An Open Label Phase 2 Clinical Trial of Retinal Gene Therapy for Choroideremia Using an Adeno-associated Viral Vector (AAV2) Encoding Rab-escort Protein 1 (REP1)
Phase: PHASE2
Conditions: Choroideremia
Sponsor: Byron Lam

P R O P RI E T A R Y I N F O R M A TI O N H A S B E E N R E D A C T E D  
Pa ge 1 of 2 6  
 
C LI NI C A L S T U D Y P R O T O C O L   
 
N C T 0 2 5 5 3 1 3 5  
A A V 2 - R E P 1 
A n o pe n la bel P hase 2 cli nical trial of reti nal ge ne t hera p y f or 
c h or oi dere mia usi n g a n a de n o-ass ociate d viral vect or ( A A V 2) 
e nc o di n g Ra b-esc ort pr otei n 1 ( R E P 1) 
I N DI C A TI O N:    
  
 
C h or oi dere mia  
S T U D Y P H A S E :    
  
 
P hase II  
P R I N CI P A L I N V E S TI G A T O R: 
B yr o n L. La m M D  
S P O N S O R :   
  
  
 
Basc o m Pal mer E ye I nstit ute   
U ni versit y of Mia mi  
9 0 0 N W 1 7 Street  
Mia mi, Fl ori da , U S A 3 3 1 3 6  
FI N A L P R O T O C O L D A T E :   
1 8 Ma y  2 0 1 5  

P R O P RI E T A R Y I N F O R M A TI O N H A S B E E N R E D A C T E D  
Pa ge 2 of 2 6  
 
S P O N S O R A P P R O V A L P A G E 
 
Pr ot oc ol Title : 
A n o pe n la bel P hase 2 cli nical trial of reti nal 
ge ne t hera p y f or c h or oi dere mia usi n g a n a de n o-
ass ociate d viral vect or ( A A V 2) e nc o di n g Ra b-
esc ort pr otei n 1 ( R E P 1) 
Pr ot oc ol D ate :  
  
  
  
1 8 Ma y 2 0 1 5 
A p pr o ve d B y : 
T he pers o n(s) liste d bel o w are a ut h orize d t o si g n t he pr ot oc ol o n be half of Basc o m Pal mer 
E ye I nstit ute, U ni versit y of Mia mi. 
Si g ne d:  
  
  
                    
  
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
  
 
Na me : B yr o n L La m 
Title : Pr ofess or of O p ht hal m ol o g y  

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Pa ge 3 of 2 6  
 
P RI N CI P A L I N V E S TI G A T O R’ S SI G N A T U R E P A G E  
 
Pr ot oc ol Title : 
A n o pe n la bel P hase 2 cli nical trial of reti nal 
ge ne t hera p y f or c h or oi dere mia usi n g a n a de n o-
ass ociate d viral vect or ( A A V 2) e nc o di n g Ra b-
esc ort pr otei n 1 ( R E P 1) 
Pr ot oc ol D ate :  
  
  
  
1 8 M A Y 2 0 1 5 
I ha ve rea d t he I n vesti gat or’s Br oc h ure f or A A V 2- R E P 1 I ha ve rea d Pr ot oc ol C H M- 0 1 a n d 
a gree t o c o n d uct t he st u d y as o utli ne d a n d i n c o m plia nce wit h t he Declarati o n of Helsi n ki, t he 
I nter nati o nal C o nfere nce o n Har m o nizati o n g ui deli ne f or G o o d Cli nical Practice, all 
a p plica ble l ocal a n d fe deral re g ulat or y re q uire me nts a n d state/l ocal la ws. I a gree t o mai ntai n 
c o nfi de ntialit y of m y  s u bjects a n d all i nf or mati o n recei ve d or de vel o pe d i n relati o n t o t his 
pr ot oc ol. 
Si g ne d:  
  
  
                    
  
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
  
 
B yr o n L. La m, M. D. 
Pr ofess or 
Basc o m Pal mer E ye I nstit ute 
U ni versit y of Mia mi Sc h o ol of Me dici ne 
Mia mi, Fl ori da 

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Pa ge 4 of 2 6  
 
C O N T A C T I N F O R M A TI O N  
I nf or mati o n is c o nsi dere d c o nfi de ntial.  
 
 

P R O P RI E T A R Y I N F O R M A TI O N H A S B E E N R E D A C T E D  
Pa ge 5 of 2 6  
 
1  P R O T O C O L S Y N O P SI S  
 
N a me of S p o ns or/ C o m p a n y: I n vesti gat or S p o ns ore d St u d y 
N a me of Test Pr o d uct: A A V 2. R E P 1  
D ose(s): 0. 1 ml c o ntai ni n g 1 0 1 1 A A V 2 ge n o me particles  
Title of St u d y: A n o pe n la bel P hase 2 cli nical trial of reti nal ge ne t hera p y f or c h or oi dere mia 
usi n g a n a de n o -ass ociate d viral vect or ( A A V 2) e nc o di n g Ra b -esc ort pr otei n 1 ( R E P 1)  
St u d y ce ntr e(s): Si n gle ce nter I n vesti gat or S p o ns ore d trial 
St u d y peri o d: 2 4 m o nt hs (a d diti o nal f oll o w u p will occ ur 
as per l ocal re q uire me nts, b ut will n ot be c o vere d wit hi n 
t he sc o pe of t his st u d y/ pr ot oc ol)  
P h ase of de vel o p me nt: P hase 2  
 
Ke y O bjecti ve of St u d y:  
T o assess t he a nat o mical a n d f u ncti o nal o utc o mes, as well as t he safet y of a si n gle s u breti nal 
i njecti o n of A A V 2. R E P 1 i n s u bjects wit h ge neticall y c o nfir me d c h or oi dere mia f or u p t o 2 4 
m o nt hs.  
Pri m ar y E n d p oi nt:  
C ha n ge fr o m baseli ne  i n best c orrecte d vis ual ac uit y  i n treate d e ye, c o m pare d t o u ntreate d c o ntr ol 
e ye 
Sec o n d ar y E n d p oi nts:  
n  C ha n ge fr o m baseli ne i n a ut ofl u oresce nce e val uati o n  i n treate d e ye, c o m pare d t o 
u ntreate d  c o ntr ol e ye  
n  C ha n ge fr o m baseli ne i n ce ntral vis ual fiel d usi n g micr o peri metr y rea di n gs  i n treate d e ye, 
c o m pare d t o u ntreate d c o ntr ol e ye  
 
  
 
    
  
  
  
  
  
  
  
  
  
  
   
  
 
 
n  Saf et y e val uati o n d uri n g t he st u d y   
Met h o d ol o g y: O pe n la bel  si n gle ce nter st u d y 
N u m ber of s u bjects ( pl a n ne d):  6 patie nts  
Ke y I ncl usi o n Criteri a:  
•  
Partici pa nt is willi n g a n d a ble t o gi ve i nf or me d c o nse nt f or partici pati o n i n t he st u d y.  
•  
Male a ge d 1 8 years or a b o ve.  
•  
Ge neticall y c o nfir me d dia g n osis of c h or oi dere mia . 
Acti ve disease visi ble cli nicall y wit hi n t he mac ula re gi o n  
Best -c orrecte d vis ual ac uit y e q ual t o or w orse t ha n 6/ 9 ( 2 0/ 3 2; Deci mal 0. 6 3; L o g M A R 
0. 2) b ut better t ha n or e q ual t o 6/ 6 0 ( 2 0/ 2 0 0; Deci mal 0. 1; L o g M A R 1. 0) i n t he st u d y e ye.  
Ke y E xcl usi o n Criteri a:  
•  
Fe male a n d c hil d partici pa nts ( u n der t he a ge of 1 8)  
•  
Partici pa nts wit h a hist or y of a m bl y o pia i n t he st u d y e ye  
•  
Me n u n willi n g t o use barrier c o ntrace pti o n met h o ds, if rele va nt  
•  
Gr ossl y as y m metrical d isease or ot her oc ular m or bi dit y w hic h mi g ht c o nf o u n d use of t he 
fell o w e ye as a l o n g-ter m c o ntr ol 

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Pa ge 6 of 2 6  
 
 
A n y ot her si g nifica nt oc ular a n d n o n -oc ular disease /dis or der 
    
  
    
 
  
  
  
  
  
    
  
   
    
  
 
  
  
  
  
    
  
    
  
  
    
    
 
  
  
  
  
  
    
   
    
 
 
      
    
  
    
  
 
 
 
C o ntrai n dicati o n t o use of me dicati o ns or c o ntrast a ge nts 
  
  
 
  
  
  
 
  
  
  
  
 
 
•  
Partici pa nts w h o ha ve partici pate d i n a n ot her researc h st u d y i n v ol vi n g a n i n vesti gati o nal 
pr o d uct i n t he past 1 2 wee ks ; or recei ve d a ge ne/cell-base d t hera p y at a n y  ti me 
pre vi o usl y . 
Test pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n:  0. 1 ml of A A V 2. R E P 1, c o ntai ni n g 1 0 1 1 
ge n o me particles, a d mi nistere d as a si n gle s u breti nal i njecti o n  
Refere nce t her a p y ( C o m p ar at or), d os a ge a n d m o de of a d mi nistr ati o n:  
Fell o w e ye as c o m parat or . T he fell o w e ye will n ot recei ve a n y st u d y treat me nt. 
O utc o me Me as ures use d t o e v al u ate e n d p oi nts : per pr ot oc ol 
St atistic al met h o ds:  
S o me i nf or m ati o n is c o nsi dere d c o nfi de nti al.  
S u m mar y statistics will be prese nte d f or b ot h e yes ( Treate d E ye vers us C o ntr ol E ye gr o u ps). N o 
f or mal statistical c o m paris o n will be perf or me d ( n o p-val ue will be c o m p ute d). F or 
cate g orical / bi nar y data, t he n u m ber a n d pr o p orti o n of patie nts pertai ni n g t o eac h cate g or y will be 
prese nte d wit h its 9 5 % C o nfi de nce I nter val ( CI). F or c o nti n u o us data, mea n (a n d its 9 5 % CI) a n d 
Sta n dar d De viati o n ( S D) will be prese nte d.  
  
  
  
 
    
 
    
  
    
  
  
 
        
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
  
  
    
  
  
    
  
  
  
 
 
  
  
 
    
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
    
  
 
 
  
    
  
  
  
  
  
  
  
    
  
  
  
 
  
  
  
  
  
  
  
  
   
    
  
  
  
  
  
  
    
  
 
    
  
  
  
  
  
  
  
  
   
  
 
   
  
  
  
  
  
  
  
  
  
 
 
A d ve rse e ve nts will be liste d. 
  
  
  
  
  
      
  
    
  
   
    
  
  
 
   
    
  
  
  
 
  
  
    
 
  
 
 
  
 
 
 

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2   T A B L E O F C O N T E N T S  
1  
P R O T O C O L S Y N O P SI S .......................................................................... 5  
2  
T A B L E O F C O N T E N T S .......................................................................... 7  
3  
A B B R E VI A TI O N S A N D D E FI NI TI O N S ............................................... 9  
4  
I N T R O D U C TI O N ................................................................................... 1 0 
4. 1  
C h or oi dere mia ...................................................................................................... 1 0  
4. 2  
Ge ne T hera p y wit h A de n o- Ass ociate d Viral ( A A V) Vect ors .............................. 1 0  
4. 3  
Rati o nale ............................................................................................................... 1 0  
5  
S T U D Y O BJ E C TI V E S ........................................................................... 1 1  
5. 1  
Ke y O bjecti ve ....................................................................................................... 1 1  
5. 1. 1  
Pri mar y E n d p oi nt ................................................................................................. 1 1  
5. 1. 2  
Sec o n dar y E n d p oi nts ............................................................................................ 1 1  
6  
I N V E S TI G A TI O N A L P L A N ................................................................. 1 1 
6. 1  
S u m mar y of St u d y Desi g n ................................................................................... 1 1  
6. 2  
Scree ni n g Visit ..................................................................................................... 1 2  
6. 3  
S ur ger y ................................................................................................................. 1 2  
6. 4  
F oll o w u p Visits ................................................................................................... 1 3  
6. 4. 1  
6. 1. 4 Earl y Ter mi nati o n Visit ............................................................................... 1 3  
6. 4. 2  
6. 1. 5 U nsc he d ule d Visit ....................................................................................... 1 4  
6. 5  
Disc ussi o n of St u d y Desi g n a n d C h oice of C o ntr ol ............................................. 1 4  
7  
S T U D Y P O P U L A TI O N ......................................................................... 1 5  
7. 1  
I ncl usi o n Criteria .................................................................................................. 1 5 
7. 2  
E xcl usi o n Criteria ................................................................................................. 1 5  
7. 3  
Disc o nti n uati o ns ................................................................................................... 1 5  
8  
S T U D Y T R E A T M E N T  .......................................................................... 1 6 
8. 1  
Treat me nts A d mi nistere d ..................................................................................... 1 6  
8. 2  
Met h o d of Assi g n me nt t o Treat me nt E ye ............................................................ 1 6  
8. 3  
Rati o nale f or D ose Selecti o n ................................................................................ 1 6  
8. 4  
St u d y Mas ki n g ...................................................................................................... 1 7  
8. 5  
C o nc o mita nt T hera p y ........................................................................................... 1 7  
8. 6  
Treat me nt C o m plia nce ......................................................................................... 1 7  
9  
S T U D Y S C H E D U L E .............................................................................. 1 7  
9. 1  
Efficac y Meas ures ................................................................................................ 1 7  
9. 2  
Best C orrecte d Vis ual Ac uit y ............................................................................... 1 7  
9. 3  
F u n d us A ut ofl u oresce nce ..................................................................................... 1 7  
9. 4  
Micr o peri metr y ..................................................................................................... 1 7  

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Pa ge 8 of 2 6  
 
9. 5  
O ptical C o here nce T o m o gra p h y ( O C T) ............................................................... 1 8  
9. 6  
Vis ual Fiel ds ......................................................................................................... 1 8  
9. 7  
C o ntrast Se nsiti vit y .............................................................................................. 1 8  
9. 8  
C ol or Visi o n ......................................................................................................... 1 8  
9. 9  
Safet y Meas ure ..................................................................................................... 1 8  
9. 9. 1  
F ull O p ht hal mic E xa mi nati o n .............................................................................. 1 8  
9. 9. 2  
7- Fiel d C ol or F u n d us P h ot o gra p h y ...................................................................... 1 9  
9. 9. 3  
Fl u orescei n a n d I n d oc ya ni ne A n gi o gra p h y .......................................................... 1 9  
9. 9. 4  
Vital Si g ns ............................................................................................................ 1 9  
9. 9. 5  
Bl o o d C he mistr y .................................................................................................. 1 9  
9. 9. 6  
Viral S he d di n g ...................................................................................................... 1 9  
9. 9. 7  
I m m u n o ge nicit y .................................................................................................... 1 9 
9. 9. 7. 1  
I m m u n oassa y ........................................................................................................ 1 9 
9. 9. 7. 2  
I m m u n oc he mistr y ................................................................................................. 1 9 
9. 9. 8  
A d verse E ve nts a n d Seri o us A d verse E ve nts ....................................................... 1 9  
9. 9. 8. 1  
Defi niti o n ............................................................................................................. 2 0  
9. 9. 8. 2  
Seri o us a d verse e ve nt ( S A E) ................................................................................ 2 0  
9. 9. 9  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n ( S U S A R) ............................... 2 0  
9. 9. 1 0  
Re p orti n g a n d Rec or di n g of A d verse E ve nts ....................................................... 2 1  
9. 9. 1 1  
Re p orti n g Pr oce d ures f or Seri o us A d verse E ve nts .............................................. 2 2  
1 0  
D A T A Q U A LI T Y C O N T R O L A N D A S S U R A N C E ............................. 2 3  
1 1  
S A M P L E SI Z E A N D S T A TI S TI C A L M E T H O D S ............................... 2 3  
1 1. 1  
Deter mi nati o n of Sa m ple Size .............................................................................. 2 3  
1 1. 2  
Statistical a n d A nal ytical Pla ns ............................................................................ 2 3  
1 2  
I N F O R M E D C O N S E N T, E T HI C A L R E VI E W, A N D R E G U L A T O R Y 
C O N SI D E R A TI O N S .............................................................................. 2 4  
1 2. 1  
I nf or me d C o nse nt ................................................................................................. 2 4 
1 2. 2  
Et hical Re vie w ..................................................................................................... 2 4  
1 2. 3  
Re g ulat or y C o nsi derati o ns ................................................................................... 2 5  
1 3  
A C C E S S T O S O U R C E D O C U M E N T A TI O N ....................................... 2 5  
1 4  
D A T A H A N D LI N G A N D R E C O R D S M A N A G E M E N T ..................... 2 5  
1 5  
R E F E R E N C E LI S T ................................................................................. 2 6  
 
 
 
 
 

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3  A B B R E VI A TI O N S A N D D E FI NI TI O N S  
A b bre vi ati o n or Ter m  
Defi niti o n  
A A V 2  
A de n o -ass ociate d viral vect or (ser ot y pe 2)  
A E  
A d verse e ve nt 
B C V A  
Best c orrecte d vis ual ac uit y  
B S S  
Bala nce d salt s ol uti o n  
C B A  
C hic ke n Beta Acti n pr o m oter  
C H M  
C h or oi dere mia  
CI  
C o nfi de nce i nter val  
C R F  
Case Re p ort F or m  
C R P  
C- reacti ve pr otei n 
D M C  
Data m o nit ori n g c o m mittee  
D N A  
De o x yri b o n ucleic aci d  
E T D R S  
Earl y treat me nt dia betic reti n o pat h y st u d y  
E T  
Earl y ter mi nati o n  
G C P  
G o o d Cli nical Practice  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I g G 
I m m u n o gl o b uli n G 
I g M 
I m m u n o gl o b uli n M 
I M P 
I n vesti gati o nal me dici nal pr o d uct  
L O C S  
Le ns O pacities Classificati o n S yste m  
P C R  
P ol y merase c hai n reacti o n  
PI  
Pri nci pal I n vesti gat or  
R E P 1  
Ra b esc ort pr otei n 1  
S A E  
Seri o us A d verse E ve nt  
O C T  
O ptical C o here nce T o m o gra p h y  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
 
 
 

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4  I N T R O D U C TI O N  
4. 1  C h or oi dere mi a  
C h or oi dere mia ( C H M) is a rare, u ntreata ble reti nal de ge nerati o n t hat be gi ns i n c hil d h o o d 
wit h l oss of ni g ht visi o n a n d gra d uall y pr o gresses t o bli n d ness b y mi d dle a ge. C H M is ca use d 
b y l oss of f u ncti o n of t he ge ne e nc o di n g Ra b esc ort pr otei n 1 ( R E P 1) w hic h is l ocate d o n t he 
X-c hr o m os o me ( Cre mers et al., 1 9 9 0; Sea bra et al., 1 9 9 3). T he disease has a n X-li n ke d 
recessi ve m o de of i n herita nce a n d affects a p pr o xi matel y 1 i n 5 0, 0 0 0 pe o ple, m ostl y d ue t o 
l oss of f u ncti o n ( n ull) m utati o ns ( Sa n kila et al., 1 9 9 2; Mac D o nal d et al., 2 0 0 9). 
4. 2  Ge ne T her a p y wit h A de n o - Ass oci ate d V ir al ( A A V) V ect ors  
A de n o-ass ociate d vir us ( A A V) is a par v o vir us c o ntai ni n g si n gle stra n de d D N A. T here are 
ma n y differe nt A A V s u bt y pes, eac h wit h sli g htl y differe nt D N A se q ue nces a n d ca psi d 
pr otei ns. A A V ser ot y pe 2 ( A A V 2) is t he vect or pr o p ose d i n t his st u d y. T he wil d-t y pe A A V 2 
ge n o me lac ks ma n y of t he viral se q ue nces necessar y f or pac ka gi n g of viral particles a n d has 
e v ol ve d t o bec o me de pe n de nt o n a de n o vir us f or re plicati o n a n d s prea d fr o m i nfecte d cells. 
F or m ost of t he ti me t he A A V 2 ge n o me m ust re mai n d or ma nt i n t he h ost cell w hic h ma y 
ha ve hel pe d it t o e v ol ve t o re mai n u n detecte d b y t he e u kar y otic i m m u ne s yste m, alt h o u g h 
wil dt y pe A A V 2 a nti b o dies ca n be detecte d i n a b o ut 3 0 % of h u ma ns ( Mi n g ozzi et al, 2 0 0 7). 
O ver ti me, t he wil dt y pe A A V 2 ge n o me ma y bec o me i nte grate d i nt o c hr o m os o me 1 9 ( D ut heil 
et al., 2 0 0 9). 
T he n o n-i m m u n o ge nic feat ures of A A V 2 ma ke it i deal f or ge ne t hera p y. T he pri nci ple bei n g 
t o re m o ve t he wil dt y pe A A V 2 ge n o me a n d re place it wit h a s pecific t hera pe utic tra ns ge ne, 
t here b y creati n g a “rec o m bi na nt vect or” w hic h ca n deli ver t he t hera pe utic ge ne t o disease d 
cells. T he t otal size of t he A A V 2 ge n o me is 4, 7 0 0 base pairs a n d t his m ust i ncl u de t he 
i n verte d ter mi nal re peat (I T R) se q ue nces w hic h re mai n at eit her e n d of t he tra ns ge ne ( L us b y 
et al., 1 9 8 0). He nce t he mai n dra w bac k of A A V 2 is t he relati vel y s mall size of ge ne it ca n 
carr y. At 1, 9 0 0 base pairs h o we ver t he R E P 1 c D N A c o di n g se q ue nce is well wit hi n t his 
carr yi n g ca pacit y.  
Ge ne t hera p y t o t he reti na has a d va nta ges c o m pare d t o ot her or ga ns beca use t he tar get area is 
s mall a n d m uc h l o wer d oses of vect or ca n be a p plie d b y i njecti o n i nt o t he s u breti nal s pace, 
w hic h is a n e ncl ose d nat ural a nat o mical c o m part me nt. F urt her m ore, t he e ye is a relati vel y 
i m m u ne- pri vile ge d or ga n w hic h re d uces f urt her t he de gree of i m m u ne- me diate d reacti o ns t o 
t he A A V 2 vect or. A A V vect ors tar get ne ur o ns effecti vel y a n d A A V 2 ca n i nfect r o ds, c o nes 
a n d t he reti nal pi g me nt e pit heli u m after s u breti nal i njecti o n i n n o n- h u ma n pri mates (Jac o bs o n 
et al., 2 0 0 6; Stie ger et al., 2 0 0 6; Va n de n ber g he et al., 2 0 1 1). T hese are t he cells w hic h are 
pri maril y affecte d b y t he a bse nce of R E P 1 i n c h or oi dere mia, w hic h c orrelates wit h t he 
nat ural tar geti n g of A A V 2 deli vere d b y s u breti nal i njecti o n. He nce t he A A V 2 ser ot y pe is a n 
i deal vect or t o treat t his c o n diti o n. 
4. 3  R ati o n ale  
C h or oi dere mia is a disease t hat ca uses bli n d ness, wit h n o a vaila ble treat me nt o pti o n. T he 
i nitial res ults fr o m 6 patie nts i ncl u de d i n a P hase I/II st u d y ( Mac Lare n et al., 2 0 1 4) s h o w t he 
i n vesti gati o nal ge ne t hera p y me dici nal pr o d uct bei n g well t olerate d a n d alt h o u g h t he st u d y is 
n ot p o were d t o s h o w efficac y t here are f u ncti o nal i m pr o ve me nts i n visi o n f oll o wi n g reti nal 
detac h me nt a n d s u bf o veal i njecti o n of A A V 2- R E P 1 ( 0. 6- 1. 0 x 1 0 1 0 ge n o me particles), 

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Pa ge 1 1  of 2 6  
 
perf or me d u n der ge neral a nest hesia. T he i nitial res ults of t his i n vesti gati o nal reti nal ge ne 
t hera p y trial are c o nsiste nt wit h i m pr o ve d r o d a n d c o ne f u ncti o n t hat o verc o me a n y ne gati ve 
effects of reti nal detac h me nt. T hese fi n di n gs le n d s u p p ort t o f urt her assess me nt of A A V 2-
R E P 1 ge ne t hera p y i n t he treat me nt of c h or oi dere mia.  
5  S T U D Y O B J E C TI V E S  
5. 1  Ke y  O bjecti ve  
T o assess t he a nat o mical a n d f u ncti o nal o utc o mes, as well as t he safet y of a si n gle s u breti nal 
i njecti o n of A A V 2- R E P 1 i n s u bjects wit h ge neticall y c o nfir me d c h or oi dere mia f or u p t o 2 4 
m o nt hs. 
5. 1. 1  Pri m ar y E n d p oi nt 
•  C ha n ge fr o m baseli ne i n best c orrecte d vis ual ac uit y i n treate d e ye, c o m pare d t o 
u ntreate d c o ntr ol e ye 
5. 1. 2  Sec o n d ar y E n d p oi nts 
•  C ha n ge fr o m baseli ne i n a ut ofl u oresce nce e val uati o n i n treate d e ye, c o m pare d t o 
u ntreate d c o ntr ol e ye 
•  C ha n ge fr o m baseli ne i n ce ntral vis ual fiel d usi n g micr o peri metr y rea di n gs i n treate d 
e ye, c o m pare d t o u ntreate d c o ntr ol e ye 
 
  
  
    
  
  
  
  
  
  
  
   
  
  
    
  
  
 
•  Safet y e val uati o n d uri n g t he st u d y 
6  I N V E S TI G A TI O N A L P L A N  
I nf or mati o n is c o nsi dere d c o nfi de ntial. 
6. 1  S u m m ar y of  St u d y Desi g n  
T his is a P hase II, o pe n la bel st u d y i n v ol vi n g a t otal of 6 male patie nts wit h a cli nical 
p he n ot y pe of c h or oi dere mia a n d a c o nfir me d C H M ge n ot y pe. T he st u d y will be c o n d ucte d at 
t he Basc o m Pal mer E ye I nstit ute, U ni versit y of Mia mi. F oll o wi n g c o nse nt, patie nts will be 
re q uire d t o atte n d a n i nitial scree ni n g visit.  
    
    
  
  
 patie nts will 
u n der g o a s ur gical pr oce d ure u n der ge neral a nest hesia w hic h will i ncl u de a sta n dar d 
vitrect o m y, reti nal detac h me nt a n d a d mi nistrati o n of a s u breti nal i njecti o n of A A V 2- R E P 1 
( 1 x 1 01 1 ge n o me particles). Patie nts will be re q uire d t o atte n d    
   st u d y visits  
 
 o ver a 2 4 m o nt h peri o d f or f u ncti o nal, a n d a nat o mical assess me nts as well as m o nit ori n g 
of a d verse e ve nts. 
  
  
  
    
  
  
  
    
  
    
  
  
  
 
  
  
  
  
  
  
  
  
  
   
 
 
  
  
  
  
  
  
  
  
    
 
  
  
    
  
  
  
  
  
  
  
   
  
  
  
  
  
  
  
    
  
  
    
   
    
  
  
  
  
    
  
 

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Pa ge 1 2  of 2 6  
 
  
   
  
  
    
  
    
  
  
  
    
 
 
6. 2  Scree ni n g Visit  
  
    
  
   
  
    
    
  
    
  
 
  
  
  
  
  
  
    
  
  
  
 
    
      
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
    
  
  
  
    
  
  
 
  
    
      
  
  
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
    
 
  
  
  
  
  
  
  
  
    
  
    
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6. 3  S ur ger y  
    
  
  
    
    
  
  
 Patie nts will be q uesti o ne d f or t he 
occ urre nce of a d verse e ve nts. A sta n dar d o p ht hal mic e xa mi nati o n will occ ur pri or t o s ur ger y 
t o e xcl u de a n y c ha n ges t hat mi g ht ha ve occ urre d si nce t he scree ni n g visit (see Ta ble 1).  
  
 
  
  
  
  
  
    
  
 
    
  
  
    
      
  
    
 
  
 
  
    
  
  
    
  
  
  
  
  
  
 
    
  
  
  
    
  
  
  
  
  
  
    
  
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All s ur ger y will ta ke place i n t he A n ne Bates Leac h E ye H os pital usi n g t he sta n dar d 
vitrect o m y s yste m. A 2 3 ga u ge s ut ure d a p pr oac h w o ul d be use d t o a v oi d a n y p ote ntial ris ks 
of w o u n d lea ka ge. Patie nts w o ul d u n der g o a sta n dar d vitrect o m y a n d detac h me nt of t he 
p osteri or h yal oi d ( Fi g ure 1).  
T he vect or nee ds t o be pri me d i n t he 1 ml s yri n ge i n or der t o a v oi d f or mati o n of air b u b bles. 
I njecti o n ca n be ma n uall y perf or me d or b y c o n necti o n t o t he visc o us fl ui d i nject or f u ncti o n of 
t he vitrect o m y mac hi ne.  T he s u breti nal i njecti o n will tar get a n y area of t he mac ula b ut als o 
i ncl u de t he f o vea if p ossi ble. I n eac h case t he vect or will be i njecte d s o t hat t he s u breti nal 
fl ui d o verlies all e d ge b o u n daries of t he ce ntral re gi o n t hat has yet t o u n der g o c h ori oreti nal 
de ge nerati o n, as i de ntifie d b y f u n d us a ut ofl u oresce nce. Tar geti n g of A A V 2- R E P 1 t o t he m ost 
d y na mic lea di n g e d ge of t he de ge nerati o n will ma xi mize t he c ha nce of i de ntif yi n g a 
treat me nt effect wit hi n t he t w o year st u d y ti mefra me. Care will be ta ke n d uri n g a n d after t he 
s ur ger y t o li mit p ote ntial vect or s prea d  b y a p pr o pirate barrier pr otecti o n f or staff a n d 
a p pr o priate dis p osal of dra pes, i nstr u me nts a n d fl ui ds use d d uri n g t he s ur ger y.   

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Pa ge 1 4  of 2 6  
 
6. 4. 2  6. 1. 5  U nsc he d ule d Visit 
At t he I n vesti gat ors discreti o n, a patie nt ma y atte n d f or a n u nsc he d ule d st u d y visit.     
  
  
  
  
  
    
      
    
 
  
  
  
  
  
 
  
 
 
6. 5  Disc ussi o n of St u d y Desi g n a n d C h oice of C o ntr ol  
T his is a n o pe n la bel st u d y, si nce b ot h t he I n vesti gat or a n d t he patie nt are u n mas ke d t o t he 
st u d y pr oce d ure (i.e. s u breti nal i njecti o n). T he st u d y pr oce d ure i n v ol ves a s ur gical 
i nter ve nti o n a n d t heref ore it is n ot et hicall y via ble t o ha ve a mas ke d s ur gical pr oce d ure 
perf or me d. Male patie nts are c h ose n beca use c h or oi dere mia is a n X-li n ke d recessi ve 
dis or der, w hic h aff ects pri maril y males. Fe males are carriers of t he disease. S o me fe males 
ma y ma nifest a cli nical p he n ot y pe si milar t o t hat see n i n affecte d males, h o we ver, f or t he 
p ur p ose of t his st u d y o nl y males will be treate d a n d f oll o we d u p.  
Si nce c h or oi dere mia is k n o w n ge nerall y t o be a s y m metrical disease, t he fell o w e ye of 
affecte d s ufferers ca n be utilize d as a n i nter nal c o ntr ol f or t he st u d y. T he fell o w e ye will n ot 
recei ve a n y st u d y treat me nt. 
 
 

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Pa ge 1 5  of 2 6  
 
7  S T U D Y P O P U L A TI O N  
A t otal of 6 patie nts will be e nr olle d i nt o t he st u d y. All patie nts m ust meet t he f oll o wi n g 
eli gi bilit y criteria f or i ncl usi o n a n d e xcl usi o n: 
7. 1  I ncl usi o n Criteri a 
1.  Partici pa nt is willi n g a n d a ble t o gi ve i nf or me d c o nse nt f or partici pati o n i n t he st u d y. 
2.  Male a ge d 1 8 years or a b o ve. 
3.  Ge neticall y c o nfir me d dia g n osis of c h or oi dere mia. 
4.  Acti ve disease visi ble cli nicall y wit hi n t he mac ula re gi o n  
5.  Best-c orrecte d vis ual ac uit y e q ual t o or w orse t ha n 6/ 9 ( 2 0/ 3 2; Deci mal 0. 6 3; L o g M A R 
0. 2) b ut better t ha n or e q ual t o 6/ 6 0 ( 2 0/ 2 0 0; Deci mal 0. 1; L o g M A R 1. 0) i n t he st u d y e ye. 
7. 2  E xcl usi o n Criteri a  
1.  Fe male a n d c hil d partici pa nts ( u n der t he a ge of 1 8)  
2.  Partici pa nts wit h a hist or y of a m bl y o pia i n t he st u d y e ye 
3.  Me n u n willi n g t o use barrier c o ntrace pti o n met h o ds, if rele va nt 
4.  Gr ossl y as y m metrical disease or ot her oc ular m or bi dit y w hic h mi g ht c o nf o u n d use of t he 
fell o w e ye as a l o n g-ter m c o ntr ol 
 A n y ot her si g nifica nt oc ular a n d n o n- oc ular disease/ dis or der    
  
  
   
  
    
 
  
  
  
  
  
    
  
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6.  C o ntrai n dicati o n t o use of me dicati o ns or c o ntrast a ge nts  
   
  
 
  
  
  
 
  
  
  
  
 
 
7.  Partici pa nts w h o ha ve partici pate d i n a n ot her researc h st u d y i n v ol vi n g a n i n vesti gati o nal 
pr o d uct i n t he past 1 2 wee ks, or ha vi n g ha d ge ne or cell ular t hera p y at a n y ti me pri or t o 
t his st u d y. 
7. 3  Disc o nti n u ati o ns  
Eac h partici pa nt has t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me. I n a d diti o n, t he 
i n vesti gat or ma y disc o nti n ue a partici pa nt fr o m t he st u d y at a n y ti me if t he i n vesti gat or 
c o nsi ders it necessar y f or a n y reas o n i ncl u di n g:  
•  Si g nifica nt pr ot oc ol de viati o n 
•  Si g nifica nt n o n-c o m plia nce wit h st u d y re q uire me nts 
•  A n  a d verse  e ve nt  w hic h  res ults  i n  i na bilit y  t o  c o nti n ue  t o  c o m pl y  wit h  st u d y 
assess me nts  
•  C o nse nt wit h dra w n 

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Pa ge 1 6  of 2 6  
 
•  L ost t o f oll o w u p 
A n n ual c hec ks of ge neral healt h a n d fa mil y pla n ni n g will h o we ver nee d t o be m o nit ore d 
c o nti n u o usl y a n d e ver y eff ort will be ma de t o e ns ure t hat patie nts u n dersta n d t he nee d f or t his 
m o nit ori n g at c o nse nt.  Wit h dra wal fr o m t he st u d y will n ot necessaril y res ult i n e xcl usi o n of 
t he data ac q uire d u p t o t he p oi nt of wit h dra wal. T he reas o n f or wit h dra wal will be rec or de d i n 
t he C R F. If t he partici pa nt is wit h dra w n d ue t o a n a d verse e ve nt, t he i n vesti gat or will arra n ge 
f or f oll o w- u p visits u ntil t he a d verse e ve nt has res ol ve d or sta bilize d. 
8  S T U D Y T R E A T M E N T  
8. 1  Tre at me nts A d mi nistere d  
0. 1 ml of A A V 2. R E P 1, c o ntai ni n g 1 x 1 0 1 1 ge n o me particles, a d mi nistere d as a si n gle 
s u breti nal i njecti o n. 
T here is n o place b o or c o m parat or pr o d uct i n t his st u d y. Si nce c h or oi dere mia affects b ot h 
e yes i n a ge nerall y s y m metrical patter n, t he fell o w e ye ( w hic h d oes n ot recei ve a n y st u d y 
treat me nt) will be use d as a c o m parat or. 
8. 2  Met h o d of Assi g n me nt t o Tre at me nt  E ye  
T he st u d y is o pe n la bel.  T he treat me nt e ye will be t he w orse e ye, base d o n cli nical 
e xa mi nati o n. T his will be disc usse d i n detail a n d a gree d wit h eac h patie nt as part of t he 
i nf or me d c o nse nt pr ocess. Patie nt c h oice will be c o nsi dere d i n cases w here t he de ge nerati o n 
is relati vel y s y m metrical bet wee n t he t w o e yes. Partici pa nts will als o be re mi n de d t hat t he y 
are free t o wit h dra w c o nse nt at a n y sta ge. 
8. 3  R ati o n al e f or D ose Selecti o n 
I nf or m ati o n is c o nsi dere d c o nfi de nti al. 
  
    
  
    
  
    
  
  
  
  
  
 
  
    
  
  
  
  
  
  
  
    
  
  
 
  
    
  
  
  
  
    
    
  
    
  
      
 
  
  
  
  
  
  
  
  
    
  
  
 
  
  
  
    
    
  
    
  
  
    
  
 
  
  
  
  
  
  
 
  
  
  
 
    
  
  
  
  
  
  
  
  
  
  
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Pa ge 1 7  of 2 6  
 
8. 4  St u d y M as ki n g  
T his is a n o pe n la bel st u d y wit h n o mas ki n g. H o we ver, t o mi ni mize bias e val uati o n of t he 
treate d a n d n o n-treate d e ye, s o me assess me nts will be c o n d ucte d b y a n a p pr o priatel y 
q ualifie d mas ke d o bser ver: F u n d us A ut ofl o uresce nce, Micr o peri metr y, O C T, Vis ual Fiel ds, 
F u n d us P h ot o gra p h y. 
8. 5  C o nc o mit a nt  T her a p y  
Details of c o nc o mita nt me dicati o n will be c ollecte d at t he scree ni n g visit, a n d u p date d at 
e ver y st u d y visit (i ncl u di n g a n y u nsc he d ule d visits). T hr o u g h o ut t he st u d y, I n vesti gat ors ma y 
prescri be a n y c o nc o mita nt me dicati o ns or treat me nts dee me d necessar y t o pr o vi de a de q uate 
s u p p orti ve care. A n y me dicati o n, (i ncl u di n g a naest hetic a n d ot her s ur gical me dicati o ns, b ut 
e xcl u di n g st u d y me dicati o n), ta ke n d uri n g t he st u d y will be rec or de d i n t he patie nts’ me dical 
rec or ds a n d C R F.  
8. 6  Tre at me nt C o m pli a nce  
T his is si n gle s u breti nal i njecti o n of 0. 1 ml A A V 2. R E P 1, c o ntai ni n g 1 x 1 0 1 1 ge n o me 
particles. Treat me nt c o m plia nce meas ure me nt is u n necessar y. 
9  S T U D Y S C H E D U L E  
I nf or mati o n is c o nsi dere d c o nfi de ntial. 
9. 1  Effic ac y  Me as ures  
I nf or mati o n is c o nsi dere d c o nfi de ntial.  
9. 2  Best C orrecte d Vis u al Ac uit y  
C ha n ges fr o m baseli ne i n vis ual ac uit y c o m pare d t o t he c o ntr ol e ye is t he st u d y pri mar y 
e n d p oi nt. 
  
  
    
  
  
  
    
  
  
  
  
  
 
  
  
  
  
  
  
    
  
  
  
    
   
  
    
  
  
  
  
  
    
    
  
  
    
  
 
    
  
  
  
    
      
  
  
 
9. 3  F u n d us A ut ofl u oresce nce  
C ha n ges fr o m baseli ne i n a ut ofl u oresce nce e val uati o n is a sec o n dar y efficac y e n d p oi nt. 
  
    
  
  
  
    
  
    
    
  
  
    
 
  
  
    
      
  
  
  
9. 4  Micr o peri metr y  
C ha n ges fr o m baseli ne i n micr o peri metr y rea di n gs is a sec o n dar y efficac y e n d p oi nt. 
  
    
    
  
  
 
    
  
 
  
  
  
  
  
      
 
  
    
    
 
    
  
  
  
  
    
  
  
  
    
     
  
  
 

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Pa ge 1 8  of 2 6  
 
9. 5  O ptic al C o here nce T o m o gr a p h y ( O C T)  
O C T will be perf or me d i n b ot h st u d y a n d n o n-st u d y e y e 
  
  
  
  
    
 
  
  
    
  
      
  
  
  
  
  
  
   
  
  
  
  
  
  
  
  
    
  
  
  
    
  
 
  
  
  
  
  
    
  
  
  
  
 
  
  
  
    
  
  
    
  
  
    
  
  
 
  
    
      
  
  
 
 
9. 6  Vis u al Fiel ds  
C o n d ucte d i n b ot h e yes    
  
    
  
    
    
    
  
 
  
 
  
  
    
    
  
  
 
    
  
  
  
 
  
  
  
      
  
  
  
  
    
  
  
  
       
     
  
  
  
  
9. 7  C o ntr ast Se nsiti vit y  
C o ntrast se nsiti vit y will be meas ure d i n b ot h e yes  
    
  
  
  
  
   
    
  
  
  
  
  
    
  
9. 8  C ol or Visi o n  
T he R ot h 2 8 test will be use d. 
    
  
    
  
  
  
    
    
  
  
    
  
   
  
  
  
  
  
    
    
  
  
  
  
  
 
  
  
  
 
 
9. 9  S afet y  Me as ure  
9. 9. 1  F ull O p ht h al mic E x a mi n ati o n 
T he f ull o p ht hal mic e xa m will be use d as a safet y assess me nt t hr o u g h o ut t he st u d y  
  
 
  
  
  
  
 
  
  
  
  
  
 
 
 T his e xa mi nati o n will be c o n d ucte d i n b ot h e yes.  
 
  
  
  
  
    
    
    
    
  
  
    
  
 
  
    
      
  
  
 
  
  
  
  
  
  
  
  
    
  
  
  
  
   
  
 
  
    
  
  
  
  
  
    
  
  
  
 
    
 
  
  
 
  
  
  
  
   
  
    
  
  
  
  
  
  
  
  
 
 
    
  
  
  
  
  
    
    
  
  
 
  
 
  
  
    
  
  
  
  
  
  
   
    
  
 
  
  
  
  
  
  
    
  
 
  
  
  
    
    
  
  
    
  
    
     
  
 

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Pa ge 1 9  of 2 6  
 
9. 9. 2  7- F iel d C ol or F u n d us P h ot o gr a p h y 
C o n d ucte d i n b ot h e yes    
  
    
  
    
  
    
 
  
  
  
  
  
  
    
    
  
  
 
    
  
  
  
  
    
  
  
  
   
  
    
  
 
9. 9. 3  Fl u oresc ei n a n d I n d oc y a ni ne A n gi o gr a p h y 
Fl u orescei n a n d i n d oc ya ni ne a n gi o gra p h y will be c o n d ucte d i n b ot h e yes    
  
 
  
  
    
    
 
9. 9. 4  Vit al Si g ns 
Resti n g p ulse a n d bl o o d press ure will be ta ke n.   
  
    
  
    
  
   
    
    
  
  
    
  
  
  
  
  
9. 9. 5  Bl o o d C he mistr y 
Bl o o d sa m ples will be ta ke n f or urea, electr ol ytes a n d li ver f u ncti o n tests.    
  
 
  
        
    
    
    
    
  
  
 
9. 9. 6  Vir al S he d di n g 
  
  
  
  
  
  
    
  
  
    
 
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9. 9. 7  I m m u n o ge nicit y 
 
 
  
    
    
  
  
  
  
  
  
 
 
  
    
    
  
    
  
  
  
  
  
 
  
    
  
    
  
  
  
  
  
   
    
  
  
    
  
    
    
    
  
  
  
  
 
  
    
  
    
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
    
  
 
  
  
 
 
 
  
    
    
  
  
    
    
  
  
  
  
    
 
      
    
  
  
    
  
    
    
  
9. 9. 8  A d verse E ve nts a n d Seri o us A d verse E ve nts 
A d verse e ve nts will be c ollecte d fr o m t he ti me t he patie nt pr o vi des writte n i nf or me d c o nse nt 
f or partici pati o n u ntil t he e n d of Visit 1 1 (a n d at E T  a n d U nsc he d ule d Visits, if a p pr o priate). 
Patie nts will be q uesti o ne d o n t he occ urre nce of a n A d verse E ve nt at e ver y visit, b y usi n g 
n o n lea di n g q uesti o ni n g s uc h as ‘ h o w ha ve y o u bee n see n t he last visit?’. 

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9. 9. 8. 1  Defi niti o n 
A n A d verse E ve nt ( A E ) is a n y u nt o war d me dical occ urre nce i n a cli nical i n vesti gati o n 
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 ns hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d 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 te m p orall y ass ociate d wit h 
t he use of a n i n vesti gati o nal pr o d uct, w het her or n ot relate d t o t he i n vesti gati o nal pr o d uct or 
wit h t he s ur gical pr oce d ure descri be d i n t his pr ot oc ol. W he n a n A E is dee me d t o be relate d t o 
a st u d y dr u g, it ma y be ter me d as a n A d verse Dr u g Reacti o n. 
I n or der t o sta n dar dize a d verse e ve nt re p orts f or a nal ysis, t he descri pti o ns pr o vi de d b y 
patie nts a n d/ or i n vesti gat ors will s u bse q ue ntl y be c o de d i nt o a sta n dar dize d ter mi n ol o g y b y 
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). Ot her relate d varia bles 
li ke se verit y, o utc o me a n d relati o ns hi p t o i n vesti gati o nal pr o d uct or pr oce d ure will be 
ca pt ure d i n a sta n dar dize d wa y i n t he Case Re p ort F or m. 
M ore o ver, a n u m ber of e ve nts will be f urt her c haracterize d b y t he o p ht hal mic e xa ms 
perf or me d at eac h visit as part of t he st u d y pr oce d ures. 
9. 9. 8. 2  Seri o us a d verse e ve nt ( S A E) 
A S A E is defi ne d as a n y u nt o war d me dical occ urre nce t hat: 
•  Res ults i n deat h 
•  Is life-t hreate ni n g * 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n * * 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
•  Is a c o n ge nital a n o mal y/ birt h defect 
•  Vis ual l oss or visi o n t hreate ni n g 
•  Ot her i m p orta nt me dical e ve nt(s) * * *  
* T he ter m ‘life-t hreate ni n g’ i n t he defi niti o n of ‘seri o us’ refers t o a n e ve nt i n w hic h t he 
patie nt is at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt t hat 
h y p ot heticall y mi g ht ca use deat h if it were m ore se vere. 
* * H os pitalizati o n f or a pre-e xisti n g c o n diti o n, i ncl u di n g electi ve pr oce d ures, w hic h has n ot 
w orse ne d, d oes n ot c o nstit ute a seri o us a d verse e ve nt. 
* * * Ot her e ve nts t hat ma y n ot res ult i n deat h, are n ot life t hreate ni n g, or d o n ot re q uire 
h os pitalisati o n, ma y be c o nsi dere d a seri o us a d verse e ve nt w he n, base d u p o n a p pr o priate 
me dical j u d ge me nt, t he e ve nt ma y je o par dise t he patie nt 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. 
9. 9. 9  S us pecte d U ne x pecte d Seri o us A d verse Re acti o n ( S U S A R) 
A S U S A R is a seri o us a d verse dr u g reacti o n, t he nat ure or se verit y of w hic h is n ot c o nsiste nt 
wit h t he a p plica ble pr o d uct i nf or mati o n (e. g. I n vesti gat or’s Br oc h ure).  
W he n deter mi ni n g t he e x pecte d ness of a n a d verse reacti o n c o nsi derati o n s h o ul d be gi ve n t o: 
•  t he u n derl yi n g c o n diti o n of t he s u bject 
•  c o- m or bi dit y 

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•  c o nc o mita nt me dicati o ns 
•  patie nt p o p ulati o n 
•  se verit y a n d fre q ue nc y of t he occ urre nce 
A n u ne x pecte d a d verse reacti o n meets o ne or m ore of t he f oll o wi n g criteria: 
•  n ot attri b ute d t o t he u n derl yi n g c o n diti o n of t he s u bject bei n g st u die d 
•  n ot attri b ute d t o t he patie nt p o p ulati o n bei n g st u die d 
•  n ot a ntici pate d o n t he basis of pri or e x perie nce wit h t he dr u g u n der i n vesti gati o n or 
wit h relate d dr u gs 
•  n ot i de ntifie d i n t he pr o d uct i nf or mati o n (e. g., I n vesti gat or’s Br oc h ure f or a n 
u na p pr o ve d i n vesti gati o nal pr o d uct or pac ka ge i nsert/s u m mar y of pr o d uct 
c haracteristics f or a n a p pr o ve d pr o d uct) 
9. 9. 1 0  Re p orti n g a n d Rec or di n g of A d verse E ve nts 
A d verse e ve nts will be c ollecte d fr o m t he ti me t he patie nt pr o vi des writte n i nf or me d c o nse nt 
f or partici pati o n u ntil t he e n d of Visit 1 1 ( or E T). Patie nts will be q uesti o ne d o n t he 
occ urre nce of a n A d verse E ve nt at e ver y visit i ncl u di n g a n y u nsc he d ule d visit, b y usi n g n o n 
lea di n g q uesti o ni n g s uc h as ‘ h o w ha ve y o u bee n see n t he last visit?’.  
All A Es occ urri n g d uri n g t he st u d y o bser ve d b y t he i n vesti gat or or re p orte d b y t he 
partici pa nt, w het her or n ot attri b ute d t o st u d y me dicati o n or t he s ur gical pr oce d ure, will be 
rec or de d i n t he C R F.   
T he f oll o wi n g i nf or mati o n will be rec or de d i n t he C R F f or all A Es: descri pti o n, date of o nset 
a n d e n d date, o utc o me, se verit y, assess me nt of relate d ness t o st u d y me dicati o n/st u d y 
pr oce d ure, t he acti o n ta ke n a n d c o nfir mati o n of w het her t he e ve nt is c o nsi dere d Seri o us (see 
S A E defi niti o n).  F oll o w- u p i nf or mati o n s h o ul d be pr o vi de d as necessar y.  
W he n assi g ni n g relate d ness of t he A E, c o nsi derati o n will be gi ve n t o w het her t here is a 
pla usi ble relati o ns hi p t o eit her t he st u d y me dicati o n or t he s ur gical pr oce d ure. T he f oll o wi n g 
are defi niti o ns of relate d ness t hat will be use d i n t his st u d y. 
•  U nrelate d: is n ot reas o na bl y relate d i n ti me t o t he a d mi nistrati o n of t he I n vesti gati o nal 
Me dici nal Pr o d uct (I M P) or e x p os ure of t he I M P has n ot occ urre d. 
•  U nli kel y t o be Relate d: t here are fact ors (e vi de nce) e x plai ni n g t he occ urre nce of t he 
e ve nt (e. g. pr o gressi o n of t he u n derl yi n g disease or c o nc o mita nt me dicati o n m ore 
li kel y t o be ass ociate d wit h t he e ve nt) or a c o n vi nci n g alter nati ve e x pla nati o n f or t he 
e ve nt. 
•  P ossi bl y Relate d: cli nicall y or bi ol o gicall y reas o na ble relati ve t o t he a d mi nistrati o n of 
t he I M P, b ut t he e ve nt c o ul d ha ve bee n d ue t o a n ot her e q uall y li kel y ca use 
•  Pr o ba bl y Relate d: is cli nicall y/ bi ol o gicall y reas o na ble relati ve t o t he a d mi nistrati o n of 
t he I M P, a n d t he e ve nt is m ore li kel y e x plai ne d b y e x p os ure t o t he I M P t ha n b y ot her 
fact ors a n d ca uses. 
•  Defi nitel y relate d: a ca usal relati o ns hi p of t he o nset of t he e ve nt, relati ve t o 
a d mi nistrati o n of t he I M P a n d t here is n o ot her ca use t o e x plai n t he e ve nt.  

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A Es c o nsi dere d relate d t o t he st u d y me dicati o n/st u d y pr oce d ure as j u d ge d b y a me dicall y 
q ualifie d i n vesti gat or or t he s p o ns or will be f oll o we d u ntil res ol uti o n or t he e ve nt is 
c o nsi dere d sta ble.  All relate d A Es t hat res ult i n a partici pa nt’s wit h dra wal fr o m t he st u d y or 
are prese nt at t he e n d of t he st u d y, s h o ul d be f oll o we d u p u ntil a satisfact or y res ol uti o n 
occ urs. 
T he relati o ns hi p of A Es t o t he st u d y me dicati o n will be assesse d b y a me dicall y q ualifie d 
i n vesti gat or a n d disc usse d wit h t he PI. 
It will be left t o t he i n vesti gat or’s cli nical j u d g me nt w het her or n ot a n A E is of s ufficie nt 
se verit y t o re q uire t he partici pa nt’s re m o val fr o m treat me nt.  A partici pa nt ma y als o 
v ol u ntaril y wit h dra w fr o m treat me nt d ue t o w hat he or s he percei ves as a n i nt olera ble A E. If 
eit her of t hese occ urs, t he partici pa nt m ust u n der g o a n e n d of st u d y assess me nt ( E T visit) a n d 
be gi ve n a p pr o priate care u n der me dical s u per visi o n u ntil s y m pt o ms cease or t he c o n diti o n 
bec o mes sta ble.  
T he se verit y of e ve nts will be assesse d o n t he f oll o wi n g scale:   
1.   = mil d (a ware ness of si g n or s y m pt o m, b ut easil y t olerate d)  
2.  = m o derate ( disc o mf ort s ufficie nt t o ca use i nterfere nce wit h n or mal acti vities)   
3.  = se vere (i nca pacitati n g, wit h i na bilit y t o perf or m n or mal acti vities)    
A n y pre g na nc y occ urri n g d uri n g t he cli nical st u d y a n d t he o utc o me of t he pre g na nc y fat here d 
b y trial partici pa nts, s h o ul d be rec or de d a n d f oll o we d u p f or c o n ge nital a b n or malit y or birt h 
defect. 
9. 9. 1 1  Re p orti n g Pr oce d ures f or Seri o us A d verse E ve nts 
T he Data M o nit ori n g C o m mittee ( D M C) will u n derta ke t o re vie w all S A Es f or t he 
st u d y. T h e y ma y h ol d electr o nic meeti n gs. T he D M C will meet at i nter vals a n d c o nsi der:  
•  Occ urre nce a n d nat ure of a d verse e ve nts  
•  W het her a d diti o nal i nf or mati o n o n a d verse e ve nts is re q uire d  
•  C o nsi der ta ki n g a p pr o priate acti o n w here necessar y t o halt trials (see bel o w) 
•  Act / a d vise o n i nci de nts occ urri n g bet wee n meeti n gs t hat re q uire ra pi d assess me nt 
(e. g. S U S A Rs)  
All S A Es will be re p orte d t o t he D M C wit hi n o ne da y of disc o ver y or n otificati o n of t he 
e ve nt.  All S A E i nf or mati o n will be rec or de d o n a n S A E f or m w hic h will be se nt 
electr o nicall y t o me m bers of t he D M C. A d diti o nal i nf or mati o n recei ve d f or a case (f oll o w- u p 
or c orrecti o ns t o t he ori gi nal case) will be detaile d o n a ne w S A E f or m. 
T he PI will als o re p ort all S U S A Rs t o t he C o m pete nt A ut h orities, Et hics C o m mittee a n d a n y 
ot her g o ver na nce b o d y as re q uire d b y l ocal re g ulati o ns. Fatal or life-t hreate ni n g S U S A Rs 
will be re p orte d wit hi n 7 da ys a n d all ot her S U S A Rs wit hi n 1 5 da ys. T he PI will als o i nf or m 
all i n vesti gat ors c o ncer ne d of rele va nt i nf or mati o n a b o ut S U S A Rs t hat c o ul d a d versel y affect 
t he safet y of partici pa nts. 
I n a d diti o n t o t he e x pe dite d re p orti n g a b o ve, t he PI s hall s u b mit o nce a year t hr o u g h o ut t he 
cli nical trial or o n re q uest a safet y re p ort t o t he C o m pete nt A ut h orit y, Et hics C o m mittee, a n d 
a n y ot her g o ver na nce b o d y as re q uire d b y l ocal re g ulati o ns. 

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1 0  D A T A Q U A LI T Y C O N T R O L A N D A S S U R A N C E  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he c urre nt a p pr o ve d pr ot oc ol, I C H G C P, 
rele va nt re g ulati o ns a n d sta n dar d o perati n g pr oce d ures.  
Re g ular m o nit ori n g will be perf or me d acc or di n g t o I C H G C P. Data will be e val uate d f or 
c o m plia nce wit h t he pr ot oc ol a n d acc urac y i n relati o n t o s o urce d oc u me nts. F oll o wi n g 
writte n sta n dar d o perati n g pr oce d ures, t he m o nit ors will verif y t hat t he cli nical trial is 
c o n d ucte d a n d data are ge nerate d, d oc u me nte d a n d re p orte d i n c o m plia nce wit h t he pr ot oc ol, 
G C P a n d t he a p plica ble re g ulat or y re q uire me nts.  
1 1  S A M P L E SI Z E A N D S T A TI S TI C A L M E T H O D S  
I nf or mati o n is c o nsi dere d c o nfi de ntial. 
1 1. 1  Deter mi n ati o n of S a m ple Size  
Si x patie nts will be e nr olle d i nt o t his st u d y. N o f or mal sa m ple size calc ulati o ns ha ve bee n 
perf or me d. 
1 1. 2  St atistic al a n d A n al ytic al Pl a ns  
I nf or m ati o n is c o nsi dere d c o nfi de nti al. 
S u m mar y statistics will be prese nte d f or b ot h e yes ( Treate d E ye vers us C o ntr ol E ye gr o u ps). 
N o f or mal statistical c o m paris o n will be perf or me d ( n o p- val ue will be c o m p ute d). F or 
cate g orical/ bi nar y data, t he n u m ber a n d pr o p orti o n of patie nts pertai ni n g t o eac h cate g or y 
will be prese nte d wit h its 9 5 % C o nfi de nce I nter val ( CI). F or c o nti n u o us data, mea n (a n d its 
9 5 % CI) a n d Sta n dar d De viati o n ( S D) will be prese nte d. 
  
  
  
    
  
    
  
  
  
    
  
 
  
    
  
  
  
    
  
  
    
  
  
  
  
 
  
    
  
  
    
  
  
  
  
  
  
  
 
    
  
  
    
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
    
 
   
  
    
  
  
  
  
  
  
  
    
  
 
  
  
  
  
  
  
  
  
  
  
   
    
  
  
  
  
  
  
    
 
  
    
  
  
  
  
  
  
  
  
    
  
 
    
  
  
  
  
  
  
  
  
  
  
 
  
  
    
 
  
  
  
  
  
      
  
    
  
   
    
  
  
  
    
    
  
  
  
 
  
  
    
 
  
    
   

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1 2  I N F O R M E D C O N S E N T, E T HI C A L R E VIE W, A N D R E G U L A T O R Y 
C O N SI D E R A TI O N S  
1 2. 1  I nf or me d C o nse nt 
C h or oi dere mia patie nts f ulfilli n g t he i ncl usi o n criteria w h o mi g ht be e x pecte d t o be nefit fr o m 
ge ne t hera p y will be i n vite d t o ta ke part i n t he st u d y. Partici pa nts m ust pers o nall y si g n a n d 
date t he latest a p pr o ve d versi o n of t he i nf or me d c o nse nt f or m bef ore a n y st u d y s pecific 
pr oce d ures are perf or me d.  
Writte n a n d ver bal versi o ns of t he partici pa nt i nf or mati o n a n d I nf or me d c o nse nt will be 
prese nte d t o t he partici pa nts detaili n g n o less t ha n: t he e xact nat ure of t he st u d y; t he 
i m plicati o ns a n d c o nstrai nts of t he pr ot oc ol; t he k n o w n si de effects a n d a n y ris ks i n v ol ve d i n 
ta ki n g part.  It will be clearl y state d t hat t he partici pa nt is free t o wit h dra w fr o m t he st u d y at 
a n y ti me f or a n y reas o n wit h o ut prej u dice t o f ut ure care, a n d wit h n o o bli gati o n t o gi ve t he 
reas o n f or wit h dra wal. 
T he partici pa nt will be all o we d as m uc h ti me as wis he d t o c o nsi der t he i nf or mati o n, a n d t he 
o p p ort u nit y t o q uesti o n t he I n vesti gat or, t heir pri mar y care p h ysicia n/ ge neral practiti o ner or 
ot her i n de pe n de nt parties t o deci de w het her t he y will partici pate i n t he st u d y.  Writte n 
I nf or me d C o nse nt will t he n be o btai ne d b y mea ns of partici pa nt date d si g nat ure a n d date d 
si g nat ure of t he pers o n w h o prese nte d a n d o btai ne d t he i nf or me d c o nse nt. T he pers o n w h o 
o btai ne d t he c o nse nt m ust be s uita bl y q ualifie d a n d e x perie nce d, a n d ha ve bee n a ut h orise d t o 
d o s o b y t he Pri nci pal I n vesti gat or. A c o p y of t he si g ne d I nf or me d C o nse nt will be gi ve n t o 
t he partici pa nts.  T he ori gi nal si g ne d f or m will be retai ne d at t he st u d y site a n d a n a d diti o nal 
c o p y will re mai n i n t he patie nt me dical rec or ds. 
I n de pe n de nt c o u nselli n g will be pr o vi de d pri or t o ac q uiri n g si g ne d i nf or me d c o nse nt. T he 
f oll o wi n g s pecific iss ues will be disc usse d: 
1.  T he p ote ntial f or n o be nefit  
2.  T h e p ote ntial f or l oss of visi o n d ue t o c o m plicati o ns of s ur ger y, s uc h as i nfecti o n, 
reti nal detac h me nt, hae m orr ha ge a n d cataract. 
3.  T he p ote ntial f or l oss of visi o n d ue t o i m m u ne reacti o ns i n t he e ye 
4.  T he t he oretical p ote ntial f or mali g na nc y s prea d of vect or t o ot her or ga ns a n d ger mli ne 
tra ns missi o n. 
5.  T he nat ure a n d d urati o n of f oll o w- u p tests re q uire d f or t he st u d y. 
T he decisi o n a b o ut w hic h e ye t o treat will be ma de o n cli nical gr o u n ds a n d will ge nerall y be 
t he w orse e ye affecte d. T his will be disc usse d i n detail a n d a gree d wit h eac h patie nt as part of 
t he i nf or me d c o nse nt pr ocess. Patie nt c h oice will be c o nsi dere d i n cases w here t he 
de ge nerati o n is relati vel y s y m metrical bet wee n t he t w o e yes. Partici pa nts will als o be 
re mi n de d t hat t he y are free t o wit h dra w c o nse nt at a n y sta ge. 
1 2. 2  Et hic al Re vie w  
T he pr ot oc ol, i nf or me d c o nse nt f or m, partici pa nt i nf or mati o n s heet a n d a n y pr o p ose d 
a d vertisi n g material will be s u b mitte d t o a n a p pr o priate Researc h Et hics C o m mittee, 
re g ulat or y a ut h orities, a n d h ost i nstit uti o n(s) f or writte n a p pr o val. T he I n vesti gat or will 
s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he a b o ve parties f or all s u bsta ntial 
a me n d me nts t o t he ori gi nal a p pr o ve d d oc u me nts.    

P R O P RI E T A R Y I N F O R M A TI O N H A S B E E N R E D A C T E D  
Pa ge 2 5  of 2 6  
 
1 2. 3  Re g ul at or y C o nsi der ati o n s 
T he st u d y will be c o n d ucte d i n f ull c o nf or mit y wit h all a p plica ble la w a n d re g ulati o ns, 
i ncl u di n g t he I C H G ui deli nes f or G o o d Cli nical Practice ( C P M P/I C H/ 1 3 5/ 9 5) J ul y 2 0 0 2. 
1 3  A C C E S S T O S O U R C E D O C U M E N T A TI O N  
Direct access will be gra nte d t o a ut h orise d re prese ntati ves fr o m t he s p o ns or, h ost i nstit uti o n, 
Ni g htsta R x Lt d a n d re g ulat or y a ut h orities t o per mit trial-relate d m o nit ori n g, a u dits a n d 
i ns pecti o ns. 
T he trial staff will e ns ure t hat t he partici pa nts’ a n o n y mit y is mai ntai ne d.  T he partici pa nts 
will be i de ntifie d o nl y b y i nitials a n d a partici pa nts I D n u m ber o n t he C R F a n d a n y electr o nic 
data base. All d oc u me nts will be st ore d sec urel y a n d o nl y accessi ble b y trial staff a n d 
a ut h orise d pers o n nel. T he st u d y will c o m pl y wit h t he Data Pr otecti o n Act w hic h re q uires data 
t o be a n o n y mise d as s o o n as it is practical t o d o s o.   
1 4  D A T A H A N D LI N G A N D R E C O R D S M A N A G E M E N T  
All st u d y data will be e ntere d o n a n e ncr y pte d electr o nic data ca pt ure s yste m wit h pass-c o des 
k n o w n t o all i n vesti gat ors a n d a p pr o priatel y dele gate d st u d y tea m me m bers. T hese electr o nic 
data e ntr y s yste ms ha ve bee n vali date d. T he partici pa nts will be i de ntifie d b y a st u d y s pecific 
partici pa nts n u m ber a n d/ or c o de i n a n y data base.  T he na me a n d a n y ot her i de ntif yi n g detail 
will N O T be i ncl u de d i n a n y st u d y data electr o nic file.  
 
 

P R O P RI E T A R Y I N F O R M A TI O N H A S B E E N R E D A C T E D  
Pa ge 2 6  of 2 6  
 
1 5  R E F E R E N C E LI S T  
Be n nicelli J, Wri g ht J F, K o mar o m y A, et al.  Re versal of bli n d ness i n a ni mal m o dels of le ber 
c o n ge nital a ma ur osis usi n g o pti mize d A A V 2- me diate d ge ne tra nsfer.  M ol T her.  
2 0 0 8; 1 6( 3): 4 5 8- 4 6 5. 
Cre mers F P, va n de P ol DJ, va n Ker k h off L P, et al.  Cl o ni n g of a ge ne t hat is rearra n ge d i n 
patie nts wit h c h or oi dere mia.  Nat ure.  1 9 9 0; 3 4 7( 6 2 9 4): 6 7 4 – 6 7 7. 
D ut heil N, He nc kaerts E, K o hl bre n ner E, et al, Tra nscri pti o nal a nal ysis of t he a de n o-
ass ociate d vir us i nte grati o n site. J Vir ol. 2 0 0 9 Dec; 8 3( 2 3): 1 2 5 1 2- 2 5. 
E d war ds T L, Gr o p pe M, Mac Lare n R E. O utc o mes f oll o wi n g cataract s ur ger y i n 
c h or oi dere mia. E ye ( L o n d). 2 0 1 5 Ja n 1 6. 1 0. 1 0 3 8 
Jac o bs o n S G, B o ye S L, Ale ma n T S, et al Safet y i n n o n h u ma n pri mates of oc ular A A V 2-
R P E 6 5, a ca n di date treat me nt f or bli n d ness i n Le ber c o n ge nital a ma ur osis. H u m Ge ne T her. 
2 0 0 6; 1 7: 8 4 5- 5 8. 
L us b y E, Fife K H, Ber ns KI. N ucle oti de se q ue nce of t he i n verte d ter mi nal re petiti o n i n 
a de n o-ass ociate d vir us D N A. J Vir ol 1 9 8 0 3 4: 4 0 2- 4 0 9 
Mac d o nal d I M, R ussell L, C ha n C C.  C h or oi dere mia: ne w fi n di n gs fr o m oc ular pat h ol o g y 
a n d re vie w of rece nt literat ure.  S ur v O p ht hal m ol.  2 0 0 9; 5 4( 3): 4 0 1- 4 0 7. 
Mac Lare n R E, Gr o p pe M, Bar nar d A R, et al.  Reti nal ge ne t hera p y i n patie nts wit h 
c h or oi dere mia: i nitial fi n di n gs fr o m a p hase 1/ 2 cli nical trial.  La ncet.  2 0 1 4; 3 8 3( 9 9 2 3): 1 1 2 9-
1 1 3 7. 
Ma g uire A M, Hi g h K A, A uricc hi o A, et al.  A ge- de pe n de nt effects of R P E 6 5 ge ne t hera p y 
f or Le ber's c o n ge nital a ma ur osis: a p hase 1 d ose-escalati o n trial.  La ncet.  
2 0 0 9; 3 7 4( 9 7 0 1): 1 5 9 7- 1 6 0 5. 
Ma g uire A M, Si m o nelli F, Pierce E A, et al.  Safet y a n d efficac y of ge ne tra nsfer f or Le ber’s 
c o n ge nital a ma ur osis.  N E n gl J Me d.  2 0 0 8; 3 5 8( 2 1): 2 2 4 0- 2 2 4 8. 
Mi n g ozzi F, Ma us M V, H ui DJ, et al.  C D 8( +) T-cell res p o nses t o a de n o-ass ociate d vir us 
ca psi d i n h u ma ns.  Nat Me d.  2 0 0 7; 1 3( 4): 4 1 9- 4 2 2. 
Sa n kila E M, T ol va ne n R, va n de n H ur k J A, et al.  A berra nt s plici n g of t he C H M ge ne is a 
si g nifica nt ca use of c h or oi dere mia.  Nat Ge net.  1 9 9 2; 1( 2): 1 0 9- 1 1 3. 
Sea bra M C, Br o w n M S, G ol dstei n J L.  Reti nal de ge nerati o n i n c h or oi dere mia: deficie nc y of 
ra b gera n yl gera n yl tra nsferase.  Scie nce.  1 9 9 3; 2 5 9( 5 0 9 3): 3 7 7- 3 8 1. Stie ger K, Le Me ur G, 
Las ne F et al. M ol T her. 2 0 0 6; 1 3: 9 6 7- 7 5. L o n g-ter m d o x yc ycli ne-re g ulate d tra ns ge ne 
e x pressi o n i n t he reti na of n o n h u ma n pri mates f oll o wi n g s u breti nal i njecti o n of rec o m bi na nt 
A A V vect ors.  
Va n de n ber g he L H, Bell P, Ma g uire A M et al D osa ge t hres h ol ds f or A A V 2 a n d A A V 8 
p h ot orece pt or ge ne t hera p y i n m o n ke y. Sci Tra nsl Me d. 2 0 1 1; 2 2: 8 8ra 5 4. Errat u m i n: Sci 
Tra nsl Me d. 2 0 1 1; 3: 1 1 2er 9