against time.
Furthermore, exploratory analysis will be carried out using a general linear model that includes the mean daily 
dose during OLE period (categorized as low, medium, and high) as explanatory variable, and the same factors 
used in the MMRM described above.
Due to certain portions of the core studies remaining blinded, the MMRM analyses described in this section 
will not be submitted with the Japanese interim analysis.
PUBLIC COPY 
me
Y
me
O
measur
PY
measur
the conv
COP
the conv
ed in the 
CO
ed in the 
ays, ove
C C
ays, ove
ime (14 l
LIC
ime (14 l
18, Mo
BLI
18, Mo
effect;
UB
effect;
andom ef
PU
andom ef
to
P
to
be used to support any marketing authorization 
s
t
s of 
tio
of 
of 1 
at
of 1 
mates
iza
mates and
za
and
g a nonpar
utho
g a nonpar
be
a
be used
aut
used toto
e response
g au
e response
NCOVA.
ng 
NCOVA.
nalyses
ketin
nalyses de
n
de
s (i.e.
an
(i.e. MM
ny
MM
ulsive seiz
rt a
ulsive seiz
model. A M
ort 
model. A M
time, for 
ppo
time, for 
evels for M
upp
evels for M
nth 19
su
nth 19-
su
-21,
up
21,
ge
to
ge stratum
o s
stratum
fect.
d t
fect.
analysis,
sed
analysis, a
ument cannot b
s
b
s to
be
to obtain
e u
obtain
days along
t be
days along
ate the me
not 
ate the me
to provid
nno
to provid
ariance ma
can
ariance ma
cture
t ca
cture ma
ca
ma
th
n
th the sma
nt c
the sma
docu
del
m
del adjust
men
adjust
thermore,
cum
thermore,
dose durin
ocu
dose durin
This do
used in 
do
used in 
Du
s 
Du
n
ny extensions or variations thereof. 
o
f
o ana
f
ana
e (CSF
of
e (CSFE1
f.
E1
escribed
her
escribed inin
MRM) des
aria
MRM) des
zure freque
var
zure freque
MMRM w
r va
MMRM w
each treat
or 
each treat
Month1, M
ns o
Month1, M
Month 2
ons
Month 2
(2
si
(2 levels
sio
levels
nd
xt
nd a
xte
a valu
te
valu
plication and an
n
n
n least
ny e
least-
y
-sq
y
sq
g with 95%
any
g with 95%
eans over 
nd a
eans over 
de associat
and
de associat
atrix will b
n a
atrix will b
y be
on
be explo
on 
explo
allest AIC
atio
allest AIC
app
ted
lic
ted means
ica
means
, explorato
ppli
explorato
ng
a
g OLE
app
OLE
a
pe
p
pe
MMR
ap
MMR


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 40 of 76
v3.0:
04Aug2020
6.3.1.5 Seizure Frequency by Dose
Additional analyses will be performed to examine the convulsive seizure frequency over time, reported as per 
28 days, by the actual dose administered.
Subjects will be grouped into low, medium, and high dose groups depending on their mean daily dose of 
ZX008 during the OLE Treatment period:
•
Low: 0.2 to <0.4 mg/kg
•
Medium: 0.4 to <0.6 mg/kg
•
High: >0.6 mg/kg.
The parametric ANCOVA for the endpoint analysis will be repeated using these three dose groups in place of 
the four treatment groups, excluding de novo subjects.
Similarly, a nonparametric ANCOVA will be performed using these dose groups, excluding de novo subjects.
Due to certain portions of the core studies remaining blinded, the ANCOVA analyses described in this section 
will not be submitted with the Japanese interim analysis.
6.3.1.6 Impact of Concomitant AED Medication Use on Seizure Frequency
Subjects in the study were required to be on stable background therapy for the first 6 months of treatment, after 
which background AEDs could be reduced or withdrawn so long as one background AED remained. The 
percentage of subjects who had changes in dose or type of concomitant AED medications during the first, 
second, third, fourth, fifth, and sixth months will be summarized by treatment group and overall.
6.3.2 Other Effectiveness Analyses – Seizure Related
6.3.2.1 Non-convulsive Seizure Frequency per 28 Days
Similar methods as described above will be used to assess the frequency of non-convulsive seizures per 28 
days.
6.3.2.2 Convulsive and Non-convulsive Seizure Frequency per 28 Days
The frequency of seizures (convulsive and non-convulsive) will be analyzed using methods similar for the 
analysis of convulsive seizure frequency per 28 days as described above.
6.3.2.3 Percentage of Subjects with ≥50% Reduction from Baseline
A response curve will be generated for the mITT population. This graph will plot the percentage of subjects
(y-axis) against percentage reduction in seizure frequency per 28 days in the OLE treatment period (x-axis). In 
the graph, subjects experiencing an increase in seizure frequency will be regarded as having a 0% reduction in 
seizure frequency. Hence, the ordinate for time point 0 may not necessarily be at 100%. For example, if 15% 
of subjects have no reduction in seizure frequency between baseline and OLE Treatment period, the graph will 
start on the y-axis at 85%. The graph will be generated for all subjects (excluding de novo subjects), and for 
each age stratum and each treatment group. A separate graph will be generated for de novo subjects.
PUBLIC COPY 
Y
blinded,
PY
blinded,
alysis.
OPY
alysis.
Medica
IC 
Medica
be
B
be on
BL
on st
LI
st
reduced 
UB
reduced 
changes 
PU
changes 
xth m
P
xth m
nt cannot be used to support any marketing authorization 
rted
iza
rted as
za
as pe
a
pe
daily
tho
daily dose
ho
dose
these
rke
these thre
ke
thre
e
y
e dose
y m
dose gro
m
gro
e
a
e ANCOV
any
ANCOV
on
p
on Use
pp
Use o
ble
s
ble backgr
sup
backgr
or withdra
to s
or withdra
n dose or 
d to
n dose or 
months wil
ed 
months wil
yses
u
yses –
us
– Sei
s
Sei
eizure
be
eizure Fr
e 
Fr
ibed
ot
ibed abov
t b
abov
This documen
sive
ca
sive and
an
and
cy
n
cy of
nt
of seizu
t c
seizu
f convulsi
ent
f convulsi
3 Perce
ume
Perce
response
ocu
response
(y
do
(y-
do
-axis) 
doc
axis) 
the gr
s d
the gr
sei
s 
sei
n
tion and any extensions or variations thereof. 
ee
s
ee dose
s th
dose gr
h
gr
oups,
tio
oups, exclu
on
exclu
VA
ria
VA analy
riat
analy
on
s
on Seizur
s o
Seizur
ground the
ions
ground the
awn so lon
sio
awn so lon
type of co
ens
type of co
ll be summ
ten
ll be summ
izure
ex
izure Rel
ex
Rel
Frequency
any
Frequency
ve
d
ve will
d a
will be
a
be
applica
Non
n a
Non-
a
-con
a
con
ures
tio
ures (conv
ion
(conv
ive seizure
catio
ive seizure
entage
plic
entage of
c
of
curve
app
curve wi
pp
wi
gainst
ap
ainst p
p
p
bj


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 41 of 76
v3.0:
04Aug2020
A point estimate and 95% confidence interval for the percentage of subjects achieving a ≥50% reduction from 
baseline (Core) to OLE Treatment period, and monthly periods of the OLE will be computed. This will be 
repeated for the Month 2 to EOS endpoint. The confidence interval for the proportion will be based on the 
normal approximation to the binomial distribution. The analysis will be computed for the mITT population 
excluding de novo subjects, and, separately, for the de novo subjects.
Similar methods will be used to estimate the proportion of subjects who achieve a 25%, reduction, 75% 
reduction, and 100% reduction in seizures.
6.3.2.4 Duration of the Longest Interval between Seizures
The duration of the longest interval (in days) between convulsive seizures will be analyzed.
For each subject, the longest interval between convulsive seizures will be calculated over the entire OLE 
period. This will be derived as the maximum of the number of days between consecutive convulsive seizures. 
The intervals between consecutive convulsive seizures (gaps) will be calculated as below, after which the 
longest interval between convulsive seizures will be derived.
If a subject has two consecutive days of missing diary data, the current seizure-free interval will be ended on 
the first date of missing diary data, and a new one begun on the next date that diary data are available and no 
seizure occurs. [In that case, for purpose of calculation of this variable, all intervening days, after the 2nd day, 
with missing diary data, will be assumed to have a convulsive seizure occurrence, until the first available date 
with non-missing diary data.]
Let Date0 (=Day1) be the first day of treatment. If convulsive seizures occur on five days having dates as 
Date1, Date2, Date3, Date4 and Date5, where Date5 > Date4 > Date3 > Date2 > Date1 ≥Date0, and let LDT = 
Last date of treatment in the OLE treatment period, where LDT ≥ Date5, then the time interval between 
convulsive seizures will be calculated as follows:
I1=Date2 - Date1 
I2=Date3 - Date2 
I3=Date4 – Date3, 
I4=Date5 – Date4.
For completeness, we calculate the time to the first seizure as 
I0=Date1 – Date0,
and the time from the last seizure to end of treatment as 
I5 = LDT – Date5.
Here the duration of the longest interval =Maximum (I0, I1, I2, I3, I4, I5).
If the subject does not experience a seizure during treatment, then the last available diary date will be used to 
compute the duration of the longest interval as follows:
The longest interval=last available diary date – Date0
PUBLIC COPY 
gaps
Y
gaps
erived.
PY
erived.
g diary d
COP
g diary d
w one beg
C CO
w one beg
f calcula
IC C
f calcula
d
L
d to
LI
to have
LIC
have
ay of trea
PU
ay of trea
Date5
P
Date5
ent cannot be used to support any marketing authorization 
n
t
n from
tion
from
will be
ati
will be
ed on the
riza
ed on the
T populati
oriz
T populati
reduction
aut
reduction
ll
k
ll be
ket
be analy
et
analy
be calculat
ark
be calculat
etween
ma
etween co
a
co
be calcula
y m
be calcula
ta, the 
ort a
ta, the cur
a
cur
un on the 
por
un on the 
ion
p
ion of this
ppo
of this
a convuls
upp
convuls
tment. If c
d to
tment. If c
where
ed t
where Da
Da
atment 
sed
atment pe
d
pe
ated as fo
us
ated as fo
2
Date3,
nno
Date3,
5 –
c
– Date4
can
Date4
eteness,
nt c
eteness, w
This docume
I0=Date
men
I0=Date
d
c
d the
cu
the time
um
time
Her
s d
Her
n
application and any extensions or variations thereof. 
n,
f
n, 75
f
75
yzed.
the
yzed.
ted over th
ns t
ted over th
nsecutive
ons
nsecutive
ated as be
atio
ated as be
rrent seizu
va
rrent seizu
next date
or v
next date
s variable
s o
s variable
ive
n
ive seizur
ns 
seizur
convulsive
nsi
convulsive
ate5
te
ate5 >
en
> Dat
n
Dat
eriod, wh
exte
eriod, wh
llows:
ex
llows:
.
we
t
we calcula
tio
calcula
a
1
i
1 –
ic
– Date
ca
Date
e from
ppl
from th
p
th
= LDT
ap
= LDT


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 42 of 76
v3.0:
04Aug2020
The median time of the longest convulsive seizure-free interval will be presented. Additional summary 
statistics will be presented, including mean, minimum, maximum, and the 25th and 75th percentiles, 95% 
confidence intervals for the percentiles using the normal approximation to the binomial distribution. Analyses 
will be presented for the mITT population (excluding de novo subjects), de novo mITT subjects, and all mITT 
subjects.
A boxplot of the duration of the longest interval (in days) between seizures will be presented. The boxplot will 
be presented for the mITT population (excluding de novo subjects), de novo mITT subjects, and all mITT 
subjects.
A summary of the recurrences of seizures and the gap times between seizures will also be presented. [The 
duration of the longest interval between convulsive seizures is closely related to the maximum gap time.]
6.3.2.5 The Number of Convulsive Seizure-free Days
Convulsive seizure-free days will be assessed based on the parent/caregiver diary data.
A convulsive seizure-free day will be defined as a day for which no convulsive seizures have been reported. 
Refer to Section 6.1.7, Missing Data. For each subject, the total number of convulsive seizure free days per 28-
day period will be summed for the entire OLE Treatment period, the Month 3 to EOS period, and similarly for 
the baseline (Core) period.
Seizure free days per 28 days at baseline = (number of seizure free days during baseline in Core study)*28/ 
(number of days during baseline with non-missing diary data)
Seizure free days per 28 days during OLE Treatment Period = (number of seizure free days during OLE 
Treatment Period)*28/ (number of days during OLE Treatment Period with non-missing diary data)
A summary of this effectiveness endpoint will be provided over time (baseline (Core), Core Study (T+M), and 
OLE Month.
A MMRM will be employed with factors for subject (random effect), age group (2 levels), time, age 
group*time interaction as factors, and baseline (Core) and Core Study (T+M) as covariates. Least squares 
estimates for each age group, over time, will be obtained, along with associated 95% CIs.
Additional analysis will be done using the mean daily dose over time by grouping subjects into low, medium, 
and high dose groups. An MMRM will be employed, and least squares estimates of means for each age group 
will be obtained, along with associated 95% CIs. The MMRM will exclude de novo subjects.
6.3.2.6 Healthcare Utilization
6.3.2.6.1 Inpatient Hospitalizations Due to Seizures (All subjects)
Hospitalization data will be captured in the CRF.
Details of the hospitalizations, including reasons for hospitalization and use of resources will be summarized.
Summary statistics will include the number and percentage of subjects who experience at least one 
hospitalization to treat a seizure, as well as the incidence density.
6.3.2.6.2 Healthcare Utilization Questions (subjects from core study ZX008-1504 only)
PUBLIC COPY 
e
Y
e p
Y
p
ay for wh
OPY
ay for wh
bject,
COP
bject, the
OP
the
Treatme
CO
Treatme
=
L
= (num
LIC
(num
h non
UBL
h non-
BL
-mi
BL
mi
ring
PU
ring OLE
PU
OLE
of day
P
of day
be used to support any marketing authorization 
95% 
ati
95% 
on. Analys
riza
on. Analys
s,s, and
ori
and all
riz
all
z
ented.
aut
ented. The
ut
The
ubjects, an
g au
ubjects, an
will
et
will also
etin
also b
n
b
ed to
rke
ed to the m
ke
the m
caregiver
y m
caregiver
ch no con
any
ch no con
otal
t
otal numb
t a
numb
nt period, t
ort 
nt period, t
ber
su
ber of
up
of seizu
upp
seizu
sing diary
o su
sing diary
Treatmen
d to
Treatmen
s during O
ed t
s during O
ndpoint
use
ndpoint wi
e
wi
This document cannot b
d with fac
t be
d with fac
factors,
ot b
factors,
b
 group, ov
no
 group, ov
is
c
is will be
an
will be
groups.
t ca
groups. A
a
A
ined, alon
nt c
ined, alon
Healthc
men
Healthc
2.6.1
cum
2.6.1 In
m
In
Hospitali
doc
Hospitali
Deta
s d
Deta
n
ny extensions or variations thereof.
e
f
e box
f
box
nd all mIT
of. 
nd all mI
be
h
be present
her
present
maximum
th
maximum
diary
atio
diary data
o
data
nvulsive se
aria
nvulsive se
ber
v
ber of
var
of con
ar
con
the Month
r va
the Month
ure
n
ure free
ns 
free d
y data)
ion
y data)
ntnt Period
nsi
Period
OLE Treat
ten
OLE Treat
ll
e
ll
application and an
be
ext
be prov
xt
prov
ctors for su
any
ctors for su
and baseli
d a
and baseli
ver time, w
nd 
ver time, w
done
n a
done usin
an
usin
n
o
n MMRM
on 
MMRM
ng with ass
atio
ng with ass
care
ica
care Util
ca
Util
npatient
ppl
npatient H
ation
ap
ation da
p
da


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 43 of 76
v3.0:
04Aug2020
In order to better understand the healthcare resource burden associated with the management of Dravet 
syndrome, caregivers will be asked which of the following hospital and community based healthcare services 
they interacted with over the preceding month: emergency room services, ambulance, planned and unplanned 
hospitalization, family physician services, speech and language therapy, occupational therapy, and physical 
therapy. This information will be captured in the CRF.
Summary statistics will include the number and percentage of subjects who utilized these services.
6.3.2.7 Incidence of Status Epilepticus Episodes
The incidence of status epilepticus during the OLE treatment period will be evaluated based on cases captured 
as such with treatment at hospitals or other treatment centers, those entered as adverse events (including SAEs) 
into the safety database, and also as convulsive seizures lasting longer than 10 min from the seizure diary. A 
single seizure meeting more than one of these criteria will be counted once. According to the ILAE, seizures of 
this duration are to be considered SE.
The number and percentage of subjects with status epilepticus recorded as an AE will be presented by 
treatment group and overall.
In addition, from the diary data, the number and percentage of subjects having convulsive seizures with 
duration >10 min during OLE will be reported by treatment group and overall.
Additionally, the number and percentage of subjects having an SE episode or a seizure with duration > 10 
minutes will be summarized by treatment group and overall.
6.3.2.8 Duration of Prolonged Seizures
Duration of convulsive seizures at baseline and on treatment will be presented by treatment group and overall 
using categories as <2 min, 2-10 min and >10 min.
To obtain a baseline probability distribution for the three categories, we will proceed as follows: For each 
subject, we will calculate the percentage of their total number of baseline seizures that is in each category. (For 
example, if the subject had 5 seizures, with 2 in the first category and 3 in the last category, their percentage 
distribution would be 40%, 0%, and 60% in the <2, 2-10, and >10 categories. We can calculate similar 
numbers for the next subject, and so on.) We will then average these over all subjects to obtain the percentage 
of subjects’ seizures that were <2 min in duration, the percentage between 2-10 min in duration, and the 
percentage >10 min in duration. These 3 percentages should total 100%. Thus, we will obtain a distribution of 
seizure duration for baseline.
Using the seizure duration data obtained for the OLE period, we will proceed similarly, to obtain a distribution 
for the OLE period.
No formal analytic method will be used to assess the distribution of seizure duration during baseline vs. during 
the OLE treatment period. However, it is expected that the distribution may shift in such a way that a greater 
proportion of seizures during the OLE period will have shorter interval duration when compared to the 
baseline period.
PUBLIC COPY
lepticus
PY 
lepticus
d
C
d percen
CO
percen
ed by tre
C C
ed by tre
e
BL
e of
LI
of subj
LIC
subj
ment gro
UBL
ment gro
ed
P
ed Seizu
PU
Seizu
ba
P
ba
sed to support any marketing authorization 
services 
atio
services 
unplanne
riza
unplanne
and physi
oriz
and physi
e
a
e services.
aut
services.
aluated ba
eting
aluated ba
s
k
s adverse
ket
adverse
an 10 min 
arke
an 10 min 
nce.
ma
nce. Acco
ar
Acco
ecorded
ny
ecorded a
y
a
age
o
age of
ort
of subj
rt 
subj
atment gro
ppo
atment gro
ects
su
ects having
supp
having
up and ove
o su
up and ove
res
d t
res
eline
ed
eline and
ed
and
ument cannot be us
in and >1
use
in and >1
ty distribu
be u
ty distribu
e
t
e percent
t be
percent
ad 5 seizu
ot b
ad 5 seizu
40%, 0%
no
40%, 0%
xt subject
ann
xt subject
ures that w
can
ures that w
10 min in 
nt c
10 min in 
ration for 
ent
ration for 
This docu
the
m
the seizur
me
seizur
the OLE 
cum
the OLE 
No
do
No form
oc
form
the OL
s do
the OL
pro
s 
pro
n
y extensions or variations thereof. 
ased on ca
here
ased on ca
events
the
events (in
e
(in
from the 
s th
from the 
ording
ons
ording to
s
to
s
r
s an
ria
an AE
at
AE w
bjects
r v
bjects havi
va
havi
oup and o
or 
oup and o
g an
ns
an SE
ns 
SE ep
ep
erall.
ion
erall.
on
xt
on treatm
xte
treatm
application and any
0 min.
ext
0 min.
ution for th
ny e
ution for th
tage
a
tage of
any
of the
ny
the
ures, with 
d a
ures, with 
, and 60%
nd
, and 60%
t, and so
an
t, and so o
were <2 m
on a
were <2 m
n duration.
tion
n duration.
baseline.
atio
baseline.
re
l
re duratio
lica
duratio
period.
ppl
period.
a
analyti
ap
analyti
tm
a
t


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 44 of 76
v3.0:
04Aug2020
6.3.2.9 Incidence of Rescue Medication Usage
Use of rescue medication is recorded on the daily diary. In the event of prolonged seizures or status 
epilepticus, rescue medication is administered according to each subject’s personalized regimen consisting of 
one or more medications. If the first rescue administration does not control the seizures, a second or even third 
round might be administered. The second and third round might use different medications or different doses 
than the first round of rescue meds.
Rescue medication will be summarized:
•
The number of days rescue medication was taken (normalized to 28 days) will be summarized 
separately for the Baseline (Core), Month 1, Month 2, and Month 3 of the OLE Treatment Period by 
the mean (SD) as well as the median and range.
6.3.3 Other Effectiveness Analyses
For effectiveness rating scales administered at study visits, the overall goal is to analyze the data by visit. 
However, it is recognized that for a long-term study such as this, the time of the study visits might vary from 
pre-planned times established in the protocol. Therefore, in order to provide a common framework for the 
assessment of these measures, the time windows specified in Table 3 will be used. If multiple visits (scheduled 
or unscheduled) fall within a time window, the measurements obtained closest to the target time point will be 
used.
For each time point and parameter or subscale considered in these patient reported outcomes, an individual 
subject’s value is to be obtained for the parameter and time point. The subjects’ values are then the basis for 
obtaining treatment group means, standard deviations, etc. for the summary stats and changes form baseline.
6.3.3.1 Clinical Global Impression – Improvement Rating, as assessed by the Parent/Caregiver
The parent/caregiver will rate their global impression of the subject’s condition at each visit except Visit 2.
The CGI-I scale measures the perception in the change in the subject’s clinical status from a specific point in 
time, i.e., the Baseline Period. The CGI-I 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
At each assessment time point during the OLE treatment period, and at End Point (End of Study or Early 
Termination), frequency counts (and %) of scores by severity rating will be produced overall, and by treatment 
group.
PUBLIC COPY 
its, th
Y
its, th
such as t
OPY
such as t
refore, in
OP
refore, in
s
C
s specifi
CO
specifi
he meas
C C
he meas
subscale
UBL
subscale
r
U
r the
UB
the par
UB
par
,
P
, standa
PU
standa
ent cannot be used to support any marketing authorization 
i
consisting
oriz
consisting
ond
ho
ond or
hor
or ev
or
ev
or differen
utho
or differen
s) will be 
ting
s) will be 
f
k
f the
ket
the OLE
eti
OLE
verall goal
ny m
verall goal
is, the tim
any
is, the tim
order to p
rt a
order to p
ed
o
ed in
ort
in Table
ort 
Table
rements o
ppo
rements o
considere
su
considere
ameter and
to s
ameter and
d
d
d deviatio
d to
deviatio
ion
s
ion –
se
– Imp
ed
Imp
eir
e
eir global
e us
global
he percept
t be
he percept
riod.
ot b
riod. The
t b
The
y of a pa
no
y of a patiti
ry much w
ann
ry much w
y
t
y much
t ca
much imp
a
imp
much impr
nt c
much impr
This docume
=minimal
men
=minimal
4= no ch
me
4= no ch
5=mi
um
5=mi
6=
u
6=
At 
s 
At 
n
plication and any extensions or variations thereof. 
summariz
ere
summariz
Treatmen
he
Treatmen
l is to anal
iatio
l is to anal
me of the s
aria
me of the s
provide a 
var
provide a 
e 3
r
3 will
r va
will be
a
be
obtained c
or 
obtained c
ed in these
ion
ed in these
d time poi
sio
d time poi
ons,
en
ons, etc.
ns
etc. fo
fo
provemen
exte
provemen
impressio
y e
impressio
tion in the
any
tion in the
CGI
d a
CGI-
a
-I
a
I rat
a
rat
ient’s con
nd 
ient’s con
worse) as f
an
worse) as f
mproved
on
mproved
roved 
atio
roved 
app
ally
c
ally improv
cat
improv
change
plica
change
minimally w
ppli
minimally w
=much wo
app
much wo
very
ap
very m
p
m


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 45 of 76
v3.0:
04Aug2020
Descriptive statistics will be presented for the following dichotomized categories for each time point where 
measured, and for the last available or final (EOS/ET) assessment, and will include the number and % of 
subjects responding in the combined categories, along with an associated exact two-sided 95% CI.
(1) Very much improved or much improved, i.e., number of subjects with a score of 1 or 2; vs. others (3, 
4, 5, 6, 7)
(2) Improved, i.e., number of subjects with a score of 1, 2, or 3; vs others (4, 5, 6, 7)
This will be presented for the mITT population as a whole, by treatment group, and for de novo subjects. 
Individual subject data will be listed for CGI-I scale as assessed by the parent/caregiver.
6.3.3.2 Clinical Global Impression – Improvement Rating, as assessed by the Principal
Investigator
CGI-I score data assessed by the principal investigator will be analyzed by the same methods used for CGI-I 
score data recorded by parent/caregiver as above.
6.3.3.3 Quality of Life in Childhood Epilepsy (QOLCE) Scale
The parent/caregiver will complete the QOLCE. This assessment evaluates how epilepsy affects day-to-day 
functioning of a child with epilepsy in various life areas, including physical activities, well-being, cognition, 
social activities, behavior and general health, at baseline period (Core study) during the OLE Treatment 
period, and at EOS/ET (Visit 12). There is also one question on overall quality of life, administered as part of 
the QOLCE.
The QOLCE scores items with a possible 5-point response. [Not including “6”, “Not Applicable.”] To 
calculate subscale scores, the 5-point item scores will first be reverse coded as necessary so that scores of 5 
represent the best possible response and 1 represents the worst possible response. Item scores will then be 
transformed to a 0-100 scale as follows: 1 maps to 0, 2 maps to 25, 3 maps to 50, 4 maps to 75, and 5 maps to
100. After transformation, a score for each subject for each subscale is calculated by averaging that subject’s 
responses to each item in the subscale. [A value of 0 represents the lowest or poorest score and 100 reflects the 
highest level of functioning.] The 16 subscale scores per subject are then averaged to obtain an overall quality 
of life score for each subject. The mean and standard deviation across all subjects are then calculated for each 
subscale, including the overall quality of life score. The higher the subscale and overall quality of life scores, 
the better the response.
Table 10: Subscales of the QOLCE
Domain
Subscale
Item
Section 3: Physical
Physical Restrictions
3.1 a-j
Section 3: Physical
Energy/Fatigue
3.2 a,b
Section 4: Well-being
Depression
4.1 a,d,e,l
Section 4: Well-being
Anxiety
4.1 b,g,j,n,o,p
Section 4: Well-being
Control/helplessness
4.1 c,f,h,i
Section 4: Well-being
Self-esteem
4.1 k,m,q,r,s
PUBLIC COPY 
or
OP
or will
OPY
will b
Y
b
ilepsy
C C
ilepsy (Q
C
(Q
QOLCE. 
LIC
QOLCE. 
n various
BLI
n various
ra
U
ral healt
UB
l healt
).
P
). There
PU
There
ot be used to support any marketing authorization 
ere
tio
ere
% of 
ati
% of 
2;
h
2; vs.
hor
vs. oth
or
oth
,
g
, 7)
g
7)
p,
k
p, and
eti
and for
tin
for d
rent/careg
arke
rent/careg
assessed
ma
assessed
analyzed
any
analyzed
QOLCE)
por
QOLCE) S
This assess
upp
This assess
life areas, 
sup
life areas, 
, at baseli
to s
, at baseli
s
d
s also
d to
also one
to
one
ossible 5
use
ossible 5
point item
e u
point item
esponse an
be 
esponse an
ale
ot
ale as
ot b
as follo
b
follo
This document canno
ion, a scor
not
ion, a scor
m
n
m in
nn
in the s
n
the s
unctioning
can
unctioning
or each sub
t ca
or each sub
ncluding th
ent 
ncluding th
r the respo
men
r the respo
le
u
le 10:
um
10: Sub
m
Sub
Domain
oc
Domain
cu
d
Secti
do
Secti
do
d
S
d
S
d
n
d any extensions or variations thereof. 
de
h
de novo
he
novo s
giver.
s th
giver.
d by
ion
by the
ons
the P
s
P
by
ari
by the
aria
the sa
a
sa
Scale
or v
Scale
sment eva
ns o
sment eva
including
ons
including
ine period
sio
ine period
question
ens
question
point resp
ext
point resp
m scores w
y e
m scores w
nd 1 repre
any
nd 1 repre
ows:
d a
ows: 1 ma
an
1 ma
application and
re for each
nd 
re for each
subscale.
and
subscale.
g.]
n
g.] The
n a
The 1
bject. The
ion
bject. The
he overall
atio
he overall
onse.
icat
onse.
bscales
plic
bscales of
c
of
pp
Physi
a
Physi
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 46 of 76
v3.0:
04Aug2020
Domain
Subscale
Item
Section 5: Cognition
Attention/Concentration
5.1 a,d,e,f,g
Section 5: Cognition
Memory
5.1 j,k,l,m,n,o
Section 5: Cognition
Language
5.1 p,q,r,s,t,u,v,w
Section 5: Cognition
Other Cognitive
5.1 b,c,h
Section 6: Social Activities
Social Interactions
6.1 c,f,h
Section 6: Social Activities
Social Activities
6.1 a, e ; 6.2
Section 6: Social Activities
Stigma Item
6.1 i
Section 7: Behavior
Behavior
7.1 a, c,f,g,h,i,j,k,l,m,o,q,r,s,t
Section 8: General Health
General Health Item
8.1
Section 2 (USA Version) or Section 9 (Australia Version)
Quality of Life Item
2.1 or 9.1
Overall Quality of Life*
Average of 16 subscale scores*
*For each subject, an Overall Quality of Life Score will be computed by adding each subscale score for each individual and then 
dividing by 16.
Individual subject data for the domains will be listed.
For each subscale, descriptive statistics will be provided for the baseline, EOS/ET, and change from baseline 
subscale mean, overall, by treatment group and for de novo subjects.
For each treatment group at Baseline and End of Study/ET, the mean and standard deviation of the subscale 
score will be presented for each QOLCE subscale and for the Overall Quality of Life score.
In addition, the change from baseline in the Overall QOL score will be calculated for each subject by 
subtracting the baseline overall score from the overall score measured at End of Study/ET. The change from 
baseline for each treatment group will be summarized using the mean and standard deviation. Statistical 
significance of the within group change from baseline will be assessed using a Wilcoxon signed rank test.
Individual subject data for the subscales will be listed.
6.3.3.4 Quality of Life of the Parent/Caregiver using EQ-5D-5L Scale
The impact on the quality of life of the parent/caregiver responsible for a patient with DS will be assessed at 
Baseline (Core Study) and during the OLE Treatment period using the EQ-5D-5L.
The EQ-5D-5L health questionnaire is a health-related quality of life instrument with five dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five possible 
levels: no problems, slight problems, moderate problems, severe problems and extreme problems.
The summary of results will follow the EQ-5D-5L guideline results presentation. For the “Health Profiles” 
descriptive system summary results will show the number, and percentage of subjects in each Item score (No 
Problems, Slight Problems, Moderate Problem, Severe Problem, Extreme Problems) overall and by treatment 
group, at baseline (Core), during the OLE treatment period and at EOS/ET. In addition, the item scores will be 
classified into two categories as “No Problems” and “Problems” comprised of items: slight, moderate, severe 
and extreme problems. Summary results will show number of patients and percentage with “No Problems” and 
with “Problems” overall, by treatment group and for de novo subjects, at baseline, during OLE Treatment 
period, and at EOS/ET.
PUBLIC COPY 
rovided
COP
rovided f
P
f
d for de 
C CO
d for de 
End
LIC
End of
C
of S
C 
S
CE
B
CE subsc
BLIC
subsc
ine in the
PUB
ine in the
core
PU
core fro
PU
fro
wil
P
wil
nnot be used to support any marketing authorization 
on
tio
za
riz
ho
th
2
au
a
a,
t
a, c,f,g,h,i,j,
ting
c,f,g,h,i,j,
ng
8.1
ke
8.1
tin
2.1 or
rke
2.1 or 9
e
9
ke
Aver
ar
Aver
rk
ma
subscale
ma
subscale s
a
s
r the
rt
the base
t a
base
novo subje
port
novo subje
udy/ET,
upp
udy/ET, th
p
th
le and for 
sup
le and for 
Overall Q
to s
Overall Q
m
d
m the
d t
the over
to
over
be summ
ed 
be summ
ange from
use
ange from
ubscales
e u
ubscales
of
t
of the
t be
the Pa
be
Pa
lity
n
lity of
not
of life
ot
life
ocument can
dy) and du
ann
dy) and du
L health qu
t ca
L health qu
f
n
f-
n
-f-f
n
f-f care,
nt 
care, usu
c
usu
o problems
en
o problems
summary o
um
summary o
This do
scr
c
scriptive s
cum
iptive s
Problems
doc
Problems
group,
s do
group,
clas
s d
clas
s
n
nd any extensions or variations thereof. 
f
of
,k,l,m,o,q,r,s
ere
,k,l,m,o,q,r,s
eo
er
1
th
rage
ns
rage of
ns
of 16
s 
16 s
s t
ns
core
o
core for
on
for eac
n
eac
eline,
va
eline, EOS
a
EOS
ects.
or
ects.
he
s
he mean a
s o
mean a
r the Over
ons
r the Over
QOL score
sio
QOL score
rall
en
rall score
ens
score
marized usi
xten
marized usi
m baseline 
ext
m baseline 
will
y
will be
y e
be lis
e
lis
arent/Car
d any
arent/Car
e of
nd
of
plication a
the
nd
the pa
pa
uring the O
an
uring the O
uestionnai
on 
uestionnai
ual
ti
ual activit
tio
activit
s, slight p
cati
s, slight p
of results 
plic
of results 
app
system su
pp
system su
Slight P
ap
Slight P
seli
a
seli


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 47 of 76
v3.0:
04Aug2020
In addition, the item scores will be again be classified into two categories as “Slight/No Problems” and 
“Moderate/Severe/Extreme Problems”. Summary results will show number of patients and percentage with 
“Slight/No Problems” and with “Moderate/Severe/Extreme Problems” overall and by treatment group, at 
baseline, during OLE Treatment period, and at EOS/ET.
For the VAS measure of overall self-rated health status, descriptive statistics will be presented for the VAS 
absolute score and change from baseline showing number of subjects, mean, standard deviation, median, and 
range overall and by treatment group at baseline (Core), during OLE treatment period, and at EOS/ET. 
Statistical significance of the within group change from baseline will be assessed using a Wilcoxon signed 
ranks test.
The quality of life of parent/caregiver individual data will be listed using EQ-5D-5L scale.
6.3.3.5 Parent/Caregiver HADS Rating Scale
The HADS is a tool commonly used to determine the levels of anxiety and depression that a person is 
experiencing and is validated as a patient screening tool in the outpatient setting though it has not been 
validated specifically for caregivers. It is a 14-item scale that generates ordinal data for two dimensions: 1) 
Anxiety, and 2) Depression. Seven of the items relate to anxiety and seven relate to depression. Each item has 
four possible answers rated 0-3. All answers to the items for a dimension with their respective rating are added 
resulting in a range for each dimension from 0-21. Scores for the entire scale (emotional distress) range from 0 
to 42, with higher scores indicating more distress.
For the Anxiety and Depression dimensions, summary descriptive statistics including the mean and SD will be 
generated separately for the Anxiety and Depression dimensions at each visit. In addition, for the anxiety and 
depression scales but not the total score, each subject will be categorized at each visit based on the score cut-
offs below:
Score
Interpretation
0-7
Normal
8-10
Borderline abnormal
11-21
Abnormal
Summary statistics will include number and percentage of subjects in each of the categories above at each 
study visit.
In addition, the total score for Anxiety and total score for Depression will be calculated. Descriptive statistics 
including mean, standard deviation, median, minimum and maximum will be provided overall and for each 
treatment group, at baseline, during OLE treatment period and at EOS/ET. The change from baseline for each 
subject will be calculated by subtracting the total Anxiety and Depression score measured at Baseline from the 
analogous score measured at End of Study/ET. The change from baseline will be summarized by descriptive 
statistics as well as 95% CI for the change from baseline. A Wilcoxon signed ranks test will be used to obtain a 
p-value for change from baseline.
The individual item outcomes will be presented in the subject data listing.
PUBLIC COPY
els 
Y
els 
ol in the
PY 
ol in the
scale th
OPY
scale th
relate to 
CO
relate to 
o
C
o the
C C
the item
CO
item
m
IC
m 0
IC
0-
C
-21.
C C
21.
re distres
BLIC
re distres
mensions
UB
mensions
iety and
PU
iety and
l scor
P
l scor
be used to support any marketing authorization 
e with
atio
with
roup, at 
riza
roup, at 
nted for th
utho
nted for th
eviation,
aut
eviation, m
d, and at E
g a
d, and at E
using a W
ng 
using a W
Q
r
Q-
k
-5D
rke
5D-
ke
-5L
e
5L
xiety and d
y m
xiety and d
outpatient 
any
outpatient 
t generate
t an
t generate
anxiety and
ort a
anxiety and
ms
p
ms for
po
for a
or
a dim
r
dim
cores
pp
cores for
ppo
for
s
summary
to s
summary
Depression
d to
Depression
e, each sub
ed 
e, each sub
u
I
u
I
ent cannot be u
be
t b
o
nn
ume
tics
c
tics will
ca
will inin
on, the tot
men
on, the tot
ding mean
ume
ding mean
This docu
atment gr
cum
atment gr
subject w
doc
subject w
analog
do
analog
stat
s d
stat
n
y extensions or variations thereof. 
medi
f
medi
EOS/ET. 
of. 
EOS/ET.
Wilcoxon s
reo
Wilcoxon s
scale.
th
scale.
depression
atio
depression
t setting th
riat
t setting th
es ordinal 
ari
es ordinal 
nd seven re
va
nd seven re
mension
or v
mension
v
the
s
the entire
s o
entire
y descriptiv
sio
descriptiv
n dimensi
nsi
n dimensi
bject will 
ten
bject will 
ny e
Interpret
ny e
Interpret
ation and any e
Norma
any
Norma
ny
a
Bor
a
Bor
a
d a
A
d
and
plica
nclude
on
nclude nu
nu
otal score f
icat
otal score f
n, standard
plic
n, standard
app
roup, at ba
ppl
roup, at ba
ll be calc
app
l be calc
core
a
core


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 48 of 76
v3.0:
04Aug2020
6.3.3.6 Pediatric Quality of Life Inventory (PedsQL 4.0 Generic Core) Scale
The PedsQL 4.0 is a quality of life scale that measures four functional areas (physical, emotional, social, and 
school functioning). The scale is available in age-appropriate instruments with child self-report and parent 
proxy-report formats. In this study, the age appropriate categories for the administration of the instrument were 
ages 2-4, 5-7, 8-12 and 13-18 years, and the Parent Reports were used.
There are eight items for Physical Functioning (PF), and five questions each for Emotional Functioning (EF), 
Social Functioning (SoF), and School Functioning (ScF). Each of the responses to the 23 items is initially 
scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Scores will be linearly transformed to a 
scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores mean better health related 
quality of life. If more than 50% of the items in the scale are missing, the scale scores should not be computed. 
For each subject, a mean score is calculated for each scale (PF, EF, SoF, ScF) as the sum of the scores for 
items in that scale over the number of items answered. If some of the answers on a scale are missing but 50% 
or more of the items in the scale are completed, then impute the mean of the competed items in a scale. The 
scaled results will be combined across age categories to produce a single score for each functional area.
A Psychosocial Health Summary score is computed as the sum of the items over the number of items answered 
in the Emotional, Social, and School Functioning Scales.
A Physical Health Summary score is made up of the Physical Functioning Scale Score.
The Total Score is computed as the sum of all the items over the number of items answered on all the Scales.
Descriptive statistics for all subjects and by treatment group, at baseline, during OLE treatment period and at 
EOS/ET will be provided for the Psychosocial Health Summary score, the Physical Health Summary score and 
Total score.
The change from baseline for the Total score will be calculated for each subject by subtracting the Total score 
measured at Baseline from the Total score measured at End of Study/ET. The change from baseline will be 
summarized with descriptive statistics and the within group changes from baseline will be tested from 
significance from 0 using a Wilcoxon signed ranks test.
6.3.3.7 Pediatric Quality of Life Inventory (PedsQL 2.0 Family Impact Module) Scale
The PedsQL™ Family Impact Module was designed to measure the impact of pediatric chronic health 
conditions on parents and the family. The PedsQL™ Family Impact Module measures parent self-reported 
physical, emotional, social, and cognitive functioning, communication, and worry. The Module also measures 
parent-reported family daily activities and family relationships.
There are six items for Physical Functioning (PF), five items each for Emotional Functioning (EF), Cognitive 
Functioning (CF) and Worry (W), four for Social Functioning (SoF), and three for Communication (c). There 
are additionally three questions for Daily Activities (DA) and five for Family Relationships (FR).
Each of the responses to the 36 items is initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost 
always). Scores will be linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, 
and higher scores mean better health related quality of life. If more than 50% of the items in the scale are 
missing, the scale scores should not be computed. For each subject a mean scale score is calculated for each 
scale (PF, EF, CF, W, SoF, C, DA, FR) as the sum of the scores for items in that scale over the number of
PUBLIC COPY
ute 
Y
ute 
to produ
PY 
to produ
ed
O
ed as
OP
as the
OP
the
ng Scale
CO
ng Scale
up
IC
up of
C C
of th
C C
th
m
B
m of
BL
of all
LI
all
cts and b
PUB
cts and b
Psycho
PU
Psycho
annot be used to support any marketing authorization 
ocial, and
izat
ocial, and
and parent
oriz
and parent
instrume
hor
instrume
ional Func
au
ional Func
the 23 item
ng a
the 23 item
ll
t
ll be linear
ting
be linear
mean bet
ketin
mean bet
ale score
rke
ale score
, ScF) as t
mark
, ScF) as t
answers o
ma
answers o
mean of the
y m
mean of the
e a single 
any
e a single 
um
rt
um of
t a
of the
a
the
s.s.
Physical
ppo
Physical
e items
sup
items ov
p
ov
treatment
to 
treatment
social
d to
social Hea
to
Hea
Total scor
us
Total scor
Total sco
be u
Total sco
e statistic
t be
e statistic
g a Wilcox
ot b
g a Wilcox
Quality
nno
Quality of
o
of
cument ca
Family Im
can
Family Im
n parents a
nt c
n parents a
emotional,
ent
emotional,
reported f
me
reported f
ere
c
ere are
cum
are six
m
six
This doc
Functionin
docu
Functionin
are add
do
are add
Ea
s 
Ea
n
n and any extensions or variations thereof. 
ctioning
of. 
ctionin
ms is initia
eof
ms is initia
arly transfo
ere
arly transfo
tter health
ther
tter health
s should
th
should
the sum o
ns t
the sum o
on a scale
ions
on a scale
e compete
atio
e compete
e score for
riat
e score for
e items
var
items ov
ov
Functioni
s o
Functioni
ver the
ons
ver the nu
s
nu
nt group, a
nsio
nt group, a
alth
en
alth Summ
ens
Summ
rere will
ex
will be
x
be
ore measur
ny e
ore measur
cs and the 
any
cs and the 
xon s
d a
xon signe
a
igne
of
a
of Life
and
Life
application
In
d
In
mpact Mod
on a
mpact Mod
and the fam
tion
and the fam
, social,
atio
social, an
o
an
family dai
lica
family dai
x items
ppl
items for
pl
for
ng
a
g (CF)
app
(CF) a
p
a
nally 
a
nally


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 49 of 76
v3.0:
04Aug2020
items answered. If some of the answers on a scale are missing but 50% or more of the items in the scale are 
completed, then impute the mean of the competed items in a scale.
The Parent HRQL Summary Score (20 items) is computed as the sum of the items divided by the number of 
items answered in the Physical, Emotional, Social, and Cognitive Functioning scales.
The Family Functioning Summary Score (8 items) is computed as the sum of the items divided by the number 
of items answered in the Daily Activities and Family Relationships scales.
The Total Score is the sum of all 36 items divided by the number of items answered.
Descriptive statistics for baseline and EOS/ET will be provided for the summary scores. The change between 
baseline and EOS/ET in the Summary Scores and Total score will be assessed for significance using a 
Wilcoxon signed-rank test.
6.3.3.8 Study Medication Palatability Assessment
The palatability and acceptability of the IMP will be assessed indirectly by the parent/caregiver responsible for 
the patient according to the schedule in Table 1 using three questions:
QUESTION 1: Over the past month, on the basis of the reaction ⁄ facial expression of your child, do you think 
that the medicine’s taste and texture are:
•
Acceptable to your child
•
Not acceptable to your child
QUESTION 2: Over the past month, please rate how much your child likes/dislikes the medicine’s taste using 
the following grading scale:
•
5 (likes it very much)
•
4 (likes it)
•
3 (neither likes it or dislikes)
•
2 (dislikes it)
•
1 (dislikes it very much)
QUESTION 3: Over the past month, do you sometimes have problems giving the medicine to your child due 
to its taste or texture?
•
No
•
Yes
o
How often?
▪
Every day in the past month
▪
Once to several times every week in the past month
▪
Once or several times in the past month
Palatability will be assessed through descriptive statistical methods. For example, the percentage of parents or 
caregivers who consider the medicine’s taste and texture to be acceptable to the child will be presented along 
with a 95% CI at each time point data are available.
PUBLIC COPY 
sessed
PY
sessed
ng three 
OPY
ng three 
is
C
is of
CO
of the
CO
the
nth,
PU
nth, plea
PU
plea
be used to support any marketing authorization 
are 
tio
are 
number
riza
number
a
vided
uth
vided by
th
by t
d.
n
d.
ary
ke
ary scores.
etin
scores.
sed for sig
rke
sed for sig
ndirectly
any
ndirectly b
y
b
questions:
t an
questions:
eaction
ort
eaction ⁄
t 
⁄ f
se
d
se
This document cannot b
rate
d to
rate how
o
how
dislikes)
be
dislikes)
ery
n
ery much)
not
much)
ver
a
ver the
an
the pa
n
pa
xture?
ca
xture?
Yes
me
Yes
o
m
o
Pa
s
Pa
n
and any extensions or variations thereof. 
h
The
he
The chan
er
chan
gnificance
the
gnificance
by
ri
by the
iat
the pare
at
pare
facial
r v
facial exp
va
exp
application an
w much
nsi
much y
)
st
n
st month,
n an
month,
How
plic
How of
c
of
▪
pp
▪
E
▪
p
▪


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 50 of 76
v3.0:
04Aug2020
6.3.4 Exploratory Analysis (in subjects from core study ZX008-1504 only)
The following exploratory effectiveness endpoints will be assessed for subjects from ZX008-1504 from whom 
these data are obtained.
6.3.4.1 Sleep Quality and Mealtime Behavior Questions
The parent/caregiver will be asked to indicate the appropriate response that adequately describes their child’s 
sleep quality and eating behavior since starting IMP based on the following questions:
1.
Since your child has started taking the study medication in this study, have you noticed that s/he has 
been waking in the middle of the night or very early in the morning more than usual?
o
My child’s sleep is more disturbed than it was before s/he started the study medication
o
My child’s sleep patterns are the same as they were before starting the study medication
o
My child sleeps better than s/he did before starting the study medication
2.
Since your child has started taking the study medication in this study, have you noticed that s/he has 
had a change in their mealtime behavior?
o
My child has worse mealtime behavior since starting the study medication
o
My child’s mealtime behavior has not changed since starting the study medication
o
My child has improved his/her mealtime behavior since starting the study medication
The responses will be summarized using counts and percentages.
6.3.4.2 Karolinska Sleepiness Scale
The Karolinska Sleepiness Scale will be administered according to the schedule in Table 1. The Karolinska 
Sleepiness scale is a self-report scale that measures the subject’s drowsiness. It is a 9-point verbally anchored 
scale, which ranges from ‘extremely alert’ at one end of the scale to ‘extremely sleepy – fighting sleep’ at the 
other end of the scale. Within this study, the scale will be completed by the observer. The scale scores 
(responses) are as follows:
Table 11: Karolinska Sleepiness Scale Score Description
PUBLIC COPY 
re
Y
re st
Y
st
y
O
y medicat
OPY
medicat
C
e
C
e behavi
C C
behavi
avior
LIC
avior ha
C
ha
ved
UB
ved his/h
BL
his/h
us
P
us
support any marketing authorization 
rom
za
rom whom
zat
whom
escribes
aut
escribes t
s:
g
s:
ve
ti
ve you
ting
you not
g
not
more than u
ketin
more than u
started
arke
started th
e
th
efore
ma
efore start
ma
start
g
n
g the
y
the stud
y m
stud
on
a
on in
an
in this
any
this
r since
por
since sta
or
sta
not
up
not chang
upp
chang
This document cannot be used to s
mealtime
su
mealtime
ng
e
ng counts
ed
counts
Scale
us
Scale
cale will b
be 
cale will b
eport
t b
eport scale
b
scale
m
n
m ‘extrem
not 
‘extrem
e. Within 
nno
e. Within 
follows:
can
follows:
rolinska
t c
rolinska
n
document
ons or variations thereof. 
heir
f
heir
ticed
ere
ticed that
re
that
usual?
ther
usual?
he
s
he study
s th
study m
h
m
ting
on
ting the
ons
the st
s
st
dy
a
dy medicat
atio
medicat
study,
aria
study, ha
a
ha
arting
or
arting the
r v
the
ged
ns
ged since
s o
since
ation and any extension
e
i
e behavio
ion
behavio
and
te
and perc
ten
perc
be adminis
ny 
be adminis
e that
an
that me
an
me
mely
nd
mely alert’
d a
alert’
this study
and
this study
Sleepines
tion
Sleepines
applicati


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 51 of 76
v3.0:
04Aug2020
Scores of 1-6 may be categorized as “active” and scores of 7-9 may be categorized as “sleepy”. 
Assessments will be made at Visit1 (Baseline), and each visit from Visit 3 through Visit 16.
The categories will be summarized using counts and percentages for each time point.
The scores will be summarized using mean, standard deviation, median, minimum and maximum, for baseline 
and time point.
6.4 SAFETY ANALYSIS
Safety will be assessed through evaluation of AEs, Laboratory data (hematology, chemistry, urinalysis), vital 
signs (blood pressure, heart rate, temperature, and respiratory rate), Physical examination, Neurological 
examination, 12-lead ECGs, Doppler ECHOs, Tanner Staging, BRIEF to measure cognition, and Columbia–
Suicide Severity Rating Scale.
All safety analyses will be performed for the SAF population and will be reported for all subjects overall. 
Select analyses may be repeated by treatment group, for example, treatment-emergent adverse events initiating 
on or before Visit 2 (Week 2), Visit 3 (Month 1), and Visit 4 (Month 2).
6.4.1 Adverse Events
An AE is defined as 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 15 days after the 
last dose of study drug or the last visit, whichever is later. For patients who continue into the open-label 
extension study, AEs from the core studies will be considered medical history unless there is an increase in the 
frequency or severity of the condition from the core study.
A TEAE is defined as any AE that based on start date information occurs after the first intake of study 
treatment. All other AEs occurring after enrollment and prior to the first administration of study treatment are 
defined as non-treatment emergent AEs (non-TEAEs).
AEs are categorized as related or not related to IMP. Per protocol, the following rule was used to assess 
causality of an AE to IMP:
•
Not Related: Concomitant illness, accident or event with no reasonable association with study drug.
•
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.
Any missing relationship/causality assessment will be considered as “related.”
The severity of AEs (whether non-serious or serious) will be assessed by the investigator as follows:
PUBLIC COPY 
populatio
OPY
populatio
oup,
CO
oup, for
COP
for
P
h 1), a
C CO
h 1), and 
CO
nd 
e and un
UBL
e and un
disease t
PUB
disease t
ed rela
PU
ed rela
This document cannot be used to support any marketing authorization 
maximum
au
maximum
atology,
arke
atology, ch
e
ch
ysical exa
mar
ysical exa
EF
y
EF to mea
m
to mea
n and will 
t an
n and will 
xample,
ort a
xample, tr
a
tr
Visit 4 (Mo
por
Visit 4 (Mo
ntended si
o su
ntended si
emporally 
d to 
emporally 
ted to the m
ed t
ted to the m
ds
s
ds from
sed
from th
d
th
visit, whic
use
visit, whic
core
e
core studi
e u
studi
condition 
be
condition 
ny AE tha
not 
ny AE tha
AEs
nn
AEs occur
nno
occur
atment em
ann
atment em
orized
t ca
orized as
c
as
a
f an AE to
ent 
f an AE to
Not
me
Not Rela
me
Rela
•
Relat
um
Relat
de
u
de
n
pplication and any extensions or variations thereof. 
m,
of
m, for
of.
for b
 
b
hemistry,
s th
hemistry,
amination,
ons
amination,
asure
tio
asure cogn
on
cogn
be report
aria
be report
eatment
va
eatment
Month 2).
or v
Month 2).
ign (includ
sion
ign (includ
y associate
nsio
y associate
medicinal
tens
medicinal
e
x
e time
xte
time the
e
the
chev
ex
chever is l
ex
er is l
es
y
es will
y e
will be
e
be
n from the 
any
n from the 
at based on
d a
at based on
rring
and
rring after
nd
after
mergent A
n an
mergent A
related
ion
related or
n
or
o IMP:
atio
o IMP:
ated:
lic
ated: Con
ca
Con
ted:
pp
ted: The
ppli
The e
ap
efinitive p
app
finitive p
dicati
ap
dicati


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 52 of 76
v3.0:
04Aug2020
•
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.
Per the CDISC SDTM Severity Intensity Scale for Adverse Event Terminology, any missing severity will be 
imputed as “severe.”
The original terms used by the investigators in the eCRFs to identify AEs will be coded using the most recent 
version of the MedDRA implemented by the sponsor at the end of the study.
6.4.1.1 Overview of Adverse Events:
The number and percent of patients with at least one of the following events will be summarized in an overall 
summary table:
•
TEAE
•
Serious TEAE
•
Related TEAE
•
Related serious TEAE
•
Severe TEAEs
•
Adverse events of special interest
•
Deaths
The percentage denominator for the calculation of percentage will be the number of subjects in the SAF 
population. The above summary will be provided for the OLE treatment period.
6.4.1.2 Treatment Emergent Adverse Events
The following summaries will display the number and percentage of subjects with an adverse event as well as 
the corresponding number of events by system organ class (SOC) and preferred term (sorted alphabetically):
•
All TEAEs
•
All TEAEs occurring in ≥5% of subjects
•
Serious TEAEs
•
TEAEs by Maximum Severity
•
TEAEs by prior treatment group, with onset before or up to Visit 1, Visit 2; Visit 3; Visit 4
•
Study Drug Related TEAEs
PUBLIC COPY 
e
O
e of
OP
of the
OPY
the f
Y
f
ent cannot be used to support any marketing authorization 
utic
tio
utic
ervention.
riza
ervention.
no
o
no signific
horiz
signific
tly
au
tly affects
uth
affects
any
tin
any miss
ing
miss
will be
ark
will be c
e study.
ma
e study.
ollowing
t an
ollowing e
ial
e
ial interest
e u
interest
nator
not
nator for
ot
for
ve summa
nn
ve summa
ment
ca
ment Em
ca
Em
ing
en
ing summ
nt 
summ
This docume
esponding
men
esponding
•
All
um
All T
m
T
•
oc
•
A
n
ation and any extensions or variations thereof. 
s c
sing
er
sing sever
ere
sever
coded
s t
coded usin
 t
usin
vents
aria
vents wil
ria
wil
t
the
nd
the calcu
nd 
calcu
ary will b
and
ary will b
mergent
on a
mergent A
a
A
aries
atio
aries
applica
will
tio
will
g number o
icat
g number o
EAEs
pli
EAEs
ll
a
l TEAE
ap
TEAE


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 53 of 76
v3.0:
04Aug2020
•
Study Drug Related TEAEs occurring in ≥5% of subjects
•
All AEs that lead to premature discontinuation from the study
No inferential statistical methods (i.e., methods that yield p-values) will be used to compare treatment groups 
on the frequency or severity of AEs.
These summaries will be provided for the OLE treatment period. 
Additionally, the following listings will be produced for all enrolled subjects:
•
All AEs, events considered to be TEAE will be identified in the listing
•
Serious AEs
•
AEs that lead to premature discontinuation from the study
6.4.2 Adverse Events of Special Interest (AESI)
As per ICH guidance (E2F Development Safety Update Report [2011]), the Sponsor has identified the 
following AESIs for the ZX008 program.
Table 12 Adverse Events of Special Interest:
Metabolic/Endocrine
1.
Elevated prolactin level ≥2x above the upper limit of normal (ULN)
2.
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.
Suicidal thoughts, ideation or gestures
LLN = lower limit of normal; ULN = upper limit of normal
The following summary tabulations will be provided to explore the AEs of special interest:
•
AEs with decreased appetite or hypophagia
Adverse events of special interest will be summarized overall, and by treatment group, ZX008 combined and 
overall by system organ class and preferred term for the OLE treatment period.
All adverse events of special interest will be listed separately.
6.4.3 Physical Examination
A complete physical examination will be performed at Visit 1 and EOS/ET visit (Visit 16), and at the Cardiac 
follow-up visits (Visit 17 and 18). An abbreviated physical exam is performed at Day 15 (Visit 2), Visit 3 
through Visit 16 (Days 30, 60, 90, 180, 270, 365, 455, 545, 635, 725, 815, 905 and 995)
All physical examination results will be presented in a subject data listing, including the description of 
abnormalities.
BLIC COPY 
date
OP
date Rep
PY
Rep
OP
st
C
st:
C
:
IC
e
B
e the
BL
the upp
BL
upp
LI
PUB
glucose
UB
glucose m
B
m
referenc
PU
referenc
PUB
P
support any marketing authorization 
atment
oriz
atment gr
i
gr
ort
t
ort [2011]
t an
[2011])
t a
pp
r limit
su
limit of
su
of n
sup
d to s
re
t
re than
to s
than 20%
s
20%
range
d to
range 60
to
60
ment cannot be used 
s
d t
stures
se
stures
ed
s
pper
pper limit
us
limit of
s
of
ulations
be
ulations w
e
w
ased
ot
ased appe
ot 
appe
special
ann
special int
n
int
m organ c
can
m organ c
events
nt
events of
c
of
This docum
Physical
me
Physical
complete
cum
complete
follow
doc
follow-
c
-up
c
up
throug
s do
throug
Al
s
Al
n
ions or variations thereof. 
),
a
), the
ari
the Spo
ria
Spo
s o
ormal
on
ormal (UL
ns
(UL
ns
ensio
%
s
% below
sio
below thth
140
ns
140 mg/d
ns
mg/d
ation and any exten io
en
te
ex
normal
y ex
normal
will
a
will be
any
be pro
ny
pro
etite
nd
etite or
d 
or hyp
a
hyp
terest
an
terest will
an
will
class and p
on a
class and p
applicatio
special
atio
special inin
Examina
lica
Examina
physical
pp
physical
visits (V
ap
visits (V
it 16
a
it 16


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 54 of 76
v3.0:
04Aug2020
6.4.4 Neurological Examination
A complete neurological examination will be performed at baseline (OLE) Visit (Visit 1) and at EOS / ET 
(Visit 16).
All neurological examination results will be presented in a subject data listing, including the description of 
abnormalities.
6.4.5 Vital Signs, Weight, and BMI
Vital signs data including blood pressure, heart rate, temperature, respiratory rate, weight, and BMI will be 
documented for subjects during study Visits 1 through Visit 16 (EOS/ET).
The actual value and change from baseline (OLE) to each on-study evaluation time point will be summarized 
for vital signs and weight overall and by treatment group. Vital signs, weight and BMI data will be presented 
for each patient in a data listing.
A listing of subjects with Potentially Clinical Significant vital sign results will be provided. In this listing, 
those values outside the sponsor defined alert ranges will be marked and further available details about clinical 
relevance and diagnosis will be added.
Descriptive statistics will be provided for weight over time at baseline (OLE), and every 3 months during the 
OLE treatment period, for all subjects in the safety population. For the same time periods, the percent of 
subjects who lost at least 7% or 10% of their body weight during OLE when compared to baseline (OLE) will 
be summarized. Similarly, the percent of subjects who gained 7% or 10% of their body weight during OLE 
when compared to baseline (OLE) will be summarized. For subjects who lost at least 7% of their body weight, 
the number who achieved a recovery to their baseline (OLE) weight, and the duration of time to recovery, will 
be summarized. Recovery will be defined as achieving a weight, after the ≥ 7% reduction, which is at least 
99% of the baseline (OLE) weight at two separate, consecutive assessments. The number of days until weight 
recovery will be determined using the date of the first date where the weight loss was observed and the first 
date where the subject’s weight had recovered to, and maintained for at least two consecutive study visits, at 
least 99% of the baseline (OLE) weight. A similar analysis of 5% weight loss and weight gain will be 
conducted.
In addition, weight will be summarized by age group (2-<4; 4-<6; 6 to<12; and ≥12 years). 
A scatterplot will plot height and age for subjects at the end of the OLE period.
6.4.6 Electrocardiogram
12-Lead ECGs data will be obtained during study at baseline (Core study), baseline (OLE), Visit 1, and Visit 3 
through Visit 16 (End of Study/ET) and at Cardiac Follow-up (Visits 17 and 18).
A separate report will be provided by the ECG vendor.
6.4.7 Doppler Echocardiography
Doppler echocardiography will be conducted at a facility with experience for the subject’s age at baseline 
(Core study), baseline (OLE), Visit 1, and Visit 3 through Visit 11, at End of Study/ET (Visit 16) and at 
Cardiac Follow-up (Visits 17 and 18).
PUBLIC COPY
ant vital
PY 
ant vital
es
O
es will
OP
will b
P
b
weight ov
C C
weight ov
the safe
LIC
the safe
of
B
of their b
BLI
their b
ent of su
UB
ent of su
E)
P
E) will
PU
will b
U
b
ery
P
ery
be used to support any marketing authorization 
S
z
S /
z
/ ET
zat
ET
descriptio
tho
descriptio
e,
t
e, weight,
ting
weight,
ation
ark
ation time
rk
time
we
m
weight an
ma
ight an
sign result
any
sign result
marked
t an
marked a
n
a
r time at b
ppo
r time at b
y populati
upp
y populati
ody
s
ody weigh
sup
weigh
bjects who
to s
bjects who
summari
d to
summari
o their
ed
their bas
d 
bas
efined as a
use
efined as a
ht at two s
us
ht at two s
using the
be u
using the d
u
d
This document cannot b
eight had r
t be
eight had r
e (OLE) w
ot 
e (OLE) w
ht
c
ht will
can
will be
n
be
will plot 
nt c
will plot 
Electrocar
me
Electrocar
Lead
cum
Lead ECG
um
ECG
through V
ocu
through V
A
do
A sep
do
sep
6
s
6
n
ny extensions or variations thereof. 
t,t, and
ere
and BM
re
BM
e point wi
s t
point wi
nd
o
nd BMI
ons
BMI da
s
da
ts will be 
riat
ts will be 
nd
a
nd further
ari
further
baseline (O
or
baseline (O
ion. For th
ns o
ion. For th
ht during
ions
ht during O
s
O
o gained 7
sio
o gained 7
zed.
ns
zed. For
ns
For
seline
ten
seline (OL
en
(OL
achieving
exte
achieving
separate, c
y ex
separate, c
date of the
ny 
date of the
application and a
recovered
any
recovered
weight. A 
d a
weight. A 
summariz
n a
summariz
height an
tion
height an
rdiogram
lica
rdiogram
Gs
p
Gs data
ppl
data w
isit 16 (E
app
sit 16 (E
ep
a


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 55 of 76
v3.0:
04Aug2020
A separate report will be provided by the ECHO vendor.
6.4.8 Tanner Staging
Tanner Staging will be assessed for subjects >7 years old during the study at baseline (Core) period, baseline 
(OLE), and at Visit 3 through Visit 15 and EOS/ET (Visit 16). 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 onset and 
progress of pubertal changes will be recorded on a 5-point scale for boys and girls separately. Boys are rated 
for genital development and pubic hair growth through stage I to stage V. Girls are rated for breast 
development and pubic hair growth through stage I to stage V.
The number and percentage of subjects in each Tanner Stage will be presented for baseline (Core) and EOS by 
treatment group separately for boys and girls.
All Tanner staging data will be presented in the subject data listing.
6.4.9 Laboratory Parameters
Blood samples for clinical laboratory evaluation will be obtained at each study visit as indicated in the 
schedule of assessments given in Table 1. Laboratory safety parameters will be analyzed by a central 
laboratory using standard validated methods.
The following continuous laboratory parameters will be analyzed:
•
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular volume, leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets
•
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine aminotransferase (ALT; 
SGPT), aspartate aminotransferase (AST; SGOT), 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, thyroid stimulating hormone (TSH), 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.
PUBLIC COPY 
ata
Y
ata
will
CO
will be
O
be
aboratory
C C
aboratory
ods.
LIC
ods.
paramete
BL
paramete
n,
P
n, hemato
PUB
hemato
s, mon
PU
s, mon
This document cannot be used to support any marketing authorization 
eriod, bas
hori
eriod, bas
ration can
tho
ration can
table even
auth
table even
alal groups
g au
groups
separately
ng 
separately
are rated f
ting
are rated f
ented
ark
ented for 
rk
for 
btained
ort 
btained a
safety par
po
safety par
rsrs will
su
will be
u
be
crit,
d t
crit, erythr
to 
erythr
ocytes, eo
ed t
ocytes, eo
min (ALB)
use
min (ALB)
ransferas
us
ransferas
ide (Cl), c
be 
ide (Cl), c
lactate de
t be
lactate de
d stimulat
not 
d stimulat
ycerides, u
nno
ycerides, u
growth
can
growth an
n
an
ensitivity)
t c
ensitivity)
stosterone
ent 
stosterone
Epilepsy
me
Epilepsy
•
c
•
Coa
u
Coa
n
pplication and any extensions or variations thereof. 
nts,
f
nts,
s.s. The
of
The on
f. 
on
y. Boys ar
reo
y. Boys ar
for breast 
ere
for breast 
baseline
s t
baseline (
t each
r va
each stu
va
stu
rameters w
or 
rameters w
analyz
ions
analyzed:
ns
ed:
hrocytes,
nsi
hrocytes, e
osinophils,
ten
osinophils,
), alkaline
ext
), alkaline
e
y
e (AST;
y e
(AST; S
creatinine,
ny 
creatinine,
ehydrogen
any
ehydrogen
ating horm
nd a
ating horm
uric acid.
and
uric acid.
nd
n
nd precoc
n a
precoc
y), prolacti
tion
y), prolacti
e, estradiol
atio
e, estradiol
sy
pl
sy genotyp
plic
genotyp
ap
agulation
app
agulation
rombop
ap
rombop


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 56 of 76
v3.0:
04Aug2020
•
Urine pregnancy test: Urine pregnancy testing will be performed in female subjects of childbearing 
potential.
•
Urine THC panel
Observed continuous laboratory data will be descriptively summarized by type of laboratory test/parameter 
overall and by treatment group. Changes from baseline will also be presented for all continuous laboratory 
parameters overall and by treatment group over time.
Categorical laboratory parameters will be summarized by presenting the number and percentage of subjects by 
visit for all subjects and by treatment group.
All laboratory values (including invalid values, reference ranges, and possible flags (low, high,)) will be 
presented in the subject data listings.
A listing of subjects with extreme laboratory results will be provided.
6.4.10 Columbia-Suicide Severity Rating Scale
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates suicidal ideation 
(including intent), and behavior. Baseline (core study) data were collected in the screening visit (Visit 1) of the 
Core study using the C-SSRS Children’s Baseline/Screening Assessment. For the current study, baseline 
(OLE) Treatment period data and Visits 3 through Visit 15 and EOS/ET (Visit 16) data are collected using the 
C-SSRS Children’s ‘Since Last Visit Assessment.
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 reaches 7 years of age during the study, use 
of the C-SSRS should be initiated at subsequent visits.
6.4.10.1 Suicidal Ideation
The following outcomes are C-SSRS categories and have binary responses (yes/no):
PUBLIC COPY 
SSRS) i
COP
SSRS) i
e
C
e study)
C CO
study)
aseline/S
C C
aseline/S
3
L
3 throug
LIC
throug
Assessm
BL
Assessm
years
PU
years ch
UB
ch
e ques
PU
e ques
This document cannot be used to support any marketing authorization 
ring 
tio
ring 
y test/param
tho
test/param
inuous lab
uth
inuous lab
nd
n
nd percen
ing 
percen
ble
rk
ble flags
rke
flags (
d.
y
d.
an assess
rt a
an assess
ata
po
ata were
por
were
creening A
ppo
creening A
Visit 15 
upp
Visit 15 
nt.
s
nt.
onologica
d to 
onologica
ions as sp
ed t
ions as sp
ment to sub
sed
ment to sub
al
b
al capacity
be 
capacity
nitiated at 
t be
nitiated at 
deation
not
deation
comes
an
comes are
n
are
n
document ca
n and any extensions or variations thereof. 
bo
f
ntage
re
ntage of
eo
of su
o
su
(low,
s th
(low, high
th
high
sment tool
va
sment tool
collected
or v
collected
Assessmen
s or
Assessmen
and EOS/
ns 
and EOS/
ally,
ns
ally, or
nsi
or wh
io
wh
pecified on
ten
pecified on
bstitute in
xte
bstitute in
tyty to
ny
to comp
ny 
comp
t subseque
any
t subseque
e C-
a
-SSRS
an
SSRS
application 


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 57 of 76
v3.0:
04Aug2020
Suicidal ideation is assessed as a “yes” answer at any time during the OLE treatment period to any one of the 
five questions (1-5) above. The number and percentage of subjects with suicidal ideation will be presented, as 
well as the number and percentage having a “yes” response to each category (1-5) at least once during the 
OLE period. The denominator will be the number of subjects completing the C-SSRS at least once during the 
OLE treatment period.
6.4.10.2 Suicidal Behavior
The following outcomes are C-SSRS categories and have binary responses (yes/no):
Suicidal behavior is assessed as a “yes” answer at any time during the OLE treatment period to any one of the 
five questions (6-10) above. The number and percentage of subjects who had suicidal behavior, as well as the 
number and percentage having a “yes” response to each category (6-10) at least once during the OLE period. 
The denominator will be the number of subjects completing the C-SSRS at least once during the OLE 
treatment period.
6.4.10.3 Suicidal Ideation or Behavior
An overall composite will be provided similar to the suicidal ideation and behavior composite endpoints but 
will instead count a subject if any of the C-SSRS questions 1 through 10 is marked as “yes” any time during 
the OLE period.
6.4.10.4 Self-injurious Behavior without Suicidal Intent
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide related) and has 
a binary response (yes/no).
The number and percentage of subjects having reported anytime during the OLE treatment period experiencing 
a ‘Self-injurious behavior without suicidal intent’ event (Question 11) will be provided.
6.4.11 Brief Rating Inventory of Executive Function (BRIEF, BRIEF-P, BRIEF-A)
The Behavior Rating Inventory of Executive Function (BRIEF™) , preschool version, BRIEF-P, and adult 
version (used for subjects aged 19-35), are standardized, validated rating scales to measure executive function 
in children within the home and school environments that will be assessed by the parent according to the 
schedule in Table 1.
PUBLIC C
B
answer
BLIC
answer
mber and
UBL
mber and
“yes” res
PUB
“yes” res
mber of
PU
mber of
C COPY 
This document cannot be used to support any marketing authorization 
of the 
tion
of the 
ented,
atio
ented, as 
ti
as 
uring the
riza
uring the
nce durin
oriz
nce durin
t
s
t any
sup
any time
up
time
percentag
o su
percentag
ponse to e
to 
ponse to e
subjects c
ed t
subjects c
Behavio
us
Behavio
e provided
be
provided
ct
o
ct if
ot
if any
t b
any o
jurious
ann
jurious B
n
B
behavior
t ca
behavior
sponse (ye
ent 
sponse (ye
mber
me
mber and
e
and
elf
u
elf-
u
-f-f
u
f-f injurio
cum
injurio
6.4.11
doc
6.4.11 B
The 
s d
The 
v
s
v
n
port any marketing
application and any extensions or variations thereof. 
e during
ons 
during thth
ge
i
ge of subje
ion
of subje
each categ
nsio
each categ
completing
tens
completing
or
y
or
d
a
d similar
any
similar t
y
t
of
d
of the
d a
the C
an
C-S
n
S
Behavior
an
Behavior
without
ion
without
es/no).
atio
es/no).
percenta
lica
percenta
ous behav
ppli
ous behav
rief
ap
ief Rat
ap
Rat
or variations there


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 58 of 76
v3.0:
04Aug2020
The BRIEF measures multiple aspects of executive functioning; scales include Inhibit, Shift, Emotional 
Control, Initiate, Working Memory, Plan/Organize, Organization of Materials and Monitor.
The original BRIEF was the basis for the development of the BRIEF-P. The BRIEF-P Rating Form consists of 
63 items that measure various aspects of executive functioning: Inhibit Shift, Emotional Control, Working 
Memory, and Plan/Organize.
The BRIEF-A Rating Form consists of 75 items that measure various aspects of executive functioning. Nine 
overlapping scales are created.in two different indexes. For the BRIEF-A, the BRI is composed of four scales: 
Inhibit, Shift, Emotional Control, and Self-Monitor. The Metacognition Index is composed of five scales: 
Initiate, Working Memory, Plan/Organize, Task Monitor, and Organization of Materials. The BRI and MI 
combine to yield the GEC Index.
For the BRIEF, BRIEF-P, and BRIEF-A, mean scores at Baseline, End of Study/ET and mean change from 
baseline to End of Study/ET, and descriptive statistics will be presented by treatment group and overall for the 
Safety population (SAF).
6.5 PK/PD ANALYSIS
Not applicable.
6.6 ANALYSIS OF OTHER ASSESSMENTS
Not applicable
6.7 INTERIM ANALYSIS
Accumulating safety data from this study may be provided to and be reviewed by the Sponsor and its 
representatives and/or to an Independent Data and Safety Monitoring Committee (IDSMC) or regulatory 
authority as needed in order to fulfill regulatory requirements.
A planned interim analysis was conducted to support product registration. All subjects who had enrolled in the 
study on or before March 13, 2018 were included in the analysis. The data cutoff for the interim analysis was 
April 27, 2018. All CRF and vendor data obtained on or before April 27, 2018 were included, and electronic 
diary data obtained up to June 18, 2018, for subjects enrolled on or before March 13, 2018, were included.
The specific list of TFLs that were presented in the interim analysis were delineated in the Table of Contents 
for the TFL shells.
Additionally, data on all subjects were included in the Integrated Summary of Effectiveness and the Integrated 
Summary of safety for the ZX008 NDA. Within the ISS and ISE, data presentations for subjects from Study 1 
and Study ZX008-1504 Cohort 2 were designated by their double-blind treatment regimens since those data 
had been unblinded at the time of the NDA submission.
An interim cut and analysis of subjects enrolled from Japan will be completed after all subjects from Japan 
have reached the 3 Month time point in the study. The specific list of TFLs that will be presented in the interim 
analysis are delineated in the Table of Contents for the TFL shells.
A final analysis and report of all data obtained from this study will be provided within 6 months of completion 
of the last subject’s final study visit.
PUBLIC COPY 
MENTS
LIC
MENTS
cument cannot be used to support any marketing authorization 
m
r
m consist
riza
consist
rol, Work
hor
rol, Work
tive functi
au
tive functi
compose
g a
compose
composed
ting
composed
f Materials
ketin
f Materials
d of Study
mar
d of Study
nted
m
nted by
m
by tre
m
tre
tudy may 
sed
tudy may 
endent
use
endent Da
se
Da
fulfill regu
be u
fulfill regu
was
t b
was cond
be
cond
ch 13, 201
not 
ch 13, 201
CRF and v
nno
CRF and v
d up to Jun
ann
d up to Jun
st
t
st of
t c
of TFL
ca
TFL
shells.
nt
shells.
onally,
me
onally, dat
e
dat
mmary
cum
mmary of s
m
of s
This doc
nd Study 
ocu
nd Study 
had been
doc
had been
An 
s d
An 
h
s
h
n
application and any extensions or variations thereof. 
tioning.
of. 
tioning
ed
e
ed of
eof
of four
of
four
d of five s
ereo
d of five s
ls. The BR
her
ls. The BR
y/ET and m
ons 
y/ET and m
eatment
tion
eatment gr
n
gr
y be provid
xte
y be provid
ata
e
ata and
ex
and Sa
x
Sa
gulatory re
ny e
gulatory re
ducted
an
ducted to
ny
to
8 were in
d a
8 were in
vendor dat
and
vendor dat
une 18, 20
n an
une 18, 20
s
i
s that wer
ion
that wer
ta
li
ta on
lic
on all
ca
all s
a
s
safety
ppli
safety
ap
for 
pli
for 
ZX008
app
ZX008-
p
-1
p
1
nblind
ap
nblind


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 59 of 76
v3.0:
04Aug2020
6.8 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 IDSMC 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. 
Tables, listings, and figures will be provided to the IDSMC as per IDSMC charter.
6.9 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 IDMSC 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.
6.10 CHANGES TO METHODS PLANNED IN THE PROTOCOL
There were no changes in this SAP when comparing to the protocol are specified below.
7. REFERENCES
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: 
Dravet syndrome. Adv Neurol 2005; 95: 71-102.
PUBLIC COPY 
r
O
r data
OPY
data th
PY
th
continua
CO
continua
ed to the
IC C
ed to the
RIC
B
RIC CAR
BL
CAR
to the spo
PUB
to the spo
The
PU
The IP
PU
IP
be used to support any marketing authorization 
ress
za
ress of
zat
of the
t
the
guide its
oriza
guide its
sponsor w
hor
sponsor w
rogress,
au
rogress, A
u
A
the charter
g a
the charter
ounding
rke
ounding st
e
st
nificant
y m
nificant saf
m
saf
t
t
t may
t an
may affe
an
affe
ion,
o
ion, suspe
ort
suspe
IDSMC as
ppo
IDSMC as
DIAC
su
DIAC AD
u
AD
nsor that m
d to 
nsor that m
AB
d
AB chart
d t
chart
ndi
s
ndividual s
sed
vidual s
ence in ca
use
ence in ca
IDMSC o
be u
IDMSC o
This document cannot b
t managem
t be
t managem
s performe
not 
s performe
edical Sys
nno
edical Sys
dicative o
an
dicative o
diac adver
t ca
diac adver
the
nt
the IPCA
nt c
IPCA
will perform
en
will perform
CHANG
um
CHANG
There
oc
There we
c
we
7
s
7
n
ny extensions or variations thereof. 
Es
f
Es and
f. 
and
er.
e
er.
tudy
th
tudy cond
th
cond
afety
tio
afety conc
on
conc
ect
a
ect subjec
ari
subjec
ension,
or v
ension, or
v
or
s per IDSM
s o
s per IDSM
DVISORY
ion
DVISORY
monitors 
nsi
monitors 
er
te
er outline
ten
outline
subject ca
xte
subject ca
ardiology,
ex
ardiology,
on the car
ny e
on the car
application and an
ment relat
any
ment relat
med throug
d a
med throug
stems, Inc
and
stems, Inc
of potentia
n an
of potentia
erse event,
on 
erse event,
B
t
B accordi
tio
accordi
m audits o
cati
m audits o
GES
pli
GES TO
plic
TO
e
a
e no
ap
no chan
pp
chan


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 60 of 76
v3.0:
04Aug2020
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.
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.
Sabaz M, Carins D, Lawson J, Nheu N et al. The health-related quality of life of children with refractory 
Epilepsy: A comparison of those with and without intellectual disability 2001; 42(5):621-628.
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.
COPY 
ectua
Y
ectua
epilepsy
OPY
epilepsy
hildhood
CO
hildhood
PUBLIC C
ances M
C C
ances M
ort any marketing authorization 
uma
tho
uma
31:397
g a
31:397-
a
-40
a
40
Life
ke
Life Mea
et
Mea
tyty of
m
of life
ma
life
ability 200
y m
ability 200
Lancet
any
Lancet 20
ny
20
Epilepsy
ort 
Epilepsy (
This document cannot be used to suppo
d. Sci 200
por
d. Sci 200
n
r variations thereof. 
00. 
eo
00. 
asure
th
asure for
he
for C
e
C
of
io
of childre
ion
childre
001; 42(5)
atio
001; 42(5)
011;378:
aria
011;378: 2
a
2
(QOLCE)
r va
(QOLCE)
application and any extensions or
07; 52 sup
or v
07; 52 sup


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 61 of 76
v3.0:
04Aug2020
8. APPENDICES
APPENDIX 1: LIST OF PLANNED TABLES, FIGURES AND LISTINGS FOR FINAL
REPORT
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
14.1
Subject Information
14.1.1
Subject disposition, protocol deviations, and study
populations
Table
14.1.1.1
Subject disposition – all enrolled subjects
Y
Y
Table
14.1.1.1.1
Subject disposition – all enrolled subjects (Japan)
Y
Table
14.1.1.2
Major protocol deviations – Safety Population
Y
Y
Table
14.1.1.2.1
Major protocol deviations – Safety Population (Japan)
Y
Table
14.1.1.3
Study Populations
Y
Table
14.1.1.3.1
Study Populations (Japan)
Y
14.1.2
Demographic and baseline characteristics
Table
14.1.2.1
Demographic and baseline Characteristics – Safety
Population
Y
Y
Table
14.1.2.1.1
Demographic and baseline Characteristics – Safety
Population (Japan)
Y
Table
14.1.2.2
Demographic and baseline Characteristics – mITT
Population
Y
Table
14.1.2.2.1
Demographic and baseline Characteristics – mITT
Population (Japan)
Y
14.1.3
Medical history
Table
14.1.3.1
Medical history – Safety Population
Table
14.1.3.1.1
Medical history – Safety Population (Japan)
Y
14.1.4
Prior/Baseline and concomitant medications and
therapies/treatments
Table
14.1.4.1
Prior/Baseline medications and therapies/treatments – Safety
Population
Table
14.1.4.2
Concomitant medications and therapies/treatments – Safety
Population
Table
14.1.4.3
Prior/Baseline antiepileptic treatment – Safety Population
Y
PUBLIC COPY 
viations,
PY
viations,
Y
nrolled
COP
nrolled sub
OP
sub
OP
all
C
all enrolle
C C
enrolle
CO
eviations
IC
eviations
C
ocol
BL
ocol deviat
BLI
deviat
LIC
Population
UB
Population
B
dy
P
dy Popul
PU
Popul
PU
P
This document cannot be used to support any marketing authorization 
L
iz
L
Included
ke
Included i
Inter
rk
Inter
An
r
An
I
g
I
ng
ng
ng
a
ng
m
d study
any
study
y
cts
cts
t a
subjects
por
subjects (Japa
or
(Japa
or
Safety
up
Safety Popula
pp
Popula
p
s –
s
– Safety
sup
Safety Po
p
Po
up
s
ons
d
ons (Japan)
d t
(Japan)
to
phic
se
phic and
sed
and ba
d
ba
ed
ographic
us
ographic and
s
and
opulation
e u
opulation
se
Demograp
be
Demograp
Populat
t b
Populat
be
ot
De
t
De
ot
ot
ot
ot
1.2.2.1
an
1.2.2.1
nn
14.1.3
nt c
14.1.3
t c
n
14.1
n
14.1
nt
en
me
um
d
Table
do
Table
do
d
n
application and any extensions or variations thereof. 
n
m
alysis?
ns
alysis?
nclude
ere
nclude in
re
in
120
he
120-
e
-day
e
day
safety
th
safety
upd
t
upd
re
s t
e
on
ati
ria
ar
an)
o
an)
r v
tion
s
tion
o
opulation
ons
opulation (Jap
s
(Jap
ns
io
ns
seline
xte
seline chara
xte
chara
te
baseline
ex
baseline Ch
x
Ch
ex
hic
a
hic and
any
and base
ny
base
tion (Japan)
d an
tion (Japan)
ny
mographic
nd 
mographic an
an
Population
and
Population
d a
Demogra
n a
Demogra
Popul
n 
Popul
an
on
M
on
on
on
on
.3.1
ca
.3.1
ati
14.1.3.1.1
lic
14.1.3.1.1
ica
14.1.4
pp
14.1.4
pl
ap
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 62 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.1.4.3.1
Prior/Baseline antiepileptic treatment – Safety Population
(Japan)
Y
Table
14.1.4.4.1
Concomitant antiepileptic treatment – Safety Population
Y
Y
Table
14.1.4.4.1.1
Concomitant antiepileptic treatment – Safety Population
(Japan)
Y
Table
14.1.4.4.2
Frequency Distribution for Number of Concomitant
Antiepileptic Treatments-Safety Population
Y
Table
14.1.4.4.2.1
Frequency Distribution for Number of Concomitant
Antiepileptic Treatments-Safety Population (Japan)
Y
14.1.5
Treatment Exposure and compliance
Table
14.1.5.1
Duration of Treatment Exposure – Safety Population
Y
Y
Table
14.1.5.1.1
Duration of Treatment Exposure by Age Group – Safety
Population
Y
Table
14.1.5.1.2
Duration of Treatment Exposure by Sex – Safety Population
Y
Table
14.1.5.1.3
Duration of Treatment Exposure – Safety Population (Japan)
Y
Table
14.1.5.1.4
Duration of Treatment Exposure by Age Group – Safety
Population (Japan)
Y
Table
14.1.5.1.5
Duration of Treatment Exposure by Sex – Safety Population
(Japan)
Y
Table
14.1.5.1.6
Duration of Treatment Exposure in ZX008-1502 and
ZX008-1503 Combined (Subjects Treated in ZX008-1502
or ZX008-1503) (Japan)
Y
Table
14.1.5.1.7.1
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study
Visit – Safety Population
Table
14.1.5.1.7.2
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study
Visit – Safety Population (Japan)
Y
Table
14.1.5.1.8.1
Number of Subjects Receiving ZX008 According to Mean
Daily Dose and Duration of Treatment – Safety Population
Table
14.1.5.1.8.2
Number of Subjects Receiving ZX008 According to Mean
Daily Dose and Duration of Treatment – Safety Population
(Japan)
Y
Table
14.1.5.1.9.1
Number of Subjects Receiving ZX008 According to Mean
Dose (mg/day) and Duration of Treatment – Safety
Population
Table
14.1.5.1.9.2
Number of Subjects Receiving ZX008 According to Mean
Dose (mg/day) and Duration of Treatment – Safety
Population (Japan)
Y
Table
14.1.5.1.10.1
Number of Subjects Receiving ZX008 According to Actual
Dose (mg/kg) and Duration of Treatment – Safety
Population
PUBLIC COPY
ce
Y
ce
–
P
– Safety
PY
Safety P
Y 
P
Y
osure
OP
osure by
OP
by Ag
P
Ag
OPY
nt
C
nt Exposur
C C
Exposur
CO
atment
LIC
atment Exp
C
Exp
C
f
B
f Treatmen
BL
Treatmen
ion (Japan)
UB
ion (Japan)
LI
ation
PU
ation of
PU
of Tr
U
Tr
pan)
P
pan)
UB
P
ent cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
Y
au
Y
au
g
ng
Y
ket
Y
ti
rk
a
m
ulation
any
ulation
y 
Group
t a
Group –
a
– Safe
a
Safe
an
by
p
by Sex
po
Sex –
po
– Safe
o
Safe
or
sure
up
sure –
p
– Safety
pp
Safety
pp
Exposure
su
Exposure by
u
by A
up
tment
d to
tment Expos
to
Expos
to
of Treatmen
sed
of Treatmen
-
u
-1503
us
1503 Comb
se
Comb
X008
u
X008-
u
-1503)
us
1503)
ed
Shift
be
Shift in
be
in Ass
e 
Ass
Visit 
t be
Visit –
b
– S
e
S
e u
t
Shift
t 
Shift
V
t b
ot
5.1.8.1
ann
5.1.8.1
n
14.1.5.1.8.
t c
14.1.5.1.8.
ca
This document
en
e
Table
doc
Table
c
d
cation and any extensions or variations thereof. 
f
of
o
eo
her
s t
s t
s t
s t
s t
ion
a
Y
at
ria
ety
v
ety
ariririri
ety
o
ety Population
or 
Population
r v
Population
s o
Population (
o
(
o
Age
o
Age Group
ons
Group –
ns
ure
n
ure by
ns
by Sex
ns
Sex –
sio
t Exposure in
xte
t Exposure in
ined
ex
ined (Subjec
ext
(Subjec
(Japan)
y e
(Japan)
te
igned
ny
igned ZX008
ny 
ZX008
afety Populat
any
afety Populat
y
in
d
in Assigned
d a
Assigned
sit 
n
sit –
nd
– Safety P
nd 
Safety P
a
Number
an
Number of
of
Daily
n a
Daily D
nd
n
2
i
2
Nu
n
Nu
n
applica on
4.1.5.1.9.1
lica
4.1.5.1.9.1
ca
p
14
p
14
ap
ap
app
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 63 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.1.5.1.10.2
Number of Subjects Receiving ZX008 According to Actual
Dose (mg/kg) and Duration of Treatment – Safety
Population (Japan)
Y
Table
14.1.5.2.1
Compliance to IMP intake – Safety Population
Y
Y
Table
14.1.5.2.1.1
Compliance to IMP intake – Safety Population (Japan)
Y
Table
14.1.5.2.2
Compliance to IMP intake – mITT Population
Y
Y
Table
14.1.5.2.2.1
Compliance to IMP intake – mITT Population (Japan)
Y
14.2
Effectiveness
14.2.1
Effectiveness – Convulsive Seizure Frequency
Table
14.2.1.1.1
Convulsive seizure frequency per 28 days during OLE
Treatment Period: Summary Statistics and Tests of Changes
from Baseline
Y
Y
Table
14.2.1.1.2
Convulsive seizure frequency per 28 days during OLE
Treatment Period, by Age Group: Summary statistics and
Tests of Changes from Baseline – mITT Population
Y
Table
14.2.1.1.3
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose: Summary
Statistics and Tests of Changes from Baseline –mITT
Population
Y
Table
14.2.1.1.4
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose, , by Age Group:
Summary Statistics and Tests of Changes from Baseline –
mITT Population
Y
Table
14.2.1.1.5
Convulsive seizure frequency per 28 days during OLE
Treatment Period: Summary Statistics – 1504 Cohort 1
Subjects
Y
Table
14.2.1.1.6
Convulsive seizure frequency per 28 days during OLE
Treatment Period: Summary Statistics and Tests of Changes
from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.7
Convulsive seizure frequency per 28 days during OLE
Treatment Period, by Age Group: Summary Statistics and
Tests of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.8
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose: Summary
statistics and Tests of Changes from Baseline –mITT
Population (Japan)
Y
Table
14.2.1.1.9
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose, by Age Group:
Summary statistics and Tests of Changes from Baseline –
mITT Population (Japan)
Y
Table
14.2.1.2
Convulsive seizure frequency per 28 days - Endpoint:
Parametric analysis – mITT Population
PUBLIC COPY 
Freq
Y
Freq
er 28 days 
PY
er 28 days 
Statistics
OP
Statistics a
P
a
Y
equency pe
C CO
equency pe
by
C
by Age
C C
Age Gro
C
Gro
s from Bas
LIC 
s from Bas
CO
seizure
BLI
seizure fre
LI
fre
nt Period U
UBL
nt Period U
tics and Te
PUB
tics and Te
pulation
PU
pulation
LIC
ulsiv
P
ulsiv
P
ocument cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
Y
a
Y
a
ng
ng
ng
ng
ng
Y
ket
Y
eti
ke
a
m
uring OLE
any
uring OLE
Tests
t a
Tests of
an
of Cha
n
Cha
ny
28 days durin
por
28 days durin
p:
p
p: Summary
ppo
Summary
ine
u
ine –
p
– mITT P
pp
mITT P
ort
ency
su
ency per
sup
per 28
up
28 d
p
d
ng Mean Dai
o s
ng Mean Dai
s of Changes 
to 
s of Changes 
up
seizure frequ
ed 
seizure frequ
ntnt Period
sed
Period Usi
ed
Usi
mary Statistic
use
mary Statistic
TT
TT Populatio
e u
Populatio
d
Convulsive
be 
Convulsive
Treatme
t be
Treatme
Subje
t b
Subje
e
ot
6
C
ot
ot
ot
ot
14.2.1.1.7
t ca
14.2.1.1.7
ca
en
en
1
This doc
en
en
en
en
Table
do
Table
oc
d
cation and any extensions or variations thereof. 
of
of
of
of
eof
re
Y
he
Y
he
th
s t
ns
io
a
anges
a
anges
Y
iaiat
ria
ng OLE
or v
ng OLE
tatistics
or
tatistics and
r
and
Population
s o
Population
v
days
on
days during
ons
during O
ly Dose: Sum
ion
ly Dose: Sum
from Baselin
sio
from Baselin
ns
uency per 28 
ten
uency per 28 
ng
x
ng Mean
xte
Mean Dai
e
Dai
s and Tests o
ex
s and Tests o
on
y
on
en
seizure
ny
seizure freq
y
freq
ntnt Period:
any
Period: Su
ny
Su
cts
d
cts
y
Convulsive se
nd
Convulsive se
Treatment
an
Treatment
from Ba
n a
from Ba
d
n
Con
n
Con
T
n
on
applica
4.2.1.1.8
lica
4.2.1.1.8
appl ca
ap
1
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 64 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.2.1.3
Convulsive seizure frequency per 28 days - Endpoint:
Nonparametric analysis – mITT Population
Table
14.2.1.4
Convulsive seizure frequency per 28 days, Over Time -
Parametric analysis – mITT Population
Table
14.2.1.5
Convulsive seizure frequency per 28 days, Over Time,
Using Mean Daily Dose: Parametric Analysis – mITT
Population
Table
14.2.1.6
% of subjects with Changes in AED medications during the
first 6 months of the OLE Treatment Period – mITT
Population
Figure
14.2.1.7
Graph of means for convulsive seizure frequency per 28
days - mITT Population
Figure
14.2.1.8
Graph of model adjusted means for Convulsive seizure
frequency per 28 days – mITT Population
Figure
14.2.1.9
Graph of convulsive frequency per 28 days, Over Time,
Using Mean Daily Dose – mITT Population
14.2.2
Effectiveness – Proportion of responders for convulsive
seizure frequency
Table
14.2.2.1
Percent reduction in convulsive seizure frequency, OLE
Treatment Period– mITT population
Y
Y
Table
14.2.2.1.1
Percent reduction in convulsive seizure frequency, OLE
Treatment Period– mITT population (Japan)
Y
Figure
14.2.2.2
Cumulative response curves for percent reduction in CSF
during OLE Treatment Period – mITT population
Y
Y
Figure
14.2.2.2.1
Cumulative response curves for percent reduction in CSF
during OLE Treatment Period – mITT population
Y
14.2.3
Effectiveness – Duration of Longest interval between
convulsive seizures
Table
14.2.3.1
Duration of Longest interval between convulsive seizures
during OLE Treatment Period – mITT Population
Figure
14.2.3.2
Boxplot of distribution of duration of longest interval
between convulsive seizures during OLE Treatment Period
– mITT Population
14.2.4
Effectiveness – Summary of duration of convulsive
episodes
Table
14.2.4.1
Summary of Duration of Convulsive Seizure Episodes
during OLE Treatment Period - mITT Population
Table
14.2.4.2
Summary of Gaps between Convulsive Seizure Episodes
during OLE Treatment Period
mITT Population
14.2.5
Effectiveness – Number of convulsive seizure free days
Table
14.2.5.1
Convulsive seizure-free days – summary statistics – mITT
Population
PUBLIC COPY 
re
Y
re fre
Y
fre
ns
O
ns for
OP
for Conv
PY
Conv
ITT Popul
COP
ITT Popul
PY
requency
CO
requency p
CO
p
Dose 
C C
Dose –
C C
– mI
C
mI
CO
Proporti
LIC
Proporti
quency
BLI
quency
C
reduction
UB
reduction i
ment Perio
PUB
ment Perio
BL
PU
cent
P
cent red
PU
red
me
P
me
PU
d to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
au
ng
ng
ng
ng
ng
ke
a
per
y
per 28
y
28
m
sive
a
sive seizure
an
seizure
on
rt
on
any
28
28 days,
por
days, Ove
r
Ove
T Population
ppo
T Population
rt
of
u
of responde
upp
responde
pp
onvulsive
o s
onvulsive se
se
mITT popu
to 
mITT popu
su
sed to
ion
d
ion in
d t
in convu
d t
convu
Period
ed
Period–
ed
–
d–
d
ed
d–
d mIT
d
mIT
ument cannot be used to
ative
us
ative respon
use
respon
ing OLE Tre
us
ing OLE Tre
se
Cumulative
be 
Cumulative
during O
t be
during O
e u
t
Effe
t 
Effe
co
co
t b
ot
3.1
a
3.1
nn
14.2.3.2
t c
14.2.3.2
ca
en
This docu
e
Table
ocu
Table
u
d
Ta
d
Ta
d
nsions or variations thereof. 
f
eof
eo
eo
eo
t
eo
th
s t
io
ria
riria
ria
ria
r Time,
or v
Time,
v
ers
n
ers for
s
for convu
s o
convu
o
izure
sio
izure frequen
io
frequen
ulation
nsi
ulation
on
xtens
lsive
en
lsive seizure
en
seizure
TT population
xte
TT population
cation and any ext ns
se
se curves
ex
curves for
x
for
atment Perio
y e
atment Perio
xt
response
ny
response cu
y
cu
LE Treatmen
any
LE Treatmen
y
ctiveness
d a
ctiveness –
a
– D
a
D
nvulsive sei
nd
nvulsive sei
a
Duration
an
Duration
during 
n a
during 
n
n
Bo
n
Bo
n
applica on
14.2.4
lic
14.2.4
ca
p
14.2.4
pp
14.2.4
pp
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 65 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.2.5.2
Convulsive seizure-free days – Parametric Analysis by Age
Group - mITT Population
Table
14.2.5.3
Convulsive seizure-free days – Parametric Analysis by
Mean Daily Dose - mITT Population
Table
14.2.5.4
Convulsive seizure-free days – summary statistics for
subjects from Study 1504 –Cohort 1
14.2.6
Effectiveness –non-convulsive and convulsive seizure
frequency
Table
14.2.6.1
Non-convulsive seizure frequency during OLE Treatment
Period – mITT Population
Table
14.2.6.2
Convulsive + non-convulsive seizure frequency during OLE
Treatment Period – mITT Population
14.2.7
Effectiveness – Incidence of rescue medication
Table
14.2.7.1
Days with Rescue medication usage during OLE Treatment
Period – mITT Population
Y
Table
14.2.7.2
Days with Rescue medication usage during OLE Treatment
Period – mITT Population (Japan)
Y
14.2.8
Effectiveness – Incidence of hospitalization to treat
seizure
Table
14.2.8.1
Hospitalization and Other Healthcare Resource Utilization
to Treat Seizure - mITT Population– mITT Population
Table
14.2.8.2
Hospitalization and Other Healthcare Resource Utilization
to Treat Seizure - mITT Population– mITT Population
(Japan)
Y
14.2.9
Effectiveness – Incidence of status epilepticus
Table
14.2.9.1
Number of episodes of status epilepticus during OLE
Treatment Period - mITT Population
Table
14.2.9.1.1
Number of episodes of status epilepticus during OLE
Treatment Period - mITT Population (Japan)
Y
Table
14.2.9.2
Duration of Seizures – mITT Population
14.2.10
Effectiveness – Clinical Global Impression of
Improvement, – Rating by Parent/Caregiver and
Investigator
Table
14.2.10.1
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population
Y
Table
14.2.10.1.1
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population (Japan)
Y
Figure
14.2.10.2
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population
Y
Figure
14.2.10.2.1
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population (Japan)
Y
C COPY 
re
Y
re frequ
Y
frequ
ation
PY
ation
Y
f
O
f rescue
OP
rescue m
P
m
PY
cation
CO
cation usa
CO
usa
ulation
C C
ulation
CO
BLIC 
ue
LI
ue medicat
LIC
medicat
TT Populati
BLIC
TT Populati
PUBL C
ness
UB
ness –
B
– Inc
BL
Inc
e
U
e
BL
spitalizat
PU
spitalizat
eat S
P
eat S
PU
pport any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
au
ng
ng
ng
ng
ng
ket
a
nt
m
nt
ar
a
during
ny
during OLE
y 
OLE
y m
dication
t a
dication
an
during
ort
during OLE
rt
OLE
rt
supp
usage
upp
usage durin
pp
durin
n (Japan)
sup
n (Japan)
ment cannot be used to supp
ence
o s
ence of
o s
of hosp
s
hosp
su
n
d
n and
d
and Other
d t
Other H
zure
ed
zure -
ed
- mITT 
ed 
mITT 
to
alization
use
alization and
e
and
eat Seizure
us
eat Seizure
Japan)
e
Japan)
e
Effective
be
Effective
be 
t
Num
t 
Num
Tr
Tr
t b
ot
9.1.1
n
9.1.1
n
14.2.9.2
t ca
14.2.9.2
ca
n
14.2.1
nt
14.2.1
nt
This documen
able
cu
able
m
Table
do
Table
oc
d
or variations thereof. 
f
eof
eo
eo
eo
eo
he
s t
ns
tio
ria
ariririri
Treatment
r v
Treatment
va
ons o
g OLE
s o
OLE Treat
o
Treat
plication and any extension o
pitalization
ion
pitalization t
n
t
on
Healthcare
ens
Healthcare Re
s
Re
Population
ten
Population–
ns
Other
ext
Other Health
ext
Health
mITT Popu
ex
mITT Popu
xte
ness
a
ness –
an
– Incide
any
Incide
ny
ber
d
ber of
d a
of episod
d a
episod
eatment Peri
nd 
eatment Peri
a
Number
an
Number of
of
Treatme
n a
Treatme
nd
n
Dur
n
Dur
n
on
0
tio
appli
o
14.2.10.
ppl
14.2.10.
pli
ap
ap
ap
1
p
1
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 66 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.2.10.3
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population
Y
Table
14.2.10.3.1
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population (Japan)
Y
Figure
14.2.10.4
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population
Y
Figure
14.2.10.4.1
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population (Japan)
Y
14.2.11
Effectiveness – Quality of Life in Childhood Epilepsy
Scale
Table
14.2.11.1
Quality of Life in Childhood Epilepsy (QOLCE) – mITT
population
14.2.12
Effectiveness – Peds QL
Table
14.2.12.1
PedsQL Pediatric Quality of Life Inventory (Version 4.0) -
Parent Report – mITT Population
Table
14.2.12.2
PedsQL Family Impact Module (Version 2.0) – Parent
Report – mITT Population
14.2.13
Effectiveness –Quality of Life of the Parent /Caregiver
using EQ-5D-5L Sale
Table
14.2.13.1
QOL of Parent/Caregiver using EQ-5D-5L –QOL of
Parent/Caregiver Based on EQ-5D-5L: Health Profile
Summary Original Response Categories – mITT Population
Table
14.2.13.2
QOL of Parent/Caregiver Based on EQ-5D-5L: Health
Profile Summary Using Dichotomized Response Categories
– mITT Population
Table
14.2.13.3
QOL of Parent/Caregiver Based on EQ-5D-5L: Overall
Health Status Using VAS (0-100) Scale - mITT Population
14.2.14
Effectiveness –Quality of Life of the Parent /Caregiver
using HADS Scale
Table
14.2.14.1
Parent/Caregiver Ratings Based on Hospital Anxiety and
Depression Scale (HADS): Normal; Borderline Abnormal;
and Abnormal Categories – mITT population
Table
14.2.14.2
Parent/Caregiver ratings Based on Hospital Anxiety and
Depression Scale (HADS): Total Score – mITT population
14.2.15
Exploratory objectives (feeder study ZX008-1504
subjects only)
Table
14.2.15.1
Study medication palatability assessment
Y
Table
14.2.15.2
Sleep quality and mealtime behavior – mITT population
Table
14.2.15.3
Karolinska sleepiness scale – mITT population
14.3
Safety
14.3.1
Summary of adverse events
COPY 
psy
Y
psy (QO
Y
(QO
Y
PY
C CO
ity
C
ity of
CO
of Life
CO
Life
TT Populati
C C
TT Populati
PUBLIC CO
Impact
LIC
Impact Mo
C
Mo
TT Populat
BLIC
TT Populat
C
ness
UB
ness –
B
–Qu
BL
Qu
EQ
PU
EQ-
U
-5D
UB
5D-
UB
-5L
B
5L
BL
L of Pare
PU
L of Pare
t/Ca
P
t/Ca
PU
rt any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
au
ng
Y
ti
Y
ng
ng
ng
ng
ket
a
y
m
y
ar
a
) – mITT
ny
mITT
y m
an
pport 
ventory
ort
ventory (Ver
rt
(Ver
not be used to supp rt
ule
ule (Version
upp
(Version
s pp
ty
o
ty of
o s
of Life
o s
Life of
of
Sale
to
Sale
su
t/Caregiver u
d t
t/Caregiver u
giver Based 
ed 
giver Based 
y Original
sed
Original Re
Re
to
L of Parent/C
us
L of Parent/C
ofile
e
ofile Summ
e u
Summ
–
b
– mITT Pop
be 
mITT Pop
s
ot b
QOL o
t b
QOL o
Hea
t 
Hea
ument canno b
ot
no
14.2.14.1
ca
14.2.14.1
an
en
14
n
14
en
en
en
en
This docum
um
Table
do
Table
oc
d
T
d
T
d
variations thereof. 
f
eof
eo
eo
eo
eo
he
s t
ns
tio
ria
ariririri
or va
sion
r
sion 4.0)
r v
4.0) -
v
-
any extensions o va
2.0)
s
2.0) –
s
– Parent
s o
Parent
o
the
i
the Parent
ion
Parent /
on
using EQ
ens
using EQ-
n
-5D
s
5D
on EQ
te
on EQ-
e
-5D
en
5D-5
n
5
esponse
xte
esponse Cate
te
Cate
ns
aregiver Bas
ex
aregiver Bas
ary
y
ary Using
y e
Using Dic
e
Dic
pulation
ny
pulation
ex
nd an
f Parent/Care
d an
f Parent/Care
th
d
th Status
d a
Status Us
a
Us
plication and any
Effectivenes
and
Effectivenes
using HA
an
using HA
nd
Paren
n 
Paren
De
n
De
n a
on
2.14.2
ca
2.14.2
at
appli
14.2.15
ppl
14.2.15
applpli
ap
1
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 67 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.3.1.1
Overview of number of subjects with TEAE during OLE
Treatment Period – Safety Population
Y
Y
Table
14.3.1.1.1
Overview of number of subjects with TEAE during OLE
Treatment Period – Safety Population (Japan)
Y
Table
14.3.1.2.1
Treatment-Emergent Adverse Events by MedDRA System
Organ Class and Preferred Term –– Safety Population
Y
Y
Table
14.3.1.2.1.1
Treatment-Emergent Adverse Events during Open-label
Treatment Periods by Age Group (< 6 yrs, ≥6 yrs) by
MedDRA System Organ Class and Preferred Term – Safety
Population
Y
Table
14.3.1.2.1.2
Treatment-Emergent Adverse Events with Decreased
Appetite, Loss of appetite, or Hypophagia during Open-
Label Treatment Periods – Safety Population
Y
Table
14.3.1.2.2
Treatment-Emergent Adverse Events occurring in ≥5% of
subjects by MedDRA System Organ Class and Preferred
Term– Safety population
Y
Y
Table
14.3.1.2.2.1
Treatment-Emergent Adverse Events occurring in ≥5% of
subjects by MedDRA System Organ Class and Preferred
Term– Safety Population (Japan)
Y
Table
14.3.1.2.1.3
Treatment-Emergent Adverse Events by MedDRA System
Organ Class and Preferred Term –– Safety Population
(Japan)
Y
Table
14.3.1.2.1.4
Treatment-Emergent Adverse Events during Open-label
Treatment Periods by Age Group (<6 yrs, ≥6 yrs) by
MedDRA System Organ Class and Preferred Term – Safety
Population (Japan)
Y
Table
14.3.1.2.1.5
Treatment-Emergent Adverse Events with Decreased
Appetite, Loss of appetite, or Hypophagia during Open-
Label Treatment Periods – Safety Population (Japan)
Y
Table
14.3.1.3
TEAEs leading to study discontinuation by MedDRA
System Organ Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.3.1
TEAEs leading to study discontinuation by MedDRA
System Organ Class and Preferred Term – Safety Population
(Japan)
Y
Table
14.3.1.4
Serious TEAEs by MedDRA System Organ Class and
Preferred Term – Safety Population
Y
Y
Table
14.3.1.4.1
Serious TEAEs by MedDRA System Organ Class and
Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.5.1
Related TEAEs MedDRA System Organ Class and
Preferred Term – Safety Population
Y
Y
Table
14.3.1.5.2
Related TEAEs occurring in at least 5% of subjects by
MedDRA System Organ Class and Preferred Term -Safety
population
Y
Y
Table
14.3.1.5.3
Related TEAEs MedDRA System Organ Class and
Preferred Term – Safety Population (Japan)
Y
PUBLIC COPY
s wit
Y
s wit
ophagia
PY
ophagia d
Y 
d
ety Popula
OPY
ety Popula
rse
CO
rse Events
COP
Events
ystem Org
CO
ystem Org
ation
C C
ation
OP
gent
LIC
gent Adve
IC 
Adve
MedDRA Sy
LIC
MedDRA Sy
fety Popula
BL
fety Popula
C C
ment
U
ment-
UB
-Emerg
UB
Emerg
gan Class a
PU
gan Class a
pan)
P
pan)
B
P
This document cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
Y
t
Y
ho
ho
ho
ho
au
ng
Y
ti
Y
ng
ng
ng
ng
ety
m
ety
ket
a
ased
y
ased
ng
ng Open
ny
Open-
y
-
n
m
ccurring
rt a
ccurring in
a
in ≥
a
≥
Class and P
ort
Class and P
a
Events
pp
Events occu
pp
occu
tem Organ C
sup
tem Organ C
on (Japan)
su
on (Japan)
po
nt
t
nt Adverse
to s
Adverse E
s
E
Preferred T
d to
Preferred T
s
t-
s
-Emergent A
sed
Emergent A
ment Periods 
use
ment Periods 
dDRA
u
dDRA Syste
us
Syste
Population (J
be u
Population (J
ed
Treatmen
t be
Treatmen
Appet
t b
Appet
Lab
t
Lab
be
ot
3
no
14.3.1.3.1
t ca
14.3.1.3.1
ca
en
1
en
en
en
en
Table
cu
Table
um
d
Table
do
Table
do
d
application and any extensions or variations thereof. 
f
eof
Y
er
Y
eo
eo
eo
eo
Y
h
Y
he
s t
io
ria
5%
v
5% of
va
of
referred
r v
referred
ar
urring
s
urring in
s o
in ≥5%
o
≥5%
lass and Pref
ns 
lass and Pref
o
vents
si
vents by
sio
by Med
o
Med
erm
n
erm ––
ns
–– Safet
s
Safet
io
Adverse Eve
xte
Adverse Eve
by Age Grou
ex
by Age Grou
m
y
m Organ
y e
Organ Cla
e
Cla
apan)
ny
apan)
te
t-
a
-Emergent 
any
Emergent 
ite,
d
ite, Loss
d a
Loss of
a
of a
el Treatmen
d 
el Treatmen
ny
TEAEs lead
an
TEAEs lead
System
n a
System O
nd
n
TEA
n 
TEA
S
n
on
4.3.1.4
ica
4.3.1.4
a
14.3.1.
pp
14.3.1.
pl
ap
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 68 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.3.1.5.4
Related TEAEs occurring in at least 5% of subjects by
MedDRA System Organ Class and Preferred Term -Safety
Population (Japan)
Y
Table
14.3.1.6
TEAEs by Maximum Severity, MedDRA System Organ
Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.6.1
TEAEs by Maximum Severity, MedDRA System Organ
Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.7
Overview of AESIs
Y
Y
Table
14.3.1.7.1
Overview of AESIs - Safety Population (Japan)
Y
Table
14.3.1.8
Adverse events of special interest (AESI) by MedDRA
System Organ Class and Preferred Term– Safety Population
Y
Y
Table
14.3.1.8.1
Adverse events of special interest (AESI) by MedDRA
System Organ Class and Preferred Term – Safety Population
(Japan)
Y
Table
14.3.1.9.1
Non-treatment Emergent Adverse Events Starting between
Visits 12 and 13 of the Feeder Study, by MedDRA System
Organ Class, Preferred Term and Prior Treatment in Feeder
Study – Safety Population
Y
Table
14.3.1.9.1.1
Non-treatment Emergent Adverse Events Starting between
Visits 12 and 13 of the Feeder Study, by MedDRA System
Organ Class, Preferred Term and Prior Treatment in Feeder
Study – Safety Population (Japan)
Y
Table
14.3.1.9.2
TEAEs starting in the 1st month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population
Y
Table
14.3.1.9.2.1
TEAEs starting in the 1st month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.9.3
TEAEs starting in the 2nd month of OLE by MedDRA
System Organ Class, , Preferred Term and Prior Treatment
in Feeder Study – Safety Population
Y
Table
14.3.1.9.3.1
TEAEs starting in the 2nd month of OLE by MedDRA
System Organ Class, , Preferred Term and Prior Treatment
in Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.9.4
TEAEs starting in the 3rd month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population
Y
Table
14.3.1.9.4.1
TEAEs starting in the 3rd month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.10.1
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind Treatment Period
by MedDRA System Organ Class and Preferred Term with
Mean Time to Onset (days) and Mean Duration (days) –
Safety Population
PUBLIC COPY
ESI
Y
ESI
Term
PY
Term–
Y
–
m–
m
Y
m–
m S
Y 
S
erest (AESI
OPY
erest (AESI
eferred
OP
eferred Te
OP
Te
PY
rgent Adve
C C
rgent Adve
of the Feed
IC 
of the Feed
Preferred
LIC
Preferred T
C
T
fety Popula
BL
fety Popula
C
eatment Em
UB
eatment Em
its 12 and 1
PU
its 12 and 1
gan
P
gan Clas
PU
Clas
B
cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
Y
a
Y
a
ng
ting
ng
ng
ng
Y
k
Y
ke
a
DRA
y
DRA
tyty Population
ny 
Population
m
by MedDRA
t an
by MedDRA
–
t
– Safety
rt a
Safety Po
a
Po
ny
e Events Sta
po
e Events Sta
r Study, by
pp
r Study, by M
p
M
m and
up
and Prior
up
Prior T
on
on
or
rgent Advers
to s
rgent Advers
of the Feede
d to
of the Feede
Preferred
d t
Preferred Ter
t
Ter
fety Populati
ed
fety Populati
s
s starting in t
use
s starting in t
tem
tem Organ
us
Organ C
s
C
Feeder Study
be u
Feeder Study
se
TEAEs s
t be
TEAEs s
System
t b
System
Fee
t
Fee
be
ot
9.3
n
9.3
no
ent c
14.3.1.9.
t c
14.3.1.9.
ocument c
en
e
me
This doc
Table
doc
Table
oc
d
ication and any extensions or variations thereof. 
of
of
of
of
eof
ere
t
e
Y
th
s t
ns
Y
tio
Y
io
ria
pulation
va
pulation
riria
ria
ria
rting between
or 
rting between
MedDRA
s o
MedDRA Sys
o
Sys
Treatment
ns 
Treatment inin
r
se Events Sta
sio
se Events Sta
r Study, by
nsi
r Study, by M
m
e
m and
en
and Prior
ens
Prior
on (Japan)
xte
on (Japan)
ion
he 1
e
he 1st
ex
st month 
ext
month 
lass,
y
lass, Preferre
ex
Preferre
– Safety Pop
ny e
Safety Pop
xte
tarting in the
any
tarting in the
m
d
m Organ
d a
Organ Clas
a
Clas
der Study 
nd a
der Study –
any
TEAEs start
and
TEAEs start
System
an
System O
n
O
in Fee
n a
in Fee
nd
on
.1
ti
.1
on
TE
n
TE
applica on
on
on
on
14.3.1.9.4
plic
14.3.1.9.4
ica
ap
ap
1
p
1
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 69 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.3.1.10.1.1
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind Treatment Period
by MedDRA System Organ Class and Preferred Term with
Mean Time to Onset (days) and Mean Duration (days) –
Safety Population (Japan)
Y
Table
14.3.1.10.2
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind through Open-
label Treatment Periods by MedDRA System Organ Class
and Preferred Term, Mean Average Dose in ZX008-1503
with Mean Time to Onset (days) and Mean Duration (days)
– Safety Population
Table
14.3.1.10.2.1
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind through Open-
label Treatment Periods by MedDRA System Organ Class
and Preferred Term, Mean Average Dose in ZX008-1503
with Mean Time to Onset (days) and Mean Duration (days)
– Safety Population (Japan)
Y
14.3.2
Listings of Deaths, Other Serious and Significant
Adverse Events
Table
14.3.2.1
Listing of Deaths
Y
Y
Table
14.3.2.1.1
Listing of Deaths (Japan)
Y
Table
14.3.2.2
Listing of SAEs
Y
Y
Table
14.3.2.2.1
Listing of SAEs (Japan)
Y
Table
14.3.2.3
Listing of Discontinuations Due to AE
Y
Y
Table
14.3.2.3.1
Listing of Discontinuations Due to AE (Japan)
Y
14.3.4
Laboratory value
Table
14.3.4.1
Laboratory parameters – Hematology– Safety Population
Y
Y
Table
14.3.4.1.1
Laboratory parameters – Hematology– Safety Population
(Japan)
Y
Table
14.3.4.2
Laboratory parameters – Biochemistry– Safety Population
Y
Y
Table
14.3.4.2.1
Laboratory parameters – Biochemistry– Safety Population
(Japan)
Y
Table
14.3.4.4.1
Laboratory parameters – Urinalysis (Quantitative variables)
– Safety Population
Y
Y
Table
14.3.4.4.1.1
Laboratory parameters – Urinalysis (Quantitative variables)
– Safety Population (Japan)
Y
Table
14.3.4.4.2
Laboratory parameters – Urinalysis (Qualitative variables) –
Safety Population
Y
Y
Table
14.3.4.4.2.1
Laboratory parameters – Urinalysis (Qualitative variables) –
Safety Population (Japan)
Y
Table
14.3.4.5
Laboratory parameters – Tests of growth, precocious
puberty and thyroid function – Safety Population
Y
Y
PUBLIC COPY
s that
Y
s that
le
PY
le-
PY
-blind t
PY 
blind t
edDRA Sys
OPY
edDRA Sys
Average D
OP
Average D
(day
CO
(days)
CO
s) an
O
an
apan)
C
apan)
s,
C
s, Other
C C
Other S
C
S
s
L
s
C C
Deaths
BL
Deaths
LI
g
P
g of
U
of Death
UB
Death
UB
ting
P
ting of
PU
of S
U
S
PU
P
nnot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ng
ho
ys)
m
ys)
ng
ng
ng
a
ng
ed in at
y m
ed in at
ugh Open
ny
ugh Open-
y
-
m Organ Cla
any
m Organ Cla
e in ZX008
t a
e in ZX008-1
Mean
ort
Mean Duratio
ort 
Duratio
m
ious
p
ious and
pp
and Sig
p
Sig
po
up
Japan)
to
Japan)
o s
Es
d
Es
d to
f SAEs
sed
SAEs (Japa
ed
(Japa
ed
ing
ing of
u
of Discon
us
Discon
us
Listing
be
Listing of
e 
of D
e u
Labor
t b
Labor
b
ot
cument cannot
La
La
ot
ot
ot
ot
4.1.1
an
4.1.1
nn
14.3.4.2
t c
14.3.4.2
ca
n
14.3.
nt
14.3.
nt
en
le
u
le
me
This docu
Table
doc
Table
cu
d
Ta
d
Ta
d
d any extensions or variations thereof. 
eof
re
s t
e
ass
a
ass
503
va
503
n (days)
va
(days)
tio
ria
nificant
s o
nificant
or
ns
io
ns
n)
n)
te
tinuations
ex
tinuations D
x
D
ex
iscontinuatio
ny
iscontinuatio
y
atory
d a
atory value
an
value
any
application and 
aboratory
nd
aboratory par
d 
par
d a
Laborator
an
Laborator
(Japan)
n a
(Japan)
an
n
Lab
n
Lab
n
on
4.2.1
at
4.2.1
tio
14.3.4.4.1
plic
14.3.4.4.1
lic
p
app
14.3
p
14.3
pp
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 70 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.3.4.5.1
Laboratory parameters – Tests of growth, precocious
puberty and thyroid function – Safety Population (Japan)
Y
14.4.1
Vital Signs
Table
14.4.1.1
Vital signs parameters – Safety Population
Y
Y
Table
14.4.1.1.1
Vital signs parameters – Safety Population (Japan)
Y
Figure
14.4.1.2
Scatterplot of Age (X-axis) and Height (Y-axis) at End of
Study during the Open-label Treatment Period – Safety
Population
Y
Figure
14.4.1.2.1
Scatterplot of Age (X-axis) and Height (Y-axis) at End of
Study during the Open-label Treatment Period – Safety
Population (Japan)
Table
14.4.1.3
Weight during the Open-Label Study Period over Time by
Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary
Statistics – Safety Population
Y
Table
14.4.1.3.1
Weight during the Open-Label Study Period over Time by
Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary
Statistics – Safety Population (Japan)
Y
Table
14.4.1.4
Weight during the Open-Label Study Period over Time for
De Novo Subjects: Summary Statistics – Safety Population
Table
14.4.1.4.1
Weight during the Open-Label Study Period over Time for
De Novo Subjects: Summary Statistics – Safety Population
(Japan)
Y
Table
14.4.1.5
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period – Safety Population
Y
Table
14.4.1.5.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period – Safety Population (Japan)
Y
Table
14.4.1.6
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period by Concomitant Topiramate –
Safety Population
Y
Table
14.4.1.6.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period by Concomitant Topiramate –
Safety Population (Japan)
Y
Table
14.4.1.7
Weight Summary (Lost/Gain ≥5%) during the Open-Label
Study Period – Safety Population
Y
Table
14.4.1.7.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label
Study Period – Safety Population (Japan)
Y
Table
14.4.1.8
Weight Summary (Lost/Gain ≥5%) during Open-Label
Study Period by Concomitant Topiramate – Safety
Population
Y
Table
14.4.1.8.1
Weight Summary (Lost/Gain ≥5%) during Open-Label
Study Period by Concomitant Topiramate – Safety
Population (Japan)
Y
14.4.4
Tanner Staging
PUBLIC COPY 
ent P
Y
ent P
l
O
l Study
OPY
Study Pe
PY
Pe
; 6 to <12; 
COP
; 6 to <12; 
ulation
CO
ulation
PY
Open
C
Open-
C C
-Labe
C C
Labe
<4; 4
LIC
<4; 4 -
C
- <6;
C 
<6;
afety Popu
BLIC
afety Popu
C
uring
UB
uring the
BL
the O
L
O
vo
U
vo Subject
UB
Subject
BL
ight
PU
ight durin
PU
durin
ovo
P
ovo
PU
This document cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
au
g
ng
ing
ng
ng
ng
ket
a
nd
nd of
m
of
Safety
y
Safety
ma
d
t
d over
t a
over Time
an
Time
d ≥12): Sum
rt a
d ≥12): Sum
any
Study
pp
Study Period
po
Period
to <12; and ≥
upp
to <12; and ≥
ion (Japan)
sup
ion (Japan)
o
en
o
en-Label
su
Label Stu
su
Stu
Summary
to 
Summary St
s
St
su
the
d
the Open
d to
Open-
t
-La
o
La
ubjects:
ed
ubjects: Sum
d 
Sum
to
ght
ght Summary
us
Summary
pen
e
pen-
e
-Label St
e u
Label St
se
Weight
be
Weight Su
e
Su
Open
t b
Open-L
be
ot
We
t
We
ot
ot
ot
ot
14.4.1.6.1
ca
14.4.1.6.1
an
en
14
n
14
en
en
en
en
able
cu
able
m
doc
Table
do
Table
oc
d
application and any extensions or variations thereof. 
f
of
Y
r
Y
o
eo
re
Y
h
Y
he
s t
on
ria
by
a
by
mary
va
mary
riria
ria
ria
over
o
over Time
or
Time by
by
≥12): Summa
s o
≥12): Summa
or
dy
i
dy Period ov
ion
Period ov
atistics
sio
atistics –
io
– Saf
o
Saf
on
bel
e
bel Study
ens
Study Pe
s
Pe
mary
te
mary Statistic
ten
Statistic
ns
y (Lost/Gain
ex
(Lost/Gain ≥
udy Period
y e
udy Period
ex
ummary
any
ummary (Los
ny
(Los
Label Study P
d an
Label Study P
ny
eight
nd
eight Summa
nd 
Summa
Open
an
Open-
nd
-Label
nd
Label
Safety
an
Safety Pop
n
Pop
d a
Weigh
n 
Weigh
Op
n
Op
a
on
4.1.7
ca
4.1.7
at
14.4.1.7
ppl
14.4.1.7
pli
ap
ap
1
p
1
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 71 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.4.4.1
Tanner staging by age group for Boys– Safety Population
Y
Table
14.4.4.1.1
Tanner staging by age group for Boys– Safety Population
(Japan)
Y
Table
14.4.4.2
Tanner staging by age group for Girls– Safety Population
Y
Table
14.4.4.2.1
Tanner staging by age group for Girls– Safety Population
(Japan)
Y
14.4.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
Table
14.4.5.1
Number of Subjects with Suicidal Ideation, Suicidal
Behavior, and Self-Injurious Behavior without Suicidal
Intent Based on the C-SSRS during Treatment – Safety
Population
Y
Y
Table
14.4.5.1.1
Number of Subjects with Suicidal Ideation, Suicidal
Behavior, and Self-Injurious Behavior without Suicidal
Intent Based on the C-SSRS during Treatment – Safety
Population (Japan)
Y
Table
14.4.5.2
Number of Subjects with Suicide-Related Treatment-
Emergent Events Based on the C-SSRS during Treatment –
Safety Population
Y
Table
14.4.5.2.1
Number of Subjects with Suicide-Related Treatment-
Emergent Events Based on the C-SSRS during Treatment –
Safety Population (Japan)
Y
14.4.6
Brief Rating Inventory of Executive Function-Preschool
version (BRIEF)
Table
14.4.6.1
Behavior Rating Inventory of Executive Function-Preschool
Version (BRIEF-P) – Scoring summary table – Safety
population
Y
Y
Table
14.4.6.1.1
Behavior Rating Inventory of Executive Function-Preschool
Version (BRIEF-P) – Scoring summary table –Safety
population (Japan)
Y
Table
14.4.6.2
Behavior Rating Inventory of Executive Function (BRIEF) –
Scoring summary table – Safety population
Y
Y
Table
14.4.6.2.1
Behavior Rating Inventory of Executive Function (BRIEF) –
Scoring summary table – Safety population (Japan)
Y
Table
14.4.6.3
Behavior Rating Inventory of Executive Function- Adult
Version (BRIEF-A) – Scoring summary table– Safety
population (De Novo Subjects)
Table
14.4.6.3.1
Behavior Rating Inventory of Executive Function- Adult
Version (BRIEF-A)– Scoring summary table– Safety
population (Japan) (De Novo Subjects)
Y
16.2
Subject data listing
16.2.1
Subject disposition and discontinuation
Listing
16.2.1.1
Subject completion/discontinuation
Y
Y
PUBLIC COPY 
Treat
Y
Treat
cidal Ideat
OPY
cidal Ideat
us
CO
us Behavio
COP
Behavio
SRS
CO
SRS durin
CO
durin
PY
ects with S
LIC 
ects with S
ents
L
ents Based
LIC
Based
pulation
BL
pulation
C
er of Subje
UB
er of Subje
ergent
PU
ergent Eve
U
Eve
ety Pop
P
ety Pop
UB
P
annot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
ut
g
ng
ing
ng
ng
ng
ke
a
dal
dal
Safety
y
Safety
ar
a
n, Suicidal
t an
n, Suicidal
without
rt a
without Suici
a
Suici
Treatment
ort
Treatment –
any
cide
up
cide-
p
-Related
pp
Related
the
u
the C
up
C-
up
-SSRS
up
SSRS
p
s with Suicid
to s
s with Suicid
s
d
s Based
d to
Based on
to
on thth
ation (Japan)
ed t
ation (Japan)
s
ting
se
ting Invento
sed
Invento
n
u
n (BRIEF)
use
(BRIEF)
ed
ehavior
e u
ehavior Ratin
u
Ratin
Version (BR
be 
Version (BR
populatio
t be
populatio
us
t
Beha
t 
Beha
V
t b
ot
t can
4.4.6.2
ca
4.4.6.2
ocument can
14.4.6.
nt 
14.4.6.
t c
en
me
This doc
e
Table
doc
Table
oc
d
and any extensions or variations thereof. 
of
o
eo
re
t
e
th
s t
Y
on
Y
ns
ria
s
dal
v
dal
Safety
r v
Safety
riria
ria
ria
Treatment
s o
Treatment-
o
-
during
ns
during Trea
s
Trea
o
de
de-
s
-Related Tr
sio
Related Tr
e C
n
C-
n
-SSRS
ns
SSRS du
du
io
ry
x
ry of
xt
of Execut
xte
Execut
te
ng
ng Inventory
y e
Inventory
RIEF
n
RIEF-
ny
-P) 
ny
P) –
y
– Sc
y
Sc
on
on
e
vior
d
vior Rating
d a
Rating
ersion (BRIE
nd
ersion (BRIE
population 
an
population 
a
ion a
Behavi
n a
Behavi
Scor
n 
Scor
applicatio
a
on
2.1
at
2.1
io
14.4.6.3
lic
14.4.6.3
ca
appl
ap
14
p
14
ap
ap
app
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 72 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Listing
16.2.1.2
Subject completion/discontinuation (Japan)
Y
16.2.2
Protocol deviations
Y
Listing
16.2.2.1
Major Protocol Deviations
Y
Y
Listing
16.2.2.2
Major Protocol Deviations (Japan)
Y
16.2.3
Subjects excluded from analysis
Listing
16.2.3.1
Subjects excluded from analysis populations
Y
Y
Listing
16.2.3.1.1
Subjects excluded from analysis populations (Japan)
Y
Listing
16.2.3.2
Subject allocation to trial populations
Y
Y
Listing
16.2.3.2.1
Subject allocation to trial populations (Japan)
Y
16.2.4
Demographic data and other baseline characteristics
Listing
16.2.4.1.1
Demographic data
Y
Y
Listing
16.2.4.1.1.1
Demographic data (Japan)
Y
Listing
16.2.4.1.2
% Change from baseline in weight and BMI
Y
Y
Listing
16.2.4.1.2.1
% Change from baseline in weight and BMI (Japan)
Y
Listing
16.2.4.2
Medical history
Listing
16.2.4.3
Prior and concomitant medications and therapies/treatments
Y
Listing
16.2.4.3.1
Prior and concomitant medications and therapies/treatments
(Japan)
Y
Listing
16.2.4.4.1
Prior antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.2
Concomitant antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.3
Prior antiepileptic Drugs (AEDs) (Japan)
Y
Listing
16.2.4.4.4
Concomitant antiepileptic Drugs (AEDs) (Japan))
Y
Listing
16.2.4.5
Rescue medications
Y
Listing
16.2.4.5.1
Rescue medications (Japan)
Y
16.2.5
Treatment exposure and compliance
Listing
16.2.5.1
IMP Intake per day during Treatment
Y
Y
Listing
16.2.5.1.1
IMP Intake per day during Treatment (Japan)
Y
Listing
16.2.5.2
IMP Intake – self reported % compliance
Y
Y
Listing
16.2.5.2.1
IMP Intake – self reported % compliance (Japan)
Y
Listing
16.2.5.3
Drug Accountability and Compliance to Study Treatment by
Visit
Listing
16.2.5.3.1
Drug Accountability and Compliance to Study Treatment by
Visit (Japan)
Y
PUBLIC COPY 
tions
PY
tions (Japa
PY
(Japa
Y
her
O
her baselin
OP
baselin
OP
CO
(Japan)
IC
(Japan)
C C
m
L
m baseline
LIC
baseline
LIC
ge
U
ge from
UBL
from bas
BL
bas
BL
dical
PU
dical histo
PU
histo
U
and
P
and
P
annot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
ut
Y
a
Y
a
ng
ng
ng
ng
ng
eti
Y
k
Y
ke
ar
a
m
ny
characterist
t a
characterist
an
rt
po
weight
sup
weight and
p
and
upp
ne
o
ne in
o s
in weight
s
weight
su
to
oncomitant
ed
oncomitant m
d
nd
u
nd concomit
use
concomit
pan)
e
pan)
se
Prior
be
Prior antiep
e 
antiep
e u
Conco
t b
Conco
b
ot
Pr
Pr
ot
ot
ot
ot
4.4.4
an
4.4.4
nn
cument ca
16.2.4.5
ca
16.2.4.5
a
16.2.4.5
nt 
16.2.4.5
t c
en
16
n
16
en
en
en
en
ting
u
ting
This docum
Listing
ocu
Listing
cu
doc
Listing
do
Listing
doc
d
L
d
L
d
n and any extensions or variations thereof. 
of
of
of
of.
eof
eo
eo
eo
eo
he
t
Y
th
s t
ns
Y
tio
Y
io
at
ria
cs
v
cs
ar
va
or
BMI
n
BMI
s
and
io
and BMI
ion
BMI (Ja
n
(Ja
on
si
medications
te
medications a
en
ant
e
ant medicatio
ex
medicatio
xt
ileptic
ny
ileptic Drugs
ny
Drugs
y
mitant
d a
mitant antiep
an
antiep
an
ior
n
ior antiepilep
nd 
antiepilep
d
Concomit
an
Concomit
an
lication a
n
Resc
n 
Resc
n a
on
.1
t
.1
io
2.5
c
2.5
at
pplic
16.2.5.1
plic
16.2.5.1
applic
p
16.2.5
pp
16.2.5
pp
ap
ap
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 73 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
16.2.6
Effectiveness data
Listing
16.2.6.1
Convulsive seizure – duration and number of occurrences
per subject (Diary data)
Y
Y
Listing
16.2.6.1.1
Convulsive seizure – duration and number of occurrences
per subject (Diary data) (Japan)
Y
Listing
16.2.6.2
Non-Convulsive seizure – by type, duration and number of
occurrences per subject (Diary data)
Y
Listing
16.2.6.2.1
Non-Convulsive seizure – by type, duration and number of
occurrences per subject (Diary data) (Japan)
Y
Listing
16.2.6.3
Duration of the Longest interval between convulsive
seizures and convulsive seizure free days per subject
Listing
16.2.6.3.1
Duration of the Longest interval between convulsive
seizures and convulsive seizure free days per subject (Japan)
Y
Listing
16.2.6.4
Percent reduction in convulsive seizure frequency from
baseline
Y
Y
Listing
16.2.6.4.1
Percent reduction in convulsive seizure frequency from
baseline (Japan)
Y
Listing
16.2.6.5
Clinical Global Impression – Improvement rating as
assessed by the Parent/Caregiver and Investigator
Y
Y
Listing
16.2.6.5.1
Clinical Global Impression – Improvement rating as
assessed by the Parent/Caregiver and Investigator (Japan)
Y
Listing
16.2.6.6
Quality of Life in Childhood Epilepsy Scale
Listing
16.2.6.7
Quality of life of the Parent/Caregiver using EQ-5D-5L
scale
Listing
16.2.6.8
Quality of life of the Parent/Caregiver using HADS scale
Listing
16.2.6.9.1
Pediatric Quality of Life Inventory (Peds QL) - for
TODDLERS (age 2-4 years)
Listing
16.2.6.9.2
Pediatric Quality of Life Inventory (Peds QL) - for Young
Children (age 5-7 years)
Listing
16.2.6.9.3
Pediatric Quality of Life Inventory (Peds QL) - for Children
(age 8-12 years)
Listing
16.2.6.9.4
Pediatric Quality of Life Inventory (Peds QL) - for TEENS
(age 13-18 years)
Listing
16.2.6.9.5
Pediatric Quality of Life Inventory (Peds QL) – Family
Impact Module
Listing
16.2.6.10
Study medication palatability assessment
Y
Listing
16.2.6.11
Sleep quality and mealtime behavior
Listing
16.2.6.12
Karolinska sleepiness scale
Listing
16.2.6.13
Healthcare utilization questions
16.2.7
Adverse events
COPY
een
Y
een
e
Y
e days
PY
days pe
Y 
pe
al between
OPY
al between
ure
O
ure free
OP
free da
P
da
PY
C CO
nvulsive
CO
nvulsive se
O
se
PUBLIC CO
n
L
n in
LIC
in convu
LIC
convu
an)
BL
an)
C
Global
UBL
Global Imp
BL
Imp
ed by the P
PUB
ed by the P
BL
nical Glo
PU
nical Glo
sed
P
sed b
P
b
PU
rt any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
Y
au
Y
ut
g
ng
Y
ket
Y
ti
f
rk
a
e
y
e
bject
ny
bject
m
onvulsive
any
onvulsive
per
rt
per subject 
rt a
subject 
ny
port 
ure
o
ure frequency
ort
frequency
nnot be used to supp rt
ve
ve seizure
pp
seizure fre
p
fre
pp
ssion
o s
ssion –
s
– Impr
s
Impr
rent/Caregive
to 
rent/Caregive
su
l Impression
d t
l Impression
the
e
the Parent/C
ed 
Parent/C
to
of
of Life
se
Life in
se
in Ch
e
Ch
e
uality
e
uality of
e u
of life
u
life
scale
be
scale
us
Quality
t b
Quality
be
ot
ot 
Ped
t
Ped
ument cannot
ot
ot
ot
2.6.9.2
an
2.6.9.2
nn
16.2.6.9.
nt c
16.2.6.9.
t c
en
1
en
en
en
en
docum
Listing
cu
Listing
This docum
d
Listin
do
Listin
do
d
L
d
variations thereof. 
of
o
eo
her
s t
s t
s t
s t
s t
ion
ia
(Japan)
var
(Japan)
iaia
ria
or va
y from
r v
from
d any extensions o va
equency
s o
equency from
o
from
o
ovement
ion
ovement ratin
n
ratin
er and Invest
sio
er and Invest
on
–
e
– Improvem
ens
Improvem
aregiver
ten
aregiver and
en
and
ns
hildhood
ext
hildhood Epi
xt
Epi
xte
f
y
f the
y
the Parent/
y e
Parent/
ex
of
of life
a
life of
an
of the
n
the
ny
and a
iatric
d
iatric Qualit
d 
Qualit
TODDLERS
and
TODDLERS
application and a
Pediatric
a
Pediatric
Child
n 
Child
an
on
3
t
3
P
on
on
on
on
6.2.6.9.4
ica
6.2.6.9.4
a
appl
16.2.6.
pp
16.2.6.
appl
ap
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 74 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Listing
16.2.7.1
Adverse events
Y
Y
Listing
16.2.7.2
Adverse events of special interests (AESI)
Y
Y
16.2.7.3
Adverse events for de novo subjects
Y (New)
16.2.8
Laboratory data
Listing
16.2.8.1.1
Laboratory Data Hematology parameters
Y
Y
Listing
16.2.8.1.1.1
Laboratory Data Hematology parameters (Japan)
Y
Listing
16.2.8.1.2
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Hematology
Y
Y
Listing
16.2.8.1.2.1
Most Abnormal Laboratory Parameters during Open-label
Treatment Period – Hematology (Japan)
Y
Listing
16.2.8.2.1
Laboratory Data Biochemistry parameters
Y
Y
Listing
16.2.8.2.1.1
Laboratory Data Biochemistry parameters (Japan)
Y
Listing
16.2.8.2.2
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Biochemistry
Y
Y
Listing
16.2.8.2.2.1
Most Abnormal Laboratory Parameters during Open-label
Treatment Period – Biochemistry (Japan)
Y
Listing
16.2.8.3
Laboratory Data Coagulation parameters
Y
Y
Listing
16.2.8.3.1
Laboratory Data Coagulation parameters (Japan)
Y
Listing
16.2.8.4.1
Laboratory Data Urinalysis parameters
Y
Y
Listing
16.2.8.4.1.1
Laboratory Data Urinalysis parameters (Japan)
Y
Listing
16.2.8.4.2
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Urinalysis
Y
Y
Listing
16.2.8.4.2.1
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Urinalysis (Japan)
Y
Listing
16.2.8.5
Tests of growth, precocious puberty and thyroid function
Y
Y
Listing
16.2.8.5.1
Tests of growth, precocious puberty and thyroid function
(Japan)
Y
Listing
16.2.8.6
Urine Pregnancy test
Y
Y
Listing
16.2.8.6.1
Urine Pregnancy test (Japan)
Y
Listing
16.2.8.7
Urine THC panel
Y
Y
Listing
16.2.8.7.1
Urine THC panel (Japan)
Y
Listing
16.2.8.8
Whole blood cannabidiol
Y
Y
Listing
16.2.8.8.1
Whole blood cannabidiol (Japan)
Y
16.2.9
Other Safety Data
Listing
16.2.9.1.1
Vital signs
Y
Y
PUBLIC COPY 
ters
Y
ters dur
Y 
dur
y (Japan)
PY
y (Japan)
Y
try
O
try parame
OP
parame
OP
emistry
CO
emistry pa
CO
pa
CO
aboratory
C C
aboratory P
C
P
od
L
od -
LIC
- Bioch
LIC
Bioch
C C
rmal
BL
rmal Labo
BL
Labo
nt Period
UB
nt Period
LI
boratory
PU
boratory Da
U
Da
UB
rato
P
rato
P
This document cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
Y
t
Y
ho
ho
ho
ho
Y
au
Y
ut
Y
g a
Y (Ne
a
(Ne
a
ng
ng
ng
ng
ng
Y
ket
Y
eti
ke
a
bel
m
bel
ar
a
Open
ny
Open-
ny
-label
ny 
label
y m
rsrs
an
meters
ort
meters (Japan
ort
(Japan
rt
ameters
ppo
ameters dur
po
dur
mistry
up
mistry
po
tory
s
tory Paramet
su
Paramet
Biochemistry
o s
Biochemistry
up
Coagulation
d to
Coagulation
to
Data
ed
Data Coagul
ed
Coagul
d
atory
us
atory Data
use
Data Ur
e
Ur
se
aboratory
e u
aboratory Da
u
Da
us
Most
be
Most Abn
e
Abn
Treatm
t b
Treatm
be
ot
1
n
1
M
t
M
ot
ot
ot 
ot
2.8.5
a
2.8.5
n
16.2.8.5.1
t c
16.2.8.5.1
ca
n
16.
n
16.
en
en
en
en
ing
u
ing
me
Listing
ocu
Listing
um
Listing
do
Listing
oc
d
Li
d
Li
d
application and any extensions or variations thereof. 
of
ew)
e
ew)
of
of
of.
eof
eo
eo
eo
eo
Y
he
Y
he
th
s t
Y
on
Y
ns
tio
ria
ariririr
n)
n)
va
ing
s
ing Open
s o
Open-
o
-lab
o
lab
or
ers
o
ers during
on
during Op
Op
(Japan)
sio
(Japan)
ns
parameters
ns
parameters
si
ation
te
ation parame
ten
parame
en
rinalysis
ext
rinalysis para
xt
para
xte
tata Urinalysis
y e
Urinalysis
e
ormal
an
ormal Labor
ny
Labor
ent Period
d an
ent Period
ny
ost
n
ost Abnorma
nd 
Abnorma
Treatment P
and
Treatment P
d a
Tests
n a
Tests of
a
of
an
n
Tes
n
Tes
n
on
2.8.6
ca
2.8.6
at
16.2.8.6.1
plic
16.2.8.6.1
ic
16.2.8
pp
16.2.8
p
ap
1
p
1
ap
ap
ap
ap


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 75 of 76
v3.0:
04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Listing
16.2.9.1.1.1
Vital signs (Japan)
Y
Listing
16.2.9.1.2
Abnormal Vital Signs Data
Y
Y
Listing
16.2.9.1.2.1
Abnormal Vital Signs Data (Japan)
Y
Listing
16.2.9.1.9
Subjects with Weight Decrease >5% during Treatment
Y
Y
Listing
16.2.9.1.9.1
Subjects with Weight Decrease >5% during Treatment
(Japan)
Y
Listing
16.2.9.2
Columbia-Suicide Severity Rating Scale (C-SSRS)
Y
Y
Listing
16.2.9.2.1
Columbia-Suicide Severity Rating Scale (C-SSRS) (Japan)
Y
Listing
16.2.9.3.1
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Individual Responses
Y
Y
Listing
16.2.9.3.1.1
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Individual Responses
(Japan)
Y
Listing
16.2.9.3.2
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Summary Scales
Y
Y
Listing
16.2.9.3.2.1
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Summary Scales (Japan)
Y
Listing
16.2.9.3.3
Behavior Rating Inventory of Executive Function (BRIEF) –
Individual Responses
Y
Y
Listing
16.2.9.3.3.1
Behavior Rating Inventory of Executive Function (BRIEF) –
Individual Responses (Japan)
Y
Listing
16.2.9.3.4
Behavior Rating Inventory of Executive Function (BRIEF) –
Summary Scales
Y
Y
Listing
16.2.9.3.4.1
Behavior Rating Inventory of Executive Function (BRIEF) –
Summary Scales (Japan)
Y
Listing
16.2.9.3.5
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Individual Responses
Y
Y
Listing
16.2.9.3.5.1
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Individual Responses (Japan)
Y
Listing
16.2.9.3.6
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Summary Scales
Y
Y
Listing
16.2.9.3.6.1
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Summary Scales (Japan)
Y
Listing
16.2.9.4
Tanner Staging
Y
Y
Listing
16.2.9.4.1
Tanner Staging (Japan)
Y
Listing
16.2.9.5
Physical Examination
Y
Y
Listing
16.2.9.5.1
Physical Examination (Japan)
Y
Listing
16.2.9.6
Neurological Examination
Y
Y
Listing
16.2.9.6.1
Neurological Examination (Japan)
Y
PUBLIC COPY 
cutive Fu
PY 
cutive Fu
Individual
PY
Individual
Y
of Executiv
OP
of Executiv
EF
C
EF-
C
-P)
CO
P) –
CO
– Ind
O
Ind
OP
Inventory
IC 
Inventory o
sion (BRIE
LIC
sion (BRIE
C C
Rating Inve
BL
Rating Inve
ol
U
ol Version
UB
Version
LI
havior
PU
havior Rati
PU
Rati
vidual
P
vidual
U
P
This document cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
Y
au
Y
ut
a
ng
Y
ti
Y
ng
ng
ng
ng
eti
rk
a
Japan)
m
Japan)
ma
on 
n
on –
ny
–
esponses
any
esponses
y m
Function 
t a
Function –
a
–
dual
ort
dual Respon
ort 
Respon
an
Executive
pp
Executive Fu
p
Fu
P)
u
P) –
u
– Summa
upp
Summa
po
tory of Execu
su
tory of Execu
BRIEF
to s
BRIEF-
o s
-P)
s
P) –
s
– S
up
g
d
g Inventory
d to
Inventory o
o
o
esponses
ed
esponses
to
Rating
sed
Rating Inve
ed
Inve
dual Respon
use
dual Respon
ed
ehavior
e u
ehavior Ratin
u
Ratin
Summary
be 
Summary S
u
Behavi
t b
Behavi
Sum
t 
Sum
be
ot
.5
n
.5
no
16.2.9.3.5.1
ca
16.2.9.3.5.1
an
n
16.2.9
nt
16.2.9
nt
en
ing
u
ing
me
Listing
doc
Listing
cu
d
Listi
do
Listi
do
d
application and any extensions or variations thereof. 
of
of
of
of.
eof
Y
er
Y
eo
eo
eo
eo
he
s t
Y
n
Y
s t
s t
s t
s t
on
Y
ti
Y
tio
ria
nses
r
nses
ariririr
nction
s o
nction –
o
–
ry Scales
ns 
ry Scales
or
utive Functio
ion
utive Functio
Summary
sio
Summary Sca
o
Sca
ns
f Executive
ns
Executive F
si
ntory
xt
ntory of
xte
of Exec
te
Exec
ses (Japan)
ex
ses (Japan)
te
ng
ng Inventory
y e
Inventory
cales
n
cales
e
or
or Rating
d an
Rating Inv
n
Inv
mmary Scales
d a
mmary Scales
any
Behavior
and
Behavior Ra
d
Ra
Version (B
an
Version (B
nd
Behav
n 
Behav
Ve
n
Ve
a
on
.3.6
at
.3.6
tio
16.2.9.3.6.1
plic
16.2.9.3.6.1
ic
p
16.2
pp
16.2
pp
ap
a


STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 76 of 76
v3.0:
04Aug2020
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
n
application and any extensions or variations thereof. 


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 1 of 234
Draft 3.0: 04Aug2020
Shells of Tables, Data Listings, and Figures for Zogenix Study ZX008-1503
Programming notes are provided, as applicable, for each table and data listing.
The data listings will be sorted by treatment group in the Core Study and subjects will be identified and sorted by subject number.
The following programming notes apply to all tables (where applicable):
General Programming notes:
-
In the Table header, Gp1, Gp2 etc should be replaced with the actual treatment group names
-
Add missing categories where appropriate
-
Percentages should be based on the number of non-missing subjects in the population in each treatment group (no percentage calculation should be performed and presented against the
missing category)
-
All listing displays for this open-label study are to be done by treatment group in the feeder study
Updated (01/15/2018)
-
This Document provides TFLs for the study for the eventual final report. However, for interim reports, a subset of TFLs will be needed, and not all columns indicated in the TFL shells will be
needed. For the NDA submission, programming will provide TFLs for only Group 9 (the “All subjects” column) in the TFLs.
Updated (14-Jul-2020)
-
Adding in separate outputs for Japan. These will be replicate tables/listings of the existing outputs.
PUBLIC COPY 
p
OP
p names
PY
names
e populati
C C
e populati
ment
BLI
ment grou
LI
grou
fi
P
fi
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
er.
k
er.
 in each trea
po
 in each trea
n
s
n the
su
the feeder
sup
feeder
l report. How
sed
l report. How
TFLs fo
use
TFLs for onl
se
r onl
will
will be
ot
be replic
ot
replic
xtensions or variations thereof. 
tment group
or 
tment group
study
ns
study
wever, for int
xte
wever, for int
application and any ex
a
y Group 9 (th
ext
y Group 9 (th
ate
d
ate tables/lis
d a
tables/lis


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 2 of 234
Draft 3.0: 04Aug2020
REVISION HISTORY
PUBLIC COPY 
document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
This do
do
TIAL
s d
TIAL
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 3 of 234
Draft 3.0: 04Aug2020
Date
Revision
Initials
13December2017
Based on SAP Version 0.3 for Protocol Amendment 3.0 dated 05may2017
GAS
01January
Clarified that only Group 9 (All Subjects) column will be used in the data presentations for the interim analysis
GAS
09January2018
Revised; included TFL shells for all efficacy and safety, and prioritization for interim analysis.
GAS
18Feb2018
Added age, gender and race to the AE listing mock
GAS
21Feb2018
Clarifying language added to QOLCE and PedsQL
GAS
11May2018
Updated Listings 16.2.9.3.1 – 16.2.9.3.4 - Headings for BRIEF-P and BRIEF
GAS
12Jul2018
Updated TFLs to include “n’s” for the PROs
GAS
14JUL2020
Added Tables / listings for Japan
MLW
30JUL2020
Finalization for Japan Interim Analysis
MLW
04AUG2020
Signoff
MLW
PUBLIC COPY 
prioritizatio
PY
prioritizatio
Y
CO
nd
B
nd PedsQL
BL
PedsQL
LIC
.9.3.4
P
.9.3.4
PU
nnot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ut
ng
ns
m
ns for
ma
for the
ma
the inte
a
inte
rk
for
a
for interim
any
interim an
y
an
y
rt
up
Headings
ed 
Headings fo
fo
to
for
e
for the
e u
the PROs
u
PROs
us
ngs
n
ngs for
not
for Japan
ot
Japan
t b
nt can
on
on for
ca
for Japan
ca
Japan
This document
do
TIAL
s d
TIAL
n
Signoff
me
Signoff
nt
um
and any extensions or variations thereof. 
re
rim
on
rim analysis
ons
analysis
s t
nalysis.
ria
nalysis.
ati
va
s
BRIEF
ten
BRIEF-
en
-P
n
P an
n
an
ns
ex
an
tion a
nterim
on
nterim Anal
n 
Anal
applicati
a
an
ati
p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 4 of 234
Draft 3.0: 04Aug2020
PUBLIC COPY 
document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
This do
do
TIAL
s d
TIAL
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 5 of 234
Draft 3.0: 04Aug2020
Treatment Groups in Study ZX008-1503
Name of Treatment Group
Treatment
Group Code
Description
AED Treatment from Feeder study
Feeder Study(s)
Approximate n
PBO-ZX008 OL
1
Placebo arms in all studies
Placebo in feeder study along with any protocol-
approved background AED combination; no active ZX008
1501, 1502, 1504
Cohort 2
120
ZX 0.2 – ZX008 OL
2
0.2 arm in DB Studies
Any protocol-approved background AED combination; plus,
ZX008 0.2 mg/kg/day max 30 mg
1501, 1502
80
ZX 0.8 – ZX008 OL
3
0.8 arm in DB studies
Any protocol-approved background AED combination; plus,
ZX008 0.8 mg/kg/day max 30 mg
1501, 1502
80
ZX 0.5 – ZX008 OL
4
Active arm in 1504 cohort 2
Protocol-approved background regimen including STP +
VPA + CBZ; plus ZX008 0.5 mg/kg/day max 20 mg
1504 Cohort 2
40
PK – ZX008 OL
5
Cohort 1 PK Study - Open label
study
1504 Cohort 1
40
Summary Treatment
Groups1
ZX DBA – ZX008 OL
6 (Groups2-4)
All Active arms in the DB studies
Any protocol-approved background regimen, plus ZX008 at
any protocol-approved dose – DB Studies only
1501, 1502, 1504
Cohort 2
200
ZX DB – ZX008 OL
7 (Groups1-4)
All subjects in randomized
double-blind (DB) studies
Any protocol-approved background regimen at any protocol-
approved dose – DB Studies only
ZX – ZX008 OL
8 (Groups2-5)
All Active arms
Any protocol-approved background regimen, plus ZX008 at
any protocol-approved dose – All studies
1501, 1502, 1504
Cohort 1, 1504
Cohort 2
240
ZX008 OL
9 (Groups1-5)
All Subjects in 1503 excluding de
novo subjects
Any protocol-approved background regimen at any protocol-
approved dose – All studies
1501, 1502, 1504
(both cohorts)
360
De Novo Subjects
10
Subjects entering 1503 who had not participated in any of the
core studies
None
35
Notes:1: Subjects in 1504 cohort 1 do not have a pre-study treatment baseline for seizures and are not included in analyses requiring baseline (Core) seizure frequency.
Analysis Summary types
Type
Treatment By Groups (Codes as above)
A
1, 2, 3, 4,5,9, 10
B
1, 8, 9, 10
C
1, 6, 7, 10
PUBLIC COPY
8 0.8 m
Y
8 0.8 m
ocol
PY
ocol-
PY
-appr
PY 
appr
VPA
OP
VPA +
OPY
+ CBZ
PY
CBZ
Y
OP
CO
C
C C
e
B
e DB
BL
DB studi
LI
studi
LIC
randomize
UB
randomize
d
P
d (DB)
PU
(DB) stud
U
stud
UB
ms
P
ms
PU
used to support any marketing authorization 
uth
national
zat
national L
03
03
ng
any
ke
any protoco
ket
protoco
mbination;
rke
mbination; n
et
kground
ar
kground AED
ar
AED
x
m
x 30
m
30 mg
ma
mg
ark
d
y
d background
y m
background
day max 30 m
ny m
day max 30 m
m
ed
a
ed backgroun
any
backgroun
plus
a
plus ZX008
an
ZX008
ny
t a
rt
po
Any
sup
Any pro
up
pro
any p
su
any p
up
s
s
d
s
An
An
o s s
d t
be us
n 1503
us
1503 exclu
us
exclu
ects
e
ects
cannot be us
be
t b
y treatment
ot 
treatment
t ca
t
(Codes
t ca
(Codes as
a
as
ment ca
t c
nt
me
This docum
do
TIAL
s d
TIAL
m
y extensions or variations thereof. 
re
active
s th
active ZX00
th
ZX00
he
combination
ns 
combination
s t
t
AED
tio
AED comb
on
comb
mg
a
mg
on
nd
r
nd regimen
riat
regimen in
t
in
0.5
a
0.5 mg/kg/da
aria
mg/kg/da
at
ar
va
or
tocol
on
tocol-
n
-approv
ns
approv
rotocol
ion
rotocol-
on
-appr
on
appr
ns
ny
ny protocol
sio
protocol-
o
-a
approved
ns
approved do
do
io
Any
ten
Any prot
n
prot
any pr
te
any pr
n
xt
uding
e
uding de
ex
de
n and any ex
A
ex
ny
a
baseline
d a
baseline for
a
for
ion 
above)
ion
above)
lication
io
ati
ca
applic
a plic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 6 of 234
Draft 3.0: 04Aug2020
NOTES:
The TFL shells provided are for the final study report. For the interim analysis, please note the following:
Programming Prioritization for Interim Analysis, 2018
Provide summaries for ZX008 OL (Group 9), i.e., “All Subjects” column only
1 = High priority -
2 = Medium Priority
3 = Low Priority
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
uth
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 7 of 234
Draft 3.0: 04Aug2020
LIST OF TABLES, FIGURES AND LISTINGS FOR FINAL REPORT
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
14.1
Subject Information
14.1.1
Subject disposition, protocol deviations, and study populations
Table
14.1.1.1
Subject disposition – all enrolled subjects
Y
Y
Table
14.1.1.1.1
Subject disposition – all enrolled subjects (Japan)
Y
Table
14.1.1.2
Major protocol deviations – Safety Population
Y
Y
Table
14.1.1.2.1
Major protocol deviations – Safety Population (Japan)
Y
Table
14.1.1.3
Study Populations
Y
Table
14.1.1.3.1
Study Populations (Japan)
Y
14.1.2
Demographic and baseline characteristics
Table
14.1.2.1
Demographic and baseline Characteristics – Safety Population
Y
Y
Table
14.1.2.1.1
Demographic and baseline Characteristics – Safety Population (Japan)
Y
Table
14.1.2.2
Demographic and baseline Characteristics – mITT Population
Y
Table
14.1.2.2.1
Demographic and baseline Characteristics – mITT Population (Japan)
Y
14.1.3
Medical history
Table
14.1.3.1
Medical history – Safety Population
Table
14.1.3.1.1
Medical history – Safety Population (Japan)
Y
14.1.4
Prior/Baseline and concomitant medications and therapies/treatments
Table
14.1.4.1
Prior/Baseline medications and therapies/treatments – Safety Population
Table
14.1.4.2
Concomitant medications and therapies/treatments – Safety Population
Table
14.1.4.3
Prior/Baseline antiepileptic treatment – Safety Population
Y
PUBLIC COPY 
Y
PY
OP
on
C
on (Japan)
C C
(Japan)
C
C
LI
haracterist
PUB
haracterist
UB
Charact
P
Charact
PU
thorization 
national
zat
national L
03
03
cument cannot be used to support any marketing auth
g a
g a
g a
g
rk
ma
y m
ny
t a
or
pp
up
o s
istics
d
istics –
d
– Safet
d t
Safet
d to
acteristics
se
acteristics –
ed
Characterist
us
Characterist
us
eline
be
eline Charact
be
Charact
e
b
ory
n
ory –
n
– Safety
no
Safety
ot
history
an
history –
n
– Sa
Sa
nn
or/Baseline
t ca
or/Baseline
ca
Prior/Base
ent 
Prior/Base
t c
e
Conc
e
Conc
en
me
This docum
do
TIAL
s d
TIAL
m
cum
uth
lication and any extensions or variations thereof. 
Included
ere
Included inin
Interi
er
Interi
Ana
e
Ana
o
th
s t
n
tio
ria
va
r v
o
ns
io
y
t
y Population
ten
Population
ns
Safety
ext
Safety Popul
xte
Popul
te
cs
y
cs – mITT
y e
mITT Po
Po
ex
eristics
ny
eristics –
y
– mI
y
mI
y
an
Population
nd
Population
d
fety
fety Populat
an
Populat
an
and
o
and concom
on
concom
n
line
at
line medicat
atio
medicat
tio
omitant
ica
omitant med
ca
med
at
applic
a
Prior/Baselin
pli
Prior/Baselin
lic
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 8 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.1.4.3.1
Prior/Baseline antiepileptic treatment – Safety Population (Japan)
Y
Table
14.1.4.4.1
Concomitant antiepileptic treatment – Safety Population
Y
Y
Table
14.1.4.4.1.1
Concomitant antiepileptic treatment – Safety Population (Japan)
Y
Table
14.1.4.4.2
Frequency Distribution for Number of Concomitant Antiepileptic Treatments-Safety Population
Y
Table
14.1.4.4.2.1
Frequency Distribution for Number of Concomitant Antiepileptic Treatments-Safety Population
(Japan)
Y
14.1.5
Treatment Exposure and compliance
Table
14.1.5.1
Duration of Treatment Exposure – Safety Population
Y
Y
Table
14.1.5.1.1
Duration of Treatment Exposure by Age Group – Safety Population
Y
Table
14.1.5.1.2
Duration of Treatment Exposure by Sex – Safety Population
Y
Table
14.1.5.1.3
Duration of Treatment Exposure – Safety Population (Japan)
Y
Table
14.1.5.1.4
Duration of Treatment Exposure by Age Group – Safety Population (Japan)
Y
Table
14.1.5.1.5
Duration of Treatment Exposure by Sex – Safety Population (Japan)
Y
Table
14.1.5.1.6
Duration of Treatment Exposure in ZX008-1502 and ZX008-1503 Combined (Subjects Treated in
ZX008-1502 or ZX008-1503) (Japan)
Y
Table
14.1.5.1.7.1
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit – Safety Population
Table
14.1.5.1.7.2
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit – Safety Population (Japan)
Y
Table
14.1.5.1.8.1
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment –
Safety Population
Table
14.1.5.1.8.2
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment –
Safety Population (Japan)
Y
UBLIC COPY 
eptic
Y
eptic
iepileptic
PY
iepileptic T
Y
T
Y
CO
Population
C C
Population
C
ge
L
ge Group
LIC
Group
IC
by
UB
by Sex
UBL
Sex –
B
– S
L
S
BL
PUB
osure
PU
osure –
PU
– Saf
U
Saf
PUB
ure
P
ure
P
to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
ke
ar
nts
y
nts-
y
-Safety
y m
Safety P
m
P
m
atments
any
atments-
ny
-Saf
y
Saf
ny
rt
po
afety
u
afety Popula
up
Popula
pp
ety
o
ety Populatio
o s
Populatio
su
d to 
y
d
y Population
d to
Population
be used to
Age
ed
Age Group
ed 
Group
d t
re
u
re by
us
by Sex
use
Sex –
e
– S
e
S
se
posure
e u
posure in
u
in ZX
u
ZX
1503) (Japan
be
1503) (Japan
us
ot b
ZX008
ot b
ZX008 Dosag
t b
Dosag
nnot b
gned
n
gned ZX008
no
ZX008 D
ot
t cann
r of
a
of Subjects
an
Subjects
ety
ety Populatio
ca
Populatio
nn
This document c
do
TIAL
s d
TIAL
Number
nt 
Number of
of
Safety P
en
Safety P
t c
me
me
me
me
sions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
th
th
th
th
ns
opulation
atio
opulation
io
ety
ri
ety Populatio
ria
Populatio
at
va
or
tion
n
tion
s o
n
on
ensio
(Japan)
ns
(Japan)
any extensio
Safety
ten
Safety Popu
en
Popu
en
afety
ex
afety Popula
ext
Popula
xte
008
y
008-
y
-1502
y e
1502 an
e
an
n)
n)
e
d an
e
d
e in
d
in ZX008
d a
ZX008-1
and an
Dosage
nd
Dosage in
nd
in ZX0
d
ZX0
d
on an
Receiving
a
Receiving ZX
ZX
n
o
n
an
cation
Subjects
tio
Subjects Rec
o
Rec
opulation (Ja
cat
opulation (Ja
on
applica
a
ica


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 9 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.1.5.1.9.1
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment –
Safety Population
Table
14.1.5.1.9.2
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment –
Safety Population (Japan)
Y
Table
14.1.5.1.10.1
Number of Subjects Receiving ZX008 According to Actual Dose (mg/kg) and Duration of Treatment –
Safety Population
Table
14.1.5.1.10.2
Number of Subjects Receiving ZX008 According to Actual Dose (mg/kg) and Duration of Treatment –
Safety Population (Japan)
Y
Table
14.1.5.2.1
Compliance to IMP intake – Safety Population
Y
Y
Table
14.1.5.2.1.1
Compliance to IMP intake – Safety Population (Japan)
Y
Table
14.1.5.2.2
Compliance to IMP intake – mITT Population
Y
Y
Table
14.1.5.2.2.1
Compliance to IMP intake – mITT Population (Japan)
Y
14.2
Effectiveness
14.2.1
Effectiveness – Convulsive Seizure Frequency
Table
14.2.1.1.1
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics and Tests
of Changes from Baseline
Y
Y
Table
14.2.1.1.2
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group: Summary
statistics and Tests of Changes from Baseline – mITT Population
Y
Table
14.2.1.1.3
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose:
Summary Statistics and Tests of Changes from Baseline –mITT Population
Y
Table
14.2.1.1.4
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, , by
Age Group: Summary Statistics and Tests of Changes from Baseline – mITT Population
Y
Table
14.2.1.1.5
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics – 1504
Cohort 1 Subjects
Y
PUBLIC COPY 
Dose
Y
Dose (mg
Y
(mg
Y
Actual
COP
Actual Do
OP
Do
OP
tion
C
tion
C C
opulation
BLIC
opulation (
C
(
LIC
T
U
T Populati
UB
Populati
BL
mITT
PU
mITT Pop
U
Pop
UB
P
cument cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
f
k
f Treatment
ket
Treatment
ti
ration
ma
ration of
ar
of Tr
Tr
ar
and
ny
and Duratio
ny 
Duratio
y m
(mg/kg)
rt a
(mg/kg) and
a
and
a
po
pan)
su
pan)
pp
su
ation
d t
ation (Japan)
to
(Japan)
to
d
zure
us
zure Freque
use
Freque
se
ency
be
ency per
e u
per 28
u
28 d
eline
b
eline
u
re
o
re frequency
ot 
frequency
Tests of Cha
no
Tests of Cha
t b
ve
a
ve seizure
ann
seizure fr
n
fr
mary Statisti
ca
mary Statisti
nn
Convulsive
nt c
Convulsive
c
Age Grou
ent
Age Grou
t c
e
me
Con
e
Con
e
This docu
do
TIAL
s d
TIAL
cume
cation and any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
–
her
th
atment
ns
atment –
s
–
s
n of
at
of Treatm
ati
Treatm
tio
Duration
va
Duration of
of
ar
or
s
on
si
en
ncy
e
ncy
xt
days
y
days during
y e
during O
e
O
e
per
d
per 28
d a
28 days
a
days
nges from B
nd 
nges from B
an
equency
an
equency pe
n
pe
cs and Tests 
n a
cs and Tests 
an
eizure
tio
eizure frequ
o
frequ
up: Summary
ati
up: Summary
on
pplica
vulsive
lic
vulsive seizu
c
seizu
Cohort 1 Sub
ppli
Cohort 1 Sub
ca
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 10 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.2.1.1.6
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics and Tests
of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.7
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group: Summary
Statistics and Tests of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.8
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose:
Summary statistics and Tests of Changes from Baseline –mITT Population (Japan)
Y
Table
14.2.1.1.9
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, by
Age Group: Summary statistics and Tests of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.2
Convulsive seizure frequency per 28 days - Endpoint: Parametric analysis – mITT Population
Table
14.2.1.3
Convulsive seizure frequency per 28 days - Endpoint: Nonparametric analysis – mITT Population
Table
14.2.1.4
Convulsive seizure frequency per 28 days, Over Time - Parametric analysis – mITT Population
Table
14.2.1.5
Convulsive seizure frequency per 28 days, Over Time, Using Mean Daily Dose: Parametric Analysis –
mITT Population
Table
14.2.1.6
% of subjects with Changes in AED medications during the first 6 months of the OLE Treatment
Period – mITT Population
Figure
14.2.1.7
Graph of means for convulsive seizure frequency per 28 days - mITT Population
Figure
14.2.1.8
Graph of model adjusted means for Convulsive seizure frequency per 28 days – mITT Population
Figure
14.2.1.9
Graph of convulsive frequency per 28 days, Over Time, Using Mean Daily Dose – mITT Population
14.2.2
Effectiveness – Proportion of responders for convulsive seizure frequency
Table
14.2.2.1
Percent reduction in convulsive seizure frequency, OLE Treatment Period– mITT population
Y
Y
Table
14.2.2.1.1
Percent reduction in convulsive seizure frequency, OLE Treatment Period– mITT population (Japan)
Y
Figure
14.2.2.2
Cumulative response curves for percent reduction in CSF during OLE Treatment Period – mITT
population
Y
Y
IC COPY 
ment
Y
ment P
Y
P
–
P
–mITT Po
PY
mITT Po
Y
OLE
CO
OLE Treatm
COP
Treatm
hanges fro
CO
hanges fro
OP
Endpoint
C C
Endpoint
C C
BLIC
days
BLI
days -
LI
- End
LIC
End
PUBLIC
er
U
er 28
UB
28 days,
UB
days,
BL
cy
P
cy per
PU
per 28
U
28
UB
pport any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
tics
ke
tics and
ket
and Test
t
Test
ti
Group:
ma
Group: Sum
a
Sum
ar
Using
ny
Using Mea
y 
Mea
ulation (Japa
any
ulation (Japa
y m
t Period
rt a
Period Usi
a
Usi
Baseline
ort
Baseline –
r
– m
t
m
a
arametric
ppo
arametric an
o
an
po
supp
oint:
su
oint: Nonpar
sup
Nonpar
ot be used to supp
ver
o
ver Time
o s
Time -
s
- P
su
ys,
d
ys, Over
d to
Over Tim
to
Tim
to
ED
s
ED medicati
se
medicati
ed
nvulsive
be
nvulsive seiz
e 
seiz
e u
djusted
ot b
djusted mea
b
mea
b
nnot
vulsive
no
vulsive frequ
o
frequ
This document cann
do
TIAL
s d
TIAL
ot
eness
an
eness –
an
– Prop
nn
Prop
nn
cent
c
cent reducti
ca
reducti
a
Percent
nt 
Percent re
re
t c
e
Cumu
e
Cumu
po
po
en
ume
m
s or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
s
t
s
her
th
mary
n
mary
s
Daily
iati
Daily Dose:
ati
Dose:
n)
a
n)
tio
ng
ng Mean
va
Mean Dai
a
Dai
ITT Populatio
r v
ITT Populatio
ar
nalysis
s o
nalysis –
o
– mITT
o
mITT
or
ons 
ametric
ns
ametric anal
s
anal
d any extensions
rametric
io
rametric an
n
an
on
e,e, Using
ns
Using Mea
s
Mea
si
ons
e
ons during
ext
during th
th
xte
ure
n
ure frequenc
ny
frequenc
y
s
d
s for
d a
for Convul
an
Convul
any
and 
ency
nd
ency per
nd
per 28
d 
28
ation and
ortion
a
ortion of
an
of res
n
res
an
on
o
on in
on
in convuls
on 
convuls
n a
uction
atio
uction in
io
in co
o
co
io
plicat
ative
ica
ative respo
ca
respo
pulation
plic
pulation
at
app
a p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 11 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Figure
14.2.2.2.1
Cumulative response curves for percent reduction in CSF during OLE Treatment Period – mITT
population
Y
14.2.3
Effectiveness – Duration of Longest interval between convulsive seizures
Table
14.2.3.1
Duration of Longest interval between convulsive seizures during OLE Treatment Period – mITT
Population
Figure
14.2.3.2
Boxplot of distribution of duration of longest interval between convulsive seizures during OLE
Treatment Period – mITT Population
14.2.4
Effectiveness – Summary of duration of convulsive episodes
Table
14.2.4.1
Summary of Duration of Convulsive Seizure Episodes during OLE Treatment Period - mITT Population
Table
14.2.4.2
Summary of Gaps between Convulsive Seizure Episodes during OLE Treatment Period
mITT Population
14.2.5
Effectiveness – Number of convulsive seizure free days
Table
14.2.5.1
Convulsive seizure-free days – summary statistics – mITT Population
Table
14.2.5.2
Convulsive seizure-free days – Parametric Analysis by Age Group - mITT Population
Table
14.2.5.3
Convulsive seizure-free days – Parametric Analysis by Mean Daily Dose - mITT Population
Table
14.2.5.4
Convulsive seizure-free days – summary statistics for subjects from Study 1504 –Cohort 1
14.2.6
Effectiveness –non-convulsive and convulsive seizure frequency
Table
14.2.6.1
Non-convulsive seizure frequency during OLE Treatment Period – mITT Population
Table
14.2.6.2
Convulsive + non-convulsive seizure frequency during OLE Treatment Period – mITT Population
14.2.7
Effectiveness – Incidence of rescue medication
Table
14.2.7.1
Days with Rescue medication usage during OLE Treatment Period – mITT Population
Y
Table
14.2.7.2
Days with Rescue medication usage during OLE Treatment Period – mITT Population (Japan)
Y
PUBLIC COPY 
Y
between
OPY
between
Y
PY
vulsive
C
vulsive ep
C
ep
CO
ure
IC
ure Episod
IC 
Episod
C C
ive
BL
ive Seizure
BLI
Seizure
LIC
convulsiv
PU
convulsiv
PU
P
not be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
mITT
ket
mITT
ti
ar
ment
y m
ment Period
y m
Period
m
vulsive
an
vulsive seizu
an
seizu
ny
odes
po
odes
ort
during
pp
during OLE
pp
OLE T
p
T
po
pisodes
su
pisodes duri
up
duri
up
seizure
d to
seizure free
to
free
to
mmary
ed
mmary statist
ed
statist
d
Parametric
us
Parametric
se
days
be
days –
e
– Param
e u
Param
u
free
t b
free days
t b
days –
b
– s
be
non
no
non-
ot
-convul
ot
convul
ot
anno
ulsive
nn
ulsive seizur
nn
seizur
This document can
do
TIAL
s d
TIAL
no
ulsive
ca
ulsive +
ca
+ non
a
non
an
Effectivenes
nt c
Effectivenes
t c
Days
en
Days w
n
w
nt
me
Da
Da
me
me
me
ume
m
nd any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
s
–
t
– mITT
tio
mITT
on
res
a
res during
aria
during O
a
O
ria
v
reatment
s o
reatment Pe
o
Pe
o
ng
o
ng OLE
on
OLE Treat
ns
Treat
ns
days
en
days
si
ics
xt
ics –
t
– mITT
xte
mITT Po
Po
en
Analysis
ex
Analysis by
x
by
xt
etric
ny
etric Analysi
ny 
Analysi
y e
ummary
an
ummary stat
ny
stat
ny
sive
d
sive and
d
and con
con
d a
and
e frequency
an
frequency
plication and
convulsive
n a
convulsive
a
s
t
s –
ti
– Incidence
tio
Incidence
on
th
c
th Rescue
cat
Rescue m
t
m
ati
ys
p
ys with
plic
with Resc
ic
Resc
ica
app
a pl


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 12 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
14.2.8
Effectiveness – Incidence of hospitalization to treat seizure
Table
14.2.8.1
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure - mITT Population– mITT
Population
Table
14.2.8.2
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure - mITT Population– mITT
Population (Japan)
Y
14.2.9
Effectiveness – Incidence of status epilepticus
Table
14.2.9.1
Number of episodes of status epilepticus during OLE Treatment Period - mITT Population
Table
14.2.9.1.1
Number of episodes of status epilepticus during OLE Treatment Period - mITT Population (Japan)
Y
Table
14.2.9.2
Duration of Seizures – mITT Population
14.2.10
Effectiveness – Clinical Global Impression of Improvement, – Rating by Parent/Caregiver and
Investigator
Table
14.2.10.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population
Y
Table
14.2.10.1.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population (Japan)
Y
Figure
14.2.10.2
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population
Y
Figure
14.2.10.2.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population (Japan)
Y
Table
14.2.10.3
Clinical Global Impression of Improvement, Investigator Rating – mITT Population
Y
Table
14.2.10.3.1
Clinical Global Impression of Improvement, Investigator Rating – mITT Population (Japan)
Y
Figure
14.2.10.4
Clinical Global Impression of Improvement,, Investigator Rating – mITT Population
Y
Figure
14.2.10.4.1
Clinical Global Impression of Improvement,, Investigator Rating – mITT Population (Japan)
Y
14.2.11
Effectiveness – Quality of Life in Childhood Epilepsy Scale
Table
14.2.11.1
Quality of Life in Childhood Epilepsy (QOLCE) – mITT population
14.2.12
Effectiveness – Peds QL
PUBLIC COPY 
PY
OLE
CO
OLE Treatm
CO
Treatm
OP
uring
C C
uring OLE
C C
OLE T
C
T
C
C
pression
BL
pression o
L
o
LI
of
P
of Improv
PU
Improv
PU
P
not be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
opulation
ark
opulation–
k
–
ke
- mITT
y m
mITT Popu
m
Popu
m
ny
nt
nt Period
rt 
Period -
t a
atment
po
atment Perio
po
Perio
or
pp
mprovement
su
mprovement
up
ment,
d t
ment, Parent
d to
Parent
to
ovement,
sed
ovement, Pa
d
Pa
ed
Improveme
us
Improveme
se
on
b
on of
be
of Improv
be 
Improv
u
ression
t b
ression of
b
of Im
Im
be
Impression
not
Impression
ot
ann
lobal
an
lobal Impres
nn
Impres
ument cann
cal
c
cal Global
ca
Global Im
Im
an
Effectivene
nt 
Effectivene
t c
e
Quality
en
Quality
en
me
This docume
do
TIAL
s d
TIAL
Ef
Ef
me
me
me
ume
nd any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
mITT
s
mITT
th
th
th
th
lation
tio
lation–
io
– mITT
o
mITT
on
ria
mITT
v
mITT Populat
va
Populat
va
d -
o
- mITT
or
mITT Po
Po
r v
o
,
i
, –
o
– Rating
ion
Rating by
by
ns
/Caregiver
ens
/Caregiver R
s
R
ns
rent/Caregiv
xte
rent/Caregiv
te
nt,
nt, Parent/Ca
ex
Parent/Ca
ex
ement,
ny
ement, Pare
y 
Pare
y e
provement,
an
provement,
any
of
n
of Improvem
nd 
Improvem
d a
and
sion
a
sion of
an
of Impr
an
Impr
lication and
mpression
on 
mpression of
of
a
ss
t
ss –
ti
– Quality
tio
Quality
on
y of
c
of Life
cat
Life in
a
in Ch
t
Ch
at
plic
fectiveness
plic
fectiveness
lic
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 13 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.2.12.1
PedsQL Pediatric Quality of Life Inventory (Version 4.0) - Parent Report – mITT Population
Table
14.2.12.2
PedsQL Family Impact Module (Version 2.0) – Parent Report – mITT Population
14.2.13
Effectiveness –Quality of Life of the Parent /Caregiver using EQ-5D-5L Sale
Table
14.2.13.1
QOL of Parent/Caregiver using EQ-5D-5L –QOL of Parent/Caregiver Based on EQ-5D-5L: Health
Profile Summary Original Response Categories – mITT Population
Table
14.2.13.2
QOL of Parent/Caregiver Based on EQ-5D-5L: Health Profile Summary Using Dichotomized Response
Categories – mITT Population
Table
14.2.13.3
QOL of Parent/Caregiver Based on EQ-5D-5L: Overall Health Status Using VAS (0-100) Scale - mITT
Population
14.2.14
Effectiveness –Quality of Life of the Parent /Caregiver using HADS Scale
Table
14.2.14.1
Parent/Caregiver Ratings Based on Hospital Anxiety and Depression Scale (HADS): Normal; Borderline
Abnormal; and Abnormal Categories – mITT population
Table
14.2.14.2
Parent/Caregiver ratings Based on Hospital Anxiety and Depression Scale (HADS): Total Score – mITT
population
14.2.15
Exploratory objectives (feeder study ZX008-1504 subjects only)
Table
14.2.15.1
Study medication palatability assessment
Y
Table
14.2.15.2
Sleep quality and mealtime behavior – mITT population
Table
14.2.15.3
Karolinska sleepiness scale – mITT population
14.3
Safety
14.3.1
Summary of adverse events
Table
14.3.1.1
Overview of number of subjects with TEAE during OLE Treatment Period – Safety Population
Y
Y
Table
14.3.1.1.1
Overview of number of subjects with TEAE during OLE Treatment Period – Safety Population (Japan)
Y
BLIC COPY
reg
Y
reg
opulation
PY 
opulation
h
O
h Profile
OP
Profile Su
P
Su
PY
L:
C
L: Overall
C C
Overall
C
e
B
e Parent
BLI
Parent /C
LI
/C
LIC
PUB
d
U
d on
UB
on Hosp
UB
Hosp
Categories
PU
Categories
P B
d
P
d
P
support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
on
k
on
ti
ke
ar
d on
y
on EQ
y m
EQ-
y m
-5D
m
5D
m
mary
t a
mary Using
a
Using
an
alth
p
alth Status
po
Status U
or
regiver
su
regiver using
up
using
up
d to s
t
Anxiety
to s
Anxiety and
s
and
mITT popula
d to
mITT popula
cannot be used 
s
Hospital
ed
Hospital Anx
d
Anx
d
eder
e
eder study
e u
study Z
us
atability
be
atability asse
e
asse
be
mealtime
ot 
mealtime b
t b
leepiness
nno
leepiness sc
o
sc
o
nn
nt ca
ummary
t ca
ummary of
ca
of a
a
a
This document 
do
TIAL
s d
TIAL
ca
Overview
ent
Overview
nt
e
Ove
e
Ove
en
me
m
ions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
th
th
th
th
ns
L:
t
L: Health
tio
Health
io
Dichotomize
ar
Dichotomize
ria
sing
o
sing VAS
or
VAS (0
r 
(0
r v
g HADS
ons
HADS Scale
ns
Scale
ns
ensio
Depression
sio
Depression
tion
n
tion
n and any exten ion
xiety
xt
xiety and
te
and Dep
e
Dep
en
X008
y
X008-
y e
-1504
y e
1504 s
ex
ssment
any
ssment
ny
ehavior
d a
ehavior –
a
– mI
a
mI
an
ale
ale –
n
– mITT
nd
mITT po
d
po
d 
an
tion 
dverse
ion
dverse even
on
even
applicatio
a
n
of
a
of number
atio
number o
o
o
tio
view
lic
view of
ica
of num
ca
num
ca
pli


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 14 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.3.1.2.1
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term –– Safety
Population
Y
Y
Table
14.3.1.2.1.1
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (< 6 yrs, ≥6
yrs) by MedDRA System Organ Class and Preferred Term – Safety Population
Y
Table
14.3.1.2.1.2
Treatment-Emergent Adverse Events with Decreased Appetite, Loss of appetite, or Hypophagia
during Open-Label Treatment Periods – Safety Population
Y
Table
14.3.1.2.2
Treatment-Emergent Adverse Events occurring in ≥5% of subjects by MedDRA System Organ Class
and Preferred Term– Safety population
Y
Y
Table
14.3.1.2.2.1
Treatment-Emergent Adverse Events occurring in ≥5% of subjects by MedDRA System Organ Class
and Preferred Term– Safety Population (Japan)
Y
Table
14.3.1.2.1.3
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term –– Safety
Population (Japan)
Y
Table
14.3.1.2.1.4
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (<6 yrs, ≥6
yrs) by MedDRA System Organ Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.2.1.5
Treatment-Emergent Adverse Events with Decreased Appetite, Loss of appetite, or Hypophagia
during Open-Label Treatment Periods – Safety Population (Japan)
Y
Table
14.3.1.3
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term – Safety
Population
Y
Y
Table
14.3.1.3.1
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term – Safety
Population (Japan)
Y
Table
14.3.1.4
Serious TEAEs by MedDRA System Organ Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.4.1
Serious TEAEs by MedDRA System Organ Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.5.1
Related TEAEs MedDRA System Organ Class and Preferred Term – Safety Population
Y
Y
C COPY 
etite,
Y
etite, Lo
Y
Lo
tion
P
tion
Y
≥5%
CO
≥5% of
OP
of su
OP
su
OP
BLIC C
urring
C
urring in
C C
in ≥
C
≥
on (Japan)
LIC
on (Japan)
PUBL C C
ents
B
ents by
BL
by Me
BL
Me
BL
rse
P
rse Even
PU
Even
PU
port any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
m
k
m ––
ket
–– Safety
et
Safety
ti
Age
m
Age Group
ma
Group (<
r
(<
n
ar
appetite,
ny
appetite, or
y
or
y m
cts
rt
cts by
rt
by MedD
t a
MedD
a
suppo
of
p
of subjects
ppo
subjects
ot be used to su po
DRA
DRA System
su
System
su
during
d t
during Open
t
Open
ass and Prefe
ed
ass and Prefe
to
e Events
us
Events with
s
with
ment Periods
e u
ment Periods
se
dy
dy discontinu
be
discontinu
be
annot
ng
ng to
n
to study
no
study d
on
a
on (Japan)
ann
(Japan)
This document can
do
TIAL
s d
TIAL
ot
ous
c
ous TEAEs
ca
TEAEs by
by
an
Serious
nt
Serious TEA
TEA
t c
e
Relate
en
Relate
en
me
me
me
me
or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
6 yrs,
ns
yrs, ≥6
ns
≥6
s
Hypophagia
iati
Hypophagia
tio
RA
v
RA System
va
System O
ar
ns or
by
s
by MedDRA
o
MedDRA S
d any extensions or
Organ
io
Organ Class
on
Class
ns
label
en
label Treatm
en
Treatm
rred Term
xte
rred Term –
ns
Decreased
ex
Decreased
– Safety Pop
y e
Safety Pop
xt
ation
an
ation by
any
by Me
y
Me
ny
and 
scontinuatio
nd
scontinuatio
lication a d
y
o
y MedDRA
on 
MedDRA Sy
Sy
a
Es
t
Es by
tio
by MedDR
tio
MedDR
on
d TEAEs
ca
TEAEs Med
a
Med
at
applic
a
lic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 15 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.3.1.5.2
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred
Term -Safety population
Y
Y
Table
14.3.1.5.3
Related TEAEs MedDRA System Organ Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.5.4
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred
Term -Safety Population (Japan)
Y
Table
14.3.1.6
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.6.1
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term – Safety Population
(Japan)
Y
Table
14.3.1.7
Overview of AESIs
Y
Y
Table
14.3.1.7.1
Overview of AESIs - Safety Population (Japan)
Y
Table
14.3.1.8
Adverse events of special interest (AESI) by MedDRA System Organ Class and Preferred Term– Safety
Population
Y
Y
Table
14.3.1.8.1
Adverse events of special interest (AESI) by MedDRA System Organ Class and Preferred Term – Safety
Population (Japan)
Y
Table
14.3.1.9.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by
MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study – Safety
Population
Y
Table
14.3.1.9.1.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by
MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study – Safety
Population (Japan)
Y
Table
14.3.1.9.2
TEAEs starting in the 1st month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population
Y
Table
14.3.1.9.2.1
TEAEs starting in the 1st month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population (Japan)
Y
PUBLIC COPY 
Y
Class
OP
Class and
PY
and
PY
rgan
CO
rgan Class
CO
Class
OP
C C
on
B
on (Japan)
BLI
(Japan)
LIC
est
U
est (AESI)
UB
(AESI)
B
re
P
re
P
cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
referred
ket
referred
ti
ation
ma
ation (Japan)
mar
(Japan)
ar
an
y
an Class
y m
Class and
m
and
m
ferred
an
ferred Term
an
Term
ny
d Preferred
rt 
Preferred
t a
po
up
MedDRA
to s
MedDRA Sy
s
Sy
s
(AESI)
ed
(AESI) by
ed
by Me
d
Me
d
Adverse
e u
Adverse Eve
u
Eve
n Class, Prefe
be 
n Class, Prefe
us
t
n
t Emergent
not
Emergent A
ystem Organ
nno
ystem Organ
tion
a
tion (Japan)
an
(Japan)
ot
ent ca
AEs
t
AEs starting
t ca
starting
Treatment 
nt 
Treatment 
This documen
do
TIAL
s d
TIAL
ca
e
TEAEs
en
TEAEs
Tre
e
Tre
en
ume
m
n and any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
s
Preferred
tio
Preferred
on
–
a
– Safety
aria
Safety Pop
a
Pop
ria
Term 
v
Term –
va
– Safet
va
Safet
va
o
ns
stem
si
stem Organ
sio
Organ
ion
dDRA
te
dDRA System
te
System
en
nts
y
nts Starting
y e
Starting b
erred Term a
ny
erred Term a
ex
Adverse
d
Adverse Even
d 
Even
Class, Prefe
and
Class, Prefe
d a
ation 
n the
on
the 1
on
1st
n
st mo
n
mo
n Feeder Stu
tio
n Feeder Stu
applicat
a
n
starting
ca
starting in
a
in th
th
atment in Fe
plic
atment in Fe
at
pl


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 16 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.3.1.9.3
TEAEs starting in the 2nd month of OLE by MedDRA System Organ Class, , Preferred Term and Prior
Treatment in Feeder Study – Safety Population
Y
Table
14.3.1.9.3.1
TEAEs starting in the 2nd month of OLE by MedDRA System Organ Class, , Preferred Term and Prior
Treatment in Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.9.4
TEAEs starting in the 3rd month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population
Y
Table
14.3.1.9.4.1
TEAEs starting in the 3rd month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.10.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
Treatment Period by MedDRA System Organ Class and Preferred Term with Mean Time to Onset
(days) and Mean Duration (days) – Safety Population
Table
14.3.1.10.1.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
Treatment Period by MedDRA System Organ Class and Preferred Term with Mean Time to Onset
(days) and Mean Duration (days) – Safety Population (Japan)
Y
Table
14.3.1.10.2
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean
Average Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days) – Safety
Population
Table
14.3.1.10.2.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean
Average Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days) – Safety
Population (Japan)
Y
14.3.2
Listings of Deaths, Other Serious and Significant Adverse Events
Table
14.3.2.1
Listing of Deaths
Y
Y
Table
14.3.2.1.1
Listing of Deaths (Japan)
Y
PUBLIC COPY 
Organ
Y
Organ
Y
A
C
A System
COP
System O
P
O
n (Japan)
CO
n (Japan)
OP
Occurred
C C
Occurred
m Organ
LIC
m Organ Cl
C
Cl
Safety Po
BL
Safety Po
C C
Events
UB
Events th
B
th
DRA
PU
DRA Syste
PU
Syste
ays)
P
ays)
UB
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
Inclu
au
Inclu
ut
g a
m
k
m and
ket
and Prior
et
Prior
ti
red
m
red Term
ma
Term an
r
an
ar
Preferred
ny 
Preferred T
y m
an
r
an Class,
rt a
Class, Pre
a
Pre
a
at
p
at least
ppo
least 5%
po
5%
and
up
and Prefer
upp
Prefer
lation
su
lation
po
Occurred
to 
Occurred inin
Organ
d to
Organ Class
to
Class
Safety Popu
ed 
Safety Popu
s
Events that 
use
Events that 
ent
ent Periods
us
Periods
1503 with M
be 
1503 with M
se
ergent Adver
ot 
ergent Adver
en
n
en-label
nno
label Tre
o
Tre
Dose in ZX0
ann
Dose in ZX0
ulation
ca
ulation (Japa
a
(Japa
t
Listings
nt c
Listings of
c
of D
c
D
t c
Listing
en
Listing
nt
me
Lis
Lis
me
me
me
ume
m
ication and any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
d Prior
ns
Prior
s
erm
a
erm and
ati
and Prio
ti
Prio
tio
ferred
va
ferred Term
va
Term
ar
of
of Subjects
s o
Subjects d
ed
n
ed Term wit
ns 
Term wit
or
at
at least
sio
least 5%
io
5%
and
n
and Preferr
ns
Preferr
ation (Japan
ten
ation (Japan
io
Occurred in a
ext
Occurred in a
by
y
by MedDRA
y e
MedDRA
Mean Time to
ny 
Mean Time to
xte
se Events th
d a
se Events th
tment
nd
tment Perio
nd
Perio
08
08-1503 with
an
1503 with
n)
n)
a
eaths,
tio
eaths, Other
o
Other
on
of
c
of Deaths
cat
Deaths
ati
plic
ting
pl
ting of
plic
of Death
ic
Death
app
a
ica
p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 17 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.3.2.2
Listing of SAEs
Y
Y
Table
14.3.2.2.1
Listing of SAEs (Japan)
Y
Table
14.3.2.3
Listing of Discontinuations Due to AE
Y
Y
Table
14.3.2.3.1
Listing of Discontinuations Due to AE (Japan)
Y
14.3.4
Laboratory value
Table
14.3.4.1
Laboratory parameters – Hematology– Safety Population
Y
Y
Table
14.3.4.1.1
Laboratory parameters – Hematology– Safety Population (Japan)
Y
Table
14.3.4.2
Laboratory parameters – Biochemistry– Safety Population
Y
Y
Table
14.3.4.2.1
Laboratory parameters – Biochemistry– Safety Population (Japan)
Y
Table
14.3.4.4.1
Laboratory parameters – Urinalysis (Quantitative variables) – Safety Population
Y
Y
Table
14.3.4.4.1.1
Laboratory parameters – Urinalysis (Quantitative variables) – Safety Population (Japan)
Y
Table
14.3.4.4.2
Laboratory parameters – Urinalysis (Qualitative variables) – Safety Population
Y
Y
Table
14.3.4.4.2.1
Laboratory parameters – Urinalysis (Qualitative variables) – Safety Population (Japan)
Y
Table
14.3.4.5
Laboratory parameters – Tests of growth, precocious puberty and thyroid function – Safety
Population
Y
Y
Table
14.3.4.5.1
Laboratory parameters – Tests of growth, precocious puberty and thyroid function – Safety
Population (Japan)
Y
14.4.1
Vital Signs
Table
14.4.1.1
Vital signs parameters – Safety Population
Y
Y
Table
14.4.1.1.1
Vital signs parameters – Safety Population (Japan)
Y
Figure
14.4.1.2
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment
Period – Safety Population
Y
LIC COPY 
Y
ulation
COP
ulation
OP
Populatio
CO
Populatio
CO
Safety
IC
Safety Pop
C 
Pop
C C
BLIC
try
BL
try–
BL
– Safety
BLI
Safety
PUBLIC
lysis
UB
lysis (Quan
UB
(Quan
BL
rinalysis
PU
rinalysis (
U
(
PU
l
P
l
P
upport any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
ke
ar
m
ny
a
Japan)
por
Japan)
rt
tion
p
tion
po
sup
opulation
sup
opulation (Ja
p
(Ja
t be used to sup
tative
to
tative variab
o s
variab
s
uantitative
d to
uantitative va
o
va
to
s
s
s (Qualitativ
ed
(Qualitativ
d
nalysis
us
nalysis (Qual
us
(Qual
se
Tests
be
Tests of
e u
of gro
u
gro
u
nnot b
meters
ot
meters –
t 
– Te
Te
Japan)
no
Japan)
ument cann t b
gns
a
gns
nn
al
t
al signs
t ca
signs para
ca
para
ca
Vital
nt
Vital signs
nt 
signs
t c
e
men
Scatt
e
Scatt
P
This docu
do
TIAL
s d
TIAL
en
ume
s or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
th
th
th
th
ns
io
at
ar
v
or
ons 
pan)
on
pan)
any extensions
es)
si
es) –
i
– Safety
sio
Safety
on
ariables)
ens
ariables) –
s
– Sa
s
Sa
s
e
x
e variables)
xte
variables)
en
tative
ex
tative variab
ex
variab
xt
owth,
ny
owth, precoc
ny 
precoc
y e
and a
ts
d
ts of
d
of growth
d a
growth
ation an
a
an
meters
on
meters –
n
– Saf
n
Saf
n
parameters
atio
parameters
tio
plica
erplot
lic
erplot of
ca
of Age
a
Age
riod
pli
riod –
pli
– Safet
plic
Safet
app
a
at
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 18 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Figure
14.4.1.2.1
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment
Period – Safety Population (Japan)
Table
14.4.1.3
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and
≥12): Summary Statistics – Safety Population
Y
Table
14.4.1.3.1
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and
≥12): Summary Statistics – Safety Population (Japan)
Y
Table
14.4.1.4
Weight during the Open-Label Study Period over Time for De Novo Subjects: Summary Statistics –
Safety Population
Table
14.4.1.4.1
Weight during the Open-Label Study Period over Time for De Novo Subjects: Summary Statistics –
Safety Population (Japan)
Y
Table
14.4.1.5
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period – Safety Population
Y
Table
14.4.1.5.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period – Safety Population
(Japan)
Y
Table
14.4.1.6
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant
Topiramate – Safety Population
Y
Table
14.4.1.6.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant
Topiramate – Safety Population (Japan)
Y
Table
14.4.1.7
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period – Safety Population
Y
Table
14.4.1.7.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period – Safety Population (Japan)
Y
Table
14.4.1.8
Weight Summary (Lost/Gain ≥5%) during Open-Label Study Period by Concomitant Topiramate –
Safety Population
Y
Table
14.4.1.8.1
Weight Summary (Lost/Gain ≥5%) during Open-Label Study Period by Concomitant Topiramate –
Safety Population (Japan)
Y
14.4.4
Tanner Staging
UBLIC COPY 
Age
Y
Age Gro
Y
Gro
Y
Time
CO
Time for
OP
for D
OP
D
OP
od
C
od over
C
over Tim
C C
Tim
C C
,
U
, or
B
or ≥10%)
UBL
≥10%)
BL
PUB
≥7%,
PU
≥7%, or
U
or ≥
U
≥
PUB
P
o support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
atment
ket
atment
ti
<6;
m
<6; 6
ma
6 to
ma
to <12
a
<12
ar
-
n
- <4;
ny
<4; 4
ny
4 -
y
- <6;
y 
<6;
y m
ovo
rt
ovo Subject
rt a
Subject
a
for
p
for De
pp
De Novo
ppo
Novo
po
uring
s
uring the
su
the Ope
su
Ope
su
ed to 
%)
t
%) during
to
during th
th
t cannot be used o
%,
%, or
s
or ≥10%)
sed
≥10%) d
d
d
on
u
on
ed
Gain
be
Gain ≥7%,
e u
≥7%, o
Population (
be
Population (
u
ryry (Lost/Gain
ot 
(Lost/Gain
t b
mmary
nn
mmary (Lost/
no
(Lost/
no
ht
c
ht Summary
can
Summary (
fety
t
fety Populat
t ca
Populat
n
ment 
Weight
ent
Weight Su
Su
Safety 
en
Safety 
This documen
do
TIAL
s d
TIAL
t
me
T
me
me
me
ume
sions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
and
n
and
s
6 to
a
to <12;
iati
<12; and
i
and
tio
s:s: Summary
va
Summary S
ar
Subjects:
s o
Subjects: Su
Su
or
en
i
en-Label
ion
Label Stud
n
Stud
ns
tensio
e Open
nsi
Open-
s
-Labe
si
Labe
tion and any exte sio
uring
xt
uring the
xte
the Op
e
Op
te
≥10%)
ny
≥10%) durin
y 
durin
Japan)
an
Japan)
y e
≥5%)
d
≥5%) during
d a
during
a
Gain
an
Gain ≥5%)
and
≥5%) d
d
d
nd
Lost/Gain
n a
Lost/Gain ≥5
a
≥5
on
o
on
an
licatio
mmary
atio
mmary (Lost
tio
(Lost
Population (
cat
Population (
pplic tio
nner
pli
nner Staging
plic
Staging
lic
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 19 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.4.4.1
Tanner staging by age group for Boys– Safety Population
Y
Table
14.4.4.1.1
Tanner staging by age group for Boys– Safety Population (Japan)
Y
Table
14.4.4.2
Tanner staging by age group for Girls– Safety Population
Y
Table
14.4.4.2.1
Tanner staging by age group for Girls– Safety Population (Japan)
Y
14.4.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
Table
14.4.5.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior, and Self-Injurious Behavior without
Suicidal Intent Based on the C-SSRS during Treatment – Safety Population
Y
Y
Table
14.4.5.1.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior, and Self-Injurious Behavior without
Suicidal Intent Based on the C-SSRS during Treatment – Safety Population (Japan)
Y
Table
14.4.5.2
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the C-SSRS during
Treatment – Safety Population
Y
Table
14.4.5.2.1
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the C-SSRS during
Treatment – Safety Population (Japan)
Y
14.4.6
Brief Rating Inventory of Executive Function-Preschool version (BRIEF)
Table
14.4.6.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary
table – Safety population
Y
Y
Table
14.4.6.1.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary
table –Safety population (Japan)
Y
Table
14.4.6.2
Behavior Rating Inventory of Executive Function (BRIEF) – Scoring summary table – Safety population
Y
Y
Table
14.4.6.2.1
Behavior Rating Inventory of Executive Function (BRIEF) – Scoring summary table – Safety population
(Japan)
Y
Table
14.4.6.3
Behavior Rating Inventory of Executive Function- Adult Version (BRIEF-A) – Scoring summary table–
Safety population (De Novo Subjects)
PUBLIC COPY 
pan)
Y
pan)
Y
Behavior,
OP
Behavior,
atment 
CO
atment –
CO
– S
O
S
OP
Suicidal
C C
Suicidal B
C
B
ring Treatm
LIC
ring Treatm
C
Related
BL
Related Tr
L
Tr
U LI
uicide
PU
uicide-
PU
-Re
PU
Re
n (
P
n (
PU
nnot be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
ke
ar
m
ny
d
t
d Self
t a
Self-
t a
-Injuri
a
Injuri
ety Populatio
ort
ety Populatio
a
avior,
pp
avior, and
ppo
and Se
o
Se
ent 
u
ent –
up
– Safety P
upp
Safety P
po
ment
s
ment-
su
-Emerg
su
Emerg
up
ed
d
ed Treatme
d t
Treatme
pan)
ed
pan)
to
utive
us
utive Functi
use
Functi
se
y
b
y of
e
of Executiv
e u
Executiv
tion
b
tion
u
Inventory
ot 
Inventory of
of
 population 
no
 population 
t b
ann
r
a
r Rating
ann
Rating Inve
nn
Inve
nt cann
avior
ca
avior Rating
ca
Rating
(Japan)
nt c
(Japan)
a
This document
do
TIAL
s d
TIAL
Behavio
en
Behavio
Safe
e
Safe
nt
ume
m
and any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
th
th
th
th
ns
io
at
ous
v
ous Behavior
var
Behavior
on
on
ar
lflf-Injurious
or
Injurious
Population (J
ns o
Population (J
or
gent
io
gent Events
on
Events B
ns
t
e
t-Emergent
ens
Emergent
ns
on
e
on-
e
-Preschoo
ex
Preschoo
xt
e Function
y e
Function-P
e
P
e
Executive
d a
Executive Fu
a
Fu
(Japan)
nd
(Japan)
an
n an
ntory
a
ntory of
an
of Exec
an
Exec
ation an
Inventory
on 
Inventory of
of
n a
plicati
r
c
r Rating
cat
Rating Inv
t
Inv
ety populatio
lica
ety populatio
ati
appli
a pli


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 20 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.4.6.3.1
Behavior Rating Inventory of Executive Function- Adult Version (BRIEF-A)– Scoring summary table–
Safety population (Japan) (De Novo Subjects)
Y
16.2
Subject data listing
16.2.1
Subject disposition and discontinuation
Listing
16.2.1.1
Subject completion/discontinuation
Y
Y
Listing
16.2.1.2
Subject completion/discontinuation (Japan)
Y
16.2.2
Protocol deviations
Y
Listing
16.2.2.1
Major Protocol Deviations
Y
Y
Listing
16.2.2.2
Major Protocol Deviations (Japan)
Y
16.2.3
Subjects excluded from analysis
Listing
16.2.3.1
Subjects excluded from analysis populations
Y
Y
Listing
16.2.3.1.1
Subjects excluded from analysis populations (Japan)
Y
Listing
16.2.3.2
Subject allocation to trial populations
Y
Y
Listing
16.2.3.2.1
Subject allocation to trial populations (Japan)
Y
16.2.4
Demographic data and other baseline characteristics
Listing
16.2.4.1.1
Demographic data
Y
Y
Listing
16.2.4.1.1.1
Demographic data (Japan)
Y
Listing
16.2.4.1.2
% Change from baseline in weight and BMI
Y
Y
Listing
16.2.4.1.2.1
% Change from baseline in weight and BMI (Japan)
Y
Listing
16.2.4.2
Medical history
Listing
16.2.4.3
Prior and concomitant medications and therapies/treatments
Y
PUBLIC COPY 
Y
PY
CO
C
IC
BL
lysis
PU
lysis popul
PU
popul
UB
ysis
P
ysis
P
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
Inclu
au
Inclu
ut
g a
mary
ke
mary table
ket
table–
ti
ar
m
y
an
rt
po
pp
su
ons
d t
ons
to
pulations
ed
pulations (Ja
 
(Ja
d t
lations
use
lations
se
populations
e u
populations
us
nd
b
nd other
be
other bas
e
bas
be
ta
o
ta
t b
hic
n
hic data
nno
data (Jap
no
(Jap
no
nge
a
nge from
an
from bas
n
bas
n
%
n
% Change
nt c
Change fr
c
fr
t c
e
Med
e
Med
en
me
m
cum
application and any extensions or variations thereof. 
a
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
s
on
ati
ria
va
or
s o
on
sio
pan)
te
pan)
en
xte
(Japan)
y e
(Japan)
e
eline
an
eline charac
any
charac
ny
a
an)
a
an)
nd
eline
n
eline in
a
in weig
a
weig
an
om
ti
om baseline
tio
baseline
on
cal
i
cal history
lica
history
ca
Prior
p
Prior and
pl
and con
con
lic
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 21 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.4.3.1
Prior and concomitant medications and therapies/treatments (Japan)
Y
Listing
16.2.4.4.1
Prior antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.2
Concomitant antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.3
Prior antiepileptic Drugs (AEDs) (Japan)
Y
Listing
16.2.4.4.4
Concomitant antiepileptic Drugs (AEDs) (Japan))
Y
Listing
16.2.4.5
Rescue medications
Y
Listing
16.2.4.5.1
Rescue medications (Japan)
Y
16.2.5
Treatment exposure and compliance
Listing
16.2.5.1
IMP Intake per day during Treatment
Y
Y
Listing
16.2.5.1.1
IMP Intake per day during Treatment (Japan)
Y
Listing
16.2.5.2
IMP Intake – self reported % compliance
Y
Y
Listing
16.2.5.2.1
IMP Intake – self reported % compliance (Japan)
Y
Listing
16.2.5.3
Drug Accountability and Compliance to Study Treatment by Visit
Listing
16.2.5.3.1
Drug Accountability and Compliance to Study Treatment by Visit (Japan)
Y
16.2.6
Effectiveness data
Listing
16.2.6.1
Convulsive seizure – duration and number of occurrences per subject (Diary data)
Y
Y
Listing
16.2.6.1.1
Convulsive seizure – duration and number of occurrences per subject (Diary data) (Japan)
Y
Listing
16.2.6.2
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data)
Y
Listing
16.2.6.2.1
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data)
(Japan)
Y
Listing
16.2.6.3
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per
subject
PUBLIC COPY 
Y
OP
CO
C C
t
B
t
LIC
tment
UB
tment (Jap
B
(Jap
BL
%
P
% complia
PU
complia
PU
P
d to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
ke
ar
m
ny
a
rt
po
up
n)
t
n)
s
e
d
e
to
sed 
pliance
sed
pliance (Japa
ed
(Japa
not be used
pliance
us
pliance to
s
to StSt
se
Compliance
be u
Compliance
u
be
ure
no
ure –
ot
– durati
ot
durati
ot
anno
e seizure
nn
seizure –
n
– d
canno
Convulsive
ca
Convulsive
an
cument c
Non
nt
Non-
t
-Convul
nt c
Convul
(Japan)
ent
(Japan)
t c
e
me
Dur
e
Dur
This docu
do
TIAL
s d
TIAL
e
cume
ensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
th
th
th
th
ns
io
at
ar
v
or
s
on
s
xten
n)
x
n)
nd any exten
udy
e
udy Treatme
ex
Treatme
xt
to
n
to Study
ny
Study Tre
y
Tre
y e
ny
on
d
on and
d
and numb
d 
numb
d a
and
uration
an
uration and
n
and
on and
eizure
n
eizure –
n
– by
a
by t
a
t
a
cation
ive
ti
ive seizure
tio
seizure
on
pplica
ation
lic
ation of
lica
of the
ca
the
subject
ppli
subject
ca
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 22 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.6.3.1
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per
subject (Japan)
Y
Listing
16.2.6.4
Percent reduction in convulsive seizure frequency from baseline
Y
Y
Listing
16.2.6.4.1
Percent reduction in convulsive seizure frequency from baseline (Japan)
Y
Listing
16.2.6.5
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and
Investigator
Y
Y
Listing
16.2.6.5.1
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and
Investigator (Japan)
Y
Listing
16.2.6.6
Quality of Life in Childhood Epilepsy Scale
Listing
16.2.6.7
Quality of life of the Parent/Caregiver using EQ-5D-5L scale
Listing
16.2.6.8
Quality of life of the Parent/Caregiver using HADS scale
Listing
16.2.6.9.1
Pediatric Quality of Life Inventory (Peds QL) - for TODDLERS (age 2-4 years)
Listing
16.2.6.9.2
Pediatric Quality of Life Inventory (Peds QL) - for Young Children (age 5-7 years)
Listing
16.2.6.9.3
Pediatric Quality of Life Inventory (Peds QL) - for Children (age 8-12 years)
Listing
16.2.6.9.4
Pediatric Quality of Life Inventory (Peds QL) - for TEENS (age 13-18 years)
Listing
16.2.6.9.5
Pediatric Quality of Life Inventory (Peds QL) – Family Impact Module
Listing
16.2.6.10
Study medication palatability assessment
Y
Listing
16.2.6.11
Sleep quality and mealtime behavior
Listing
16.2.6.12
Karolinska sleepiness scale
Listing
16.2.6.13
Healthcare utilization questions
16.2.7
Adverse events
Listing
16.2.7.1
Adverse events
Y
Y
PUBLIC COPY
sed
PY
sed by
PY
by th
Y 
th
Y
as
C
as assesse
CO
assesse
OP
e
I
e
C C
ver
B
ver using
BLI
using E
I
E
LIC
regiver
UB
regiver us
B
us
BL
entory
PU
entory (P
U
(P
PU
P
not be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
e
k
e days
ket
days per
et
per
ti
ar
m
arent/Caregi
ny
arent/Caregi
y
by
o
by the
rt
the Paren
rt 
Paren
t a
po
5D
s
5D-
s
-5L
su
5L scale
sup
scale
up
g
t
g HADS
to
HADS scale
o s
scale
s
ds
d
ds QL)
d t
QL) -
d t
- for
t
for T
to
y (Peds
sed
(Peds QL)
ed
QL) -
ed
ntory
u
ntory (Peds
us
(Peds Q
se
Inventory
be 
Inventory (P
(P
u
Life
t b
Life Invento
t b
Invento
be
ion
n
ion palatabi
not
palatabi
ot
ann
ality
an
ality and
nn
and me
n
me
ument cann
linska
ca
linska sleepi
ca
sleepi
an
Healthcare
nt 
Healthcare
t c
e
Advers
en
Advers
en
me
This docume
do
TIAL
s d
TIAL
A
me
me
me
ume
nd any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
s
on
ver
ri
ver and
iat
and
ati
t/Caregiver
va
t/Caregiver
va
o
ns
ion
ODDLERS
ens
ODDLERS (ag
s
(ag
ns
or
x
or Young
xte
Young Ch
e
Ch
ten
QL)
QL) -
e
- for
ex
for Child
ex
Child
ex
eds
n
eds QL)
ny
QL) -
y
- for
y
for
y e
ory
ory (Peds
an
(Peds QL)
n
QL)
any
lity
nd
lity assessme
nd 
assessme
d a
and
ltime
a
ltime behav
an
behav
lication and
ness
on
ness scale
on 
scale
a
utilization
tio
utilization qu
o
qu
on
e events
ca
events
at
plic
dverse
pli
dverse event
plic
event
lic
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 23 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.7.2
Adverse events of special interests (AESI)
Y
Y
16.2.7.3
Adverse events for de novo subjects
Y (New)
16.2.8
Laboratory data
Listing
16.2.8.1.1
Laboratory Data Hematology parameters
Y
Y
Listing
16.2.8.1.1.1
Laboratory Data Hematology parameters (Japan)
Y
Listing
16.2.8.1.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Hematology
Y
Y
Listing
16.2.8.1.2.1
Most Abnormal Laboratory Parameters during Open-label Treatment Period – Hematology (Japan)
Y
Listing
16.2.8.2.1
Laboratory Data Biochemistry parameters
Y
Y
Listing
16.2.8.2.1.1
Laboratory Data Biochemistry parameters (Japan)
Y
Listing
16.2.8.2.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Biochemistry
Y
Y
Listing
16.2.8.2.2.1
Most Abnormal Laboratory Parameters during Open-label Treatment Period – Biochemistry (Japan)
Y
Listing
16.2.8.3
Laboratory Data Coagulation parameters
Y
Y
Listing
16.2.8.3.1
Laboratory Data Coagulation parameters (Japan)
Y
Listing
16.2.8.4.1
Laboratory Data Urinalysis parameters
Y
Y
Listing
16.2.8.4.1.1
Laboratory Data Urinalysis parameters (Japan)
Y
Listing
16.2.8.4.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Urinalysis
Y
Y
Listing
16.2.8.4.2.1
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Urinalysis (Japan)
Y
Listing
16.2.8.5
Tests of growth, precocious puberty and thyroid function
Y
Y
Listing
16.2.8.5.1
Tests of growth, precocious puberty and thyroid function (Japan)
Y
Listing
16.2.8.6
Urine Pregnancy test
Y
Y
Listing
16.2.8.6.1
Urine Pregnancy test (Japan)
Y
PUBLIC COPY 
Y
en
CO
en-
O
-label
OP
label Tr
OP
Tr
OP
g Open
CO
Open-
C
-lab
CO
lab
CO
s
I
s
C C
meters
BLI
meters (Jap
LI
(Jap
LIC
ameters
UB
ameters d
B
d
BL
y
P
y Paramet
PU
Paramet
PU
P
cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
ke
ar
m
ny
ment
t a
ment Period
t a
Period
a
Treatment
or
Treatment P
rt
po
)
up
ng
to
ng Open
to s
Open-
s
-lab
s
lab
s
during
d to
during Ope
to
Ope
to
meters
sed
meters
d
parameters
us
parameters
se
sis
b
sis paramete
be u
paramete
u
inalysis
t b
inalysis para
b
para
be
l
n
l Laboratory
not
Laboratory
ot
ormal
nn
ormal Labor
nn
Labor
no
of
c
of growth,
ca
growth,
an
nt c
Tests
nt
Tests of
t c
of grow
c
grow
This document
do
TIAL
s d
TIAL
t c
Urine
en
Urine P
nt
me
Ur
Ur
me
me
me
ume
m
on and any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
th
th
th
th
ns
io
at
-
v
- Hematolog
var
Hematolog
ar
eriod
r
eriod –
r v
– Hem
v
Hem
v
or
s
el
s
el Treatment
sio
Treatment
on
n
e
n-label
ns
label Treat
ns
Treat
s
en
(Japan)
ex
(Japan)
xt
rs
n
rs
y e
meters
an
meters (Japa
any
(Japa
ny
Parameters
d 
Parameters
d a
atory
a
atory Param
an
Param
nd
precocious
n a
precocious p
a
p
a
ation
wth,
ti
wth, precocio
tio
precocio
applicati
a
on
regnancy
cat
regnancy tes
t
tes
ati
ne
pl
ne Pregnanc
plic
Pregnanc
ica
pl


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 24 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.8.7
Urine THC panel
Y
Y
Listing
16.2.8.7.1
Urine THC panel (Japan)
Y
Listing
16.2.8.8
Whole blood cannabidiol
Y
Y
Listing
16.2.8.8.1
Whole blood cannabidiol (Japan)
Y
16.2.9
Other Safety Data
Listing
16.2.9.1.1
Vital signs
Y
Y
Listing
16.2.9.1.1.1
Vital signs (Japan)
Y
Listing
16.2.9.1.2
Abnormal Vital Signs Data
Y
Y
Listing
16.2.9.1.2.1
Abnormal Vital Signs Data (Japan)
Y
Listing
16.2.9.1.9
Subjects with Weight Decrease >5% during Treatment
Y
Y
Listing
16.2.9.1.9.1
Subjects with Weight Decrease >5% during Treatment (Japan)
Y
Listing
16.2.9.2
Columbia-Suicide Severity Rating Scale (C-SSRS)
Y
Y
Listing
16.2.9.2.1
Columbia-Suicide Severity Rating Scale (C-SSRS) (Japan)
Y
Listing
16.2.9.3.1
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Individual Responses
Y
Y
Listing
16.2.9.3.1.1
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Individual Responses
(Japan)
Y
Listing
16.2.9.3.2
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Summary Scales
Y
Y
Listing
16.2.9.3.2.1
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Summary Scales
(Japan)
Y
Listing
16.2.9.3.3
Behavior Rating Inventory of Executive Function (BRIEF) – Individual Responses
Y
Y
Listing
16.2.9.3.3.1
Behavior Rating Inventory of Executive Function (BRIEF) – Individual Responses (Japan)
Y
Listing
16.2.9.3.4
Behavior Rating Inventory of Executive Function (BRIEF) – Summary Scales
Y
Y
PUBLIC COPY 
Y
OP
CO
C C
LIC
>5%
UB
>5% durin
UB
durin
BL
ease
PU
ease >5%
PU
>5%
PU
P
d to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
ke
ar
m
ny
a
rt
po
up
Treatment
o s
Treatment
s
ring
d
ring Treatme
d to
Treatme
to
sed 
cale
e
cale (C
ed
(C-
ed
-SSRS
d
SSRS
ment cannot be used
ting
u
ting Scale
us
Scale (C
(C
se
ry
b
ry of
be
of Executi
e u
Executi
u
entory
t b
entory of
b
of Ex
Ex
be
ating
nn
ating Invento
nno
Invento
no
or
ca
or Rating
can
Rating In
n
In
pan)
t c
pan)
n
Behavior
nt 
Behavior
t c
e
men
Beha
e
Beha
cumen
me
.4.4
This docum
do
TIAL
s d
TIAL
m
cum
ensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
th
th
th
th
ns
io
at
ar
v
or
s
on
nt
nt (Japan)
ens
(Japan)
s
xten
)
ation and any exten
SSRS)
ex
SSRS) (Japan
ex
(Japan
xt
ve
n
ve Function
ny 
Function
y e
ecutive
an
ecutive Func
an
Func
ny
ory
a
ory of
an
of Execut
and
Execut
nd
ventory
n a
ventory of
a
of Ex
Ex
an
Rating
ati
Rating Invent
tio
Invent
tio
lica
vior
ic
vior Rating
ica
Rating InIn
at
pplic
Behavior
pli
Behavior Rat
i
Rat
lic
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 25 of 234
Draft 3.0: 04Aug2020
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.9.3.4.1
Behavior Rating Inventory of Executive Function (BRIEF) – Summary Scales (Japan)
Y
Listing
16.2.9.3.5
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Individual Responses
Y
Y
Listing
16.2.9.3.5.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Individual Responses
(Japan)
Y
Listing
16.2.9.3.6
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Summary Scales
Y
Y
Listing
16.2.9.3.6.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Summary Scales (Japan)
Y
Listing
16.2.9.4
Tanner Staging
Y
Y
Listing
16.2.9.4.1
Tanner Staging (Japan)
Y
Listing
16.2.9.5
Physical Examination
Y
Y
Listing
16.2.9.5.1
Physical Examination (Japan)
Y
Listing
16.2.9.6
Neurological Examination
Y
Y
Listing
16.2.9.6.1
Neurological Examination (Japan)
Y
PY
Version
PY
Version (B
Y 
(B
PUBLIC COPY
dult
OP
dult Versio
OP
Versio
PY
CO
C
IC
BL
UB
P
pan)
P
pan)
P
y marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
ual
a
ual Response
ark
Response
ke
dividual
ma
dividual Res
a
Res
ar
any 
F-A)
n
A) –
ny
– Summ
ny
Summ
d to support any
(BRIEF
t a
(BRIEF-
a
-A)
a
A) – S
an
rt
po
pp
su
to
ed t
d t
This document cannot be use
do
TIAL
s d
TIAL
se
ations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
es
es
th
th
th
th
ponses
on
ponses
ns
riati
ary
ri
ary Scales
iat
Scales
ensions or variati
ummary
var
ummary Sca
r
Sca
ria
va
or
s o
on
sio
xten
en
application and any exte
a
xte


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 26 of 234
Draft 3.0: 04Aug2020
Part 1 of 2
Table 14.1.1.1
Subject Disposition
All Enrolled Subjects
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=xx)
De Novo Subjects
(N=xx)
Enrolled
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Subjects discontinued trial
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reasons for trial discontinuation
Reason 1
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reason 2
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Completed Study*
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Note: Percentages for summaries where only a Total column is present use number of enrolled subjects as the denominator.
*Study is an ongoing open-label extension. Amendment 4 allows de novo subjects to be enrolled.
Programming Notes:
-
Information on this table comes from CRF pages 6, 14, 33 and 34.
-
For 120 day safety update – One column only for this table– ZX008 OL
-
For 15Feb2019 IDSMC, please add the following note:
"Note: A total of 10 de novo subjects enrolled as of the data cutoff date for this report (15FEB2019) are not included in the tables but are included in the listings. None of those subjects has withdrawn from
the study as of the data cutoff date." Add only for the IDSMC output.
For 120-day output: *Study is an ongoing open-label extension. Amendment 4 allows de novo subjects to be enrolled. A total of 10 de novo subjects enrolled as of the data cutoff date for this report
(15FEB2019) are not included in the tables, figures and listings.”
UBLIC COPY 
x
Y
x
Y
PY
PY
PY
PY
PY
%)
O
%)
OP
CO
x
C
x (xxx.x%)
C C
(xxx.x%)
CO
xx
IC
xx (xxx.x
C 
(xxx.x
C C
xx
LIC
xx (x
C
(x
IC
B
UBL
x
L
x
PUBL
UB
UB
UB
UB
UB
.x%)
PU
.x%)
PU
P
support any marketing authorization 
uth
national
zat
national L
03
03
Gp
rk
Gp 4
(N
(N
rke
m
x.x%)
ny
x.x%)
y
ny
xx
t
xx (xxx.x%)
t a
(xxx.x%)
an
rt
xx
o
xx (x(x
or
po
pp
x%)
u
x%)
pp
pp
pp
pp
su
xxx.x%)
su
xxx.x%)
cannot be used to sup
s
xx
d t
xx (xxx.x%
to
(xxx.x%
to
d t
ed
e number
sed
number of
d
of
vo
u
vo subjects
us
subjects
,
t
, 14,
t b
14, 33
be
33 and
be
and
or
o
or this
ot b
this table
t b
table
ent c
wing
no
wing note:
no
note:
s of
a
s of the
an
the data
n
data
nly for the ID
t ca
nly for the ID
oing
en
oing open
en
open-lala
This docume
do
TIAL
s d
TIAL
he tables, fig
me
he tables, fig
ns or variations thereof. 
N=xx)
on
N=xx)
th
th
th
th
on
xx
at
xx (xxx.x%
ati
(xxx.x%
tio
ia
a
xx
r
xx
ar
va
va
va
va
va
xx.x%)
or
xx.x%)
r v
x
s
x (xxx.x%)
s o
(xxx.x%)
or
xx
ns
xx (xxx.x%
ns 
(xxx.x%
s
ions
xx
on
xx (xxx
n
(xxx
and any extensions
io
si
%)
%)
sisisi
ns
en
ten
enrolled
xte
enrolled sub
e
sub
o be
e
be enrolled
ex
enrolled
34.
a
34.
ZX008
d a
ZX008 OL
a
OL
cation a
cutoff date
n a
cutoff date f
SMC output.
on 
SMC output.
bel
a
bel extensio
ati
extensio
applic
a
ures and listi
ica
ures and listi


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 27 of 234
Draft 3.0: 04Aug2020
Table 14.1.1.1
Subject Disposition
All Enrolled Subjects
Part 2 of 2
Gp1
(N = XX) [1]
Gp8
(N = XX) [2]
Gp9
(N = XX)
Enrolled
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Subjects discontinued trial early:
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reasons for early trial discontinuation:
Reason 1
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reason 2
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Completed study
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Programming Notes:
-
Information on this table comes from CRF 6, 14, 33 and 34.
Treatment Group for Part 2 of 2:
Groups 1, 6 and 7
Programming Notes: Use the shell for 14.1.1.1 for
Table 14.1.1.1.1
Subject disposition
All Enrolled Subject (Japan).
PUBLIC COPY 
x%)
C
x%)
xxx.x%)
IC
xxx.x%)
x
L
x (xxx.x%)
LIC
(xxx.x%)
xx
BL
xx (xxx.x
BL
(xxx.x
UB
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ke
x.x%)
y
x.x%)
m
xx
a
xx (xxx.x%)
any
(xxx.x%)
xx
rt
xx (xx
(xx
x
to 
sions or variations thereof. 
th
Gp9
s th
Gp9
(N
ns
(N =
s
= XX
XX
x
ion
x.x%)
r v
x.x%)
(xxx.x%)
or
(xxx.x%)
xx
s
xx (xxx.x%)
s o
(xxx.x%)
xx
ns
xx (xxx.x
s 
(xxx.x
xx
n
xx (x(x
application and any extensi
a
si


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 28 of 234
Draft 3.0: 04Aug2020
Table 14.1.1.2
Major protocol deviations
Safety Population
Gp1
(N = XX) [1]
Gp8
(N = XX) [2]
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
No. (%) Subjects with at Least One MPD
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Type of MPD
MPD 1
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
MPD 2
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
MPD 3
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
MPD = Major protocol deviation
Note: Subjects may have had more than one MPD.
Programming Note: Use the shell for 14.1.1.2 for
Table 14.1.1.2.1
Major protocol deviations
Safety Population (Japan)
PUBLIC COPY 
x
xx
P
xx
LIC
LIC
LIC
thorization 
national
zat
national L
03
03
pport any marketing auth
ting
ma
xx.x%)
t a
xx.x%)
x (xxx.x%)
rt a
(xxx.x%)
xx
o
xx (xxx.x%)
ort
(xxx.x%)
This document cannot be used to supp
do
TIAL
s d
TIAL
pp
uth
s or variations thereof. 
ere
ZX008
th
ZX008 OL
he
OL
(N
s t
(N =
t
= XX)
th
XX)
x
ns
application and any extensions 
a
s
T
Ma
x
Ma


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 29 of 234
Draft 3.0: 04Aug2020
Table 14.1.1.3
Study Populations
Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
Gp9
(N=XXX)
De Novo Subjects
(N=xxx)
Enrolled (ITT) Population[1]
XX
XX
XX
XX
XX
XX
XX
Modified ITT (mITT) Population[2]
XX
XX
XX
XX
XX
XX
XX
Safety (SAF) Population [3]
XX
XX
XX
XX
XX
XX
XX
Notes:
[1] Enrolled (ITT) population: All subjects who gave informed consent or assent for entry into Study ZX008-1503.
[2] Modified ITT Population: All enrolled subjects who receive at least one dose of ZX008 and for whom at least 30 days of diary data are available. [All subjects on study from Day 30 of OLE period onward
are included in the mITT population.]
[3] Safety population: All subjects who received at least one dose of ZX008 during the open label extension.
Programming note: For [2] include any subject who has any data from Study Day 30 onward.
Programming note: Use the shell for 14.1.1.3 for
Table 14.1.1.3.1
Study Populations (Japan)
PUBLIC COPY 
Y
XX
PY
XX
PY 
OP
O
try
C
try into
C C
into Stu
C
Stu
ZX008
C
ZX008 and
C 
and
during
BL
during the
BL
the
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Gp5
ng
Gp5
(N
n
(N
ng
e
ke
ke
ket
ke
rke
ke
ke
k
ar
XX
m
XX
ma
y m
ny
an
an
an
an
rt an
y ZX008
po
ZX008-
po
-1503
o
1503
or
p
or whom at
pp
whom at l
pen
pen label
su
label ext
u
ext
dy
s
dy Day
sed
Day 30
ed
30 on
d
on
uth
application and any extensions or variations thereof. 
a
=xx)
he
=xx)
re
he
XX
s t
XX
th
s
on
tio
tio
tio
tio
tio
XX
r
XX
iat
ari
va
.
east 30
s o
east 30 days
o
days
nsion.
on
nsion.
ward.
xt
ward.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 30 of 234
Draft 3.0: 04Aug2020
Table 14.1.2.1
Demographic and Baseline Characteristics
Safety Population
Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=XXX)
De Novo Subjects
(N=xxx)
Age (years)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
Age Group, n (%)
<6 Years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6-18 Years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>18 Years
Sex
Male
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Female
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Race[ADSL.RACE]
White
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Black or African American
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Asian
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
American Indian or Alaska native
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Native Hawaiian or Other Pacific Islander
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Other[ADSL.RACEOTH]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
Y
PY
OP
OP
OP
OP
OP
CO
XX
C
XX
C
XX
LIC
XX
C
LIC
BL
UB
PU
PU
PU
PU
PU
P
be used to support any marketing authorization 
uth
national
zat
national L
03
03
G
k
G
rk
ma
m
X
n
X
y
XX.X
an
XX.X
ny
XX.XX
rt a
XX.XX
a
XX.
t
XX.
rt
po
pp
p
up
su
X (XX.X%)
to
(XX.X%)
o
XX
d
XX (XX.X%)
d t
(XX.X%)
d to
ed
se
us
e u
X%)
b
X%)
ent cannot be 
e
XX.X%)
t b
XX.X%)
be
t
no
XX
nn
XX (XX
n
(XX
nn
a
XX
XX
an
ca
ca
ca
ca
ca
nt
This documen
do
TIAL
s d
TIAL
c
m
c Islander
men
Islander
en
me
um
y extensions or variations thereof. 
p4
n
p4
(N=xx)
ons
(N=xx)
t
ion
XX
XX
ati
ria
ar
ar
ar
ar
ar
X
va
XX
o
XX
or
XX
s o
XX
o
ns
on
s
X
sio
ns
ns
ns
ns
ns
ten
xt
ex
ny 
XX
ny
XX (XX.X
y 
(XX.X
ation and any
XX
an
XX (X
y
(X
ny
a
d
nd
X.X%)
a
X.X%)
an
(XX.X%)
n a
(XX.X%)
a
XX
io
XX (XX.X%)
ion
(XX.X%)
on
XX
atio
XX (XX.X
io
(XX.X
tio
applicat
a
XX
a
XX (
at
icicicic
plplic
plpl


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 31 of 234
Draft 3.0: 04Aug2020
Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=XXX)
De Novo Subjects
(N=xxx)
Not Reported
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Ethnic Group
Hispanic or Latino
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Not Hispanic or Latino
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Not Reported[*]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Unknown[*]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Baseline Height (m)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Baseline Weight (kg)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Baseline BMI (kg/m2)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
SD
XX.XXX
XX.XXX
XX.XXX
XX.XXX
XX.XXX
XX.XXX
XX.XXX
PUBLIC COPY
X
Y 
X
Y
PY
OP
OP
OP
OP
OP
CO
XX
C
XX
C C
XXX.X
LIC
XXX.X
IC
XXX
L
XXX
LI
B
U
PU
P
be used to support any marketing authorization 
uth
national
zat
national L
03
03
ut
a
X.X%)
ng
X.X%)
g
ing
eti
ke
a
XX
r
XX
ar
ma
ma
ma
ma
X%)
y
X%)
m
XX.X%)
any
XX.X%)
ny
an
t a
ort
po
pp
p
X
up
XX.X
o
XX.X
s
XXX
d to
XXX
to
XXX
d 
XXX
d t
ed
se
u
e u
t cannot be 
X
b
X
be
XX.XX
t b
XX.XX
b
XXX.X
not
XXX.X
ot
XXX
no
XXX
no
X
nn
ca
ca
ment ca
ca
ca
ca
t c
nt
e
This docum
do
TIAL
s d
TIAL
m
u
ny extensions or variations thereof. 
Gp5
f
Gp5
(N=xx)
of
(N=xx)
XX
reo
XX (XX.X
eo
(XX.X
eo
re
he
he
he
he
th
(XX.X%)
ns
(XX.X%)
s
XX
io
XX (XX.X%)
ion
(XX.X%)
n
XX
atio
XX (XX.X%
tio
(XX.X%
tio
XX
at
XX (X
t
(X
at
ria
ar
va
v
XX
o
XX
or
XXX.X
ns 
XXX.X
s o
XXX.X
n
XXX.X
ns
X
io
si
ns
en
te
ex
XX
y e
XX
e
n and any
XXX.
ny
XXX.
ny
XX
n
XX
an
d a
nd
nd
nd
nd
nd
XX
XX
an
application 
a
n a
on
XX
XX
tio
ca
lic
lic
lic
lic
plic
p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 32 of 234
Draft 3.0: 04Aug2020
Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=XXX)
De Novo Subjects
(N=xxx)
Median
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Max
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
*Not reported, or missing: Privacy laws in some regions/countries preclude disclosure of certain personal information.
BMI=Body Mass Index, where BMI = weight (kg) / height (m2).
Note: Percentages are calculated based on the number of subjects with non-missing data in the Safety population.
Subjects do not necessarily reside in the country in which they attend clinic for the purpose of this study.
Programming note: Use the shell for Table 14.1.2.1 for
Table 14.1.2.1.1
Demographic and Baseline Characteristics
Safety Population (Japan)
Table 14.1.2.2
Demographic and Baseline Characteristics
mITT Population
Table 14.1.2.2.1
Demographic and Baseline Characteristics
mITT Population (Japan)
PUBLIC COPY 
Safety
PY
Safety pop
Y
pop
of this stud
OP
of this stud
Dem
LI
Dem
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ar
ma
ut
a
XX
n
XX
g
XX.X
tin
XX.X
ing
XX.X
ket
XX.X
eti
ke
n.n.
ation.
an
ation.
Table
upp
Table 14
pp
14
graphic
su
graphic and
up
and
Safety 
o s
Safety 
Dem
ed
Dem
ions or variations thereof. 
s
on
Gp5
f
Gp5
(N=xx)
of
(N=xx)
XX.XX
eo
XX.XX
eo
X
e
X
re
he
he
he
the
h
1.2.1.1
s
1.2.1.1
application and any extensio
a
Baseline
ons
Baseline Cha
ns
Cha
Population (
sio
Population (
Table
en
Table 1
ographic
xte
ographic and
e
and
m
De
ny
De


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 33 of 234
Draft 3.0: 04Aug2020
Table
14.1.3.1
Medical
History
Safety Population
Gp1
Gp8
Gp9
De Novo Subjects
MedDRA [1] System Organ Class and Preferred Term
(N = XX)
(N = XX)
(N = XX)
(N = XX)
Subjects with at Least One Previous or Concurrent
Medical History
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] MedDRA : Medical Dictionary for Regulatory Activities – latest version at the time of data collection.
Programming note: Use the shell for 14.1.3.1 for
Table 14.1.3.1.1
Medical History
Safety Population (Japan)
PUBLIC COPY 
BL
n
U
n at
UB
at the
UB
the tim
B
tim
thorization 
national
zat
national L
03
03
support any marketing auth
ting
ma
This document cannot be used to s
do
TIAL
s d
TIAL
(XX.X%)
t an
(XX.X%)
XX
rt
XX (XX.X%)
rt a
(XX.X%)
XX
ort
XX (XX.X
ort
(XX.X
s
of
o
of data
o s
data colle
s
colle
uth
ons or variations thereof. 
ere
Gp9
s th
Gp9
(N
s
(N = X
X
ns
%)
%)
application and any extension
a
ion
ction.
sio
ction.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 34 of 234
Draft 3.0: 04Aug2020
Table 14.1.4.1
Prior Medications and Therapies/Treatments
Safety Population
Drug Class ATC Level 2 [1]
Preferred Term
Gp1
(N = XX)
Gp8
(N = XX)
Gp9
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One prior Medication
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
UBLIC COPY 
Y
)
C
)
PUB
X%)
C
X%)
XX.X%)
C C
XX.X%)
UB
(WHO)
PU
(WHO) Dr
U
Dr
to support any marketing authorization 
uth
national
zat
national L
03
03
ke
p8
m
p8
N
y
N = XX)
y m
XX)
XX
any
XX (XX.X
ny
(XX.X
y m
X
a
X
to 
to
This document cannot be used to
do
TIAL
s d
TIAL
Dictionary
d to
Dictionary –
sions or variations thereof. 
th
X%)
r
X%)
tio
(XX.X%)
va
(XX.X%)
application and any extensio
a
XX
r
XX (XX.X%)
r v
(XX.X%)
XX
or
XX (XX.X
or 
(XX.X
sio
sio
sio
atest
ns
atest versio
nsi
versio


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 35 of 234
Draft 3.0: 04Aug2020
Table 14.1.4.2
Concomitant Medications and Therapies/Treatments
Safety Population
Drug Class ATC Level 2
Preferred Term [1]
Gp1
(N = XX)
Gp8
(N = XX)
Gp9
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One Concomitant Medication
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
BLIC COPY 
)
C
)
X%)
C
X%)
PUBL
(WHO)
PU
(WHO) Dru
U
Dru
support any marketing authorization 
uth
national
zat
national L
03
03
eti
XX)
m
XX)
XX
ny
XX (XX.X%)
ny 
(XX.X%)
m
XX
an
XX (X
n
(X
X
a
X
to s
This document cannot be used to
do
TIAL
s d
TIAL
Dictionary
to
Dictionary –
ions or variations thereof. 
he
on
on
on
X.X%)
ar
X.X%)
X (XX.X%)
va
(XX.X%)
XX
r
XX (XX.X%)
r v
(XX.X%)
application and any extensio
a
ioioion
atest
ns
atest versio
nsi
versio


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 36 of 234
Draft 3.0: 04Aug2020
Table 14.1.4.3
Prior/Baseline Antiepileptic Treatment
Safety Population
Drug Class ATC Level 2
Preferred Term [1]
Gp1
(N = XX)
Gp8
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One prior Antiepileptic treatment
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
Note: Multiple occurrences of the same Antiepileptic treatment are counted once for each subject within a drug class and preferred drug name.
Programming Note: Use the shell for 14.1.4.3 for
Table 14.1.4.3.1
Prior/Baseline Antiepileptic Treatment
Safety Population (Japan)
PUBLIC COPY 
X%)
C
X%)
BL
HO)
UB
HO) Drug
UB
Drug D
B
D
ounted
PU
ounted on
U
on
support any marketing authorization 
uth
national
zat
national L
03
03
eti
XX)
m
XX)
XX
ny
XX (XX.X%)
ny 
(XX.X%)
m
XX
an
XX (X
n
(X
This document cannot be used to s
do
TIAL
s d
TIAL
X
a
X
s
tionary
to s
tionary –
s
– lat
s
lat
for
t
for each
to
each sub
o
sub
ions or variations thereof. 
he
on
on
on
X.X%)
ar
X.X%)
application and any extensio
a
X (XX.X%)
va
(XX.X%)
XX
r
XX (XX.X%)
r v
(XX.X%)
ioioion
est
s
est version
sio
version.
bject
n
bject within
nsi
within a
Prior/
y e
Prior/


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 37 of 234
Draft 3.0: 04Aug2020
Table 14.1.4.4.1
Concomitant Antiepileptic Treatment
Safety Population
Drug Class ATC Level 2
Preferred Term [1]
Gp1
(N = XX)
Gp8
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One Concomitant antiepileptic treatment
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
Note: Multiple occurrences of the same antiepileptic treatment are counted once for each subject within a drug class and preferred drug name.
Note: A concomitant antiepileptic treatment (AEDs) defined as antiepileptic treatment with a start or stop date after the first dose of study treatment. Missing or partial start or stop dates for concomitant
AEDs are handled as specified in SAP Section 6.2.5
Programming Note: Use the shell for 14.1.4.4.1 for
Table 14.1.4.4.1.1
Concomitant Antiepileptic Treatment
Safety Population (Japan)
PUBLIC COPY 
X%)
C
X%)
BL
HO)
UB
HO) Drug
UB
Drug
ounted
PU
ounted on
U
on
epileptic
PU
epileptic
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
eti
XX)
m
XX)
XX
ny
XX (XX.X%)
ny 
(XX.X%)
m
XX
an
XX (X
n
(X
X
a
X
s
tionary
to s
tionary –
s
– lat
s
lat
for
t
for each
to
each sub
o
sub
eatment
d t
eatment with
t
with
application and any extensions or variations thereof. 
a
he
on
on
on
X.X%)
ar
X.X%)
X (XX.X%)
va
(XX.X%)
XX
r
XX (XX.X%)
r v
(XX.X%)
ioioion
est
s
est version
sio
version.
ject
n
ject within
nsi
within a
a
e
a start or
en
start or stst


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 38 of 234
Draft 3.0: 04Aug2020
Table 14.1.4.4.2
Frequency Distribution for Number of Concomitant Antiepileptic Drugs
Safety Population
Gp1
Gp8
Gp9
De Novo Subjects
(N = XX)
(N = XX)
(N = XX)
(N = XX)
Number of Concomitant AED
1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
---
AED=Antiepileptic Drugs.
Programming Note: Use the shell for 14.1.4.4.2 for
Table 14.1.4.4.2
Frequency Distribution for Number of Concomitant Antiepileptic Drugs
Safety Population (Japan)
PUBLIC COPY 
XX
Y
XX
XX
PY
XX (X
Y
(X
X
P
X
IC
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
tin
rke
)
X%)
an
X%)
(XX.X%)
t an
(XX.X%)
XX
r
XX (XX.X%)
rt a
(XX.X%)
XX
por
XX (XX.X%
or
(XX.X%
pp
quency
se
quency Distri
se
Distri
uth
application and any extensions or variations thereof. 
a
Gp9
h
Gp9
er
(N
t
(N =
th
= XX)
the
XX)
th
XX
n
XX
%)
o
%)
s o
Table
e
Table
bution
ext
bution for
xt
for Nu
Nu
Saf
x
Saf


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 39 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.1
Duration of Treatment Exposure
Safety Population
Time on Treatment (days)
Gp1
(N = XX)
Gp8
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
n
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX
XX
XX
XX
Q1
XX
XX
XX
XX
Q2 (Median)
XX.X
XX.X
XX.X
XX.X
Q3
XX
XX
XX
XX
Max
XX
XX
XX
XX
SD: Standard Deviation. Q1=Lower Quartile; Q2=Median; Q3=Upper Quartile.
Note: Time on treatment (in days) will be calculated per subject as the number of days with IMP intake during the trial. This will be calculated as Date of last IMP intake – Date of first IMP intake + 1.
Programming Note: Use the shell for 14.1.5.1 for
Table 14.1.5.1.3
Duration of Treatment Exposure
Safety Population (Japan)
C COPY 
XX.X
OP
XX.X
PUBLIC 
XX
COP
XX
XX
CO
XX
C C
of
L
of days
LIC
days w
C
w
thorization 
national
zat
national L
03
03
port any marketing auth
tin
tin
ting
XX
a
XX
ke
XX.X
ma
XX.X
XX.XX
m
XX.XX
X
This document cannot be used to supp
do
TIAL
s d
TIAL
p
IMP
u
IMP intake
up
intake d
uth
or variations thereof. 
ZX008
her
ZX008 OL
r
OL
(N
he
(N =
e
= X
ere
th
XX
ri
XX
XX.X
ari
XX.X
application and any extensions o
a
XX
va
XX
XX
v
XX
o
during
ns
during the
ns 
the tri
tri
Tabl
e
Tabl
Duration
ext
Duration
Saf
x
Saf


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 40 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.1.1
Duration of Treatment Exposure by Age Group
Safety Population
Subjects <6 years at Entry in Core Study
(N=xxx)
Subjects ≥6 years at Entry in Core Study
(N=xxx)
ALL ZX008 Treated Subjects
(N=xx)
Summary Stats
n
XX
XX
XX
Mean (days)
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min, Max
XX, XX
XX, XX
XX, XX
Duration of Exposure
<1 month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
1 to <3 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3 to <6 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6 to <12 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
12 to <18 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
18 to <24 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
24 to <30 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
30 to <36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
≥36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Note: De novo subjects are not included in this update. Duration of exposure is calculated from date of first dose in this study to the last date of treatment or data cutoff date for this report, whichever is
earlier.
Programming note:
Similar to DX21 in ISS, but population here is the 1503 safety population, and the duration is from day 1 in OLE study; add rows for 24-30 and 30-36 as show in shell
You may present two tables using by group of Age Group or present as above, whichever works best for programming.
Programming note: Use the shell for 14.1.5.1 for
Table 14.1.5.1.4
Duration of Treatment Exposure by Age Group
Safety Population (Japan)
UBLIC COPY 
Y
PY
OP
O
CO
C C
X.X%)
LIC
X.X%)
C
(XX.X%)
BLIC
(XX.X%)
LIC
X
B
X (XX.X%
BL
(XX.X%
BL
XX
UB
XX (XX
UB
(XX
UB
PU
XX
PU
XX (X
U
(X
U
XX
P
XX
PU
P
to support any marketing authorization 
uth
national
zat
national L
03
03
ke
ears
a
ears at
ark
at Entry
ark
Entry
(N=xxx)
mar
(N=xxx)
rk
ma
m
y
ny
a
t a
ort
po
po
po
po
po
pp
up
su
%)
to
%)
o s
used to
X.X%)
d to
X.X%)
to
XX.X%)
d t
XX.X%)
d t
X (XX.X%)
ed
(XX.X%)
ed
XX
s
XX (XX.X%
se
(XX.X%
se
us
XX
us
XX (XX
s
(XX
nnot be us
u
be
on
b
on of
b
of exposu
be
exposu
3
n
3 safety
nno
safety pop
o
pop
This document can
do
TIAL
s d
TIAL
ge Group or p
an
ge Group or p
for
c
for
nsions or variations thereof. 
th
n Core
s t
Core Study
s t
Study
)
t
on
XX
ti
XX
tio
XX.X
iat
XX.X
ati
XX.XX
ria
XX.XX
ia
XX.
ar
XX.
ar
XX
a
XX
va
r v
or
o
s 
on
oio
extensisi
ns
te
%)
e
%)
xte
y ex
.X%)
e
.X%)
and any ex
y e
ny
re
a
re is
an
is calculat
any
calculat
pulation,
and
pulation,
application a
a
and
d
and
present as ab
an
present as ab


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 41 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.1.2
Duration of Treatment Exposure by Sex
Safety Population
Female Subjects
Male Subjects
ALL ZX008 Treated Subjects
Summary Stats
n
XX
XX
XX
Mean (days)
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min, Max
XX, XX
XX, XX
XX, XX
Duration of Exposure
<1 month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
1 to <3 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3 to <6 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6 to <12 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
12 to <18 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
18 to <24 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
24 to <30 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
30 to <36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
≥36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Note: Duration of exposure is calculated from date of first dose in this study to the last date of treatment or data cutoff date for this report, whichever is earlier
Programming note:
Similar to DX22 in ISS, but add rows for 24-30, 30-36;
Programming note: Use the shell for 14.1.5.2 for
Table 14.1.5.1.5
Duration of Treatment Exposure by Sex
Safety Population (Japan)
LIC COPY
X
Y 
X
Y
PY
OP
O
CO
CO
CO
CO
CO
C C
)
L
)
C
PUBLIC
X%)
BL
X%)
LIC
X.X%)
BL
X.X%)
BL
(XX.X%)
UB
(XX.X%)
UB
XX
P
XX (XX.X%
PU
(XX.X%
U
PU
XX
P
XX (XX
PU
(XX
PU
(X
P
(X
P
to support any marketing authorization 
uth
national
zat
national L
03
03
ke
ALL
ark
ALL Z
rk
ar
ma
ma
ma
ma
ma
m
XX
n
XX
y
XX.X
a
XX.X
ny
XX,
t a
XX, XX
t a
XX
a
t a
ort
XX
po
XX (X
o
(X
po
XX
p
XX
pp
u
d to sup
su
su
su
su
su
o s
to
ed t
X%)
d
X%)
used t
X.X%)
ed
X.X%)
ed
(XX.X%)
use
(XX.X%)
se
This document cannot be us
do
TIAL
s d
TIAL
us
u
this
e
this study
e u
study to
u
to
r
s or variations thereof. 
th
X008
s
X008 Treate
s t
Treate
t
ns
X
on
tio
ati
ia
ari
ar
ar
ar
ar
va
r v
XX.X%)
or
XX.X%)
or
X (XX.X%)
s o
(XX.X%)
o
extensions
XX
n
XX (XX.X%
ns
(XX.X%
s 
XX
ion
XX (XX.
on
(XX.
on
XX
sio
XX (X
o
(X
io
XX
s
XX
si
tens
ns
te
te
te
te
te
xte
te
te
t
application and any ex
a
ex
y e
the
y
the last
y e
last date
y e
date


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 42 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.1.6
Duration of Treatment Exposure in ZX008-1502 and ZX008-1503 Combined
Subjects Treated in ZX008-1502 and ZX008-1503 Combined (Japan)
Time on Treatment (days)
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
All Subjects
(N = XX)
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX
XX
XX
XX
XX
Q1
XX
XX
XX
XX
XX
Q2 (Median)
XX.X
XX.X
XX.X
XX.X
XX.X
Q3
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
SD: Standard Deviation. Q1=Lower Quartile; Q2 = Median; Q3=Upper Quartile
Note: Time on treatment (in days) will be calculated per subject as the number of days with IMP intake during the trial. This will be calculated as Date of last IMP intake in ZX008-1502 or ZX008-1503 – Date
of first IMP intake in ZX008-1503 + 1. The duration includes the transition period in ZX008-1502.
BLIC COPY 
C
of
L
of days
LIC
days w
C
w
PUBL
period in ZX
BL
period in ZX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Gp3
etin
Gp3
(N
ket
(N =
et
= XX)
et
XX)
ting
ke
X
a
X
XX.X
t a
XX.X
XX
rt a
XX
XX
rt
XX
p
IMP
u
IMP intake 
up
intake 
08
08-
s
-1502.
su
1502.
uth
application and any extensions or variations thereof. 
a
ere
XX
n
XX
th
XX.X
on
XX.X
XX.XX
tio
XX.XX
XX
i
XX
o
during
ns
during the
s 
the trtr


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 43 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.1.7.1
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit
Safety Population
Subject dosage (mg/kg) assigned at Visit
Visit
Last Assigned Dose
Prior to Visit
Number
of
Subjects
0.2 mg/kg/day
0.3 mg/kg/day
0.4 mg/kg/day
0.5 mg/kg/day
0.6 mg/kg/day
0.8 mg/kg/day
Visit 2 – Day 15
Subjects attending Visit
0.2 mg/kg/day
XXX
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.3 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.4 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.5 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.6 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.8 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
Visit 3 – Month 1
Subjects attending Visit
0.2 mg/kg/day
xxx
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.3 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.4 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.5 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.6 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.8 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
Note: For each visit after Visit 1, the number of subjects who attended the visit is presented. The assigned dosage of ZX008 that the subject was on prior to that visit is provided in the row and the assigned
dosage at the conclusion of the visit is provided in the columns. Percentages are based on the number of subjects who attended the visit.
Programming Notes: This table was MAA34 in the ISS package. Continue for other scheduled visits in 1503 through Month 36. Use the Table 14.1.5.1.7.1 shell for
Table 14.1.5.1.7.2
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit
Safety Population (Japan)
PUBLIC COPY 
X
O
X (XX.X%)
OPY
(XX.X%)
XXX
CO
XXX (XX.X
CO
(XX.X
XXX
CO
XXX (X
CO
(X
XX
C
XX
%)
L
%)
X.X%)
BL
X.X%)
XXX
P
XXX (XX
P
(XX
thorization 
national
zat
national L
03
03
nnot be used to support any marketing auth
tin
o
kg)
e
kg) assigned
etin
assigned
/kg/day
ma
/kg/day
rke
XXX
t an
XXX (XX.
an
(XX.
m
XXX
t a
XXX
X%)
po
X%)
X
(XX.X%)
ppo
(XX.X%)
XX
u
XX (XX.X%)
upp
(XX.X%)
XXX
su
XXX (XX.X%
sup
(XX.X%
%)
d
%)
XX.X%)
sed
XX.X%)
X
u
X (XX.X%)
use
(XX.X%)
XXX
e u
XXX (XX.X%
u
(XX.X%
XXX
be
XXX (XX
(XX
XXX
be
XXX
cts
cts who
no
who atte
o
atte
This document can
do
TIAL
s d
TIAL
the columns
ann
the columns
n the
c
the ISS
ca
ISS pa
a
pa
uth
and any extensions or variations thereof. 
ere
d 
at
h
at Visit
he
Visit
0.5
io
0.5 mg/kg/d
ion
mg/kg/d
th
X%)
a
X%)
X
tio
XX.X%)
va
XX.X%)
XX
o
XX (XX.X%)
or v
(XX.X%)
XXX
o
XXX (XX.X%
or
(XX.X%
XXX
s 
XXX (X
o
(X
%)
o
%)
XXX
s
XXX
XXX
e
XXX (XX.X%)
en
(XX.X%)
XXX
xte
XXX (XX.X
e
(XX.X
XXX
x
XXX (
)
X
.X%)
n
.X%)
(XX.X%)
an
(XX.X%)
nded the
nd
nded the
application a
a
visi
d
visi
s. Percentage
an
s. Percentage
ckage.
on
ckage. Contin
n 
Contin


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 44 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.8.1
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment
Safety Population
Number of Subjects[2] Receiving ZX008
Duration
(Months)
Mean Dose (mg/kg)[1]
Any Dose
>0 to 0.2 (n)
>0.2 to 0.4 (n)
>0.4 to 0.6 (n)
>0.6 to 0.8 (n)
Total(N)
(%)
≤1
XX
XX
XX
XX
XX
XX.X
>1 to ≤2
XX
XX
XX
XX
XX
XX.X
>2 to ≤3
XX
XX
XX
XX
XX
XX.X
>3 to ≤4
XX
XX
XX
XX
XX
XX.X
>4 to ≤5
XX
XX
XX
XX
XX
XX.X
>5 to ≤6
XX
XX
XX
XX
XX
XX.X
>6 to ≤7
XX
XX
XX
XX
XX
XX.X
>7 to ≤8
XX
XX
XX
XX
XX
XX.X
>8 to ≤9
XX
XX
XX
XX
XX
XX.X
>9 to ≤10
XX
XX
XX
XX
XX
XX.X
>10 to ≤11
XX
XX
XX
XX
XX
XX.X
>11 to ≤12
XX
XX
XX
XX
XX
XX.X
>12 to ≤18
XX
XX
XX
XX
XX
XX.X
>18 to ≤24
XX
XX
XX
XX
XX
XX.X
>24 to ≤30
XX
XX
XX
XX
XX
XX.X
>30 to ≤36
XX
XX
XX
XX
XX
XX.X
>36 to ≤42
XX
XX
XX
XX
XX
XX.X
>42 to ≤48
XX
XX
XX
XX
XX
XX.X
Total (Any Duration)
XX
XX
XX
XX
XX
XX.X
%
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
(%): (n/N) * 100  n: Number in each dosage group. N: total number for the month
[1] The mean daily dose is calculated over a subject’s entire treatment period in the trial.
[2] The tabulated frequency in a given cell is the number of subjects whose exposure duration is in that row, and whose mean daily dose over the entire treatment period falls in the specified column. The
duration endpoints, in days, are 30, 60, 90, 120, … , 330, 360; for example, a subject exposed for 70 days will be counted in the >2 to ≤3 months row. The mean daily dose is then calculated for each subject
for dose categorization. For example, if the above subject had a mean daily dose of 0.7 mg/kg during 70 days of exposure, that subject will be counted in the >0.6 to 0.8 mg/kg column.
Programming Note: This table is calculated by first categorizing subjects on the basis of the interval of exposure for each (e.g., a subject exposed for 6 and a half months would be counted in the >6 to ≤7
row. The mean daily dose is then calculated for each subject for dose categorization (e.g., a subject with a mean daily dose of 0.5 mg/kg would be counted in the >0.4 to 0.6 column). Subjects are
enumerated in only 1 cell of the matrix (i.e., this is a mutually exclusive display). Mean doses in the >4 to ≤5 row refer to mean doses over 0-5 months, not month 4-5.
PUBLIC COPY 
XX
Y
XX
XX
PY
XX
Y
XX
PY
XX
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
LIC
XX
UB
XX
BL
XX
UB
XX
UB
XX
PU
XX
PU
X
P
X
P
thorization 
national
zat
national L
03
03
be used to support any marketing auth
Treatment
au
Treatment
X008
ti
X008
ting
eti
>0.6
rk
>0.6 to
rke
to 0.8 
ke
0.8 (n
(n
ke
XX
rk
XX
rk
X
a
ma
m
y y
any
X
t
X
a
XX
ort
XX
rt
XX
por
XX
or
XX
ppo
XX
po
XX
pp
XX
pp
up
su
o s
o
to
d t
XX
s
XX
ed
XX
us
XX
se
us
XX
u
XX
u
annot be
XX
e
XX
be
b
number
t b
number for
b
for
re
re treatmen
ot
treatmen
mber of subje
nno
mber of subje
…
This document ca
do
TIAL
s d
TIAL
,
a
, 33
an
330, 360;
an
0, 360;
bove subject
ca
bove subject
ted
n
ted by
nt
by first
nt 
first
lculated for e
en
lculated for e
matrix (i.e., t
me
matrix (i.e., t
uth
ny extensions or variations thereof. 
ere
he
th
n)
s
n)
th
th
th
th
s t
X
ns
XX
io
XX
on
XX
atio
XX
tio
XX
at
XX
at
X
a
X
ria
ar
va
r v
r v
r v
r v
r v
or
X
s o
XX
n
XX
ns
XX
ion
XX
on
XX
sio
XX
io
XX
s
XX
s
en
te
xtxtxt
ext
ex
ex
ex
ex
y e
n and any e
X.X
a
X.X
ny
an
the
d a
the month
an
month
t period
d a
period in
a
in th
a
th
cts whose ex
and
cts whose ex
application
a
for
for example
an
example
had a mean 
on a
had a mean 
categorizing
atio
categorizing
each subject 
cat
each subject 
his is a mut
lica
his is a mutu
a
u


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 45 of 234
Draft 3.0: 04Aug2020
Programming Note: Use the same shell for Table 14.1.5.1.8.1 shell for
Table 14.1.5.8.2
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment
Safety Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
of
of Treatmen
g a
Treatmen
uth
application and any extensions or variations thereof. 
a
t


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 46 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.1.9.1
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment
Safety Population
Number of Subjects[2] Receiving ZX008
Duration
(Months)
Mean Dose (mg/day) [1]
Any Dose
< 5 (n)
5 - <10 (n)
10 - < 20 (n)
20 – 30 (n)
Total(N)
(%)
≤1
XX
XX
XX
XX
XX
XX.X
>1 to ≤2
XX
XX
XX
XX
XX
XX.X
>2 to ≤3
XX
XX
XX
XX
XX
XX.X
>3 to ≤4
XX
XX
XX
XX
XX
XX.X
>4 to ≤5
XX
XX
XX
XX
XX
XX.X
>5 to ≤6
XX
XX
XX
XX
XX
XX.X
>6 to ≤7
XX
XX
XX
XX
XX
XX.X
>7 to ≤8
XX
XX
XX
XX
XX
XX.X
>8 to ≤9
XX
XX
XX
XX
XX
XX.X
>9 to ≤10
XX
XX
XX
XX
XX
XX.X
>10 to ≤11
XX
XX
XX
XX
XX
XX.X
>11 to ≤12
XX
XX
XX
XX
XX
XX.X
>12 to ≤18
XX
XX
XX
XX
XX
XX.X
>18 to ≤24
XX
XX
XX
XX
XX
XX.X
>24 to ≤30
XX
XX
XX
XX
XX
XX.X
>30 to ≤36
XX
XX
XX
XX
XX
XX.X
>36 to ≤42
XX
XX
XX
XX
XX
XX.X
>42 to ≤48
XX
XX
XX
XX
XX
XX.X
Total (Any Duration)
XX
XX
XX
XX
XX
XX.X
%
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
(%): (n/N) * 100  n: Number in each dosage group. N: total number for the month
[1] The mean daily dose is calculated over a subject’s entire treatment period in the trial.
[2] The tabulated frequency in a given cell is the number of subjects whose exposure duration is in that row, and whose mean daily dose over the entire treatment period falls in the specified column. The
duration endpoints, in days, are 30, 60, 90, 120, … , 330, 360. For example, a subject exposed for 70 days will be counted in the >2 to <=3 months row. The mean daily dose, in mg/day, is then calculated for
each subject for dose categorization.
Programming Note: See MAA Table 14.1.5.3_120_mg_day.
Use the same shell for Table 14.1.5.1.9.1. shell for
Table 14.1.5.1.9.2
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment
Safety Population (Japan)
PUBLIC COPY 
XX
Y
XX
XX
PY
XX
Y
XX
PY
XX
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
LIC
XX
UB
XX
BL
XX
UB
XX
UB
XX
PU
XX
PU
X
P
X
P
thorization 
national
zat
national L
03
03
be used to support any marketing auth
of
of Treatmen
au
Treatmen
X008
ti
X008
ting
eti
20
rk
20 –
k
– 30
ke
30 (n)
e
(n)
ke
XX
rk
XX
rk
X
a
ma
m
y y
any
X
t
X
a
XX
ort
XX
rt
XX
por
XX
or
XX
ppo
XX
po
XX
pp
XX
pp
up
su
o s
o
to
d t
XX
s
XX
ed
XX
us
XX
se
us
XX
u
XX
u
t cannot be
XX
e
XX
be
b
number
t b
number for
b
for
tire
no
tire treatme
not
treatme
mber of subj
nno
mber of subj
… ,
a
, 33
an
330,
an
0, 360
n
360
This document 
do
TIAL
s d
TIAL
.3_120_mg_
nt c
.3_120_mg_
.1. shell for
nt
.1. shell for
uth
ny extensions or variations thereof. 
ere
he
th
th
th
th
th
s t
X
ns
XX
io
XX
on
XX
atio
XX
tio
XX
at
XX
at
X
a
X
ria
ar
va
r v
r v
r v
r v
r v
or
X
s o
XX
n
XX
ns
XX
ion
XX
on
XX
sio
XX
io
XX
s
XX
s
en
te
xtxtxt
ext
ex
ex
ex
ex
y e
application and any e
a
e
X.X
a
X.X
ny
an
the
d a
the month
an
month
nt
nt period
nd 
period inin t
ects whose e
and
ects whose e
For
For example
an
example
_day.
tio
_day.
Num
ca
Num


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 47 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.1.10.1
Number of Subjects Receiving ZX008 According to Actual Daily Dose (mg/kg) and Duration of Treatment
Safety Population
Number of Subjects[2] Receiving ZX008
Duration
(Months)
Actual Daily Dose (mg/kg) [1]
Any Dose
>0 to 0.2 (n)
>0.2 to 0.4 (n)
>0.4 to 0.6 (n)
>0.6 to 0.8 (n)
Total(N)
(%)
≤1
XX
XX
XX
XX
XX
XX.X
>1 to ≤2
XX
XX
XX
XX
XX
XX.X
>2 to ≤3
XX
XX
XX
XX
XX
XX.X
>3 to ≤4
XX
XX
XX
XX
XX
XX.X
>4 to ≤5
XX
XX
XX
XX
XX
XX.X
>5 to ≤6
XX
XX
XX
XX
XX
XX.X
>6 to ≤7
XX
XX
XX
XX
XX
XX.X
>7 to ≤8
XX
XX
XX
XX
XX
XX.X
>8 to ≤9
XX
XX
XX
XX
XX
XX.X
>9 to ≤10
XX
XX
XX
XX
XX
XX.X
>10 to ≤11
XX
XX
XX
XX
XX
XX.X
>11 to ≤12
XX
XX
XX
XX
XX
XX.X
>12 to ≤18
XX
XX
XX
XX
XX
XX.X
>18 to ≤24
XX
XX
XX
XX
XX
XX.X
>24 to ≤30
XX
XX
XX
XX
XX
XX.X
>30 to ≤36
XX
XX
XX
XX
XX
XX.X
>36 to ≤42
XX
XX
XX
XX
XX
XX.X
>42 to ≤48
XX
XX
XX
XX
XX
XX.X
Total (Any Duration)
XX
XX
XX
XX
XX
XX.X
%
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
(%): (n/N) * 100  n: Number in each dosage group. N: total number for the month
[1] The actual dosage in mg/day assigned by the investigator over the course of the study..
[2] The times on a particular dosate may not be concurrent. The tabulated frequency in a given cell is the number of subjects whose exposure duration is in that row, and whose assigned dosage over the
entire treatment period falls in the specified column. The duration endpoints, in days, are 30, 60, 90, 120, … , 330, 360;
Programming Note: Use the same shell for Table 14.1.5.1.10.1. shell for
Table 14.1.5.1.10.2
Number of Subjects Receiving ZX008 According to Actual Dose (mg/day) and Duration of Treatment
Safety Population (Japan)
PUBLIC COPY 
XX
Y
XX
XX
PY
XX
Y
XX
PY
XX
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
LIC
XX
UB
XX
BL
XX
UB
XX
UB
XX
PU
XX
PU
X
P
X
P
thorization 
national
zat
national L
03
03
used to support any marketing auth
n of
a
of Treatm
au
Treatm
X008
ti
X008
ting
eti
>0.6
rk
>0.6 to
rke
to 0.8 
ke
0.8 (n
(n
ke
XX
rk
XX
rk
X
a
ma
m
y y
any
X
t
X
a
XX
ort
XX
rt
XX
por
XX
or
XX
ppo
XX
po
XX
pp
XX
pp
up
su
o s
o
to
d t
XX
s
XX
ed
XX
us
XX
se
us
annot be u
XX
u
XX
u
XX
e
XX
be
b
number
t b
number for
b
for
tigator
nno
tigator over
no
over
This document ca
do
TIAL
s d
TIAL
oncurrent.
ann
oncurrent. T
n
T
olumn. The 
can
olumn. The 
for
n
for Table
nt 
Table 14
14
uth
y extensions or variations thereof. 
nt
o
nt
ere
he
th
n)
s
n)
th
th
th
th
s t
X
ns
XX
io
XX
on
XX
atio
XX
tio
XX
at
XX
at
X
a
X
ria
ar
va
r v
r v
r v
r v
r v
or
X
s o
XX
n
XX
ns
XX
ion
XX
on
XX
sio
XX
io
XX
s
XX
s
en
te
xtxtxt
ext
ex
ex
n and any ex
ex
ex
y e
X.X
a
X.X
ny
an
the
d a
the month
an
month
he
n
he course
nd
course
application 
a
o
he
he tabulated
an
tabulated
duration end
n a
duration end
1.5.1.10.1.
tio
1.5.1.10.1.
Num
ca
Num


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 48 of 234
Draft 3.0: 04Aug2020
Table 14.1.5.2.1
Compliance to IMP intake
Safety Population
Gp1
Gp8
ZX008 OL
De Novo Subjects
(N = XX)
(N = xx)
(N = XX)
(N = XX)
Overall compliance % during OLE Treatment Period
N
XX
XX
XX
XX
Mean
XX.XX
XX.XX
XX.XX
XX.XX
SD
XX.XXX
XX.XXX
XX.XXX
XX.XXX
Median
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX.X
XX.X
XX.X
XX.X
Max
XX.X
XX.X
XX.X
XX.X
Compliance category
<80%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
80-<90%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
90-<100%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
100-<110%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
>110%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
IMP = Investigational medicinal product; OL=Open-label; OLE=Open-label Extension.
Note: Percentages are calculated based on the number of subjects with non-missing data in the Safety population.
Programming Note: For each day, based on the response to the daily diary, a missed dose=0% of dose consumed, partial=50% of dose consumed, and full=100% of dose consumed. For each subject, a daily
compliance score will be thus obtained. The total score for the subject during the study will then be divided by the number of days on study and multiplied by 100.
PUBLIC COPY 
XX.XX
Y
XX.XX
XX.XXX
PY
XX.XXX
XX.X
PY
XX.X
%)
B
%)
X.X%)
UB
X.X%)
(XX.X%)
PUB
(XX.X%)
XX
P
XX (XX.X%
PU
(XX.X%
thorization 
national
zat
national L
03
03
ed to support any marketing auth
ZX008
et
ZX008
eti
(N
e
(N
ark
X
XX.X
o
XX.X
XXX
up
XXX (X
pp
(X
XXX
u
XXX
X
t be used
ed
Extension.
se
Extension.
h non
us
non-
us
-missin
us
missin
he
t
he daily
t be
daily diar
be
diar
This document cannot
do
TIAL
s d
TIAL
r the subject
ot b
r the subject
uth
tensions or variations thereof. 
OL
th
OL
he
= XX)
s th
XX)
XX
XX
s t
X
X.X%)
ns
X.X%)
(XX.X%)
ons
(XX.X%)
XX
i
XX (XX.X%)
sio
(XX.X%)
XXX
nsi
XXX (XX.X%
si
(XX.X%
any exte
XXX
ens
XXX (XX
s
(XX
xte
g data
ex
data in
ex
in the
x
the
y,y, a
a
a missed
any
missed d
y
d
application and a
a
t during the s
d a
t during the s


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 49 of 234
Draft 3.0: 04Aug2020
Programming note: use table shell for 14.1.5.2.1 for the production of
Table 14.1.5.2.1.1
Compliance to IMP intake
Safety Population (Japan)
Table 14.1.5.2.2
Compliance to IMP intake
mITT Population
Table 14.1.5.2.2.1
Compliance to IMP intake
mITT Population (Japan)
PY 
14.1.
Y
14.1.
liance
PY
liance to
Y
to IM
Y
IM
PUBLIC COP
TT Popula
OPY
TT Popula
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
intake
any
intake
n (Japan)
t an
n (Japan)
uth
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 50 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.1.1
Convulsive seizure frequency per 28 days during Baseline (Core), Double-blind and OLE Treatment Period:
Summary statistics and Tests of Changes from Baseline
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
Baseline[1]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) [2]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M [3]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
X)
O
X)
OP
O
, XX.X
CO
XX.X
CO
C C
C
XX
IC
XX
LIC
XX.X
BL
XX.X
BL
UB
U
PU
PU
PU
PU
PU
P
cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
E Treatment
g 
Treatment
OL
m
OL
)
ZX
ar
ZX 0
rk
ma
m
y
XX
an
XX
ny
XX.X
t a
XX.X (XX.X
a
(XX.X
an
XX.X
t 
XX.X
t a
XX.X
or
XX.X
ort
po
pp
pp
pp
pp
pp
up
XX.XX)
su
XX.XX)
su
XX.X
o
XX.X
s
XX.X,
d to
XX.X, XX.X
to
XX.X
to
d t
d
se
u
XX
s
XX
us
u
XX.X
be
XX.X
be
be
t b
XX
no
XX
ot
XX.X
nn
XX.X (XX
n
(XX
no
X
n
ca
XX
a
XX
This document ca
do
TIAL
s d
TIAL
a
ca
c
t
en
e
m
um
n and any extensions or variations thereof. 
Period:
eo
Period:
.8
n
.8 –
n
– ZX008
ns
ZX008
(N = XX
ion
(N = XX
t
io
ati
ia
ari
XX)
va
XX)
ari
ari
ari
ar
X
va
X,
o
X, XX.X
r v
XX.X
v
or
o
XX
s
XX
s
XX.X
on
XX.X (
n
io
sisisisi
nsi
ns
ns
ns
ns
ten
XX
ex
XX
xte
X.X
X.X (XX.XX
ex
(XX.XX
ex
XX.X
y e
XX.X
e
XX.X,
ny
XX.X, X
y
any
a
d
X.XX)
an
X.XX)
nd
X.X
X.X
an
on a
X.X,
on
X.X, XX.X
n a
XX.X
application
a
n a
on
tio
X
at
XX.X
ca
XX.X
ca
lilililic
plpli
plpl


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 51 of 234
Draft 3.0: 04Aug2020
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M Change
from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M % Change
from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month1 (OLE)
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month1 (OLE) Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month1 (OLE) % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
OP
XX
C
XX
CO
X
C
X (XX.XX
C C
(XX.XX
C C
XX.X
LIC
XX.X
C
XX.X,
BLIC
XX.X,
LIC
BL
UB
U
PU
PU
X)
P
X)
PU
PU
PU
PU
P
d to support any marketing authorization 
uth
national
zat
national L
03
03
008
a
008 OL
au
OL
= XX)
g
= XX)
ut
ut
ut
ut
X.X,
in
X.X, XX.X
ng
XX.X
g
ing
eti
rk
a
)
m
)
X
ar
ma
ma
ma
ma
ma
XX.X
y
XX.X
m
y
ny
a
ort
p
XX
po
XX
po
pp
pp
pp
pp
pp
X.X
su
X.X
up
su
o s
XX
d to
XX
to
t cannot be used t
XX.X
d t
XX.X (XX
 t
(XX
d t
XX
d
XX
ed
XX
e
XX
se
us
u
be
(XX.XX)
t b
(XX.XX)
be
XX.X
ot
XX.X
t b
XX.X,
no
XX.X, XX.
o
XX.
ot
no
n
a
c
ment c
X
c
nt
en
me
This docum
do
TIAL
s d
TIAL
m
um
nsions or variations thereof. 
All
f
All
comb
of. 
com
(N 
f
(N 
e
X
o
X
eo
re
re
re
re
ere
he
XX
s
XX
t
X.X
n
X.X (XX.XX
ns
(XX.XX
ns
XX.X
on
XX.X
on
XX.X,
tio
XX.X,
tio
ati
ia
ari
ar
ar
ar
ar
XX
o
XX
r v
X (XX.XX)
or
(XX.XX)
or
XX.X
s o
XX.X
o
XX.X,
ns
XX.X, X
s 
on
io
sisi
on and any extensisi
nsi
XX)
te
XX)
ns
ns
ns
ns
.X
xt
.X
te
X,
e
X, XX.X
ext
XX.X
xte
ex
y e
XX
y
XX
ny
XX.X
an
XX.X
any
a
d
X
d
nd
an
XX
n
XX
n a
application
a
XX.X
io
XX.X (XX.XX
on
(XX.XX
on
XX.X
tio
XX.X
tio
XX.X
at
XX.X
at
ca
lilililic
pli
p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 52 of 234
Draft 3.0: 04Aug2020
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
Month2 (OLE)
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month2 (OLE) Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month2 (OLE) % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
……
Repeat for Month3, Month4-6, Month7-9,
Month10-12, Month13-15, Month16-18,
Month19-21, Month22-24, Month 25-27,
Month 28-30, Month 31-33, Month 34-36
ENDPOINT1: Overall OLE Treatment
Period
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT1: Overall OLE Treatment
Period Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
PUBLIC COPY
XX
Y 
XX
Y
PY
PY
PY
PY
PY
X
O
X
OP
O
CO
XX
C C
XX
C C
XX.X
LIC
XX.X (XX
IC
(XX
C 
XX
LIC
XX
LIC
XX
BL
XX
BL
UB
U
PU
PU
PU
PU
PU
PU
PU
PU
PU
to support any marketing authorization 
uth
national
zat
national L
03
03
008
a
008 OL
au
OL
= XX)
g
= XX)
ut
ut
ut
ut
g
XX
ting
XX
ing
XX.X
ket
XX.X (XX
ti
(XX
eti
XX
e
XX
ke
XX
k
XX
rk
ar
ma
ma
ma
ma
ma
X
m
(XX.XX)
ny
(XX.XX)
y
XX.X
any
XX.X
ny
XX.X,
t a
XX.X, XX
a
XX
a
rt
or
po
pp
X)
u
X)
pp
pp
pp
pp
up
, XX.X
su
XX.X
su
X.XXX
to s
X.XXX
o s
This document cannot be used to
do
TIAL
s d
TIAL
to
d t
u
be
XX
ot
XX
t b
XX.X
no
XX.X (XX.X
no
(XX.X
ot
XX.X
n
XX.X
no
XX.X
an
XX.X
nn
a
ca
c
n
e
m
um
cu
sions or variations thereof. 
All
f
All
comb
of. 
com
(N 
f
(N 
eo
re
re
re
re
ere
X.XX)
th
X.XX)
he
X.X
t
X.X
th
X.X,
s
X.X, XX.X
s t
XX.X
s t
ns
on
X
o
X
tio
XX.X
at
XX.X
at
riririria
ari
X
v
X
ar
ar
ar
ar
va
r v
XX
o
XX
or
XX.X
s
XX.X (XX.X
s o
(XX.X
o
XX.X
s
XX.X
ns
XX.X
on
XX.X
on
io
application and any extensi
a
sisisisi
ns
n
e
ny
a
d
X)
n
X)
d
nd
, XX.X
a
XX.X
an
n a
on
X
ati
XX.X
ca
XX.X
ca
lilililic
pli
plplpl
pplp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 53 of 234
Draft 3.0: 04Aug2020
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
ENDPOINT1: Overall OLE Treatment
Period % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
ENDPOINT2: Month02-EOS
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS Change from
Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS % Change
from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
*Includes subjects randomizedto placebo and all doses of ZX008 during DB.
** For De Novo subjects, the baseline period is the 28 days prior to dosing in ZX008-1503. Change from baseline for this group is calculated relative to this baseline period.
T+M = Titration + Maintenance; OLE = Open-label extension; SD = Standard deviation; Chg = Change; EOS = End of study
Data from core study includes subjects on Placebo as well as ZX008.
[1] Baseline=Baseline prior to double-blind treatment in the core study or 28 days prior to dosing in ZX008-1503 for De Novo Subjects. Subjects in 1504-C1 do not have a Baseline(Core).
[2] Core Study (T+M) is the entire Titration+Maintenance Period during the Core study; does not include the transition period.
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
OP
X.XX)
CO
X.XX)
O
X.X
C
X.X
CO
X.X,
C
X.X, XX.X
C C
XX.X
C C
C
LIC
UB
U
X)
P
X)
U
PU
PU
PU
PU
PU
P
ot be used to support any marketing authorization 
uth
national
zat
national L
03
03
008
a
008 OL
au
OL
= XX)
g
= XX)
ut
ut
ut
ut
g
ing
X
ke
XX.X
rk
XX.X
rk
ar
ma
.X
.X
ma
ma
ma
ma
XX
y
XX
m
y
ny
XX
a
XX
a
XX.X
ort 
XX.X (X
(X
t
X
or
p
X
o
X
po
pp
pp
pp
pp
pp
up
XX
to
XX
o s
X.X
d t
X.X (XX.XX
to
(XX.XX
to
XX.X
d t
XX.X
d t
XX.X,
ed
XX.X,
ed
se
us
u
be
(XX.XX)
t b
(XX.XX)
be
XX.X
ot
XX.X
t b
not
XX.X,
no
XX.X, XX.
o
XX.
This document canno
do
TIAL
s d
TIAL
ot
X.XX
nn
X.XX
no
n
a
d all
c
all doses
ca
doses of
a
of
iod
nt
iod is the
t c
is the 28
c
28
= Open
ent
= Open-
n
-labe
nt
labe
ects
m
ects on
me
on Plac
e
Plac
ouble
um
ouble-
m
-blind
m
blind
ntire
cu
ntire Titratio
cum
Titratio
nd any extensions or variations thereof. 
All
f
All
comb
of. 
com
(N 
f
(N 
eo
re
re
re
re
ere
X
th
X (XX.XX)
s t
(XX.XX)
t
XX.X
ns
XX.X
ns
XX.X,
ion
XX.X, XX
n
XX
on
X.X
o
X.X
tio
ati
ia
ari
ar
ar
ar
ar
X.XX)
va
X.XX)
va
X.X
or
X.X
r v
X.X,
o
X.X, XX.X
or
XX.X
or
o
s
io
si
X)
X)
X
sisisi
nsi
ns
ns
ns
ns
XX.X
xte
XX.X
te
xte
ex
XX
y
XX
ny
XX.X
an
XX.X
any
a
d
X
plication and 
d
X
a
X
nd
an
n a
ZX008
on
ZX008 durin
n 
durin
days
tio
days prior
ion
prior to
to
extension;
ati
extension;
ebo
ic
ebo as
ica
as well
ca
well a
reatment
plic
reatment in
c
in
app
a
n+Maintena
pp
n+Maintena


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 54 of 234
Draft 3.0: 04Aug2020
[3] Core Study Final Week of T+M is the last 7 days of the T+M period.
[4]P-value for within group % change from baseline is based on Wilcoxon signed rank test that the % change from baseline is statistically significantly different from 0.
Programming note:
P-values are only calculated for the OLE Period, starting from Month1 onward. The p-value will be obtained for the percentage change from baseline, not the change from baseline. Please see SAP section
6.1.6. It does does matter whether we attach the p-value to the change stats or the percent change stats; Zogenix wantsthe p-value from the analysis of the percentage changes from baseline. Use the
round function to get the percentage change to 3 or 4 decimal places before calculating pccs25yn, pccs50yn, pccs75yn and especially pccs00yn.]
Code to get p-value for percentage change at each time point:: calculate the percentage change from baseline:
For example:
Data temp;
Set data1;
if base ne . and twval ne .;
chng = base – twval;
pctchng=(base – twval)/base;
run;
ods trace on;
ods output TestsForLocation=univout;
proc univariate data=anal;
var pctchng;
run;
ods trace off;
data dpout;
set univout;
where Test='Signed Rank' and Testlab='S';
pout=pValue; **be sure to write “<0.001” if the p-value is <0.001;
keep pctchng Test pout;
run;
Programming Note: Use the same 14.2.1.1.1 shell for
Table 14.2 1.1.6
Convulsive seizure frequency per 28 days during Baseline (Core), Double-blind and OLE Treatment Period:
Summary statistics and Tests of Changes from Baseline
mITT Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
nificantly dif
g a
nificantly dif
nge
ket
nge from
eti
from ba
ba
value
ke
value from t
ke
from t
 especially p
ark
 especially p
s <0.001;
ot b
<0.001;
for
a
for
Conv
ca
Conv
uth
application and any extensions or variations thereof. 
a
ferent
of
ferent from
of.
from
seline,
he
seline, not
e
not th
r
th
he
he analysis
th
analysis o
ccs00yn.]
s t
ccs00yn.]
ulsive
on
ulsive seizur
on
seizur


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 55 of 234
Draft 3.0: 04Aug2020
Programming Note: Use the shell for 14.2.1.1.1 to produce:
Table 14.2.1.1.2
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group:
Summary statistics and Tests of Changes from Baseline
mITT Population
Table 14.2.1.1.7
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group:
Summary statistics and Tests of Changes from Baseline
mITT Population (Japan)
Programming Note: Add Header, top left, prior to the table proper, “Age Group: <6 years” or “Age Group: >= 6 years”
PUBLIC COPY 
Popu
Y
Popu
Table
OPY
Table 14
P
14
per
CO
per 28
CO
28 day
O
day
statistics
CO
statistics a
O
a
m
C
m
oup:
BL
oup: <6
BLI
<6 yea
LI
yea
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ment
ma
ment Period,
mar
Period,
from
m
from Baselin
m
Baselin
1.1.7
t a
1.1.7
during
rt
during OLE
t a
OLE T
a
T
Tests
o
Tests of
or
of Cha
r
Cha
T Population
ppo
T Population
or
s
or “Age
sup
“Age Gr
p
Gr
application and any extensions or variations thereof. 
a
by
by Age
ns
Age Grou
ns
Grou
e
i
e
eatment
va
eatment Pe
a
Pe
nges
or
nges from
or v
from B
v
B
(Japan)
or
(Japan)
oup:
on
oup: >=
ons
>= 6
ns
6 yea
s
yea


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 56 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.1.3
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose: Summary Statistics and Tests of Changes from Baseline
mITT Population
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
Baseline[1]
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) [2]
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) % Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M [3]
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
PUBLIC COPY 
Y
XX.X
PY
XX.X
PY
OP
OP
CO
C
C C
C
X)
BL
X)
LIC
BL
XX.X
UB
XX.X
UB
UB
PU
XX
P
XX
P
t be used to support any marketing authorization 
uth
national
zat
national L
03
03
atistics
ng
atistics and
g 
and T
ZX008
ke
ZX008 H
tin
ar
ma
m
y
XX.XX)
any
XX.XX)
ny
XX.X
t a
XX.X
an
XX.X,
rt
XX.X, XX.X
rt 
XX.X
t a
ort
po
pp
XX
p
XX
up
su
s
o
to 
o
d t
d
XX.XX)
se
XX.XX)
e
XX.X
u
XX.X
us
XX.X,
e
XX.X, XX.X
e u
XX.X
u
e
be
ment cannot b
t b
XX
o
XX
ot
no
nn
an
an
an
an
a
ca
t
n
e
This docum
do
TIAL
s d
TIAL
m
um
cu
any extensions or variations thereof. 
ests
e
ests of
eo
of Chan
eo
Chan
High
t
High Mean
th
Mean Da
Da
(>0.6 mg/
s t
(>0.6 mg/
(N
s
(N =
her
n
io
ati
iaiaiaia
ria
ariririri
va
v
or
XX
s
XX
o
X.X
n
X.X (XX.XX
ns 
(XX.XX
s
XX.X
on
XX.X
n
XX.X,
sio
XX.X,
io
si
ns
ten
xte
ex
ex
ex
ex
ex
e
y 
any
lication and a
XX
d
XX
a
.X
n
.X (XX.XX)
nd 
(XX.XX)
d
XX.X
and
XX.X
nd
XX.X,
a
XX.X, X
an
n a
on
tio
at
ca
ca
ca
applica
a
ca
ca
lic
pl
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 57 of 234
Draft 3.0: 04Aug2020
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
Core Study Final Week of T+M Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M % Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month 1 (OLE)
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month 1 (OLE) Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
Month 1 (OLE) % Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
PUBLIC COPY 
Y
OP
O
CO
C C
C C
C C
C C
C C
C 
C
LIC
BL
XX.XX)
UB
XX.XX)
UB
XX.X
PU
XX.X
PU
X.X,
P
X.X, XX
P
XX
PU
P
ent cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
gh
gh Mean
au
Mean Dai
au
Dai
(>0.6 mg/k
g a
(>0.6 mg/k
(N
ng
(N =
g
= X
g
X
ut
ting
ke
rk
ar
ar
ar
ar
ar
ma
m
y
XX
t a
XX
a
X.X
ort
X.X (XX.XX
ort 
(XX.XX
rt
XX.X
or
XX.X
or
XX.X
ppo
XX.X
po
pp
up
su
o s
o
to
d t
ed
se
XX
u
XX
us
X.X
e
X.X (XX.XX
e u
(XX.XX
u
XX.X
be
XX.X
be 
XX.X,
t b
XX.X,
b
X
t
o
n
n
an
an
an
an
ca
t c
nt
men
en
me
This docum
do
TIAL
s d
TIAL
m
um
cation and any extensions or variations thereof. 
ly
o
ly Dose*
of
Dose*
kg)
e
kg)
XX)
r
XX)
ere
XX
th
XX
th
XX.X
s t
XX.X (XX
t
(XX
s t
X
s
X
ns
XX
n
XX
on
tio
at
ria
ar
X)
X)
va
r v
, XX.X
or
XX.X
or
o
ns
XX
on
XX
on
XX.X
sio
XX.X (X
o
(X
io
si
X
n
te
xt
ex
ex
ex
ex
ex
X)
n
X)
y e
ny
XX.X
a
XX.X
any
.XXX
d a
.XXX
d a
d
nd
XX
a
XX
a
XX.X
n 
XX.X
n a
on
tio
a
plicat
at
ca
ca
ca
ca
ca
applic
a
lic
p c


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 58 of 234
Draft 3.0: 04Aug2020
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
Month 2 (OLE)
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month 2 (OLE) Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month2 (OLE) % Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
……
Repeat for Month3, Month6, Month9, Month12,
Month15, Month18, Month21, Month24
ENDPOINT1: Overall OLE Treatment Period
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT1: Overall OLE Treatment Period
Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
PUBLIC COPY 
Y
XX.
PY
XX.
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
XX)
BL
XX)
LIC
X
U
X
BL
X,
U
X, XX.X
UB
XX.X
UB
X.XXX
PU
X.XXX
PU
P
ment cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
gh
gh Mean
au
Mean Dai
au
Dai
(>0.6 mg/k
g a
(>0.6 mg/k
(N
ng
(N =
g
= X
g
X
ut
ting
eti
X
ke
rk
ar
a
ma
m
y 
(XX.XX)
any
(XX.XX)
any
XX.X
t a
XX.X
a
XX.X,
ort
XX.X, XX.X
rt 
XX.X
rt
or
po
pp
X
p
X
up
su
o s
o
to
d t
ed
us
u
be
X
b
XX.X
ot 
XX.X
ot
o
n
an
an
an
an
an
od
od
ca
nt
en
me
um
This docu
do
TIAL
s d
TIAL
um
lication and any extensions or variations thereof. 
ly
o
ly Dose*
of
Dose*
kg)
e
kg)
XX)
r
XX)
ere
XX
the
XX
he
XX.X
th
XX.X (XX.X
th
(XX.X
th
XX.X
s t
XX.X
s t
XX.X
ns
XX.X
ns
on
tio
at
ria
ria
ria
ria
ria
ar
X
va
r v
or
XX
s
XX
s o
X.X
n
X.X (XX.XX
ons
(XX.XX
ns
XX.X
on
XX.X
on
XX.X
sio
XX.X
io
X
s
en
te
ex
ex
ex
ex
ex
y e
ny
X
an
(XX.XX)
d a
(XX.XX)
d a
XX.X
nd
XX.X
d
XX.X,
an
XX.X, XX
n
XX
nd
a
n
tio
at
ca
ca
ca
plica
ca
ca
lic
applic
a
c
p c


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 59 of 234
Draft 3.0: 04Aug2020
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
ENDPOINT1: Overall OLE Treatment Period %
Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
ENDPOINT2: Month02-EOS
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS % Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
T+M = Titration + Maintenance; OLE = Open-label extension; SD = Standard deviation; Chg = Change; EOS = End of study
Data from core study includes subjects on Placebo as well as ZX008
*Note: The calculated (weight adjusted) daily doses over the entire OLE period were averaged to get a mean dialy dose, which was then categorized as follows: > 0 – <0.4 mg/kg = Low; 0.4 – 0.6 mg/kg =
Medium; >0.6 mg/kg = High
UBLIC COPY
XX
Y
XX
X.
Y 
X.
Y
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
LIC
BL
PU
XX
PU
XX
PU
X
P
X (XX.X
P
(XX.X
PU
X
P
X
P
support any marketing authorization 
uth
national
zat
national L
03
03
gh
gh Mean
au
Mean Dai
au
Dai
(>0.6 mg/k
g a
(>0.6 mg/k
(N
ng
(N =
g
= X
g
X
ut
ting
eti
rk
ar
ar
ar
ar
ar
ma
X
m
X
y
ny
a
XX
ort
XX
rt
XX.X
por
XX.X (XX
or
(XX
or
XX
o
XX
po
XX
pp
XX
pp
up
to
annot be used to su
su
o
to
X)
e
X)
d t
ed
XX.X
se
XX.X
se
us
u
XX
XX
be
XX.X
ot 
XX.X
t
ot
n
n
nt can
an
ca
ca
This documen
do
TIAL
s d
TIAL
pen
nt
pen-
t
-label
t c
label ext
c
ext
s on Placebo
ent
s on Placebo
usted)
me
usted) daily
me
daily d
ons or variations thereof. 
ly
o
ly Dose*
of
Dose*
kg)
e
kg)
XX)
r
XX)
ere
he
XX
t
XX
s t
XX.X
ns
XX.X (
ns
on
tio
at
ria
ria
ria
ria
ria
ar
va
X.XX)
or
X.XX)
r v
X.X
X.X
or
X.X,
s
X.X, XX.X
s o
XX.X
s o
ns
and any extension
on
si
XX
XX
n
te
xt
ex
ex
ex
ex
ex
y e
X
any
(XX.XX)
d a
(XX.XX)
d a
XX.X
nd
XX.X
d
XX.X,
an
XX.X, XX
n
XX
nd
on a
X.XX
a
X.XX
an
n a
application
a
on
ension;
tio
ension; SD
on
SD =
as well as ZX
atio
as well as ZX
oses
ic
oses over
ca
over th
a
th


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 60 of 234
Draft 3.0: 04Aug2020
[1] Baseline=For subjects who participated in a doube-blind study, the Baseline prior to double-blind treatment in the core study. Subjects in 1504-C1 do not have a Baseline(Core), and are not included in
this table. For De Novo subjects, the baseline period is the 28 days prior to dosing in ZX008-1503. Change from baseline for this group is calculated relative to this baseline period.
[2] Core Study is the entire Titration+Maintenance Period during the Core study; does not include the transition period.
[3] Core Study Final Week of T+M is the last 7 days of the T+M period.
[4]P-value for within group change from baseline is based on Wilcoxon signed rank test that the change from baseline is statistically significantly different from 0.
Programming note: Need to use exposure data to determine mean daily dose during OLE for each subject, and categorize each subject as having had Low, Medium or High dose of ZX008 as follows:
0 – <0.4 mg/kg = Low;
0.4 – 0.6 mg/kg = Medium;
>0.6 mg/kg = High
Programming note: Use the shell for Table 14.2.1.1.3 for
Table 14.2.1.1.8
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose: Summary Statistics and Tests of Changes from Baseline
mITT Population (Japan)
PUBLIC COPY 
>0.6
Y
>0.6
Tab
O
Tab
tment
C C
tment Per
C
Per
m
C
m
thorization 
national
zat
national L
03
03
port any marketing auth
04
a
04-
a
-C1
au
C1 do
ut
do no
t
no
culated relat
g a
culated relat
y
k
y significant
keti
significant
ze
m
ze each
ma
each subj
a
subj
High
y
High
14.2.1.1.8
ort 
14.2.1.1.8
d Using
por
Using Mea
or
Mea
This document cannot be used to supp
do
TIAL
s d
TIAL
T Population
ppo
T Population
uth
application and any extensions or variations thereof. 
a
have
f
have
ive to this b
of.
ive to this 
y
h
y different
he
different frfr
ect
o
ect as
on
as having
ns
having
n Daily
or
Daily Dose
r 
Dose
n (Japan)
s o
n (Japan)


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 61 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.1.4
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, by Age Group: Summary Statistics and Tests of Changes from Baseline
mITT Population
Programming Note: Repeat 14.2.1.1.3 for Age groups <6, and ≥6.
Add Header, top left, prior to the table proper, “Age Group: <6 years” or “Age Group: >= 6 years”.
Programming Note: Use the same shell fo produce
Table 14.2.1.1.9
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, by Age Group: Summary Statistics and Tests of Changes from Baseline
mITT Population (Japan)
PUBLIC COPY 
Tab
O
Tab
eriod
C C
eriod Usin
C
Usin
m
C
m
thorization 
national
zat
national L
03
03
port any marketing auth
mary
ng
mary Statisti
ng 
Statisti
14.2.1.1.9
ort 
14.2.1.1.9
Mean
po
Mean Daily
por
Daily D
This document cannot be used to supp
do
TIAL
s d
TIAL
TT Population
ppo
TT Population
uth
application and any extensions or variations thereof. 
a
s and
eo
and Tests
eo
Tests
Dose,
or
Dose, by
or v
by Age
r v
Age
n (Japan)
s o
n (Japan)


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 62 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.1.5
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics
Subjects from 1504 Cohort 1
ZX008 OL[1]
(N = XX)
Core Study Day 2 through End of PK Follow-up Period *
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Core Study Transition Period**
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Month1 (OLE)
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Month2 (OLE)
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
……
Repeat for Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24, Month 27, Month 30, Month 33, Month 36
ENDPOINT1: Overall OLE Treatment Period
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
PUBLIC COPY 
Y
PY
OPY
OP
CO
C
C
LIC
BL
B
UB
PU
P
thorization 
national
zat
national L
03
03
used to support any marketing auth
Statistics
a
Statistics
tin
rke
ar
ma
m
y
ny
an
t a
ort
po
pp
upp
sup
s
to
d to
d
ed
s
ument cannot be u
e
be
t b
ot
no
nn
h12,
c
h12, Month15
ca
Month15
an
ca
Period
nt
Period
t c
nt
e
m
This docum
do
TIAL
s d
TIAL
um
cu
uth
extensions or variations thereof. 
er
th
s
ns
ns
ns
ns
n
io
ti
ia
ari
va
v
or
o
s
ns
io
sio
ns
en
xte
ex
plication and any e
y
ny
a
d
nd
an
5,5, Month18,
n a
Month18, M
a
M
a
on
tio
ati
ca
lic
appl
a pl
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 63 of 234
Draft 3.0: 04Aug2020
ZX008 OL[1]
(N = XX)
ENDPOINT2: Month02-EOS
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Notes:
[1]Subjects were on open-label ZX008 0.2 mg/kg during the entire 6 months of the Transition Period. Starting from Day 1 in the OLE Period, their dose was set at 0.2 mg/kg for the first month, and
subsequently adjusted by the PI to achieve optimal dose for effectiveness/tolerability.
*For most subjects this ends on Day 15; for some subjects the PK Period ends on Day 14 or Day 16.
**Transition Period starts 1 day after end of PK Follow-up Period and ends 1 day prior to OLE Visit 1 Day 1.
PUBLIC COPY
od.
PY
od. Starti
PY 
Starti
Day
CO
Day 16.
CO
16.
o OLE
CO
OLE Visi
CO
Visi
thorization 
national
zat
national L
03
03
marketing auth
ut
a
g
ng
ting
ng
ng
eti
ke
rk
ar
This document cannot be used to support any ma
do
TIAL
s d
TIAL
ma
m
from Day
any
from Day 1
y
1 i
y
i
Day
po
Day 1.
or
1.
uth
ons thereof. 
Z
f
Z
(N
 
(
of
eo
re
he
th
s t
ns
ns
ns
application and any extensions or variations
a
ns
ns
on
tion
n the
ria
the OLE
riat
OLE Pe
t
Pe


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 64 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.2
Convulsive seizure frequency per 28 days - ENDPOINT: Parametric Analysis
mITT Population
PBO-ZX008 OL
ZX 0.2 – ZX008 OL
ZX 0.5 – ZX008 OL
ZX 0.8 – ZX008 OL
ZX008 OL
Statistics
(N = XX)
(N = XX)
(N = XX)
(N = XX)
(N = XX)
ENDPOINT1: OLE TREATMENT PERIOD ANALYSIS
Baseline (Core) Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period: Parametric Model Summary[1]
Results on log scale[2]
Least Squares Mean (SE) [2]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
XX
BL
XX
XX
B
XX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
s
g
s
0.5
et
0.5 –
ti
– ZX008
etin
ZX008
tin
(N
ket
(N =
e
= XX
t
XX
ke
X.X
a
X.X
XX.XX
t a
XX.XX
XX.X
ort 
XX.X
XX
r
XX
XX
d
XX
XX.X
ed
XX.X
XX
sed
XX
XX
se
XX
y[1]
nt
y[1]
n [2]
m
[2]
uth
application and any extensions or variations thereof. 
a
OL
h
OL
er
er
ere
X)X)
th
XX
XX
XX
n
XX
X
o
X
XX
any
XX
XX.X
an
XX.X
XX.X
a
XX.X


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 65 of 234
Draft 3.0: 04Aug2020
Original scale
Least Squares Mean[3]
XX.X
XX.X
XX.X
XX.X
95% CI[3]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
ENDPOINT2: MONTH2 TO EOS ANALYSIS
Baseline (Core) Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS: Parametric Model Summary[1]
Results on log scale[2]
Least Squares Mean (SE) [2]
95% CI for Least Squares Mean [2]
XX.X (XX.XX)
(XX.X,XX.X)
XX.X (XX.XX)
(XX.X,XX.X)
XX.X (XX.XX)
(XX.X,XX.X)
XX.X (XX.XX)
(XX.X,XX.X)
Original scale
Least Squares Mean[3]
XX.X
XX.X
XX.X
XX.X
95% CI[3]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
X.X
LI
X.X
XX.XX
BLI
XX.XX
XX.X
BL
XX.X
X
B
X
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
ut
uth
uth
XX.X)
ng
XX.X)
X
XX
a
XX
XX
rt a
XX
XX
d
XX
XX
se
XX
X
application and any extensions or variations thereof. 
a
XX
 
X
(XX
o
(XX
XX
ons
XX
XX.X
on
XX.X
XX.X
io
XX.X
XX
XX
XX.X
ns
XX.X
XX.XX
ons
XX.XX
XX.X
on
XX.X
X.X
y
X.X
XX.XX
ny
XX.XX
XX.X
any
XX.X
XX
a
XX
X


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 66 of 234
Draft 3.0: 04Aug2020
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error.
Note: this table excludes de Novo subjects.
[1] Baseline and overall OLE values were log transformed prior to analysis. To avoid taking log of 0, a value of 1 was added to each subject’s convulsive seizure frequency value (with the exception of the
Baseline (Core) value) before log transformation.
[2] Results are based on an ANCOVA model with treatment group (four levels excluding group that contained all subjects enrolled in 1503 – regardless of feeder study) and age group (< 6 years, ≥6 years) as
factors, log baseline convulsive seizure frequency as a covariate, CSF during Core Study as another covariate, and log convulsive seizure frequency (overall OLE period, or Month2 to EOS) as response.
[3]Values obtained from the ANCOVA model were exponentiated to get the corresponding values on the original scale.
Programming note: Use PROC MEANS for summary stats, and PROC GLM for parametric model analysis.
PUBLIC COPY 
sis.
Y
sis.
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ject’s
tin
ject’s convu
ng
convu
ed in
ke
ed in 1503
ke
1503
lsive 
ark
lsive seizure
ark
seizure
au
application and any extensions or variations thereof. 
a
sive
r
sive seizure
re
seizure
regardless
the
regardless o
e
o
frequency (o
s t
frequency (o
f


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 67 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.3
Convulsive seizure frequency per 28 days - ENDPOINT: Nonparametric Analysis
mITT Population
PBO-ZX008 OL
ZX 0.2 – ZX008 OL
ZX 0.5 – ZX008 OL
ZX 0.8 – ZX008 OL
ZX008 OL
Statistics
(N = XX)
(N = XX)
(N = XX)
(N = XX)
(N = XX)
ENDPOINT1: OLE TREATMENT PERIOD ANALYSIS
Baseline (Core) Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period: Nonparametric Model Summary[1]
Results on rank scale
Least Squares Mean (SE) [2]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
.X
C
.X
XX
C
XX
XX
LIC
XX
ent cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
nalysis
ng
nalysis
ZX
ke
ZX 0.5
e
0.5
ket
ar
ar
ar
XX
an
XX
XX.X
a
XX.X
XX
t
XX
This documen
do
TIAL
s d
TIAL
XX
t
XX
XX.X
d to
XX.X
XX.XX
ed 
XX.XX
XX.
ed
XX.
Summary[1]
ent
Summary[1]
Mean
cu
Mean [2]
um
[2]
application and any extensions or variations thereof. 
a
ZX008 
th
ZX008 OL
h
OL
he
(N
s
(N =
s t
= XX)
s t
XX)
s 
XX
r
XX
XX.X
or
XX.X
XX
s o
XX
XX
s 
XX
X
XX
e
XX
XX
y e
XX


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 68 of 234
Draft 3.0: 04Aug2020
Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
MONTH2 to EOS ANALYSIS
Baseline (Core) Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS Analysis: Nonparametric Model Summary[1]
Results on rank scale
Least Squares Mean (SE) [2]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error.
Note: this table excludes de Novo subjects.
[1] Baseline, Core Study, Month3 to EOS and overall OLE values were rank transformed prior to analysis.
PUBLIC COPY 
X
C
X
XX.X
IC
XX.X
XX.XX
LIC
XX.XX
XX.
L
XX.
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
nt
uth
008 
a
008 OL
au
OL
= XX)
g a
XX)
ut
g a
X
X.X
n
X.X
XX
an
XX
XX
an
XX
X
XX
t
XX
XX
XX
mmary[1]
nno
mmary[1]
ulation;
en
ulation; CI
n
CI = C
subjects.
me
subjects.
h3
u
h3 to
um
to EOS
um
EOS an
m
an
cation and any extensions or variations thereof. 
ati
ZX
f
ZX
of
XX
ns
XX
XX.X
ns
XX.X
XX
XX
XX
o
XX
XX.X
s o
XX.X
XX.XX
s 
XX.XX
XX
s
XX
XX.X
e
XX.X
XX.XX
y e
XX.XX
XX.X
ny 
XX.X
XX
y
XX
applica
a
onfidence
cat
onfidence InIn
d overall
plic
overall OLE
c
OLE


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 69 of 234
Draft 3.0: 04Aug2020
[2]The results are on the rank scale. Results are based on an ANCOVA model with treatment group (four levels excluding group that contained all subjects enrolled in 1503 – regardless of feeder study) and
age group (< 6 years, ≥6 years) as factors, rank of baseline convulsive seizure frequency as a covariate, rank of Core Study CSF as another covariate, and rank of convulsive seizure frequency (overall OLE
period, or Month2 to EOS) as response.
Programming note: Rank the baseline and OLE period convulsive seizure frequency, then use PROC MEANS for summary stats, and PROC GLM for parametric model analysis. See stats manual.
PUBLIC COPY 
thorization 
national
zat
national L
03
03
auth
ll
a
ll subjects
aut
subjects
This document cannot be used to support any marketing a
do
TIAL
s d
TIAL
e
ovariate, and
g a
ovariate, and
d
k
d PROC
keti
PROC GLM
ti
GLM
uth
application and any extensions or variations thereof. 
a
nrolle
f
nrolle
rank of con
of.
rank of co
for
h
for paramet
he
paramet


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 70 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.4
Convulsive seizure frequency per 28 days, Over Time – Parametric Analysis
mITT Population
PBO-ZX008 OL
ZX 0.2 – ZX008 OL
ZX 0.5 – ZX008 OL
ZX 0.8 – ZX008 OL
ZX008 OL
Statistics
(N = XX)
(N = XX)
(N = XX)
(N = XX)
(N = XX)
SUMMARY STATISTICS
Baseline (Core)
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
RESULTS FROM GENERAL LINEAR MODEL
Month1: Parametric Model Summary
Results on log scale[1]
Least Squares Mean (SE) [1]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [1]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
Original scale
Least Squares Mean[2]
XX.X
XX.X
XX.X
XX.X
95% CI[2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
XX
L
XX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
lysis
ng
lysis
ZX
k
ZX 0.5
ke
0.5 –
e
– ZX
e
ZX
ke
(N
k
(N
ar
XX
t a
XX
XX.X
rt a
XX.X
XX.XX
ort
XX.XX
XX
o
XX
X.X
d
X.X
XX.XX
ed
XX.XX
XX.X
se
XX.X
XX
s
XX
uth
application and any extensions or variations thereof. 
a
008 
th
008 OL
th
OL
the
= XX)
s
XX)
ns
X
XX
s
XX
XX
ns
XX
XX
y
XX


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 71 of 234
Draft 3.0: 04Aug2020
…. (Repeat for months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33,
and 36
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error.
Note: this table excludes de Novo subjects.
[1] Baseline and overall OLE values were log transformed prior to analysis. To avoid taking log of 0, a value of 1 was added to each subject’s convulsive seizure frequency value (the response variable) for
each timepoint in the OLE period before taking the natural logarithm.
[2] Results are based on a general linear model with fixed effects for treatment group (four levels excluding group that contained all subjects enrolled in 1503 – regardless of feeder study) and age group (< 6
years, ≥6 years), time (Months 1, 2, 3, 6, 9, 12, 15, 18, 21,and 24) and log baseline convulsive seizure frequency as a covariate; and random effects for subject (repeated over time). The dependent variable is
log convulsive seizure frequency (overall OLE period) as response.
[3] Values obtained from the ANCOVA model were exponentiated to get the corresponding values on the original scale.
Programming note: Use PROC MEANS for summary stats
For MMRM model, use PROC MIXED. Before calling the PROC, please add 1 to the Month1, Month2, … Month24 CSF values, then take the natural log (log to base e) of these values to be used in the model.
PROC MMRM for parametric model analysis. The LSMeans are the LSMeans for the time*treatment interaction terms. See stats manual.
COPY
on
PY
on the
PY
the or
Y 
or
h1,
C
h1, Month
CO
Month
PUBLIC C
me*treatm
C C
me*treatm
thorization 
national
zat
national L
03
03
ort any marketing auth
ng
h
k
h subject’s
ket
subject’s c
ntained
ar
ntained all
r
all
ovariate;
ma
ovariate; an
a
an
alal scale.
ny
scale.
…
o
… Month24 
ort 
Month24 
This document cannot be used to suppo
do
TIAL
s d
TIAL
nt interactio
por
nt interactio
uth
r variations thereof. 
eo
onvulsive se
the
onvulsive se
ubjects
ns
ubjects enro
s 
enro
d random eff
on
d random eff
CSF
r
CSF values,
r va
values, t
a
t
application and any extensions or
a
n terms. See
or 
n terms. See


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 72 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use the shell for 14.2.1.4 for
Table 14.2.1.5
Convulsive seizure frequency per 28 days, Over Time – Parametric Analysis Using Mean Daily Dose
mITT Population
In place of treatment groups, categorize subjects into three treatments depending on their mean daily dose during the OLE Treatment period as Low, Medium, and High. See SAP.
Categories for Low, Medium, High depending on the following doses of ZX008
<0.4 mg/kg = Low
0.4-0.6 mg/kg = Medium
>0.6 mg/kg = High
PUBLIC COPY 
thorization 
national
zat
national L
03
03
arketing auth
ng
ti
ng Mean
ting
Mean
This document cannot be used to support any mar
do
TIAL
s d
TIAL
Da
g
Da
Treatment
ark
Treatment
uth
application and any extensions or variations thereof. 
a
ly
e
ly Dose
ere
Dose
period
ns t
period as
s
as Lo
t
Lo


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 73 of 234
Draft 3.0: 04Aug2020
Table 14.2.1.6
% of Subjects with Changes in AED medications during 1st 6 months of OLE Treatment Period
mITT Population
OLE Period
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
Any Change in AED medication during the 1st 6 months
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 1
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 2
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 3
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 4
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 5
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 6
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
mITT = Modified intent-to-treat population ; Months are defined in 30 day increments. Month1=Day1-Day30, Month2=Day31-Day60, and so on.
Programming Note: we need to determine what a change in AED medication is
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
%)
CO
%)
OP
CO
XX
C
XX (XX%)
C C
(XX%)
C
C C
XX
LIC
XX (X
C
(X
IC
BLI
BL
UB
UB
UB
UB
UB
PU
P
thorization 
national
zat
national L
03
03
e used to support any marketing auth
ting
nt
nt Period
au
Period
ZX
ke
ZX 0.5
ke
0.5 –
ke
ar
ar
ar
ar
%)
%)
ma
m
XX
n
XX (XX%)
ny
(XX%)
y
any
XX
t a
XX (XX
a
(XX
t a
rt
or
po
po
po
pp
%)
%)
pp
pp
pp
pp
sup
XX
o
XX (XX%)
o s
(XX%)
s
to
XX
d t
XX (XX
t
(XX
d to
d
se
ay
u
ay incremen
se
incremen
medication
e u
medication
This document cannot be 
do
TIAL
s d
TIAL
be
uth
application and any extensions or variations thereof. 
a
ere
ZX008
th
ZX008 OL
th
OL
(N = XX)
s t
(N = XX)
the
ns
XX
on
XX (XX
n
(XX
on
tio
at
ria
ria
ria
ria
ria
%)
v
%)
ar
va
XX
o
XX (XX%)
or
(XX%)
r
o
XX
s
XX (XX
(XX
s
ns
oioioion
sio
sio
sio
sio
sio
%)
e
%)
ns
ten
xte
ts.
e
ts. Month1=
ext
Month1=
isis
n


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 74 of 234
Draft 3.0: 04Aug2020
Figure 14.2.1.7
Graph of means for convulsive seizure frequency per 28 days during OLE Treatment Period
mITT Population
mITT = Modified intent-to-treat population
Programming Note: This plots the means from Table 14.2.1.1.1
45
40
ZX008 OL
35
30
25
20
15
10
5
0
Study Period
Convulsive seizure frequency per 28 days
PUBLIC COPY 
PUBLIC COPY
BLIC
UBL C 
ting authorization 
uth
national
zat
national L
03
03
ment
g
ment Period
g a
Period
cannot be used to support any marketing
mar
ar
used to suppor an
be
sed to
used
s pp
to s pp
be used to support any market
not b
This document c
do
TIAL
s d
TIAL
ation
en
ation
e means
me
means fro
e
fro
t cannot be used to support any marketing
d any extensions or variations thereof. 
tio s
r v ria
e
n
xten
s o
y ext
io
nsio s
ny extensions or variations the
application and a
a
m Table
lic
Table 14.2
c
14.2
nd an
on and any extensions or variations there


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 75 of 234
Draft 3.0: 04Aug2020
Figure 14.2.1.8
Graph of model adjusted means for Convulsive seizure frequency per 28 days – mITT Population
Programming note: Forest plots for the model adjusted means and CIs
Programming note: Repeat Figure 14.2.1.7 using the following 3 treatment groups: Low, Medium, and High to produce
Figure 14.2.1.9
Graph of convulsive frequency per 28 days, Over Time, Using Mean Daily Dose
mITT Population
PUBLIC COPY 
and
PY
and High
PY
High
Figur
OP
Figur
quency
CO
quency pe
O
pe
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ys
e
ys –
t
– mITT
etin
mITT Pop
n
Pop
produce
ny
produce
4.2.1.9
rt a
4.2.1.9
8 days,
ort
days, Over
rt
Over
TT
p
TT Populatio
po
Populatio
application and any extensions or variations thereof. 
a
pulation
her
pulation
Time,
r v
Time, Using
va
Using
n


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 76 of 234
Draft 3.0: 04Aug2020
Table 14.2.2.1
Percent Reduction in Convulsive Seizure Frequency, OLE Treatment Period
mITT Population
Distribution of Percentage
Change from Baseline(Core) in
De Novo
Time Period
convulsive Seizure
Frequency[1]
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL #
(N = XXX)
Subjects
(N = XXX)
OLE Period
≥25%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥50%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥75%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
=100%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
Month 1
≥25%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥50%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥75%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
=100%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
mITT = Modified Intent-to treat; CI = Confidence Interval; *Exact Clopper-Pearson CI. # Excludes the De Novo subjects.
PUBLIC COPY 
.X%
PY
.X%
X
C
X (XX.X%)
CO
(XX.X%)
XX.X%,
CO
XX.X%, XX
CO
XX
X
C
X
X.X%)
PU
X.X%)
P
XX.X%
PU
XX.X%
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
m
08 
a
08 OL
ark
OL
XX)
ma
XX)
XX
y
XX (XX.X%
y m
(XX.X%
ma
XX.X%,
any
XX.X%, X
y
X
%
(XX.X%)
upp
(XX.X%)
X.X%,
su
X.X%, XX.X%
sup
XX.X%
XX
o
XX (X
(X
XX.
t
XX.
%)
u
%)
, XX.X%
us
XX.X%
XX
t b
XX (XX.X%
be
(XX.X%
XX.X%,
ot 
XX.X%, X
at;
u
at; CI
u
CI =
um
= Confi
m
Confi
tin
uth
application and any extensions or variations thereof. 
a
lic
ZX
s
ZX 0.8
s t
0.8 –
t
– ZX
ZX
(N
s
(N
on
X.X%
ria
X.X%
XX
XX (XX.X%)
va
(XX.X%)
XX.X%,
or v
XX.X%, XX
v
XX
XX
o
XX
X.X%)
ns
X.X%)
X%,
e
X%, XX.X%
en
XX.X%
XX
ext
XX (XX.X
xt
(XX.X
XX.X%
e
XX.X%
)
X.X%
d
X.X%
XX
a
XX (XX.X%)
an
(XX.X%)
XX.X%,
n a
XX.X%, XX
a
XX
XX
XX
dence
pli
dence Interv
pli
Interv
ere


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 77 of 234
Draft 3.0: 04Aug2020
[1]Baseline=Baseline prior to double-blind treatment in the core study. Subjects in 1504-C1 do not have a Baseline(Core), and are not included in this table.
Programming Note: …. Repeat for months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36. Use the Table 14.2.2.1 shell for
Table 14.2.2.1.1
Percent Reduction in Convulsive Seizure Frequency, OLE Treatment Period
mITT Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
this
au
this table.
aut
table.
atment
ke
atment Perio
e
Perio
uth
application and any extensions or variations thereof. 
a
d


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 78 of 234
Draft 3.0: 04Aug2020
Figure 14.2.2.2
Cumulative Response Curves for Percent Reduction in CSF during OLE Treatment Period
mITT Population
Example graph: From PROC LIFETEST.
Example graph above: use rgkmtest_strpntl.sas
PUBLIC COPY 
thorization 
national
zat
national L
03
03
arketing auth
ent
g
ent Period
g a
Period
This document can
do
TIAL
s d
TIAL
sas
t
sas
uth
annot be used to support any mar
application and any extensions or variations thereof. 
a
and any extensions or variations 


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 79 of 234
Draft 3.0: 04Aug2020
Programming Note: Use the Figure 14.2.2.2 shell for
Footnote: mITT = Modified intent-to-treat population.
Figure 14.2.2.2.1
Cumulative Response Curves for Percent Reduction in CSF during OLE Treatment Period
mITT Population (Japan).
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
atment
ting
atment Perio
ng
Perio
uth
application and any extensions or variations thereof. 
a
d
e
d


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 80 of 234
Draft 3.0: 04Aug2020
Table 14.2.3.1
Duration of the Longest interval (days) between convulsive seizures
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
n
XX
XX
XX
XX
XX
XX
mean
XX.x
XX.x
XX.x
XX.x
XX.x
XX.x
SD
XX.xx
XX.xx
XX.xx
XX.xx
XX.xx
XX.xx
Min
XX
XX
XX
XX
XX
XX
25th Percentile
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
75th Percentile
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Max
XX
XX
XX
XX
XX
XX
mITT = Modified Intent-to-treat; CI = Confidence Interval;
Note: Percentages are calculated based on the number of subjects with non-missing data in the modified ITT population.
C COPY 
.X
O
.X
XX.X
CO
XX.X
PUBLIC 
XX
CO
XX
C
issing
LIC
issing data
LIC
data
thorization 
national
zat
national L
03
03
port any marketing auth
ZX
in
ZX 0
n
0
titing
X
ke
XX.x
m
XX.x
XX.xx
y m
XX.xx
XX
y 
XX
XX
y
XX
This document cannot be used to supp
do
TIAL
s d
TIAL
p
the
u
the modifie
up
modifie
uth
or variations thereof. 
8
h
8 –
he
– ZX008
her
ZX008 OL
OL
(N = XX)
the
(N = XX)
ere
th
X
XX.X
a
XX.X
XX.X
va
XX.X
application and any extensions o
a
XX
v
XX
o
d ITT
ns
ITT populat
ns 
populat


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 81 of 234
Draft 3.0: 04Aug2020
Figure 14.2.3.2
Boxplot of Distribution of Duration of Longest Interval between Convulsive Seizures during OLE Treatment Period
mITT Population
Programming notes:
Footnote: mITT = Modified intent-to-treat population
Example only: Separate boxplot for each group.
For interim analysis, if done, use only one box, for Group 9 (ZX008 OL, All Subjects)
PY 
PUBLIC COPY
thorization 
national
zat
national L
03
03
any marketing auth
ing
in
ing OLE
ing
OLE
This docume
do
TIAL
s d
TIAL
Trea
g
Trea
uth
ent cannot be used to support any
application and any extensions or variations thereof. 
a
tment
re
tment Perio
eo
Perio
cation and any extensions or varia


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 82 of 234
Draft 3.0: 04Aug2020
Table 14.2.4.1
Summary of Duration of Convulsive Seizure Episodes during OLE Treatment Period
mITT Population
Convulsive Seizure
Duration
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Total no. with at least one episode[1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Total no. of episodes
XXX
XXX
XXX
XXX
XXX
XXX
< 2-minute duration
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No. of episodes
XXX
XXX
XXX
XXX
XXX
XXX
2 – 10-minute duration
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No. of episodes
XXX
XXX
XXX
XXX
XXX
XXX
>10 minutes duration
XX (XX.X%)
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XXX
No. of episodes
XXX
XXX
XXX
XXX
XXX
Clusters of Convulsive Seizures
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XXX
No. of episodes
XXX
XXX
XXX
XXX
XXX
mITT = Modified Intent-to-treat; % = n/N*100 where n is number in category and N is number in cohort(except Total Recurring Seizures)
[1] % = ((Number in Cohort)/(Grand Total))*100.
PUBLIC COPY 
X.X%)
PY
X.X%)
XXX
OP
XXX
XX
C
XX (
C
(
X.X%)
UB
X.X%)
XXX
PU
XXX
thorization 
national
zat
national L
03
03
e used to support any marketing auth
riod
a
riod
ZX
etin
ZX 0.8
n
0.8
ting
.X%)
a
.X%)
ke
ke
ke
XXX
m
XXX
XX
ny
XX (XX
y
(XX
.X%)
p
.X%)
This document cannot be 
do
TIAL
s d
TIAL
XXX
p
XXX
XX
o s
XX (XX
s
(XX
.X%)
se
.X%)
XXX
u
XXX
e u
in
b
in category
be 
category
uth
y extensions or variations thereof. 
ZX008 
her
ZX008 OL
er
OL
(N
th
(N =
th
= XX)
the
XX)
ere
XX
ns
XX (XX.
 
(XX.
th
X%)
ri
X%)
XXX
a
XXX
application and any 
a
XX
or
XX (XX.X
r 
(XX.X
X
X%)
si
X%)
XXX
s
XXX
XX
xte
XX (XX.X
te
(XX.X
X
y
and
n
and N
ny
N is
y
is num
y 
num


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 83 of 234
Draft 3.0: 04Aug2020
Table 14.2.4.2
Summary of Gaps between Convulsive Seizure Episodes during OLE Treatment Period
mITT Population
Duration by Number of Days* between
Convulsive Seizure Episodes
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
1 Recurrence
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
2 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
3 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
4 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
>= 5 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
mITT = Modified Intent-to-treat; % = n/N*100 where n is number in category and N is number in cohort(except Total Recurring Seizures)
*A Recurrence day is a day on which a subject has a seizure, given that the subject has had a seizure on another day previously.
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
OP
X
C
X
CO
XX
C C
XX
C
XX
C
XX
C C
IC
LI
BL
UB
PU
PU
PU
PU
PU
P
thorization 
national
zat
national L
03
03
ot be used to support any marketing auth
eriod
a
eriod
ZX
et
ZX 0.8
etin
0.8 –
i
– ZX
n
ZX
(N
t
(N
ting
rk
rk
rk
rk
ark
ar
ar
ar
ar
ma
XX
y
XX
m
XX
ny
XX
y
any
XX
a
XX
a
rt
or
po
po
po
po
ppo
pp
pp
pp
pp
X
up
XX
o
XX
s
XX
to
XX
to
XX
t
XX
d to
d
e
us
u
X
b
X
be
be
XX
ot
XX
t
This document canno
do
TIAL
s d
TIAL
XX
o
XX
no
X
nn
an
ca
ca
ca
ca
t ca
c
*100
nt
*100 where
nt c
where
subject
ent
subject has
nt
has
uth
d any extensions or variations thereof. 
008
he
008 OL
her
OL
 = XX)
th
 = XX)
ere
t
s 
XX
XX
on
tio
at
at
at
at
iat
riaiaia
ar
XX
r
XX
va
XX
or
XX
r v
XX
o
XX
or
s o
ns
on
sio
sio
sio
sio
sio
ns
en
XX
ex
XX
xte
XX
ex
XX
ex
XX
y e
XX
e
X
y
X
ny
any
d
application and a
a
d a
d 
d
X
n
XX
n
XX
a
n
ion
n is
ti
is number
tio
number
a seizure,
ati
seizure, giv
giv


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 84 of 234
Draft 3.0: 04Aug2020
Programming Note: Use shell for Table 14.2.1.1.1 to produce
Table 14.2.5.1
Convulsive seizure-free days – summary statistics
mITT Population
Note: Percentage of convulsive seizure free days will be calculated as the total of seizure free days / total number of days with non-missing diary data*100.
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
on
k
on-
ke
-missing
ket
missing d
uth
application and any extensions or variations thereof. 
a
iary
th
iary data*10
the
data*10


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 85 of 234
Draft 3.0: 04Aug2020
Table 14.2.5.2
Convulsive seizure-free days - Parametric Analysis - MMRM by Age Group
mITT Population
Statistics
Age < 6 years
(N = XX)
Age >= 6 years
(N = XX)
ZX008 OL
(N = XX)
SUMMARY STATISTICS
Baseline (Core)
N
XX
XX
XX
Mean
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min
XX
XX
XX
Max
XX
XX
XX
Core Study
N
XX
XX
XX
Mean
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min
XX
XX
XX
Max
XX
XX
XX
Month 1 (Original Scale) Summary Statistics
N
XX
XX
XX
Mean
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min
XX
XX
XX
Max
XX
XX
XX
RESULTS FROM MMRM MODEL
Results on log scale[1]
Least Squares Mean (SE) [1]
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [1]
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
X.X
CO
X.X
XX.XX
CO
XX.XX
XX.X
C C
XX.X
XX
C 
XX
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
oup
ng
oup
=
r
= 6
rk
6 years
rke
years
(N
a
(N =
ar
= XX)
ark
XX)
ke
a
X
XX
o
XX
XX
t
XX
Mean
cu
Mean [1]
um
[1]
application and any extensions or variations thereof. 
a
th
ns
XX
r
XX
XX
a
XX
X
e
X
XX.XX
te
XX.XX
XX.X
ext
XX.X
XX
ex
XX
XX
e
XX


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 86 of 234
Draft 3.0: 04Aug2020
Original scale
Least Squares Mean[2]
XX.X
XX.X
95% CI[2]
(XX.X,XX.X)
(XX.X,XX.X)
…. (Repeat for months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36.
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error. MMRM = Mixed Model Repeated Measures.
[1] Baseline and overall OLE values were log transformed prior to analysis. Results are scaled to the number of seizure free days per 28 days. To avoid taking log of 0, a value of 1 was added to each subject’s
convulsive seizure frequency value (the response variable) for each timepoint in the OLE period before taking the natural logarithm.
[2]Results are based on a MMRM with fixed effects for age group (< 6 years, ≥6 years), time (Months 1, 2, 3, 6, 9, 12, 15, 18, 21,and 24), and log baseline convulsive seizure-free days and log T+M seizure
free days as covariates; and random effects for subject (repeated over time). The dependent variable is log convulsive seizure-ree fdays / 28 days frequency.
[3]Values obtained from the MMRM model were exponentiated to get the corresponding values on the original scale.
PUBLIC COPY
1,
Y
1,
ble is log
PY 
ble is log
s
O
s on
OP
on the
PY
the o
Y
o
y marketing authorization 
uth
national
zat
national L
03
03
Mixed
rk
Mixed Mode
ke
Mode
e days
ar
days per
ar
per 2
ural log
ma
ural logarithm
ma
arithm
This document cannot be used to support any
do
TIAL
s d
TIAL
2,
y
2, 15, 18,
y m
15, 18, 21
m
21
vulsive seizu
ny 
vulsive seizu
nal
a
nal scale.
any
scale.
application and any extensions or variations thereof. 
a
Repeated
s th
Repeated M
8 days. To
ns 
days. To av
av
m.
o
m.
and
ti
and 24),
tio
24), and
o
and
r
i
re
i
e-
a
-ree fdays
iat
ree fdays


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 87 of 234
Draft 3.0: 04Aug2020
Table 14.2.5.3
Convulsive seizure-free days - Parametric Analysis - MMRM by Mean Daily Dose
mITT Population
Statistics
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
SUMMARY STATISTICS
Baseline (Core)
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
Core Study
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
Month 1 (Original Scale) Summary Statistics
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
RESULTS FROM MMRM MODEL
Results on log scale[1]
Least Squares Mean (SE) [1]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [1]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
XX
PU
XX
XX.X
PU
XX.X
X X
P
X X
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ose
ose
ZX0
ti
ZX0
tin
ar
XX
t an
XX
XX.X
t a
XX.X
XX.
rt
XX.
X
XX
u
XX
XX
e u
XX
Mean
cu
Mean [1]
um
[1]
uth
application and any extensions or variations thereof. 
a
8
h
8 High
the
High Mean
e
Mean
(>0.6
th
(>0.6
her
ns
XX
XX
XX.X
o
XX.X
XX
s o
XX
XX
s
XX
XX
d
XX
XX.X
nd
XX.X
XX.XX
and
XX.XX
XX.X
an
XX.X


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 88 of 234
Draft 3.0: 04Aug2020
Original scale
Least Squares Mean[2]
XX.X
XX.X
XX.X
XX.X
95% CI[2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
…. (Repeat for months2, 3, 6, 9, 12, 15, 18, 21
and 24
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error. MMRM = Mixed Model Repeated Measures.
*Note: The calculated (weight adjusted) daily doses over the entire OLE period were averaged to get a mean dialy dose, which was then categorized as follows: > 0 – <0.4 mg/kg = Low; 0.4 – 0.6 mg/kg =
Medium; >0.6 mg/kg = High.
[1] Baseline and overall OLE values were log transformed prior to analysis. Results are scaled to the number of seizure free days per 28 days. To avoid taking log of 0, a value of 1 was added to each subject’s
convulsive seizure frequency value (the response variable) for each timepoint in the OLE period before taking the natural logarithm.
[2]Results are based on a MMRM with fixed effects for mean daily dose (3 levels), time (Months 1, 2, 3, 6, 9, 12, 15, 18, 21,and 24), and log baseline convulsive seizure-free days and log T+M seizure free
days as covariates; and random effects for subject (repeated over time). The dependent variable is log convulsive seizure-ree fdays / 28 days frequency.
[3]Values obtained from the MMRM model were exponentiated to get the corresponding values on the original scale.
PUBLIC COPY 
numbe
Y
numbe
d before ta
OPY
d before ta
nths
O
nths 1,
OP
1, 2,
OP
2, 3
P
3
variable is
CO
variable is
ding
C C
ding value
C C
value
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
=
a
= Mixed
ark
Mixed Mo
k
Mo
e,e, which
ma
which was
a
was
seizure free d
ny 
seizure free d
ng the natura
any
ng the natura
6,6, 9,
t
9, 12,
t a
12, 15,
a
15, 1
g convulsive
ort 
g convulsive
n the
po
the origina
po
origina
application and any extensions or variations thereof. 
a
XX.X
eo
XX.X
(XX.X,XX.X)
reo
(XX.X,XX.X)
del
n
del Repeate
ns 
Repeate
then
on
then catego
ons
catego
days
ia
days per
iat
per 28
ti
28 d
l log
ari
l logarithm.
ria
arithm.
8,
v
8, 21,and
var
21,and 24
r
24
seizure
r va
seizure-
v
-ree 
va
ree 
scale.
or
scale.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 89 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use shell for Table 14.2.1.5.1 to produce
Table 14.2.5.4
Convulsive seizure-free days – summary statistics for subjects from Study 1504 –Cohort 1
Treatment group is Group 5.
Time periods do not include a Baseline(Core), as cohort 1 subjects did not have the extended baseline period that those in cohort 2 and 1501, 1502 subjects had.
PUBLIC COPY
eline
PY
eline peri
Y 
peri
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
from
ma
from Study
ar
Study
hat
n
hat those
ny
those in
y
in
application and any extensions or variations thereof. 
a
1504
ns
1504 –
ns
–Cohor
ns 
Cohor
cohort
iat
cohort 2
at
2 and
t
and


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 90 of 234
Draft 3.0: 04Aug2020
Table 14.2.6.1
Non-convulsive seizure frequency during OLE Treatment Period
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = xx)
Non-convulsive seizure frequency (All types)
Baseline *
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
OLE Treatment Period
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
P_value**
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
% Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
xx
CO
xx
OP
CO
C C
X
C
X
IC
XX
L
XX
BLI
B
UB
UB
UB
UB
PU
P
thorization 
national
zat
national L
03
03
ot be used to support any marketing auth
ZX
et
ZX 0.8
etin
0.8 –
i
– ZX
n
ZX
(N
t
(N
tin
ke
ark
ar
ar
ar
ar
ma
XX
y
XX
m
XX.X
an
XX.X (xx.xx)
any
(xx.xx)
ny
XX.X
an
XX.X
an
XX
XX
t a
or
po
po
po
po
ppo
pp
pp
pp
pp
(xx.xx)
su
(xx.xx)
sup
XX.X
to s
XX.X
s
XX, 
to
XX, xx
o
xx
to
d t
ed
se
us
xx)
e
xx)
u
X.X
b
X.X
be
XX,
ot
XX, xx
t b
xx
t b
This document cannot
do
TIAL
s d
TIAL
x.xxx
not
x.xxx
ot
no
n
ca
ca
ca
ca
ca
t c
nt
e
m
cu
uth
nd any extensions or variations thereof. 
008
he
008 OL
her
OL
= XX)
th
= XX)
ere
th
s
on
tio
at
ia
ri
, xx
v
xx
va
r v
or
XX
XX
s o
XX
n
XX
ns
ioioioio
sio
sisisis
en
te
XX
ex
XX
ex
XX.X
y e
XX.X (xx
e
(xx
e
ny
an
d a
application and a
a
d a
d a
d a
nd
an
XX
on
XX
n
XX.X
tio
XX.X (xx
o
(xx
ion
X
ati
ca
lic
lic
lic
lic
pplic
p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 91 of 234
Draft 3.0: 04Aug2020
Least Squares Mean (SE)***
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean***
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
mITT = Modified Intent-to-treat; CI = Confidence Interval; ANCOVA = Analysis of Covariance;
SE = Standard Error.
* Note: The baseline for De Novo subjects is based on the 28 day period prior to dosing in the ZX008-1503 study.
**P-value from the Wilcoxon signed ranks test of the change from baseline being significantly different from 0.
*** Note: Results are based on an ANCOVA model on change from baseline in non-convulsive seizure frequency, with baseline non-convulsive seizure frequency and age as covariates and treatment as a
fixed effect. The model excludes the de novo subjects.
Programming note: Use the table shell for Table 14.2.6.1 to produce the following tables.
Table 14.2.6.1.1
Non-convulsive seizure frequency during OLE Treatment Period
mITT Population (Japan)
Table 14.2.6.2
Convulsive + non-convulsive seizure frequency during OLE Treatment Period
mITT Population
Table 14.2.6.2.1
Convulsive + non-convulsive seizure frequency during OLE Treatment Period
mITT Population (Japan)
PUBLIC COPY 
Table
OPY
Table 14
PY
14
zure
CO
zure frequ
OP
frequ
P
mITT P
CO
mITT P
non
LI
non-
LIC
-conv
LIC
conv
onvulsive
PU
onvulsive
thorization 
national
zat
national L
03
03
ort any marketing auth
.XX)
a
.XX)
ut
X,XX.X)
g a
X,XX.X)
au
g
ing
baseline
ma
baseline no
a
no
6.1.1
t a
6.1.1
cy
rt
cy during
rt a
during OL
a
OL
This document cannot be used to suppor
do
TIAL
s d
TIAL
pulation (Jap
ort
pulation (Jap
Table
pp
Table 14.
p
14.
ive
u
ive seizure
up
seizure f
p
f
mITT
su
mITT
non
d
non-
d
-convuls
d t
convuls
uth
ons or variations thereof. 
f
o
eo
eo
eo
reo
e
convulsive
ons
convulsive
E Treatment
va
Treatment
application and any extension
a
an)
r
an)
2.6.2
s
2.6.2
requency
ns
requency du
s 
du
Population
on
Population
Table
nsi
Table 14.2
si
14.2
ve
e
ve seizure
ens
seizure fr
s
fr
mITT Pop
xte
mITT Pop


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 92 of 234
Draft 3.0: 04Aug2020
Table 14.2.7.1
Days with Rescue Medication Usage during the OLE Treatment Period
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Number (%) of Subjects with at Least One rescue
medication used during OLE Treatment Period
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
NUMBER OF DAYS RESCUE MEDICATION USED DURING
OLE, BY OLE TREATMENT PERIOD
Number of days rescue medication used per 28 days OLE
Month1 [1]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
Median
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
…
Repeat for OLE Months 2 and 3, Month 4-6, Month 9-12,
Month 13-15, Month 16-18, Month 19-21, Month 21-24..
etc, Month 33-36.
Number of days rescue medication used per 28 days
during OLE Treatment Period [1]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, XX
XX, xx
XX, XX
XX, XX
XX, XX
mITT = Modified Intent-to-treat
[1]This is normalized to 28 days.
UBLIC COPY 
PY
O
C C
IC
XX)
L
XX)
IC
IC
IC
IC
X
B
X
BLI
.X,
U
.X, XX.X
UB
XX.X
UB
PU
PU
P
thorization 
national
zat
national L
03
03
to support any marketing auth
ZX
tin
ZX 0.8
n
0.8
tin
et
X%)
ar
X%)
rke
ma
y m
an
t a
t a
t a
t a
t a
XX
p
XX
po
X.XX
u
X.XX (XX.XXX
upp
(XX.XXX
pp
XX.XX
su
XX.XX
sup
XX.
s
XX.
s
cannot be used to 
to
t
d t
u
be
ot
ot
ot
ot
ot
no
nn
This document ca
do
TIAL
s d
TIAL
nt ca
t c
uth
sions or variations thereof. 
–
h
– ZX008 
her
ZX008 OL
r
OL
(N
th
(N =
th
= XX)
he
XX)
ere
XX
s t
XX (XX.X
t
(XX.X
th
on
io
tioioioio
ri
va
or
s
X)
X)
XX
XX
s o
ns
ns
ns
ns
ns
X,X, XX.X
sio
XX.X
io
application and any extens
a
tio
si
en
e
y e
ny
XX
d
XX
d a
XX.X
and
XX.X (xx.x
d
(xx.x
nd
X
an
n a
on
on
on
on


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 93 of 234
Draft 3.0: 04Aug2020
Programming note:“Rescue medications” are those marked in the diary as such. Need to identify these and note usage during the baseline and treatment periods.
Programming note: Use the Table 14.2.7.1 shell fo produce
Table 14.2.7.2
Days with Rescue Medication Usage during the OLE Treatment Period
mITT Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
d
a
d treatmen
aut
treatmen
t Period
eti
Period
uth
application and any extensions or variations thereof. 
a
perio
f
perio


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 94 of 234
Draft 3.0: 04Aug2020
Table 14.2.8.1
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure
mITT Population
Event or Procedure
PBO-ZX008 OL
(N = XX)
ZX 0.2 - ZX008 OL
(N = XX)
ZX 0.5 - ZX008 OL
(N = XX)
ZX 0.8 - ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
No. (%) of Subjects with at least one hospital admission
to treat seizures
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
Number of Hospital Admissions to treat seizures
No. of subjects (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
Number of occurrences for subjects with at least one
Mean (SD)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Occurrences per 100 subject years [1]
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
EEG
No. of subjects (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
Number of occurrences for subjects with at least one
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, XX
XX, xx
XX, XX
XX, XX
XX, XX
Occurrences per 100 subject years [1]
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Repeat for the following
ECG
ECHO
PET Scans
MRI
X Ray
CT Scan
PUBLIC COPY 
Y
PY
XX
OP
XX (%)
OP
(%)
OP
CO
C
C
IC
LIC
IC
IC
IC
,
U
, xx
UB
xx
BL
xxx.xx
PU
xxx.xx
UB
PU
P
thorization 
national
zat
national L
03
03
sed to support any marketing auth
ZX
eti
ZX 0.0.
tin
ket
rk
XX
m
XX (%)
ma
(%)
a
y
ny
a
rtrtrtrt
o
x.x
x.x (xx.xx)
upp
(xx.xx)
pp
xx.x
up
xx.x
up
Xx,
s
Xx,
su
o
to
d t
d
use
X
u
X (%)
us
(%)
annot be use
us
XX.X
be
XX.X (xx.
(xx.
e u
X
e
X
be
t b
ot
o
ment cann
nn
an
ca
nt
en
This docume
do
TIAL
s d
TIAL
me
um
cu
uth
xtensions or variations thereof. 
8 -
h
- ZX008
he
ZX008 OL
e
OL
(N = XX)
th
(N = XX)
er
s t
X
s
X
ns
tio
titititi
ia
XX
va
XX (%)
var
(%)
ar
va
r
xx
o
xx
o
s 
ns
xx
i
xx
on
xxx.xx
si
xxx.xx
sio
ns
ten
and any ext
XX
t
XX
xt
ex
y e
xx)
n
xx)
y
X.X
a
X.X
ny
XX,
d
XX, xx
d a
xx
a
xxx.xx
nd
xxx.xx
d
ication an
an
a
on
on
on
on
on
tio
at
applic
a
ica
pli
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 95 of 234
Draft 3.0: 04Aug2020
Surgery
Lumber Puncture / Spinal Tap
Other
mITT = Intent-to-treat;
The mean, median, min and max describe the number of events or procedures per subject for those subjects who had at least one event or procedure.
[1] Occurrence rate is based on the total number of occurrences during the study divided by the total number of subject years of followup for subjects in the column. Multiple occurrences for the same
subject are included.
PUBLIC COPY 
thorization 
national
zat
national L
03
03
ng auth
ut
au
g
This document cannot be used to support any marketing
do
TIAL
s d
TIAL
ng
et
et
eti
one
rk
one event
rke
event o
e
o
ears of
ar
ears of follo
ar
follo
uth
reof. 
f
of
eo
thereo
re
he
application and any extensions or variations th
a
r procedure.
s th
procedure.
wup for
ns
wup for subj
s 
subj


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 96 of 234
Draft 3.0: 04Aug2020
Programming note: Use the same Table 14.2.8.1 shell to produce
Table 14.2.8.2
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure
mITT Population (Japan)
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
zure
ng
zure
uth
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 97 of 234
Draft 3.0: 04Aug2020
Table 14.2.9.1
Number of episodes of status epilepticus (SE)
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 - ZX008 OL
(N = XX)
ZX 0.5 - ZX008 OL
(N = XX)
ZX 0.8 - ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One episode of status epilepticus
reported as AE[1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Number of seizures reported greater than 10 min[2]
No. of subjects
XX
XX
XX
XX
XX
XX
Mean per subject
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Std. Error
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
Total unique events: SE as an AE, plus seizures >10 min
No. (%) of Subjects with at least one event
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Age group <6 years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% Exact CI
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
Age group ≥6 years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% Exact CI
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
Total unique events: SE as an AE, plus seizures >10 min
Unique events
1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3
……….
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
mITT = Intent-to-treat;
PUBLIC COPY 
XX
OP
XX
XX.X
CO
XX.X
XX.X
C
XX.X
XX
P
XX (XX.
P
(XX.
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
m
ZX
ti
ZX 0
tin
XX.X%)
ma
XX.X%)
rk
.X
p
.X
XX
up
XX
XX
su
XX
%)
%)
.X%)
se
.X%)
%,xx.x%)
use
%,xx.x%)
XX
be
XX (XX.X
e 
(XX.X
(xx.x%
be
(xx.x%
min
n
min
uth
application and any extensions or variations thereof. 
a plic
8
h
8 -
h
- ZX008
he
ZX008 OL
e
OL
(N
th
(N =
th
= XX)
h
XX)
her
XX
ns
XX (X
(X
t
XX
a
XX
XX.X
va
XX.X
XX.XX
r v
XX.XX
XX
XX
XX
e
XX (XX.X%)
ten
(XX.X%)
XX
xte
XX (XX.X%
xte
(XX.X%
(xx.x%,
ex
(xx.x%,
%)
n
%)
,xx.x%)
an
,xx.x%)
XX
a
XX


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 98 of 234
Draft 3.0: 04Aug2020
[1] Any AE with Status Epilepticus or presumed Epilepticus
[2] This includes all single seizures >10 minutes in duration as recorded in the subject’s seizure diary. For each subject, the number of episodes is calculated; then the number per subject for each treatment
group is obtained by summing across subjects in each group and dividing by number of subjects in that treatment group who had single seizures > 10 min.
Programming note: Use the same Table 14.2.9.1 shell for
Table 14.2.9.1.1
Number of episodes of status epilepticus (SE)
mITT Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
g auth
des is
g a
des is calcula
g a
calcula
This document cannot be used to support any marketing
do
TIAL
s d
TIAL
seizures > 1
ng 
seizures > 1
cus
m
cus (SE)
ma
(SE)
uth
application and any extensions or variations thereof. 
a
ted;
of
ted; then
of.
then th
.
t
0 min.
eo
0 min.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 99 of 234
Draft 3.0: 04Aug2020
Table 14.2.9.2
Duration of Seizures
mITT Population
Percentage of seizures by duration
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Baseline
<2 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
NA
2-10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
NA
>10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
NA
OLE Treatment Period
<2 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
2-10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
>10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
mITT = modified Intent-to-treat; 95% CI are based on the exact (Clopper-Pearson) method. NA = Not Applicable.
Programming notes:
To calculate the probability of a seizure <2 min. for a given treatment group: for each subject, calculate the proportion of seizures < 2 min. For example, if the subject has a total of 5 seizures with 2 being <2
min in duration, their proportion is 2/5. Add these proportions for all subjects in the treatment group, and divide the total by the number of subjects to get the treatment group proportion of subjects with
seizure duration <2 min. Then multiply the result by 100 to get the percentage.
Repeat for the other treatment groups. Repeat for seizure durations 2-10 min., and for >10 min.
BLIC COPY 
Y
X
P
X
PY
XX.XX
OP
XX.XX
OP
CO
C
C
L
PUBLIC
LIC
BL
BL
BL
BL
BL
UB
PU
per
P
per-
P
-Pear
PU
Pear
thorization 
national
zat
national L
03
03
upport any marketing auth
ZX
eti
ZX 0.8
ti
0.8
tin
rk
rk
rk
rk
rk
a
m
XX.XX
ny 
XX.XX
y
XX.X
ny
XX.X
ny
X
a
rtrtrtrt
ort
or
or
or
o
.XX
p
.XX
pp
e used to sup
XX.XX
sup
XX.XX
up
XX.XX
s
XX.XX
su
o s
to
n)
d
n) method.
d t
method. N
This document cannot be
do
TIAL
s d
TIAL
t group:
us
group: for
us
for
or all subjects
be u
or all subjects
et the percen
t be
et the percen
durations
ot b
durations 2
b
2
uth
s or variations thereof. 
ZX008 
he
ZX008 OL
e
OL
(N
t
(N =
th
= XX)
th
XX)
er
t
ns
on
titititio
ati
X
ia
X.XX
va
X.XX
ar
va
r
XX
o
XX
o
y extensions s
on
on
on
on
on
sio
ns o
A
e
A =
e
= Not
ens
Not App
ns
App
application and any
a
ach
ach subject,
y ex
subject,
s in the treat
ny 
s in the treat
tage.
an
tage.
10
d
10 min.,
d a
min., and
a
and


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 100 of 234
Draft 3.0: 04Aug2020
Table 14.2.10.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population
Categorical Description
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Month 1 (Visit 3)
Summary Statistics
n [1]
Xx
Xx
xx
Xx
xx
xx
Mean (SE)
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Number (%) of subjects responding at visit, by response
category
1=Very much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2=Much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3=Minimally improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4=No change
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5=Minimally worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6=Much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
7=Very much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Much/very much Improved (1, 2): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Minimally/much/very much Improved(1,2,3): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Repeat for:
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
PUBLIC COPY 
xx.x
OP
xx.x
Xx,
CO
Xx, xx
O
xx
%)
B
%)
.X%)
UB
.X%)
(XX.X%)
PUB
(XX.X%)
X
P
X (XX.X%)
PU
(XX.X%)
XX.X
P
XX.X
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ZX
tin
ZX 0.8
n
0.8
ting
ke
ke
ke
xx
y
xx
xx.x
y
xx.x
X (XX.X%)
upp
(XX.X%)
XX
s
XX (XX.X%)
su
(XX.X%)
XX
o s
XX (XX.X
s
(XX.X
XX
o 
XX (X
(X
XX
XX
)
X%)
s
X%)
X
e
X (XX.X%)
e u
(XX.X%)
(xx.x,
be
(xx.x, xx.x)
e 
xx.x)
XX
b
XX (X
b
(X
(x(x
uth
application and any extensions or variations thereof. 
a
ZX008 
her
ZX008 OL
r
OL
(N
th
(N =
th
= XX)
he
XX)
ere
th
x.x
a
x.x
Xx,
v
Xx, xx
va
xx
XX
XX
%)
si
%)
X.X%)
nsi
X.X%)
(XX.X%)
ens
(XX.X%)
XX
t
XX (XX.X%)
ten
(XX.X%)
XX
xt
XX (XX.X
xte
(XX.X
XX
e
XX
XX.X%)
d a
XX.X%)
xx.x,
nd
xx.x, xx.x)
nd
xx.x)


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 101 of 234
Draft 3.0: 04Aug2020
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
Summary Statistics
n [1]
Xx
Xx
xx
Xx
xx
xx
Mean (SE)
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Number (%) of subjects at visit, by response category
1=Very much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2=Much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3=Minimally improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4=No change
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5=Minimally worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6=Much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
7=Very much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Much/very much improved (1, 2): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Minimally/much/very much Improved(1,2,3): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
mITT = Modified Intent-to-treat; CI = Confidence Interval; SE = Standard Error; N= Number of subjects in population.
[1]n=number of subjects at time point; this is used as the denominator when calculating the percent of subjects responding in each CGI category and the percent who show improvement or much/very
much improvement.
*Exact Clopper-Pearson two-sided confidence interval for the percentage of subjects with that response.
,
PUBLIC COPY 
XX
C
XX (XX
CO
(XX
XX
C 
XX
%)
B
%)
XX.X%)
PUB
XX.X%)
X
P
X (XX.X%)
PU
(XX.X%)
X
P
X
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
c
uth
x.x
m
x.x
xx.x
y m
xx.x
Xx,
ny
Xx, xx
y
xx
%)
p
%)
X.X%)
pp
X.X%)
X (XX.X%)
up
(XX.X%)
XX
s
XX (XX.X%
su
(XX.X%
XX
o 
XX (XX
(XX
XX
XX
%)
%)
(XX.X%)
us
(XX.X%)
(xx.x,
be
(xx.x, xx.x)
e 
xx.x)
XX
XX
dence
t c
dence Interv
c
Interv
this
n
this is used
nt 
is used
ed
m
ed confiden
me
confiden
application and any extensions or variations thereof. 
a
on
Xx
Xx
XX
or
XX (XX.X%
r v
(XX.X%
XX
o
XX (XX
(XX
X
)
i
)
X.X%)
si
X.X%)
(XX.X%)
ens
(XX.X%)
XX
xt
XX (XX.X%)
xte
(XX.X%)
XX
e
XX (
x
(
(XX.X%)
d a
(XX.X%)
(xx.x,
nd
(xx.x, xx.x)
nd
xx.x)
val;
ti
val; SE
tio
SE =
o
= Stan
on
Stan
as
a
as the
ati
the denom
tio
denom
ce
l
ce interval
lica
interval fo
a
fo


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 102 of 234
Draft 3.0: 04Aug2020
Programming note:
n – use the total for nonmissing responses
Here we are doing no comparisons, the 95% CI is for the percentage or proportion for that group (for interim, it’s ZX008 OL) at that time point. Include all visits out through EOS visit.
Use the Table 14.2.10.1 shell for
Table 14.2.10.1.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
marketing auth
me
ti
me point.
ting
point.
This document cannot be used to support any ma
do
TIAL
s d
TIAL
In
g
In
t/Caregiver
ma
t/Caregiver
y
uth
application and any extensions or variations thereof. 
a
clude
er
clude all
ere
all visit
e
visit
Rating
on
Rating


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 103 of 234
Draft 3.0: 04Aug2020
Treatment Group=ZX008 0L
Programming Note:
Include all visits where the data is collected.
Use Labels
OLE Month 1 (Visit 3)
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
Figure 14.2.10.2
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population
40
35
30
25
20
15
10
5
0
Month 1
Month 6
Month 12
EOS/ET
Minimally Improved
Much Worse
Much Improved
Minimally Worse
Very Much Improved
No Change
Percentage of Subjects, by Category
UBLIC COPY 
IC CO
P BL
PY
PUB
UBL
keting authorization 
national
zat
national L
03
03
uth
nnot be used to support any marke
pport
t be
ed t
s
an
t any
e us
used
e
ot be used to support any m
This document cann
do
TIAL
s d
TIAL
.
marke
k
nnot be used to support any market
M
d
a
d
nd any extensions or variations thereof. 
s
xt nsions o varia
s or
d any extensions o
d any e
y e
d any extensions or variatio
application an
a
ions th
o
nd any extensions or variations the
M
Much
s t
Much Impro
s t
Impro
Minima
ons
Minima


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 104 of 234
Draft 3.0: 04Aug2020
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/ET.
Note EOS/ET = Last Available Data Point during OLE. [For interim we are plotting for ZX008 OL.]
For interim analysis, only the ZX008 OL group (ie all subjects) is plotted.
Use the Figure 14.2.10.2 shell for
Figure 14.2.10.2.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population (Japan)
PUBLIC COPY 
X008
C C
X008 OL.]
C
OL.]
inical
UB
inical Glob
UB
Glob
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Figur
su
Figur
Impression
to s
Impression
m
uth
ions or variations thereof. 
e 14.2.10.2.1
on
14.2.10.2.1
sio
f Improvem
sio
Improvem
application and any extens
a
ITT Populati
ns
ITT Populati


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 105 of 234
Draft 3.0: 04Aug2020
Programming note: Use shell for Table 14.2.10.1 shell to produce the following.
Table 14.2.10.3
Clinical Global Impression of Improvement, Investigator Rating
mITT Population
Table 14.2.10.3.1
Clinical Global Impression of Improvement, Investigator Rating
mITT Population (Japan)
Programming note: Use shell for Figure 14.2..10.2 shell to produce the following.
Figure 14.2.10.4
Clinical Global Impression of Improvement, Investigator Rating
mITT Population
Figure 14.2.10.4.1
Clinical Global Impression of Improvement, Investigator Rating
mITT Population (Japan)
PUBLIC COPY 
m
Y
m
opulatio
Y
opulatio
Figu
O
Figu
Impressio
C CO
Impressio
Clinical
UB
Clinical Gl
B
Gl
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
r
k
r Rating
ket
Rating
Investigato
y m
Investigato
pan)
ny
pan)
14.2.10.4
rt 
14.2.10.4
of
p
of Improvem
por
Improvem
mITT
pp
mITT Popula
ppo
Popula
Figure
sup
Figure
al
o
al Impressio
o s
Impressio
m
ns or variations thereof. 
Rating
tio
Rating
ent,
or
ent, Investig
or v
Investig
sion
tion
tion
14.2.10.4.1
ons
14.2.10.4.1
of
si
of Improve
sio
Improve
application and any extens
a
TT Populatio
nsi
TT Populatio


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 106 of 234
Draft 3.0: 04Aug2020
Table 14.2.11.1
Quality of Life in Childhood Epilepsy (QOLCE)
mITT Population
Domain
Subscale
Visit
Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XXX)
De Novo Subjects
(N = XX)
Physical
Physical
Restriction
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
PUBLIC COPY 
Y
X
C
X (XX.X)
CO
(XX.X)
OP
CO
X
C
X
C C
X
C
X
IC
LI
LI
LI
LI
LI
BL
Mean
PU
Mean (SD)
PU
(SD)
UB
PU
P
t be used to support any marketing authorization 
uth
national
zat
national L
03
03
ZX
rk
ZX 0.5
rke
0.5 –
e
– ZX
e
ZX
(N
k
(N
ket
ma
ma
ma
ma
ma
m
XX
ny
XX
ny
XX
t a
XX (X
a
(X
t a
ort
po
po
po
po
po
(XX.X)
up
(XX.X)
pp
up
XX
s
XX
s
XX
to
XX (X
(X
to 
d t
ed
ed
ed
ed
ed
This document cannot b
do
TIAL
s d
TIAL
n
9)
n
9)
Visit
an
Visit 10)
ann
10)
1
c
1 (Visit
can
(Visit 11)
an
11)
th
t
th 24
t c
24 (Visit
c
(Visit 1
Month
nt
Month 27
nt
27 (Vi
(Vi
LE
LE Month
en
Month 30
n
30
OLE
m
OLE Month
me
Month
OLE
um
OLE EO
m
EO
cu
cu
cu
cu
t b
ed
tensions or variations thereof. 
008
t
008 OL
th
OL
N = XX)
ns
N = XX)
Z
the
he
he
he
n
tio
at
ari
XX.X)
v
XX.X)
a
v
XX
or
XX
or
XX
s 
XX (XX
(XX
s o
ns
oioioion
io
X.X)
n
X.X)
si
n
ny exte
te
pplication and any
2)
i
2)
sit
a
sit 13)
ati
13)
(Visit
ca
(Visit 14)
cat
14)
33
li
33 (Visit
lic
(Visit 15)
c
15)
S/EOT
ppl
S/EOT (Visit
pl
(Visit
app
app
n a
ny


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 107 of 234
Draft 3.0: 04Aug2020
EOS/EOT
REPEAT
FOR
Physical
Physical
Restrictions
Physical
Energy/Fatig
ue
Well-being
Depression
Well-being
Anxiety
Well-being
Control/help
lessness
Well-being
Self-esteem
Cognition
Attention/Co
ncentration
Cognition
Memory
Cognition
Language
Cognition
Other
Cognitive
Social
Activities
Social
Interactions
Social
Activities
Social
Activities
Social
Activities
Stigma Item
Behavior
Behavior
General
Health
General
Health Item
Quality of
Life
Quality of
life Item
UBLIC COPY 
Y
PY
OP
C
C
LI
BL
PUB
UB
PU
o support any marketing authorization 
uth
national
zat
national L
03
03
ut
au
g
ti
ke
ma
ma
ma
ma
ma
y
ny
t a
o
po
pp
su
annot be used to 
o
d to
ed
se
e u
t b
t b
t b
t b
t b
n
This document can
do
TIAL
s d
TIAL
an
t c
me
m
cu
cu
cu
cu
nsions or variations thereof. 
o
he
he
he
her
he
th
ns
ati
iririria
ari
ar
ar
ar
ar
or
o
on
io
and any extensio
sioioioio
ns
xt
y
ny
a
nd
pplication an
a
n a
tio
ca
pli
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 108 of 234
Draft 3.0: 04Aug2020
Overall
Quality of
Life
Overall
Quality of
Life
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = Modified intent-to-treat; SD= Standard Deviation; N=Nmber of subjects with resposnes for that visit/time point.
*P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
Programming notes:
Note: For the interim, only the last column is analyzed and reported.
Note: For the final, to conserve space may use the domain and subscale as headers and start table using the Vist column
Note: Use question list for above tables as given below:
OPY 
Y
x
O
x
PUBLIC COPY
PY
OP
LI
ny marketing authorization 
uth
national
zat
national L
03
03
ut
au
XX
ti
XX (XX.X)
ting
(XX.X)
ng
ti
XX
e
XX
ke
X
rk
ma
ma
ma
ma
ma
XX
y
XX
m
XX
n
XX (XX.X)
ny
(XX.X)
y
ment cannot be used to support any
0.xxx
an
0.xxx
any
t a
not b
ed
po
ation;
nn
ation; N=Nm
n
N=Nm
est
a
est that
an
that the
n
the
umn
en
umn is
en
is anal
nt
anal
pace
m
pace may
me
may us
e
us
This docum
do
TIAL
s d
TIAL
ove tables as
um
ove tables as
ariations thereof. 
XX
f
XX
XX
e
XX
re
he
he
he
he
he
th
X (XX.X)
ns
(XX.X)
s t
ns
XX
o
XX
io
XX
t
XX
ati
ri
lication and any extensions or varia
ririria
ari
ar
ar
ar
nd
ny
io
ar
ber
a
ber of
an
of subje
n
subje
within
n a
within-
a
-grou
a
grou
yzed
a
yzed and
ati
and rep
ti
rep
the
ic
the domain
ica
domain
appl
a
s given below
plic
s given below


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 109 of 234
Draft 3.0: 04Aug2020
Domains and Subscales of QOLCE:
Domain
Subscale
Item
Section 3: Physical
Physical Restrictions
3.1 a-j
Section 3: Physical
Energy/Fatigue
3.2 a,b
Section 4: Well-being
Depression
4.1 a,d,e,l
Section 4: Well-being
Anxiety
4.1 b,g,j,n,o,p
Section 4: Well-being
Control/helplessness
4.1 c,f,h,i
Section 4: Well-being
Self-esteem
4.1 k,m,q,r,s
Section 5: Cognition
Attention/Concentration
5.1 a,d,e,f,g
Section 5: Cognition
Memory
5.1 j,k,l,m,n,o
Section 5: Cognition
Language
5.1 p,q,r,s,t,u,v,w
Section 5: Cognition
Other Cognitive
5.1 b,c,h
Section 6: Social Activities
Social Interactions
6.1 c,f,h
Section 6: Social Activities
Social Activities
6.1 a, e; 6.2
Section 6: Social Activities
Stigma Item
6.1 i
Section 7: Behavior
Behavior
7.1 a,c,f,g,h,i,j,k,l,m,o,q,r,s,t
Section 8: General Health
General Health
8.1
Section 2 (USA Version) or Section 9 (Australia Version)
Quality of lifeitem
2.1 or 9.1
For each treatment group at Baseline and End of Study/ET, the mean (SD) score will be presented for each QOLCE subscale and for the overall quality of life score. In addition, the change from baseline in
the overall QOLCE will be calculated for each subject by subtracting the baseline overall score from the overall score measured at each visit. The change from baseline for each treatment group will be
summarized by the mean (SD) and assiessed for significance using Wilcoxon signed-rank tests.
Revised 5/30/2017
Programming Note: see below for reverse coding and transformation of scores
To calculate subscale scores, the 5 point item scores will first be reverse coded as necessary so that scores of 5 represent the best possible response and 1 represents the worst possible response. Item
scores will then be transformed to a 0-100 scale as follows: 1-0, 2-25, 3-50, 4-75, 5-100.
LIC COPY 
es
Y
es
m
Y
m
Y
on/Concen
OPY
on/Concen
PY
emory
COP
emory
OP
Language
CO
Language
CO
Other
C C
Other
C
C 
So
C
So
PUBLIC
LIC
BL
UB
PU
P
pport any marketing authorization 
uth
national
zat
national L
03
03
ng
.1 a
ket
.1 a-
et
-j
eti
j
tin
3.2 
rke
3.2 a,b
ke
a,b
ke
r
4.1 
ark
4.1 a,
k
a,
rk
ar
4.
a
4.
a
m
y
ation
a
ation
ny
a
rt
ognitive
po
ognitive
o
upp
l Interaction
pp
Interaction
ed to supp
ocial
su
ocial Activiti
sup
Activiti
up
Stigma
o s
Stigma Ite
Ite
su
o
Behav
to 
Behav
o
to
Ge
t
Ge
d to
to
to
t cannot be used to
ed
se
n (SD)
e u
n (SD) score
u
score
ing the base
be 
ing the base
using Wilcox
t be
using Wilcox
nt 
g and
a
and transfo
an
transfo
tem scores
nt c
tem scores
This documen
do
TIAL
s d
TIAL
-
e
-100 scale a
ent
100 scale a
or variations thereof. 
re
er
the
d,e,l
ns
d,e,l
s t
1 b,g,j,n,o,p
ons
b,g,j,n,o,p
ns
4.1
ti
4.1 c,f,h,i
tio
c,f,h,i
on
4.1 
at
4.1 k,m
t
k,m
ati
ia
5.1
a
5.1
iaiaia
ria
ar
va
or
s o
s
tensions o
s
ns
m
i
m
on
or
n
or
sio
neral
en
neral Health
ens
Health
ns
and any exten
Quality
xte
Quality of
e
of lili
ten
xt
will be
y e
will be prese
y e
prese
line overall s
ny 
line overall s
on signed
any
on signed
ation a
-
n
-ra
y
ra
rmation of
n a
rmation of
will first
tio
will first
applicat
a
be
o
be r
s follows: 1
ati
s follows: 1-0


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 110 of 234
Draft 3.0: 04Aug2020
Item/Question No.
Reverse coded items*
Scale
Comments
3.1
c, d, e, f, g, h, I, j
1-5
3.2
b
1-5
4.1
b, d, f, k, l, m, q
1-5
5.1
i
1-5
6.1
b, d, g
1-5
6.2
1-5
1=0; 2=25, 3=50, 4=75, 5=100
6.3**
6.3
1-5
Recode 1 to 4; 2 to 3; 3 to 2; 4 to 1. Do not
recode “5”
6.4**
6.4
1-5
Recode 1 to 4; 2 to 3; 3 to 2; 4 to 1. Do not
recode “5”
7.1
e, i, l, m, n, o, s, t,v
1-5
8.1
8.1
1-5
9.1
9.1
1-5
Usual coding: 1=0,  2=25, 3=50, 4=75, 5=100.
*Reverse coded items.
For these, please code as follows: 1=100, 2=75, 3=50, 4=25, 5=0
**For 6.3 and 6.4, the (reverse coded)scores will be as follows:
1=75, 2=50 3=25, 4=0, 5=.
For 6.2, score as follows:
1=0,  2=25, 3=50, 4=75, 5=100.
OPY 
Y
C COP
1
C
1-
C
-5
CO
5
BLIC COP
C
1
C 
1
C C
C
LIC
PUBL
BL
U
P
t any marketing authorization 
uth
national
zat
national L
03
03
ut
a
ng
eti
ke
ar
ma
m
ny
support a
t a
po
1
s
1-
s
-5
s
5
upp
This document cannot be used to su
do
TIAL
s d
TIAL
1
o s
1-
o s
-5
s
5
su
to
to
to
to
d to
, 5=0
be
5=0
ollows:
not
ollows:
3=50,
ca
3=50, 4=7
a
4=7
or variations thereof. 
of.
eo
he
th
ns
1=0;
ti
1=0; 2=25,
tio
2=25, 3
io
Recode
ria
Recode
rec
ri
rec
at
ari
ons or va
va
or
s
application and any extension
a
on
si
en
5,
o
5, 5=100.
n 
5=100.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 111 of 234
Draft 3.0: 04Aug2020
Table 14.2.12.1
Pediatric Quality of Life Inventory (Peds QL)- (Version 4.0) – Parent Report
mITT Population
Functioning Area
Visit
Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XXX)
De Novo Subjects
(N = XXX)
Physical
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
PUBLIC COPY 
XX
Y
XX
Y
XX
PY
XX (
Y
(
PY
OP
CO
CO
CO
CO
CO
X.X)
C
X.X)
C C
IC
XX
BL
XX
LI
XX
UB
XX (X
B
(X
BL
U
PU
P
ed to support any marketing authorization 
uth
national
zat
national L
03
03
eport
ng
eport
.5.5 –
a
– ZX008
ar
ZX008 O
(N = XX)
ma
(N = XX)
rk
m
y 
ny
.X)
t
.X)
any
ny
ny
n
t a
XX
or
XX
ort
XX
ppo
XX (XX.X
po
(XX.X
po
pp
up
s
X)
to
X)
s
xxx
d t
xxx
to
d t
cument cannot be used
)
a
)
t 11)
ca
11)
Visit
t
Visit 12)
t c
12)
27
27 (Visit
nt
(Visit 13)
t 
13)
th
th 30
e
30 (Visit
en
(Visit 1
Month
m
Month 33
me
33 (Vi
e
(Vi
LE
LE EOS/EOT
cum
EOS/EOT
This docu
do
TIAL
s d
TIAL
ed
cu
a
e
nd any extensions or variations thereof. 
L
n
L
ZX
s
ZX 0.8
 
0.8
t
ns
tio
XX
ia
XX
at
XX
ari
XX (XX.X)
ari
(XX.X)
ria
a
v
or
X)
X)
or
or
or
or
s o
XX
on
XX
ns
XX
sio
XX (XX.X)
io
(XX.X)
ion
0.xx
s
0.xx
si
n
te
pplication and any exte
14)
c
14)
sit
l
sit 15)
lic
15)
Visit
pp
Visit 16)
ppl
16)
app
a
te
te
te
pp ca
nd
xte


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 112 of 234
Draft 3.0: 04Aug2020
EOS/EOT
REPEAT FOR
Emotional
Social
School
Physical Health
Summary[1]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
COPY
XX
PY
XX (XX.
Y 
(XX.
Y
PY
OP
CO
CO
CO
UBLIC CO
CO
CO
C C
XX
LIC
XX
C
XX
BL
XX (XX.X)
BLI
(XX.X)
LIC
0.x
B
0.x
BL
PUB
UB
P
rt any marketing authorization 
uth
national
zat
national L
03
03
ut
au
g
ninining
tin
etitititi
ke
ark
XX
ma
XX
ma
y
X
y
ny
any
ny
ny
ny
XX
rt
XX
t a
port
XX
o
XX (XX.X)
ort
(XX.X)
to support
po
X
p
X
pp
X
p
X
up
s
This document cannot be used to s
do
TIAL
s d
TIAL
s
13)
ca
13)
Visit
t
Visit 14)
t ca
14)
3 (Visit
nt
(Visit 15)
t 
15)
EOT (Visit 16
en
EOT (Visit 16
OT
m
OT
to
cu
a
e
or variations thereof. 
f
eo
re
he
th
s t
ns
ns
ns
ns
ns
X
i
X (XX.X)
iat
(XX.X)
ati
ria
XX
a
XX
ar
or v
XX
v
XX
ons or v
or
or
or
or
or
X
o
X
o
X (XX.X)
ons
(XX.X)
ns
sion
0.xxx
io
0.xxx
tension
sio
application and any exte
a
)
pp ca
nd
xte


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 113 of 234
Draft 3.0: 04Aug2020
Psychosocial Health
Summary[2]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Total Score[3]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
PUBLIC COPY
X
Y
X (X
Y
(X
0.xxx
PY 
0.xxx
Y
PY
P
CO
not be used to support any marketing authorization 
uth
national
zat
national L
03
03
XX
aut
XX
ut
XX
g 
XX (
g
ng
tin
etitititi
(XX.X)
rk
(XX.X)
ke
rk
XX
ma
XX
ma
XX
m
XX (X
m
(X
m
y
ny
any
ny
ny
e
s
ny
ot
ment canno
n
n
n
no
Mea
an
Mea
an
a
ca
(Visit
nt
(Visit 3)
nt
3)
t c
nt
me
cum
E Month
um
Month 1
m
1 C
m
C
This docu
do
TIAL
s d
TIAL
m
cu
nd any extensions or variations thereof. 
f
XX.X)
re
XX.X)
o
re
XX
he
XX
he
XX
th
XX (XX
h
(XX
th
s t
ns
ns
ns
ns
ns
XX.X)
ti
XX.X)
io
0.xxx
iat
0.xxx
ati
ria
d
xte
or
d
pplication and 
d
nd
nd
nd
nd
nd
(SD)
n
(SD)
a
n
n
ti
n
io
a
Mean
at
Mean (
ati
ca
ca
ca
ca
ca
hg
hg BL
pl
BL
applic
a
lic
pp c


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 114 of 234
Draft 3.0: 04Aug2020
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = Modified intent-to-treat; SD = Standard Deviation; N=Number of subjects in population; n=number of subjects with responses for that visit/time point. EOS/ET=Last available measurement in OLE
Treatment Period.
*Higher scores indicate better functioning
[1] The Physical Health Summary score is equal to the Physical Functioning Scale Score.
[2] Computed as the sum of the items over the number of items answered in the Emotional, Social, and School Functioning Scales.
[3]Computed as the sum of all the items over the number of items answered on all the Scales.
[4]P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
Programming note: Please see ZX008-1503 SAP section 6.3.3.7 for scoring instructions.
PUBLIC COPY 
P
CO
PU
P
of
P
of su
P
su
d to support any marketing authorization 
uth
national
zat
national L
03
03
XX
a
XX (XX.X)
aut
(XX.X)
ut
0.xxx
a
0.xxx
au
g
s
ny
tin
to
This document cannot be used 
do
TIAL
s d
TIAL
d
ects
ed
ects in
ed
in popu
d 
popu
ctioning
e u
ctioning Scale
u
Scale
s answered
be
answered i
of items answ
ot b
of items answ
at
n
at the
not
the within
ot
within
ection
an
ection 6.3.3
nn
6.3.3
any extensions or variations thereof. 
f
eo
or
ns
s
application and a
a
en
lation;
te
lation; n=nu
en
n=nu
Score.
y e
Score.
n
a
n the
an
the Emotio
any
Emotio
wered on all t
d an
wered on all t
group
nd
group chan
d 
chan
7 for
a
for scoring
an
scoring


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 115 of 234
Draft 3.0: 04Aug2020
Table 14.2.12.2
PedsQL Family Impact Module (Version 2.0) – Parent Report
mITT Population
Functioning Area
Visit
Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo
Subjects
(N = XX)
Physical Functioning
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
REPEAT FOR
Emotional
Functioning
COPY 
XX
Y
XX (
Y
(
Y
PY 
PY
OP
O
CO
PUBLIC CO
XX
C
XX
C C
XX
LIC
XX (XX.X)
LIC
(XX.X)
C
LIC
BL
PU
PU
port any marketing authorization 
uth
national
zat
national L
03
03
–
k
– ZX008
ke
ZX008 OL
e
OL
(N = XX)
ark
(N = XX)
eti
ma
m
y m
y
ny
XX
t
XX
an
XX
r
XX (XX.X)
rt a
(XX.X)
t a
ort
used to suppo
XX
o
XX
po
XX
p
XX
pp
up
u
su
nt cannot be u
16)
c
16)
a
cument c
u
u
t c
nt 
en
me
This docu
do
TIAL
s d
TIAL
cu
or variations thereof. 
ZX
th
ZX 0.8
th
0.8 –
he
s
ns
XX
ti
XX
on
XX
a
XX (XX.X)
ati
(XX.X)
tio
iat
XX
XX
ri
v
XX
a
XX
va
v
ensions or v
r v
or
(XX.X)
s
(XX.X)
o
s 
on
pplication and any exten
d
en
on
tio
at
ca
ic
applic
a
c
pp c


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 116 of 234
Draft 3.0: 04Aug2020
Social Functioning
Cognitive
Functioning
Communication
Worry
Daily Activities
Family Relationships
Parent HRQL[1]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value[4]
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Family
Functioning[2]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
PUBLIC COPY 
XX
Y
XX (X
Y 
(X
Y
PY
OP
O
CO
XX
C
XX
C C
XX
LIC
XX (XX.X)
LIC
(XX.X)
C
x.xxx
LI
x.xxx
LIC
BL
PU
ment cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ut
au
ng
ng
ng
ng
ng
tin
et
ke
ark
ma
m
y
ny
XX
t
XX
an
XX
or
XX (XX.X)
ort 
(XX.X)
t a
or
XX
o
XX
po
XX
p
XX
pp
up
u
)
16)
c
16)
su
a
u
u
(Visit
nt
(Visit 1)
nt c
1)
t c
en
ume
me
cum
LE
c
LE Month
cum
Month 1
m
1
This docu
do
TIAL
s d
TIAL
um
cu
plication and any extensions or variations thereof. 
f
eo
ere
he
th
s
ns
XX
ti
XX
io
XX
ia
XX (XX.X)
iati
(XX.X)
ati
ia
XX
XX
ari
v
XX
a
XX
va
r v
r v
r v
r v
r v
or
(XX.X)
ns
(XX.X)
s o
x.xxxx
ons
x.xxxx
ns
on
d
en
n
ti
n
io
ca
Mea
a
Mea
ca
ca
ca
ca
pplic
lic
(Visit
pp
(Visit 3)
ppl
3)
appl
a pl
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 117 of 234
Draft 3.0: 04Aug2020
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value[4]
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Total Score[3]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
n
XX
XX
XX
XX
XX
XX
PUBLIC COPY 
U
O
UB
PU
PU
PU
PU
PU
P
cument cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
XX
aut
XX (XX.X
ut
(XX.X
ut
au
g a
ng
ng
ng
ng
ng
xx
e
xx
tin
et
u
y
to
XX
d t
XX
d to
XX
ed
XX (XX.X
d
(XX.X
d
e
us
u
be
be
ean
o
ean (SE)
ot
(SE)
t
P-
n
-value[4]
no
value[4]
no
nn
a
it
t
it 4)
t c
4)
Visit
nt
Visit 5)
nt c
5)
6
e
6 (Visit
ent
(Visit 6)
nt
6)
nth
m
nth 9
me
9 (Visit
men
(Visit 7
n
7
Month
m
Month 12
me
12 (V
e
(V
E Month
um
Month 15
m
15
an
n
an
n
This docu
do
TIAL
s d
TIAL
an
cu
a
and any extensions or variations thereof. 
)
f
)
f
XX
e
XX
of
XX
r
XX (XX.X)
ere
(XX.X)
eo
x.xxxx
er
x.xxxx
ere
he
r v
s
sio
ns
en
X)
x
X)
en
en
en
en
xte
XX
e
XX
ex
XX
y
XX (XX.X)
y e
(XX.X)
e
ny
X
any
d
X
a
X
d a
d 
d
n
cation a
pplica
)
i
)
sit
pl
sit 8)
pli
8)
(Visit
ppl
(Visit 9)
ppli
9)
app
app ca


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 118 of 234
Draft 3.0: 04Aug2020
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = Modified intent-to-treat; SD = Standard Deviation.
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
[1] Computed as the sum of the items divided by the number of items answered in the Physical, Emotional, Social, and Cognitive Functioning scales.
[2] Computed as the sum of the items divided by the number of items answered in the Daily Activities and Family Relationships scales.
[3] Computed as the sum of all 36 items divided by the number of items answered.
[4]P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
Programming note:
For each subject, be sure to calculate a scale score for each functioning area. Please see SAP for rules.
[1] Computed as the sum of the items divided by the number of items answered in the Physical, Emotional, Social, and Cognitive Functioning scales.
[2] Computed as the sum of the items divided by the number of items answered in the Daily Activities and Family Relationships scales.
[3] Computed as the sum of all 36 items divided by the number of items answered.
Please see SAP section 6.3.3.15 for full instructions.
UBLIC COPY 
Y
ical,
CO
ical, Emot
OP
Emot
Daily
C
Daily Activit
CO
Activit
e
I
e from
C
from bas
C 
bas
PUB
area.
UB
area. Pleas
UB
Pleas
UB
answered
PUB
answered
ms
P
ms answe
PU
answe
ms
P
ms an
P
an
o support any marketing authorization 
uth
national
zat
national L
03
03
ut
ng
m
y m
nal,
rt
nal, Social,
rt a
Social, an
a
an
and
or
and Family
ort
Family
ne
p
ne is
p
is differen
pp
differen
This document cannot be used to 
do
TIAL
s d
TIAL
see
o
see SAP
o s
SAP for
s
for
o
the
t
the Physical
to 
Physical
in
d
in the
d t
the Daily
to
Daily
wered.
ed
wered.
sions or variations thereof. 
s
on
tio
d Cognitive
va
Cognitive
Relationship
r v
Relationship
t
s
t from
s o
from 0.
o
0.
application and any extens
a
ules.
io
ules.
sio
Emotional,
nsio
Emotional,
o
Activities
ens
Activities an
s
an


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 119 of 234
Draft 3.0: 04Aug2020
Table 14.2.13.1
QOL of Parent/Caregiver Based on EQ-5D-5L – Health Profile Summary Original Response Categories
mITT Population
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Mobility
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Extreme problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Self-care
Baseline
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Extreme problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
XX
Y
XX (
Y
(
XX
PY
XX (X
Y
(X
X
P
X
%)
C
%)
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
se
se Categorie
au
Categorie
008
et
008 OL
etin
OL
= XX)
ke
= XX)
Z
ting
ng
ng
XX
ar
XX
ke
XX
ma
XX (XX
a
(XX
XX
m
XX (
)
n
)
X
X%)
an
X%)
XX.X%)
t an
XX.X%)
X (XX.X%)
rt a
(XX.X%)
No
ca
No problem
ca
problem
Slight
t c
Slight p
Mod
t 
Mod
S
uth
application and any extensions or variations thereof. 
a
s
X
h
X 0.8
he
0.8 –
her
– ZX008
er
ZX008
(N = X
he
(N = X
ere
th
X%)
o
X%)
XX.X%)
tio
XX.X%)
X
a
X (XX.X%)
ati
(XX.X%)
XX
ria
XX (XX.X%
ria
(XX.X%
XX
ari
XX (XX.
ri
(XX.
XX
a
XX (
ms
ms
roblems
ion
roblems
erate
ti
erate proble
tio
proble
evere
cat
evere proble
at
proble
Extreme
ica
Extreme pr
a
pr
Missing
plic
Missing


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 120 of 234
Draft 3.0: 04Aug2020
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Repeat summary for the domains:
Usual activities
Pain/discomfort
Anxiety/depression
Mobility
Self-care
Usual activities
Pain/discomfort
mITT = Modified Intent-to-treat;
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
us
uth
application and any extensions or variations thereof. 
a
ex


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 121 of 234
Draft 3.0: 04Aug2020
Table 14.2.13.2:
QOL of Parent/Caregiver Based on EQ-5D-5L – Health Profile Summary Using Dichotomized Response Categories - mITT Population
mITT Population
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Mobility
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Self-care
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
COPY 
Y
X
Y
X
Y
PY
%)
O
%)
PY
PY
PY
PY
X.X%)
CO
X.X%)
OP
CO
UBLIC C
XX
C
XX (XX.X%
C C
(XX.X%
C
XX
IC
XX (XX
C 
(XX
C
BL
BL
BL
BL
BL
UB
PUB
U
port any marketing authorization 
uth
national
zat
national L
03
03
se
se Categorie
g a
Categorie
0.5
k
0.5 –
ke
– ZX008
ket
ZX008
OL
rke
OL
(N
ark
(N = X
k
X
eti
a
m
y m
y m
y m
y m
y m
XX.X%)
any
XX.X%)
ny
XX
XX (XX.X%)
t an
(XX.X%)
an
XX
rt
XX (XX.X%
rt a
(XX.X%
t a
rt
to suppor
XX
o
XX
po
pp
%)
u
%)
pp
pp
pp
pp
(XX.X%)
su
(XX.X%)
su
s
ment cannot be used to
to
sit
m
sit 1)
me
1)
n
en
n
en
en
en
en
e
N
e
N
cume
m
This docu
do
TIAL
s d
TIAL
cu
or variations thereof. 
s -
e
- mITT
eof
mITT Pop
of
Pop
X)
n
X)
ZX
he
ZX 0.8
e
0.8
he
s th
ns
on
XX
atio
XX
tio
XX
ria
XX (XX.X
a
(XX.X
iat
XX
ri
XX (X
(X
ria
a
)
X
a
va
v
ation and any extensions or v
(XX.X%)
or
(XX.X%)
or
XX
s
XX (XX.X%)
s o
(XX.X%)
o
XX
on
XX (XX
n
(XX
ns
io
icat
sisisisi
at
plica
o problems
lic
problems
ica
appli
a
Problems
pli
Problems
pli
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 122 of 234
Draft 3.0: 04Aug2020
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Usual
activities
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
PUBLIC COPY 
Y
not be used to support any marketing authorization 
uth
national
zat
national L
03
03
ZX
au
ZX 0.8
aut
0.8 – Z
ut
g
X%)
tin
X%)
ng
ting
X
k
X (XX.X%)
ket
(XX.X%)
et
XX
rk
XX (XX.X%
rke
(XX.X%
ke
m
XX
a
XX (
ma
m
y m
y m
y m
y m
u
e
be
ms
n
ms
ot
ment cann
ms
ms
n
sing
a
sing
an
ca
No/slight
nt c
No/slight
t c
n
Moder
ent
Moder
prob
en
prob
nt 
en
cume
M
e
M
me
m
This docu
do
TIAL
s d
TIAL
cu
nd any extensions or variations thereof. 
X008
f
X008
OL
o
OL
(N
e
(N =
e
= XX)
eof
XX)
XX
r
XX (XX.X%)
re
(XX.X%)
eo
ere
XX
he
XX (X
e
(X
he
th
)
X
h
X
th
th
th
s th
XX.X%)
on
XX.X%)
ns
on
tio
e
y 
an
an
an
any
an
d
ication and
nd
a
n
problems
tion
problems
on
ate/severe/e
atio
ate/severe/e
blems
ica
blems
tio
plic
Missing
plic
Missing
ica
ppli
pli
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 123 of 234
Draft 3.0: 04Aug2020
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Pain/discomf
ort
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
PUBLIC COPY 
IC
LI
BL
UB
PU
P
t be used to support any marketing authorization 
uth
national
zat
national L
03
03
ZX
au
ZX 0.8
aut
0.8 – Z
ut
g
ng
pp
pp
pp
pp
XX
s
XX
up
XX
to
XX (XX.X%
to 
(XX.X%
o
XX
d t
XX (XX
to
(XX
to
d
XX
d
XX
d
ed
ed
ed
se
s
eme
e
eme
u
be
ument cannot t b
This docu
do
TIAL
s d
TIAL
u
plication and any extensions or variations thereof. 
X008
f
X008
OL
o
OL
(N
e
(N =
e
= XX)
eof
XX)
eo
s o
XX
s
XX
ns
si
)
X
sisisio
si
X%)
e
X%)
ns
XX.X%)
te
XX.X%)
en
xte
XX
e
XX (XX.X%
ex
(XX.X%
ex
XX
y e
XX (XX
e
(XX
e
an
an
an
any
an
a
app
a p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 124 of 234
Draft 3.0: 04Aug2020
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Anxiety/depr
ession
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
C COPY 
Y
PY
PY
PY
PY
PY
(XX.X%)
CO
(XX.X%)
CO
XX
C
XX (XX.X%
C C
(XX.X%
C
LIC 
XX
IC
XX (XX
C 
(XX
PUBLIC
LIC
BL
BL
BL
BL
BL
UB
PU
PU
P
support any marketing authorization 
uth
national
zat
national L
03
03
ZX
au
ZX 0.8
aut
0.8 – Z
ut
g
ng
m
y m
y m
y m
y m
y m
ny
XX
t a
XX
an
XX
ort
XX (XX
rt
(XX
rt
XX
o
XX
o
pp
%)
%)
d to supp
pp
pp
pp
pp
upp
pp
pp
p
(XX.X%)
su
(XX.X%)
su
XX
to
XX (XX.X%)
to s
(XX.X%)
s
ed t
XX
d t
XX (XX
t
(XX
ument cannot be used 
d t
ed
ed
ed
sed
se
se
se
This docu
do
TIAL
s d
TIAL
cu
or variations thereof. 
X008
f
X008
OL
o
OL
(N
e
(N =
e
= XX)
eof
XX)
eo
on
tio
iat
ria
va
X%)
r
X%)
v
XX.X%)
or
XX.X%)
or
tensions o
XX
s
XX (XX.X%)
s o
(XX.X%)
o
s
XX
on
XX (XX
n
(XX
ns
i
XX
o
XX
io
si
X.X%)
te
X.X%)
pplication and any extens
ns
te
xt
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 125 of 234
Draft 3.0: 04Aug2020
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
mITT = Modified Intent-to-treat;
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
Programming note: This table repeats Table 14.2.13.1, with responses categorized into two levels.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ZX
au
ZX 0.8
aut
0.8 – Z
ut
g
ng
ting
ereof. 
X008
f
X008
OL
o
OL
(N
e
(N =
e
= XX)
eof
XX)
eo
application and any extensions or variations there
a
ere


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 126 of 234
Draft 3.0: 04Aug2020
Table 14.2.13.3
QOL of Parent/Caregiver Based on EQ-5D-5L – Overall Health Status Using VAS (0-100) Scale
mITT Population
Overall Health Status
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Visit
Visit Value
Change
from
baseline
Visit Value
Change
from
baseline
Visit
Value
Change
from
baseline
Visit Value
Change
from
baseline
Visit Value
Change
from
baseline
Visit
Value
Change
from
baseline
OLE Baseline (Visit 1)
n
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Max
Xx
Xx
Xx
Xx
Xx
Xx
OLE Month 1 (Visit 3)
n
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Max
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
P-value [1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
…. Repeat for all visits
OLE
EOS/EOT
(Month
36) Visit 16)
n
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
PUBLIC COPY 
ba
Y
ba
Y
PY
PY
PY
PY
PY
x
O
x
OP
xx.x
CO
xx.x
CO
xx.xx
C C
xx.xx
C
C
Xx
C 
Xx
C C
C
IC
BLI
BL
UB
UB
UB
UB
UB
PU
PU
P
d to support any marketing authorization 
uth
national
zat
national L
03
03
AS
i
AS (0
in
(0-
n
-100)
ng
100) Sc
g
Sc
8 –
rk
– ZX008
rke
ZX008 O
e
O
(N = XX
ark
(N = XX
ke
isit
m
isit Value
ma
Value
a
y
n
any
n
t a
rt
or
po
pp
x
pp
pp
pp
pp
Xx
s
Xx
sup
s
to
to
to
to
to
d t
t be used t
Xx
ed
Xx
d
xx.x
se
xx.x
se
us
xx.x
s
xx.x
us
us
us
us
X
u
be
Xx
t
Xx
be
nt cannot b
t b
ot
n
n
Xx
t c
Xx
c
ment c
t
xx.x
nt
xx.x
nt
nt
nt
nt
x
en
x
n
x
men
x.x
m
x.x
me
This docum
do
TIAL
s d
TIAL
Xx
um
Xx
m
um
tensions or variations thereof. 
ale
r
ale
OL
s
OL
)
th
th
th
th
Change
ons
Change
from
on
from
base
io
base
ns
tio
at
ria
Xx
v
Xx
ar
xx.x
r v
xx.x
va
r
xx.xx
or 
xx.xx
r
or
Xx
o
Xx
o
s
ns
ion
sisisisio
si
ns
d any extens
Xx
te
Xx
ten
x
xx.x
ext
xx.x
xte
ex
x
xx.x
ex
xx.x
ex
ex
ex
x.x
y
x.x
X
e
X
e
Xx
n
Xx
y 
Xx
an
Xx
any
a
tion and a
x.xx
a
x.xx
a
d a
d
nd
a
o
tion
Xx
on
Xx
cation
tio
xx.x
o
xx.x
tio
tio
tio
tio
.xx
c
.xx
t
licat
Xx.x
lic
Xx.x
ca
applic
a
Xx
pli
Xx
lic
p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 127 of 234
Draft 3.0: 04Aug2020
Max
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
P-value [1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
EOS/EOT
n
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Max
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
P-value [1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
[1] P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
PUBLIC COPY 
x.x
Y
x.x
Y
aseline
COP
aseline is
OP
is d
P
d
arketing authorization 
uth
national
zat
national L
03
03
Xx
aut
Xx
ut
au
g a
g a
g a
g a
g a
ng
Xx
etin
Xx
tin
e
xx.x
et
xx.x
et
ke
xx
e
xx
ke
ke
ke
ke
rk
This document cannot be used to support any ma
do
TIAL
s d
TIAL
k
x
m
x
a
Xx
m
Xx
m
y m
ny
erent
rt
erent from
t a
from
ns thereof. 
f
x.x
.
x
f
of
eo
Xx
her
Xx
ere
h
xx.x
he
xx.x
he
th
xx
xx
xx
h
xx
th
th
th
th
Xx.x
ns
Xx.x
s t
application and any extensions or variations t
a
t
Xx
on
Xx
ns
o
Xx
ion
Xx
on
tio
x.x
i
x.x
tio
tio
tio
atio
t
0.0.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 128 of 234
Draft 3.0: 04Aug2020
Table 14.2.14.1
QOL of Parent/Caregiver Based on Hospital Anxiety and Depression Scale (HADS): Normal, Borderline Abnormal and Abnormal Categories
mITT Population
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Anxiety
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Normal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Borderline abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
End of study visit
Depression
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Normal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Borderline abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 8 (during
Maintenance period)
…
End of study visit
Total (Emotional
Distress)
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Normal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Borderline abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
End of study visit
mITT = Intent-to-treat; Note: This table includes those subjects from 1501 and 1502, and excludes subjects from 1504; the HADS was not assessed in subjects from 1504.
PUBLIC COPY 
Y
%)
P
%)
PY
PY
OP
CO
C C
C
LIC
BL
mal
B
mal
BL
BL
BL
BL
UB
PU
P
thorization 
national
zat
national L
03
03
t be used to support any marketing auth
ormal
a
ormal and
au
and A
u
A
ZX
etin
ZX 0.8
tin
0.8 –
n
–
ting
ke
rk
ark
rk
rk
rk
X.X%)
m
X.X%)
ma
(XX.X%)
y m
(XX.X%)
m
XX
n
XX (XX.X%)
ny 
(XX.X%)
y m
XX
an
XX (XX.X%
ny
(XX.X%
ny
an
t a
ort
po
po
po
po
po
X
pp
(XX.X%)
sup
(XX.X%)
up
XX
XX (XX.X%)
su
(XX.X%)
su
XX
to
XX (XX.X%
o s
(XX.X%
o s
XX
to
XX (XX
o
(XX
to
d t
ed
ed
ed
ed
ed
us
e u
be
This document cannot b
do
TIAL
s d
TIAL
t b
Normal
nno
Normal
no
n
Bord
nn
Bord
nn
an
A
an
an
an
an
ca
t
f study
en
study visit
n
visit
en
me
m
This
u
This table
um
table inc
m
inc
uth
any extensions or variations thereof. 
bnormal
of.
bnormal Ca
. 
C
ZX008
he
ZX008 OL
er
OL
N = XX)
the
N = XX)
ere
th
XX
s 
XX
s t
XX
ns
XX (X
s
(X
ns
X
on
titititio
ati
%)
%)
ia
ari
va
v
or
X
o
X
o
XX
s
XX
s
on
io
%)
%)
ioioioio
X.X%)
n
X.X%)
s
en
te
ex
y
ny
application and an
a
n
an
nd
erline
a
erline abnorm
an
abnorm
an
bnormal
n a
bnormal
a
Missing
ion
Missing
on
tio
at
at
at
at
cat
ca
ca
ca
lica
c
ludes
pl
ludes those
pli
those


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 129 of 234
Draft 3.0: 04Aug2020
Table 14.2.14.2
QOL of Parent/Caregiver Based on Hospital Anxiety and Depression Scale (HADS): Summary Descriptive Statistics
mITT Population
Scale
Visit
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Anxiety
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
End of study visit
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Change from Baseline
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
95% CI
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
P-value[1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Repeat for Depression and
Total (Emotional Distress)
Scores
mITT = Intent-to-treat; SE = Standard Error. CI = Confidence Interval.
Note: The 95% confidence interval is based on the t-distribution.
[1] p-value from Wilcoxon signed-rank test.
PUBLIC COPY 
X
O
X
XX
CO
XX
thorization 
national
zat
national L
03
03
ent cannot be used to support any marketing auth
Descriptive
au
Descriptive St
u
St
ZX
eti
ZX 0.8
etin
0.8 –
n
– ZX
n
ZX
(N
t
(N
ting
ke
X
m
X
XX.X
m
XX.X
XX.XX
y 
XX.XX
XX.X
ny
XX.X
X
n
X
me
X
XX.X
u
XX.X
XX.XX
su
XX.XX
XX.X
s
XX.X
XX
XX
en
ard
m
ard Error.
me
Error. CI
e
CI
This docum
do
TIAL
s d
TIAL
rval is based
um
rval is based
igned
cu
igned-
cu
-rank
um
rank t
m
t
uth
cation and any extensions or variations thereof. 
atistics
of
atistics
008
he
008 OL
her
OL
= XX)
th
= XX)
ere
th
XX
s
XX
X
X
XX
v
XX
ca
X
XX
e
XX
XX
x
XX
X
ca
applica
a
Confidence
ica
Confidence
on the t
plic
on the t-dis
c
dis
st.
p
st.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 130 of 234
Draft 3.0: 04Aug2020
Table 14.2.15.1
Study Medication Palatability Assessment
mITT Population
Visit
Response
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL (N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Item/Question
OLE Month 1 (Visit 3)**
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
1.
Medication Taste and
Texture
Acceptable
Not acceptable
Missing response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
2.
Rating of Medication
Taste
5 (likes very much)
4 (likes it)
3 (neutral)
2 (dislikes)
1 (dislikes very much)
Missing Response
% liking it (4, 5)
95% CI*
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
3.
Problems administering
medication due to taste or
texture?
No
Yes
Every day
Once or more every week
Once or more during the
month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
OLE Month 2 (Visit 4)**
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
1.
Medication Taste and
Texture
Acceptable
Not acceptable
Missing response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
2.
Rating of Medication
Taste
5 (likes very much)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
PUBLIC COPY
XX.XX%)
PY 
XX.XX%)
X
O
X (XX.XX%
OPY
(XX.XX%
XX
O
XX (XX.X
OP
(XX.X
Y
)
C
)
X%)
LIC
X%)
X.XX%)
BLIC
X.XX%)
(XX.XX%
UBL
(XX.XX%
XX
U
XX (XX.XX
PUB
(XX.XX
XX
P
XX (
P
(
XX
CO
XX (X
O
(X
XX
C
XX
CO
C C
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
8
k
8
XX)
ar
XX)
Z
tin
et
ar
n=xxx
m
n=xxx
m
X%)
rt
X%)
XX
ny
XX (XX
y 
(XX
XX
any
XX (
y
(
X
a
X
y
a
%)
t
%)
X.XX%)
ed
X.XX%)
X.X, XX.X
se
X.X, XX.X
X.XX%)
ort
X.XX%)
(XX.XX%)
po
(XX.XX%)
X (XX.XX%
upp
(XX.XX%
XX
su
XX (XX.X
up
(XX.X
XX
su
XX (X
u
(X
XX
XX
rt
to
week
ot
week
ring the
not
ring the
XX
u
XX (XX.X%
us
(XX.X%
XX
e u
XX (XX
u
(XX
XX
e
XX
X
us
t b
nn
a
ptable
nt
ptable
ot
e
ot acceptable
ent
acceptable
Missing
me
Missing rere
t c
m
5
m
5 (likes
m
(likes
me
cum
u
uth
pplication and any extensions or variations thereof. 
X 0.8
th
0.8 –
th
– ZX00
he
ZX00
OL (N = X
s th
OL (N = X
er
s
on
io
.XX%)
iat
.XX%)
XX.XX%)
aria
XX.XX%)
X
v
X (XX.XX%
var
(XX.XX%
ati
%)
%)
XX%)
n
XX%)
X.XX%)
ion
X.XX%)
(XX.XX%)
sio
(XX.XX%)
XX
ten
XX (XX.
en
(XX.
XX.X
xte
XX.X
XX
r v
XX (XX.X
v
(XX.X
XX
or
XX (X
(X
XX
o
XX
va
ex
s
%)
%)
X.X%)
ny
X.X%)
(XX.X%)
any
(XX.X%)
X
d
X (XX.X%)
d a
(XX.X%)
XX
d
XX (XX.X
d 
(XX.X
X
x
X
ex
ex
ex
a
ex
an
n a
n a
n a
n a
n a
sponse
ica
sponse
on
very
pli
very much)
plic
much)
lic
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 131 of 234
Draft 3.0: 04Aug2020
4 (likes it)
3 (neutral)
2 (dislikes)
1 (dislikes very much)
Missing Response
% liking it (4, 5)
95% CI*
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
3.
Problems administering
medication due to taste or
texture?
No
Yes
Every day
Once or more every week
Once or more during the
month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
mITT = modified Intent-to-treat.
*Exact Clopper-Pearson Confidence interval
** Study Medication Palatability Assessment was performed at Visits 3 and 4 only.
proc format;
value likfmt 1='Very much improved'
5=likes very much
4=likes it
3=neutral
2=dislikes
1=dislikes very much
.=Missing Response;
value likynfmt
0='No: Neutral or dislikes it'
1='Yes: Likes it ';
run;
data effdat;
set alleff;
if mittfl="Y";
PUBLIC COPY 
Y
XX.X%)
Y
XX.X%)
X
P
X (XX.X%)
PY
(XX.X%)
XX
OP
XX (XX.X
OP
(XX.X
XX
CO
XX (X
O
(X
C C
C C
C C
4
B
4 only.
BL
only.
thorization 
national
zat
national L
03
03
marketing auth
%)
k
%)
X.XX%)
ark
X.XX%)
X.X, XX.X
ma
X.X, XX.X
XX.XX%)
aut
XX.XX%)
X (XX.XX%
g a
(XX.XX%
XX
ng
XX (XX.X
g 
(XX.X
XX
ting
XX (XX
g
(XX
XX
ti
XX
ut
et
any m
XX
XX (XX.X%
y m
(XX.X%
XX
ny
XX (XX
y 
(XX
XX
ny
XX (
y
(
X
m
port a
%)
t
%)
.X%)
ort
.X%)
This document cannot be used to suppo
do
TIAL
s d
TIAL
po
a
uth
application and any extensions or variations thereof. 
a
%)
%)
X%)
e
X%)
X.XX%)
ere
X.XX%)
(XX.XX%)
the
(XX.XX%)
XX
s t
XX (XX.X
s t
(XX.X
XX.X
ns
XX.X
X
f
X
XX
f.
XX
X
o
of
ion
%)
t
%)
.X%)
iat
.X%)
XX.X%)
ria
XX.X%)
X
v
X (XX.X%)
var
(XX.X%)
XX
v
XX (XX.X
va
(XX.X
X
on
or
io


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 132 of 234
Draft 3.0: 04Aug2020
if anl01fl="Y";
if aval ne .;
likeityn=(aval ge 4.0);
run;
proc sort data=effdat out=effdat;
by paramcd avisitn;
%macro exci_(type,param, paramfmt);
ods trace on;
ods output Binomial=bin_&type;
proc sort data=effdat; by paramcd avisitn descending &param;
proc freq data=effdat order=data;
tables &param / out=outp&type exact binomial; **outp11 has percentages for table;
by paramcd avisitn;
format aval &param. &paramfmt.. ;
run;
data bin_&type;
set bin_&type;
if Name1 in ('XL_BIN', 'XU_BIN');
cValue1=cValue1*100.0; *****convert endpoint values from proportions to percentages;
nValue1=nvalue1*100.0;
run;
%mend;
%exci_(lkt, likeityn, likynfmt);
PUBLIC COPY 
rtions
P
rtions
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
percentage
ed 
percentage
uth
application and any extensions or variations thereof. 
a
s;
t
s;


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 133 of 234
Draft 3.0: 04Aug2020
Table 14.2.15.2
Sleep quality and mealtime behavior
mITT Population
Visit/Question
Response Category
PBO-ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
PK – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Baseline (Visit 1)
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
1.
Child waking in night or
very early in morning more
than usual?
More disturbed than before
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Sleep pattern is same as before
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Sleeps better than before
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Missing response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
2.
Change in mealtime
behavior since taking study
medication?
Worsened mealtime behavior
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
No change in mealtime behavior
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Improved in mealtime behavior
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Missing Response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = modified Intent-to-treat. Only subjects in feeder study 1504 were given this assessment. N=Total number of subjects in the population. n=number of subjects answering.
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
OPY 
Y
X%)
OP
X%)
COPY
PY
XX%)
COP
XX%)
OP
XX.XX%)
CO
XX.XX%)
CO
PUBLIC C
C
UB
thorization 
national
zat
national L
03
03
any marketing auth
PK
ti
PK –
tin
– ZX008
ting
ZX008
(N = X
tin
(N = X
ng
n
ket
rk
%)
%)
X
k
X
rk
rk
rk
ark
X%)
m
X%)
a
X.XX%)
m
X.XX%)
ma
XX.XX%)
y m
XX.XX%)
m
X (XX.XX%
any
(XX.XX%
ny
t any
XX
a
XX (XX.X
an
(XX.X
port any
XX
t a
XX (XX
a
(XX
t a
XX
rt 
XX (
rt
o
This document cannot be used to suppor
do
TIAL
s d
TIAL
or
po
p
c
us
p
ects
nt
ects in
t c
in feede
c
feede
t in
e
in OLE
en
OLE Trea
en
Trea
uth
ariations thereof. 
OL
e
OL
XX)
h
XX)
re
re
re
re
=xxx
th
=xxx
he
X (XX.XX%
ns t
(XX.XX%
s t
XX
n
XX (XX.X
ns
(XX.X
ns
XX
ion
XX (XX
n
(XX
on
t
XX
io
XX (
tio
at
%)
%)
X
at
at
at
at
X%)
a
X%)
r varia
ria
X.XX%)
va
X.XX%)
ar
XX.XX%)
r va
XX.XX%)
va
application and any extensions or v
a
r v
o
on
d a
sio
r
t
r study
tion
study 1504
on
1504
tment
cat
tment Period
at
Period


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 134 of 234
Draft 3.0: 04Aug2020
Table 14.2.15.3
Karolinska sleepiness scale: Frequency Distribution
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
PK – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Baseline (Visit 1)
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
Score/Description
1.
Extremely alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2.
Very alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3.
Alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4.
Rather alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5.
Neither alert nor sleepy
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6.
Some signs of sleepiness
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
7.
Sleepy, but no effort to keep awake
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
8.
Sleepy, some effort to keep awake
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
9.
Very sleepy, great effort to keep awake, fighting sleep
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Active (1-6)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Sleepy (7-9)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
COPY 
%)
P
%)
Y
X.X%)
OP
X.X%)
PY
X
C
X (XX.X%)
CO
(XX.X%)
O
PUBLIC CO
XX
C C
XX (XX.X
C
(XX.X
CO
XX
C 
XX (
C C
IC
BL
UB
UB
UB
UB
PUB
PU
P
thorization 
national
zat
national L
03
03
port any marketing auth
L
tititing
eti
xx
a
xx
rke
ar
XX
m
XX (XX.X%)
ma
(XX.X%)
ma
XX
y m
XX (XX.X
y m
(XX.X
m
XX
ny
XX (X
y
(X
ny
X
n
X
an
t a
rt
to suppor
)
or
.X%)
p
.X%)
po
(XX.X%)
up
(XX.X%)
pp
XX
s
XX (XX.X%)
su
(XX.X%)
su
o s
cument cannot be used to
XX
to
XX (X
o
(X
to
X
d t
ed
se
se
This document cannot be use
do
TIAL
s d
TIAL
se
se
cu
se
uth
r variations thereof. 
PK
h
PK –
he
– ZX008
her
ZX008 O
(N = XX
the
(N = XX
ere
n
th
s
n
on
%)
a
%)
tio
XX.X%)
ria
XX.X%)
at
X (XX.X%)
ari
(XX.X%)
ri
XX
v
XX (XX.X%
va
(XX.X%
va
sions or v
XX
r 
XX (XX
v
(XX
r v
XX
XX
or
s
ns
n
io
xtens
XX.X%)
ns
XX.X%)
s
X
t
X (XX.X%)
ten
(XX.X%)
en
te
application and any ext
a
xt
pp
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 135 of 234
Draft 3.0: 04Aug2020
mITT = modified Intent-to-treat. Only subjects in feeder study 1504 were given this assessment. N=nmber of subjects eligible for assessment (subjects from 1504 who entered 1503). N=number answering at
visit.
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
PUBLIC COPY 
thorization 
national
zat
national L
03
03
auth
ut
au
This document cannot be used to support any marketing a
do
TIAL
s d
TIAL
t (subjects
a
(subjects frfr
uth
application and any extensions or variations thereof. 
a
f
om 1504
of.
om 1504 w
. 
w


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 136 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.1
Overview of number of subjects with TEAE during OLE Treatment Period
Safety Population
De Novo
Gp1
Gp 2
Gp3
Gp 4
Gp5
ZX008 OL
Subjects
Number of Subjects with…
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Treatment-Emergent Adverse Events
At least one TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Serious TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Fatal TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Related TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Related Serious TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one TEAE Leading to Discontinuation of Study Treatment
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in the Safety population in each treatment group.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment.
Adverse events with partial or missing start dates are classified as treatment-emergent, unless the non-missing components of
the start date confirm otherwise.
Programming note: Use the Table 14.3.1.1 shell to produce
Table 14.3.1.1.1
Overview of number of subjects with TEAE during OLE Treatment Period
Safety Population (Japan)
LIC COPY
XX
P
XX (XX.X%
PY 
(XX.X%
XX
OP
XX (X
P
(X
PUBLIC
P
X%)
C
X%)
X
L
X (XX.X%)
LIC
(XX.X%)
XX
UBL
XX (XX
BL
(XX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
d
ting
XX
XX (XX.X%)
m
(XX.X%)
rk
XX
ny
XX (X
y
(X
X%)
rt
X%)
X
p
X (XX.X%)
po
(XX.X%)
XX
upp
XX (XX.
pp
(XX.
%)
o
%)
X
Safety
se
Safety popul
se
popul
ted
u
ted on
us
on or
s
or afaf
reatment
e u
reatment-
u
-em
em
duce
no
duce
uth
application and any extensions or variations thereof. 
a
en
ere
Gp
th
Gp 4
th
4
(N=xx)
s th
(N=xx)
XX
on
XX (
s t
X.X%)
ria
X.X%)
XX
v
XX (XX.X%)
va
(XX.X%)
XX
or 
XX (XX
(XX
X%)
n
X%)
X (XX.X%)
ion
(XX.X%)
ation
xt
ation in
xte
in each
te
each
er
e
er the
ex
the date
ex
date
mergent,
y e
mergent, unle
e
unle
Ove
a
Ove


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 137 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.2.1
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term
Safety Population
MedDRA System Organ Class and Preferred Term
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=xx)
De Novo
Subjects
(N=xx)
Subjects with any TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in the Safety population.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: A subject with more than one TEAE with the same preferred term is counted once for that term. A subject with more than one TEAE under a system organ class is counted once for that class.
Programming note: Use the Table 14.3.1.2.1 shell to produce same shell for 14.3.1.2.1.3 (Japan).
Table 14.3.1.2.1.3
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
OPY 
XX
Y
XX
Y
XX
Y
XX
Y
PY
PUBLIC COP
OP
OP
OP
OP
COP
O
ulation.
C C
ulation.
fter
IC
fter the
IC
the da
C 
da
rwise.
BLIC
rwise.
ounted
BL
ounted o
L
o
hell
PU
hell for
PU
for 14
U
14
thorization 
national
zat
national L
03
03
t any marketing auth
ed
ed Term
au
Term
Gp
ke
Gp 4
ke
4
(N=xx)
rke
(N=xx)
ting
ng
ng
ng
rk
XX
ma
XX (XX
a
(XX
a
m
y m
%)
n
%)
y m
y m
y m
y m
X.X%)
an
X.X%)
ny
(XX.X%)
t an
(XX.X%)
an
This document cannot be used to support a
do
TIAL
s d
TIAL
t a
ort
of first
pp
of first dose
pp
dose
for
s
for that
su
that ter
u
ter
1.2.1.3
to
1.2.1.3 (Japa
o
(Japa
mergent
use
mergent Adv
e
Adv
uth
ariations thereof. 
Gp5
e
Gp5
(N
(N
ere
s t
s t
s t
s t
s t
X.X%)
on
X.X%)
ns
on
XX
a
XX (XX.X%)
atio
(XX.X%)
tio
XX
ria
XX (XX.X
a
(XX.X
iat
XX
ari
XX (X
(X
ria
application and any extensions or vari
a
a
va
v
of
s
of study
s o
study tre
o
tre
m.
m. A
o
A subject
on
subject
n).
n
n).
Tabl
e
Tabl
erse
ex
erse Events
ext
Events
Sa
x
Sa


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 138 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.2.1.1
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (<6 yrs, ≥6 yrs), MedDRA System Organ Class and Preferred Term
Safety Population
Programming note: Similar to Table SADS21 in ISS, but population is 1503 Safety, and only use AEs occurring during 1503. One column only, ALL subjects in ZX008 OL. Alternatively, this is just the above
Table, 14.3.1.2.1, by Age Group.
Programming Note: Use the shell for 14.3.1.2.1.1 to produce same format for 14.3.1.2.1.4.
Table 14.3.1.2.1.4
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (< 6 yrs, ≥6 yrs), MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
PY
14.3
Y
14.3
ods
PY
ods by
PY
by Ag
Y 
Ag
PUBLIC COP
ety Popula
OPY
ety Popula
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
System
au
System Org
au
Org
mn
et
mn only,
etin
only, ALL
n
ALL
roup
n
roup (<
ny
(< 6
y
6 yr
y
yr
on (Japan)
an
on (Japan)
uth
application and any extensions or variations thereof. 
a
an
o
an Cl
of
Class
of
ass an
. 
an
subjects
her
subjects in
r
in Z
, ≥6
i
≥6 yrs),
riat
yrs), Me
t
Me


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 139 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.2.1.2
Treatment-emergent Adverse Events with Decreased Appetite or Hypophagia during Open-Label Treatment Period
Safety Population
Placebo
(N = xxx )
ZX008 0.2 mg
(N = XXX)
ZX008 0.5 mg
(N = XXX)
ZX008 0.8 mg
(N = XXX)
ZX008 OL
(N = XXX)
De Novo Subjects
(N = XXX)
Decreased Appetite
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Had adverse event unresolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Duration of event for subjects who had event
resolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
n
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX
XX
XX
XX
XX
XX
Min, Max
XX
XX
XX
XX
XX
XX
Hypophagia
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Had adverse event unresolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Duration of event for subjects who had event
resolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
n
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX
XX
XX
XX
XX
XX
Min, Max
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
TEAE = Treatment-Emergent Adverse Event.
Note: Events considered are all TEAEs occurring during OLE. Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with
partial or missing start dates are classified as treatment-emergent, unless the non-missing components of the start date confirm otherwise.
Programmin note: Please see annotations in ISS for SST16
Programming notes:If subjects has multiple events with the same preferred term, count the worst case (if one event is unresolved, count the unresolved one).
Programming Note: Use the same shell for 14.3.1.2.1.5 (Japan).
PUBLIC COPY 
%)
PY
%)
Y
XX
O
XX
PY
XX.X
CO
XX.X
OP
XX.XX
CO
XX.XX
CO
X
C
X
C
C
LI
LI
LIC
BLI
%)
B
%)
BL
BL
BL
BL
X%)
UB
X%)
BL
BL
BL
B
XX.X%)
PU
XX.X%)
UB
X
P
X
P
thorization 
national
zat
national L
03
03
t cannot be used to support any marketing auth
Label
g
Label Treat
g 
Treat
X)
a
X)
ZX
e
ZX
ket
rk
ar
XX.X%)
ma
XX.X%)
ma
X
y
X (XX.X%)
y m
(XX.X%)
m
XX
ny
XX (XX.X%
ny 
(XX.X%
y
X
n
X
an
t a
rt
ort
ort
ort
ort
po
X
pp
upp
XX
s
XX (XX.X%
su
(XX.X%
sup
XX
o s
XX (XX.X
s
(XX.X
s
XX
to
XX (X
(X
to
d
ed
ed
ed
ed
ed
XX
u
XX
se
XX
e
XX
u
XX
be
XX
e
XX
be
XX
be
t b
g OLE.
no
g OLE. Adver
no
Adver
ment
n
ment-
nn
-emerg
nn
emerg
ISS
t c
ISS for
t ca
for
ent
SST1
ca
SST1
ple events w
nt 
ple events w
This documen
do
TIAL
s d
TIAL
ell for 14.3.1
en
ell for 14.3.1
uth
and any extensions or variations thereof. 
ment
e
ment Period
eo
Period
008
th
008 0.8
th
0.8 mg
h
mg
(N = XXX
s t
(N = XXX
the
s
XX
on
XX (X
(X
ns
i
XX
o
XX
io
ti
%)
i
%)
ati
ati
ati
ati
X
ari
XX.X
va
XX.X
va
XX.XX
r v
XX.XX
v
XX
or 
XX
or
X
o
X
o
s
n
)
X
ns
on
X%)
si
X%)
ion
on
on
o
X.X%)
nsi
X.X%)
sio
XX
ten
XX
en
XX.X
xte
XX.X
xte
XX.X
ex
XX.X
ex
e
y
ny
ny
ny
ny
any
e
n
e events
nd
events ar
ar
ation an
ent, unless t
an
ent, unless t
6
with
t
with the same
tio
the same
applica
a
.2.1.5 (Japan
cat
.2.1.5 (Japan


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 140 of 234
Draft 3.0: 04Aug2020
Programming Note: Use the shell for Table 14.3.1.2.1) for the following Tables:
Table 14.3.1.2.2
Treatment-Emergent Adverse Events occurring in at least 5% of the subjects by MedDRA System Organ Class and PT
Safety Population
For the interim: Since we are only tabulating for “All subjects”,
Add the footnote: “Events listed are those for which the % of subjects having that AE is ≥5.0% of subjects.”
Table 14.3.1.3
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.3.1
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Table 14.3.1.4
Serious TEAEs by MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.4.1
Serious TEAEs by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Table 14.3.1.5.1
Related TEAEs MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.5.2
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred Term
Safety population
Table 14.3.1.5.3
Related TEAEs MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Table 14.3.1.5.4
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred Term
Safety population (Japan)
PUBLIC COPY
Med
Y
Med
fety
PY
fety Popu
PY 
Popu
Table
OP
Table
nuation
CO
nuation b
O
b
Safet
C
Safet
EAEs
LIC
EAEs by
IC
by M
C
M
Serious
PU
Serious
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
System
ing
System Orga
g
Orga
tem
y
tem Organ
y m
Organ C
m
C
on
on
.3.1.3.1
rt a
.3.1.3.1
MedDRA
ort
MedDRA Syst
t
Syst
Population (J
po
Population (J
Table
pp
Table 14.3
p
14.3
DRA
up
DRA System
upp
System
Safety
sup
Safety
EAEs
d t
EAEs by
d to
by Med
to
Med
Related
us
Related
ated
o
ated TEAEs
ot
TEAEs
uth
application and any extensions or variations thereof. 
a
an
an Class
re
Class and
e
and
ass
at
ass and
atio
and Pref
io
Pref
em
r
em Organ
r va
Organ Cl
a
Cl
apan)
or
apan)
1.4
1.4
Organ
ns
Organ Class
s 
Class
Population
ons
Population
Table
si
Table 14.3.1
sio
14.3.1
DRA
n
DRA System
ens
System
Safety Pop
ten
Safety Pop
TEAEs
y e
TEAEs MedD
y e
MedD
occurring
d 
occurring inin
Rela
c
Rela


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 141 of 234
Draft 3.0: 04Aug2020
For the interim: Since we are only tabulating for “All subjects”,
Add the footnote: “Events listed are those for which the % of subjects having that AE is ≥5.0% of subjects.”
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
uth
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 142 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.6
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term
Safety Population
MedDRA System Organ Class and Preferred
Term
Maximum
Severity
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
Gp 9
(N=xx)
De Novo
Subjects
(N=xx)
Subjects with any TEAE
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
.
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…..
System Organ Class 2
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…..
PUBLIC COPY 
X.X%)
Y
X.X%)
Y
XX
O
XX (XX.X%
OPY
(XX.X%
PY
XX
CO
XX (XX.
OP
(XX.
OP
XX
CO
XX (
O
(
CO
C
C C
X.X%)
LIC
X.X%)
C
(XX.X%)
BLIC
(XX.X%)
LIC
XX
B
XX (XX.X%
BL
(XX.X%
BL
UB
XX
U
XX (
U
(
U
PU
P
thorization 
national
zat
national L
03
03
not be used to support any marketing auth
m
Gp
ket
Gp 4
t
4
(N=x
ke
(N=x
ting
rk
a
X%)
m
X%)
X
a
ma
XX.X%)
m
XX.X%)
m
XX
XX (XX.X%)
ny 
(XX.X%)
y m
ny
XX
an
XX (XX
n
(XX
an
t
%)
%)
XX
a
XX
t a
rt
.X%)
o
.X%)
ortrtrtrt
po
XX
XX (XX.X%)
pp
(XX.X%)
pp
XX
u
XX (XX.X%
up
(XX.X%
up
XX
su
XX (XX
u
(XX
su
o s
o
X.X%)
d t
X.X%)
to
(XX.X%)
ed t
(XX.X%)
d t
XX
s
XX (XX.X%)
sed
(XX.X%)
ed
se
XX
us
XX (XX
s
(XX
us
e
e
b
e
XX
XX
e u
e
ere
b
ere
be
t b
Mild
not
Mild
ot
nt canno
Moderat
nno
Moderat
no
Sev
n
Sev
nn
an
ca
ca
ca
ca
ca
t
This document 
do
TIAL
s d
TIAL
um n
me
m
uth
and any extensions or variations thereof. 
x)
s
x)
ere
he
s t
X
o
X (XX.X%)
ons
(XX.X%)
ns
XX
tio
XX (XX.X%
ion
(XX.X%
on
XX
atio
XX (XX.
io
(XX.
tio
iat
ri
X%)
a
X%)
X
ririria
ari
XX.X%)
va
XX.X%)
a
XX
XX (XX.X%)
r v
(XX.X%)
v
or
XX
s o
XX (XX
o
(XX
o
s
%)
%)
XX
s
XX
s
ns
X.X%)
io
X.X%)
n
io
XX
n
XX (XX.X%)
ns
(XX.X%)
si
XX
ten
XX (XX.X%
en
(XX.X%
n
XX
te
XX (XX
e
(XX
te
xt
ex
X.X%)
y e
X.X%)
ex
ex
ex
ex
(XX.X%)
ny
(XX.X%)
y e
XX
a
XX (XX.X%)
any
(XX.X%)
ny
an
d
XX
d 
XX (XX
(XX
d a
nd
tion and
e
a
e
XX
d
XX
nd
nd
nd
nd
ere
ere
an
a
Mild
ion
Mild
on
atio
Moderat
tio
Moderat
applicat
a p
tio
Sev
t
Sev
at
ca
licicicic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 143 of 234
Draft 3.0: 04Aug2020
TEAE = Treatment-Emergent Adverse Event.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: A subject with more than one TEAE with the same preferred term is counted once at the maximum severity for that term. A subject with more than one TEAE under a system organ class is counted
once at the maximum severity for that class
Note: TEAEs with missing severity are considered severe in this summary
Programming Note: Use Table 14.3.1.6 shell for
Table 14.3.1.6.1
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Programming Note: use shell from Table 14.3.1.1 to produce the following tables.
Table 14.3.1.7
Overview of number of subjects with Treatment-Emergent Adverse Events of Special Interest
Safety Population
Table 14.3.1.7.1
Overview of number of subjects with Treatment-Emergent Adverse Events of Special Interest
Safety Population (Japan)
Add footnote: AESI=Adverse event of sepcial interest.
Programming Note: use shell from Table 14.3.1.2.1 for
Table 14.3.1.8
Treatment Emergent Adverse events of special interest (TE AESI) by MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.8.1
Treatment Emergent Adverse events of special interest (TE AESI) by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Please change footnote from TEAE to TE AESI=Treatment emergent adverse event of special interest.
PUBLIC COPY
RA
Y
RA Sy
Y
Sy
Populatio
PY 
Populatio
of
L
of subjects
LIC
subjects
of
P
of numbe
PU
numbe
thorization 
national
zat
national L
03
03
not be used to support any marketing auth
tsts with
a
with parti
au
parti
ect
in
ect with
ing
with m
g
mo
g
o
rgan
y
rgan Class
y m
Class an
m
an
Japan)
ny
Japan)
Table
pp
Table 14.3
p
14.3
th
u
th Treatmen
upp
Treatmen
Safety
sup
Safety
canno
f
d
f subjects
d to
subjects wi
o
wi
Emergent
not
Emergent A
This document c
do
TIAL
s d
TIAL
Treatment
t ca
Treatment
E
m
E to
m
to TE
me
TE AESI=
e
AESI=
uth
ensions or variations thereof. 
al
o
al or
of
or missin
of. 
missi
e than
re
e than one
e
one T
d
a
d Preferred
atio
Preferred T
1.7
1.7
t
n
t-Emergent
ns 
Emergent A
Population
ons
Population
Table
si
Table
cation and any exten
14.3.1
sio
14.3.1
th
th Treatmen
ns
Treatmen
Safety Pop
ten
Safety Pop
dverse
d
dverse even
d 
even
Emergent
on
Emergent Ad
Ad
applica
a
Treatment
ica
Treatment


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 144 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.9.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population
MedDRA System Organ Class and Preferred Term
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
Gp 9
(N=xx)
Subjects with Any Non-TEAE Starting
Between Visits 12 and 13 of Feeder Study
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
.
.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in the Safety population.
Note: Adverse events in this table have a start date preceding the start of treatment in Study 1503, hence were classified as “non-treatment-emergent”.
Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: A subject with more than one non-TEAE with the same preferred term is counted once for that term. A subject with more than one Non-TEAE under a system organ class is counted once for that class.
Programming Note: Include only events whose start date is between Day -30 (inclusive) and Day -1 (inclusive), counting study days from beginning of OLE Treatment period, not core. There will be no De
Novo Column for this table.
Use the Table 14.3.1.9.1 shell for
Table 14.3.1.9.1.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population (Japan)
PUBLIC COPY 
LIC
%)
PY
%)
Y 
X.X%)
OPY
X.X%)
PY
(XX.X%)
OP
(XX.X%)
OP
O
CO
C C
C
PU
Safety
UBL
Safety pop
BL
pop
of
PU
of treatm
PUB
treatm
on
P
on or afte
PU
or afte
rm o
P
rm o
thorization 
national
zat
national L
03
03
not be used to support any marketing auth
up
Term
a
Term and
au
and Pr
u
Pr
G
n
G
ting
ke
rk
X%)
ma
X%)
ar
m
XX
ny
XX (XX.X%
ny 
(XX.X%
y
XX
any
XX (XX.
ny
(XX.
ny
XX
a
XX (
a
trtrtrt
ort
or
or
or
or
po
ppo
ation.
o s
ation.
t in
t
in Study
to 
Study 15
15
he
d
he date
d to
date of
to
of fi
o
fi
erwise.
ed
erwise.
m
s
m is
se
is counte
sed
counte
n Day 
e u
Day -
u
-30
u
30 (in
s
(in
This document canno
do
TIAL
s d
TIAL
s
n
s Starting be
nno
Starting be
uth
s or variations thereof. 
or
o
or Treatme
of. 
Treatm
p
h
p 4
h
4
(N=xx)
th
(N=xx)
ere
th
XX
ns
XX (XX.X
s
(XX.X
s
io
ati
)
ati
ati
ati
ati
X%)
ar
X%)
ia
XX.X%)
var
XX.X%)
ar
va
r v
or
application and any extensions o
a
ns o
03,
s
03, hence
sio
hence w
o
w
rst
rst dose
ns
dose of
s
of stst
once
xt
once for
xte
for th
e
th
nclusive)
y e
nclusive) and
e
and
tween
and
tween Visits
nd
Visits


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 145 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.9.2
TEAEs starting in the 1st month of OLE by System Organ Class, Preferred, Term and Prior Treatment in Feeder Study
Safety Population
MedDRA System Organ Class and Preferred Term
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
De Novo Subjects
(N=xx)
Subjects with any TEAE starting in the first month.
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
TEAE = Treatment-Emergent Adverse Event.
Note: A subject with more than one TEAE with the same preferred term is counted once for that term. A subject with more than one
TEAE under a system organ class is counted once for that class.
Programming note:
Include only events starting on or after Day 1 up to Day 30 (counting from beginning of OLE Treatment period, NOT Core).
Use same Table 14.3.1.9.2 shell for
Table 14.3.1.9.2.1
TEAEs starting in the 1st month of OLE by System Organ Class, Preferred, Term and Prior Treatment in Feeder Study
Safety Population (Japan)
PUBLIC COPY 
)
O
)
O
once
C
once for
C C
for th
C
th
om
U
om begin
UB
begin
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ment
a
ment in
a
in Feed
au
Feed
Gp
tin
Gp 4
n
4
(N=
e
(N=
ting
rk
X.X%)
y
X.X%)
(XX.X%)
ny
(XX.X%)
XX
a
XX (XX.X%)
any
(XX.X%)
t
term.
pp
term. A
po
A sub
po
sub
ng
t
ng of
to
of OLE
to 
OLE Tre
Tre
onth
us
onth of
se
of OLE
e
OLE
uth
application and any extensions or variations thereof. 
a
er
o
er Study
of.
Study
xx)
t
xx)
ere
re
re
XX
n
XX (XX.X%)
ns
(XX.X%)
t
XX
io
XX (X
o
(X
XX
XX
va
ject
ject with
or
with mo
mo
atment
sio
atment perio
io
perio
Tabl
e
Tabl
by
e
by System
ext
System O
Sa
x
Sa


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 146 of 234
Draft 3.0: 04Aug2020
Programing note: Use the 14.3.1.9.1 shell to produce the following tables. Include only events starting on or after Study Day31 up to Day 60 (counting from beginning of OLE Treatment period, NOT Core)
Table 14.3.1.9.3
TEAEs starting in the 2nd month of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population
Table 14.3.1.9.3.1
TEAEs starting in the 2nd month of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population (Japan)
Programing note: Use the Table 14.3.1.9.1 shell for the following tables. Include only events starting on or after Study Day61 up to day 90(counting from beginning of OLE Treatment period, NOT Core)
Table 14.3.1.9.4
TEAEs starting in the 3rdmonth of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population
Table 14.3.1.9.4 .1
TEAEs starting in the 3rdmonth of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population (Japan)
PUBLIC COPY 
pulat
Y
pulat
starting
COP
starting o
P
o
OLE
LIC
OLE by
LIC
by Sy
C
Sy
3
P
3rd
P
rdmonth
PU
month
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
0 (counting
g a
(counting
Prior
ket
Prior Treatm
et
Treatm
ed
ed Term
m
Term and
m
and
an)
y
an)
r after
t a
after Study
a
Study
Table
pp
Table 14.3.
pp
14.3.
em
u
em Organ
upp
Organ Cl
p
Cl
Safety
sup
Safety
T
OLE
d t
OLE by
d to
by Syst
to
Syst
uth
ns or variations thereof. 
rom
eo
rom beginn
eof
beginn
ment
th
ment in
the
in Feede
he
Feede
Prior
tio
Prior Treatm
ion
Treatm
y Day61
va
Day61 up
a
up to
to
.9.4
.9.4
ension
ass,
ns
ass, Preferre
ns 
Preferre
Population
ons
Population
able
s
able 14.3.1.
sio
14.3.1.
em
e
em Organ
ens
Organ
application and any exten
a
Cla
s
Cla
Safety Pop
ten
Safety Pop


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 147 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.10.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind Treatment Period by MedDRA System Organ Class and Preferred Term
with Mean Time to Onset (days) and Mean Duration (days)
Safety Population
Placebo
(N=xx)
n (%)/
Mean Onset/
ZX008 0.2 mg/kg/day
(N=xx)
n (%)/
Mean Onset/
ZX008 0.5 mg/kg/day
(N=xx)
n (%)/
Mean Onset/
ZX008 0.8 mg/kg/day
(N=xx)
n (%)/
Mean Onset/
Any DB ZX008
(N=xx)
n(%)
Mean Onset/
TEAE = Treatment-Emergent Adverse Event.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in each treatment group.
Note: Mean Onset and Mean Duration are measured in days. The onset day is the study day at the adverse event onset. The duration is the number of days from onset to resolution or from onset to last
follow-up day if the event was ongoing.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: In subjects with more than one occurrence of the same event, the time to onset and duration is based on the earliest occurring event.
Note: Time to onset is the number of days since first treatment with either ZX008 or placebo. The duration of an event is limited to the period of the double-blind study.
Note: A subject with more than one TEAE with the same preferred term is counted once for that term. A subject with more than one TEAE under a system organ class is counted once for that class.
Programing note: Use shell for 14.3.1.10.1 for 14.3.1.10.1.1
Table 14.3.1.10.1.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind Treatment Period by MedDRA System Organ Class and Preferred Term
with Mean Time to Onset (days) and Mean Duration (days)
Safety Population (Japan)
MedDRA System Organ Class and Preferred Term
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Subjects with any TEAE starting in the first month.
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
System Organ Class 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 2
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
PUBLIC COPY 
ch
U
ch treatm
UB
treatm
set
P
set day
PU
day is
U
is
U
e
P
e
r
Y
r
.X%)
PY
.X%) /
PY
/ xx.x
PY
xx.x
Y
XX
C
XX (XX.X%)
CO
(XX.X%)
XX
C
XX (XX.X
CO
(XX.X
XX
C C
XX (X
C
(X
LIC
IC
IC
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
edDRA
au
edDRA Syst
au
Syst
5
k
5 mg/kg/day
ket
mg/kg/day
(N=xx)
ark
(N=xx)
n
ar
n (%)/
r
(%)/
Mean
ma
Mean O
group.
to s
group.
study
d to
study day
to
day a
n or
ed
or after
ed
after th
d
th
otherwise.
se
otherwise.
he
he time
us
time to
s
to o
h
e
h either
e u
either ZX0
u
ZX0
red
b
red term is c
be
term is c
0.1.1
no
0.1.1
Adverse
nt c
Adverse Eve
c
Eve
eti
uth
Mea
m
Mea
x.x
a
x.x
XX
y
XX
y
xx.x
rt
xx.x /xx.x
rt a
/xx.x
)
p
) / xx.x
or
xx.x /xx.x
ort
/xx.x
X%)
pp
X%) /
pp
/ xx.x
po
xx.x /x
o
/x
up
application and any extensions or variations thereof. 
a
em
o
em Organ
of.
Organ C
y
Onset/
on
Onset/
ZX0
e
ZX0
t the
ns
the adverse
ns
adverse
e
x
e date
xte
date of firs
te
of firs
nset
e
nset and
ex
and dur
x
dur
08
08 or
y
or placeb
y e
placeb
ounted
ny
ounted once
y
once
ts
ti
ts that
tio
that Occu
on
Occu
he
n
t
n Duration
tio
Duration
(XX.X%)
ria
(XX.X%) /
a
/ x
a
x
tio
XX
va
XX (XX.X
va
(XX.X
XX
r v
XX (XX
v
(XX
x.x
x.x
XX
r
XX
s


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 148 of 234
Draft 3.0: 04Aug2020
Table 14.3.1.10.2
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean Average
Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days)
Safety Population
ZX008
0 - < 0.2 mg/kg [1]
(N=xx)
n (%)/
ZX008
0.2 - < 0.4 mg/kg
(N=xx)
n (%)/
ZX008
0.4 - < 0.6 mg/kg
n (%)/
ZX008
0.6 - < 0.8 mg/kg
(N=xx)
n (%)/
Any OLE ZX008
(N=xx)
n(%)
Mean Onset/
Mean Onset/
Mean Onset/
Mean Onset/
Mean Onset/
MedDRA System Organ Class and Preferred Term
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Subjects with any TEAE starting in the first month.
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
System Organ Class 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 2
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
.
.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in each treatment group.
Note: Mean Onset and Mean Duration are measured in days. The onset day is the study day at the adverse event onset. The duration is the number of days from onset to resolution or from onset to last
follow-up day if the event was ongoing.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: In subjects with more than one occurrence of the same event, the time to onset and duration is based on the earliest occurring event.
Note: Onset day is measured from the first date of ZX008 treatment to onset. Duration for the TEAEs in the placebo group start after the subject starts ZX008 treatment in the OLE.
[1] For subjects treated with Placebo in the core study, TEAEs are counted only after the subject started ZX008 treatment.
Programming note: Use the shell for Table 14.3.1.10.2.1.
Table 14.3.1.10.2.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean Average
Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days)
Safety Population (Japan)
PUBLIC COPY 
PU
Y
Durati
Y
Durati
XX.X%)
OPY
XX.X%) /
PY
/ x
P
x
Y
XX
C
XX (XX.X
CO
(XX.X
XX
C C
XX (X
C
(X
x
I
x
XX
C 
XX
ach
P
ach
thorization 
national
zat
national L
03
03
be used to support any marketing auth
to
y MedDRA Sy
au
MedDRA Sy
(days)
g
(days)
ZX008
rke
ZX008
0.4
a
0.4 -
a
- <
ar
< 0.6
ar
0.6 m
n
a
n (%
(%
et
Mea
m
Mea
M
/xx.x
t a
/xx.x
ny
/ xx.x
ort
xx.x /xx.x
ort
/xx.x
X%)
p
X%) /
p
/ xx.x
po
xx.x /xx
o
/xx
XX.X%)
pp
XX.X%) /
pp
/ xx.x
pp
xx.x
eatment
ed
eatment gro
d
gro
day
s
day is
se
is the
se
the stu
e
stu
started
e u
started on
u
on
This document cannot be
do
TIAL
s d
TIAL
o
e confirm oth
be 
e confirm oth
event,
t b
event, the
be
the t
e
t
reatment
ot
reatment to
to
TEAEs
not
TEAEs are
o
are co
t
co
1.10.2.1.
an
1.10.2.1.
Occurred
t c
Occurred inin
uth
application and any extensions or variations thereof. 
a
ns
ystem Orga
of. 
ystem Orga
g/kg
ns
g/kg
%)/
o
%)/
he
n
t
n Onset/
tio
Onset/
ean
at
ean Duration
atio
Duration
XX
a
XX (XX.X%)
ari
(XX.X%) /
iat
XX
r v
XX (XX
v
(XX
.x.x
XX
r 
XX
/xx.x
s
/xx.x
up.
xt
up.
dy
e
dy day
ext
day at
xte
at the
e
the
after
y
after the
y e
the da
e
da
erwise.
ny
erwise.
me
a
me to
an
to onset
any
onset
onset.
d a
onset. Dura
a
Dura
unted
nd
unted only
d 
only
at
i
at least
ion
least 5%
n
5%


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 149 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use the Listing 16.2.7.1 shell for the following tables.
Table 14.3.2.1
Listing of Deaths
Table 14.3.2.1.1
Listing of Deaths (Japan)
Table 14.3.2.2
Listing of SAEs
Table 14.3.2.2.1
Listing of SAEs (Japan)
Table 14.3.2.3
Listing of Discontinuations Due to AE
Table 14.3.2.3.1
Listing of Discontinuations Due to AE (Japan)
PUBLIC COPY 
ng
Y
ng o
Y
o
Table
OPY
Table 14
PY
14
Listing
CO
Listing
P
Listin
IC
Listin
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
2.2.1
a
2.2.1
AEs
rt
AEs (Japan)
rt a
(Japan)
Table
ppo
Table 14.3.2
po
14.3.2
of
u
of Discontin
upp
Discontin
Ta
Ta
Listing
to
Listing of
to
of Dis
o 
Dis
uth
sions or variations thereof. 
.3.3
ations
s
ations Due
s o
Due t
o
t
ble
i
ble 14.3.2.3.
ion
14.3.2.3.
application and any extens
a
ontinuation
nsi
ontinuation


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 150 of 234
Draft 3.0: 04Aug2020
Laboratory Data
Please see below (also in SAP) for time windows
Time Intervals for Analysis Visits for Laboratory Data and Vital Signs
Analysis
Phase/Period
Scheduled Visit Number
in ZX008-1503
Analysis Visit
Number*
Time Interval
(label on output)
Time Interval
(Day)
Target Time Point
(Day)
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
2
2
Week 2 (OLE)
2 to 20
15
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
OLE last Visit**
99
Last Value
Day 2 to Visit 17
date
Programming Notes:
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on the end date of a phase/period or start date of a new phase/period
are assigned to the preceding phase/period. For example, measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
LIC COPY 
Y
PY
PY
PY
PY
PY
E)
CO
E)
OP
(OLE)
CO
(OLE)
CO
6
C
6 (OLE)
C C
(OLE)
C
nth
IC
nth 9
IC
9 (OLE
C 
(OLE
C
Month
LIC
Month 12
IC
12 (
C
(
IC
PUBL
Month
BL
Month
BLI
Mon
UB
Mon
B
M
U
M
UB
PU
P
support any marketing authorization 
uth
national
zat
national L
03
03
Target
ark
Target
rk
ma
ma
ma
ma
ma
m
to
n
to 20
ny
20
ny
21
a
21 to
an
to 44
an
44
any
45
rt a
45 to
a
to 74
a
74
t a
75
rt
75 to
to
rt
13
13
o
p
pp
LE)
LE)
pp
pp
pp
sed to supp
(OLE)
s
(OLE)
sup
18
o
18 (OLE)
to s
(OLE)
s
nth
t
nth 21
to
21 (OLE)
to
(OLE)
to
Month
d t
Month 24
d t
24 (O
t
(O
d t
Month
ed
Month 27
d
27
ed
use
Month
se
Month
annot be use
Mo
s
Mo
us
u
be
be
be
ot be
This document ca
do
TIAL
s d
TIAL
dow, please
can
dow, please
. For exampl
t ca
. For exampl
w
n
w will
nt
will be
t c
be use
c
use
ns or variations thereof. 
Time
s
Time Point
s t
Point
(Day)
ons
(Day)
s t
on
1
o
1
tio
at
ria
ar
ar
ar
ar
ar
134
r
134
va
5 to
o
to 224
or
224
r
225
s
225 to
s o
to 314
o
314
o
315
ns
315 to
s 
to 4
s
xtensions
410
n
410 t
ns
i
50
50
ion
sisisisio
si
LE)
e
LE)
ns
(OLE)
xte
(OLE)
ten
ext
30
e
30 (OLE)
ext
(OLE)
d any exte
nth
nth 33
e
33 (OLE)
ex
(OLE)
ex
Month
y
Month 36
y e
36 (O
e
(O
y e
Last
any
Last Va
y
Va
ny
application and a
a
d a
use
n
use the
n a
the close
a
close
e, measurem
on 
e, measurem
d.
t
d. [This
tio
[This is
o
is an
an


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 151 of 234
Draft 3.0: 04Aug2020
Laboratory Test: Parameter (units)
Table 14.3.4.1
Laboratory parameters – Hematology
Safety Population
ZX008 OL
(N=xxx)
De Novo Subjects
(N=xxx)
Visit
Visit Values
Change from Baseline
Visit Values
Change from Baseline
Baseline (OLE)
N
XX
XX
Mean
XX.X
XX.X
SD
XX.XX
XX.XX
Median
XX.X
XX.X
Min
XX
XX
Max
XX
XX
Week 2 (OLE)
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
Repeat for other time periods:
Month 2 (OLE), 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, and
Last Value (OLE)
PUBLIC COPY 
Y
OP
OP
OP
OP
CO
X
C
X
C C
XX
BLI
XX
LIC
XX
B
XX
BL
PU
P
ot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ke
ke
ke
ke
aseline
ma
aseline
a
m
ny
a
rt
po
up
up
up
up
up
s
to
d
XX
se
XX
se
u
b
t cannot be
be
b
ot
no
an
ment c
21,
e
21, 24,
en
24, 27,
n
27, 3
This docum
do
TIAL
s d
TIAL
t c
m
ny extensions or variations thereof. 
th
ns
ioioioio
tio
at
ar
v
or
s
on
s
en
en
en
en
en
xt
XX.X
y
XX.X
y e
d any
XX.XX
any
XX.XX
plication and any
XX
a
XX
d a
nd
a
0,
c
0, 33,
cat
33, 36,
at
36, and
t
and
application
a
on
plic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 152 of 234
Draft 3.0: 04Aug2020
Laboratory Test: Parameter (units)
Table 14.3.4.1
Laboratory parameters – Hematology
Safety Population
Visit [1]
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
De Novo Subjects
(N =XX)
Baseline (OLE)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
Week 2 (OLE)
Observed
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
CFB
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
…
Repeat for all time
points
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
X
C
X
OP
XX
C
XX
CO
XX
C C
XX
C
C
LIC
BL
UB
UB
UB
UB
UB
U
PU
P
nnot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ke
a
m
XX
y
XX
y m
XX.X
any
XX.X
ny
XX.XX
an
XX.XX
an
XX.
a
XX.
t a
rt
po
pp
pp
pp
pp
pp
up
su
XX
to
XX
s
XX.X
to
XX.X
to
XX.X
t
XX.X
d t
ed
se
us
us
us
us
us
e u
be
XX
ot b
XX
t b
XX.X
ot
XX.X
ot
XX.X
no
XX.X
no
ment cann
nn
an
ca
ca
ca
ca
ca
t c
n
This docum
do
TIAL
s d
TIAL
m
um
and any extensions or variations thereof. 
Gp5
s t
Gp5
(N
n
(N =
s
= XX)
s t
XX)
th
ns
on
tio
aiaiaiat
ria
ria
ria
ria
ria
X
a
XX
r
XX
v
XX
or
XX
or
o
s
n
io
sisisisisi
X
t
X
ns
XX.X
xt
XX.X
te
XX
ext
XX
xt
XX
e
XX
ex
y e
ny
an
a
d a
X
a
X
nd
an
XX.X
a
XX.X
ation an
XX
n
XX
a
XX
on
XX
on
tio
applicat
a
ati
ic
licicic
plic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 153 of 234
Draft 3.0: 04Aug2020
CFB = Change from Baseline.
Note: Time windows are specified in the Statistical Analysis Plan. For multiple measurements within a time window, the closest to the target time point was used. Measurements occurring on the end date
of an interval or start date of a new interval are assigned to the preceding interval: For example, measurements taken on OLE Study Day1 are assigned as Baseline(OLE). However, for the Last value (OLE) ,
the last observation in the time window is used.
[1] Laboratory tests were performed at all visits
Programming Note:
-
Repeat for all other laboratory parameters.
-
Use correct number of decimal places for summary statistics depending on the raw data recorded for each parameter. Please do not use more than 3 decimal places unless there are 2 significant
digits or fewer. Two decimal places are preferred.
-
Include correct units for the lab tests in the titles.
Programming Notes: Use the table shell for 14.3.4.1 for the following tables.
Table 14.3.4.1.1
Laboratory parameters – Hematology
Safety Population (Japan)
Table 14.3.4.2 Laboratory parameters –Biochemistry
Safety Population
Table 14.3.4.2.1 – Laboratory parameters – Biochemistry
Safety Population (Japan)
Table 14.3.4.4.1
Laboratory Parameters - Urinalysis (Quantitative Parameters)
Safety Population
Table 14.3.4.4.1.1
Urinalysis (Quantitative Parameters)
Safety Population (Japan)
PUBLIC COPY 
Labor
IC
Labor
Tab
UB
Tab
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
t time
a
time point
au
point
1 are
g
1 are assigne
g a
assigne
meter.
ma
meter. Pleas
a
Pleas
Table
pp
Table 14.3.4
ppo
14.3.4
ory
u
ory paramet
upp
paramet
Safety Popu
sup
Safety Popu
4.3.4.2
to s
4.3.4.2 Labo
s
Labo
Table
ed
Table 14.3.4
ed
14.3.4
uth
any extensions or variations thereof. 
was
of
was used.
of.
used. M
ed
e
ed as
eo
as Baselin
eof
Baselin
e
o
e do
on
do not
ons
not use
s
use
1.1
1.1
ers
s
ers –
s
– Hemato
s o
Hemato
lation (Japan
ns
lation (Japan
ratory
sio
ratory param
io
param
Safety
ns
Safety Popu
s
Popu
.2.1
xt
.2.1 –
te
– Labora
te
Labora
application and a
a
Safety
xt
Safety
Laboratory
an
Laboratory


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 154 of 234
Draft 3.0: 04Aug2020
Table 14.3.4.4.2
Laboratory parameters - Urinalysis (Categorical)
Safety Population
Laboratory Test: Parameter [Example Table below for illustrative purpose only]
Programming Note: For interims and 120-day, please use only last column ZX008 OL
Gp1
(N=39)
Gp2
(N=40)
Gp3
(N=5)
Gp4
(N=43)
Gp5
(N=14)
Gp9
(N=141)
De Novo Subjects(
(N=XXX)
Baseline (OLE)
n
34
36
3
38
0
111
111
NEGATIVE
34 (100.0%)
36 (100.0%)
3 (100.0%)
38 (100.0%)
0 (0.0%)
111 (100.0%)
111 (100.0%)
Week 2 (OLE)
n
2
2
0
1
0
5
5
NEGATIVE
2 (100.0%)
2 (100.0%)
0 (0.0%)
1 (100.0%)
0 (0.0%)
5 (100.0%)
5 (100.0%)
Month 1 (OLE)
n
29
31
2
34
10
106
106
NEGATIVE
29 (100.0%)
31 (100.0%)
2 (100.0%)
34 (100.0%)
10 (100.0%)
106 (100.0%)
106 (100.0%)
Month 2 (OLE)
n
26
30
2
33
10
101
101
NEGATIVE
26 (100.0%)
30 (100.0%)
2 (100.0%)
33 (100.0%)
10 (100.0%)
101 (100.0%)
101 (100.0%)
………
Repeat for all visits
Last Value (OLE)
n
26
30
2
33
10
101
101
NEGATIVE
26 (100.0%)
30 (100.0%)
2 (100.0%)
33 (100.0%)
10 (100.0%)
101 (100.0%)
101 (100.0%)
Note: Time windows are specified in the Statistical Analysis Plan. For multiple measurements within a time window, the closest to the target time point was used. Measurements occurring on the end date
of an interval or start date of a new interval are assigned to the preceding interval: For example, measurements taken on OLE Study Day1 are assigned as Baseline(OLE). However, for the Last value (OLE) ,
the last observation in the time window is used.
PUBLIC COPY 
Y
3
P
3
3
CO
3 (10
O
(10
0.0%)
BL
0.0%)
3
U
3
31
P
31
thorization 
national
zat
national L
03
03
ment cannot be used to support any marketing auth
e
Gp4
ma
Gp4
(N=43)
y m
(N=43)
a
y m
0%)
or
0%)
0
pp
0
0
up
0 (0.0
up
(0.0
00.0%)
ed
00.0%)
30
u
30
30
e
30 (1
(1
26
ca
26
26
t c
26 (100.0%
t ca
(100.0%
um
d in the
me
in the Stati
e
Stati
new interv
um
new interv
This docu
do
TIAL
s d
TIAL
ime window
cu
ime window
uth
application and any extensions or variations thereof. 
a
ca
ns
tio
38
ar
38
38
va
38 (100.0
va
(100.0
0%)
o
0%)
2
ns
2
2
en
2 (100
en
(100
00.0%)
ny
00.0%)
)
stical
lic
stical Analys
ica
Analys
l are
pli
are assigne
plic
assigne
is used.
pp
is used.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 155 of 234
Draft 3.0: 04Aug2020
Programming Note: Use the Table 14.3.4.4.2 shell to produce the following table.
Table 14.3.4.4.2.1
Laboratory parameters - Urinalysis (Categorical)
Safety Population (Japan)
Table 14.3.4.5.1
Laboratory parameters – Tests of growth, precocious puberty and thyroid function
Safety Population (Japan)
PY 
wth,
Y
wth,
PUBLIC COPY
pr
Y
pr
y Populati
PY
y Populati
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ous
ny
ous puberty
ny 
puberty
n (Japan)
any
n (Japan)
application and any extensions or variations thereof. 
a
and
at
and thyroid
atio
thyroid


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 156 of 234
Draft 3.0: 04Aug2020
Programming Note: Use Table 14.3.4.1 shell for the following tables.
Table 14.3.4.5
Laboratory parameters – Tests of growth, precocious puberty and thyroid function
Safety Population
Table 14.3.4.5.1
Laboratory parameters – Tests of growth, precocious puberty and thyroid function
Safety Population (Japan)
For interims and 120-day, please use only last column
For IDMC uses all columns
Programming Note: Use shell for Table 14.3.4.1 Include correct units in the titles for the Vital sign parameter
Table 14.4.1.1
Vital Signs
Safety Population
Table 14.4.1.1.1
Vital Signs
Safety Population (Japan)
PUBLIC COPY
wth,
Y
wth, p
Y
p
Populatio
PY 
Populatio
tles
L
tles for
LIC
for the
IC
the
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
nd
rk
nd thyroid
rke
thyroid f
e
f
us
us puberty
y m
puberty a
m
a
Japan)
ny
Japan)
ital
u
ital sign
up
sign par
p
par
application and any extensions or variations thereof. 
a
nction
th
nction
nd
a
nd thyroid
atio
thyroid fu
o
fu
ameter
ns
ameter
Table
sio
Table 14.4.1
sio
14.4.1
Vital
ns
Vital Sig
Sig
Safety
en
Safety P


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 157 of 234
Draft 3.0: 04Aug2020
Programming Note:
Use shell for Figure 1b in ISS for the the following figures.
Figure 14.4.1.2
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment Period
Safety Population
Figure 14.4.1.2.1
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment Period
Safety Population (Japan)
Y-axis: ADVS.AVAL where PARAMCD=HEIGHT and AVISIT=EOS/ET and SAFFL=’Y’
X-axis: ADSL.AGEEOS
OPY 
ure
Y
ure 14.4
Y
14.4
is)
P
is) at
PY
at End
PY
End
Y
PUBLIC CO
afety Popu
OP
afety Popu
t any marketing authorization 
uth
national
zat
national L
03
03
he
a
he Open
ark
Open-
r
-lab
k
lab
Study
an
Study during
any
during
This document cannot be used to support a
do
TIAL
s d
TIAL
tion (Japan)
t a
tion (Japan)
application and any extensions or variations thereof. 
a
l Treatment
s t
Treatment
the
r
the Open
ria
Open-
a
-la
a
la


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 158 of 234
Draft 3.0: 04Aug2020
Table 14.4.1.3
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary Statistics
Safety Population
Age Group: 2-<4 years/ 4 -<6 years/ 6 - <12 years/>=12 years
Visit [1]
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
Baseline (OLE)
N
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
Week 2 (OLE)
Observed
N
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
CFB
N
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
…
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
OP
X.XX
C
X.XX
CO
XX.X
C C
XX.X
C
XX
C
XX
C
X
C
X
LIC
BL
B
UB
UB
UB
UB
U
PU
P
cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
nd
n
nd ≥12):
ng
≥12): Sum
g
Sum
X)X)
a
y m
ny
XX
an
XX
an
XX.X
a
XX.X
t a
X
rt
o
pp
pp
pp
pp
pp
upp
pp
pp
p
su
s
to
XX
t
XX
d t
ed
se
us
us
us
us
us
e u
XX
b
XX
be
t b
ot
XX
o
XX
no
nn
a
ment can
an
ca
ca
ca
ca
ca
t c
XX
e
XX
nt
e
This docum
do
TIAL
s d
TIAL
m
um
and any extensions or variations thereof. 
mmary
eo
mmary Statis
eo
Statis
Gp5
ns
Gp5
(N
on
(N = X
ns
tio
at
ria
ria
ria
ria
ria
a
X.XX
r
X.XX
v
XX.X
or
XX.X
or
XX
o
XX
o
XX
XX
s
ns
io
sisisisisi
ns
XX.X
xt
XX.X
te
XX.XX
ext
XX.XX
xt
XX.X
e
XX.X
ex
XX
XX
y e
ny
an
d a
d a
d a
d a
nd
XX.X
a
XX.X
an
n a
XX.XX
n a
XX.XX
lication a
XX.X
on
XX.X
n
XX
o
XX
tio
ati
c
applica
a
ca
ic
licicic
plic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 159 of 234
Draft 3.0: 04Aug2020
Repeat for all time
points
Note: If a test is repeated at any given visit, the last non-missing result is used in the summary.
Note: this table excludes the De Novo Subjects.
Programming note: Use the Table 14.4.1.3 shell for
Table 14.4.1.3.1
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary Statistics
Safety Population (Japan)
PUBLIC COPY 
pulat
Y
pulat
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ut
ut
ut
ut
g a
ng
4;4; 4
m
4 -
m
- <6;
m
<6; 6
m
6 to
to
an)
y
an)
application and any extensions or variations thereof. 
a
of
eo
<12;
io
<12; and
on
and ≥1
n
≥1


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 160 of 234
Draft 3.0: 04Aug2020
Table 14.4.1.4
Weight Over Time during the Open-Label Study Period for De Novo Subjects: Summary Statistics
Safety Population – De Novo Subjects
Visit [1]
De Novo Subjects
(N = XX)
Baseline (OLE)
N
XX
Mean
XX.X
SD
XX.XX
Median
XX.X
Min
XX
Max
XX
Week 2 (OLE)
Observed
N
XX
Mean
XX.X
SD
XX.XX
Median
XX.X
Min
XX
Max
XX
CFB
N
XX
Mean
XX.X
SD
XX.XX
Median
XX.X
Min
XX
Max
XX
…
Repeat for all time points
Note: If a test is repeated at any given visit, the last non-missing result is used in the summary.
PUBLIC COPY 
Y
PY
OP
CO
C
C C
IC
LI
BL
UB
PU
P
thorization 
national
zat
national L
03
03
ment cannot be used to support any marketing auth
ry
g
ry Statistics
a
Statistics
ects
ke
ects
X)
k
X)
tin
rk
ar
XX
m
XX
ma
XX.X
m
XX.X
m
X
y
X
y
ny
a
rt
or
po
pp
up
s
to
d to
d
e
us
u
be
be
t
o
nn
an
ca
t c
nt
nt
nt
nt
nt
en
This documen
do
TIAL
s d
TIAL
n
men
y
u
y given
um
given visit,
m
visit,
uth
ation and any extensions or variations thereof. 
er
t
s 
on
tio
X.XX
ia
X.XX
at
XX.X
ari
XX.X
ria
XX
var
XX
ar
XX
va
XX
va
r v
or
s o
ns
on
sio
ns
en
xte
ex
e
ny
any
d a
d
n
a
n
on
tio
applica
a
ca
lic
the
pl
the last
plic
last non
ic
non


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 161 of 234
Draft 3.0: 04Aug2020
Programming note: Use the Table 14.4.1.4 shell for
Table 14.4.1.4.1
Weight Over Time during the Open-Label Study Period for De Novo Subjects: Summary Statistics
Safety Population – De Novo Subjects – Japan
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
mmary
ng
mmary Statist
g 
Statist
uth
application and any extensions or variations thereof. 
a
cs
e
cs


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 162 of 234
Draft 3.0: 04Aug2020
Table 14.4.1.5
Weight Summary (Lost/Gain ≥7% or ≥10%) during the Open-Label Study Period
Safety Population
Placebo/
ZX 008 OL
(N = XX)
ZX008 0.2 mg/
ZX 008 OL
(N = XX)
ZX008 0.5 mg/
ZX008 OL
(N = XX)
ZX008 0.8 mg/
ZX 008 OL
(N = XX)
All Subjects
(N = XX)
De Novo Subjects
(N = XX)
Baseline (OLE) n
xx
xx
xx
xx
xx
xx
At Any Visit in OLE, n
xx
xx
xx
xx
xx
xx
Lost >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Recovered lost weight [2]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Days until Recovery
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
Lost >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gain >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gain >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Month 1 (OLE), n
xx
xx
xx
xx
xx
xx
Lost >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Recovered lost weight [2]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Days until Recovery
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
Lost >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gain >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
%)
C
%)
XXX.X
C C
XXX.X
XXX.XX
LIC
XXX.XX
XX
LI
XX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
od
od
ZX008
keti
ZX008 0
ZX
e
ZX
tin
ar
ar
ar
xx
an
xx
XX
t a
XX (XX.X%
an
(XX.X%
XX
rt 
XX (XX
a
(XX
X
XXX
o
XXX
XXX
to
XXX
XX
d t
XX (XX.X%
d t
(XX.X%
XX
ed
XX (XX
d
(XX
XX
e
XX
.X%)
t b
.X%)
(XX.X%)
ot
(XX.X%)
XXX.X
nn
XXX.X
XX
n
XX
uth
application and any extensions or variations thereof. 
a
8
h
8 mg/
the
mg/
008
t
008 OL
th
OL
(N
s
(N =
s
= XX)
s t
XX)
her
xx
n
xx
s
)
X%)
v
X%)
XXX.X
or
XXX.X
XXX.XX
s 
XXX.XX
XX
s
XX
%)
%)
X.X%)
xt
X.X%)
(XX.X%)
ext
(XX.X%)
xx
y
xx
XX
ny
XX (X
y
(X
X
X.XX
n
X.XX
XXX.X
on
XXX.X
XXX
tio
XXX
XXX
t
XXX
XX
ca
XX (


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 163 of 234
Draft 3.0: 04Aug2020
Gain >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Note: Time windows are specified in the statistical analysis plan. In the event of 2 or more assessments in the interval, the assessment completed closest to the target time point are assessed. For the last
assessment, the last non-missing value observed.
[1] Percentages are based on the number of subjects with a baseline weight and a weight at the visit meeting the criteria noted in the row.
[2] A subject recovered, if they had a weight recorded after the visit being summarized that was within 1% of the baseline body weight at 2 consecutive visits. Percentages are based on the number of
subjects who had the 7%/10% weight loss and had a value meeting the criteria noted in the row.
Programming Notes: Use the Table 14.4.1.5 shell for the following tables.
Table 14.4.1.5.1
Weight Summary (Lost/Gain ≥7% or ≥10%) during the Open-Label Study Period
Safety Population (Japan)
Table 14.4.1.6
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population
Table 14.4.1.6.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population (Japan)
Programming notes: Repeat Table 14.4.1.5 for 14.4.1.6 and 14.4.1.6.1 by subset by (a) subjects on concomitant topiramate, and (b) subjects not on concomitant topiramate.
Programming note: Use the Table 14.4.1.5 shell but only present for 5% to produce the following tables.
Table 14.4.1.7
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period
Safety Population
Table 14.4.1.7.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period
Safety Population (Japan)
PUBLIC COPY 
Table
OP
Table 1
P
1
ain
CO
ain ≥7%
CO
≥7% o
O
o
Safety
CO
Safety
P
n
B
n ≥7%,
BLI
≥7%, o
LI
o
ost/G
P
ost/G
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
%)
a
%)
ompleted
ng 
ompleted clo
clo
the
ke
the row.
keti
row.
y
r
y weight
rke
weight at
e
at
.1.5.1
t a
.1.5.1
10%)
ort
10%) during
rt 
during
opulation (Ja
por
opulation (Ja
Table
upp
Table 1
p
1
10%)
s
10%) during
sup
during
p
Saf
s
Saf
≥7%,
ed
≥7%, or
d 
or ≥1
≥1
6.1
6.1 by
e u
by subset
us
subset
ent
t b
ent for
be
for 5%
be
5% to
e
to
uth
application and any extensions or variations thereof. 
a
sest
e
sest to the
eo
to the t
consecutive
th
consecutive
he
he Open
va
Open-
a
-Lab
a
Lab
apan)
or
apan)
4.4.1.6
ns
4.4.1.6
he
o
he Open
ons
Open-Lab
s
Lab
ety
i
ety Populatio
ion
Populatio
Table
ns
Table 14.
s
14.
0%)
te
0%) during
ten
during t
Safety P
xte
Safety P
by
y
by (a)
y e
(a) subje
e
subje
produce
any
produce the
y
the
Weight
and
Weight


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 164 of 234
Draft 3.0: 04Aug2020
Table 14.4.1.8
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population
Table 14.4.1.8.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
keting auth
t Topiramate
au
Topiramate
This document cannot be used to support any marke
do
TIAL
s d
TIAL
Concomitan
ket
Concomitan
uth
hereof. 
application and any extensions or variations the
a
t
t
t Topiramate
the
Topiramate


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 165 of 234
Draft 3.0: 04Aug2020
Table 14.4.4.1
Tanner Staging by Age Group for Boys
Safety Population
Age Group
Visit [1]
Tanner
Stage
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
<7years
Baseline (OLE)(Day 1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 12 (Month 24)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>7years to <=11
Baseline (OLE)(Day1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
X%)
Y
X%)
XX.X%)
PY
XX.X%)
XX
O
XX (XX.X%)
OPY
(XX.X%)
XX
CO
XX (XX.X
O
(XX.X
X
C
X
X%)
LI
X%)
XX.X%)
BLI
XX.X%)
X
U
X (XX.X%)
UBL
(XX.X%)
XX
PU
XX (XX.X
UB
(XX.X
X
P
X
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Gp4
ket
Gp4
(N
rk
(N =
k
= XX
XX
tin
ar
XX.X%)
m
XX.X%)
X
X (XX.X%)
y m
(XX.X%)
XX
n
XX (XX.X%
ny
(XX.X%
XX
an
XX (XX
n
(XX
)
XX
a
XX
(XX.X%)
ppo
(XX.X%)
XX
u
XX (XX.X%)
upp
(XX.X%)
XX
su
XX (XX.X
up
(XX.X
XX
s
XX (X
(X
)
X
(XX.X%)
ed
(XX.X%)
XX
u
XX (XX.X%)
use
(XX.X%)
XX
u
XX (XX.X
us
(XX.X
XX
e 
XX (X
(X
V
t
V
X
e
X
Stage
no
Stage I
o
I
Stage
nn
Stage IIII
Stag
an
Stag
S
a
S
e
m
e (OLE)(Day
me
(OLE)(Day
uth
application and any extensions or variations thereof. 
a
X)
X)
G
(
her
s
X
i
X (XX.X%)
ion
(XX.X%)
XX
ati
XX (XX.X%
atio
(XX.X%
XX
iat
XX (XX
at
(XX
X%)
a
X%)
XX
i
XX
(XX.X%)
va
(XX.X%)
XX
o
XX (XX.X%
or
(XX.X%
XX
s o
XX (XX
o
(XX
%)
o
%)
XX
s
XX
X.X%)
sio
X.X%)
X
n
X (XX.X%)
nsi
(XX.X%)
XX
xte
XX (XX.
e
(XX.
XX
xt
XX (
%)
y
%)
X.X%)
ny
X.X%)
X (XX.X%)
any
(XX.X%)
XX
nd
XX (XX.
d 
(XX.
XX
n
XX (
e III
n
III
tage
o
tage IV
on
IV
Stage
tio
Stage V
o
V
1)
l
1)
Sta
a
Sta


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 166 of 234
Draft 3.0: 04Aug2020
Stage III
Stage IV
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 12 (MNonth 24)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>11years to <=15
Baseline (OLE) (Day 1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
)
Y
)
(XX.X%)
PY
(XX.X%)
XX
O
XX (XX.X%
OP
(XX.X%
XX
CO
XX (XX
O
(XX
XX
C
XX
%)
I
%)
(XX.X%)
BL
(XX.X%)
XX
U
XX (XX.X%
UB
(XX.X%
XX
PU
XX (XX
U
(XX
XX
P
XX
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
X%)
n
X%)
XX
aut
XX (XX.X%
ut
(XX.X%
XX
a
XX (XX
(XX
XX
XX
uth
X
k
X (XX.X%)
keti
(XX.X%)
XX
rk
XX (XX.X%
ke
(XX.X%
)
XX
ark
XX (XX
k
(XX
X%)
m
X%)
XX
a
XX
(XX.X%)
y m
(XX.X%)
XX
an
XX (XX.X%
ny
(XX.X%
XX
a
XX (X
(X
%)
o
%)
XX
XX
X.X%)
po
X.X%)
X (XX.X%)
pp
(XX.X%)
XX
su
XX (XX.
u
(XX.
XX
s
XX (
%)
d
%)
X.X%)
ed
X.X%)
X (XX.X%)
sed
(XX.X%)
XX
e u
XX (XX.
u
(XX.
XX
e
XX
e III
t
III
tage
o
tage IV
ot
IV
Stage
nno
Stage V
o
V
Sta
a
Sta
application and any extensions or variations thereof. 
a
%)
f
%)
X.X%)
of
X.X%)
(XX.X%)
eo
(XX.X%)
XX
he
XX (XX.X
e
(XX.X
)
XX
h
XX (X
(X
.X%)
ns
.X%)
X
(XX.X%)
ons
(XX.X%)
XX
ti
XX (XX.X%)
tio
(XX.X%)
%)
%)
XX
ia
XX (X
a
(X
X.X%)
va
X.X%)
X
(XX.X%)
r va
(XX.X%)
XX
o
XX (XX.X%)
or 
(XX.X%)
XX
s o
XX (XX.X
o
(XX.X
X%)
o
X%)
X
XX.X%)
sio
XX.X%)
XX
n
XX (XX.X%)
ns
(XX.X%)
XX
ten
XX (XX.X%
en
(XX.X%
XX
xte
XX (XX
e
(XX
X%)
y
X%)
XX.X%)
ny
XX.X%)
XX
XX (XX.X%)
an
(XX.X%)
XX
d
XX (XX.X%
d a
(XX.X%
XX
nd
XX (XX
d
(XX
ge
ge I
n
I
Stage
io
Stage II
on
II
Stage
atio
Stage III
o
III
Stage
at
Stage
StSt


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 167 of 234
Draft 3.0: 04Aug2020
Visit 12
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>15years to <=18
Baseline (OLE) (Day 1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 12 (Month 24)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
)
Y
)
.X%)
Y
.X%)
(XX.X%)
PY
(XX.X%)
XX
CO
XX (XX
O
(XX
XX
C
XX
%)
I
%)
.X%)
LI
.X%)
(XX.X%)
BL
(XX.X%)
XX
PU
XX (XX
U
(XX
XX
P
XX
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
XX
aut
XX (XX.X%
ut
(XX.X%
uth
XX
a
XX (XX
(XX
X%)
n
X%)
XX
XX
XX.X%)
tin
XX.X%)
X
k
X (XX.X%)
keti
(XX.X%)
)
XX
ark
XX (XX
k
(XX
X%)
m
X%)
XX
a
XX
(XX.X%)
y m
(XX.X%)
XX
n
XX (XX.X%)
ny 
(XX.X%)
XX
an
XX (XX.X%
ny
(XX.X%
%)
o
%)
XX
XX
X.X%)
po
X.X%)
X (XX.X%)
pp
(XX.X%)
XX
u
XX (XX.X%)
up
(XX.X%)
XX
su
XX (XX.
u
(XX.
%)
d
%)
X.X%)
ed
X.X%)
X (XX.X%)
sed
(XX.X%)
XX
u
XX (XX.X%)
us
(XX.X%)
XX
e u
XX (XX.
u
(XX.
e I
t
I
tage
o
tage II
ot
II
Stage
nno
Stage III
o
III
Stage
ann
Stage
Sta
a
Sta
t/EOS
nt
t/EOS
application and any extensions or variations thereof. 
a
%)
f
%)
X.X%)
of
X.X%)
(XX.X%)
eo
(XX.X%)
XX
e
XX (XX.X%)
ere
(XX.X%)
XX
he
XX (XX.X
e
(XX.X
.X%)
ns
.X%)
X
(XX.X%)
ons
(XX.X%)
XX
ti
XX (XX.X%)
tio
(XX.X%)
XX
ati
XX (XX.X
ati
(XX.X
%)
%)
XX
ia
XX (X
a
(X
(XX.X%)
r va
(XX.X%)
XX
o
XX (XX.X%)
or 
(XX.X%)
XX
s o
XX (XX.X
o
(XX.X
XX
s 
XX (
X%)
io
X%)
X
XX
n
XX (XX.X%)
ns
(XX.X%)
XX
ten
XX (XX.X%
en
(XX.X%
XX
xte
XX (XX
e
(XX
XX
x
XX
X%)
y
X%)
XX
XX (XX.X%)
an
(XX.X%)
XX
d
XX (XX.X%
d a
(XX.X%
XX
nd
XX (XX
d
(XX
V
XX
n
XX
ge
ge V
n
V
Stage
atio
Stage I
o
I
Stage
at
Stage
StSt


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 168 of 234
Draft 3.0: 04Aug2020
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
[1] Per protocol amendment 3.0, Tanner Staging was to be completed at Baseline (Visit 1), and Months 6, 15, 27 and 36.
Programming Note: use shell from Table 14.4.4.1 for
Table 14.4.4.1.1
Tanner Staging by Age Group for Boys
Safety Population (Japan)
Table 14.4.4.1.2
Tanner Staging by Age Group for Girls
Safety Population
Table 14.4.4.1.2.1
Tanner Staging by Age Group for Girls
Safety Population (Japan)
PUBLIC COPY 
g
Y
g by
Y
by Age
Y
Age
ty Populati
PY
ty Populati
Tab
O
Tab
Tanner
C C
Tanner Sta
C
Sta
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ng
XX
au
XX (XX.X%
ut
(XX.X%
up
n
up for
ny
for Boys
y 
Boys
 (Japan)
any
 (Japan)
14.4.4.1.2
ort 
14.4.4.1.2
ng
p
ng by
po
by Age
po
Age Gr
Gr
Safety
pp
Safety Popu
pp
Popu
Table
su
Table
Tanner
to s
Tanner Stag
s
Stag
Sa
o
Sa
uth
ons or variations thereof. 
re
%)
f
%)
oup
o
oup for
or
for Girls
r 
Girls
ation
s o
ation
nsion
14.4.4.1.2.1
on
14.4.4.1.2.1
ging
s
ging by
sio
by Age
io
Age G
application and any extens
a
fety Populat
ns
fety Populat


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 169 of 234
Draft 3.0: 04Aug2020
Table 14.4.5.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior and Self Injurious Behavior Without Suicidal Intent
Based on the (C-SSRS) during Treatment
Safety Population
Period
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
De Novo
Subjects
(N = XX)
Baseline (Visit 1 of OLE) [1]
No.of Subjects Completing CSSRS
No.of Subjects with Any Suicidal Ideation
No.of Subjects with Any Suicidal Behavior
No.of Subjects without Suicidal Ideation or Suicidal Behavior
No. of Subjects with ‘Self-injurious behavior without suicidal
intent’
OLE Period [2]
No.of Subjects Completing CSSRS
No.of Subjects with Any Suicidal Ideation
No.of Subjects with Any Suicidal Behavior
No.of Subjects without Suicidal Ideation or Suicidal Behavior
No. of Subjects with ‘Self-injurious behavior without suicidal
intent’
C-SSRS: Columbia Suicide Severity-Rating Scale
[1] Counts are based on response at Visit 1 of the OLE Period.
[2] Counts are based on responses during the OLE period.
Note: each subject is counted only once, using the most severe C-SSRS response category during treatment. No event=0; suicidal ideation=1, 2, 3, 4, 5; suicidal behavior=6, 7, 8, 9, 10. See SAP Section 6.4.10.
N=number of subjects with baseline AND post-baseline C-SSRS assessment. Cell frequencies are to be divided by the total N in the relevant treatment group and multiplied by 100 to get the cell %.
LIC COPY 
Y
PY
OP
CO
CO
CO
CO
CO
C
C C
PUBLI
C
LIC
BL
UB
PU
PU
PU
PU
PU
P
thorization 
national
zat
national L
03
03
port any marketing auth
Without
ng
Without Suic
g 
Suic
p3
m
p3
= XX)
ma
XX)
rk
rk
rk
rk
m
y
ny
a
t a
rt
or
ed to suppo
po
up
su
s
o
to
d
This document cannot be used
do
TIAL
s d
TIAL
ed
se
e
d.
t
d.
d.d.
ost
ost severe
no
severe C
o
C
eline C
ann
eline C-
n
-SSRS
n
SSRS
uth
or variations thereof. 
dal
e
dal Intent
eo
Intent
Gp4
ons
Gp4
(N
on
(N =
n
= XX
n
XX
s t
tio
at
at
at
at
at
ria
ar
va
r v
tensions or
or
ns
ns
ns
ns
on
sio
ns
e
and any exten
en
te
xte
xte
xte
xte
ex
y
x
SSRS
nd
SSRS respon
nd
respon
application a
a
S assessment
an
S assessment


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 170 of 234
Draft 3.0: 04Aug2020
Programming note: Use the Table 14.4.5.1 shell for:
Table 14.4.5.1.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior and Self Injurious Behavior Without Suicidal Intent
Based on the (C-SSRS) during Treatment
Safety Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Without
ng
Without Suic
g 
Suic
uth
application and any extensions or variations thereof. 
a
dal
e
dal Intent
eo
Intent


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 171 of 234
Draft 3.0: 04Aug2020
Table 14.4.5.2
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the (C-SSRS) during Treatment
Safety Population
-----Most Severe Post Baseline Potentially Suicide-Related Category----
BASELINE (OLE)
No suicidal ideation or
behavior
Suicidal ideation
Suicidal behavior
Total
Gp1 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp2 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp3 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp4 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp5 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
)
C
)
OP
.X%)
C
.X%)
CO
C C
C
XX
BL
XX (XX
LI
(XX
LI
XX
B
XX
BL
UB
PU
P
thorization 
national
zat
national L
03
03
ed to support any marketing auth
)
g
) during
g a
during Trea
a
Trea
tentially
ket
tentially Suic
t
Suic
tin
deation
ma
deation
ke
m
y
XX
an
XX (XX
n
(XX
any
XX
a
XX
t a
ort
po
po
po
ppo
pp
pp
pp
pp
%)
s
%)
up
XX.X%)
o s
XX.X%)
s
X (XX.X%)
d to
(XX.X%)
to
d t
t cannot be used
ed
XX
XX
se
u
e
be
be
be
be
b
ot
no
nn
a
ment c
t c
nt
tion
m
tion or
me
or beha
e
beha
en
um
dal
u
dal ideation
um
ideation
This docum
do
TIAL
s d
TIAL
m
um
uth
tensions or variations thereof. 
tment
of
tment
ide
th
ide-
th
-Related
the
Related
er
Suic
ns
Suic
th
io
tioioioio
at
.X%)
a
.X%)
ria
(XX.X%)
va
(XX.X%)
a
XX
r
XX (XX.X%)
or v
(XX.X%)
v
or
s o
X
ns
on
sio
sisisisi
ns
on and any extens
te
(XX.X%)
ex
(XX.X%)
xt
XX
y
XX (XX.X%)
y e
(XX.X%)
e
XX
ny
XX (XX.X
ny
(XX.X
y 
any
d a
nd
an
an
an
an
an
n a
lication a
on
tio
vior
ic
vior
ca
applic
a
lic
p


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 172 of 234
Draft 3.0: 04Aug2020
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp9 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
De Novo Subjects (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
C-SSRS: Columbia Suicide Severity-Rating Scale
Programming Notes: Use the 14.4.5.2.shell for
Table 14.4.5.2.1
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the (C-SSRS) during Treatment
Safety Population (Japan)
PY 
Y
OPY
PY
PY
PY
PY
PUBLIC COP
OPY
Suicide
UBL
Suicide-
B
-R
BL
R
thorization 
national
zat
national L
03
03
ny marketing auth
XX
a
XX (XX.X%)
aut
(XX.X%)
ut
au
g
X
g
X
ng
et
et
et
eti
et
ke
ar
(XX.X%)
y m
(XX.X%)
m
XX
n
XX (XX.X%)
ny 
(XX.X%)
y m
t any
XX
an
XX (XX.X
ny
(XX.X
ny
This document cannot be used to support a
do
TIAL
s d
TIAL
t a
Table
up
Table
ted
o
ted Treatme
o s
Treatme
Safe
o 
Safe
uth
iations thereof. 
f
eo
X (XX.X%)
ere
(XX.X%)
re
XX
th
XX (XX.X%)
he
(XX.X%)
he
XX
th
XX (XX.
h
(XX.
th
ns
on
io
tioio
variatioioio
%)
a
%)
ia
sions or va
va
14.4.5.2.1
ons
14.4.5.2.1
nt
i
nt-
i
-Emergen
sion
Emergen
application and any extens
a
ety Populatio
nsi
ety Populatio


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 173 of 234
Draft 3.0: 04Aug2020
Table 14.4.6.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary table
Safety Population
Scale/Index
Visit
Statistics
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
SCALES
Inhibit
OLE Baseline
n
Mean (SE)
OLE Month 1
n
Mean (SE)
OLE Month 1 Chg BL
n
Mean (SE)
OLE Month 2
n
Mean (SE)
OLE Month 2 Chg BL
n
Mean (SE)
OLE Month 3
n
Mean (SE)
OLE Month 3 Chg BL
n
Mean (SE)
OLE Month 6
n
PUBLIC COPY 
Y
PY
OP
CO
C C
C
IC
LI
BL
UB
PU
P
thorization 
national
zat
national L
03
03
not be used to support any marketing auth
ummary
a
ummary tab
au
tab
Gp4
keti
Gp4
(N
ke
(N =
e
= XX
e
XX
tin
ark
ma
ma
ma
ma
ma
m
y
any
t a
or
or
or
ort
por
po
po
po
po
pp
up
s
to
d t
d t
d t
d t
d t
ed
se
u
e
b
t b
ot
nno
an
n
an (SE)
nno
(SE)
ment canno
nn
n
ca
n
a
t c
Mea
c
Mea
t c
t c
t c
t c
nt
en
um
onth
um
onth 6
um
6
This docum
do
TIAL
s d
TIAL
m
um
uth
nd any extensions or variations thereof. 
e
o
e
)
G
er
th
s
ns
io
at
riririria
ari
a
v
or
s o
ns
on
on
on
on
on
si
ns
te
xt
e
y e
y y
any
d a
application and
a
nd
an
n a
n a
n a
n a
n a
n
t
n (SE)
tio
(SE)
on
tio
ca
li
n
plic
n
lililic
plpli
plpl


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 174 of 234
Draft 3.0: 04Aug2020
Mean (SE)
OLE Month 6 Chg BL
n
Mean (SE)
OLE Month 9
n
Mean (SE)
OLE Month 9 Chg BL
n
Mean (SE)
OLE Month12
n
Mean (SE)
OLE Month 12 Chg BL
n
Mean (SE)
… Repeat for OLE
Months 15, 18, 21,
24, 27, 30, 33, 36
OLE Last Visit
n
Mean (SE)
OLE Last Visit Chg BL
n
Mean (SE)
….
[REPEAT for
Shift
PUBLIC COPY 
Y
PY
OP
CO
C C
C
IC
LI
BL
UB
PU
nnot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ut
au
g a
g
ing
eti
ke
ark
ma
ma
ma
ma
ma
m
y
any
t a
r
or
or
ort
por
po
po
po
po
pp
up
s
to
d t
d t
d t
d t
d t
us
e
be
t b
t
no
ent cann
Mean
an
Mean (SE)
nn
(SE)
nn
an
c
t c
nt
This document 
do
TIAL
s d
TIAL
t
en
me
and any extensions or variations thereof. 
f
eo
re
he
th
th
th
th
th
s t
ns
io
at
riririria
ari
ar
ar
ar
a
v
or 
s o
ns
on
on
on
on
on
sio
ns
e
y e
y
any
d a
nd
a
tion an
an
a
n a
on
applicatio
a
tio
at
lilililic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 175 of 234
Draft 3.0: 04Aug2020
Emotional Control
(EC)
Working Memory
(WM)
Plan/Organize
(PO)]
INDEXES
Inhibitory Self-
Control Index
(ISCI) (Inhibit +
EC)[1]
OLE Baseline
n
Mean (SE)
OLE Month 1
n
Mean (SE)
OLE Month 1 Chg BL
n
Mean (SE)
OLE Month 2
n
Mean (SE)
OLE Month 2 Chg BL
n
Mean (SE)
OLE Month 3
n
Mean (SE)
OLE Month 3 Chg BL
n
Mean (SE)
PUBLIC COPY 
Y
PY
C
Y
C
IC
LIC
IC
IC
IC
BL
UB
PU
P
ent cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ut
g a
g
ti
rk
ma
ma
ma
ma
ma
m
y
ny
por
pp
up
su
o
t
d t
d t
d to
d t
d
se
us
e u
be
t b
t b
t b
t b
t b
o
Mean
an
Mean (SE)
nn
(SE)
nn
an
c
n
c
n
ca
t c
This document 
do
TIAL
s d
TIAL
M
nt
en
nth
m
nth 3
m
3 Chg
me
Chg B
e
B
me
um
cu
tion and any extensions or variations thereof. 
o
her
th
s t
ns
io
ati
riririria
ari
o
s
on
on
on
on
on
sio
ns
ten
xt
ex
y e
y
ny
a
d
an
a
n a
on
applicatio
a
n
ean
at
ean (SE)
atio
(SE)
tio
at
i
n
plic
n
ica
pli
Me
pl
Me
plplpl
pp
ppl
pp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 176 of 234
Draft 3.0: 04Aug2020
OLE Month 6
n
Mean (SE)
OLE Month 6 Chg BL
n
Mean (SE)
OLE Month 9
n
Mean (SE)
OLE Month 9 Chg BL
n
Mean (SE)
OLE Month12
n
Mean (SE)
OLE Month 12 Chg BL
n
Mean (SE)
… Repeat for OLE
Months 15, 18, 21,
24, 27, 30, 33, 36
OLE Last Visit
n
Mean (SE)
OLE Last VisitChg BL
n
Mean (SE)
PUBLIC COPY 
Y
PY
OP
CO
C C
C
IC
LI
BL
UB
PU
P
annot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ut
au
g a
g
ing
eti
ke
ark
ma
ma
ma
ma
ma
m
y
any
t a
r
or
or
ort
por
po
po
po
po
pp
up
s
to
d t
d t
d t
d t
d t
ed
se
us
e
t b
no
n
a
n
nn
This document can
do
TIAL
s d
TIAL
Mean
ca
Mean (S(S
an
c
t c
Chg
e
Chg BL
ent
BL
n
nt
en
me
on and any extensions or variations thereof. 
f
eo
re
he
th
th
th
th
th
s t
ns
io
at
riririria
ari
ar
ar
ar
a
v
or 
s o
ns
on
on
on
on
on
sio
ns
te
xt
e
y e
y
nd
an
a
application a
a
E)E)
a
n a
on
tio
Mean
ica
Mean (SE)
a
(SE)
at
lilililic


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 177 of 234
Draft 3.0: 04Aug2020
90% CI for
change from
BL[5]
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
…..
REPEAT FOR
Flexibility Index
(FI) (Shift + EC)[2]
Emergent
Metacognition
Index (EMI) (WM +
PO)[3]
Global Executive
Composite (GEC)
(Inhibit + Shift + EC
+ WM + PO) [4]
The BRIEF-P questionnaire was administered to preschool age children. N=# subjects in analysis population; n=number of subjects assessed at time point.
mITT = Modified Intent-to-Treat; SE=Standard Error; Chg. BL=Change from Baseline; EOS/ET=End-of-Study/Early Termination or Last available measurement.
Notes:
[1] ISCI: Computed as the sum of the scale raw scores obtained for Inhibit and Emotional Control.
[2] FI: Computed as the sum of the raw scale scores obtained for Shift and Emotional Control
[3] EMI: Computed as the sum of the raw scale scores for Working Memory and Plan/Organize.
[4] GEC: Inhibit + Shift + EC + WM + PO
[5] Based on T distribution. Endpoints of the interval are Mean ± T*SE, where T is obtained as the 95% percentile from the Student’s T distribution with n-1 degrees of freedom
Programming notes:
1.
The rater’s responses are scored as follows: 1=Never, 2=Sometimes, and 3=Often
BLIC COPY 
Y
PY
C
Y
C
IC
LIC
IC
IC
IC
PUBL
BL
support any marketing authorization 
uth
national
zat
national L
03
03
(xxx.x,
aut
(xxx.x,
ut
g a
ng
ti
ke
rk
ma
m
y
ny
por
pp
up
This document cannot be used to su
do
TIAL
s d
TIAL
su
d t
se
us
e u
hildren. N=# 
be 
hildren. N=# 
=Change
t be
=Change from
be
from
btained
no
btained for
o
for
obtained
nn
obtained fo
n
fo
cores
a
cores for
an
for Wo
n
Wo
the
n
the interval
nt 
interval
ored
m
ored as
me
as follo
e
follo
ons or variations thereof. 
xxx.x)
f
xxx.x)
re
he
th
th
th
th
th
s t
io
ati
riririria
ari
o
s
application and any extension
a
on
on
on
on
on
xte
ex
y e
y e
y e
y e
subjects in a
ny 
subjects in a
m Baseline;
any
Baseline; E
y
E
nhibit
nd
nhibit and
d 
and Em
Em
Shift
an
Shift and
an
and Em
Em
orking
n a
orking Memo
a
Memo
re
t
re Mean
tio
Mean ±
o
± T
ws:
li
ws: 1=Never
lica
1=Never


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 178 of 234
Draft 3.0: 04Aug2020
Scales of the BRIEF-P
Scale
No. of items
Items
Scoring Instructions (for each individual)*
Inhibit
16
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Add up scores for items on the scale
Shift
10
5, 10, 15, 20, 25, 30, 35, 40, 45, 50
Add up scores for items on the scale
Emotional Control
10
1, 6, 11, 16, 21, 26, 31, 36, 41, 46
Add up scores for items on the scale
Working Memory
17
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Add up scores for items on the scale
Plan/Organize
10
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
Add up scores for items on the scale
Validity scales
Inconsistency
10 pairs
(1, 11), (3, 33), (5, 45), (10, 20), (11, 26), (16, 21), (18, 52), (33, 38), (43,
52), (48, 54)
For each item in a pair, obtain the score for each item, and
subtract the scores, keeping the absolute difference. Sum the 10
absolute differences to get the Inconsistency score.
Classification[1]:
0-6: Acceptable
7  Acceptable
≥8: Inconsistent
Negativity
10
30, 44, 46, 47, 53, 55, 56, 57, 59, 63
Count the number of items with a score of 3. That is the
negativity score.
Classification[1]:
0-2 Acceptable
3 Acceptable
≥4 Elevated
2. *Missing data handling for the BRIEF-P[2]
1. First obtain the number of missing responses for the entire questionnaire of 63 items.
2. If the total number of unanswered items is >12, do not compute any of the (five) scale raw scores (I, S, EC, WM, PO) for the BRIEF-P, as per the authors, the “protocol should be considered invalid”.
In that case, all the scale raw scores will be missing, and the index scores will be missing as well.
3. If more than 2 (of the 63) items on the BRIEF-P have missing responses for a Scale (any of the 5 listed above), then a scale raw score should not be calculated. However, for any scale with 2 or fewer
missing responses, impute a score of “1” for the missing item
References:
[1] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Pages 15-16.
[2] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Page 7.”Missing Responses”.
PUBLIC COPY 
Y
(16,
OP
(16, 21),
PY
21), (
Y
(
PY
53,
PU
53, 55,
PUB
55, 56,
UB
56,
UB
thorization 
national
zat
national L
03
03
t cannot be used to support any marketing auth
ring
ng
ring Instruct
ng 
Instruct
g a
Add
ti
Add up
ting
up scor
ng
scor
ng
Add
keti
Add up
ti
up s
tin
k
Add
ke
Add
ke
rk
A
k
A
rk
rk
rk
rk
ma
m
y
, 52),
a
52), (33,
any
(33, 38
y
38
ny
7,
t
7, 59,
to
59, 63
to
63
o s
be
he
n
he entire
not
entire qu
t
qu
2,
n
2, do not
nn
do not co
co
ll be missing
an
ll be missing
BRIEF
ca
BRIEF-
ca
-F-F
ca
F-F
This document 
do
TIAL
s d
TIAL
P
ca
P hav
a
hav
re of “1” for
nt c
re of “1” for
K.
u
K. BRIEF
um
BRIEF-
m
-F-F
m
F-F P:
m
P: B
th
c
th PK.
cu
PK. BRIEF
cu
BRIEF
uth
ion and any extensions or variations thereof. 
ons
e
ons (for
eo
(for each
o
each
of
s
e
s for
er
for items
ere
items o
re
ores
he
ores for
he
for item
e
item
er
up
up scores
th
scores for
h
for
th
dd
n
dd up
ns
up scores
s 
scores
s t
Add
on
Add up
n
up sco
sco
ns
ion
ati
ati
ati
ati
ati
),
a
), (43,
ari
(43,
ria
io
ny
uestionnaire
nd 
uestionnaire
mpute
and
mpute any o
nd
any o
, and the ind
n a
, and the ind
applicatio
a
e
o
e missing
on 
missing res
res
the missing 
tio
the missing 
ehavior
plic
ehavior Rat
c
Rat
P:
p
P: Behavior
pp
Behavior


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 179 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use the sheel for 14.4.6.1 for the following tables.
Table 14.4.6.1.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary table
Safety Population (Japan)
Table 14.4.6.2
Behavior Rating Inventory of Executive Function- (BRIEF)
Safety Population
For 14.4.6.2 and 14.4.6.2.1,
Scales are:
Inhibit
Shift
Emotional Control (EC)
Initiate
Working Memory (WM)
Plan/Organize (PO)
Organization of Materials (OM)
Monitor
Table 14.4.6.2.1
Behavior Rating Inventory of Executive Function- (BRIEF)
Safety Population (Japan)
For Indexes Part, where we use the 90% CI for the EOS/ET measurement, the following are used, along with relevant footnotes;
Behavioral Regulation Index (BRI)[1]
Metacognition Index (MI)[2]
Global Executive Composite (GEC) [3]
For the following line, include [4] as footnote
90% CI for change from BL[4]
PUBLIC COPY 
Pop
Y
Pop
Table
OPY
Table 14
PY
14
Inventory
COP
Inventory
Safety P
CO
Safety P
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Scoring
keti
Scoring su
su
nction
m
nction-
m
- (BRIE
ma
(BRIE
6.2.1
a
6.2.1
Executive
rt a
Executive F
a
F
pulation
ort
pulation (Jap
t
(Jap
/ET
n
/ET measure
not
measure
footnote
men
footnote
uth
application and any extensions or variations thereof. 
a
mmary
he
mmary table
er
table
EF)
i
EF)
nction
va
nction-
a
- (BRI
a
(BRI
an)
r
an)
ment,
d
ment, the
d a
the fo
a
fo


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 180 of 234
Draft 3.0: 04Aug2020
Footnotes
The BRIEF questionnaire was administered to school age children. N=# subjects in analysis population; n=number of subjects assessed at time point.
mITT = Modified Intent-to-Treat; SE=Standard Error; Chg. BL=Change from Baseline; EOS/ET=End-of-Study/Early Termination or Last available measurement
Notes:
[1] Computed as the sum of the scale raw scores obtained for Inhibit, Shift, and Emotional Control.
[2] Computed as the sum of the raw scale scores obtained for Initiate, Working Memory, Plan/Organize, Organization of Materials, and Monitor.
[3]Computed as the sum of the raw scale scores for BRI and MI.
[4]Based on T distribution. Endpoints of the interval are Mean ± T*SE, where T is obtained as the 95% percentile from the Student’s T distribution with n-1 degrees of freedom
Programming notes:
1.
The rater’s responses are scored as follows: 1=Never, 2=Sometimes, and 3=Often
Scales of the BRIEF
Scale
Item
Total No. of Items for Parent Form
Inhibit
38, 41, 43, 44, 49, 54, 55, 56, 59, 65, 73, 78, 79, 81, 82
15
Shift
5, 6, 8, 12, 13, 23, 30, 39, 80, 84, 85
11
Emotional Control
1, 7, 20, 25, 26, 45,50, 62, 64, 70
10
Initiate
3, 10, 16, 47, 48, 61, 66, 71
8
Working Memory
2, 9, 17, 19, 24, 27, 32, 33, 37, 57, 83
11
Plan/Organize
11, 15, 18, 22, 28, 35, 36, 40, 46, 51, 53, 58, 76, 77, 86
15
Organization of Materials
4, 29, 67, 68, 69, 72, 74, 75
8
Monitor
14, 21, 31, 34, 42, 52, 60, 63
8
Total No. of Items
86
Validity scales
Scoring Instructions for Validity Scales
Inconsistency
(7,25), (11, 22), (27, 17), (33, 32), (38, 59), (41, 65), (42, 63), (44, 54), (53, 60), (55, 44)
For each item in a pair, obtain the score for each
item, and subtract the scores, keeping the
absolute difference. Sum the 10 absolute
differences to get the Inconsistency score.
Classification[1]:
0-6: Acceptable
7-8: Questionable
PUBLIC COPY 
C C
65,
L
65, 73,
LIC
73, 78,
IC
78,
IC
4,
B
4, 85
BL
85
LI
64,
U
64, 70
UB
70
B
6,
P
6, 71
PU
71
U
P
33,
P
33, 37
P
37
P
thorization 
national
zat
national L
03
03
d to support any marketing auth
e point.
g a
point.
able
ng
able measu
g 
measu
ials,
rk
ials, and
rke
and Mo
e
Mo
e
m
e Student’s
ma
Student’s
po
, 81,
u
81, 82
up
82
pp
up
s
to
ed t
7,
e
7, 83
ed
83
not be used t
46,
se
46, 51,
sed
51, 53,
ed
53,
ed
75
75
se
60,
e
60, 63
e u
63
u
be
b
ot
ent canno
(11,
nn
(11, 22),
nno
22), (27
o
(27
This document
do
TIAL
s d
TIAL
no
ument
uth
nsions or variations thereof. 
ement
eo
ement
nitor.
th
nitor.
T
o
T distributio
ons
distributio
or
s o
ns
ion
si
nd any exten
en
58,
x
58, 76,
xt
76, 77,
xte
77, 86
e
86
te
ex
e
ny
an
d a
application and
a
, 17),
an
17), (33,
and
(33, 32
d
32
nd
pl


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 181 of 234
Draft 3.0: 04Aug2020
≥9: Inconsistent
Negativity
8, 13, 23, 30, 62, 71, 80, 83, 85
Count how many of the 9 items in the scale have a
score of 3. That is the negativity score.
Classification[1]:
0-4 Acceptable
5-6 Elevated
≥7 Highly Elevated
To calculate the Behavioral Regulation Index (BRI) raw score, sum the scale raw scores obtained for Inhibit, Shift, and Emotional Control scales.
To calculate the Metacognition Index (Ml) raw score, sum the raw scale scores obtained for Initiate, Working Memory, Plan/Organize, Organization of Materials, and Monitor scales.
To calculate the Global Executive Composite (GEC) raw score, sum the raw scores for BRI and MI.
Missing data handling (For items 1-72 only; items 73-86 are additional clinical items)
1.
If the total number of unanswered items is >14, do not compute any of the (eight) scale raw scores (INH, S, EC, INI, WM, PO, OM, m) for the BRIEF, as per the authors, the “protocol should be
considered invalid”. In that case, all the scale raw scores will be missing, and the index scores will be missing as well.
2.
If more than 2 (of the first 72) items have missing responses for a Scale (any of the 8 listed above), then a scale raw score should not be calculated. However, for any scale with 2 or fewer missing
responses, impute a score of “1” for the missing item.
3.
IMPORTANT: When calculating index scores, please first obtain the scale raw scores, and then the index scores are derived from the scale raw scores. Do not simply add up the scores for the
individual questions.
References:
[1] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Pages 15-16, Tables 2 and 4.
[2] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Page 7.”Missing Responses”.
BLIC COPY
Inhibit,
PY
Inhibit,
Y 
ate,
OP
ate, Work
PY
Work
nd MI.
OP
nd MI.
ems)
IC
ems)
IC
the
L
the
PUBL
(eight
LIC
(eight
sing, and t
BL
sing, and t
Scale
UB
Scale (any
UB
(any
ain
P
ain the
PU
the sc
PU
sc
thorization 
national
zat
national L
03
03
support any marketing auth
≥9:
aut
≥9: In
t
In
ut
a
Cou
a
Cou
au
a
a
m
and
ny
and Emotio
ny 
Emotio
g Memory,
any
Memory, P
y
P
This document cannot be used to s
do
TIAL
s d
TIAL
cale
u
cale raw
up
raw sco
p
sco
e index score
su
e index score
f
t
f the
o
the 8
o s
8 listed
s
listed
e raw
d t
e raw score
d t
score
tory
be
tory of
be
of Execu
e u
Execu
ventory
be
ventory of
be
of Ex
e
Ex
uth
ons or variations thereof. 
onsis
f
onsis
nt
o
nt how
of
how man
f.
ma
score of 3. T
reo
score of 3. T
Classifica
ere
Classifica
0
he
0-
e
-4
e
4 A
5
h
5
f
he
ns
on
nal
ia
nal Control
iati
Control s
an/Organize
aria
an/Organize
application and any extension
a
res
n
res (INH,
ns
(INH, S,
s
S, E
s will be mis
ion
s will be mis
above),
sio
above), the
o
the
, and
en
and then
ens
then th
s
th
tive
y
tive Function
y 
Function
ecutive
any
ecutive Func
ny
Func


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 182 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use the sheel for 14.4.6.1 for the following tables.
Table 14.4.6.3
Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) – Scoring summary table
Safety Population (De Novo Subjects)
Table 14.4.6.3.1
Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) – Scoring summary table
Safety Population (De Novo Subjects) (Japan)
Scales are:
Inhibit
Shift
Emotional Control (EC)
Self Monitor
Initiate
Working Memory (WM)
Plan/Organize (PO)
Organization of Materials (OM)
For Indexes Part, where we use the 90% CI for the EOS/ET measurement, the following are used, along with relevant footnotes;
Behavioral Regulation Index (BRI)[1]
Metacognition Index (MI)[2]
Global Executive Composite (GEC) [3]
For the following line, include [4] as footnote
90% CI for change from BL[4]
[1] Computed as the sum of the scale raw scores obtained for Inhibit, Shift, Emotional Control, and Self Monitor.
[2] Computed as the sum of the raw scale scores obtained for Initiate, Working Memory, Plan/Organize, Organization of Materials, and 
Monitor.
[3] Computed as the sum of the raw scale scores for BRI and MI.
[4] Confidence interval of the mean change from baseline based on the t distribution.
PUBLIC COPY 
ment,
PU
ment, the
PU
the
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ring
ti
ring summar
ting
summar
IEF
a
IEF-
a
-A)
ar
A) –
ar
– Scor
r
Scor
(Japan)
ma
(Japan)
llowing
d to
llowing are
t
are
o
raw
nno
raw sco
no
sco
w
a
w scale
an
scale
e
t
e raw
t c
raw sc
c
sc
the
nt
the mean
nt 
mean
uth
application and any extensions or variations thereof. 
a
y
e
y table
re
table
ing
n
ing summar
ns 
summar
sed,
en
sed, along
ens
along w
s
w
res
an
res obtai
nd
obtai
cores
an
cores ob
n
ob
ale
io
ale score
on
score
change
atio
change f


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 183 of 234
Draft 3.0: 04Aug2020
Scales of the BRIEF-A
Scale
No. of items
Items
Scoring Instructions (for each individual)*
Inhibit
8
5, 16, 29, 36, 43, 55, 58, 73
Add up scores for items on the scale
Shift
6
8, 22, 32, 44, 61, 67
Add up scores for items on the scale
Emotional
Control
10
1, 12, 19, 28, 33, 42, 51, 57, 69, 72
Add up scores for items on the scale
Self-Monitor
6
13, 23, 37, 50, 64, 70,
Add up scores for items on the scale
Initiate
8
6, 14, 20, 25, 45, 49, 53, 62
Add up scores for items on the scale
Working
Memory
8
4, 11, 17, 26, 35, 46, 56, 68
Add up scores for items on the scale
Plan/Organize
10
9, 15, 21, 34, 39, 47, 54, 63, 66, 71
Add up scores for items on the scale
Task Monitor
6
2, 18, 24, 41, 52, 75
Add up scores for items on the scale
Organization of
Materials
8
3, 7, 30, 31, 40, 60, 65, 74
Add up scores for items on the scale
Validity scales
Infrequency
10, 27, 38, 48, 59
Number of question responses where:(Question 10 = 3),
(Question 27 = 1), (Question 38 = 3), (Question 48 = 1),
Question 59 = 1)
Number of questions meeting conditions: 0-2 is Acceptable.
>= 3 is Infrequent.
Inconsistency
10 pairs
(2, 41), (25, 49), (28, 42), (33, 72), (34, 63), (44, 61), (46, 56), (51, 75), (60,
74), (64, 70).
For each item in a pair, obtain the score for each item, and
subtract the scores, keeping the absolute difference. Sum the 10
absolute differences to get the Inconsistency score.
PUBLIC COPY 
PY
OP
3,
I
3, 66,
IC
66, 71
C
71
C C
LIC
0,
U
0, 65,
UB
65, 74
B
74
BL
P
thorization 
national
zat
national L
03
03
ny marketing auth
ring
ng
ring Instructi
g 
Instructi
g a
Add
ti
Add up
ting
up scor
ng
scor
ng
Add
ket
Add up
t
up
eti
rk
Ad
k
Ad
rk
rk
rke
rk
m
nt cannot be used to support any
ny
t a
po
up
su
d
se
48,
e
48, 59
e u
59
u
an
This document 
do
TIAL
s d
TIAL
pairs
en
pairs
nt
um
uth
iations thereof. 
ons
e
ons (for
eo
(for each
o
each
of
s
e
s for
er
for items
ere
items o
re
cores
the
cores for
he
for ite
e
ite
he
d up
s
up scores
s t
scores f
th
tititi
atio
Add
tio
Add u
plication and any extensions or variatio
ati
A
ia
ar
o
ns
on
en
xt
e
catio
(2,
ati
(2, 41),
ti
41),
74),
a
74),
appl
a
tio
pl ca


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 184 of 234
Draft 3.0: 04Aug2020
Classification[1]:
0-7: Acceptable
≥8: Inconsistent
Negativity
10
1, 8, 19, 21, 22, 23, 29, 36, 39, 40
Count the number of items with a score of 3. That is the
negativity score.
Classification[1]:
0-5 Acceptable
≥6 Elevated
2. *Missing data handling for the BRIEF-A
1. If the total number of unanswered items is >= 1 in the Shift, Self-Monitor, and Task Monitor, the raw domain score is invalidated and won’t be calculated.
2. If the total number of unanswered items is >= 2 in the Inhibit, Emotional Control, Initiate, Working Memory, Plan/Organize, and Organization of Materials, the raw domain score is invalidated and
won’t be calculated. However, for any scale with 1 missing responses, impute a score of “1” for the missing item.
3. IMPORTANT: When calculating index scores, please first obtain the scale raw scores, and then the index scores are derived from the scale raw scores. Do not simply add up the scores for the individual
questions.
PUBLIC COPY 
itor,
OP
itor, the
OPY
the ra
PY
ra
tiate,
CO
tiate, Wor
OP
Wor
a score of
CO
a score of
ores,
C C
ores, and
C C
and t
C
t
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
on[1]:
au
on[1]:
cceptable
g a
cceptable
Inconsiste
ng 
Inconsiste
ut
Count
tin
Count the
ng
the n
g
n
negativit
keti
negativit
Class
ke
Class
0
k
0
ng
m rk
domain
an
domain sco
n
sco
ng
r
ng Memory,
rt a
Memory,
1” for the mi
ort
1” for the mi
n the
po
the index
po
index
uth
application and any extensions or variations thereof. 
a
t
mber
ere
mber of
re
of item
e
item
y
th
y score.
he
score.
fication[1]:
th
fication[1]:
5
n
5 Acceptable
ns 
Acceptable
≥
o
≥6
on
6 Elevate
ons
Elevate
re
on
e
a
e is
a
is invalida
aria
invalida
Plan/Organi
va
Plan/Organi
ssing item.
r v
ssing item.
scores
or
scores are
or
are de
de


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 185 of 234
Draft 3.0: 04Aug2020
LISTINGS
All listing displays for this open-label study are to be done by country and study site. Then by subject number.
Programming Note: May keep the by Treatment group, but treatment group = ZX008 OL for all subjects in this open-label study.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
n by
g
by subject
g a
subject
r
e
r all
ti
all subjects
etin
subjects
uth
application and any extensions or variations thereof. 
a
number.
eof
number.
in
h
in this
her
this open
er
open


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 186 of 234
Draft 3.0: 04Aug2020
Listing 16.2.1.1
Subject completion/discontinuation
Subject
Identifier
Country
Site/
Investigator
Withdrawal/
Completion
Date/Day#
Completed
as Scheduled
Reason for Premature Discontinuation*
XXXX
TEXT
XXX/TEXT
DDMMMYYYY/XX
Yes/No
Adverse Event/Serious Adverse Event
Death
Investigator Decision
Lack of Efficacy
Lost to follow-up
Protocol Violation
Sponsor Decision
Voluntary Withdrawal
Inclusion/Exclusion Criteria not met
Other reason: TEXT
# Relative to first dose of study treatment.
* If more than one reason is given for premature discontinuation, the first reason listed is the primary reason.
Note to Programmers: Please put the primary reason first in the list. Use the same shell for
Listing 16.2.1.2
Subject completion/discontinuation (Japan)
PUBLIC COPY 
th
Y
th
nvestigato
PY
nvestigato
Lack of
OP
Lack of
Lost
O
Lost
thorization 
national
zat
national L
03
03
arketing auth
ng
ntinuation*
ark
ntinuation*
This document cannot be used to support any ma
do
TIAL
s d
TIAL
se
us
us Adverse
m
Adverse E
ecision
any
ecision
ficacy
t a
ficacy
o follow
ort
o follow-
t
-up
t 
up
otocol
po
otocol Violat
por
Violat
Sponsor
pp
Sponsor De
p
De
Volunta
upp
Volunta
Inclu
u
Inclu
O
he
e
he first
e u
first reas
u
reas
n
t
n the
t b
the list.
b
list. Us
Us
a
uth
ns thereof. 
re
application and any extensions or variations
a
xt
vent
tio
vent
on
o
on
cision
s o
cision
ry
n
ry Withdraw
ns 
Withdraw
sion/Exclusio
on
sion/Exclusio
ther reason
sio
ther reason
n listed
y e
listed is
e
is th
e
th
e the
a
the same
an
same
ns


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 187 of 234
Draft 3.0: 04Aug2020
Treatment group: xxx
Subject
Identifier
Country
Listing 16.2.2.1
Major Protocol Deviations
Site/
Investigator
Type
Major Protocol Deviation
XXXX
Inclusion/Exclusion
Compliance <80% or >120%
TEXT
TEXT
TEXT*
XXXX
TEXT
XXXX
.
.
.
Programming Note: Please put the primary reason first in the list. Use the same shell for
Listing 16.2.2.2
Major Protocol Deviations (Japan)
PUBLIC COPY 
U
se
P
se the
P
the
thorization 
national
zat
national L
03
03
rketing auth
rotocol
ke
rotocol Devi
e
Devi
This document cannot be used to support any mark
do
TIAL
s d
TIAL
to
EXT
m
EXT
TEXT
m
TEXT
TEXT*
y 
TEXT*
me
d
me shell
d t
shell for
t
for
rk
uth
tin
thereof. 
tion
th
tion
application and any extensions or variations t
a
si
Major
y e
Major
t er


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 188 of 234
Draft 3.0: 04Aug2020
Listing 16.2.3.1
Subjects Excluded from Analysis Populations
Subject Identifier
Deviation/Reason
Analysis Population(s) Excluded from
XXXX
TEXT
XXXX
XXXX
.
.
.
Programming note: For inclusion/exclusion criteria not met use the wording of the criteria not met from the CRF.
Use the 16.2.3.1 shell for:
Listing 16.2.3.1.1
Subjects Excluded from Analysis Populations (Japan)
COPY 
Y
PY
OP
CO
PUBLIC C
C
LIC
BL
wording
PUB
wording of
UB
of
thorization 
national
zat
national L
03
03
ort any marketing auth
ng
ke
rk
a
m
y
ny
a
rt
This document cannot be used to suppo
do
TIAL
s d
TIAL
o
pp
up
su
e criteria
to
criteria no
no
Subject
se
Subject
uth
r variations thereof. 
re
the
s t
ns
on
tio
ia
ar
va
application and any extensions or 
a
r
o
s 
on
met
si
met from
nsio
from th
o
th
Listin
e
Listin
s
e
s Excluded
xte
Excluded fr
e
fr


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 189 of 234
Draft 3.0: 04Aug2020
Treatment group: xxx
Country: xxxx
Listing 16.2.3.2
Subject allocation to trial Populations
Subject Identifier
Site
Core Study
Enrolled population
Safety Population
mITT Population
XXXXX
VS01, VS02, 1504-C1,
1504-C2
Yes
Yes/No
Yes/No
XXXXX
XXXXX
.
.
.
mITT = Modified Intent-to-Treat.
Note: Blank core study indicates de novo subject.
Programming note: Use the 16.2.3.2 shell for:
Listing 16.2.3.2.1
Subject allocation to trial Populations (Japan)
C COPY 
Y
PY
OP
CO
CO
CO
CO
CO
C
PUBLIC C
C
LIC
BL
UB
thorization 
national
zat
national L
03
03
port any marketing auth
Saf
e
Saf
tin
et
rk
a
y
ny
a
rt
or
This document cannot be used to supp
do
TIAL
s d
TIAL
pp
up
su
o s
uth
or variations thereof. 
fety
t
fety Populatio
th
Populatio
er
t
Yes/No
ons
Yes/No
ns
io
tioioioio
ia
ar
va
r
ions o
s
on
application and any extensio
a
io
Subject
y e
Subject al
e
al


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 190 of 234
Draft 3.0: 04Aug2020
Treatment group: xxx
Listing 16.2.4.1.1
Demographic Data
Date of
Baseline
Baseline
Baseline
Subject
Visit 1
Informed Consent/Assent
Date of
Age*
Weight*
Height*
BMI*
Identifier
Country
Date
Parent
Child
Birth
(years)
Sex
Race
Ethnic Group
(kg)
(m)
(kg/m2)
XXXX
TEXT
DDMMMYYYY
DDMMMYYYY
DDMMMYYYY
DDMMMYYYY
XX
Male
Female
Caucasian
Black/African
American
Asian
Pacific Islander
Etc.
Latino
NonLatino
XXX
XXX
XX.X
XXXX
XXXX
.
.
.
* Age at Visit 1.
Programming note: Informed consent/assent date should be the initial consent obtained at Visit 1 of 1503 (or Visit 13 of the core study)
Use the shell for 16.2.4.1.1 for
Listing 16.2.4.1.1.1
Demographic Data (Japan)
PUBLIC COPY 
MYYYY
PY
MYYYY
Y
C C
Y
LIC
BL
UB
PU
PU
P
thorization 
national
zat
national L
03
03
to support any marketing auth
tin
rk
rk
rk
rk
ark
ex
m
ex
R
a
m
y
Male
y 
Male
Fe
y
Fe
y
ort
ny
up
su
o
This document cannot be used to s
do
TIAL
s d
TIAL
be
o s
o
to
d
e
us
e u
uld
n
uld be
no
be the
o
the inin
uth
nsions or variations thereof. 
er
he
s t
ace
o
ace
ns
on
male
ari
male
Cauca
at
Cauca
Bla
a
Bla
ati
or
ia
s
on
on
on
on
on
application and any extensio
a
ny
io
ns
en
xte
ex
ex
ex
ex
y ex
e
itial
nd
itial consent
nd
consent


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 191 of 234
Draft 3.0: 04Aug2020
Treatment group: xxx
Listing 16.2.4.1.2
% Change from baseline in weight and BMI
Weight
BMI
Subject
Identifier
Visit
Date/Day
Result
(kg)
Base
Flag
Change
from
Baseline
% change
from
Baseline *
Result
(kg/m2)
Base
Flag
Change
from
Baseline
% change
from
Baseline *
1501-0101-02
Visit 1 - Day 1
ddmonyyyy/hh:mm
45.9
Y
17.17
Y
Visit 3 - Month 1 (Clinic)
ddmonyyyy/hh:mm
45
-0.9
-1.96
16.77
-0.4
-2.33
Visit 4 - Month 2 (Clinic)
ddmonyyyy/hh:mm
44.59
-1.31
-2.85
16.77
-0.4
-2.33
….
Visit 12 - Month 24 (Clinic)
45
-0.9
-1.96 *
16.85
-0.32
-1.86
……
BMI = Body mass index; * Indicates a decrease from baseline in weight or BMI >= 7%.
Programming note: Use the shell for 16.2.4.1.2 for
Listing 16.2.4.1.2.1
% Change from baseline in weight and BMI (Japan)
PUBLIC COPY 
P
Y
PY
Y
45
C
45
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ed
ine
m
ine
%
rk
% change
ark
change
from
ar
from
Bas
a
Bas
ke
m
-
n
-0.9
ny
0.9
-1
MI
MI >=
ed
>= 7%.
ed
7%.
tin
uth
application and any extensions or variations thereof. 
a
te
eline
on
eline *
on
*
th
ion
-
ria
-1.96
ria
1.96
.31
v
.31
-2
r
2
-
o
-0.9
o
0.9
%
a
% Ch
Ch
ere


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 192 of 234
Draft 3.0: 04Aug2020
Treatment group: xxx
Listing 16.2.4.2
Medical History
Subject Identifier
Previous or Concurrent Medical History Term/
Medical Condition/Surgical Procedure
Onset
Date/Day#
Stop
Date/Day#
Ongoing at
Screening
XXXX
TEXT
DDMMMYYYY/XX
Ongoing
DDMMMYYYY/XX
DDMMMYYYY/XX
Stopped
XXXX
TEXT
XXXX
.
.
.
# Relative to first dose of study treatment.
PUBLIC COPY 
UB
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
o s
Stop
e
Stop
MYYYY/XX
y m
MYYYY/XX
MMMYYYY/XX
ny 
MMMYYYY/XX
a
tin
uth
application and any extensions or variations thereof. 
a
io
p
Date/Day#
ns t
Date/Day#
DD
DD
ns
er


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 193 of 234
Draft 3.0: 04Aug2020
Treatment group: xxx
Listing 16.2.4.3
Prior and concomitant medications and therapies/treatments
Subject
Identifier
Medication/
ATC Classification [1]
Dose
Unit
Route
Frequency*
Indication
Start
Date/Day#
Stop
Date/Day#
XXXX
TEXT
TEXT
XXXX
TEXT
B1M1
TEXT
DDMMMYYYY/XX
DDMMMYYYY/XX
& TEXT
BID
Ongoing
PRN
Q4H
Q6H
Q12H
Q24H
QID
QM
# Relative to first dose of study treatment.
* B1M1 = Twice per month, BID = Twice per day, PRN = As needed, Q4H = Every four hours, Q6H = Every Six hours, Q12H = Every Twelve hours, Q24H = Every Twenty-four hours, QID = Four times a day, QM
= Every Month.
& Prior medication.
[1] WHO Drug Dictionary (latest version).
Programming note: Use the shell for 16.2.4.3 for
Listing 16.2.4.3.1
Prior and concomitant medications and therapies/treatments (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
be
y*
k
y*
Ind
Ind
tin
M1
m
M1
rk
BID
m
BID
PRN
y 
PRN
Q4H
ny
Q4H
Q
s needed,
ot 
needed, Q4
Q4
4.3
t
4.3 for
t c
for
t c
uth
application and any extensions or variations thereof. 
a
ny
ication
th
ication
er
er
er
TEXT
ns
TEXT
t
Q6H
a
Q6H
Q12H
va
Q12H
Q24H
or v
Q24H
QID
o
QID
4H
d
4H =
d
= Every
d a
Every fo
a
fo


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 194 of 234
Draft 3.0: 04Aug2020
Listing 16.2.4.4.1
Prior antiepileptic Drugs (AEDs)
Subject
Identifier
Medication
/ATC Classification [1]
Type of
treatment
Route
Dose
Frequency*
Start
Date/Day#
Stop
Date/Day#
XXXX
TEXT
Non-medication
TEXT
TEXT
B1M1
BID
PRN
Q4H
Q6H
Q12H
Q24H
QID
QM
DDMMMYYYY/XX
DDMMMYYYY/XX
Ongoing
& TEXT
Risk medication
* B1M1 = Twice per month, BID = Twice per day, PRN = As needed, Q4H = Every four hours, Q6H = Every Six hours, Q12H = Every Twelve hours, Q24H = Every Twenty-four hours, QID = Four times a day, QM
= Every Month. Qd or QD=Daily, or Everyday, or once a day.
# Relative to first dose of study treatment.
& Prior medication.
[1] WHO Drug Dictionary
Programming note: Use the shell for 16.2.4.4.1 for the following listings.
Listing 16.2.4.4.2
Concomitant antiepileptic Drugs (AEDs)
PUBLIC COPY 
ion
B
ion
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
b
TEXT
ar
TEXT
eeded,
t b
eeded, Q4H
b
Q4H
day.
no
day.
6.2.4.4.1
nt
6.2.4.4.1 for
t
for
ke ng
uth
application and any extensions or variations thereof. 
a
an
Frequency*
the
Frequency*
B1M
B1M
= Every
d an
Every four
an
four
the
at
the followin
atio
followin
th re


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 195 of 234
Draft 3.0: 04Aug2020
Listing 16.2.4.4.3
Prior antiepileptic Drugs (AEDs) (Japan)
Liisting 16.2.4.4
Concomitant antiepileptic Drugs (AEDs) (Japan)
Listing 16.2.4.5
Rescue medications
Liisting 16.2.4.5.1
Rescue medications (Japan)
PY 
ng
Y
ng 16.2
Y
16.2
PUBLIC COPY
e
P
e medicatio
PY
medicatio
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
s (Japan)
any
(Japan)
uth
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 196 of 234
Draft 3.0: 04Aug2020
Country:
Listing 16.2.5.1
IMP Intake per day during Treatment
Subject Identifier
Date+Time
Study Day#
Epoch
Dose Taken? (None/Partial/Full)
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
[1] Study date and time is the time the dose was entered into diary
[2] Study medication was administered twice daily, and compliance was recorded each time in the eDiary as full, partial or none.
Programming note: Use the shell for 16.2.5.1 for
Listing 16.2.5.1.1
IMP Intake per day during Treatment (Japan)
COPY 
Y
PY
OP
CO
PUBLIC C
C
orded
BL
orded eac
BL
eac
thorization 
national
zat
national L
03
03
ort any marketing auth
Dose
rke
Dose Ta
e
Ta
ng
rk
rk
rk
rk
ark
a
m
y
ny
a
rt
This document cannot be used to suppo
do
TIAL
s d
TIAL
o
pp
me
s
me in
s
in the
su
the e
u
e
IM
IM
uth
r variations thereof. 
ken?
th
ken? (None/
th
(None/
re
s t
ns
on
t
at
at
ati
at
ia
ar
va
application and any extensions or 
a
or
o
Diary
io
Diary as
on
as full,
n
full,
MP
MP Intake
ex
Intake pe
x
pe


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 197 of 234
Draft 3.0: 04Aug2020
Treatment group: xxx
Subject Identifier: <subject no.> Age: < >  Sex:<x>
Listing 16.2.5.2
IMP Intake – self reported % compliance
Study Week
Day1
Day2
Day3
Day4
Day5
Day6
Day7
Compliance %
1
2
3
4
Month1
Xxx.xx%
5
6
7
8
Month2
xxx.x%
…
…..
Note: Study medication was administered twice daily, and compliance was recorded each time in the eDiary as full, partial or none. (See Listing 16.2.5.1) From this, compliance was calculated by assuming
that a missed dose=0% of dose consumed, partial=50%, full=100%.
Programming Note: from daily diary record.
Programming note: Use the shell for 16.2.5.2 for
Listing 16.2.5.2.1
IMP Intake – self reported % compliance (Japan)
C COPY 
Y
PY
OP
CO
C
PUBLIC 
C
LIC
LIC
LIC
LIC
LIC
BL
UB
PU
P
thorization 
national
zat
national L
03
03
upport any marketing auth
Day6
rke
Day6
ke
rk
a
m
y
ny
a
rt
o
po
sed to supp
pp
up
su
o
d to
d
ed
e used
se
us
This document cannot be 
do
TIAL
s d
TIAL
e
ompliance
t be
ompliance w
ull=100%.
ot 
ull=100%.
or
c
or
uth
or variations thereof. 
D
th
s t
ns
on
ati
iaiaia
ria
ar
va
or
xtensions o
ns
on
io
sioioio
ns
ten
application and any ext
a
xt
ex
y
s recorded e
any
recorded e


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 198 of 234
Draft 3.0: 04Aug2020
Listing 16.2.5.3
Drug Accountability and Compliance to Study Treatment by Visit
Treatment group: xxx
Subject Identifier
Visit
Bottle
Number
Amount
Of volume
Dispensed
Date/Day#
Dispensed
Amount of Volume Returned
Date/Day#
Returned
XXXX
V1, etc.
XXXXXX
XXXXXX
NA
XXX
XXX
TEXT
NA
DDMMMYYYY/XX
DDMMMYYYY/XX
NA
NA
DDMMMYYYY/XX
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
Programming Notes: Use 28 days, keep in ADEC. Use the shell for 16.2.5.3 for
Listing 16.2.5.3.1
Drug Accountability and Compliance to Study Treatment by Visit (Japan)
PUBLIC COPY 
MMMY
Y
MMMY
DDMMMY
PY
DDMMMY
NA
OP
NA
Y
CO
CO
CO
CO
CO
C C
IC
BL
UB
PU
P
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
s
Am
Am
ket
ark
ma
X
n
X
Y/XX
an
Y/XX
y m
or
po
pp
su
su
su
sup
su
s
to
d
ed
ell
t
ell for
t b
for 16.2.5
b
16.2.5
uth
application and any extensions or variations thereof. 
a
ex
mount
n
mount of
ns
of Volu
s
Volu
he
on
NA
atio
NA
DDM
a
DDM
tio
ria
r v
or
s
ns
io
s
en
te
te
te
te
.3.3 for
a
for
Drug
nd
Drug Acco
d
Acco


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 199 of 234
Draft 3.0: 04Aug2020
Listing 16.2.6.1
Convulsive seizure – duration and number of occurrences per subject (Diary data)
Randomized Treatment: XXX
Subject
Identifier
Period
Seizure
Date/Study Day**
Time of Seizure
Single/
Cluster/Discrete
Type of
convulsive seizure
Duration of
seizure
Approximate
duration of
cluster
Number of seizures
XXXX
<Baseline(Core)>
Yyyy-mm-dd
<Single, or Cluster>
Type 1
<2 min
1
<Core Study(T+M)>
Yyyy-mm-dd
Type 2
2-10 min
2
<OLE Treatment>
Yyyy-mm-dd
Type 3
>10min
3*
…
4
…
XXXX
XXXX
.
.
.
*Note: Clusters of seizures could be recorded by duration, by number of seizures, or both. When reported by duration only, the number of seizures was set equal to 3 for analysis.
**With reference to start of OLE Study
Programming note: Present the subject identifier (grayed out) on all lines after the first line for a subject.
Convulsive seizures:
A: HEMICLONIC (Note lateralization: R body, L body, or independent R and L)
B1: FOCAL WITH CLEAR OBSERVABLE MOTOR SIGNS (i.e. automatisms,dystonic posturing, focal tonic stiffening)
C: SECONDARILY GENERALIZED TONIC CLONIC (evolving to bilateral convulsive seizure from focal seizure)
D: GENERALIZED TONIC CLONIC CONVULSION
G: TONIC
I: CLONIC (Note bilateral: symmetric R and L)
J: TONIC/ATONIC (cannot differentiate) - ‘drop attacks’ should be placed here
PUBLIC COPY 
ngle,
PY
ngle, or
Y
or
Y
CO
CO
CO
C
C C
LIC
BL
UB
PU
PU
PU
PU
PU
P
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
data)
g
data)
Type
a
Type of
ark
of
convulsiv
ma
convulsiv
ke
m
y m
er>
n
er>
Ty
Ty
y
p
upp
su
su
su
su
su
o s
to
d
e
us
e u
mber
be
mber of
be
of seizu
e 
seizu
out)
ot
out) on
ot
on all
t 
all l
ody,
ca
ody, or
an
or indep
an
indep
R SIGNS (i.e.
ca
SIGNS (i.e.
ONIC
t
NIC (evolvi
t c
(evolvi
ULSION
ent
ULSION
etric
m
etric R
m
R and
me
and L)
e
L)
erentiate)
um
erentiate) -
m
-
uth
n and any extensions or variations thereof. 
e
o
e seizure
ons
seizure
Dur
t
Dur
th
s t
on
ype
ia
ype 1
iat
1
tio
Type
aria
Type 2
ria
2
Type
var
Type 3
r
3
v
…
v
…
v
o
s
on
io
ns
en
te
xte
te
te
te
ex
y e
res,
n
res, or
ny
or both.
y 
both.
nes
d
nes after
d a
after the
a
the
pendent
n a
pendent R
a
R an
a
an
application
a
automatisms
on 
automatisms
ng to bilater
tion
ng to bilater
drop
pl
drop attacks
pli
attacks


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 200 of 234
Draft 3.0: 04Aug2020
Use the shell fo 16.2.6.1 for
Listing 16.2.6.1.1
Convulsive seizure – duration and number of occurrences per subject (Diary data) (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
y
t
y data)
ting
data) (Japa
ng
(Japa
uth
application and any extensions or variations thereof. 
a
n)
e
n)


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 201 of 234
Draft 3.0: 04Aug2020
Listing 16.2.6.2
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data)
Treatment group: XXX
Subject
Identifier
Period
Seizure Date/Study
Day**
Single/ Cluster
Type of non-
convulsive seizure
Duration of seizure
Approximate
duration of cluster
Number of
seizures
XXXX
Baseline(Core)
Yyyy-mm-dd
<Single, or Cluster>
Type 1
<2 min
1
Core Study(T+M)
Yyyy-mm-dd
Single, or Cluster>
Type 2
2-10 min
2
OLE Treatment
Yyyy-mm-dd
Single, or Cluster>
Type 3
>10min
3*
…
4
…
XXXX
XXXX
.
.
.
*Imputed – the number of seizures in the cluster was not stated. It was imputed as 3.
**With reference to start of OLE Study.
Programming note: Present the subject identifier (grayed out) on all lines after the first line for a subject.
Non-convulsive Seizures:
B2: FOCAL WITHOUT CLEAR OBSERVABLE MOTOR SIGNS (i.e. autonomicchanges like color change or pupillary dilation, and no motor signs)
E: ABSENCE OR ATYPICAL ABSENCE
F: MYOCLONIC
H: ATONIC – not resulting in a drop
K: INFANTILE SPASMS (if under 3 years of age)
L: EPILEPTIC SPASMS (if 3 years of age and older)
PUBLIC COPY 
r>
P
r>
C
C
LIC
BL
UB
UB
UB
UB
UB
PU
P
thorization 
national
zat
national L
03
03
to support any marketing auth
Diary
g a
Diary data)
g a
data)
-
ve
a
ve seizure
ark
seizure
ke
a
Type
y
Type 1
y m
1
m
Type
ny
Type 2
y 
2
n
Type
any
Type
n
an
…
a
…
a
or
p
up
su
o s
This document cannot be used to
do
TIAL
s d
TIAL
to
d
e
use
s
as
as imputed
us
imputed
out)
ot
out) on
ot
on all
t b
all lin
b
lin
TOR
c
TOR SIGNS
ca
SIGNS (
years
m
years of
me
of age)
e
age)
s of
u
of age
um
age and
m
and
uth
nsions or variations thereof. 
Duration
s t
Duration
th
ns
ns
ns
ns
<
on
3
r v
o
s o
s
on
io
application and any extens
a
ns
en
xte
ex
s 3.3.
es
d
es after
d a
after the
a
the
.e.
o
.e. autonom
on 
autonom
older)
pli
older)


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 202 of 234
Draft 3.0: 04Aug2020
M: NON CONVULSIVE STATUS (greater than 30 min)
O: OTHER
Programming Note: Use the 16.2.6.2 shell for
Listing 16.2.6.2.1
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data) (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ect
et
ect (Diary
etin
(Diary da
n
da
uth
application and any extensions or variations thereof. 
a
ta)
h
ta) (Japan)
her
(Japan)


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 203 of 234
Draft 3.0: 04Aug2020
Listing 16.2.6.3
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per subject
Treatment group: XXX
Subject
Identifier
Period
Number of Days with a Seizure
Occurrence
Longest interval between convulsive
seizures
Convulsive seizure free days
XXXX
Baseline(Core)
Core Study(T+M)
OLE Treatment
Xxx
Xxx
xxx
xx
Xxx
xxx
XX
Xxx
xxx
XXXX
XXXX
.
.
.
Programming Note: Present the subject identifier (grayed out) on all lines after the first line for a subject. Use the 16.2.6.3 shell for
Listing 16.2.6.3.1
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per subject (Japan)
PUBLIC COPY 
OP
CO
C
C
LIC
BL
UB
PU
PU
PU
PU
PU
P
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
days
g a
days per
g a
per sub
a
sub
nterval
rke
nterval betw
ke
betw
es
a
es
ke
a
xx
y
xx
Xxx
ny
Xxx
xxx
ny
xxx
m
an
a
rt
or
pp
up
su
o s
to
d
s after
se
after the
se
the f
the
ot
the Longest
ot b
Longest
uth
application and any extensions or variations thereof. 
a
ject
of
ject
een
t
een convulsiv
th
convulsiv
th
ns
on
ar
va
r
o
s
on
sio
ns
en
rst
e
rst line
ext
line for
xt
for a
interval
d a
interval betw
a
betw


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 204 of 234
Draft 3.0: 04Aug2020
Listing 16.2.6.4
Percent reduction in convulsive seizure frequency from baseline
Treatment group: XXX
Subject ID
mITT Population?
Period
CSF per 28 Days
% Change from
Baseline(Core)
>=25%? (Y/N)
>=50%? (Y/N)
>=75% (Y/N)
=100%? (Y/N)
XXXX
Y
Baseline (Core)
xxx.x
Core Study (T+M)
xxx.x
xxx.x
Y
N
Y
N
Month1-EOT
xxx.x
xxx.x
Y
Y
N
N
Month2-EOT
xxx.x
xxx.x
Y
N
N
N
XXXX
Y
Baseline (Core)
xxx.x
Core Study (T+M)
xxx.x
xxx.x
Y
Y
Y
N
Month1-EOT
xxx.x
xxx.x
Y
Y
Y
N
Month2-EOT
xxx.x
xxx.x
Y
Y
Y
N
XXXX
Y
Baseline (Core)
xxx.x
Core Study (T+M)
xxx.x
xxx.x
Y
Y
Y
N
Month1-EOT
xxx.x
xxx.x
Y
Y
Y
N
XXXX
Y
Month2-EOT
xxx.x
xxx.x
Y
Y
Y
Y
Programming Note: Present the subject identifier (grayed out) on all lines after the first line for a subject.
Use the 16.2.6.4 shell for
Listing 16.2.6.4.1
Percent reduction in convulsive seizure frequency from baseline (Japan)
PUBLIC COPY 
Y
PY
PY
PY 
PY
PY
PY
PY
PY
x
C
x
OP
xx.x
C
xx.x
CO
xxx.x
C C
xxx.x
C
C
xx
C
xx
IC
LI
BL
UB
OT
PU
OT
UB
UB
UB
UB
PU
P
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
>=25%
rke
>=25%
ket
ar
a
ma
x
y
x
m
xx.x
ny
xx.x
y
ny
an
xxx.
a
xxx.
t a
x
rt
o
p
pp
x
pp
pp
pp
pp
xx.x
s
xx.x
sup
xxx.x
o s
xxx.x
s
xxx.x
to
xxx.x
to
to
d
ed
se
se
se
se
) on
b
on all
be
all lines
e
lines
uth
tensions or variations thereof. 
? (Y/N)
s th
(Y/N)
he
he
he
he
s
Y
on
Y
ns
Y
o
Y
ion
Y
tio
iat
ririririri
a
x.x
r
x.x
v
xxx.x
or
xxx.x
r
o
s
xx
xx
ns
on
sisisisio
si
ns
en
application and any exte
a
xte
ex
after
n
after the
ny
the firs
y
firs
Percent
nd
Percent re
re


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 205 of 234
Draft 3.0: 04Aug2020
Listing 16.2.6.5
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and Investigator
Subject
Identifier
Age/sex
Assessment Date
Clinic Visit
Analysis Visit
CGI score by parent/caregiver
CGI score by Investigator
XXXX
Visit 1,
Visit 3,
Visit 4,
Visit 5,
Visit 6,
Visit 7,
Visit 8,
….
Very much improved
Much improved
Minimally improved
No change
Minimally worse
Much worse
Very much worse
Very much improved
Much improved
Minimally improved
No change
Minimally worse
Much worse
Very much worse
Visit 12
XXXX
…
…
…
XXXX
.
.
.
Note: CGI = Clinical Global Impression
Programming note: Present the subject identifier (grayed out) on all lines after the first line for a subject. Use the shell for 16.2.6.5 for
Listing 16.2.6.5.1
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and Investigator (Japan)
PUBLIC COPY 
5,
PY
5,
sit
P
sit 6,
OPY
6,
Visit
OP
Visit 7,
OP
7,
Visit
CO
Visit
C
C
LIC
BL
UB
PU
P
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
be
d Investigat
g a
Investigat
parent/care
keti
parent/care
ng
ke
much
ar
much impro
ark
impro
uch
m
uch improve
ma
improve
Minimally
y m
Minimally
No
ny
No cha
y 
cha
Min
ny
Min
rk
n
Visit
p
Visit 12
pp
12
p
upp
s
…
s
…
su
o s
o s
o s
o s
to
d
e
out)
ot
out) on
ot
on all
t b
all lin
b
lin
Clinical
an
Clinical Glo
n
Glo
uth
application and any extensions or variations thereof. 
a
ny
or
o
or
giver
the
giver
re
th
ved
n
ved
ed
o
ed
improved
tio
improved
nge
ia
nge
nimally
aria
nimally wors
ria
wors
Much
va
Much worse
ar
worse
Very
r va
Very muc
va
muc
s t
or
o
s
on
io
ns
en
xtxtxtxte
es
d
es after
d a
after the
a
the f
bal
n
bal Impressi
n a
Impressi


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 206 of 234
Draft 3.0: 04Aug2020
Treatment group: ZX008 OL
Listing 16.2.6.6
Quality of life in Childhood Epilepsy Scale
Subject
Identifier
Age/Sex
Visit
Response
(Raw Score)
Transformed
Score
XXXX
Baseline
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
n
an
ca
t
en
me
um
um
um
um
cum
u
uth
nnot be used to support any marketin
plication and any extensions or variations thereof. 
t
at
ica
ppli
pli
app
app
ation and any extensions or variations ther


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 207 of 234
Draft 3.0: 04Aug2020
XXXXX
XXXXX
XXXXX
XXXXX
XXXX
PARCAT1=’QOLCE’
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ut
used to support any marketing aut
application and any extensions or variations thereof
a
extensions or variations thereof. 


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 208 of 234
Draft 3.0: 04Aug2020
Listing 16.2.6.7
Quality of life of the Parent/Caregiver using EQ-5D-5L scale
Subject
Identifier
Age/Sex
Visit
Assessment
Date/Day #
Was the assessment
done
Response
XXXX
Baseline
End of study visit
DDMMMYYYY/XX
Yes
No
XXXXXX
XXXXXX
XXXXXX
XXXXXX
XXXXXX
XX
XXXX
…
…
…
XXXX
.
.
.
PUBLIC COPY 
ting authorization 
uth
national
zat
national L
03
03
tin
This document cannot be used to support a
do
TIAL
s d
TIAL
ot
…
t
…
any marketi
thereof. 
her
application and any extensions o
a
d a
s or variations th


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 209 of 234
Draft 3.0: 04Aug2020
Listing 16.2.6.8
Quality of life of the Parent/Caregiver using HADS scale
Subject
Identifier
Visit [1]
Was the assessment done
Response
XXXX
Baseline Visit 1
XXXXX
XXXXX
XXXXX
Visit 3
XXXXX
XXXXX
Visit 4
XXXXX
XXXXX
XXXXX
Visit 5
XXXXX
XXXXX
XXXXX
---
XXXXX
XXXXX
XXXXX
Visit 12
XXXXX
XXXXX
XXXX
…
…
XXXX
[1] repeated for Visit 1 and each clinical visit from Visit 3 through Visit 16
Programming note:  This table for ZX008 – 1501 and ZX008-1502 subjects only. Do not include ZX008-1504 Cohort 2
PUBLIC COPY 
ing authorization 
national
zat
national L
03
03
g
uth
This documen
do
TIAL
s d
TIAL
…
a
…
nical
me
nical visit
men
visit fro
n
fro
for
m
for ZX008
me
ZX008 –
en
ent cannot be use
sed to support any marketing
thereof. 
th re
applicat
a
m Visit
ca
Visit 3
a
3 thro
a
thro
1501
pli
1501 and
plic
and ZX
c
ZX
at
ation and an
any extensions or variations th


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 210 of 234
Draft 3.0: 04Aug2020
Treatment Group: ZX008 OL
Listing 16.2.6.9.1
Pediatric Quality of Life Inventory (Peds QL)- for TODDLERS (age 2-4 years)
Subject
Identifier
Visit [1]
Response
XXXX
Baseline
AVALC
XXXXX
Visit 1
XXXXX
XXXXX
Visit 3
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
---
XXXXX
XXXXX
…
…
Visit 12
XXXX
…
…
XXXX
.
.
.
[1] Repeated for Visit 1 and Visit 3 through Visit 16
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
)
g
)
Visit
cu
Visit 3
cu
3 throug
um
throug
uth
um
not be used to support any marketin
application and any extensions or variations thereof. 
a
gh
p
gh Visit
ppl
Visit 16
pl
16
pli
nd any extensions or variations ther


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 211 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use Listing shell 16.2.6.9 for below listings:
Listing 16.2.6.9.2
Pediatric Quality of Life Inventory (Peds QL) - for Young Children (age 5-7 years)
Listing 16.2.6.9.3
Pediatric Quality of Life Inventory (Peds QL) - for Children (age 8-12 years)
Listing 16.2.6.9.4
Pediatric Quality of Life Inventory (Peds QL) - for TEENS (age 13-18 years)
Listing 16.2.6.9.5
Pediatric Quality of Life Inventory (Peds QL) – Family Impact Module
PUBLIC COPY 
ng
Y
ng 16.2
Y
16.2
ntory
PY
ntory (Ped
PY
(Ped
Listi
CO
Listi
y
C
y of
C C
of Life
C C
Life In
C
In
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
(age
ket
(age 5
eti
5-
et
-7
eti
7 year
ti
year
ldren
ma
ldren (age
ma
(age 8
QL)
a
QL) -
a
- for
any
for TEEN
ny
TEEN
g 16.2.6.9.5
ort 
16.2.6.9.5
ntory
po
ntory (Peds
por
(Peds Q
uth
application and any extensions or variations thereof. 
a
rs)
h
rs)
12
o
12 years)
ons
years)
S (age
ria
(age 13
ia
13-
a
-18
a
18
QL)
o
QL) –
or
– Family
or 
Family


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 212 of 234
Draft 3.0: 04Aug2020
Treatment Group: ZX008 OL
Listing 16.2.6.10
Study Medication Palatability Assessment
Subject
Identifier
Age/Sex
Visit
Was the assessment
done
Question
Response
XXXX
Visit 3
Yes
No
1 – Over the past month, on the basis of the reaction ⁄ facial expression of your child, do
you think that the medicine’s taste and texture are acceptable/not acceptable to your
child?
XXXXXX
2 – Over the past month, please rate [1]how much your child likes/dislikes the medicine’s
taste
XXXXXX
3 - Over the past month, do you sometimes have problems giving the medicine to your
child due to its taste or texture?
XX
XXXX
…
…
XXXX
.
.
.
[1]Rating scale: 5=likes it very much; 4=likes it; 3=neither likes or dislikes it; 2=dislikes it; 1=dislikes it very much
PUBLIC COPY 
th
Y
th
Over
PY
Over the
PY
the
taste
OP
taste
PY
3
CO
3 -
CO
- Ov
O
Ov
ch
C
ch
CO
C
C
LIC
BL
UB
PU
P
thorization 
national
zat
national L
03
03
e used to support any marketing auth
tin
rk
n
m
n the
ma
the basis
ma
basis
dicine’s taste
y m
dicine’s taste
a
stst month,
any
month, ple
y
ple
ny
the
o
the past
ort
past mo
t
mo
due
p
due to
po
to its
po
its ta
ta
rt
pp
…
su
…
up
su
o s
o s
o s
o s
to
d
se
us
This document cannot be u
do
TIAL
s d
TIAL
e u
dislikes
be
dislikes it;
e 
it; 2=
2=
uth
y extensions or variations thereof. 
er
s t
f
o
f the
on
the reactio
ons
reactio
and texture 
tio
and texture 
ns
ase
ar
ase rate
aria
rate [1]h
a
[1]h
ia
nth,
r
nth, do
r v
do you
v
you s
te
o
te or
or
or texture
or 
texture
va
o
s
on
io
ns
en
xtxtxtxte
ext
ex
application and any ex
a
ex
y ex
dislikes
ny
dislikes it;
y 
it; 1=
1=


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 213 of 234
Draft 3.0: 04Aug2020
Treatment Group: ZX008 OL
Listing 16.2.6.11
Sleep quality and mealtime behavior
Subject
Identifier
Age/Sex
Visit
Date of
Assessment /Day #
Sleep Quality Question Response
Mealtime Behavior Question Response
XXXX
xxx/x
Visit 3
DDMMMYYYY/XXX
More Disturbed
Same
Better
Worse Behavior
Not Changed
Improved Behavior
XXXX
…
XXXX
.
.
.
Note: This scale is collected only for subjects from core study ZX008-1504.
# Relative to first dose of study treatment.
UBLIC COPY 
PY
OP
CO
C
C
LIC
BL
BL
PUBL
BL
BL
BL
UB
PU
P
thorization 
national
zat
national L
03
03
support any marketing auth
tin
rk
a
ny
a
rt
o
pp
up
This document cannot be used to su
do
TIAL
s d
TIAL
su
o
to
d 
sed
e
4.
u
4.
uth
ons or variations thereof. 
Mealtime
he
Mealtime B
er
s t
s
W
s
W
ns
ia
ar
va
r
o
s 
xtension
on
sio
ns
ten
application and any ext
a
xt


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 214 of 234
Draft 3.0: 04Aug2020
Treatment Group: ZX008 OL
Listing 16.2.6.12
Karolinska sleepiness scale
Subject
Identifier
Age/Sex
Visit
Date of
Assessment /Day #
XXXX
xxx/x
Visit 3
DDMMMYYYY/XXX
XXXX
…
XXXX
.
.
.
Note: This scale is collected only for subjects from core study ZX008-1504.
# Relative to first dose of study treatment.
[1] Values 1 – 6 are categorized as Alert. Values 7 – 9 are categorized as sleepy.
PUBLIC
BL
BL
UB
PU
P BLIC COPY 
thorization 
national
zat
national L
03
03
t be used to support any marketing auth
o s
to
d
…
d
…
d
ed
ed
ed
ed
e
us
u
be
This document cannot b
do
TIAL
s d
TIAL
t b
ot
no
ore
n
ore study
nn
study ZX
n
ZX
ues
t
ues 7
t c
7 –
ca
– 9
ca
9 are
a
are
uth
support any marketin
any extensions or variations thereof. 
io
ns
en
xte
ex
y e
n
n and any
ny
n
an
d
nd
application
a
008
a
008-
a
-1504.
an
1504.
categorized
on 
categorized
ns or variations ther


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 215 of 234
Draft 3.0: 04Aug2020
Listing 16.2.7.1
Adverse Events
Adverse Event
Age/
(System Organ
Start
stop
Action
Other
Subject
Gender/
Class/
Date/
Date/
Related to study
Taken with Study
Action
Identifier
Race
Preferred Term)
Day#
Day#
Drug
Severity
treatment
Taken
Outcome
Serious
XXXX
Xx/
& TEXT (SOC/PT)
DDMMMYYYY DDMMMYYYY Yes
Mild
Dose not changed
None
Not resolved
Yes:
X/
/XX
x
/XX
No
Moderate
Severe
Dose Increased
Dose reduced
Drug Interrupted
Drug Withdrawal
NA
withdrawn
from study
Treated with
Medication
Other: TEXT
Resolved
Resolved
w/sequelae
Resolving
Unknown
Fatal
Death
Life-
Threatening
Hospitalization
Disability/Permanent Damage
Congenital Anomaly/Birth defect
Medically significant
No
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
& Treatment-emergent adverse event.
NA = Not applicable
PUBLIC COPY 
Moderat
Y
Moderat
Severe
PY
Severe
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
nn
ng
Othe
ti
Othe
Study
rk
Study
A
e
A
nt
nt
a
ose
y
ose not
y m
not chan
m
chan
Dose
ny
Dose Incre
y 
Incre
Dose
any
Dose r
y
r
Dru
a
Dru
uth
ns thereof. 
re
ction
th
ction
Taken
s t
Taken
ariations
ns
ged
ti
ged
Non
o
Non
ased
iat
ased
application and any extensions or var
a
an
duced
ria
duced
g
v
g Interrupte
var
Interrupte
Drug
r v
Drug Withdr
va
Withdr
NA
or
NA


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 216 of 234
Draft 3.0: 04Aug2020
Programming note:
Use the shell for 16.2.7.1 for the following listings:
Listing 16.2.7.1.1 Adverse events (Japan)
Listing 16.2.7.2 Adverse events of special interests (AESI)
Listing 16.2.7.2.1 Adverse events of special interests (AESI) (Japan)
Note: Please record only Adverse event of special interest as per definition provided in Protocol
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
uth
application and any extensions or variations thereof. 
a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 217 of 234
Draft 3.0: 04Aug2020
Listing 16.2.8.1.1
Laboratory Data: Hematology parameters
Subject
Identifier
Visit
Sample Date/Day# and
Parameter
Value*
Reference
Range
Unit
XXXX
Screening (Visit 1)
DDMMMYYYY/XX
Haemoglobin
XX.X H
XX.X-XX.X
TEXT
Visit 2
ND: TEXT
Haematocrit
XX.X L
Visit 3
…
XX.X
Visit 4
…
Visit 5
Visit 6
…
Visit 12
XXXX
XXXX
.
.
.
ND = Not Done.
# Relative to first dose of study treatment.
* H = Above reference range, L = Below reference range
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
be
ence
tin
ence
ange
ket
ange
ng
XX.X
ark
XX.X-XX
k
XX
ke
X
y
X
…
n
…
e
uth
application and any extensions or variations thereof. 
a
ny
re
.X
n
.X
th


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 218 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use the shell for 16.2.8.1.1 for the following listings:
Listing 16.2.8.1.1.1
Laboratory Data: Hematology parameters (Japan)
Listing 16.2.8.2.1
Laboratory Data: Biochemistry parameters
Listing 16.2.8.2.1.1
Laboratory Data: Biochemistry parameters (Japan)
Listing 16.2.8.3
Laboratory Data: Coagulation parameters
Listing 16.2.8.3.1
Laboratory Data: Coagulation parameters (Japan)
Listing 16.2.8.4.1
Laboratory Data: Urinalysis parameters
Listing 16.2.8.4.1.1
Laboratory Data: Urinalysis parameters(Japan)
For Listing 16.2.8.4 and 16.2.8.4.1, Urinalysis – add column “Result” (as 5th column) with result “Normal” or “Abnormal”.
Listing 16.2.8.5
Tests of growth, precocious puberty and Thyroid Function
Listing 16.2.8.5.1
Tests of growth, precocious puberty and Thyroid Function (Japan)
PUBLIC COPY 
Listing
PY
Listing 16.
Y
16.
ry
O
ry Data:
OP
Data: Co
P
Co
L
C
L
oratory
IC
oratory Da
C 
Da
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
meters
y m
meters (Japan
m
(Japan
8.3
a
8.3
gulation
t a
gulation para
a
para
ting
p
ting 16.2.8.3
po
16.2.8.3
: Coagulatio
pp
Coagulatio
Listin
su
Listin
aboratory
to s
aboratory D
s
D
Labor
ed
Labor
t”
e
t” (as
e u
(as 5th
e u
5th co
u
co
uth
application and any extensions or variations thereof. 
a
n)
t
n)
ameters
var
ameters
1
o
1
on
s
on paramete
s o
paramete
g 16.2.8.4.1
on
16.2.8.4.1
ata:
si
ata: Urinalys
sio
Urinalys
Listing
ten
Listing 1
atory
xt
atory Data:
xte
Data: U
lumn)
y
lumn) with
y e
with r
e
r
Tests
d a
Tests o
a
o
T


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 219 of 234
Draft 3.0: 04Aug2020
Programming Notes: Please use STLB11 from ISS but only include Baseline (OLE) through End of Study in OLE for the following listngs.
Listing 16.2.8.1.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Hematology
Listing 16.2.8.1.2 .1
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Hematology (Japan)
Programming Notes: Use shell for ISS STLB12 but only include Baseline (OLE) through End of Study in OLE for the following listings.
Listing 16.2.8.2.2
Most Abnormal Laboratory Parameters during Open-label Study Periods – Biochemistry
Listing 16.2.8.2.2.1
Most Abnormal Laboratory Parameters during Open-label Study Periods – Biochemistry (Japan)
Programming Notes: Please use shell for ISS Listing STLB13 but only include Baseline (OLE) through End of Study in OLE for the following listings.
Listing 16.2.8.4.2
Most Abnormal Laboratory Parameters during Open-label Study Periods -- Urinalysis
Listing 16.2.8.4.2.1
Most Abnormal Laboratory Parameters during Open-label Study Periods -- Urinalysis (Japan)
Use shell from 16.2.8.2.2 – add column “Result” (as 5th column) with result.
PUBLIC COPY 
dy
P
dy in
PY
in OLE
PY
OLE f
Y
f
L
C
L
atory
C
atory Param
C C
Param
aboratory
UBL
aboratory
clude
P
clude
thorization 
national
zat
national L
03
03
not be used to support any marketing auth
eriod
ket
eriod -
et
- Hema
ti
Hema
ment
m
ment Period
ma
Period
the
a
the followin
any
followin
ing
p
ing 16.2.8.2.
por
16.2.8.2.
ters
p
ters during
ppo
during O
o
O
Listing
sup
Listing
rameters
s
rameters du
u
du
aseline
ed
aseline (OLE
d 
(OLE
Abnormal
e u
Abnormal La
La
Most
ot
Most Abnorm
ot b
Abnorm
This document cann
do
TIAL
s d
TIAL
s 5th column
nno
s 5th column
uth
nd any extensions or variations thereof. 
atology
he
atology
Hematology
ons
Hematology
g listings.
ria
listings.
2
o
2
Open
o
Open-
o
-label
or
label St
r
St
6.2.8.2.2.1
ns
6.2.8.2.2.1
ring
io
ring Open
ion
Open-
n
-la
n
la
)
t
) through
ten
through En
n
En
boratory
y e
boratory Pa
e
Pa
al
d
al Laborator
d a
Laborator
application an
a
n) with result
and
n) with result


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 220 of 234
Draft 3.0: 04Aug2020
Listing 16.2.8.6
Urine Pregnancy Test
Subject Identifier
Was Pregnancy test performed
Date of Urine pregnancy test / (Visit)
Result
XXXX
NA(female of non-child bearing potential)
Not Done
Done
DDMMMYYYY/ Visit X
Negative
Positive
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
PUBLIC COPY 
PU
thorization 
national
zat
national L
03
03
to support any marketing auth
ng
This document cannot be used to
do
TIAL
s d
TIAL
d to
g
uth
nsions or variations thereof. 
re
application and any extens
a
ns
Result
eo
Result
N
o


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 221 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use the shell for 16.2.8.6 for the following:
Listing 16.2.8.6.1
Urine Pregnancy Test (Japan)
Listing 16.2.8.7
Urine THC panel
Listing 16.2.8.7.1
Urine THC panel (Japan)
Listing 16.2.8.8
Whole blood cannabidiol
Listing 16.2.8.8.1
Whole blood cannabidiol (Japan)
PUBLIC COPY 
p
Listing
PY
Listing 16.
Y
16.
Whole
OP
Whole bloo
OP
bloo
L
C
L
Whol
C 
Whol
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
8.8
a
8.8
annabidiol
t a
annabidiol
ting
p
ting 16.2.8.8
po
16.2.8.8
blood
pp
blood canna
pp
canna
uth
application and any extensions or variations thereof. 
a
1
o
1
bidiol
s o
bidiol (Japan
o
(Japan


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 222 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.1.1
Vital Signs
Treatment group: xxx
Subject
Identifier
Age/Sex
Visit
Visit
Date/Day#
Systolic
Blood
Pressure
(mmHg)
Diastolic
Blood Pressure
(mmHg)
Heart
Rate
(bpm)
Respira-
tory
(Breaths/
min)
Body
Weight
(kg)
Body
Height
(cm)
BMI
(kg/m^2)
Temper-
ature
(C)
XXXX
XX/X
Screening (Visit 1)
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
…..
DDMMMYYYY/XX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
NA
NA
NA
NA
XXX
NA
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Visit 16
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXXX
XXXX
.
NA = Not Applicable.
# Relative to first dose of study treatment.
PUBLIC COPY 
Y
XX
BL
XX
XXX
UB
XXX
X
U
X
XX
P
XX
XXX
OP
XXX
XXX
CO
XXX
X
C
X
PY
P
IC
thorization 
national
zat
national L
03
03
ot be used to support any marketing auth
pm)
pm)
Respira
rke
Respira
to
k
to
(
ket
a
y m
XXX
p
XXX
XXX
sup
XXX
XX
s
XX
XXX
ny
XXX
X
ny
to
ort
XXX
se
XXX
nnot b
XXX
us
XXX
XX
XX
be
be
be
be
b
ot
no
t cann
nn
a
This document c
do
TIAL
s d
TIAL
t c
ent.
en
ent.
uth
y extensions or variations thereof. 
ryry
Breaths/
ons
Breaths/
min)
tion
min)
th
th
the
th
tio
ia
X
s
X
XXX
ns
XXX
XX
v
XX
XXX
or v
XXX
XXX
o
XXX
iaiaia
on
ria
and any e
XXX
e
XXX
y e
X
n
X
y e
any
d a
n
on and
nd
an
an
an
an
n a
application a
a
a
on a


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 223 of 234
Draft 3.0: 04Aug2020
Programming Note; Use shell for 16.2.9.1.1or the following listings.
Listing 16.2.9.1.1.1
Vital signs (Japan)
Listing 16.2.9.1.2
Abnormal Vital signs data (Japan)
Listing 16.2.9.1.2.1
Abnormal Vital signs data (Japan)
Programming Note : The lows and highs for determination of abnormality will be supplied by Zogenix. Abnormal weight range: subjects with weight decrease of >=7% or increase of >=7%. For these
subjects, include the baseline, treatment value, change from baseline, their age and sex.
PUBLIC COPY 
al
Y
al sign
Y
sign
Listing
OPY
Listing 16.
PY
16.
ormal
COP
ormal Vita
OP
Vita
pplied
C C
pplied by
C
by Z
C
Z
and sex.
IC
and sex.
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
Japan)
y
Japan)
.1.2.1
an
.1.2.1
igns
rt
igns data
rt a
data (Ja
a
(Ja
genix.
p
genix. Abnorm
po
Abnorm
application and any extensions or variations thereof. 
a
pan)
v
pan)
mal
o
mal weight
or 
weight r


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 224 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.1.9
Subjects with Weight Decrease >5% during Treatment
Treatment Group: xxx
Did Subject have
a TEAE of
Change
%Change
Subject
decreased
Weight
Baseline
From
From
Identifier
Age
Sex
appetite? (Yes/No)*
Visit
Visit Date/Day
(kg)
flag
Baseline
Baseline
ZX008-1504-1001-43
13
M
No
Xxxx
16JAN2017/-109
62.69
Y
Xxxx
29MAY2017/25
60.33
-2.36
-3.76
Xxxx
27JUN2017/54
38.83
-23.86
-38.06#
Xxxx
24JUL2017/81
57.79
-4.9
-7.82
ZX008-1504-1001-45
9
M
No
Xxxx
27JAN2017/-116
22.77
Y
Xxxx
20JUN2017/29
21.5
-1.27
-5.58#
Xxxx
25JUL2017/64
21.82
-0.95
-4.17
Xxxx
18AUG2017/88
22.72
-0.05
-0.22
ZX008-1504-1001-46
16
F
No
Xxxx
25JAN2017/-124
113.76
Y
Xxxx
29MAY2017/1
106
-7.76
-6.82
xxxx
27JUN2017/30
105.01
-8.75
-7.69
Programming note: use shell as used for the IDMC. Use the shell for 16.2.9.1.9 for
Listing 16.2.9.1.9.1
Subjects with Weight Decrease >5% during Treatment (Japan)
PUBLIC COPY 
xxx
IC
xxx
Xxxx
BLIC
Xxxx
Xxxx
BL
Xxxx
X
B
X
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
be
ke
t Date/Day
ma
Date/Day
16JAN20
ny
16JAN20
m
29MA
an
29MA
27
a
27
x
t
x
Xxxx
ed
Xxxx
Xxxx
sed
Xxxx
xxx
s
xxx
se
se the
no
the shell
no
shell f
application and any extensions or variations thereof. 
a
ny
the
Weigh
ns
Weigh
(kg
n
(kg
17/
ri
17/-
ia
-109
iat
109
tio
AY2017/25
aria
AY2017/25
7JUN2017/54
va
7JUN2017/54
24JUL2017/
r v
24JUL2017/
27JA
o
27JA
2
x
or
or 16.2.9.1.9
nd
16.2.9.1.9


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 225 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.2
Listing of Items on Columbia-Suicide Severity Rating Scale (C-SSRS)for Individual Subjects
Safety Population
Subject
Visit/Time-
reatment
number
point
Response
Comment
XXXX
XXXXX
Visit 1,
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
PUBLIC COPY 
eting authorization 
uth
national
zat
national L
03
03
alal Subjects
g a
Subjects
et
et
This document c
do
TIAL
s d
TIAL
um
t cannot be used to support any market
ns thereof. 
he
s
applica
a pli
plication and any extensions or variations


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 226 of 234
Draft 3.0: 04Aug2020
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
Xxxx
xxxxxxxxxx
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXX
Visit 3
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
PUBLIC COPY 
ting authorization 
uth
national
zat
national L
03
03
ut
This docum
do
TIAL
s d
TIAL
um
ument c
t cannot be used to support any marketin
ns thereof. 
XX
o
XX
app
a plica
plication and any extensions or variation


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 227 of 234
Draft 3.0: 04Aug2020
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
…….
XXXX
XXXXX
Visit 4, Visit 5,
Visit 6, Visit 7,
Visit 8…Visit 16
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXX
Programming notes:
-
List only for subjects who answered “yes” to at least one question. For those subject, list all their C-SSRS data for all time points.
-
Use the 16.2.9.2 shell for
Listing 16.2.9.2.1
Listing of Items on Columbia-Suicide Severity Rating Scale (C-SSRS)for Individual Subjects (Japan)
Safety Population
PUBLIC COPY 
marketing authorization 
uth
national
zat
national L
03
03
ut
This document cannot be used
do
TIAL
s d
TIAL
e question.
e u
question.
Listing
ot
Listing of
ot
of Item
t 
Item
ed
ed to suppo
port any m
variations thereof. 
XXXX
f
XXXX
XXXX
of
XXXX
XXX
eo
XXX
application and any exte
a
or
y
or those
y e
those sub
e
sub
ms
d
ms on
d
on Colum
d a
Colum
te
tensions or 
or va


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 228 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.3.1
Behavior Rating Inventory of Executive Function (BRIEF-P) Individual Responses
Randomized Treatment: XXX
Subject
Identifier
Visit
Question Category
Question
Response
SUBJID
AVISITN/AVISI
T
AVALC
XXXX
Baseline
XXXXX
Visit 8
XXXXX
Visit 12/EOS
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
.
Programming Note: Organize by items within scale scores, for all five scales.
Programming Note: provide the raw responses, not imputed responses
Programming Note: Use the shell for 16.2.9.3.1 for
Listing 16.2.9.3.1.1
Behavior Rating Inventory of Executive Function (BRIEF-P) Individual Responses (Japan)
PUBLIC COPY 
arketing authorization 
uth
national
zat
national L
03
03
ses
ses
ket
ar
t ca
in
t
in scale
t ca
scale sco
c
sco
This document
do
TIAL
s d
TIAL
ponses, not 
nt 
ponses, not 
16.2.9.3.1 f
en
16.2.9.3.1 f
cannot be used to support any mar
ns thereof. 
he
ns
tion
es,
o
es, for
on
for all
on
all five
n
five
applicati
a
imputed resp
atio
imputed resp
or
c
or
n and any extensions or variations


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 229 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.3.2
Behavior Rating Inventory of Executive Function (BRIEF-P) Summary Scales
Subject
Identifier
Visit
Summary Scale
Score
SUBJID
AVISITN/AVISIT
PARCATx?
AVAL
XXXX
Baseline(Core)
Inhibit
XXXXX
Visit 12/EOS
Shift
Emotional Control
Working Memory
Plan/Organize
Inhibitory Self-Control Index (ISCI) (Inhibit + EC)[1]
Flexibility Index (FI) (Shift + EC)[2]
…
Emergent Metacognition Index (EMI) (WM + PO)[3]
Global Executive Composite (GEC) (Inhibit + Shift + EC + WM + PO) [4]
Inconsistency Score
Inconsistency Classification
…
Negativity Score
Negativity Classification
.
PUBLIC COPY 
Y
OPY
O
CO
C C
ze
L
ze
LIC
BL
bitory
UB
bitory Self
UB
Self
UB
PU
xibili
P
xibili
P
annot be used to support any marketing authorization 
uth
national
zat
national L
03
03
y
t
y Scales
ting
Scales
tin
rke
ar
ma
y m
ny
an
t
or
po
pp
su
ntrol
to
ntrol Index
o s
Index (
s
(
o s
to
ndex
ed
ndex (FI)
ed
(FI) (Sh
(Sh
d
ed
mergent
us
mergent Meta
us
Meta
us
u
Global
be
Global E
be
t b
t b
t b
t b
t b
ot
no
ment can
an
ca
t c
nt
cume
me
m
This docu
do
TIAL
s d
TIAL
cu
and any extensions or variations thereof. 
ere
th
s 
on
tio
iat
ari
va
r v
or
s
ns
SCI)
si
SCI) (Inhibit
sio
(Inhibit
io
ns
hift
t
hift +
te
+ EC)[2]
ten
EC)[2]
en
xte
acognition
ex
acognition In
x
In
ex
y e
xecutive
any
xecutive Com
y
Com
ny
an
nconsistency
nd 
nconsistency
d
nd
cation an
Incon
a
Incon
a
n
io
ati
pplica
ca
plic
app
app


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 230 of 234
Draft 3.0: 04Aug2020
.
Programming note: the scores take into account the algorithm for handling missing responses.
Programming Note: Organize by scales, then index, and list inconsistency and negativity last.
Programming note: Use the shell for 16.2.9.3.2 for
Listing 16.2.9.3.2.1
Behavior Rating Inventory of Executive Function (BRIEF-P) Summary Scales (Japan)
PUBLIC COPY 
sting
PY
sting 16.2.9
PY
16.2.9
xecutive
OP
xecutive Fu
P
Fu
g authorization 
uth
national
zat
national L
03
03
ut
au
This document cannot be used to support any marketing 
do
TIAL
s d
TIAL
g
2.1
an
2.1
tion
t a
tion (BRIEF
an
(BRIEF
of. 
f
application and any extensions or variations thereo
a
eo
P)
P) Summary
ari
Summary


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 231 of 234
Draft 3.0: 04Aug2020
Programming Note: Use Listing shell 16.2.9.3.1 for the following listigns. Organize by items within scale scores, for all eight scales.
Listing 16.2.9.3.3
Behavior Rating Inventory of Executive Function (BRIEF) Individual Responses
Listing 16.2.9.3.3 1
Behavior Rating Inventory of Executive Function (BRIEF) Individual Responses (Japan)
Listing 16.2.9.3.5
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Individual Responses
Listing 16.2.9.3.5.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Individual Responses (Japan)
Footnote: OLE Last Visit = Last available measurement during the OLE study
Programming Note: Use Listing shell 16.2.9.3.2 to produce the following listings. Organize by scales, then index, and list inconsistency and negativity last.
Listing 16.2.9.3.4
Behavior Rating Inventory of Executive Function (BRIEF) Summary Scales
Listing 16.2.9.3.4.1
Behavior Rating Inventory of Executive Function (BRIEF) Summary Scales (Japan)
Listing 16.2.9.3.6
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Summary Scales
Listing 16.2.9.3.6.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Summary Scales (Japan)
Footnote: OLE Last Visit = Last available measurement during the OLE study
PUBLIC COPY 
ction
Y
ction –
Y
–
Listing
OP
Listing 1
P
1
e
C
e Function
CO
Function
tings.
BL
tings. Orga
BL
Orga
eh
P
ehavi
P
avi
thorization 
national
zat
national L
03
03
nt cannot be used to support any marketing auth
esponses
ting
esponses
dual
ar
dual Respon
ark
Respon
Version
ny
Version (BRI
y 
(BRI
.9.3.5.1
t a
.9.3.5.1
Adult
ort
Adult Versio
rt 
Versio
ze
ze by
s
by scales,
su
scales,
Rating
ed
Rating Inven
d 
Inven
havior
e u
havior Rating
u
Rating
Behavior
ot 
Behavior
Beh
a
Beh
This documen
do
TIAL
s d
TIAL
e measurem
nt 
e measurem
n
uth
y extensions or variations thereof. 
ses
ns
ses (Japan)
ns t
(Japan)
EF
ia
EF-
a
-A)
iat
A) Individ
ati
Individ
n (BRIEF
r va
(BRIEF-
v
-A)
a
A)
hen
o
hen index,
on
index, a
Listing
ns
Listing 16.
s
16.
tion and any 
tory
te
tory of
ten
of Execu
en
Execu
L
g Inventory
y e
Inventory o
e
o
Rating
d
Rating Invent
d a
Invent
avior
n
avior Rating
n a
Rating
applicat
a
ent during th
atio
ent during th
at


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 232 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.4
Tanner Staging
Sex:  Boys
Tanner Stage for
Subject Identifier
Age Group
Sex [1]
Visit
Was the Exam performed
Visit Date/Day#
Genital/Breast
Development [2]
Pubic Hair Growth [3]
XXXX
>7years to <=11/>11years to
<=15/>15years to <=18
Male
Visit 1
Visit 3
---
Visit 8
Yes/No
DDMMMYYYY/XX
X
x
XXXX
---
XXXX
---
.
.
# Relative to first dose of study treatment. [1] Table for girls registers Female in this column.
[2] Boys are rated for genital development and pubic hair growth
[3] Girls are rated for breast development and pubic hair growth
Programming Note: Use the 16.2.9.4 shell for
Listing 16.2.9.4.1
Tanner Staging (Japan)
PUBLIC COPY 
Y
sit
C
sit 8
C C
8
Yes/No
OPY
Yes/No
PY
O
C
LIC
BL
BL
BL
BL
BL
UB
PU
P
thorization 
national
zat
national L
03
03
ed to support any marketing auth
rk
a
rformed
y m
rformed
a
y
ny
p
up
su
su
su
su
o s
to
d
This document cannot be use
do
TIAL
s d
TIAL
ed
e
use
Female
us
Female in
s
in t
s
t
h
b
h
wth
t b
wth
uth
xtensions or variations thereof. 
s t
Visit
tio
Visit Date/D
tio
Date/D
ns
tio
i
DDM
ia
DDM
ia
ri
o
s
on
io
ns
en
en
application and any exten
a
en
en
en
xte
ex e
isis column.
ex
column.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 233 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.5
Physical Examination
Subject
Identifier
Visit [1]
Was the physical
Exam performed
Visit Date/
Day #
Category
Result
Details of Abnormality
XXXX
Complete(Visit 1,Visit 8)
Abbreviated(Visit 2 -7)
Yes
No
DDMMMYYYY/
XX
General Appearance
Skin
HEENT
Respiratory
Abdomen
Cardiovascular
Abdomen
Lymph Node
Spine
Extremities
Other: TEXT
Not done
Normal
Abnormal
TEXT
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
[1]Complete physical examination done at Visit 1 and Visit 16/ET/EOS, and at the 3 and 6 month cardiac follow-up visits; an abbreviated physical examination is done at clinic Visit 2 through Visit 16.
Programming note: Use the Listing 16.2.9.5 shell for
Listing 16.2.9.5.1
Physical Examination (Japan)
PUBLIC COPY 
HEEN
Y
HEEN
Resp
PY
Resp
A
P
A
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
no
nce
m
nce
atory
an
atory
omen
t a
omen
Cardiovascu
ort 
Cardiovascu
Abdome
po
Abdome
Lymp
pp
Lymp
S
p
S
and
an
and Visit
ann
Visit 16
n
16
5 shell
t c
shell for
c
for
rk tin
uth
application and any extensions or variations thereof. 
a
nd
Resu
h
Resu
ar
ar
n
h
s
h Node
s o
Node
pine
n
pine
Extremities
on
Extremities
Other:
sio
Other:
/ET/EOS,
an
/ET/EOS, and
n
and
s t er


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 234 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.6
Neurological Examination
Subject
Identifier
Visit [1]
Visit Date/
Day #
Was the
neurological exam
performed
Category
Result
Details of Abnormality
XXXX
Complete(Visit 1,
Visit 8)
Abbreviated(Visit 2 -7)
DDMMMYYYY/
XX
Yes
No
Cranial nerves
Muscle strength and tone
Sensory function
Coordination
Gait
Reflexes
Normal
Abnormal
TEXT
XXXX
XXXX
#: Relative to first dose of study treatment.
[1]Complete neurological examination done at Visit 1 and Visit 16/ET/EOS; an abbreviated neurological examination is done at clinic Visit 2 through Visit 16.
Programming note: Use the Listing 16.2.9.6 shell for
Listing 16.2.9.6.1
Neurological Examination (Japan)
PUBLIC COPY 
anial
Y
anial ne
Y
ne
Muscle
PY
Muscle
Y
Sens
OP
Sens
C
O
C
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
be
ength
an
ength and
any
and to
y
to
y function
t a
function
rdination
ort
rdination
Gait
p
Gait
Reflexes
pp
Reflexes
isit
t
isit 16/ET/EO
t b
16/ET/EO
m
tin
uth
ons thereof. 
Resu
ns
Resu
application and any extensions or variation
a
ny
ne
ne
OS;
OS; an
a
an abbrev
an
abbrev
on
er