Post on 24-Mar-2020
NCT02395042
Study ID: 201025‐001
Title: A Multicenter, Randomized, Double‐blind, Placebo‐controlled Study, Evaluating Safety and Efficacy of LiRIS® 400 mg in Females With Interstitial Cystitis With Hunner’s Lesions
Statistical Analysis Plan Date: 27‐Mar‐2018
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TITLE
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STATISTIC
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ity Statemen
nt is the proped, publishedhout the expr
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-blind, Placeemales With
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27MAR2018 CSR 201025-001 1
2
2.
3.
4.
5.
6.
7.
8.
9.
10
11
12
.0
TABLE.0
LIST O.0
INTRO.0
OBJEC.0
PATIE.0 6.1 6.2 6.3 6.4 6.5 6.6
PATIE.0
DEMO.0 8.1 8.2 8.3
Prior o.0 9.1 9.2
EXTEN0.0 10.1 10.2
EFFICA1.0 11.1
11.2
2.0 12.1 12.2 12.3
TABL
E OF CONTEN
OF ABBREVIA
ODUCTION ...
CTIVES ..........
ENT POPULATIntent-to-TreMODIFIEDSafety PopuPer-ProtocolPharmacokinData Collect
ENT DISPOSIT
OGRAPHICS ADemographiDisease ChaPast Medica
r ConcomitantBladder PainMedication o
NT OF EXPOSExtent of ExMeasuremen
ACY ANALYPrimary Effi
Oth11.1.1Secondary E
Adverse EveClinical LabVital Signs .
LE OF CON
NTS ................
ATIONS .........
.......................
.......................
TIONS ............eat Population . Intent-to-Trealation ..............l Population ....netic Evaluableted but not Ana
TION ..............
AND OTHER Bic ....................aracteristics .....al History .........
t Medication ....n Medication ..other than Blad
SURE AND TRxposure (Duratnt of Treatmen
YSES ...............icacy Parameteher Analysis ofEfficacy Param
ents .................boratory Param.......................
NTENTS
.......................
.......................
.......................
.......................
.......................
.......................at Population ................................................e Population ..alyzed ............
.......................
BASELINE CH.....................................................................
.......................
.......................dder Pain Med
REATMENT Cion of Effect) .t Compliance a
.......................er(s) ................f Primary Effic
meter(s) ............
.......................meters ..............
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
HARACTERI.....................................................................
.......................
.......................dication ...........
COMPLIANC.......................and Tolerabilit
.......................
.......................cacy Variable .........................
.......................
.......................
.......................
TI 1
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
STICS ....................................................................................
........................
........................
........................
CE ............................................ty ....................
........................
........................
........................
............................................................................................................
......................................................................................
TLE PAGE
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
1.0
........ 2
........ 4
........ 6
...... 10
...... 11
...... 11
...... 11
...... 11
...... 11
...... 11
...... 11
...... 12
...... 13
...... 13
...... 13
...... 13
...... 14
...... 14
...... 14
...... 15
...... 15
...... 15
...... 17
...... 17
...... 18
...... 19
...... 20
...... 20
...... 20
...... 21
...... 21
...... 21
...... 23
...... 23
...... 25
...... 26
27MAR2018 CSR 201025-001 2
14
15
16
17
18
19
12.4 12.5
INTER4.0
DETER5.0
STATI6.0
DATA7.0 17.1 17.2
17.3 17.4 17.5 17.6 17.7 17.8
17.9
CHAN8.0
REFER9.0
ElectrocardiOther Safety
Bla12.5.1 Phy12.5.2 Cys12.5.3 Inv12.5.4 Pre12.5.5 Uri12.5.6 Uri12.5.7 Sui12.5.8 Pot12.5.9
RIM ANALYS
RMINATION
ISTICAL SOFT
A HANDLING Visit Time WDerived Var
Pain17.2.1 Voi17.2.2
Repeated or Missing DatMissing SevMissing CauMissing DatMissing Dat
Inc17.8.1 Inc17.8.2
Character V
NGES TO ANA
RENCES ........
ogram .............y Parameters ...adder Post-Voidysical Examinastoscopic Exam
vestigational Pregnancy Test ...ine Cytology ...ine Culture ......icidality Assesstential Hy’s La
IS ...................
OF SAMPLE
TWARE .........
CONVENTIOWindows .........riables .............n Data Derivatid Data DerivaUnscheduled A
te of the Last Dverity Assessmeusal Relationshte Information te Information omplete Start Domplete Stop Dalues of Clinic
ALYSES SPEC
.......................
.......................
.......................d Residual .....ation ...............m ....................roduct ..................................................................................sment .............
aw ...................
.......................
SIZE .............
.......................
ONS ..............................................................tions ...............ations ..............Assessments o
Dose of Study Tent for Advers
hip to Study Trfor Adverse Evfor Prior or CoDate ...............Date ...............cal Laboratory
CIFIED IN PRO
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................of Safety ParamTreatment .......se Events .........reatment for Advents ..............oncomitant Me..............................................Parameters .....
OTOCOL .......
.......................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................meters ..............................................................dverse Events .........................edications ................................................................................
........................
........................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
.......................
...... 26
...... 26
...... 26
...... 27
...... 27
...... 27
...... 27
...... 27
...... 27
...... 27
...... 27
...... 30
...... 31
...... 32
...... 33
...... 33
...... 36
...... 37
...... 38
...... 39
...... 40
...... 40
...... 40
...... 40
...... 41
...... 41
...... 42
...... 43
...... 45
...... 46
27MAR2018 CSR 201025-001 3
3
A
A
L
C
C
C
eC
E
G
H
IC
IC
IC
IC
IL
IT
IP
L
L
M
M
m
N
PD
.0
AE
ANCOVA
OCF
I
RF
V
CRF
Q-5D
GM
HRQoL
C
C/BPS
CPI
CSI
L-1β
TT
P
iRIS
S
MedDRA
MCP-1
mITT
NRS
D
LIST O
adv
ana
Las
Con
cas
Coe
elec
Eur
Geo
Hea
info
inte
Inte
Inte
Inte
inte
inv
lido
leas
Me
Mo
Mo
Num
pha
OF ABBRE
verse event
alysis of covari
st observation c
nfidence interv
e report form
efficient of var
ctronic case rep
roQol EQ-5D-5
ometric mean
alth related qua
ormed consent
erstitial cystitis
erstitial Cystiti
erstitial Cystiti
erleukin-1 beta
ent to treat
estigational Pr
ocaine-releasin
st squares
edical Dictionar
onocyte chemoa
odified intent to
meric Rating S
armacodynamic
EVIATIONS
iance
carried forward
val
riation
port form
5L
ality of life
s/bladder pain s
s Problem Inde
s Symptom Ind
a
roduct
ng intravesical
ry for Regulato
attractant prote
o treat
Scale
cs
S
d
syndrome
ex
dex
system
ory Activities
ein-1
27MAR2018 CSR 201025-001 4
PID patient identification
PK pharmacokinetics
PP Per Protocol
PVR post-void residual
QoL Quality of life
RBC red blood cell
SAE serious adverse event
SAP statistical analysis plan
SD Standard deviation
TEAE treatment-emergent adverse event
WBC white blood cell
27MAR2018 CSR 201025-001 5
4Tthfiamd
Scoptoo
G
G
G
Ppsc
Tprinpinpr0inin
.0This statisticahe statistical inal protocolmendment (Aata listings a
tudy 201025ontrolled, stuatients with o 2 treatmentf 3 treatmen
Group 1: 2 c
Group 2: 2 c
Group 3: LiR
atients who eriod followcreening bas
The primary arimary timepnvestigationaatients compncluded in thrimary and f01 is presentnsertion and n the Treatm
INTRO
al analysis planalyses of
l of Study 20Amendmentare contained
5-001 is a phudy to evaluinterstitial cts. To receiv
nt groups rec
onsecutive L
onsecutive L
RIS Placebo
qualify for Twed by 4 weeseline pain sc
analysis willpoint that is al product (Iplete or exit he analysis. Tfinal analysited in Table ends with th
ment 1 period
ODUCTION
lan (SAP) prthe efficacy
01025-001 (vt 2 dated [28d in a separa
hase 2 multiuate the safetcystitis (IC) wve Treatmeneiving over
LiRIS 400 m
LiRIS Placeb
followed by
Treatment 2,eks of observcore (≤ 5 or
l be conductWeek 4 foll
IP) removal. the study. FoThe analysesis timepoints4–1. The d
he last assessd.
N
rovides a moy and safety dversion date
8 April 2016]ate document
icenter, randty and efficawith Hunnernt 1, patientsa 28-day tre
mg (N = 38)
bo (N = 19)
y LiRIS 400
, will receivevation until e> 5).
ted at the timlowing remo The final aor each anals outputs to bs. The sched
double-blind sment prior t
ore technicaldata as outlind 20 January]). Specificat.
domized, douacy of the LiRr’s lesions (Hs will be randatment perio
mg (N = 19
e LiRIS 400exit. Patient
me when the oval of the Tranalysis will lysis timepoibe included dule of evalutreatment peto Treatmen
l and detailened and/or sy 2015) and ations of tabl
uble-blind, pRIS 400 mgHL). This stdomized in aod either:
)
0 mg over a 1ts will be str
last patient creatment 1 sbe conducteint all data awill be the s
uations for Seriod starts w
nt 2 IP inserti
ed elaboratiospecified in tthe most rec
les, figures,
placebo-g in female tudy includea 2:1:1 ratio
14-day treatmratified based
completes thsecond ed when all available willsame for theStudy 20102with the firstion or Exit v
on of the cent and
s up to 1
ment d on
he
l be e 5-t IP visit
27MAR2018 CSR 201025-001 6
Table 4–1. Schedule of Evaluation for Study 201025-001
27MAR2018 CSR 201025-001 7
Table 4–1. Schedule of Evaluation for Study 201025-001
27MAR2018 CSR 201025-001 8
Table 4–1. Schedule of Evaluation for Study 201025-001
27MAR2018 CSR 201025-001 9
5Tco4Hrehtr
Tpgr G
G
G
P14
T(Nthin2Twpwp
D
.0The study objontinuous re00 mg comp
HL in femaleelease of lidoave an accepreatment and
The study wileriod (Treatmroups receiv
Group 1: 2 c
Group 2: 2 c
Group 3: LiR
atients, who4-day treatm
The central raNRS) (≤ 5 orhe study andncluding a m0 weeks of f
Treatment 2 (weeks (if qua
ost removal weeks (if qua
ost removal
Details of the
OBJE
jective is to elease of lidopared with pl patients. Thocaine insertptable safetyd correspond
ll consist of ment 1) pati
ving over a 2
onsecutive L
onsecutive L
RIS Placebo
o qualify for ment period f
andomizationr > 5) collec
d receive onlymaximum of follow-up po(open label Lalification an
of Treatmenalification an
of Treatmen
e study desig
CTIVES
evaluate theocaine insertlacebo for thhe clinical hted into the b
y profile and ding symptom
up to two treents will be
28-day treatm
LiRIS 400 m
LiRIS Placeb
followed by
Treatment 2followed by
n will be strcted during thy Treatment4 weeks of s
ost IP removLiRIS 400 mnd Treatmentnt 1 IP) and tnd Treatmentnt 1 IP).
gn and object
e safety and eted into the bhe treatment hypotheses isbladder utilizwill be mor
ms of IC wit
eatment perirandomized
ment period e
mg (N = 38)
bo (N = 19)
y LiRIS 400
2, will receiv4 weeks of o
atified by bahe Screeningt 1, the maximscreening, 4
val. For patiemg), the minit 2 IP insertithe maximumt 2 IP inserti
tives are giv
efficacy of abladder utilizand corresp
s that a 28-dzing two con
re efficaciouth HL in fem
iods. At thed in a 2:1:1 raeither:
mg (N = 19
ve open labelobservation
aseline pain g period. Fomum duratioweeks of ra
ents who quimum duratiion occurs onm duration oion occurs on
ven in the stu
a 28-day perizing 2 conse
ponding symday period ofnsecutive Li
us than placebmale patients
e start of the atio to 1 of 3
)
l LiRIS 400 until exit.
Numeric Raor patients won will be 28
andomized trualify and rec
on of particin Week 4 Foof study partn Week 20 F
udy protocol
iod of ecutive LiRI
mptoms of ICf continuous iRIS 400 mgbo for the .
first treatme3 treatment
mg over a
ating Scale who participa8 weeks, reatment, andceive ipation is 16ollow-up Visticipation is Follow-up V
.
S C with
g will
ent
ate in
d
6 sit 36
Visit
27MAR2018 CSR 201025-001 10
6
6N
6Traef
6Ton
6TTinTd
6Thin14
6T
.0
.1Not applicabl
.2The Modifiedandomized afficacy data
.3The safety po
ne IP. The s
.4The Per-ProtoTreatment 1 fnsertion) and
Treatment 1 wetermined pr
.5The pharmaco
ave at least onsertion and 4 visit.
.6The Investiga
PATIE
INTENle.
MODId Intent-to-Tand received will be analy
SAFEopulation wilsafety data w
PER-Pocol (PP) pofor the 28 dad complete thwithout any rior to datab
PHAR
okinetic popone plasma ofor whom th
DATAator’s signatu
ENT POPU
NT-TO-TR
IFIED INTETreat (mITT)
at least oneyzed as rand
TY POPULll include all
will be analy
PROTOCOopulation wilays of the trehe 4 Week Fsignificant p
base lock.
RMACOKIN
pulation will or urine pharhe IP is succ
A COLLECure will not b
ULATIONS
EAT POPU
ENT-TO-TR) Population e IP insertiondomized usin
LATION l patients enr
yzed as treate
OL POPULAll include alleatment perioFollow-up Vprotocol dev
NETIC EVA
include all prmacokinetic
cessfully rem
TED BUT Nbe analyzed
ULATION
REAT POPwill include
n in the Treang the mITT
rolled in thised using the
ATION l patients whod (complete
Visit post remviations. Pro
ALUABLE
patients enroc concentrat
moved at the
NOT ANAL.
PULATIONe all patientsatment 1 perT population.
s study and rsafety popu
ho retain the e the two cy
moval of the otocol deviat
POPULAT
olled in this tion measurescheduled T
LYZED
N that are iod. The .
received at llation.
2 IP insertedycles of IP 2nd IP of
tions will be
TION study and w
ement post-ITreatment 1 D
east
d in
who IP Day
27MAR2018 CSR 201025-001 11
7Tbb
SrepthgrthsuPpre
.0The number a
e summarizee summarize
creen-failureeasons for faercentage ofhe same periroups for thehe study as rummarized (opulation. Fatients that reasons for pr
PATIE
and percentaed by treatmed overall by
e patients (i.ailure to randf patients whiod will be pe mITT and recorded on (number and
Furthermore,receive Trearemature stu
ENT DISPO
age of patienment group an
y study cente
e., patients sdomize will bho complete resented for PP Populatithe terminat
d percentage) this summa
atment 2. Assudy discontin
OSITION
nts in 2 of thend study cener.
screened butbe presentedthe study aneach treatmon. The reastion pages o) by treatme
ary table willsociated patinuation will b
e study popunter; the num
t not randomd in a patientnd who prem
ment group ansons for premf the electro
ent group forl be generateient listing cbe generated
ulations (mITmber of patien
mized) and tht listing. The
maturely discnd pooled acmature disconic case rep
r the mITT aed for cohortcontaining ind.
TT and PP) wnts screened
he associatede number ancontinue duricross treatmeontinuation fort form wil
and PP t of mITT
nformation o
will d will
d nd ing ent from ll be
on
27MAR2018 CSR 201025-001 12
8
8DliwmCman
8Tdth
•
•
•
•
•
•
•
•
8ADoanst
.0
.1Demographicifestyle),base
weight [kg]/(hmITT and PPContinuous vminimum, annd percentag
.2The following
emographic he cohort of
informatio
daily aver
daily aver
Pain Cata
daily aver
daily ave
daily aver
result of p
.3AbnormalitieDictionary fo
f patients wind preferredtatistical com
DEMOCHAR
DEMOc parameterseline charactheight [m])2
P populationsvariables willnd maximumge of patient
DISEAg baseline diinformationmITT patien
on on stratif
rage 24-hour
rage worst p
astrophizing
rage number
erage numbe
rage pre- and
pelvic exami
PAST s in patients
or Regulatoryith abnormal
d term will bemparisons w
OGRAPHICRACTERIS
OGRAPHIC (age; age grteristics (wei2), will be sums and for thel be summar
m values. Catts.
ASE CHARisease inform
n, by treatments that recei
fication facto
r pain Nume
ain NRS,
Scale (PCS)
r of micturiti
r of urgency
d post-void b
ination at ba
MEDICAL’ medical any Activities,lities in mede summarizeill be perform
CS AND OTSTICS
C roup; race; eight; height;mmarized d
e cohort of mrized by numegorical vari
RACTERISTmation will bent group forived Treatm
ors baseline
eric Rating S
) total score,
ion episodes
y episodes,
bladder pain
aseline.
L HISTORYnd surgical hversion 18.1
dical and surged by treatmmed.
THER BAS
ethnicity; sex; and body m
descriptively mITT patientmber of patieriables will b
TICS be summarizr the mITT aent 2:
average pai
Scale (NRS),
s,
n NRS, and
Y histories will1 or newer. Tgical historie
ment group fo
ELINE
x, smoking smass index, c
by treatments that receivents and meabe summariz
zed as descriand PP popu
in score ≤ 5
,
l be coded usThe number es in each sy
or the mITT
status and dicalculated asnt group for tved Treatmenan, SD, medized by numb
ibed for the lations and f
vs. > 5 ),
sing the Medand percent
ystem organ Population.
etary s the nt 2. ian, er
for
dical tage class No
27MAR2018 CSR 201025-001 13
9Pinou
9Ddbthpa ththin
P
Tb
9
Mmfr(dC
Tmm
.0Prior medicansertion. Conf first IP insesed to classi
.1Daily bladder
iary for the sladder pain mhese prior anercentage ofspecific me
herapeutic clherapeutic clngredient wi
rior and con
The number oe summarize
.2
Medication omedication eCrequency anddrug) name (
Class and Pre
The clinical tmedication eCmedication ta
PRIOR
tion is definncomitant mertion. The Wify prior and
BLAD
r pain and rescreening pemedication w
nd concomitaf patients in dication mullass, that patlass. Formulll be pooled
ncomitant res
of days a gived by treatm
MEDIMEDI
ther than blaCRF. For bod percentage(WHODDE)eferred Term
eam will alsCRF prior toable will be s
R OR CON
ed as any mmedication is WHO drug dconcomitan
DDER PAIN
escue bladdeeriod and trewill be codedant medicatieach treatmeltiple times otient would bations (incluunder the co
scue bladder
ven patient toment group an
ICATION OICATION adder pain moth prior and e of medicati) with the sa
m of the MedD
o identify pao data base losimilarly gen
NCOMITAN
edication takdefined as a
dictionary, vnt medication
N MEDICAT
r pain medicatment period by drug naons will be sent group foror took multbe counted ouding salts, eoded drug na
r pain medic
ook concomnd overall fo
OTHER TH
medication wconcomitan
ions will be ame active inDRA diction
ain medicatiock. For thesnerated.
NT MEDICA
ken before thany medicativersion 2015ns by therap
TION
cation is recood. Both prioame and thersummarizedr the mITT Ptiple medicatonly once foresters, etc.) came of the b
ation will be
mitant rescue or the mITT
HAN BLADD
will be collecnt medicationsummarized
ngredients bynary.
ion recordedse medicatio
ATION
he date of thion taken on quarter 4 oreutic class a
orded in the or and concorapeutic clas
d by the numPopulation. Itions within r the coded dcontaining thbase compou
e similarly su
bladder painpopulation.
DER PAIN
cted in the con collected id for the basey the Primar
d in the concoons a prior an
he first IP n or after the r newer, willand drug nam
bladder painomitant dailyss. The use o
mber and If a patient ta specific
drug name ohe same activund.
ummarized.
n medication
oncomitant n the eCRF, e preferred
ry System Or
omitant nd concomit
date l be
me.
n y of
took
or ve
n will
the
rgan
tant
27MAR2018 CSR 201025-001 14
1Ininrehtrwco
1TgrTfo
fo
If
1
Inisrefo
0.0n this study pn Treatment e-treatment. ad been remreatment per
was completeompleted the
0.1Treatment du
roups as welTreatment 1 pollowing for
Cumulative
Cumula
Treatment 1
exit date
or patients th
Date of
Treatment 2
exit date
f the date of
0.2
n this study, s assessed byemoval eCRor each treatm
EXTE
patients rece2. TreatmenA request fo
moved. Henceriod (Treatmed as per the e 14 days cy
EXTEuration for eall as the cumperiod, the trrmula will be
e treatment d
ative duration
1 duration:
e – Date of T
hat exit with
f Treatment 2
2 duration:
e – Date of T
exit date is m
MEASTOLE
compliance y the investig
RFs. The infoment period
ENT OF EX
eive two insent 2 is providor re-treatmee, what are rent 1 and 2)instruction p
ycle for each
ENT OF EXach Treatmen
mulative studreatment dure used to der
duration:
n = exit date
Treatment 1
out receiving
2 IP insertion
Treatment 2
missing, the
SUREMENERABILITY
to the insertgator. This in
ormation in td. Furthermor
XPOSURE A
ertions of IPded if the patent can only relevant in th, whether orprovided in inserted IP.
XPOSURE (Dnt period (1
dy duration oration could rive treatmen
e – Date of T
first IP inse
g Treatment
n - Date of T
IP insertion
date of the l
T OF TREAY tion and remnformation ihese eCRFsre, associate
AND TREA
in Treatmentient makes be made 4-
his study wor not the insethe protocol
DURATIONor 2) will be
over the entirbe thought o
nt duration:
Treatment 1 f
rtion + 1,
t 2 or,
Treatment 1
n + 1,
last visit wil
ATMENT C
moval procedis collected i will be sumed listing wi
ATMENT CO
nt 1 and one a request an
-weeks after ould be the duertion and rel and whethe
N OF EFFEe displayed bre study periof as duratio
first IP inser
first IP inse
ll be used.
COMPLIAN
dures outlinein the IP ins
mmarized by ill be produc
OMPLIAN
insertion ofnd qualifies f
the second Iuration of eaemoval of ther or not a pa
ECT) by treatmentiod. For
on of effect.
rtion + 1
ertion
NCE AND
ed in the protertion and treatment gr
ced.
CE f IP for IP ach he IP atient
t
The
tocol
roup
27MAR2018 CSR 201025-001 15
For patients that spontaneously abort the IP or ask the IP to be removed prior to the Day 14 post-IP insertion, a summary table of such events will be presented by treatment group and overall.
27MAR2018 CSR 201025-001 16
1TtaefIPoin
1T(S
Trebpinan
TinthcopNdavcodasto
FthththU
FFthla
1.0The efficacy ables being rfficacy is deP insertion. Af significancntervals, unle
1.1The primary eSee Section
The primary eemoval of thladder pain Neriod and thnsertion in thnalysis.
The baseline nformation fhe Week 4 Follected fromatients that r
NRS will be day assessmevailable is foonsidered merived if thessessment wo Day 42 for
or the primahe Week 4 Fhat just receihe IP remova
Up assessmen
For the primaollow-Up N
he average datest of the tw
EFFIC
analyses wilrepeated usinfined as the All statisticace for main eess stated oth
PRIMefficacy mea17.2.1 for de
efficacy varihe last IP inNRS score. Pen a Week 4he study and
7-day mean from Day -7 Follow-Up mm Day 50 to receive just oderived if th
ent window or less than 5
missing for thre are at leas
window (Dayr patients tha
ary analysis, Follow-up is ived one IP bal date. Hencnt are from l
ary analysis,NRS assessmdaily bladderwo values th
CACY ANA
ll be primaring the PP polast non-mis
al tests will beffects. All cherwise.
MARY EFFIasure is the 7efinition of a
iable is the cn Treatment Patients are
4 Follow-Upd has Week 4
daily averagto Day -1. In
mean 7-day avDay 56 from
one insertionere are at lea(i.e., for bas5 consecutiv
hat patient. Sst any 5 cons
y 50 to Day 5at received j
for patients counted frombefore exitince, for Treatlast IP remov
, for patientsent and there
r pain NRS, that is availab
ALYSES
ly based on opulation. Unssing efficacbe 1-sided hyconfidence in
CACY PAR7-day mean average daily
change from 1 period, usscheduled to
p visit. Howe4 Follow-Up
ge NRS scorn contrast, foverage daily
m date of 1nd
n during Treast any 5 conseline it wouve days, as deimilarly, thesecutive vali56 for patienust one IP in
that get twom the 2nd IP ng the study,tment 1 perioval, whether
s that have IPe is a valid Wthe Week 4 ble (i.e., Wee
the mITT Ponless stated ocy assessmenypothesis tesntervals will
RAMETERof the averay bladder pa
baseline to sing the 7-dao have two Iever, if a patip assessment
re will be defor patients thy pain score wd IP insertioneatment 1 pernsecutive va
uld be day -7escribed aboe Week 4 Foid assessmen
nts that receivn Treatment
o IP inserted removal tim
, the Week 4od, Week 1 Fr or not a pat
P inserted, ifWeek 2 or 3 Follow-Up
ek 2 or 3 Fol
opulation wiotherwise, bnt prior to firsts performel be 2-sided 9
R(S) ge daily blad
ain score).
Week 4 Follay mean of thIP insertion iients receivet, it will be c
erived using hat receive twill be derivn or Day 36 riod. The me
alid assessme7 to day -1). Iove, then theollow-Up NRnts within thved two inse1).
during Treame. In contra4 Follow-Up Follow-Up- tient received
f there is no Follow-Up,value will bllow-Up).
ith selected baseline for rst Treatmen
ed at the 5% 90% confide
dder pain NR
low-Up posthe average din Treatmentes only one Ionsidered in
the diary two IP insertved from datto Day 42 fean baselineents within tIf the data th
e value will bRS will be he 7-day ertion or Day
atment 1 periast, for patien
is counted fWeek 4 Fold one or two
valid Week weekly mea
be imputed b
nt 1 level ence
RS
t daily t 1 IP n the
tion, ta for e the 7-hat is be
y 36
iod, nts from llow-o IPs.
4 an of y the
27MAR2018 CSR 201025-001 17
F
NWutco
AN2 L
Tufroubd[Lthcoinisfi9L
1Ttho
AalTanm
or the prima
Null hypotheWeek 4 Follo
tilizes 2 cononsecutive L
Alternative hyNRS at Week
consecutiveLiRIS Placeb
The change frsing descriprom baselinef Treatment sing the baseladder pain Nerive the adjLS] mean dihat utilizes 2onsecutive Ln the treatmes rejected in itted model w0% CI betw
LiRIS 400 mg
1.1.1The ANCOVhe PP populaf the averag
Average dailylso be summ
Table 17.2.1–nalysis outli
missing value
ary efficacy a
sis: The meaow-Up post Insecutive LiRLiRIS Placeb
ypothesis: Tk 4 Follow-Ue LiRIS 400 bo.
from baselinetive statistic
e in average 1 will be aneline values NRS: ≤ 5 orjusted mean fference) an
2 consecutiveLiRIS Placebent group thafavor of the
will also be ueen treatmeng versus the
Other VA Analyses ation and witge daily blad
y 24-hour pamarized for e–1). For eachned for the pes.
analysis, the
an change froIP removal iRIS 400 mg bo.
The mean chaUp post IP re
mg compar
e in averagecs by treatmedaily bladde
nalyzed usingas the covar
r > 5) and tretreatment di
nd associatede LiRIS 400 bo. If the 1-sat utilizes 2 ctreatment gr
used to estimnt group thattreatment gr
Analysis ofof the primath no imputa
dder pain NR
ain NRS andach week poh weekly (mprimary time
e null and the
om baselines the same ocompared to
ange from baemoval is grered to the tre
daily bladdeent group. Beer pain NRS g the analysiriate, and streatment as faifferences fo
d 90% CI, fomg versus
sided p-valueconsecutive roup that uti
mate the adjut utilizes conroup that uti
f Primary Eary efficacy ations for mi
RS.
d the correspost randomizean) changeepoint will b
e alternate h
in average dor worse foro the treatm
aseline in aveater for theeatment grou
er pain NRSetween grouat Week 4 F
is of covariaratification faactors. The for the primarr the comparthe treatmene is < 5% anLiRIS 400 m
ilizes 2 consusted treatmensecutive treilizes 2 cons
Efficacy Varvariable wilissing Week
onding chanzation for thee from baselibe applied wi
hypothesis ar
daily bladdethe treatmen
ment group th
verage daily treatment gr
up that utiliz
S score will bup comparisoFollow-Up pance (ANCOfactor (baselifitted model ry variable (lrison of the nt group thatnd there is grmg then the ecutive LiRIent differenc
eatment of Lecutive LiRI
riable ll also be per
k 4 Follow-U
nge from base Treatment ine values, thithout any im
re as follows
er pain NRS nt group thathat utilizes 2
bladder painroup that uties 2 consecu
be summarizon of the chapost IP remov
OVA) model,ine average dwill be usedleast-squaretreatment grt utilizes 2 reater reductnull hypotheIS 400 mg. Tce and associRIS placeboIS Placebo.
rformed usinUp weekly m
seline values1 Period (se
he ANCOVAmputation fo
s:
at t
n ilizes utive
zed ange val , daily d to s roup
tion esis The ciated o and
ng mean
s will ee A or
27MAR2018 CSR 201025-001 18
A(MTpgranth
Pfr
1Aasa btowanbp
Dprfrtr
A sensitivity Mallinckrodt
Treatment 1 Wost-baseline roup, assessmnd baseline vhe correlatio
lots of weekrom baseline
1.2A standardizessess any chresult of treaseline visito categories
worsened disenalyzed by taseline visitain NRS wil
During each creforming throm baselinereatment gro
analysis usint et al, 2001aWeek 4 Follweek (see Tment week, value as covn over time
kly mean of e values will
SECOed video cap
hanges in theatment. Thes. These wilsuch as comease. The nutreatment gro, the numberll be summar
cystoscopy, he bladder sce in the numboup.
ng a mixed-ea and 2001bow-Up, will
Table 17.2.1–and treatmen
variate. An uin change fr
the average be presente
ONDARY EFpture protoco number, the video imagel be used to
mplete responumber and peoup. Furtherr of patients rized by trea
the investigacan for bladdber of lesion
effects modeb) based on al be performe–1). The MMnt group–by
unstructured rom baseline
daily bladded by treatme
FFICACY Pol for bladdee size and the will be capcategorize thnders, partiaercentage ofrmore, for eawith 1, 2 an
atment group
ator will couder mappingns will be sum
el for repeateall post-baseled to compa
MRM analysy-assessmentcovariance m
e values for t
er pain valueent group ov
PARAMETr mapping w
he severity, optured at bashe change fral respondersf patients in ach categorynd ≥ 3 point rp.
unt the numbg. The numbemmarized fo
ed measuresline weekly
are treatmentsis will inclut week interamatrix will bthe primary e
es and the asver time.
TER(S) will be followof lesions duseline and atrom baselines, stable diseeach categor
y of respondereduction in
ber of lesioner of lesionsor each relev
s (MMRM) mean data ut effect at eaude treatmenaction as facbe used to mefficacy vari
ssociated cha
wed in orderuring the studt scheduled pe bladder imaease and ry will be ers, at each p
n daily averag
s visible whs and the chavant visit by
up to ach nt ctors
model iable.
ange
r to dy as post-ages
post-ge
hile ange
27MAR2018 CSR 201025-001 19
27MAR2018 CSR 201025-001 20
27MAR2018 CSR 201025-001 21
27MAR2018 CSR 201025-001 22
1Twphthusuv
Asuv
T
1AD
Aafstsefigrp
AthinstT
2.0The safety anwill include a
hysical and he last non-msed as the baummarized balues. Categ
All safety anaubjects will bisit (i.e., “as
The following
• Summ
• SummTreatmanalysi
2.1Adverse evenDictionary fo
An AE will bfter the first tudy treatmeerious after tirst dose of sreatest severeriod.
Analysis of thhe Safety popncidence of Ttudy period (
TEAEs at eac
SAFE
nalysis will badverse even
pelvic assesmissing safetaseline for alby number o
gorical variab
alyses will bbe analyzed treated” rath
g safety anal
maries by trea
maries for patment 2 periodis, the treatm
ADVEnts will be coor Regulatory
be considereddose of stud
ent and increthe first dosestudy treatmerity will be u
he incidencepulation. FoTEAEs will (Treatment 1ch treatment
TY ANALY
be performednts (AEs) andssments. Forty assessmenll analyses o
of patients anbles will be s
be performedaccording toher than “as
lyses will be
atment group
tients who pad by treatmement groups
ERSE EVENoded by systy Activities,
d a treatmentdy treatment eased in sevee of study treent and codeused for com
e of TEAEs wr the cohort be summari
1 and 2 perioperiod.
YSES
d using the Sd clinical labr each clinicant before theof that safetynd mean, SDsummarized
d using the sao actual trearandomized
e performed
p and overall
articipated inent group anwill be the s
NTS em organ claversion 18.1
t-emergent aor was pres
erity after theeatment. If med to the sam
mparison with
will be perfoof safety pazed over theod). The foll
Safety Populboratory andal laboratory
e first Treatmy parameter. D, median, md by number
afety populaatment receivd”).
unless other
l for the Trea
n both the Trnd overall pasafety treatm
ass and pref1 or newer.
adverse evenent before the first dose omore than 1 Ame preferred h the AEs oc
ormed for theatients that re Treatment lowing rules
lation. The sad vital signs py and vital siment 1 IP ins
Continuous minimum, and
and percent
ation. For suved at the stu
rwise mentio
atment 1 per
reatment 1 patient populament groups.
ferred term u
nt (TEAE) ifhe date of thof study treaAE was repoterm, the AE
ccurring dur
e Treatment received Tre2 Period and
s will be used
afety parameparameters, ign parametesertion will bvariables wd maximum tage of patien
uch analysesudy treatmen
oned:
riod
period and ation. In this
using the Me
f it was presehe first dose oatment or becorted before E with the ing the study
1 Period usatment 2 IP,d over the end to count
eters
ers, be
will be nts.
s, nt
edical
ent of came the
y
ing , the ntire
27MAR2018 CSR 201025-001 23
• For the analyses of TEAEs by treatment period, an event will be counted once in the particular period if the onset of this event begins during that corresponding period.
• If an event occurs during the Treatment 1 period and continues to the Treatment 2 period without increasing in severity, this event will be counted as an event during the Treatment 1 period but will not be counted again as an event in the Treatment 2 period.
• If an event occurs during the Treatment 1 period or earlier and continues to the Treatment 2 period and the severity increases to a grade that is greater than the maximum severity of the Treatment 1 period or the pre-treatment period or becomes serious in Treatment 2 period then the event will be counted as an event in the Treatment 2 period.
For each treatment phase and for the overall treatment period the number and percentage of patients reporting TEAEs in each treatment group will be tabulated by descending percentage in any group, by system organ class and preferred term, and further categorized by severity and causal relationship to the study treatment. If more than 1 AE is coded to the same preferred term for the same patient, the patient will be counted only once for that preferred term using the greatest severity and strictest causality for the summarization by severity and causal relationship. All AE summary tables will be by treatment group and the overall safety population.
The total number of TEAEs by severity and causal relationship to the study treatment will be summarized by treatment group.
The number and percentage of patients who have Treatment emergent SAEs will be summarized by preferred term and treatment group. In addition, the incidence of treatment emergent SAEs that led to death will be summarized separately by preferred term for each treatment group.
The number and percentage of patients in the Safety Population who have AEs leading to premature discontinuation of the study treatment will be summarized by preferred term and treatment.
Pretreatment AEs are the AEs that occur after signing of the informed consent (IC) and prior to first dose of study medication. Such AEs will be presented in a patent listing.
27MAR2018 CSR 201025-001 24
TlionFTevfou
MwMD SoNFeFeCCCSeVDHPa HHBRRTTrMLV
1Dbfo
The table beloidocaine treaf special inteeed to occuror Treatmen
Treatment 2 ivents by treaor consistencsed for the a
MedDRA v1with of lidocMedDRA PreferDizziness
omnolence Nervousness
eeling cold eeling hot onfusional statardiac arrest irculatory collaeizure
Vision blurred Diplopia Hypoaesthesia
araesthesia ora
Hypoaesthesia oHypotension
radycardia Respiratory arreRespiratory dep
innitus remor
Muscle twitchinoss of consciou
Vomiting
2.2Descriptive st
aseline valueollowing lab
ow presents atment. Sincerest for lidor on or after tnt 1 period itit will be theatment groupcy with the Manalysis.
8.1 PT for Aaine toxicityrred term
te
apse
al
oral
est ression
ng usness
CLINItatistics for ces at each as
boratory para
the preferrece lidocaine hocaine treatmthe day of IPt will be up te day after thp and overalMedDRA ve
AEs associaty
ICAL LABOclinical labossessment timameters:
d terms idenhas a short h
ment and to bP insertion ato the day afthe IP removal. This table
ersion (versio
ted
ORATORYoratory valueme point wil
ntified to behalf-life, for be further suand up to thefter the 2nd IPal. The summ will be updon presented
Y PARAMEes (in SI unitll be presente
e of special inthese AEs to
ummarized ine day after thP removal wmary table wdated prior tod below is 18
ETERS ts) and changed by treatm
nterest for o be considen a table the
he IP removawhile for will present so database lo8.1) that will
ges from thement group fo
ered ey al.
uch ock l be
e or the
27MAR2018 CSR 201025-001 25
H
C
U
Sprar
1Drath
1N
1
1Pmw
Hematology:
Chemistry:
Urinalysis:
hift tables frresented by re provided b
2.3Descriptive state, pulse rathe end of eac
2.4Not Applicab
2.5
2.5.1ost-void resi
measurementwhere PVR a
red blocorpusconcendiffereeosino
albumiaminotcalciumnonfas
color, ketoneurobilileukoc
rom baselinetreatment grby lab vendo
VITALtatistics for vte, body temch treatment
ELEC
ble.
OTHE
Bladdidual (PVR)ts will be wilassessment is
ood cells (RBscular hemogntration, RBCential (% andophils, basop
in, alkaline ptransferase, tm, chloride, sting glucose
appearance oes, occult bloinogen, crystcyte, occult b
e to end of stroup for the or.
L SIGNS vital signs (s
mperature ) ant phase and s
CTROCARD
ER SAFETY
er Post-Voi volume mell be summas done) usin
BC); RBC inglobin, and mC morphologd absolute): nphils, hemato
phosphatasetotal and dircreatinine, g
e, potassium
of urine, speood, leukocytals; microscblood, nitrite
tudy for clinfollowing ca
systolic and nd changes fstudy will be
DIOGRAM
Y PARAME
id Residualasurement a
arized by treang descriptiv
ndices: meamean corpusgy; white blneutrophils, ocrit, hemog
, alanine amrect bilirubingamma gluta, total protei
ecific gravityyte esterase, ncopic examine, or crystals
nical laboratoategories: low
diastolic blofrom baseline presented b
M
ETERS
and change fratment phase
ve statistics.
an corpusculascular hemoglood cells (Wlymphocytelobin, and p
minotransferan, blood ureaamyltransferin, and sodiu
y, pH, proteinitrite, bilirunation if pos
s
ory parametew, normal, a
ood pressurene values at eby treatment
from baselinee for each vi
ar volume, mglobin
WBC); WBCes, monocytelatelets
ase, aspartatea nitrogen, rase, globulinum
in, glucose, ubin, sitive for pro
ers will be and high, wh
es, respiratoreach visit ant group.
e volume isit (for visit
mean
C es,
e
n,
otein,
hich
ry nd at
ts
27MAR2018 CSR 201025-001 26
1Ctrphp
1Aoin
1Tthre
1P
1Upr
1A
1N
1N
2.5.2Complete Phyreatment phahase. The coatient listing
2.5.3All patients w
f the IP, Trento Treatmen
2.5.4The investigahe bladder. Temoval will
2.5.5regnancy tes
2.5.6Urine Cytolog
resented in p
2.5.7A listing of pa
2.5.8Not applicabl
2.5.9Not applicabl
Physic
ysical examiase. Abnormomplete and g
Cystos
will undergo atment 1 Went 2 period.
Investational produThe findings be presented
Pregnst results for
Urine gy test will bpatient listin
Urine atient’s urine
Suicid
le.
Potentle.
cal Examina
inations are pmal findings a
abbreviated
scopic Exam
a cystoscopeek 4 FollowAbnormal f
tigational Pruct will be as
on the condd in a listing
ancy Test r patients wil
Cytology be performed
ng.
Culture e culture res
dality Assess
tial Hy’s La
ation
performed aat these visit
d physical ex
m ic examinati
w-up and at sfindings will
roduct ssessed priordition of the .
ll be provide
d at screenin
sults will be p
sment
aw
at the baselints will be sumxaminations r
ion on the dastudy exit if l be summari
r to insertionIP prior to in
ed in a data l
ng. The resu
presented by
ne and at themmarized byresults will b
ays of insertf the patient dized by treat
n and after thnsertion and
listing.
ults of this tes
y treatment g
end of eachy treatment be presented
tion and remdoes not contment phase.
he removal fd after the
sts will be
group and vi
h
d in a
moval ntinue .
from
isit.
27MAR2018 CSR 201025-001 27
27MAR2018 CSR 201025-001 28
27MAR2018 CSR 201025-001 29
14Aanraencogrin
4.0Assuming thanalysis, to enandomized innsures that thonsecutive Lroup that getn the treatme
INTER
at 5% of the nsure that thnto the studyhere will be
LiRIS 400 mts Placebo anent group tha
RIM ANAL
randomizedhere are 72 evy. At a randabout 36 pa
mg (LiRIS 40nd then LiRat gets two c
LYSIS
d patients wilvaluable pat
domization raatients in the 00 mg/LiRISIS 400 mg (P
consecutive P
ll not be evatients approxatio of 2:1:1 treatment g
S 400 mg), 1Placebo/LiRPlacebo (Pla
aluable for thximately 76 p, 72 evaluab
group that ge8 patients in
RIS 400 mg)acebo/Placeb
he primary patients will
ble patients ets two n the treatme, and 18 pati
bo).
l be
ent ients
27MAR2018 CSR 201025-001 30
1Apm1wasF
5.0A sample size
atients in themean daily av
.67 using a 1was performessumption isollow-Up ra
DETE
e of 36 patiee Placebo/Plverage bladd1-sided two ed using the s based on thaw average d
ERMINATIO
ents in the Llacebo groupder Pain NRSsample t-tescommercial
he TAR-100daily NRS.
ON OF SAM
LiRIS 400 mp has 76% pS, assuming t with a typesoftware
-105 open la
MPLE SIZE
mg/LiRIS 400power to dete
that the come 1 error rate
Tabel study, w
E
0 mg group ect a differen
mmon standae of 0.05. ThThe standardwhere the SD
versus 18 nce of 1.152ard deviationhe calculatio
d deviation D is the Wee
2 in n is on
k 4
27MAR2018 CSR 201025-001 31
27MAR2018 CSR 201025-001 32
1
1T(era
FTDdTwliA
S
st
T
T
T
7.0
7.1Table 17.1–1 excluding efange of study
ollowing SDTreatment 1 DDay 1. Howe
ocument andTreatment 2 Dwill follow thisting will al
ADaM standa
creening & b
tudy day = v
Treatment 1 p
study day =
Treatment 2 P
study day =
Throughout th
DATA
VISITpresents, fo
fficacy basedy days (wind
DTM and ADDay 1. Similver, in the ad in the eCRDay 0, respehese protocolso display stards study da
baseline per
visit date - 1s
period :
= visit date -
Period :
= visit date -
his documen
A HANDLIN
T TIME WINor both treatmd on daily padow) during
DaM standarlarly, the datssessment ta
RF pages thisectively. For l and eCRF vtudy day usiay is calcula
riod (prior to
st IP insertio
1st IP insert
- 2st IP inser
nt ,unless oth
NG CONVE
NDOWS ments periodain diary) and
which an ac
rd, the date te of 2nd IP ables of the ps is considereby visit anavisit definiting the SDTM
ated as follow
o IP insertion
on date
tion date +1
rtion date +1
herwise state
ENTIONS
ds, the derivd safety anactual visit m
of first IP ininsertion wiprotocol anded to be Trea
alysis tables aions (3rd colM definitionws (see 2nd
n)
ed, this defin
ved visits foralyses and thay occur.
nsertion will ill be consided in Section 4atment 1 Daand listings lumn in tablen. Hence, usicolumn in T
nition of stud
r efficacy e correspond
be considerered Treatm4 of this ay 0 and the visit labee 17.1-1). Soing SDTM a
Table 17.1-1)
dy day is use
ding
red as ent 2
el ome and ):
ed.
27MAR2018 CSR 201025-001 33
27MAR2018 CSR 201025-001 34
If not stated otherwise, all by visit analysis will be using the visit windows specified above. The target day for each treatment period is referenced to days after first IP insertion within each treatment period. Treatment 1 Day 1 refers to the first IP insertion date while Treatment 2 Day 1 refers to the IP insertion date in Treatment 2 period. In contrast, if the assessment date is before date of Treatment 1 IP insertion, the study day is calculated as follows:
assessment date – date of Treatment 1 IP insertion.
The visit window for each treatment period is defined as follows:
[(target day of current visit + target day of previous visit)/2+1] to [(target day of current visit + target day of next visit)/2]
If a patient has 2 or more visits within the same visit window, the last visit with a non-missing value will be used for the analysis.
For laboratory and vital signs analysis, baseline refers to study baseline, i.e. the baseline information collected at the start of Study 201025-001.
27MAR2018 CSR 201025-001 35
1Td
•
•
•
•
•
•
•
•
7.2The data deriv
escribed in t
In this stu
• TranIPbophin
• Trex
Study day
• St
The baselbeing inse
Unless othanalyses w
For analyrandomiz
Data will
Descriptivstandard dconfidenc
Summary(n), and p
DERIV
vations and this analysis
udy there are
reatment pernd blinded phP insertion tooth the randohase of the stsertion up to
reatment perxit.
ys for each tr
tudy day of T
line value oferted with fir
herwise statewill be based
ses that are bation stratifi
be pooled a
ve statistics deviation (SDce intervals.
y statistics fopercentage (%
VED VARI
definitions lplan, unless
e two treatme
riod 1: for pahase of the tr
o study exit. omized phastudy (Treatmo Treatment
riod 2: cover
reatment per
Treatment X
f an assessmerst Treatmen
ed no imputad on the obse
by stratificatication levels
cross the inv
for continuoD), median,
or categorica%).
IABLES
listed in this s otherwise s
ent periods:
atients that jurial, it coverIn contrast, e of the stud
ment 2) it cov2 IP insertio
rs the period
riod X (X=1
X = visit date
ent will be thnt 1 IP on Da
ation will beerved data.
tion factor, as will be use
vestigational
ous/ordinal dminimum (M
al variables in
section are tstated.
ust receive trs the period for patients
dy (Treatmenvers the perion,
from Treatm
or 2) will b
e – (day 1 of
he last valueay 1.
e performed
actual stratifed.
l sites.
data include tMin), and m
nclude samp
to be applied
treatment ind from the fir
that receive nt 1) and theiod from firs
ment 2 IP in
e calculated
f Treatment X
e recorded pr
for missing
fication level
the sample smaximum (M
ple size (N),
d to all analy
n the randomrst TreatmenIP insertion
e open label st Treatment
sertion to stu
as:
X) + 1.
rior to the pa
data. All
ls rather than
size (N), meaMax) and 95%
frequency c
yses
mized nt 1 ns in
t 1 IP
udy
atient
n
an, %
count
27MAR2018 CSR 201025-001 36
1Athrafod
TpTorepthav
Appth
TfrwdbeasuinininalsucoIPwas5 reth
T
7.2.1A pain assesshe daily worate their dailor “no pain” ay up to and
The patient’s ain in your b
Treatment 1 Df the 7 day “eported daysain will onlyhe 7 days privailable, the
Average dailyost- randomeriod and thhe study the
Table 17.2.1–rom first IP i
weekly summays from thiaseline weekach weekly summary weensertion or rensertion, the ncluded in thll available vummarized (ontrast, for tP removal w
week will be ssessments tday criteria
educe the imhe disease un
Table 17.2.1–
Pain D
sment tool wst pain scorely pain on a pto 10 for “w
d including th
baseline avebladder overDay 1. Simil“worst pain is prior to Trey be calculatior to Day 1 baseline sco
y pain NRS ization. Patien Follow-Ufollow up vi
–1, presents insertion wit
mary. For patis IP insertioks that do nosummary if tek presentedemoval a difday of inser
he weekly avvalues, provi(the days thathe week wh
will be removbased on all
to be summa). The ration
mpact of painnder conside
–1 presents t
Data Deriva
will be utilizees on an elecpain NRS co
worst pain imhe day prior
erage daily pr the last 24 hlarly, a patiein your bladdeatment 1 Dated if the info(i.e., Day -7
ore will be s
and daily woents are sche
Up visit. Howisits follow a
for patients thin each tretients that on
on the days toot cover IP inthey have at
d in Table 17fferent rule irtion and theverage summided there arat are to be rehere IP removved from the l available vaarized (the danal for excludn or pain mederation.
the weekly p
ations
ed in the studctronic hand onsisting of amaginable”.
to the Exit v
pain NRS wihours” scoreent’s baselinder over the ay 1. Baselin
formation is c7 to Day -1). et to missing
orst pain NReduled to hawever, if a paafter the IP r
that receiveeatment perionly receive oo be includensertion or rt least 5 cons7.2.1–1 . Fors applied. Fo
e two days afmary. The sure at least thremoved willval occurs, tweekly ave
alues providays that are tding these IPdication that
pain assessm
dy to captureheld devicean 11 point iThe pain as
visit.
ill be the mees from the 7ne daily wors
last 24 hourne average dcollected for If less than g.
RS will be suave two IP inatient receivremoval.
e more than ood the days tone IP, Tabled in each we
removal, a pasecutive dayr the week inor assessmenfter the day o
ummary for sree days of dl be considerthe IP removrage summa
ded there are to be removP insertion at is related to
ment window
e the average. Patients winteger scalesessment wi
ean of the 7 d7 reported dast pain NRS rs” scores frdaily pain anr any 5 cons5 consecutiv
ummarized fnsertion in Tves only one
one IP insertto be includee 17.2.1-1 aleekly summaatient will be
ys of informantervals thatnt weeks whof insertion wsuch a week daily assessmred in the 5 dval date and ary. The sum at least threed will be co
and removal o the procedu
s.
e daily pain will be asked e ranging froill continue e
day “averageays prior to will be the m
rom the 7 nd average wecutive dayve days are
for each weereatment 1 IP insertion
tion, in daysed in each lso presents ary. For the e included ination within t cover IP here there is will not be will be base
ments to be day criteria)the day after
mmary for suee daily onsidered indates is to ure rather th
and to
om 0 every
e
mean
worst ys in
ek
n in
s
in post-
n the
IP
ed on
). In r the
uch a
n the
han
27MAR2018 CSR 201025-001 37
1
•
7.2.2
For baselibased on tinterval cothe time o
Void D
ine and posttthe diary datonsists of 3
of the first ur
Data Deriva
treatment vita collected consecutive rinary episod
ations
sits, analyseduring a 3-d24-hour per
de on the firs
es on void diday interval friods, with thst of the 3 da
iary efficacyfor each visihe first perioays.
y variables wit. Each 3-daod starting fr
will be ay rom
27MAR2018 CSR 201025-001 38
•
•
1
Iffrb
A valid diurinary epepisodes (
For baselifollowing
• Apth
• De(indato dathth
• UsApfrois 24Ap
• Atvi
7.3
f a patient harom the finale used as ba
7:30am 2:30pm 5:00pm
Apr 3
iary day is dpisodes. Dat(i.e., an inva
ine and posttg algorithm:
pply visit wie date of stu
etermine then the examplays. Note: t
or on the laata will not be urinary epe IP insertio
sing the exampril 3 and enom 7:30am oconsidered a
4 hours. Thepr 5 and end
t least one vasit. Otherwi
REPEPARA
as repeated al non-missinseline.
6:15am 9:00pm
Apr 4
defined as anta collected
alid diary day
treatment vi
indows definudy first treat
e time of the le below, 7:3the last 24-host day specif
be used for thisodes that on time will b
mple below,nds at 7:29 amon Apr 4 andas an invalide third or theds at 7:29 am
alid 24-hourise, the 3-da
EATED OR AMETERSassessments ng assessmen
5:30pm
Apr 5
ny of the threfrom a 24-hoy) will be se
sits, the 3-da
ned in Sectiotment in eac
first urinary30 am on Apour period shfied in the whe corresponoccurred on tbe counted a
, the first 24-m on Apr 4.d ends at 7:2d diary day se last 24-hou
m on Apr 6.
r diary day wy diary data
UNSCHED
before the stnt made prio
11:23am 4:23pm
Apr 6
ee 24-hour pour period w
et to missing
ay diary will
on 17.1, which treatment
y episode thapril 3). Counhould end w
window definnding windothe day of fias baseline d
-hour time p. The second29 am on Apsince it has juur time perio
within the wiwill be miss
DULED ASS
tart of the firor to the start
periods with with less than.
l be determin
ich are basedperiod.
at is within thnt forwards
within the winnition; otherwow. For baseirst IP insertidiary data.
period starts d 24-hour tim
pr 5. Note thust one episod starts from
indow is reqsing for the v
SESSMENT
rst treatmentt of the study
2 or more n 2 urinary
ned based on
d on days fro
he visit windfor 3 consecndow, i.e., pwise, the 24-eline diary dion but befo
from 7:30amme period sthat this 24-hoode during th
m 7:30 am on
quired for thevisit.
TS OF SAFE
t, the resultsy treatment w
n the
om
dow cutive prior -hour ata, re
m on tarts our he n
e
ETY
s will
27MAR2018 CSR 201025-001 39
1
N
1Iftrstbsu
1
Ifafimsu
1Tin
M•
•
•
M•
7.4
Not applicabl
7.5f severity is mreatment, an tarted on or ae assigned. Tummary; the
7.6
f the causal rfter the date mputed valueummary; the
7.7The followingncomplete (i
Missing monIf the yeartreatmentthe missin
If the yeartreatment
If the yeartreatment
Missing monIf only theand the da
MISSITREA
le.
MISSImissing for aintensity of after the dateThe imputede values will
MISSITREA
relationship of the first des for causale values will
MISSIg imputation.e., partly m
nth and day r of the inco, the month ng fields
r of the inco, December
r of the inco, January 1 w
nth only e month is may will be re
ING DATEATMENT
ING SEVERan AE that s
f mild will bee of the first
d values for s be shown a
ING CAUSAATMENT FO
to the study dose of studyl relationship be shown a
ING DATEn rules only a
missing).
omplete start and day of th
omplete start 31 will be a
omplete start will be assig
missing, the deplaced accor
OF THE L
RITY ASSEstarted before assigned. It dose of studseverity asses missing in
AL RELATOR ADVERtreatment is
y treatment, p to study tres missing in
INFORMAapply to case
date is the she first dose
date is befossigned to th
date is aftergned to the m
day will be trding to the
LAST DOSE
ESSMENT Fre the date ofIf severity is dy treatmentessment willn the data list
TIONSHIP RSE EVENs missing fora causality oeatment will
n the data list
ATION FORes in which t
same as the ye of study tre
ore the year ohe missing fi
r the year of missing field
treated as miabove proce
E OF STUD
FOR ADVEf the first domissing for
t, an intensitl be used for tings.
TO STUDYNTS
r an AE that of yes will bl be used fortings.
R ADVERSthe start date
year of the featment will
of the first dfields
f the first dosds
issing and boedure
DY
ERSE EVENse of study an AE that
ty of severe wthe incidenc
Y
started on obe assigned. r the inciden
SE EVENTSe for AEs is
first dose of sbe assigned
ose of study
se of study
oth the mont
NTS
will ce
or The
nce
S
study d to
y
th
27MAR2018 CSR 201025-001 40
M•
•
•
Ifst
Ifal
•
•
1
Fpst
1Tinimu
Missing day If the monof the firsassigned t
If either thdose of ststart date day of the
If either thdose of ststart date day of the
f the stop dattart date will
f the start dalgorithm wil
If the stopdose of st
If the stopbe assigne
7.8
or prior or cartly missingtop date are
7.8.1The followingncomplete prmputed) andsing the stop
only nth and yearst dose of stuto the missin
he year of thtudy treatmeis before the
e month will
he year of thtudy treatmeis after the m
e month will
te is complel be imputed
te is complell be used to
p date is aftetudy treatme
p date is befoed to the mis
MISSICONC
concomitant g) start datesboth incomp
Incom
g rules will brior or conco
d the imputedp date.
r of the incomudy treatmenng day
he incompletnt or if both e month of thl be assigned
he incompletnt or if both month of thel be assigned
te and the imd by the stop
etely missingimpute the s
er the date ofnt will be as
ore the date ssing start da
ING DATECOMITANTmedicationss and/or stopplete for a pa
mplete Start
be applied toomitant medd start date is
mplete start nt, the day of
te start date iyears are th
he date of thd to the missi
te start date iyears are th
e date of the d to the missi
mputed start date.
g and the stopstart date:
f the first dosssigned to th
of the first date
INFORMAT MEDICAs, including rp dates will batient, the sta
Date
o impute thedication start s after the st
date are the f the first do
is before thehe same but the first dose ing day
is after the yhe same but tfirst dose ofing day
date as abov
p date is com
se of study the missing st
dose of study
ATION FORATIONS rescue medicbe imputed. art date will
missing num date. If the
top date, the
same as the se of study t
e year of the the month ofof study trea
year of the dathe month off study treatm
ve is after th
mplete, the f
treatment, thtart date
y treatment,
R PRIOR O
cations, incoWhen the stbe imputed
meric fields stop date is start date w
month and ytreatment wi
date of the ff the incompatment, the l
ate of the firf the incompment, the fir
he stop date,
following
he date of the
the stop date
OR
omplete (i.e.tart date and first.
for an complete (oill be impute
year ill be
first plete last
rst plete st
the
e first
e will
, the
r ed
27MAR2018 CSR 201025-001 41
M•
•
•
M•
M•
•
•
1Tinthth
M•
Missing monIf the yeartreatmentthe missin
If the yeartreatment
If the yeartreatment
Missing monIf only theand the da
Missing day If the monof the firsassigned t
If either thdose of ststart date day of the
If either thdose of ststart date day of the
7.8.2The followingncomplete prhe start date he start date.
Missing monIf the yeartreatmentfields
nth and day r of the inco, the month ng fields
r of the inco, December
r of the inco, January 1 w
nth only e month is may will be re
only nth and yearst dose of stuto the missin
he year of thtudy treatmeis before the
e month will
he year of thtudy treatmeis after the m
e month will
Incomg rules will brior or conco(imputed or
nth and day r of the inco, the month
omplete start and day of th
omplete start 31 will be a
omplete start will be assig
missing, the deplaced accor
r of the incomudy treatmenng day
he incompletnt or if both e month of thl be assigned
he incompletnt or if both month of thel be assigned
mplete Stop Dbe applied toomitant mednon-impute
omplete stop and day of th
date is the she first dose
date is befossigned to th
date is aftergned to the m
day will be trding to the
mplete start nt, the day of
te start date iyears are th
he date of thd to the missi
te start date iyears are th
e date of the d to the missi
Date o impute thedication stop ed start date)
date is the she study exi
same as the ye of study tre
ore the year ohe missing fi
r the year of missing field
treated as miabove proce
date are the f the first do
is before thehe same but the first dose ing day.
is after the yhe same but tfirst dose ofing day
missing numdate. If the
), the impute
same as the yit date will b
year of the featment will
of the first dfields
f the first dosds
issing and boedure
same as the se of study t
e year of the the month ofof study trea
year of the dathe month off study treatm
meric fields imputed stop
ed stop date w
year of the labe assigned t
first dose of sbe assigned
ose of study
se of study
oth the mont
month and ytreatment wi
date of the ff the incompatment, the l
ate of the firf the incompment, the fir
for an p date is befwill be equa
ast dose of so the missin
study d to
y
th
year ill be
first plete last
rst plete st
fore al to
study ng
27MAR2018 CSR 201025-001 42
•
•
M•
M•
•
•
1
Ifsunuand
Tfo
If the yeartreatment
If the yeartreatment
Missing monIf only theand the da
Missing day If the monof the lastmissing d
If either thdose of ststop date day of the
If either thdose of ststop date of the mo
7.9
f the reportedummary tablumeric typenalyses. Theata listings.
Table 17.9–1 or the analys
r of the inco, December
r of the inco, January 1 w
nth only e month is may will be re
only nth and yeart dose of stud
day
he year of thtudy treatmeis before the
e month will
he year of thtudy treatmeis after the mnth will be a
CHARPARA
d value of a le because, f, a coded val
e actual valu
shows examsis.
omplete stop 31 will be a
omplete stop will be assig
missing, the deplaced accor
r of the incomdy treatment
he incompletnt or if both e month of thl be assigned
he incompletnt or if both
month of theassigned to t
RACTER VAMETERS
clinical labofor example,lue must be es, however
mples of how
date is befossigned to th
date is aftergned to the m
day will be trding to the
mplete stop dt, the day of
te stop date iyears are th
he date of thd to the missi
te stop date iyears are th
e date of the the missing d
VALUES OF
oratory param a character appropriatel, as reported
w some possi
ore the year ohe missing fi
r the year of missing field
treated as miabove proce
date are the f the study ex
is before thehe same but the last dose oing day
is after the yhe same but tlast dose of day
F CLINICA
meter cannostring is rep
ly determined in the datab
ible laborato
of the last dofields
the last doseds
issing and boedure
same as the xit will be as
e year of the the month ofof study treat
year of the dathe month ofstudy treatm
AL LABORA
t be used in ported for a ped for use in base will be
ory results sh
ose of study
e of study
oth the mont
month and yssigned to th
date of the lf the incomptment, the la
ate of the lasf the incomp
ment, the firs
ATORY
a statistical parameter ofthe statisticapresented in
hould be cod
th
year he
last plete ast
st plete st day
f the al n the
ded
27MAR2018 CSR 201025-001 43
Table 17.9–1. Examples of Coding Special Character Values for Clinical Laboratory Parameters
Laboratory Test, SI Unit
Possible Laboratory Results Coded Value for Analysis
CHEMISTRY
ALT, U/L < 5 5
AST, U/L < 5 5
Bilirubin, total, µmol/L < 2 2
URINALYSIS
Glucose, mmol/L = OR > 55, ≥ 55, > 0 Positive
≤ 0, negative Negative
pH > 8.0, ≥ 8.0 8.0
≥ 8.5 8.5
Protein = OR > 3.0, ≥ 3.0, > 0 Positive
≤ 0 Negative ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités (International System of Units).
27MAR2018 CSR 201025-001 44
1 8.0
• The Aassess
• The premov
CHAN
AE analysis bsed to be not
rimary efficved. This has
NGES TO A
by time of int relevant to
acy analysiss been replac
ANALYSES
nsertion or rethis study
s with LOCFced with rep
S SPECIFIE
emoval has b
F method of peated measu
ED IN PROT
been remove
imputation hures mixed m
TOCOL
ed. It was
has been model analyssis.
27MAR2018 CSR 201025-001 45
1Eli
Mmim
Mm
ML
OC
9.0EuroQol Grouife. Health P
Mallinckrodt model repeatemputed via l
Mallinckrodt mixed-effects
Maruish ME Lincoln, RI: Q
O’Leary MP, Cystitis Symp
REFE
up. EuroQololicy. 1990;
CH, Clark Wed measuresast observati
CH, Clark Ws models. J. B
(Ed.). (2012QualityMetr
Sant GR, Foptom Index a
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l-a new facil 16(3):199-2
WS, David S versus fixedion carried f
WS, David, SBiopharmac
2) User’s maric Incorpora
owler FJ, Wand Problem
lity for the m208
SR (2001a). d effects anaforward. Dru
S. R. (2001bceutical Stati
nual for the ated.
hitmore KE,m Index. Uro
measurement
Type I erroralysis of variug Informati
b). Accountinistics. 2001b
SF-12v2 He
, Spolarich-Kology. 1997;4
t of health-re
r rates from miance with mon J. 2001a;
ng for dropob; 11:9-21.
ealth Survey
Kroll J. The 49(Suppl 5A
elated quality
mixed-effecmissing value;35:1215-122
out bias using
y (3rd ed.),
Interstitial A):58-63.
y of
ts es 25.
g
27MAR2018 CSR 201025-001 46
DOCUMENT HISTORY PAGE
Effect Date Revision Number
Primary Author Description of Change
01 July 2015 0.1 Initial Release
06 June 2016 0.2 Changes to conform with Protocol Amendment 2
27MAR2018 CSR 201025-001 47
ALLERGAN
Date (DD/MMM/YYYY)/Time (PT) Signed by: Justification
LiRIS 201025-001 Analysis Plan - Amd_2_v_1
27MAR2018 CSR 201025-001 48