Conditions: Exudative Age-related Macular Degeneration
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
This is a multi-center, open label, extension study of NCT04200248 assessing the efficacy and safety of additional intravitreal injections of RBM-007 in subjects with wet age-related macular degeneration.

Detailed description:

Arms:
arm 1: intravitreal injection

Interventions: intervention 1: RBM-007
Intervention descriptions: intervention 1: Intravitreal injection

Protocol document:
Prot_000.pdf: 
Cli nical pr ot oc ol:  
Title:  A M ulti - Ce nter, O pe n La bel, T O F U E xte nsi o n St u d y Assessi n g t he Efficac y a n d Saf et y of 
A d diti o nal I ntr a vitreal I njecti o ns of R B M - 0 0 7 i n S u bjects wit h Wet A ge-relate d Mac ul ar 
De ge nerati o n – R A M E N St u d y 
N C T 0 4 6 4 0 2 7 2 
Date: 0 1 Oct o ber 2 0 2 1 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
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R B M
R B M -0 0 7
0 0 7  
Pr ot oc ol
Pr ot oc ol  R B M 0 0 7
R B M 0 0 7 -0 0 3
0 0 3  
 
TI T L E: A M ulti - C e nt er, O p e n L a b el, T O F U E xt e n si o n St u d y A s s e s si n g t h e Effic ac y 
a n d S af et y of A d diti o n al I ntr a vitr e al I nj ecti o n s of  R B M
B M -0 0 7
0 0 7  i n S u bj ect s w it h Wet 
A g e -r el at e d M ac ul ar D
ac ul ar D e g e n er ati o
g e n er ati o n  – RA M E N  St u d y  
 
 
S P O N S O R : 
RI B O MI C U S A I nc.  
2 1 2 0 U ni versit y Ave.  
Ber kele y, C A 9 4 7 0 4 
S T U D Y D R U G:  
2. 0 m g ( 1 0 0 µ L of 2 0 m g/ m L) R B M - 0 0 7 
i njecta ble s ol uti o n 
 
 
 
I h a v e r e a d t h e pr ot oc ol a n d a gr e e t o c o n d uct t h e st u d y a s o utli n e d a n d i n acc or d a nc e wit h 
t h e et hic al pri nci pl e s i n t h e D ecl ar ati o n of H el si n ki, I C H G C P s, a n d a p plic a bl e l oc al 
r e g ul ati o n s. I will n ot i niti at e t h e st u d y u ntil I h a v e o bt ai n e d writt e n a p pr o v al b y t h e 
a p pr o pri at e I n stit uti o n al R e vi e w B o ar d (I R B) or Et hic s C o m mitt e e ( E C) a n d h a v e c o m pli e d 
wit h all fi n a nci al a n d a d mi ni str ati v e r e q uir e m e nt s of t h e g o v er ni n g b o d y of t h e cli nic al 
i n stit uti o n a n d RI B O MI C a s t h e S p o n s or. I will o bt ai n writt e n i nf or m e d c o n s e nt fr o m e ac h 
st u d y s u bj ect pri or t o p erf or mi n g a n y st u d y -s p ecific pr oc e d ur e s.  
I u n d er st a n d t h at m y el ectr o nic si g n at ur e o n a n el ectr o nic c a s e r e p ort f or m i n dic at e s t h at t h e 
d at a t h er ei n h a s b e e n r e vi e w e d a n d acc e pt e d b y m e a s t h e I n v e sti g at or. I a gr e e t o m ai nt ai n 
t h e c o nfi d e nti alit y of all i nf or m ati o n r ec ei v e d or d e v el o p e d i n c o n n ecti o n wit h t hi s pr ot oc ol.  
 
 
 
I N V E S TI GA T O R:  
Si g n at ur e/ D at e:    
 /   
 
 
N a m e:  
  
_ _ _ _ _ _ _  
( T y p e d or Pri nt e d) 
 
A d dr e s s:  
  
_ _ _ _ _ _ _  
 
P h o n e:  
  
_  


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A P P R O V E R S  
C o m p a n y/ S p o n s or si g n at or y  
  
 
  
. 
 
 
 
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 6 A 7 D A A C E- B 9 7 F- 4 5 F 6- A D 6 D- A 4 E 4 8 8 3 F 6 4 4 7




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2  S Y N O P SI S  
 
N a me of S p o ns or/ C o m p a n y: 
      
RI B O MI C U S A I nc.  
2 1 2 0 U ni versit y Ave.  
Ber kele y, C A 9 4 7 0 4  
 
N a me of I n vesti g ati o n al Pr o d uct:  R B M - 0 0 7 i njecta ble s ol uti o n 
N a me of Acti ve I n gre die nt:  R B M -0 0 7  
Title of St u d y:  A M ulti - Ce nter, O pe n La bel, T O F U E xte nsi o n St u d y A ssessi n g t he Efficac y a n d 
Safet y of A d diti o nal I ntra vitreal I njecti o ns of  R B M - 0 0 7 i n S u bjects wit h Wet A ge- relate d M ac ular  
D ege nerati o n  – R A M E N  St u d y 
St u d y Peri o d:  A p pr o xi matel y 1 2 m o nt hs   
Esti mate d date first  s u bject e nr olle d: Oct o ber 2 0 2 0 
Esti mate d date last s u bject c o m plete d: N o ve m ber 2 0 2 1 
P h ase of De vel o p me nt:  
P hase II  
Pri m ar y O bjecti ve:  
To assess t he  safet y a n d efficac y of a d diti o nal i ntra vitreal i njecti o ns of R B M-0 0 7 ( 2. 0 m g/e ye ) 
i n s u bjects wit h wet a ge-relate d mac ular de ge nerati o n ( A M D) r olle d o ver fr o m T O F U St u d y 
( Pr ot oc ol R B M- 0 0 7- 0 0 2). 
Sec o n d ar y O bjecti ve:  
To e val uate a nti -fi br otic effect f or R B M -0 0 7 i n s u bjects wit h e x u dati ve a g e-relate d mac ular 
de ge nerati o n. 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
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Met h o d ol o g y: 
T his is a m ulti -ce nter, o pe n  la bel, e xte nsi o n st u d y a ssessi n g t he efficac y a n d safet y of a d diti o nal 
intra vitreal injecti o ns of R B M- 0 0 7  i n su bjects  wit h w et a ge-relate d mac ular d e ge nerati o n . 
S u bjects w h o meet all eli gi bilit y criteria at t he ti me of e xit visit of T O F U st u d y will recei ve 
treat me nt f or u p t o three m o nt hs i n t he st u d y e y e. S u bjects t hat s uccessf ull y e xite d T O F U 
st u d y o n or bef ore  a p pr o xi matel y Se pte m ber 1, 2 0 2 1 will be c o nsi d ere d f or R A M E N 
St u d y. 
A p pr o xi matel y f ort y s u bjects wit h e x u d ati v e a g e -r el at e d m a c ul ar de ge nerati o n ( A M D) 
will recei ve R B M- 0 0 7 i njecta ble sol uti o n ( 2. 0 m g/e ye)  
T he pri mar y e n d p oi nt of t he st u d y is at o ne m o nt h p ost t he last i njecti o n wit h safet y 
e val uati o n  t hr o u g h t w o m o nt hs p ost t he last i nje cti o n . 
F or eli gi bilit y, s u bjects m ust be dia g n ose d wit h  e x u dati ve A M D i n t he st u d y e ye, f or w hic h 
pre vi o us T O F U mas ke d treat me nt ar ms wit h i ntra vitreal a nti -vasc ular e n d ot helial gr o wt h 
fact or (a nti-V E G F) a ge n t E ylea ®  a n d/ or R B M - 0 0 7 has n ot de m o nstrate d i m pr o ve me nt i n 
visi o n, wit h less t ha n 1 5 letter B C V A i m pr o v e me nt i n T O F U st u d y at t h e e xit visit of 
T O F U o ver its baseli n e. S u bjects m ust ha ve c o m plete d all visits i n t he T O F U st u d y. 
S u bject m ust de m o nstr ate  a bs e nce of ce ntral atr o p h y or reti nal e pit helial tear i n t h e f o vea 
or a n y c o n diti o n pre v e nti n g V A i m pr o ve me nt i n t he st u d y e ye.  
Eli gi ble s u bjects w h o are e nr olle d i n t he st u d y will be see n f or at least 6 visits t hat i ncl u de a 
Ba seli ne/ Da y 1 ( Visit 1), a n d m o nt hs 1- 5 ( Visit 2- 6) 
S u bjects are eli gi ble f or resc ue wit h E ylea ®  or ot her treat me nt at t he discreti o n of i n vesti gat or 
a n yti me d uri n g t he st u d y if o ne of t he f oll o wi n g resc ue criteria is met. 
 
Resc ue Criteri a:  
•  B C V A decrease of > 1 0 letters A N D  ce ntral s u bfiel d t hic k ness ( C S T) i ncrease of > 5 0 
µ m fr o m baseli ne ( visit 1 R A M E N).  
•  T he discreti o n of i n vesti gat or  
N u m ber of S u bjects ( pl a n ne d):  
A p pr o xi matel y 4 0  s u bjects wit h wet A M D will be e nr olle d at a p pr o xi matel y 1 0  sites. S u bjects 
t hat s ucc essf ull y e xite d T O F U st u d y o n or bef ore a p pr o xi matel y Se pte m ber 1, 2 0 2 1 will 
be c o nsi der e d f or R A M E N St u d y  
  
D ur ati o n of t he St u d y:  
T he t otal st u d y peri o d f or eac h s u bject will i n cl u de a treat me nt peri o d a n d f oll o w u p peri o d 
(t otal u p t o fi ve m o nt hs ). 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
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M as ki n g:  
T his is a n o pe n la bel st u d y. 
T he  desi g nate d  Safet y  Re vie w  Tea m  ( S R T)  will  re vie w  t he  safet y  data  peri o dicall y  t o  
deter mi ne if t he safet y a n d t olera bilit y of t he d oses are acce pta ble.  
 
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
I ncl usi o n Criteri a: 
At Visit 1 ( B aseli ne ( D ay 1)) , s u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria: 
1.  Pr o vi de si g ne d writte n i nf or me d c o nse nt o n t he I nstit uti o nal Re vie w B oar d  (I R B)/ Et hics 
C o m mittee ( E C) a p pr o ve d I nf or me d C o nse nt F or m (I C F) a n d pr o vi de a ut h orizati o n as 
a p pr o priate f or l ocal pri vac y re g ulati o ns. 
2.  Male or fe male 5 5 years of a ge or ol der o n t he date of si g ni n g t he I C F a n d a ble a n d 
willi n g t o c o m pl y wit h all treat me nt a n d st u d y  pr oce d ures.  
3.  S u bjects m ust ha ve c o m plete d all sc he d ule d visits of T O F U st u d y. S u bjects ca n o nl y 
e nter t his st u d y after e xiti n g T O F U st u d y 
4.  S u bjects f or w hic h pre vi o us T O F U mas ke d treat me nt ar ms wit h i ntra vitreal a nti -
vasc ular e n d ot helial gr o wt h fact or (a nti -V E G F) a ge nts  E ylea ®  a n d/ or R B M - 0 0 7 has 
n ot  de m o nstrate d i m pr o ve me nt i n visi o n; s u bjects wit h less t ha n 1 5 letter B C V A 
i m pr o ve me nt i n T O F U st u d y at e xit visit o ver its baseli ne . 
5.  Dia g n osis of e x u dati ve A M D i n t he st u d y e ye, as assesse d b 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). 
6.  A bse nce of ce ntral atr o p h y or reti nal e pit helial te ar i n t h e f o vea or a n y c o n diti o n 
pre ve nti n g V A i m pr o ve me nt  i n t he st u d y e ye. 
7.  B C V A of 2 4 E T D R S letters ( 2 0/ 3 2 0) or better i n t he fell o w e ye . 
8.  Reas o na bl y clear me dia a n d s o me fi xati o n i n t he st u d y e ye t o all o w f or g o o d q ualit y  S D -
O C T a n d f u n d us  p h ot o gra p h y.  


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E xcl usi o n Criteri a:  
A s u bject wit h a n y of t he f oll o wi n g c o n diti o ns is n ot eli gi ble t o partici pate i n t he st u d y: 
Oc ul ar:  
1.  S u bjects w h ose visi o n ha ve i m pr o ve d > 1 5 B C V A letters  at e xit visit of T O F U st u d y  o ver 
its baseli ne 
2.  S u bjects w h o e x perie nce d a n y dr u g r elate d seri o us a d verse e ve nt d uri n g T O F U st u d y  
3.  Use  of  a n y  of  t he  f oll o wi n g  treat me nts  or  a ntici pate d  use  of  a n y  of  t he  f oll o wi n g  
treat me nts t o t he st u d y e ye: 
a. I ntra vitreal or peri oc ular c ortic oster oi d, wit hi n 9 0 da ys pri or t o Visit 1 ( Da y 1) 
a n d t hr o u g h o ut t he st u d y. 
b.  Fl u oci n ol o ne acet o ni de i ntra vitreal i m pla nt, wit hi n 1 2 m o nt hs pri or t o Visit 1 
( Da y 1) a n d t hr o u g h o ut t he st u d y. 
c. Vis u d y ne ®  p h ot o d y na mic t hera p y, wit hi n 9 0 da ys pri or t o Visit 1 ( Da y 1) a n d  
t hr o u g h o ut t he st u d y. 
4.  U nc o ntr olle d or a d va nce d gla uc o ma, e vi de nce d b y a n i ntra oc ular press ure (I O P) of > 2 1 
m m H g or c u p/ disc rati o > 0. 8 w hile o n me dical t hera p y, or c hr o nic h y p ot o n y ( < 6 m m H g) 
i n t he st u d y e ye. 
5.  E vi de nce of a n y ot her oc ular disease ot her t ha n wet A M D i n t he st u d y e ye t hat ma y 
c o nf o u n d t he o utc o me of t he st u d y (e. g., acti ve dia betic reti n o pat h y, p osteri or u veitis,  
pse u d o vitellif or m mac ular de ge nerati o n, m o derate/se vere m y o pi a). 
6.  Hist or y of vitrect o m y i n t he st u d y  e ye. 
7.  Nee d f or oc ular s ur ger y i n t he st u d y e ye d uri n g t he c o urse of t he st u d y. 
8.  Y A G laser ca ps ul ot o m y wit hi n 3 0 da ys pri or t o Visit 1 ( Da y 1) i n t he st u d y  e ye. 
9.  I ntra oc ular s ur ger y, i ncl u di n g le ns re m o val or laser, wit hi n 9 0 da ys pri or t o Visit 1 
(Baseli ne ( Da y 1)) i n t he st u d y e ye. 
1 0.  Oc ular or peri oc ular i nfecti o n i n eit her  e ye. 
1 1.  P u pillar y dilati o n i na de q uate f or q ualit y f u n d us p h ot o gra p h y i n t he st u d y e ye. 
1 2.  Me dia  o pacit y  t hat  w o ul d  li mit  cli nical  vis ualizati o n,  f u n d us  p h ot ogra p h y,  f u n d us 
a ut ofl u orescence, or 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 ) 
e val uati o n i n t he st u d y e ye. 
1 3.  Hist or y of her petic i nfecti o n i n t he st u d y e ye or a d ne xa. 
1 4.  Prese nce of k n o w n acti ve t o x o plas m osis, i nacti ve t o x o plas m osis or t o x o plas m osis scar 
i n eit her e ye. 
1 5.  Prese nce of a n y f or m of oc ular mali g na nc y i ncl u di n g c h or oi dal mela n o ma i n eit her  e ye. 
 


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N o n -Oc ul ar:  
1 6.  Pri or s yste mic treat me nt wit h R B M- 0 0 7 i njecta ble s ol uti o n. 
1 7.  Use  of  a n y  of  t he  f oll o wi n g  treat me nts  or  a ntici pate d  use  of  a n y  of  t he  f oll o wi n g  
treat me nts d uri n g t he st u d y: 
a. S yste mic treat me nt wit h a nti - V E G F a ge nts (e. g., be vaciz u ma b)  
b.  A ge nts tar geti n g t he F G F- 2 pat h wa y 
1 8.  Aller g y or h y perse nsiti vit y t o st u d y dr u g pr o d uct, fl u orescei n d ye, or ot her st u d y relate d 
pr oce d ures/ me dicati o ns.  
1 9.  Maj or s ur ger y wit hi n 9 0 da ys pri or t o Visit 1 ( Baseli ne ( Da y 1) ). Maj or s ur ger y is defi ne d 
as a n y s ur ger y i n v ol vi n g a ris k t o t he life of t he s u bject, i ncl u di n g a n y o perati o n u p o n a n 
or ga n wit hi n t he cra ni u m, c hest, a b d o me n, or pel vic ca vit y. 
2 0.  T hera pe u tic ra diati o n t o t he hea d or nec k wit hi n 9 0 da ys pri or t o Visit 1 ( Da y 1). 
2 1.  Partici pati o n i n ot her i n vesti gati o nal dr u g or de vice cli nical trials wit hi n 3 0 da ys pri or t o 
Visit 1 ( Baseli ne ( Da y 1) ) or pla n ni n g t o partici pate i n ot her i n vesti gati o nal dr u g or 
de vice cli nical trials f or t he d urati o n of t he st u d y. T his i ncl u des b ot h oc ular a n d n o n -
oc ular cli nical  trials. 
2 2.  Hist or y of ot her disease, meta b olic d ysf 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 gi vi n g reas o na ble s us pici o n of a disease c o n diti o n t hat c o ntrai n dicates 
t he use of a n i n vesti gati o nal dr u g, mi g ht affect t he i nter pretati o n of t he res ults of t he 
st u d y, or re n ders t he s u bject at hi g h ris k f or treat me nt c o m plicati o ns. 
2 3.  Fe males w h o are pre g na nt or lactati n g a n d fe males of c hil d-beari n g p ote ntial w h o are 
n ot  usi n g a de q uate  c o ntrace pti ve preca uti o ns (i.e., I U D, oral  c o ntrace pti ves, barrier  
met h o d, or ot her c o ntrace pti o n dee me d a de q uate b y t he Cli nical I n vesti gat or). 
2 4.  U na ble t o c o m pl y wit h st u d y pr oce d ures or f oll o w- u p visits. 
 
I n a d diti o n, t he Cli nical I n vesti gat or or RI B O MI C Me dical M o nit or ma y declare a s u bject 
i neli gi ble f or a n y s o u n d reas o n. 
 


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St u d y E ye  
T he st u d y e ye m ust meet all i ncl usi o n a n d e xcl usi o n criteria . T he st u d y e ye m ust be t he sa me 
as t he e ye i n T O F U st u d y.  
R o ute of A d mi nistr ati o n of I n vesti g ati o n al pr o d uct:  
I ntra vitreal i njecti o n i n t he st u d y e ye. 
Criteri a f or E v al u ati o n:  
Effic ac y:  
T he pri mar y efficac y varia bl e assesse d at M o nt h 4: 
• Mea n c ha n ge i n B C V A fr o m Baseli ne   
 
T he sec o n dar y efficac y varia bles assesse d at M o nt h 4 : 
• Pr o p orti o n of s u bjects gai ni n g m ore t ha n 1 5 letters as meas ure d b y B C V A fr o m Baseli ne 
( 3-li ne gai ners)  
• Pr o p orti o n of s u bjects wit h B C V A : 1) gai n of ≥10 E T D R S letters; 2) gai n of ≥5 E T D R S 
letters; a n d 3)  l oss of ≥ 1 5 letter s fr o m B aseli ne 
• C ha n ge fr o m B aseli ne i n C S T a n d mac ular v ol u me b y S D- O C T  
• C ha n ge fr o m B aseli ne i n c haracteristics of s u breti nal h y per reflecti ve material (S H R M ) 
• C ha n ge fr o m B aseli ne i n c haracteristics of fi br osis  
• Pr o p orti o n of s u bjects t hat d o n ot re q uire a nti -V E G F resc ue treat me nt d uri n g f oll o w-u p 
peri o d 
• Mea n n u m ber of resc ue i njecti o ns   
• Pr o p orti o n of s u bjects re q uiri n g resc ue 
S afet y: 
T he safet y assess me nts will i ncl u de a d verse e ve nts ( A Es), pre g na nc y test, e xter nal oc ular 
e xa m, B C V A,  I O P,  slit  la m p  bi o micr osc o p y,  i n direct  o p ht hal m osc o p y,  S D -O C T ,  f u n d us 
p h ot o gra p h y, f u n d us a ut ofl u oresce nce, vital si g ns a n d p h ysical e xa mi nati o n. 
 
St atistic al Met h o ds:  
T he pri mar y a nal ysis will be after t he st u d y is c o m plete d . All safet y a n d efficac y data will be 
s u m marize d wit h descri pti ve statistics. B C V A a n d C S T data will als o be prese nte d gra p hicall y. 
D ue t o t he e x pl orat or y nat ure of t his st u d y, t he sa m ple size was n ot base d o n a statistical p o wer.  
 


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3  T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F FI G U R E S  
T A B L E O F C O N T E N T S  
A P P R O V E R S  ......................................................................................................................................................... 2 
1  
P R O C E D U R E S I N C A S E O F  E M E R G E N C Y  .......................................................................................... 3 
2  
S Y N O P SI S .................................................................................................................................................... 4 
3  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F FI G U R E S  ............................................. 1 0  
4  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ........................................................... 1 4  
A b bre vi ati o ns a n d Ter ms  ................................................................................................................................ 1 4  
5  
I N T R O D U C TI O N ...................................................................................................................................... 1 5  
6  
O B J E C TI V E S  ............................................................................................................................................. 1 7  
7  
I N V E S TI G A TI O N A L P L A N ..................................................................................................................... 1 8  
7. 1  O ver all St u d y Desi g n a n d Pl a n  ............................................................................................................. 1 8  
7. 1. 1  
Selecti o n of C o nce ntrati o ns i n t he St u d y  ....................................................................................... 1 9  
7. 2  N u m ber of S u bjects  ............................................................................................................................... 2 1  
7. 3  Tre at me nt Assi g n me nt  ........................................................................................................................... 2 1  
7. 4  D ose A dj ust me nt Criteri a  ..................................................................................................................... 2 1  
7. 5  St u d y  Pr oce d ures  ................................................................................................................................... 2 1  
7. 5. 1  
St u dy Visits  ..................................................................................................................................... 2 3  
7. 5. 2  
U nsc he d ule d Visits  ......................................................................................................................... 2 9  
8  
S E L E C TI O N A N D WI T H D R A W A L O F  S U B J E C T S  ............................................................................. 3 0  
8. 1  S u bject I ncl u si o n Criteri a  ..................................................................................................................... 3 0  
8. 2  S u bject E xcl usi o n  Criteri a  .................................................................................................................... 3 0  
8. 3  S u bject Wit h dr a w al Criteri a  ................................................................................................................ 3 2  
9  
T R E A T M E N T O F  S U B J E C T S  ................................................................................................................. 3 3  
9. 1  Descri pti o n of St u d y  Dr u g ..................................................................................................................... 3 3  
9. 2  C o nc o mit a nt  Me dic ati o ns  ..................................................................................................................... 3 3  
9. 2. 1  
Pr o hi bite d Me dicati o ns or Treat me nts ............................................................................................ 3 3  
9. 2. 2  
Resc ue  T hera p y  .............................................................................................................................. 3 3  
9. 3  Tre at me nt  C o m pli a nce  .......................................................................................................................... 3 4  
9. 4  R a n d o miz ati o n a n d  M as ki n g  ................................................................................................................ 3 4  
1 0  
S T U D Y D R U G M A T E RI A L S A N D  M A N A G E M E N T  ........................................................................... 3 5  
1 0. 1  
St u d y  Dr u g  ......................................................................................................................................... 3 5  
1 0. 1. 1  
I n vesti gati o nal Dr u g .................................................................................................................. 3 5  
1 0. 1. 2  
C o nc o mita nt  dr u g  ...................................................................................................................... 3 5  
1 0. 1. 3  
St u d y Dr u g C o m plai nt  Re p orti n g  .............................................................................................. 3 5  
1 0. 1. 4  
Ot her St u d y S u p plies  ................................................................................................................. 3 5  
1 0. 2  
St u d y Dr u g P ac k a gi n g a n d  L a beli n g  ............................................................................................... 3 5  
1 0. 3  
St u d y Dr u g St or a ge  ........................................................................................................................... 3 5  
1 0. 4  
St u d y Dr u g Pre p ar ati o n  ................................................................................................................... 3 5  
1 0. 5  
L o a di n g t he  S yri n ge  .......................................................................................................................... 3 6  
1 0. 6  
E ye  Pre p ar ati o n  ................................................................................................................................. 3 7  
1 0. 7  
St u d y Dr u g A d mi nistr ati o n  .............................................................................................................. 3 7  
1 0. 8  
St u d y Dr u g Acc o u nt a bilit y  ............................................................................................................... 3 7  
1 0. 9  
St u d y Dr u g H a n dli n g a n d  Ret ur n  ................................................................................................... 3 8  
11  
A S S E S S M E N T O F  E F FI C A C Y  ................................................................................................................ 3 9  
11. 1  
Best C orrecte d Vis u al Ac uit y  ( B C V A) ............................................................................................. 3 9  
11. 2  
Ce ntr al S u bfiel d T hic k ness ( C S T), M ac ul ar Vol u me ( M V), Fi br osis a n d S H R M  ....................... 3 9  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 1  of  7 4  
 
1 2  
A S S E S S M E N T O F  S A F E T Y  ..................................................................................................................... 4 0  
1 2. 1  
A d verse  E ve nts  .................................................................................................................................. 4 0  
1 2. 1. 1  
Defi niti o n of A d verse E ve nts  .................................................................................................... 4 0  
1 2. 1. 2  
Seri o us A d verse  E ve nts  ............................................................................................................. 4 2  
1 2. 1. 3  
E ve nts of S pecial I nterest  .......................................................................................................... 4 4  
1 2. 1. 4  
F oll o w -u p of A d verse  E ve nts  .................................................................................................... 4 4  
1 2. 1. 5  
Ma n ual Bac k -U p Re p orti n g  Pr oce d ures  .................................................................................... 4 4  
1 2. 2  
S afet y P ar a meters  ............................................................................................................................. 4 5  
1 2. 2. 1  
P h ysical  E xa mi nati o n  ................................................................................................................ 4 5  
1 2. 2. 2  
Vital Si g ns  ................................................................................................................................. 4 5  
1 2. 2. 3  
Best C orrecte d Vis ual Ac uit y  .................................................................................................... 4 5  
1 2. 2. 4  
E xter nal oc ular e xa m  ................................................................................................................. 4 5  
1 2. 2. 5  
Slit -la m p Bi o micr osc o p y  ........................................................................................................... 4 5  
1 2. 2. 6  
I ntra oc ular Press ure ................................................................................................................... 4 5  
1 2. 2. 7  
I n direct O p ht hal m osc o p y  .......................................................................................................... 4 6  
1 2. 2. 8  
Uri ne Pre g na nc y Test  ................................................................................................................. 4 6  
1 2. 2. 9  
F u n d us P h ot o gra p h y  .................................................................................................................. 4 6  
1 2. 2. 1 0  
F u n d us A ut ofl u oresce nce  .......................................................................................................... 4 6  
1 2. 2. 1 1  
S pectral D o mai n O ptical C o here nce To m o gra p h y ( S D -O C T)  .................................................. 4 6  
1 2. 2. 1 2  
A d verse  E ve nts  .......................................................................................................................... 4 6  
1 3  
O T H E R  A S S E S S M E N T S  .......................................................................................................................... 4 7  
1 3. 1  
De m o gr a p hics a n d B aseli ne  C h ar acteristics  ................................................................................... 4 7  
1 3. 2  
O C T  A n gi o gr a p h y  ............................................................................................................................ 4 7  
1 4  
S T A TI S TI C A L  M E T H O D S  ...................................................................................................................... 4 7  
1 4. 1  
A n al ysis Ti me P oi nts  ......................................................................................................................... 4 7  
1 4. 1. 1  
Pri mar y  A nal ysis  ....................................................................................................................... 4 7  
1 4. 2  
Ge ner al C o nsi der ati o ns  .................................................................................................................... 4 8  
1 4. 2. 1  
Sa m ple  Size  ............................................................................................................................... 4 8  
1 4. 2. 2  
Statistical H y p ot heses a n d Le vel of  Si g nifica nce  ...................................................................... 4 8  
1 4. 2. 3  
Ra n d o mizati o n  ........................................................................................................................... 4 8  
1 4. 2. 4  
St u d y E ye  .................................................................................................................................. 4 8  
1 4. 3  
St u d y  P o p ul ati o ns  ............................................................................................................................. 4 8  
1 4. 4  
H a n dli n g of Missi n g  Val ues  .............................................................................................................. 4 9  
1 4. 5  
De m o gr a p hics a n d B aseli ne  C h ar acteristics  ................................................................................... 4 9  
1 4. 6  
Effic ac y A n al yses  ............................................................................................................................... 4 9  
1 4. 6. 1  
A nal ysis of Pri mar y Efficac y  E n d p oi nts  ................................................................................... 4 9  
1 4. 6. 2  
A nal ysis of Sec o n dar y Efficac y  E n d p oi nts  ............................................................................... 4 9  
1 4. 7  
S afet y A n al ysis  ................................................................................................................................... 5 0  
1 5  
DI R E C T A C C E S S T O S O U R C E  D A T A/ D O C U M E N T S  ....................................................................... 5 0  
1 5. 1  
St u d y  M o nit ori n g  .............................................................................................................................. 5 0  
1 5. 2  
A u dits a n d  I ns pecti o ns ...................................................................................................................... 5 1  
1 5. 3  
I nstit uti o n al Re vie w B o ar d  .............................................................................................................. 5 1  
1 6  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y  A S S U R A N C E  ......................................................................... 5 1  
1 6. 1  
Q u alit y C o ntr ol  ................................................................................................................................. 5 1  
1 6. 2  
Q u alit y Ass ur a nce  ............................................................................................................................. 5 2  
1 7  
E T HI C S  ....................................................................................................................................................... 5 3  
1 7. 1  
Et hics Re vie w  .................................................................................................................................... 5 3  
1 7. 2  
Et hic al C o n d uct of t he  St u d y  ........................................................................................................... 5 3  
1 7. 3  
Writte n I nf or me d  C o nse nt  ............................................................................................................... 5 3  
1 8  
D A T A H A N D LI N G A N D  R E C O R D K E E PI N G  ....................................................................................... 5 4  
1 8. 1  
I ns pecti o n of Re c or ds ........................................................................................................................ 5 4  
1 8. 2  
Rete nti o n of  Rec or ds  ......................................................................................................................... 5 4  
1 8. 2. 1  
S o urce  D oc u me nts  ..................................................................................................................... 5 4  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 2  of  7 4  
 
1 8. 2. 2  
Data  C ollecti o n  .......................................................................................................................... 5 5  
1 9  
P U B LI C A TI O N  P O LI C Y  .......................................................................................................................... 5 6  
2 0  
R E F E R E N C E S  ........................................................................................................................................... 5 7  
2 1  
A P P E N DI C E S  ............................................................................................................................................ 5 9  
2 1. 1  
A p pe n di x A - O bli g ati o ns of  I n vesti g at ors ...................................................................................... 5 9  
I. 
Pri or t o t he Be gi n ni n g of t he St u d y  ...................................................................................................... 5 9  
II. 
W hile t he St u d y Is i n  Pr o gress  .............................................................................................................. 5 9  
III. 
O nce t he St u d y Is  C o m plete d  ........................................................................................................... 6 0  
2 1. 2  
A p pe n di x B - Ele me nts of I nf or me d  C o nse nt  ................................................................................. 6 1  
2 1. 2. 1  
El e me nts of I nf or me d  C o nse nt  .................................................................................................. 6 1  
2 1. 2. 2  
A d diti o nal Ele me nts of I nf or me d  C o nse nt  ................................................................................ 6 1  
2 1. 3  
A p pe n di x C - Decl ar ati o n of  Helsi n ki  ............................................................................................. 6 3  
W M A Decl ar ati o n of Helsi n ki - Et hic al Pri nci ples f or Me dic al Rese arc h I n v ol vi n g H u m a n S u bjects  ... 6 3  
2 1. 4  
A p pe n di x D - Pr oce d ures f or  E x a mi n ati o ns  ................................................................................... 6 9  
2 1. 4. 1  
De m o gra p hics/ Eli gi bilit y, Me dical/ S ur gical Hist or y a n d C o nc o mita nt Me dicati o n  ................. 6 9  
2 1. 4. 2  
P h ysical  E xa mi nati o n  ................................................................................................................ 6 9  
2 1. 4. 3  
Vital Si g ns  ................................................................................................................................. 6 9  
2 1. 4. 4  
Ur i ne Pre g na nc y Test ................................................................................................................. 7 0  
2 1. 4. 5  
Best C orrecte d Vis ual  Ac uit y  .................................................................................................... 7 0  
2 1. 4. 6  
E xter nal Oc ular E xa mi nati o n  .................................................................................................... 7 0  
2 1. 4. 7  
Slit -La m p  Bi o micr osc o p y  ......................................................................................................... 7 0  
2 1. 4. 8  
I ntra oc ular Press ure ................................................................................................................... 7 1  
2 1. 4. 9  
I n direct O p ht hal m osc o p y  .......................................................................................................... 7 3  
2 1. 4. 1 0  
S pectral D o mai n O ptical C o here nce To m o gra p h y  .................................................................... 7 3  
2 1. 4. 1 1  
O ptical C o here nce To m o gra p h y  A n gi o gra p h y  .......................................................................... 7 3  
2 1. 4. 1 2  
F u n d us  P h ot o gra p h y  .................................................................................................................. 7 4  
2 1. 4. 1 3  
F u n d us A ut ofl u oresce nce  .......................................................................................................... 7 4  
 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 3  of  7 4  
 
LI S T O F T A B L E S  
T A B L E 1:  E M E R G E N C Y C O N T A C T IN F O R M A TI O N  .................................................................................. 3 
T A B L E 2:  S C H E D U L E O F E V E N T S  ....................................................................................................... 2 2  
T A B L E 3:  R B M -0 0 7  D O SI N G  .............................................................................................................. 3 5  
 
LI S T O F FI G U R E S  
 
F I G U R E 1:  D E CI SI O N I O P P R O C E S S F O R I V T IN J E C TI O N  ................................................................... 2 5  
F I G U R E 2:  0. 5  ML  FI L L I N A 2  ML  VI A L  ............................................................................................... 3 6  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 4  of  7 4  
 
4  LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
T he f oll o wi n g a b bre viati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
 
A b brevi ati o ns a n d Ter ms  
A b bre vi ati o n  
E x pressi o n ( N a me) i n f ull  
A E(s)  
a d verse e ve nt(s)  
A M D  
a ge-relate d mac ular de ge nerati o n 
B C V A  
best c orrecte d vis ual ac uit y  
C N V  
c h or oi dal ne o -vasc ularizati o n  
C R F  
Case re p ort f or m  
C S T  
ce ntral s u bfiel d t hic k ness  
e C R F(s) 
Electr o nic Case Re p ort F or m(s)  
E D C  
E C  
Electr o nic Data Ca pt ur e  
Et hics C o m mitte e  
E SI(s)  
e ve nt(s) of s pecial i nter est  
E T D R S  
Earl y Treat me nt of Dia betic R eti n o pat h y St u d y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F G F  
fi br o blast gr o wt h fact or 
G C P  
G o o d Cli nical Practice  
G L P  
G o o d La b orat or y Practice  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nc e o n Har m o nizati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I N D 
I n vesti gati o nal Ne w Dr u g A p plicati o n 
I O P 
i ntra oc ular press ure 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
i nte nt-t o-treat 
I V T 
i ntra vitre al 
L O C F  
Last O bs er vati o n C arrie d F or w ar d  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
N O A E L  
milli gra m  
n o o bser ve d a d verse eff ect le vel  
µ L  
micr oliter  
m L  
milliliter  
m m H g  
milli meter of merc ur y  
S A E(s)  
seri o us a d verse e ve nt(s) 
S A P  
statistical a nal ysis pla n 
S D -O C T  
S H R M  
s pectral d o mai n o ptical c o here nce t o m o gra p h y 
s u breti nal h y per reflecti ve material 
S R T  
Safet y Re vie w Tea m  
V E G F  
vasc ular e n d ot helial gr o wt h fact or  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 5  of  7 4  
 
5  I N T R O D U C TI O N 
A ge -relate d  mac ular  de ge nerati o n  ( A M D)  is  t he  lea di n g  ca use  of  irre versi ble  visi o n  l oss  i n  
de vel o pe d c o u ntries. A M D is c haracterize d b y e xtracell ular matri x de p osits, k n o w n as dr use n, 
acc u m ulati n g bet wee n t he reti nal pi g me nt e pit heli u m a n d Br uc h’s me m bra ne. I n e x u dati ve or wet 
A M D , u n wa nte d bl o o d vessels gr o w i nt o t he  mac ula w hic h lea ds t o he m orr ha ge a n d s u breti nal 
fl ui d. I n a d diti o n, reti nal pi g me nt e pit helial detac h me nt, reti nal tears, fi br o vasc ular scarri n g a n d 
vitre o us  he m orr ha ge  ma y  occ ur.  T he  a berra nt  gr o wt h  of  lea k y  vessels  is  t he  res ult  of  l ocal  
i nfla m mat or y res p o nses lea di n g t o disr u pti o n of t he bala nce of c yt o ki nes t hat c o ntr ol a n gi o ge nesis 
(Li m et al., 2 0 0 7 ). 
A n gi o ge nesis is a c o m ple x a n d c o or di nate d pr ocess of t he gr o wt h a n d s pr o uti n g of ne w bl o o d 
vessels fr o m pre -e xisti n g vasc ulat ure. Alt h o u g h se veral a n gi o ge nic fact ors ha ve bee n i de ntifie d, 
V E G F fa mil y pr otei ns, t heir rece pt ors a n d i ntracell ular si g nali n g m o lec ules a p pear t o be t he ke y 
me diat ors of a n gi o ge nesis ( Ka ne et al., 2 0 0 7). 
A p pr o xi matel y 1. 2 milli o n pers o ns i n t he U nite d States are esti mate d t o ha ve ne o vasc ular A M D 
a n d 9 7 0 0 0 0 t o ha ve ge o gra p hic atr o p h y; > 8 milli o n ha ve  at least lar ge dr use n i n 1 e ye a n d 3. 6 
milli o n of t hese ha ve bilateral lar ge dr use n. T hese pre vale nce fi g ures are e x pecte d t o i ncrease b y 
a p pr o xi matel y 5 0 % ( C he w et al, 2 0 1 2 ; Frie d ma n et al, 2 0 0 4 ). Fr o m t he i nitial sta ge of dr y A M D, 
c haracterize d b y li p of usci n de p osits u n der t he reti na k n o w n as dr use n, 1 0 % are at ris k f or se vere, 
ac ute l oss of ce ntral visi o n d ue t o t he o nset of wet A M D, c haracterize d b y t he gr o wt h of a b n or mal 
c h or oi dal  ne o vasc ularizati o n ( C N V ) i n  t he  mac ula,  w hic h lea ds  t o  s u breti nal  blee di n g,  fl ui d 
e x u dati o n a n d fi br otic scar f or mati o n. O ver 2 0 0, 0 0 0 ne w patie nts eac h year i n t he U. S. de vel o p 
wet A M D ( Ferris et al ., 1 9 8 4). 
C urre nt F D A -a p pr o ve d t hera pies f or A M D are pe ga pta ni b ( Mac u ge n ® ), ra ni biz u ma b (L uce ntis ® ), 
afli berce pt ( E ylea ® ) a n d br ol uciz u ma b ( Be o v u ® ). Als o , off -la bel use of  ali q u ote d be vaciz u ma b 
( Avasti n® ) is use d t o treat A M D. All of t hese m olec ules act a gai nst t he sa me tar get: vasc ular 
e n d ot helial  gr o wt h  fact or  ( V E G F).  V E G F,  a  p ote nt  e n d ot helial  cell  mit o ge n  a n d  vasc ular  
per mea bilit y fact or, is a maj or c o ntri b ut or t o t he pat h o ge nesis of ne o vasc ular A M D. Treat me nts 
wit h  a nti -V E G F  dr u gs,  w hic h  are  deli vere d  b y  fre q ue nt  i ntra vitreal  i njecti o ns,  ha ve  s h o w n  
dra matic vis ual be nefits f or A M D patie nts ( Br o w n et al ., 2 0 0 6; Heier et  al., 2 0 1 2; Marti n et al ., 
2 0 1 2 ). H o we ver, t here are s o me critical li mitati o ns; i n f or mal cli nical trials, des pite c o nsiste nt 
m o nt hl y treat me nt, 2 3 % of e yes treate d m o nt hl y wit h ra ni biz u ma b pr ocee de d t o visi o n w orse t ha n 
2 0/ 2 0 0, a n d 2 0 % t o 4 0 % fail t o res ol ve mac ular fl ui d e ve n after 2 years of t hera p y ( Br o w n et al ., 
2 0 0 6 ; Heier et  al., 2 0 1 2). F urt her m ore, i n t he “real-w orl d” setti n g, patie nts recei ve i ntra vitreal 
i njecti o ns at m uc h l o wer fre q ue nc y t ha n t he esta blis he d pr ot oc ols, s o t hat o n a vera ge, l o n g-ter m 
vis ual o utc o mes i n A M D treat me nt are p o or ( R ofa g ha et al ., 2 0 1 3; Ma g uire et al ., 2 0 1 6). Fact ors 
ass ociate d wit h p o or visi o n o utc o mes, i n a d diti o n t o persiste nt e x u dati o n, i ncl u de mac ular atr o p h y 
a n d s u b mac ular fi br otic scar f or mati o n. T h us, t here is a n ee d f or a d diti ve or alter nati ve t hera p y t o 
a nti-V E G F treat me nts f or wet A M D.  
Fi br o blast gr o wt h fact or ( F G F) has bee n i m plicate d i n t he pat h o p h ysi ol o g y of b ot h a n gi o ge nesis 
a n d fi br osis i n reti nal diseases ( Sc h ultz a n d Gra nt, 1 9 9 1 ; Vi n di n g, 1 9 9 0 ). F G F c o m prises a fa mil y 
of 2 2 me m bers, i ncl u di n g F G F 2, ha vi n g ma n y bi ol o gical acti vities ( Bi kfal vi et al., 1 9 9 7 ). F G F 2 
pr o m otes gr o wt h of vasc ular e n d ot helial cells a n d t u b ular str uct ure f or mati o n ( Str utz et al ., 2 0 0 2) 
a n d sti m ulates b ot h V E G F pr o d ucti o n a n d scar f o r mati o n i n reti na.  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 6  of  7 4  
 
R B M -0 0 7  I njecta ble  S ol uti o n  is  a  n o vel  oli g o n ucle oti de -base d  a pta mer  ha vi n g  p ote nt  
a nti-Fi br o blast Gr o wt h F act or (F G F 2 ) acti vit y (Ji n et al, 2 0 1 6), w hic h h ol ds anti-a n gi o ge nic a n d 
a nti-scarri n g d ual acti o n (Mats u da et al., 2 0 1 9 ) as well as a ne gati ve acti o n f or V E G F e x pressi o n 
(Bel g ore et al, 2 0 0 3 ). I n t he rat a n d m o use m o dels of laser-i n d uce d c h or oi dal ne o vasc ularizati o n, 
it s h o we d acti vit y after i ntra vitreal i njecti o n at d oses as l o w as 5 µ g/e ye (Mats u da et al., 2 0 1 9 ). I n 
t he laser-i n duce d c h or oi dal ne o vasc ularizati o n ( C N V) fi br osis m o del i n rats, it s h o we d acti vit y 
after i ntra vitreal i njecti o n at d oses as l o w as 1 5 µ g/e ye ( Mats u da et al., 2 0 1 9 ). It is h y p ot hesize d 
t o ha ve p ote ntial effects i n t he treat me nt of wet A M D beca use of t hese acti vities. T h us, t he S p o ns or 
pla ns t o e val uate t he safet y a n d bi oacti vit y of R B M -0 0 7 I njecta ble S ol uti o n as a n i ntra vitreal 
treat me nt f or e x u dati ve A M D. 
RI B O MI C  has  c o n d ucte d  a  P hase  I/II,  o pe n -la bel,  d ose-escalati n g,  se q ue ntial  c o h ort  st u d y  
assessi n g t he safet y, t olera bilit y a n d bi oacti vit y of a si n gle I V T i njecti o n of R B M-0 0 7 i njecta ble 
s ol uti o n i n t he st u d y e ye of ni ne s u bjects wit h refract or y wet A M D ( Pr ot oc ol R B M - 0 0 7- 0 0 1). 
T hree d ose le vels of R B M -0 0 7 ha ve bee n assesse d i n t his P hase I/II st u d y,  0. 2 m g/e ye, 1. 0 m g/e ye 
a n d 2. 0 m g/e ye. I n t his st u d y ( S U S HI), t here were n o re p orte d S A Es. N o d ose -de pe n de nt e ve nts 
were re p orte d a n d n o safet y c o ncer ns were i de ntifie d at all i n vesti gate d d oses. Oc ular A Es were 
re p orte d i n 3 s u bjects ( 3 3. 3 %). M ost c o m m o n A E was s u bc o nj u ncti val he m orr ha ge ( 2 s u bjects) 
a n d t his was c o nsi dere d t o be d ue t o t he i njecti o n pr oce d ure. T he o nl y dr u g relate d A E was mil d 
iritis t hat was res ol ve d after o ne day of t o pical ster oi d e ye dr o ps. 
T he P hase II T O F U  st u d y ( R B M- 0 0 7- 0 0 2) is c urre ntl y o n g oi n g, wit h t he first patie nt ra n d o mize d 
o n 1 7 Fe br uar y 2 0 2 0 a n d a n e x pecte d last patie nt visit (at wee k 2 4 ) i n J ul y 2 0 2 1. As of t he data 
c ut- off date of De vel o p me nt Safet y  U p date Re p ort ( D S U R) - R B M - 0 0 7 ( 1 9 J ul y 2 0 2 0), a t otal of 
2 3 s u bjects ha ve bee n ra n d o mize d i n t he P hase II T O F U st u d y, a n d t he treat me nt assi g n me nts 
ha ve n ot bee n u n mas ke d. A t otal of o ne S A E has bee n re p orte d i n T O F U, b ut was c o nsi dere d 
u nrelate d t o t he st u d y me dicati o n. A t otal of 2 4 A Es ha ve bee n re p orte d. C o nj u ncti val 
he m orr ha ge was m ost c o m m o n A E a n d it was relate d t o i njecti o n pr oce d ure. O nl y o ne p ossi bl y 
dr u g relate d A E was n ote d w hic h was Injecti o n site i nfla m mati o n  t hat res ol ve d after 
a d mi nistrati o n of t o pical ster oi d dr o ps . T w o  patie nts wit h dre w fr o m t he st u d y d ue t o C O VI D- 1 9 
sc he d ule iss ues a n d o ne s u bject was f o u n d t o be i neli gi ble after ra n d o mizati o n. 
St u d y res ults me nti o ne d a b o ve, i n a d diti o n t o t he res ults of t he n o n- cli nical st u dies, s u p p ort t he 
use of re peate d I V T i njecti o ns of 2. 0 m g /e ye of R B M - 0 0 7 i n h u ma ns i n t he P hase II T O F U 
e xte nsi o n cli nical trial, na mel y R A M E N  ( Pr ot oc ol R B M- 0 0 7- 0 0 3).


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 7  of  7 4  
 
6  
O B J E C TI V E S  
Pri m ar y O bjecti ve:  
To assess t he  safet y a n d efficac y of a d diti o nal i ntra vitreal i njecti o ns of R B M-0 0 7 ( 2. 0 m g/e ye ) 
i n s u bjects wit h wet a ge-relate d mac ular de ge nerati o n ( A M D) r olle d o ver fr o m T O F U St u d y. 
 
Sec o n d ar y O bjecti ve : 
To e val uate a nti -fi br otic effect f or R B M- 0 0 7 i n s u bjects wit h e x u dati ve a ge-relate d mac ular 
de ge nerati o n . 
 
 
 
 
 
 
 
 
 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 8  of  7 4  
 
7  
I N V E S TI G A TI O N A L P L A N 
7. 1  
Over all St u dy Desi g n a n d Pl a n 
T his is a m ulti -ce nter, o pe n la bel, e xte nsi o n st u d y assessi n g t he efficac y a n d safet y of a d diti o nal 
intra vitreal injecti o ns of  R B M -0 0 7 i n su bjects wit h w et a ge-relate d mac ular de ge nerati o n r olle d 
o ver fr o m T O F U St u d y. 
S u bjects w h o meet all eli gi bilit y criteria at t he ti me of e xit visit of T O F U st u d y will r ecei ve 
treat me nt f or u p t o t hree m o nt hs i n t he st u d y e ye. S u bjects t hat s ucc essf ull y e xite d T O F U 
st u d y o n or bef ore a p pr o xi matel y S e pte m ber  1, 2 0 2 1 will b e c o nsi dere d f or R A M E N St u d y.    
A p pr o xi matel y  f ort y s u bjects wit h e x u d ati v e a g e -r el at e d m a c ul ar de ge nerati o n ( A M D) 
will recei ve R B M- 0 0 7 I njecta ble S ol uti o n ( 2. 0 m g/e ye) . 
T he  pri mar y  e n d p oi nt  of  t he  st u d y  is  at  o n e  m o nt h  p ost  t he  last  i njecti o n  wit h  safet y  
e val uati o n  t hr o u g h a d diti o nal t w o m o nt hs p ost t he last i nje cti o n . 
F or el igi bilit y, s u bjects m ust be dia g n ose d wit h  e x u dati ve A M D i n t he st u d y e ye, f or w hic h 
pre vi o us T O F U mas ke d treat me nt  ar ms wit h i ntra vitr eal a nti -vasc ular e n d ot helial gr o wt h 
fact or (a nti-V E G F) a ge nt  E ylea ®  a n d/ or R B M - 0 0 7 has n ot de m o nstrate d i m pr o v e me nt i n 
visi o n , wit h less t ha n 1 5 letter B C V A i m pr o ve me nt i n T O F U st u d y at t he e xit visit of T O F U 
o ver its b aseli ne. S u bje cts m ust ha ve c o m plete d all visits i n t he T O F U st u d y .  
S u bject m ust de m o nstr ate  a bse nc e of ce ntral atr o p h y or reti nal e pit helial tear i n t h e f o vea or 
a n y c o n diti o n pre ve nti n g V A i m pr o ve me nt i n t he st u d y e y e.      
Eli g i ble s u bjects w h o are e nr olle d i n t he st u d y are e x pecte d t o be see n f or at least 6 visits t hat 
i ncl u de a Baseli ne/ Da y 1 ( Visit 1), a n d m o nt hs 1- 5 ( Visit 2- 6). 
S u bjects are eli gi ble f or resc ue wit h E ylea ®  or ot her treat me nt at t he discreti o n of i n vesti gat or  
a n yti me d uri n g t he st u d y if o ne of t he f oll o wi n g resc ue criteria is met.  
  
 
 
Resc ue Criteri a:  
Eli gi bilit y criteria f or Resc ue are as f oll o w:  
 
 
•  B C V A decrease of > 1 0 letters A N D  ce ntral s u bfiel d t hic k ness ( C S T) i ncrease of > 5 0 µ m 
fr o m R A M E N baseli ne visit . 
•  T he discreti o n of i n vesti gat or. 
Resc ue t hera p y is defi ne d as I V T i njecti o n of E ylea ®  or ot her treat me nt at t he discreti o n of 
i n vesti gat or i n t he st u d y e ye.   
W he ne ver p ossi ble, RI B O MI C s h o ul d be n otifie d bef ore a n y resc ue pr oce d ure. 
If resc ue wit h a nti-V E G F a ge nt is c o nsi dere d, t he s u bject m ust recei ve t he i njecti o n of 
R B M - 0 0 7 sc he d ule d f or t he s pecific visit pri or t o t he i njecti o n of a nti-V E G F a ge nt f or 
resc ue. 
If resc ue is perf or me d, t he f oll o wi n g assess me nts m ust be perf or me d after t he a d mi nistrati o n of 
eac h o ne o f t he i njecti o ns ( R B M- 0 0 7 a n d Resc ue treat me nt ):  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
1 9  of  7 4  
 
(all o p ht hal mic pr oce d ures t o be perf or me d i n t he treate d e ye) 
- Wit hi n 3 0 mi n utes f oll o wi n g eac h o ne of t he i njecti o ns: 
o  Slit -la m p bi o micr osc o p y 
o  I n direct o p ht hal m osc o p y 
 
- 
I O P will be meas ure d at 3 0 ( ± 1 0) mi n utes f oll o wi n g t he i ntra vitreal i njecti o n. 
- 
If p ost-i njecti o n I O P is > 2 1 m m H g after e ye massa ge a n d/ or a q ue o us ta p perf or me d per 
i n vesti gat or discreti o n, I O P meas ure me nt will be re peate d at 6 0 ( ± 1 0) mi n utes p ost-
i njecti o n.   
- 
If p ost-i njecti o n I O P at 6 0 ( ± 1 0) mi n utes is > 2 1 m m H g after e ye massa ge a n d/ or 
a q ue o us ta p perf or me d per i n vesti ga t or discreti o n, I O P meas ure me nt will be re peate d at 
9 0 ( ± 1 0) mi n utes p ost-i njecti o n.   
- 
If t here is a n i ncrease of ≥ 1 0 m m H g at 9 0 ( ± 1 0) mi n utes p ost-i njecti o n c o m pare d t o p re-
i njecti o n I O P, t he s u bject s h o ul d be prescri be d a t o pical I O P-l o weri n g me dicati o n u ntil 
he or s he ret ur ns f or f oll o w- u p per t he Cli nical I n vesti gat or’s discreti o n (a n u nsc he d ule d 
visit ma y a p pl y).  
- 
O n t he ot her ha n d, a s u bject wit h I O P meas ure me nt of > 2 1 m m H g will be ma na ge d 
acc or di n g t o t he discreti o n of t he Cli nical I n vesti gat or.  
- 
T he  I O P i ncrease of ≥ 1 0 m m H g fr o m p re-i njecti o n A N D I O P meas ure me nt of > 2 1 
m m H g will be re p orte d as a n  A E.  
• A q ue o us ta p ca n be perf or me d at a n y ti me per t he Cli nical I n vesti gat or`s discreti o n f or 
treat me nt or pre ve nti o n of i ncreasi n g i n t he I O P. 
 
7. 1. 1  Selecti o n of  C o nce ntr ati o ns i n t he St u d y  
I n t his cli nical st u d y  (Pr ot oc ol N o. R B M - 0 0 7- 0 0 3), R B M-0 0 7 ( 2. 0 m g /e ye)  is bei n g teste d i n 
s u bjects wit h wet A M D. T he ma xi m u m a m o u nt of R B M-0 0 7 t hat a s u bject ca n p ossi bl y recei ve is 
8 m g o ver a 5- m o nt h peri o d. S yste mic e x p os ure of R B M -0 0 7 i n t his st u d y gi ve n 4 ti mes b y I V T 
i njecti o n is a ntici pate d t o be si g nifica ntl y l o wer. I n t he S U S HI st u d y, t he s yste mic h u ma n e x p os ure 
was meas ure d a n d s h o w n t o be ver y s mall. T heref ore, n o c o ncer ns re gar di n g s yste mic t o xicit y are 
a ntici pate d i n t his st u d y.     
F urt her m ore, i n t he S U S HI st u d y  (Pr ot oc ol N o. R B M - 0 0 7- 0 0 1), t hree d ose le vels of R B M- 0 0 7 
( 0. 2 m g, 1. 0 m g a n d 2. 0 m g) were teste d i n ni ne s u bjects wit h refract or y wet A M D. N o d ose-
de pe n de nt e ve nts were re p orte d a n d n o safet y c o ncer ns were i de ntifie d at all i n vesti gate d d oses. 
M ost c o m m o n A E was s u bc o nj u ncti val he m orr ha ge ( 2 s u bjects, 2 2 %) . One case of mil d irritati o n 
was re p orte d. A ll oc ular A Es , e xce pt o ne , were c o nsi dere d t o be d ue t o t he i njecti o n pr oce d ure. 
O nl y  o ne  dr u g  relate d  A E  was  n ote d , w hic h  was  mil d  iritis  t hat  res o lve d  after  o ne  da y  
a d mi nistrati o n of t o pical ster oi d dr o ps.    
A d diti o nall y, P hase II T O F U  st u d y ( Pr ot oc ol N o. R B M- 0 0 7-0 0 2) i n t he U nite d States is a 
ra n d o mize d, d o u ble mas ke d, acti ve c o ntr olle d st u d y assessi n g t he safet y a n d efficac y of re peate d 
i ntra vitreal i njecti o ns of R B M - 0 0 7 ( 2. 0 m g/e ye) m o n ot hera p y a n d i n c o m bi nati o n wit h E ylea ®  
c o m pare d t o E ylea ®  m o n ot hera p y i n s u bjects wit h e x u dati ve a ge -relate d mac ular de ge nerati o n 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 0  of  7 4  
 
( w A M D). Ei g ht y- o ne ( 8 1 ) s u bjects wit h w A M D will be ra n d o ml y assi g ne d t o o ne of t hree 
treat me nt ar ms:  
Ar m 1: S ha m + R B M - 0 0 7 2. 0 m g/e ye   
Ar m 2: R B M - 0 0 7 2. 0 m g/e ye  + E ylea ®  2. 0 m g/e ye   
Ar m 3: S ha m  + E ylea ®  2. 0 m g /e ye 
S u bjects recei ve 4  m o nt hl y i ntra vitreal i njecti o ns of R B M - 0 0 7 ( 2. 0 m g) or R B M 0 - 0 0 7 ( 2. 0 m g) + 
s ha m i n t he first treat me nt ar m, 4 m o nt hl y i ntra vitreal i njecti o ns of R B M - 0 0 7 ( 2. 0 m g) or R B M -
0 0 7 ( 2. 0 m g) i n c o m bi nati o n wit h t w o E ylea®  i njecti o ns at e ver y ot her m o nt h f or t he sec o n d ar m, 
a n d 4 m o nt hl y i ntra vitreal i njecti o ns of s ha m  or s ha m +  E ylea ®  e ver y ot her m o nt h i n t he t hir d 
treat me nt ar m.   
T he P hase II T O F U  st u d y ( R B M- 0 0 7- 0 0 2) is c urre ntl y o n g oi n g, wit h t he first patie nt ra n d o mize d 
o n 1 7 Fe br uar y 2 0 2 0 a n d a n e x pecte d last patie nt visit (at wee k 2 4) i n J ul y 2 0 2 1. As of t he data 
c ut- off date of De vel o p me nt Safet y  U p date Re p ort ( D S U R) - R B M - 0 0 7 ( 1 9 J ul y 2 0 2 0), a t otal of 
2 3 s u bjects ha ve bee n ra n d o mize d i n t he P hase II T O F U st u d y, a n d t he treat me nt assi g n me nts 
ha ve n ot bee n u n mas ke d. A t otal of o ne S A E has bee n re p orte d i n T O F U, b ut was c o nsi dere d 
u nrelate d t o t he st u d y me dicati o n. A t otal of 2 4 A Es ha ve bee n re p orte d . C o nj u ncti val 
he m orr ha ge was t he m ost c o m m o n A E a n d it was relate d t o i njecti o n pr oce d ure. O nl y o ne 
p ossi bl y dr u g relate d A E was n ote d w hic h was I njecti o n site i nfla m mati o n t hat res ol ve d after 
ad mi nistrati o n of t o pical ster oi d dr o ps . T w o  patie nts wit h dre w fr o m t he st u d y d ue t o C O VI D- 1 9 
sc he d ule iss ues a n d o ne s u bject was f o u n d t o be i neli gi ble after ra n d o mizati o n. 
 
 
A wi de ra n ge of a ni mal t o xic ol o g y st u dies were c o n d ucte d wit h R B M -0 0 7 I njecta ble S ol uti o n b y 
b ot h s yste mic a n d oc ular r o utes. S yste mic t o xicit y was see n o nl y wit h hi g h d oses far a b o ve t h ose 
d oses c o nte m plate d f or oc ular a d mi nistrati o n. T he N O A E L i n G o o d La b orat or y Practice  (G L P ) 
i ntra vitreal m o n ke y st u dies is 1 m g/e ye. Usi n g a v ol u me of vitre o us of 2. 2 m L f or m o n ke y, t his is 
a c o nce ntrati o n of 0. 4 5 m g/ m L ( At su mi et al ., 2 0 1 3). T he h u ma n d oses f or t he first i n h u ma n st u d y 
( R B M- 0 0 7- 0 0 1) were  0. 2 m g, 1. 0 m g a n d 2. 0 m g per e ye a d mi nistere d o nce. C o nsi deri n g t he val ue 
of h u ma n vitre o us t o be 5. 2 m L ( Pa n da -J o nas, 1 9 9 4), t hese c o nce ntrati o ns are 0. 0 3 8, 0. 1 9 a n d 0. 3 8 
m g/ m L f or t hese cli nical d oses. T heref ore, t he N O A E L i n m o n ke y is 1 1 -f ol d hi g her t ha n t he 
i nte n de d starti n g cli nical d ose a n d 1. 1-f ol d hi g her t ha n i nte n de d ma xi m u m h u ma n d ose. T he safet y 
fact or w o ul d ha ve bee n e ve n hi g her if t he visc osit y a n d i njecta ble v ol u me f or R B M-0 0 7 I njecta ble 
S ol uti o n i n a ni mals ( m o n ke y a n d ra b bit) were n ot li miti n g para meters. A d diti o nall y, t he l o n g -ter m 
oc ular m o n ke y st u d y wit h m o nt hl y i njecti o n of R B M -0 0 7 at 1 m g/e ye m o n ot hera p y a n d R B M -
0 0 7 at 0. 5 or 1 m g/e ye  i n a d diti o n t o E ylea®  at 2 m g/e ye f or u p t o se ve n i njecti o ns di d n ot s h o w  
a n y treat me nt-relate d a d verse eff ect.  
Wit h re gar d t o s yste mic e x p os ure, t he hi g hest c o nce ntrati o n of R B M -0 0 7 see n i n plas ma after 
si n gle i ntra vitreal d osi n g was 2, 1 0 0 n g/ m L at a d ose of 1 m g/e ye i n m o n ke y a n d 6 5. 1  n g/ m L at a 
d ose of 0. 5 m g/e ye (i njecti o n t o b ot h e yes at a d ose of 0. 5 m g/e ye, t otal 1 m g/ b o d y) i n ra b bit. 
To xic o ki netic e val uati o n i n G L P s yste mic st u dies i n m o n ke y s u g gests t hat bl o o d le vel at w hic h 
t o xicit y  mi g ht  occ ur  is  6 9 1, 0 0 0  n g/ m L.  T h us,  e ve n  wit h o ut  c orrecti n g  f or  t he  b o d y  wei g ht  
differe nces bet wee n a ni mals a n d h u ma ns, t he sa fet y mar gi n is 1 6 5 – 5, 2 0 7 at t he ma xi m u m d ose of 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 1  of  7 4  
 
2. 0 m g/e ye f or h u ma n. If t he b o d y wei g ht f or a ni mals is ta ke n i nt o acc o u nt (ra b bit a n d m o n ke y at 
3 k g a n d h u ma n at 7 0 k g ), t he safet y mar gi n is 3, 8 5 0 – 1 2 3, 8 3 0.   
T h us, t he S p o ns or c o nte n ds t hat t he precli nical t o xic ol o g y as well as cli nical  trials wit h R B M- 0 0 7 
s u p p ort t he pla n ne d cli nical st u dies. 
 
7. 2  
N u m ber of S u bjects  
A p pr o x i matel y 4 0 s u bjects wit h wet A M D will  be e nr olle d at a p pr o xi matel y 1 0  sites. T he fi nal 
n u m ber of s u bjects e nr olle d ma y be a dj uste d base d o n d r o p-o ut rate.  S u bjects t hat s ucc essf ull y 
e xite d T O F U st u d y o n or bef ore a p pr o xi matel y Se pte m ber 1, 2 0 2 1 will be c o nsi dere d f or 
R A M E N St u d y  
7. 3  
Tre at me nt Assi g n me nt  
R B M -0 0 7 i njecta ble s ol uti o n 2. 0 m g ( 1 0 0 µ L of 2 0  m g/ m L)  will be a d mi nistere d b y I V T i njecti o n 
i n t he st u d y e ye.   
 
7. 4  
D ose A dj ust me nt Criteri a  
T he Safet y Re vie w Tea m will re vie w safet y para meters peri o dicall y a n d i n t he e ve nt of a n y S A E 
f or a dj usti n g or st o p pi n g d oses. 
7. 5  
St u dy  Pr oce d ures  
All s u bjects m ust si g n a writte n I C F bef ore partici pati n g  i n a n y st u d y-relate d acti vit y. O nce t he 
s u bject meets all eli gi bilit y re q uire me nts at Scree ni n g Pr oce d ure - Visit 1 ( Baseli ne ( Da y 1)) , eac h 
su bject will c o nti n ue t o be assi g ne d wit h t he u ni q ue s u bject n u m ber  pr o vi de d i n T O F U st u d y. If a 
s u bject is disc o nti n ue d fr o m t he st u d y f or a n y reas o n, t he s u bject n u m ber will re mai n i n effect a n d 
will n ot be re use d. 
A Sc he d ule of E ve nts ca n be f o u n d bel o w a n d detaile d pr oce d ures f or e xa mi nati o ns ca n be f o u n d 
i n Secti o n 2 1. 4 , A p pe n di x D – Pr oce d ures f or E xa mi nati o ns.  




R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 3  of  7 4  
 
 
7. 5. 1  St u dy Visits  
 Visit 1  ( B aseli ne ( D ay 1)) 
Scree ni n g  Pr oce d ure : 
- 
Ascertai n t h e patie nt has s uccessf ull y e xite d T O F U st u d y. 
- 
Visit 1 s h o ul d ha p pe n d uri n g 0 t o 6 0 da ys after t he e xit Visit i n T O F U St u d y.  
- 
Ascertai n t he patie nt has e x u dati ve A M D . 
- 
Ascertai n t he patie nt di d n ot ha ve i m pr o ve me nt of visi o n m ore t ha n 1 5 letters of B C V A 
at t he e xit visit of T O F U st u d y o ver its baseli ne. 
• 
E x plai n t he p ur p ose a n d details of t he st u d y t o t he s u bject a n d o btai n writte n i nf or me d 
c o nse nt pri or t o t he s u bject’s partici pati o n i n a n y st u d y relate d acti vit y. 
• 
Re vie w s u bject’s de m o gra p hic i nf or mati o n, me dical, s ur gical a n d me dicati o n  hist or y. 
• 
If t he s u bject c o nti n ues t o be eli gi ble f or t he st u d y, as k fe male s u bject w het her s he is 
p ost me n o pa usal ( Secti o n  2 1. 4. 4 ). Perf or m uri ne pre g na nc y test t o t he s u bject w h o a ns were d 
“ N o” t o t he q uesti o n. 
• 
Perf or m t he f oll o wi n g assess me nts (all o p ht hal mic pr oce d ures t o be perf or me d  o n b ot h 
e yes): 
- 
P h ysical e xa mi nati o n 
- 
Vital  si g ns 
- 
B C V A  ( E T D R S) 
- 
E xter nal oc ular e xa m  
- 
I O P  
- 
Slit -la m p bi o micr osc o p y 
- 
I n direct o p ht hal m osc o p y 
- 
S D -O C T  
- 
O C T  A n gi o gra p h y 
- 
F u n d us p h ot o gra p h y 
- 
F u n d us A ut ofl u oresce nce 
• 
Re vie w t he i ncl usi o n a n d e xcl usi o n criteria. D o n ot c o nti n ue scree ni n g a n y  s u bject w h o 
d oes n ot meet t he scree ni n g eli gi bilit y re q uire me nts. 
 
 
Tre at me nt Pr oce d ur e


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 4  of  7 4  
 
 
• After re vie w,  if t he s u bject c o nti n ues meeti n g all eli gi bilit y criteria, c o nfir m  t he st u d y e ye is 
sa me as i n T O F U st u d y, a n d pr ocee d f or  t he i njecti o n t hat will be a d mi nistere d as per dr u g 
la beli n g.   
• A d mi nister I V T R B M - 0 0 7 as per dr u g la beli n g. 
• T he f oll o wi n g assess me nts m ust be perf or me d after t he i njecti o n  ( o nl y o n t he treate d St u d y 
E ye):  
 
- 
Wit hi n 3 0 mi n utes p ost-i njecti o n: 
 Slit -la m p bi o micr osc o p y 
 I n direct o p ht hal m osc o p y 
- 
I O P will be meas ure d at 3 0 ( ± 1 0) mi n utes p ost- i njecti o n. 
- 
If p ost-i njecti o n I O P is > 2 1 m m H g after e ye massa ge  a n d/ or a q ue o us ta p perf or me d per 
i n vesti gat or discreti o n, I O P meas ure me nt will be re peate d at 6 0 ( ± 1 0) mi n utes p ost-
i njecti o n.   
- 
If p ost-i njecti o n I O P at 6 0 ( ± 1 0) mi n utes is > 2 1 m m H g after e ye massa ge a n d/ or 
a q ue o us ta p perf or me d per i n vesti gat or discreti o n, I O P meas ure me nt will be re peate d at 
9 0 ( ± 1 0) mi n utes p ost-i njecti o n.   
- 
If t here is a n i ncrease of ≥ 1 0 m m H g at 9 0 ( ± 1 0) mi n utes p ost-i njecti o n c o m pare d t o p re-
i njecti o n I O P, t he s u bject s h o ul d be prescri be d a t o pical I O P-l o weri n g me dicati o n u ntil 
he or s he ret ur ns f or f oll o w- u p per t he Cli nical I n vesti gat or’s discreti o n (a n u nsc he d ule d 
visit ma y a p pl y).  
- 
O n t he ot her ha n d, a s u bject wit h I O P meas ure me nt of > 2 1 m m H g will be ma na ge d 
acc or di n g t o t he discreti o n of t he Cli nical I n vesti gat or. 
- 
T he  I O P i ncrease of ≥ 1 0 m m H g fr o m p re-i njecti o n A N D I O P meas ure me nt of > 2 1 
m m H g will be re p orte d as a n  A E.  
 
• A q ue o us ta p ca n be perf or me d at a n y ti me per t he Cli nical I n vesti gat or`s discreti o n f or 
treat ment or pre ve nti o n of a n i ncrease i n t he I O P (see Fi g ure 1 ). 
 
• A E assess me nts m ust be perf or me d after I V T  i njecti o n. 
 • U pl oa d c ollecte d i ma ges ( S D -O C T  a n d F u n d us p h ot o gra p h y) of t he st u d y e ye t o t he E g n yte 
ser ver. 
• Sc he d ule t he s u bject t o ret ur n f or Visit 2 ( M o nt h 1  ( D 2 9 ± 4)). 
 
 
 
 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 5  of  7 4  
 
Fi g ur e 
Fi g ur e 1 : : D eci si o n I O P Pr oc e s s
D eci si o n I O P Pr oc e s s  f or I V T I nj ecti o n
f or I V T I nj ecti o n 
 
 
 
 
 Visit 2 ( M o nt h 1  ( D 2 9 ± 4)) 
• Pe rf or m t he f oll o wi n g assess me nts (all o p ht hal mic pr oce d ures t o be perf or me d o n b ot h 
e yes): 
- 
Q uer y f or A Es  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 6  of  7 4  
 
- 
U p date me dical hist or y a n d  me dicati o ns  
- 
B C V A  ( E T D R S) 
- 
E xter nal oc ular  e xa m 
- 
I O P  
- 
Slit -la m p bi o micr osc o p y 
- 
I n direct o p ht hal m osc o p y 
- 
S D -O C T  
- 
F u n d us p h ot o gra p h y 
 
• I njecti o n/ I O P c o ntr ol pr oce d ures are s a me as Visit 1 ( B aseli ne ( D a y 1)), descri be d i n 
Secti o n  7. 5. 1. 1  
 
• U pl oa d c ollecte d i ma ges ( S D -O C T  a n d F u n d us p h ot o gra p h y) of t he st u d y e ye t o t he E g n yte 
ser ver. 
• Sc he d ule t he s u bject t o ret ur n f or Visit 3 ( M o nt h 2 ( D 5 7 ± 4)). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 7  of  7 4  
 
 Visit 3 ( M o nt h 2  ( D 5 7 ± 4)) 
• Perf or m t he f oll o wi n g assess me nts (all o p ht hal mic pr oce d ures t o be perf or me d  o n b ot h e yes): 
- 
Q uer y f or A Es  
- 
U p date me dical hist or y a n d  me dicati o ns 
- 
B C V A  ( E T D R S) 
- 
E xte rnal oc ular e xa m  
- 
I O P  
- 
Slit -la m p bi o micr osc o p y 
- 
I n direct o p ht hal m osc o p y 
- 
S D -O C T  
- 
F u n d us p h ot o gra p h y 
 
• I njecti o n/ I O P c o ntr ol pr oce d ures are s a me as Visit 1 ( B aseli ne ( D a y 1)), descri be d i n 
Secti o n 7. 5. 1. 1  
 
• U pl oa d c ollecte d i ma ges ( S D -O C T  a n d F u n d us p h ot o gra p h y) of t he st u d y e ye t o t he E g n yte 
ser ver. 
• Sc he d ule t he s u bject t o ret ur n f or Visit 4 ( M o nt h 3  ( D 8 5 ± 4)).   
 
 Visit 4 ( M o nt h 3 ( D 8 5 ± 4)) 
• Perf or m t he f oll o wi n g assess me nts (all o p ht hal mic pr oce d ures t o be perf or me d  o n b ot h e yes): 
- 
Q uer y f or A Es  
- 
U p date me dical hist or y a n d  me dicati o ns  
- 
B C V A  ( E T D R S) 
- 
E xter nal oc ular e xa m  
- 
I O P 
- 
Slit -la m p bi o micr osc o p y 
- 
I n direct o p ht hal m osc o p y 
- 
S D -O C T  
- 
F u n d us p h ot o gra p h y 
 
• I njecti o n/ I O P c o ntr ol pr oce d ures are s a me as Visit 1 ( B aseli ne ( D a y 1)), descri be d i n 
Secti o n  7. 5. 1. 1  
 
• U pl oa d c ollecte d i ma ges ( S D - O C T a n d F u n d us p h ot o gra p h y) of t he st u d y e ye t o t he E g n yte 
ser ver. 
• Sc he d ule t he s u bject t o ret ur n f or Visit 5 ( M o nt h 4 ( D 1 1 3 ± 7 )). 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 8  of  7 4  
 
 
 Visit 5 ( M o nt h 4  ( D 11 3 ± 7)): Pri m ary E n d p oi nt 
• Perf or m t he f oll o wi n g assess me nts (all o p ht hal mic pr oce d ures t o be perf or me d  o n b ot h 
e yes): 
- 
Q uer y f or A Es  
- 
U p date me dical hist or y a n d  me dicati o ns  
- 
B C V A  ( E T D R S) 
- 
E xter nal oc ular e xa m  
- 
I O P  
- 
Slit -la m p bi o micr osc o p y 
- 
I n direct o p ht hal m osc o p y 
- 
S D -O C T  
- 
O C T  A n gi o gra p h y 
- 
F u n d us p h ot o gra p h y 
- 
F u n d us a ut ofl u oresce nce    
• U pl oa d c ollecte d i ma ges ( S D - O C T, F u n d us p h ot o gra p h y a n d F u n d us a ut ofl u oresce nce ) of 
t he st u d y e ye t o t he E g n yte ser ver. 
• Sc he d ule t he s u bject t o ret ur n f or Visit 6 ( M o nt h 5  ( D1 4 1 ± 7 )).  
 
 Visit 6 / E xit ( M o nt h 5 ( D 1 4 1 ± 7)) 
• Perf or m t he f oll o wi n g  assess me nts: 
- 
Q uer y f or A Es  
- 
P h ysical E xa m  
- 
Vital Si g ns  
- 
U p date me dical hist or y a n d  me dicati o ns 
- 
Perf or m uri ne pre g na nc y test t o t he s u bject w h o a ns were d “ N o” t o t he q uesti o n o n 
p ost me n o pa usal at Visit 1 ( B aseli ne ( D ay 1)).  
- 
B C V A  ( E T D R S) 
- 
E xter nal oc ular e xa m  
- 
I O P 
- 
Slit -la m p bi o micr osc o p y 
- 
I n direct o p ht hal m osc o p y 
- 
S D -O C T  
- 
F u n d us p h ot o gra p h y 
• U pl oa d c ollecte d i ma ges ( S D -O C T a n d F u n d us p h ot o gra p h y) of t he st u d y e ye t o t he E g n yte 
ser ver. 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
2 9  of  7 4  
 
7. 5. 2  U nsc he d ule d Visits  
If a s u bject re q uires e val uati o n bet wee n sc he d ule d visits, c o m plete all a p plica ble st u d y s pecifie d 
pr oce d ures as necessar y a n d rec or d t he i nf or mati o n o n t he U nsc he d ule d Visit f or m(s). 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 0  of  7 4  
 
8  S E L E C TI O N A N D WI T H D R A W A L O F  S U B J E C T S  
Eli gi ble s u bjects m ust meet all eli gi bilit y criteria descri be d i n Secti o n 8. 1  a n d Secti o n  8. 2. 
 
8. 1  
S u bject I ncl usi o n  Criteri a  
 
At Visit 1 ( B aseli ne ( D ay 1)) , s u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria: 
1.  Pr o vi de si g ne d writte n i nf or me d c o nse nt o n t he I nstit uti o nal Re vie w B oar d  (I R B)/ Et hics 
C o m mittee ( E C) a p pr o ve d I nf or me d C o nse nt F or m (I C F) a n d pr o vi de a ut h orizati o n as 
a p pr o priate f or l ocal pri vac y  re g ulati o ns. 
2.  Male or fe male 5 5 years of a ge or ol der o n t he date of si g ni n g t he I C F a n d a ble a n d willi n g 
t o c o m pl y wit h all treat me nt a n d st u d y pr oce d ures. 
3.  S u bjects m ust ha ve c o m plete d all sc he d ule d visits of T O F U st u d y. S u bjects ca n o nl y e nter 
t his st u d y after e xiti n g T O F U st u d y 
4.  S u bjects f or w hic h pre vi o us T O F U mas ke d treat me nt ar ms wit h i ntra vitreal a nti -
vasc ular e n d ot helial gr o wt h fact or (a nti -V E G F) a ge nts  E ylea ®  a n d/ or R B M - 0 0 7 h as 
n ot  de m o nstrate d i m pr o ve me nt i n visi o n; s u bjects wit h less t ha n 1 5 letter B C V A 
i m pr o ve me nt i n T O F U st u d y at e xit visit o ver its baseli ne. 
5.  Dia g n osis of e x u dati ve A M D i n t he st u d y e ye, as assesse d b 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). 
6.  A bse nce of ce ntral atr o p h y or reti nal e pit helial tear i n t he f o vea or a n y c o n diti o n 
pre ve nti n g V A i m pr o ve me nt  i n t he st u d y e ye. 
7.  B C V A of 2 4 E T D R S letters ( 2 0/ 3 2 0) or better i n t he fell o w e ye  
8.  Reas o na bl y clear me dia a n d s o me fi xati o n i n t he st u d y e ye t o all o w f or g o o d q ualit y  S D -
O C T a n d f u n d us p h ot o gra p h y. 
 
8. 2  
S u bject E xcl usi o n  Criteri a  
 
A s u bject wit h a n y of t he f oll o wi n g c o n diti o ns is n ot eli gi ble t o partici pate i n t he st u d y: 
Oc ul ar:  
1.  S u bjects w h ose visi o n ha ve i m pr o ve d > 1 5 B C V A letters at e xit visit of T O F U st u d y o ver 
its baseli ne 
2.  S u bjects w h o e x perie nce d a n y dr u g relate d seri o us a d verse e ve nt d uri n g T O F U st u d y 
3.  Use  of  a n y  of  t he  f oll o wi n g  treat me nts  or  a ntici pate d  use  of  a n y  of  t he  f oll o wi n g  
treat me nts t o t he st u d y e ye: 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 1  of  7 4  
 
a. I ntra vitreal or peri oc ular c ortic oster oi d, wit hi n 9 0 da ys pri or t o Visit 1 ( Da y 1) 
a n d t hr o u g h o ut t he st u d y. 
b.  Fl u oci n ol o ne acet o ni de i ntra vitreal i m pla nt, wit hi n 1 2 m o nt hs pri or t o Visit 1 
( Da y 1) a n d t hr o u g h o ut t he st u d y. 
c. Vis u d y ne ®  p h ot o d y na mic t hera p y, wit hi n 9 0 da ys pri or t o Visit 1 ( Da y 1) a n d  
t hr o u g h o ut t he st u d y. 
4.  U nc o ntr olle d or a d va nce d gla uc o ma, e vi de nce d b y a n I O P of > 2 1 m m H g or c u p/ disc 
rati o > 0. 8 w hile o n me dical t hera p y, or c hr o nic h y p ot o n y ( < 6 m m H g) i n t he st u d y e ye. 
5.  E vi de nce of a n y ot her oc ular disease ot her t ha n wet A M D i n t he st u d y e ye t hat ma y 
c o nf o un d t he o utc o me of t he st u d y (e. g., acti ve dia betic reti n o pat h y, p osteri or u veitis,  
pse u d o vitellif or m mac ular de ge nerati o n, m o derate/se vere m y o pia).  
6.  Hist or y of vitrect o m y i n t he st u d y  e ye. 
7.  Nee d f or oc ular s ur ger y i n t he st u d y e ye d uri n g t he c o urse of t he st u d y. 
8.  Y A G laser ca ps ul ot o m y wit hi n 3 0 da ys pri or t o Visit 1 ( Da y 1) i n t he st u d y  e ye. 
9.  I ntra oc ular s ur ger y, i ncl u di n g le ns re m o val or laser, wit hi n 9 0 da ys pri or t o Visit 1 
(Baseli ne ( Da y 1)) i n t he st u d y e ye. 
1 0.  Oc ular or peri oc ular i nfecti o n i n eit her  e ye. 
1 1.  P u pillar y dilati o n i na de q uate f or q ualit y f u n d us p h ot o gra p h y i n t he st u d y e ye. 
1 2.  Me dia  o pacit y  t hat  w o ul d  li mit  cli nical  vis ualizati o n,  f u n d us  p h ot o gra p h y ,  f u n d us 
a ut ofl u orescence, or S D - O C T e val uati o n i n t he st u d y e ye. 
1 3.  Hist or y of her petic i nfecti o n i n t he st u d y e ye or a d ne xa. 
1 4.  Prese nce of k n o w n acti ve t o x o plas m osis, i nacti ve t o x o plas m osis or t o x o plas m osis scar 
i n eit her e ye. 
1 5.  Prese nce of a n y f or m of oc ular mali g na nc y i ncl u di n g c h or oi dal mela n o ma i n eit her  e ye. 
 
N o n -Oc ul ar:  
1 6.  Pri or s yste mic treat me nt wit h R B M- 0 0 7 i njecta ble s ol uti o n. 
1 7.  Use  of  a n y  of  t he  f oll o wi n g  treat me nts  or  a ntici pate d  use  of  a n y  of  t he  f oll o wi n g  
treat me nts d uri n g t he st u d y: 
a. S yste mic treat me nt wit h a nti - V E G F a ge nts (e. g., be vaciz u ma b)  
b.  A ge nts tar geti n g t he F G F- 2 pat h wa y 
1 8.  Aller g y or h y perse nsiti vit y t o st u d y dr u g pr o d uct, fl u orescei n d ye, or ot her st u d y relate d 
pr oce d ures/ me dicati o ns.  
1 9.  Maj or s ur ger y wit hi n 9 0 da ys pri or t o Visit 1 ( Baseli ne ( Da y 1) ). Maj or s ur ger y is defi ne d 
as a n y s ur ger y i n v ol vi n g a ris k t o t he life of t he s u bject, i ncl u di n g a n y o perati o n u p o n a n 
or ga n wit hi n t he cra ni u m, c hest, a b d o me n, or pel vic ca vit y. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 2  of  7 4  
 
2 0.  T hera pe utic ra diati o n t o t he hea d or nec k wit hi n 9 0 da ys pri or t o Visit 1 ( Da y 1). 
2 1.  Partici pati o n i n ot her i n vesti gati o nal dr u g or de vice cli nical trials wit hi n 3 0 da ys pri or t o 
Visit 1 ( Baseli ne ( Da y 1) ) or pla n ni n g t o partici pate i n ot her i n vesti gati o nal dr u g or de vice 
cli nical trials f or t h e d urati o n of t he st u d y. T his i ncl u des b ot h oc ular a n d n o n -oc ular 
cli nical trials. 
2 2.  Hist or y of ot her disease, meta b olic d ysf 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 gi vi n g reas o na ble s us pici o n of a disease c o n diti o n t hat c o ntrai n dicates 
t he use of a n i n vesti gati o nal dr u g, mi g ht affect t he i nter pretati o n of t he res ults of t he 
st u d y, or re n ders t he s u bject at hi g h ris k f or treat me nt c o m plicati o ns. 
2 3.  Fe males w h o are pre g na nt or lactati n g a n d fe males of c hil d -beari n g p ote ntial w h o are n ot 
usi n g a de q uate c o ntrace pti ve preca uti o ns (i.e., I U D, oral c o ntrace pti ves, barrier met h o d, 
or ot her c o ntrace pti o n  dee me d a de q uate b y t he Cli nical I n vesti gat or).  
2 4.  U na ble t o c o m pl y wit h st u d y pr oce d ures or f oll o w- u p visits. 
 
I n a d diti o n, t he Cli nical I n vesti gat or or RI B O MI C Me dical M o nit or ma y declare a s u bject 
i neli gi ble f or a n y s o u n d reas o n. 
 
8. 3  
S u bject Wit h dr a w al Criter i a 
A n  earl y  ter mi nati o n  occ urs  w he n  a  s u bject  w h o  pr o vi des  writte n  i nf or me d  c o nse nt  ceases  
partici pati o n i n t he st u d y, re gar dless of circ u msta nces, bef ore t he c o m pleti o n of t he st u d y. S u bjects 
ma y v ol u ntaril y wit h dra w fr o m t he st u d y at a n y ti me f or a n y rea s o n. I n a d diti o n, t he Cli nical 
I n vesti gat or or t he Me dical M o nit or ma y ter mi nate a s u bject’s st u d y partici pati o n f or reas o ns 
relate d t o t he best i nterest of t he s u bject. S u bjects w h o ter mi nate fr o m t he st u d y ma y be re place d. 
S u bjects ma y be ter mi nate d fr o m  t he st u d y d ue t o a n y of t he f oll o wi n g reas o ns: 
 • N o n -c o m plia nce 
• L ost t o  f oll o w- u p 
• Pr ot oc ol vi olati o n  
• Wit h dra wal b y  s u bject 
• A Es  
• Deat h  
• Ot her  
If a s u bject is disc o nti n ue d fr o m t he st u d y bef ore c o m pleti n g Visit 6/ E xit ( M o nt h 5) ( D 1 4 1 ± 7)), 
t he n t o t he e xte nt p ossi ble, all assess me nts, i ncl u di n g safet y, t hat are sc he d ule d t o be perf or me d at 
Visit 6/ E xit s h o ul d be perf or me d o n t he da y of disc o nti n uati o n. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 3  of  7 4  
 
9  T R E A T M E N T O F  S U B J E C T S  
9. 1  
Descri pti o n of St u dy Dr u g  
R B M -0 0 7  is  a  pe g ylate d  oli g o n ucle oti de -base d  a pta mer.  R B M -0 0 7  i njecta ble  s ol uti o n  is  a  
f or m ulati o n desi g ne d f or i ntra vitreal i njecti o n. R B M-0 0 7 has a n a p pr o xi mate m olec ular wei g ht of 
5 4 k Da.   
9. 2  
C o nc o mit a nt Me dic ati o ns  
T he use of a n y c o nc o mita nt prescri pti o n or o ver -t he-c o u nter me dicati o n will be rec or de d d uri n g 
t he st u d y. T hera p y c o nsi dere d necessar y f or t he s u bject’s welfare ma y be gi ve n at t he discreti o n of 
t he Cli nical I n vesti gat or d uri n g t he st u d y. W he ne ver p ossi ble, c o nc o mita nt me dicati o ns s h o ul d be 
a d mi nistere d i n d osa ges t hat re mai n c o nsta nt t hr o u g h o ut t he st u d y. T he ge neric na me, i n dicati o n, 
r o ute of a d mi nistrati o n, fre q ue nc y, d ose, start date a n d st o p date (if a p plica ble) will be rec or de d 
f or eac h me dicati o n. 
9. 2. 1  Pr o hi bite d Me dic ati o ns or Tre at me nts  
A n y s yste mic treat me nts w it h a nti-V E G F a ge nts (e. g., be vaciz u ma b) are pr o hi bite d d uri n g t he 
st u d y. 
T he decisi o n t o a d mi nister a pr o hi bite d c o nc o mita nt me dicati o n or treat me nt d uri n g t he st u d y 
s h o ul d be ma de wit h t he safet y of t he s u bject as t he pri mar y c o nsi derati o n. W he ne ver p oss i ble, 
RI B O MI C s h o ul d be n otifie d bef ore a n y pr o hi bite d me dicati o n or treat me nt is a d mi nistere d or if 
t he per missi bilit y of a s pecific me dicati o n or treat me nt is i n q uesti o n. 
9. 2. 2  Resc ue  T her a p y  
Resc ue t hera p y is defi ne d as I V T i njecti o n of E ylea ®  or a n y ot her treat me nt at t he discreti o n of 
i n vesti gat or i n t he st u d y e ye.   
W he ne ver p ossi ble, RI B O MI C s h o ul d be n otifie d bef ore a n y resc ue pr oce d ure. 
If resc ue wit h a nti-V E G F a ge nt is c o nsi dere d, t he s u bject m ust recei ve t he i njecti o n of 
R B M - 0 0 7 pri or t o  t he i njecti o n of a nti-V E G F a ge nt f or resc ue.  
Eli gi bilit y  criteria f or Resc ue are as f oll o w:  
•  B C V A decrease of > 1 0 letters A N D  ce ntral s u bfiel d t hic k ness ( C S T) i ncrease of > 5 0 µ m 
fr o m t he R A M E N  baseli ne  visit . 
•  T he discreti o n of i n vesti gat or.   
If resc ue is perf or me d, t he f oll o wi n g assess me nts m ust be perf or me d after t he a d mi nistrati o n of 
eac h o ne of t he i njecti o ns ( R B M-0 0 7 a n d Resc ue treat me nt ) (all o p ht hal mic pr oce d ures t o be 
perf or me d  i n t he treate d e ye): 
 
- Wit hi n 3 0 mi n utes f oll o wi n g eac h o ne of t he i njecti o ns:  
o  Slit -la m p bi o micr osc o p y 
o  I n direct o p ht hal m osc o p y 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 4  of  7 4  
 
- 
IO P will be meas ure d at 3 0 ( ± 1 0) mi n utes f oll o wi n g t he i ntra vitreal i njecti o n.  
- 
If p ost-i njecti o n I O P is > 2 1 m m H g after e ye massa ge a n d/ or a q ue o us ta p perf or me d per 
i n vesti gat or  discreti o n, I O P meas ure me nt  will  be  re peate d  at  6 0  ( ± 1 0)  mi n utes  p ost-
i njecti o n.   
- 
If p ost-i njecti o n I O P at 6 0 ( ± 1 0) mi n utes is > 2 1 m m H g after e ye massa ge a n d/ or a q ue o us 
ta p perf or me d per i n vesti gat or discreti o n, I O P meas ure me nt will be re peate d at 9 0 ( ± 1 0) 
mi n utes p ost-i njecti o n.   
- 
If t here is a n i ncrease of ≥ 1 0 m m H g at 9 0 ( ± 1 0) mi n utes p ost-i njecti o n c o m pare d t o pre-
i njecti o n I O P, t he s u bject s h o ul d be prescri be d a t o pical I O P-l o weri n g me dicati o n u ntil he 
or s he ret ur ns f or f oll o w -u p per t he Cli nical I n vesti gat or’s discreti o n (a n u nsc he d ule d visit 
ma y a p pl y). 
- 
O n t he ot her ha n d, a s u bject wit h I O P meas ure me nt of > 2 1 m m H g will be ma na ge d 
acc or di n g t o t he discreti o n of t he Cli nical I n vesti gat or. 
- 
T he I O P i ncrease of ≥ 1 0 m m H g fr o m pre -i njecti o n A N D I O P meas ure me nt of > 2 1 m m H g 
will be re p orte d as a n A E.  
•  A q ue o us  ta p  ca n  be  perf or me d  at  a n y  ti me  per  t he  Cli nical  I n vesti gat or`s  discreti o n  f or  
treat me nt or pre ve nti o n of i ncreasi n g i n t he I O P. 
 
9. 3  
Tre at me nt  C o m pli a nce 
I n or der t o o btai n efficac y a n d safet y data, it is critical t hat t he treat me nt re gi me n a n d visit sc he d ule 
s pecifie d i n t his pr ot oc ol are f oll o we d. T he Cli nical I n vesti gat or is re q uire d t o a d mi nister   t he 
R B M -0 0 7 i njecti o n a n d is res p o nsi ble f or sc he d uli n g t he s u bject f or f oll o w -u p visits as s pecifie d 
i n t he pr ot oc ol. St u d y m o nit ors will verif y perti ne nt data t o c o nfir m t he st u d y is c o n d ucte d 
acc or di n g t o t he pr ot oc ol. 
 
9. 4  
R a n d o miz ati o n a n d M as ki n g 
Ra n d o mizati o n is n ot e m pl o ye d i n t his st u d y d ue t o t he o pe n-la bel desi g n. 




R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 6  of  7 4  
 
O nce a n i n vesti gati o nal dr u g kit has b ee n assi g ne d t o a s u bject, t he vial of i n vesti gati o nal dr u g f or 
t he visit will be re m o ve d fr o m t he kit i n t he freezer. T he c o nte nt s h o ul d be t ha we d b y r otati n g t he 
vial bet wee n t he pal ms of t he ha n ds, or b y setti n g t he vial at r o o m te m perat ure. Care s h o ul d be 
ta ke n t o pr otect t he pr o d uct fr o m li g ht.   
I n vesti gati o nal dr u g s h o ul d be use d f or i ntra vitreal i njecti o n i n t he st u d y s u bject w it hi n 1 h o ur 
after re m o vi n g t he vial fr o m t he freezer.  
St u d y dr u g pre parati o n s h o ul d be perf or me d b y t he desi g nate d i njecti n g p h ysicia n. 
Eac h vial c o ntai ns e n o u g h R B M -0 0 7 t o i nject o ne s u bject. Eac h vial will be use d o ne ti me o nl y. 
Write t he s u bject n u m ber o n t he cart o n la bel. After use, ret ur n t he vial i n t he cart o n, seal a n d i nitial 
t he cart o n. 
1 0. 5  L o a di n g t he Syri n ge  
<I n vesti gati o nal dr u g: R B M- 0 0 7 > 
1.  A sterile, si n gle -use 2 5 0 μ L s yri n ge wit h se veral c ust o m mar ki n g s, i ncl u di n g 0. 1 m L ( 1 0 0  
µ L ), will be pr o vi de d se paratel y f or I V T i njecti o n of R B M -0 0 7. I nstr ucti o ns f or filli n g t he 
s yri n ge are as f oll o ws: 
2.  Re m o ve t he sterile, si n gle - use 2 5 0 μ L s yri n ge fr o m t he pac ka gi n g. 
3.  Attac h a 1 9 -ga u ge x 1 ½ i nc h filter nee dle t o t he s yri n ge. R B M -0 0 7 is dis pe nse d i n a  0. 5 ml 
fill i n a 2 m L vial. See Fi g ure 2 . 
4.  Usi n g sterile tec h ni q ue, caref ull y dra w u p a p pr o xi matel y 2 0 0 μ L of R B M -0 0 7 i nt o t he 
s yri n ge (suffic ie ntl y lar ger v ol u me t ha n 1 0 0 µ L is nee de d t o all o w f or dea d s pace i n s yri n ge 
a n d nee dles pri or t o I V T i njecti o n).  
5.  Re m o ve t he 1 9 -ga u ge x 1 ½ i nc h filter nee dle fr o m t he s yri n ge a n d re place wit h a 3 0 - ga u ge 
x 0. 5 i nc h nee dle f or t he I V T i nj ecti o n. 
A.  E ns ure t hat t he 3 0- ga u ge x 0. 5 i nc h nee dle is affi xe d ti g htl y t o t he s yri n ge. 
B.  Ali g n t he t o p e d ge of t he re d O -ri n g of t he pl u n ger wit h t he 1 0 0 µ L blac k mar k o n t he 
s yri n ge, e x pelli n g t he e xcess fl ui d dra w n u p. 
C.  E ns ure t here are n o air b u b bles wit hi n  t he s yri n ge or t he nee dle h u b pri or t o i njecti o n, 
a n d pri or t o e x pelli n g t he e xcess fl ui d dra w n u p. 
Fi g ur e 
Fi g ur e 2 : 0.0. 5  m L fill i n a 2 m L vi al
m L fill i n a 2 m L vi al  
 
<I n vesti gati o nal dr u g > 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 7  of  7 4  
 
1 0. 6  Eye  Pre p ar ati o n 
Pri or t o R B M - 0 0 7 a d mi nistrati o n, t he st u d y e ye s h o ul d be pre pare d as f oll o ws: 
1.  Dilate  p u pil  ( 1  %  m y driac yl  a n d  2. 5  %  p he n yle p hri ne  or  e q ui vale nt  a p plie d  t o picall y) 
a p pr o xi matel y 1 0 mi n utes pri or t o  i njecti o n. 
2.  A d mi nister 1 e ye dr o p of t o pical a nest hetic ( 0. 5 % pr o paracai ne h y dr oc hl ori de o p ht hal mic 
s ol uti o n or a n e q ui vale nt t o pical o p ht hal mic a nest hetic). 
3.  A d mi nister 5 % p o vi d o ne i o di ne. 
4.  Use a sterile c ott o n -ti p pe d a p plicat or t o re m o ve e xcess fl ui d fr o m t he l o wer c o nj u ncti val sac. 
5.  Ta ke 2 sterile c ott o n ti p pe d a p plicat ors a n d t h or o u g hl y s oa k wit h 0. 5 % pr o paracai ne t o pical 
a nest hetic e ye dr o ps or a n e q ui vale nt t o pical o p ht hal mic a nest hetic. Place t he s oa ke d 
a p plicat ors, si de b y si de, ge ntl y b ut fir ml y o n t he c o nj u ncti val s urface at t he  area of t he 
e ntr y site descri be d bel o w i n Ste p 2 ( Secti o n 1 0. 7 ) a n d h ol d i n place f or a p pr o xi matel y 1  
mi n ute. 
6.  I nsert sterile e yeli d s pec ul u m. 
 
1 0. 7  St u dy Dr u g A d mi nistr ati o n  
<I n vesti gati o nal dr u g: R B M- 0 0 7 > 
1.  Pr i or t o starti n g t he i njecti o n pr oce d ure, R B M- 0 0 7 s h o ul d ha ve bee n pre pare d as descri be d i n 
Secti o n  1 0. 4  a n d Secti o n  1 0. 5 , a n d t he st u d y e ye s h o ul d ha ve bee n pre pare d as descri be d i n 
Secti o n  1 0. 6 . 
2.  T he e ntr y site f or i njecti o n is 4. 0 m m p osteri or t o t he c or neal li m b us. A cali per ma y be use d 
t o i de ntif y t he nee dle e ntr y site. 
3.  I nsert t he nee dle per pe n dic ular t o t he e ye wall at t he l ocati o n s pecifie d i n Ste p 2 (Secti o n 
1 0. 7 ) t o i nject t he st u d y s ol uti o n i nt o t he vitre o us ca vit y. N ote: If a q ue o us ta p is c o nsi dere d 
necessar y, it s h o ul d be perf or me d prefera bl y pri or t o i njecti o n of t he R B M - 0 0 7 a n d n ote d i n 
t he s o urce d oc u me nts. 
4.  Ver y sl o wl y, i nject t he e ntire R B M - 0 0 7 d ose v ol u me ( 1 0 0 µ L) a n d sl o wl y wit h dra w t he 
nee dle. D o n ot p ull bac k o n t he pl u n ger at a n y ti me pri or t o wit h dra wi n g t he nee dle.  
5.  Briefl y a p pl y press ure f or a p pr o xi matel y 3 0 sec o n ds t o t he nee dle e ntr y site wit h sterile 
c ott o n ti p pe d a p plicat or ( ma y be s ki p pe d per Cli nical I n vesti gat or's discreti o n). 
6.  Re m o ve t he e yeli d s pec ul u m a n d ri nse t he e ye wit h sterile e y e was h s ol uti o n.  
7.  Patc h t he st u d y e ye at t he Cli nical I n vesti gat or's discreti o n.  
8.  Prescri be t o pical a nti bi otic per PI discreti o n.  
 
1 0. 8  St u dy Dr u g Acc o u nt a bility  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e ns uri n g t hat a n i n ve nt or y is c o n d ucte d u p o n recei pt 
of t he cli nical s u p plies. T he te m perat ure rec or der fr o m t he s hi p me nt will be deacti vate d a n d 
a ut h orize d st u d y staff will verif y t hat t he te m perat ure was mai ntai ne d at -2 0° C d uri n g tra nsit. T he 
cli nical s u p plies s hi p me nt f or m s h o ul d be c o m plete d, si g ne d, a n d ret ur ne d as directe d. A c o p y 
m ust be mai ntai ne d at t he site f or t he Pri nci pal I n vesti gat or's rec or ds.  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 8  of  7 4  
 
T he Pri nci pal I n vesti gat or will kee p a c urre nt rec or d of t he i n ve nt or y, st ora ge c o n diti o ns a n d 
dis pe nsi n g of all st u d y dr u gs. T his rec or d will be ma de a va ila ble t o RI B O MI C ( or desi g nee) f or 
acc o u nti n g  f or  all  cli nical  s u p plies.  A n y  si g nifica nt  discre pa nc y  a n d/ or  deficie nc y  m ust  be  
rec or de d wit h a n e x pla nati o n. 
All s u p plies se nt t o t he Pri nci pal I n vesti gat or m ust be acc o u nte d f or a n d i n n o case will st u d y dr u gs 
be use d i n a n y u na ut h orize d sit uati o n. It is t he res p o nsi bilit y of t he Pri nci pal I n vesti gat or t o e ns ure 
t hat a n y use d a n d u n use d s u p plies are a vaila ble t o RI B O MI C ( or desi g nee) t hr o u g h o ut t he st u d y. 
 
 
1 0. 9  St u dy Dr u g H a n dli n g a n d  Ret ur n  
All i n vesti gati o nal pr o d ucts i ncl u di n g u n use d vials of R B M- 0 0 7 will be f ull y acc o u nte d f or b y t he 
m o nit or wit h t he hel p of t he  pers o n res p o nsi ble f or dis pe nsi n g t he R B M -0 0 7 a n d will be ret ur ne d 
t o  RI B O MI C or  its  Re prese ntati ve.  Acc o u nta bilit y  will  be  d oc u me nte d  b y  use  of  dr u g  
acc o u nta bilit y f or ms.   
T he  use d  vials  of  R B M - 0 0 7 will  be  st ore d  at  t he  i n vesti gati o nal  site  u p o n  c o m pleti o n  of  
acc o u nta bilit y pr oce d ures a n d ret ur ne d t o RI B O MI C or desi g nee after t he trial is c o m plete d . 
Refer t o St u d y Dr u g Ma n ual f or st u d y dr u g ha n dli n g. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
3 9  of  7 4  
 
1 1  A S S E S S M E N T  O F  E F FI C A C Y  
1 1. 1  Best C orrecte d Vis u al Ac uity  ( B C V A) 
Mea n c ha n ge i n B C V A fr o m Baseli ne at M o nt h 4 is t he pri mar y efficac y varia ble f or t his st u d y. 
Pr o p orti o n of s u bjects wit h B C V A: 1) gai n of ≥1 5 E T D R S letters ( 3 -line gai ners); 2) gai n of ≥1 0 
E T D R S letters; 3) gai n of ≥5 E T D R S letters a n d 4) ≥ 1 5 letter l oss fr o m Baseli ne at M o nt h 4 are 
ot her sec o n dar y e n d p oi nts. 
T he vis ual ac uit y will be rec or de d usi n g t he E T D R S c hart a n d t otal n u m ber of letters at 4 meter 
a n d 1 meter will be rec or de d. T he “ n o n st o p pi n g” r ule m ust be a p plie d d uri n g t he E T D R S B C V A 
e val uati o n, c o nsi deri n g e ver y letter t he s u bject ca n rea d. If a s u bject c o ul d n ot rea d E T D R S c hart, 
Fi n ger C o u nts, Ha n d M oti o n, Li g ht Perce pti o n, or N o Li g ht Perce pti o n will be rec or de d.  
1 1. 2  Ce ntr al S u bfiel d T hic k ness ( C S T),  M ac ul ar Vol u me ( M V) , Fi br osis a n d S H R M 
C S T,  M V,  fi br osis a n d S H R M are sec o n dar y efficac y varia bles, a n d c ha n ge i n C S T, M V, fi br osis 
a n d S H R M fr o m B aseli ne at M o nt h 4 are sec o n dar y e n d p oi nts.   


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 0  of  7 4  
 
1 2  A S S E S S M E N T  O F  S A F E T Y  
1 2. 1  A dverse  Eve nts  
1 2. 1. 1  Defi niti o n of A d verse E ve nts  
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a p har mace utical pr o d uct 
a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o n s hi p wit h t he st u d y dr u g(s). A n A E, t heref ore, 
ca n be a n 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), s y m pt o m, or disease t hat 
has cli nical si g nifica nce a n d is te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) 
pr o d uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.  
I n cli nical st u dies, a n u n desira ble me dical c o n diti o n occ urri n g at a n y ti me, i ncl u di n g B aseli ne or 
pre-treat me nt peri o d, ma y be rec or de d as a n A E e ve n if n o st u d y dr u g has bee n a d mi nistere d. 
A n y si g nifica nt a d verse c ha n ge i n a s u bject’s c o n diti o n fr o m B aseli ne, re gar dless of ca usalit y, is 
t o be c o nsi dere d a n A E, u nless t he c ha n ge is deter mi ne d t o be a c o nti n uati o n of a pre-e xisti n g 
c o n diti o n t hat is d oc u me nte d i n t he s u bject’s me dical hist or y.  H o we ver, a cli nicall y si g nifica nt 
w orse ni n g i n se verit y, i nte nsit y, or fre q ue nc y of a pre -e xisti n g c o n diti o n ma y i n dicate a n A E. I n 
a d diti o n, all c o n diti o ns t hat lea d t o h os pitalizati o ns, defi ne d as a n o ver ni g ht h os pital sta y, are 
c o nsi dere d as A Es. T his i ncl u des pla n ne d electi ve s ur geries. 
Lac k of efficac y of t he st u d y dr u g(s) f or t he c o n diti o n bei n g i n vesti gate d is n ot c o nsi dere d a n A E 
u nless a cli nicall y si g nifica nt c ha n ge is assesse d b y t he Cli nical I n vesti gat or.    A n electi ve s ur gical 
pr oce d ure sc he d ul e d or pla n ne d pri or t o st u d y e ntr y is n ot c o nsi dere d a n A E if a n o ver ni g ht 
h os pital sta y is n ot re q uire d, a n d t he u n derl yi n g dia g n osis f or w hic h s ur ger y is t o be perf or me d 
s h o ul d be ca pt ure d i n t he me dical hist or y as a pre-e xisti n g c o n diti o n. T he s ur gical pr oce d ure 
s h o ul d als o i ncl u de t he ter m “electi ve” i n all re p orts. 
E n d o p ht hal mitis a n d reti nal detac h me nts ma y occ ur f oll o wi n g i ntra vitreal i njecti o ns. Patie nts 
s h o ul d be m o nit ore d f oll o wi n g t he i njecti o n. 
 
 Assess me nt of A dverse Eve nts  
Cli nical I n vesti gat or s will see k i nf or mati o n o n A Es at eac h s u bject c o ntact. S u bjects s h o ul d be 
as ke d, usi n g a ge neral, n o n -direct q uesti o n, if t here has bee n a n y c ha n ge i n t heir ge neral healt h. 
Direct q uesti o ni n g a n d e xa mi nati o n s h o ul d t he n be perf or me d as a p pr o priate. 
Se veri t y of t he A E s h o ul d be assesse d acc or di n g t o t he f oll o wi n g criteria: 
 • Mil d: N o i nterfere nce wit h t he s u bject’s dail y acti vities; n o me dical i nter ve nti o n/t hera p y  
re q uire d 
• M o der ate: P ossi ble i nterfere nce wit h t he s u bject’s dail y acti vit ies; n o or mi ni mal me d ical 
i nter ve nti o n/t hera p y re q uire d 
• Se vere: C o nsi dera ble i nterfere nce wit h t he s u bj ect’s dail y acti vities; me dical 
i nter ve nti o n/t hera p y re q uire d 
Re gar dless of se verit y, s o me A Es ma y als o meet re g ulat or y seri o us criteria. Refer t o defi niti o ns 
a n d re p orti n g o f seri o us a d verse e ve nts ( S A Es) i n Secti o n 1 2. 1. 2 . 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 1  of  7 4  
 
A  Cli nical  I n vesti gat or  w h o  is  q ualifie d  i n  me dici ne  m ust  ma ke  t he  deter mi nati o n  of  t he  
relati o ns hi p of t he st u d y dr u g(s) t o eac h A E (relate d or n ot relate d). T he Cli nical I n vesti gat or 
s h o ul d deci de w het her, i n his or her me dical j u d g me nt, t here is a reas o na ble p ossi bilit y t hat t he 
R B M -0 0 7 i njecti o n c o ul d ha ve ca use d t he A E/ S A E base d o n facts, e vi de nce, scie ntific rati o nales, 
a n d  cli nical  j u d g me nt.  W he n  assessi n g  ca usalit y,  t he  Cli nical  I n vest i gat or  ma y  c o nsi der  t he  
f oll o wi n g  i nf or mati o n  w he n  deter mi ni n g  t he  relati o ns hi p  t o  t he  st u d y  dr u g(s)  f or  eac h  A E:  
mec ha nis m  of  acti o n,  bi ol o gic  pla usi bilit y,  c o nf o u n di n g  ris k  fact ors  (i.e.,  me dical  hist or y,  
c o nc o mita nt me dicati o ns), te m p oral relati o ns hi p, dec halle n ge/rec halle n ge, a n d lac k of alter nati ve 
e x pla nati o n. It s h o ul d be s pecifie d if t he A E is relate d t o t he i njecti o n pr oce d ure a n d n ot t he st u d y 
dr u g. 
•  
T he A E ma y be rec or de d as Rel ate d t o t he st u d y dr u g(s) if t here is a pla usi ble te m p oral 
relati o ns hip bet wee n t he o nset of t he A E a n d a d mi nistrati o n of t he st u d y dr u g(s ); a n d t he A E 
ca n n ot be rea dil y e x plai ne d b y t he s u bject’s cli nical state, c o nc urre nt ill ness, or c o nc o mita nt 
t hera pies; a n d/ or t he A E f oll o ws a k n o w n patter n of res p o nse t o  t he st u d y dr u g(s); a n d/ or t he 
A E a bates or res ol ves u p o n disc o nti n uati o n of t he st u d y dr u g(s). 
•  
Re p orti n g t he A E as N ot Rel ate d t o st u d y dr u g(s), ma y be c o nsi dere d if, f or e xa m ple, t here 
is g o o d e vi de nce t hat t he A E has a n eti ol o g y ot her t ha n t he st u d y dr u g(s) (e. g., pre-e xisti n g 
me dical  c o n diti o n,  u n derl yi n g  disease,  c o nc urre nt  ill ness,  or  c o nc o mita nt  me dicati o n);  
a n d/ or t he A E has n o pla usi ble te m p oral relati o ns hi p t o a d mi nistrati o n of t he st u d y dr u g(s) 
(e. g., ca ncer dia g n ose d 2 da ys after d ose of st u d y dr u g(s)). 
 
 Re p or ti n g A dverse Eve nts  
A Es, w het her s p o nta ne o usl y re p orte d b y t he s u bject or n ote d b y a ut h orize d st u d y pers o n nel, will 
be rec or de d i n t he s u bject’s me dical rec or d a n d o n t he a p pr o priate A E e C R F . Eac h rec or de d A E 
will  be  descri be d  b y  its  d urati o n  (i.e.,  start  a n d  e n d  dates),  fre q ue nc y,  se verit y,  re g ulat or y  
seri o us ness criteria if a p plica ble, s us pecte d relati o ns hi p t o t he st u d y dr u g(s), relati o n t o i njecti o n 
pr oce d ure, l ocati o n, acti o ns ta ke n a n d o utc o me. 
A Es t hat occ ur after a n y s u bject has pr o vi de d writte n i nf or me d c o nse nt, bef ore treat me nt, d uri n g 
treat me nt, or wit hi n 3 0 da ys f oll o wi n g t he cessati o n of treat me nt, w het her or n ot t he y are relate d 
t o t he st u d y, m ust be rec or de d. To i m pr o ve t he q ualit y a n d precisi o n of ac q uire d A E data, Cli nical 
I n vesti gat ors s h o ul d o bser ve t he f oll o wi n g g ui deli nes: 
•  
W he ne ver  p ossi ble,  use  rec o g nize d  me dical  ter ms  w he n  rec or di n g.  D o  n ot  use 
c oll o q uialis ms a n d/ or  a b bre viati o ns. 
•  
If k n o w n, rec or d t he dia g n osis (i.e., disease or s y n dr o me) rat her t ha n c o m p o ne nt si g ns a n d 
s y m pt o ms a n d / or la b orat or y or test fi n di n gs (e. g., rec or d c o n gesti ve heart fail ure rat her t ha n 
d ys p nea, rales, a n d c ya n osis, a n d e nlar ge d heart o n c hest x -ra y). H o we ver, ot her e ve nts t hat 
are c o nsi dere d u nrelate d t o a n e nc o u ntere d s y n dr o me or disease s h o ul d be rec or de d as 
i n di vi d ual A Es (e. g., if c o n gesti ve heart fail ure a n d se vere hea dac he are o bser ve d at t he sa me 
ti me a n d are cli nicall y u nrelate d, eac h e ve nt s h o ul d be rec or de d as a n i n di vi d ual A E).  
•  
If t he dia g n osis is n ot k n o w n, t he n rec or d t he lea di n g c o m p o ne nt si g n, s y m pt o m or test 
fi n di n g a n d descri be t he ot her cli nicall y relate d fi n di n gs i n t he narrati ve descri pti o n of t he 
case. A s us pecte d dia g n osis ca n be use d a n d descri be d as  s uc h. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 2  of  7 4  
 
•  
(e. g., rec or d s us pecte d or pr o ba ble m y ocar dial i nfarcti o n); t his has t o be u p date d i n t he 
cli nical data base o nce t he dia g n osis is c o nfir me d.  
•  
A Es occ urri n g sec o n dar y t o ot her e ve nts (e. g., se q uelae) s h o ul d be i de ntifie d b y t he pri mar y 
ca use. A pri mar y A E, if clearl y i de ntifia ble, ge nerall y re prese nts t he m ost acc urate cli nical 
ter m. If a pri mar y A E is rec or de d, e ve nts occ urri n g sec o n dar y t o t he pri mar y e ve nt s h o ul d 
be descri be d i n t he narrati ve descri pti o n of t he case. F or e xa m ple: the s u bject de vel o pe d 
ort h ostatic  h y p ote nsi o n  a n d  s u bse q ue ntl y  fai nte d  a n d  fell  t o  t he  fl o or  w herei n  s he  
e xperie nce d a hea d tra u ma a n d nec k pai n. T he pri mar y A E i n t his e xa m ple is ort h ostatic 
h y p ote nsi o n. T he fall, hea d tra u ma a n d nec k pai n s h o ul d be descri be d i n t he narrati ve 
descri pti o n of t he case.  
•  
F or i nter mitte nt e ve nts (e. g., i nter mitte nt hea dac he), t he e v e nt o nset date s h o ul d be rec or de d 
as t he date t he s u bject first starte d t o e x perie nce t he e ve nt a n d res ol uti o n date s h o ul d reflect 
w he n t he last occ urre nce res ol ve d or st o p pe d. Se parate A Es f or eac h e ve nt s h o ul d n ot be 
rec or de d. F or e xa m ple, if a s u bject e x perie nce d hea dac he o n 1 4 S E P 2 0 1 5 lasti n g f or t hree 
h o urs,  t he n  s u bse q ue ntl y  e x perie nce d  i nter mitte nt  e pis o des  of  hea dac he  e ver y  da y  f or  
a p pr o xi matel y 3 h o urs u ntil 2 1 S E P 2 0 1 5, t he n t he A E date of o nset is 1 4 S E P 2 0 1 5 a n d t he 
res ol uti o n date is 2 1 S E P 2 0 1 5. 
•  
F or i nter mitte nt e ve nts, rec or d t he ma xi m u m se verit y of t he i n di vi d ual e ve nts. F or e xa m ple, 
if a s u bject c o m plai ns of i nter mitte nt hea dac hes f or o ne wee k a n d t he se verit y of eac h 
hea dac he ra n ges fr o m mil d t o m o derate, t he n t he se verit y w o ul d be m o derate. 
•  
F or i nter mitte nt h os pitalizati o ns occ urri n g f or a pri mar y A E (e. g., i n a s u bject wit h m ulti ple 
scler osis, c o m m o nl y k n o w n f or its rela psi n g a n d re mitti n g c o urse, i n s o me cases lea di n g t o 
m ulti ple h os pital c o nfi ne me nts), t he s u bse q ue nt h os pitalizati o ns s h o ul d be descri be d i n t he 
narrati ve descri pti o n of t he  case. 
•  
If treat me nt was i nitiate d, i ncl u de t he treat me nt a n d d urati o n of t he me dicati o n(s) i n t he 
e C R F.  
 
1 2. 1. 2  Seri o us A d verse  E ve nts  
S A Es are defi ne d as a n y fi n di n gs t hat s u g gest a si g nifica nt hazar d, c o ntrai n dicati o n, si de effect, or 
preca uti o n. A n y a d verse e ve nt is c o nsi dere d a seri o us a d verse e ve nt if it res ults i n a n y of t he 
f oll o wi n g o utc o mes: 
•  
Deat h  
•  
Life  t hreate ni n g: 
A life -t hreate ni n g e ve nt is a n y e ve nt t hat places t he s u bject at i m me diate ris k of 
deat h fr o m t he  e ve nt as it occ urre d; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y 
mi g ht ha ve ca use d deat h if it were m ore se vere.  
•  
H os pitalizati o n, at t he mi ni m u m a n o ver ni g ht sta y 
•  
A persiste nt or si g nifica nt  disa bilit y/i nca pacit y  
•  
A c o n ge nital a n o mal y/ birt h defect  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 3  of  7 4  
 
•  
Ot her me dicall y si g nifica nt  e ve nts: 
Ot her me dicall y si g nifica nt e ve nts are e ve nts 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 c o nsi dere d a seri o us a d verse dr u g 
e x perie nce w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize 
t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
o utc o mes liste d a b o ve. 
•  
Si g ht t hreate ni n g e ve nt: 
A si g ht -t hreate ni n g e ve nt is a n y e ve nt t hat places t he s u bject at i m me diate ris k of 
per ma ne ntl y l osi n g visi o n i n eit her e ye as a direct res ult of t he e ve nt. It is defi ne d 
as a l oss of ≥ 3 0 letters or 6 li nes of visi o n fr o m Baseli ne.  
 
 Re p orti n g Seri o us A dverse  Eve nts  
A n A E C R F m ust be c o m plete d i n E D C wit h as m uc h i nf or mati o n a vaila ble wit hi n 2 4 h o urs of 
k n o wle d ge of t he e ve nt. 
To i m pr o ve t he q ualit y a n d precisi o n of ac q uire d S A E data, Cli nical I n vesti gat ors s h o ul d o bser ve 
t he f oll o wi n g g ui deli nes: 
•  
De at h - Deat h is a n o utc o me of a n e ve nt. T he e ve nt t hat res ulte d i n t he deat h s h o ul d be 
rec or de d a n d re p orte d as a S A E.  
•  
H os pit aliz ati o ns  f or  S ur gic al  or  Di a g n ostic  Pr oce d ures - T he  ill ness  lea di n g  t o  t he  
s ur gical or dia g n ostic pr oce d ure s h o ul d be rec or de d as t he S A E, n ot t he pr oce d ure itself. T he 
pr oce d ure s h o ul d be ca pt ure d i n t he case narrati ve as part of t he acti o n ta ke n i n res p o nse t o 
t he ill ness. 
W he n ne w si g nifica nt i nf or mati o n (i ncl u di n g t he o utc o me of t he e ve nt) is o btai ne d, t he Cli nical 
I n vesti gat or s h o ul d e nter t he i nf or mati o n directl y i nt o t he e C R F wit hi n 2 4 h o urs or as s o o n as 
p ossi ble after k n o wl e d ge of t he i nf or mati o n. 
De pe n di n g  o n  t he  nat ure  a n d  seri o us ness  of  t he  A E,  RI B O MI C  ma y  re q uest  a d diti o nal  
d oc u me ntati o n, f or e xa m ple, c o pies of t he o p ht hal mic a n d me dical rec or d of t he s u bject as well as 
res ults of la b orat or y tests. If t he s u bject was h ospitalize d, t he site s h o ul d s u m marize t he h os pital 
disc har ge s u m mar y a n d pr o vi de t o RI B O MI C u p o n re q uest. 
 
 E x pe dite d Re p orti n g of Seri o us A dverse Eve nts  
RI B O MI C ( or desi g nee) will pr o vi de t he Pri nci pal I n vesti gat or wit h a re p orti n g c o ver letter a n d 
a n a n o n y mize d Me d Watc h 3 5 0 0 A or CI O Ms f or m as a p pr o priate f or e x pe dite d re p orti n g of S A Es 
t o t he I R B or I E C. T he Pri nci pal I n vesti gat or is res p o nsi ble f or recei vi n g a n d re vie wi n g e x pe dite d 
safet y re p orts, s u b mitti n g e x pe dite d safet y re p orts t o t he I R B or I E C, a n d mai ntai ni n g c o pies of 
e x pe dite d safet y re p orts i n t he st u d y rec or ds. 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 4  of  7 4  
 
1 2. 1. 3  E ve nts of S peci al I nterest  
E ve nts of S pecial I nterest ( E SIs) are e ve nts t hat ma y re q uire s pecial atte nti o n f or t he p ur p oses of 
o n- g oi n g patie nt safet y re vie w d uri n g t his st u d y. T he f oll o wi n g are c o nsi dere d E SIs a n d s h o ul d be 
re p orte d o n t he a p pr o priate e C R F wit h as m uc h i nf or mati o n as a vaila ble wit hi n 2 4 h o urs of  
k n o wle d ge of t he e ve nt: 
•  
St u d y  me dic ati o n  a d mi nistr ati o n  err or – St u d y  me dicati o n  a d mi nistrati o n  err ors  
deter mi ne d t o be si g nifica nt b y t he Cli nical I n vesti gat or will be re p orte d a n d e val uate d as 
E SIs. E xa m ples of st u d y me dicati o n a d mi nistrati o n err ors ma y  i ncl u de, b ut are n ot li mite d 
t o: o ver d ose of st u d y me dicati o n a n d a d mi nistrati o n of st u d y me dicati o n fr o m a n i nc orrect 
k it. 
•  
Pre g n a nc y  – T here  are  n o  c o ntr olle d  data  wit h  t he  i n vesti gati o nal  pr o d uct  i n  h u ma n  
pre g na nc y. It is re q uire d t hat w o me n of c hil d beari n g p ote ntial use effecti ve c o ntrace pti o n 
d uri n g t he st u d y a n d rec o m me n d f or 1 2 wee ks after t he c o m pleti o n of t he st u d y.   A n y 
pre g na nc y occ urri n g d uri n g st u d y treat me nt s h o ul d be re p orte d a n d t he s u bject re m o ve d 
fr o m t he st u d y. T he s u bject s h o ul d be f oll o we d u ntil t he e n d of pre g na nc y or u ntil t he e n d of 
t he st u d y, w hic he ver is l o n ger. 
1 2. 1. 4  F oll o w- u p of A d verse  E ve nts  
All re p orte d A Es at st u d y e xit will be f oll o we d b y t he Cli nical I n vesti gat or ( or his/ her desi g nee) 
u ntil t he e ve nt is res ol ve d or deter mi ne d t o be irre versi ble, c hr o nic, or sta ble.  If t he s u bject is bei n g 
f oll o we d f or a S A E  be y o n d t he last pr ot oc ol sc he d u le d visit ( Mo nt h 5 ), t he visit s h o ul d be 
c o m plete d w he n sc he d ule d acc or di n g t o t he pr ot oc ol a nd t he A E  Date of Res ol uti o n a n d t he E n d 
of St u d y Date of C o m pleti o n s h o ul d be t he date w he n f oll o wi n g t he S A E e n de d. 
I n a d diti o n, o n a case- b y-case basis, RI B O MI C ( or des i g nee) ma y re q uest f oll o w u p be y o n d t he 
e n d of t he st u d y. 
If t he RI B O MI C P har mac o vi gila nce De part me nt re q uests f oll o w-u p o n a n i n di vi d ual S A E or 
desi g nate d  E SI,  t he  site’s  res p o nse  t o  f oll o w -u p  re q uests  s h o ul d  be  e maile d  t o  RI B O MI C  
P har mac o vi gila nc e: t of u.safet y @ri b o mic.c o m.  
1 2. 1. 5  M a n u al B ac k- U p Re p orti n g  Pr oce d ures  
T his st u d y is utilizi n g a n electr o nic data ca pt ure ( E D C) s yste m f or data c ollecti o n. I n t he e ve nt 
t hat  t he  E D C  s yste m  is  u na vaila ble  f or  electr o nic  re p orti n g,  t he  ma n ual  bac k -u p  re p orti n g  
pr oce d ures bel o w s h o ul d be f oll o we d: 
 
• C o m plete a n A E f or m  ma n uall y. 
• Attac h a c o ver s heet wit h y o ur c o ntact i nf or mati o n, i ncl u di n g site  n u m ber. 
• E mail t he A E f or m t o RI B O MI C P har mac o vi gila nce at t of u.safet y @ri b o mic.c o m 
W he n t he E D C s yste m bec o mes a vaila ble, u p date t he E D C s yste m wit h all pre vi o usl y re p orte d 
i nf or mati o n. 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 5  of  7 4  
 
1 2. 2  S afety P ar a meters  
T he  safet y  assess me nts  will  i ncl u de  A Es,  slit  la m p  bi o micr osc o p y,  i n direct  o p ht hal m osc o p y,  
B C V A, I O P, f u n d us  p h ot o gra p h y, f u n d us a ut ofl u orescenc e, vital si g ns , pre g na nc y test a n d p h ysical 
e xa mi nati o n.  
 
1 2. 2. 1  P h ysic al  E x a mi n ati o n 
A f ull b o d y s yste matic p h ysical e xa mi nati o n will be c o n d ucte d b y t he Cli nical I n vesti gat or or a n 
e xter nal i nter nist. 
 
1 2. 2. 2  Vit al Si g ns  
Bl o o d press ure a n d heart rate will be meas ure d usi n g a n a ut o mate d or ma n ual bl o o d press ure 
m o nit or. S yst olic a n d diast olic bl o o d press ures will be rec or de d i n milli meters of merc ur y ( m m H g) 
a n d heart rate will be rec or de d i n beats per mi n ute ( b p m).  
 
1 2. 2. 3  Best C orrecte d Vis u al Ac uit y  
T he B C V A will be rec or de d usi n g t he E T D R S c hart a n d t otal n u m ber of letters at 4 meters a n d 1 
meter will be rec or de d. T he “ n o n st o p pi n g” r ule m ust be a p plie d d uri n g t he E T D R S B C V A 
e val uati o n, c o nsi deri n g e ver y letter t he s u bject ca n rea d. If a s u bject c o ul d n ot rea d E T D R S c hart, 
Fi n ger C o u nts, Ha n d M oti o n, Li g ht Perce pti o n, or N o Li g ht Perce pti o n will be rec or de d. 
 
1 2. 2. 4  E xter n al oc ul ar e x a m 
T he Cli nical I n vesti gat or will assess  e xter nal oc ular e xa mi nati o n e val uati n g li d a n d las hes. 
 
1 2. 2. 5  Slit -l a m p Bi o micr osc o p y  
T he  Cli nical  I n vesti gat or  will  assess  Slit -la m p  bi o micr osc o p y  e xa mi nati o n  usi n g  Slit-la m p 
micr osc o pe. O n t he visit of a n y I V T treat me nt, a bi o micr osc o p y e xa mi nati o n will be perf or me d 
pri or t o  t he first i njecti o n a n d a sec o n d o ne wit hi n 3 0 mi n utes after t he sec o n d i njecti o n. T his will 
be als o a p plie d f or t he p ost I V T i njecti o n of Resc ue treat me nt.  
 
1 2. 2. 6  I ntr a oc ul ar Press ure  
I O P will be meas ure d i n eac h visit as descri be d i n Secti o n 7. 5. 1  
T he I O P  f or t he p ost I V T i njecti o n of Resc ue treat me nt will be meas ure d as descri be d i n Secti o n  
2 1. 4. 8 . 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 6  of  7 4  
 
1 2. 2. 7  I n direct O p ht h al m osc o p y  
T he Cli nical I n vesti gat or will assess i n direct o p ht hal m osc o p y usi n g i n direct o p ht hal m osc o pe. O n 
t he visit of a n y I V T treat me nt, a n o p ht hal m osc o p y e xa mi nati o n will be perf or me d pri or t o  t he 
injecti o n a n d a sec o n d o ne wit hi n 3 0 mi n utes after t he i njecti o n. T his will be als o a p plie d f or t he 
p ost I V T i njecti o n of Resc ue  treat me nt. 
1 2. 2. 8  Uri ne Pre g n a nc y Test  
A uri ne pre g na nc y test will be c o n d ucte d f or all fe males of c hil d beari n g p ote ntial.  
 
1 2. 2. 9  F u n d us P h ot o gr a p h y  
Di gital c ol or f u n d us p h ot o gra p h y will be ta ke n f oll o wi n g t he pr oce d ure pr o vi de d b y t he s p o ns or. 
It will be perf or me d pri or t o a n y i ntra vitreal i njecti o ns. 
 
1 2. 2. 1 0 F u n d us A ut ofl u ores ce nce 
F u n d us  a ut o fl u orescence  will be ta ke n o n Visit 1 ( Baseli ne ( Da y 1))  a n d Visi t 5 ( M o nt h 4), 
f oll o wi n g t he pr oce d ure pr o vi de d b y t he s p o ns or. It will be perf or me d pri or t o a n y i ntra vitreal 
i njecti o ns. 
 
1 2. 2. 1 1 S pectr al D o m ai n O ptic al C o here nce To m o gr a p h y ( S D -O C T)  
S D -O C T  i ma ges  will  be  ta ke n  f oll o wi n g  t he  pr oce d ure  pr o vi de d  b y  t he  s p o ns or.   It  will  be  
perf or me d pri or t o a n y i ntra vitreal i njecti o ns.  
 
1 2. 2. 1 2 A d verse  E ve nts  
A Es will be elicite d fr o m t he s u bjects starti n g at t he Scree ni n g t hr o u g h st u d y e xit. T he i nf or mati o n 
will i ncl u de at least a descri pti o n of t he e ve nt, w het her or n ot it is seri o us, o nset a n d d urati o n, , 
se verit y, relati o n t o mas ke d st u d y t hera p y, relati o n t o i njecti o n pr oce d ure, l ocati o n ( O D, O S, O U 
or n o n- oc ular ), acti o n ta ke n a n d o utc o me. Pri or t o e val uati n g t he i nci de nces, all A Es will be c o de d 
usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities (Me d D R A ). 
Oc ular  a n d  n o n -oc ular  A Es  will  be  s u m marize d  se paratel y.  See  Secti o n  1 2. 1  f or  c o m plete  
i nf or mati o n re gar di n g A Es re p orti n g. 
 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 7  of  7 4  
 
1 3  O T H E R  A S S E S S M E N T S  
1 3. 1  De m o gr a p hics a n d B aseli ne C h ar acteristics  
S u bject  de m o gra p hics  i ncl u de  a ge,  race,  se x,  a n d  et h nicit y.  Baseli ne  c haracteristics  i ncl u de  
me dical hist or y, pri or  or c o nc o mita nt me dicati o ns, a n d B aseli ne res ults of p h ysical e xa mi nati o n, 
vital si g ns, uri ne pre g na nc y test,  B C V A, slit -la m p bi o micr osc o p y, I O P, i n direct o p ht hal m osc o p y, 
S D -O C T, f u n d us p h ot o gra p h y, a n d f u n d us a ut ofl u orescence . F or assess me nts perf or me d m ulti ple 
ti mes bef ore t he I V T i njecti o n of R B M-0 0 7, t he last pre -i njecti o n val ue will be use d as t he B aseli ne 
val ue. 
 
1 3. 2  O C T  A n gi o gr a p hy 
 
F or f ut ure e x pl orat or y researc h, O C T A n gi o gra p h y will be ta ke n at selecte d sites  o n Vis it 1 
( Baseli ne ( Da y 1)) a n d Visit 5 ( M o nt h 4) i n all s u bjects. 
1 4  S T A TI S TI C A L  M E T H O D S  
1 4. 1  A n alysis Ti me P oi nts  
T he  pri m ar y a nal ysis w ill be perf or me d  after t he st u d y is c o m plete d. 
 
1 4. 1. 1  Pri m ar y  A n al ysis 
Descri pti ve s u m maries of t he f oll o wi n g efficac y a n d safet y meas ures will be pr o vi de d at t he M o nt h 
4 visit : 
• 
Mea n c ha n ge i n B C V A fr o m Baseli ne  
• 
Pr o p orti o n of s u bjects wit h B C V A: 1) gai n of ≥1 5 E T D R S letters ( 3 -li ne  gai ners);  2)  gai n       
of ≥1 0 E T D R S letters; 3) gai n of ≥5 E T D R S letters a n d 4) ≥ 1 5 letter l oss fr o m Baseli ne at 
M o nt h 4 are ot her sec o n dar y e n d p oi nts 
•  
C ha n ge fr o m Baseli ne i n C S T, a n d mac ular v ol u me b y S D-O C T  
• 
C ha n ge fr o m Baseli ne i n c haracteristics of S H R M  
• 
C ha n ge fr o m Baseli ne i n c haracteristics of fi br osis  
• 
Pr o p orti o n of s u bjects t hat d o n ot re q uire a nti -V E G F treat me nt d uri n g f oll o w -u p peri o d 
(i ncl u di n g M o nt h 5) 
•  
Mea n n u m bers of resc ue i njecti o ns i n t he m o n ot hera p y ar m 
•  
Pr o p orti o n of s u bjects re q uiri n g resc ue (i ncl u di n g M o nt h 5) 
 
•  Safet y assess me nt i ncl u de A Es,  p h ysical e xa mi nati o n, vital si g ns, e xter nal oc ular e xa m, 
B C V A,  I O P, slit la m p bi o micr osc o p y, i n direct o p ht hal m osc o p y, S D -O C T, f u n d us 
p h ot o gra p h y,  f u n d us a ut ofl u oresce nce a n d pre g na nc y test   
•  A d diti o nal varia bles of i nterest will als o be pr o vi de d  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 8  of  7 4  
 
 
1 4. 2  Ge ner al C o nsi der ati o ns  
All  st u d y  para meters  will  be  liste d  a n d  a  selecte d  list  of  para meters  will  be  s u m marize d  
descri pti vel y. T he descri pti ve statistics will i ncl u de n u m ber of o bser vati o ns ( n), mea n, sta n dar d 
de viati o n, mi ni m u m, a n d ma xi m u m f or c o nti n u o us para meter a n d fre q ue nc y ( n) a n d perce nt ( %) 
f or cate g orical para meters. 
Details a b o ut t he statistical a nal yses f or t his st u d y will be pr o vi de d i n t he statistical a nal ysis pla n 
( S A P). 
All data ma ni p ulati o ns a n d descri pti ve s u m maries will be i m ple me nte d usi n g S A S ® , Versi o n 9. 1. 3 
or later.  
1 4. 2. 1  S a m ple  Size  
A p pr o xi matel y 4 0  s u bjects wit h wet A M D will  be e nr olle d at a p pr o xi matel y 1 0  sites. S u bjects 
t hat s uccessf ull y e xite d T O F U st u d y o n or bef ore a p pr o xi matel y Se pte m ber 1, 2 0 2 1 will 
be c o nsi der e d f or R A M E N St u d y . T he fi nal n u m ber of s u bjects e nr olle d ma y be a dj uste d 
base d o n t he j u d g me nt s fr o m Safet y Re vie w Tea m.    
 
1 4. 2. 2  St atistic al H y p ot heses a n d Le vel of  Si g nific a nce  
N o statistical h y p ot hesis is defi ne d f or t his st u d y. 
 
1 4. 2. 3  R a n d o miz ati o n 
Ra n d o mizati o n is n ot e m pl o ye d i n t his st u d y d ue t o t he o pe n-la bel desi g n. 
 
1 4. 2. 4  St u d y E ye  
T he st u d y e ye m ust meet all i ncl usi o n a n d e xcl usi o n criteria  a n d m ust be t he sa me as i n T O F U 
st u d y. 
 
1 4. 3  St u dy  P o p ul ati o ns 
T he f oll o wi n g st u d y p o p ulati o ns are defi ne d f or a nal ysis: I nte nti o n- t o-treat (I T T) a n d Safet y. 
•  
I T T P o p ul ati o n: T he I T T p o p ulati o n will i ncl u de all s u bjects i n t he st u d y.  
•  
S afet y P o p ul ati o n: T he Safe t y p o p ulati o n will i ncl u de all s u bjects w h o recei ve d at least o ne 
st u d y me dicati o n. It will be t he st u d y p o p ulati o n f or safet y a nal ysis. 
•  
F ull A n al ysis Set: T he F ull A nal ysis Set ( F A S) will i ncl u de all s u bjects w h o recei ve d at 
least o ne st u d y me dicati o n a n d pr o vi de d at least o ne p ost - Baseli ne B C V A meas ure me nt. T he 
efficac y a nal ysis will be perf or me d o n t he F A S or a s u bset of t he F A S.  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
4 9  of  7 4  
 
•  
Per -Pr ot oc ol  P o p ul ati o n: T he Per -Pr ot oc ol ( P P) P o p ulati o n is a s u bset of t he F A S. It 
i ncl u des all F A S s u bjects wit h o ut maj or pr ot oc ol vi olati o ns t hat c o ul d affect t he pri mar y 
efficac y e n d p oi nt. 
 
1 4. 4  H a n dli n g of Missi n g  Va l u e s  
F or safet y meas ures, missi n g sc ores will n ot be i m p ute d f or data s u m maries.  
C o m pletel y or partiall y missi n g o nset a n d res ol uti o n dates f or A Es a n d c o m pletel y or  partiall y 
missi n g start a n d e n d dates of c o nc o mita nt me dicati o ns will be i m p ute d i n a c o nser vati ve fas hi o n 
t hat will be detaile d i n t he S A P. 
F or efficac y e n d p oi nts, missi n g p ost -i njecti o n val ues will be i m p ute d usi n g t he last- o bser vati o n- 
carrie d-f or war d ( L O C F) a p pr oac h. 
 
1 4. 5  De m o gr a p hics a n d B aseli ne C h ar acteristics  
A ge, se x, race, et h nicit y, a n d B aseli ne assess me nts will be s u m marize d descri pti vel y.  
S u bjects wit h a b n or mal me dical hist or y will be ta b ulate d b y b o d y s yste m. 
S u bjects usi n g a n y pri or me dicati o ns will be ta b ulate d, A nat o mical T hera pe utic C he mical le vels, 
a n d preferre d ter m s pecifie d i n t he Worl d Healt h Or ga nizati o n W H O Dr u g  Gl o bal. 
 
1 4. 6  Effic acy A n alyses  
1 4. 6. 1  A n al ysis of Pri m ar y Effic ac y  E n d p oi nts  
• Mea n c ha n ge i n B C V A fr o m Baseli ne at M o nt h 4 will be a nal yze d usi n g descri pti ve 
statistics. O bser ve d B C V A i n t he st u d y e ye will be prese nte d descri pti vel y a n d gra p hicall y 
b y st u d y visit. 
T he pri mar y a nal ysis will be base d o n t he F A S a n d re peat a nal ysis will be perf or me d o n t he P P 
P o p ulati o n. 
 
1 4. 6. 2  A n al ys is of Sec o n d ar y Effic ac y E n d p oi nts  
T he f oll o wi n g will be a nal yze d at M o nt h 4: 
 •  Pr o p orti o n of s u bjects wit h B C V A: 1) gai n of ≥1 5 E T D R S letters ( 3 -li ne gai ners); 2) gai n of 
≥1 0 E T D R S letters; 3) gai n of ≥5 E T D R S letters a n d 4) ≥ 1 5 letter l oss fr o m Baseli ne  
•  C ha n ge fr o m Baseli ne i n C S T, a n d mac ular v ol u me b y S D- O C T  
•  C ha n ge fr o m Baseli ne i n c haracteristics of S H R M  
•  C ha n ge fr o m B aseli ne i n c haracteristics of fi br osis  
•  Pr o p orti o n of s u bjects t hat d o n ot re q uire a nti -V E G F treat me nt  d uri n g f oll o w - u p peri o d 
(i ncl u di n g M o nt h 5) 
•  Mea n n u m bers of resc ue i njecti o ns  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
5 0  of  7 4  
 
•  Pr o p orti o n of s u bjects re q uiri n g resc ue (i ncl u di n g M o nt h 5) 
 
1 4. 7  S afety A n alysis  
All safet y o utc o me meas ures will be s u m marize d descri pti vel y f or t he Safet y P o p ulati o n. T he 
safet y o utc o me meas ures i ncl u de a d verse e ve nts ( A Es), e xter nal oc ular e xa m, B C V A, slit -la m p 
bi o micr osc o p y, i n direct o p ht hal m osc o p y, i ntra oc ular press ure (I O P), vital si g ns,  pre g na nc y test, 
p h ysical e xa mi nati o n, f u n d us p h ot o gra p h y, f u n d us a ut ofl u oresce nce, a n d S D -O C T . 
A Es will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A).  
S u bjects wit h a n y A Es will be ta b ulate d b y s yste m or ga n classificati o n a n d preferre d ter m s pecifie d 
i n t he Me d D R A. Si milarl y, s u bjects wit h a n y oc ular a n d n o n-oc ular A Es a n d E SIs will be ta b ulate d 
se paratel y. A Es, oc ular a n d n o n-oc ular, as well as E SIs will als o be s u m marize d b y relati o ns hi p t o 
treat me nt a n d ma xi m u m se verity. I n a d diti o n, S A Es a n d disc o nti n uati o ns d ue t o A Es will be 
s u m marize d. 
Oc ular safet y o utc o me meas ures will be s u m marize d usi n g descri pti ve statistics.  
 
 
1 5  DI R E C T A C C E S S T O S O U R C E  D A T A/ D O C U M E N T S  
T he  Pri nci pal  I n vesti gat or  will  all o w  re prese ntati ves  of  RI B O MI C’s  m o nit ori n g  tea m  ( or  
desi g nee),  t he  g o ver ni n g  i nstit uti o nal  re vie w  b oar d  (I R B),  t he  F D A,  a n d  ot her  a p plica ble  
re g ulat or y a ge ncies t o i ns pect all st u d y rec or ds, e C R Fs, recr uit me nt materials a n d c orres p o n di n g 
p orti o ns  of  t he  s u bject’s  me dical  rec or ds  at  re g ular  i nter vals  t hr o u g h o ut  t he  st u d y.  T hese  
i ns pecti o ns are f or t he p ur p ose of verif yi n g a d here nce t o t he pr ot oc ol, c o m plete ness, a n d e xact ness 
of t he data bei n g e ntere d o nt o t he e C R F, a n d c o m plia nce wit h t he  F D A or ot her re g ulat or y a ge nc y 
re gulati o ns. 
 
1 5. 1  St u dy  M o nit ori n g  
Bef ore a n i n vesti gati o nal site ca n e nter a s u bject i nt o t he st u d y, RI B O MI C or a re prese ntati ve of 
RI B O MI C ( or desi g nee) will e val uate t he i n vesti gati o nal st u d y site t o:  
 • Deter mi ne t he a de q uac y of t he st u d y facilities. 
• Re vie w wit h t he Pri nci pal I n vesti gat or(s) a n d a ut h orize d st u d y staff t heir res p o nsi bilities 
wit h re gar d t o pr ot oc ol pr oce d ures a d here nce, a n d t he res p o nsi bilities of RI B O MI C ( or 
desi g nee). 
D uri n g t he st u d y, RI B O MI C ( or desi g nee) will ha ve re g ular c o ntact wit h t he i n vesti gati o nal site, 
f or t he f oll o wi n g: 
• Pr o vi de i nf or mati o n a n d s u p p ort t o t he Pri nci pal I n vesti gat or(s).  
• C o nfir m t hat facilities re mai n  acce pta ble. 
• Assess a d here nce t o t he pr ot oc ol a n d  G o o d Cli nical Practice (G C P ). 
• Perf or m i n vesti gati o nal pr o d uct acc o u nta b ilit y c hec ks a n d q ualit y c o ntr ol pr oce d ures. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
5 1  of  7 4  
 
• E ns ure t he o n- g oi n g i m ple me ntati o n of acc urate data e ntr y i n t he  e C R F. 
• Perf or m s o urce data verificati o n, i ncl u di n g a c o m paris o n of t he data i n t he e C R Fs wit h t he 
s u bject’s me dical rec or ds a n d ot her rec or ds rele va nt t o t he st u d y. T his will re q uire direct 
access t o all ori gi nal rec or ds f or eac h s u bject (e. g., cli nic  c harts). 
• Rec or d a n d re p ort a n y pr ot oc ol de viati o ns n ot pre vi o usl y se nt t o RI B O MI C.  
• C o nfir m A Es a n d S A Es ha ve bee n pr o perl y d oc u me nte d o n e C R Fs a n d c o nfir m a n y S A Es 
ha ve bee n f or war de d t o RI B O MI C a n d t h ose S A Es t hat met criteria f or re p orti n g ha ve bee n 
f or war de d t o t he I R B or I E C. 
RI B O MI C  ( or  desi g nee)  ma y  re m otel y  access  t he  e C R Fs  at  a n y  ti me  d uri n g  t he  st u d y  f or  
ce ntralize d m o nit ori n g. RI B O MI C ( or desi g nee) will be a vaila ble bet wee n visits if a ut h orize d 
st u d y staff nee ds st u d y relate d i nf or mati o n or s u p p ort. 
 
1 5. 2  A u dits a n d  I ns pecti o ns 
T he Pri nci pal I n vesti gat or will all o w RI B O MI C ( or desi g n ee), t he g o ver ni n g I R B or I E C, a n d 
a p plica ble re g ulat or y a ge ncies t o a u dit a n d i ns pect a n y as pect of t he st u d y, i ncl u di n g all st u d y  
rec or ds, e C R Fs, recr uit me nt materials, a n d c orres p o n di n g p orti o ns of t he s u bject’s c harts a n d 
me dical rec or ds at a n y ti me d u ri n g t he st u d y. T hese st u d y rec or ds m ust be retai ne d at t he st u d y 
site a n d ma de a vaila ble f or a u dits a n d i ns pecti o ns. T he p ur p ose of t hese a u dits a n d i ns pecti o ns is 
t o verif y a d here nce t o t he pr ot oc ol, c o m plete ness a n d acc urac y of t he e C R F data, a n d c o m plia nce 
wit h G o o d Cli nical Practice ( G C P) g ui deli nes a n d a p plica ble re g ulat or y re q uire me nts.  
T he Pri nci pal I n vesti gat or or a ut h orize d st u d y staff will n otif y RI B O MI C ( or desi g nee) s h o ul d t he 
site be a u dite d or i ns pecte d b y t he g o ver ni n g I R B or I E C, a n d a p plica ble re g ulat or y a ge ncies. 
RI B O MI C ( or desi g nee) will als o n otif y t he i n vesti gati o nal site of a n y k n o w n pe n di n g site a u dits 
or i ns pecti o ns pla n ne d b y RI B O MI C ( or desi g nee), g o ver ni n g I R B or I E C a n d re g ulat or y a ge ncies.  
 
1 5. 3  I nstit uti o n al Revie w B o ar d 
T he Pri nci pal I n vesti gat or m ust o btai n I R B a p pr o val f or t he i n vesti gati o n. I nitial I R B a p pr o val, 
a n d all materials a p pr o ve d b y t he I R B f or t his st u d y i ncl u di n g t he s u bject c o nse nt f or m a n d 
recr uit me nt materials m ust be mai ntai ne d b y t he Pri nci pal I n vesti gat or a n d ma de a vaila ble f or 
i ns pecti o n. 
 
1 6  Q U A LI T Y C O N T R O L A N D Q U A LI T Y  A S S U R A N C E  
1 6. 1  Q u ality C o ntr ol  
RI B O MI C ( or desi g nee) will pr o vi de i nstr ucti o nal material t o t he st u d y sites, as a p pr o priate; 
i ncl u di n g b ut n ot li mite d t o i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti o n of e C R Fs, a n d st u d y 
pr oce d ures. RI B O MI C ( or desi g nee) will c o m m u nicate re g ularl y wit h site pers o n nel via mail, 
e mail, tele p h o ne, a n d/ or fa x; a n d ma ke peri o dic visits t o t he st u d y site. D uri n g t h ose visits, 
RI B O MI C ( or desi g nee) will perf or m s o urce data verificati o n wit h t he s u bject’s me dical rec or ds 
a n d ot her rec or ds rele va nt t o t he st u d y. U p o n recei vi n g t he e C R Fs, RI B O MI C ( or desi g nee) will 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
5 2  of  7 4  
 
re vie w a n d e val uate e C R F data a n d use sta n dar d s yste m e dits a n d ma y use ce ntralize d m o nit ori n g 
t o detect err ors i n data c ollecti o n. 
 
1 6. 2  Q u ality Ass ur a nce  
RI B O MI C ( or desi g nee) ma y c o n d uct a q ualit y ass ura nce a u dit at a n y ti me. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
5 3  of  7 4  
 
1 7  E T HI C S  
1 7. 1  Et hics Revie w  
T he fi nal st u d y pr ot oc ol a n d t he fi nal versi o n of t he I C F, a n d ot her st u d y relate d material, as 
a p pr o priate, m ust be a p pr o ve d or gi ve n a fa v ora ble o pi ni o n i n writi n g b y a n I R B or I E C as 
a p pr o priate. T he Pri nci pal I n vesti gat or m ust s u b mit writte n a p pr o val t o RI B O MI C ( or desi g nee) 
bef ore st u d y i nitiati o n. See Secti o n 2 1. 1  A p pe n di x A f or a list of o bli gati o ns of I n vesti gat ors. 
T he Pri nci pal I n vesti gat or is res p o nsi ble f or i nf or mi n g t he I R B or I E C of a n y a me n d me nt t o t he 
pr ot oc ol i n acc or da nce wit h l ocal re g ulati o ns a n d g ui deli nes. I n a d diti o n, t he I R B or I E C m ust 
a p pr o ve all a d vertisi n g use d t o recr uit s u bjects f or t he st u d y. T he pr ot oc ol m ust be re -a p pr o ve d b y 
t he I R B or I E C u p o n recei pt of a me n d me nts a n d at least a n n uall y. 
T he Pri nci pal I n vesti gat or is als o res p o nsi ble f or pr o vi di n g t he I R B or I E C wit h pr o gress re p orts 
a n d n otificati o ns of a n y re p orta ble seri o us a d verse dr u g reacti o ns fr o m t he i n vesti gati o nal pr o d uct.  
 
1 7. 2  Et hic al C o n d uct of t he  St u dy  
T his st u d y will be c o n d ucte d i n c o m plia nce wit h I R B or I E C, a n d re g ulat or y re q uire me nts. T his 
st u d y will als o be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, G C P g ui deli nes, I nter nati o nal 
C o nfere nce o n Har m o nizati o n (I C H) g ui deli nes, t he Declarati o n of Helsi n ki. 
 
1 7. 3  Writte n I nf or me d  C o nse nt  
T he Pri nci pal I n vesti gat or at eac h ce nter will e ns ure t hat t he s u bject is gi ve n f ull a n d a de q uate oral 
a n d writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris k a n d p ossi ble be nefit of t he st u d y. 
S u bjects m ust als o be n otifie d t hat t he y are free t o w it h dra w fr o m t he st u d y at a n y ti me. S u bjects 
s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me t o c o nsi der t he i nf or mati o n 
pr o vi de d. Bef ore partici pati n g i n a n y st u d y -relate d acti vit y, v ol u ntar y i nf or me d c o nse nt m ust be 
d oc u me nte d b y t he use of a writte n I C F a p pr o ve d b y t he I R B or I E C a n d si g ne d a n d date d b y t he 
s u bject or t he s u bject’s le gall y a ut h orize d re prese ntati ve at t he ti me of c o nse nt. T he ori gi nal si g ne d 
a n d date d I C F will be retai ne d wit h t he st u d y rec or ds, a n d a c o p y of t he si g ne d  I C F will be gi ve n 
t o t he s u bject or t he s u bject’s le gall y a ut h orize d re prese ntati ve. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
5 4  of  7 4  
 
1 8  D A T A H A N D LI N G A N D  R E C O R D K E E PI N G  
1 8. 1  I ns pecti o n of Rec or ds  
T he Pri nci pal I n vesti gat or will all o w RI B O MI C ( or desi g nee), t he g o ver ni n g I R B or I E C a n d 
a p plicable re g ulat or y a ge ncies t o i ns pect a n y as pect of t he st u d y, i ncl u di n g all st u d y rec or ds, 
e C R Fs, recr uit me nt materials a n d c orres p o n di n g p orti o ns of t he s u bject’s c harts a n d me dical 
rec or ds at a n y ti me d uri n g t he st u d y. T he p ur p ose of t hese i ns pecti o ns is to verif y a d here nce t o t he 
pr ot oc ol, c o m plete ness a n d acc urac y of t he e C R F data, a n d c o m plia nce wit h G C P g ui deli nes a n d 
a p plica ble re g ulat or y re q uire me nts.  
 
1 8. 2  Rete nti o n of  Rec or ds  
All rec or ds relati n g t o t he c o n d uct of t his st u d y are t o be retai ne d b y t he Pri nci pal I n vesti gat or 
u ntil n otifie d b y RI B O MI C ( or desi g nee) t hat t he rec or ds ma y be destr o ye d. 
 
1 8. 2. 1  S o urce  D oc u me nts  
T he Pri nci pal I n vesti gat or m ust mai ntai n detaile d s o urce d oc u me nts o n all st u d y s u bjects w h o 
pr o vi de i nf or me d c o nse nt. S o urce d oc u me nts i ncl u de  s u bject me dical rec or ds, h os pital c harts, 
st u d y files, as well as t he res ults of dia g n ostic tests (e. g., la b orat or y tests). 
T he f oll o wi n g mi ni m u m i nf or mati o n s h o ul d be e ntere d i nt o t he s u bject’s me dical rec or d: 
 • T he date t he s u bject was e nr olle d a n d t he s u bject  n u m ber 
• T he st u d y pr ot oc ol n u m ber a n d t he na me of RI B O MI C U S A I nc. 
• T he date t hat i nf or me d c o nse nt was  o btai ne d 
• E vi de nce t hat t he s u bject meets st u d y eli gi bilit y re q uire me nts (e. g., me dical  hist or y, st u d y 
pr oce d ures a n d/ or e val uati o ns) 
• T he dates of all st u d y -relate d s u bject visits  
• E vi de nce t hat re q uire d pr oce d ures a n d/ or e val uati o ns were  c o m plete d 
• Use of a n y c o nc o mita nt me dicati o ns  
• D oc u me ntati o n of st u d y dr u g acc o u nta bilit y 
• Occ urre nce a n d stat us of a n y  A Es  
• T he date t he s u bject e xite d t he st u d y a n d a n otati o n as t o w het her t he s u bject c o m plete d or 
ter mi nate d earl y fr o m t he st u d y, i ncl u di n g t he reas o n f or earl y ter mi nati o n 


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1 8. 2. 2  D at a  C ollecti o n  
T he Pri nci pal I n vesti gat or m ust mai ntai n detaile d rec or ds o n all s u bjects w h o pr o vi de i nf or me d 
c o nse nt. Data f or scree ne d a n d e nr olle d s u bjects will be e ntere d i nt o e C R Fs. Re vie w of t he e C R Fs 
will be c o m plete d re m otel y b y RI B O MI C ( or desi g nee). At desi g nate d i nter vals, a st u d y m o nit or 
will perf or m s o urce data verificati o n o n  site. D uri n g t h ose visits, RI B O MI C ( or desi g nee) will 
m o nit or  t he  s u bject  data  rec or de d  i n  t he  e C R F  a gai nst  s o urce  d oc u me nts  at  t he  st u d y  site.  
RI B O MI C ( or desi g nee) will re vie w a n d e val uate e C R F data a n d use sta n dar d s yste m e dits, a n d 
ma y use ce ntralize d  m o nit ori n g e val uati o ns, t o detect err ors i n data c ollecti o n. At t he e n d of t he 
st u d y, a c o p y of t he c o m plete d e C R Fs will be se nt t o t he site t o be mai ntai ne d as st u d y rec or ds. 


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1 9  P U B LI C A TI O N  P O LI C Y  
T he e xiste nce of t his cli nical st u d y is c o nfi de ntial, a n d it s h o ul d n ot be disc usse d wit h pers o ns 
o utsi de of t he st u d y. A d diti o nall y, t he i nf or mati o n i n t his d oc u me nt a n d re gar di n g t his st u d y 
c o ntai ns tra de secrets a n d c o m merciall y se nsiti ve i nf or mati o n t hat is c o nfi de ntial a n d ma y n ot  be 
discl os e d u nless s uc h discl os ure is re q uire d b y fe deral or state la w or re g ulati o ns. S u bject t o t he 
f ore g oi n g, t his i nf or mati o n ma y be discl ose d o nl y t o t h ose pers o ns i n v ol ve d i n t he st u d y w h o ha ve 
a nee d t o k n o w, b ut all s uc h pers o ns m ust be i nstr ucte d n ot t o f u rt her disse mi nate t his i nf or mati o n 
t o ot hers.    T hese restricti o ns of discl os ure will a p pl y e q uall y t o all f ut ure i nf or mati o n s u p plie d 
t hat  is  i n dicate d  as  c o nfi de ntial.     I nf or mati o n  pertai ni n g  t o  t his  st u d y  will  be  p u blis he d  o n  
w w w.cli nicaltrials. g o v .   
T he data ge nerate d b y t his cli nical st u d y are t he pr o pert y of RI B O MI C a n d s h o ul d n ot be discl ose d 
wit h o ut t he pri or writte n per missi o n of RI B O MI C. T hese data ma y be use d b y RI B O MI C n o w a n d 
i n  t he  f ut ure  f or  prese ntati o n  or  p u blicati o n  at  RI B O MI C’s  discreti o n  or  f or  s u b missi o n  t o  
g o ver n me ntal re g ulat or y a ge ncies. RI B O MI C reser ves t he ri g ht of pri or re vie w of a n y p u blicati o n 
or prese ntati o n of data fr o m t his st u d y.  
I n si g ni n g t his pr ot oc ol, t he Pri nci pal I n vesti gat or a grees t o t he release of t he data fr o m t his st u d y 
a n d ac k n o wle d ges t he a b o ve p u blicati o n p olic y. 


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2 0  R E F E R E N C E S  
1.  Bel g ore F, Li p G Y H, Bla n n A D. Basic fi br o blast gr o wt h fact or i n d uces t he secreti o n of 
vasc ular  e n d ot helial  gr o wt h  fact or  b y  h u ma n  a ortic  s m o ot h  m uscle  cells  b ut  n ot  b y  
e n d ot helial cells. E ur o pea n J o ur nal of Cli nical I n vesti gati o n 2 0 0 3; 3 3: 8 3 3- 8 3 9. 
2.  Bi kfal vi A, Klei n S, Pi nt ucci G, Rif ki n D B. Bi ol o gical r oles of fi br o blast gr o wt h fact or - 2. 
E n d ocr Re v 1 9 9 7; 1 8( 1): 2 6- 4 5. 
3.  B r o w n D M, Kaiser P K, Mic hels M, et al. A N C H O R St u d y Gr o u p: ra ni biz u ma b vers us 
verte p orfi n  f or  ne o vasc ular  a ge -relate d  mac ular  de ge nerati o n.  Ne w  E n gla n d  J o ur nal  of  
Me dici ne 2 0 0 6; 3 5 5: 2 8 3 2 - 4 4. 
4.  C he w  E Y,  Cle m o ns  T,  Sa n gi o va n ni  J P,  et  al.  T he  A ge -relate d  E ye  Disease  St u d y  2  
( A R E D S 2):  St u d y  Desi g n  a n d  Baseli ne  C haracteristics  ( A R E D S 2  Re p ort  N u m ber  1).  
O p ht hal m ol o g y 2 0 1 2; 1 1 9: 2 2 8 2- 8 9. 
5.  Ferris F L, III, Fi ne S L, H y ma n L. A ge -relate d mac ular de ge nerati o n a n d bli n d ness d ue t o 
ne o vasc ular mac ul o pat h y. Arc h. O p ht hal m ol 1 9 8 4; 1 0 2( 1 1): 1 6 4 0- 4 2. 
6.  Frie d ma n  D S,  O' C ol mai n  BJ,  M u n oz  B,  et  al.  Pre vale nce  of  a ge -relate d  mac ular  
de ge nerati o n i n t he U nite d States. Arc h O p ht hal m ol 2 0 0 4; 1 2 2( 4): 5 6 4- 7 2. 
7.  G or d o n , M., Kass, M. ( 2 0 0 1). Oc ular H y perte nsi o n Treat me nt St u d y ( O H T S), Ma n ual of 
Pr oce d ures, Versi o n 3. 0. Nati o nal Tec h nical I nf or mati o n Ser vice.  
8.  Heier J S, Br o w n D M, C h o n g V, et al. VI E W 1 a n d VI E W 2 St u d y Gr o u ps: I ntra vitreal 
afli berce pt  ( V E G F tra p-e ye) i n wet a ge -relate d mac ular de ge nerati o n. O p ht hal m ol o g y 2 0 1 2; 
1 1 9: 2 5 3 7- 4 8.  
9.  Ja bs  D A,  N usse n blatt  R B,  R ose n ba u m  J T.  Sta n dar dizati o n  of  u veitis  n o me nclat ure  f or  
re p orti n g cli nical data. Res ults of t he First I nter nati o nal Wor ks h o p. A m J O p ht hal m ol 2 0 0 5; 
2 8 0: 5 0 9- 1 6 
1 0.  Ji n L, N o na ka Y, Mi ya ka wa S, F uji wara M, Na ka m ura Y. D ual T hera pe utic Acti o n of a 
Ne utralizi n g A nti -F G F 2 A pta mer i n B o ne Disease a n d B o ne Ca ncer Pai n. M ol T her 2 0 1 6; 
2 4: 1 9 7 4- 8 6. 
1 1.  Ka ne, F., Ca m p oc hiar o, P. C h or oi dal Ne o vasc ularizati o n. I n: Li m J, e dit or. A ge -Relate d 
Mac ular De ge nerati o n. 2
n d e diti o n, 2 0 0 7. p. 8 7- 9 5. 
1 2.  Li m JI a n d Ts o n g J W. Cli nical Feat ures of A ge -Relate d Mac ular De ge nerati o n. I n: Li m J, 
e dit or. Part II A ge -Relate d Mac ular De ge nerati o n. 2 n d e diti o n, 2 0 0 7. p. 1 2 5- 1 5 7. 
1 3.  Mats u d a  Y, N o na ka Y , Sat os hi F uta ka wa , et al. A nti -A n gi o ge nic a n d A nti -Scarri n g D ual 
Acti o n of a n A nti -Fi br o blast Gr o wt h Fact or 2 A pta mer i n A ni mal M o dels of Reti nal Disease. 
M ol T her 2 0 1 9; 1 7: 8 1 9- 8 3 2.   
1 4.  Ma g uire M G, Marti n D F, Yi n g G S,  et al. C A T T Researc h Gr o u p. Fi ve -year o utc o mes wit h 
a nti-vasc ular  e n d ot helial  gr o wt h  fact or  treat me nt  of  ne o vasc ular  a ge -relate d  mac ular  
de ge nerati o n: T he C o m paris o n of A ge -Relate d Mac ular De ge nerati o n Treat me nts Trials. 
O p ht hal m ol o g y 2 0 1 6; 1 2 3: 1 7 5 1- 6 1. 


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1 5.  Marti n D F, Ma g uire M G, Fi ne S L et al. C o m paris o n of A ge -Relate d Mac ular De ge nerati o n 
Treat me nts Trials ( C A T T) Researc h Gr o u p. Ra ni biz u ma b a n d be vaciz u ma b f or treat me nt of 
ne o vasc ular  a ge -relate d  mac ular  de ge nerati o n:  2-year  res ults.  O p ht hal m ol o g y  2 0 1 2;  
1 1 9 : 1 3 8 8- 8. 
1 6.  Me d Dra. Me d D R A M S S O, Me dical Dicti o nar y f or Re g ulat or y Acti vities, Versi o n 1 6. 1 2 0 1 3.  
1 7.  N usse n blatt R B, Palesti ne A G, C ha n C C, R o ber ge F. Sta n dar dizati o n of vitreal i nfla m mat or y 
acti vit y i n i nter me diate a n d p osteri or u veitis. O p ht hal m ol o g y 1 9 8 5; 9 2: 4 6 7 - 7 1. 
1 8.  Pa n da- J o nas S, J o nas J B, Ja k o bcz y k M, Sc h nei der U. Reti nal p h ot orece pt or c o u nt, reti nal 
s urface area, a n d o ptic disc size i n n or mal h u ma n e yes. O p ht hal m ol o g y 1 9 9 4; 1 0 1: 5 1 9- 2 3. 
1 9.  R ofa g ha S, B hisit k ul R B, B o yer D S, et al. Se ve n -year o utc o mes i n ra ni biz u ma b -treate d 
patie nts i n A N C H O R, M A RI N A, a n d H O RI Z O N a m ultice nter c o h ort st u d y ( S E V E N -U P). 
O p ht hal m ol o g y 2 0 1 3; 1 2 0: 2 2 9 2- 9 9 
2 0.  Sc h ultz G S a n d Gra nt A B. Ne o vasc ular gr o wt h fact ors. Eye  1 9 9 1; 1: 7 0- 8 0. 
2 1.  S her w o o d M, Bra n dt J. Si x -m o nt h c o m paris o n of bi mat o pr ost o nc e-dail y a n d t wice - dail y 
wit h ti m ol ol t wice -dail y i n patie nts wit h ele vate d i ntra oc ular press ure. S ur v O p ht hal m ol 
2 0 0 1; 4 5( 6 S u p pl 2): S 3 6 1- S 6 8. 
2 2.  Str utz F, Zeis ber g M, Zi ya de h F N, et al. R ole of basic fi br o blast gr o wt h fact or -2 i n e pit helial -
mese nc h y mal tra nsf or mati o n. Ki d ne y I nt 2 0 0 2; 6 1: 1 7 1 4 – 2 8. 
2 3.  S u n Wor ki n g, G. ( 2 0 0 5). P E R S P E C TI V E S Sta n dar dizati o n of  U veitis N o me nclat ure  or 
Re p orti n g Cli nical Data. Res ults of t he First I nter nati o nal Wor ks h o p. A merica n J o ur nal of 
O p ht hal m ol o g y. 2 8 0( 3): 5 0 9- 1 6. 
2 4.  U S _ De pt _ Healt h _ A n d _ H u ma n _ Ser vices.  T he  Se ve nt h  Re p ort  of  t he  J oi nt  Nati o nal  
C o m mittee o n Pre ve nti o n, Detecti o n, E val uati o n, a n d Treat me nt of Hi g h Bl o o d  Press ure. 
T he Se ve nt h Re p ort of t he J oi nt Nati o nal C o m mittee o n Pre ve nti o n, Detecti o n, E val uati o n, 
a n d Treat me nt of Hi g h Bl o o d Press ure. Bet hes da  ( M D) 2 0 0 4. 
2 5.  Vi n di n g T. Occ urre nce of dr use n, pi g me ntar y c ha n ges a n d e x u dati ve c ha n ges i n t he mac ula 
wit h refere nce t o a ge -relate d mac ular de ge nerati o n. A n e pi de mi ol o gical st u d y of 1 0 0 0 a ge d 
i n di vi d uals. Acta O p ht hal m ol o gica 1 9 9 0; 6 8: 4 1 0 – 2 8. 
2 6.  Worl d Healt h Or ga nizati o n Dr u g Dicti o nar y, E. Worl d Healt h Or ga nizati o n  Dr u g Dicti o nar y 
E n ha nce d ( W H O- D D E), Se pte m ber 2 0 1 1  Versi o n 2 0 1 1. 
 


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2 1  A P P E N DI C E S  
2 1. 1  A p pe n di x A - O bli g ati o ns of I nvesti g at ors 
I n s u m mar y, t he Cli nical I n vesti gat or has a gree d t o t he f oll o wi n g o bli gati o ns: 
•  O btai ni n g i nf or me d c o nse nt fr o m e ver y s u bject pri or t o t he s u bject’s partici pati o n i n a n y 
st u d y relate d acti vit y a n d mai ntai ni n g rec or ds of c o nse nt as part of t he st u d y rec or ds. 
•  O btai ni n g a p pr o val fr o m t he I R B bef ore i n v ol vi n g a n y s u bject i n a n y st u d y relate d acti vit y; 
s u b mitti n g verificati o n of t he a p pr o val t o t he S p o ns or; s u b mitti n g peri o dic pr o gress re p orts 
(at least a n n uall y) a n d fi nal re p ort t o I R B a n d t o t he S p o ns or. 
•  A p pr o vi n g t he pr ot oc ol a n d c o n d ucti n g t he st u d y acc or di n g t o t he pr ot oc ol a n d a p plica ble 
re g ulati o ns; i nf or mi n g t he S p o ns or of all de viati o ns fr o m t he pr ot oc ol. 
•  I nf or mi n g t he I R B of all pr ot oc ol a me n d me nts/ m o dificati o ns; se n di n g t he S p o ns or a c o p y 
of t he letter fr o m t he I R B a p pr o vi n g t h e a me n d me nt/ m o dificati o n. 
•  Re p orti n g t o t he S p o ns or a n d t he I R B a n y a d verse e x perie nces t hat occ ur i n t he c o urse of 
t he i n vesti gati o n, t his i ncl u des Seri o us A d verse E ve nts wit hi n 2 4 h o urs. 
•  Kee pi n g caref ul a n d acc urate rec or ds of all cli nical st u d y data (st u d y rec or ds m ust be 
c o nsi dera bl y m ore  e xact a n d c o m plete t ha n t h ose ke pt  i n or di nar y me dical practice); 
mai ntai ni n g rec or ds of all materials s u b mitte d t o t he I R B a n d of all acti o n b y t he I R B 
re gar di n g t he st u d y. 
•  Ma ki n g st u d y rec or ds a vaila ble f or i ns pecti o n  b y t he S p o ns or a n d re prese ntati ves of t he F o o d 
a n d Dr u g A d mi nistrati o n a n d ot her re g ulat or y a ge ncies; kee pi n g rec or ds u ntil n otifie d b y 
t he S p o ns or t hat t he y ma y be destr o ye d. 
•  Mai ntai ni n g pr o per c o ntr ol a n d d oc u me ntati o n of all test a n d c o ntr ol articles.  
•  S u b mitti n g t he f oll o wi n g rec or ds a n d re p orti n g t o t he S p o ns or. 
I. 
Pri or t o t he Be gi n ni n g of t he  St u dy  
•  A c urre nt c urric ul u m vitae ( C V) if n ot s u b mitte d t o RI B O MI C pre vi o usl y or if u p date d.  
•  C Vs f or all s u b -I n vesti gat ors. 
•  A letter fr o m t he I R B i n dicati n g t hat t h e pr ot oc ol was a p pr o ve d, i ncl u di n g t he na me a n d 
a d dress of t he I R B.  
•  A c o p y of t he c o nse nt f or m a p pr o ve d b y I R B. 
•  A list of c urre nt me m bers of t he I R B.  
 
II. 
W hile t he St u dy Is i n  Pr o gress  
•  Ac k n o wle d g me nt of recei pt of t he test a n d c o ntr ol articles; d oc u me ntati o n of dis p ositi o n of 
all test a n d c o ntr ol  articles. 


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•  Ori gi nal Case Re p ort F or ms f or eac h s u bject e nr olle d i n t he  st u d y. 
•  I nf or mati o n re gar di n g all de viati o ns fr o m t he pr ot oc ol. 
•  I nf or mati o n re gar di n g all a d verse me dical e ve nts occ urri n g t o a s u bject w hile e nr olle d i n t he 
st u d y. 
•  A n n ual pr o gress re p ort (if st u d y is o n g oi n g f or m ore t ha n o ne year). Letter fr o m t he I R B 
i n dicati n g a p pr o val of t he a n n ual pr o gress re p ort. 
III. 
O nce t he St u dy Is  C o m plete d  
•  Dis p ositi o n of all use d a n d/ or u n use d test a n d c o ntr ol articles, as well as d oc u me ntati o n of 
all dr u g acc o u nta bilit y. 


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2 1. 2  A p pe n di x B - Ele me nts of I nf or me d  C o nse nt  
2 1. 2. 1  Ele me nts of I nf or me d  C o nse nt  
T he f oll o wi n g i nf or mati o n m ust be pr o vi de d t o eac h s u bject i n o btai ni n g i nf or me d c o nse nt. If 
writte n c o nse nt is bei n g o btai ne d, t he s u bject ( or s u bject’s le gal re prese ntati ve) s h o ul d be pr o vi de d 
wit h a c o p y of t he si g ne d writte n I C F. 
1.  State t hat t he st u d y i n v ol ves  R E S E A R C H.  
2.  E x plai n t he P U R P O S E of t he researc h. 
3.  Trial treat me nts a n d t he pr o ba bilit y f or ra n d o m assi g n me nt t o eac h  treat me nt. 
4.  State t he e x pecte d D U R A TI O N of t he s u bject’s  partici pati o n.  
5.  Descri be t he P R O C E D U R E S t o be  f oll o we d. 
6.  I de ntif y a n y E X P E RI M E N T A L pr oce d ures. 
7.  Descri be a n y reas o na bl y f oreseea ble RI S K S O R DI S C O M F O R T S t o t he  s u bject. 
8.  Descri be a n y B E N E FI T S t o t he s u bject a n d res p o nsi bilit y f or t he s u bject or t o ot hers 
t hat ma y reas o na bl y be e x pecte d fr o m t he researc h. 
9.  N ote a p pr o priate A L T E R N A TI V E pr oce d ures or c o urses of treat me nt, if a n y, t hat mi g ht 
be a d va nta ge o us t o t he s u bject. 
1 0.  A.  
Descri be t he e xte nt, if a n y, t o w hic h C O N FI D E N TI A LI T Y of rec or ds  
i de ntif yi n g t he s u bject will be mai ntai ne d.  
B.  
N ote t hat t he F D A M A Y I N S P E C T t he rec or ds.  
1 1.  F or researc h i n v ol vi n g m ore t ha n mi ni mal ris k, e x plai n if a n y C O M P E N S A TI O N or 
me dical treat me nts are a vaila ble s h o ul d i nj ur y occ ur. If s o, e x plai n (a) w hat t he y c o nsist 
of, O R ( b) w here f urt her i nf or mati o n ma y be  o btai ne d. 
1 2.  A.   
Tell w h o m t o c o ntact f or A N S W E R S t o perti ne nt q uesti o ns a b o ut (a) t he 
researc h, a n d ( b) researc h s u bjects’ ri g hts. 
B.  
Tell w h o m t o c o ntact i n t he e ve nt of a researc h -relate d I NJ U R Y t o t he s u bject. 
1 3.  State  t hat: 
A.  
Partici pati o n is  V O L U N T A R Y,  
B.  
Ref usal t o partici pate will i n v ol ve N O P E N A L T Y or l oss of be nefits t o w hic h  
t he s u bject is ot her wise e ntitle d 
C.  
T he s u bject M A Y DI S C O N TI N U E partici pati o n at a n y ti me wit h o ut pe nalt y or 
l oss of be nefits t o w hic h t he s u bject is ot her wise e ntitle d. 
2 1. 2. 2  A d diti o n al Ele me nts of I nf or me d  C o nse nt  
W he n a p pr o priate, o ne or m ore of t he f oll o wi n g ele me nts of i nf or mati o n s hall als o be pr o vi de d t o 
eac h s u bject:  


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1.  A state me nt t hat partic ular treat me nt or pr oce d ure ma y i n v ol ve ris ks t o t he s u bject ( or  t o t he 
e m br y o or fet us, if t he s u bject is or ma y bec o me pre g na nt) w hic h are c urre ntl y u nf oreseea ble.  
2.  A ntici pate d circ u msta nces u n der w hic h t he s u bject’s partici pati o n ma y be ter mi nate d b y t he 
I n vesti gat or wit h o ut re gar d t o t he s u bject’s c o nse nt. 
3.  A n y a d diti o nal c osts t o t he s u bject t hat ma y res ult fr o m partici pati o n i n t he  researc h. 
4.  T he c o nse q ue nces of a s u bject’s decisi o n t o wit h dra w fr o m t he  researc h a n d pr oce d ures f or 
or derl y ter mi nati o n of partici pati o n b y t he s u bject. 
5.  A state me nt t hat si g nifica nt ne w fi n di n gs de vel o pe d d uri n g t he c o urse of t he researc h, w hic h 
ma y relate t o t he s u bject’s willi n g ness t o c o nti n ue partici pati o n, will be pr o vi d e d t o t he 
s u bject. 
6.  T he a p pr o xi mate n u m ber of s u bjects i n v ol ve d i n t he st u d y. 
T he i nf or me d c o nse nt re q uire me nts i n t his pr ot oc ol are n ot i nte n de d t o pree m pt a n y  a p plica ble 
Fe deral, State, or l ocal la ws w hic h re q uire a d diti o nal i nf or mati o n t o be discl ose d f o r i nf or me d 
c o nse nt t o be le gall y effecti ve. 
N ot hi n g i n t his pr ot oc ol is i nte n de d t o li mit t he a ut h orit y of a p h ysicia n t o pr o vi de e mer ge nc y 
me dical care t o t he e xte nt t he p h ysicia n is per mitte d t o d o s o u n der a p plica ble Fe deral, State, or 
l ocal la w. 
 
R E F E R E N C E: 2 1 C F R P art 5 0. 2 5 - P R O T E C TI O N O F H U M A N S U B J E C T S, El e m e nt s of 
I nf or m e d C o n s e nt. 


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2 1. 3  A p pe n di x C - Decl ar ati o n of Helsi n ki  
W M A Decl ar ati o n of Helsi n ki - Et hic al Pri nci ples f or Me dic al Rese arc h I nv olvi n g 
H u m a n S u bjects  
 
Pre a m ble  
1.  
T he Worl d Me dical Ass ociati o n ( W M A) has de vel o pe d t he Declarati o n of Helsi n ki as a 
state me nt of et hical pri nci ples f or me dical researc h i n v ol vi n g h u ma n s u bjects, i ncl u di n g researc h 
o n i de ntifia ble h u ma n material a n d  data.  
T he Declarati o n is i nte n de d t o be rea d  as a w h ole a n d eac h of its c o nstit ue nt para gra p hs 
s h o ul d be a p plie d wit h c o nsi derati o n of all ot her rele va nt para gra p hs. 
2.  
C o nsiste nt wit h t he ma n date of t he W M A, t he Declarati o n is a d dresse d pri maril y t o 
p h ysicia ns. T he W M A e nc o ura ges ot hers w h o are i n v ol v e d i n me dical researc h i n v ol vi n g  h u ma n 
s u bjects t o a d o pt t hese pri nci ples.  
Ge ner al Pri nci ples  
3.  
T he Declarati o n of Ge ne va of t he W M A bi n ds t he p h ysicia n wit h t he w or ds, “ T he healt h 
of m y patie nt will be m y first c o nsi derati o n,” a n d t he I nter nati o nal C o de of Me dical Et hics 
declares t hat, “ A p h ysicia n s hall act i n t he patie nt's best i nterest w he n pr o vi di n g me dical  care.” 
4.  
It is t he d ut y of t he p h ysicia n t o pr o m ote a n d safe g uar d t he healt h, well- bei n g a n d ri g hts 
of patie nts, i ncl u di n g t h ose w h o are i n v ol ve d i n me dical researc h. T he p h ysicia n's k n o wle d ge 
a n d c o nscie nce are de dicate d t o t he f ulfil me nt of t his  d ut y. 
5.  
Me dical pr o gress is base d o n researc h t hat ulti matel y m ust i ncl u de st u dies  i n v ol vi n g 
h u ma n s u bjects. 
6.  
T he pri mar y p ur p ose of me dical researc h i n v ol vi n g h u ma n s u bjects is t o u n dersta n d t he 
ca uses, de vel o p me nt a n d effects of diseases a n d i m pr o ve pre ve nti ve, dia g n ostic a n d t hera pe utic 
i nter ve nti o ns ( met h o ds, pr oce d ures a n d treat me nts). E ve n t he best pr o ve n i nter ve nti o ns m ust be 
e val uate d c o nti n uall y t hr o u g h researc h f or t heir safet y, effecti ve ness, efficie nc y, accessi bilit y a n d  
q ualit y. 
7.  
Me dical researc h is s u bject t o et hical sta n dar ds t hat pr o m ote a n d e ns ure res pect f or  all 
h u ma n s u bjects a n d pr otect t heir healt h a n d ri g hts. 
8.  
W hile t he pri ma r y p ur p ose of me dical researc h is t o ge nerate ne w k n o wle d ge, t his g oal 
ca n ne ver ta ke prece de nce o ver t he ri g hts a n d i nterests of i n di vi d ual researc h  s u bjects. 
9.  
It is t he d ut y of p h ysicia ns w h o are i n v ol ve d i n me dical researc h t o pr otect t he life, 
healt h, d i g nit y, i nte grit y, ri g ht t o self- deter mi nati o n, pri vac y, a n d c o nfi de ntialit y of pers o nal 
i nf or mati o n of researc h s u bjects. T he res p o nsi bilit y f or t he pr otecti o n of researc h s u bjects m ust 
al wa ys rest wit h t he p h ysicia n or ot her healt h care pr ofessi o nals a n d  ne ver wit h t he researc h 
s u bjects, e ve n t h o u g h t he y ha ve gi ve n c o nse nt. 
1 0.  
P h ysicia ns m ust c o nsi der t he et hical, le gal a n d re g ulat or y n or ms a n d sta n dar ds f or 
researc h i n v ol vi n g h u ma n s u bjects i n t heir o w n c o u ntries as well as a p plica ble i nter nati o nal 


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n or ms a n d sta n dar ds. N o nati o nal or i nter nati o nal et hical, le gal or re g ulat or y re q uire me nt s h o ul d 
re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h s u bjects set f ort h i n t his Declarati o n.  
1 1.  
Me dical researc h s h o ul d be c o n d ucte d i n a ma n ner t hat mi ni mizes p ossi ble har m t o  t he 
e n vir o n me nt. 
1 2.  
Me dical researc h i n v ol vi n g h u ma n s u bjects m ust be c o n d ucte d o nl y b y i n di vi d uals wit h 
t he a p pr o priate et hics a n d scie ntific e d ucati o n, trai ni n g a n d q ualificati o ns. Researc h o n patie nts 
or healt h y v ol u nteers re q uires t he s u per visi o n of a c o m pete nt a n d a p pr o priatel y q ualifie d 
p h ysicia n or ot her healt h care  pr ofessi o nal. 
1 3.  
Gr o u ps t hat are u n derre prese nte d i n me dical researc h s h o ul d be pr o vi de d a p pr o priate 
access t o partici pati o n i n  researc h. 
1 4.  
P h ysicia ns w h o c o m bi ne me dical researc h wit h me dical care s h o ul d i n v ol ve t heir 
patie nts i n researc h o nl y t o t he e xte nt t hat t his is j ustifie d b y its p ote ntial pre ve nti ve, dia g n ostic 
or t hera pe utic val ue a n d if t he p h ysicia n has g o o d reas o n t o belie ve t hat partici pati o n i n t he 
researc h st u d y will n ot a d versel y affect t he healt h of t he patie nts w h o ser ve as researc h s u bjects. 
1 5.  
A p pr o priate c o m pe nsati o n a n d treat me nt f or s u bjects w h o are har me d as a res ult  of 
partici pati n g i n researc h m ust be e ns ure d.  
Ris ks, B ur de ns a n d Be nefits  
1 6.  
I n me dical practice a n d i n me dical researc h, m ost i nter ve nti o ns i n v ol ve ris ks a n d 
b ur de ns. 
Me dical researc h i n v ol vi n g h u ma n s u bjects ma y o nl y be c o n d ucte d if t he i m p orta nce of 
t he o bjecti ve o ut wei g hs t he ris ks a n d b ur de ns t o t he researc h s u bjects. 
1 7.  
All me dical researc h i n v ol vi n g h u ma n s u bjects m ust be prece de d b y caref ul assess me nt 
of pre dicta ble ris ks a n d b ur de ns t o t he i n di vi d uals a n d gr o u ps i n v ol ve d i n t he researc h i n 
c o m paris o n wit h f oreseea ble be nefits t o t he m a n d t o ot her i n di vi d uals or gr o u ps affecte d b y t he 
c o n diti o n u n der i n vesti gati o n. 
Meas ures t o mi ni mize t he ris ks m ust be i m pl e me nte d. T he ris ks m ust be c o nti n u o usl y 
m o nit ore d, assesse d a n d d oc u me nte d b y t he researc her.  
1 8.  
P h ysicia ns ma y n ot be i n v ol ve d i n a researc h st u d y i n v ol vi n g h u ma n s u bjects u nless 
t he y are c o nfi de nt t hat t he ris ks ha ve bee n a de q uatel y assesse d a n d ca n be satisfact oril y 
ma na ge d. 


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W he n t he ris ks are f o u n d t o o ut wei g h t he p ote ntial be nefits or w he n t here is c o ncl usi ve 
pr o of of defi niti ve o utc o mes, p h ysicia ns m ust assess w het her t o c o nti n ue, m o dif y or i m me diatel y 
st o p t he st u d y. 
V ul ner a ble Gr o u ps a n d I n di vi d u als  
1 9.  
S o me gr o u ps a n d i n di vi d uals are partic ularl y v ul nera ble a n d ma y ha ve a n i ncrease d 
li keli h o o d of bei n g wr o n ge d or of i nc urri n g a d diti o nal har m.  
All v ul nera ble gr o u ps a n d i n di vi d uals s h o ul d recei ve s pecificall y c o nsi dere d pr otecti o n.  
2 0.  
Me dical researc h wit h a v ul nera ble gr o u p is o nl y j ustifie d if t he researc h is res p o nsi ve 
t o t he healt h nee ds or pri orities of t his gr o u p a n d t he researc h ca n n ot be carrie d o ut i n a n o n- 
v ul nera ble gr o u p. I n a d diti o n, t his gr o u p s h o ul d sta n d t o be nefit fr o m t he k n o wle d ge, practices  or 
i nter ve nti o ns t hat res ult fr o m t he researc h. 
Scie ntific Re q uire me nts a n d Rese arc h Pr ot oc ols  
2 1.  
Me dical researc h i n v ol vi n g h u ma n s u bjects m ust c o nf or m t o ge nerall y acce pte d 
scie ntific pri nci ples, be base d o n a t h or o u g h k no wle d ge of t he scie ntific literat ure, ot her rele va nt 
s o urces of i nf or mati o n, a n d a de q uate la b orat or y a n d, as a p pr o priate, a ni mal e x peri me ntati o n. 
T he welfare of a ni mals use d f or researc h m ust be res pecte d.  
2 2.  
T he desi g n a n d perf or ma nce of eac h researc h st u d y i n v ol vi n g h u ma n s u bjects m ust be 
clearl y descri be d a n d j ustifie d i n a researc h  pr ot oc ol.  
T he pr ot oc ol s h o ul d c o ntai n a state me nt of t he et hical c o nsi derati o ns i n v ol ve d a n d s h o ul d 
i n dicate h o w t he pri nci ples i n t his Declarati o n ha ve bee n a d dresse d. T he pr ot oc ol s h o ul d i ncl u de 
i nf or mati o n re gar di n g f u n di n g, s p o ns ors, i nstit uti o nal affiliati o ns, p ote ntial c o nflicts of i nterest, 
i nce nti ves f or s u bjects a n d i nf or mati o n re gar di n g pr o visi o ns f or treati n g a n d/ or c o m pe nsati n g 
s u bjects w h o are har me d as a c o nse q ue nce of partici pati o n i n t he researc h st u d y. 
I n cli nical trials, t he pr ot oc ol m ust als o descri be a p pr o priate arra n ge me nts f or p ost-trial 
pr o visi o ns. 
Rese arc h Et hics C o m mittees  
2 3.  
T he researc h pr ot oc ol m ust be s u b mitte d f or c o nsi derati o n, c o m me nt, g ui da nce a n d 
a p pr o val t o t he c o ncer ne d researc h et hics c o m mittee bef ore t he st u d y be gi ns. T his c o m mittee 
m ust be tra ns pare nt i n its f u ncti o ni n g, m ust be i n de pe n de nt of t he researc her, t he s p o ns or a n d 
a n y ot her u n d ue i nfl ue nce a n d m ust be d ul y q ualifie d. It m ust ta ke i nt o c o nsi derati o n t he la ws 
a n d re g ulati o ns of t he c o u ntr y or c o u ntries i n w hic h t he researc h is t o be perf or me d as well as 
a p plica ble i nter nati o nal n or ms a n d sta n dar ds b ut t hese m ust n ot be all o we d t o re d uce or 
eli mi nate a n y of t he pr otecti o ns f or researc h s u bjects set f ort h i n t his  Declarati o n.  
T he c o m mittee m ust ha ve t he ri g ht t o m o nit or o n g oi n g st u dies. T he researc her m ust 
pr o vi de m o nit ori n g i nf or mati o n t o t he c o m mittee, es peciall y i nf or mati o n a b o ut a n y seri o us 
a d verse e ve nts. N o a me n d me nt t o t he pr ot oc ol ma y be ma de wit h o ut c o nsi derati o n a n d a p pr o val 
b y t he c o m mittee. After t he e n d of t he st u d y, t he researc hers m ust s u b mit a fi nal re p ort t o t he 
c o m mittee c o ntai ni n g a s u m m ar y of t he st u d y’s fi n di n gs a n d c o ncl usi o ns. 
Pri v ac y a n d C o nfi de nti alit y   
2 4.  
E ver y preca uti o n m ust be ta ke n t o pr otect t he pri vac y of researc h s u bjects a n d t he 


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c o nfi de ntialit y of t heir pers o nal  i nf or mati o n. 
I nf or me d C o nse nt 
2 5.  
Partici pati o n b y i n di vi d uals ca pa ble of gi vi n g i nf or me d c o nse nt as s u bjects i n me dical 
researc h m ust be v ol u ntar y. Alt h o u g h it ma y be a p pr o priate t o c o ns ult fa mil y me m bers or 
c o m m u nit y lea ders, n o i n di vi d ual ca pa ble of gi vi n g i nf or me d c o nse nt ma y be e nr olle d i n a 
researc h st u d y u nless he or s he freel y a grees. 
2 6.  
I n me dical researc h i n v ol vi n g h u ma n s u bjects ca pa ble of gi vi n g i nf or me d c o nse nt, eac h 
p ote ntial s u bject m ust be a de q uatel y i nf or me d of t he ai ms, met h o ds, s o urces of f u n di n g, a n y 
p ossi ble c o nflicts of i nterest, i nstit uti o nal affiliati o ns  of t he researc her, t he a ntici pate d be nefits 
a n d p ote ntial ris ks of t he st u d y a n d t he disc o mf ort it ma y e ntail, p ost-st u d y pr o visi o ns a n d a n y 
ot her rele va nt as pects of t he st u d y. T he p ote ntial s u bject m ust be i nf or me d of t he ri g ht t o ref use 
t o partici pate i n t he st u d y or t o wit h dra w c o nse nt t o partici pate at a n y ti me wit h o ut re prisal. 
S pecial atte nti o n s h o ul d be gi ve n t o t he s pecific i nf or mati o n nee ds of i n di vi d ual p ote ntial 
s u bjects as well as t o t he met h o ds use d t o deli ver t he i nf or mati o n. 
After e ns uri n g t hat t he p ote ntial s u bject has u n derst o o d t he i nf or mati o n, t he p h ysicia n or 
a n ot her a p pr o priatel y q ualifie d i n di vi d ual m ust t he n see k t he p ote ntial s u bject’s freel y- gi ve n 
i nf or me d c o nse nt, prefera bl y i n writi n g. If t he c o nse nt ca n n ot be e x presse d i n writi n g, t he n o n- 
writte n c o nse nt m ust be f or mall y d oc u me nte d a n d wit nesse d. 
All me dical researc h s u bjects s h o ul d be gi ve n t he o pti o n of bei n g i nf or me d a b o ut t he 
ge neral o utc o me a n d res ults of t he st u d y. 
2 7.  
W he n see ki n g i nf or me d c o nse nt f or partici pati o n i n a researc h st u d y t he p h ysicia n m ust 
be partic ularl y ca uti o us if t he p ote ntial s u bject is i n a de pe n de nt relati o ns hi p wit h t he p h ysicia n 
or ma y c o nse nt u n der d uress. I n s uc h sit uati o ns t he i nf or me d c o nse nt m ust be s o u g ht b y a n 
a p pr o priatel y q ualifie d i n di vi d ual w h o is c o m pletel y i n de pe n de nt of t his relati o ns hi p. 
2 8.  
F or a p ote ntial researc h s u bject w h o is i nca pa ble of gi vi n g i nf or me d c o nse nt, t he 
p h ysicia n m ust see k i nf or me d c o nse nt fr o m t he le gall y a ut h orize d re prese ntati ve. T hese 
i n di vi d uals m ust n ot be i ncl u de d i n a researc h st u d y t hat has n o li keli h o o d of be nefit f or t he m 
u nless it is i nte n de d t o pr o m ote t he healt h of t he gr o u p re prese nte d b y t he p ote ntial s u bject, t he 
researc h ca n n ot i nstea d be perf or me d wit h pers o ns ca pa ble of pr o vi di n g i nf or me d c o nse nt,  a n d 
t he researc h e ntails o nl y mi ni mal ris k a n d mi ni mal b ur de n. 
2 9.  
W he n a p ote ntial researc h s u bject w h o is dee me d i nca pa ble of gi vi n g i nf or me d c o nse nt 
is a ble t o gi ve asse nt t o decisi o ns a b o ut partici pati o n i n researc h, t he p h ysicia n m ust see k t hat 
asse nt i n a d diti o n t o t he c o nse nt of t he le gall y a ut h orize d re prese ntati ve. T he p ote ntial s u bject’s 
disse nt s h o ul d be  res pecte d. 
3 0.  
Researc h i n v ol vi n g s u bjects w h o are p h ysicall y or me ntall y i nca pa ble of gi vi n g c o nse nt, 
f or e xa m ple, u nc o nsci o us patie nts, ma y be d o ne o nl y if t he p h ysical or me ntal c o n diti o n t hat 
pre ve nts gi vi n g i nf or me d c o nse nt is a necessar y c haracteristic of t he researc h gr o u p. I n s uc h 
circ u msta nces t he p h ysicia n m ust see k i nf or me d c o nse nt fr o m t he le gall y a ut h orize d 
re presentati ve. If n o s uc h re prese ntati ve is a vaila ble a n d if t he researc h ca n n ot be dela ye d, t he 
st u d y ma y pr ocee d wit h o ut i nf or me d c o nse nt pr o vi de d t hat t he s pecific reas o ns f or i n v ol vi n g 
s u bjects wit h a c o n diti o n t hat re n ders t he m u na ble t o gi ve i nf or me d c o nsent ha ve bee n state d i n 
t he researc h pr ot oc ol a n d t he st u d y has bee n a p pr o ve d b y a researc h et hics c o m mittee. C o nse nt 
t o re mai n i n t he researc h m ust be o btai ne d as s o o n as p ossi ble fr o m t he s u bject or a le gall y 


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a ut h orize d re prese ntati ve.  
3 1.  
T he p h ysicia n m ust f ull y i nf or m t he patie nt w hic h as pects of t heir care are relate d t o t he 
researc h. T he ref usal of a patie nt t o partici pate i n a st u d y or t he patie nt’s decisi o n t o wit h dra w 
fr o m t he st u d y m ust ne ver a d versel y affect t he patie nt- p h ysicia n relati o ns hi p. 
3 2.  
F or me dical researc h usi n g i de ntifia ble h u ma n material or data, s uc h as researc h o n 
material or data c o ntai ne d i n bi o ba n ks or si milar re p osit ories, p h ysicia ns m ust see k i nf or me d 
c o nse nt f or its c ollecti o n, st ora ge a n d/ or re use. T here ma y be e xce pti o nal sit uati o ns w here 
c o nse nt w o ul d be i m p ossi ble or i m practica ble t o o btai n f or s uc h researc h. I n s uc h sit uati o ns t he 
researc h ma y be d o ne o nl y after c o nsi derati o n a n d a p pr o val of a researc h et hics c o m mittee. 
Use of Pl ace b o  
3 3.  
T he be nefits, ris ks, b ur de ns a n d effecti ve ness of a ne w i nter ve nti o n m ust be teste d 
a gai nst t h ose of t he best pr o ve n i nter ve nti o n(s), e xce pt i n t he f oll o wi n g circ u msta nces:  
W here n o pr o ve n i nter ve nti o n e xists, t he use of place b o, or n o i nter ve nti o n, is acc e pta ble; 
or 
W here f or c o m pelli n g a n d scie ntificall y s o u n d met h o d ol o gical reas o ns t he use of a n y 
i nter ve nti o n less effecti ve t ha n t he best pr o ve n o ne, t he use of place b o, or n o i nter ve nti o n is 
necessar y t o deter mi ne t he efficac y or safet y of a n i nter ve nti o n  a n d t he patie nts w h o recei ve a n y 
i nter ve nti o n less effecti ve t ha n t he best pr o ve n o ne, place b o, or n o i nter ve nti o n will n ot be 
s u bject t o a d diti o nal ris ks of seri o us or irre versi ble har m as a res ult of n ot recei vi n g t he best 
pr o ve n i nter ve nti o n. 
E xtre me c are m ust be ta ke n t o a v oi d a b use of t his o pti o n. 
P ost -Tri al Pr o visi o ns  
3 4.  
I n a d va nce of a cli nical trial, s p o ns ors, researc hers a n d h ost c o u ntr y g o ver n me nts s h o ul d 
ma ke pr o visi o ns f or p ost- trial access f or all partici pa nts w h o still nee d a n i nter ve nti o n i de ntifie d 
as be neficial i n t he trial. T his i nf or mati o n m ust als o be discl ose d t o partici pa nts d uri n g t he 
i nf or me d c o nse nt pr ocess.  
Rese arc h Re gistr ati o n a n d P u blic ati o n a n d Disse mi n ati o n of Res ults  
3 5.  
E ver y researc h st u d y i n v ol vi n g h u ma n s u bject s m ust be re gistere d i n a p u blicl y 
accessi ble data base bef ore recr uit me nt of t he first  s u bject. 
3 6.  
Researc hers, a ut h ors, s p o ns ors, e dit ors a n d p u blis hers all ha ve et hical o bli gati o ns wit h 
re gar d t o t he p u blicati o n a n d disse mi nati o n of t he res ults of researc h. Researc hers ha ve a d ut y  t o 
ma ke p u blicl y a vaila ble t he res ults of t heir researc h o n h u ma n s u bjects a n d are acc o u nta ble f or 
t he c o m plete ness a n d acc urac y of t heir re p orts. All parties s h o ul d a d here t o acce pte d g ui deli nes 
f or et hical re p orti n g. Ne gati ve a n d i nc o ncl usi ve as well as p ositi ve res ults m ust be p u blis he d or 
ot her wise ma de p u blicl y a vaila ble. S o urces of f u n di n g, i nstit uti o nal affiliati o ns a n d c o nflicts of 
i nterest m ust be declare d i n t he p u blicati o n. Re p orts of researc h n ot i n acc or da nce wit h t he 
pri nci ples of t his Declarati o n s h o ul d n ot be acce pte d f or p u blicati o n. 
 
U n pr o ve n I nter ve nti o ns i n Cli nic al Pr actice  
3 7.  
I n t he treat me nt of a n i n di vi d ual patie nt, w here pr o ve n i nter ve nti o ns d o n ot e xist or 
ot her k n o w n i nter ve nti o ns ha ve bee n i neffecti ve, t he p h ysicia n, after see ki n g e x pert a d vice, wit h 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
6 8  of  7 4  
 
i nf or me d c o nse nt fr o m t he patie nt or a le gall y a ut h orize d re prese ntati ve, ma y use a n u n pr o ve n 
i nter ve nti o n if i n t he p h ysicia n's j u d g me nt it offers h o pe of sa vi n g life, re-esta blis hi n g healt h or 
alle viati n g s ufferi n g. T his i nter ve nti o n s h o ul d s u bse q ue ntl y be ma de t he o bject of researc h, 
desi g ne d t o e val uate its safet y a n d efficac y. I n all cases, ne w i nf or mati o n m ust be rec or de d a n d, 
w here a p pr o priate, ma de p u blicl y  a vaila ble. 
 
 
W M A Declarati o n of Helsi n ki - Et hical Pri nci ples f or Me dical Researc h I n v ol vi n g H u ma n S u bjects  
A d o pte d b y t he 1 8t h W M A Ge neral Asse m bl y, Helsi n ki, Fi nla n d, J u ne 1 9 6 4 a n d a me n de d b y t he:  
2 9t h W M A Ge neral Asse m bl y, To k y o, Ja pa n, Oct o ber 1 9 7 5  
3 5t h W M A Ge neral Ass e m bl y, Ve nice, Ital y, Oct o ber 1 9 8 3  
4 1st W M A Ge neral Asse m bl y, H o n g K o n g, Se pte m ber 1 9 8 9  
4 8t h' Wl' v.I A Ge neral Asse m bl y; S o merset West, Re p u blic of S o ut h Africa, Oct o ber 1 9 9 6  
5 2 n d W M A Ge neral Asse m bl y, E di n b ur g h, Sc otla n d, Oct o ber 2 0 0 0  
5 3r d W M A Ge neral Asse m bl y, Was hi n gt o n D C, U S A, Oct o ber 2 0 0 2 ( N ote of Clarificati o n a d de d) 5 5t h 
W M A Ge neral Asse m bl y, To k y o, Ja pa n, Oct o ber 2 0 0 4 ( N ote of Clarificati o n a d de d)  
5 9t h W M A Ge neral Asse m bl y, Se o ul, Re p u blic of K orea, Oct o ber 2 0 0 8  
6 4t h W M A Ge neral Ass e m bl y, F ortaleza, Brazil, Oct o ber 2 0 1 3


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
6 9  of  7 4  
 
 
2 1. 4  A p pe n di x D - Pr oce d ures f or  E x a mi n ati o ns 
2 1. 4. 1  De m o gr a p hics/ Eli gi bilit y, Me dic al/ S ur gic al Hist or y a n d C o nc o mit a nt Me dic ati o n 
De m o gra p hics/ Eli gi bilit y, me dical/s ur gical hist or y a n d c o nc o mita nt me dicati o n will be o btai ne d 
t hr o u g h s u bject i nter vie ws at Scree ni n g ( Da y - 2 8 t o Da y -1). Me dical hist or y a n d c o nc o mita nt 
me dicati o ns will be o btai ne d t hr o u g h s u bject i nter vie ws at eac h visit.  
 
2 1. 4. 2  P h ysic al  E x a mi n ati o n 
A f ull b o d y s yste matic p h ysical e xa mi nati o n will be c o n d ucte d d uri n g Visit 1 ( Baseli ne ( Da y 1)) . 
Cli nical I n vesti gat or o r a n e xter nal i nter nist will c o nfir m s u bject’s o verall c o n diti o n n oti n g a n y 
a b n or malities b y a re vie w of t he f oll o wi n g s yste ms: e. g., hea d, nec k, t h yr oi d, ears, n ose, t hr oat, 
m o ut h, t o n g ue, res pirat or y, car di o vasc ular, a b d o me n, a n d ne ur ol o gical. 
T he Cli nical I n vesti gat or will assess s u bject’s o verall c o n diti o n t o deter mi ne q ualificati o n f or st u d y 
e ntr y c o nsi deri n g p ossi ble class effects of R B M - 0 0 7.   
 
2 1. 4. 3  Vit al Si g ns  
Bl o o d press ure a n d heart rate will be meas ure d at Visit 0/ Scree ni n g ( Da y - 2 8 t o Da y - 1) usi n g an 
a ut o mate d  or  ma n ual  bl o o d  press ure  m o nit or.  S yst olic  a n d  diast olic  bl o o d  press ures  will  be 
rec or de d i n milli meters of merc ur y ( m m H g) a n d heart rate will be rec or de d i n beats per mi n ute 
( b p m). 
I n  acc or da nce  wit h  t he  rec o m me n dati o ns  of  t he  J oi nt  Nati o nal  Co m mittee  o n  Pre ve nti o n,  
Detecti o n,
 E val uati o n,
 a n d
 Treat me nt
 of
 Hi g h
 Bl o o d
 Press ure
 
(U S _ De pt _ Healt h _a n d _ H u ma n _ Ser vices, 2 0 0 4 ), t he f oll o wi n g meas ure me nt pr oce d ure will be 
use d t o meas ure vital si g ns:  
•  
S u bject s h o ul d n ot s m o ke or i n gest caffei ne wit hi n t he 3 0 -mi n ute peri o d i m me diatel y bef ore 
t he meas ure me nt.  
•  
S u bject s h o ul d be seate d q uietl y i n a c hair wit h t he bac k s u p p orte d, feet o n t he  fl o or, ar m 
bare d, a n d ar m s u p p orte d at heart le vel. 
•  
Be gi n t he meas ure me nt after at lea st 5 mi n utes of rest. 
•  
To e ns ure a n acc urate meas ure me nt, use a n a p pr o priatel y size d c uff. T he c uff bla d der s h o ul d 
e ncircle at least 8 0 % of t he ar m. Ma n y a d ults nee d a lar ge  c uff. 
•  
Ta ke t w o ( 2) s yst olic/ diast olic press ure a n d heart rate meas ure me nts se parat e d b y at least 3 0 
sec o n ds. Rec or d eac h meas ure me nt i n t he s u bject’s s o urce d oc u me nt. 
•  
If t he t w o press ure meas ure me nts differ b y 5 m m H g or less, t he n t he a vera ge of t he t w o 
bec o mes t he rec or de d press ure. F or e xa m ple, if t he t w o meas ure me nts are 1 2 0/ 9 0 a n d 
1 2 5/ 9 5, t he n 1 2 2. 5/ 9 2. 5 is t he rec or de d s yst olic/ diast olic press ure.  


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
7 0  of  7 4  
 
•  
If  t he  t w o  press ure  meas ure me nts  differ  b y  m ore  t ha n  5  m m H g,  t he n  a  t hir d  rea di n g  
meas ure me nt is ma de, a n d t he a vera ge of t he t hree bec o mes t he rec or de d press ure. F or 
e xa m ple, if t he t hree meas ure me nts are 1 1 5/ 9 0, 1 2 4/ 9 6, a n d 1 2 0/ 9 2, t he n 1 1 9. 7/ 9 2. 7 is t he 
rec or de d s yst olic/ diast olic press ure. T he rec or de d bl o o d press ure will be t he a vera ge of t he 
meas ure me nts.  
•  
Rec or d  t he  heart  rate.  F or  heart  rate,  t he  a vera ge  of  t he  t w o  ( or  t hree,  if  perf or me d) 
meas ure me nts o btai ne d bec o mes t he rec or de d heart  rate. 
 
2 1. 4. 4  Uri ne Pre g n a nc y Test  
A uri ne pre g na nc y test will be c o n d ucte d bef ore I V T i njecti o n at Vi sit 1 ( B a s eli n e ( D a y 1))  a n d 
Visit 6 f or all fe males of c hil d beari n g p ote ntial. A fe male is c o nsi dere d of c hil d beari n g p ote nti al 
u nless s he is p ost me n o pa usal (at least 2 4 m o nt hs si nce last me nses occ urre d),  has ha d her uter us 
a n d/ or b ot h o varies re m o ve d, or has ha d a bilateral t u bal li gati o n. To o btai n t he pre g na nc y test, 
t he s u bject s h o ul d f oll o w i nstr ucti o ns pr o vi de d b y t he ma n ufact urer of t he uri ne pre g na nc y test 
kit.  
 
2 1. 4. 5  Best C orrecte d Vis u al  Ac uit y  
E T D R S c hart will be use d t o e xa mi ne a n d rec or d  B C V A at eac h st u d y visit . 
 
2 1. 4. 6  E xter n al Oc ul ar E x a mi n ati o n 
E xter nal oc ular e xa mi nati o n will be d o ne e val uati n g li d  a n d las hes as n or mal a n d a b n or mal wit h 
n otes if a b n or mal.  
 
2 1. 4. 7  Slit -L a m p  Bi o micr osc o p y 
Slit -la m p bi o micr osc o p y will be use d t o e xa mi ne e ye str uct ures at eac h st u d y visit. Slit-la m p 
bi o micr osc o p y will be perf or me d pri or t o t he injecti o n a n d t he n a gai n wit hi n 3 0 mi n utes after t he 
injecti o n . T his will be als o a p plie d f or t he p ost I V T i njecti o n of Resc ue treat me nt.  T he c o nj u ncti va, 
c or nea, a n d le ns will be o bser ve d wit h t he slit -la m p bea m a p pr o xi matel y 0. 3 m m i n wi dt h a n d 1. 0 
m m i n le n gt h. C o nj u ncti va, Sclera a n d C or nea will be descri be d  as n or mal / a b n or mal  wit h n otes 
if a b n or mal. 
 
L e n s
L e n s  
T h e l e n s will b e n ot e d a s  n or m al/ a b n or m al, p h a kic, a p h a kic, or p s e u d o p h a kic. P h a kic l e n s 
will b e gr a d e d f or c at ar act a s n ucl e ar, p o st eri or s u bc a p s ul ar, a n d c ortic al a s d e scri b e d 
b el o w:  
N o n e  
( 0) = N o l e n s di sc ol or ati o n n or o p acific ati o n  
Mil d  
( 1) = Yell o w l e n s di sc ol or ati o n or s m all l e n s o p acit y ( a xial or p eri p h er al) 
M o d er at e 
 ( 2) = A m b er l e n s di sc ol or ati o n or m e di u m l e n s o p acit y ( a xi al or p eri p h er al) 
S e v er e  
( 3) = Br u n e sc e nt l e n s di sc ol or ati o n or c o m pl et e l e n s o p acific ati o n ( n o r e d r efl e x) 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
7 1  of  7 4  
 
A nteri or c ha m ber cells a n d flare will be o bser ve d wit h a 1. 0 m m i n wi dt h a n d 1. 0 m m i n le n gt h 
slit  bea m  a n d  gra de d  usi n g  t he  Sta n dar dizati o n  of  U veitis  N o me nclat ure  ( S U N)  scale  (S u n  
Wor ki n g, 2 0 0 5 ). T he iris a n d t he p u pil will be e val uate d f or t he prese nce of cli nicall y si g nifica nt 
a b n or malities.  
 
A nt eri or C h a m b er C ell s
A nt eri or C h a m b er C ell s  
( 0) = N o c ell s  
( 0. 5) = 1- 5 c ells 
( 1) = 6-1 5  c ell s 
( 2) = 1 6-2 5  c ell s 
( 3) = 2 6-5 0  c ell s 
( 4) = > 5 0 c ell s 
 
A nt eri or C h a m b er Fl ar e
A nt eri or C h a m b er Fl ar e  
( 0) = N o n e  
( 1) = F ai n  
( 2) = M o d er at e (iri s/l e n s d et ail s cl e ar) 
( 3) = M ar k e d (iri s/l e n s d et ail s h a z y) 
( 4) = I nt e n s e (fi bri n/ pl a stic a q u e o u s) 
 
Iri s
Iri s 
T he iris will be e val uate d f or t he prese nce of a n y cli nicall y si g nifica nt a b n or malities, a n d 
gra de d as eit her n or mal ( wit hi n n or mal li mits) or a b n or mal (cli nicall y si g nifica nt a b n or malit y 
prese nt). A descri pti o n of a n y cli nicall y si g nifica nt a b n or malities will be n ote d.  
 
P u pil
P u pil  
T he p u pil will be e val uate d f or t he prese nce of a n y cli nicall y si g nifica nt a b n or malities, a n d 
gra de d as eit her n or mal ( wit hi n n or mal li mits) or a b n or mal (cli nicall y si g nifica nt a b n or malit y 
prese nt). A descri pti o n of a n y cli nicall y si g nifica nt a b n or malities will be n ote d.  
 
2 1. 4. 8  I ntr a oc ul ar Press ure 
I O P will be meas ure d b y a p pla nati o n t o n o metr y at each st u d y visit . Pr oce d ures i n eac h visit are 
descri be d i n Secti o n 7. 5. 1 . 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
7 2  of  7 4  
 
F or R e sc u e I V T i nj ecti o n, I O P will b e m e a s ur e d a s f oll o w s:  
- I O P will b e m e a s ur e d at 3 0 (± 1 0) mi n ut e s p o st -i nj ecti o n. 
- If p o st-i nj ecti o n I O P i s > 2 1 m m H g aft er e y e m a s s a g e a n d/ or a q u e o u s t a p p erf or m e d p er 
i n v e sti g at or di scr eti o n, I O P m e a s ur e m e nt will b e r e p e at e d at 6 0 (± 1 0) mi n ut e s p o st -
i nj ecti o n.  
- If p o st-i nj ecti o n I O P at 6 0 (± 1 0) mi n ut e s i s > 2 1 m m H g aft er e y e m a s s a g e a n d/ or a q u e o u s 
t a p p erf or m e d p er i n v e sti g at or di scr eti o n, I O P m e a s ur e m e nt will b e r e p e at e d at 9 0 ( ± 1 0) 
mi n ut e s p o st -i nj ecti o n.  
- If t h er e i s a n i ncr e a s e of ≥ 1 0 m m H g at 9 0 ( ± 1 0) mi n ut e s p o st -i nj ecti o n c o m p ar e d t o pr e-
i nj ecti o n I O P, t h e s u bj ect s h o ul d b e pr e scri b e d a t o pic al I O P -l o w eri n g m e dic ati o n u ntil h e 
or s h e r et ur n s f or f oll o w -u p p er t h e Cli nic al I n v e sti g at or ’s di scr eti o n ( a n u n sc h e d ul e d vi sit 
m a y a p pl y).  
- O n t h e ot h er h a n d, a s u bj ect wit h I O P m e a s ur e m e nt of > 2 1 m m H g will b e m a n a g e d 
acc or d i n g t o t h e di scr eti o n of t h e Cli nic al I n v e sti g at or. 
- T h e I O P i ncr e a s e of ≥ 1 0 m m H g fr o m pr e -i nj ecti o n A N D I O P m e a s ur e m e nt of > 2 1 m m H g 
will b e r e p ort e d a s a n A E.  
 
• 
A q u e o u s t a p c a n b e p erf or m e d at a n y ti m e p er t h e Cli nic al I n v e sti g at or` s di scr eti o n f or 
tr e at m e nt or pr e v e nti o n of i ncr e a si n g i n t h e I O P. 
 
T he a p pla nati o n t o n o meter m ust be cali brate d f or acc urac y bef ore t he first s u bject u n der g oes 
scree ni n g, a n d peri o dicall y u ntil t he last s u bject has e xite d t he st u d y. F or c hec ki n g cali brati o n, 
f oll o w t he ma n ufact urer’s i nstr ucti o ns.  
T he f oll o wi n g I O P meas ure me nt pr oce d ure is i n acc or da nce wit h t he pr oce d ure use d i n t he Oc ular 
H y perte nsi o n Treat me nt St u d y (G or d o n et al., 2 0 0 1 ) at eac h visit: 
At least t w o, a n d s o meti mes t hree, c o nsec uti ve meas ure me nts are ma de t o o btai n a deter mi nati o n 
of  i ntra oc ular  press ure.  Eac h  I O P  meas ure me nt  s h o ul d  be  rec or de d  i n  t he  s u bject’s  s o urce  
d oc u me nt a n d i n t he e C R Fs. 
 
 
• If t he t w o meas ure me nts differ b y 2 m m H g or less, t he n t he a vera ge of t he t w o 
meas ure me nts bec o mes t he rec or de d I O P. F or e xa m ple, if t he t w o meas ure me nts  are 2 2 a n d 
2 3, t he n 2 2. 5 is t he fi nal rec or de d I O P. 
• H o we ver, if t he t w o meas ure me nts differ b y 3 m m H g or m ore, t he n a t hir d meas ure me nt is 
ma de, a n d t he me dia n of t he t hree meas ure me nts bec o mes t he rec or de d I O P (t he me dia n is 
t he mi d dle meas ure me nt after arra yi n g t he meas ure me nts fr o m l o w t o hi g h).    F or e xa m ple, 
if t he t hree meas ure me nts are 1 5, 1 9, a n d 1 6, t he n 1 6 is t he fi nal rec or de d I O P. 
• T he I O P i n t he left e ye is t he n meas ure d usi n g t he sa me  tec h ni q ue. 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
7 3  of  7 4  
 
2 1. 4. 9  I n direct O p ht h al m osc o p y  
I n direct o p ht hal m osc o p y will be perf or me d f or eac h e ye at eac h visit u n der p har mac ol o gical  p u pil 
dilati o n . 
I n direct  o p ht hal m osc o p y will  be  use d  t o  e xa mi ne  t he  reti na  at  eac h  st u d y  visit.  I n direct 
o p ht hal m osc o p y will be perf or me d pri or t o t he  i njecti o n a n d t he n a gai n wit hi n 3 0 mi n utes after 
t he i njecti o n. Areas t o be assesse d i ncl u de c u p t o disc rati o,  peri p heral reti na, mac ula, c h or oi d, a n d 
vitre o us. T his will be als o a p plie d f or t he p ost I V T i njecti o n of Resc ue treat me nt.  
 
C u p/ Disc R ati o  
T he c u p/ disc rati o will be deter mi ne d b y t he e xa mi ner a n d rec or de d usi n g t w o deci mal places (e. g., 
0. 8 0). 
 
Reti n a, M ac ul a a n d C h or oi d  
T he reti na, mac ula a n d c h or oi d will be e val uate d f or t he prese nce of a n y cli nicall y si g nifica nt 
a b n or malities,  a n d  gra de d  as  eit her  n or mal  ( wit hi n  n or mal  li mits)  or  a b n or mal  (cli nicall y  
si g nifica nt a b n or malit y prese nt). A descri pti o n of a n y a b n or malities will be n ote d. 
 
Vitre o us  
T he f oll o wi n g Nati o nal E ye I nstit ute Gra di n g Sc he me will be use d t o meas ure vitre o us haze a n d 
o pacificati o n (N usse n blatt et al., 1 9 8 5 ). 
 
Vitre o us H aze Sc ale  
St e p
St e p  
D e scri pti o n
D e scri pti o n  
( 0) 
Cl e ar  
( Tr ac e or 0. 5 +)  
Tr ac e  
( 1 +) 
F e w o p aciti e s, mil d  bl urri n g  
( 2 +) 
Si g nific a nt bl urri n g b ut still  vi si bl e  
( 3 +) 
O ptic n er v e vi si bl e, n o v e s s el s  s e e n  
( 4 +) 
D e n s e o p acit y o b sc ur e s t h e o ptic n er v e  h e a d  
 
2 1. 4. 1 0 S pectr al D o m ai n O ptic al C o here nce To m o gr a p h y  
S pectralis, Cirr us or 3 D O C T will be utilize d t o ta ke o ptical i ma ges at eac h st u d y visit. T he i ma ges 
ma y be st ore d i n t he E g n yte ser ver a n d se nt t o t he ce ntral rea di n g ce nter at a later date at S p o ns or 
discreti o n.  
2 1. 4. 1 1 O ptic al C o here nce To m o gr a p h y  A n gi o gr a p h y 
O C T A n gi o gra p h y i ma ges will be ta ke n at selecte d sites at st u d y Visit 1 ( Baseli ne  Da y 1 ) a n d Visit 
5 ( M o nt h 4) i n all s u bjects. T he i ma ges ma y be st ore d i n t he E g n yte ser ver . 


R B M -0 0 7 I nj ect a bl e S ol uti o n 
 
Pr ot oc ol R B M -0 0 7 -0 0 3  
 
7 4  of  7 4  
 
2 1. 4. 1 2 F u n d us  P h ot o gr a p h y 
Di gital c ol or f u n d us p h ot o gra p h y will be ta ke n at eac h st u d y visit. T he i ma ges ma y be  st ore d i n 
t he E g n yte ser ver a n d se nt t o t he ce ntral rea di n g ce nter at a later date at S p o ns or discreti o n. 
2 1. 4. 1 3 F u n d us A ut of l u orescence    
F u n d us a ut ofl u oresce nce will be perf or me d  at Visit 1 (Baseli ne ( Da y 1) ) a n d Visit 5 ( M o nt h 4). 
T he i ma ges ma y be st ore d in t he E g n yte ser ver  a n d se nt t o t he ce ntral rea di n g ce nter at a later date 
at S p o ns or discreti o n.