Clinical trial NCT02434328
Conditions: Neovascular Age-Related Macular Degeneration Choroidal Neovascularization
Keywords: AMD CNV IVT
Sponsor: Alcon Research
Start date: 2015-07-28; Completion date: 2018-03-08
Enrollment: 1048 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare brolucizumab (RTH258) ophthalmic solution for intravitreal (IVT) injection (6 mg) to aflibercept ophthalmic solution for IVT injection (2 mg) in subjects with untreated active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in the study eye.

Detailed description:
Subjects were randomized to brolucizumab 6 mg and aflibercept 2 mg in a 1:1 ratio. Subjects in both treatment arms received 3 monthly loading doses (Day 0, Week 4 and Week 8), followed by a maintenance regimen, until the end of the study (Week 96/Exit). All subjects attended pre-specified visits every 4 weeks.

Subjects in the brolucizumab 6 mg arm followed a q12w/q8w maintenance regimen. Within the q12w/q8w regimen, the initial treatment after the loading phase was q12w (1 injection every 12 weeks). If disease activity was identified by the masked investigator at any of the disease activity assessments, dosing was adjusted to q8w (1 injection every 8 weeks) ("q12w/q8w regimen"). Once subjects were adjusted to the q8w interval, they stayed on that interval until the end of the study.

Subjects in the aflibercept 2 mg arm followed a q8w maintenance regimen until the end of the study.

Results reported up to Week 48 are based on the database locked for the primary analysis at Week 48. Results reported after Week 48 are based on the database locked at the end of study (final analysis).

Arms: arm 1: Single intravitreal (IVT) injection of brolucizumab at Day 0, Week 4, and Week 8, followed by 1 injection every 8 weeks/1 injection every 12 weeks (q8w/q12w) maintenance regimen until study exit arm 2: Single IVT injection of aflibercept ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit
Interventions: intervention 1: Brolucizumab ophthalmic solution intervention 2: Aflibercept ophthalmic solution
Intervention descriptions: intervention 1: Ophthalmic solution for IVT injection administered as a 6 mg/50 µL dose intervention 2: Ophthalmic solution for IVT injection administered as a 2 mg/50 µL dose

Protocol documents:
Prot_002.pdf: 
Page 1 of 95
a Novartis company
Short Title
Efficacy and Safety of RTH258 versus Aflibercept
Long Title
A Two-Year, Randomized, Double-Masked, Multicenter, Two-Arm Study 
Comparing the Efficacy and Safety of RTH258 6 mg Versus Aflibercept in 
Subjects with Neovascular Age-Related Macular Degeneration
Protocol Number:
Study Phase:
Sponsor Name and 
Address:
Investigational Product:
US IND# / EudraCT
Indication Studied:
Investigator Agreement:
RTH258-C002 / NCT02434328 
3
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 76134-2099
RTH258 solution for intravitreal injection, 6 mg / 50 µL
IND# 112023 / 2014-004886-26
Neovascular Age-Related Macular Degeneration
I have read the clinical study described herein, recognize its 
confidentiality, and agree to conduct the described trial in 
compliance with Good Clinical Practices (GCP), the ethical 
principles contained within the Declaration of Helsinki, this 
protocol, and all applicable regulatory requirements. 
Additionally, I will comply with all procedures for data 
recording and reporting, will permit monitoring, auditing, and 
inspection of my research center, and will retain all records until 
notified by the Sponsor.
Principal Investigator:
Signature
Date
Name:
Address:
Alcon - Business Use Only 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
Print Date:  
Effective
4.0; Most-Recent; Effective; CURRENT
TDOC-0050250
10-Feb-2017


Pa ge 2 of 9 5
1
S Y N O P SI S
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2
I n vesti g ati o n al 
Pr o d uct:
R T H 2 5 8, f or merl y 
E S B A 1 0 0 8
St u d y P h ase:
1
2
3
4
N/ A
Acti ve I n gre die nt: 
R T H 2 5 8 6 m g
Pr ot oc ol Title:
A T w o -Year, Ra n d o mize d, D o u ble -Mas ke d, M ultice nter, T w o -
Ar m St u d y  C o m pari n g t he Efficac y a n d Safety of R T H 2 5 8 6 m g 
vers us Afli berce pt i n S u bjects wit h Ne o vasc ular A ge -Relate d 
Mac ular De ge nerati o n
I n vesti g at or(s)/ N o. of Sites: M ultice nter;
a p pr o xi matel y 2 0 0 sites
N o. of S u bjects
A p pr o xi matel y  6 6 0 ra n d o mize d
D ur ati o n of Tre at me nt:
9 6 wee ks
St u d y P o p ul ati o n: 
S u bjects ≥ 5 0 y ears of a ge wit h u ntreate d acti ve c h or oi dal 
ne o vasc ularizati o n ( C N V) d ue t o a ge -relate d mac ular 
de ge nerati o n ( A M D) i n t he st u d y e ye
O bjecti ve(s):
Pri m ar y:

To  de m o nstrate t hat RT H 2 5 8 6 m g is n ot i nferi or t o afli berce pt 
2 m g wit h res pect t o t he c ha n ge i n best -c orrecte d vis ual ac uit y 
( B C VA) fr o m Baseli ne t o We e k 4 8
Sec o n d ar y:

To  de m o nstrate t hat RT H 2 5 8 6 m g is n ot i nferi or t o afli berce pt 
2 m g wit h res pect t o t he c ha n ge i n B C VA fr o m Baseli ne 
a vera ge d o ver t he peri o d Wee k 3 6 t o Wee k 4 8

To  esti mate t he pr o p orti o n of q 1 2 ( 1 i njecti o n e ver y 1 2 wee ks) 
s u bjects u p t o Wee k 4 8 i n t he RT H 2 5 8 6 m g treat me nt ar m

To  esti mate t he pre dicti ve val ue of t he first q 1 2 c ycle f or 
mai nte na nce of q 1 2 treat me nt u p t o Wee k 4 8 i n t he R T H 2 5 8 6 
m g treat me nt ar m

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
To  e val uate t he efficac y of RT H 2 5 8 6 m g relati ve t o 


Pa ge 3 of 9 5
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2
afli berce pt 2 m g o ver t he ti me peri o d u p t o Wee k 9 6 b y 
assessi n g c ha n ges i n:
o
B C V A
o
A nat o mica l para meters of disease acti vit y 
i ncl u di n g ce ntral s u bfiel d t hic k ness ( C S F T) a n d 
C N V area
o
Prese nce of “ q 8 treat me nt nee d”, i ncl u di n g 
assess me nt of q 1 2 stat us f or patie nts i n t he 
R T H 2 5 8 6 m g treat me nt ar m

T o assess vis ual f u ncti o n -relate d, s u bject re p orte d, o utc o mes 
f oll o wi n g treat me nt wit h R T H 2 5 8 6 m g relati ve t o afli berce pt 
2 m g

T o assess t he safet y a n d t olera bilit y of R T H 2 5 8 6 m g relati ve 
t o afli berce pt 2 m g
Met h o d ol o g y:
T his st u d y  has 2 ar ms wit h 1: 1 ra n d o mizati o n.  S u bjects i n b ot h 
ar ms will ha ve visits e ver y  4 wee ks t hr o u g h Wee k 9 6.  T he 
pri mar y  a nalys is will be perf or me d at Wee k 4 8.
I n Ar m 1 ( R T H 2 5 8 6 m g):
R T H 2 5 8 6 m g will be i nitiall y  i njecte d 3 ti mes at 4 wee k i nter vals, 
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
at Visit 1/ Baseli ne, Visit 2/ Wee k 4 a n d Visit 3/ Wee k 8.
F oll o wi n g t hese 3 l oa di n g d oses, eac h s u bject will be i njecte d 
e ver y 1 2 wee ks ( q 1 2) u p t o Visit 2 4/ Wee k 9 2 u nless t here is 
disease acti vit y  assesse d acc or di n g t o t he g ui da nce pr o vi de d at 
Visit 5/ Wee k 1 6, Visit 6/ Wee k 2 0, Visit 8/ Wee k 2 8, Visit 9/ Wee k 
3 2, Visit 1 1/ Wee k 4 0, Visit 1 2/ Wee k 4 4, Visit 1 4/ Wee k 5 2, Visit 
1 5/ Wee k 5 6, Visit 1 7/ Wee k 6 4, Visit 1 8/ Wee k 6 8, Visit 2 0/ Wee k 
7 6, Visit 2 1/ Wee k 8 0 or Visit 2 3/ Wee k 8 8. I f disease acti vity is 
i de ntifie d, t he s u bject will be reassi g ne d t o recei ve i njecti o ns 
e ver y 8 wee ks ( q 8) t hereafter, u p t o st u d y  e xit. T he i nteracti ve 
res p o nse tec h n ol o g y (IR T) s y ste m will ma ke t he necessar y 
c ha n ges t o t he d osi n g per t he mas ke d I n vesti gat or’s assess me nt. 
T he disease acti vit y  assess me nt will als o be perf or me d at visit 
2 4/ Wee k 9 2 b ut will n ot be e ntere d i nt o I R T a n d will ha ve n o 


Pa ge 4 of 9 5
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2
effect o n t he s u bject’s treat me nt re gi me n.
Dise ase acti vit y Criteri a at Wee k 1 6:

Decrease i n B C V A of ≥ 5 letters c o m pare d wit h 
Baseli ne

Decrease i n B C V A of ≥ 3 letters a n d C S F T 
i ncrease ≥7 5 µ m c o m pare d wit h Wee k 1 2

Decrease i n B C V A of ≥ 5 letters d ue t o 
ne o v asc ul ar A M D dise ase acti vit y c o m pare d 
wit h Wee k 1 2

Ne w or w orse i ntrareti nal c y sts (I R C)/ i ntrareti nal 
fl ui d (IR F) c o m pare d wit h Wee k 1 2
Dise ase Acti vit y Criteri o n at W ee ks 2 0, 2 8, 3 2, 4 0 a n d 
4 4:

Decrease i n B C V A of ≥ 5 letters d ue t o 
ne o vasc ular A M D disease acti vit y  c o m pare d wit h 
Wee k 1 2
Dise ase Acti vit y Criteri o n at Wee ks 5 2, 5 6, 6 4, 6 8, 7 6, 
8 0, 8 8 a n d 9 2:

Decrease i n B C V A of ≥ 5 letters d ue t o 
ne o vasc ular A M D disease acti vit y c o m pare d wit h 
Wee k 4 8
I n Ar m 2 ( afli berce pt 2 m g):
Afli berce pt 2 m g, ( E Y L E A, c o m parat or) will be i njecte d 3 ti mes 
at 4 wee k i nter vals ( Visit 1/ Baseli ne, Visit 2/ Wee k 4 a n d visit 
3/ Wee k 8), f oll o we d b y i njecti o ns q 8 u p t o Visit 2 4/ Wee k 9 2.
Tre at me nts:
I n vesti g ati o n al Pr o d uct:
R T H 2 5 8 6 m g / 5 0 µ L
R o ute of A d mi nistr ati o n:
I VT i njecti o n
D ur ati o n of Tre at me nt:
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
9 6 Wee ks


Page 5 of 95
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number: RTH258-C002
Dosage:
6 mg RTH258 in 50 µL (120 mg/mL 
formulation)
Control Article:
Aflibercept 2 mg / 50 µL
Route of Administration:
IVT injection
Duration of Treatment:
96 Weeks
Dosage:
2 mg of aflibercept in 50 µL
Subject Selection:
Inclusion Criteria:
1. Subjects must give written informed consent before any 
study level related procedures are performed
2. Subjects must be 50 years of age or older at Screening
3. Active CNV lesions secondary to AMD that affect the 
central subfield (including retinal angiomatous proliferation 
[RAP] lesions with a CNV component) in the study eye at 
Screening and confirmed by the Central Reading Center 
(CRC)
4. Total area of CNV (including both classic and occult 
components) must comprise > 50% of the total lesion area in 
the study eye at Screening and confirmed by the CRC
5. Intra and/or subretinal fluid affecting the central subfield of 
the study eye at Screening and confirmed by the CRC
6. BCVA between 78 and 23 letters, inclusive, in the study eye 
at Screening and Baseline using Early Treatment Diabetic 
Retinopathy Study (ETDRS) testing
Exclusion Criteria:
1. Any active intraocular or periocular infection or active 
intraocular inflammation (e.g., infectious conjunctivitis, 
keratitis, scleritis, endophthalmitis, infectious blepharitis) 
in either eye at Baseline
2. Central subfield of the study eye affected by fibrosis or 
geographic atrophy assessed by color fundus photography 
at Screening and confirmed by the CRC
3. Total area of fibrosis ≥ 50% of the total lesion in the study 
eye at Screening and confirmed by the CRC
4. Subretinal blood affecting the foveal center point and/or ≥ 
50% of the lesion of the study eye at Screening and 
confirmed by the CRC
5. Subject has received any approved or investigational 
treatment for neovascular AMD (other than vitamin 
supplements) in the study eye at any time
Alcon - Business Use Only 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
Print Date:  
Effective
4.0; Most-Recent; Effective; CURRENT
TDOC-0050250
10-Feb-2017


Pa ge 6 of 9 5
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2
6.
A n y  hist or y or e vi de nce of a c o nc urre nt i ntra oc ular 
c o n diti o n i n t he st u d y  e ye, i ncl u di n g reti nal diseases ot her 
t ha n ne o vasc ular A M D, t hat, i n t he j u d g me nt of t he 
I n vesti gat or, c o ul d re q uire me dical or s ur gical i nter ve nti o n 
d uri n g t he c o urse of t he st u d y  t o pre ve nt or treat vis ual l oss 
t hat mi g ht res ult fr o m t hat c o n diti o n, or t hat li mits t he 
p ote ntial t o gai n vis ual ac uit y  u p o n treat me nt wit h t he 
i n vesti gati o nal pr o d uct.
7.
Reti nal pi g me nt e pit heli u m ( R P E) ri p/tear i n t he st u d y  e ye 
at Scree ni n g
8.
C urre nt vitre o us he m orr ha ge or hist or y  of vitre o us 
he m orr ha ge i n t he st u d y  e ye wit hi n 4 wee ks pri or t o 
Baseli ne
9.
Hist or y  or e vi de nce of t he f oll o wi n g i n t he st u d y e ye:

i ntra oc ular or refracti ve s ur ger y wit hi n t he 9 0 da y 
peri o d pri or t o Baseli ne

pre vi o us pe netrati n g kerat o plast y  or vitrect o m y

pre vi o us pa nreti nal p h ot oc oa g ulati o n

pre vi o us s u b mac ular s ur ger y , ot her s ur gical 
i nter ve nti o n or laser treat me nt f or A M D
1 0. U nc o ntr olle d gla uc o ma i n t he st u d y  e ye defi ne d as 
i ntra oc ular press ure (I O P) > 2 5 m m H g o n me dicati o n or 
acc or di n g t o I n vesti gat or’s j u d g me nt at Scree ni n g
1 1. A p ha kia a n d/ or a bse nce o f t he p osteri or ca ps ule i n t he 
st u d y e ye at Scree ni n g
1 2. I ntra- or peri oc ular use of c ortic oster oi ds i n t he st u d y  e ye 
d uri n g t he 6 m o nt h peri o d pri or t o Baseli ne
1 3. Use of t o pical oc ular c ortic oster oi ds i n t he st u d y  e ye f or 6 0 
or m ore c o nsec uti ve da y s wit hi n t he 9 0 da y  peri o d pri or t o 
Baseli ne
1 4. Use of s ys te mic c ortic oster oi ds f or 3 0 or m ore c o nsec uti ve 
da y s wit hi n t he 9 0 da ys pri or t o Baseli ne, wit h t he 
e xce pti o n of l o w sta ble d oses of c ortic oster oi ds ( defi ne d as 
≤ 1 0 m g pre d nis ol o ne or e q ui vale nt d ose use d f or 9 0 da y s 
or m ore pri or t o Baseli ne). I n hale d, nasal or der mal 
ster oi ds are  per mitte d
1 5. Pre vi o us t hera pe utic ra diati o n near t he re gi o n of t he st u d y  
e ye
1 6. Treat me nt wit h afli berce pt ( E Y L E A ®), be vaciz u ma b 
( A V A S TI N ®) or pe ga pta ni b ( M A C U G E N ®) wit hi n t he 4  
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
wee k peri o d pri or t o Baseli ne, or wit h Ra ni biz u ma b, 0. 5 
m g ( L U C E N TI S ®) wit hi n t he 2 wee k peri o d pri or t o 


Pa ge 7 of 9 5
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2
Baseli ne i n t he n o nst u d y e ye
1 7. Hist or y  of a me dical c o n diti o n ( disease, meta b olic 
d y sf u ncti o n, p h ysical e xa mi nati o n fi n di n g, or cli nical 
la b orat or y fi n di n g) t hat, i n t he j u d g me nt of t he 
I n vesti gat or, w o ul d precl u de sc he d ule d st u dy visits, 
c o m pleti o n of t he st u d y, or a safe a d mi nistrati o n of 
i n vesti gati o nal pr o d uct
1 8. Hist or y  of hy p erse nsiti vit y t o a n y c o m p o ne nt of t he test 
article, c o ntr ol article, or cli nicall y rele va nt se nsiti vit y  t o 
fl u orescei n dye , as assesse d b y t he I n vesti gat or
1 9. Pre g na nt or n ursi n g (lactati n g) w o me n, w here pre g na nc y  is 
defi ne d as t he state of a fe male after c o nce pti o n a n d u ntil 
t he ter mi nati o n of gestati o n, c o nfir me d by a p ositi ve h C G 
pre g na nc y  test.
2 0. W o me n of c hil d - beari n g p ote ntial, defi ne d as all w o me n 
less t ha n 1 year p ost me n o pa usal or less t ha n 6 wee ks si nce 
sterilizati o n (f urt her defi niti o n ca n be f o u n d i n Secti o n 
1 2. 7) at Baseli ne, u nless t he y  are usi n g hi g hly effecti ve 
met h o ds of c o ntrace pti o n d uri n g d osi n g of st u d y treat me nt. 
Effecti ve c o ntrace pti o n met h o ds i ncl u de:

T otal a bsti ne nce ( w he n t his is i n li ne wit h t he 
preferre d a n d us ual lifest y le of t he s u bject). 
Peri o dic a bsti ne nce (e g, cale n dar, o v ulati o n, 
s ym pt ot her mal, p ost o v ulati o n met h o ds) a n d 
wit h dra wal are n ot acce pta ble met h o ds of 
c o ntrace pti o n

Fe male sterilizati o n ( ha ve ha d s ur gical bilateral 
o o p h orect o m y wit h or wit h o ut h y sterect o m y) or 
t u bal li gati o n at least 6 wee ks bef ore Baseli ne. I n 
case of o o p h orect o m y al o ne, o nl y  w he n t he 
re pr o d ucti ve stat us of t he w o ma n has bee n 
c o nfir me d b y f oll o w u p h or m o ne le vel assess me nt

Male sterilizati o n (at least 6 m o nt hs pri or t o 
Baseli ne). F or fe male s u bjects i n t he st u d y , t he 
vasect o mize d male part ner s h o ul d be t he s ole 
part ner f or t hat s u bject

Use of oral, i njecte d or i m pla nte d h or m o nal 
met h o ds of c o ntrace pti o n or ot her f or ms of 
h or m o nal c o ntrace pti o n t hat ha ve c o m para ble 
efficac y (fail ure rate < 1 %), f or e xa m ple h or m o ne 
va gi nal ri n g or tra ns der mal h or m o ne c o ntrace pti o n

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
Place me nt of a n i ntra uteri ne de vice (I U D) or 


Pa ge 8 of 9 5
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2
i ntra uteri ne sys te m (I U S)
2 1. Partici pati o n i n a n i n vesti gati o nal dr u g, bi ol o gic, or de vice 
st u d y wit hi n 3 0 da ys or t he d urati o n of 5 half-li ves of t he 
i n vesti gati o nal pr o d uct ( w hic he ver is l o n ger) pri or t o 
Baseli ne N ote: o bserv ati o n al cli nic al st u dies s olely 
i nv olvi n g over-t he-c o u nter vit a mi ns, s u p ple me nts, or diets 
are n ot excl usi o n ary
2 2. S y ste mic a nti- vasc ular e n d ot helial gr o wt h fact or ( V E G F) 
t hera py wit hi n t he 9 0 da y peri o d pri or t o Baseli ne
2 3. Str o ke or m y ocar dial i nfarcti o n i n t he 6 m o nt h peri o d pr i or 
t o Baseli ne
2 4. U nc o ntr olle d bl o o d press ure defi ne d as a s ys t olic val ue ≥ 
1 6 0 m m H g or diast olic val ue ≥ 1 0 0 m m H g at Scree ni n g
I n cases w here b ot h e yes are eli gi ble, t he e ye wit h t he w orse 
B C V A at Baseli ne will be selecte d as t he st u d y  e ye. If b ot h 
e yes ha ve t he sa me B C VA, it is rec o m me n de d t o select t he 
ri g ht e ye as t he st u d y e ye.
Assess me nts:
Effic ac y:

B C V A usi n g E T D R S met h o d ol o g y

S pectral d o mai n o ptical c o here nce t o m o gra p h y ( S D- O C T)

Fl u orescei n a n gi o gra p h y ( F A)

Nati o nal E y e Instit ute Vis ual F u ncti o n Q uesti o n naire - 2 5 
( V F Q- 2 5)
S afet y:

Ge neral p h y sical e xa m

Vital si g ns

Bl o o d c he mistr y / he mat ol o g y/ uri nalys is

A nti- dr u g a nti b o d y  ( A D A) assess me nts

S y ste mic R T H 2 5 8 assess me nt

C o m plete o p ht hal mic e xa m:
o
Slit -la m p e xa m
o
I O P meas ure me nt ( pre/ p osti njecti o n)
o
F u n d us e xa m ( dilati o n at t he discreti o n of t he 
I n vesti gat or)

P osti njecti o n assess me nts

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
Treat me nt e mer ge nt a d verse e ve nts i ncl u di n g e ve nts of 
s pecial i nterest ( E SIs; Secti o n 1 2. 3)


Pa ge 9 of 9 5
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2
Ot her:

C ol or f u n d us p h ot o gra p h y

F u n d us a ut ofl u oresce nce (at a s u bset of sites)
St atistic al Met h o ds:
Pri m ar y Effic ac y E n d p oi nt:

C ha n ge i n B C V A fr o m Baseli ne t o Wee k 4 8
Ke y S ec o n d ar y Effic ac y E n d p oi nt:

A vera ge c ha n ge i n B C V A fr o m Baseli ne o ver t he peri o d 
Wee k 3 6 t hr o u g h Wee k 4 8. F or eac h s u bject, t his e n d p oi nt 
is defi ne d as t he a vera ge of t he c ha n ges fr o m Baseli ne t o 
Wee ks 3 6, 4 0, 4 4 a n d 4 8.

q 1 2 treat me nt stat us at Wee k 4 8 (f or s u bjects ra n d o mize d 
t o R T H 2 5 8 6 m g o nl y)

q 1 2 treat me nt stat us at Wee k 4 8 wit h n o q 8 nee d d uri n g 
t he 1st q 1 2 c ycle (at Wee k 1 6, Wee k 2 0) (f or s u bjects 
ra nd o mize d t o R T H 2 5 8 6 m g o nl y)
Sec o n d ar y Effic ac y E n d p oi nts:

C ha n ge i n B C V A fr o m Baseli ne t o eac h p ost baseli ne visit

A vera ge c ha n ge i n B C V A fr o m Baseli ne o ver t he peri o d 
Wee k 8 4 t hr o u g h Wee k 9 6

A vera ge c ha n ge i n B C V A fr o m Baseli ne o ver t he peri o d 
Wee k 4 t o Wee k 4 8/ 9 6

A vera ge c ha n ge i n B C V A fr o m Baseli ne o ver t he peri o d 
Wee k 1 2 t o Wee k 4 8/ 9 6

Gai n i n B C V A of 1 5/ 1 0/ 5 letters or m ore fr o m Baseli ne t o 
eac h p ost baseli ne visit

L oss i n B C V A of 1 5/ 1 0/ 5 letters or m ore fr o m baseli ne t o 
eac h p ost baseli ne visit

q 1 2 trea t me nt stat us at Wee k 9 6 (f or s u bjects ra n d o mize d 
t o R T H 2 5 8 6 m g o nl y)

q 1 2 treat me nt stat us at Wee k 9 6 wit hi n t he s u bjects wit h 
n o q 8 nee d d uri n g t he 1st q 1 2 c y cle ( Wee k 1 6, Wee k 2 0) 
(f or s u bjects ra n d o mize d t o R T H 2 5 8 6 m g o nl y)

C ha n ge i n C S F T fr o m Baseli ne t o eac h p ost baseli ne visit

C ha n ge i n ne ur ose ns or y  reti nal t hic k ness fr o m Baseli ne t o 
eac h p ost baseli ne visit

C ha n ge i n C N V lesi o n size fr o m Baseli ne t o Wee ks 1 2, 4 8 
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
a n d 9 6


Pa ge 1 0 of 9 5
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: R T H 2 5 8 -C 0 0 2

A bse nce of s u breti nal fl ui d at eac h p ost baseli ne visit

A bse nce of i ntrareti nal fl ui d at eac h p ost baseli ne visit

q 8 treat me nt nee d at Wee ks 1 6, 2 0, 2 8, 3 2, 4 0, 4 4, 5 2, 5 6, 
6 4, 6 8, 7 6, 8 0, 8 8 a n d 9 2

C ha n ge i n patie nt re p orte d o utc o mes ( V F Q- 2 5) t otal a n d 
s u bscale sc ores fr o m Baseli ne t o Wee ks 2 4, 4 8, 7 2 a n d 9 6
S afet y E n d p oi nts:

I nci de nce a n d c haracteristics of treat me nt e mer ge nt 
a d verse e ve nts

Treat me nt e mer ge nt c ha n ges i n oc ular a n d s ys te mic 
para meters

C ha n ge i n A D As fr o m Baseli ne t o Wee ks 1 2, 2 4, 3 6, 4 8, 
6 8 a n d 8 8

E xte nt of s y ste mic R T H 2 5 8 at Wee ks 1 2, 2 4, 3 6, 4 8, 6 8 
a n d 8 8
St atistic al Met h o ds:
C o nfir m at or y testi n g f or effic ac y:
H y p ot heses: T he f oll o wi n g n o n -i nferi ority h y p ot heses are relate d 
t o a n o n-i nferi ority mar gi n of 4 letters.
4 8 = Wee k 4 8, 3 6 -4 8 = Wee k 3 6 t hr o u g h 4 8, R 6 = R T H 2 5 8 
6 m g, A =afli berce pt 2 m g
H 0 1: µ4 8 R 6 - µ4 8 A ≤ -4 letters vs H A 1 : µ 48 R 6 - µ 4 8 A > - 4 
letters
µ 4 8 R 6 a n d µ 4 8 A bei n g t he c orres p o n di n g u n k n o w n tr ue 
mea n B C V A c ha n ges fr o m Baseli ne t o Wee k 4 8.
H 0 2: µ3 6 -4 8 R 6 - µ3 6 - 4 8 A ≤ -4 letters vs H A 2 : µ3 6 -4 8 R 6 - µ3 6 - 4 8 A > 
-4 letters
µ 3 6 -4 8 R 6 a n d µ 3 6 -4 8 A bei n g t he c orres p o n di n g u n k n o w n tr ue 
mea n val ues f or t he a vera ge c ha n ge i n B C V A fr o m 
Baseli ne o ver t he peri o d Wee k 3 6 t hr o u g h 4 8.
Pri m ar y a n al ysis d at a set:
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
T he pri mar y  efficac y a nal ysis data set is t he f ull a nal ysis set 
( F A S) wit h missi n g val ues i m p ute d b y last o bser vati o n carrie d 
f or war d ( L O C F). T he F A S i ncl u des all s u bjects w h o are 


Page 11 of 95
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number: RTH258-C002
randomized and received at least one IVT injection. Sensitivity 
analyses will be performed using the per protocol analysis set 
(PPS) and alternative imputation for missing values including a 
mixed model repeated measures (MMRM) and observed data only 
analyses.
Statistical testing strategy:
The 2 hypotheses will be tested in the pre-specified hierarchical 
sequence according to their numbering (HAn, n=1,2). 
Consequently, confirmatory testing of the second hypothesis 
requires rejection of the first null hypothesis. In this setting, each 
hypothesis will be assessed at a two-sided α = 0.05, while keeping 
the global type I error rate at 0.05.
Statistical method:
Two-sided 95% confidence intervals (CI) for the differences in 
means, RTH258 6 mg – aflibercept 2 mg, based on analysis of 
variance (ANOVA) model with treatment, Baseline BCVA 
categories (≤ 55, 56-70, ≥71 letters), and age categories (< 75, ≥ 
75 years) as fixed effects will be presented for the primary 
efficacy analysis. The same ANOVA model will be fitted for the 
key secondary endpoint, average change in BCVA from Baseline 
over the period Week 36 through 48.
Within the specified hierarchical testing strategy, noninferiority 
will be established if the lower limit of the corresponding 95% CI 
is greater than -4 letters (corresponding to the noninferiority 
margin of 4 letters).
Sample size:
A sample size of 297 subjects per treatment arm is sufficient to 
demonstrate noninferiority (margin = 4 letters) of RTH258 6 mg 
versus aflibercept 2 mg with respect to the BCVA change from 
Baseline to Week 48 at a two-sided alpha level of 0.05 with a 
power of approximately 90% assuming equal efficacy and a 
common standard deviation of 15 letters. A power of at least 90% 
can be expected for the first key secondary endpoint assuming that 
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Page 12 of 95
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number: RTH258-C002
averaging over the 4 time points will not lead to an increase in the 
standard deviation.
To account for a drop-out rate of 10%, a total of 330 subjects will 
be randomized per treatment arm.
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Page 13 of 95
1.1
Amendments
Amendment 3
Purpose of amendment:
The primary purpose of this amendment is to allow ADA analysis of the samples collected 
from aflibercept treated patients (Section 10.7.5). Minor clarifications have also been made to 
Sections 9.4, 10.1, 10.7.4, 10.9 and 12.3
Amendment 2
Purpose of amendment:
The primary purpose of this amendment is to incorporate changes which resulted from 
interactions with Regulatory Authorities.  In addition changes have been made to clarify 
some inclusion/exclusion criteria and study procedures.
Rationale:
Revision 1: (Section 1 Synopsis, Section 2 Overview of Study Plan, Section 10.2.1 Screening 
Visit (Day -14 to Day -2) and Section 10.2.2 Visit 1 Baseline (Day 0) Requirement of BCVA 
in the study eye to be between 78 and 23 letters, inclusive, at Screening as well as Baseline.
Rationale: The purpose of this change is to further clarify the intention of the protocol that 
the criterion must be met at both the Screening and Baseline Visit by stating it explicitly.
Revision 2: (Section 10.7.6 Analysis of Pharmacogenetics) the statement that instruction 
regarding the Pharmacogenetic samples can be found in the MOP has been removed.
Rationale: This was a typo in the original protocol, instructions for the samples can be found 
in the Central Laboratory Manual.
Revision 3: (Section 2. Overview of Study Plan and Section 10.7.16 Postinjection 
Assessment): Simplification of the postinjection assessment.
Rationale: This change is to make post injection fundoscopy at the discretion of the 
investigator, thereby reducing the risk of postinjection IOP rise due to pupil dilatation.
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Page 14 of 95
Revision 4: (Section 10.8 Concomitant Treatment and Section 10.9 Prohibited Treatment) 
Allowance of all treatments in the nonstudy eye which are approved for exudative AMD in 
the respective country.
Rationale: This change has been made to ensure subjects have unrestricted access to 
approved treatment in the nonstudy eye.
Revision 5: (Section 11.9 Safety) Section 11.9.4 Safety parameters several bullet points were 
added and  Section 11.9.5 Adverse Events, Section 11.10 Interim Analyses and Section 11.11 
Sample Size Justification were added.
Rationale: Inadvertently between the original protocol and version 2 of the protocol these 
bullet points and sections had been removed.  This is to correct this and place them back into 
the protocol.
Current study status:
Case Report Form Revision Required:
Yes
No
Informed Consent Modification Required:
Yes
No
Applicable Investigators:
Yes
Selected (list below)
Itemized Changes:
Notable changes to the protocol are listed in the summary below using strike through for 
deletions and underlined font for insertions Notable changes to the protocol are listed in the 
summary below using strike through for deletions and underlined font for insertions.
Section 1 SYNOPSIS
Inclusion criteria:
6.
BCVA between 78 and 23 letters, inclusive, in the study eye at Screening and Baseline 
using Early Treatment Diabetic Retinopathy Study (ETDRS) testing
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Page 15 of 95
In cases where both eyes are eligible, the eye with the worse BCVA at Baseline will be 
selected as the study eye. If both eyes have the same BCVA, it is recommended to select the 
right eye as the study eye.
Section 2 OVERVIEW OF STUDY PLAN
Subscript:
7.
If BCVA cannot must be performed at the Screening Visit, the BCVA may be only performed and at 
the Baseline Visit to qualify the subject.
13.
Whether the subject receives an active injection or sham injection, the study eye will be evaluated 0-5 
minutes and 30 (±15) minutes postinjection to ensure that the injection procedure and/or the 
investigational product have not endangered the health of the eye. This includes an evaluation of 
central retinal artery perfusion via includes gross assessment of vision, status of central retinal artery, 
presence of retinal detachment, presence of new intraocular hemorrhage(s), and measurement of IOP. 
Direct visualization to assess the central retinal artery, presence of retinal detachment, presence of new 
intraocular hemorrhage(s) might be appropriate at the discretion of the investigator and/or based on the 
results of gross assessment of vision and IOP measurement.
Section 10.2.1 Screening Visit (Day -14 to Day -2)
7
Perform BCVA on both eyes. If BCVA cannot be performed at the Screening visit, the 
BCVA may be performed at the baseline visit to qualify the subject.
Section 10.2.2 Visit 1/Baseline (Day 0)
Subject eligibility will be determined at Screening. However, if the BCVA is not able to be 
assessed at the Screening Visit, the Baseline BCVA may be used to qualify the subject. 
Baseline BCVA of the study eye must be between 78 and 23 letters, inclusive, for the subject 
to qualify.
14.
Have the unmasked Investigator perform an IVT injection according to the 
randomization/kit assignment. The injection procedure may be performed at a later 
time, as long as it is within 7 days of the scheduled visit and within the visit window.
Section 10.7.6 Analysis of Pharmacogenetics
Details on the collections and shipment of the samples are provided to Investigators in the 
laboratory manual and MOP.
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Pa ge 1 6 of 9 5
Secti o n 1 0. 7. 1 6 P osti njecti o n Assess me nt
T he st ud y e ye will be ass e sse d befo re, i m me diatel y ( 0- 5 mi n ut es) after a n d 3 0 ( ± 1 5) mi n ut es 
after eac h IV T /s ha m i nje ctio n t o e ns ure that th e p roce d ure a n d/ or t he st u d y me dicatio n ha ve 
n ot e n dan ger e d t he health of t h e e ye. T h e p os tinj ectio n assessm e nts in c l u de a n e val uati o n of 
ce ntral reti nal arter y perf usi o n via a gr oss assess me nt of visi o n (e g, c o u nt fi n gers) , t he stat us 
of t he ce ntral reti nal arter y, prese nce of reti nal detac h me nt, prese nce of ne w i ntra oc ular 
he m orr ha ge(s) a n d me as ur e me nt of IO P  acc or di n g t o t he s che d u le detaile d i n t he M O P.
Direct vis ualizati o n t o assess t he ce ntral reti nal arter y , prese nce of reti nal detac h me nt, 
prese nce of ne w i ntra oc ular he m orr ha ge(s) mi g ht be a p pr o priate at t he discreti o n of t he 
i n vesti gat or a n d/ or base d o n t he res ults of gr oss assess me nt of visi o n a n d I O P  meas ure me nt.
Secti o n 1 0. 8. C o nc o mit a nt Tr e at me nt
T he I n vesti gat or s h o ul d i nstr uct t he s u bject t o n otif y  t he st u d y site a b o ut a n y ne w 
me dicati o ns he/s he ta kes after e nr olli n g i nt o t he st u d y .
S h o ul d t he n o nst u d y  e ye re q uire treat me nt d uri n g t he st u d y wit h a n a nti -V E G F , ra ni biz u ma b
a dr u g w hic h is a p pr o ve d f or t he treat me nt of e x u dati ve A M D i n t he res pecti ve c o u ntr y
s h o ul d be a p plie d at t he discreti o n of t he I n vesti gat or a n d f oll o wi n g t he pr oced ures 
esta blis he d at t he res pecti ve site. T he n o nst u d y  e ye treat me nt ma y occ ur at a n y ti me o nce t he 
Baseli ne st u d y e ye  i njecti o n has bee n a d mi nistere d.
Ta ble 1 0. 9. -1: Pr o hi bite d Tr e at me nt
N o nst u d y  e ye: U na p pr o ve d or I n vesti gati o nal treat me nt A nti- V E G F t hera p y ot her t ha n 
ra ni biz u ma b
Secti o n 11. 9. 4 S afet y p ar a meters 
T he f oll o wi n g safet y para meters will be descri pti vel y a nal yz e d t o assess treat me nt e mer ge nt 
c ha n ges or c ha n ges s pecificall y  relate d t o t he i njecti o n pr oce d ure usi n g p osti njecti o n 
assess me nts:

A d verse e ve nts

Ge neral p h y sical e xa m

Vi tal si g ns

La b orat o r yt ests ( bl o o d c he mist r y, he m at ol og y a n d uri na l ysis)
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7


Pa ge 1 7 of 9 5

W orse ni n g i n B C V A

Slit -lam p e x ami n ati o n

F u n d us e x a m

IO P

P osti nj ecti o n assess me nt

A D A le vels

S y ste mic R T H 2 5 8 le vels
Secti o n 1 1. 9. 5 A d verse E ve nts
A Es will be c o de d usi n g t he Me d D R A  dicti o nar y a n d prese nte d b y sys te m or ga n class a n d 
preferre d ter m. T reat me nt e mer ge nt A Es will be a nal y ze d base d o n t he n u m ber a n d 
perce nta ge of s u bjects wit h at least o ne A E i n t he cate g or y  of i nterest. Se parate prese ntati o ns 
will be pr o vi de d relate d t o oc ular e ve nts i n t he st u d y  e ye a n d n o nst u d y e ye a n d n o n -oc ular 
e ve nts. A d diti o nal s u m maries will be pr o vi de d b y se verity a n d ca usalit y (se paratel y assesse d 
f or t he i njecti o n pr oce d ure a n d t he dr u g). Seri o us A d verse E ve nts a n d a d verse e ve nts lea di n g 
t o disc o nti n uati o n of st u d y treat me nt will als o be s u m marize d se parately.
S u bject listi n gs of all a d verse e ve nts will be pr o vi de d. Deat hs a n d ot her seri o us or cli nicall y  
si g nifica nt n o n-fatal a d verse e ve nts will be liste d se paratel y.
E ve nts of s pecial i nterest ( E SI s; as defi ne d i n secti o n 1 2. 3) will be prese nte d base d o n t heir 
i nci de nces.
Secti o n 1 1. 1 0 I nteri m A n al yses
T he pri mar y  efficac y a nal ysis will be base d o n t he We e k 4 8 data. T he data base, i ncl u di n g all 
We e k 4 8 data, will be l oc ke d o nce all acti ve s u bjects ha ve c o m plete d t he Wee k 4 8 Visit. 
S y ste mic RT H 2 5 8 a n d A D A  data u p t o We e k 3 6 will be a nal yz e d f or t he Wee k 4 8 pri mar y 
a nal ys is. T he pri mar y  a nal ysis at We e k 4 8 will be perf or me d wit h a n u n mas ki n g of s pecifie d 
N o vartis/ Alc o n i n di vi d uals w h o are n ot i n v ol ve d i n t he direct c o n d uct of t he trial.
S u bjects will re mai n i n t he st u d y  a n d will c o nti n ue t o recei ve mas ke d treat me nt t hr o u g h t he 
pla n ne d d urati o n ( 9 6 Wee ks) t o all o w f or f urt her mas ke d e val uati o n of efficac y a n d safet y. 
T reat me nt mas ki n g of i n di vi d ual s u bjects will re mai n i ntact f or all s u bjects, In vesti gat ors, 
a n d Alc o n staf f w h o ha ve c o ntact wit h s u bjects or I n vesti gat ors or t h ose w h o are i n v ol ve d i n 
t he direct c o n d uct of t he st u d y u ntil t he fi nal data base l oc k has occ urre d.
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7


Page 18 of 95
Section 11.11 Sample Size Justification
A sample size of 297 subjects per treatment arm is sufficient to demonstrate noninferiority 
(margin = 4 letters) of RTH258 6 mg versus aflibercept 2 mg with respect to the BCVA 
change from Baseline to Week 48 at a two-sided alpha level of 0.05 with a power of 
approximately 90% assuming equal efficacy and a common standard deviation of 15 letters. 
A power of at least 90% can be expected for the first key secondary endpoint assuming that 
averaging over the 4 time points will not lead to an increase in the standard deviation.
To account for a drop-out rate of 10%, a total of 330 subjects will be randomized per 
treatment arm.
Amendment 1
Purpose of amendment:
The primary purpose of this amendment is to implement required changes received from 
regulatory authorities and address aspects of the study that would avoid unnecessary 
exclusions of patients who would be appropriate for the study inclusion.
Rationale:
Revision 1: (Section 1 Synopsis, Section 2 Overview of Study Plan, Section 5.1.2 Treatment 
Regimen Rationale, Section 10.1 Outline of Study, Figure 10.1-1 Dosing Schedule by 
Treatment, Section 10.2.4 Visit 4/Week 12 through Visit 24/Week 92, Section 10.7.13 Disease 
Activity Assessment and Section 11.5.2 Statistical Methods) Disease Activity Assessments 
have been added for Visit 8/Week 28, Visit 11/Week 40, Visit 14/Week 52, Visit 17/Week 64, 
Visit 20/Week 76, Visit 23/Week 88.
Rationale: Regulatory Authority request to include Disease Activity Assessments at these 
time points.
Revision 2: (Section 1. Synopsis) Exclusion criteria no. 4 central subfield has been changed 
to foveal center point.
Rationale: The current wording unnecessarily excludes patients who are appropriate for anti-
VEGF treatment. The change would reduce unnecessary screen failures and improve 
recruitment.
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Revision 3: (Section 1. Synopsis, Section 12.7 Pregnancy in the Study) Exclusion criteria no. 
20 refers to section 12.7 for further definitions of women of childbearing potential and post-
menopausal.  Additionally the of use of highly effective birth control for use during the study 
and for a period of up to 3 months post final study injection as per EYLEA label has been 
added to section 12.7.
Rationale: Request from Regulatory Authorities to add highly effective wording and provide 
expanded definition of WOBC and menopausal and add the 3 months use of study mandated 
birth control after last study injection as per comparator label.
Revision 4: (Section 1. Synopsis) Exclusion criteria no. 23 has changed the period prior to 
Baseline for stroke and myocardial infarction from 90 days to 6 month period.
Rationale: Request from Regulatory Authorities to extend this period.
Revision 5: (Section 5.1.2. Treatment Regimen Rationale) providing justification of the 
choice of a 2-arm trial in relation to a 3-arm trial with a placebo arm included in the study 
protocol.
Rationale: Request from Regulatory Authorities to provide this justification.
Revision 6: (Section 5.1 Study Rationale and Background) Addition of a sub-section 5.1.3. 
Non-inferiority margin rationale.
Rationale: Regulatory Authority request to justify the chosen non-inferiority margin.
Revision 7: (Section 7 Amendments) Clarification on sponsor responsibility gain approval 
from Regulatory Authorities for amendments prior to implementation.
Rationale: Regulatory Authority request to clarify this approval in the protocol.
Revision 8: (Section 9 Treatment Administration) Additional information to clarify the 
randomization process. 
Rationale: Regulatory Authority request for more information relating to the process of 
randomization, the explanation should be extended about the procedure how the sequence 
assignment is generated.
Revision 9: (Section 10.5 Discontinuation of Study Treatment and Section 10.6 Clinical 
Study Termination) Details more instances where there should be consideration to discontinue 
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Page 20 of 95
study treatment for a patient and provides additional guidance or instances when a clinical 
study would be terminated.
Rationale: Regulatory Authority request to provide more rules on the discontinuation of 
study treatment and clinical study termination.
Revision 10: (Section 10.7.4 Laboratory Analysis of Blood and Urine) Information regarding 
the details around the samples to be collected for blood and urine that can be found in the 
MOP.
Rationale: Clarification based on a request from the Regulatory Authority regarding 
specificity of samples to be collected for the study.
Revision 11: (Section 11.5. Primary and Key Secondary Efficacy Analyses) addition of text to 
describe that analysis of the primary and first key secondary endpoints will also be performed 
based on the per protocol set.
Rationale: Analysis would allow for the direct comparison of full analysis set results and per 
protocol set results within the assessment of the robustness of the efficacy conclusion.  To 
further strengthen the importance of the per protocol set for the overall efficacy conclusions 
the additional text has been provided as per request for an update to the analysis plan by the 
Regulatory Authorities.
Revision 12: (Section 11.6 Additional Secondary Efficacy Analyses) Aligning with the 
synopsis as intended analysis.
Rationale: Change in synopsis not carried through to section 11 during review, correction.
Revision 13: (Section 12.3 Procedures for Recording and Reporting AEs and SAEs) SAE 
reporting requirements have been updated in the protocol according to GCP guidelines.
Rationale: Regulatory Authority instruction that Sponsor is required to amend the Protocol 
and clarify the Sponsor’s reporting responsibility in the protocol.
Revision 14: (Section 13 Data Handling and Administrative Requirements) Section 13.5 
Data Monitoring Committee added
Rationale: Regulatory Authority instruction that Sponsor is required to implement DMC.
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Pa ge 2 1 of 9 5
C urr e nt st u dy st at us:
Case Re p ort F or m Re visi o n Re q uire d:
Yes
N o
I nf or me d C o nse nt M o dificati o n Re q uire d:
Yes
N o
A p plica ble I n vesti gat ors:
Yes
Selecte d (list bel o w)
Ite mize d C h a n ges:
N ota ble c ha n ges t o t he pr ot oc ol are liste d i n t he s u m mar y  bel o w usi n g stri ke t hr o u g h f or 
deleti o ns a n d u n derli ne d f o nt f or i nserti o ns N ota ble c ha n ges t o t he pr ot oc ol are liste d i n t he 
s u m mar y bel o w usi n g stri ke t hr o u g h f or deleti o ns a n d u n derli ne d f o nt f or i nserti o ns.
Secti o n 1 S y n o psis
Met h o d ol o g y :
I n Ar m 1 ( R T H 2 5 8 6 m g):
R T H 2 5 8 6 m g will be i nitiall y  i njecte d 3 ti mes at 4 wee k i nter vals, at Visit 1/ Baseli ne, 
Visit 2/ Wee k 4 a n d Visit 3/ Wee k 8.
F oll o wi n g t hese 3 l oa di n g d oses, eac h s u bject will be i njecte d e ver y  1 2 wee ks ( q 1 2) u p t o 
Visit 2 4/ Wee k 9 2 u nless t here is disease acti vit y  assesse d acc or di n g t o t he g ui da nce pr o vi de d
at Visit 5/ Wee k 1 6, Visit 6/ Wee k 2 0, Visit 8/ Wee k 2 8 , Visit 9/ Wee k 3 2, Visit 1 1/ Wee k 4 0,
Visit 1 2/ Wee k 4 4 , Visit 1 4/ Wee k 5 2, Visit 1 5/ Wee k 5 6, Visit 1 7/ Wee k 6 4, Visit 1 8/ Wee k 6 8,
Visit 2 0/ Wee k 7 6, or Visit 2 1/ Wee k 8 0 or Visit 2 3/ Wee k 8 8 . If disease acti vit y is i de ntifie d, 
t he s u bject will be reassi g ne d t o recei ve i njecti o ns e ver y 8 wee ks ( q 8) t hereafter, u p t o st u d y 
e xit. T he i nteracti ve res p o nse tec h n ol o g y  (I R T) syste m will ma ke t he necessar y  c ha n ges t o 
t he d osi n g per t he mas ke d In vesti gat or’s asses s me nt. T he disease acti vit y assess me nt will 
als o be perf or me d at visit 2 4/ Wee k 9 2 b ut will n ot be e ntere d i nt o I R T a n d will ha ve n o 
effect o n t he s u bject’s treat me nt re gi me n.
Dise ase acti vit y Criteri a at Wee k 1 6:

Decrease i n B C V A of ≥ 5 letters c o m pare d w it h Baseli ne

Decrease i n B C V A of ≥ 3 letters a n d C S F T i ncrease ≥7 5 µ m c o m pare d wit h 
Wee k 1 2

Decrease i n B C V A of ≥ 5 letters d ue t o ne o v asc ul ar A M D dise ase acti vit y
c o m pare d wit h Wee k 1 2

Ne w or w orse i ntrareti nal c y sts (I R C)/ i ntrareti nal fl ui d (IR F) c o m par e d wit h 
Wee k 1 2
Dise ase Acti vit y Criteri o n at Wee ks 2 0, 2 8 , 3 2, 4 0 a n d 4 4:

Decrease i n B C V A of ≥ 5 letters d ue t o ne o v asc ul ar A M D dise ase acti vit y 
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
c o m pare d wit h Wee k 1 2


Pa ge 2 2 of 9 5
Dise ase Acti vit y Criteri o n at Wee ks 5 2, 5 6, 6 4, 6 8, 7 6, 8 0, 8 8 a n d 9 2:

Decrease i n B C V A of ≥ 5 letters d ue t o ne o v asc ul ar A M D dise ase acti vit y
c o m pare d wit h Wee k 4 8
E xcl usi o n criteria:
4.
S u breti nal bl o o d af fecti n g t he ce ntral s u bfiel d f o veal ce nter p oi nt a n d/ or ≥ 5 0 % of t he 
lesi o n of t he st u d y e ye at Scree ni n g a n d c o nfir me d b y  t he C R C
2 0.
W o me n of c hil d -beari n g p ote ntial, defi ne d as all w o me n less t ha n 1 year 
p ost me n o pa usal or less t ha n 6 wee ks si nce sterilizati o n (f urt her defi niti o n ca n be f o u n d 
i n Secti o n 1 2. 7) at Baseli ne, u nless t he y are usi n g hi g hl y effecti ve met h o ds of 
c o ntrace pti o n d uri n g d osi n g of st u d y treat me nt. Effecti ve c o ntrace pti o n met h o ds 
i ncl u de:

T otal a bsti ne nce ( w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yl e of 
t he s u bject). Peri o dic a bsti ne nce (e g, cale n dar, o v ulati o n, s ym p t ot her mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of 
c o ntrace pti o n

Fe male sterilizati o n ( ha ve ha d s ur gical bilateral o o p h orect o m y wit h or wit h o ut 
h y sterect o my) or t u bal li gati o n at least 6 wee ks bef ore Baseli ne. I n case of 
o o p h orect o m y al o ne, o nl y w he n t he re pr o d ucti ve stat us of t he w o ma n has 
bee n c o nfir me d b y f oll o w u p h or m o ne le vel assess me nt

Male sterilizati o n (at least 6 m o nt hs pri or t o Baseli ne). F or fe male s u bjects i n 
t he st u d y, t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat 
s u bject

Barrier met h o ds of c o ntrace pti o n: c o n d o m or occl usi ve ca p ( dia p hra g m or 
cer vical/ va ult ca ps) wit h s per mici dal f oa m/ gel/fil m/crea m/ va gi nal s u p p osit or y

Use of oral, i njecte d or i m pla nte d h or m o nal met h o ds of c o ntrace pti o n or ot her 
for ms of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y  (fail ure rate < 
1 %), f or e xa m ple h or m o ne va gi nal ri n g or tra ns der mal h or m o ne c o ntrace pti o n

Place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s ys te m (I U S)
2 3.
Str o ke or m y ocar dial i nfarcti o n i n t he 9 0 da y 6 m o nt h peri o d pri or t o Baseli ne
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7


Page 23 of 95
Scre
enin
g
Visi
t 1/
Base
line
Visi
t 2/
W
ee
k
4
Visi
t 3/
W
ee
k
8
Visi
t 4/
W
ee
k
1
2
Visi
t 5/
W
ee
k
1
6
Visi
t 6/
W
ee
k
2
0
Visi
t 7/
W
ee
k
2
4
Visi
t 8/
W
ee
k
2
8
Visi
t 9/
W
ee
k
3
2
V
is
it
10
/ 
W
ee
k
3
6
V
is
it
11
/ 
W
ee
k
4
0
V
is
it
12
/ 
W
ee
k
4
4
V
is
it
1
3/ 
W
ee
k
48
D
a
y
-
14
to
-2
Da
y 0
Da
y
28 ±
3
Da
ys
Da
y
56 ±
3
Da
ys
Da
y
84 ±
7
Da
ys
D
a
y
112
± 7
Da
ys
D
a
y
140
± 7
Da
ys
D
a
y
168
± 7
Da
ys
D
a
y
196
± 7
Da
ys
D
a
y
224
± 7
Da
ys
D
a
y
252
± 7
Da
ys
D
a
y
280
± 7
Da
ys
D
a
y
308
± 7
Da
ys
D
a
y
336
± 7
Da
ys
Disease 
Activity 
Assessment
X
X
X
X
X
X
Visi
t 14/ 
Wee
k 52
Visi
t 15/ 
Wee
k 56
Visi
t 16/ 
Wee
k 60
Visi
t 17/ 
Wee
k 64
Visi
t 18/ 
Wee
k 68
Visi
t 19/ 
Wee
k 72
Visi
t 20/ 
Wee
k 76
Visi
t 21/ 
Wee
k 80
Visi
t 22/ 
Wee
k 84
Visi
t 23/ 
Wee
k 88
Visi
t 24/ 
Wee
k 92
Visit 
25/
Wee
k 96
E
xi
t1
4
D
a
y
364 
± 7
Day
s
D
a
y
392 
± 7
Day
s
D
a
y
420 
± 7
Day
s
D
a
y
448 
± 7
Day
s
D
a
y
476 
± 7
Day
s
D
a
y
504 
± 7
Day
s
D
a
y
532 
± 7
Day
s
D
a
y
560 
± 7
Day
s
D
a
y
588 
± 7
Day
s
D
a
y
616 
± 7
Day
s
D
a
y
644 
± 7
Day
s
D
a
y
67
2 ± 
7
Da
ys
Disease 
Activity 
Assessment
X
X
X
X
X
X
X
X
Section 5 Introduction
Section 5.1 Study Rationale and Background
The primary statistical analysis compared RTH258 4.5 mg and 6.0 mg versus ranibizumab 
0.5 mg with both doses achieving noninferiority. Notable however was the median time to 
receiving standard of care which was 45.0 days for ranibizumab but was longer for the 
RTH258 3.0 mg, 4.5 mg and 6.0 mg doses (75.0 days (p=0.0374), 60.0 days (p=0.1805) and 
75.0 days (p=0.0360) respectively).  The interquartile range was 30 – 75 days for 
ranibizumab, and 45 – 120 days, 30 – 120 days and 37.5 – 150 days for the RTH258 3.0 mg, 
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Pa ge 2 4 of 9 5
4. 5 m g a n d 6. 0 m g res pecti vel y. i n t he 6. 0 m g gr o u p c o m pare d wit h 4 5 da ys i n t he 
ra ni biz u ma b gr o u p), s u g gesti n g a l o n ger d urati o n of treat me nt ef fect. R T H 2 5 8 6 m g was t he 
hi g hest d ose teste d i n t he st u d y  a n d n o u ne x pecte d safety iss ues were re p orte d t hat w o ul d 
precl u de f urt her cli nical de vel o p me nt.
Secti o n 5. 1. 2 T reat me nt Re gi me n Rati o nale
I n t he c urre nt st u d y, RT H 2 5 8 patie nts will recei ve q 1 2 mai nte na nce d osi n g. Disease acti vit y 
assess me nts will be c o n d ucte d b y a mas ke d i n vesti gat or at W ee ks 1 6, 2 0 , 2 8, 3 2, 4 0 a n d 4 4, 
all o wi n g 4 6 ti me p oi nts u p t o t he pri mar y e n d p oi nt of t he st u d y ( Wee k 4 8) w here RT H 2 5 8 
q 1 2 s u bjects ca n be reassi g ne d t o q 8 treat me nt. It is e x pecte d t hat earl y deter mi nati o n at 
We e k 1 6 a n d Wee k 2 0 of s u bjects w h o are m ore s uite d t o a q 8 d osi n g re gi me n will mi ni mize 
t he perce nta ge of q 1 2 s u bjects w h o will re q uire reassi g n me nt at later ti me p oi nts.
D ue t o t he w ell -esta blis he d efficac y of a nti -V E G F treat me nts i n t he i n dicati o n of ne o vasc ular 
A ge -Relate d Mac ular De ge nerati o n, a n i nter nal vali dati o n of t his st u d y  via a place b o ar m is 
et hicall y n ot feasi ble. T he a vaila ble hist orical e vi de nce of t he ef ficac y of L uce ntis ( A nc h or 
a n d Mari na) a n d of afli berce pt ( VI E W 1 a n d 2) all o ws f or a relia ble esti mate of t he dr u g’s 
eff ect size c o m pare d t o place b o a n d d ue t o t he si milarit y  of t he c urre nt NI trial t o t he 
hist orical st u dies i n ter ms of st u d y  p o p ulati o n, efficac y assessme nts a n d d urati o n, t here is a 
s o u n d basis f or e xter nal vali dati o n of t he res ults of t his st u d y.
Secti o n 5. 1. 3 N o n -i nferi orit y Mar gi n Rati o nale
5. 1. 3
N o n -i nferi orit y Mar gi n Rati o nale
N o n -i nferi orit y testi n g relate d t o t he pri mar y efficac y para meter best correcte d vis ual ac uit y 
[letters] will be base d o n a mar gi n of 4 letters. T his n o n-i nferi ority mar gi n pr o vi des ass ura nce 
t hat b ot h a bs ol ute efficac y a n d acce pta ble efficac y relati ve t o t he acti ve c o m parat or 
afli berce pt ca n be esta blis he d.

A bs ol ute ef ficac y: T he acti ve c o m parat or afli berce pt t o get her wit h L uce ntis bel o n gs 
t o a class of a nti- V E G F treat me nts w here f or t he i n di vi d ual pr o d ucts si milar efficac y 
has bee n esta blis he d ( VI E W 1 a n d 2). T his si milarit y j ustifies t he use of t he o nl y 
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7


Pa ge 2 5 of 9 5
a vaila ble relate d s u peri orit y data  vers us  S ha m or Vis u d yne  re p orte d f or m o nt hl y  
L uce ntis i n t he st u dies M A RI N A  ( vs S ha m) a n d A N C H O R ( vs Vi s u d yne)  t o q ua ntif y  
t he or der of ma g nit u de of t he a bs ol ute treat me nt effect f or t his class of treat me nts. F or 
t he e n d p oi nt ‘c ha n ge i n BC V A fr o m baseli ne t o M o nt h 1 2 [letters]’ t his a bs ol ute 
treat me nt effect was esti mate d f or m o nt hl y Luce ntis 0. 5 m g i n t he M A RI N A st u d y as 
1 7. 5 letters  ( 9 5 % CI [ 1 4. 8 , 2 0, 2] ) c o m pare d t o S ha m -i njecti o ns a n d i n t he A N C H O R 
st u d y as 2 1. 1 letters ( 9 5 % CI [ 1 7. 5 , 2 4. 6]) c o m pare d t o Vis u d yne . Relati ve t o t hese 
a bs ol ute treat me nt effects, n o n-i nferi ority esta blis he d at a 4 letter mar gi n will 
g uara ntee a n a bs ol ute treat me nt effect i n t he ma g nit u de of at least 1 0 letters e ve n 
u n der t he c o nser vati ve a p pr oac h of usi n g t he l o wer li mits of t hese 9 5 % c o nfi de nce 
i nter vals as refere nce. 

Esta blis hi n g acce pta ble ef ficac y relati ve t o t he acti ve c o m parat or afli berce pt: F or a 
n o n -i nferi ority mar gi n of 4 letters t o get her wit h t he ass u me d sta n dar d de viati o n of 1 5 
letter f or t he pri mar y e n d p oi nt B C VA c ha n ge fr o m baseli ne at We e k 4 8 a n d a sa m ple 
size of 3 0 0 patie nts, it is e x pecte d t hat n o n-i nferi orit y ca n o nl y be clai me d if t he 
o bser ve d differe nce bet wee n R T H 2 5 8 a n d afli berce pt is > -1. 6 letters. Si g nif y i n g t hat 
t he o bser ve d mea n B CV A  c ha n ge f or RT H 2 5 8 is n o m ore t ha n 1. 6 letters w orse t ha n 
f or afli berce pt.  
T he p o wer calc ulati o n is base d o n t he ass u m pti o n of e q ual ef ficac y f or RT H 2 5 8 a n d 
afli berce pt wit h a res ulti n g p o wer of a b o ut 8 0 % f or t w o s uccessf ul P hase III st u dies, 
w hile i n case of a real treat me nt differe nce of - 1. 6 letters t he p o wer g oes d o w n t o 
2 5 %. E ve n if t he treat me nt dif fere nce is o nly -1 letter , t he c ha nce f or t w o s uccessf ul 
P hase III st u dies falls bel o w 5 0 %. 
W hile a 4 letter dif fere nce i n t he B C VA res p o nse bet wee n tw o re gi me ns ca n be 
c o nsi dere d of rele va nce, a 4 letter n o n- i nferi ority mar gi n i n a cli nical trial lea ds t o a 
discri mi nati o n of treat me nts alrea d y f or m uc h s maller delta -le vels f or w hic h mi n or 
u n derl y i n g cli nical rele va nce ca n be attri b ute d.
Secti o n 7 A me n d me nts
M o dificati o n of t he pr ot oc ol is pr o hi bite d wit h o ut pri or writte n a gree me nt i n t he f or m of a 
pr ot oc ol a me n d me nt. All a me n d me nts will be create d b y  t he S p o ns or a n d m ust be a p pr o ve d 
b y  t he I E C/I R B a n d Re g ulat or y Aut h orities pri or t o i m ple me ntati o n e xce pt w he n re q uire d t o 
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7


Pa ge 2 6 of 9 5
miti gate i m me diate safet y  ris ks or w he n t he c ha n ges i n v ol ve o nly l o gistical or a d mi nistrati ve 
re visi o ns.
Secti o n 9 T re at me nt A d mi nistr ati o n
Secti o n 9. 4 S u bject C o nfi de ntialit y  a n d Met h o ds Use d t o Mi ni mize Bias
Tr eat me nt will be assi g ne d t o s u bjects t hr o u g h t he I R T  sys te m. Eac h s u bject n u m ber will be 
ass ociate d wit h treat me nt gr o u ps acc or di n g t o a ra n d o m pr ocess ge nerate d usi n g c o m p uter 
s oft ware ( S A S 9. 2 P R O C P LA N) . S u bjects will be assi g ne d treat me nt i n n u merical or der i n 
se q ue nce n u m ber or der acc or di n g t o ti me of ra n d o mizati o n; t he ra n d o mizati o n sc he d ule will 
be bl oc ke d t o e ns ure a bala nce of treat me nt all ocati o ns acr oss t he st u d y . T here are n o 
stratificati o n fact ors i n t his st u d y. T he I RT s yste m will be utilize d t o i m ple me nt t he o utc o me 
of t he disease acti vit y  assess me nts at t he a p pr o priate visits.
Secti o n 1 0 St u d y Pr oce d ur es
Secti o n 1 0. 1 O utli ne of St u d y
I n Ar m 1 ( R T H 2 5 8 6 m g):
R T H 2 5 8 6 m g will be i nitiall y  i njecte d 3 ti mes at 4 wee k i nter vals, at Visit 1/ Da y 0, Vi sit 
2/ Wee k 4 a n d Vi sit 3/ Wee k 8.
F oll o wi n g t he l oa di n g d oses, eac h s u bject will be i njecte d q 1 2 u p t o V isit 2 4/ Wee k 9 2 u nless 
t here is disease acti vit y assesse d acc or di n g t o t he g ui da nce pr o vi de d at Vi sit 5/ Wee k 1 6, Visit 
6/ Wee k 2 0, Vi sit 8/ Wee k 2 8, Vi sit 9/ Wee k 3 2, Vi sit 11/ Wee k 4 0, Vi sit 1 2/ Wee k 4 4, Vi sit 
1 4/ Wee k 5 2, Vi sit 1 5/ Wee k 5 6, Vi sit 1 7/ Wee k 6 4, Vi sit 1 8/ Wee k 6 8, Visit 2 0/ Wee k 7 6, or
Vi sit 2 1/ Wee k 8 0 or Visit 2 3/ Wee k 8 8. If disease acti vit y is i de ntifie d, t he s u bject will be 
reassi g ne d t o recei ve i njecti o ns q 8 t hereafter, u p t o st u d y e xit. T he I R T  sys te m will ma ke t he 
necessar y  c ha n ges t o t he d osi n g per t he mas ke d I n vesti gat or’s assess me nt. T he disease 
acti vit y assess me nt will als o be perf or me d at visit 2 4/ Wee k 9 2 b ut will n ot be e ntere d i nt o 
I RT a n d will ha ve n o eff ect o n t he s u bject’s treat me nt re gi me n.
Dise ase Acti vit y Criteri a at We e k 1 6:

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
Decrease i n B C V A of ≥ 5 letters c o m pare d wit h Baseli ne


Pa ge 2 7 of 9 5

Decrease i n B C V A of ≥ 3 letters a n d C S F T  i ncrease ≥ 7 5 µ m c o m pare d wit h We e k 
1 2

Decrease i n B C V A of ≥ 5 letters d ue t o ne o va sc ular A M D disease acti vit y  
c o m pare d wit h Wee k 1 2

Ne w or w orse I R C/I R F c o m pare d wit h We e k 1 2
Dise ase Acti vit y Criteri o n at We e ks 2 0, 2 8, 3 2, 4 0 a n d 4 4:

Decrease i n B C V A of ≥ 5 letters d ue t o ne o vasc ular A M D disease acti vit y  
c o m pare d wit h Wee k 1 2
Dise ase A c ti vit y Criteri o n at We e ks 5 2, 5 6, 6 4, 6 8, 7 6, 8 0, 8 8 a n d 9 2:

Decrease i n B C V A of ≥ 5 letters d ue t o ne o vasc ular A M D disease acti vit y  
c o m pare d wit h Wee k 4 8
A s u bject ra n d o mize d t o RT H 2 5 8 6 m g w h o misses V isit 5/ Wee k 1 6, Vi sit 8/ Wee k 2 8, Visit 
1 1 / Wee k 4 0, Visit 1 4/ Wee k 5 2, Visit 1 7/ Wee k 6 4, Visit 2 0/ Wee k 7 6 a n d/ or Visit 2 3/ Wee k 8 8
will u n der g o t he disease acti vit y  assess me nt at t he ne xt sc he d ule d visit Vi sit 6/ Wee k 2 0 as 
he/s he w o ul d ha ve d o ne if t he visit ha d n ot bee n misse d. If, h o we ver , a s u bject ra n d o mize d t o 
R T H 2 5 8 6 m g misses a n y of t he f oll o wi n g disease acti vit y  assess me nt visits ( Visit 6/ Wee k 
2 0, Vi sit 9/ Wee k 3 2, Visit 1 2/ Wee k 4 4, Visit 1 5/ Wee k 5 6, Visit 1 8/ Wee k 6 8 or Visit 2 1/ Wee k 
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
8 0) t he n t he s u bject will be ass u me d t o ha ve met t he disease acti vit y  criteri o n at t he misse d 
visit a n d will be reassi g ne d t o a q 8 re gi me n u p t o st u d y  e xit. T he I R T  sys te m will ma ke t he 
necessar y  c ha n ges o nce t he misse d visit is re gistere d.


Page 28 of 95
Figure 10.1-1 Dose schedule by treatment
Figure 10.1.-1 
Dosing schedule by treatment
Section 10.2.4 Visit 4/Week 12 (Day 84 ± 7 days) through Visit 24/Week 92 (Day 644 ± 7 
days)
16.
Have the masked Investigator perform the visit appropriate disease activity assessment 
for the study eye (Visit 5, Visit 6, Visit 8, Visit 9, Visit 11, Visit 12, Visit 14, Visit 15, 
Visit 17, Visit 18, Visit 20, Visit 21, Visit 23 and Visit 24).
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Pa ge 2 9 of 9 5
Secti o n 1 0. 5 Disc o nti n uati o n of St u d y  Treat me nt
T he I n vesti gat or ma y  disc o nti n ue st u d y treat me nt f or a gi ve n s u bject a n d/ or wit h dra w t he 
s u bject fr o m st u d y if he/she belie ves t hat c o nti n uati o n w o ul d p ose a ris k t o t heir healt h. 
S u bjects ca n be disc o nti n ue d fr o m st u d y treat me nt beca use of

a p peara nce of a ne w healt h c o n diti o n s us pecte d t o re q uire a p pr o priate care or re q uire 
me dicati o ns pr o hi bite d b y t he pr ot oc ol

ref usal t o c o nti n ue treat me nt, or at t he I n vesti gat or ’s discreti o n base d o n his/ her 
cli nical j u d ge me nt t he s u bject re q uires resc ue me dicati o n

use of pr o hi bite d treat me nt d uri n g t he st u d y

i n vesti gat or’s discreti o n base d o n his/ her cli nical j u d g me nt

p ositi ve uri ne/ser u m pre g na nc y  test
Secti o n 1 0. 6 Cli nical St u d y  Ter mi nati o n
T he I n vesti gat or als o ma y ter mi nate t he st u d y at his/ her site f or reas o na ble ca use. If t he 
S p o ns or ter mi nates t he st u d y  f or safet y reas o ns, it will i m me diatel y n otif y t he I n vesti gat or(s) 
b y tele p h o ne a n d s u bse q ue ntl y will pr o vi de writte n c o nfir mati o n of a n d i nstr ucti o ns f or st u d y 
ter mi nati o n.  T he i n vesti gat or ma y  be i nf or me d of a d diti o nal pr oce d ures t o be f oll o we d i n 
or der t o e ns ure t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he patie nt’s i nterests. 
T he i n vesti gat or will be res p o nsi ble f or i nf or mi n g t he I R Bs/I E Cs of t he earl y  ter mi nati o n of 
t he trial.  
Secti o n 1 0. 7. 1 3 Disease Acti vit y  Assess me nt
T he mas ke d I n vesti gat or will assess t he st u d y  e ye of all s u bjects at Vi sit 5/ Week 1 6, Visit 
6/ Wee k 2 0, Vi sit 8/ Wee k 2 8, Vi sit 9/ Wee k 3 2, Vi sit 11/ Wee k 4 0, Vi sit 1 2/ Wee k 4 4, Visit 
1 4/ Wee k 5 2 , Visit 1 5/ Wee k 5 6, Vi sit 1 7/ Wee k 6 4, Vi sit 1 8/ Wee k 6 8, Vi sit 2 0/ Wee k 7 6, Vi sit 
2 1/ Wee k 8 0 a n d Visit 2 3/ Wee k 8 8 . T he I RT s yste m will ma ke t he necessar y c ha n ges t o t he 
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
d osi n g per t he mas ke d I n vesti gat or ’s assess me nt. T he disease acti vit y assess me nt will als o be 
perf or me d at Visit 2 4/ Wee k 9 2, b ut will n ot be e ntere d i nt o I RT,  a n d will ha ve n o effect o n 
t he s u bject’s treat me nt re gi me n. Details of t he disease acti vit y assess me nts are f urt her 
o utli ne d i n t he M O P.


Pa ge 3 0 of 9 5
Secti o n 1 0. 7. 4 L a b orat or y Anal ys is of Bl o o d a n d Uri ne
Bl o o d a n d uri ne sa m ples will be s hi p pe d t o a ce ntral la b orat or y . Res ults of t he a nalys is will 
be pr o vi de d t o t he I n vesti gat or w h o will assess t h ose fr o m Scree ni n g pri or t o ra n d o mizi n g t he 
s u bject t o deter mi ne if t here is a nyt hi n g t hat w o ul d precl u de partici pati o n of t he s u bject a n d 
at s u bse q ue nt visits t o assess a n y c ha n ges fr o m Scree ni n g. A sta n dar dize d pr oce d ure f or t he 
c ollecti o n a n d pr ocessi n g of bl o o d a n d uri ne is pr o vi de d b y  t he ce ntral la b orat or y.  A list of 
la b orat or y para meters is pr o vi de d i n t he M O P. If a s u bject s h o ul d prese nt wit h a cli nicall y 
si g nifica nt c ha n ge res ulti n g i n a n a d verse e ve nt, as assesse d by t he I n vesti gat or , a decisi on 
will be ma de b y t he I n vesti gat or a n d S p o ns or as t o s u bject c o nti n uati o n i n t he trial. T his 
decisi o n will ta ke i nt o acc o u nt t he a d verse e ve nt c haracteristics i ncl u di n g b ut n ot li mite d t o 
seri o us ness a n d relati o ns hi p t o st u d y dr u g.
Secti o n 1 1 A n al ysis Pl a n
Secti o n 1 1. 5 Pri mar y  a n d Ke y Sec o n dar y Efficac y Anal y ses
T he pri mar y  a n d first ke y sec o n dar y e n d p oi nts will be a nalyz e d base d o n t he FA S wit h last -
o bser vati o n -carrie d -f or war d ( L O C F) i m p utati o n of missi n g B C VA val ues ( pri mar y  a n d first 
ke y  sec o n dar y e n d poi nt) a n d a ne gati ve q 1 2 treat me nt stat us at We e k 4 8 i n t he case of 
i nc o m plete acti ve treat me nt u p t o We e k 4 8 (sec o n d a n d t hir d ke y  sec o n dar y e n d p oi nt). T he 
a nal ys is of t he pri mar y a n d ke y sec o n dar y e n d p oi nts base d o n t he P P S will be c o nsi dere d 
s u p p orti ve. W he n assessi n g t he r o b ust ness of t he o verall ef ficac y c o ncl usi o ns, e q ual 
i m p orta nce will be gi ve n t o t he FA S a n d P P S res ults u n dersta n di n g t hat a r o b ust st u d y  will 
de m o nstrate si milar c o ncl usi o ns fr o m b ot h a nal y sis data sets.
Secti o n 1 1. 5. 2 Statistical M et h o ds
T he q 1 2 treat me nt stat us of s u bjects i n t he R T H 2 5 8 6 m g treat me nt ar m will be prese nte d 
descri pti vel y t o get her wit h e xact 9 5 % c o nfi de nce i nter vals f or t he pr o p orti o n of s u bjects wit h 
a p ositi ve stat us.

F or t he o verall pr o p orti o n of s u bjects wit h a p ositi ve q 1 2 treat me nt stat us at wee k 4 8, 
t he de n o mi nat or is all FA S s u bjects i n t he R T H 2 5 8 6 m g gr o u p, a n d t he n u merat or is 
t he c orres p o n di n g n u m ber of s u bjects wit h n o i de ntifie d nee d f or treat me nt at q 8 at 
We e k 1 6, 2 0, 2 8, 3 2, 4 0 a n d 4 4 ( w hile missi n g Wee k 1 6, We e k 2 8 a n d/ or Wee k 4 0
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
assess me nt is c o nsi dere d as n o q 8 treat me nt nee de d)


Pa ge 3 1 of 9 5

F or t he pre dicta bilit y  of t he a de q uac y of q 1 2 treat me nt, base d o n t he a bse nce of 
disease acti vit y  d uri n g t he first q 1 2 c ycle, t he de n o mi nat or is all FA S s u bjects i n t he 
R T H 2 5 8 6 m g gr o u p wit h n o i de ntifie d nee d f or treat me nt q 8 at W ee k 1 6 a n d We e k 
2 0 ( w hile missi n g Wee k 1 6 assess me nt is c o nsi dere d as n o q 8 treat me nt nee de d), a n d 
t he n u merat or is t he c orres p o n di n g n u m ber of s u bjects wit h a p ositi ve q 1 2 treat me nt 
stat us at We e k 4 8, i.e., wit h n o i de ntifie d nee d f or treat me nt at q 8 at Wee k 1 6, 2 0, 2 8, 
3 2, 4 0 a n d 4 4 ( w hile missi n g Wee k 1 6, Wee k 2 8 a n d/ or We e k 4 0 assess me nt is 
c o nsi dere d as n o q 8 treat me nt nee de d)
Secti o n 1 1. 6 A d diti o nal Sec o n dar y  Efficac y Anal y ses
T he f oll o wi n g se c o n dar y efficac y e n d p oi nts will be a nalyz e d pri maril y base d o n t he FA S:

C ha n ge i n B C V A fr o m Baseli ne t o eac h p ost baseli ne visit

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 8 4 t hr o u g h Wee k 
9 6

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 4 t o Wee k 4 8/ 9 6

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 1 2 t o Wee k 4 8/ 9 6

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 4 8 t hr o u g h Wee k 
9 6

Gai n i n B C V A of 1 5/ 1 0/ 5 letters or m ore fr o m Baseli ne t o eac h p ost baseli ne v isit

L oss i n B C V A of 1 5/ 1 0/ 5 letters or m ore fr o m Baseli ne t o eac h p ost baseli ne visit

q 1 2 treat me nt stat us at Wee k 9 6 (f or s u bjects ra n d o mize d t o RT H 2 5 8 6 m g o nl y )

q 1 2 treat me nt stat us at Wee k 9 6 wit hi n t he s u bjects wit h n o q 8 - nee d d uri n g t he 
1st q 1 2 c y cle (ie, at We e k 1 6 a n d We e k 2 0) (f or s u bjects ra n d o mize d t o RT H 2 5 8 
6 m g o nl y)

C ha n ge i n C S F T  fr o m Baseli ne t o eac h p ost baseli ne visit

C ha n ge i n ne ur ose ns or y  reti nal t hic k ness fr o m Baseli ne t o eac h p ost baseli ne visit

C ha n ge i n C N V  lesi o n size fr o m Baseli ne t o We e ks 1 2, 4 8 a n d 9 6

A bse nce of s u breti nal fl ui d at eac h visit

A bse nce of i ntrareti nal fl ui d at eac h visit

q 8 treat me nt nee d stat us assesse d at W ee ks 1 6, 2 0, 2 8, 3 2, 4 0, 4 4, 5 2, 5 6, 6 4, 6 8, 
7 6, 8 0, 8 8 a n d 9 2

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
C ha n ge i n patie nt re p orte d o utc o mes ( V F Q- 2 5) t otal a n d s u bscale sc ores fr o m 
Baseli ne t o W ee ks 2 4, 4 8, 7 2 a n d 9 6 


Page 32 of 95
Section 12 Safety
12.3 Procedures for Recording and Reporting AEs and SAEs
In addition to the reporting of SAEs to the Sponsor, the SAE must be reported to the 
IEC / IRB according to their requirements. In addition, SAEs will be reported to 
regulatory agencies based upon local reporting requirements.
If the SAE is not previously documented in the Investigator’s Brochure and is thought 
to be related to the investigational treatment the Sponsor may urgently require further 
information from the investigator for Health Authority reporting. Sponsor may need to 
issue an Investigator Notification (IN) to inform all investigators involved in any study 
with the same investigational treatment that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
If the SAE was due to a hospitalization of the subject, a copy of the discharge summary is to 
be forwarded to the Sponsor as soon as it becomes available. In addition, a letter from the 
Investigator that summarizes the events related to the case as well as results of any relevant 
laboratory tests may also be requested. Further, depending upon the nature of the SAE, the 
Sponsor may request copies of applicable portions of the subject’s medical records.
Section 12.7 Pregnancy in the Study
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized or women considered post-menopausal. Women of 
childbearing potential are defined as fertile as all women and physiologically capable of 
becoming pregnant, following menarche and until becoming post-menopausal unless 
permanently sterile.  Women are considered post-menopausal if they have had 12 months of 
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential.  All women of 
childbearing potential are required to use Aadequate birth control methods which are 
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Page 33 of 95
summarized in the protocol’s exclusion criteria and should be used during the study and 
continued up to 3 months post final study injection.
Section 13 Data Handling and Administrative requirements
Section 13.5 Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be established to monitor the safety 
of the trial participants, to ensure that the trial is being conducted with the highest scientific 
and ethical standards, and make appropriate recommendations based on the data seen.
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communication 
with the Sponsor. The DMC will only make recommendations for changes in study conduct.
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Print Date:  
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TDOC-0050250
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Page 40 of 95
3
ABBREVIATIONS
Abbreviation
Definition
ADA
Anti-drug antibody
AE
Adverse event
AEF
Adverse event form
AMD
Age-related macular degeneration
ANOVA
Analysis of variance
BCVA
Best-corrected visual acuity
CI
Confidence interval
CNV
Choroidal neovascularization
CRC
Central reading center
CRF
Case report form
CSFT
Central subfield thickness
CSM
Clinical site management
CTM
Clinical trial management
DEP
Deviations and evaluability plan
EDC
Electronic data capture
ESI
Event of special interest
ETDRS
Early treatment diabetic retinopathy study
FA
Fluorescein angiography
FAF
Fundus autofluorescence
FAS
Full analysis set
GCP
Good clinical practice
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IOP
Intraocular pressure
IP
Investigational product
IRB
Institutional review board
IRC
Intraretinal cysts
IRF
Intraretinal fluid
IRT
Interactive response technology
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine system
IVT
Intravitreal
LOCF
Last observation carried forward
Mg
Milligram
mL
Milliliter
Alcon - Business Use Only 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
Print Date:  
Effective
4.0; Most-Recent; Effective; CURRENT
TDOC-0050250
10-Feb-2017


Page 41 of 95
Abbreviation
Definition
mmHg
Millimeters of mercury
MMRM
Mixed model repeated measures
MOP
Manual of procedures
PPS
Per protocol analysis set
PRN
Pro re nata
q8
Every 8 weeks
q12
Every 12 weeks
RAP
Retinal angiomatous proliferation
RPE
Retinal pigment epithelium
SAE
Serious adverse event
SAP
Statistical analysis plan
scFv
Single chain variable fragment
SD-OCT
Spectral-domain optical coherence tomography
SUSAR
Suspected unexpected serious adverse reaction
µL
Microliter
VEGF
Vascular endothelial growth factor
VFQ-25
Visual Function Questionnaire
3.1
Glossary of terms
Term
Definition
AMD
Clinical and/or angiographic signs of retinal degeneration (including drusen, hypo-
or hyper-pigmentation, geographic atrophy, and choroidal neovascularization) with 
no other likely etiologic explanations for the degenerative changes
CNV 
(subfoveal) 
secondary to 
AMD
Angiographic evidence of new blood vessel growth within the central subfield. The 
lesion containing the new vessel growth may be classic and/or occult and can 
include thick contiguous blood or an area of elevated blocked fluorescence 
corresponding to pigment that obscures the boundaries of the neovascular 
components, or serous detachment of the retinal pigment epithelium
Central subfield
The circular area within 1 mm diameter around the foveal center on imaging
Alcon - Business Use Only 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
Print Date:  
Effective
4.0; Most-Recent; Effective; CURRENT
TDOC-0050250
10-Feb-2017


Page 42 of 95
4
TABLE OF CONTENTS
A Two-Year, Randomized, Double-Masked, Multicenter, Two-Arm Study Comparing the 
Efficacy and Safety of RTH258 6 mg Versus Aflibercept in Subjects with 
Neovascular Age-Related Macular Degeneration ..................................................1
1
SYNOPSIS .............................................................................................................2
1.1
Amendments.....................................................................................................13
2
OVERVIEW OF STUDY PLAN..........................................................................34
3
ABBREVIATIONS ..............................................................................................40
3.1
Glossary of terms..............................................................................................41
4
TABLE OF CONTENTS......................................................................................42
5
INTRODUCTION................................................................................................45
5.1
Study Rationale and Background.....................................................................45
5.1.1
Dose Rationale..............................................................................................47
5.1.2
Treatment Regimen Rationale......................................................................47
5.1.3
Non-inferiority Margin Rationale.................................................................48
5.2
Benefits and Risks............................................................................................49
6
ETHICS ................................................................................................................51
7
PROTOCOL AMENDMENTS ............................................................................53
8
SUBJECT POPULATION....................................................................................54
9
TREATMENTS ADMINISTERED......................................................................55
9.1
Identity of Study Treatments ............................................................................55
9.2
Usage................................................................................................................55
9.3
Accountability Procedures................................................................................56
9.4
Subject Confidentiality and Methods Used to Minimize Bias.........................56
10
STUDY PROCEDURES......................................................................................59
10.1
Outline of Study ...............................................................................................59
10.2
Visits and Examinations ...................................................................................61
10.2.1
Screening Visit (Day -14 to Day -2).............................................................61
10.2.2
Visit 1/Baseline (Day 0) ...............................................................................63
10.2.3
Visit 2/Week 4 (Day 28 ± 3 days) and Visit 3/Week 8 (Day 56 ± 3 days) ...64
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10.2.4
10.2.4 Visit 4/Week 12 (Day 84 ± 7 days) through Visit 24/Week 92 (Day 
644 ± 7 days) ................................................................................................65
10.2.5
Visit 25/Week 96/Exit Visit (Day 672 ± 7 days) or Early Exit.....................67
10.3
Unscheduled Visits ...........................................................................................68
10.4
Discontinued Subjects ......................................................................................68
10.5
Discontinuation of Study Treatment.................................................................69
10.6
Clinical Study Termination...............................................................................70
10.7
Study Methods and Measurements...................................................................70
10.7.1
Visual Function Questionnaire-25................................................................70
10.7.2
General Physical Exam and Vital Signs .......................................................70
10.7.3
Pregnancy Tests ............................................................................................71
10.7.4
Laboratory Analysis of Blood and Urine......................................................71
10.7.5
Analysis of Anti-Drug Antibodies (ADA) and Systemic RTH258 ..............71
71
10.7.7
Best-Corrected Visual Acuity.......................................................................72
10.7.8
Complete Ophthalmic Examination .............................................................72
10.7.9
Spectral Domain Optical Coherence Tomography Imaging.........................73
10.7.10
Fluorescein Angiography..............................................................................73
10.7.11
Color Fundus Photography...........................................................................73
10.7.12
Fundus Autofluorescence .............................................................................74
10.7.13
Disease Activity Assessment ........................................................................74
10.7.14
Intravitreal Administration of Investigational Product.................................74
10.7.15
Administration of Sham Injection ................................................................74
10.7.16
Postinjection Assessment..............................................................................74
10.8
Concomitant Treatment ....................................................................................75
10.9
Prohibited Treatment ........................................................................................75
11
ANALYSIS PLAN ...............................................................................................77
11.1
General considerations .....................................................................................77
11.2
Subject Evaluability..........................................................................................77
11.3
Analysis Data Sets............................................................................................77
11.4
Demographic and Baseline Characteristics......................................................78
11.4.1
Demographic Characteristics........................................................................78
11.4.2
Baseline Characteristics................................................................................78
11.5
Primary and Key Secondary Efficacy Analyses...............................................78
11.5.1.1
Statistical Hypotheses...............................................................................79
11.5.2
Statistical Methods .......................................................................................79
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11.5.3
Sensitivity Analysis ......................................................................................80
11.5.4
Subgroups.....................................................................................................80
11.6
Additional Secondary Efficacy Analyses .........................................................81
11.7
Handling of Missing Data ................................................................................82
11.8
Multiplicity.......................................................................................................82
11.9
Safety................................................................................................................82
11.9.1
Treatment exposure ......................................................................................82
11.9.2
Medical History............................................................................................82
11.9.3
Concomitant Therapies.................................................................................82
11.9.4
Safety parameters .........................................................................................83
11.9.5
Adverse Events.............................................................................................83
11.10
Interim Analyses...............................................................................................84
11.11
Sample Size Justification..................................................................................84
12
ADVERSE EVENTS ...........................................................................................85
12.1
General Information .........................................................................................85
12.2
Monitoring for Adverse Events ........................................................................85
12.3
Procedures for Recording and Reporting AEs and SAEs.................................85
12.4
Intensity and Causality Assessments................................................................89
12.5
Unmasking of the Study Treatment..................................................................89
12.6
Follow-up of Subjects with Adverse Events ....................................................90
12.7
Pregnancy in the Study.....................................................................................90
13
DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS ..................91
13.1
Completion of Source Documents and Case Report Forms.............................91
13.2
Data Review and Clarifications........................................................................91
13.3
Regulatory Documentation and Records Retention .........................................92
13.4
Quality Assurance and Quality Control............................................................92
13.5
Data Monitoring Committee.............................................................................92
14
References.............................................................................................................93
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5
INTRODUCTION
5.1
Study Rationale and Background
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people 
affecting 10%-13% of individuals over the age of 65 in North America, Europe, and Australia 
(Kawasaki 2010, Rein 2009, Smith 2001). Genetic, environmental and health factors play an 
important role in the pathogenesis of the disease.
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or dry form and 
the neovascular (exudative) or wet form (Ferris 1984, Lim 2012, Miller 2013). Neovascular 
AMD is characterized by the growth of abnormal new blood vessels (neovascularization) 
under the retinal pigment epithelium (RPE) or subretinal space from the subjacent choroid, 
termed choroidal neovascularization (CNV) (Ferris, 1984). These newly formed vessels have 
an increased likelihood to leak blood and serum, damaging the retina by stimulating 
inflammation and scar tissue formation. This damage to the retina results in progressive, 
severe, and irreversible vision loss (Shah 2007, Shah 2009). Without treatment, most affected 
eyes will have poor central vision (20/200) within 12 months (TAP 2003). Although the 
neovascular form of the disease is only present in about 10% of all AMD cases, it accounted 
for approximately 90% of the severe vision loss from AMD prior to the introduction of anti-
vascular endothelial growth factor (VEGF) treatments (Ferris 1983, Sommer 1991, Wong 
2008).
VEGF has been shown to be elevated in patients with neovascular AMD, and is thought to 
play a key role in the neovascularization process (Spilsbury 2000). The use of intravitreal 
(IVT) pharmacotherapy targeting VEGF has significantly improved visual outcomes in 
patients with neovascular AMD (Bloch 2012, Campbell 2012). Anti-VEGF treatments, such 
as ranibizumab (LUCENTIS) and aflibercept (EYLEA), inhibit VEGF signaling pathways 
and have been shown to halt the growth of neovascular lesions and resolve retinal edema.
Ranibizumab
In two Phase 3 studies of ranibizumab with monthly dosing regimens, approximately 95% of 
ranibizumab treated subjects experienced stabilization of vision (defined as a loss of fewer 
than 15 early treatment diabetic retinopathy study [ETDRS] letters) or improvement in vision 
at 12 months compared with 62% and 64% in the control groups (Rosenfeld 2006, Brown 
2009). Twenty-five to 40% of subjects in the ranibizumab groups gained ≥ 15 letters at 12 
months compared with 5-6% in the 2 control groups. On average, ranibizumab treated 
subjects gained 7-11 letters of vision after 12 months, whereas control subjects lost an 
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average of approximately 10 letters. This gain in visual acuity was essentially maintained 
during the second year of both Phase 3 studies while vision, on average, continued to decline 
in the control group. The visual acuity benefits, which indicate a suspension of neovascular 
AMD rather than a slowdown of its progression, were supported by corresponding effects on 
lesion anatomy and subject reported outcomes. The latter demonstrated statistically and 
clinically meaningful improvements in near activities, distance activities, and vision specific 
dependency as measured by the National Eye Institute Visual Function Questionnaire-25 
(VFQ-25).
Aflibercept
In two parallel Phase 3 trials of aflibercept, treatment naïve subjects with neovascular AMD 
were randomized to 2 doses (0.5 and 2.0 mg) and 2 regimens (every 4 weeks and every 8 
weeks with 2.0 mg) or the control arm (ranibizumab 0.5 mg every 4 weeks). At 52 weeks, all 
aflibercept groups, independent of doses and regimens, were noninferior to the ranibizumab 
group with equal stabilization of vision in 95% of eyes (Heier 2012). In the 2 mg aflibercept 
every 4 weeks group, there was a mean best-corrected visual acuity (BCVA) improvement of 
9.3 letters and in the 2 mg aflibercept every 8 weeks group there was an improvement of 8.4 
letters compared to the control group which had a mean improvement of 8.7 letters. In the 
second year of the study subjects were switched to a capped (treatment required at least 
every12 weeks) pro re nata (PRN) regimen. The proportion of subjects who maintained 
BCVA ranged between 91% and 92% for all groups. Mean BCVA improvements ranged from 
7.9 (ranibizumab), 7.6 (aflibercept 2 mg every 4 weeks and every 8 weeks) to 6.6 (aflibercept 
0.5 mg every 4 weeks). The retreatment frequency was similar between the aflibercept and 
ranibizumab arms during the capped PRN year, with a mean of 4.1 injections for the 
aflibercept 2 mg every 4 weeks arm, 4.2 injections for the aflibercept 2 mg every 8 weeks 
arm and 4.7 for the ranibizumab arm (Schmidt-Erfurth 2014).
RTH258
RTH258, formerly known as ESBA1008, is a humanized single-chain Fv (scFv) antibody 
fragment inhibitor of VEGF with a molecular weight of ~26 kDa that is being developed for 
the treatment of CNV associated with neovascular AMD. It is an inhibitor of VEGF-A and 
works by binding to the receptor binding site of the VEGF-A molecule, thereby preventing 
the interaction of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface of 
endothelial cells. Increased levels of signaling through the VEGF pathway are associated 
with pathologic ocular angiogenesis and retinal edema. Inhibition of the VEGF pathway has 
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been shown to inhibit the growth of neovascular lesions and resolve retinal edema in patients 
with neovascular AMD.
In an ascending single dose study, Alcon protocol C-10-083, several doses of RTH258 (0.5, 
3.0, 4.5 and 6 mg), were evaluated versus ranibizumab 0.5 mg with regard to the mean 
change from Baseline to Month 1 in central subfield thickness (CSFT) as measured by 
spectral- domain optical coherence tomography (SD-OCT) (primary efficacy endpoint). 
Treatment with RTH258 provided similar reductions for all doses in CSFT to ranibizumab. 
The primary statistical analysis compared RTH258 4.5 mg and 6.0 mg versus ranibizumab 
0.5 mg with both doses achieving non-inferiority. Notable however was the median time to 
receiving standard of care which was 45.0 days for ranibizumab but was longer for the 
RTH258 3.0 mg, 4.5 mg and 6.0 mg doses (75.0 days(p=0.0374), 60.0 days (p=0.1805) and 
75.0 days (p=0.0360) respectively). The interquartile range was 30 – 75 days for 
ranibizumab, and 45 – 120 days, 30 – 120 days and 37.5 – 150 days for the RTH258 3.0 mg, 
4.5 mg and 6.0 mg respectively. RTH258 6 mg was the highest dose tested in the study and 
no unexpected safety issues were reported that would preclude further clinical development. 
Subsequently the safety and efficacy of the RTH258 6 mg dose were evaluated versus 
aflibercept 2 mg in a 56 week multiple dose study (Alcon protocol C-12-006) with a primary 
endpoint at 12 weeks. The efficacy data from this study showed that RTH258, when it was 
given every 8 weeks (q8), was as effective as the active control in terms of BCVA change 
from Baseline. There were numerical advantages with RTH258 over aflibercept with regard 
to the change in CSFT from Baseline. The majority (72%) of the RTH258 treated subjects 
who completed an extension of the study, who received treatment every 12 weeks (q12), 
showed visual stability. There were no adverse events in the RTH258 group that negatively 
differentiated the drug from the control. The majority of adverse events were mild or 
moderate in nature and either resolved spontaneously or with treatment.
5.1.1
Dose Rationale
Studies C-10-083 and C-12-006 suggest that a 6 mg dose of RTH258 is effective and safe.
5.1.2
Treatment Regimen Rationale
While VEGF inhibitors have vastly improved patient outcomes for neovascular AMD, there 
still remains a need for treatments and regimens which offer a reduced frequency of 
injections. Frequent treatment and monitoring schedules remain a significant burden to 
patients, caregivers and physicians. The proposed Phase 3 study aims to address these.
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In the current study, RTH258 patients will receive q12 maintenance dosing. Disease activity 
assessments will be conducted by a masked investigator at Weeks 16, 20, 28, 32, 40 and 44, 
allowing 6 time points up to the primary endpoint of the study (Week 48) where RTH258 q12 
subjects can be reassigned to q8 treatment. It is expected that early determination at Week 16 
and Week 20 of subjects who are more suited to a q8 dosing regimen will minimize the 
percentage of q12 subjects who will require reassignment at later time points.
Analyses from the PIER (Regillo 2008) and EXCITE (Schmidt-Erfurth 2011) studies have 
shown that visual and anatomic response during, and for the 12 weeks after the loading 
phase, are associated with visual acuity outcomes over the remainder of the first year of 
treatment. In addition, recent analyses from the EXCITE (Chong 2013) study have also 
shown that subjects who lose vision during the initial loading phase will have better visual 
outcomes with more frequent treatment versus q12 treatment. Finally, analyses from CATT 
(Kim 2014, Ying 2014) and EXCITE (Simader 2014) have also shown that new intraretinal 
fluid (IRF)/intraretinal cysts (IRC), and to a lesser degree CSFT increase, are associated with 
later visual acuity decline.
Due to the well-established efficacy of anti-VEGF treatments in the indication of neovascular 
Age-Related Macular Degeneration, an internal validation of this study via a placebo arm is 
ethically not feasible. The available historical evidence of the efficacy of Lucentis (Anchor 
and Marina) and of aflibercept (VIEW 1 and 2) allows for a reliable estimate of the drug’s 
effect size compared to placebo and due to the similarity of the current NI trial to the 
historical studies in terms of study population, efficacy assessments and duration,  there is a 
sound basis for external validation of the results of this study.
5.1.3
Non-inferiority Margin Rationale
Non-inferiority testing related to the primary efficacy parameter best corrected visual acuity 
[letters] will be based on a margin of 4 letters. This non-inferiority margin provides assurance 
that both absolute efficacy and acceptable efficacy relative to the active comparator 
aflibercept can be established.
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Pa ge 4 9 of 9 5

A bs ol ute ef ficac y: T he acti ve c o m parat or afli berce pt t o get her wit h L uce ntis bel o n gs t o a 
class of a nti -V E G F treat me nts w here f or t he i n di vi d ual pr o d ucts si milar efficac y has bee n 
esta blis he d ( VI E W 1 a n d 2). T his si milarit y  j ustifies t he use of t he o nly a vaila ble relate d 
s u peri orit y data  vers us  S ha m or Vi s u d yne re p orte d f or m o nt hl y  Luce ntis i n t he st u dies 
M A RI N A  ( vs S ha m) a n d A N C H O R ( vs V is u d yne) t o q ua ntif y  t he or der of ma g nit u de of 
t he a bs ol ute treat me nt effect f or t his class of treat me nts. F or t he e n d p oi nt ‘c ha n ge i n 
B C V A fr o m baseli ne t o M o nt h 1 2 [letters]’ t his a bs ol ute treat me nt effect was esti mate d 
f or m o nt hl y Luce ntis 0. 5 m g i n t he M A RI N A  st u d y as 1 7. 5 letters  ( 9 5 % CI [ 1 4. 8 , 2 0, 2] ) 
c o m pared t o S ha m -i njecti o ns a n d i n t he A N C H O R st u d y  as 2 1. 1 letters ( 9 5 % CI [ 1 7. 5 , 
2 4. 6]) c o m pare d t o Vis u d yne . Relati ve t o t hese a bs ol ute treat me nt effects, n o n- i nferi ority 
esta blis he d at a 4 letter mar gi n will g uara ntee a n a bs ol ute treat me nt effect i n t he 
ma g nit u de of at least 1 0 letters e ve n u n der t he c o nser vati ve a p pr oac h of usi n g t he l o wer 
li mits of t hese 9 5 % c o nfi de nce i nter vals as refere nce. 

Esta blis hi n g acce pta ble ef ficac y relati ve t o t he acti ve c o m parat or afli berce pt: F or a n o n-
i nferi orit y mar gi n of 4 letters t o get her wit h t he ass u me d sta n dar d de viati o n of 1 5 letter f or 
t he pri mar y e n d p oi nt B C VA c ha n ge fr o m baseli ne at We e k 4 8 a n d a sa m ple size of 3 0 0 
patie nts, it is e x pecte d t hat n o n -i nferi ority ca n o nl y be clai me d if t he o bser ve d dif fere nce 
bet wee n RT H 2 5 8 a n d afli berce pt is > -1. 6 letters. Si g nif y i n g t hat t he o bser ve d mea n 
B C V A c ha n ge f or RT H 2 5 8 is n o m ore t ha n 1. 6 letters w orse t ha n f or afli berce pt.  
T he p o wer calc ulati o n is base d o n t he ass u m pti o n of e q ual ef ficac y f or RT H 2 5 8 a n d 
afli berce pt wit h a res ulti n g p o wer of a b o ut 8 0 % f or t w o s uccessf ul P hase III st u dies, 
w hile i n case of a real treat me nt dif fere nce of - 1. 6 letters t he p o wer g oes d o w n t o 2 5 %. 
E ve n if t he treat me nt dif fere nce is o nl y -1 letter , t he c ha nce f or t w o s uccessf ul P hase III 
st u dies falls bel o w 5 0 %. 
W hile a 4 letter dif fere nce i n t he B C VA res p o nse bet wee n t w o re gi me ns ca n be 
c o nsi dere d of rele va nce, a 4 letter n o n- i nferi ority mar gi n i n a cli nical trial lea ds t o a 
discri mi nati o n of treat me nts alrea d y f or m uc h s maller delta -le vels f or w hic h mi n or 
u n derl y i n g cli nical rele va nce ca n be attri b ute d.
5. 2
Be nefits a n d Ris ks
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
R T H 2 5 8 is a n i n hi bit or of V E G F wit h a mec ha nis m of acti o n si milar t o ra ni biz u ma b b ut wit h 
a s maller m olec ular size ( 2 6 k Da a n d 4 8 k Da res pecti vel y).
N o ncli nical st u dies ha ve de m o nstrate d t hat R T H 2 5 8 is at least as p ote nt as ra ni biz u ma b, wit h 
a si milar vitreal half -life a n d a si g nifica ntly l o wer s yste mic e x p os ure. T he l o w s yste mic 
e x p os ure s h o ul d c o nfer a g o o d safet y pr ofile e ve n at a hi g h d ose. T he hi g her d ose, si milar 


Page 50 of 95
half-life, and potency of RTH258 may confer a longer treatment duration compared to 
currently available treatments. Two clinical studies, C-10-083 and C-12-006, have 
demonstrated that RTH258 is as effective as ranibizumab and aflibercept in improving BCVA 
outcomes whilst having a reduced treatment frequency, thus providing a potential benefit to 
patients and their caregivers/physicians. The ocular and systemic safety profile of single or 
repeated doses of RTH258 were also evaluated in the C-10-083 and C-12-006 studies, 
respectively, and demonstrated similar safety profiles to ranibizumab and aflibercept. Further 
details of the known and potential risks and benefits associated with RTH258 are presented in 
the Investigator’s Brochure.
Summarized, the results from the Phase 2 studies demonstrate that RTH258 has similar 
efficacy to currently available treatment options with potentially greater duration of effect. 
These data support the further development of RTH258 with a treatment regimen including 
q12 maintenance dosing.
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6
ETHICS
This clinical study will be conducted in accordance with the principles of the Declaration of 
Helsinki, and in compliance with the International Conference on Harmonization (ICH) E6 
Good Clinical Practice (GCP) Consolidated Guideline and other regulations as applicable. 
The Investigator and all clinical study staff will conduct the clinical study in compliance with 
the protocol. The Investigator will ensure that all personnel involved in the conduct of the 
study are qualified to perform their assigned responsibilities through relevant education, 
training, and experience.
Before clinical study initiation, this protocol, the informed consent form (and assent form, if 
applicable), any other written information given to subjects, and any advertisements planned 
for subject recruitment must be approved by an Independent Ethics Committee/Institutional 
Review Board (IEC/IRB). The Investigator must provide documentation of the IEC/IRB 
approval to the Sponsor. The approval must be dated and must identify the applicable 
protocol, amendments (if any), informed consent form, assent form (if any), all applicable 
recruiting materials, written information for subject, and subject compensation programs. The 
IEC/IRB must be provided with a copy of the Investigator’s Brochure, any periodic safety 
updates, and all other information as required by local regulation and/or the IEC/IRB. At the 
end of the study, the Investigator will notify the IEC/IRB about the study’s completion. The 
IEC/IRB also will be notified if the study is terminated prematurely. Finally, the Investigator 
will report to the IEC/IRB on the progress of the study at intervals stipulated by the IEC/IRB.
Voluntary informed consent will be obtained from every subject (and/or legal representative, 
as applicable) prior to the initiation of any screening or other study-related procedures. The 
Investigator must have a defined process for obtaining consent. Specifically, the Investigator, 
or designee, will explain the clinical study to each potential subject and the subject must 
indicate voluntary consent by signing and dating the approved informed consent form. The 
subject must be provided an opportunity to ask questions of the Investigator, and if required 
by local regulation, other qualified personnel. The Investigator must provide the subject with 
a copy of the consent form written in a language the subject understands. The consent 
document must meet all applicable local laws and will provide subjects with information 
regarding the purpose, procedures, requirements, and restrictions of the study, along with any 
known risks and potential benefits associated with the investigational product, the available 
compensation, and the established provisions for maintaining confidentiality of personal, 
protected health information. Subjects will be told about the voluntary nature of participation 
in the study and will be provided with contact information for the appropriate individuals 
should questions or concerns arise during the study. The subject also will be told that their 
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records may be accessed by appropriate authorities and Sponsor-designated personnel. The 
Investigator must keep the original, signed copy of the consent and must provide a duplicate 
copy to each subject.
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7
PROTOCOL AMENDMENTS
Modification of the protocol is prohibited without prior written agreement in the form of a 
protocol amendment. All amendments will be created by the Sponsor and must be approved 
by the IEC/IRB and Regulatory Authorities prior to implementation except when required to 
mitigate immediate safety risks or when the changes involve only logistical or administrative 
revisions.
Amendments may necessitate that the ICF and other study-related material be revised. If the 
ICF is revised, all subjects currently enrolled in the study may be required by the IEC/IRB to 
sign the approved, revised ICF.
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8
SUBJECT POPULATION
The study population includes approximately 660 subjects to be randomized at approximately 
200 sites. To participate in the study, subjects must be ≥ 50 years of age with untreated active 
CNV secondary to AMD in the study eye. The expected duration of subject participation in 
the randomized portion of the study is 96 weeks. The complete inclusion and exclusion 
criteria are presented in Section 1.
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9
TREATMENTS ADMINISTERED
At Visit 1/Baseline Visit (Day 0), all eligible subjects will be randomized centrally using 
Interactive Response Technology (IRT) in a 1:1 ratio to receive either RTH258 6 mg/50 µL or 
aflibercept 2 mg/50 µL. In the event that IRT is not available for randomization, the site 
should contact the Sponsor about how to proceed. In these cases subjects may be manually 
randomized.
Throughout the study, the Investigator will be responsible for the accounting of all study 
materials and investigational products, and will ensure that the investigational products are 
not used in any unauthorized manner.
9.1
Identity of Study Treatments
Test Article: 
RTH258 solution for IVT injection, 6 mg in 50 µL (120 mg/mL 
formulation)
Control Article: 
Aflibercept solution for IVT injection, 2 mg in 50 µL
The trial kits will consist of a carton that contains 1 single use, sterile glass vial containing 
RTH258 6 mg or aflibercept 2 mg.
Kit labels on all trial kits include the kit number, protocol number, storage conditions, and a 
statement that the product is for investigational use only.
All trial kits should be stored at 2º to 8ºC (35.6º to 46.4ºF); do not freeze. To ensure proper 
conditions are maintained, a daily (7 days/week) temperature log will be maintained 
documenting appropriate investigational product storage conditions.
9.2
Usage
RTH258 6 mg will be administered by IVT injection. All doses will be delivered in 50 µL 
(0.05 mL). Subjects in the RTH258 6 mg arm will receive loading doses at Visit 1/Day 0, 
Visit 2/Week 4 and Visit 3/Week 8. After the loading doses subjects will receive q12 
treatment unless there is disease activity according to the guidance provided in Section 10.1.
If disease activity is identified, the subject will be reassigned to receive injections q8 
thereafter, up to Visit 24/Week 92.
Aflibercept 2 mg will be administered as a 50 µL (0.05 mL) IVT injection. Subjects 
randomized to receive aflibercept will receive loading doses at Visit 1/Day 0, Visit 2/Week 4 
and Visit 3/Week 8 followed by injections q8 to Visit 24/Week 92.
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To maintain masking, beginning at Visit 6/Week16, if a subject should not receive an active 
treatment, a sham injection will be performed.
If at any visit, a subject is accidentally treated with investigational product (IP) from the arm 
other than the one to which they were assigned, they will be treated with the IP they were 
randomized to by IRT, and follow the treatment schedule of that arm for the remainder of the 
study. In the event this occurs, it must be reported to the Sponsor immediately.
9.3
Accountability Procedures
Each site must have designated unmasked site personnel who, upon receipt of the IP, will 
conduct an inventory. At the appropriate study visits, designated unmasked study staff will 
provide the IP to the unmasked injecting physician in accordance with the IRT procedures.
During the study, the Investigator must maintain records of IP dispensation and collection for 
each subject. This record must be made available to the unmasked study monitor for the 
purposes of verifying the accounting of clinical supplies. Any discrepancies and/or 
deficiencies between the observed disposition and the written account must be recorded along 
with an explanation. At the conclusion of the study, the Investigator will be responsible for 
returning all used and unused study supplies unless otherwise instructed by the Sponsor.
9.4
Subject Confidentiality and Methods Used to Minimize Bias
The Investigator must ensure that the subject’s anonymity is maintained throughout the 
course of the study. In particular, the Investigator must keep an enrollment log with 
confidential identifying information that corresponds to the subject number of each study 
participant. At the end of the clinical study, the Sponsor will collect a copy of the enrollment 
log without any identifying subject information. All documents submitted to the Sponsor will 
identify the subject exclusively by number and demographic information. No other 
personally identifying information should be transmitted to the Sponsor.
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. The essential aim of masking, therefore, is to 
prevent identification of the treatments by the Investigator, subject, and others associated 
with the conduct of the study until all such opportunities for bias have passed.
This study will be double-masked, with subjects randomized to be treated with RTH258 6 mg 
or aflibercept 2 mg. All members of the Clinical Study Team will be masked to treatment 
assignments while the study is in progress. In addition, the biostatistician who is directly 
involved in the conduct of the study (i.e. involved in patient level discussions or direct 
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interaction with sites) will remain masked to treatment assignments while the study is in 
progress. Sponsor personnel who have access to treatment codes (eg, SAS Programming 
personnel directly involved with bioanalysis of serum samples, unmasked monitors 
performing IP accountability, and Clinical Supplies personnel) will not divulge the codes to
subjects, Investigators, site staff, Sponsor Clinical Trial Management (CTM), or Sponsor 
Clinical Site Management (CSM). If necessary, the Sponsor may be required to unmask a 
subject if an adverse event (AE) meets criteria of a Suspected Unexpected Serious Adverse 
Reaction (SUSAR) in order to fulfill expedited regulatory reporting requirements. In this 
event, the Sponsor Safety Review Team will not divulge the treatment code to any other 
personnel involved in reporting, obtaining, and/or reviewing the clinical evaluations. This 
level of masking will be maintained throughout the conduct of the study.
Each site must have both masked and unmasked physicians available. The physician who 
performs the injection will be unmasked to the treatments as will any other site personnel 
who have been delegated responsibility for working with the IP. The unmasked site personnel 
and unmasked injecting physician must not perform any study assessments which may 
compromise the efficacy (ie, BCVA, complete ophthalmic examination, disease activity 
assessments or administer the VFQ-25). Also, the unmasked site personnel and unmasked 
injecting physician must not perform assessment of any ocular or nonocular safety 
parameters, or assess causality AEs for subjects during the course of the study except an 
event reported immediately following IVT injection. The unmasked physician/site personnel 
should, however, assess subject safety immediately following injection (ie, they will perform 
the postinjection assessment; the masked physician/site personnel should not perform this 
assessment). Unmasked monitors will be provided to perform IP accountability.
Treatment will be assigned to subjects through the IRT system. Each subject number will be 
associated with treatment groups according to a random process generated using computer 
software (SAS 9.2 PROC PLAN). Subjects will be assigned in sequence number order 
according to time of randomization; the randomization schedule will be blocked to ensure a 
balance of treatment allocations across the study. There are no stratification factors in this 
study. The IRT system will be utilized to implement the outcome of the disease activity 
assessments at the appropriate visits.
The randomization scheme will be generated and maintained by the Sponsor. Once all study 
data have been verified, validated, and the database locked, individual subjects will be 
unmasked to their treatment. In the event of a medical emergency during the study where the 
knowledge of subject treatment is required, an individual Principal Investigator will have the 
ability to unmask the treatment assignment for a specific subject. The Investigator should 
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notify the Sponsor prior to unmasking a subject, if there is sufficient time. Further, the 
Sponsor must be informed whenever the randomization code is broken and the reasons for 
unmasking.
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10
STUDY PROCEDURES
10.1
Outline of Study
This is a prospective, randomized, double masked, multicenter, two arm study. Subjects with 
untreated active CNV secondary to AMD who meet all inclusion/exclusion criteria will be 
included in the study. The study will be conducted at approximately 200 sites and will 
randomize approximately 660 subjects.
The Investigator or a designee is responsible for scheduling study visits and ensuring subject 
compliance with the visit schedule. Subjects missing a scheduled visit should be contacted 
immediately to reschedule the examination, preferably within the specified study visit period.
SD-OCT imaging, fluorescein angiography (FA) and color fundus photography will be 
performed at the Screening Visit and the images will be assessed by CRC. The CRC will 
review these images to confirm subject eligibility based upon the lesion attributes specified in 
the inclusion/exclusion criteria. Subjects who meet all inclusion and no exclusion criteria and 
are confirmed as eligible by the CRC will return to the site for the Visit 1/Baseline (Day 0).
At Visit 1/Baseline Visit, subjects will be randomized to one of two arms in a 1:1 ratio.
In Arm 1 (RTH258 6 mg):
RTH258 6 mg will be initially injected 3 times at 4 week intervals, at Visit 1/Day 0, Visit 
2/Week 4 and Visit 3/Week 8.
Following the loading doses, each subject will be injected q12 up to Visit24/Week 92 unless 
there is disease activity assessed according to the guidance provided at Visit 5/Week 16, Visit 
6/Week 20, Visit 8/Week 28, Visit 9/Week 32, Visit 11/Week 40, Visit 12/Week 44, Visit 
14/Week 52, Visit 15/Week 56, Visit 17/Week 64, Visit 18/Week 68, Visit 20/Week 76, Visit 
21/Week 80 or Visit 23/Week 88. If disease activity is identified, the subject will be 
reassigned to receive injections q8 thereafter, up to study exit. The IRT system will make the 
necessary changes to the dosing per the masked Investigator’s assessment. The disease 
activity assessment will also be performed at visit 24/Week 92 but will not be entered into 
IRT and will have no effect on the subject’s treatment regimen.
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Pa ge 6 0 of 9 5
Disease Acti vit y  Criteria at We e k 1 6:

Decrease i n B C V A of ≥ 5 letters c o m pare d wit h Baseli ne

Decrease i n B C V A of ≥ 3 letters a n d C S F T  i ncrease ≥ 7 5 µ m c o m pare d wit h We e k 
1 2

Decrease i n B C V A of ≥ 5 letters d ue t o ne o vasc ular A M D disease acti vit y  
c o m pare d wit h Wee k 1 2

Ne w or w orse I R C/I R F c o m pare d wit h We e k 1 2
Disease Acti vit y  Criteri o n at We e ks 2 0, 2 8, 3 2, 4 0 a n d 4 4:

Decrease i n B C V A of ≥ 5 letters d ue t o ne o vasc ular A M D disease acti vit y  
c o m pare d wit h Wee k 1 2
Disease Acti vit y  Criteri o n at We e ks 5 2, 5 6, 6 4, 6 8, 7 6, 8 0, 8 8 a n d 9 2:

Decrease i n B C V A of ≥ 5 letters d ue t o ne o vasc ular A M D disease acti vit y  
c o m pare d wit h Wee k 4 8
A s u bject ra n d o mize d t o RT H 2 5 8 6 m g w h o misses Vi sit 5/ Wee k 1 6, Visit 8/ Wee k 2 8, Visit 
1 1 / Wee k 4 0, Visit 1 4/ Wee k 5 2, Visit 1 7/ Wee k 6 4, Visit 2 0/ Wee k 7 6 a n d/ or Visit 2 3/ Wee k 8 8 
will u n der g o t he disease acti vit y  assess me nt at t he ne xt sc he d ule d visit as he/s he w o ul d ha ve 
d o ne if t he visit ha d n ot bee n misse d. If, h o we ver , a s u bject ra n d o mize d t o RT H 2 5 8 6 m g 
misses a n y  of t he f oll o wi n g disease acti vit y assess me nt visits ( Visit 6/ Wee k 2 0, Visit 9/ Wee k 
3 2, Visit 1 2/ Wee k 4 4, Visit 1 5/ Wee k 5 6, Visit 1 8/ Wee k 6 8 or Visit 2 1/ Wee k 8 0) t he n t he 
s u bject will be ass u me d t o ha ve met t he disease acti vit y  criteri o n at t he misse d visit a n d will 
be reassi g ne d t o a q 8 re gi me n u p t o st u d y  e xit. T he I R T  sys te m will ma ke t he necessar y 
c ha n ges o nce t he misse d visit is re gistere d.
If a s u bject misses Visit 4/ Wee k 1 2, t he n t he Visit 3/ Wee k 8 val ues will be a p plie d as t he 
refere nce f or disease acti vit y assess me nts u p t o a n d i ncl u di n g Visit 1 2/ Wee k 4 4. If a s u bject 
misses Vi sit 1 3/ Wee k 4 8, t he n t he Visit 1 2/ Wee k 4 4 val ues will be a p plie d as t he refere nce 
f or disease acti vit y assess me nts i n t he sec o n d year of t he st u d y.
I n Ar m 2 ( afli ber ce pt 2 m g):
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
Afli berce pt 2 m g, ( E Y L E A, c o m parat or) treat me nt is i nitiate d wit h i njecti o ns at 4 wee k 
i nter vals ( Visit 1/ Da y 0, Visit 2/ Wee k 4 a n d Visit 3/ Wee k 8), f oll o we d b y i njecti o ns q 8
t hereafter ( Fi g ure 1 0. 1.-1).


Page 61 of 95
Figure 10.1.-1 
Dosing schedule by treatment
10.2
Visits and Examinations
Details of all procedures, definitions and grading criteria for test parameters can be found in 
the Manual of Procedures (MOP) for this protocol.
10.2.1
Screening Visit (Day -14 to Day -2)
The completion of assessments for this visit may occur on different days. The screening 
period starts with the signing of the ICF.
One time rescreening of subjects will be allowed in the following circumstances: a) 
laboratory test(s) need to be repeated, b) when a subject has a temporary medical condition 
precluding participation. As long as testing can be repeated within 14 days of the first 
screening, the other screening assessments do not need to be repeated. If rescreening is to 
occur beyond 14 days from the original screening visit date, then all screening procedures 
must be repeated. Rescreening will not be permitted for the purpose of capturing new BCVA 
or imaging assessments that previously failed to qualify the subject. Medical judgment should 
be exercised to ensure that treatment is not withheld in order for a subject to participate in the 
study.
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1
Explain the purpose and nature of the study, and have the subject or legally authorized
representative read, sign, and date the IRB/IEC-approved ICF (including the optional 
pharmacogenetics consent, if applicable). Additionally, have the individual obtaining 
ICF the subject and a witness, if applicable, sign and date the ICF. Provide a copy of 
the signed document to the subject (or additional original signed document where 
required) and maintain an original signed document at the site. The ICF must be 
signed/dated prior to performing study procedures including screening.
2
Obtain demographic information and medical history, including information on all
medications used within the past 90 days.
3
Perform a general physical exam.
4
Collect vital signs (blood pressure and pulse).
5
Perform a pregnancy test if the subject is female and of childbearing potential.
6
Obtain blood and urine samples for blood chemistry/hematology and urinalysis and 
submit the samples to the central laboratory Sample collection should be performed 
prior to injection of the fluorescein dye.
7
Perform BCVA on both eyes. 
8
Perform a complete ophthalmic examination on both eyes including slit-lamp exam,
intraocular pressure (IOP) measurement and fundus exam (dilation to be performed at 
the discretion of the Investigator).
9
Perform SD-OCT on both eyes. Submit the images (within 24 hours, if possible) to the
CRC for determination of eligibility.
10
Perform FA on both eyes. Submit the images (within 24 hours, if possible) to the CRC
for determination of eligibility.
11
Perform 3-field color fundus photography on both eyes. Submit the images (within 24
hours, if possible) to the CRC for determination of eligibility.
12
Register the subject (including screen fails) in the electronic data capture (EDC) system 
and obtain a subject ID number.
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13
Contact IRT to enter the subject ID number.
14
Monitor for AEs.
15
Schedule Visit 1/Baseline (Day 0) to take place 2 to 14 days after the start of the
Screening assessments.
10.2.2
Visit 1/Baseline (Day 0)
At the Baseline Visit, subjects will be randomized only if the subject has successfully met all 
of the eligibility criteria.
1.
Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2.
Record any AEs that are observed or reported, including those associated with changes 
in concomitant medication dosing.
3.
Administer the VFQ-25, using validated translations as applicable and available. The 
VFQ-25 should be administered prior to any examination.
4.
Collect vital signs (blood pressure and pulse).
5.
Obtain a blood sample for anti-drug antibody (ADA) analysis. Blood draws should 
take place prior to the injection.
6.
Obtain a blood sample for systemic RTH258 analysis. Blood draws should take place 
prior to the injection.
7.
Obtain a blood sample for genetic analysis (optional). Blood draws should take place 
prior to the injection.
8.
Perform BCVA on both eyes. Baseline BCVA of the study eye must be between 78 and 
23 letters, inclusive, for the subject to qualify.
9.
Perform a complete ophthalmic examination on the study eye including slit-lamp 
exam, IOP measurement, and fundus exam (dilation to be performed at the discretion 
of the Investigator).
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10.
Perform SD-OCT imaging on study eye and submit the images to the CRC.
11.
Where applicable, perform fundus autofluorescence (FAF) imaging on the study eye
and submit the images to the CRC. FAF will only be performed at a subset of sites.  
Dilation to be performed at the discretion of the Investigator.
12.
Verify that all eligibility criteria have been met, including the required screening 
imaging eligibility from the CRC. The Investigator should also review the results from 
the central laboratory for the samples collected at Screening to determine if there is 
anything that would preclude participation of the subject.
13.
Contact IRT to obtain a kit number.
14.
Have the unmasked Investigator perform an IVT injection according to the 
randomization/kit assignment. The injection procedure may be performed at a later 
time, as long as it is within 7 days of the scheduled visit.
15.
After the injection, perform a postinjection assessment of the study eye 0-5 minutes 
and 30 (± 15) minutes after injection (and at further time points, as needed).
16.
Schedule Visit 2/Week 4 to take place 28 ± 3 days after the Visit 1/Baseline.
10.2.3
Visit 2/Week 4 (Day 28 ± 3 days) and Visit 3/Week 8 (Day 56 ± 
3 days)
1.
Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2.
Record any AEs that are observed or reported, including those associated with changes 
in concomitant medication dosing.
3.
Collect vital signs (blood pressure and pulse).
4.
Perform BCVA on the study eye.
5.
Perform a complete ophthalmic examination on the study eye including slit-lamp 
exam, IOP measurement, and fundus exam (dilation to be performed at the discretion 
of the Investigator).
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6.
Perform SD-OCT imaging on study eye and submit the images to the CRC.
7.
Contact IRT and obtain a kit number.
8.
Have the unmasked Investigator perform an IVT injection according to the 
randomization/kit assignment. The injection procedure may be performed at a later 
time, as long as it is within 7 days of the scheduled visit and within the visit window.
9.
After the injection, perform a postinjection assessment of the study eye 0-5 minutes 
and 30 (± 15) minutes after injection (and at further time points, as needed).
10.
Schedule Visit 4/Week 12 to take place 84 ± 7 days after the Visit 1/Baseline.
10.2.4
10.2.4
Visit 4/Week 12 (Day 84 ± 7 days) through Visit 
24/Week 92 (Day 644 ± 7 days)
1.
Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2.
Record any AEs that are observed or reported, including those associated with changes 
in concomitant medication dosing.
3.
Administer the VFQ-25 using validated translations as applicable and available (Visit 
7, Visit 13 and Visit 19 only).
4.
Perform a general physical exam (Visit13 only).
5.
Collect vital signs (blood pressure and pulse).
6.
Perform a pregnancy test if the subject is female and of childbearing potential (Visit 13 
only).
7.
Obtain blood and urine samples for blood chemistry/hematology and urinalysis and 
submit the samples to the central laboratory (Visit 4 and Visit 13 only). Sample 
collection should be performed prior to any IVT or sham injection and prior to 
injection of fluorescein dye.
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8.
Obtain a blood sample for anti-drug antibody (ADA) analysis (Visit 4, Visit 7, Visit 10, 
Visit 13, Visit 18, Visit 23 only). Blood draws should be performed prior to any IVT or 
sham injection and prior to injection of fluorescein dye.
9.
Obtain a blood sample for systemic RTH258 analysis (Visit 4, Visit 7, Visit 10, Visit 13, 
Visit 18, Visit 23 only). Blood draws should be performed prior to any IVT or sham 
injection and prior to injection of fluorescein dye.
10.
Perform BCVA on the study eye.  Perform BCVA on both eyes (Visit 4, Visit 7, Visit 
10, Visit 13, Visit 16, Visit 19 and Visit 22 only).
11.
Perform a complete ophthalmic examination on the study eye including slit-lamp 
exam, IOP measurement and fundus exam (dilation to be performed at the discretion 
of the Investigator).  Perform a complete ophthalmic exam on both eyes (Visit 13 
only).
12.
Perform SD-OCT imaging on study eye and submit the images to the CRC.  Perform 
SD-OCT on both eyes and submit the images to the CRC (Visit 13 only).
13.
Perform FA on both eyes (study eye at Visit 4 and both eyes at Visit 13) and submit the 
images to the CRC (Visit 4 and Visit 13 only).
14.
Perform color fundus photography (on study eye at Visit 4) and submit the images to 
the CRC (Visit 4 and Visit 13).
15.
Where applicable, perform FAF imaging on the study eye and submit the images to 
the CRC (Visit 4 and Visit 13 only). FAF will be performed at a subset of sites.
16.
Have the masked Investigator perform the visit appropriate disease activity assessment 
for the study eye (Visit 5, Visit 6, Visit 8, Visit 9, Visit 11, Visit 12, Visit 14, Visit 15, 
Visit 17, Visit 18, Visit 20, Visit 21, Visit 23 and Visit 24).
17.
Contact IRT (all visits except Visit 4).
18.
Have the unmasked Investigator perform an IVT or sham injection according to the 
randomization/kit assignment (except Visit 4). The injection procedure may be 
performed at a later time, as long as it is within 7 days of the scheduled visit and 
within the visit window.
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19.
After the injection, perform a postinjection assessment of the study eye 0-5 minutes
and 30 (± 15) minutes after injection/sham (except Visit 4) (and at further timepoints, 
as needed).
20.
Schedule Visits 5 through 24 as appropriate per visit window. Schedule Visit 25/Week 
96 to take place 672 ± 7 days after Visit 1/Baseline
10.2.5
Visit 25/Week 96/Exit Visit (Day 672 ± 7 days) or Early Exit
1.
Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2.
Record any AEs that are observed or reported, including those associated with changes 
in concomitant medication dosing.
3.
Administer the VFQ-25 using validated translations as applicable and available. The 
VFQ-25 should be administered prior to any examination.
4.
Perform a general physical exam.
5.
Collect vital signs (blood pressure and pulse)
6.
Perform a pregnancy test if the subject is female and of childbearing potential
7.
Obtain blood and urine samples for blood chemistry/hematology and urinalysis and 
submit the samples to the central laboratory. Blood draws should be performed prior to 
injection of fluorescein dye.
8.
Obtain a sample for ADA analysis (if the subject exits at or before Visit 23/Week 88).  
Blood draws should be performed prior to injection of fluorescein dye.
9.
Obtain a sample for systemic RTH analysis (if the subject exits at or before Visit 
23/Week 88). Blood draws should be performed prior to injection of fluorescein dye.
10.
Perform BCVA on both eyes.
11.
Perform a complete ophthalmic examination on both eyes including slit-lamp exam, 
IOP measurement and fundus exam (dilation to be performed at the discretion of the 
Investigator).
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12.
Perform SD-OCT imaging on the both eyes and submit the images to the CRC.
13.
Perform FA on both eyes and submit the images to the CRC.
14.
Perform color fundus photography on both eyes and submit images to the CRC
15.
Where applicable, perform FAF on the study eye and submit the images to the CRC.  
FAF will only be performed at a subset of sites.
16.
Complete the Exit Form.
10.3
Unscheduled Visits
If a subject returns to the site prior to his/her next scheduled study visit for assessment of an 
adverse event (eg, follow up on elevated IOP for the study eye), the Unscheduled Visit pages 
of the electronic case report form (CRF) should be completed. Procedures conducted at the 
Unscheduled Visit are at the discretion of the Investigator apart from treatments of the study 
eye for AMD. If the subject is discontinuing from the study at the Unscheduled Visit, the 
CRFs for the Exit Visit should be completed rather than the CRFs for an Unscheduled Visit. 
Routine treatments and routine follow up of the nonstudy eye will not be considered an 
Unscheduled Visit. Any treatments of the nonstudy eye will be captured on the Concomitant 
Medication Page.
10.4
Discontinued Subjects
Discontinued subjects are those who are lost to follow up, withdraw or are withdrawn from 
the study after the Visit 1/Baseline. Subjects may discontinue from the study at any time for 
any reason. Discontinued subjects will not be replaced (ie, their subject numbers will not be 
re-assigned/re-used). The site must contact IRT to register the subject’s discontinuation from 
IP.
Should a subject exhibit any clinically relevant signs, symptoms, or other clinical 
observations that possibly could be associated with suspected sensitivity or intolerance to one 
of the study treatments, the Investigator must document those observations on an AE Form 
(AEF). If a subject discontinues the study with an ongoing AE, follow up procedures, as 
appropriate and outlined in Section 12.6, should be performed.
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Pa ge 6 9 of 9 5
A n y  s u bject w h o e xits earl y fr o m t he st u d y m ust u n der g o all pr oce d ures o utli ne d at Visit 
2 5/ Wee k 9 6 ( Secti o n 1 0. 2. 5). A d dit i o nall y, t he E xit F or m m ust be c o m plete d a n d a reas o n f or 
disc o nti n uati o n m ust be i de ntifie d.
If a s u bject e xits earl y fr o m t he st u d y bet wee n visits, t he In vesti gat or m ust atte m pt t o c o ntact 
t he s u bject a n d re q uest t he s u bject t o ret ur n f or a fi nal visit to c o m plete t he e xit pr oce d ures. If 
t he s u bject is u na ble or u n willi n g t o ret ur n f or t he E xit Vi sit, t he s u bject will be c o nsi dere d 
l ost t o f oll o w u p a n d t he ‘ date of e xit’ will be t he date t hat t he s u bject was last see n at t he site 
or c o ntacte d b y ot her c o m m u nicati o n.
Fi nall y , t o e ns ure t he safet y of all s u bjects w h o e xit earl y fr o m t he st u d y, In vesti gat ors s h o ul d 
assess eac h s u bject a n d, if necessar y, a d vise t he m of a ny t hera pies a n d/ or me dical pr oce d ures 
t hat mi g ht be nee de d t o mai ntai n t heir healt h.
1 0. 5
Disc o nti n u ati o n of St u d y Tr e at me nt
T he I n vesti gat or ma y  disc o nti n ue st u d y treat me nt f or a gi ve n s u bject a n d/ or wit h dra w t he 
s u bject fr o m st u d y if he/s he belie ves t hat c o nti n uati o n w o ul d p ose a ris k t o t heir healt h. 
S u bjects ca n be disc o nti n ue d fr o m st u d y treat me nt beca use of

a p peara nce of a ne w healt h c o n diti o n s us pecte d t o re q uire a p pr o priate care or re q uire 
me dicati o ns pr o hi bite d b y t he pr ot oc ol

ref usal t o c o nti n ue treat me nt, or at t he I n vesti gat or’s discreti o n base d o n his/ her cli nical 
j u d ge me nt t he s u bject re q uires resc ue me dicati o n

use of pr o hi bite d treat me nt d uri n g t he st u d y

i n vesti gat or’s discreti o n base d o n his/ her cli nical j u d g me nt

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
p ositi ve uri ne/ser u m pre g na nc y  test
S u bjects w h o disc o nti n ue st u d y  treat me nt s h o ul d N O T be c o nsi dere d wit h dra w n fr o m t he 
stu d y. S u bjects are e x pecte d t o c o nti n ue wit h t he st u d y visits a n d pr oce d ures as l o n g as s uc h 
pr oce d ures d o n ot p ose a ris k t o t he well bei n g of t he s u bject. Site pers o n nel m ust als o 
c o ntact I RT t o re gister t he s u bject’s disc o nti n uati o n fr o m st u d y treat me nt.
T he a p pr o priate pers o n nel fr o m t he site a n d S p o ns or will assess w het her st u d y  treat me nt 
s h o ul d be disc o nti n ue d f or a ny s u bject w h ose treat me nt c o de has bee n br o ke n i na d verte ntl y 
f or a ny reas o n.


Pa ge 7 0 of 9 5
1 0. 6
Cli nic al St u d y Te r mi n ati o n
If t he cli nical st u dy is pre mat ure l y ter mi nate d or s us pe n de d, t he S p o ns or will i nf or m t he 
I n vesti gat or a n d t he re g ulat or y a ut h orities of t he ter mi nati o n/ s us pe nsi o n a n d t he reas o n(s) 
f or t he ter mi nati o n/s us pe nsi o n. T he I n vesti gat or s h o ul d pr o m ptl y  n otif y t he I E C/IR B of t he 
ter mi nati o n or sus pe nsi o n a n d of t he reas o ns. T he S p o ns or reser ves t he ri g ht t o cl ose t he 
i n vesti gati o nal site or ter mi nate t he st u d y i n its e ntiret y at a n y ti me, f or reas o na ble ca use. 
Reas o ns f or t he cl os ure of a n i n vesti gati o nal site or ter mi nati o n of a st u d y ma y  i ncl ude: 

T he I n vesti gat or fails t o c o m pl y  wit h t he pr ot oc ol or G C P g ui deli nes

Safet y  c o ncer ns

S uf ficie nt data s u g gesti n g lac k of efficac y

I na de q uate recr uit me nt of s u bjects b y t he I n vesti gat or
T he I n vesti gat or als o ma y ter mi nate t he st u d y at his/ her site f or r eas o na ble ca use. If t he 
S p o ns or ter mi nates t he st u d y  f or safet y reas o ns, it will i m me diatel y n otif y t he I n vesti gat or(s) 
b y  tele p h o ne a n d s u bse q ue ntl y will pr o vi de writte n c o nfir mati o n of a n d i nstr ucti o ns f or st u d y 
ter mi nati o n.  T he i n vesti gat or ma y be i nf or me d of a d diti o nal pr oce d ures t o be f oll o we d i n 
or der t o e ns ure t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he patie nt’ s i nterests. 
T he i n vesti gat or will be res p o nsi ble f or i nf or mi n g t he I R Bs/I E Cs of t he earl y  ter mi nati o n of 
t he trial.  
1 0. 7
St u d y Met h o ds a n d Me as ure me nts
1 0. 7. 1
Vi s u al F u ncti o n Q uesti o n n aire-2 5
Q ualit y  of life data will be c ollecte d wit h a vis ual f u ncti o n q uesti o n naire usi n g t he Nati o nal 
E y e I nstit ute V F Q-2 5 w hic h is a vali date d i nstr u me nt t hat has bee n use d i n ma n y st u dies of 
s u bjects wit h A M D. T he V F Q -2 5 will be a d mi nistere d b y mas ke d site staf f t o s u bjects at sites 
w here l ocal la n g ua ge versi o ns are a vaila ble, vali date d, a n d a p pr o ve d b y t he I E C/I R B. T he 
V F Q - 2 5 m ust be a d mi nistere d bef ore a ny ot her e xa mi nati o n. T he U nite d States E n gl is h 
versi o n of t he V F Q - 2 5 is i ncl u de d i n t he M O P.
1 0. 7. 2
Ge ner al P h ysic al E x a m a n d Vi t al Si g ns
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
T he p h y sical e xa m will c o nsist of a r o uti ne e val uati o n of orga n s ys te ms, e g, ears, e yes, n ose, 
t hr oat, nec k, ly m p h n o des, l u n gs, heart, a b d o me n, s ki n/e xtre mities, ne ur o l o gical, a n d 
m usc ul os keletal s y ste ms. After Scree ni n g, t he p h ysical e xa m will als o i ncl u de a disc ussi o n 
wit h t he s u bject if t here ha ve bee n c ha n ges i n his/ her p h ys ical c o n diti o n si nce t he Scree ni n g 


Page 71 of 95
exam. All clinically significant findings will be recorded as medical history or adverse events, 
as appropriate.
Vital signs consist of blood pressure and pulse rate measurements. Standardized procedures 
for each are provided in the MOP.
10.7.3
Pregnancy Tests
A pregnancy test will be conducted for all women of child bearing potential at Screening, 
Visit 13/Week 48, and Exit Visit. Urine pregnancy tests will be performed unless local 
regulations require serum pregnancy tests. Additional pregnancy testing may be conducted at 
the Investigator’s discretion or if required by local regulations.
10.7.4
Laboratory Analysis of Blood and Urine
Blood and urine samples will be shipped to a central laboratory. Results of the analysis will 
be provided to the Investigator who will assess those from Screening prior to randomizing the 
subject to determine if there is anything that would preclude participation of the subject and 
at subsequent visits to assess any changes from Screening. A standardized procedure for the 
collection and processing of blood and urine is provided by the central laboratory.  A list of 
laboratory parameters is provided in the MOP. If a subject should present with a clinically 
significant change resulting in an adverse event, as assessed by the Investigator, a decision 
will be made as to subject continuation in the trial. This decision will take into account the 
adverse event characteristics including but not limited to seriousness and relationship to study 
drug.
10.7.5
Analysis of Anti-Drug Antibodies (ADA) and Systemic 
RTH258
Collection of blood for ADA and systemic RTH258 will occur at the study site. Blood draws 
should take place prior to the injection/sham. A standardized procedure for the collection, 
processing, storage and shipment of these blood samples is provided by the central 
laboratory.
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10.7.7
Best-Corrected Visual Acuity
ETDRS visual acuity testing should precede any examination requiring administration of eye 
drops to dilate the eye or any examination requiring contact with the eye. Visual acuity 
testing should be done following refraction and completed according to the procedure 
outlined in the MOP. Certification of the equipment and examiners at each investigative site 
will occur prior to any evaluation of study subjects.
Subjects in some countries will undergo BCVA testing using numerical charts rather than 
letter charts.
10.7.8
Complete Ophthalmic Examination
A complete description of standardized procedures and grading scales is outlined in the MOP. 
The ophthalmic exam will consist of the following:
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Pa ge 7 3 of 9 5

Slit -la m p e xa mi nati o n – i ncl u des e val uati o n of t he li ds/las hes, c o nj u ncti va, c or nea, 
a nteri or c ha m ber a q ue o us reacti o n (cell a n d flare), iris, le ns a n d a nteri or part of t he 
vitre o u s b o d y.

I O P meas ure me nt – a meas ure me nt of t he i ntra oc ular press ure will be c o n d ucte d 
usi n g a n a p pla nati o n t o n o meter or T o n o pe n.  T he sa me met h o d s h o ul d be use d 
t hr o u g h o ut t he st u dy f or eac h s u bject.

F u n d us E xa m – i ncl u des e val uati o n of t he vitre o us, reti na, mac ula, c h or oi d, a n d 
o ptic ner ve.  Dilati o n f or t he f u n d us e xa m is at t he discreti o n of t he I n vesti gat or .
1 0. 7. 9
S pectr al D o m ai n O ptic al C o here nce To m o gr a p h y I m a gi n g
A sta n dar dize d pr oce d ure f or t he c ollecti o n of q ua ntitati ve a n d q ualitati ve data via S D - OC T  
is pr o vi de d b y t he C R C i n a se parate ha n d b o o k. Eac h site m ust select a si n gle bra n d of 
e q ui p me nt f or use o n all s u bjects at t hat site. Certificati o n of t he e q ui p me nt a n d e xa mi ners at 
eac h i n vesti gati ve site will occ ur pri or t o e val uati o n of st u d y  s u bjects. At t he Scree ni n g V isit, 
S D -O C T  i ma ges will be s u b mitte d t o t he C R C f or deter mi nati o n of eli gi bilit y. Fee d bac k fr o m 
t he C R C f oll o wi n g e x pe dite d re vie w will be pr o vi de d t o t he sites via e mail or fa x. T he C R C 
ma y  partici pate i n assess me nt of ne w disease acti vit y, as a p pr o priate.
1 0. 7. 1 0
Fl u or escei n A n gi o gr a p h y
A sta n dar dize d pr oce d ure f or t he c ollecti o n of FA i ma ges is pr o vi de d b y t he C R C i n a 
se parate ha n d b o o k. Certificati o n of t he e q ui p me nt a n d e xa mi ners at eac h i n vesti gati ve site 
will occ ur pri or t o e val uati o n of st u d y  s u bjects. At t he Scree ni n g V isit, reti nal i ma ges will be 
s u b mitte d t o t he C R C f or deter mi nati o n of eli gi bilit y. FA i ma ges fr o m pre vi o us r o uti ne 
e val uati o ns ma y be use d f or t he scree ni n g FA as l o n g as t he y were perf or me d wit hi n 3 da ys 
of t he Scre e ni n g Visit usi n g C R C-certifie d e q ui p me nt a n d e xa mi ners. Fee d bac k fr o m t he 
C R C f oll o wi n g e x pe dite d re vie w will be pr o vi de d t o t he sites via e mail or fa x.
1 0. 7. 1 1
C ol or F u n d us P h ot o gr a p h y
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
A sta n dar dize d pr oce d ure f or t he c ollecti o n of 3-fiel d c ol or f u n d us p h ot o gra p hic i ma ges is 
pr o vi de d b y t he C R C i n a se parate ha n d b o o k. Certificati o n of t he e q ui p me nt a n d e xa mi ners 
at eac h i n vesti gati ve site will occ ur pri or t o e val uati o n of st u d y  s u bjects. At t he Scree ni n g 
Vi sit reti nal i ma ges will be se nt t o t he C R C f or deter mi nati o n of eli gi bilit y. Fee d bac k fr o m 
t he C R C f oll o wi n g e x pe dite d re vie w will be pr o vi de d t o t he sites via e mail or fa x.


Page 74 of 95
10.7.12
Fundus Autofluorescence
FAF will be performed at a subset of sites in order to assess the occurrence of geographic 
atrophy. A standardized procedure for the collection of FAF images is provided by the CRC 
in a separate hand book. Certification of the equipment and examiners at each investigative 
site will occur prior to evaluation of study subjects. FAF will not be used to determine 
eligibility, but will be included beginning at the Visit 1/Baseline.
10.7.13
Disease Activity Assessment
The masked Investigator will assess the study eye of all subjects at Visit 5/Week 16, Visit 
6/Week 20, Visit 8/Week 28, Visit 9/Week 32, Visit 11/Week 40, Visit 12/Week 44, Visit 
14/Week 52, Visit 15/Week 56, Visit 17/Week 64, Visit 18/Week 68, Visit 20/Week 76, Visit 
21/Week 80 and Visit 23/Week 88. The IRT system will make the necessary changes to the 
dosing per the masked Investigator’s assessment. The disease activity assessment will also be 
performed at Visit 24/Week 92, but will not be entered into IRT, and will have no effect on 
the subject’s treatment regimen. Details of the disease activity assessments are further 
outlined in the MOP.
10.7.14
Intravitreal Administration of Investigational Product
The IVT injection procedure for both the test article and control article is the same as that 
described for aflibercept in the product information sheet. IVT injection is contraindicated in 
subjects with active ocular or periocular infections and in subjects with active intraocular 
inflammation; therefore, the Investigator should verify that these conditions are not present in 
either eye (study and nonstudy eyes) prior to every injection. Specific instructions for 
injection procedures are provided in the MOP.
10.7.15
Administration of Sham Injection
Beginning at Week 12, at visits when subjects do not receive an active injection they will be 
administered a sham injection. For the sham injection the tip of an injection syringe (the hub 
without needles) will be used. A standardized procedure for the sham is described in the 
MOP.
10.7.16
Postinjection Assessment
The study eye will be assessed before, immediately (0-5 minutes) after and 30 (± 15) minutes 
after each IVT/sham injection to ensure that the procedure and/or the study medication have 
not endangered the health of the eye. The postinjection assessments include an evaluation of 
the central retinal artery perfusion via a gross assessment of vision (e.g., count fingers) and 
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Page 75 of 95
measurement of IOP according to the schedule detailed in the MOP. Direct visualization to 
assess the central retinal artery, presence of retinal detachment, presence of new intraocular 
hemorrhage(s) might be appropriate at the discretion of the investigator and/or based on the 
results of gross assessment of vision and IOP measurement.  Assessments will continue 
until the central retinal artery is adequately perfused and the IOP is within 10 mmHg of 
the pre-injection value and is stable in the opinion of the Investigator. Any subject who 
develops significantly raised IOP (> 30 mmHg) or a non-adequately perfused central retinal 
artery at any time during the study should be monitored according to the Investigator’s 
clinical judgment and may undergo additional procedures and measurements of IOP beyond 
those specified in the protocol. If, at the conclusion of the required evaluation period 
following an injection/sham, there are no safety concerns, the subject will leave the site. If 
any concern or immediate toxicity is noted, the subject will remain at the site and will be 
treated according to the designated evaluating physician’s clinical judgment. If any issues 
regarding IOP were noted during the postinjection assessment, then the subject should be 
scheduled for a follow up visit (Unscheduled Visit) the day following injection/sham, if 
required in the opinion of the Investigator. Clinically relevant changes that are observed 
during the postinjection assessment should be reported as adverse events.
10.8
Concomitant Treatment
The Investigator should instruct the subject to notify the study site about any new 
medications he/she takes after enrolling into the study.
Should the nonstudy eye require treatment during the study with an anti-VEGF, a drug which 
is approved for the treatment of neovascular AMD in the respective country should be 
applied at the discretion of the Investigator and following the procedures established at the 
respective site.  The nonstudy eye treatment may occur at any time once the Baseline study 
injection has been administered.
10.9
Prohibited Treatment
Use of treatments, as displayed in Table 10.9.-1. are not allowed after the start of the study 
i.e., Screening. In addition, there are certain washout periods to be respected as outlined in 
the exclusion criteria.
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Table 10.9.-1. 
Prohibited Treatment
Medication
Study eye: Intra- or periocular corticosteroids
Study eye: Laser treatment for AMD
Study eye: Anti-VEGF therapy other than IP
Nonstudy eye: Unapproved or Investigational treatment
Systemic: Use of systemic corticosteroids for 30 or more consecutive days (except low stable 
doses of corticosteroids [defined as ≤10 mg prednisolone or equivalent dose], inhaled, nasal 
or dermal steroids are permitted)
Systemic: Anti-VEGF therapy
Any investigational drug, biologic or device (with the exception of over-the –counter 
vitamins, supplements or diets)
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11
ANALYSIS PLAN
11.1
General considerations
Continuous variables will be summarized for the measured values and change from Baseline 
values using the number of observations, mean, standard deviation, median, quartiles, 
minimum and maximum. Categorical variables will be summarized with numbers and 
percent from each category. Treatment differences will be presented together with 95% 
confidence intervals as appropriate.
11.2
Subject Evaluability
Subject evaluability based on pre-specified deviations and their impact on analysis sets will 
be determined prior to breaking the masked treatment assignment code and locking the 
database for the primary analysis at Week 48. Protocol deviations and their impact on 
analysis sets will be pre-specified in the deviations and evaluability plan (DEP).
11.3
Analysis Data Sets
The following analysis sets are defined:
All enrolled analysis set: includes all subjects who signed an ICF and are assigned subject 
numbers. This analysis set will be used to summarize subject disposition and pre-treatment 
adverse events.
All randomized analysis set: includes all subjects who were randomized. This analysis set 
will be used to describe the randomized study population based on demographics and 
baseline characteristics.
Safety analysis set: includes all subjects who received at least one IVT injection. Subjects in 
the safety analysis set will be analyzed according to the first treatment received. This analysis 
set will be used for all safety analyses.
Full analysis set (FAS): includes all subjects who are randomized and received at least one 
IVT injection. Following the intent-to-treat (ITT) principle, subjects in the FAS will be 
analyzed according to the treatment group they are assigned at randomization. The FAS will 
be the primary analysis set for efficacy analyses.
The per protocol analysis set (PPS): defined for the primary and key secondary efficacy 
analysis at Week 48 includes all subjects in the FAS with no protocol deviations that are 
expected to majorly affect the assessment of efficacy at Week 48 including: lack of 
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Pa ge 7 8 of 9 5
c o m plia nce (i ncl u di n g treat me nt misall ocati o n), missi n g data, c o nc o mita nt me dicati o n a n d 
de viati o n fr o m i ncl usi o n/e xcl usi o n criteria. Disc o nti n uati o n fr o m treat me nt d ue t o lac k of 
efficac y d oes n ot c o nstit ute a reas o n f or e xcl usi o n fr o m t he P P S.
Bef ore t he W ee k 4 8 data base l oc k t he rele va nt pr ot oc ol de viati o ns will be s pecifie d i n t he 
de viati o ns a n d e val ua bilit y  pla n ( D E P) d oc u me nt a n d i de ntifie d at t he s u bject le vel i n t he 
data base.
1 1. 4
De m o gr a p hic a n d B aseli ne C h ar acteristics
De m o gra p hic a n d baseli ne c haracteristics will be s u m marize d f or all a nal ys is sets. All 
s u m maries will be prese nte d b y treat me nt gr o u p a n d o verall.
1 1. 4. 1
De m o gr a p hic C h ar acteristics
T he de m o gra p hic para meters are a ge cate g or y  ( 5 0 t o 6 4, 6 5 t o 7 4, 7 5 t o 8 4, a n d ≥8 5), 
ge n der , et h nicity a n d race. A ge will als o be s u m marize d as a c o nti n u o us varia ble.
1 1. 4. 2
B aseli ne C h ar acteristics
Baseli ne c haracteristics will i ncl u de: pri mar y dia g n osis of ne o vasc ular A M D, ti me si nce 
dia g n osis of ne o vasc ular A M D ( da y s), w het her ne o vasc ular A M D is u nilateral or bilateral, 
B C V A ( b ot h as a c o nti n u o us varia ble a n d usi n g cate g ories ( ≤ 5 5, 5 6-7 0, ≥ 7 1 letters), lesi o n 
t ype ( pre d o mi na ntl y classic, mi ni mall y  classic, occ ult), f o veal i n v ol ve me nt (s u bf o veal, 
e xtraf o veal, u n deter mi na ble), C N V lesi o n size, prese nce of s u b reti nal fl ui d, prese nce of 
i ntrareti nal fl ui d/c yst, prese nce of s u b R P E fl ui d, ne ur ose ns or y reti nal t hic k ness a n d ce ntral 
s u bfiel d t hic k ness ( C S F T) ( b ot h as a c o nti n u o us varia ble a n d usi n g cate g ories ( < 4 0 0, ≥ 4 0 0 
µ m).
1 1. 5
Pri m ar y a n d Ke y Sec o n d ar y Effic ac y A n al yses
Pri m ar y Effic ac y E n d p oi nt:

C ha n ge i n B C V A fr o m Baseli ne t o We e k 4 8
Ke y Sec o n d ar y effic ac y E n d p oi nts:

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 3 6 t hr o u g h Wee k 
4 8. F or eac h s u bject, t his e n d p oi nt is defi ne d as t h e a vera ge of t he c ha n ges fr o m 
baseli ne t o Wee ks 3 6, 4 0, 4 4 a n d 4 8.

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
q 1 2 treat me nt stat us at Wee k 4 8 f or s u bjects ra n d o mize d t o RT H 2 5 8 6 m g.


Pa ge 7 9 of 9 5

q 1 2 treat me nt stat us at Wee k 4 8 wit hi n t he s u bjects ra n d o mize d t o RT H 2 5 8 6 m g, 
wit h n o q 8 nee d d uri n g t he 1st q 1 2 c y cle ( Wee k 1 6 a n d We e k 2 0).
T he pri mar y  a n d first ke y sec o n dar y e n d p oi nts will be a nalyz e d base d o n t he FA S wit h last -
o bser vati o n -carrie d -f or war d ( L O C F) i m p utati o n of missi n g B C VA val ues ( pri mar y  a n d first 
ke y  sec o n dar y e n d p oi nt) a n d a ne gati ve q 1 2 treat me nt stat us at We e k 4 8 i n t he case of 
i nc o m plete acti ve treat me nt u p t o We e k 4 8 (sec o n d a n d t hir d ke y  sec o n dar y e n d p oi nt). T he 
a nal ys is of t he pri mar y a n d ke y sec o n dar y e n d p oi nts base d o n t he P P S will be c o nsi dere d 
s u p p orti ve. W he n assessi n g t he r o b ust ness of t he o verall efficac y c o ncl usi o ns, e q ual 
i m p orta nce will be gi ve n t o t he FA S a n d P P S res ults u n dersta n di n g t hat a r o b ust st u d y  will 
de m o nstrate si milar c o ncl usi o ns fr o m b ot h a nal y sis data sets.
1 1. 5. 1. 1
St atistic al H y p ot heses
T he statistical h y p ot hesis f or t he pri m ar y e n d p oi nt a n d first ke y sec o n dar y e n d p oi nt is t o 
de m o nstrate n o n -i nferi orit y of RT H 2 5 8 6 m g t o afli berce pt 2 m g wit hi n a mar gi n of 4 letters.
T he f oll o wi n g 2 h y p ot heses will be teste d i n t he pre -s pecifie d hierarc hical se q ue nce 
acc or di n g t o t heir n u m beri n g ( H A n, n = 1, 2). C o nse q ue ntl y, c o nfir mat or y testi n g of t he sec o n d 
h y p ot hesis re q uires rejecti o n of t he first n ull h y p ot hesis. I n t his setti n g, eac h h y p ot hesis will 
be assesse d at a t w o -si de d si g nifica nce le vel of 0. 0 5, w hile kee pi n g t he gl o bal t ype I err or
rate at 0. 0 5.
H y p ot heses: T he f oll o wi n g n o ni nferi orit y  h yp ot heses are relate d t o a n o ni nferi orit y 
mar gi n of 4 letters.
4 8 = W ee k 4 8, 3 6 -4 8 = W ee k 3 6 t hr o u g h 4 8, R 6 = R T H 2 5 8 6 m g, A = afli berce pt 2 m g
H 0 1: µ4 8 R 6 - µ 4 8 A ≤ -4 letters vs H A 1 : µ4 8 R 6 - µ4 8 A > -4 le tters
µ 4 8 R 6 a n d µ 4 8 A bei n g t he c orres p o n di n g u n k n o w n tr ue mea n B C VA c ha n ges fr o m 
Baseli ne t o W ee k 4 8.
H 0 2: µ3 6 -4 8 R 6 - µ3 6 -4 8 A ≤ -4 letters vs H A 2 : µ3 6 -4 8 R 6 - µ3 6 -4 8 A > -4 letters
µ 3 6 -4 8 R 6 a n d µ 3 6- 4 8 A bei n g t he c orres p o n di n g u n k n o w n tr ue mea n val ues f or t he a vera ge 
c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 3 6 t hr o u g h 4 8.
1 1. 5. 2
St atistic al Met h o ds
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
F or t he test of n o n -i nferi orit y, a t w o-si de d 9 5 % c o nfi de nce i nter val f or t he treat me nt 
dif fere nce will be deri ve d fr o m a n a nal y sis of varia nce ( A N O VA) m o del wit h treat me nt, 


Pa ge 8 0 of 9 5
baseli ne B C VA cate g ories ( ≤ 5 5, 5 6 -7 0, ≥ 7 1 letters) a n d a ge cate g ories ( < 7 5, ≥ 7 5 y ears) as 
fi xe d effects. I n or der t o de m o nstrate n o ni nferi orit y, t he l o wer li mit of t he t w o-si de d 9 5 % 
c onfi de nce i nter val f or t he treat me nt differe nce ( R T H 2 5 8 6 m g – afli berce pt 2 m g) m ust be 
greater t ha n -4 letters re prese nti n g t he n o ni nferi orit y  mar gi n.
T he q 1 2 treat me nt stat us of s u bjects i n t he R T H 2 5 8 6 m g treat me nt ar m will be prese nte d 
descri pti vel y t o get her wit h e xact 9 5 % c o nfi de nce i nter vals f or t he pr o p orti o n of s u bjects wit h 
a p ositi ve stat us.

F or t he o verall pr o p orti o n of s u bjects wit h a p ositi ve q 1 2 treat me nt stat us at wee k 4 8, t he 
de n o mi nat or is all F A S s u bjects i n t he R T H 2 5 8 6 m g gr o u p, a n d t h e n u merat or is t he 
c orres p o n di n g n u m ber of s u bjects wit h n o i de ntifie d nee d f or treat me nt at q 8 at We e k 1 6, 
2 0, 2 8, 3 2, 4 0 a n d 4 4 ( w hile missi n g W ee k 1 6, Wee k 2 8 a n d/ or Wee k 4 0 assess me nt is 
c o nsi dere d as n o q 8 treat me nt nee de d)

F or t he pre dicta bilit y  of the a de q uac y  of q 1 2 treat me nt, base d o n t he a bse nce of disease 
acti vit y d uri n g t he first q 1 2 c ycle, t he de n o mi nat or is all FA S s u bjects i n t he R T H 2 5 8 6 
m g gr o u p wit h n o i de ntifie d nee d f or treat me nt q 8 at W ee k 1 6 a n d Wee k 2 0 ( w hile 
missi n g W ee k 1 6 assess me n t is c o nsi dere d as n o q 8 treat me nt nee de d), a n d t he n u merat or 
is t he c orres p o n di n g n u m ber of s u bjects wit h a p ositi ve q 1 2 treat me nt stat us at Wee k 4 8, 
i.e., wit h n o i de ntifie d nee d f or treat me nt at q 8 at Wee k 1 6, 2 0, 2 8, 3 2, 4 0 a n d 4 4 ( w hile 
missi n g W ee k 16, Wee k 2 8 a n d/ or Wee k 4 0 assess me nt is c o nsi dere d as n o q 8 treat me nt 
nee de d)
1 1. 5. 3
Se nsiti vit y A n al ysis
Se nsiti vit y  a nal ysis t o e x pl ore t he r o b ust ness of t he pri mar y a n d first ke y sec o n dar y efficac y 
res ults wit h res pect t o pr ot oc ol de viati o ns will use t he P P S wit h L O C F i m p utati o n of missi n g 
val ues usi n g t he sa me m o del a n d fact ors as i n t he pri mar y  efficac y a nal ysis m o del.
Se nsiti vit y  a nal yses t o e x pl ore t he r o b ust ness of t he pri mar y a n d first ke y sec o n dar y efficac y 
a nal ys is res ults relate d t o missi n g val ues will be perf or me d o n t he o bser ve d data i n t he F A S 
a p pl yi n g t he s pecifie d A N O V A m o del, a n d a mi xe d m o del re peate d meas ures ( M M R M).
1 1. 5. 4
S u b gr o u ps
T he f oll o wi n g s u b gr o u ps will be a nal yz e d f or t he pri mar y a n d ke y sec o n dar y efficac y 
e n d p oi nts:

A ge cate g or y  ( < 7 5 years a n d ≥7 5 years)

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
Ge n der ( male a n d fe male)


Pa ge 8 1 of 9 5

Baseli ne B C V A cate g ories ( ≤ 5 5, 5 6 -7 0, ≥ 7 1 letters)

Baseli ne C S F T  cate g or y ( < 4 0 0, ≥ 4 0 0)

Baseli ne lesi o n t y pe ( pre d o mi na ntl y  classic, mi ni mall y classic, occ ult)

Baseli ne lesi o n size (tertiles) b y  lesi o n t ype ( pre d o mi na ntl y  classic vs mi ni mall y 
classic/ occ ult
1 1. 6
A d diti o n al Sec o n d ar y Effic ac y A n al yses
T he f oll o wi n g sec o n dar y ef ficac y e n d p oi nts will be a nalyz e d pri maril y base d o n t he FA S:

C ha n ge i n B C V A fr o m Baseli ne t o eac h p ost baseli ne visit

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d W ee k 8 4 t hr o u g h Wee k 9 6

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 4 t o Wee k 4 8/ 9 6

Av era ge c ha n ge i n B C VA fr o m Baseli ne o ver t he peri o d Wee k 1 2 t o Wee k 4 8/ 9 6

Gai n i n B C V A of 1 5/ 1 0/ 5 letters or m ore fr o m Baseli ne t o e ac h p ost baseli ne visit

L oss i n B C V A of 1 5/ 1 0/ 5 letters or m ore fr o m Baseli ne t o eac h p ost baseli ne visit

q 1 2 treat me nt stat us at Wee k 9 6 (f or s u bjects ra n d o mize d t o RT H 2 5 8 6 m g o nl y )

q 1 2 treat me nt stat us at Wee k 9 6 wit hi n t he s u bjects wit h n o q 8 -nee d d uri n g t he 1st q 1 2 
c ycle (ie, at We e k 1 6 a n d We e k 2 0) (f or s u bjects ra n d o mize d t o RT H 2 5 8 6 m g o nl y)

C ha n ge i n C S F T  fr o m Baseli ne t o eac h p ost baseli ne visit

C ha n ge i n ne ur ose ns or y  reti nal t hic k ness fr o m Baseli ne t o eac h p ost baseli ne visit

C ha n ge i n C N V  lesi o n size fr o m Baseli ne t o Wee ks 1 2, 4 8 a n d 9 6

A bse nce of s u breti nal fl ui d at eac h visit

A bse nce of i ntrareti nal fl ui d at eac h visit

q 8 treat me nt nee d stat us assesse d at W ee ks 1 6, 2 0, 2 8, 3 2, 4 0, 4 4, 5 2, 5 6, 6 4, 6 8, 7 6, 8 0, 
8 8 a n d 9 2

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
C ha n ge i n patie nt re p orte d o utc o mes ( V F Q -2 5) t otal a n d s u bscale sc ores fr o m Baseli ne t o 
We e ks 2 4, 4 8, 7 2 a n d 9 6 
Statistical met h o ds f or t he a nal ys is of eac h of t he sec o n dar y e n d p oi nts will be descri be d i n 
t he statistical a nal ysis pla n ( S A P).


Page 82 of 95
11.7
Handling of Missing Data
The primary presentation of efficacy results will use LOCF for the imputation of missing 
values supplemented by presentations on the observed data only.
All non-missing postbaseline values including assessments conducted at unscheduled visits 
will be used when implementing the LOCF imputation.
Imputation related to the evaluation of the q12 treatment status at week 96 will follow the 
concept described for Week 48.
11.8
Multiplicity
No alpha adjustment will be applied for testing the hypotheses for the primary and first key 
secondary efficacy analyses as the two hypotheses will be tested in the pre-specified 
hierarchical sequence according to their numbering. Consequently, confirmatory testing of 
the second hypothesis requires rejection of the first null hypotheses. In this setting each 
hypothesis will be assessed at a two-sided α = 0.05, while keeping also the global type I error 
rate at 0.05. Other key secondary endpoints are not associated with hypothesis testing.
11.9
Safety
11.9.1
Treatment exposure
The extent of treatment exposure will be presented based upon the overall number of 
injections, the number of subjects injected per visit, and frequency of the different treatment 
patterns.
11.9.2
Medical History
Relevant medical history (ocular and nonocular) will be tabulated by system organ class and 
preferred term of the MedDRA dictionary. Ocular events will be presented by study and non-
study eye.
11.9.3
Concomitant Therapies
The number and percentage of subjects taking concomitant therapies will be summarized by 
preferred term according to the WHO Drug Reference List dictionary. Ocular therapies will 
be presented by study and nonstudy eye.
Alcon - Business Use Only 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
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Effective
4.0; Most-Recent; Effective; CURRENT
TDOC-0050250
10-Feb-2017


Pa ge 8 3 of 9 5
1 1. 9. 4
S afet y p ar a meters
T he f oll o wi n g safet y para meters will be descri pti vel y a nal yz e d t o assess treat me nt e mer ge nt 
c ha n ges or c ha n ges s pecificall y  relate d t o t he i njectio n pr oce d ure usi n g p osti njecti o n 
assess me nts:

A d verse e ve nts

Ge neral p h y sical e xa m

Vi tal si g ns

La b orat o r yt ests ( bl o o d c he mist r y, he m at ol og y a n d uri na l ysis)

W orse ni n g i n B C V A

Slit -lam p e x ami n ati o n

F u n d us e x a m

IO P

P osti nj ecti o n assess me nt

A D A le vels

S y ste mic R T H 2 5 8 le vels
1 1. 9. 5
A d verse E ve nts
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
A Es will be c o de d usi n g t he Me d D R A  dicti o nar y a n d prese nte d b y sys te m or ga n class a n d 
preferre d ter m. T reat me nt e mer ge nt A Es will be a nal y ze d base d o n t he n u m ber a n d 
perce nta ge of s u bjects wit h at least o ne A E i n t he cat e g or y of i nterest. Se parate prese ntati o ns 
will be pr o vi de d relate d t o oc ular e ve nts i n t he st u d y  e ye a n d n o nst u d y e ye a n d n o n -oc ular 
e ve nts. A d diti o nal s u m maries will be pr o vi de d b y se verity a n d ca usalit y (se paratel y assesse d 
f or t he i njecti o n pr oce d ure a nd t he dr u g). Seri o us A d verse E ve nts a n d a d verse e ve nts lea di n g 
t o disc o nti n uati o n of st u d y treat me nt will als o be s u m marize d se parately.
S u bject listi n gs of all a d verse e ve nts will be pr o vi de d. Deat hs a n d ot her seri o us or cli nicall y  
si g nifica nt n o n-fatal ad verse e ve nts will be liste d se paratel y .
E ve nts of s pecial i nterest ( E SI s; as defi ne d i n secti o n 1 2. 3) will be prese nte d base d o n t heir 
i nci de nces.


Page 84 of 95
11.10
Interim Analyses
The primary efficacy analysis will be based on the Week 48 data. The database, including all 
Week 48 data, will be locked once all active subjects have completed the Week 48 Visit. 
Systemic RTH258 and ADA data up to Week 36 will be analyzed for the Week 48 primary 
analysis. The primary analysis at Week 48 will be performed with an unmasking of specified 
Novartis/Alcon individuals who are not involved in the direct conduct of the trial.
Subjects will remain in the study and will continue to receive masked treatment through the 
planned duration (96 Weeks) to allow for further masked evaluation of efficacy and safety. 
Treatment masking of individual subjects will remain intact for all subjects, Investigators, 
and Alcon staff who have contact with subjects or Investigators or those who are involved in 
the direct conduct of the study until the final database lock has occurred.
11.11
Sample Size Justification
A sample size of 297 subjects per treatment arm is sufficient to demonstrate noninferiority 
(margin = 4 letters) of RTH258 6 mg versus aflibercept 2 mg with respect to the BCVA 
change from Baseline to Week 48 at a two-sided alpha level of 0.05 with a power of 
approximately 90% assuming equal efficacy and a common standard deviation of 15 letters. 
A power of at least 90% can be expected for the first key secondary endpoint assuming that 
averaging over the 4 time points will not lead to an increase in the standard deviation.
To account for a drop-out rate of 10%, a total of 330 subjects will be randomized per 
treatment arm.
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Effective Date:  
Document:  
Version:  
Status:  
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TDOC-0050250
10-Feb-2017


Pa ge 8 5 of 9 5
1 2
A D V E R S E E V E N T S
1 2. 1
Ge ner al I nf or m ati o n
A n A E is a n y u nt o war d me dical occ urre nce i n a s u b ject w h o is a d mi nistere d a st u dy 
treat me nt re gar dless of w het her or n ot t he e ve nt has a ca usal relati o ns hi p wit h t he treat me nt. 
A n A E, t heref ore, ca n be a n y  u nfa v ora ble or u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y  ass ociate d wit h t he st u d y treat me nt, 
w het her or n ot relate d t o t he treat me nt. I n cli nical st u dies, a n A E ca n i ncl u de a n y  u nt o war d 
me dical occ urre nce occ urri n g at a n y ti me, i ncl u di n g r u n -i n or was h o ut peri o ds, e ve n if n o 
st u d y treat me nt has bee n a d ministere d. T he deter mi nati o n of cli nical rele va nce is base d u p o n 
t he me dical j u d g me nt of t he In vesti gat or.
1 2. 2
M o nit ori n g f or A d verse E ve nts
At eac h visit, after t he s u bject has ha d t he o p p ort u nit y  t o s p o nta ne o usly me nti o n a n y 
pr o ble ms, t he I n vesti gat or s h o ul d i n q uire a b o ut A Es b y  as ki n g t he sta n dar d q uesti o ns:

“ Ha ve y o u ha d a n y healt h pr o ble ms si nce y o ur last st u d y  visit?”

“ Ha ve t here bee n a n y c ha n ges i n t he me dici nes y o u ta ke si nce y o ur last st u d y  
visit?”
A Es s h o ul d be re p orte d f or a n y cli nicall y rele va nt c ha n ge i n c o nc o mita nt me dicati o n(s) t hat 
is t he res ult of a n u nt o war d ( u nfa v ora ble a n d u ni nte n de d) c ha n ge i n a s u bject's me dical 
healt h.
C ha n ges i n a n y pr ot oc ol -s pecific para meters a n d q uesti o n naires (if a p plica ble) e val uate d 
d uri n g t he st u d y are t o be re v ie we d by t he I n vesti gat or. A n y u nt o war d ( u nfa v ora ble a n d 
u ni nte n de d) c ha n ge i n a pr ot oc ol -s pecific para meter or q uesti o n naire res p o nse t hat is 
cli nicall y rele va nt is t o be re p orte d as a n A E. T hese cli nicall y rele va nt c ha n ges will be 
re p orte d re gar dless of ca usalit y.
1 2. 3
Pr oce d ures f or Rec or di n g a n d Re p orti n g A Es a n d S A Es
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
S u bse q ue nt t o si g ni n g a n I C F , all u nt o war d me dical occ urre nces t hat occ ur d uri n g t he c o urse 
of t he st u d y  m ust be d oc u me nte d o n t he a d verse e ve nt C R F. W he n p ossi ble, si g ns a n d 
s ym pt o ms i n dicati n g a c o m m o n u n derl y i n g pat h ol o g y s h o ul d be d oc u me nte d as o ne 
c o m pre he nsi ve e ve nt. F or eac h rec or de d e ve nt, t he A E d oc u me ntati o n m ust i ncl u de t he o nset 
date, o utc o me, res ol uti o n date (if e ve nt is res ol ve d), i nte nsit y  (ie, se verity), a n y acti o n wit h 
st u d y treat me nt ta ke n as a res ult of t he e ve nt, a n d a n assess me nt of t he a d verse e ve nt’s 
relati o ns hi p t o t he st u d y treat me nt.


Pa ge 8 6 of 9 5
N o nseri o us A d verse E ve nts
A n o nseri o us A E is defi ne d as a n y u nt o war d c ha n ge i n a s u bject's me dical healt h t hat d oes 
n ot meet seri o us criter ia n ote d bel o w (e g, is n ot life-t hreate ni n g, d oes n ot re q uire 
h os pitalizati o n, d oes n ot pr ol o n g a c urre nt h os pitalizati o n, is n ot disa bli n g, etc.). All a d verse 
e ve nts m ust be re p orte d re gar dless of w het her or n ot t he y  are relate d t o t he st u d y treat me nt.
F o r n o nseri o us a d verse e ve nts, details s h o ul d be e ntere d o n t he a d verse e ve nt C R F acc or di n g 
t o i nstr ucti o ns pr o vi de d b y t he S p o ns or.
Seri o us A d verse E ve nts
A seri o us a d verse e ve nt ( S A E) is defi ne d as a n y a d verse e x perie nce t hat meets a n y of t he 
f oll o wi n g criteria:

Res ults i n deat h.

Is life-t hreate ni n g.
N O T E: Life -t hre ate ni n g me a ns t h at t he s u bject w as at i m me di ate risk of de at h 
fro m t he r e acti o n as it occ urre d, ie, it d oes n ot i ncl u de a re acti o n w hic h 
hy p ot hetic ally mi g ht h ave c a use d de at h h a d it occ urr e d i n a m or e severe f or m.

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n.
N O T E: I n ge ner al, h os pit aliz ati o n si g nifies t h at t he i n divi d u al r e m ai ne d at t he 
h os pit al or e mer ge ncy w ar d f or o bserv ati o n a n d/ or tr e at me nt ( us u ally i nv olvi n g 
a n over ni g ht st ay) t h at w o ul d n ot h ave bee n a p pr o pri ate i n t he p hysici a n's office 
or a n o ut -s u bject setti n g. C o m plic ati o ns t h at occ ur d uri n g h os pit aliz ati o n are 
A Es. If a c o m plic ati o n pr ol o n gs h os pit aliz ati o n or f ulfills a ny ot her seri o us 
criteria, t he eve nt is seri o us. W he n i n d o u bt as t o w het her “ h os pit aliz ati o n ” 
occ urr e d, t he eve nt s h o ul d be c o nsi dere d seri o us.

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y. Disa bilit y is defi ne d as a 
s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns.
N O T E: T he ter m dis a bility me a ns a s u bst a nti al disr u pti o n of a pers o n’ s a bility t o 
c o n d uct n or m al life f u ncti o ns. T his defi niti o n is n ot i nte n de d t o i ncl u de 
ex perie nces of rel atively mi n or me dic al si g nific a nce s uc h as u nc o m pli c ate d 
he a d ac he, n a use a, v o miti n g, di arr he a, i nfl ue nz a, or acci de nt al tr a u m a (e g, 
s pr ai ne d a nkle) w hic h m ay i nterfere or preve nt every d ay life f u ncti o ns b ut d o n ot 
c o nstit ute a s u bst a nti al disr u pti o n.

Is a c o n ge nital a n o maly/ birt h defect.

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
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Is a n i m p orta nt medical e ve nt. A n i m p orta nt me dical e ve nt is a n e ve nt t hat ma y  
n ot res ult i n deat h, be life -t hreate ni n g, or re q uire h os pitalizati o n b ut ma y be 


Pa ge 8 7 of 9 5
c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt, it ma y 
je o par dize t he s u bject a n d ma y re q uire me dical or s urgi cal i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t he defi niti o ns f or S A Es. E xa m ples of s uc h me dical 
e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t ha t d o n ot res ult i n 
s u bject h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
All a v ail a ble i nf or m ati o n o n a seri o us a d verse e ve nt(s) a n d a n y ot her  ass oci ate d A E, if 
a p plic a ble, m ust be f or w ar de d t o t he S p o ns or  i m me di atel y (ie, wit hi n 2 4 h o urs of t he 
I n vesti g at or’s or site’s k n o wle d ge of t he e ve nt) as f oll o ws:

I n st u dies utilizi n g E D C, all a v ail a ble i nf or m ati o n f or t he S A E a n d a n y 
ass oci ate d A E(s) m ust be e nter e d i m me di atel y i nt o t he E D C s yste m.
N O T E: S h o ul d t he E D C syste m bec o me n o n- o per ati o n al, t he site m ust c o m plete 
t he a p pro pri ate Seri o us A dverse Eve nt F or m. T he c o m plete d f or m is f axe d t o t he 
S p o ns or at 
 wit hi n 2 4 h o urs of t he I nvesti g at or’s or site’s 
a w ar e ness; h o wever, t he re p orte d i nf or m ati o n m ust be e ntere d i nt o t he E D C 
syste m o nce it bec o mes o per ati o n al.

S p o ns or re prese ntati ves a n d t heir c o ntact i nf or mati o n are pr o vi de d i n t he M O P  
t hat acc o m pa nies t his pr ot oc ol.

A d diti o nal i nf or mati o n f or a n y a p plica ble e ve nt is t o be re p orte d as s o o n as it 
bec o mes a vaila ble.
I n a d diti o n t o t he re p orti n g of S A Es t o t he S p o ns or, t he S A E m ust be re p orte d t o t he 
I E C / I R B acc or di n g t o t heir re q uire me nts. I n a d diti o n, S A Es will be re p orte d t o 
re g ul at or y a ge ncies b ase d u p o n l oc al re p orti n g re q uire me nts.
If t he S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti g at or’ s Broc h ur e a n d is t h o u g ht 
t o be rel ate d t o t he i n vesti g ati o n al tr e at me nt t he S p o ns or m a y ur ge ntl y re q uire f urt her 
i nf or m ati o n fro m t he i n vesti g at or  f or He alt h A ut h orit y r e p orti n g. S p o ns or m a y nee d t o 
iss ue a n I n vesti g at or N otific ati o n (I N) t o i nf or m all i n vesti g at ors i n v ol ve d i n a n y st u d y 
wit h t he s a me i n vesti g ati o n al tr e at me nt t h at t his S A E h as bee n r e p orte d. S us pecte d 
U ne x pecte d Seri o us A d verse Re acti o ns ( S U S A Rs) will be c ollecte d a n d r e p orte d t o t he 
c o m pete nt a ut h orities a n d r ele v a nt et hics c o m mittees i n acc or d a nce wit h E U G ui d a nce 
2 0 11/ C 1 7 2/ 0 1 or  as per n ati o n al re g ul at or y re q uire me nts i n p artici p ati n g c o u ntries.
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
If t he S A E was d ue t o a h os pitalizati o n of t he s u bject, a c o py of t he disc har ge s u m mar y 
s h o ul d be ma de a vaila ble t o t he S p o ns or, u p o n re q uest. I n a d diti o n, a letter fr o m t he 
I n vesti gat or t hat s u m marizes t he e ve nts relate d t o t he case as well as res ults of a ny rele va nt 


Pa ge 8 8 of 9 5
la b orat or y tests ma y als o be re q ueste d. F urt her, de pe n di n g u p o n t he nat ure of t he S A E, t he 
S p o ns or ma y  re q uest c o pies of a p plica ble p orti o ns of t he s u bject’s me dical rec or ds.
A n assess me nt of seri o us ness will als o be perf or me d f or all a d verse e ve nts b y  a S p o ns or 
p h y sicia n utilizi n g t he sa me criteria. If a n a d verse e ve nt re p orte d f or a n I n vesti gat or’s s u bject 
is u p gra de d t o a seri o us a d verse e ve nt by a S p o ns or p h ysicia n, t he I n vesti gat or will recei ve a 
n otificati o n fr o m t he S p o ns or.
A d verse E ve nts of S peci al I nter est
A n a d verse e ve nt of s pecial i nterest ( E SI) is o ne of scie ntific a n d me dical c o ncer n s p ecific t o 
t he S p o ns or’s pr o d uct or pr o gra m w here o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n b y 
t he In vesti gat or t o t he S p o ns or ma y  be a p pr o priate. T hese a d verse e ve nts ma y  be seri o us or 
n o nseri o us. A p plica ble a d verse e ve nts ma y  re q uire f urt her i n vesti gati on i n or der t o 
c haracterize a n d u n dersta n d, a n d de pe n di n g u p o n t he nat ure of t he e ve nt, ra pi d 
c o m m u nicati o n b y t he S p o ns or t o ot her parties ma y als o be re q uire d.
T hese E SIs m ust be re p orte d usi n g t he sa me mec ha nis m ( E D C or fa x) a n d ti mefra me (ie, 
wit hi n 2 4 h o urs of t he I n vesti gat or ’s or site’s k n o wle d ge of t he e ve nt) as descri be d pre vi o usl y 
f or seri o us a d verse e ve nts. T he E SIs i ncl u de t he f oll o wi n g:

E n d o p ht hal mitis

Gra de 3 a q ue o us flare/ Gra de 4 a q ue o us cells (see M O P  f or gra di n g scale)

Gra de 2 a q ue o us flare/ Gra de 3 a q ue o us cells t hat fails t o decrease t o 1 or less 
wit hi n 3 0 da y s of t he o nset of t he e ve nt (see M O P f or gra di n g scale)

≥ 3 0 letter decrease i n B C VA c o m pare d wit h Baseli ne vis ual ac uit y

S ustai ne d ( > 1 5 mi n utes) l oss of li g ht perce pti o n d ue t o ele vat e d I O P

I O P > 3 0 m m H g at/ past 6 0 mi n utes p osti njecti o n

A n y  ele vati o n of I O P re q uiri n g s ur gical i nter ve nti o n (e g, parace ntesis)

Ne w reti nal tear or detac h me nt

Ne w vitre o us he m orr ha ge > 2 + se verit y t hat d oes n ot res ol ve wit hi n 1 4 da ys of 
t he o nset of t he e ve nt (see M O P f or gra di n g scale)

Ne w dia g n osis of ge o gra p hic atr o p h y

A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7
Arterial t hr o m b oe m b olic e ve nts
As wit h all A Es occ ur ri n g i n a st u d y s u bject, a decisi o n will be ma de b y t he I n vesti gat or
c o ncer ni n g f urt her e x p os ure t o st u d y  treat me nt a n d f urt her partici pati o n i n t he st u d y.


Page 89 of 95
12.4
Intensity and Causality Assessments
For every AE, the Investigator must assess the intensity (severity) and causality (relationship 
to study treatment). Specifically, AEs should be classified as mild, moderate, or severe. The 
assessment of causality will be based upon the categories of related and not related. These 
classifications should be based on the following definitions:
Intensity (Severity):
Mild
An AE is mild if the subject is aware of, but can easily tolerate the 
sign or symptom.
Moderate
An AE is moderate if the sign or symptom results in discomfort 
significant enough to cause interference with the subject’s usual 
activities.
Severe
An AE is severe if the sign or symptom is incapacitating and results 
in the subject’s inability to work or engage in their usual activity.
Causality:
Related
An AE considered related to the use of the study treatment.  AEs 
classified as related may be either definitely related or possibly 
related where a direct cause and effect relationship between the study 
treatment and the AE has not been demonstrated but there is a 
reasonable possibility that the AE was caused by the study treatment.
Not Related
An AE considered unrelated to the use of the study treatment.  AEs 
classified as not related may either be definitely unrelated or simply 
unlikely to be related (ie, there are other more likely causes for the 
AE).
An assessment of causality will also be performed, when appropriate, by a Sponsor physician 
utilizing the same definitions.  For a SAE reported by an Investigator as not related that is 
subsequently upgraded to be related by a Sponsor physician, the Investigator will receive a 
notification.
12.5
Unmasking of the Study Treatment
In the case of emergency, information on the identity of the masked assigned IP is available 
to Investigators.  If the treatment code needs to be broken in the interest of the subject safety, 
the Investigator is encouraged to contact an appropriate unmasked Sponsor representative 
prior to unmasking if there is sufficient time. Dependent upon the individual circumstances 
(ie, medical emergency), the code may be broken by contacting the IRT system prior to 
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contact with the Sponsor. The Sponsor must be informed in all cases in which the code was 
broken and of the circumstances involved.
Additionally, the Sponsor may be required to unmask the subject if the AE meets criteria of a 
SUSAR in order to fulfill expedited regulatory reporting requirements.
12.6
Follow-up of Subjects with Adverse Events
The Investigator is responsible for adequate and safe medical care of subjects during the trial 
and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained after the trial. Any additional data from these follow-up procedures must be 
documented and available to the Sponsor.
12.7
Pregnancy in the Study
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized or women considered post-menopausal. Women of 
childbearing potential are defined as fertile and physiologically capable of becoming 
pregnant, following menarche and until becoming post-menopausal unless permanently 
sterile. Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child bearing potential.  All women of childbearing 
potential are required to use adequate birth control methods which are summarized in the 
protocol’s exclusion criteria and should be used during the study and continued up to 3 
months post final study injection.
Prior to enrollment in the study, female subjects of childbearing potential must be advised of 
the importance of avoiding pregnancy during the trial and the potential risks associated with 
an unintentional pregnancy. During the study, female subjects are to be instructed to contact 
the Investigator immediately if they suspect they might be pregnant. The Sponsor must be 
contacted immediately and a decision will be made regarding continuation of the pregnant 
woman in the study based upon the circumstances surrounding the pregnancy. Pregnancy is 
not reportable as an AE, however, complications may be reportable and will be decided on a 
case by case basis. A Sponsor prepared form will be utilized to capture all pregnancy-related 
information until birth of the child.
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13
DATA HANDLING AND ADMINISTRATIVE 
REQUIREMENTS
13.1
Completion of Source Documents and Case Report Forms
The nature and location of all source documents will be identified to ensure that original data 
required to complete the CRFs exist and are accessible for verification by the site monitor. If 
electronic records are maintained, the method of verification must be determined in advance 
of starting the study. At a minimum, source documents should include the following 
information for each subject:
Subject identification (name, sex, race/ethnicity)
Documentation of subject eligibility
Date of informed consent
Dates of visits
Documentation that protocol specific procedures were performed
Results of study parameters, as required by the protocol
Trial medication accountability records
Documentation of AEs and other safety parameters (if applicable)
Records regarding medical histories and the use of concomitant therapies prior to and 
during the study
Date of trial completion and reason for early discontinuation, if applicable
It is required that the author of an entry in the source documents be identifiable. Direct access 
to source documentation (medical records) must be allowed for the purpose of verifying that 
the data recorded on the CRF are consistent with the original source data. 
Electronic case report forms will be provided to the sites; only designated individuals may 
complete the CRFs. The CRFs will be submitted at regular intervals based upon the study 
visit schedule. It is expected that all data reported will have corresponding entries in the 
source documents and that the Principal Investigator will review the reported data and certify 
that the CRFs are accurate and complete. No subject identifiers should be recorded on the 
CRFs beyond subject number and demographic information.
13.2
Data Review and Clarifications
The CRF data will be reviewed against the subject’s source data by the study monitors to
ensure completeness and accuracy. After monitoring has occurred at the clinical sites and the 
CRFs have been submitted, additional data clarifications and/or additions may be needed. 
Data clarifications and/or additions are documented and are part of each subject’s CRFs.
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13.3
Regulatory Documentation and Records Retention
The Investigator is required to maintain up-to-date, complete regulatory documentation as 
indicated by the Sponsor and the Investigator’s files will be reviewed as part of the ongoing 
study monitoring. Financial information is not subject to regulatory inspection and should be 
kept separately. 
Additionally, the Investigator must keep study records and source documents until the 
Sponsor provides written approval for their destruction. If the Investigator retires, relocates, 
or for any other reason withdraws from responsibility of keeping the study records, the 
Sponsor must be notified and suitable arrangements made for retention of study records and 
source documents needed to comply with national and international regulations (generally 2 
years after discontinuing clinical development or after the latest marketing approval).
13.4
Quality Assurance and Quality Control
The Sponsor will be responsible for implementing and maintaining quality assurance and 
quality control systems to ensure the study is conducted and data are generated, documented, 
and reported in compliance with the protocol, GCP and applicable regulatory requirements. 
The Sponsor will secure agreement from all involved parties to ensure direct access to all 
study related sites, source data and documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by domestic and foreign regulatory authorities. 
Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. Agreements made by the Sponsor with the 
Investigator/Institution and any other parties involved in the study will be provided in writing 
as part of the protocol or as a separate agreement.
13.5
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be established to monitor the safety 
of the trial participants, to ensure that the trial is being conducted with the highest scientific 
and ethical standards, and make appropriate recommendations based on the data seen.
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communication 
with the Sponsor. The DMC will only make recommendations for changes in study conduct.
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14
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Wiedemann P et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in 
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Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach, K, Probst 
C, Sledge I. The natural history and prognosis of neovascular age-related macular 
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loss in the comparison of age-related macular degeneration treatments trials. JAMA 
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D at e/ Ti m e 
( m m/ d d/ y y y y G M T):
Si g n e d b y:
J u stifi c ati o n :
M a n a g e m e nt of Aff e ct e d Ar e a A p pr o v al
Bi o st at s
P ati e nt S af et y
0 2/ 1 0/ 2 0 1 7 1 7: 1 6: 0 0
0 2/ 1 0/ 2 0 1 7 1 7: 0 7: 4 5
0 2/ 1 0/ 2 0 1 7 1 5: 5 8: 0 7
A lc o n - B usi ness Use O nl y  
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  
Pri nte d B y:  
Pri nt Date:  
E f f e c t i v e
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 2 5 0
1 0- Fe b- 2 0 1 7

SAP_001.pdf: 
Alcon - Business Use Only Statistical 
Effective Date: 19-May-2017 
Analysis Plan 
Document: TDOC-0053361 
Status: Effective 
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Clinical Development 
 
 
RTH258/Brolucizumab 
 
RTH258A2302 (HARRIER) / NCT02434328 
 
A Two-Year, Randomized, Double-Masked, Multicenter, 
Two-Arm Study Comparing the Efficacy and Safety of 
RTH258 6 mg versus Aflibercept in Subjects with 
Neovascular Age-Related Macular Degeneration 
 
 
 
Statistical Analysis Plan (SAP) 
 
 
Author: 
 
Document type: 
SAP Documentation 
Document status: 
Final 2.0 
Release date: 
19-May-2017 
Number of pages: 
56 
 
 
 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History - Changes compared to previous final version 
 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update 
Sectionand title 
impacted (Current) 
11-Jan-2017 
P1i or to 
DB lock 
Creation of final version 
N/A 
First final 
version (Vl .0) 
approved in 
documentum 
system. 
NIA 
19-May-2017 
P1ior to 
DB lock 
Creation of amendment-I 
• 
Adjustments in relations 
to obse1ved protocol 
deviations and analysis 
restrictions, e.g. detailed 
specifications for the 
per-protocol set 
including censoring and 
the assessment of the 
ql 2 proportion based on 
a time-to-eventanalysis 
• 
• 
Introduction of "Other 
safety events of interest" 
under "Adverse events 
(AEs)" sub-section 
(2.8.2) 
Updated . 
Sub-sections 1.2, 2.2, 2.4, 
2.5. 2.6, 2.7, 2.8 and 5 


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List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design ............................................................................................................. 6 
1.1.1 
Randomization ........................................................................................ 7 
1.1.2 
Masking ................................................................................................... 7 
1.1.3 
Primary analysis ...................................................................................... 8 
1.1.4 
Data monitoring committee (DMC) ........................................................ 8 
1.2 
Study objectives and endpoints................................................................................ 8 
1.2.1 
Objectives ................................................................................................ 8 
1.2.2 
Endpoints................................................................................................. 9 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
All Enrolled and All Randomized Analysis Sets .................................. 13 
2.2.2 
Efficacy Analysis Sets ........................................................................... 13 
2.2.3 
Subgroups of interest ............................................................................. 14 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 14 
2.3.1 
Subject disposition ................................................................................ 14 
2.3.2 
Demographic and baseline characteristics ............................................ 15 
2.4 
Treatments (study treatment / compliance, rescue medication, concomitant 
therapies) ................................................................................................................ 15 
2.4.1 
Study treatment / compliance ................................................................ 15 
2.4.2 
Medical history, prior/concomitant medication and concomitant 
procedures ............................................................................................. 16 
2.5 
Analysis of the primary and first key secondary objectives .................................. 17 
2.5.1 
Primary and first key secondary endpoints ........................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 18 
2.5.4 
Supportive analyses ............................................................................... 18 
2.6 
Analysis of the second and third key secondary objectives ................................... 19 
2.6.1 
Second and third key secondary endpoints ........................................... 19 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.6.4 
Supportive analyses ............................................................................... 21 
2.7 
Analysis of additional secondary efficacy objective(s) ......................................... 25 


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2.7.1 
Secondary endpoints ............................................................................. 25 
27 
2.7.3 
Statistical hypothesis, model, and method of analysis .......................... 27 
2.7.4 
Handling of missing values/censoring/discontinuations ....................... 28 
2.8 
Safety analyses ....................................................................................................... 29 
2.8.1 
Extent of exposure ................................................................................. 29 
2.8.2 
Adverse events (AEs) ............................................................................ 30 
2.8.3 
Deaths .................................................................................................... 36 
2.8.4 
Laboratory data ..................................................................................... 36 
2.8.5 
Other safety data.................................................................................... 38 
2.8.6 
Presence of geographic atrophy and fibrosis ......................................... 40 
2.8.7 
Post-injection assessment ...................................................................... 40 
2.8.8 
Presence of anti-drug antibody (ADA) ................................................. 40 
2.9 
Pharmacokinetic endpoints .................................................................................... 41 
2.10 
Subject-reported outcome ...................................................................................... 41 
2.10.1 
Visual function questionnaire (VFQ-25)............................................... 41 
2.11 
Interim analysis ...................................................................................................... 42 
3 
Sample size calculation ..................................................................................................... 42 
4 
Change to protocol specified analyses ............................................................................... 43 
5 
Appendix ........................................................................................................................... 43 
5.1 
Imputation rules ..................................................................................................... 43 
5.1.1 
AE date imputation ............................................................................... 43 
5.1.2 
Concomitant medication date imputation ............................................. 45 
5.2 
Statistical models ................................................................................................... 47 
5.2.1 
Primary and first key secondary analysis .............................................. 47 
5.2.2 
Key secondary analysis ......................................................................... 48 
5.3 
Rule of exclusion criteria of analysis sets .............................................................. 50 


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List of abbreviations 
 
AE 
Adverse event 
AR 
Analysis Restrictions 
nAMD 
Neovascular Age-related Macular Degeneration 
BCVA 
Best Corrected Visual Acuity 
CI 
Confidence Interval 
CNV 
Choroidal Neovascularization 
CSFT 
Central Subfield Thickness 
CSFTnr 
Central Subfield Thickness-neurosensory retina 
CSFTtot 
Central Subfield Thickness-total 
CSM 
Clinical Site Management 
CSR 
Clinical Study report 
CTM 
Clinical Trial Management 
DA 
Disease Activity 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IVR 
Interactive Voice Response 
IVT 
Intravitreal 
LSM 
Least Squares Mean 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
q8 
Treatment every 8 weeks 
q12 
Treatment every 12 weeks 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
SAP 
Statistical Analysis Plan 
SAF 
Safety Analysis Set 
SE 
Standard Error 
SOC 
System Organ Class 
SoC 
Standard of Care 
TFLs 
Tables, Figures, Listings 
VA 
Visual Acuity 
WHO 
World Health Organization 


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RTH258A2302 
 
 
 
1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of 
statistical analysis planned in the study protocol, and to provide detailed statistical methods 
that will be used for the Clinical Study Report (CSR) of study RTH258A2302. 
Data will be analyzed according to the data analysis Section 11 of the study protocol which 
will be available in Appendix 16.1.1 of the CSR. Important information is given in the 
following sections and details will be provided, as applicable, in Appendix 16.1.9 of the CSR. 
The SAP will be finalized before treatment unmasking. Any changes to the SAP after 
approval will be documented. 
 
1.1 
Study design 
This is a prospective, randomized, double-masked, multicenter, two-arm study comparing the 
safety and efficacy of RTH258 IVT injections versus aflibercept IVT injections in subjects 
with neovascular age-related macular degeneration (AMD). 
The two treatment arms are: 
Arm 1: Brolucizumab 6 mg/50 μL (a.k.a RTH258 6 mg/50 μL) 
Arm 2: Aflibercept 2 mg/50 μL (a.k.a Eylea 2 mg/50 μL) 
Subjects in both arms will have visits every 4 weeks through Week 96. 
According to protocol, approximately 330 subjects per arm (total 660 subjects) will be 
randomized in this trial. More details of the sample size calculation can be found in Section 3. 
By the time this first amendment is implemented, 743 subjects were randomized in the study. 
In Arm 1, RTH258 6 mg will be initially injected 3 times at 4-week intervals, at Visit 
1/Baseline, Visit 2/Week 4 and Visit 3/Week 8. Following these 3 loading doses, each subject 
will be injected every 12 weeks (q12) up to Visit 24/Week 92 unless there is disease activity 
assessed according to the guidance provided at Visit 5/Week 16, Visit 6/Week 20, Visit 
8/Week 28, Visit 9/Week 32, Visit 11/Week 40, Visit 12/Week 44, Visit 14/Week 52, Visit 
15/Week 56, Visit 17/Week 64, Visit 18/Week 68, Visit 20/Week 76, Visit 21/Week 80 or 
Visit 23/Week 88. If disease activity is identified, the subject will be reassigned to receive 
injections every 8 weeks (q8) thereafter, up to study exit. Refer to protocol Section 10.1 for 
disease activity guidance criteria. 
In Arm 2, aflibercept 2 mg, (EYLEA, comparator) will be injected 3 times at 4-week intervals 
(Visit 1/Baseline, Visit 2/Week 4 and Visit 3/Week 8),  followed  by injections  q8  up  to 
Visit 23/Week 88. 
The dosing schedule by treatment is presented graphically below. 


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Figure 1 Dosing schedule by treatment 
 
 
1.1.1 
Randomization 
A member of the Statistical Programming group at Alcon who is not part of the study team 
will generate the randomized allocation for the study treatment assignment based on a 
randomization plan providing study specific criteria for randomization including block size 
and randomization ratio. Treatment is assigned to subjects through the Interactive Response 
Technology (IRT) system. Each subject number is associated with a treatment group 
according to the randomized allocation generated using the computer software SAS version 
9.2 PROC PLAN. Subjects are assigned numbers sequentially according to time of 
randomization. 
Eligible subjects will be randomized to one of the two treatment arms, Brolucizumab 6 mg/50 
µL or Aflibercept 2 mg/50 µL, in a 1:1 ratio at Visit 1/Baseline. There are no stratification 
factors in this study. Central randomization, without stratification by investigational site, will 
be employed. The randomization schedule will be blocked to ensure a balance of treatment 
allocations across the study. 
 
1.1.2 
Masking 
This is a double–masked study. The investigator, investigator staff (except for the unmasked 
site personnel and unmasked injecting physician), subjects and Sponsor personnel (except for 
those who have been delegated responsibility for working with the IP) involved with conduct 
of the trial are masked with regard to treatment assignment while the study is in progress. 
Sponsor personnel who have access to treatment codes (e.g., randomization specialist, 
personnel directly involved with bioanalysis of serum samples, unmasked monitors 
performing investigational product accountability and Clinical Supplies personnel) will not 
divulge the codes to subjects, Investigators, site staff, and Sponsor personnel involved in the 
conduct of the study. Masking is maintained by providing sham injections. With this setup, 
subjects will continue to receive masked treatment through the planned study duration (96 
Weeks) to allow for further masked evaluation of efficacy and safety. Treatment masking will 
remain intact also for Investigators, and staff from the Sponsor who have contact  with 
subjects or Investigators or those who are involved in the direct conduct of the study until the 
final database lock (Week 96) has occurred. 


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The prima1y analysis at Week 48 will be perfonned with an unmasking of specified 
individuals from the Sponsor who are not involved in the direct conduct of the trial. The 
biostatistician who is directly involved in the conduct of the study will remain masked to 
treatment assignments while the study is in progress. 
Details on the conduct and logistics of the unmasked team that will perform the prima1y 
analysis will be provided in a separate document (process map for Week 48 unmasking). Two 
process map documents detailing the work-flow were prepared, reviewed and agreed upon by 
the study team prior to Week 48 database lock and unmasking. These are 
1. Process map for maintaining the mask during protocol deviation and analysis 
restriction determination for RTH258 in wet AMD during the submissions: This 
document describes how study team managed protocol deviation and analysis 
restriction assessment which require access to unmasked info1mation. 
2. Maintaining the masking of the Phase III studies (RTH258A2301and RTH258A2302) 
after the 1 year primaiy analysis database lock: This document describes who will 
have access to unmasked infmmation post-DBL and the steps to be taken to minimize 
risks of unmasking and introduction of bias to the analysis. 
 
1.1.3 
Primary analysis 
The prima1y safety and efficacy analysis will be based on the Week 48 data, i.e. all data up to 
and including Week 48. This analysis will be perfmmed once all subjects completed their 
Week 48 visits or ternlinated the study before Week 48, while subjects continue to receive 
masked treatment through the plalllled study duration of 96 Weeks. The analysis of the data 
collected after the Week 48 visit will be performed once all subjects completed or 
discontinued from the study. 
 
1.1.4 
Data monitoring committee(DMC} 
An independent Data Momtming Committee (DMC) will be established to momtor the safety of 
the trial pa1ticipants, and make appropriate recommendations based on the safety data reviewed. 
Details on the DMC membership, responsibilities, timing of meetings, data to be reviewed, 
and commumcation with the Sponsor will be described in the DMC chaiter. All statistical 
analysis conducted for the purpose of the DMC is outside the scope of this SAP and is 
covered in the DMC chatter and other suppo1ting documents. The unmasked analyses for the 
DMC will be conducted by an independent contract research organization. Access to the 
unmasked analysis results will be limited to the DMC members only. 
 
1.2 
Study objectivesand endpoints 
1.2.1 
Objectives 
Primary Objectives: 
• To demonstrate that RTH258 6 mg is not inferior to aflibercept 2 mg with respect to 
the change in best-conectedvisual acuity (BCVA) from Baseline to Week 48 
Key Secondary Objectives: 


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• 
To demonstrate that RTH258 6 mg is not inferior to aflibercept 2 mg with respect to 
the change in BCVA from Baseline averaged over the period Week 36 to Week 48 
• 
To estimate the propo1tion of ql 2 subjects up to Week 48 in the RTH258 6 mg 
treatment rum 
• 
To estimate the predictive value of the first ql 2 cycle for maintenance of  ql2  
treatment up to Week 48 in the RTH258 6 mg treatment aim 
Other Secondary Objectives: 
• 
To evaluate the efficacy of RTH258 6 mg relative to aflibercept 2 mg over the time 
period up to Week 96 by assessing changes in: 
o BCVA 
o Anatomical parameters of disease activity including central subfield thickness 
(CSFT), choroidal neovascularization (CNV) area, presence of subretinal, 
intraretinal, and subRPE fluid, and absence of intraretinal and subretinal fluid 
o Presence of "q8 treatment need", including assessment of ql 2 status for 
subjects in the RTH258 6 mg treatment rum 
o V isual fun ct ion rela ted subje c t repo1ted outcomes 
• 
To assess the safety and tolerability of RTH258 6 mg relative to aflibercept 2 mg 
 
1.2.2 
Endpoints 
 
1.2.2.1 
Efficacy Endpoints 
PrimaryEndpoint 
The prima1y efficacy endpoint is change in BCVA from baseline to Week 48 
Key Secondary Endpoints 
The key seconda1yefficacy endpoints are: 
• 
Average change in BCVA from Baseline over the period Week 36 through Week 48 
• 
ql 2 treatment status at Week 48 for subjects randomized to RTH258 6 mg 
• 
ql 2 treatment status at Week 48 within the subjects randomized to RTH258 6 mg and 
with no q8 need dming the first ql 2 cycle (Week 16 and Week 20) 
Additional Secondary Efficacy Endpoints 
• 
Change in BCVA from Baseline to each postbaseline visit 
• 
Average change in BCVA from Baseline over the period Week 84 through Week 96 
• 
Average change in BCV A from B aselin e ove r the peli od Wee k 4 to Wee k 48/96 
• 
Ave rage change in BCV A from Baselin e ove r the period Wee k 12 to Week 48/96 
• 
Gain in BCVA of 15/10/5 letters or more from Baseline to each postbaseline visit 
• 
Number and percentage of subjects with BCVA of 73 letters or more at each visit 


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• 
Loss in BCVA of 15/10/5 letters or more from Baseline to each postbaseline visit 
• 
q12 treatment status at Week 96 (for subjects randomized to RTH258 6 mg only) 
• 
q12 t1eatment status at Week 96 within the subjects with no q8 need dming the 1st q12 
cycle (Week 16, Week 20) (for subjects randomized to RTH258 6 mg only) 
• 
' q8 treatment need' at Week 16 
• 
Change in CSFT from Baseline to each postbaseline visit 
• 
Average change in CSFT from Baseline over the period Week 36 through Week 48/ 
over the period Week 84 through Week 96 
• 
Average change in CSFT from Baseline over the period Week 4 to Week 48/96 
• 
Average change in CSFTns from Baseline over the pe1iod Week 12 to Week 48/96 
• 
Change in CSFTns from Baseline to each postbaseline visit 
• 
Change in area of CNV within the lesion from Baseline to Weeks 12, 48 and 96 
• 
Presence of subretinal fluid (central subfield) at each postbaseline visit 
• 
Presence of intraretinal fluid (central subfield) at each postbaseline visit 
• 
Presence of sub RPE fluid (central subfield) at each postbaseline visit 
• 
Simultaneous absence of subretinal and intraretinal fluid (central subfield) at each 
postbaseline visit 
• 
Presence of subretinalhemonhage (central subfield) at each assessment visit 
• 
Presence of intraretinal hemonhage (central subfield) at each assessment visit 
• 
Simultaneous absence of subretinal and intraretinal hemonhage (central subfield) at 
each assessment visit 
• 
Change in subject repo1ted outcomes (VFQ-25) total and subscale scores from 
Baseline to Weeks 24, 48, 72 and 96 


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1.2.2.2 Safety Endpoinst 
The safety endpoints are based on the following assessments: 
• 
Extent of exposure 
• 
Adverse events 
• 
General physical exam 
• 
Vital signs 
• 
Laborato1y tests (Blood chemistly, hematology and urinalysis) 
• 
Loss in BCVA 
• 
Slit-lamp examination (aqueous reaction [cells and flare]) 
• 
Fundus exam (retinal hemon hage/detachment, vitreal hemonhage density and vitl"eous 
cells) 
• 
Co lor fundus photography (presence of geographic atl"ophy and fibrosis) 
• 
Fundus autofluorescence (for presence and area of atrophy) 
• 
IOP 
• 
Post-injection assessment (gross assessment of vision, IOP, status of centi·al retinal 
arte1y and presence of retinal detachment/new inti-aocu lar hemonhage) 
• 
Anti-diug antibodies (ADA) and sernm concenti·ation of RTH258 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The prima1y analysis at Week 48 and the final analysis after all subjects completed / 
te1minated the study will be performed by the Biostatistics and statistical programming groups 
ofNova1tis using SAS 9.4 or higher. 
Tables will be presented based on the unit subject, with ocular parameters presented 
separately for the study- and fellow-eye as applicable. 
Continuous variables will be summarized using the number of observations, mean, median, 
standard deviation, standard enors, quaitiles, minimum and maximum values. Categorical 


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variables will be summarized with the number of observations, the number of observations for 
each category and the corresponding frequency and percent. Where appropriate, two-sided 
95% confidence intervals for point estimates of the mean or proportion will be provided. Point 
estimates and two-sided 95% confidence intervals of treatment group differences and p-values 
will be provided as appropriate. 
Output will be presented by treatment and for the study population descriptions at baseline, 
also for the overall populations. Listings will include the following identifying variables: 
treatment, investigator number, country, subject number, age, sex, race, and visit. In addition, 
ocular assessments will include identification of the study and fellow eye. 
 
2.1.1 General definitions 
Investigational product (IP) or treatment refers to both Broclucizumab 6 mg and Aflibercept 2 
mg IVT injections. 
Baseline (Day 1) is the date of the first study treatment in the study. The Baseline value for 
efficacy and safety variables is the last available value collected prior to the first treatment 
which can occur at the Baseline or Screening visits. 
All data collected after the first study treatment are defined as post-Baseline. The 
study day for a post-Baseline scheduled or unscheduled visit is defined as: 
Study day = (date of visit) – (date of first study treatment) + 1 
The study day for a scheduled or unscheduled visit before Baseline is defined as 
Study day = (date of visit) – (date of first study treatment) 
End of study/end of treatment day mapping: 
The end of study date (from the ‘Visit date’ form in CRF) is the date when a subject 
completes or discontinues the study. The “Date of Last Exposure” (from CRF 
‘Exposure’ form) is the date of the last study treatment on or prior to the end of study 
date. For reporting data by visit in outputs, the end of study/end of treatment visit will 
be allocated to the actual (reported) visit number. If end of study date is not on a 
scheduled visit, then end of study visit will be allocated based on study day to the 
closest future scheduled study visit. 
Unscheduled visits: 
All data collected at unscheduled visits will not be used in ‘by-visit’ tabulation or 
graphs, but they will be included for analyses based on all post-Baseline values such 
as LOCF imputation, safety narratives, summary of maximum decrease or increase 
from baseline for laboratory and vital signs data. 
All data collected at unscheduled visits will be included in listings. 
 
2.2 
Analysis sets 
Subject evaluability based on pre-specified deviations from the protocol and/or analysis 
requirements and their impact on analysis sets will be determined prior to locking the database 
for the primary analysis at Week 48 and breaking the masked treatment assignment code. 


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Before the Week 48 database lock, the relevant protocol deviations and analysis restrictions 
will be specified in the deviations and evaluability plan (DEP) document with the analysis 
restrictions also presented in Section 5.3. The corresponding identifications at the subject level will be 
captured in the database and locked prior to unmasking. 
 
2.2.1 
All Enrolled and All Randomized Analysis Sets 
All enrolled analysis set includes all subjects who signed informed consent and are assigned 
subject numbers. 
All randomized analysis set (RAN) includes all subjects who were randomized in IRT. 
 
2.2.2 
Efficacy Analysis Sets 
All efficacy analyses will be conducted according to the randomized treatment assignment. 
 
 
2.2.2.1 
Full analysis set 
The full analysis set (FAS) includes all randomized subjects who receive at least one IVT 
injection of the study treatment. The full analysis set (FAS) will serve as the primary analysis 
set for all efficacy analyses. The FAS represents the analysis set which is as close as possible 
to the intent-to-treat (ITT) principle of including all randomized subjects. 
 
2.2.2.2 
Per protocol analysis set 
Supportive analyses of the primary and secondary endpoints will include analysis using the 
per protocol set (PPS). PPS is a subset of the FAS and will exclude subjects with protocol 
deviations and analysis restrictions that are expected to majorly affect the validity of the 
assessment of efficacy at Week 48 including for e.g. lack of compliance (including missed 
treatments and treatment misallocation), missing data, prohibited concomitant medication and 
deviation from inclusion/exclusion criteria. Discontinuation from treatment due to lack of 
efficacy and/or safety does not constitute a reason for exclusion from the PPS. 
Before the Week 48 database lock the relevant protocol deviations and analysis restrictions 
will be identified at the subject level in the database. 
When assessing the robustness of the overall efficacy conclusions, equal importance will be 
given to the FAS and PPS results understanding that a robust study will demonstrate similar 
conclusions from both analysis sets. Inconsistencies in key efficacy study results between the 
FAS and PPS will be examined and discussed in the clinical study report (CSR). 
 
2.2.2.3 
Safety Analysis Set 
The safety analysis set (SAF) will include all subjects who receive at least one IVT injection. 
Subjects in the safety analysis set will be analyzed according to the treatment arm from which 
they received majority of treatments up to and including Week 44. 
To capture potential procedure related AEs occurring in subjects without having received at 
least one IVT injection, all AEs of randomized subjects not belonging to the SAF occurring at 
or after the day of randomization will be listed separately. 


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2.2.3 
Subgroups of interest 
The subgroups of interest are listed below: 
• 
Age category (<75 years and ?.75 years) 
• 
Gender (male and female) 
• 
Baseline BCVA categories (:S55 ,56-70 , ?.7 1 letters) 
• 
Ba se line CSFT category (<400, ?.400 microns) 
• 
Baseline lesion type ( predominantly classic, minimally classic, occult) 
• 
Baseline CNV lesion size (tertiles) 
• 
Baseline lesion size by lesion type (predominant classic vs. minimally classic/occult) 
(tertiles) 
• 
Baseline fluid status (intraretinal fluid (IRF), subretinal fluid (SRF), sub-retinal 
pigment epithelium (sub-RPE) fluid) 
Subgroup analysis will be performed for the primary and key secondary efficacy variables. 
More details can be found in Sections 2.5.4, and 2.6.4. 
 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
Subject characteristics and study conduct summaries include tables and listings such as a 
subject disposition table, demographics and baseline characteristics tables, listing of treatment 
assignment by investigator, summary of scree n failures by reason and listing of subjects 
excluded from the full analysis, per-protocol and safety analysis sets including the 
conesponding reasons and censoring. 
No tests for differences in background and demographic characteristics between tt·eatment 
groups will be performed. Potential related differences will be assessed based on clinical 
relevance. 
 
2.3.1 
Subject disposition 
Subject disposition table will be based on the All-randomized analysis set. The following 
summar·ies will be included in the disposition table: number and percent of subjects who were 
randomized and treated (= received at least one injection), completed the study, discontinued 
from tt·eatment / study overall and by reason of discontinuation. Percentages will be based on 
the number of subjects who are randomized. If there were dosing enors where subjects 
received treatment other than what they were randomized to, separate summaries will be 
presented based on 'as tt·eated', while the 'as treated' status will be derived from the majori ty 
of tt·eatmenst received. 
A subject is considered to have completed a study period (Week 48 / Week 96) if he/she did 
not discontinue study prior to the end of this period. Discontinuation at Week 48 with exit  
visit assessment performed is considered as 'co mpleted' for the Week 48 analysis. 


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Number and percent of subjects who failed screening (i.e. were not randomized) will be 
presented by reason using the All-emolled analysis set. Appropriate table and listing of all 
screen failures along with the con esponding reason will also be presented as necessa1y. 
Number and percent of subjects who were excluded (i.e. not evaluable) from each of the SAF, 
FAS, and PPS will be presented using the All-randomized analysis set. A listing of subjects 
along with the analysis set that they were excluded from and the con esponding reasons will 
also be presented. 
Number and percent of subjects with major protocol deviations and analysis restrictions will 
be presented by deviation/restriction catego1y. A listing of all relevant deviations/restrictions 
will be presented. 
A listing of subjects who discontinue from the study and/or treatment early will be provided. 
The listing will identify the visits completed and when the study or treatment was 
discontinued including the con esponding reasons. 
2.3.2 
Demographic and baseline characteristics 
Demograp hic table will include: age (both as a continuous variable and using categories (:564, 
65 to 74, 75 to 84, and 2:85), gender, race, ethnicity. Demographic summaiy tables will be 
presentedfor the All-randomized, SAF, FAS and PPS. 
Baseline characteristics table will include: prima1ydiagnosis of nAMD, time since diagnosis 
of n AMD (days), whether nAMD is unilateral or bilateral, BCVA (both as a continuous 
variable (letters read) and using categories (:555, 56-70, 2:71 letters rea d), type of CNV 
(predominantly classic, minimally classic, occult), CNV location (subfoveal, juxtafoveal, 
extrafoveal, absent), area of CNV associated with the lesion (mm2 
presence of subretinal 
fluid, presence of intraretinal fluid, presence of sub RPE fluid, presence of RAP lesion, central 
subfield neurosenso1y retinal thickness (CSFTns) and central subfield thickness total 
(CSFTtot) (both as a continuous variable and using categories (<250, 2:250 µm) / (<400, 2:400 
lm) respectively). The baseline characteristics table will be presented separately for the study 
and fellow eye. 
A subject listing containing all demographics info1m ation by investigator will be presented 
using the All-randomized analysis set. The listing will also include columns for the 
randomized treatment, the number of active injections by treatment and the majority of the 
actual treatment received for a subject. 
2.4 
 Treatments (study treatment/ compliance, rescue 
medication, concomitant therapies) 
2.4.1 
Study treatment I compliance 
Extent of exposure to investigational product is calculated as the number of injections 
received. The following summaries will be presented based on the FAS and PPS. 
• 
Overall number of treatments will be presented separately (active and sham, active only, 
sham only) in the following time periods: 
o Baseline to Week 8 
) , 


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o Week 12 to Week 44 
o Baseline to Week 44 
o Week  48 to Week 92 
o Baseline to Week 92 
• Treatment exposme by visit: The number and percent of subjects who received active, 
sham injections, missed a tTeat ment (active or sham) and missed visits will be presented 
separately by visit and by treatment status (q8, q12) for the Brolucizumab treatment group. 
• Frequency of all observed dosing patterns up to and including Week 44 and up to Week 
92 differentiating between active and sham treatments, missed treatments and wrong 
treatments will be presented. 
• Q12/q8 allocation for RTH258subjects by visit: Number and percent of RTH258 subjects 
on q12 and q8 including the number of subjects switched from q12 to q8 with related 
reasons. 
 
2.4.2 
Medical history, prior/concomiat nt medication and concomitant 
procedures 
2.4.2.1 
Medical history 
Medical history (ocular and non-oculai') will be tabulated by system organ class and prefened 
te1m of the MedDRA dictionaiy using the All-randomized analysis set. Ocular events will be 
presented sepai·ately by study and fellow eye. A listing of all medical histo1y data will be 
provided. 
 
2.4.2.2 
Prior medication 
Prior medications (ocular and non-ocular) will be summarized  using  number  and  percentage 
of subjects by ATC class and prefen ed term according to the WHO Drug reference list 
dictiona1y using the all-randomized analysis set. Prior medications are those that have a start 
date prior to the first IVT injection date. Ocular medications will be  presented separately for 
the study and fellow eye. Prior medications will be classified in addition as whether  or  not 
they were endedprior to the first IVT injection date. A listing of all prior medications will be 
provided. 
2.4.2.3 
Concomiat nt medication 
The number and percentage of subjects taking concomitant  medications  will  be summarized 
by ATC class and prefened te1m according to the WHO Drug Reference List dictionary using 
the safety analysis set. Medications that were taken dming the  treatment  period,  including those 
that sta1ted prior to first injection but continued after treatment sta1t , will be summarized as 
concomitant medications. Concomitant medications will be  classified in addition as whether  or  
not  they  sta1ted  prior  to  first  IVT  injection  for  ocular  medications,  separate summaries 
will be presented for study and fellow eye. A listing of all concomitant medication will be 
provided. 


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2.4.2.4 
Concomiatnt procedures 
The number and percentage of subjects who had procedures done during the study will be 
summarized by system organ class and prefe1Ted te1m according to the MedDRA dictiona1y 
using the safety analysis set. For ocular procedures, separate summaries will be presented for 
study and fellow eye. A listing of all concomitant procedures will be provided. 
 
2.5 
Analysis of the primary and first key secondary 
objectives 
2.5.1 
Primary and first key secondary endpoinst 
• 
The prima1y efficacy endpoint is change in BCVA from baseline to Week 48. Best- 
conected visual acuity will be measured based on the procedures developed for the 
Early Treatment Diabetic Retinopathy Study (ETDRS) and the results will be rep01ted 
in letters. 
• 
The first key seconda1y endpoint is average change in BCVA from Baseline over the 
period Week 36 through Week 48. For each subject, this endpoint is defined as the 
average of the changes from baseline to Weeks 36, 40, 44 and 48. The motivation for 
the choice of this endpoint is that, averaging the BCVA values over Week 36 to Week 
48 will smooth out both random fluctuations and potential trough and peak values 
during the different treatment cycles. During the period Week 36 to Week 48, 
aflibercept and RTH258 subjects on q8 will have 2 assessments 4 weeks after the last 
dose, and 2 assessments 8 weeks after the last dose. RTH258 subjects on a  ql2 
regimen will have 2 assessments 4 weeks after the last dose, 1 assessment 8 weeks 
after the last dose, and 1 assessment 12 weeks after the last dose. 
The primary efficacy analyses of these two endpoints will be based on the FAS with last-
observation-ca1Tied-f 01ward (LOCF) imputation of missing BCVA values. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The statistical hypothesis for the prima1y and first key secondary endpoints is that RTH258 6 
mg is not inferior to aflibercept 2 mg within a non-inferiority margin of 4 letters. 
The following 2 hypotheses will be tested  in the  pre-specified hierarchical sequence  according  
to their numbering HAn , n= 1 , 2 
48 = Week 48, 36-48 = Week 36 through 48, R6= RTH258 6mg , A= aflibercept 2 mg 
Hoi: µ48R6 - µ48A :S -4 letters vs. HAi: µ48R6 - '48A > -4 letters 
l4 8R6 and µ48A being the co1Tesponding unknown hue mean BCVA changes from Baseline to 
Week48. 
Ho2: µ36-48R6 - µ36-48A :S -4 letters vs. HA2: µ36-48R6 - µ36-48A > -4 letters 
µ3648R6and  t3648Abe ing  the  co1Tesponding unknown hue  mean values for the average change 
in BCVA from Baseline over the period Week 36 through 48. 
The prima1y and first key secondary endpoints will be analyzed by fitting an analysis of 
var·iance (ANOVA) model with treatment, baseline BCVA categories (:S55, 56-70 , 2':71 letters) 


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and age categories (<75, ≥75 years) as fixed effects. Least square means for each treatment 
group and treatment differences together with corresponding two-sided 95% CIs will be 
derived from the fitted model. Non-inferiority is demonstrated if the lower limit of the two- 
sided 95% confidence interval for the treatment difference (RTH258 6 mg– aflibercept 2 mg) 
is greater than -4 letters. The 2 hypotheses listed above will be tested in the pre-specified 
hierarchical sequence according to their numbering (HAn, n=1, 2). Consequently, confirmatory 
testing of the second hypothesis requires rejection of the first null hypothesis. In this setting, 
each hypothesis will be assessed at a two-sided significance level of 0.05, while keeping the 
global type I error rate at 0.05. 
 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing data will be imputed using last observation carried forward (LOCF) method. 
Observed values from both scheduled and unscheduled visits will be used for the LOCF 
imputation. For subjects with no postbaseline value, the baseline value will be carried forward. 
For subjects who discontinue treatment but continue in the study, the efficacy data will be 
censored at the time the subject started alternative anti-VEGF treatment in the study eye. 
Censored or missing data will be imputed by the last observation prior to receiving alternative 
anti-VEGF treatment. 
 
2.5.4 
Supportive analyses 
The following supportive analyses will be done: 
1. Descriptive statistics for the primary and first key secondary endpoints will be 
presented based on LOCF imputation for missing /censored values using the FAS and 
PPS. In addition observed data with and without censoring will be presented 
descriptively using the FAS. For the PPS, observed values will be presented 
descriptively excluding censored data. As a result, for the primary endpoint, all 
subjects with missing Week 48 BCVA value will not be considered. Similarly, for the 
endpoint ‘average change in BCVA from Baseline over the period Week 36 through 
Week 48’, only non-missing values at Weeks 36, 40, 44, and 48 will be averaged for 
the ‘observed data’ analysis. 
2. ANOVA using the PPS with LOCF imputation for missing/censored values. The same 
model as in the primary analyses will be fitted for this supportive analysis. 
3. Mixed model repeated measures (MMRM) using the FAS and PPS with observed data 
(including censoring for alternative anti-VEGF). The MMRM will include treatment, 
visit, baseline BCVA category, age category and treatment by visit interactions as 
fixed-effect terms and visit as a repeated measure. An unstructured covariance matrix 
will be used to model the within-subject error. For the MMRM analysis: 
a. The treatment difference at Week 48 will be estimated using the LSM and 95% 
percent confidence interval. 
b. For the endpoint of average change from Baseline over the period Week 36 
through Week 48, a SAS code utilizing the ESTIMATE statement in PROC 
MIXED will be provided in the programming specification document to obtain 


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the LSM estimate for the coITes p ondin g trea tment difference and 95% 
confidence interval. 
c. If an MMRM model with unstrnctured covariance matrix does not converge, a 
more restricted covariance matrix can be considered in the  following  order 
until convergence is reached: variance components (VC), compound symmetJ.y 
(CS), first-order autoregressive (AR) and Toeplitz (TOEP). 
4. Subgroup analyses will be conducted to assess the consistency of tJ.e·a tm e nt effect 
across various subgroups described in Section 2.2.3. The FAS with missing values 
imputed using LOCF and observed case analysis will be used  for  the  subgroup 
analyses. 
a. Subgroup  analyses  will  be  conducted  using  the  same  model   and   analysis 
stJ·.a teg ies d escr ibed for the prima1y and first key seconda1yanalyses but fitted 
by catego1y of each of the subgroups. Subgroup variables that are used as fixed 
effects  in  the  model  will  be  removed  from  the  model  statement  for  the 
subgroup analysis. 
b. Subgroup analysis results will be presented using forest plots. 
 
2.6 
Analysis of the second and third key secondary 
objectives 
2.6.1 
Second and third key secondary endpoints 
The second and third key secondary endpoints are: 
1. q12 tJ·.e a tment status at Week 48 for subjects randomized to RTH258 6 mg. 
2. q12 treatment status at Week 48 within the subjects randomized to RTH258 6 mg, 
with no q8 need during the first q12 cycle (Week 16 and Week 20), i.e. for how many 
subject was a positive q12- status for the first q12 cycle predictive for the adequacy of 
q12 n-ea tment up to Week 48. 
 
2.6.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis will be tested for the second and third key seconda1y efficacy endpoints. 
Propo1tion of subjects with positive q12 tJ·.eat men t s tatu s at We ek 4 8 in th e RTH 258 tJ.e· atment 
ai m ov eral l an d w it h in th e s ub jec ts w ith no q 8 n-ea tment need dming the first q12 cycle (Week 
16 and Week 20) will be presented togetherwith two-sided 95% confidence inte1vals.. 
While for the analysis of the overall q12 propmtion, all subjects in the FAS will be considered, the 
analysis of the predictive value of 'no q8-need dming the first q12 cycle' is based on the subset of 
FAS subjects with no identified q8-needat Week 16 and Week 20. For this subset a valid Week 20 
disease activity is required while missing the Week 16 assessment is considered as no q8-need. 
Thuing the conduct of the study, confounding effects emerged requiring consideration to allow for 
a sensitive assessment of the q12 potential of RTH258. These include the following findings: 
• 
Eai·ly treatment / study discontinuation 
• 
Single missed visit 


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• 
Forbidden concomitant medications / procedures 
• 
Discrepancy between the disease activity assessment by masked investigator and the actual 
treatment received (specifically over-treatment, i.e. switch to q8 treatment without 
identified need. Remark: related under-treatment is not of concern as the analysis is based 
on the identified q8-need and not on the actual treatment). 
• 
Other treatment allocations /applications deviating from the concept of' disease activity'. 
Following the estimand concept of the study protocol that consequences of lack of efficacy and/or 
lack of safety need adequate reflection in the efficacy estimates, the proportions of patients with a 
positive q12 treatment status will be derived as follows requiiing duration of effect (as assessed by 
the q8-need) together with 'sufficientefficacy and safety': 
• 
For the ' durationof effect' requirement subjects will need to have the status of' q8-need = 
no' at all performed disease activity assessments relevant for the con esponding endpoint 
unless the status 'q8-need =yes' is confounded by reasons other than lack of efficacy and/or 
safety (see censoring details below) . 
• 
The requiI·ement regarding 's ufficient efficacy and safety' will be addressed by considering 
subjects - even without an explicit 'q8-need=yes' - as having a negative q12 status in case 
any of the following confounding factors is attributable to lack of efficacy and/or lack of 
safety of the study treatment (assessed based on a masked medical  review):  early 
treatment / study discontinuation, use of forbidden concomitant medications / procedures 
and/or other deviation from treatment schedule ( e.g. due to a missed visit/treatment) . The 
conesponding q8-need will be allocated to the next disease activity assessment visit 
(according to protocol) following the occmTence of such a confounding factor. 
In case the missing or confounded data regarding the q12-status are attributable to reasons other 
than lack of efficacy and/or safety the subject is censored within the q12-status analysis according 
to the following specifications: 
o Early treatment / study discontinuation: Censoring at the last valid disease activity 
assessment at or prior to the discontinuation. Single missed visit with a relevant 
disease activity assessment: Censoring at the last valid disease activity assessment 
prior to the missed visit. 
o Forbidden concomitant medications / procedures: Censoring at the last valid 
disease activity assessment prior to the con esponding application. 
o Discrepancy between disease activity assessment by masked investigator and the 
actual treatment received: Censoring at the visit of the discrepancy (assuming this 
disease activity assessment is valid) 
o Other treatment alloca.tions /applications deviating from the concept of 'disease 
activity' . Censoring: at the last valid disease activity assessment at or prior to the 
deviation. 
The estimate for the proportion of patients with a positive q12-status at Week 48 will be derived 
from Kaplan Meier time-to-event analyses for the event ' first q8-need' applying event allocations 
( in case of lack of efficacy and/or lack of safety) and censoring as described above. A 
corTesponding 95% CI will be derived from the LOGLOG transformation ( see SAS Proc Lifetest, 
CONFTYPE = LLOGLOG). 
The outcome of the Kaplan Meier analyses will be presented graphically by the estimated 
q12-probabilityover time, i.e. at each DAA-visit. 


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Remark: Subjects without any relevant valid disease activity assessment are considered censored at 
BL for the overall q12-proportion and at Week 20 for the analysis of the predictive value of the 
first q12 cycle. 
 
2.6.3 
Handling of missing values/censoring/discontinuations 
The details regarding handling of missing values and discontinuations including the timing of 
censoring within the time-to-event analyses for the event ‘first q8-need’ are specified above. 
 
2.6.4 
Supportive analyses 
1. ‘ Conservative ’ approach: 
a. For the overall q12-proportion at Week 48 the denominator is the number of FAS 
subjects in the RTH258 3 mg/6 mg groups, and the numerator is the 
corresponding number of subjects with no identified q8-need at Week 16, 20, 
28, 32, 40 and 44 (while missing the Week 20, 32 and/or Week 44 assessment 
leads to an allocation of q8-need as compared to a missing assessment at   
Week 16, 28 and 40 which is considered as no q8- need at this visit) and no 
episode of overtreatment, i.e. treatments after Week 8 are limited to Week 20, 32 
and 44 ( and Week 56, 68, 80 and 92 for the Week 96 analysis) . 
b. Correspondingly for the q12-proportion at Week 48 in subjects with ‘q8-need 
=no’ during the first q12 cycle (Week 16 and Week 20) the denominator is the 
number of FAS subjects in the RTH258 3 mg/6 mg groups with no identified q8- 
need at Week 16 and Week 20 (requiring a valid assessment at Week 20 while 
missing the Week 16 assessment is considered a no q8-need), and the numerator 
being the number of corresponding subjects with a positive q12 treatment status at 
Week 48 i.e. with additionally ‘ q8 need =no’ at Week 28, 32, 40 and 44 and no 
episode of overtreatment (see above). 
 
2. ‘LOCF’ approach: This approach follows in principle the same concepts as described 
above under the ‘conservative’ approach with the difference that the numerator is the 
number of subjects with no identified q8-need and no episode of overtreatment, while only 
the available disease activity assessments are considered, i.e. missing assessments are not 
translated into a q8-need. 


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3. ‘Efficacy only’ approach: This approach follows the concept of time-to-event analysis 
as described above for the primary analysis approach of the q12-status with the 
difference only requiring ‘sufficient efficacy’, i.e. an allocation of a negative q12- 
status - even without an explicit ‘q8-need=yes’ - in case any of the following confounding 
factors is attributable to lack of efficacy of the study treatment (assessed based on a masked 
medical review): early treatment / study discontinuation, use of forbidden concomitant 
medications / procedures and/or other deviation from treatment schedule ( e.g. due to a 
missed visit/treatment) In case of a corresponding safety reason the subject will  be 
censored at the last valid disease activity assessment at or prior to the corresponding event. . 
 
4. The analyses described above for the FAS will be repeated using PPS applying the 
same censoring and imputation concepts. 
 
5. Subgroup analyses will be conducted to assess the consistency of the q12 proportion 
across various subgroups described in Section 2.2.3. These analysis will be based on 
the Kaplan Meier time-to-event analyses for the event ‘ first q8-need’ as specified in 
section 2.6.2 using the FAS. Subgroup analysis results will be presented by the 
estimated q12-probability over time, i.e. at each DAA-visit and forest plots based on 
the 95% CI of the corresponding Week 48 probability. 
6. Supportive analyses to assess the relationship between the actual investigator  
decisions and the treatment guidance provided in the protocol will be performed using 
the following analyses: 
a. 
 For each DA assessment visit, the number and percentage of subjects who 
according to the treatment guidance have a q8-need (see below) will be 
described separately for those with and without q8 treatment-need as assessed 
by the investigator for both treatment arms. For RTH258 subjects, the same 
analysis will be repeated, but only up to and including the first q8 treatment 
need decision. 
 
Visit 
Q8 Treatment need as derived from protocol guidance: A 
subject is considered to have a q8 treatment need at a given 
visit if at least one of the corresponding criteria is fulfilled. 
Week 16 
Decrease in BCVA of ≥ 5 letters compared with Baseline 
Decrease in BCVA of ≥ 3 letters and CSFT increase ≥ 75 μm 
compared with Week 12 
Presence of IRF at Week 16 while absent at Week 12 
Increase in CSFTns of at least 10 microns from Week 12 to Week 
16 (worsening of IRF) 
Decrease in BCVA of ≥ 5 letters from Week 12 AND presence of 
at least one of the following fluids at Week 16: IRF, SRF, and 
subRPE 
Weeks 20, 28, 
Decrease in BCVA of ≥ 5 letters from Week 12 AND presence of 


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32, 40 and 44: 
at least one of the following fluids at the relevant visit: IRF, SRF, 
and subRPE 
Weeks  52, 56, 
64,  68,  76, 80, 
88 and 92 
Decrease in BCVA of ≥ 5 letters from Week 48 AND presence of 
at least one of the following fluids at the relevant visit: IRF, SRF, 
and subRPE 
 
b. For RTH258 subjects who were identified by the investigator as having their 
first q8-treatment need after Week 20, their status regarding the treatment 
guidance criteria at Week 16 and Week 20 will be presented. For this analysis, 
the number of subjects who met/did not meet the treatment guidance criteria at 
Week 16 and Week 20 will be presented in a cross tabulation. 
c. For subjects on q12 treatment at Week 48 and who lost 5 letters or more from 
Week 12 to Week 48, the treatment guidance status at each of the DA 
assessment visits will be presented. For this analysis, the number of subjects 
for each of the patterns of the treatment guidance status at Weeks 16, 20, 28, 
32, 40 and 44 will be presented in a summary table similar to the one shown 
below: 
 
Week 
16 
20 
28 
32 
40 44 
n (%) 
Patterns 
n 
n 
n 
n 
n 
n 
xx (xx.x%) 
p 
n 
n 
n 
n 
n 
xx(xx.x%) 
… 
… 
… 
… 
… 
… … 
.. 
Total 
N (100%) 
Treatment guidance status: n= negative status, p=positive status 
Assessment of the relevance of the disease activity assessment visits 8 weeks after the last 
q12 treatment in the RTH258A2302 study 
The RTH258A2302 study has disease activity assessment visits 8 weeks after the last q12 
treatment at Weeks 28, 40, 52, 64, 76 and 88. The relevance of these additional DA 
assessment visits will be investigated using the following analyses: 
a. Quantitative comparison within a treatment cycle and treatment group: 
For RTH258 within each q12 cycle following Week 20 (i.e. Week 20 to Week 32, week 32 to 
week 44, Week 44 to Week 56, Week 56 to Week 68, Week 68 to Week 80, and Week 80 to 
Week92), the number of new q8-treatment needs will be compared between those identified 8 
weeks after the last injection and those identified 12 weeks after the last injection. The 
following format will be used: 
q12-cycle 
Number of 
subjects at risk 
at the beginning 
of cycle 
Total new q8-need 
New Q8-need after 
8 weeks from last 
injection 
New Q8-need 
only after 12 
weeks from last 
injection 
Week 20 – Week 32 
N = number of 
patient on q12 at 
Week 20 
X (100*X/N %) 
k ( 100*k/X %) 
k ( 100*k/X %) 


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Week 32 – Week 44 
N = number of 
patient on q12 at 
Week 32 
.. 
.. 
.. 
.. 
.. 
Week 80 – Week 92 
N = number of 
patient on q12 at 
Week 80 
Total 
N = number of 
patient on q12 at 
Week 20 
b. Quantitative comparison of new q8 needs identified at 8 week-assessments  for  
RTH58 subjects versus 4 week-assessments for Eylea 
For each q12-cycle, the proportion of RTH258 subjects (relative to the subjects still on q12) 
with a newly identified q8-need 8 weeks after the last injection will be compared to those 
Eylea subjects where a new q8 treatment need is identified 4-weeks from the last injection. 
The following format will be used to present the result: 
RTH258 
Eylea 
RTH258 
Q12-cycle 
Disease 
activity 
assessment 
visit 
Number 
of 
subjects 
at risk 
New Q8-need 
after 8 weeks 
since last 
treatment 
Disease 
activity 
assessment 
visit 
Number of 
subjects at 
risk 
New Q8-need after 
8 weeks since last 
visit 
Week 20 – 
Week 32 
Week 28 
(last 
treatment 
Week 20) 
N = 
number 
of patient 
on q12 at 
Week 20 
K1r ( 100*k1r/N %) 
Week 28 
(last 
treatment 
Week 24) 
N=number 
of patients 
on ‘q12’ 
(=wo q8- 
need) at 
week 20 
K1e ( 100* ki/N %) 
Week 32 – 
Week 44 
Week 40 
(last 
treatment 
week 32) 
N = 
number 
of patient 
on q12 at 
Week 32 
K2r( 100*k2r/N %) 
Week 44 
(last 
treatment 
week 40) 
N=number 
of patients 
on ‘q12’ 
(=wo q8- 
need) at 
week 40 
K2e( 100*k2e/N %) 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
Week 80 – 
Week 88 
N = 
K7r( 100*k2r/N %) 
Week 92 
N=number 
K7e( 100*k7e/N %) 
Week 92 
(last 
number 
(last 
of patients 
treatment 
of patient 
treatment 
on ‘q12’ 
week 80) 
on q12 at 
week 88) 
(=wo q8- 
Week 80 
need) at 
week 80 
Where Kir  =number of RTH258 subjects with new Q8-need after 8 weeks since last treatment on the ith q12  
cycle; Kie = number of Eylea subjects with new Q8-need after 4 weeks since last treatment during the ith RTH258 
q12 cycle 
c. Qualitative comparison of the disease activity between treatments regarding subjects 
with a new q8 need identified at 8 week-assessments for RTH58 subjects versus 4 
week-assessments for Eylea 


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For the coho1t s Kir, Kie, i= l ,..,7 (see above), the number and percentage of subjects with a 
positive disease activity status DA assessed according to the treatment guidance criteri a given 
in Section 2.6.4 will be presented. 
 
2.7 
Analysis of additional secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The seconda1y endpoints are: 
• 
Change in BCVA from Baselineto each postbaseline visit 
• 
Average change in BCVA from Baseline over the pe1iod Week 84 through Week 96. 
For each subject this endpointis derived as the average of the changes from Baseline 
to Weeks 84, 88, 92 and 96 
• 
Average change in BCVA from Baseline over the period Week 4 to Week 48. For 
each subject this endpoint is derived as the average of the monthly changes from 
Baseline up to Weeks 48 
• 
Average change in BCVA from Baseline over the period Week 4 to Week 96. For 
each subject this endpoint is derived as the average of the monthly changes from 
Baselineup to Weeks 96 
• 
Average change in BCVA from Baseline over the period Week 12 to Week 48. For 
each subject this endpoint is derived as the average of the monthly changes from 
Baseline to Weeks 12 up to week 48 
• 
Average change in BCVA from Baseline over the period Week 12 to Week 96. For 
each subject this endpoint is derived as the average of the monthly changes from 
Baseline to Weeks 12 up to Week 96 
• 
Number and percentage of subjects with a gain in BCVA from Baseline to each 
postbaseline visit will be presentedfor the following criteria: 
o 2::15 - letter ga in 
o 2::10 - letter ga in 
o 2::5 -l etter gai n 
o Note: Subjectswith BCVA value of 84 letters or more at a postbaseline visit 
will be considered as having met the criteria for the con esponding endpoint. 
This is to account for a ceiling effect, e.g. for the' 2::1 5 -l e tter gain' endpoint, for 
those subjects with BCVA values at baseline >= 70 letters. 
• 
Number and percentage of subjects with BCVA of 73 letters or more at each 
postbaseline visit 
• 
Number and percentage of subjects with a loss in BCVA from Baseline to each 
postbaseline visit will be presentedfor the following criteria: 
o 2::1 5 - le tter loss 
o 2::10 - le tter loss 


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o 2':5- letter loss 
• 
ql2 treatment status at Week 96 (for subjects randomized to RTH258 6 mg only). This 
endpoint is analyzed using the KM method as given for the conesponding Week 48 
endpoint. 
• 
ql2 treatment status at Week 96 within the subjects with no q8 need dming the 1st ql2 
cycle (Week 16, Week 20) for subjects randomized to RTH258 6 mg only. This 
endpoint is analyzed using the same KM method as given for the c01Tesponding Week 
48 endpoint. 
• 
Number and percent of subjects with q8 treatment need at Week 16. 
• 
Change in CSFT from Baseline to each postbaseline visit 
• 
Average change in CSFT from Baseline over the period Week 36 through Week 48. 
• 
Average change in CSFT from Baselineover the period Week 84 through Week 96 
• 
Average change in CSFT from Baseline over the period Week 4 to Week 48 
• 
Average change in CSFT from Baseline over the period Week 4 to Week 96 
• 
Average change in CSFTns from Baseline over the period Week 12 through Week 48 
• 
Average change in CSFTns from Baseline over the period Week 12 through Week 96 
• 
Change in CSFTns from Baseline to each postbaseline visit 
• 
Change in area of CNV within the lesion (CNV lesion size) from Baseline to Weeks 
12, 48 and 96 
• 
Number and percent of subjects with presence of subretinalfluid (central subfield) at 
each postbaseline visit. 
• 
Number and percent of subjects with presence of intraretinal fluid (central subfield) at 
each postbaseline visit. 
• 
Number and percent of subjects with presence of sub RPE fluid (central subfield) at 
each postbaseline visit. 
• 
Number and percent of subjects with simultaneous absence of subretinal and 
intraretinal fluid (central subfield)at each postbaseline visit. 
• 
Number of subjects with presence of subretinal hemonhage (central subfield)at each 
assessment visit 
• 
Number of subjects with presence of intraretinal hemonhage (central subfield)at each 
assessment visit 
• 
 Number of subjects with simultaneous  absence  of  subretinal  and  intraretinal 
hemon hage (centralsubfield) at each assessmentvisit 
• 
Change in patient-repmted outcomes (VFQ-25) total and subscale scores from 
Baseline to Weeks 24, 48, 72 and 96. 


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2.7.3 
Statistical hypothesis, model, and method of analysis 
No formal statistical hypotheses will be tested for the additional secondary 
endpoints. 
The analysis of these additional efficacy endpoints will be based on the FAS with LOCF 
imputation for missing values. For the endpoints of q12 status at Week 96, 
incomplete/missing/confounded data will be handled using the same methods as specified for 
the KM analysis for the key secondary endpoints ‘q12 treatment status at Week 48 for 
subjects randomized to RTH258 6 mg’. Supportive analyses based on the PPS will be 
performed for endpoints related to BCVA and related to the q12 status. Additional analyses 
using the PPS will be conducted if the sensitivity analysis for the primary efficacy hypothesis 
suggests relevant differences between FAS and PPS results. In addition, these endpoints will 
also be summarized and presented descriptively. 
a. Continuous endpoints: 


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The continuous variables will be summarized using ANOVA models similar to the one 
specifiedfor the primary endpoint. Estimates of least square means for each treatment and for 
the treatment differences including 95% confidence inte1vals and p-values for the treatment 
differences will be presented. In addition, descriptive statistics based on the observed data 
only will be presented by treatment and visit. 
Note: 
• 
For CNV lesion size, lesion type will be added as a class variable and baseline lesion 
size categories ( see conesponding subgroup categories) instead of baseline BCVA 
category 
• 
For the ANOVA analysis of change in CSFT, baseline CSFT categories (<  400, 2': 400 
tm) will be used instead of baseline BCVA category as a class variable 
• 
For the ANOVA analysis of change in neurosensory retinal thickness, the baseline 
neurosensory retina l thickness categories (<250, 2:250 µm) will be used instead of 
BCVA catego1y as a class variable 
• 
Line plots (LSM± 1 SE) will be presented for all the 'by visit' analyses 
b. Categorical variables 
Proporiions and treatment differences in proporiions along with 95% confidence intervals and 
p-values will be presented using a logistic regression with baseline BCVA and age categories 
as fixed effects. 
Bar cha11s wi ll be produ ce d for all the categorical variables. 
For the endpoints related to fluid / hemorThage status 
o Shift tables comparing the status at Baseline to each/specified postbaseline visit will be 
presented 
o For the analysis of presence of fluid by visit, additional analyses  will be perfonned  by 
only including subjects where the con esponding fluid was present at Baseline. 
o For the analysis of the endpoint ' simultaneous absence of subretinal and intraretinal fluid ' , 
additional analysis will be performed by only including subjects where the conesponding 
fluids (at least one fluid type is present) were present at Baseline. 
o 95% exact confidence interv als for the risk differnces for the unstratfied analyses will be 
based on the Fan ington-Manning score statistic. 
 
2.7.4 
Handling of missing values/censoring/discontinuations 
Missing data will be handled using LOCF and observed case analysis (i.e. no imputation). For 
the endpoints of ql 2 status , incomplete I confounded data will be handled using the same 
method as specified for the KM analysis for the key secondary endpoint, ql2 treatment status 
at Week 48. 


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2.8 
Safety analyses 
There are no formal safety hypotheses in this study. The focus of the safety analysis will be a 
comprehensive descriptive assessment of all the safety endpoints including, shift tables and 
graphical presentation. 
Safety analyses described in this section will be conducted using the safety analysis set on a 
treatment-emergent basis. For treatment-emergent safety analyses, subjects will be analyzed 
according to the actual treatment they received. If a subject received both study treatments, 
then the subject will be analyzed based on the majority of treatments received up to and 
including Week 44. 
In addition to capturing specific safety assessments on the corresponding eCRF pages, 
findings from such assessments that are deemed to be clinically significant by the investigator 
will also be reported as adverse events. For the safety parameters of slit lamp, fundus exam 
and post injection assessments (except for post-injection IOP), data captured on the 
corresponding eCRF pages will be presented in listings while related clinically relevant 
findings will be part of the overall adverse event analysis. 
Except for imputation of partial dates for adverse events, no imputation will be done for 
missing values for all safety analyses. 
Ocular and non-ocular findings (e.g. adverse events) will be presented separately. All results 
related to ocular assessments will be presented using data from the study eye only except for 
adverse events where summaries will be presented separately for both the study and fellow 
eyes. 
The primary safety analyses will include all treatment-emergent data, including data collected 
after the subject discontinued study treatment and started alternative anti-VEGF treatment. A 
sensitivity analysis will be conducted in which, for subjects who discontinued treatment but 
continued in the study, with application of alternative anti-VEGF, their safety data are 
censored at the time the subject started alternative anti-VEGF treatment. That is, only safety 
data collected prior to receiving alternative anti-VEGF treatment will be used for these 
analyses. These sensitivity analyses will be specified in the respective endpoint analysis. 
For listings that present data from a subset of subjects who satisfy a certain criteria at one visit, 
data at all visits will be presented. 
 
2.8.1 
Extent of exposure 
Analysis of extent of exposure is discussed in Section 2.4.1. Based on the SAF, the overall 
number of active and sham injections up to and including Week 48 and Week 96 will be 
presented descriptively (both as continuous and categorical variable). For the categorical 
presentation, the observed frequencies will be presented as the categories. 
The number and percent of subjects who received wrong active treatment will also be 
presented using a shift table for ‘as randomized’ vs ‘as treated’ by visit. A listing will be 
provided for patients who received at least once a wrong treatment. 


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2.8.2 
Adverse events (AEs) 
The definition of Adverse Event (AE) in the study protocol is restricted to events occuning 
after the first treatment exposure, while for this study AEs were collected from the time of 
infonned consent. In this analysis plan, events that staiied prior to the subject receiving 
treatment are presented separately as pre-treatment adverse events. All AEs occuning from 
when a subject signs infmmed consent to when a subject exits the study will be accounted for 
in the reporting. Analysis and presentation of AEs occmTingdming the screening period will 
be separated from those occmTing during the investigational period where a comparative 
evaluation of treatment-emergent AEs is intended. A treatment-emergent AE is an event not 
present prior to exposure to investigational product or any pre-existing event that worsens 
following exposme to investigational product. The period for treatment-emergentAE analysis 
staiis from the first exposme to the investigational product until the subject exits the study. 
Summaries (counts and percentages) for specific AEs will be presented by system organ class 
and prefened te1m according to the MedDRA dictiona1y. Ocular and non-oculai· (sys temic) 
AEs will be presented separately. Ocular AEs will be presented by study and fellow eye 
separate ly. In addition to an overall presentation of AEs, repo1si will be generated for special 
classes of AEs such as serious AEs (SAE), AEs resulting in treatment and/or study 
discontinuation, most frequent AEs ( 2 % in any treatment group for each  PT),  
investigational product/administration procedure-related AEs and AEs by maximum severity. 
Subject listings for all AEs, serious AEs, AEs that lead to discontinuation from treatment  
and/or study, will be presented. 
A sensitivity analysis excluding AEs that sta1ied after a subject discontinued study treatment 
and sta1ted alternative anti-VEGF will be presented for the overall AE and SAE tables. 
Additionally, for subjects who discontinue treatment and sta1ted alternative anti-VEGF, a 
separate table (ocular for the study eye only, and non-ocular) by SOC and PT for AEs with 
onset date after start of alternative anti-VEGF will be presented. Additionally, for subjects 
who received both treatments, a separate table by system organ class and PT for AEs with 
onset date after the subject received the non-randomized treatment will be presented. 
For subjects who were randomized but never treated, a subject listing will be provided that 
include all AEs that occmTed after signing info1med consent until the subject 
discontinued/exited from the study using the All-randomized analysis set. 
A subject listing will be provided for AEs that occur after signing infmmed consent but prior 
to exposme to investigational product using the All-emolled analysis set. These listings will 
comprise all events occun ing during this period in any subject who consented to pa1ticipate in 
the study. 
The SOCs will be presented in alphabetical order. PrefeITed te1ms will be ordered within each 
SOC by decreasing incidence in the Brolucizumab 6 mg treatment aim. The MedDRA version 
used for repo1ting the study will be the latest available prior to the database lock and will be 
described in a footnote. 
Summa1y tables for in-text presentations will be summarizedby PT. 


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2.8.2.1 
Adverse events of special interest (AESls), arterial thromboembolic 
events (ATEs) and Venous Thromboembolic Events (VTEs) 
The AESls specified in the protocol are the following: 
• 
Endophthalmitis 
• 
Grade 3 aqueous flare/Grade 4 aqueous cells (see MOP for grading scale) 
• 
Grade 2 aqueous flare/Grade 3 aqueous cells that fails to decrease to 1 or less within 
30 days of the onset of the event (see MOP for grading scale) 
• 
2': 30 l etter dec rease in  B CV A  co m pared w i th B ase l ine visua l acuity 
• 
Sustained (> 15 minutes) loss of light perception due to elevated IOP 
• 
IOP > 30 mmH g at/past 60 minutes post-inject ion 
• 
Any elevat ion ofI OP requ iring surg ical in te1vention (e.g., paracentesis) 
• 
New retinal tear or detachment 
• 
New vitreous hemoIThage > 2+ severity that does not resolve within 14 days of the 
onset of the event (see MOP for grading scale) 
• 
New diagnosis of geographic atrophy 
AESis will be identified on the AE eCRF page and will be summarized using counts and 
percentages by system organ class and prefeITed te1m according to the MedDRA dictiona1y. A 
subject listing will also be presente d for AESis. 
A sensitiv ity analysis excluding AES is that sta1ted after a subject discontinued study 
treatment and staited alternative anti-VEGF will be presented for the AESI table. Additionally, 
for subjects who discontinue treatment, a separate table  for AESis  with onset date after start 
of alternative anti-VEGF will also be presented. 
ATEs and VTEs will be identified from the AE dataset by using  a  MedDRA SMQ  search and  
will be summarized using counts and percentages  by system organ  class and prefeITed  te1m 
accor d i n g to the Me dD RA d ictiona ry. A subject listing will also be presente d for ATEs and 
VTEs. The following SMQs will be used: 
Arterial Thromboembolic Events (ATEs) 
• 
Heart: Ischae mic heart disease (SMQ) [SMQ Code: 20000043] 
• 
CNS: Central nervous system haemoffhages and cerebrovasc ular condit ions (SMQ) 
[SMQ Code: 20000061] 
• 
Other locations: Embolic and thro mbot ic events, aiterial (SMQ) [SMQ Code: 
20000082] 
Venous Thromboembolic Events (VTEs) 
• 
Embolic and thrombotic events, venous (excl uding the ocular PTs: Retinal vein 
occlusion and Retinal vein thrombosis): Embolic and thromboticevents, venous (SMQ) 
[SMQ Code: 20000084] 


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Note: A ‘narrow’ PT search will be used for all SMQs. List of the PTs based on appropriate 
version of MedDRA will be provided during analysis. 
In addition to the ATE and VTE events, a separate table will be presented for the following 
AE risks: 
Intraocular Inflammation 
Preferred terms are presented in Table 9. 
In addition, the intraocular inflammation AEs will be evaluated in pre-specified sub-groups 
(Endophthalmitis, Anterior Uveitis, Posterior Uveitis, and Other). Preferred terms for these 
intraocular inflammation sub-groups are presented in Table 9. 
Retinal arterial occlusive events 
The following NMQ PT searches will be used: 
Angiogram Retina Abnormal, Arteriosclerotic Retinopathy, 'Macular Ischaemia, Retinal 
Aneurysm, Retinal Arteriovenous Malformation, Retinal Artery Embolism, Retinal Artery 
Occlusion, Retinal Artery Spasm, Retinal Artery Stenosis, Retinal Artery Thrombosis, Retinal 
Collateral Vessels, Retinal Infarction, Retinal Ischaemia, Retinal Perivascular Sheathing, 
Retinal Vascular Disorder, Retinal Vascular Occlusion, Retinal Vascular Thrombosis, Retinal 
Vasculitis, Retinogram Abnormal, Ocular Ischaemic Syndrome. 
 
2.8.2.2 
Other Safety Events of Interest 
In addition to AESIs, other prespecified safety events of interest occurring after the first 
treatment exposure to when a subject exits the study will also be accounted for in the 
reporting. These AEs are presented in the table below. The other safety events of interest will 
be summarized (counts and percentages) by system organ class and preferred term according 
to the MedDRA dictionary. Ocular and non-ocular (systemic) AEs will be presented 
separately. Ocular AEs will be presented by study and fellow eye separately. 


 
 
 
 
 
 
 
 
 
 
 
 
Safety Topic Of 
Interest 
SOC 
Data 
Domain 
Search Criteria Details 
MedDRA 
Code 
MedDRA Term 
MedDRA 
Level 
MedDRA 
Qualifier 
Venous 
thromboembolic 
events 
Vascular 
disorders 
MEDDRA 
For detailed description, please 
refer to the one in Embolic and 
thrombotic events (SMQ). In 
addition, PT Embolism was 
added. PT Vessel puncture site 
thrombosis was not considered 
for inclusion. 
90000105 
Venous thromboembolic 
events (excl. ocular) 
[LUCENTIS] (CMQ) 
NMQ1 
Arterial 
Thromboembolic 
Events 
Vascular 
disorders 
MEDDRA 
20000061 
Central nervous system 
haemorrhages and 
cerebrovascular conditions 
(SMQ) 
MQ2 
NARROW 
Arterial 
Thromboembolic 
Events 
Vascular 
disorders 
MEDDRA 
20000043 Ischaemic heart disease (SMQ) 
MQ1 
NARROW 
Arterial 
Thromboembolic 
Events 
Vascular 
disorders 
MEDDRA 
20000082 Embolic and thrombotic 
events, arterial (SMQ) 
MQ2 
Infectious 
Endophthalmitis 
Infections 
and 
infestations 
MEDDRA 
90000101 Infectious endophthalmitis 
[LUCENTIS] (CMQ) 
NMQ1 
NARROW 
Intraocular 
pressure 
increase 
Investigations MEDDRA 
90001788 Increased intraocular pressure 
[RETINA] (CMQ) 
NMQ1 
Traumatic 
Cataract 
Eye disorders 
MEDDRA 
90001787 Traumatic cataract [RETINA] 
(CMQ) 
NMQ1 
Retinal arterial 
occlusive events 
Eye disorders 
MEDDRA 
90004735 Retinal artery occlusive events 
[RTH258] (CMQ) 
NMQ1 
Systemic 
Immune 
MEDDRA 
20000214 Hypersensitivity (SMQ) 
MQ1 
NARROW 
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SAP V2.0 
RTH258A2302 
Safety Topic Of 
Interest 
SOC 
Data 
Domain 
Search Criteria Details 
MedDRA 
Code 
MedDRA Term 
MedDRA 
Level 
MedDRA 
Qualifier 
Hypersensitivity 
system 
disorders 
Non-ocular 
haemorrhage 
Vascular 
disorders 
MEDDRA 
90000106 Non-ocular haemorrhages 
[LUCENTIS] (CMQ) 
NMQ1 
Systemic 
hypertension 
Vascular 
disorders 
MEDDRA 
20000147 Hypertension (SMQ) 
MQ1 
NARROW 
Glaucoma 
Eye disorders 
MEDDRA 
90001789 Glaucoma without IOP 
[RETINA] (CMQ) 
NMQ1 
Vitreous 
haemorrhage 
Eye disorders 
MEDDRA 
10047655 Vitreous haemorrhage 
PT 
Retinal pigment 
epithelial tear 
Eye disorders 
MEDDRA 
10062971 Retinal pigment epithelial tear 
PT 
Retinal 
detachment and 
retinal tear 
Eye disorders 
MEDDRA 
Retinal detachment and retinal 
tear should be performed with 
and without LLT Serous 
detachment of macula 
90001746 
Retinal detachment and 
retinal tear [STANDARD] 
(NMQ) 
NMQ1 
NARROW 
Intraocular 
inflammation 
Eye disorders 
MEDDRA 
90004793 Intraocular inflammation 
[RTH258] (CMQ) 
NMQ1 
Diastolic Blood 
Pressure 
OTHER 
CT only (No Argus) 
Diastolic High: either >105 with 
an increase from baseline >20 
or >115 absolute 
Diastolic Low: either <50 with a 
decrease from baseline >20 or 
<40 absolute 
Intraocular 
pressure 
increase 
OTHER 
CT only (No Argus) 
IOP >/= 30 mmHg occurring 
at/past 60 minutes post- 
injection study visit 
IOP >/= 30 mmHg at any 
medical visit 
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SAP V2.0 
RTH258A2302 
Safety Topic Of 
Interest 
SOC 
Data 
Domain 
Search Criteria Details 
MedDRA 
Code 
MedDRA Term 
MedDRA 
Level 
MedDRA 
Qualifier 
IOP >/= 30 mmHg on at least 
two separate medical visits 
Systolic Blood 
Pressure 
OTHER 
CT only (No Argus) 
Systolic High: either >180 with 
an increase from baseline >30 
or >200 absolute 
Systolic Low: either <90 with a 
decrease from baseline >30 or 
<75 absolute 
Long term safety 
two years and 
beyond 
OTHER 
Safety data in patients treated 
> 2 years 
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2.8.3 
Deaths 
All deaths that occurred during the treatment period will be identified on the AE eCRF page 
and will be summarized using counts and percentages by system organ class and preferred 
term according to the MedDRA dictionary. A subject listing will be presented for all deaths 
including date and cause of death. 
 
2.8.4 
Laboratory data 
Clinical laboratory evaluations consist of hematology, blood chemistry and urinalysis. 
Hematology (Complete Blood Count) 
The following hematology parameters will be collected: hematocrit, hemoglobin, red blood 
cell (RBC) count, white blood cell (WBC) count with differential (absolute and percentage of 
neutrophils, lymphocytes, monocytes, eosinophils and basophils) and quantitative platelet 
count. 
Observed values and change from baseline values for each hematology parameter will be 
presented descriptively by visit and treatment group. In addition, descriptive summaries will 
be presented graphically using boxplots. For the parameters presented in Table 1, each value 
will be categorized as low, normal or high using the clinically notable ranges as given in the 
table. A shift table showing category of each parameter at baseline relative to each post- 
baseline visit, to the last assessment, to the most extreme increase and most extreme decrease 
will be presented by treatment group. 
The number and percent of subjects satisfying the liver event and/or liver laboratory trigger 
criteria shown in Table 2 will also be presented by visit. 


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A subject listing will be provided for all laboratory data collected. Additional listings for 
subjects with at least one value satisfying the clinically notable criteria given on Table 1 and 
the liver event or liver laboratory triggers given on Table 2 will be presented. 
Blood Chemistry 
The following blood chemistry parameters will be collected: blood urea nitrogen (BUN), 
serum creatinine, BUN/creatinine ratio, uric acid, cholesterol, triglycerides, albumin, total 
globulin, A/G ratio, total serum iron, total protein, serum electrolytes (sodium, potassium, 
bicarbonate, chloride, calcium, magnesium), phosphorus, glucose and the following liver 
function tests (LFT): serum aspartate transaminase [AST (SGOT)], serum alanine 
transaminase [ALT (SPGT)], alkaline phosphatase, gamma glutamyl transaminase (GGT), 
total bilirubin, direct bilirubin, indirect bilirubin and lactate dehydrogenase (LDH). 
The blood chemistry parameters will be analyzed and presented in the same manner as the 
hematology variables. 
Urinalysis 
The following urinalysis parameters will be collected: specific gravity, pH, color, protein, 
glucose, blood, ketones, bilirubin and microscopic examination (WBC, RBC, epithelial cells, 
bacteria, mucus, casts and crystals). 
Two of the urinalysis variables (specific gravity and reaction pH) are continuous variables and 
will be presented in the same manner as the hematology and chemistry variables. Specific 
gravity will be represented with 3 decimal places in relation to the normal range provided by 
the laboratory. The remaining variables are categorical and will be presented in shift tables as 
described above. 
 
Table 1 Clinically notable laboratory values 
 
Panel/Test 
Type 
Gender/ 
Age 
Conventio 
nal Unit 
Conventio 
nal Low 
Conventio 
nal High 
SI Unit 
SI 
Low 
SI 
High 
Non- 
numeric 
Chemistry/ 
Calcium 
alert 
All 
mg/dL 
6.1 
12.9 
mmol/L 
1.52 
3.22 
Chemistry/ 
Creatinine 
reference 
All 
mg/dL 
0.7 
1.4 
mmol/L 
62 
124 
Chemistry/ 
Glucose (non 
fasting) 
alert 
All 
mg/dL 
40 
450 
mmol/L 
2.22 
24.98 
Chemistry/ 
Potassium 
alert 
All 
mEq/L 
2.8 
6.3 
mmol/L 
2.8 
6.3 
Chemistry/ 
Sodium 
alert 
All 
mEq/L 
117 
160 
mmol/L 
117 
160 
HCG 
alert 
All 
Negative, 
inconclusi 
ve 
Hematology/ 
Hematocrit 
alert 
All 
% 
18 
60 
% 
18 
60 
Hematology/ 
Hemoglobin 
alert 
All 
g/dL 
8 
22 
g/L 
80 
220 


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Hematology/ 
Platelet 
alert 
All 
K/cu mm 
30 
900 
x10^9/L 
30 
900 
Hematology/ 
WBC 
alert 
All 
K/cu mm 
2 
25 
x10^9/L 
2 
25 
 
Table 2 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY 
TRIGGERS 
3 x ULN < ALT/AST 5 x ULN 
1.5 x ULN <TBL 2 x ULN 
LIVER EVENTS 
ALT or AST >5 × ULN 
ALP >2 × ULN (in the absence of known bone pathology) 
TBL >2 × ULN (in the absence of known Gilbert syndrome) 
Potential Hy’s Law cases (defined as ALT or AST >3 × ULN and 
TBL >2 × ULN [mainly conjugated fraction] without notable increase in 
ALP to >2× ULN) 
Any clinical event of jaundice (or equivalent term) 
ALT or AST >3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia* 
Any adverse event potentially indicative of a liver toxicity** 
* 
The Lab time of ALT/AST detection has to be within the start and end date of any of the AEs. 
The PTs for these events are: Malaise, Fatigue, Abdominal pain, Nausea, Vomiting, Drug 
reaction with eosinophilia and systemic symptoms, Eosinophilic cellulitis, Allergic 
eosinophilia. 
** 
These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage 
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
 
 
2.8.5 
Other safety data 
 
2.8.5.1 
Loss in BCVA 
Counts and percentages of subjects with a predefined decrease in BCVA from Baseline to 
each post-baseline visits, to the last assessment and maximum loss from Baseline to any post- 
baseline assessment visit will be presented for the following cut off points: ≥10-letter loss, 
≥15-letter loss ≥30-letter loss. 
A listing of all subjects with a ≥15-letter loss in BCVA from baseline to any post-baseline 
visit will be presented. For subjects who had ≥15-letter loss at any visit, BCVA values at all 
visits will be presented. 


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2.8.5.2 
Intraocular pressure 
Intraocular pressure (IOP) measurements will be recorded in mmHg and rounded to the 
nearest whole number. 
Descriptive summaries of pre-injection observed values and change from baseline IOP values 
will be presented at each study visit by treatment. Line plots of the mean change in IOP values 
with error bars representing ± standard error by visit and treatment will be presented. The x- 
axis will be study visit and the y-axis will be the change from Baseline value. 
A summary table with counts and percentages of subjects with observed IOP of >30 mmHg 
will be presented separately for pre- and post-injection by visit. In addition, counts and 
percentages of subjects with IOP >30 mmHg at the last assessment and at any postbaseline 
visit will be presented. 
A summary table with counts and percentages of subjects with observed IOP ≥21 mmHg in 3 
consecutive scheduled visits will also be presented. 
A subject listing of all IOP measurements will be pressed by visit. In addition, a 
listing of all subjects with observed IOP of more than 30 mmHg at any visit will be 
presented. For subjects with observed IOP >30 mmHg at any visit, IOP values at all 
visits will be presented. 
 
2.8.5.3 
Vital signs 
Descriptive summaries of observed values and change from baseline in each vital sign 
parameters at each study visit will be presented. 
A summary table with counts and percentage of subjects satisfying the criteria given in Table 
3 will be presented by visit, to the last assessment visit and to at least one visit. 
 
Table 3 Clinically notable changes in vital signs 
 
Variable 
Category 
Critical Values 
Systolic blood 
pressure (mmHg) 
High 
Either >180 with an increase from baseline >30 or >200 
absolute 
Low 
Either <90 with a decrease from baseline >30 or 
<75 absolute 
Diastolic blood 
pressure (mmHg) 
High 
Either >105 with an increase from baseline >20 or >115 
absolute 
Low 
Either <50 with a decrease from baseline > 20 or 
<40 absolute 
Pulse rate (bpm) 
High 
Either >120 with an increase from baseline of >25 or > 130 
absolute 
Low 
Either <50 with a decrease from baseline >30 or 
<40 absolute 
A line plot of mean change from baseline in the vital sign parameter by study visit and 
treatment with error bars representing ±1 standard error will be presented. The x-axis will be 
study visit and the y-axis will be the mean change from baseline value. 
A subject listing of all vital sign parameters will be presented. In addition, a separate listing 
for subjects satisfying at least one criterion in Table 3 will also be presented. 


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2.8.5.4 
Slit Lamp examination 
A slit-lamp examination will be performed to evaluate the anterior segment of the eye, 
including lid/lashes, conjunctiva, cornea, lens, iris, aqueous cells and aqueous flare. All data 
collected on the corresponding eCRF page will be presented in a subject listing. 
 
2.8.5.5 
Fundus examination 
Fundus examination will be performed to evaluate the health of the retina, macula, choroid, 
optic nerve, and vitreous. The retina will also be assessed for retinal detachment/tear and 
hemorrhage and the vitreous will be evaluated for hemorrhage and vitreal cells. All data 
collected on the fundus exam eCRF page will be presented in a subject listing. 
 
2.8.6 
Presence of geographic atrophy and fibrosis 
Shift tables comparing Baseline vs post baseline values for presence of geographic atrophy 
(central subfield) and fibrosis (central subfield) from color fundus photography, as graded by 
the central reading center, will be presented. In addition, shift tables comparing the Baseline 
value to the last assessment visit, and to any visit with a presence of geographic atrophy and 
fibrosis will also be presented. 
 
2.8.7 
Post-injection assessment 
Post-injection parameters to be evaluated in the study eye are gross assessment of vision, the 
status of the central retinal artery, presence of retinal detachment, new intraocular 
hemorrhage(s) and IOP. 
A summary table with counts and percentage of subjects with IOP increase of ≥10, ≥20 
mmHg from pre-injection to post-injection will be presented by visit, to the last visit, and to 
any visit. IOP assessment done at 30 (±15) minutes post-injection will be used for this 
analysis. Separate summaries will be presented for active and sham injections. 
The difference in the pre-and post-injection IOP values will be presented descriptively by 
treatment and visit. Separate summaries will be presented for active and sham injections. 
All post-injection assessment data collected on the eCRF will be presented in subject listings. 
In addition, a separate listing for subjects with post-injection IOP increase of ≥10 mmHg from 
pre-injection IOP will also be presented. 
 
2.8.8 
Presence of anti-drug antibody (ADA) 
Blood samples to test for serum anti-drug antibody (ADA) will be collected following pre- 
determined sample collection time points. Number and percent of subjects according to their 
ADA status (ADA negative, ADA positive without boost, induced, boosted) will be presented 
by treatment and by intraocular inflammation AE status. In addition, ADA titer pattern and 
shift table showing ADA titer at baseline relative to each post-baseline assessment visit, 
relative to the last assessment visit, and to any visit with most extreme increase in ADA titer 
will be presented by treatment. Subject listing of all ADA titer values will be presented for 
subjects with and without intraocular inflammation. 


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SAP V2.O 
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Patient profile plots (including both efficacy and safety endpoints) will be presented for 
subjects with new positive ADA status after Baseline and/or two-fold increase in their titer. 
The visits where a positive ADA result is confilmed will be shown on the subject profile plot. 
ADA data up to Week 36 will be analyzed for the Week 48 primaiy analysis. The final 
analysis will include all ADA data. 
 
2.9 
Pharmacokinetic endpoints 
A subject listing will be provided for all subjects that have detectable sernm concentration 
value at any of the PK assessment visits. 
PK data up to Week 36 will be analyzed for the Week 48 primary analysis. The final analysis 
will include all PK data. 
 
2.10 
Subject-reported outcome 
2.10 .1 
Visual funct ion que stionn aire (VFQ-25) 
Each subscale score has a range of Oto 100 inclusive and will be calculated from the 
re-scaled raw data as described in Table 4. A missing response will not be re-scaled 
(except for the response to question 15c, see below, which will be re-set to O if the 
response to question 15b is 1). 
The answers to questions will be re-scaled as follows to calculate the total and 
subscale scores. 
Table 4 
Rescaling of VFQ-25 questions 
Answer to 
question 
Rescaling for 
questions 1, 3, 4 
and 15c 
Rescaling for 
question 2 
Rescaling for 
questions 5 - 14, 
16 and 16a 
Rescaling for - 
questions 17 - 25 
1 
100 
100 
100 
0 
2 
75 
80 
75 
25 
3 
50 
60 
50 
50 
4 
25 
40 
25 
75 
5 
0 
20 
0 
100 
6 
NA 
0 
NA 
N/A 
• 
Note that the answer to question15c will subsequently be adjusted based on the 
answer to question 15b. 
• 
If the answer to 15b is 1 then the answer to 15c will be re-set to O. 
• 
If th e an s wer to 15b is 2 or 3 then the answer to 15c will be re-set to missing 
The general health rating is the re-scaled answer to question1. 
Response choice "6" indicates that the person does not perform the activity because 
of non-vision related problems. If this choice is selected, the item is coded as 
"missing." 


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Subscales will be calculated where at least one of the (re-scaled) questions 
contributing to that subscale is non-missing, and otherwise set to missing. The 
scales and corresponding questions are shown in Table 5. 
 
Table 5 
Questions contributing to VFQ subscales 
 
Subscale 
Questions 
General vision 
2 
Ocular pain 
4 and 19 
Near activities 
5, 6 and 7 
Distance activities 
8, 9 and 14 
Social functioning 
11 and 13 
Mental health 
3, 21, 22 and 25 
Role difficulties 
17 and 18 
Dependency 
20, 23 and 24 
Driving 
15c, 16 and 16a 
Color vision 
12 
Peripheral vision 
10 
The composite score is the average of the 11 subscales shown in Table 5. It will be set to 
missing if at least six of the subscales are missing. 
Descriptive summary statistics for observed values and change from baseline to post baseline 
VFQ assessment visits will be presented using the full analysis set for the composite and 
subscale scores. Mean changes from baseline to each post baseline VFQ assessments visits 
will be compared between the study treatment group and the control group, based on adjusted 
means generated by an appropriate ANCOVA Model. Additionally, descriptive statistics will 
also be presented for the general health score. All analysis will be done on the rescaled values. 
The change from baseline will derived based the changes in the individual items scores and 
then averaged for the subscale score. 
The VFQ-25 composite score and subscale scores will also be presented in a subject listing. 
 
2.11 
Interim analysis 
No interim analysis prior to the primary analysis at Week 48 is planned for this study. 
 
 
3 
Sample size calculation 
A sample size of 297 subjects per treatment arm is sufficient to demonstrate non-inferiority 
(margin = 4 letters) of RTH258 versus Ranibizumab with respect to the BCVA change from 
Baseline to Week 48 at a two-sided alpha level of 0.05 with a power of approximately 90% 
assuming equal efficacy and a common standard deviation of 15 letters. A power of at least 
90% can be expected for the key secondary endpoint assuming that averaging over the 4 time 
points will not lead to an increase in the standard deviation. 
To account for a drop-out rate of 10%, a total of 330 subjects will be randomized per 
treatment arm. 


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• • 
• 
4 
Change to protocol specified analyses 
The following additional seconda1y- 
endpoints that were not specified in the 
protocol were added to this statistica 
• Average change in CSFT from Baseline over the period Week 36 through Week 48 
• Presence of geographic atrophy- 
from color fundus photography 
• Number and percentage of subjects with BCVA of 73 letters or more at each 
postbaseline visit 
• 
 
• Average change in CSFT from Baseline over the period Week 4 to Week 48/96 
• Average change in CSFT from Baseline over the period Week 36 through Week 48/ 
over the period Week 84 through Week 96 
The followingsubgroupsof interest were added: 
• Baseline fluid status (IRF, SRF, sub-RPE) 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
AE date imputation 
 
5.1.1.1 
Adverse event end date imputation 
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the ( 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
If the imputed AE end date is less than the existing AE sta1tdate then use AE strut date as AE 
end date. 
5.1.1.2 
Adverse event start date imputation 
The following table explains the notation used in the logic matrix. Please note that completely 
missing stait dates will not be imputed. 
The following table explains the notation used in the logic matrix. 


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Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
 
 
The following matrix explains the logic behind the imputation. 
 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
YYYY < TRTY 
( 2.aError! Reference 
source not found. ) 
Before 
Treatment 
Start 
( 2.bError! Reference 
source not found. ) 
Before 
Treatment 
Start 
( 2.bError! Reference 
source not found. ) 
Before 
Treatment 
Start 
( 
Error! 
Reference 
source not found. ) 
Before 
Treatment 
Start 
YYYY = TRTY 
(4.a ) 
Uncertain 
(4.b ) 
Before 
Treatment Start 
(4.c) 
Uncertain 
(4.c ) 
After Treatment 
Start 
YYYY > TRTY 
(3.a ) 
After Treatment 
Start 
(3.b ) 
After Treatment 
Start 
(3.b ) 
After Treatment 
Start 
(3.b ) 
After Treatment 
Start 
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment 
start date then AE start reference date = min (informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
Impute AE start date - 
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set  
to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 


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b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date. 
 
5.1.2 
Concomitant medication date imputation 
 
5.1.2.1 
Concomitant medication (CM) end date imputation 
1. 
If the CM end date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM end 
date is set to NULL. 
2. 
Else, if the CM end date month is missing, the imputed end date should be set to the 
earliest of the (treatment follow up period date, 31DECYYYY, and date of death). 
3. 
If the CM end date day is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, last day of the month, date of death). 
If the imputed CM end date is less than the existing CM start date, use the CM start date as the 
imputed CM end date. 
 
5.1.2.2 
Concomitant medication start date imputation 
In order to classify a medication as prior and prior/concomitant, it may be necessary 
to impute the start date. 
Completely missing start dates will be set to one day prior to treatment start date. As  
a conservative approach, such treatments will be classified as prior and concomitant 
(and summarized for each output). 
Concomitant treatments with partial start dates will have the date or dates imputed. 
The following table explains the notation used in the logic matrix 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 


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MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
YYYY < TRTY 
( a ) 
Before Treatment 
Start 
( b ) 
Before Treatment 
Start 
( b ) 
Before Treatment 
Start 
( b ) 
Before Treatment 
Start 
YYYY = TRTY 
( a ) 
Uncertain 
( b ) 
Before Treatment 
Start 
( a ) 
Uncertain 
( c ) 
After 
Start 
Treatment 
YYYY > TRTY 
( a ) 
After 
Start 
Treatment 
( b ) 
After 
Start 
Treatment 
( b ) 
After 
Start 
Treatment 
( b ) 
After 
Start 
Treatment 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid- 
month point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior to treatment start date. 
b. Else if the CM month is less than the treatment start date month, the imputed CM start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date. 
 
5.1.2.3 
Medical history date of diagnosis imputation 
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date. 


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• 
IfDIAG year < treatment sta1t date year and DIAG month is missing, the imputed DIAG 
date is set to the mid-year point (0 l JULYYYY) 
• 
else if DIAG month is not missing, the imputed DIAG date is set to the mid-month 
point (15MONYYYY) 
• 
If DIAG year = treatment sta1t date year 
• 
and (DIAG month is missing OR DIAG month is equal to treatment sta1t month), the 
imputed DIAG date is set to one day before treatment sta1t date 
• 
else if DIAG month < treatment sta1t month , the imputed DIAG date is set to the mid- 
month point (15MON YYYY) 
• 
else if DIAG month > treatment start month => data enor 
IfDIAG year > treatment start date year => data e1rnr 
5.2 
Statistical models 
5.2.1 
Primary and first key secondary analysis 
Analysis of Variance (ANOVA) 
The following ANOVA model will be used for the primary and first key seconda1y efficacy 
endpoints: 
<change from Baseline in BCVA at Week 48> <average change from Baseline in BCVA from 
Week 36 to Week 48> = intercept + treatment + Baseline BCVA categ01y + age category+ 
eITOL 
The followingpseudo SAS code will be used to perform the ANOVA analyses: 
PROC MIXED DATA=<Dataset>order=Internal; 
CLASS <Treatment> <BCVA CAT> <AGE CAT> ; 
MODEL <Chg_VA> = <Treatment> <BCVA CAT> <AGE CAT>/ SOLUTION 
LSMEANS Treatment> / DIFF CL ALPHA = 0.05 OM; 
ODS OUTPUT LSMEANS=outLsm DIFFS=Diffs; 
RUN; 
Where 
<Chg_VA> = primary /first key secondary efficacy endpoint 
<BCVA CAT> = baseline BCVA categ01y 
<AGE CAT> = age categ01y 
<Treatment>= randomized treatment assignment 
The ternis in the brackets are to be adjusted according to the real data set and variable names. 
For the above analysis, the data stiucture is one record per FAS subject. Data will include all 
subjects in the FAS. 
Mixed Model Repeated Measures (MMRM) 


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The following MMRM model will be used for the supportive analysis of the primary and first 
key secondary efficacy variables: 
<change from Baseline in BCVA at Week 48> <average change from Baseline in BCVA from 
Week 36 to Week 48> = intercept + treatment + Baseline BCVA category + age category + 
visit + treatment*visit + error. 
The following pseudo SAS code will be used to perform the MMRM analyses: 
 
PROC MIXED DATA=<Dataset> order=Internal; 
CLASS USUBJID <Treatment> <VISIT> <BCVA CAT> <AGE CAT>; 
MODEL <Chg_VA> = <Treatment> <VISIT> <BCVA CAT> <AGE CAT> 
<VISIT>*<Treatment> 
/ solution DDFM=KENWARDROGER ALPHA=0.05; 
REPEATED <VISIT>/type=UN subject=USUBJID; 
LSMEANS <VISIT>*<Treatment> / DIFF CL ALPHA = 0.05 om; 
ODS OUTPUT LSMEANS=outLsm DIFFS=Diffs; 
RUN; 
 
where 
<Chg_VA> = primary/first key secondary efficacy endpoint 
<BCVA CAT> = baseline BCVA category 
<AGE CAT> = age category 
<Treatment> = randomized treatment assignment 
…<VISIT> = ordered visit number 
Note: 
a. For the above MMRM analysis, the data structure is one record per FAS subject per 
scheduled visit. The data will include all subjects and have records for all scheduled 
visits, regardless of whether the assessment was missed or not at a given visit. Missing 
values will NOT be imputed using LOCF. Instead, the value will be passed to the 
model as missing. 
 
5.2.2 
Key secondary analysis 
The following pseudo SAS code will be used for the logistic regression analysis 
PROC LOGISTIC DATA= data; 
CLASS <Treatment> (REF = "C" ) <BCVA CAT> <AGE CAT> /PARAM=REF; 
MODEL <RESP> (EVENT = '1') = <Treatment> <AGE CAT> <BCVA CAT> 
/ALPHA = 0.05; 
ODS OUTPUT PARAMETERESTIMATES=parameters; 


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RUN; 
where, 
 
 
 
 
 
Note: 
ODS OUTPUT ODDSRATIOS= OR; 
 
 
 
<RESP> = binomial endpoint. 
<BCVA CAT>= baseline BCVA category 
<AGE CAT> = age category 
<Treatment> = randomized treatment assignment 
o For the above analyses, the data structure is one record per subject and visit. 
o The least square mean estimates obtained from the above model are for the log-odds ratios. 
The estimated difference in proportions and the corresponding 95% confidence intervals 
will be obtained by applying the delta method. The pseudo SAS code to derive the 
treatment difference and 95% CI from the least square mean output of the fitted model  
will be provided in the programming specification document. 


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5.3 
Rule of exclusion criteria of analysis sets 
Protocol deviations and analysis restrictions that are considered as major and will lead to 
exclusion of subjects from an analysis set are documented in Deviations and Evaluability Plan 
(DEP) document. 
Table 6 shows subject classification conditions that will lead to exclusion from one or more 
analysis sets. 
 
Table 6 
Subject Classification 
Analysis Set Criteria 
that cause subjects to be 
excluded 
RAN 
Not randomized 
FAS 
Not in the RAN 
Did not receive at least one study treatment 
SAF 
Did not receive at least one study treatment 
 
 
The following table specify all relevant analysis restrictioncriteria with their impact on the 
different analysis sets. 
 
In case a subject has multiple PDs/ARs with impact on his/her evaluability the following mies 
are applied: 
 
• 
A subject is excluded from an analysis set if at least one PD or AR with this 
consequence was identified. This rnle is built on the concept of the medical assessment 
of the 'reason' which considers the reason of an earlier event to potentially also be the 
reason for following PDs or ARs. 
 
• 
In case of multiple censoring time points censoring will be perfmmed at the earliest. 


 
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Table 7 
Analysis Restrictions 
 
Analysis 
restriction 
(AR) 
Description of AR code 
Excl. 
from 
SAF 
Y/N 
Excl. 
from 
FAS 
Y/N 
Excl. 
from 
PPS 
Y/N 
PPS: 
Censoring of 
BCVA: 0, 1, 
2, 3, 4, 5* 
PPS: 
Censoring of 
DAA: 0, 
1, 2, 3, 4, 5* 
Reason 
0=other 
1=LoE 
2=LoS 
Comment 
AR_EST_01 
Early study termination due to lack 
of efficacy 
N 
N 
N 
0 
0 
1 
Early termination reason = lack of efficacy 
AR_EST_02 
Early study termination due to lack 
of safety* 
*- per definition provided in section 
6.3.b 
N 
N 
N 
0 
0 
2 
Early termination reason= AE; AE reviewed 
by clinical regarding link to treatment (lack 
of efficacy / safety)/ Censoring for the KM- 
analysis ‘efficacy only’ 
AR_EST_03 
Early study termination due to 
reasons other than lack of efficacy 
/ safety 
N 
N 
Y/N 
0 
0 
0 
Y: if before Week 36 
N: otherwise 
AR_ETD_01 
Early treatment discontinuation 
due to lack of efficacy 
N 
N 
N 
0 
0 
1 
Early discontinuation reason = lack of 
efficacy 
AR_ETD_02 
Early treatment discontinuation 
due to lack of safety* 
*- per definition provided in section 
6.3.b 
N 
N 
N 
0 
0 
2 
Early discontinuation reason= AE; AE 
reviewed by clinical regarding link to 
treatment (lack of efficacy / safety)/ 
Censoring for the KM-analysis ‘efficacy only’ 
AR_ETD_03 
Early treatment discontinuation 
due to reasons other than lack of 
efficacy / safety 
N 
N 
Y/N 
4 /5 ( case by 
case ) 
0 
0 
Y: if no valid BCVA value between Week 36 
and 48 (case by case assessment including 
q8-status) ) 
N: if at least Week 36 can be considered 
valid= under regular treatment’ 
Remark: there are no DAA after treatment 
discontinuation, therefore no censoring 
related to DAA 
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Analysis 
restriction 
(AR) 
Description of AR code 
Excl. 
from 
SAF 
Y/N 
Excl. 
from 
FAS 
Y/N 
Excl. 
from 
PPS 
Y/N 
PPS: 
Censoring of 
BCVA: 0, 1, 
2, 3, 4, 5* 
PPS: 
Censoring of 
DAA: 0, 
1, 2, 3, 4, 5* 
Reason 
0=other 
1=LoE 
2=LoS 
Comment 
AR_TRT_03 
Missed active treatment during 
loading phase for reasons other 
than lack of efficacy or related 
safety event or PD (=TRT03) 
N 
N 
Y/N 
0 
0 (FAS:3) 
0 
Exclude from PPS=NO, If only W4 is missing 
Exclude from PPS=YES, if otherwise 
AR_TRT_03_S Missed active treatment during 
loading phase for related safety 
event 
N 
N 
N 
0 
0 
2 
AR_TRT_05 
Missed active treatment after 
loading for reasons other than lack 
of efficacy or related safety event 
or PD (=TRT05) 
N 
N 
Y/N 
3 
3 
0 
Exclude from PPS =YES, if any missed active 
treatment between W16 and W32 
Exclude from PPS =NO, if otherwise 
AR_TRT_05_S Missed active treatment after 
loading phase for related safety 
event 
N 
N 
N 
0 
0 
2 
AR_ MD_01 
No valid BCVA assessments 
between Week 36 to 48 due to lack 
of efficacy 
N 
N 
N 
0 
0 
1 
This AR should be allocated to the Week 36. 
AR_ MD_02 
No valid BCVA assessments 
between Week 36 to 48 due to lack 
of safety 
N 
N 
N 
0 
0 
2 
This AR should be allocated to the Week 36. 
AR_ MD_03 
No valid BCVA assessments 
between Week 36 to 48 due to 
reasons other than lack of efficacy 
or safety 
N 
N 
Y 
0 
0 (FAS: 2 ) 
0 
This AR should be allocated to the Week 36. 
For Analysis Sets in above table: Y = excluded from analysis set; N = not excluded from analysis set 
For Reason in above table: LoE = lack of efficacy; LoS = lack of safety 
*Censoring: 0=no censoring, 1=exclusion of value at PD visit, 2=censoring at visit preceding PD visit (exclusion of values from all visits starting from PD visit), 
3=censoring at PD-visit (exclusion of values from all visits following the PD visit), 4=censoring at the second visit following the PD-visit (exclusion of values from all 
visits starting from the third visit after the PD visit), 5= censoring at the first visit following the PD-visit (exclusion of values from all visits starting from the second 
visit after the PD visit,; censoring is applied within subjects qualifying for PPS 
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LoE – lack of efficacy; LoS – lack of safety 
 
Table below presents the prohibited medication list. 
 
Table 8 
Prohibited Medications 
 
Medication 
Examples 
(list may not be all inclusive) 
Specification 
Study eye: Intra- or 
periocular corticosteroids Triamcinolone Dexamethasone 
Within 6 months of 
Baseline or at any time 
during the study 
Study eye: Anti-VEGF 
treatments 
Ranibizumab (Lucentis) 
Aflibercept (Eylea) Pegaptanib 
(Macugen) Bevacizumab 
(Avastin) 
Any time 
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Non study eye: Treatment 
with unapproved or 
investigational treatment 
At any time during the 
study 
Non study eye: Treatment 
with aflibercept, 
bevacizumab, pegaptanib 
or ranibizumab 
Ranibizumab (Lucentis) 
Aflibercept (Eylea) Pegaptanib 
(Macugen) Bevacizumab 
(Avastin) 
Within 4 weeks of 
Baseline for aflibercept, 
bevacizumab, pegaptanib 
Within 2 weeks of 
Baseline for ranibizumab 
Systemic: Chronic use 
(≥ 30 consecutive days) of 
systemic corticosteroids 
Dexamethasone 
Hydrocortisone Prednisolone 
Within 90 days of 
Baseline or any time 
during the study 
exceptions: low stable 
doses (defined as ≤ 10 mg
prednisolone or 
equivalent for 90 days or 
Anti-VEGF therapy 
systemically 
Bevacizumab (Avastin) 
Within 90 days of 
Baseline or at any time 
during the study 
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Within 30 days of 
Baseline or within 5 half- 
Investigational drug or 
lives of the 
biologic 
investigational product 
(whichever is longer) or 
any time during the study 
 
 
Table 9 
Preferred Terms for Intraocular Inflammation 
 
List of PTs: Other 
List of PTs: Anterior Uveitis 
List of PTs: Posterior Uveitis 
List of PTs: Endophthalmitis 
Optic neuritis 
Anterior chamber cell 
Vitritis 
Pseudoendophthalmitis 
Cogan's syndrome 
Anterior chamber fibrin 
Ocular vasculitis 
Non-infectious endophthalmitis 
Idiopathic orbital inflammation 
Ciliary hyperaemia 
Vitreous haze 
Endophthalmitis 
Toxic anterior segment syndrome 
Aqueous fibrin 
Retinitis 
Panophthalmitis 
Uveitis-glaucoma-hyphaema syndrome 
Anterior chamber flare 
Retinal vasculitis 
Acute zonal occult outer retinopathy 
Anterior chamber inflammation 
Noninfective retinitis 
Macular oedema 
Iritis 
Noninfective chorioretinitis 
Oculomucocutaneous syndrome 
Iridocyclitis 
Chorioretinitis 
Periorbital oedema 
Cyclitis 
Choroiditis 
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List of PTs: Other 
List of PTs: Anterior Uveitis 
List of PTs: Posterior Uveitis 
List of PTs: Endophthalmitis 
Ocular sarcoidosis 
Cholesterolosis bulbi 
Uveitis 
Effe 
Birdshot chorioretinopathy 
tive 
Cyclitic membrane 
Tubulointerstitial nephritis and uveitis syndrome 
Ophthalmia neonatorum 
Vogt-Koyanagi-Harada syndrome 
Ocular pemphigoid 
Eye inflammation 
Ocular hyperaemia 
Retinal oedema 
Oculorespiratory syndrome 
Autoimmune uveitis 
Chorioretinopathy 
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Date/Time 
(mm/dd/yyyy GMT): 
Signed by: 
Justification: 
05/19/2017 19:31:48 
Management of Affected Area Approval 
05/19/2017 19:51:53 
Biostats 
 
 
 
 
 
 
 
 
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