Conditions: Urinary Bladder, Overactive Urinary Incontinence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of onabotulinumtoxinA 100 U (BOTOX®), compared to placebo, when injected into the bladder using an alternative injection paradigm in reducing the number of daily urinary incontinence episodes in patients with overactive bladder (OAB) and urinary incontinence whose symptoms have not been adequately managed with an anticholinergic.

Detailed description:

Arms:
arm 1: BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 and a second injection BOTOX® 100 U after Week 12 if applicable. arm 2: Placebo (saline) injection into the bladder on Day 1 and a second injection BOTOX® 100 U after Week 12 if applicable.

Interventions: intervention 1: onabotulinumtoxinA intervention 2: Placebo (saline)
Intervention descriptions: intervention 1: OnabotulinumtoxinA (BOTOX®) injection into the bladder. intervention 2: Placebo (saline) injection into the bladder.

Protocol document:
Prot_001.pdf: 
NCT03052764 
 
Study ID: CMO‐US‐URO‐0470 
 
 
 
Title: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study to 
Evaluate an Alternative Injection Paradigm for OnabotulinumtoxinA (BOTOX®) in the 
Treatment of Overactive Bladder in Patients with Urinary Incontinence (LO‐BOT). 
 
Protocol Amendment 1: 08 May 2018 
 
 
 


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Protocol Summary 
 
Study Compound(s): */*3W*E89FKLC@ELDKFO@E+LI@=@<;)<LIFKFO@EFDGC<O
Phase:  IV
Study Objective(s): /F<M8CL8K<K?<<==@:8:P8E;J8=<KPF=*/*30FE89FKLC@ELDKFO@E:FDG8I<;KF
GC8:<9FN?<E@EA<:K<;@EKFK?<9C8;;<ILJ@E>8E8CK<IE8K@M<@EA<:K@FEG8I8;@>DKI@>FE8C8E;G<I@	KI@>FE8C
@EA<:K@FEJ@EI<;L:@E>K?<ELD9<IF=;8@CPLI@E8IP@E:FEK@E<E:<<G@JF;<J@EG8K@<EKJN@K?FM<I8:K@M<9C8;;<I
*8E;LI@E8IP@E:FEK@E<E:<N?FJ<JPDGKFDJ?8M<EFK9<<E8;<HL8K<CPD8E8><;N@K?8E8EK@:?FC@E<I>@:

Key Clinical Hypotheses
 
*/*30@JDFI<<==<:K@M<:FDG8I<;KFGC8:<9FN?<E@EA<:K<;@EKFK?<9C8;;<ILJ@E>K?<
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@E:FEK@E<E:<<G@JF;<J=IFD98J<C@E<8K2<<B

 
*/*30?8J8E8::<GK89C<9<KK<IJ8=<KPGIF=@C<@E:CL;@E>K?<I@JBF=@E:FDGC<K<9C8;;<I
<DGKP@E>8E;E<<;=FI:C<8E@EK<ID@KK<EK:8K?<K<I@Q8K@FE$N?<E8;D@E@JK<I<;8J@EA<:K@FEJ@EKF
K?<CFN<IG8IKF=K?<9C8;;<IKI@>FE8C8E;G<I@	KI@>FE8CF=G8K@<EKJN@K?*N@K?LI@E8IP
@E:FEK@E<E:<

Study Design 
Structure(LCK@:<EK<II8E;FD@Q<;;FL9C<	9C@E;GC8:<9F	:FEKIFCC<;G8I8CC<C	>IFLG
Duration+8K@<EKJN@CCG8IK@:@G8K<@EK?<JKL;PLEK@CK?<=FCCFN@E>JKL;P<O@K:I@K<I@88I<D<K
 
FDGC<K@FEF=N<<BJGFJK-8E;FD@Q8K@FE8P8E;
 
$=8J<:FE;@EA<:K@FEN8JI<:<@M<;8KC<8JKN<<BJGFJK	KI<8KD<EK=FCCFN	LG8=K<I/I<8KD<EK

/?<I<=FI<=FI=LCCJKL;PG8IK@:@G8K@FEG8K@<EKJN@CC9<<OG<:K<;KFG8IK@:@G8K<@EK?<JKL;P=FI8D@E@DLD
;LI8K@FEF=N<<BJ@<@=G8K@<EKHL8C@=@<J=FIJ<:FE;KI<8KD<EK8K2<<B:C@E@:M@J@K8E;GIF:<<;JKFJ<:FE;
KI<8KD<EK8E;8D8O@DLD;LI8K@FEF=8GGIFO@D8K<CPN<<BJ@<@=8G8K@<EKI<HL<JK<;8E;HL8C@=@<;=FI
/I<8KD<EK8K2<<BI<:<@M<;8E@EA<:K@FE8K2<<B8E;:FDGC<K<JFK?<IJKL;PM@J@KJ8KK?<D8O@DLD
8CCFN89C<M@J@KN@E;FN

Study Treatment Group*/*30$EA<:K@FE 
Control+C8:<9FJ8C@E<$EA<:K@FE
Dosage/Dose RegimenCCG8K@<EKJN@CCI<:<@M<8JKL;PKI<8KD<EKFE8P=FCCFN@E>=LC=@CCD<EKF=8CCF=K?<
8PF=/I<8KD<EKI@K<I@8
E8;;@K@FE8CKI<8KD<EKD8P8CJF9<8;D@E@JK<I<;=FCCFN@E>=LC=@CCD<EKF=GI<	
JG<:@=@<;HL8C@=@:8K@FE=FI/I<8KD<EK:I@K<I@88E;8PF=/I<8KD<EKI@K<I@8


.KL;PKI<8KD<EK
/I<8KD<EKF=*/*30FIGC8:<9FN@CC9<8;D@E@JK<I<;8J@EA<:K@FEJ<8:?F=
D'@EKFK?<CFN<I
GFIK@FEF=K?<GFJK<I@FIN8CCF=K?<9C8;;<I8E;@EKFK?<KI@>FE<M@8:PJKFJ:FGP



CC<I>8EConfidential 
+IFKF:FC(*	0.	0-*	
+IFKF:FCD<E;D<EK(8P


Treatment 1: 
CC<C@>@9C<G8K@<EKJN?FD<<K@E:CLJ@FE<O:CLJ@FE:I@K<I@8N@CCI<:<@M<K?<@I=@IJKKI<8KD<EKN@K?
*/*30FIGC8:<9F8=K<II8E;FD@Q8K@FEFE8P
CC8PF=/I<8KD<EKI@K<I@8DLJK9<
=LC=@CC<;GI@FIKFK?<@EA<:K@FEGIF:<;LI<

8PF=/I<8KD<EKI@K<I@8
 
<EKI8CC89FI8KFIPLI@E8CPJ@JI<JLCKJ8E;@=8GGC@:89C<LI@E<:LCKLI<8E;J<EJ@K@M@KPI<JLCKJ
=FIGFJJ@9C<LI@E8IPKI8:K@E=<:K@FE0/$=IFD.:I<<E@E>?8M<9<<EI<M@<N<;
 
)<>8K@M<LI@E<;@GJK@:BI<8><EKJKI@GK<JK=FIE@KI@K<J8E;C<LBF:PK<<JK<I8J<2FE
K?<;8PF=/I<8KD<EK

 
+8K@<EK@J8JPDGKFD8K@:=FI80/$FEK?<;8PF=KI<8KD<EK@EK?<FG@E@FEF=K?<
@EM<JK@>8KFI

 
+8K@<EK?8J;@J:FEK@EL<;8EP8EK@GC8K<C<KFI8EK@:F8>LC8EKK?<I8GPFID<;@:8K@FEJN@K?
8EK@:F8>LC8K@M<<==<:KJ;8PJGI@FIKFKI<8KD<EK
.FD<D<;@:8K@FEJD8PE<<;KF9<
N@K??<C;=FI;8PJG<I:C@E@:8CAL;>D<EKF=K?<@EM<JK@>8KFI

 
)<>8K@M<LI@E<GI<>E8E:PK<JK=FINFD<EF=:?@C;9<8I@E>GFK<EK@8CFEK?<;8PF=
/I<8KD<EK

 
+8K@<EK?8J@E@K@8K<;8GGIFGI@8K<8EK@9@FK@:D<;@:8K@FE8GGIFO@D8K<CP?FLIJKF
;8PJGI@FIKFKI<8KD<EK@EA<:K@FE8E;N@CC:FEK@EL<@KFEK?<;8PF=KI<8KD<EK@EA<:K@FE
8E;=FIKF;8PJ8=K<IKI<8KD<EK@EA<:K@FEJ<<.<:K@FE

+IFG?PC8:K@:EK@9@FK@:J
 
)FJPDGKFDJFI?@JKFIPF=9C8;;<IJKFE<JFI9C8;;<ID8C@>E8E:@<J98J<;FE:C@E@:8C
8JJ<JJD<EK
 
$EM<JK@>8KFI;<<DJJKL;PKI<8KD<EK@JD<;@:8CCP8GGIFGI@8K<8E;EF:FE;@K@FEFIJ@KL8K@FE
<O@JKJN?@:?@EK?<@EM<JK@>8KFISJFG@E@FEGLKJK?<G8K@<EK8KJ@>E@=@:8EKI@JB=IFD
I<:<@M@E>JKL;PKI<8KD<EK

Treatment 2: 
J<:FE;KI<8KD<EKD8P9<8;D@E@JK<I<;GIFM@;<;K?<G8K@<EKHL8C@=@<J=FI/I<8KD<EKJ<<9<CFN
:I@K<I@88E;FECP@=K?<8PF=/I<8KD<EKI@K<I@88I<=LC=@CC<;
CCG8K@<EKJN@CCI<:<@M<*/*3
0=FIK?<@IJ<:FE;KI<8KD<EK
/?<,L8C@=@:8K@FE=FI/I<8KD<EK:8EF::LI8EPK@D<JK8IK@E>8K
2<<BLGKF2<<BGFJK/I<8KD<EK8E;DLJKF::LI;LI@E>8:C@E@:M@J@K<@K?<I8K8I<>LC8I
GI<J:?<;LC<;M@J@KFI8E8;;@K@FE8CLEJ:?<;LC<;M@J@K;<G<E;@E>FEK?<K@D@E>F=K?<I<HL<JK=FI8
J<:FE;KI<8KD<EK
$=K?<G8K@<EK;F<JEFKI<HL<JK8J<:FE;KI<8KD<EKK?<EK?<2<<B:C@E@:M@J@KN@CC
9<8E<O@KM@J@K

,L8C@=@:8K@FE=FI/I<8KD<EK:I@K<I@8
 
+8K@<EKDLJK@E@K@8K<I<HL<JK=FI/I<8KD<EK

 
+8K@<EK<OG<I@<E:<J≥<G@JF;<JF=LI@E8IPLI><E:P@E:FEK@E<E:<N@K?EFDFI<K?8EFE<
LI><E:P@E:FEK@E<E:<	=I<<;8P8J;<K<ID@E<;9P:FEJ<:LK@M<;8PJF=9C8;;<I;@8IP
:FDGC<K@FE@EK?<N<<BGI@FIKFK?<,L8C@=@:8K@FE=FI/I<8KD<EKM@J@K



CC<I>8EConfidential 
+IFKF:FC(*	0.	0-*	
+IFKF:FCD<E;D<EK(8P


 
+FJK	MF@;I<J@;L8C+1-LI@E<MFCLD<DLJK9<D'8KK?<,L8C@=@:8K@FE=FI
/I<8KD<EKM@J@K

 
$EM<JK@>8KFI;<<DJK?8K/I<8KD<EK@JD<;@:8CCP8GGIFGI@8K<8E;EF:FE;@K@FEFI
J@KL8K@FE<O@JKJN?@:?@EK?<@EM<JK@>8KFISJFG@E@FEGLKJK?<G8K@<EK8KJ@>E@=@:8EKI@JB
=IFDI<:<@M@E>8J<:FE;KI<8KD<EK

 
D@E@DLDF=N<<BJDLJK?8M<<C8GJ<;J@E:</KI<8KD<EK

*E:<K?<J<:I@K<I@8?8M<9<<ED<KK?<G8K@<EKN@CC9<:FEJ@;<I<;HL8C@=@<;=FI/I<8KD<EK

/I<8KD<EK8;D@E@JKI8K@FEJ?FLC;F::LIN@K?@E;8PJF=K?<,L8C@=@:8K@FE=FI/I<8KD<EKM@J@K
/?<
GI<M@FLJCP;<J:I@9<;8PF=/I<8KD<EK:I@K<I@8DLJK9<D<K8KK?</I<8KD<EKM@J@KGI@FIKF@EA<:K@FE

Randomization:
!FCCFN@E>K?<J:I<<E@E>G<I@F;G8K@<EKJN?FD<<KK?<JKL;P@E:CLJ@FE<O:CLJ@FE:I@K<I@8N@CC9<I8E;FDCP
8JJ@>E<;9P8E@EK<I8:K@M<N<9I<JGFEJ<JPJK<D$2-.KFF=KI<8KD<EK8IDJ*/*30FIGC8:<9F
@E8I8K@F
*E<I8E;FD@Q8K@FEELD9<IN@CC9<8JJ@>E<;KF<8:?G8K@<EKGI@FIKFK?<=@IJKKI<8KD<EK8E;N@CC9<
8JJF:@8K<;N@K?FE<F=K?<=FCCFN@E>KI<8KD<EK8IDJ
 */*30
 +C8:<9F


CC<I>8EConfidential 
+IFKF:FC(*	0.	0-*	
+IFKF:FCD<E;D<EK(8P




CC<I>8EConfidential 
+IFKF:FC(*	0.	0-*	
+IFKF:FCD<E;D<EK(8P


Study Population Characteristics 
Number of Patients or SubjectsKC<8JKG8K@<EKJN@CC9<I8E;FD@Q<;8K8GGIFO@D8K<CPJ@K<J@EK?<
0E@K<;.K8K<J0.@EFI;<IKF8:?@<M<G8K@<EKJ@EK?<*/*30KI<8KD<EK>IFLG8E;G8K@<EKJ@EK?<
GC8:<9FKI<8KD<EK>IFLG8KK?<GI@D8IPK@D<GF@EK@<G8K@<EKJ8K2<<B8I<I<HL@I<;
KC<8JKG8K@<EKJ
N@CC9<I8E;FD@Q<;KFK8B<@EKF8::FLEK8E8KKI@K@FEI8K<F=

LanguageCCJKL;PD8K<I@8CJN?<K?<IGI@EK<;FI<C<:KIFE@:@E:CL;@E>@E=FID<;:FEJ<EK=FIDJ<	@8IP
GIFKF:FC8E;8CCG8K@<EK8E;J@K<@E=FID8K@FEN@CC9<@EK?< E>C@J?'8E>L8><
/?<I<8I<EFGC8EJKFKI8EJC8K<
JKL;PD8K<I@8CJ@EKFFK?<IC8E>L8><J

Condition/Disease+8K@<EKJN@K?JPDGKFDJF=*=I<HL<E:P8E;LI><E:P8E;LI@E8IP@E:FEK@E<E:<N?FJ<
JPDGKFDJ?8M<EFK9<<E8;<HL8K<CPD8E8><;N@K?8E8EK@:?FC@E<I>@:

Key Inclusion Criteria/?<G8K@<EKDLJKD<<KK?<=FCCFN@E>B<P:I@K<I@88KJ:I<<E@E>8E;-8E;FD@Q8K@FE8P
@EFI;<IKF9<@E:CL;<;@EK?<JKL;P
/?<J<8I<K?<B<P:I@K<I@8N?@:?;<=@E<K?<GFGLC8K@FEEFK8:FDGC<K<C@JK
F=8CC@E:CLJ@FE:I@K<I@8
 
+8K@<EK@JD8C<FI=<D8C<8><;≥P<8IJFC;

 
+8K@<EKN<@>?J≥B>C9J

 
+8K@<EK?8JJPDGKFDJF=*=I<HL<E:P8E;LI><E:PN@K?LI@E8IP@E:FEK@E<E:<=FI8G<I@F;F=8K
C<8JKDFEK?J@DD<;@8K<CPGI@FIKFJ:I<<E@E>;<K<ID@E<;9P;F:LD<EK<;G8K@<EK?@JKFIP

 
+8K@<EKLE;<IJK8E;JK?8KK?<P8I<EFKKF8CK<IK?<@I:LJKFD8IPC@=<G8KK<IEJ8IFLE;=CL@;:FEJLDGK@FEFI
D@:KLI@K@FEN?@C<G8IK@:@G8K@E>@EK?@JJKL;P



CC<I>8EConfidential 
+IFKF:FC(*	0.	0-*	
+IFKF:FCD<E;D<EK(8P


Key Exclusion Criteria/?<G8K@<EKN@CC9<<O:CL;<;=IFDG8IK@:@G8K@E>@EK?<JKL;P=FI8EPF=K?<=FCCFN@E>
B<P:I@K<I@88JJ<JJ<;;LI@E>K?<J:I<<E@E>G<I@F;8E;-8E;FD@Q8K@FE8PGI@FIKFJKL;PKI<8KD<EK
/?<J<8I<
K?<B<P:I@K<I@8N?@:?;<=@E<K?<GFGLC8K@FEEFK8:FDGC<K<C@JKF=8CC<O:CLJ@FE:I@K<I@8
 
+8K@<EK?8JJPDGKFDJF=*;L<KF8EPBEFNEE<LIFCF>@:8CI<8JFE<>JG@E8C:FI;@EALIPDLCK@GC<
J:C<IFJ@J:<I<9IFM8J:LC8I8::@;<EKCQ?<@D<ISJ;@J<8J<+8IB@EJFESJ;@J<8J<<K:


 
+8K@<EK?8JI<:<@M<;G?8ID8:FCF>@:K?<I8GPKFKI<8KJPDGKFDJF=*@E:CL;@E>EF:KLI@8N@K?@E
;8PJF=K?<JK8IKF=K?<J:I<<E@E>G<I@F;GIF:<;LI<J

 
+8K@<EKLJ<J$FI@E;N<CC@E>:8K?<K<IKFD8E8><LI@E8IP@E:FEK@E<E:<

 
+8K@<EK?8J8	?FLIKFK8CMFCLD<F=LI@E<MF@;<;D':FCC<:K<;FM<I:FEJ<:LK@M<?FLIJ
;LI@E>K?<	;8P9C8;;<I;@8IP:FCC<:K@FEG<I@F;GI@FIKF-8E;FD@Q8K@FE8P

 
+8K@<EK?8J?8;GI<M@FLJFI:LII<EK9FKLC@ELDKFO@EK?<I8GPF=8EPJ<IFKPG<=FI8EPLIFCF>@:8C
:FE;@K@FE

 
+8K@<EK?8J?8;GI<M@FLJFI:LII<EK9FKLC@ELDKFO@EK?<I8GPF=8EPJ<IFKPG<=FI8EPEFE	LIFCF>@:8C
:FE;@K@FEN@K?@EN<<BJGI@FIKF-8E;FD@Q8K@FE8P

 
+8K@<EK?8J?@JKFIPFI<M@;<E:<F=8EPG<CM@:FILIFCF>@:8C89EFID8C@K@<J9C8;;<IJLI><IPFI;@J<8J<
FK?<IK?8E*K?8KD8P8==<:K9C8;;<I=LE:K@FE@E:CL;@E>9LKEFKC@D@K<;KF
 
+8K@<EK?8J<M@;<E:<F=LI<K?I8C8E;FI9C8;;<IFLKC<KF9JKIL:K@FE@EK?<FG@E@FEF=K?<@EM<JK@>8KFI8K
J:I<<E@E>FI-8E;FD@Q8K@FE8P

 
+8K@<EK?8J8+1-LI@E<MFCLD<F=D'8KJ:I<<E@E>
/?<+1-LI@E<MFCLD<D<8JLI<D<EK:8E
9<I<G<8K<;FE:<K?<G8K@<EK@JKF9<<O:CL;<;@=K?<I<G<8K<;D<8JLI<@J89FM<D'



CC<I>8EConfidential 
+IFKF:FC(*	0.	0-*	
+IFKF:FCD<E;D<EK(8P


Response Measures 
Efficacy:   
Primary:  
 
?8E><=IFD98J<C@E<@EELD9<IF=<G@JF;<JF=LI@E8IP@E:FEK@E<E:<8K2<<B8JI<:FI;<;9P
K?<G8K@<EK@EK?<	;8P9C8;;<I;@8IP

Secondary:  
 
+IFGFIK@FEF=G8K@<EKJN?F8:?@<M<I<;L:K@FE@ELI@E8IP@E:FEK@E<E:<<G@JF;<J:FDGC<K<
:FEK@E<E:<=IFD98J<C@E<@<98J<C@E<GI@FIKF/I<8KD<EK
 
?8E><=IFD98J<C@E<@E;8@CP8M<I8><ELD9<IF=D@:KLI@K@FE<G@JF;<J
 
?8E><=IFD98J<C@E<@E;8@CP8M<I8><ELD9<IF=LI><E:P<G@JF;<J
 
?8E><=IFD98J<C@E<@E;8@CP8M<I8><ELD9<IF=EF:KLI@8<G@JF;<J
 
+IFGFIK@FEF=G8K@<EKJN?F?8M<8GFJ@K@M<KI<8KD<EKI<JGFEJ<FEK?</.J:FI<F=<@K?<IFI
I<GI<J<EK@E>R>I<8KCP@DGIFM<;SFIR@DGIFM<;SI<JG<:K@M<CP

Safety:   
 
;M<IJ<<M<EKJ8E;J<I@FLJ8;M<IJ<<M<EKJ. J
 
+?PJ@:8C<O8D@E8K@FE
 
1@K8CJ@>EJ
 
+1-LI@E<MFCLD<9P9C8;;<IJ:8EFILCKI8JFLE;
 
+I<>E8E:PK<JK=FINFD<EF=:?@C;9<8I@E>GFK<EK@8C8KJ:I<<E@E>9<=FI<JKL;PKI<8KD<EKJ8E;8K
JKL;P<O@K
 
0I@E<;@GJK@:BI<8><EKJKI@GK<JK
 
<EKI8CC89FI8KFIPLI@E<8E8CPJ@J
 
0I@E<:LCKLI<8E;J<EJ@K@M@KP
 
FE:FD@K8EKD<;@:8K@FEJ
 
FE:LII<EKGIF:<;LI<J@E:CL;@E>:8K?<K<I@Q8K@FEN@K?8JJF:@8K<;=I<HL<E:P8E;I<8JFE=FI
:8K?<K<I@Q8K@FE



CC<I>8EConfidential 
+IFKF:FC(*	0.	0-*	
+IFKF:FCD<E;D<EK(8P


General Statistical Methods and Types of Analyses: ==@:8:P<E;GF@EKJN@CC9<8E8CPQ<;LJ@E>K?<DF;@=@<;
@EK<EK	KF	KI<8KD$//+FGLC8K@FE
/?<GI@D8IP<==@:8:P<E;GF@EK@JK?<:?8E><=IFD98J<C@E<8K2<<B@EK?<
;8@CP8M<I8><ELD9<IF=<G@JF;<JF=LI@E8IP@E:FEK@E<E:<8JI<:FI;<;@EK?<	;8P9C8;;<I;@8IP

FDG8I@JFEF=*/*308E;GC8:<9F8K2<<B=FIK?<GI@D8IP<==@:8:P<E;GF@EK8E;FK?<I:FEK@ELFLJ
<E;GF@EKJN@CC9<G<I=FID<;LJ@E>8E8CPJ@JF=:FM8I@8E:<N@K?KI<8KD<EK8J8=8:KFI8E;98J<C@E<M8CL<8E;K?<
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1. 
Background and Clinical Rationale  
Overactive Bladder and Urinary Incontinence 
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Epidemiology and Impact of Overactive Bladder 
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2. 
Study Objectives and Clinical Hypotheses  
2.1 
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4. 
Study Population and Entry Criteria 
4.1 
Number of Subjects  
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Study Population Characteristics 
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4.3 
Inclusion Criteria 
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4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
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4.5.1.1 
Definition of Females of (Non-) Childbearing Potential and/or 
Acceptable Contraceptive Methods 
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4.5.2 
Prohibited Medications/Treatments 
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5. 
Study Treatments 
5.1 
Study Treatment and Formulation 
BOTOX 








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5.2 
Control Treatment 
BOTOX Placebo (Saline)  



5.3 
Methods for Masking/Blinding 
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5.4 
Treatment Allocation Ratio 
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Method for Assignment to Treatment Groups/Randomization 
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5.6 
Treatment Regimen and Dosing 
5.6.1 
Study Treatments 
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5.7 
Storage of Study Medications/Treatments 
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5.8 
Preparation/Dispensing of Study Medications 
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5.9 
Study Medication Administration 
5.9.1 
Day of Treatment 1 Criteria 
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5.9.2 
Prophylactic Antibiotics 
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5.9.3 
Use of Anesthesia 
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5.9.4 
Treatment Procedure 
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5.10 
Retreatment 
5.10.1 
Request/Qualification for Treatment 2 
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5.10.2 
Day of Treatment 2 Criteria 
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6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Measure 
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6.1.2 
Secondary Measures  
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6.2 
Safety Measures 
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6.3 
Examination Procedures, Tests, Equipment, and Techniques 
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6.3.1 
Medical History 
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6.3.2 
Physical Examination 
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6.3.3 
Vital Signs 
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6.3.4 
Bladder Diary 
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6.3.5 
Total Volume Voided 
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6.3.6 
Full Bladder Volume and Post-void Residual Urine Volume 
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6.3.6.1 
Post-void Residual Urine Volume < 200 mL  
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6.3.6.2 
Post-void Residual Urine Volume ≥ 200 mL and < 350 mL 
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6.3.6.3 
Post-void Residual Urine Volume ≥ 350 mL  
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6.3.7 
Clean Intermittent Catheterization 
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@E;N<CC@E>:8K?<K<I@JE<<;<;

6.3.7.1 
Initiation of Clean Intermittent Catheterization 
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6.3.7.2 
Cessation of Clean Intermittent Catheterization 
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6.3.8 
Adverse Events of Urinary Retention and Residual Urine 
Volume 
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6.3.9 
Dipstick Reagent Strip Test (Urine Dipstick) 
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6.3.10 
Urinalysis, Culture and Sensitivity 
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6.3.10.1 
Adverse Events of Urinary Tract Infection 
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6.3.11 
Pregnancy Test 
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6.3.12 
Screening Laboratory Tests 
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6.3.14 
Treatment Benefit Scale (TBS) 
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6.4 
Other Study Supplies 
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6.5 
Summary of Methods of Data Collection 
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7. 
Statistical Procedures 
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7.1 
Analysis Populations 
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7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
7.2.1 
Primary Efficacy Variables  
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7.2.2 
Secondary Efficacy Variables 
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7.3 
Hypothesis and Methods of Analysis 

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7.3.1 
Primary Efficacy Analyses 
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7.3.2 
Secondary Efficacy Analyses 
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7.3.4 
Safety Analyses 
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7.5 
Sample Size Calculation 
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7.6 
Primary Analysis   
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8. 
Study Visit Schedule and Procedures 
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8.1 
Subject Entry Procedures  
8.1.1 
Overview of Entry Procedures 
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8.1.2 
Informed Consent and Subject Privacy 
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8.2 
Washout Intervals 
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KFK?<JK8IKF=K?<J:I<<E@E>G<I@F;GIF:<;LI<J

8.3 
Procedures for Patient Rescreening 
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8.4 
Procedures for Final Study Entry 
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8.5 
Visits and Associated Procedures  
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D8B<K?<@IE<OKJ:?<;LC<;JKL;PM@J@K
8.6 
Unscheduled Visits 
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@EM<JK@>8KFI
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8.7 
Compliance with Protocol 
+8IK@:@G8K@E>G8K@<EKJDLJK9<89C<KF8;?<I<KFK?<;@8IP:FDGC<K@FE8E;K<JK@E>G8I8D<K<IJ
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K?<;<J@>E8K<;=@<C;@EK?<-!

8.8 
Early Discontinuation of Subjects 
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K?<G8IK@:@G8EK@JCFJKKF=FCCFN	LG

8.9 
Withdrawal Criteria 
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8.10 
Study Termination 
/?<JKL;PD8P9<JKFGG<;8K?@J?<IJKL;PJ@K<8K8EPK@D<9PK?<J@K<@EM<JK@>8KFI
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9. 
Adverse Events  
;M<IJ<<M<EKJF::LII@E>;LI@E>K?<JKL;PN@CC9<I<:FI;<;FE8E8;M<IJ<<M<EK:8J<I<GFIK
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9.1 
Definitions 
9.1.1 
Adverse Event 
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G?8ID8:<LK@:8CGIF;L:K8E;K?8K;F<JEFKE<:<JJ8I@CP?8M<8:8LJ8CI<C8K@FEJ?@GN@K?K?@J
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D<;@:@E8C@EM<JK@>8K@FE8CGIF;L:KN?<K?<IFIEFKI<C8K<;KFK?<D<;@:@E8C@EM<JK@>8K@FE8C
GIF;L:K
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F=K?<8;D@E@JKI8K@FEF=8G?8ID8:<LK@:8CGIF;L:K

9.1.2 
Study-specific Definitions for Particular Adverse Events 
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8JJF:@8K<;JPDGKFDJ@<MF@;@E>;@==@:LCK@<JJ<EJ8K@FEF=9C8;;<I=LCCE<JJK?8K@EK?<
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K?<0/$N8JTJPDGKFD8K@:UFIT8JPDGKFD8K@:UFEK?<8;M<IJ<<M<EK<-!

9.1.3 
Serious Adverse Event 
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FLK:FD<J;<8K?8C@=<	K?I<8K<E@E>8;M<IJ<<M<EK@EG8K@<EK?FJG@K8C@Q8K@FEFIGIFCFE>8K@FE
F=<O@JK@E>?FJG@K8C@Q8K@FE8G<IJ@JK<EKFIJ@>E@=@:8EK;@J89@C@KP@E:8G8:@KPFI8:FE><E@K8C
8EFD8CP9@IK?;<=<:K
$DGFIK8EKD<;@:8C<M<EKJK?8KD8PEFKI<JLCK@E;<8K?9<C@=<	
K?I<8K<E@E>FII<HL@I<?FJG@K8C@Q8K@FED8P9<:FEJ@;<I<;8E. N?<E98J<;LGFE
8GGIFGI@8K<D<;@:8CAL;>D<EKK?<PD8PA<FG8I;@Q<K?<G8K@<EKFIJL9A<:K8E;D8PI<HL@I<
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9.1.4 
Severity 
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9.1.5 
Relationship to Study Drug or Study Procedure 
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9<<E:8LJ<;9PK?<;IL>FIJKL;PGIF:<;LI<

9.2 
Procedures for Reporting Adverse Events 
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:FEJ<EKK?IFL>?JKL;P<O@K
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G8IK@:@G8EK@J:FEJ@;<I<;CFJKKF=FCCFN	LG

9.3 
Procedures for Reporting a Serious Adverse Event 
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K?<FLK:FD<JI<GFIK<;KFCC<I>8E
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9.4 
Procedure for Reporting Pregnancy 
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KI<8KD<EK
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9.5 
Procedures for Unmasking of Study Medication 
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10. 
Administrative Items 
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"L@;<C@E<FE"+

10.1 
Protection of Human Subjects 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
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8:K@M@K@<JFIGIF:<;LI<J@EK?<JKL;P8E;FI=IFDK?<JL9A<:KJC<>8CCP8LK?FI@Q<;
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CF:8CI<>LC8KFIPI<HL@I<D<EKJ

10.1.2 
Compliance with IRB or IEC Regulations 
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N@K?K?<@EM<JK@>8KFIJ?FLC;9<GIFM@;<;KFCC<I>8E

10.1.3 
Compliance with Good Clinical Practice 
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>L@;<C@E<J

10.1.4 
Compliance with Electronic Records; Electronic Signatures 
Regulations (21CFR Part 11) 
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<C<:KIFE@:J@>E8KLI<

10.2 
Changes to the Protocol 
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$-$ F=8GIFKF:FC8D<E;D<EK<O:<GKN?<I<E<:<JJ8IPKF<C@D@E8K<@DD<;@8K<?8Q8I;J


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JKL;P<>:?8E><@EDFE@KFIJ:?8E><F=K<C<G?FE<ELD9<IJ

10.3 
Patient Confidentiality 
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G8K@<EKSJE8D<N@CCEFK9<;@J:CFJ<;@EK?<J<;F:LD<EKJ
/?<G8K@<EKSJE8D<D8P9<
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!FF;8E;IL>;D@E@JKI8K@FE!@=K?<P@EJG<:KK?<JKL;PI<:FI;J
GGIFGI@8K<
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@E=FID8K@FE

10.3.1 
Patient Privacy 
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CF:8CGI@M8:PI<HL@I<D<EKJN?<I<8GGC@:89C<@JKF9<F9K8@E<;=IFD<8:?JL9A<:KGI@FIKF
<EIFCCD<EK@EKFK?<JKL;P8E;FI=IFDK?<JL9A<:KJC<>8CCP8LK?FI@Q<;I<GI<J<EK8K@M<@E
8::FI;8E:<N@K?K?<8GGC@:89C<GI@M8:PI<HL@I<D<EKJ<>K?<#<8CK?$EJLI8E:<+FIK89@C@KP
8E;::FLEK89@C@KP:K.K8E;8I;J=FI+I@M8:PF=$E;@M@;L8CCP$;<EK@=@89C<#<8CK?$E=FID8K@FE
T#$+U

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=FCCFN@E>
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10.4 
Documentation 
10.4.1 
Source Documents 
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@EM<JK@>8KFISJG8K@<EKJKL;P=@C<J8JN<CC8JK?<I<JLCKJF=;@8>EFJK@:K<JKJJL:?8JO	I8PJ
C89FI8KFIPK<JKJJ:8EJ8E;LCKI8JFLE;I<GFIKJ
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
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10.4.2 
Electronic Case Report Form Completion 
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10.4.3 
Study Summary 
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10.4.4 
Retention of Documentation 
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8::<JJD8@EK8@E:FE=@;<EK@8C@KPF=G8K@<EKJSD<;@:8CI<:FI;J8E;G<IJFE8C@E=FID8K@FE

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10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
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M@8CJ
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10.5.2 
Clinical Supply Inventory 
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10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
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;@JGFJ<;F=G<ICF:8CJ@K<GI8:K@:<

10.6 
Monitoring by the Sponsor 
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FE	J@K<M@J@KJKFI<M@<N8L;@K8E;:FGPJKL;P	I<C8K<;;F:LD<EKJ
/?<J<I<GI<J<EK8K@M<JN@CC
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JKL;P	I<C8K<;;8K88E;HL<JK@FEJ

10.7 
Handling of Biological Specimens 
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:C@E@:8CC89FI8KFIPN@K?:<IK@=@:8K@FE=IFD8I<:F>E@Q<;8::I<;@K8K@FE8><E:P<>FCC<><F=
D<I@:8E+8K?FCF>PFIC@E@:8C'89FI8KFIP$DGIFM<D<EKD<E;D<EKJ:<IK@=@:8K@FE



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10.8 
Publications 
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10.9 
Coordinating Investigator 
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11. 
References 
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12.1 
Preparation of Study Medication 
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Confidential 
12.6 
Treatment Benefit Scale (TBS) 
before you received any study 
treatment in this trial


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12.7 
Package Insert 
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12.8 
Glossary of Abbreviations 
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SAP_000.pdf: 
NCT03052764 
 
Study ID: CMO‐US‐URO‐0470 
 
 
 
Title: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study to 
Evaluate an Alternative Injection Paradigm for OnabotulinumtoxinA (BOTOX®) in the 
Treatment of Overactive Bladder in Patients with Urinary Incontinence (LO‐BOT). 
 
Statistical Analysis Plan Date: 07 March 2019 
 
 
 


Sponsor: Allergan 
Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
DocUUID : c7aafb22-1bf7-4990-9ffb-9ecf7d65a4e5 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
07 March 2019 
Final 2.0 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel- 
Group Study to Evaluate an Alternative Injection Paradigm for 
OnabotulinumtoxinA (BOTOX®) in the Treatment of Overactive Bladder 
in Patients with Urinary Incontinence 
 
 
 
 
Protocol Number: CMO-US-URO-0470 
Protocol Date: Amendment 1, 08 May 2018 
 
 
 
 
 
 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California 92612 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sponsor: Allergan 
Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
DocUUID : c7aafb22-1bf7-4990-9ffb-9ecf7d65a4e5 
 
 
 
Table of Contents 
1. Introduction......................................................................................................................... 8 
1.1 
Study Objectives and Design ...................................................................................... 8 
1.1.1 Study Design ................................................................................................... 9 
1.1.2 Primary Study Objective .............................................................................. 10 
1.1.3 Secondary Objectives ................................................................................... 10 
1.1.4 Sample Size ................................................................................................ 10 
2. Analysis Populations and Data Conventions .................................................................. 11 
2.1 
Analysis Populations .............................................................................................. 11 
2.1.1 Double-Blind Period ..................................................................................... 11 
2.1.1.1 Intent-to-treat (ITT) Population ................................................................... 11 
2.1.1.2 Modified Intent-to-treat (mITT) Population ................................................ 11 
2.1.1.3 Safety Population ........................................................................................ 11 
2.1.2 Open-Label Period ........................................................................................ 11 
 
 
2.3 
Data Conventions ................................................................................................... 12 
2.3.1 Handling of Missing Data .......................................................................... 13 
2.3.2 Handling of Missing Date .......................................................................... 16 
3. Disposition and Exit Status ................................................................................................. 18 
3.1 
Screening Log Data ................................................................................................ 18 
3.2 
Disposition and Exit Status ......................................................................................... 18 
3.3 
Protocol Deviations ................................................................................................... 18 
4. Demographics and Other Baseline Characteristics .......................................................... 19 
4.1 
Demographics ........................................................................................................... 19 
4.2 
Baseline Disease Characteristics .............................................................................. 19 
4.2.1 OAB Related Baseline Characteristics Recorded on the Electronic Case 
Report Form (eCRF) ..................................................................................... 19 
4.2.2 Baseline Characteristics from 3-day Bladder Diary ................................... 19 
4.3 
Prior Medications ...................................................................................................... 20 
4.4 
Past Medical History .............................................................................................. 21 
5. Efficacy Analyses ............................................................................................................. 22 
5.1 
Collection of Primary Efficacy Measurement(s) and Derivation of Primary  
Efficacy Variable(s) ................................................................................................ 22 
5.2 
Primary Efficacy Analyses ....................................................................................... 22 


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5.2.1 Primary Analyses of Primary Efficacy Variable(s) ..................................... 22 
 
 
5.3 
Secondary Efficacy Analyses ................................................................................... 23 
5.3.1 Proportion of Subjects who Achieved 100% Reduction in Urinary 
Incontinence Episodes from Baseline .......................................................... 23 
5.3.2 Change from Baseline in Daily Average Number of Micturition Episodes23 
5.3.3 Change from Baseline in Daily Average Number of Urgency Episodes ... 23 
5.3.4 Change from Baseline in Daily Average Number of Nocturia Episodes ... 24 
5.3.5 Proportion of subjects who have a positive treatment response on the 
Treatment Benefit Scale (TBS) .................................................................... 24 
5.4 
Other Analyses of Secondary Efficacy Variables ................................................... 24 
 
 
 
 
 
 
 
 
 
 
 
 
6. Safety Analyses ................................................................................................................... 28 
6.1 
Exposure to Study Treatment(s) ............................................................................... 28 
6.2 
Concomitant Medications ......................................................................................... 28 
6.3 
Concomitant Procedures ........................................................................................... 29 
6.4 
Clean intermittent catheterization (CIC) .................................................................. 30 
6.5 
Adverse Events ....................................................................................................... 30 
6.5.1 Study-specific Definitions for Particular Adverse Events ........................... 32 
6.5.2 Potential Distant Spread of Toxin Adverse Events ..................................... 32 
6.6 
Serious Adverse Events ............................................................................................ 33 
6.7 
Clinical Laboratory Evaluations ............................................................................. 33 
6.8 
Vital Signs ................................................................................................................. 34 
6.9 
Post-void residual (PVR) urine volume ................................................................. 34 
6.10 Other Safety Analyses ............................................................................................... 34 
6.10.1 Physical Examination ................................................................................. 34 
7. Primary Analysis ................................................................................................................. 35 
7.1 
Blinded Statistical Team ....................................................................................... 35 
7.2 
 Unblinded Statistical Team ................................................................................... 35 


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8. Changes from Protocol-Specified Analyses ....................................................................... 37 


Sponsor: Allergan 
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9. Reference ............................................................................................................................ 38 
10. Amendment(s) .................................................................................................................... 39 


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Protocol CMO-US-URO-0470 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
 
 
 
Term/Abbreviation 
Definition 
ANCOVA 
Analysis of Covariance
ATC 
Anatomical Therapeutic Chemical
BOTOX 
Botulinum Toxin Type A Purified Neurotoxin Complex (US adopted 
name onabotulinumtoxinA), referred to as BOTOX 
BMI 
Body Mass Index
CI 
Confidence Interval
CIC 
Clean Intermittent Catheterization
CM 
ConcomitantMedication
CMH 
CochranMantel-Haenszel
CSR 
Clinical Study Report
DB 
Double-blind
eCRF 
Electronic Case Report Form
I-QOL Questionnaire 
Incontinence Quality of Life Questionnaire
ITT 
Intent-to-Treat
IWRS 
Interactive Web Response System
LOCF 
Last Observation Carried Forward
LS 
Least Squares
MedDRA 
Medical Dictionary for RegulatoryActivities 
mITT 
ModifiedIntent-to-Treat
OAB 
Overactive Bladder
OL 
Open-label
PDSOT 
Possible Distant Spread of Toxin
PVR 
Post-void Residual
QOL 
Quality of Life
RBC 
Red Blood Cell
SAE 
SeriousAdverse Event
SAP 
StatisticalAnalysis Plan
SOC 
System Organ Class
PT 
Preferred Term
TBS 
Treatment Benefit Scale
TEAE 
Treatment-emergentAdverse Event


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SAP Final 07 March 2019
 
 
 
TLG 
Tables, Listings, and Graph
UTI 
Urinary Tract Infection
UUI 
Urgency Urinary Incontinence
WBC 
White Blood Cell
WHO 
World Health Organization
WHODDE 
World Health Organization – Drug Dictionary Enhanced 


DocUUID : c7aafb22-1bf7-4990-9ffb-9ecf7d65a4e5 
Sponsor: Allergan 
Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
 
 
 
1 
Introduction 
 
This Statistical Analysis Plan (SAP) details of the principal features of the analysis described 
in the protocol, and includes detailed procedures for executing the statistical analysis of the 
primary and secondary endpoints and other data. 
 
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock, or primary analysis data cut-off to ensure lack of bias. For operational efficiency 
an earlier time for finalizing and signing is usually targeted, i.e., prior to primary analysis 
data cut-off. If needed, revisions to the approved SAP may be made prior to database hard 
lock. Revisions will be version controlled. 
 
 is responsible for the statistical analysis and reporting of the study data. 
 
Prior to database hard lock, a final review of data and Tables, Listings, and Graphs (TLGs) 
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. A meeting to determine analysis set classifications may 
also be held prior to database hard lock. 
 
A primary analysis is planned for the study and more details in Section 7. 
 
 
1.1 
Study Objectives and Design 
1.1.1 Study Design 
 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to 
assess the safety and efficacy of a single treatment of BOTOX, administered using an 
alternative injection paradigm, followed by a second treatment (if applicable) with BOTOX 
in patients with overactive bladder (OAB) with urinary incontinence whose symptoms have 
not been adequately managed with an anticholinergic. 
 
Following the screening period, patients meeting the study inclusion/exclusion criteria will 
be randomly assigned by an interactive web response system (IWRS) to 1 of 2 treatment 
arms (BOTOX 100 U or placebo) in a ratio of 2:1 (Botox 100 U: Placebo). A central 
randomization scheme will be utilized. The overall enrollment period is estimated to be 24 
months. 
 
One randomization number will be assigned to each patient prior to the first treatment and 
will be associated with one of the following treatment arms: 
 
 Double-Blind Period 
BOTOX 100 U 


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Placebo 
 
 Open-Label Period 
 
BOTOX 100 U (DB treatment)/BOTOX 100 U (OL treatment if qualified) 
Placebo (DB treatment)/BOTOX 100 U (OL treatment if qualified) 
Subjects will be eligible to receive a second treatment if all the predefined OL treatment 
criteria are met (see protocol Section 5.10.2). All eligible subjects will receive BOTOX 100 
U for OL treatment. 
 
Subjects will be followed regularly for safety and efficacy at post-treatment visits. Subjects 
will complete up to 2 treatments with a minimum study participation of 25 weeks (i.e., if 
subject requests a second treatment at Week 12 and qualifies for second treatment) and a 
maximum duration of 53 weeks (i.e., if a subject qualifies for OL treatment at Week 30, 
receives an injection at Week 34, and completes other study visits at the maximum allowable 
visit window). 
 
1.1.2 Primary Study Objective 
 
The primary objective of this study is to evaluate the efficacy and safety of BOTOX 100 U 
(onabotulinumtoxinA), compared to placebo (PBO), when injected into the bladder using an 
alternative injection paradigm (2 trigonal and 8 peri-trigonal injections) in reducing the 
number of daily urinary incontinence episodes in subjects with OAB and urinary 
incontinence whose symptoms have not been adequately managed with an anticholinergic. 
 
1.1.3 Secondary Objectives 
 
The secondary objectives of this study are to evaluate the quality of life (QOL) impact, 
duration of treatment effect, early onset of treatment effect, and safety of BOTOX (100 U) in 
subjects with OAB and urinary incontinence whose symptoms have not been adequately 
managed with an anticholinergic. 
 
1.1.4 Sample Size 
 
Sample size calculation and power consideration is discussed in Section 7.5 of the study 
protocol. 


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Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
 
 
 
2 
Analysis Populations and Data Conventions 
 
2.1 
Analysis Populations 
2.1.1 Double-Blind Period 
 
The enrolled subjects (including all subjects who signed informed consent) will be used for 
subject disposition summary. 
 
2.1.1.1 
Intent-to-treat (ITT) Population 
The ITT Population will include all randomized subjects. Demographics and baseline 
characteristics will be analyzed using the ITT Population. Subjects will be grouped and 
analyzed according to their randomization assignment, regardless of the actual treatment 
received. 
 
2.1.1.2 
Modified Intent-to-treat (mITT) Population 
The mITT Population will include all randomized subjects who had at least one efficacy 
assessment at the baseline and a post-baseline visit. Efficacy variables will be analyzed using 
the mITT Population. Subjects will be grouped and analyzed according to their  
randomization assignment, regardless of the actual treatment received. 
 
2.1.1.3 
Safety Population 
The safety population will include all patients who receive the study drug (BOTOX 100 U or 
placebo). All safety variables will be analyzed using the Safety Population. Patients will be 
grouped and summarized according to the treatment they actually received. 
 
2.1.2  Open-Label Period 
 
Subjects who entered open-label re-treatment period will include subjects who are qualified 
for re-treatment and has an initiation of open-label (OL) BOTOX 100 U treatment. 
 
 
 
 
 
 
 


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SAP Final 07 March 2019
 
 
 
2.3 
Data Conventions 
The following are general conventions for the analysis of study data. If alternative methods 
are present in the specific evaluation sections of this SAP, those conventions will take 
precedence over these general conventions. 
 For double-blind period, summaries are based on the ITT population, mITT 
population, or safety population (described in Section 2.1) and will be presented by 
treatment group (BOTOX 100 U and Placebo). 


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SAP Final 07 March 2019
 
 
 
 For open-label period, summaries are based on the subjects who entered open-label 
re-treatment period (described in Section 2.1) and will be presented by BOTOX 100 
U/ BOTOX 100 U and Placebo/BOTOX 100 U 
 Continuous study measurements will be summarized by treatment group and time 
point (as applicable) using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum). Mean and median will be presented with one more 
decimal place than the precision of the data. Standard deviation will be presented 
with two more decimal places than the precision of the data. Minimum and  
maximum will be presented with the same precision as the original data. 
 Categorical study assessments will be summarized by treatment group and time point 
(as applicable) using frequency counts and percentages. Percentages will be presented 
with one decimal place (xx.x), with the exception of 100%, which will be displayed 
without any decimal places. 
● Statistical tests for all efficacy endpoints will be 2-sided at significance level of 0.05. 
● No adjustment for the multiplicity of the endpoints will be performed. 
● Unless stated otherwise, the baseline for DB period will be calculated as the last 
observed assessment before the DB first dose date. Baseline for OL period will be 
calculated as the last observed assessment before the OL first dose date. Change from 
baseline values will be calculated as the post-baseline value minus the respective 
baseline value. 
● All subject data, including unscheduled assessments will be displayed in subject 
listings. 
● Unless stated otherwise, available data from screen failures will be excluded from all 
tables, figures, and listings. 
● Unless stated otherwise, data from all the sites will be pooled for all the analyses. 
● Daily average number of episodes will be rounded to one decimal place. 
 
● Listings will be listed by randomized or actual treatment group in DB period if 
applicable. 
 
 
 
2.3.1 Handling of Missing Data 
 
Imputation approaches for the efficacy endpoints are described in Section 2.3.1.1, Section 
2.3.1.2 and Section 2.3.1.3. 
 
Imputation will not be performed for safety analyses. 


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2.3.1.1 
Handling of Missing Data for Primary Efficacy Variables 
The primary efficacy endpoint is: 
 Change from baseline in number of episodes of urinary incontinence at Week 12 as 
recorded by the subject in the 3-day bladder diary. 
The following algorithms will be used for diary data conventions: 
 
If there is no diary data (i.e., none of the 3 diary days is a valid diary day), the daily average 
frequency of urinary incontinence episodes will be considered as missing. A valid diary day 
is defined as any of the three 24-hour periods with 2 or more urinary episodes of any 
type. For a valid diary day, if no incontinence episodes are recorded, the number of 
incontinence episodes on that day will be summarized as zero. For an invalid diary day, the 
numbers incontinence episodes on that day will be treated as missing. 
 
If a diary is completed for at least 1 day of diary at any particular visit, then that subject’s 
daily average frequency of urinary incontinence episodes in a 3-day period for that given  
visit will be estimated by using the daily average number of urinary incontinence episodes of 
the available days in the 3-day diary period. 
 
If the number of episodes of urinary incontinence at study baseline is missing, it will be 
imputed using the median of all non-missing values regardless of treatment group at study 
baseline. For each scheduled post treatment visit within the 12-week period of the DB 
treatment period, missing values for the efficacy variable (the change from baseline in the 
daily frequency of episodes of urinary incontinence) will be replaced using the last 
observation carried forward approach. If subjects requested and received a second treatment 
on or after Week 12, they are no longer in DB treatment period and the LOCF rule for DB 
treatment period should no longer apply to them. The LOCF rule will be applied to subjects 
without a second treatment of BOTOX® through 36 weeks for endpoints where data are 
analyzed to the end of the study. 
 
When implemented, imputation of missing values will be performed only for subjects who 
receive a treatment in the pertinent treatment period. For example, only subjects receiving a 
second treatment will have values imputed in OL treatment period; subjects who 
discontinued from the study during the first treatment will not have data imputed for OL 
treatment period. 
 
2.3.1.2 
Handling of Missing Data for Secondary Efficacy Variables 
There are 5 secondary efficacy variables as follows: 
 Proportion of subjects who achieve 100% reduction in urinary incontinence episodes 
(complete continence) from baseline (i.e., baseline prior to DB treatment). 
 Change from baseline in daily average number of micturition episodes. 


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SAP Final 07 March 2019
 
 
 
 Change from baseline in daily average number of urgency episodes 
 
 Change from baseline in daily average number of nocturia episodes. 
 Proportion of subjects who have a positive treatment response on the Treatment 
Benefit Scale (TBS) (score of either 1 or 2, representing ‘greatly improved’ or 
‘improved’, respectively) at Week 12. 
The derivation of the first 4 secondary endpoints above, recorded from the 3-day bladder 
diary at each visit, will follow the same data convention and imputation approach as for the 
primary efficacy endpoint described in Section 2.3.1.1. 
 
Missing values for TBS will not be imputed. 
 


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Sponsor: Allergan 
Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
 
 
 
2.3.2 Handling of Missing Date 
 
As a general principle, imputation of missing dates for variables will not be done. Exceptions 
are for start and stop dates of AEs and concomitant medications. Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be shown. 
 
The following conventions will be used for missing adverse event dates and prior and 
concomitant dates. 
 
2.3.2.1 
Adverse Events Onset Date 
If the AE onset date is missing in which the day, month, and year are all unknown or only the 
day is known, the AE onset date is set to the date of initiation of the DB treatment. 
 
For the partial AE onset date and time, 
 If the year is present and the month and day are missing or the year and day are 
present and the month is missing: 
o If year = year of initiation of DB treatment, then set month and day to month 
and day of initiation of DB treatment 
o If year < year of initiation of DB treatment, then set month and day to 
December 31st. 
o If year > year of initiation of DB treatment, then set month and day to January 
1st. 
● If the month and year are present and the day is missing: 
o If year = year of initiation of DB treatment and: 
■ if month = month of initiation of DB treatment then set day to day 
of initiation of DB treatment 
■ if month < month of initiation of DB treatment then set day to last 
day of month 
■ if month > month of initiation of DB treatment then set day to 1st 
day of month 
o If year < year of initiation of DB treatment then set day to last day of month 
o If year > year of initiation of DB treatment then set day to 1st day of month 
● If the imputed AE onset date is after AE stop date, then set the onset date to the AE 
stop date. 
2.3.2.2 
Prior and Concomitant Medications Date 
If the start date of medication is completely missing in which the day, month, and year are all 
unknown or only the day is known, then the start date will not be imputed. Similar rules will 
be applied for the end date of medication. 


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● For the partial start date of medication, 
o If the year is present and the month and day are missing or the year and day 
are present and the month is missing, set month and day to January 1. 
o If the year and month are present and the day is missing, set day to 1st day of 
month. 
o If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
● For the partial end date of medication, 
o If the year is present and the month and day are missing or the year and date 
are present and the month is missing, set month and day to December 31. 
o If the year and month are present and the day is missing, set day to last day of 
the month. 


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3 
Disposition and Exit Status 
 
3.1 
Screening Log Data 
Number of screen failures and reason for failure will be summarized. 
 
3.2 
Disposition and Exit Status 
The number and percentage of subjects in each analysis population will be summarized by 
treatment group and overall. For the subjects who discontinued early, the primary reason for 
discontinuation will be summarized. Duration in DB and OL period will be calculated as 
below and will be summarized: 
● For subjects were not re-treated, duration in DB period will be calculated as (date of 
discontinuation/completion– date of initiation of DB treatment + 1). 
● For subjects were re-treated, duration in DB period will be calculated as (date of 
initiation of OL treatment – date of initiation of DB treatment + 1); duration in OL 
period will be calculated as (date of discontinuation/completion – date of initiation of 
OL treatment + 1); 
Study day of discontinuation will be calculated as below and listed. 
● For subjects that terminate the study early and were not re-treated, study day of 
discontinuation will be calculated as (date of discontinuation– date of initiation of DB 
treatment + 1). 
● For subjects that terminate the study early and were re-treated, study day of 
discontinuation will be calculated as (date of discontinuation– date of initiation of OL 
treatment + 1). 
Number and percentage of subjects randomized in each country and site will be presented by 
treatment group and overall. 
 
A data listing for all subjects will display disposition characteristics, including date of 
initiation of the DB treatment and OL treatment if applicable, study completion status, last 
study day/date completed, reason(s) for non-completion, date of early termination 
assessment/study day of termination, and any specific comments related to non-completion. 
 
3.3 Protocol Deviations 
Protocol deviations (PDs) will be summarized by deviation type. 
 
A data listing by treatment group, subject and time point will present details of each deviation. 


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4 
Demographics and Other Baseline Characteristics 
 
4.1 
Demographics 
Descriptive statistics for age, weight, body mass index (BMI) and height at study entry will 
be presented. Frequency tabulations for sex, ethnicity, age group (<65, >=65 years) and race 
(Caucasian, Black, Asian, American Indian or Alaskan Native, Other) and race (Caucasian 
and non-Caucasian) will be presented. This will be done for the ITT population by treatment 
group. 
 
BMI is calculated as BMI (kg/m2) = weight (kg) / height2 (m). 
 
4.2 
Baseline Disease Characteristics 
4.2.1 OAB Related Baseline Characteristics Recorded on the Electronic 
Case Report Form (eCRF) 
 
OAB related baseline characteristics summarized in Table 3 and recorded on the electronic 
case report form (eCRF) from the Screening Visit will be summarized for the ITT population 
by treatment group. 
 
Duration of the OAB symptoms in months is calculated as the number of months from onset 
date of OAB symptoms at diagnosis to the informed consent date at the screening. 
 
(Date of Informed Consent - Overactive Bladder Onset date+ 1) / 30.25 
Table 3: Overactive Bladder Related Baseline Characteristics from eCRF 
 
Characteristic 
Summarized as 
Categories 
Number of urinary tract infection (UTIs) 
occurring over the past 6 months 
Continuous 
N/A 
Duration of OAB symptoms (in months) 
Continuous 
N/A 
Post-void residual (PVR) volume (mL) 
Continuous 
N/A 
Bladder volume (mL) 
Continuous 
N/A 
4.2.2 Baseline Characteristics from 3-day Bladder Diary 
 
Baseline characteristics derived from the 3-day bladder diary prior to the Randomization 
Visit will be summarized as continuous variable for the ITT Population with following listed 
characteristics in Table 4. 


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Table 4: Baseline Characteristics from 3-Day Bladder Diary 
 
Characteristic 
Corresponding Items 
in 3-Day Bladder 
Diary 
Summarized 
as 
Categories
Daily average number of 
incontinence episodes 
Did you have 
accidental urinary 
leakage? as “Yes” 
Continuous 
N/A 
Daily average number of urgency 
episodes 
Was this episode 
associated with a 
sudden and urgent need 
to urinate? as “Yes” 
Continuous 
N/A 
Daily average number of urgency 
urinary incontinence (UUI) episodes 
Did you have 
accidental urinary 
leakage? as “Yes” + 
Was this episode 
associated with a 
sudden and urgent need 
to urinate? as “Yes” 
Continuous 
N/A 
Categorical 
≤ 9 versus 
> 9 
Daily average number of 
micturitions 
Did you urinate into 
the toilet? as “Yes” 
Continuous 
N/A 
Daily average number of nocturia 
episodes 
Did this episode wake 
you from night sleep? 
as “Yes” 
Continuous 
N/A 
Total volume voided per 24 hours 
Record volume 
collected in 24 hr for 
this urinary episode 
Continuous 
N/A 
 
4.3 
Prior Medications 
Prior medications are medications which started and ended before the initiation of DB 
treatment. 
 
Previous medications are coded with World Health Organization – Drug Dictionary 
Enhanced (WHODDE), and will be summarized by chemical subgroup (ATC 4th level) and 
preferred World Health Organization (WHO) name by treatment group for the ITT 
population. Prior medications summary will include prior OAB medications, prior urinary 
tract infection (UTI) medication, and prior non-UTI medication. 
 
Subjects taking the same medication multiple times will be counted once per medication. 


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4.4 
Past Medical History 
Medical history (other than for overactive bladder) and prior surgical procedure is coded in 
MedDRA, and will be summarized by System Organ Class (SOC) and Preferred Term (PT), 
by treatment group for the ITT Population. 


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5 
Efficacy Analyses 
Statistical tests for all efficacy endpoints will be 2-sided at significance level of 0.05. 
No adjustment for the multiplicity of the endpoints will be performed. 
 
The efficacy variables during the open-label period, no statistical tests will be performed for 
summaries of efficacy variables. 
5.1 
Collection of Primary Efficacy Measurement(s) and Derivation 
of Primary Efficacy Variable(s) 
The primary efficacy endpoint is: 
 Change from baseline in number of episodes of urinary incontinence at Week 12 as 
recorded by the subject in the 3-day bladder diary. 
Refer to Section 2.3.1.1 for the algorithms for diary data conventions. 
 
Change from baseline in number of episodes of urinary incontinence at Week 12 is derived as 
number of episodes of urinary incontinence per 24 hour at Week 12 minus number of  
episodes of urinary incontinence per 24 hour at Baseline. 
 
5.2 
Primary Efficacy Analyses 
5.2.1 Primary Analyses of Primary Efficacy Variable(s) 
Let µ1, µ2 be the true mean change from baseline at Week 12 in the daily average number of 
episodes of urinary incontinence for BOTOX 100 U and placebo, respectively. 
 
The hypothesis of the primary analysis will be formulated as 
H0: µ1 - µ2 = 0 vs 
Ha: µ1 - µ2 ≠ 0. 
 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model 
with treatment as a factor at 2 levels, and the number of UUI episodes reported at baseline (≤ 
9 versus > 9 daily episodes, during the 3-day bladder diary at baseline) and baseline daily 
average number of episodes of incontinence as covariates. Least squares (LS) mean for each 
treatment group and 95% confidence interval (CI) will be calculated. 
 
 
 
 
 


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5.3 
Secondary Efficacy Analyses 
5.3.1 Proportion of Subjects who Achieved 100% Reduction in Urinary 
Incontinence Episodes from Baseline 
 
Subject who achieves 100% reduction in urinary incontinence episodes (complete 
continence) from baseline is defined as: 
 If post-treatment urinary incontinence episodes = 0, set the 100% reduction in urinary 
incontinence episodes indicator equal to Y. 
 If post-treatment urinary incontinence episodes > 0, set the 100% reduction in urinary 
incontinence episodes indicator equal to N. 
This indicator will be derived for Week 1, Week 2, Week 6, Week 12, Week 24, and Week 
30, respectively. 
 
This endpoint will be analyzed using a Cochran Mantel-Haenszel (CMH) test adjusting for 
the number of UUI episodes reported at baseline (≤ 9 versus > 9 daily episodes, during the 3- 
day bladder diary at baseline) at each scheduled visit. Odds ratio and 95% CI 
(BOTOX/placebo) will be calculated. 
 
5.3.2 Change from Baseline in Daily Average Number of Micturition 
Episodes 
 
This endpoint will be analyzed at each scheduled visit (Week 1, Week 2, Week 6, Week 12, 
Week 24, and Week 30) using an ANCOVA model with treatment as a factor and baseline 
value corresponding to the given endpoint and the number of UUI episodes reported at 
baseline (≤ 9 versus > 9 daily episodes, during the 3-day bladder diary at baseline) as 
covariates. A 95% CI for the least-squares mean difference of a given endpoint between the 
two treatment groups will be calculated. 
 
5.3.3 Change from Baseline in Daily Average Number of Urgency Episodes 
 
Change from baseline in daily average number of urgency episodes at Week 1, Week 2, Week 
6, Week 12, Week 24, and Week 30 will be analyzed following the same algorithm as 
described in Section 5.3.2. 


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5.3.4 Change from Baseline in Daily Average Number of Nocturia 
Episodes 
 
Change from baseline in daily average number of nocturia episodes at Week 1, Week 2, Week 
6, Week 12, Week 24, and Week 30 will be analyzed following the same algorithm as 
described in Section 5.3.2. 
 
5.3.5 Proportion of subjects who have a positive treatment response on the 
Treatment Benefit Scale (TBS) 
 
Treatment Benefit Scale (TBS) is a single-item 4-point scale is used to assess the subject- 
reported benefit of treatment of OAB with respect to improvement or worsening of their 
condition at Week 12. Responses will be summarized descriptively by treatment groups. 
1- greatly improved 
2- improved 
3- not changed 
4- worsened 
TBS responders defined as subjects who rated their perception of response to treatment as 
either ‘greatly improved’ or ‘improved’ at Week 12 compared to baseline. This indicator will 
be derived for Week 12. The analysis will follow the same algorithm as described in Section 
5.3.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.2 Analysis for Continuous Endpoints 
 
Analysis for continuous endpoints at each visit will be conducted using the similar 
ANCOVA models as stated in Section 5.3.2 except for change from baseline in daily UUI 
episodes. For change from baseline in daily UUI episodes analysis, number of UUI episodes 
reported at baseline (≤ 9 versus > 9 daily episodes) will be excluded from the model. 
 
A paired t-test will be performed for the comparison between baseline and a post-treatment 
value at each visit for each endpoint. This analysis will follow the same algorithm as 
described in Section 5.4. 
 
5.5.3 Analysis of Categorical Endpoints 
 
Analysis for categorical endpoints at each visit will be conducted using CMH test in Section 
5.3.1. Point estimate and 95% CI for the odds ratio will be calculated for each endpoint at 
each visit. 


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5.5.4 Analysis of Time to Request of Re-Treatment 
 
The time-to-request of re-treatment between the two treatments will be analyzed using the 
log-rank test. Kaplan-Meier estimates of the time-to-request of re-treatment will be provided. 
A 95% CI for the median time-to-request of re-treatment for each treatment will be 
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6 
Safety Analyses 
 
All safety analyses will be conducted on the safety population. No inferential comparison 
between treatment groups will be performed for the safety analysis. 
 
6.1 
Exposure to Study Treatment(s) 
The study drug administration will be summarized by treatment group with descriptive 
statistics, including cystoscope type (Flexible, Rigid), number of injection site, total volume 
injected. The summary will be done for double-blind and open-label period separately. 
 
Details pertaining to the administration of study drug will be listed, including use of 
anesthesia, cystoscope type, date/time of injection, number of injection site, total volume 
injected, location of injections, etc. 
 
Prophylactic antibiotics are to be administered beginning 1 to 3 days before study treatment, 
on the day of study treatment, and continuing for 1 to 3 days after study treatment. The 
investigator is to prescribe the appropriate antibiotic and number of days pretreatment and 
post treatment based on clinical judgment and local site practice. Details of prophylactic 
antibiotics will be listed. Treatment period for prophylactic antibiotics will be derived using 
the similar logic as for concomitant medication. Please refer to Table 6 for the detailed 
classification. 
6.2 
Concomitant Medications 
Concomitant medications are medications which that started before initiation of DB 
treatment and continued into DB treatment or started after the initiation of the DB treatment. 
For re-treated subjects, the concomitant medications started before the initiation of OL 
treatment will be assigned to double-blind period. The concomitant medications started 
before the initiation of OL treatment and continued into OL treatment or started on or after 
the initiation of the OL treatment will be assigned to open-label period. Please refer to Table 
6 for the detailed classification. 
Concomitant medications are coded with WHODDE, and will be summarized by chemical 
subgroup (ATC 4th level) and preferred WHO name by treatment group for the Safety 
Population. Summary for concomitant medications will be based on safety population for 
those concomitant medications assigned to double-blind period and subjects who entered 
open-label re-treatment period for those concomitant medications assigned to open-label 
period. 
 
Subjects taking the same medication multiple times will be counted once per medication. A 
medication that can be classified into several chemical subgroups is presented in all chemical 
therapeutic subgroups. 


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Table 6: Classification of Concomitant Medications (CMs) by Treatment Period  
Subjects not re-treated: 
 
 
 
 
 
 
 
 
Subjects re-treated: 
 
Medication Start Date 
Medication Stop Date 
Medication Classification 
CM start date < OL 
Treatment start date 
CM stop date >=OL 
Treatment start date OR 
ongoing 
OL period 
CM start date >= OL 
Treatment start date 
 
OL period 
CM start date < OL 
Treatment start date 
CM stop date >= DB 
Treatment start date and CM 
stop date < OL Treatment 
start date 
DB period 
CM start date < OL 
Treatment start date 
CM stop date >= OL 
Treatment start date 
DB period, OL Period 
CM start date < OL 
Treatment start date 
Ongoing 
DB period, OL Period 
CM start date >= DB 
Treatment start date 
CM stop date < OL 
Treatment start date 
DB period 
CM start date >= DB 
Treatment start date 
CM stop date >= OL 
Treatment start date 
DB period, OL Period 
CM start date >= DB 
Treatment start date 
Ongoing 
DB period, OL Period 
6.3 
Concomitant Procedures 
Concomitant procedures (including catheterization with associated frequency and reason for 
catheterization) will be listed. Concomitant procedures will be coded in Medical Dictionary 
for Regulatory Activities (MedDRA, Version 19.0 or later). 
 
Treatment period for concomitant procedure will be derived using the similar logic as for 
concomitant medication. Please refer to Table 6 for the detailed classification. Concomitant 
procedures will be summarized. 
Medication Start Date 
Medication Stop Date 
Medication Classification 
CM start date < DB 
Treatment start date 
CM stop date >= DB 
Treatment start date OR 
ongoing 
DB period 
CM start date >= DB 
Treatment start date 
 
DB period 


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6.5 
Adverse Events 
Treatment-Emergent Adverse Events (TEAEs) are defined as those that begin on or after 
initiation of first dose of study treatment. For re-treated subjects, the TEAEs started on or 
after the initiation of DB treatment and before the initiation of OL treatment will be assigned 
to double-blind period. The TEAEs started on or after the initiation of OL treatment will be 
assigned to open-label period. Refer to Table 7 for the classification of TEAEs by treatment 
period as: 
 Double-blind period 
 Open-label period 
 
 
Table 7: Classification of TEAEs  
Subjects not re-treated: 
TEAE Start Date/Time 
TEAE Classification 
DB Treatment start date/time <= AE start date/time 
Double-Blind period 
 
Subjects re-treated: 
 
TEAE Start Date/Time 
TEAE Classification 
DB Treatment start date/time <= AE start date/time < OL 
Treatment start date/time 
Double-Blind period 
AE start date/time >= OL Treatment start date/time 
Open-Label period 
Adverse events will be classified by type, incidence, severity, and causality. The overall 
incidence of AEs will be summarized using the MedDRA coding system and classified by 
SOC, PT, and treatment group. 
 
An overall summary table will present the number of events and the incidence of subjects 
having at least one event in the following categories: 


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 TEAEs 
 TEAEs indicated as serious (SAEs) 
 TEAEs leading to study discontinuation 
 TEAEs leading to death 
 TEAEs related to study drug 
 Serious TEAEs related to study drug 
 Possible distant spread of toxin (PDSOT) TEAEs (refer to Section 6.5.2) 
 TEAEs of urinary retention (Refer to Section 6.5.1) 
 TEAEs of residual urine volume (Refer to Section 6.5.1) 
 TEAEs of urinary tract infection (Refer to Section 6.5.1) 
o TEAEs of asymptomatic urinary tract infection  
o TEAEs of symptomatic urinary tract infection 
Tabulation (using counts and percentages) of TEAEs classified by SOC and PT will be 
provided. In addition, Tabulation of TEAEs classified by SOC and PT will be provided for 
each of the following: 
 Serious TEAEs 
 Treatment-Related Serious TEAEs 
 TEAEs leading to study discontinuation 
 Treatment-related TEAEs leading to study discontinuation 
 
Tabulation of TEAEs classified by PT will be provided for each of the following: 
 TEAEs 
 Serious TEAEs 
 TEAEs by maximum severity 
o Subjects with multiple TEAEs with the same PT will be summarized at the 
maximum severity and counted one time for that PT. 
 TEAEs related to study drug 
 TEAEs leading to death 
When reporting the number of TEAEs, if the same TEAE occurs for a subject on multiple 
occasions the event will be counted once for each occurrence. 
 
All adverse events and related details will be listed by treatment group and subject. Non- 
treatment-emergent events will be identified in all listings, but not included in summaries. 


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6.5.1 Study-specific Definitions for Particular Adverse Events 
 
All particular AEs (AE of urinary retention, AE of residual urine volume, and AE associated 
with possible distant spread of toxin (PDSOT)) and treatment-related particular AEs will be 
tabulated by SOC and PT; in addition, all particular AEs will be listed by treatment group and 
subject. 
 
6.5.1.1 
Definition of Adverse Event of Urinary Retention: 
An adverse event of urinary retention should only be recorded when a subject has a raised 
PVR urine volume that requires intervention with CIC according to the following criteria: 
 Subject has a PVR urine volume of ≥ 350 mL (regardless of symptoms), OR 
 Subject has a PVR urine volume ≥ 200 mL and < 350 mL and the subject reports 
associated symptoms i.e., voiding difficulties, sensation of bladder fullness that in the 
investigator’s opinion require CIC. 
6.5.1.2 
Definition of Adverse Event of Residual Urine Volume: 
An adverse event of residual urine volume should be recorded if, in the investigator’s opinion, 
the raised PVR urine volume is clinically significant but does not fulfill the above definition 
for urinary retention. 
 
6.5.1.3 
Definition of Adverse Event of Urinary Tract Infection: 
An adverse event of UTI will be recorded if both the following criteria are fulfilled, 
regardless of subject symptoms: 
 A positive urine culture result with a bacteriuria count of > 105 colony forming 
units/mL 
 Leukocyturia of > 5/high-power field 
If a subject meets the criteria for the definition of a UTI, the investigator will record whether 
the UTI was “symptomatic” or “asymptomatic” on the adverse event eCRF 
 
6.5.2  Potential Distant Spread of Toxin Adverse Events 
 
To assess possible distant spread of toxin (PDSOT), 40 MedDRA preferred terms that may be 
associated with botulinum toxin effects have been identified in Table 8. All AEs associated 
with PDSOT will be tabulated by SOC and PT; in addition, all PDSOT AEs will be listed by 
treatment group and subject. The 40 terms are listed below. 


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Table 8: MedDRA Preferred Terms for Possible Distant Spread of Toxin 
Cardiac Disorders 
Bradycardia 
Eye Disorders 
Accommodation disorder 
Diplopia 
Extraocular muscle paresis 
Eyelid function disorder 
Eyelid ptosis 
Pupillary reflex impaired 
Vision blurred 
Gastrointestinal Disorders 
Constipation 
Dry mouth 
Dysphagia 
Ileus paralytic 
Infections and Infestations 
Botulism 
Musculoskeletal and Connective Tissue 
Disorders 
Muscular weakness 
Nervous System Disorders 
Bulbar palsy 
Cranial nerve palsies multiple 
Cranial nerve paralysis 
Dysarthria 
VIIth nerve paralysis 
Facial paresis 
Hyporeflexia 
Hypotonia 
Paralysis 
Paralysis flaccid 
Paresis cranial nerve 
Peripheral nerve palsy 
Peripheral paralysis 
Speech disorder 
Vocal cord paralysis 
Vocal cord paresis 
Renal and Urinary Disorders 
Urinary retention 
Respiratory, Thoracic and Mediastinal Disorders 
Aspiration 
Diaphragmatic paralysis 
Dysphonia 
Dyspnoea 
Pneumonia aspiration 
Respiratory arrest 
Respiratory depression 
Respiratory failure 
Reproductive System and Breast Disorders 
Pelvic floor muscle weakness 
 
6.6 
Serious Adverse Events 
The number and percent of subjects with serious adverse events will be tabulated by 
MedDRA system organ class and preferred term. In addition, a listing will be generated of 
subjects with serious adverse events. 
 
6.7 
Clinical Laboratory Evaluations 
Urinalysis will be performed at all study visits (excluding clinic visit at Week 24) by a central 
laboratory; a urine culture and sensitivity test will also be performed when central laboratory 


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urine results are suggestive of a UTI (positive leukocyte esterase, nitrites, blood and/or 
microscopic sediments such as white blood cells [WBCs], red blood cells [RBCs] and/or 
bacteria). 
 
For quantitative urinalysis results, actual values and changes from baseline will be 
summarized for each time point by treatment groups. Categorical urinalysis results will also 
be summarized. 
 
Urinalysis results will be classified as low, normal, or high at each visit according to the 
laboratory supplied reference ranges. Shift tables of reference range changes from Baseline 
to each visit will be summarized. 
 
At screening, prior to DB treatment, blood samples will be drawn from all subjects for 
analysis of the following laboratory tests to be performed by the central laboratory: complete 
blood count, creatinine, and blood urea nitrogen. All male subjects will undergo a prostate- 
specific antigen test also performed by the central laboratory. 
 
All laboratory results will be listed by treatment group, subject and time point. Listings of 
pregnancy testing, urine dipstick testing, and urine culture sensitivity assessment will be 
provided separately. 
 
6.8 
Vital Signs 
Collected vital signs will include pulse rate, blood pressure, and temperature. 
 
Results for each vital sign parameter will be listed by treatment group, subject, and time 
point. Actual values and changes from baseline will be summarized for each time point by 
treatment groups. 
 
6.9 
Post-void residual (PVR) urine volume 
PVR urine volume will be summarized descriptively for each treatment by visit. Change 
from baseline in PVR urine volume will be summarized. 
 
6.10 
Other Safety Analyses 
6.10.1 Physical Examination 
 
Physical examination results will be listed by treatment group, subject, and time point. 
 
 
7 
Primary Analysis 
 
A primary analysis will occur when all patients have completed 12 weeks following double- 
blind period or early terminated. Only tables will be produced (no patient listings will be 


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produced), thus maintaining patient and site/investigator treatment blinding. The primary 
analysis (topline data) will be a subset of the final analyses performed for the final CSR. 
Analyses included in the primary analysis will be flagged in the table, figure, and listing 
mocks. 
 
The main purpose of the primary analysis is for presentation of the key data as soon as 
possible at an international urological or urogynecological conference to ensure 
dissemination of results in a timely manner. The topline primary analysis data will include 
key efficacy and safety analysis from the first 12 weeks after double-blind treatment. 
 
For the purpose of the primary analysis, statistics and programming staff from the vendor 
CRO, will have blinded and unblinded teams set up for the analysis, per details contained in 
the SAP and/or other documentation listing those who will be unblinded. Unblinded 
statistical team will work in a restricted secure study location. Responsibilities of each team 
are listed in Section 7.1 and 7.2. 
 
Only Allergan study team members and corresponding co-authors will receive the topline 
primary analysis data (no analysis datasets and listings will be distributed, therefore the 
Allergan team and co-authors will not be unblinded to patient level data). Those who will be 
unblinded in Allergan will be listed in another document. No CSR will be authored following 
the primary analysis. 
 
Full unblinding will occur following the final database lock at the end of the study, for the 
final CSR. 
 
7.1 
 Blinded Statistical Team 
The responsibilities of the blinded statistical team are as follows: 
 Compile, generate, and review of all blinded TFLs and other reports as required by 
the primary analysis. 
 Secure provision of codes for blinded tables and listings to the unblinded statistical 
team, who will provide unblinded tables and listings to Allergan unblinded 
statistician. 
7.2 
 Unblinded Statistical Team 
The responsibilities of the unblinded statistical team are as follows: 
 Compile, generate, and review all unblinded TFLs as required by the primary analysis 
 Distribute all appropriate primary analysis materials to Allergan statistician via the 
secure email as password protected zip files. 


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Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
 
 
 
8 
Changes from Protocol-Specified Analyses 
 
No change from protocol-specified analysis. 


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Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
9 
Reference 
 
 
 
Patrick DL, Martin ML, Bushnell DM, Yalcin I, Wagner TH, Buesching DP. Quality of life of 
women with urinary incontinence: further development of the incontinence quality of life 
instrument (I-QOL). Urology. 1999;53:71-76. 
 
Patrick D, Khalaf K, Dmochowski R, Kowalski JW, Globe DR. Psychometric performance of 
the incontinence quality-of-life questionnaire among subjects with overactive bladder and 
urinary incontinence. Clin Ther. 2013;35(6):836-845. 


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Protocol CMO-US-URO-0470 
SAP Final 07 March 2019
10 
Amendment(s) 
 
 
 
Version 
Number/ 
Date 
Comments 
Rationale 
2.0 / 
07Mar2019 
1. Updated typo to 
specify that efficacy 
output uses the mITT 
population instead of 
ITT population. 
 
 
 
 
 
2. Updated to remove 
97.5% confidence 
intervals for the 
primary analysis of 
primary efficacy 
variables. 
 
 
 
3. Specified that CIC 
must be of duration 
greater than 1 day to 
be included in 
summary tables. 
 
 
4. Updated a typo where 
“IA” was used 
instead of “primary 
analysis” 
 
5. Other cosmetic 
updates 
1. Protocol amendment 1 (finalized 
prior to the primary analysis) 
specified to use mITT population for 
all efficacy analyses. SAP 1.0 has a 
typo specifying efficacy analyses 
will use the ITT population. This 
was changed to mITT to be 
consistent with protocol amendment 
1. 
 
2. Protocol amendment 1 only specifies 
that a 95% confidence interval will 
be provided for the primary analysis 
of efficacy variables. SAP 1.0 
included a 97.5% confidence  
interval that was not included in 
protocol amendment 1, so this was 
removed. 
 
3. The CIC duration was updated, so 
the CIC summaries will be 
consistent with the analysis 
performed in Phase III trials used for 
drug labeling. 
 
 
4. There was no interim analysis on 
this study. Using “IA” was a typo 
and should have referred to the 
primary analysis. 
 
5. Cosmetic updates include the 
following: section references that 
were incorrect were fixed, a 
sentence that was not capitalized 
was corrected, and text was made 
subscript where appropriate.