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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
Confidential Page 1 of 47
STATISTICAL ANALYSIS PLAN
Study: EP0057Product: Lacosamide
A MULTICENTER, OPEN-LABEL, LONG-TERM STUDY TO INVESTIGATE THE SAFETY OF CONVERSION TO LACOSAMIDE AT DOSES UP TO 600MG/DAY AS
MONOTHERAPY IN JAPANESE ADULTS WITH PARTIAL-ONSET SEIZURES WITH OR WITHOUT SECONDARY GENERALIZATION
SAP/Amendment Number DateFinal SAP <11 Apr 2014>Final Amendment 1 <03 Sep 2015>Final Amendment 2 <21 Apr 2016>
Confidentiality Statement
ConfidentialThis document is the property of UCB and may not – in full or in part – be passed on,
reproduced, published, or otherwise used without the express permission of UCB.
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGEThis document has been reviewed and approved per the Review and Approval of Clinical Documents Standard Operating Procedures. Signatures below indicate that the final version of the Statistical Analysis Plan (SAP) or amended SAP is released for execution.
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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TABLE OF CONTENTSLIST OF ABBREVIATIONS.................................................................................................... 61 INTRODUCTION ............................................................................................................. 82 PROTOCOL SUMMARY................................................................................................. 8
2.1 Study objectives ....................................................................................................... 82.1.1 Primary objective........................................................................................... 82.1.2 Secondary objectives ..................................................................................... 8
2.2 Study variables......................................................................................................... 82.2.1 Safety variables.............................................................................................. 8
2.2.1.1 Primary safety variables....................................................................... 82.2.1.2 Other safety variables........................................................................... 8
2.2.2 Pharmacokinetic/Pharmacodynamic variable................................................ 82.2.3 Efficacy variables .......................................................................................... 9
2.3 Study design and conduct ........................................................................................ 92.4 Determination of sample size................................................................................. 102.5 Schedule of study assessments............................................................................... 102.6 Schematic diagram................................................................................................. 15
3 DATA ANALYSIS CONSIDERATIONS ...................................................................... 173.1 General presentation of summaries and analyses .................................................. 173.2 General study level definitions .............................................................................. 17
3.2.1 Analysis time points..................................................................................... 173.2.1.1 Relative day ....................................................................................... 173.2.1.2 Relative day from the start date of Monotherapy .............................. 173.2.1.3 End date of the Treatment Period ...................................................... 18
3.2.2 Study periods ............................................................................................... 183.2.2.1 Screening Period ................................................................................ 183.2.2.2 Treatment Period................................................................................ 18
3.2.3 Mapping of assessments performed at Early Withdrawal Visit .................. 193.2.4 Mapping of assessments performed at Unscheduled Visit .......................... 193.2.5 Subjects who Completed the Study ............................................................. 19
3.3 Definition of Baseline values................................................................................. 193.4 Protocol deviations................................................................................................. 193.5 Analysis sets........................................................................................................... 20
3.5.1 Safety Set ..................................................................................................... 203.5.2 Full Analysis Set .......................................................................................... 20
3.6 Treatment assignment and treatment groups ......................................................... 203.7 Center pooling strategy.......................................................................................... 203.8 Coding dictionaries ................................................................................................ 203.9 Changes to protocol-defined analyses ................................................................... 20
4 STATISTICAL/ANALYTICAL ISSUES ....................................................................... 214.1 Adjustments for covariates .................................................................................... 21
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4.2 Handling of dropouts or missing data.................................................................... 214.3 Interim analyses and data monitoring .................................................................... 224.4 Multicenter studies................................................................................................. 224.5 Multiple comparisons/multiplicity......................................................................... 224.6 Use of an efficacy subset of subjects ..................................................................... 224.7 Active-control studies intended to show equivalence............................................ 224.8 Examination of subgroups ..................................................................................... 22
5 STUDY POPULATION CHARACTERISTICS............................................................. 225.1 Subject disposition................................................................................................. 225.2 Protocol deviations................................................................................................. 23
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 236.1 Demographics ........................................................................................................ 236.2 Other Baseline characteristics................................................................................ 24
6.2.1 Baseline epilepsy characteristics ................................................................. 246.2.2 Childbearing Potential ................................................................................. 25
6.3 Medical history and concomitant diseases............................................................. 266.4 Prior and concomitant medications........................................................................ 26
7 MEASUREMENTS OF TREATMENT COMPLIANCE............................................... 278 EFFICACY ANALYSES ................................................................................................ 27
8.1 Analysis of efficacy variable(s) ............................................................................. 278.1.1 Proportion of subjects remaining seizure free for 6 consecutive months
during the Monotherapy Period ................................................................... 278.1.2 Proportion of subjects remaining seizure free for 12 consecutive months
during the Monotherapy Period ................................................................... 288.1.3 Time to discontinuation due to AE or lack of efficacy (LOE) in the
Monotherapy Period .................................................................................... 288.1.4 Other efficacy analysis................................................................................. 28
8.1.4.1 Maximum duration of consecutive seizure free days ........................ 288.1.4.2 Time course change in LCM dose and seizure frequency per 28
days .................................................................................................... 288.1.4.3 Subgroup analysis .............................................................................. 29
9 PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 299.1 Pharmacokinetics ................................................................................................... 29
10 SAFETY ANALYSES..................................................................................................... 2910.1 Extent of exposure ................................................................................................. 2910.2 Adverse events ....................................................................................................... 3010.3 Clinical laboratory evaluations .............................................................................. 3110.4 Vital signs, physical findings, and other observations related to safety ................ 31
10.4.1 Vital signs and body weight......................................................................... 3110.4.2 Electrocardiograms ...................................................................................... 3310.4.3 Physical and neurological examinations...................................................... 3410.4.4 Assessment of suicidality............................................................................. 34
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10.4.5 Assessment of pregnancy............................................................................. 3411 OTHER ANALYSES ...................................................................................................... 34
11.1 Drug Accountability............................................................................................... 3412 REFERENCES ................................................................................................................ 3513 APPENDICES ................................................................................................................. 36
13.1 Other significant AEs............................................................................................. 3613.2 Laboratory assessments – Marked Abnormalities (MA) ....................................... 38
13.2.1 Hematology.................................................................................................. 3813.2.2 Chemistry..................................................................................................... 40
14 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) (IF APPLICABLE) ................................................................................................................ 45
14.1 AMENDMENT 1................................................................................................... 4514.2 AMENDMENT 2................................................................................................... 47
LIST OF TABLESTable 2‒1: Schedule of study assessments ............................................................................. 11
Table 10‒1: Vital sign assessments – abnormal .............................................................. 32
Table 10‒2: Electrocardiogram (ECG) – abnormal ......................................................... 33
Table 13‒1: Other significant AEs................................................................................... 36
Table 13‒2: Hematology.......................................................................................................... 38
Table 13‒3: Chemistry..................................................................................................... 40
LIST OF FIGURESFigure 2‒1: Schematic diagram................................................................................................ 15
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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LIST OF ABBREVIATIONSAE Adverse event
AED Antiepileptic drug
ALT Alanine aminotransferase
AST Aspartate aminotransferase
ATC Anatomical Therapeutic Chemical
BP Blood pressure
BMI Body Mass Index
CI Confidence interval
CT Computed tomography
CRF Case Report Form
C-SSRS Columbia-Suicide Severity Rating Scale
ECG Electrocardiogram
EEG Electroencephalogram
ESV End-of-Study Visit
ETV End-of-Taper Visit
EWV Early Withdrawal Visit
FAS Full Analysis Set
GGT Glutamiltransferase
ILAE International League Against Epilepsy
IMP Investigational medicinal product
LCM Locosamide
LOE Lack of efficacy
NDA New drug application
MedDRA Medical Dictionary for Regulatory Activities
MPV Monotherapy Visit
MRI Magnetic resonance imaging
PK Pharmacokinetic
PR Pulse rate
PT Preferred Term
SAE Serious adverse event
SAP Statistical Analysis Plan
SD Standard deviation
SOC System organ class
SPD Specification of protocol deviation
SS Safety Set
TEAE Treatment-emergent adverse event
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TEMA Treatment-emergent marked laboratory abnormalities
ULN Upper limit of normal
WHO-DRL World Health Organization Drug Reference List
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1 INTRODUCTIONThis Statistical Analysis Plan (SAP) describes the statistical principles that are applied for the analyses as well as data presentations that are foreseen for this study. Tables or listings might be added or slightly modified for the purpose of readability or clarification of results that might be seen during the process of analyzing the data. Changes in the statistical methodology will result in a SAP amendment.
This SAP should be read in conjunction with the following documents that provide all necessary background information and rationale for the current study and its design.
! Finalized Study Protocol Amendment, dated 09 October 2013
! Electronic Case Report Form (eCRF), dated 09 December 2013
2 PROTOCOL SUMMARY2.1 Study objectives2.1.1 Primary objectiveThe primary objective of this study is to evaluate the long-term safety and tolerability ofLCM 200mg/day to LCM 600mg/day taken in monotherapy in Japanese subjects who currently have partial-onset seizures with or without secondary generalization and who are treated with a single antiepileptic drug (AED) with marketing approval in Japan.
2.1.2 Secondary objectivesThe secondary objectives are to evaluate the efficacy of LCM, and the plasma concentrations of LCM at steady state.
2.2 Study variables2.2.1 Safety variables2.2.1.1 Primary safety variablesThe primary safety variables are the following:
∀ Adverse events (AEs) reported spontaneously by the subject or observed by the investigator
∀ Subject withdrawals due to AEs
∀ Serious adverse events (SAEs)
2.2.1.2 Other safety variablesThe other safety variables include:
∀ Laboratory tests (hematology, clinical chemistry, and urinalysis parameters)
∀ 12-lead electrocardiograms (ECGs)
∀ Vital sign measurements (ie, blood pressure and pulse rate)
∀ Body weight
2.2.2 Pharmacokinetic/Pharmacodynamic variableThe pharmacokinetic (PK) variable is the following:
∀ Plasma concentrations of LCM versus time postdose.
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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2.2.3 Efficacy variablesEfficacy evaluations will be based on subject diaries where seizure types, dates, and number of seizures are recorded. The exploratory efficacy variables are:
∀ Proportion of subjects remaining seizure free for 6 consecutive months (26 consecutive weeks) during the Monotherapy Period.
∀ Proportion of subjects remaining seizure free for 12 consecutive months (52 consecutive weeks) during the Monotherapy Period.
∀ Time to discontinuation is evaluated as time to withdrawal of treatment due to AE or lack of efficacy (LOE) in the Monotherapy Period.
2.3 Study design and conductEP0057 is a Phase 3, multicenter, open-label, study designed to evaluate the safety, tolerability, and efficacy of long-term administration of LCM as monotherapy at doses from 200mg/day to 600mg/day in Japanese adults with partial-onset seizures with or without secondary generalization who are not controlled by monotherapy with an AED with marketing approval in Japan.
The duration of the study per subject is up to 2.5 years, including a 1-week Screening Period and an approximately 2.5-year Treatment Period.
A Screening Visit (Visit 1) is conducted to evaluate subject suitability for enrollment. This visit can be conducted on more than 1 day but not more than 7 days. Subjects who fulfill all eligibility criteria shall be enrolled.
At the beginning of the 4-week Titration Period, subjects will start with LCM 100mg/day. The dose is increased by 100mg/day each week until the 400mg/day dose is reached at the beginning of Week 4. Subjects who are unable to tolerate LCM during the Titration Period will be withdrawn from the study.
During the AED Withdrawal Period, concomitant AEDs will be carefully tapered anddiscontinued within 4 to 12 weeks. To improve tolerability and reduce drug load, tapering of the concomitant AED may be started during the Titration Period. For safety reasons, tapering of the concomitant AED will be at the discretion of the investigator and will be allowed only if the dose of LCM has been stable at 200mg/day or greater for the previous 3 days.
Subjects who complete the AED Withdrawal Period will enter the Evaluation Period. TheEvaluation Period lasts for 52 week and followed by a long term Follow-Up Period. TheFollow-Up Period will continue until LCM is available on the market as monotherapy in Japan. Both the Evaluation Period and the Follow-Up Period are collectively termed as theMonotherapy Period.
During the AED Withdrawal and Monotherapy Period, the investigator may increase or decrease the dose of LCM to optimize tolerability and seizure control. The LCM dose may be decreased no lower than 200mg/day or increased, no faster than 100mg/day per week, up to 600mg/day.
For subjects receiving LCM at a dose less than 600mg/day at the beginning of the Monotherapy Period who experience a new seizure (first seizure during the Monotherapy Period), the LCM dose will be increased up to 600mg/day by a maximum increment of 100mg/day weekly.
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Subjects who are continuing in the Follow-Up Period until LCM is commercially available asmonotherapy will complete the End-of-Study Visit assessments. Subjects who prematurelywithdraw from the study at any time during the study will complete the Early Withdrawal Visit assessments. All subjects who enter the Monotherapy Period and prematurely terminate the study will enter a Taper Period. During the Taper Period, subjects receiving doses greater than LCM 200mg/day at the Early Withdrawal Visit/End-of-Study Visit should be tapered off gradually at a recommended decrease rate of LCM 200mg/day per week, unless the investigator feels that a more rapid withdrawal of LCM is required due to safety concerns. UCB (or designee) should be contacted if a more rapid withdrawal is required. A slower taper (eg, LCM 100mg/day per week) is permitted, if medically necessary. Subjects receiving doses of LCM 200mg/day or lower at the Early Withdrawal Visit/End-of-Study Visit are not required to taper off LCM. A Final Visit will be required 2 weeks after the last LCM dose is administered. Subjects who continue in the Monotherapy Period until LCM is commercially available as monotherapy in Japan, and decide to continue on commercial LCM are not required to enter the Taper Period; the End-of-Study Visit will be the last visit for these subjects. If LCM is not commercially available in Japan at the time the study closes, access to LCM will be provided according to the laws.
2.4 Determination of sample sizeNo formal sample size calculation has been performed. A minimum of 10 subjects areanticipated to participate in this study within the enrollment period from Jan 2014 to Jan 2015.
2.5 Schedule of study assessmentsThe schedule of study assessments is provided in Table 2-1.
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PV 2M
PV 3M
PV 4M
PV ≥5E
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ite
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it w
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±14
±14
±14
±14
±14
--
--
Info
rmed
co
nsen
tX
Dem
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phic
an
d ep
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y in
form
atio
n
X
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n/
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n cr
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XX
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com
itant
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EDX
XX
XX
XX
XX
XX
XX
X
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com
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n(s)
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XX
XX
XX
XX
XX
XX
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XX
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n X
XX
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XX
XX
XX
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XX
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XX
XX
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ion
XX
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ion
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iX
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XX
XX
XX
XX
C-S
SRS
XX
XX
XX
XX
XX
XX
XX
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rato
ry te
sts
XX
XX
XX
XX
XX
XX
Preg
nanc
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stk
XX
XX
XX
XX
XX
XX
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XX
XX
XX
XX
XX
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PX
XX
XX
XX
XX
Xl
X
IMP
retu
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view
XX
XX
XX
XX
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XX
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pens
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t di
ary
XX
XX
XX
XX
XX
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X
Subj
ect d
iary
re
turn
/revi
ewX
XX
XX
XX
XX
XX
XX
AE
repo
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XX
XX
XX
XX
XX
XX
XX
AE=
adve
rse
even
t; A
ED=a
ntie
pile
ptic
dru
g; B
P=bl
ood
pres
sure
; C-S
SRS=
Col
umbi
a-Su
icid
e Se
verit
y R
atin
g Sc
ale;
CT=
com
pute
d to
mog
raph
y; E
CG
=ele
ctro
card
iogr
am;
EEG
=ele
ctro
ence
phal
ogra
m; E
SV=E
nd-o
f-Stu
dy V
isit;
ETV
=End
-of-T
aper
Vis
it; E
WV
=Ear
ly W
ithdr
awal
Vis
it; IM
P= in
vest
igat
iona
l med
icin
al p
rodu
ct; L
CM
=lac
osam
ide;
M
PV=M
onot
hera
py P
erio
d V
isit;
MR
I=m
agne
tic re
sona
nce
imag
ing;
PR
=pul
se ra
te; w
k=w
eeks
aA
t the
beg
inni
ng o
f AED
With
draw
al P
erio
d, th
e ba
selin
e A
ED w
ill b
e ca
refu
lly ta
pere
d an
d di
scon
tinue
d w
ithin
a p
erio
d of
4 to
12
wee
ks. F
or sa
fety
reas
ons,
tape
ring
of
the
base
line
AED
will
be
at th
e di
scre
tion
of th
e in
vest
igat
or a
nd w
ill b
e al
low
ed o
nly
if th
e do
se o
f LC
M h
as b
een
stab
le a
t200
mg/
day
or g
reat
er fo
r the
pre
viou
s 3 d
ays.
bM
PVs w
ill b
e pe
rfor
med
at 1
3-w
eek
inte
rval
s. c
At t
he ti
me
of st
udy
com
plet
ion,
or i
f sub
ject
s dis
cont
inue
the
stud
y pr
emat
urel
y, a
n ES
V/E
WV
will
be
perf
orm
ed. T
he E
SV is
the
last
vis
it fo
r sub
ject
s who
cho
ose
to
cont
inue
on
to c
omm
erci
al L
CM
trea
tmen
t. Su
bjec
ts re
ceiv
ing
dose
s gre
ater
than
LC
M20
0mg/
day
at th
e ES
V/E
WV
shou
ld b
e ta
pere
d of
f gra
dual
ly a
t a re
com
men
ded
rate
of
LC
M20
0mg/
day
per w
eek,
unl
ess a
mor
e ra
pid
with
draw
alof
LC
M d
ue to
safe
ty c
once
rns i
s req
uire
d. T
he sp
onso
r sho
uld
be c
onta
cted
if th
e m
ore
rapi
d w
ithdr
awal
is
requ
ired.
A sl
ower
tape
r (eg
, LC
M10
0mg/
day
per w
eek)
is p
erm
itted
, if m
edic
ally
nec
essa
ry.
dA
Fin
al V
isit
will
be,
com
plet
ed 2
wee
ks a
fter t
he la
st d
ose
of L
CM
.e
The
inve
stig
ator
may
use
an
Uns
ched
uled
Vis
it to
incr
ease
LC
M d
ose
if a
new
seiz
ure
occu
rs, t
o ad
just
a su
bjec
t’s L
CM
dose
, to
repe
at la
bora
tory
test
s or E
CG
find
ings
, to
follo
w u
p on
AEs
. Add
ition
al a
sses
smen
ts c
an b
e co
mpl
eted
as n
eede
d at
the
inve
stig
ator
’s d
iscr
etio
n.
REDACTEDDTE
XXAC
R
COPYYYPYC
This do
cumen
t
al a
sse
asse
cann
ot
0mg
mg
wee
ks
eeks
ch
edu
ched
u
beore
ror
e r
g/da
g/d
used
disc
onis
coSu
bjec
ubje
cra
pra
p
to ntt
supp
ort
PRPR rt
e A
ED
AED
tigat
or
gato
r
any
er V
ier
VR
=pul
R=p
u
marketi
ng
Xtin
ark
olum
biol
umb
i
ar ar ar
autho
rizati
on
tio
XX
tiotiotiotio
thau
appli
catio
n tio
ca
XX
pliccc
and d
anan
y
/EW
/EW a
exten
sions
en
SVVcc
teeee
or r Pr P
varia
tions
on
Per
Perar
thereo
f.
211A
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2016
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istic
al A
naly
sis P
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sam
ide
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Con
fiden
tial
Page
14
of 4
7
fTh
e co
mpl
ete
phys
ical
exa
min
atio
n w
ill b
e pe
rfor
med
eve
ry 5
2 w
eeks
afte
r MPV
5. T
he b
rief p
hysi
cal e
xam
inat
ion
will
be
perf
orm
ed e
very
52
wee
ks a
fter M
PV3.
gH
eigh
t will
be
reco
rded
at V
isit
1 on
ly.
hTh
e co
mpl
ete
neur
olog
ical
exa
min
atio
n w
ill b
e pe
rfor
med
eve
ry 5
2 w
eeks
afte
r MPV
5. T
he b
rief n
euro
logi
cal e
xam
inat
ion
will
be
perf
orm
ed e
very
52
wee
ks a
fter M
PV3.
iR
equi
red
on V
isit
1 if
no p
revi
ous E
EG a
nd/o
r CT/
MR
I has
bee
n pe
rfor
med
dur
ing
the
last
24
mon
ths p
rior t
o V
isit
1.j
Elec
troca
rdio
gram
(12-
lead
) exa
min
atio
n w
ill b
e pe
rfor
med
Vis
it1,
Vis
it3,
Vis
it4,
and
MPV
1, M
PV3,
MPV
5 an
d ev
ery
26 w
eeks
afte
r MPV
5, a
nd a
t the
ESV
/EW
V. I
f an
EC
G a
bnor
mal
ity is
det
ecte
d at
the
EWV
, an
ECG
will
be
perf
orm
ed in
the
follo
win
g vi
sit o
f the
Tap
er P
erio
d fo
r saf
ety
follo
w u
p. If
an
ECG
abn
orm
ality
is fo
und
atth
e ES
V, i
t will
be
follo
wed
up
by p
ostm
arke
ting
surv
eilla
nce.
k
A se
rum
pre
gnan
cy te
st w
ill b
e pe
rfor
med
at V
isit
1. A
urin
e pr
egna
ncy
test
will
be
perf
orm
ed a
t eac
h vi
sit w
here
the
labo
rato
ryas
sess
men
ts a
re p
erfo
rmed
.l
At E
SV, I
MP
and
subj
ect d
iary
will
not
be
disp
ense
d fo
r sub
ject
s who
com
plet
e th
e M
onot
hera
py P
erio
d an
d ch
oose
to c
ontin
ue o
n to
com
mer
cial
LC
M tr
eatm
ent.
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd
hoo
hoo
any
he la
he la
ose
tos
e
exten
sions
y 26
we
26 w
fety
foet
y fo
b
or
e pe
rpe
varia
tions
on
very
52
ery
52
f
thereo
f.
211A
pA
p
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Apr
2016
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istic
al A
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ide
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Con
fiden
tial
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15
of 4
7
2.6
Sche
mat
ic d
iagr
amFi
gure
2‒1:
Sche
mat
ic d
iagr
am
aA
t the
beg
inni
ng o
f the
AED
With
draw
al P
erio
d, th
e ba
selin
e A
ED w
ill b
e ca
refu
lly ta
pere
d an
d di
scon
tinue
d du
ring
a pe
riod
ofa
max
imum
of 1
2 w
eeks
. For
safe
ty
reas
ons,
tape
ring
of th
e ba
selin
e A
ED w
ill b
e at
the
disc
retio
n of
the
inve
stig
ator
and
will
be
allo
wed
onl
y if
the
dose
of L
CM
has
bee
n st
able
at 2
00m
g/da
y or
gre
ater
for
the
prev
ious
3 d
ays.
bIn
the
LCM
Mon
othe
rapy
Per
iod,
a fle
xibl
e do
se ra
ngin
g be
twee
n 20
0 an
d 60
0mg/
day
will
be
used
dep
endi
ng o
n th
e co
nditi
ons o
f ind
ivid
ual s
ubje
cts.
Dur
ing
this
per
iod,
vi
sits
will
be
perf
orm
ed a
t 13-
wee
k in
terv
als.
At 4
-wee
k in
terv
als
At 1
3-w
eek
inte
rval
s
200
600
400
↑N
ew s
eizu
red
Titr
atio
nPe
riod
(4
wee
ks)
AED
With
draw
alPe
riod
a
(4-1
2 w
eeks
)
Mon
othe
rapy
Per
iodb
0
Visi
t 1(-
1)V
isit 2
(0)
LCM (mg/day)
Visi
t 3(2
)V
isit 4
(4)
Visi
t 5e
(8)
MPV
1M
PV 2
Tap
erPe
riodc
ESV
fFi
nal V
isit
(2w
eeks
afte
r fin
al L
CM d
ose
)
( )=
wee
ks;
AED
=ant
iepi
lept
ic d
rug;
ESV
= En
d-of
-Stu
dy V
isit;
ET
V= E
nd-o
f-Tap
er V
isit;
EW
V= E
arly
With
draw
al V
isit;
LCM
=lac
osam
inde
; M
PV=
Mon
othe
rapy
Per
iod
Visi
t
Visi
t 6e
(12)
Trea
tmen
tPe
riod
ESV
f
/EW
V
↑N
ew s
eizu
red
ETV
ETV
500
300
Follo
w-U
p Pe
riod
Ev
alua
tion
Pe
riod
(5
2 we
eks)
MPV
3M
PV 4
MPV
5
Base
line
AED
g
MPV
6~
REDACTED D
ACACACAC
MM
COPY
C
This do
cumen
t can
not
exibxib
inte
rvnt
erv
be
ble
ble
usedd,
ththe
at th
eat
th
to
hehedyy
supp
ort
pppppppp
y VVi
sit
isit
VVV
any m
arketi
ng
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ar
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rizati
on
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catio
n n
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exten
sions
eexeeexxxxxxexte
or va
riatio
ns
onthe
reof.
211A
pA
p
UC
B21
Apr
2016
Stat
istic
al A
naly
sis P
lan
Laco
sam
ide
EP00
57
Con
fiden
tial
Page
16
of 4
7
cSu
bjec
ts re
ceiv
ing
dose
s gre
ater
than
LC
M20
0mg/
day
at th
e ES
V/E
WV
shou
ldbe
tape
red
off g
radu
ally
at a
reco
mm
ende
d de
crea
se ra
te o
f LC
M20
0mg/
day
per w
eek,
un
less
the
inve
stig
ator
feel
s tha
t saf
ety
conc
erns
requ
ire m
ore
rapi
d w
ithdr
awal
of L
CM
. A sl
ower
tape
r (eg
, LC
M10
0mg/
day
per w
eek)
is p
erm
itted
, if m
edic
ally
ne
cess
ary.
Sub
ject
s rec
eivi
ng L
CM
200m
g/da
y at
the
ESV
/EW
V a
re n
ot re
quire
d to
tape
r off
LC
M.
dW
hen
the
subj
ects
rece
ivin
g LC
M a
t a d
ose
less
than
600
mg/
day
at th
e be
ginn
ing
of th
e M
onot
hera
py P
erio
d/A
ED W
ithdr
awal
Per
iod
have
a n
ew se
izur
e du
ring
the
Mon
othe
rapy
Per
iod/
AED
With
draw
al P
erio
d, th
e LC
M d
ose
will
be
incr
ease
d up
to 6
00m
g/da
y. In
oth
er c
ases
, the
inve
stig
ator
will
be
allo
wed
to in
crea
se o
r dec
reas
e th
e do
se o
f LC
M to
opt
imiz
e to
lera
bilit
y an
d se
izur
e co
ntro
l. Th
e LC
M d
ose
may
be
decr
ease
d to
a m
inim
um d
ose
of 2
00m
g/da
y or
incr
ease
d to
a m
axim
um d
ose
of
600m
g/da
y in
wee
kly
step
s of n
o fa
ster
than
100
mg/
day
per w
eek.
e
Dur
ing
the
AED
With
draw
al P
erio
d, if
the
conc
omita
nt A
ED w
ithdr
awal
is re
ache
d at
the
4th
wee
k af
ter V
isit
4, V
isit
5 an
d V
isit
6 w
ill b
e ca
ncel
ed. I
f the
con
com
itant
A
ED is
with
draw
n w
ithin
8 w
eeks
, Vis
it 6
will
be
canc
eled
.f
The
ESV
is th
e la
st v
isit
for s
ubje
cts w
ho c
ompl
ete
the
Mon
othe
rapy
Per
iod
and
choo
se to
con
tinue
taki
ng c
omm
erci
al L
CM
. Sub
ject
s who
com
plet
e th
e M
onot
hera
py
Perio
d an
d ch
oose
not
to c
ontin
ue ta
king
com
mer
cial
LC
M w
ill c
ompl
ete
the
ESV
and
ent
er a
Tap
er P
erio
d.g
To im
prov
e to
lera
bilit
y an
d re
duce
dru
g lo
ad, t
aper
ing
of th
e ba
selin
e A
ED m
ay b
e st
arte
d du
ring
the
Titra
tion
Perio
d. F
or sa
fety
reas
ons,
tape
ring
of th
e ba
selin
e A
ED
will
be
at th
e di
scre
tion
of th
e in
vest
igat
or, a
nd w
ill b
e al
low
ed o
nly
if th
e do
se o
f LC
M h
as b
een
stab
le a
t 200
mg/
day
or g
reat
er fo
r the
pre
viou
s 3da
ys.
COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion
Titra
tioTi
tratio
able
at 2
ble
at
and
mm
em
me
.
any si
ti
erc
exten
sions
Perier
ator
wat
or w
/day
or
day
o
t 5 a5 a
or
rioiod
varia
tions
on
e of
LC
of L
Cek
) is p
k) is
p
thereo
f.
211A
pA
p
UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
Confidential Page 17 of 47
3 DATA ANALYSIS CONSIDERATIONS3.1 General presentation of summaries and analysesStatistical analysis and generation of tables, figures subject data listings, and statistical output will be performed using SAS Version 9.2 or higher. All tables and listings will use Courier New font size 9.
Descriptive statistics will be displayed to provide an overview of the study results.
For categorical parameters, the number and percentage of subjects in each category will be presented. The denominator for percentages will be based on the number of subjects appropriate for the purpose of analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will be displayed for zero counts, and no decimal will be presented when the percentage is 100%.
For continuous parameters, descriptive statistics will include number of subjects (n), mean, standard deviation (SD), median, minimum, and maximum.
Decimal places for descriptive statistics will always apply the following rules:
∀ “n” will be an integer.
∀ Mean, SD, and median will be use 1 additional decimal place compared to the original data.
∀ Minimum and maximum will have the same number of decimal places as the original value.
A complete set of data listings containing documented data and calculated data (eg, change from Baseline) will be generated.
For plasma concentrations, no summary table of descriptive statistics will be presented due to the small number of subjects. Only subject listings will be generated.
3.2 General study level definitions3.2.1 Analysis time points3.2.1.1 Relative dayRelative day will be calculated as the current date minus the date of first dose of study drug plus 1 for days on or after the day of first dose of study drug and prior to or on the day of last study drug dose (eg, the day of first dose will be Day 1). Relative day will be calculated as date of first dose of study drug minus the current date for days prior to the first dose of study drug (the day prior to first dose will be Day -1). For days after the last dose of study drug, relative day will be calculated as the current date minus the date of last dose of study drug including a “+” to denote post treatment days (eg, the day after the last dose will be Day +1). Relative day will not be calculated for partial dates.
3.2.1.2 Relative day from the start date of MonotherapyRelative day from the start date of Monotherapy will be calculated as the current date minus the date of first dose in Monotherapy Period plus 1 for days on or after the day of first dose in Monotherapy Period and prior to or on the day of last dose in the Monotherapy Period (eg, the day of first dose in Monotherapy Period will be Day 1). Relative day from the start date of Monotherapy will be calculated as date of first dose in Monotherapy Period minus the current
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
Confidential Page 18 of 47
date for days prior to the first dose in Monotherapy Period (the day prior to first dose in Monotherapy Period will be Day -1). For days after the last dose in Monotherapy Period, relative day from the start date of Monotherapy will be calculated as the current date minus the date of last dose in Monotherapy Period including a “+” to denote post Monotherapy treatment days (eg, the day after the last dose in Monotherapy Period will be Day +1). Relative day from the start date of Monotherapy will not be calculated for partial dates.
3.2.1.3 End date of the Treatment PeriodThe end date of the Treatment Period will be either the date of End-of-Study Visit (ESV) for the subjects continuing the study until LCM is available on the market as monotherapy in Japan, or the date of Early Withdrawal Visit (EWV) for the subjects who prematurely withdraw from the study. For the subjects who enter the Monotherapy Period, the end date of the Treatment Period is equal to the end date of Monotherapy Period. If a subject does not have an ESV/EWV, then either the date of the last scheduled or unscheduled visit during the Treatment Period will define the end date of the Treatment period.
3.2.2 Study periodsThe following study periods are defined for the classification by study periods:
3.2.2.1 Screening PeriodScreening Period: the Screening Visit (Visit 1) date to the day prior to the day of first dose of study drug at Visit 2. The Screening Period can last more than 1 day but no more than 7 days.
3.2.2.2 Treatment PeriodThe Treatment Period consists of the Titration Period, the AED Withdrawal Period, and the Monotherapy Period.
3.2.2.2.1 Titration PeriodTitration Period: Visit 2 date (the date of first dose of study drug) to the day prior to Visit 4 date,or to the EWV date if a subject discontinued during the Titration Period, even though withdrawal of Baseline AED could have been started during this period. This will be a 4-week forced titration period and the dose of LCM will start from 100mg/day and increase to 400mg/day at the end of the Titration Period.
3.2.2.2.2 AED Withdrawal PeriodAED Withdrawal Period: Visit 4 date to the day prior to the Monotherapy Period Visit 1 (MPV1)date, or the EWV date if a subject discontinued during the AED Withdrawal Period. This will beup to a maximum of 12-week period including Visit 4, Visit 5, and Visit 6, in which the Baseline AED will be carefully tapered and discontinued. Visit 5 and Visit 6 can be skipped if withdrawal of Baseline AED has been reached within 4 weeks after Visit 4 (both Visit 5 and Visit 6 can be skipped) or within 8 weeks after Visit 4 (Visit 6 can be skipped). The AED withdrawal Period will not be defined for a subject if withdrawal of Baseline AED has been started and completed during the Titration Period.
3.2.2.2.3 Monotherapy PeriodThe Monotherapy Period consists of the 52-week Evaluation Period (MPV1 to MPV4) and the Follow-up Period (subsequent visits after MPV4).
REDACTED n l
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Evaluation Period: MPV1 date to the day prior to MPV5 date, or to the EWV date if a subject discontinued during the Evaluation Period.
Follow-up Period: MPV5 date to ESV date, or to the EWV date if a subject discontinued during the Follow-up Period.
3.2.2.2.4 Taper PeriodThe Taper Period includes an End of Taper Visit (ETV) and a Final Visit. The Taper Period will start from the day after the ESV for a patient who chooses not to continue on commercial LCM treatment or from the day after the EWV if a patient enters the EWV to the Final Visit date. The ETV can be skipped if the subjects receiving LCM 200mg/day or lower at the ESV/EWV as tapering off of LCM is not required for such cases.
For subjects who continue to receive commercial LCM after the ESV, the Taper Period will not be performed.
3.2.3 Mapping of assessments performed at Early Withdrawal VisitEfficacy and safety assessments at the EWV that correspond to a scheduled visit will be summarized at the scheduled visit corresponding to the EWV if the assessment was scheduled to occur at that visit. Such assessments will also be considered for Last Value.
In particular, clinical laboratory parameters, vital signs, and body weight are assessed at all Treatment Period visits, and so all assessments of these variables at the EWVs corresponding to a scheduled visit will be mapped to the corresponding scheduled visit.
3.2.4 Mapping of assessments performed at Unscheduled VisitEfficacy and safety assessments at an Unscheduled Visit will not be mapped to any Scheduled Visit. They will be considered to use for determining the last, minimum, and maximum post-Baseline value during the Treatment Period.
3.2.5 Subjects who Completed the StudyThis study will continue until the date of market approval of LCM for the monotherapy indication in Japan, otherwise until the development of LCM for the partial-onset seizure monotherapy indication is discontinued. The subjects who could continue the Monotherapy Period until the date of market approval of LCM for the monotherapy indication in Japan are defined as subjects who completed the study. “Subject status at study termination” in the Study Termination CRF is completed for all completed subjects.
3.3 Definition of Baseline valuesIn general, Baseline values for safety variables will be based on the last non-missing data collected prior to the first dose of LCM, unless otherwise noted for a specific type of data.
3.4 Protocol deviationsImportant protocol deviations are deviations from the protocol which could potentially have a meaningful impact on the interpretation of the study data. The criteria for identifying important protocol deviations and the classification of important protocol deviations will be defined separately in the Specification of Protocol Deviations (SPD) document. To the extent feasible, rules for identifying important protocol deviations will be defined without review of the data and
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without consideration of the frequency of occurrence of such deviations. Whenever possible, criteria for identifying important protocol deviations will be implemented algorithmically toensure consistency in the classification of important protocol deviations across all subjects. In general, the protocol deviations will be considered according to the following categories:
! Inclusion criteria deviation
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! Prohibited concomitant medication use
! Incorrect treatment or dose
! Treatment non-compliance
! Procedural non-compliance
Important protocol deviations will be reviewed prior to database snapshot/lock.
3.5 Analysis setsSafety and PK variables will be summarized using the Safety Set (SS), and efficacy variables will be summarized using Full Analysis Set (FAS).
3.5.1 Safety SetThe SS will consist of all enrolled subjects who have received at least 1 dose of study medication.
3.5.2 Full Analysis SetThe Full Analysis Set (FAS) will consist of subjects in the SS who have been having at least 1 seizure diary assessment.
3.6 Treatment assignment and treatment groupsAll eligible subjects will receive LCM and dose will be optimized during the Treatment Period according to the tolerability and seizure control. In terms of presentation of summary tables, all subjects will be summarized together across all dose levels. For adverse events, subject listingswill be displayed with dose level at onset.
3.7 Center pooling strategyAll analyses are presented pooled for all centers. No by-center analysis is planned as the total number of subjects is small.
3.8 Coding dictionariesMedical history and adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. Medications will be coded using the World Health Organization Drug Reference List (WHO-DRL) version Sep 2013. Medical Procedures will not be coded.
3.9 Changes to protocol-defined analysesNA
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4 STATISTICAL/ANALYTICAL ISSUES4.1 Adjustments for covariatesNo adjustment for covariates is planned for this study.
4.2 Handling of dropouts or missing dataSubjects who prematurely withdraw from the study will be evaluated based on the data collected at each visit attended.
Subjects who complete the study or who prematurely withdraw from the study not due to AEs nor LOE, will be censored as of the last dose of LCM in the time to withdrawal due to AEs or LOE analysis.
No imputation should be performed for missing study medication start dates. This field on the CRF should not be partial or missing.
For partial or missing date of last dose of study medication, the following imputation rules will be applied for the purpose of calculating overall exposure:
∀ If the day is missing (but month and year available), impute the last dose date as the minimum of the last day of the month or the date of last contact reported on the trial termination CRF; if day and month are both missing (only year available), impute the last dose date as the minimum of the last day of the year or the date of last contact on the trial termination CRF.
∀ If a subject died and has a partial or missing last administration date, the date is to set to the date of death. If there is a partial date of last dose and the month/year are prior to the month and year of the date of death, follow partial date imputation rules.
∀ If the last dose date is completely missing and no information could be obtained from data cleaning exercises, the last dose date should be imputed as the date of last contact according to the study termination CRF. A review of the data for subjects with completely missing last dose dates should be performed to ensure that the imputation does not result in a unrealistic value for duration of exposure.
Imputed date of last dose dates should only be used for calculation of the duration of exposure. The date as recorded on the CRF should be presented in subject data listings (no imputed dates should be included in subject data listings. Partial data information for dates of AEs and concomitant medications will be imputed to determine whether they are treatment emergent or concomitant. Likewise, partial data information for dates of Diagnosis of Epilepsy will be imputed in order to calculate the duration of epilepsy at study entry. Details are described in each section.
AEs with missing intensity and/or missing relationship to LCM will be considered as ones with the highest intensity and/or having relationship in the summary.
No other imputation of missing values is planned for the safety and efficacy analyses unless specified otherwise.
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4.3 Interim analyses and data monitoringNo official interim analysis and data monitoring, which are organized for any decision making on the study conduct, are planned for this study. However database will be snapshot and data analysis will be performed for the purpose of new drug application (NDA) submission after all subjects completed 26 weeks of treatment. Interim data reports for the purpose of regulatory submission are planned for this study before the final analysis.
4.4 Multicenter studiesNo by-center analysis is planned for this study.
4.5 Multiple comparisons/multiplicityNot applicable.
4.6 Use of an efficacy subset of subjectsOther than the planned analyses based on the FAS, no other efficacy subsets are defined for statistical analyses.
4.7 Active-control studies intended to show equivalenceNot applicable.
4.8 Examination of subgroupsIn order to investigate the impact of the following characteristics on efficacy, subgroup analysis will be performed on the efficacy endpoint, proportion of subjects remaining seizure free for 6 consecutive months during the Monotherapy Period. (Section 8.1.4.2).
∀ Gender (male, female)
∀ Use of CBZ as Core AED at study entry (yes, no)
∀ ILAE seizure classification history (1A, 1B, 1C)
∀ Modal dosage during Monotherapy Period (>400mg/day, =<400mg/day)
5 STUDY POPULATION CHARACTERISTICS5.1 Subject dispositionReasons for screen failures will be summarized for all the subjects screened. The number and percentage of subjects screened, and the number and percentage of screen failures by the reason and overall will be presented.
Disposition of subjects screened will be summarized for all the subjects screened. The number of subjects in SS, and FAS, dates of first subject in and out, and number of subjects screened will be presented by investigator site and overall. Number of sites, number of principal investigators, and principal investigator name at each site will also be displayed.
Disposition and discontinuation reasons will be summarized for the SS by Treatment Periods and overall. The number and percentage of subjects who completed/ongoing/discontinued the study and primary reason for discontinuation will be displayed. This would be further divided to subjects who completed/ongoing/discontinued the Treatment Period and the reason for
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discontinuation, who completed/ongoing/discontinued the Titration Period and the reason for discontinuation, who completed/ongoing/discontinued the AED Withdrawal Period and the reason for discontinuation, who completed/ongoing/discontinued the Monotherapy Period and the reason for discontinuation, who completed/ongoing/discontinued the Evaluation Period and the reason for discontinuation, who completed/ongoing/discontinued the Follow-up Period and the reason for discontinuation, who completed/ongoing/discontinued the Taper Period and the reason for discontinuation. The number and percentage of subjects who continuing commercially available LCM, and who entering the Taper Period will be displayed for overall the study.
A list of subject disposition will be created for all the subjects screened. Site and subject number, subject status, date of informed consent, dates of first and last study medication, duration in days of study medication, date and the primary reason for discontinuation, and date of a final contact will be presented.
A list of subject analysis sets will be created for all the subjects screened. Site/subject number, yes/no for each analysis sets, and the reasons of excluded from the analysis sets will be displayed.
A list of study discontinuation will be created with site/subject number, the primary reason for discontinuation, period, LCM dose at one day before the discontinuation date, and relative days for the SS.
A list of subjects who did not meet study eligibility criteria will be created for all the subjects screened.
A list of visit dates will be created for all the subjects screened.
5.2 Protocol deviationsImportant protocol deviations will be evaluated prior to database snapshot/lock.
A list of important protocol deviation will be created for the SS.
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographics and other baseline characteristics will be summarized and listed.
6.1 DemographicsDemographic variables will be summarized for the SS. The demographic variables to be summarized are:
! Age (years): continuous and categorized as (<=18, >18->65, >=65)
! Gender
! Weight (kg)
! Height (cm)
! Body Mass Index (BMI) (kg/m2)
! Ethnicity
! Racial Group (Asian, Other)
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! Racial Subgroup
Demographic variables will be listed for all subjects in the SS.
6.2 Other Baseline characteristics6.2.1 Baseline epilepsy characteristicsBaseline epilepsy characteristics will be summarized for the SS.
A table of Diagnosis of Epilepsy will be created. The followings will be summarized.
! Age at diagnosis (years)
Derived using the epilepsy diagnosis date and the date of birth. Imputation methods should be applied for missing or partial epilepsy diagnosis date. If the month and year are available, the diagnosis date is imputed as the later of the following dates: the first day of the month, or the subject’s birthdate. If only a year is available, the later of the following dates will be imputed: January 1st of the year, or the subject’s birthdate. If both month and year are missing, no imputation will be done.
! Duration of epilepsy at study entry (years)
Derived as (the date of informed consent – the date of epilepsy diagnosis)/365.25.
Imputation for partial dates of epilepsy diagnosis should be imputed as described above for the age at diagnosis.
A table of Baseline AED will be created. The following s will be summarized.
! Number of Lifetime AEDs
! Use of CBZ as Core AED at study entry (yes, no)
A table of Etiology of Epilepsy will be created. A frequency distribution will be displayed for the following.
! Etiology Unknown
! Etiology Known
In the cases of Etiology is unknown, further classification will be summarized:
! Idiopathic
! Cryptogenic
In the cases of Etiology is known, further classification will be summarized (a subject can appear in more than 1 category):
! Genetic origin
! Congenital, total and in categories defined in CRF.
! Perinatal events, total and in categories defined in CRF
! Cranial trauma
! Cerebral neoplasm
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! Brain surgery
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A table of International League Against Epilepsy (ILAE) Seizure Classification History will be created. A frequency distribution will be displayed for the following. A subject can appear in more than 1 category.
! Partial onset seizures, total and in categories defined in CRF
! Generalized seizures, total and in categories defined in CRF
! Unclassified epileptic seizures
A table of Focus Localization will be created. A frequency distribution will be displayed for the followings. A subject can appear in more than 1 category.
! Frontal
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A table of Classification of Epileptic Syndromes will be created. A frequency distribution will be displayed for the followings. A subject can appear in only 1 category.
! Localization related, total and in categories defined in CRF.
! Generalized
! Epilepsies and syndromes undetermined whether focal or generalized, total and in categories defined in CRF
! Special syndromes
A table of Baseline EEG and Baseline CT/MRI will be created. A frequency distribution will be displayed for the categories defined in CRF.
Subject Listings of all Baseline epilepsy characteristics will be created for the SS. Specification of “other” will be displayed in the listings.
6.2.2 Childbearing PotentialA list of females with child bearing potential will be created for females in the SS.
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6.3 Medical history and concomitant diseasesMedical history will be summarized by MedDRA system organ class (SOC) and Preferred Term (PT) for the SS. Number and percentage of subjects with history will be displayed in each system.All tabulations will be sorted by alphabetical SOC, descending frequency of PT within SOC.
Concomitant diseases will be summarized in a similar way. Concomitant diseases are defined as medical history events that are ongoing at Visit 1.
Medical history and concomitant diseases will be listed in the subject listing. A glossary of MedDRA terms and associated investigator’s terms for medical history will also be presented.
Procedure history will also be listed in the subject listing for the SS.
6.4 Prior and concomitant medicationsMedication will be summarized using Anatomical Therapeutic Chemical (ATC) codes from the WHO-DRL dictionary for the SS. All tabulations will be sorted by frequency of the highest level ATC code and by frequency of the lower level ATC code within the highest level ATC code.
Prior medications are medications that started prior to the date of first dose of study drug.Concomitant medications are medications taken at least one day in common with the study drug dosing period. Prior and concomitant medications will be reported on the Prior and Concomitant Medications CRF page. Additionally, lifetime use of Antiepileptic drugs (AEDs) will be reported on the Prior Medications Historical of AED CRF page. All AEDs used as regular and/or rescue will be reviewed prior to database snapshot/lock.
Medication with partial start date and/or partial end date will be imputed according to the rules defined as follows in order to determine if it is a prior medication or a concomitant medication.
Imputation of Partial Start Dates
∀ If only the month and year are specified and the month and year of first dose of study medication is not the same as the month and year of the start date, then use the first day of the month.
∀ If only the month and year are specified and the month and year of first dose is the same as the month and year of the start, then use the date of first dose.
∀ If only the year is specified, and the year of first dose of study medication is not the same as the year of the start date, then use January 1 of the year of the start date.
∀ If only the year is specified, and the year of first dose is the same as the year of the start date, then use the date of first dose.
∀ If the start date is completely unknown, then use the date of first dose.
Imputation of Partial Stop Dates
∀ If only the month and year are specified, then use the last day of the month.
∀ If only the year is specified, then use December 31 of that year.
∀ If the stop date is completely unknown, do not impute the stop date.
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AEDs will be summarized separately from the other medications (non-AEDs) for the SS. Prior and concomitant AEDs used regularly during the Treatment Period will be presented by 4-level ATC (5-digit) terms and preferred medication name.
Prior and concomitant non-AEDs will be summarized separately by 1-level and 2-level ATC (3-digit) terms, which will include any medications used as rescue for seizure.
Lifetime, prior and concomitant medications of AEDs, and prior and concomitant medication of non-AEDs will be listed separately for the SS. The reasons for discontinuation of lifetime AEDs will also be displayed in the lifetime AEDs listing. A glossary of ATC codes and associated investigator’s terms for all medications will also be listed with Core AED flag.
Concomitant medical procedure will also be listed for the SS.
7 MEASUREMENTS OF TREATMENT COMPLIANCETreatment Compliance will not be assessed due to the flexible dosing of study drug. A subject list of study medication administration will be created for the SS. Daily Dose with the start date and the end date, Dose Level at the start date of the Daily Dose, Study Period during the start date and the end date of the Daily Dose will be listed.
8 EFFICACY ANALYSESThe primary objective of this study is to evaluate the long-term safety and tolerability of LCM and the efficacy analysis is planned as an exploratory one, so no primary efficacy variables are defined in this study.
All efficacy analyses will be based on the FAS unless specified otherwise.
8.1 Analysis of efficacy variable(s)Efficacy evaluations will be based on the subject diaries where seizure types, dates, and number of seizures are recorded. The exploratory efficacy variables are:
! Proportion of subjects remaining seizure free for 6 consecutive months during the Monotherapy Period.
! Proportion of subjects remaining seizure free for 12 consecutive months during the Monotherapy Period.
! Time to discontinuation is evaluated as time to withdrawal of treatment due to AE or lack of efficacy (LOE) in the Monotherapy Period.
8.1.1 Proportion of subjects remaining seizure free for 6 consecutive months during the Monotherapy Period
A day with seizure data missing (ie, “Not Done” is noted on the Seizure Count CRF) will be considered as a day with no seizure in the efficacy analyses unless otherwise specified. A subject will be considered as seizure free if no seizure is reported during a period time.
Number and percentage of subjects achieving a seizure free status for 6 consecutive months (182 days) from the day of MPV1 in the Monotherapy Period, and the 2-sided 95% confidence interval (CI) according to the exact method will be calculated and displayed. Evaluation of 6-month seizure free status should be limited to subjects exposed to study medication for at least 6
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months and having Seizure Diary Information at least 6 months. Subjects who discontinue the study before the end date of 6 consecutive months will not be included in the analysis.
8.1.2 Proportion of subjects remaining seizure free for 12 consecutive months during the Monotherapy Period
The same methods described in Section 8.1.1 will be applied for the subjects achieving a seizure free status for 12 consecutive months (364 days) from the day of MPV1 in the Monotherapy Period.
8.1.3 Time to discontinuation due to AE or lack of efficacy (LOE) in the Monotherapy Period
Time to discontinuation due to AE or LOE in the Monotherapy Period from the first study medication dose date during the Monotherapy Period will be estimated with Kaplan-Meier methods.
The event is defined as discontinuation due to AE or LOE in the Monotherapy Period. Otherwise discontinuation due to the other reason in Monotherapy Period will be handled as censored. The end of Study Visit will also be handled as censored for the subjects completed.
Time to the event / censored for each subject will be defined as days from Date of the first administration of LCM during the Monotherapy Period until Date of the event / censored, calculated as (the date of event / censor – the date of the first dose of study medication during the Monotherapy Period +1). Subject who discontinued before Monotherapy Period will not be included in this analysis.
A Kaplan-Meier Plot will be created. Median survival time will be provided in days.
8.1.4 Other efficacy analysis8.1.4.1 Maximum duration of consecutive seizure free daysThe maximum duration of consecutive seizure free days in the Monotherapy Period and the Evaluation Period for each subject will be summarized. The maximum duration of consecutive seizure free days will be listed in a subject listing.
8.1.4.2 Time course change in LCM dose and seizure frequency per 28 daysBy subject figures of time course change of LCM dose (mg/day) and seizure frequency per 28 days will be created for overall of the study. Visit number at X-axis, LCM dose (mg/day) and seizure frequency per 28 days at Y-axis will be displayed. LCM dose (mg/day) at a particularvisit will be plotted by line plot, and seizure frequency per 28 days during a particular visit interval will be shown by bar chart, respectively. Here, seizure frequency per 28 days at a particular visit will be calculated as:
Seizure frequency per 28days at a particular visit: = (Number of seizure during the previous visit to the visit) x (28 / days during the previous visit to the visit).
The relative day, the relative day from the start date of Monotherapy, and the seizure frequency per 28 days will be displayed at each visit. Seizure count will be listed in subject listings. Time to discontinuation due to AE or LOE in Monotherapy will be listed in subject listings with the Dose level of LCM at the event occurred.
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8.1.4.3 Subgroup analysisIn order to investigate the impact of the important characteristics on efficacy, the primary efficacy analysis described in Section 8.1.1 will be repeated by gender (male, female), by usage of CBZ as Core AED at study entry (yes, no), by ILAE seizure classification history (1A, 1B, 1C), and by Modal dosage during Monotherapy Period (>400mg/day, =<400mg/day). Here, for the subgroup analysis by ILAE seizure classification history, only the same type of seizure with historical type will be considered for seizure free status, i.e., for analysis with subgroup of 1A type seizure, number and percentage of subjects achieving a seizure free only for 1A type seizure will be calculated.
9 PHARMACOKINETICS AND PHARMACODYNAMICS Pharmacokinetics analysis will be performed on the SS.
9.1 PharmacokineticsLCM plasma concentrations will be listed in the subject listing for the SS. Period, visit, date, relative days, relative days from the Monotherapy Visit, dose level, actual amount of last dose, date and time of last dose, actual time, and LCM plasma concentrations will be displayed. Here, actual amount of last dose is defined as:
! Daily dose at one day before the plasma sampling date, if sampling is conducted before the morning dose.
! Sum of Last Dose Amount corrected in CRF and a half of daily dose at one day before the plasma sampling date, if sampling is conducted before the evening dose.
10 SAFETY ANALYSESThe primary objective of this study is to evaluate the long-term safety and tolerability of LCM, and primary safety variables of AEs, subject withdrawals due to AEs, and SAEs are defined.
All safety analyses will be performed on the SS.
10.1 Extent of exposureThe number of days of exposure during the Treatment Period is calculated as (the date of final dose within Treatment Period – the date of the first dose of study medication + 1). Days with unknown or zero doses that are prior to the date of last dose are included in the calculation.Study medication duration (days) will be summarized using descriptive statistics by Period and overall. Subject-years of exposure in the study is calculated as the total LCM exposure across all subjects divided by 365.25. It will be calculated by Period and overall.
The maximum daily dose (mg/day) is defined as the highest total daily dose a subject received during the study. The total daily dose will be reported on the Drug Dosing Log CRF page. The modal dose (mg/day) is defined as the daily dose the subject received for the longest duration during the study. For any calculated modal dose falling between 2 consecutive modal dose categories should be presented with the category reflecting the lower dose. If a subject was on two different doses for the same number of days in the study, the modal dose will be assigned as the lower of the two doses. Gaps in dosing (ie., days with zero dosing or no dosing information) will be excluded from the calculation of the modal dose.
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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The maximum dose and the modal dose are presented in 100mg/day categories (eg., 100mg/day, 200mg/day, 300mg/day, etc.) by period and overall. Extent of exposure will be listed. Study medication duration (days), the maximum daily dose (mg/day), and the modal dose (mg/day) will be displayed.
10.2 Adverse eventsAdverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events (TEAEs) are defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of last study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose. If the date of the last dose of study medication is unknown, and AEs occurring or whose intensity worsened after the first dose of study medication will be considered treatment-emergent. Pre-treatment AEs are AEs with start dates prior to the first dose of study medication. It will be recorded for all subjects screened.
Missing dates of onset of AEs are imputed according to the rules as follows in order to determine if it is treatment-emergent or not.
∀ If only the month and year are specified and the month and year of first dose of study medication is not the same as the month and year of onset, then use the first day of the month.
∀ If only the month and year are specified and the month and year of first dose is the same as the month and year of onset, then use the date of first dose.
∀ If only the year is specified, and the year of first dose is not the same as the year of onset, then use January 1 of the year of onset.
∀ If only the year is specified, and the year of first dose is the same as the year of onset, then use the date/time of first dose.
∀ If the AE onset date is completely unknown, then use the date of first dose of the study medication.
TEAEs will be assigned to Titration Period, AED Withdrawal Period, Monotherapy Period, and Taper Period based on the AE onset dates or the intensity worsened dates. If the dates are missing, the same rules as above will be applied for assignment of Treatment Periods. AEs will be tabulated by MeDRA SOC and MedDRA PT. The number and percentage of subjects experiencing each event at least once will be summarized. Number of individual AE occurrences will be also presented in selected tables. All summaries will be sorted alphabetically by SOC and by frequency of events within SOC.
The following summaries will be presented for the AEs:
∀ An overview summary of AEs will be presented. It will include the numbers and percentages of subjects with at least one TEAEs, at least one serious TEAEs, at least one TEAEs leading to discontinuation, at least one drug-related TEAEs, at least one severe TEAEs, and death.
∀ An overview summary of the AEs by Periods will be presented in a similar way as above.
∀ Incidence of TEAEs will be presented by Period, and overall.
∀ Incidence of TEAEs by Maximum Intensity will be presented by Period and overall.
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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∀ Incidence of TEAEs by Maximum Relationship will be presented by Period and overall.
∀ Incidence of Treatment-Emergent Serious AEs will be presented by Period and overall.
∀ Incidence of TEAEs Leading to Study Discontinuation will be presented by Period and overall.
∀ Incidence of other significant TEAEs will be presented by Period and overall.
Individual subject data listings will be presented for all AEs, serious AEs, AEs leading to death, AEs leading to discontinuation, and other significant TEAEs which are defined by the MedDRA term in Appendix 13.1. Dose level of study drug at onset and the Period at onset will be displayed. A glossary of MedDRA terms and associated investigator’s terms will also be presented.
10.3 Clinical laboratory evaluationsFor continuous laboratory variables of hematology, chemistry, descriptive statistics of actual value and change from Baseline will be presented by visit. In addition, descriptive statistics ofthe actual value and change from Baseline will be presented for the last, minimum, and maximum post-Baseline value obtained during the Treatment Period. Repeated or unscheduled laboratory assessments during the study will not be used in by-visit summary, but will be considered when determining the last, minimum, and maximum post-Baseline values during Treatment Period. The number and percentage of subjects with treatment-emergent marked laboratory abnormalities (TEMA) for hematology and chemistry as defined in Appendix 13.2 will be summarized by period (Titration Period, AED Withdrawal Period, Monotherapy Period, and Taper Period) and overall. Treatment-emergent is defined meeting the criteria at any post-Baseline visit during the Treatment Period and not meeting the same criteria during the Screening Period. Addition to the parameters listed in Appendix 13.2, the combination of total bilirubin ≥2 x ULN and ALT ≥3 x ULN, and the combination of total bilirubin ≥2 x ULN and AST ≥3 x ULN will also be presented in the summary. Subject numbers for those meeting the treatment-emergent marked abnormality criteria will also be presented.
Actual value and change from Baseline of all laboratory parameters (hematology, chemistry, and urinalysis) will be listed with their abnormalities in the subject data listing. TEMA hematologyand chemistry values will be flagged in the listings.
10.4 Vital signs, physical findings, and other observations related to safety
10.4.1 Vital signs and body weightDescriptive statistics of the actual value and change from Baseline for vital signs and body weight will be presented by visit. In addition, descriptive statistics of the actual value and change from Baseline will be presented for the last, minimum, and maximum post-Baseline value obtained during the Treatment Period. Repeated or unscheduled assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last, minimum, and maximum post-Baseline value during the Treatment Period.
The number and percentage of subjects with abnormal will be presented by visit.
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Actual value and change from baseline of all vital signs and body weight will be listed with their abnormalities in the subject data listing.
The abnormal criteria are defined as follows:
Table 10‒1: Vital sign assessments – abnormal
Vital Sign Abnormality Criteria
Systolic Blood Pressure (mmHg) ≥180 and increase of ≥20 from baseline≤90 and decrease of ≥20 from baseline
Diastolic Blood Pressure (mmHg) ≥105 and increase of ≥15 from baseline≤50 and decrease of ≥15 from baseline
Pulse Rate (bpm) ≥120 and increase of ≥15 from baseline≤50 and decrease of ≥15 from baseline
Body weight ≥ 10% change from Baseline (an increase or a decrease)
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10.4.2 ElectrocardiogramsFor all quantitative ECG measurements (heart rate, RR interval, PR interval, QRS duration, QT interval, and corrected QT intervals using Bazett and Fridericia corrections), descriptive statistics of the actual values and change from Baseline will be presented by visit. In addition, descriptivestatistics of the actual value and change from Baseline will be presented for the last, minimum, and maximum post-Baseline value obtained during the Treatment Period. Repeated or unscheduled assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last, minimum, and maximum post-Baseline value during the Treatment Period.
The Bazett corrected QT (QTcB) will be calculated as:
QTcB =QT√RR
,where RR = 60/HR
The Fridericia corrected QT (QTcF) will be calculated as:
QTcF =QT√��� , whereRR = 60/HR
The number and percentage of subjects with classified QT intervals as <450ms, 450 to <480ms, 480 to <500ms, ≥500ms in actual values, and <30ms, 30 to <60ms, and ≥60ms in increase from Baseline will be summarized by visit.
The number and percentage of subjects with ≥500ms in actual value, with ≥60ms increase from Baseline, and with ≥500ms in actual value or ≥60ms increase from Baseline on the maximum post-Baseline value of QT intervals obtained during the Treatment Period will be summarized.
The number and percentage of subjects with treatment-emergent values of PR interval, with treatment-emergent values of QRS intervals and with abnormal values of heart rate will besummarized by Treatment Period and overall in Treatment Period.
Actual value and change from Baseline will be listed in the subject listing. Abnormal value will be marked in the listing.
The criteria of abnormalities are defined as follows:
Table 10‒2: Electrocardiogram (ECG) – abnormal
Parameter Abnormality Criteria
QT interval (ms) ≥500, or ≥60 increase from Baseline
QTcB interval (ms) ≥500, or ≥60 increase from Baseline
QTcF interval (ms) ≥500, or ≥60 increase from Baseline
PR interval (ms) Treatment-emergent value >200, >220, >250
QRS interval (ms) Treatment-emergent value >100, >120, >140
Heart rate (bpm) <50, >120
ECG interpretation and ECG findings will be provided by site investigator and the central vendor. Number and percentage of subjects with any ECG finding will be summarized by each finding
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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and any findings. In this summary, number of subjects who will have their 12-lead ECG Baseline and after the first administration of LCM, and not have the finding at Baseline will be used as the denominator. Number and percentage of subjects in each category of ECG interpretation will be summarized by visit. ECG finding by the central vendor and ECG interpretation by site investigator will be listed in the subject listing.
10.4.3 Physical and neurological examinationsPhysical examination findings will be listed in the subject data listings.
Abnormal neurological examination will be listed by subject.
10.4.4 Assessment of suicidalityThe Columbia-Suicide Severity Rating Scale (C-SSRS) assessment results will be listed by subject.
10.4.5 Assessment of pregnancyUrine pregnancy test assessment results will be listed by subject.
11 OTHER ANALYSES 11.1 Drug AccountabilityDrug accountability will be listed for the SS.
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12 REFERENCESNot applicable.
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13 APPENDICES13.1 Other significant AEs
Table 13‒1: Other significant AEs
MedDRA Preferred Term
HEPATOTOXICITY RELATED TERMS
Hepatitis toxic
Hepatotoxicity
CARDIAC AND ECG RELATED TERMS
Atrioventricular black complete
Atrioventricular block second degree
Bradyarrhythmia*
Bradycardia*
Cardiac pacemaker insertion
Atrial fibrillation
Atrial flutter
Sinus bradycardia*
Ventricular tachycardia
Ventricular fibrillation
Heart Rate decreased*
Sick sinus syndrome
SUICIDALITY RELATED TERMS
Completed suicide
Depression suicidal
Suicidal behavior
Suicidal ideation
Suicide attempt
Intentional self-injury
Self injurious behavior
Self-injurious ideation
Intentional overdose
Poisoning deliberate
ADDITIONAL TERMS
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UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
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Table 13‒1: Other significant AEs
MedDRA Preferred Term
Loss of consciousness
Syncope
*All cases with reported reduced heart rate will be reviewed and only cases with marked bradycardia (marked reduction in heart rate) with HR <45 bpm will be listed as ‘Other Significant AEs’.
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13.2
Labo
rato
ry a
sses
smen
ts –
Mar
ked
Abn
orm
aliti
es (M
A)
The
follo
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es fo
r lab
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asse
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ent v
alue
s.
13.2
.1H
emat
olog
y
Tabl
e13
‒2:H
emat
olog
y
Para
met
erA
ge
Ran
geU
NIT
(c
onve
ntio
nal
)
abno
rmal
ity
Cri
teri
a (c
onve
ntio
nal
unit)
Uni
t(s
tand
ard)
Abn
orm
ality
C
rite
ria
(sta
ndar
d un
it)
Com
men
t/rat
iona
le
Hem
atoc
rit<2
y%
≤27
>45
%≤2
7>4
5B
ased
on
clin
ical
rele
vanc
e
2y -
<17y
≤29
>47
≤29
>47
Bas
ed o
n cl
inic
al re
leva
nce
≥17y
≤85%
of L
LN≥1
15%
of U
LN≤8
5% o
f LLN
≥115
% o
f ULN
Bas
ed o
n cl
inic
al re
leva
nce
Hem
oglo
bin
<2y
g/dL
≤9.0
>15.
0g/
L≤9
0>1
50A
ppro
xim
atel
y 1/
3 H
CT
2y -
<17y
≤9.5
>16.
0≤9
5>1
60A
ppro
xim
atel
y 1/
3 H
CT
≥17y
≤85%
of L
LN≥1
15%
ofU
LN≤8
5% o
f LLN
≥115
% o
f ULN
App
roxi
mat
ely
1/3
HC
T
WB
C/L
euko
cyte
sA
ll10
9 /L≤3
.0≥1
6.0
G/L
≤3.0
≥16.
0B
ased
on
clin
ical
rele
vanc
e; A
pplie
d fr
om a
dult
LCM
MA
crit
eria
Lym
phoc
ytes
A
bsol
ute
<2y
109 /L
<1.0
>9.8
G/L
<1.0
>9.8
deriv
ed fr
om a
dult
MA
crit
eria
:~ 4
0% b
elow
LL
N &
25%
abo
ve U
LN
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ns
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Tabl
e13
‒2:H
emat
olog
y
Para
met
erA
ge
Ran
geU
NIT
(c
onve
ntio
nal
)
abno
rmal
ity
Cri
teri
a (c
onve
ntio
nal
unit)
Uni
t(s
tand
ard)
Abn
orm
ality
C
rite
ria
(sta
ndar
d un
it)
Com
men
t/rat
iona
le
2y -
<6y
<0.7
>6.9
<0.7
>6.9
deriv
ed fr
om a
dult
MA
crit
eria
:~ 4
0% b
elow
LL
N &
25%
abo
ve U
LN
≥6y
<0.6
>5.0
<0.6
>5.0
deriv
ed fr
om a
dult
MA
crit
eria
:~ 4
0% b
elow
LL
N &
25%
abo
ve U
LN
Bas
ophi
ls>1
m%
≥5.0
%≥5
.0B
ased
on
clin
ical
rele
vanc
e; a
pplie
d fr
om a
dult
LCM
MA
crit
eria
Bas
ophi
ls
Abs
olut
e>1
m10
9 /L≥0
.4G
/L≥0
.4B
ased
on
clin
ical
rele
vanc
e; a
pplie
d fr
om a
dult
LCM
MA
crit
eria
Eosi
noph
ils>1
m%
≥10
%≥1
0ap
plie
d fr
om a
dult
LCM
MA
crit
eria
Eosi
noph
ilsA
bsol
ute
>1m
109 /L
≥1.0
G/L
≥1.0
appl
ied
from
adu
lt LC
M M
A c
riter
ia
Mon
ocyt
es>1
m%
≥20.
0%
≥20.
0ap
plie
d fr
om a
dult
LCM
MA
crit
eria
Mon
ocyt
es
Abs
olut
e>1
m10
9 /L≥2
.0G
/L≥2
.0ap
plie
d fr
om a
dult
LCM
MA
crit
eria
Neu
troph
ils
Abs
olut
e>1
m10
9 /L<1
.5G
/L<1
.5B
ased
on
clin
ical
rele
vanc
e; A
NC
to b
e de
fined
on
ly fo
r MA
crit
eria
; App
lied
from
LC
M M
A
crite
ria
Plat
elet
s>1
m10
9 /L≤1
00≥6
00G
/L≤1
00≥6
00A
pplie
d fr
om a
dult
LCM
MA
crit
eria
Plat
elet
sR
BC
/ Ery
thro
cyte
s<2
y10
12/L
<3.0
T/L
<3.0
Bas
ed o
n cl
inic
al re
leva
nce
≥2y
<3.5
<3.5
Bas
ed o
n cl
inic
al re
leva
nce
Abb
revi
atio
ns: A
NC
= a
bsol
ute
neut
roph
il co
unt;
m =
mon
th, y
= y
ear.
A m
onth
is d
efin
ed a
s 30
days
; a y
ear i
s def
ined
as 3
65.2
5 da
ys.
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13.2
.2C
hem
istr
y
Tabl
e13
‒3:
Che
mis
try
Para
met
erA
ge R
ange
UN
IT
(con
vent
iona
l)ab
norm
ality
Cri
teri
a (c
onve
ntio
nal)
Uni
t(s
tand
ard)
Abn
orm
ality
C
rite
ria
(sta
ndar
d)
Com
men
t/rat
iona
le
AST
(S
GO
T)A
llU
/L≥3
.0 x
ULN
≥5.0
x U
LN≥1
0.0
x U
LN
U/L
≥3.0
x U
LN≥5
.0 x
ULN
≥10.
0 x
ULN
carr
ied
over
from
LC
M M
A &
PC
ST
ALT
(S
GPT
)A
llU
/L≥3
.0 x
ULN
≥5.0
x U
LN≥1
0.0
x U
LN
U/L
≥3.0
x U
LN≥5
.0 x
ULN
≥10.
0 x
ULN
carr
ied
over
from
LC
M M
A &
PC
ST
Alk
alin
e Ph
osph
atas
e
<4y
U/L
≥690
U/L
≥690
App
lied
from
PC
ST v
alue
bas
ed o
n cl
inic
al
rele
vanc
e
4y -
<10y
≥834
≥834
App
lied
from
PC
ST v
alue
bas
ed o
n cl
inic
al
rele
vanc
e
10y
-<17
y≥1
761
≥176
1>3
X U
LN, a
pplie
d fr
om L
CM
MA
crit
eria
≥17y
≥3.0
x U
LN≥3
.0 x
ULN
>3X
ULN
, app
lied
from
LC
M M
A c
riter
ia
GG
T<6
mU
/L≥5
22U
/L≥5
22>3
X U
LN, a
pplie
d fr
om L
CM
MA
crit
eria
6m -
<1y
≥279
≥279
>3X
ULN
, app
lied
from
LC
M M
A c
riter
ia
1y -
<13y
≥66
≥66
>3X
ULN
, app
lied
from
LC
M M
A c
riter
ia
13y
-<17
y≥1
26≥1
26>3
X U
LN, a
pplie
d fr
om L
CM
MA
crit
eria
≥17y
≥3.0
x U
LN≥3
.0 x
ULN
>3X
ULN
, app
lied
from
LC
M M
A c
riter
ia
Tota
l B
iliru
bin
>1m
mg/
dL≥2
.0um
ol/L
≥34.
208
appl
ied
from
LC
M M
A c
riter
iaREDACTED D
TEAC
R
COPY
C
This do
cumen
t can
not
nnnnnbe
mg
mgeus
ed
u
to su
pport
tpp
susss
any ≥5
2≥5y a
marketi
ng
ing
x U
LNx
ULNrk m
autho
rizati
on
U/L
U/L
tio
au
appli
catio
n
3.0
x U
0 x
U≥5≥5
.00≥1≥
on
a
and
NNU
LNU
LN
any
anex
tensio
ns
Co
Cos
ext
or ova
riatio
ns
onthe
reof.
22
UC
B21
Apr
2016
Stat
istic
al A
naly
sis P
lan
Laco
sam
ide
EP00
57
Con
fiden
tial
Page
41
of 4
7
Tabl
e13
‒3:
Che
mis
try
Para
met
erA
ge R
ange
UN
IT
(con
vent
iona
l)ab
norm
ality
Cri
teri
a (c
onve
ntio
nal)
Uni
t(s
tand
ard)
Abn
orm
ality
C
rite
ria
(sta
ndar
d)
Com
men
t/rat
iona
le
Tota
l Pr
otei
n2m
-<1y
g/dL
<3.0
>11.
9g/
L<3
0>1
190.
75X
bel
ow L
LN, 1
.5X
ULN
1y -
<17y
<4.3
>12.
0<4
3>1
200.
75X
bel
ow L
LN, 1
.5X
ULN
≥18y
<4.3
>13.
0<4
3>1
300.
75X
bel
ow L
LN, 1
.5X
ULN
Alb
umin
<1y
g/dL
<1.6
>7.2
g/L
<16
>72
0.75
X b
elow
LLN
, 1.5
X U
LN
≥1y
-<17
y<2
.4>8
.4<2
4>8
40.
75X
bel
ow L
LN, 1
.5X
ULN
≥17y
<2.6
<26
0.75
X b
elow
LLN
, 1.5
X U
LN
BU
N<1
ym
g/dL
≥24
mm
ol/L
≥8.5
6820
x th
e va
lue
for C
r
1y -
<17y
≥36
≥12.
852
20x
the
valu
e fo
r Cr
≥17y
≥40
≥14.
2820
x th
e va
lue
for C
r
Ure
a<1
ym
g/dL
>42
mm
ol/L
>7.0
14A
pplie
d fr
om P
CST
val
ue
≥1y
>60
>10.
02A
pplie
d fr
om P
CST
val
ue
Cre
atin
ine
1y -
<10y
mg/
dL>1
.2um
ol/L
>106
.8C
linic
al re
leva
nce
10y
-<16
y>1
.8>1
59.1
2C
linic
al re
leva
nce
≥16y
≥2.0
≥176
.8A
pplie
d fr
om L
CM
MA
crit
eria
Cre
atin
ine
Cle
aran
ce*
All
mL/
min
<50
mL/
s<0
.835
Clin
ical
rele
vanc
e
EEETE
66
RE
COPY
g/L
g/LP
Y
This do
cumen
t e
cann
ot nnnnn an
be us
ed
g/dLdL
dto tosu
pport
or
uuup su
any ≥3≥ ≥ny
ma
3636mark
eting
g
4
ket
ma
autho
rizati
on
aua
appli
catio
n
20
<43
<43
>>
on
pp a
and
0
any nnnny an
exten
sions
00ns
ormmmm
varia
tions
on
meva
thereo
f.
22
UC
B21
Apr
2016
Stat
istic
al A
naly
sis P
lan
Laco
sam
ide
EP00
57
Con
fiden
tial
Page
42
of 4
7
Tabl
e13
‒3:
Che
mis
try
Para
met
erA
ge R
ange
UN
IT
(con
vent
iona
l)ab
norm
ality
Cri
teri
a (c
onve
ntio
nal)
Uni
t(s
tand
ard)
Abn
orm
ality
C
rite
ria
(sta
ndar
d)
Com
men
t/rat
iona
le
Bic
arbo
nate
>1m
-<1
7ym
Eq/L
<15
>38
mm
ol/L
<15
>38
Clin
ical
rele
vanc
e
≥17y
<18
>38
<18
>38
Clin
ical
rele
vanc
e
Cal
cium
<1y
mg/
dL<6
.9>1
2.2
mm
ol/L
<1.7
25>3
.05
App
lied
from
PC
ST v
alue
bas
ed o
n cl
inic
al
rele
vanc
e
1y -
<17y
<7.4
>11.
7<1
.85
>2.9
25A
pplie
d fr
om P
CST
val
ue b
ased
on
clin
ical
re
leva
nce
≥17y
≤7.6
≥11.
0≤1
.9≥2
.75
Sold
in e
t al.
+/-1
mg/
dL o
f ref
eren
ce in
terv
al
Chl
orid
e>1
mm
Eq/L
≤90
≥112
mm
ol/L
≤90
≥112
App
lied
from
LC
M M
A c
riter
ia
Phos
phor
ous
<1y
mg/
dL<1
.8>8
.2m
mol
/L<0
.581
4>2
.648
6A
pplie
d fr
om P
CST
val
ue b
ased
on
clin
ical
re
leva
nce
1y -
<17y
<1.8
>7.4
<0.5
814
>2.3
902
App
lied
from
PC
ST v
alue
bas
ed o
n cl
inic
al
rele
vanc
e
≥17y
≤2.0
≥6.0
≤0.6
46≥1
.938
Sold
in e
t al.
+/-1
mg/
dL o
f ref
eren
ce in
terv
al
Pota
ssiu
m<1
ym
Eq/L
≤3.0
≥6.5
mm
ol/L
≤3.0
≥6.5
-.2, +
.4m
Eq/L
, A
pplie
d fr
om 2
006
PCST
cr
iteria
≥1y
≤3.0
≥6.0
≤3.0
≥6.0
App
lied
from
LC
M M
A c
riter
ia
REDACTED TE
00
DA
COPY
This do
cumen
t en
cann
ot
anbem
Em
E
used
Eq/
Eq/se
to su
pport
ususup
su
any >8>8 an
marketi
ng
1.8.8 2
rk
autho
rizati
on
auauauauau
appli
catio
n
<1.7
251.
72>3>
n
pp a
and a
ny
ny anex
tensio
ns
ns
ormmmm
varia
tions
on
meva
thereo
f.
22
UC
B21
Apr
2016
Stat
istic
al A
naly
sis P
lan
Laco
sam
ide
EP00
57
Con
fiden
tial
Page
43
of 4
7
Tabl
e13
‒3:
Che
mis
try
Para
met
erA
ge R
ange
UN
IT
(con
vent
iona
l)ab
norm
ality
Cri
teri
a (c
onve
ntio
nal)
Uni
t(s
tand
ard)
Abn
orm
ality
C
rite
ria
(sta
ndar
d)
Com
men
t/rat
iona
le
Sodi
um>1
mm
Eq/L
<127
>151
mm
ol/L
<127
>151
App
lied
from
LC
M M
A c
riter
ia
Glu
cose
>1m
-<1
7ym
g/dL
<50
≥180
mm
ol/L
<2.7
75≥9
.99
App
lied
from
200
6 PC
ST c
riter
ia, c
linic
al
rele
vanc
e
≥17y
<50
≥200
<2.7
75≥1
1.1
Clin
ical
rele
vanc
e
Tota
l C
hole
ster
ol≥1
ym
g/dL
>250
mm
ol/L
>6.4
75A
pplie
d fr
om L
CM
MA
crit
eria
LDL
(cal
cula
ted)
1y -
<17y
mg/
dL>1
40m
mol
/L>3
.626
+10
mg/
dL U
LN
≥18y
>200
>5.1
8+1
0 m
g/dL
ULN
HD
L≤2
ym
g/dL
<10
mm
ol/L
<0.2
59ap
prox
. 20%
less
than
low
er li
mit
>2y
<20
<0.5
18ap
prox
. 20%
less
than
low
er li
mit
Trig
lyce
rides
<1y
mg/
dL>7
50m
mol
/L>8
.475
1.5X
ULN
≥1y
>300
>3.3
91.
5X U
LN
Uric
Aci
d<1
ym
g/dL
>7.7
umol
/L>4
57.9
96+
1mg/
dL L
N
1y -
<13y
>6.5
>386
.62
+ 1m
g/dL
LN
13y
-<17
y>8
.6>5
11.5
28+
1mg/
dL L
N
≥17y
>9.5
>565
.06
App
lied
from
LC
M M
A c
riter
ia
Thyr
oxin
e (T
4)<1
yug
/dL
≤4.3
≥18.
4nm
ol/L
≤55.
3453
≥236
.826
4-1
, +2
belo
w/a
bove
lim
it of
nor
mal
; clin
ical
re
leva
nce
≥1y
≤3.8
≤48.
9098
carr
y ov
er fr
om a
dult
MA
crit
eria
REDACTED mmDTECTTT
0
DAR
COPY
mol
/Lm
ol/LY
C
This do
cumen
t
y
ntca
nnot
ananananbe
ugugeeus
ed to
supp
ort t
ppsusss
any >3
0>3yy a
marketi
ng
ing
750
750
rkm
autho
rizati
on
mm
ol/L
mol
/tio
auauauauau
appli
catio
n
<2.7
752.
77≥1≥
n
pla
and
9
any ny an
exten
sions
Ap
Ans
ormmmm
varia
tions
on
meva
thereo
f.
22
UC
B21
Apr
2016
Stat
istic
al A
naly
sis P
lan
Laco
sam
ide
EP00
57
Con
fiden
tial
Page
44
of 4
7
Tabl
e13
‒3:
Che
mis
try
Para
met
erA
ge R
ange
UN
IT
(con
vent
iona
l)ab
norm
ality
Cri
teri
a (c
onve
ntio
nal)
Uni
t(s
tand
ard)
Abn
orm
ality
C
rite
ria
(sta
ndar
d)
Com
men
t/rat
iona
le
≥13.
5≥1
73.7
585
Glo
bulin
<1y
g/dL
<1.0
>4.5
g/L
<10
>45
0.75
X b
elow
LLN
, 1.5
X U
LN
≥1y
<1.2
>5.3
<12
>53
0.75
X b
elow
LLN
, 1.5
X U
LN
Abb
revi
atio
ns: A
LT=
alan
ine
amin
otra
nsfe
rase
; AST
= a
spar
tate
am
inot
rans
fera
se; B
UN
= b
lood
ure
a ni
troge
n; d
L =
deci
liter
; GG
T: g
amm
a-gl
utam
yltra
nsfe
rase
; HD
L =
high
den
sity
lipo
prot
ein;
LD
L =
low
den
sity
lipo
prot
ein;
L =
lite
r; m
= m
onth
(a m
onth
is d
efin
ed a
s 30
days
) mg
= m
illig
ram
; mm
ol
= m
illim
oles
; μg
= m
icro
gram
; U =
uni
t; U
LN =
upp
er li
mit
of n
orm
al; y
= y
ears
(a y
ear i
s def
ined
as 3
65.2
5 da
ys).
*Sch
war
tz e
quat
ion
(pat
ient
s <12
): C
r Cl m
l/min
= [H
eigh
t (cm
) * 0
.55]
/ se
rum
cre
atin
ine.
Coc
krof
tequ
atio
n (p
atie
nts >
12):
Mal
e: C
r Cl m
l/min
= [(
140-
age)
x b
ody
wei
ght (
kg)]
/ (7
2 x
seru
m c
reat
inin
e); F
emal
e: C
r Cl
ml/m
in =
[(14
0-ag
e) x
bod
y w
eigh
t (kg
)] /
(72
x se
rum
cre
atin
ine)
] x 0
.85.
REDACTED
ge) x
ge) x
nine
)]ni
ne)]
COPY
L =
lL
=ye
ar i
year
i*
0.55
* 0.
5 b
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on
5] /
s5]
/ s
body
body
] x 0
.8x
0.8
appli
catio
n
>53
>53
ati
od u
rea
od u
rea
er; m
=
r; m
=de
fine
defin
e
and dan
y an
exten
sions
nsxte
ormmmm
varia
tions
on
meva
thereo
f.
22
UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
Confidential Page 45 of 47
14 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP)
Once the Statistical Analysis Plan was approved, all amendments were defined in this section.
14.1 AMENDMENT 1After the review of Dry TFLs at the 1st Dry Run, the following amendments were made. Amendment points other than typo or any other miss wording are described here.
Modifications and changes
Specific changes
∀ Section 2.4 Determination of sample size
Actual status of subject number of entry, and entry period are added.
∀ Section 3.2.1.3 Endo date of the Treatment Period
In order to correct a miss wording, terms of “for the subjects who enter the Monotherapy Period”are added.
∀ Section 3.2.5 Subjects who Completed the Study
In order to clarify how to know the subject status of completion, a sentence is added as “Subject status at study termination” in Study Termination CRF is completed for all completed subjects.
∀ Section 3.2.6 Days of 6 months and 12 months
This definition is only for the efficacy, so delete the section.
∀ Section 3.3 Definition of Baseline values
Delete the terms of “efficacy” as baseline is defined only for safety valuables in this study.
∀ Section 4.2 Handling of dropouts or missing data
Imputation method for partial date or missing date is added according to UCB global convention.
∀ Section 4.3 Interim analyses and data monitoring
Clarify the timing and objective of interim analysis.
∀ Section 4.8 Examination of subgroups
Subgroup analysis is change to be required. Subgroup factors are described.
∀ Section 5.1 Subject disposition
Number of sites and number of principal investigators are added in a disposition of subject screen table.
Disposition and discontinuation reasons table is required for Taper Period.
LCM dose at one day before the discontinuation date is used alternatively in study discontinuation listing.
∀ Section 6.2.1 Baseline epilepsy characteristics
REDACTED monthmonth
so delso del
ne vane va
COPY f comf com
n CRFn CR
This do
cumen
tscreescree
DD
cann
otction tion
mbermber
beanalanalyus
edExamExam
yy
toand and su
pport
al al
analnalysy
d objob
any
ouo
datedatemark
eting
luesues
seline ieline
outs outs
autho
rizati
onp
RF is cRF is c
hss
lete ete thth
appli
catio
n
pletionletio
and ntter ther th
any e
xtens
ions o
r vari
ation
s the
reof.
UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
Confidential Page 46 of 47
A table of baseline AED is added, and Number of Lifetime AEDs and Use of CBZ as Core AED at study entry (yes, no) are displayed in it.
∀ Section 6.4 Prior and concomitant medications
Imputation method for partial end date is added.
Summary table of Life time AED is deleted.
Clarify rescue medications for seizure is included in non-AED summary.
Core AED flag is added in a glossary of ATC codes and associated investigator’s term listing.
∀ Section 7 Measurement of treatment compliance
Variables to be listed in study medication administration are clarified.
∀ Section 8.1.3 Time to discontinuation due to AE or lack of efficacy (LOE) in the Monotherapy Period
Analysis population is clarified as subjects who discontinued before Monotherapy Period will not be included in this analysis.
∀ Section 8.1.4 Other efficacy analysis
Divide three subsections, 8.1.4.1 is for Maximum duration of consecutive seizure free days, 8.1.4.2 is for Time course change in LCM dose and seizure frequency per 28 days, and 8.1.4.3 is added for Subgroup analysis.
∀ Section 8.1.4.2 Time course change in LCM dose and seizure frequency per 28 days
Seizure frequency per 28 days is added as 2nd Y axis.
∀ Section 8.1.4.3 Subgroup analysis
Subgroup analysis is added. The primary efficacy analysis will be repeated by subgroups.
∀ Section 9.1 Pharmacokinetics
Add a definition of actual amount of last dose to be listed.
∀ Section 10.1 Extent of exposure
Analysis variables are clarified as study medication duration and subject-year exposure.
A summary of subject number and percentage in treatment duration categories is deleted.
Maximum dose and modal dose are summarized by period and overall.
∀ Section 10.2 Adverse events
Incidence of TEAEs will be summarized not only overall but also by Period.
Incidence of TEAEs by Maximum Intensity, Incidence of TEAEs by Maximum Relationship, Incidence of TESAEs, Incidence of TEAEs Leading to Study Discontinuation, and Incidence of other significant TEAEs are added by Period and overall.
∀ Section 10.3 Clinical laboratory evaluations
Taper Period is added to TEMA by period summary.
REDACTED n LLCMCM
d as 2d as 2
ss
COPYuratiouratiand seind se
This do
cumen
tncidcid
InIn
cann
ot m dm
ectionctio
ded
be
dosdosus
ed s as a
f subjf subjtoare are
supp
ortamouamo
nt of exnt of e
any cscs mark
eting
rimaryimar
autho
rizati
onizurzur
M doseM dosend Y Y
appli
catio
n
n of con of cre fre f
andMonoMon
any e
xtens
ions
E) in ) in
or stinti va
riatio
ns
ing.ng
thereo
f.
UCB 21 Apr 2016Statistical Analysis Plan Lacosamide EP0057
Confidential Page 47 of 47
∀ Section 10.4.2 Electrocardiograms
Summary of treatment-emergent values should be summarized not by visit, but by Treatment Period, so it is updated.
How to summarize ECG interpretation and ECG finding is collected.
∀ Section 13.1 Other significant AEs
Table is updated based on the preferred term at MedDRA 16.1.
14.2 AMENDMENT 2After the DEM3 conducted on 01 April 2016, the following amendments were made. Amendment points are described here.
Modifications and changes
∀ Section 8.1.1 Proportion of subjects remaining seizure free for 6 consecutive months during the Monotherapy Period
The following underlined words were insert in order avoid to misunderstanding.
Evaluation of 6-month seizure free status should be limited to subjects exposed to study medication for at least 6 months and having Seizure Diary Information at least 6 months.
∀ Section 10.4.2 Electrocardiograms
The following underlined words were insert in order avoid to misunderstanding.
ECG interpretation and ECG findings will be provided by site investigator and the central vendor. Number and percentage of subjects with any ECG finding will be summarized by each finding and any findings. In this summary, number of subjects who will have their 12-lead ECG Baseline and after the first administration of LCM, and not have the finding at Baseline will be used as the denominator. Number and percentage of subjects in each category of ECG interpretation will be summarized by visit. ECG finding by the central vendor and ECG interpretation by site investigator will be listed in the subject listing.
∀ Section 13.2.2, Table 13-3 Chemistry
The abnormal criteria of AST, ALT were added according to the UCB global convention.
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