A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Single-treatment, 2-stage, Dose-finding Study Evaluating the Efficacy and Safety of BOTOX® Intravesical Instillation in Participants With Overactive Bladder and Urinary Incontinence
Phase: PHASE2
Conditions: Urinary Incontinence, Overactive Bladder With Urinary Incontinence
Sponsor: Allergan

NCT03320850 
 
Study ID: 1839‐201‐021 
 
 
Title:  A Phase 2, Multicenter, Randomized, Double‐blind, Placebo‐controlled, Single‐treatment, 2‐stage, 
Dose‐finding Study Evaluating the Efficacy and Safety of BOTOX® Intravesical Instillation in Participants 
With Overactive Bladder and Urinary Incontinence 
 
Protocol Amendment 2 Date: 20Dec2018 

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
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Protocol Amendment Summary of Changes Table 
 
Document History 
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Amendment 2 (20 Dec 2018) 

Overall Rationale for the Amendment: 
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04DEC2020 Abbreviated CSR 1839-201-021
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Table of Contents 
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04DEC2020 Abbreviated CSR 1839-201-021
6

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
7

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
8

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
9

 
 
Approval Date: 
 
20-Dec-2018
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• 
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04DEC2020 Abbreviated CSR 1839-201-021
10

 
 
Approval Date: 
 
20-Dec-2018
*)!$
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Overall 
• /PG<
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a Up to 4 co
and 500 U
participan
to proceed
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b Stage 2 wi
results fro

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Study Desig
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nsecutive cohor
U Cohorts will be
nts reach Week 6
d with dose esca
00 U. 
ll begin after co
om the 500 U Co
Cohort
DRC
D/FO@E/PG
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gn: 
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e based on indep
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alation either to
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ohort in Stage 1 b
300 U C
G<
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s cohort. After sa
 BOTOX 400 U fo
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decision to dose
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400 U Cohort
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500 U Cohort
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tion
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:FEKIFCC<;	
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e escalate to 300
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rt, the DRC will r
ether it is safe to
ased on unblinde
5
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0 U, possibly 400
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ed review of safe
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0 U, 
all 
ether 
tly to 
ety 
04DEC2020 Abbreviated CSR 1839-201-021
11

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
12

 
 
Approval Date: 
 
20-Dec-2018
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<8:?F=K?<I<D8@E@E>:F?FIKJ 8:?:F?FIK@E.K8><N@CC9<I8E;FD@Q<;J<G8I8K<CP
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GC8:<9F=K<II<M@<NF=K?<J8=<KP;8K8=IFDK?<0F?FIKF=.K8><9PK?<
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04DEC2020 Abbreviated CSR 1839-201-021
13

 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
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• $E.K8><	G8IK@:@G8EKJN@CC9<I8E;FD@Q<;@E8I8K@FKFI<:<@M<<@K?<I*/*3
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• $E.K8><	G8IK@:@G8EKJN@CC9<I8E;FD@Q<;@E8I8K@F=FIKI<8KD<EKN@K?
<@K?<I*/*30	*/*30	*/*30	*/*30FI0	FI
GC8:<9F
• FE=@ID8K@FEF=K?<*/*3;FJ<J=FI@EM<JK@>8K@FE@E.K8><N@CCF::LI8=K<I
I<M@<NF=LE9C@E;<;J8=<KP;8K8=IFDK?<0F?FIK@E.K8><9PK?<-8J<;
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>IFLGN@K?*/*30@E.K8><
• 1@J@K.:?<;LC<
04DEC2020 Abbreviated CSR 1839-201-021
14

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
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Number of Participants:
GGIFO@D8K<CPKFG8IK@:@G8EKJN@CC9<J:I<<E<;KFI8E;FD@Q<RKFG8IK@:@G8EKJKF
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RG8IK@:@G8EKJKFJKL;PKI<8KD<EK@E.K8><
Number of Sites:
.K8><GGIFO@D8K<CPJ@K<J@EK?<0E@K<;.K8K<J
.K8><GGIFO@D8K<CPJ@K<J@E/?<0E@K<;.K8K<J8E;8E8;8
Treatment Groups and Study Duration: 
-<=<IKFJ<:K@FEFE*M<I8CC.KL;P<J@>E89FM<=FIKI<8KD<EK>IFLG@E=FID8K@FE+8IK@:@G8K@FE@E
.K8><N@CC9<8KFK8CF=N<<BJ
N<<BJ:I<<E@E>8E;
N<<BKI<8KD<EK=FCCFN
LGG<I@F;
FI	@=G8IK@:@G8K@E>@E.K8><	N@CC9<8KFK8CF=N<<BJ
N<<BJ:I<<E@E>8E;
N<<B
KI<8KD<EK=FCCFN
LGG<I@F;

04DEC2020 Abbreviated CSR 1839-201-021
15

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
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
D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

2. 
Schedule of Activities (SoA) 
04DEC2020 Abbreviated CSR 1839-201-021
16

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
04DEC2020 Abbreviated CSR 1839-201-021
17

 
 
 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
04DEC2020 Abbreviated CSR 1839-201-021
18

 
 
 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

04DEC2020 Abbreviated CSR 1839-201-021
19

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
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
D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
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3. 
Introduction 
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FI8I<@EKFC<I8EKF=8E8EK@:?FC@E<I>@:D<;@:8K@FEE<NIFLK<F=8;D@E@JKI8K@FE	@EKI8M<J@:8C
@EJK@CC8K@FE	@J9<@E>;<M<CFG<;=FIK?<KI<8KD<EKF=*8E;LI@E8IP@E:FEK@E<E:<
3.1. 
Study Rationale 
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G?PJ@FCF>@:8C8E;9<?8M@FI8CK?<I8G@<JGIFM<@EJL==@:@<EK	J<:FE;C@E<G?8ID8:FCF>@:8C8><EKJ
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I<:<GKFIJ8E;JLGGI<JJ@EMFCLEK8IP;<KILJFI:FEKI8:K@FEJ	K?<I<9P@DGIFM@E>K?<JPDGKFDJF=
*/I<8KD<EKN@K?8EK@:?FC@E<I>@:J;<DFEJKI8K<8GIF=@C<F=>FF;<==@:8:P9LKN@K?J@>E@=@:8EK
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04DEC2020 Abbreviated CSR 1839-201-021
20

 
 
Approval Date: 
 
20-Dec-2018
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3.2. 
Background 
3.2.1. 
Overactive Bladder 
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<EJLI<JK@D<CPMF@;@E>/?@J@J8::FDGC@J?<;K?IFL>?8:FDGC<OE<KNFIBF=@EE<IM8K@FE9<KN<<E
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3.2.2. 
OnabotulinumtoxinA for the Treatment of Overactive Bladder 
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04DEC2020 Abbreviated CSR 1839-201-021
21

 
 
Approval Date: 
 
20-Dec-2018
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3.2.3. 
Nonclinical Studies 
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04DEC2020 Abbreviated CSR 1839-201-021
22

 
 
Approval Date: 
 
20-Dec-2018
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3.2.4. 
Clinical Studies 
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04DEC2020 Abbreviated CSR 1839-201-021
23

 
 
Approva
l Date: 
 
 
20-Dec-2018
3.3. 
Benefit/Risk Assessment 
04DEC2020 Abbreviated CSR 1839-201-021
24

 
 
Approval Date: 
 
20-Dec-2018
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4. 
Objectives and Endpoints 
Objectives 
Endpoints 
• 
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04DEC2020 Abbreviated CSR 1839-201-021
25

 
 
Approval Date: 
 
20-Dec-2018
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5. 
Study Design 
5.1. 
Overall Design 
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04DEC2020 Abbreviated CSR 1839-201-021
26

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
27

 
 
Approval Date: 
 
20-Dec-2018
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Participant and Study Completion 
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5.3. 
End of Study Definition 
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5.4. 
Scientific Rationale for Study Design  
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04DEC2020 Abbreviated CSR 1839-201-021
28

 
 
Approval Date: 
 
20-Dec-2018
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Justification for Dose 
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04DEC2020 Abbreviated CSR 1839-201-021
29

 
 
Approval Date: 
 
20-Dec-2018
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#P;IF><C8;D@OKLI<@E=<D8C<I8KJ8E;G@>J:FLGC<;N@K?K?<N<CC
<JK89C@J?<;EFE:C@E@:8CJ8=<KP
;8K88E;:C@E@:8CJ8=<KPGIF=@C<F=*/*3@EA<:K@FE@E:CL;@E>:LDLC8K@M<@EKI8DLJ:LC8I
@EA<:K@FEJ8:IFJJ@E;@:8K@FEJF=LGKF08JN<CC8JGI<M@FLJ*8E;)*;<M<CFGD<EK
GIF>I8DJN@K?@EKI8;<KILJFI@EA<:K@FEJLGKF0	JLGGFIKK?<@E@K@8K@FEF=K?<G?8J<JKL;P@E
*G8IK@:@G8EKJN@K?8JK8IK@E>;FJ<F=0
6. 
Study Population 
+IFJG<:K@M<8GGIFM8CF=GIFKF:FC;<M@8K@FEJKFI<:IL@KD<EK8E;<EIFCCD<EK:I@K<I@8	8CJFBEFNE8J
GIFKF:FCN8@M<IJFI<O<DGK@FEJ	@JEFKG<ID@KK<;
/?<GFGLC8K@FE:FEJ@JKJF=G8IK@:@G8EKJN@K?*8E;LI><E:PLI@E8IP@E:FEK@E<E:<N?F?8M<8E
@E8;<HL8K<I<JGFEJ<KFFI8I<@EKFC<I8EKF=G?8ID8:FCF>@:K?<I8GP


6.1. 
Inclusion Criteria 
+8IK@:@G8EKJ8I<<C@>@9C<KF9<@E:CL;<;@EK?<JKL;PFECP@=8CCF=K?<=FCCFN@E>:I@K<I@88GGCP
1. 
Age 
1.01 
(LJK9<KFP<8IJFC;8KK?<K@D<F=J@>E@E>K?<@E=FID<;:FEJ<EK 
2. 
Type of Participant and Disease Characteristics 
2.01 
#8JJPDGKFDJF=*=I<HL<E:P8E;LI><E:PN@K?LI><E:PLI@E8IP@E:FEK@E<E:<
=FI8G<I@F;F=8KC<8JKDFEK?J@DD<;@8K<CPGI@FIKFJ:I<<E@E>	;<K<ID@E<;9P
;F:LD<EK<;G8IK@:@G8EK?@JKFIP
04DEC2020 Abbreviated CSR 1839-201-021
30

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

2.04 
#8JEFK9<<E8;<HL8K<CPD8E8><;N@K?≥G?8ID8:FCF>@:K?<I8G@<J=FIKI<8KD<EKF=
K?<@I*JPDGKFDJ@<	8EK@:?FC@E<I>@:JFI9<K8
8>FE@JKJ	@EK?<FG@E@FEF=K?<
@EM<JK@>8KFI
4. 
Sex 
4.01 
(8C<FI=<D8C<G8IK@:@G8EK 
5. 
Contraceptives 
5.01 
#8J8E<>8K@M<GI<>E8E:PK<JKI<JLCK=FINFD<EF=:?@C;9<8I@E>GFK<EK@8C 
6. 
Informed Consent 
6.01 
2I@KK<E@E=FID<;:FEJ<EK=IFDK?<G8IK@:@G8EK?8J9<<EF9K8@E<;GI@FIKF8EPJKL;P
I<C8K<;GIF:<;LI<J.  
6.02 
2I@KK<E;F:LD<EK8K@FE?8J9<<EF9K8@E<;@E8::FI;8E:<N@K?K?<I<C<M8EK:FLEKIP
8E;CF:8CGI@M8:PI<HL@I<D<EKJ	N?<I<8GGC@:89C<<>	2I@KK<ELK?FI@Q8K@FE=FI0J<
8E;-<C<8J<F=#<8CK?8E;-<J<8I:?.KL;P$E=FID8K@FE0.J@K<J8E;NI@KK<E8K8
+IFK<:K@FE:FEJ<EK 0J@K<J
04DEC2020 Abbreviated CSR 1839-201-021
31

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
6.2. 
Exclusion Criteria 
+8IK@:@G8EKJ8I<<O:CL;<;=IFDK?<JKL;P@=8EPF=K?<=FCCFN@E>:I@K<I@88GGCP
1. 
Medical Conditions 
1.01 
#8JJPDGKFDJF=*;L<KF8EPBEFNEE<LIFCF>@:8C:FE;@K@FE<>	JG@E8C:FI;@EALIP	
DLCK@GC<J:C<IFJ@J	:<I<9IFM8J:LC8I8::@;<EK	CQ?<@D<ISJ;@J<8J<	+8IB@EJFESJ;@J<8J<	
<K: 
1.02 
#8J8GI<;FD@E8E:<F=JKI<JJ@E:FEK@E<E:<@EK?<FG@E@FEF=K?<@EM<JK@>8KFI	8J
;<K<ID@E<;9PG8IK@:@G8EKD<;@:8C?@JKFIP 
1.03 
#8J?@JKFIPFI<M@;<E:<F=8EPG<CM@:FILIFCF>@:8C89EFID8C@K@<J
04DEC2020 Abbreviated CSR 1839-201-021
32

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
04DEC2020 Abbreviated CSR 1839-201-021
33

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
2.03 
#8J?8;GI<M@FLJFI:LII<EK9FKLC@ELDKFO@EK?<I8GPF=8EPJ<IFKPG<=FI8EPLIFCF>@:8C
:FE;@K@FE
04DEC2020 Abbreviated CSR 1839-201-021
34

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
/?<I<8I<EFJG<:@=@:I<HL@I<D<EKJI<>8I;@E>;@<K




6.4. 
Screen Failures 
.:I<<E=8@CLI<J8I<;<=@E<;8JG8IK@:@G8EKJN?F:FEJ<EKKFG8IK@:@G8K<@EK?<:C@E@:8CJKL;P9LK8I<
EFKJL9J<HL<EKCPI8E;FD@Q<;KFKI<8KD<EKD@E@D8CJ<KF=J:I<<E=8@CLI<@E=FID8K@FE@J
I<HL@I<;KF<EJLI<KI8EJG8I<EKI<GFIK@E>F=J:I<<E=8@CLI<G8IK@:@G8EKJKFD<<KK?<FEJFC@;8K<;
.K8E;8I;JF=-<GFIK@E>/I@8CJ*).*-/GL9C@J?@E>I<HL@I<D<EKJ8E;KFI<JGFE;KFHL<I@<J
=IFDI<>LC8KFIP8LK?FI@K@<J(@E@D8C@E=FID8K@FE@E:CL;<J;<DF>I8G?P	J:I<<E=8@CLI<;<K8@CJ	
<C@>@9@C@KP:I@K<I@8	8E;8EPJ<I@FLJ8;M<IJ<<M<EK. 
04DEC2020 Abbreviated CSR 1839-201-021
35

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O


7. 
Treatments 
.KL;PKI<8KD<EK@J;<=@E<;8J8EP@EM<JK@>8K@FE8CKI<8KD<EKJ	D8IB<K<;GIF;L:KJ	GC8:<9F	FI
D<;@:8C;<M@:<J@EK<E;<;KF9<8;D@E@JK<I<;KF8JKL;PG8IK@:@G8EK8::FI;@E>KFK?<JKL;P
GIFKF:FC
7.1. 
Treatments Administered 
Study 
Treatment 
Name 
*/*38E;#P;IF><C;D@OKLI<
*/*3+C8:<9F8E;#P;IF><C;D@OKLI< 
Dosage 
Formulation
*/*3

Clostridium 
botulinumKFO@E/PG<@E8JK<I@C<M8:LLD
;I@<;=FIDKF9<I<:FEJK@KLK<;N@K?
JK<I@C<J8C@E<N@K?FLKGI<J<IM8K@M<

#P;IF><C-/"<C/(

 8:?M@8CF=#P;IF><C
:FEK8@EJ



*/*38E;#P;IF><C;D@OKLI<9
-<:FEJK@KLK<;*/*3KF9<8;D@E@JK<I<;
N@K?#P;IF><C=FI@EKI8M<J@:8C@EJK@CC8K@FE
*/*3+C8:<9F

<8:?M@8C:FEK8@EJD>F=JF;@LD:?CFI@;<
@E8JK<I@C<	M8:LLD
;I@<;=FIDKF9<
I<:FEJK@KLK<;N@K?JK<I@C<J8C@E<
N@K?FLKGI<J<IM8K@M<

#P;IF><C-/"<C/(

 8:?M@8CF=#P;IF><C
:FEK8@EJ



*/*3+C8:<9F8E;#P;IF><C;D@OKLI<9
-<:FEJK@KLK<;*/*3+C8:<9FKF9<
8;D@E@JK<I<;N@K?#P;IF><C=FI@EKI8M<J@:8C
@EJK@CC8K@FE
Route of 
Administration 
$EKI8M<J@:8C@EJK@CC8K@FE
$EKI8M<J@:8C@EJK@CC8K@FE
Dosing 
Instructions 
.@E>C<KI<8KD<EKD'MFCLD<
8;D@E@JK<I<;9PK?<@EM<JK@>8KFIJFIJKL;P
J@K<G<IJFEE<CHL8C@=@<;KFGC8:<8
KI8EJLI<K?I8C:8K?<K<I
.@E>C<KI<8KD<EKD'MFCLD<
8;D@E@JK<I<;9PK?<@EM<JK@>8KFIJFIJKL;P
J@K<G<IJFEE<CHL8C@=@<;KFGC8:<8
KI8EJLI<K?I8C:8K?<K<I
Packaging and 
Labeling 
*/*3N@CC9<GIFM@;<;@EM@8CJ@E
@;<EK@:8CG8:B8>@E>8E;C89<C@E>KFGC8:<9F



*/*3+C8:<9FN@CC9<GIFM@;<;@EM@8CJ@E
@;<EK@:8CG8:B8>@E>8E;C89<C@E>KF*/*3


Manufacturer 
*/*3CC<I>8E$E:
#P;IF><C-/"<C/(

*/*3+C8:<9FCC<I>8E$E:
#P;IF><C-/"<C/(

04DEC2020 Abbreviated CSR 1839-201-021
36

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O


7.1.1. 
Treatment Regimen and Dosing 
CC<C@>@9C<G8IK@:@G8EKJ<EIFCC<;@EKFK?<JKL;PN@CCI<:<@M<8J@E>C<;FL9C<
9C@E;KI<8KD<EKF=
<@K?<I*/*3FIGC8:<9F=FI.K8><FI.K8><8J=FCCFNJ
.K8><
• 0F?FIK0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;#P;IF><C8;D@OKLI<
EFIGC8:<9FE
• 0F?FIK0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;#P;IF><C8;D@OKLI<
EFIGC8:<9FE
• 0F?FIKFGK@FE8C0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;#P;IF><C
8;D@OKLI<EFIGC8:<9FE
• 0F?FIK0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;#P;IF><C8;D@OKLI<
EFIGC8:<9FE
8J<;FEK?<F9J<IM<;J8=<KP;8K8=IFDK?<08E;0F?FIKJ	K?<-N@CCI<:FDD<E;
KFGIF:<<;N@K?<@K?<I*/*30=FCCFN<;9P*/*30FIN?<K?<I@K@JJ8=<KF;FJ<
<J:8C8K<;@I<:KCPKF*/*30
.K8><
• 0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;#P;IF><C8;D@OKLI<E
• 0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;#P;IF><C8;D@OKLI<E
• 0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;#P;IF><C8;D@OKLI<E
• 0FGK@FEKFI<GC8:<N@K?0*/*3@EKI8M<J@:8C@EJK@CC8K@FE*/*38E;
#P;IF><C8;D@OKLI<E
• */*3+C8:<9F@EKI8M<J@:8C@EJK@CC8K@FE+C8:<9F8E;#P;IF><C8;D@OKLI<E
/?<=FLI*/*3;FJ<J=FI@EM<JK@>8K@FE@E.K8><N@CC9<J<C<:K<;98J<;FEK?<I<M@<NF=
LE9C@E;<;J8=<KP;8K8=IFDK?<0F?FIK@E.K8><9PK?<-/?<-N@CC?8M<K?<
FGK@FEKFI<GC8:<K?<0KI<8KD<EK>IFLGN@K?*/*30@E.K8><
7.1.2. 
Day of Treatment Criteria 
/?<=FCCFN@E>;8PF=KI<8KD<EK:I@K<I@8DLJK9<=LC=@CC<;GI@FIKF8;D@E@JKI8K@FEF=JKL;P
KI<8KD<EK8KI8E;FD@Q8K@FE8P
• <EKI8CC89FI8KFIPLI@E<8E8CPJ@JI<JLCKJ=FIGFJJ@9C<0/$?8M<9<<EI<M@<N<;
04DEC2020 Abbreviated CSR 1839-201-021
37

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

• )<>8K@M<LI@E<;@GJK@:BI<8><EKJKI@GK<JK=FIE@KI8K<J8E;C<LBF:PK<<JK<I8J<G<I=FID<;8K
K?<JKL;PJ@K<
• +8IK@:@G8EK@J8JPDGKFD8K@:=FI80/$	@EK?<FG@E@FEF=K?<@EM<JK@>8KFI
• )<>8K@M<LI@E<GI<>E8E:PK<JK=FINFD<EF=:?@C;9<8I@E>GFK<EK@8C
• $EM<JK@>8KFI:FEK@EL<JKF;<<DK?8KEF:FE;@K@FEFIJ@KL8K@FE<O@JKJN?@:?	@EK?<
@EM<JK@>8KFISJFG@E@FE	GLKJK?<G8IK@:@G8EK8KJ@>E@=@:8EKI@JB=IFDI<:<@M@E>8E@EKI8M<J@:8C
@EJK@CC8K@FEF=*/*3
7.1.3. 
Instillation Procedure 
/I<8KD<EK8;D@E@JKI8K@FEDLJK9<G<I=FID<;9PK?<@EM<JK@>8KFI	JL9@EM<JK@>8KFIJFIJKL;PJ@K<
G<IJFEE<CHL8C@=@<;KFGC8:<8KI8EJLI<K?I8C:8K?<K<I
$EFI;<IKFGIFM@;<>L@;8E:<KFHL8C@=@<;J@K<G<IJFEE<CN?F?8M<9<<E;<C<>8K<;K?<IFC<F=
JKL;PKI<8KD<EK8;D@E@JKI8KFI	K?<@EM<JK@>8KFI@J<OG<:K<;KFG<I=FIDFI9<GI<J<EK=FI8KC<8JK
K?<=@IJK@EJK@CC8K@FEGIF:<;LI<G<I=FID<;8KK?<J@K<
04DEC2020 Abbreviated CSR 1839-201-021
38

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
04DEC2020 Abbreviated CSR 1839-201-021
39

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

7.2. 
Dose Modification 
)FK8GGC@:89C<
7.3. 
Method of Treatment Assignment 
+I@FIKF@E@K@8K@FEF=JKL;PKI<8KD<EK	<8:?G8IK@:@G8EKN?FGIFM@;<J@E=FID<;:FEJ<EKN@CC9<
8JJ@>E<;8G8IK@:@G8EKELD9<IK?8KN@CCJ<IM<8JK?<G8IK@:@G8EK@;<EK@=@:8K@FEELD9<IFE8CCJKL;P
;F:LD<EKJ
!FI.K8><	G8IK@:@G8EKJN@CC9<I8E;FD@Q<;:<EKI8CCPFEI8E;FD@Q8K@FE8PLJ@E>8E
8LKFD8K<;I8E;FD@Q8K@FEJPJK<DKFF=KI<8KD<EK>IFLGJN@K?@E<8:?:F?FIK@E8I8K@FKF
I<:<@M<*/*38E;#P;IF><C8;D@OKLI<FIGC8:<9F8E;#P;IF><C8;D@OKLI<
!FI.K8><	G8IK@:@G8EKJN@CC9<I8E;FD@Q<;8E;JKI8K@=@<;:<EKI8CCPFEI8E;FD@Q8K@FE8P9P
98J<C@E<LI><E:PLI@E8IP@E:FEK@E<E:<<G@JF;<J≤FI<G@JF;<J;8P8E;J<O:FCC<:K<;
;LI@E>K?<J:I<<E@E>G<I@F; 8:?G8IK@:@G8EKN@K?@E8JKI8K@=@:8K@FE>IFLGN@CC9<I8E;FD@Q<;
LJ@E>8E8LKFD8K<;I8E;FD@Q8K@FEJPJK<DKFF=KI<8KD<EK8IDJ*/*308E;
#P;IF><C8;D@OKLI<	*/*308E;#P;IF><C8;D@OKLI<	*/*308E;#P;IF><C
8;D@OKLI<	*/*306FI*/*3078E;#P;IF><C8;D@OKLI<	GC8:<9F8E;#P;IF><C
8;D@OKLI<@E8I8K@FF=
04DEC2020 Abbreviated CSR 1839-201-021
40

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O


7.4. 
Blinding/Masking 
CC@EM<JK@>8K@FE8CJKL;PKI<8KD<EKJ*/*38E;GC8:<9FN@CC?8M<@;<EK@:8CG8:B8>@E>8E;
C89<C@E>KFD8@EK8@ED8JB@E>F=K?<JKL;P.KL;PKI<8KD<EKJN@CC9<@;<EK@=@<;8J@EM<JK@>8K@FE8C
:FDGFLE;J

/?<#P;IF><CN@CCEFK9<D8JB<;8E;N@CC9<GIFM@;<;KFJ@K<J@E8EFG<E
C89<C=8J?@FE
#P;IF><C=FI@EKI8M<J@:8C@EJK@CC8K@FEN@K?*/*3*/*3+C8:<9FN@CC9<@;<EK@=@<;8J8E
@EM<JK@>8K@FE8C:FDGFLE;

2?<EE<:<JJ8IP=FIK?<J8=<KP8E;GIFG<IKI<8KD<EKF=K?<G8K@<EK	K?<@EM<JK@>8KFI:8ELED8JB
K?<G8IK@:@G8EKSJKI<8KD<EK8JJ@>ED<EKKF;<K<ID@E<N?@:?KI<8KD<EK?8J9<<E8JJ@>E<;8E;
@EJK@KLK<8GGIFGI@8K<=FCCFN
LG:8I<2?<EGFJJ@9C<	K?<JGFEJFICC<I>8E(<;@:8C.8=<KP
+?PJ@:@8EJ?FLC;9<EFK@=@<;GI@FIKFLED8JB@E>JKL;PD<;@:8K@FE/?<@EM<JK@>8KFIJ?FLC;
@E=FIDK?<JGFEJFICC<I>8E(<;@:8C.8=<KP+?PJ@:@8EF=K?<LED8JB@E>@=K?<I<@JEF
EFK@=@:8K@FEGI@FIKFK?<LED8JB@E>
7.5. 
Preparation/Handling/Storage/Accountability 
<K8@C<;I<:FEJK@KLK@FE@EJKIL:K@FEJN@CC9<@E:CL;<;@EK?<.KL;P+?8ID8:P(8EL8C
/?<JKL;PD<;@:8K@FEDLJK9<JKFI<;@E8J<:LI<8I<88E;8;D@E@JK<I<;FECPKFG8IK@:@G8EKJ
<EK<I<;@EKFK?<:C@E@:8CJKL;P	8KEF:FJKKFK?<G8IK@:@G8EK	@E8::FI;8E:<N@K?K?<:FE;@K@FEJ
JG<:@=@<;@EK?@JGIFKF:FC*ECP8LK?FI@Q<;J@K<JK8==D8PJLGGCPFI8;D@E@JK<IJKL;PKI<8KD<EK
04DEC2020 Abbreviated CSR 1839-201-021
41

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

CC:C@E@:8CJKL;PD<;@:8K@FEJKI<8KD<EKJ8E;FIJLGGC@<JN@CC9<I<KLIE<;KFCC<I>8EFICC<I>8E
;<J@>E<<=FI;<JKIL:K@FEFI;<JKIFP<;8KK?<J@K<8JJG<:@=@<;@ENI@K@E>9PCC<I>8E
7.6. 
Treatment Compliance 
.KL;PKI<8KD<EKN@CC9<8;D@E@JK<I<;9PK?<@EM<JK@>8KFIFIJKL;PJ@K<G<IJFEE<CHL8C@=@<;KFGC8:<
8KI8EJLI<K?I8C:8K?<K<I
7.7. 
Concomitant Therapy 
/?<LJ<F=8EP:FE:FD@K8EKD<;@:8K@FE	GI<J:I@GK@FEFIFM<I
K?<
:FLEK<I	@JKF9<I<:FI;<;FEK?<
G8IK@:@G8EKSJ<C<:KIFE@::8J<I<GFIK=FID<-!8K<8:?M@J@K8CFE>N@K?K?<I<8JFEK?<
D<;@:8K@FE@JK8B<E
7.7.1. 
Prohibited Treatments and Washout Before the Study 
+IF?@9@K<;D<;@:8K@FEN8J?FLKF=G?8ID8:FCF>@:K?<I8GPKFKI<8KJPDGKFDJF=*	@E:CL;@E>
EF:KLI@8	DLJK9<:FDGC<K<GI@FIKFK?<=@IJKJ:I<<E@E>GIF:<;LI<


7.7.2. 
Permitted Treatments 
EPD<;@:8K@FEFIM8::@E<@E:CL;@E>FM<I
K?<
:FLEK<IFIGI<J:I@GK@FED<;@:@E<J	M@K8D@EJ	
8E;FI?<I98CJLGGC<D<EKJK?8KK?<G8IK@:@G8EK@JI<:<@M@E>8KK?<K@D<F=<EIFCCD<EKFII<:<@M<J
;LI@E>K?<JKL;PDLJK9<I<:FI;<;8CFE>N@K?
• $E;@:8K@FE
• 8K<JF=8;D@E@JKI8K@FE@E:CL;@E>JK8IK8E;<E;;8K<J
• FJ8><@E=FID8K@FE@E:CL;@E>;FJ<8E;=I<HL<E:P
/?<I8GP:FEJ@;<I<;E<:<JJ8IP=FIK?<G8IK@:@G8EKSJN<C=8I<D8P9<>@M<E8KK?<;@J:I<K@FEF=K?<
@EM<JK@>8KFI$=K?<G<ID@JJ@9@C@KPF=8JG<:@=@:D<;@:8K@FEKI<8KD<EK@J@EHL<JK@FE	GC<8J<:FEK8:K
K?<JGFEJFI
/?<JGFEJFIFI;<J@>E<<J?FLC;9<:FEK8:K<;@=K?<I<8I<8EPHL<JK@FEJI<>8I;@E>:FE:FD@K8EKFI
GI@FIK?<I8GP
8LK@FE@J8;M@J<;@=K?<G8IK@:@G8EKI<HL@I<JKI<8KD<EKN@K?8D@EF>CP:FJ@;<8EK@9@FK@:JFI:LI8I<
C@B<8><EKJ;LI@E>K?<:FLIJ<F=K?<JKL;P/?@J@J;L<KFK?<GFK<EK@8C@EK<I8:K@FEF=K?<J<
04DEC2020 Abbreviated CSR 1839-201-021
42

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O


KI<8KD<EKJN@K?*/*3	N?@:?D8P8==<:KK?<E<LIFDLJ:LC8IALE:K@FE8E;D8PK?<I<=FI<I<JLCK
@E8ELEGI<;@:K89C<<==<:KFEDLJ:C<N<8BE<JJ
7.7.3. 
Prohibited Treatments During the Study 
/?<;<:@J@FEKF8;D@E@JK<I8GIF?@9@K<;D<;@:8K@FEKI<8KD<EK@J;FE<N@K?K?<J8=<KPF=K?<JKL;P
G8IK@:@G8EK8JK?<GI@D8IP:FEJ@;<I8K@FE2?<EGFJJ@9C<	CC<I>8EJ?FLC;9<EFK@=@<;9<=FI<K?<
GIF?@9@K<;D<;@:8K@FEKI<8KD<EK@J8;D@E@JK<I<;
+I@FI9FKLC@ELDKFO@EKI<8KD<EKF=8EPJ<IFKPG<=FI8EPLIFCF>@:8C:FE;@K@FE@JGIF?@9@K<;
7.8. 
Treatment after the End of the Study  
)FK8GGC@:89C<
04DEC2020 Abbreviated CSR 1839-201-021
43

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

8. 
Discontinuation/Withdrawal Criteria  
+8IK@:@G8EKJD8PMFCLEK8I@CPN@K?;I8N=IFDK?<JKL;P8K8EPK@D<
)FK@=@:8K@FEF=<8ICPG8IK@:@G8EK;@J:FEK@EL8K@FE=IFDK?<JKL;P8E;K?<I<8JFE=FI
;@J:FEK@EL8K@FEN@CC9<D8;<KFK?<JGFEJFI8E;N@CC9<:C<8ICP;F:LD<EK<;FEK?<8GGIFGI@8K<
<-!$=8G8IK@:@G8EK<O@KJK?<JKL;PGI@FIKFJKL;P:FDGC<K@FE	8CC<O@KM@J@K8JJ<JJD<EKJJ?FLC;
9<G<I=FID<;8KK?<K@D<F=<O@K
8.1. 
Discontinuation of Study Treatment  
.<<K?<J:?<;LC<F=8:K@M@K@<J=FI;8K8KF9<:FCC<:K<;8KK?<K@D<F=KI<8KD<EK;@J:FEK@EL8K@FE8E;
=FCCFN
LG8E;=FI8EP=LIK?<I<M8CL8K@FEJK?8KE<<;KF9<:FDGC<K<;
-<8JFEJ=FI;@J:FEK@EL8K@FE=IFDK?<JKL;PKI<8KD<EK8E;FIK?<JKL;PD8P@E:CL;<K?<
=FCCFN@E>
• ;M<IJ<<M<EK
• FDGC<K<;
• <8K?
• !8@CLI<KFD<<KI8E;FD@Q8K@FE:I@K<I@8
• '8:BF=<==@:8:P
• 'FJKKF=FCCFN
LG
• *K?<I
• +I<>E8E:P
• +IFKF:FC;<M@8K@FE
• .@K<K<ID@E8K<;9PJGFEJFI
• .KL;PK<ID@E8K<;9PJGFEJFI
• /<:?E@:8CGIF9C<DJ
• 2@K?;I8N8C9PG8IK@:@G8EK
04DEC2020 Abbreviated CSR 1839-201-021
44

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O


/?<J<K<IDJ8I<;<=@E<;@EGG<E;@O
8.2. 
Withdrawal from the Study 
• G8IK@:@G8EKD8PN@K?;I8N=IFDK?<JKL;P8K8EPK@D<8K?@J?<IFNEI<HL<JK	FID8P9<
N@K?;I8NE8K8EPK@D<8KK?<;@J:I<K@FEF=K?<@EM<JK@>8KFI=FIJ8=<KP	9<?8M@FI8C	:FDGC@8E:<	
FI8;D@E@JKI8K@M<I<8JFEJ
• +8IK@:@G8EKJDLJK9<;@J:FEK@EL<;=IFDK?<JKL;P8E;FII<:<@M<EF=LIK?<IJKL;PKI<8KD<EK	@=
8EPF=K?<=FCCFN@E>:I@K<I@88I<D<K
o +8IK@:@G8EK;<M<CFGJFI?8J8E<O8:<I98K@FEF=8EPD<;@:8C:FE;@K@FEFI8;M<IJ<
<M<EKK?8K	@EK?<FG@E@FEF=K?<@EM<JK@>8KFI	NFLC;GLKK?<G8IK@:@G8EK8K8E
LE8::<GK89C<D<;@:8CI@JBFI:FDGIFD@J<JK?<G8IK@:@G8EKSJ89@C@KPKFG8IK@:@G8K<@E
K?<JKL;P
o +8IK@:@G8EK9<:FD<JGI<>E8EKJ<<.<:K@FE
o +8IK@:@G8EK@J;@8>EFJ<;N@K?E<NFII<:LII<EKD8C@>E8E:P	<O:<GK98J8C:<CC
:8I:@EFD8
o +8IK@:@G8EK@JLEN@CC@E>FILE89C<KF:FEK@EL<KF:FDGCPN@K?JKL;PGIF:<;LI<J
• $=K?<G8IK@:@G8EKN@K?;I8NJ:FEJ<EK=FI;@J:CFJLI<F==LKLI<@E=FID8K@FE	K?<JGFEJFID8P
I<K8@E8E;:FEK@EL<KFLJ<8EP;8K8:FCC<:K<;9<=FI<JL:?8N@K?;I8N8CF=:FEJ<EK
• $=8G8IK@:@G8EKN@K?;I8NJ=IFDK?<JKL;P	?<J?<D8PI<HL<JK;<JKIL:K@FEF=8EPJ8DGC<J
K8B<E8E;EFKK<JK<;	8E;K?<@EM<JK@>8KFIDLJK;F:LD<EKK?@J@EK?<J@K<JKL;PI<:FI;J
• +8IK@:@G8EKJJ?FLC;9<=FCCFN<;=FI8KC<8JKN<<BJGFJKJKL;PKI<8KD<EKCCG8IK@:@G8EKJ
N?FGI<D8KLI<CP;@J:FEK@EL<=IFDK?<JKL;P	LEC<JJK?<:8LJ<@JJ:I<<E=8@CLI<	J?FLC;9<
J<<E=FI8=@E8C8JJ<JJD<EK8K<8ICPK<ID@E8K@FE=@E8C8JJ<JJD<EKN@CC9<;<=@E<;8J
:FDGC<K@FEF=K?<<M8CL8K@FEJJ:?<;LC<;=FIK?<=@E8CM@J@K8K2<<B O@K=FI.K8><FI
2<<B O@K=FI.K8><
• /?<@EM<JK@>8KFI8E;CC<I>8E8CJF?8M<K?<I@>?KKFN@K?;I8N8G8IK@:@G8EK=IFDK?<JKL;P8K
8EPK@D<=FI8EPI<8JFE
• 2?<I<GFJJ@9C<	K?<;<:@J@FEKFN@K?;I8N8G8IK@:@G8EK=IFDJKL;PKI<8KD<EKFIK?<JKL;P
J?FLC;9<;@J:LJJ<;N@K?CC<I>8E
04DEC2020 Abbreviated CSR 1839-201-021
45

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O


8.3. 
Lost to Follow Up 
G8IK@:@G8EKN@CC9<:FEJ@;<I<;CFJKKF=FCCFN
LG@=?<FIJ?<I<G<8K<;CP=8@CJKFI<KLIE=FI
J:?<;LC<;M@J@KJ8E;@JLE89C<KF9<:FEK8:K<;9PK?<JKL;PJ@K<
9. 
Study Assessments and Procedures 
• .KL;PGIF:<;LI<J8E;K?<@IK@D@E>8I<JLDD8I@Q<;@EK?<J:?<;LC<F=8:K@M@K@<J.<:K@FE
• +IFKF:FCN8@M<IJFI<O<DGK@FEJ8I<EFK8CCFN<;
• $DD<;@8K<J8=<KP:FE:<IEJJ?FLC;9<;@J:LJJ<;N@K?K?<JGFEJFI@DD<;@8K<CPLGFE
F::LII<E:<FI8N8I<E<JJKF;<K<ID@E<@=K?<G8IK@:@G8EKJ?FLC;:FEK@EL<FI;@J:FEK@EL<JKL;P
KI<8KD<EK
• ;?<I<E:<KFK?<JKL;P;<J@>EI<HL@I<D<EKJ	@E:CL;@E>K?FJ<JG<:@=@<;@EK?<J:?<;LC<F=
8:K@M@K@<J	@J<JJ<EK@8C8E;I<HL@I<;=FIJKL;P:FE;L:K
• CCJ:I<<E@E><M8CL8K@FEJDLJK9<:FDGC<K<;8E;I<M@<N<;KF:FE=@IDK?8KGFK<EK@8C
G8IK@:@G8EKJD<<K8CC<C@>@9@C@KP:I@K<I@8/?<@EM<JK@>8KFIN@CCD8@EK8@E8J:I<<E@E>CF>KF
I<:FI;;<K8@CJF=8CCG8IK@:@G8EKJJ:I<<E<;8E;KF:FE=@ID<C@>@9@C@KPFII<:FI;I<8JFEJ=FI
J:I<<E@E>=8@CLI<	8J8GGC@:89C<
• .:I<<E@E>GIF:<;LI<J:8E:FDD<E:<FE:<K?<@E=FID<;:FEJ<EK8E;;8K8
8LK?FI@Q8K@FEGIFK<:K@FE=FID?8M<9<<EF9K8@E<;.:I<<E@E>N@CC9<:FEJ@;<I<;KF?8M<
JK8IK<;8KK?<K@D<F=K?<=@IJKJ:I<<E@E>8:K@M@KPFIGIF:<;LI<	8E;:FDGC<K<;N?<E8CCK?<
I<HL@I<;@E:CLJ@FE<O:CLJ@FE:I@K<I@8?8M<9<<ED<K8E;K?<G8K@<EK@JI8E;FD@Q<;8K8P
04DEC2020 Abbreviated CSR 1839-201-021
46

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O


.:I<<E@E>GIF:<;LI<JJ?FLC;9<:FDGC<K<;8JJFFE8JGFJJ@9C<	N@K?8D8O@DLDF=
;8P
N@E;FN=IFDI8E;FD@Q8K@FE8P=FI.K8><8E;D8O@DLDF=
;8PN@E;FN=IFD
I8E;FD@Q8K@FE8P=FI.K8></?<G8K@<EKN@CC9<:FEJ@;<I<;<EIFCC<;@EKFK?<JKL;PLGFE
I8E;FD@Q8K@FE8K8P$=K?<G8K@<EK?8J8GFJ@K@M<LI@E<;@GJK@:BK<JKI<JLCK8E;E<<;JKF9<
KI<8K<;=FI80/$	K?<J:I<<E@E>G<I@F;:8E9<<OK<E;<;9PLGKF;8PJ.:I<<E@E>
GIF:<;LI<JD8P9<I<G<8K<;;LI@E>K?@JK@D<	8J;<<D<;:C@E@:8CCPE<:<JJ8IP	8KK?<;@J:I<K@FE
F=K?<@EM<JK@>8KFI<>	I<G<8KK?<
;8P9C8;;<I;@8IP@=G8K@<EK?8;8JPDGKFD8K@:0/$
;LI@E>@E@K@8C;@8IP:FCC<:K@FE
•  M8CL8K@FEJJ?FLC;9<G<I=FID<;9PK?<J8D<<M8CL8KFIK?IFL>?FLKK?<JKL;PN?<E<M<I
GFJJ@9C<
9.1. 
Efficacy Assessments 
*ECP.K8><@JGFN<I<;=FI8E@E=<I<EK@8C<==@:8:P8E8CPJ@J
9.1.1. 
Primary Efficacy Measure 
)LD9<IF=<G@JF;<JF=LI@E8IP@E:FEK@E<E:<G<I;8P	8JI<:FI;<;@EK?<G8IK@:@G8EK9C8;;<I;@8IP
FM<I:FEJ<:LK@M<;8PJ;LI@E>K?<N<<BGI@FIKF<8:?JKL;PM@J@K/?<GI@D8IPK@D<GF@EK@J8K
2<<B
9.1.2. 
Secondary Efficacy Measures 
• )LD9<IF=<G@JF;<JF=D@:KLI@K@FEG<I;8P9FK?9PMFCLEK8IPLI@E8K@FE8E;9P
:8K?<K<I@Q8K@FE	@=I<HL@I<;8JI<:FI;<;@EK?<G8IK@:@G8EK9C8;;<I;@8IPFM<I:FEJ<:LK@M<
;8PJ;LI@E>K?<N<<BGI@FIKF<8:?JKL;PM@J@K
• 1FCLD<MF@;<;G<ID@:KLI@K@FE8JI<:FI;<;FM<IFE<
?FLIG<I@F;;LI@E>K?<
;8P9C8;;<I
;@8IP;@M@;<;9PK?<ELD9<IF=D@:KLI@K@FEJ@EK?<J8D<
?FLIG<I@F;
04DEC2020 Abbreviated CSR 1839-201-021
47

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
04DEC2020 Abbreviated CSR 1839-201-021
48

 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK

04DEC2020 Abbreviated CSR 1839-201-021
49

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O
04DEC2020 Abbreviated CSR 1839-201-021
50

 
 
Approval Date: 
 
20-Dec-2018
*)!$ )/$'
+IFKF:FC

D<E;D<EK
*/*3YFKLC@ELD/FO@E/PG<
+LI@=@<;)<LIFKFO@EFDGC<O

9.2. 
Adverse Events 
/?<;<=@E@K@FEJF=8E FI. :8E9<=FLE;@EGG<E;@O
 JN@CC9<I<GFIK<;9PK?<G8IK@:@G8EK
/?<@EM<JK@>8KFI8E;8EP;<J@>E<<J8I<I<JGFEJ@9C<=FI;<K<:K@E>	;F:LD<EK@E>	8E;I<:FI;@E>
<M<EKJK?8KD<<KK?<;<=@E@K@FEF=8E FI. 8E;I<D8@EI<JGFEJ@9C<=FI=FCCFN@E>LG J
K?8K8I<J<I@FLJ	:FEJ@;<I<;I<C8K<;KFK?<JKL;PKI<8KD<EKFIJKL;PGIF:<;LI<J	FIK?8K:8LJ<;K?<
G8IK@:@G8EKKF;@J:FEK@EL<K?<JKL;PJ<<.<:K@FE
9.2.1. 
Time Period and Frequency for Collecting AE and SAE Information  
CC. J=IFDK?<J@>E@E>F=K?<$!LEK@C;8PJ8=K<IK?<C8JK=FCCFN
LGM@J@KN@CC9<:FCC<:K<;
8KK?<K@D<GF@EKJJG<:@=@<;@EK?<J:?<;LC<F=8:K@M@K@<J.<:K@FE	8E;8JF9J<IM<;FII<GFIK<;
JGFEK8E<FLJCP9PJKL;PG8IK@:@G8EKJ
CC J=IFDK?<J@>E@E>F=K?<$!LEK@CK?<C8JK=FCCFN
LGM@J@KN@CC9<:FCC<:K<;8KK?<
K@D<GF@EKJJG<:@=@<;@EK?<J:?<;LC<F=8:K@M@K@<J.<:K@FE	8E;8JF9J<IM<;FII<GFIK<;
JGFEK8E<FLJCP9PJKL;PG8IK@:@G8EKJ
(<;@:8CF::LII<E:<JK?8K9<>@E9<=FI<K?<JK8IKF=JKL;PKI<8KD<EK9LK8=K<IF9K8@E@E>@E=FID<;
:FEJ<EKN@CC9<I<:FI;<;FEK?< J<:K@FEF=K?<<-!
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9.2.2. 
Method of Detecting AEs and SAEs 
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04DEC2020 Abbreviated CSR 1839-201-021
51

 
 
Approval Date: 
 
20-Dec-2018
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9.2.3. 
Follow-up of AEs and SAEs 
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9.2.4. 
Regulatory Reporting Requirements for SAEs 
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9.2.5. 
Pregnancy 
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04DEC2020 Abbreviated CSR 1839-201-021
52

 
 
Approval Date: 
 
20-Dec-2018
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9.2.6. 
Study-Specific Definitions for Particular Adverse Events  
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04DEC2020 Abbreviated CSR 1839-201-021
53

 
 
Approval Date: 
 
20-Dec-2018
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9.3. 
Treatment of Overdose 
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9.4. 
Safety Assessments 
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04DEC2020 Abbreviated CSR 1839-201-021
54

 
 
Approval Date: 
 
20-Dec-2018
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9.4.1. 
Physical Examinations 
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9.4.2. 
Vital Signs 
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9.4.3. 
Clinical Safety Laboratory Assessments 
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04DEC2020 Abbreviated CSR 1839-201-021
55

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
56

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
57

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
58

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
59

 
 
Approval Date: 
 
20-Dec-2018
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Bladder and Kidney Ultrasound 
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9.4.7. 
Concomitant Medications and Concurrent Procedures 
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9.5. 
Pharmacokinetics 
+?8ID8:FB@E<K@:G8I8D<K<IJ8I<EFK<M8CL8K<;@EK?@JJKL;P
9.6. 
Pharmacodynamics 
+?8ID8:F;PE8D@:G8I8D<K<IJ8I<EFK<M8CL8K<;@EK?@JJKL;P
9.7. 
Genetics 
"<E<K@:J8I<EFK<M8CL8K<;@EK?@JJKL;P
9.8. 
Biomarkers 
@FD8IB<IJ8I<EFK<M8CL8K<;@EK?@JJKL;P
04DEC2020 Abbreviated CSR 1839-201-021
60

 
 
Approval Date: 
 
20-Dec-2018
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10. 
Statistical Considerations 
10.1. 
Sample Size Determination 
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Table 10-1 
Sample Size Assumptions for Stage 2 
Parameter 
Assumption/Estimate 
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04DEC2020 Abbreviated CSR 1839-201-021
61

 
 
Approval Date: 
 
20-Dec-2018
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10.2. 
Populations for Analyses 
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Table 10-2 
Analysis Populations 
Population 
Definition 
Study Treatment 
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10.3. 
Statistical Analyses 
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8E8CPJ<J=FI.K8><N@CC9<;<J:I@GK@M<@EE8KLI<FECPEF@E=<I<EK@8CK<JK@E>N@CC9<G<I=FID<;
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10.3.1. 
Key Statistical Methodology 
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Table 10-3 
Statistical Methodology 
Methodology 
Description 
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04DEC2020 Abbreviated CSR 1839-201-021
62

 
 
Approval Date: 
 
20-Dec-2018
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Methodology 
Description 
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04DEC2020 Abbreviated CSR 1839-201-021
63

 
 
Approval Date: 
 
20-Dec-2018
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Methodology 
Description 
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10.3.1.1. Hypothesis 
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GFJK
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10.3.1.2. Methods of Analysis  
$E><E<I8C	98J<C@E<@J;<=@E<;8JK?<C8JKEFED@JJ@E>8JJ<JJD<EK9<=FI<8PFEK@ELFLJ
M8I@89C<JN@CC9<JLDD8I@Q<;N@K?;<J:I@GK@M<JK8K@JK@:JJ8DGC<J@Q<	D<8E	D<;@8E	JK8E;8I;
;<M@8K@FE	D@E@DLD	8E;D8O@DLDM8CL<J8K<>FI@:8CM8I@89C<JN@CC9<JLDD8I@Q<;N@K?
=I<HL<E:P;@JKI@9LK@FEJ:FLEKJ8E;G<I:<EK8><J
04DEC2020 Abbreviated CSR 1839-201-021
64

 
 
Approval Date: 
 
20-Dec-2018
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10.3.2. 
Efficacy Analyses 
10.3.2.1. Collection and Derivation of Primary and Secondary Efficacy Measures 
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04DEC2020 Abbreviated CSR 1839-201-021
65

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
66

 
 
Approval Date: 
 
20-Dec-2018
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10.3.4. 
Safety Analyses 
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04DEC2020 Abbreviated CSR 1839-201-021
67

 
 
Approval Date: 
 
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Analyses Timepoints and Scope 
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04DEC2020 Abbreviated CSR 1839-201-021
68

 
 
Approval Date: 
 
20-Dec-2018
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11. 
References 
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04DEC2020 Abbreviated CSR 1839-201-021
69

 
 
Approval Date: 
 
20-Dec-2018
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04DEC2020 Abbreviated CSR 1839-201-021
70

 
 
Approval Date: 
 
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12. 
Appendices 
12.1. 
Appendix 1: Abbreviations and Trademarks 
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04DEC2020 Abbreviated CSR 1839-201-021
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