Study ID: 201025 001 400 With Statistical Analysis Plan ... · bo-controlle Interstitial C N -...

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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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

.......................

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.......................

.......................

.......................

.......................

.......................

.......................

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.......................

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.......................

.......................

.......................

.......................

.......................

.......................

.......................

.......................

.......................

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.......................

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.......................

.......................

.......................

.......................

.......................

.......................

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

.......................

.......................

.......................

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.......................

.......................

.......................

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.......................

.......................

.......................

.......................

.......................

.......................of Safety ParamTreatment .......se Events .........reatment for Advents ..............oncomitant Me..............................................Parameters .....

OTOCOL .......

.......................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................

........................meters ..............................................................dverse Events .........................edications ................................................................................

........................

........................

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.......................

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.......................

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.......................

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.......................

.......................

.......................

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.......................

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.......................

...... 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

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H

IC

IC

IC

IC

IL

IT

IP

L

L

M

M

m

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PD

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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

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inte

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inte

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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


27MAR2018 CSR 201025-001 8


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


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


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


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




Missing day If the monof the firsassigned t



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




only nth and yearst dose of stuto the missin


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


r of the incomudy treatmenng day


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




mplete start nt, the day of




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




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




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




only nth and yeart dose of stud

day


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


r of the incomdy treatment


he incompletnt or if both

month of theassigned to t

RACTER VAMETERS

clinical labofor example,lue must be es, however

mples of how




mplete stop dt, the day of

te stop date iyears are th


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




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

ERENCES

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

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