Can Pregabalin Reduce the Frequency and Severity of Dry Eye Symptoms After Laser-assisted in Situ Keratomileusis?
Phase: PHASE2
Conditions: Dry Eye
Sponsor: University of Miami

 
 
 
TI T L E:  
C a n pr e g a b ali n r e d uc e t h e 
fr e q u e nc y a n d s e v erit y of dr y e y e 
s y m pt o ms aft er l as er-assist e d i n 
sit u k er at o mil e usis? 
 
V E R SI O N:  
2. 0 7  
D A T E:  
2 3 F E B 2 0 1 7  
N C T N U M B E R:  N C T 0 2 7 0 1 7 6 4  

P r ot o c ol Titl e : C a n pr e g a b ali n r e d uc e t h e fr e q u e nc y a n d s e v erit y of dr y e y e s y m pt o ms aft er l as er -assist e d 
i n sit u k er at o mil e usis? 
 
I R B R e vi e w Hi st o r y *: N o n e 
 
O bj e cti v e s : 
S p ecific Ai m:  D e m o nstr at e t h e f e asi bilit y of pr e v e nti n g D E s y m pt o ms aft er L A SI K b y p eri -o p er ati v e 
a d mi nistr ati o n of a g a b a p e nti n oi d.  
 
B a c k g r o u n d : 
L as er i n -sit u k er at o mil e usis ( L A SI K) is a c o m m o nl y p erf or m e d s ur gic al pr oc e d ur e us e d t o c orr ect 
r efr acti v e err or. W hil e vis u al o utc o m es aft er s ur g er y ar e e xc ell e nt, it is w ell k n o w n t h at a pr o p orti o n of 
p ati e nts d e v el o p p ersist e nt d ys est h esi as aft er s ur g er y. L A SI K i n v ol v es c utti n g a c or n e al fl a p a n d a bl ati n g 
t h e str o m a u n d er n e at h, wit h l o n g-l asti n g disr u pti o n of c or n e al i n ner v ati o n. 3, 4 1  A v ail a bl e d at a s u g g est t h at 
a p pr o xi m at el y 2 0 -5 5 % of t h e 6 5 0, 0 0 0 c as es a n n u all y r e p ort p ersist e nt ( g e n er all y r e g ar d e d as at l e ast 6 
m o nt hs p ost -o p er ati o n) e y e s y m pt o ms aft er L A SI K s ur g er y. W hil e it w as i niti all y b eli e v e d t h at t h es e 
s y m pt o ms wer e c a us e d b y oc ul ar s urf ac e dr y n ess, a n d r ef err e d t o as “ dr y e y e”, it is n o w i ncr e asi n gl y 
u n d erst o o d t h at c or n e al n er v e d a m a g e pr o d uc e d b y L A SI K m a y r es e m bl e t h e p at h ol o gic n e ur o pl asticit y 
ass oci at e d wit h n er v e i nj uri es aft er ot h er f or ms of p ersist e nt p os t-o p er ati v e p ai n. 4  I n s usc e pti bl e p ati e nts, 
t h es e n e ur o p at h ol o gic al c h a n g es, i ncl u di n g p eri p h er al s e nsiti z ati o n, c e ntr al s e nsiti z ati o n, a n d alt er e d 
d esc e n di n g m o d ul ati o n, m a y u n d erli e c ert ai n p ersist e nt D E s y m pt o ms aft er L A SI K s ur g er y. It is n ot 
s ur prisi n g, t h er ef or e, t h at c urr e nt tr e at m e nts, w hic h t ar g et t h e oc ul ar s urf ac e, ar e oft e n n ot a d e q u at e.2 , 3  
P ersist e nt D E s y m pt o ms aft er L A SI K r a n g e i n s e v erit y, b ut t h e d el et eri o us eff ects o n q u alit y -of -lif e m a y b e 
si g nific a nt. Utilit y st u di es ar e us e d t o q u a ntif y p ati e nt e x p eri e nc es a n d pr ef er e nc es r e g ar di n g a dis e as e 
st at e, a n d t h es e h a v e f o u n d m o d er at e -t o-s e v er e dr y e y e ( D E) e q ui v al e nt t o m o d er at e -t o-s e v er e a n gi n a or 
h os pit al di al ysis, w hil e mil d D E mi g ht e q u at e wit h s e v er e mi gr ai n es. T h es e L A SI K -i n d uc e d si d e eff ects w er e 
d e e m e d i m p ort a nt e n o u g h b y t h e F o o d a n d Dr u g A d mi nistr ati o n ( F D A) t o w arr a nt a n i n v esti g ati o n o n t his 
pr oc e d ur e i n 2 0 0 9.  
 
O ur pr o gr a m is f oc us e d o n t h e c ritic al st e ps n e e d e d t o i m pr o v e o utc o m es aft er L A SI K, w hic h will r e q uir e a 
b ett er u n d erst a n di n g of t h e e pi d e mi ol o g y of t his c o n diti o n ( e. g. fr e q u e nc y, c h ar act eristics, s e v erit y, 
v ul n er a bl e p ati e nt gr o u ps), u n d erst a n di n g m ec h a nis ms of s usc e pti bilit y p ot e nti all y c o m m o n t o ot h er f or ms 
of D E a n d c o m or bi d c o n diti o ns 4  ( e. g., p eri p h er al s e nsiti z ati o n, c e ntr al s e nsitiz ati o n, c o m or bi d p ai n 
c o n diti o ns, c o m or bi d m e nt al h e alt h pr o bl e ms), as w ell as t h e st u d y of p ot e nti al n e w tr e at m e nts t ar g eti n g 
t h e p at h ol o gic n e ur o pl asticit y t h at occ urs a n d li k el y u n d erli es p ersist e nt s y m pt o ms aft er s ur g er y. 
 
O ur l o n g -t er m g o als ar e t o u n d erst a n d t h e n e ur o-o p ht h al m ol o gic p at h o p h ysi ol o g y i n d uc e d b y L A SI K, a n d 
i m pr o v e pr e v e nti v e a p pr o ac h es a n d t h er a p e utic m a n a g e m e nt of p ersist e nt c or n e al s o m at os e ns or y s yst e m 
d ysf u ncti o n c a us e d b y L A SI K. O ur c e ntr al t h esis is t h at p ersist e nt D E s y m pt o ms aft er L A SI K c a n b e 
q u a ntifi e d usi n g a c o m pr e h e nsi v e ass ess m e nt pr ot oc ol t h at w e h a v e d e v el o p e d a n d s y m pt o ms m a y b e 
pr e v e nt e d b y n e ur o m o d ul at ors.  S p ecific all y, w e will t est o ur h y p ot h esis t h at t h e us e of p eri o p er ati v e 
pr e g a b ali n will d ecr e as e t h e fr e q u e nc y of p ersist e nt D E s y m pt o ms aft er L A SI K s ur g er y.   
 
I n cl usi o n a n d E x cl u si o n C rit e ri a *  
St u d y p o p ul ati o n /r ecr uit m e nt: S u bj ects will b e r ecr uit e d fr o m B asc o m P al m er E y e I nstit ut e ( B P EI) 
r efr acti v e c e nt er a n d eli gi bl e s u bj ects will b e i nf or m e d a b o ut a n o p p ort u nit y t o p artici p at e i n t h e r es e arc h 
st u d y.  
 
I n cl u si o n c rit e ri a:  W e will e nr oll p ati e nts b et w e e n 1 8 a n d 6 5 y e ars of a g e w h o ar e u n d er g oi n g L A SI K 
( u nil at er al or bil at er al pr oc e d ur e). F e m al es of c hil d-b e ari n g a g e will n e e d a n e g ati v e uri n e or s er u m β -H C G 

t est at t h e scr e e ni n g visit. W e will e nr oll p ati e nts w h os e oc ul ar a n d s yst e mic m e dic ati o n r e gi m e n h as b e e n 
st a bl e f or 3 m o nt hs a n d w e will as k p ati e nts t o r efr ai n fr o m t a ki n g a n y e y e dr o ps (i. e. artifici al t e ars) f or at 
l e ast 2 h o urs pri or t o t esti n g. 
 
E x cl u si o n c rit e ri a:  W e will e xcl u d e p ati e nts w h o ar e pr e g n a nt  or l act ati n g, p artici p ati n g i n a n ot h er st u d y 
wit h a n i n v esti g ati o n al dr u g wit hi n o n e m o nt h pri or t o scr e e ni n g, us e g a b a p e nti n, pr e g a b ali n, a nti -
c o n v uls a nts, d ul o x eti n e, v e nl af a xi n e ( S N RI), or tri -c yclic a nti d e pr ess a nts, h a v e a hist or y of all er gic, 
a n a p h yl actic r e acti o n, or s e v er e s yst e mic r es p o ns e t o pr e g a b ali n or g a b a p e nti n; us e c ortic ost er oi ds 
c hr o nic all y or d uri n g t h e m o nt h pri or t o s ur g er y, or h a v e a hist or y of c or n e al dis e as e ( H S V or V Z V k er atitis, 
pri or c or n e al i ncisi o ns (c at ar act s ur g er y, R K, L A SI K), pri or c or n e al ulc er). W e will als o e xcl u d e p ati e nts 
wit h s yst e mic c o -m or bi diti es t h at m a y c o nf o u n d D E s uc h as HI V, s arc oi d osis, gr aft -v ers us h ost dis e as e or a 
c oll a g e n v asc ul ar dis e as e.  
 
W e will e xcl u d e t h e f oll o wi n g i n di vi d u als:  
•  
A d ults u n a bl e t o c o ns e n t 
•  
I n di vi d u als w h o ar e n ot y et a d ults (i nf a nts, c hil dr e n, t e e n a g ers) 
•  
Pr e g n a nt w o m e n  
•  
Pris o n ers 
 
E x cl u si o n of n o n -E n gli s h S p e a ki n g S u bj e ct s:  
 
F or t h e ti m e b ei n g, w e will o nl y e nr oll E n glis h s p e a ki n g s u bj ects. If t h e pr e v al e nc e of s ol el y S p a nis h -
s p e a ki n g s u bj ects dr a m atic all y i ncr e as es, w e will c o nsi d er s u b mitti n g a n I R B a p pr o v al f or a S p a nis h -
tr a nsl at e d c o ns e nt. T h e S u b-PI a n d l e a d c o or di n at or ar e b ot h fl u e nt i n S p a nis h. T h e r e as o n f or t his is d u e t o 
t h e f oll o wi n g: aft er c o nfir mi n g wit h L A SI K E y e C e nt er st aff, t h er e is o nl y a pr e v al e nc e r at e of 1 0 % of t h e 
L A SI K s ur g er y p ati e nts t h at d o n ot s p e a k / r e a d t h e E n glis h l a n g u a g e. T his l o w p erc e nt a g e is n ot si g nific a nt 
e n o u g h t o s er v e as a f act or i n c o nsi d eri n g tr a nsl ati o n of E n glis h m at eri als i nt o S p a nis h. B asc o m P al m er 
st aff h as c o nfir m e d t h at 9 0 % of t h eir p ati e nts li n e d u p f or L A SI K d o i n f act s p e a k a n d r e a d t h e E n glis h 
l a n g u a g e, eli mi n ati n g a n y p ot e nti al bi as or discri mi n ati o n i n r ecr uiti n g s u bj ects. 
 
N u m b e r of S u bj e ct s:  
1 0 0 p ati e nts ar e t o b e r ecr uit e d at all  sit es; 6 0 p ati e nts ar e t o b e r ecr uit e d at t h e Mi a mi sit e.  
 
St u d y -Wi d e R e c r uit m e nt M et h o d s : 
T h e N a v al M e dic al C e nt er S a n Di e g o will als o r ecr uit 5 0 p ati e nts u n d er a s e p ar at e I R B. T h e y will us e t h e 
s a m e r ecr uit m e nt m et h o d ol o g y /i ncl usi o n / a n d e xcl usi o n crit eri a. 
T h e U ni v ersit y of Mi a mi will b e t h e c o or di n ati n g c e nt er. Ori gi n al s o urc e d oc u m e nts will b e k e pt at e ac h 
i nstit uti o n. All d at a will b e e nt er e d i nt o a R E D C A Ps d at a b as e h o us e d at t h e U ni v ersit y of Mi a mi.  
 
St u d y Ti m eli n e s:  
•  
T h e d ur ati o n of a n i n di vi d u al s u bj ect’s p artici p ati o n i n  t h e st u d y: 6 m o nt hs 
•  
T h e d ur ati o n a ntici p at e d t o e nr oll all st u d y s u bj ects: 6 m o nt hs  
•  
T h e esti m at e d d at e f or t h e i n v esti g at ors t o c o m pl et e t his st u d y (c o m pl et e pri m ar y a n al ys es) : 1 
y e ar.  
 
St u d y E n d p oi nt s*  
D escri b e t h e pri m ar y a n d s ec o n d ar y st u d y e n d p oi nts :  
Pri m ar y: C o m p aris o n of d r y e y e s y m pt o m s e v erit y ( dr y e y e q u esti o n n air e 5 sc or e) at 6 m o nt hs b et w e e n 
t h e t w o gr o u p. 

S ec o n d ar y: C o m p aris o n of all ot h er dr y e y e m etrics a n d 3 a n d 6 m o nt hs. Ot h er q u esti o n n air es, O S DI, N P SI, 
sf-M P Q, N R S, ot h er si g ns: t e ar pr o d ucti o n, e v a p or ati o n. A n al ysis of w hic h b as eli n e f act ors ( d e m o gr a p hics, 
tr e at m e nt, etc. ) pr e dict p ersist e nt s y m pt o ms at 6 m o nt hs, i n d e p e n d e nt of r a n d o mi z ati o n gr o u p. 
D escri b e a n y pri m ar y or s ec o n d ar y s af et y e n d p oi nts: T el e p h o n e ass ess m e nt of si d e eff ects aft er t h e 2 
w e e ks o n t h er a p y ( pl ac e b o v ers us dr u g).  
 
P r o c e d u r e s I n v ol v e d*  
D escri b e a n d e x pl ai n t h e st u d y d esi g n.  
S u m m a r y of st u d y  vi sit s:  
 
V 1: B as eli n e /  
R a n d o mi z ati o n  
( 1. 5 h o urs) 
V 2:  1 d a y pri or t o 
L A SI K  
( T el e p h o n e 
R e mi n d er)  
V 3 :  1 5 d a ys  
(t el e p h o n e 
visit ) 
± 1 D a y  
V 4:  3 m o nt hs   
( 4 5 mi n ut es) 
± 1 4 D a y s  
V 5 : 6 m o nt hs   
( 4 5 mi n ut es) 
    ± 1 4 D a y s  
I nf or m e d c o ns e nt 
X  
 
 
 
 
Q u esti o n n air es + S u bj ect Di ar y  X  
 
 
X  
X  
Oc ul ar s urf ac e ass ess m e nt  
X  
 
 
X  
X  
C ut a n e o us s e nsiti vit y  
X  
 
 
 
X  
C o nf oc al sc a n  
X  
 
 
 
X  
Bl o o d Dr a w  
X  
 
 
 
 
St art m e dic ati o n  
 
X  
 
 
 
C o n M e d / A E R e vi e w  
 
 
X  
X  
X  
 
Pr o vi d e a d escri pti o n of all r es e arc h pr oc e d ur es b ei n g p erf or m e d a n d w h e n t h e y ar e p erf or m e d : All 
r es e arc h pr oc e d ur es will t a k e pl ac e at B asc o m P al m er E y e I nstit ut e, Mi a mi. ( a) bl o o d will o bt ai n e d i n t h e 
1 st fl o or cli nic al l a b or at or y; ( b) a w aiti n g ar e a will b e utili z e d f or q u esti o n n air e c o m pl eti o n ( 3r d fl o or); (c) 
o n e r o o m f or oc ul ar s urf ac e t esti n g (i ncl u di n g c ut a n e o us s e nsiti vit y) ( 3 r d fl o or); ( d) c o nf oc al micr osc o p y 
o bt ai n e d i n t h e i m a gi n g ar e a ( 3 r d fl o or).   
 
D e s c ri b e:  
- Pr oc e d ur es p erf or m e d t o l ess e n t h e pr o b a bilit y or m a g nit u d e of ris ks : All pr oc e d ur es ar e st a n d ar d of c ar e 
f or e v al u ati o n of t h e oc ul ar s urf ac e wit h t h e e xc e pti o n of c ut a n e o us s e nsiti vit y t esti n g w hic h is st a n d ar d of 
c ar e i n r es e arc h of s o m at os e ns or y f u ncti o n.  
- All dr u gs us e d i n t h e r es e arc h a n d t h e p ur p os e of t h eir us e, a n d t h eir r e g ul at or y a p pr o v al st at us: L yric a 
1 5 0 m g BI D a n d pl ac e b o will b e us e d ( 3 0 p ati e nts i n e ac h gr o u p). L yric a h as b e e n a p pr o v e d b y t h e F D A f or 
t his us e ( p eri-o p er ati v e tr e at m e nt t o l ess e n t h e ris k of p ersist e nt p ost -o p er ati v e p ai n i n ot h er s ur g eri es) 
b ut h as n ot b e e n us e d i n c o nj u ncti o n wit h L A SI K s ur g er y.  
- All q u esti o n n air es us e d i n t h e st u d y ar e att ac h e d.  
 
D E q u esti o n n ai r es ( b as eli n e, 3 m o nt hs, 6 m o nt hs): T w o v ali d at e d D E q u esti o n n air es, t h e D E Q 5 5  a n d t h e 
O S DI 6  will b e a d mi nist er e d ( b as eli n e, 3 m o nt hs, 1 y e ar). T h e D E Q 5 c oll ects p ati e nt r es p o ns es r e g ar di n g 
t e ari n g, dr y n ess, a n d disc o mf ort i n d e p e n d e nt of vis u al f u ncti o n, w hil e t h e O S DI i ncl u d es vis u al f u ncti o n a n d 
q u esti o ns r el at e d t o diffic ult y wit h d ail y acti viti es s uc h as r e a di n g, usi n g a c o m p ut er, ni g htti m e dri vi n g, a n d 
w atc hi n g t el e visi o n. 6 , 8 0    
 
Oc ul ar p ai n q u esti o n n air es ( b as eli n e, 3 m o nt hs, 6 m o nt hs):  Ass ess m e nt of p ai n c h ar act eristics pl a ys a 
critic al r ol e i n r es e arc h o n m ec h a nis ms of p ai n a n d its tr e at m e nt. 6 3  Pr eli mi n ar y d at a : W e h a v e d e m o nstr at e d 
f e asi bilit y  of  usi n g  oc ul ar  p ai n  q u esti o n n air es  (s h ort  f or m  Mc Gill  P ai n  Q u esti o n n air e  (sf-M P Q)
6 4  a n d 
n e ur o p at hic p ai n s y m pt o m i n v e nt or y ( N P SI) 8 ,  i n  1 5 4  p ati e nts  wit h  D E Q 5  sc or es ≥6  (cli nic al  r el e v a nt  D E 
s y m pt o ms). 2 2   8 2 % of s u bj ects w er e f o u n d t o e n d ors e at l e ast 1 s e ns or y or 1 aff ecti v e d escri pt or f or t h eir e y e 
p ai n o n t h e S F -M P Q. S u bj ects m ost fr e q u e ntl y d escri b e d t h eir oc ul ar p ai n as “tiri n g -e x h a usti n g” ( 5 6 %), 

f oll o w e d b y “ ac hi n g” ( 5 6 %), a n d “ h ot b ur ni n g” ( 5 3 %). R e g ar di n g t h e N P SI, t h e m ost c o m m o n n e ur o p at hic-
li k e s y m pt o ms w er e all o d y ni a a n d h y p er al g esi a pr o v o k e d b y li g ht, wi n d, or h ot /c ol d, s p o nt a ne o us b ur ni n g 
p ai n, a n d pr ess ur e p ai n. T ot al sc or es o n t h e S F -M P Q a n d t h e N P SI w er e hi g hl y c orr el at e d wit h e ac h ot h er 
( P e ars o n r = 0. 7 2; S p e ar m a n r h o 0. 7 1, p < 0. 0 0 1), a n d b ot h w er e hi g hl y c orr el at e d wit h N R S r ati n gs of e y e 
p ai n (r = 0. 6 1 ( S F -M P Q vs. N R S); r  = 0. 7 1 ( N P SI vs. N R S)). T esti n g :  
 
O c ul a r p ai n:  W e will a d mi nist er t hr e e q u esti o n n air es, e ac h t ar g eti n g diff er e nt as p ects of p ai n: N R S of oc ul ar 
p ai n i nt e nsit y (r a n g e 0 -1 0) o v er v ari o us r ec all p eri o ds; sf -M P Q
6 4 , c o nsisti n g of 1 5 w or ds i ncl u di n g s e ns or y 
a n d  aff ecti v e  d escri pt ors  of  p ai n  (r a n g e  0 -4 5);  N P SI 8 ,  s p ecific all y  d e v el o p e d  t o  e v al u at e  f or  diff er e nt  
s y m pt o ms  of  n e ur o p at hic  p ai n  (r a n g e  0 -1 0 0).  I n o ur  m o difi e d  v ersi o n  of  N P SI  w e  r e pl ac e d  st a n d ar d 
q u esti o ns 8, 9, a n d 1 0 of t h e ori gi n al it e ms r e g ar di n g all o d y ni a a n d h y p er al g esi a ( p ai n c a us e d b y ( 1) 
br us hi n g, ( 2) pr ess ur e, or ( 3) c ol d o n t h e s ki n ), wit h it e ms s p ecific t o oc ul ar all o d y ni a a n d h y p er al g esi a (e y e 
p ai n  c a us e d or w ors e n e d b y ( 1) li g ht, ( 2) wi n d, a n d ( 3) h e at or c ol d).   
 
O C U L A R S U R F A C E T E S TI N G  
(*) T e ar os m ol arit y  ( T e ar L A B, S a n Di e g o, C A) t esti n g will b e p erf or m e d o nc e i n e ac h e y e pri or t o i nstill ati o n 
of e y e dr o ps. T h e os m ol arit y h a n d -pi ec e will b e h el d o v er t h e o ut er 1 / 3 of t h e i nf eri or c o nj u ncti v a e t o 
s a m pl e t h e i nf eri or t e ar m e nisc us. P ati e nts will b e as k e d t o l o o k u p a n d n as all y d uri n g t h e t es ti n g.  
 
(*) I nfl a m m a dr y t esti n g ( R P S, T a m p a, F L):  A t e ar s a m pl e will c oll ect e d b y e x p osi n g t h e l o w er p al p e br al 
c o nj u ncti v a a n d g e ntl y d a b bi n g t h e fl e ec e of t h e s a m pl e c oll ect or t e m p or all y t o n as all y a p pr o xi m at el y 6 -8 
ti m es, all o wi n g t h e p ati e nt t o bli n k b et w e e n d a bs t o e ns ur e s at ur ati o n. T h e s a m pli n g fl e ec e will glist e n or 
t ur n pi n k w h e n a n a d e q u at e s a m pl e is c oll ect e d a n d t h e n will b e s n a p p e d i nt o t h e t est c ass ett e pri or t o 
i m m ersi o n of t h e a bs or b e nt ti p i nt o t h e b uff eri n g s ol uti o n f or a p pr o xi m at el y 2 0 s ec o n ds or u ntil a p ur pl e 
w a v e a p p e ars i n t h e c ass ett e wi n d o w. T h e c a p will t h e n b e r e pl ac e d o v er t h e a bs or b e nt ti p a n d t h e 
a p plic at or will b e l ai d fl at f or 1 0 mi n ut es b ef or e i nt er pr et ati o n of t est r es ults.  
 
(i v) T e ar fil m br e a k u p ti m e ( T B U T):  T h e e x a mi n er will g e ntl y r etr act t h e u p p er li d a n d 5 μl of pr es er v ati v e 
fr e e fl u or esc ei n will b e pl ac e d o n t h e s u p eri or b ul b ar c o nj u ncti v a e. T h e u p p er li d will b e r el e as e d a n d t h e 
s u bj ect will b e all o w e d t o bli n k n or m all y f or 1 5 s ec o n ds. T h e p ati e nt’s h e a d will b e p ositi o n e d i n t h e 
h e a dr est of t h e slit -l a m p i nstr um e nt, m a ki n g s ur e t h e p ati e nt is c o mf ort a bl y s u p p ort e d wit h t h eir f or e h e a d 
i n f ull c o nt act wit h t h e h e a dr est b a n d.  T h e p ati e nt will b e i nstr uct e d t o bli n k t hr e e ti m es n at ur all y, t h e n 
st ar e a n d N O T B LI N K. T h e i n v esti g at or will m o nit or t h e i nt e grit y of t h e t e ar fil m a n d, usi n g a st o p w atc h, 
m e as ur e t h e ti m e fr o m t h e l ast bli n k u ntil o n e or m or e bl ac k ( dr y) s p ots a p p e ar i n t h e pr ec or n e al t e ar fil m.  
Aft er t h e 1st m e as ur e m e nt, t h e p ati e nt will b e i nstr uct e d t o bli n k n at ur all y 3 a d diti o n al ti m es a n d a 2 n d 
m e as ur e m e nt is t a k e n. T h e pr oc e d ur e will t h e n b e r e p e at e d a 3 r d ti m e.  Aft er a 6 0-s ec o n d r est p eri o d, t h e 
e ntir e pr oc e d ur e will b e r e p e at e d f or t h e l eft e y e.   
 
(*) C o nj u ncti v al a n d c or n e al st ai ni n g  will b e ass ess e d usi n g t h e N EI st a n d ar d sc ori n g sc al e ass essi n g  5 
ar e as of t h e c or n e a a n d 6 ar e as of t h e c o nj u ncti v a e. 1 0 0  T his will b e d o n e dir ectl y aft er T B U T t esti n g. A gr a d e 
( 0-3) will b e assi g n e d t o e ac h s ecti o n of t h e c or n e a a n d a t ot al sc or e ( 0 -1 5) will  b e g e n er at e d b y s u m mi n g 
t h e 5 s ecti o n sc or es. R e g ar di n g t h e c o nj u ncti v a, 1 0 μl of list a mi n e gr e e n will t h e n b e pl ac e d i n t h e i nf eri or 
f or ni x of b ot h e y es. Aft er 3 mi n ut es, t h e e x a mi n er will di vi d e t h e c o nj u ncti v a i nt o a s u p eri or p ar ali m b al 
ar e a, a n i nf eri or p ar ali m b al ar e a a n d a p eri p h er al ar e a wit h a gr a di n g sc al e of 0 – 3 f or e ac h ar e a ( m a xi m al 
sc or e of 9) f or b ot h t h e n as al a n d t e m p or al c o nj u ncti v a.  
 
(*) E y eli d ass ess m e nt:  T h e pr es e nc e of l o w er e y eli d l a xit y will b e d et er mi n e d b y t h e s n a p b ac k t est 
( 0 =la xit y wit hi n n or m al li mits, 1 = a d el a y of t w o t o fi v e s ec o n ds f or t h e l o w er li d t o r et ur n t o its n ati v e st at e, 
2 = p ersist e nt s e p ar ati o n n ec essit ati n g a bli n k t o r et ur n t o t h e n or m al st at e). U p p er e y eli d l a xit y will b e 
d et er mi n e d b y t h e li d distr acti o n t est ( 0 =l a xit y wit hi n n or m al li mits, 1 i = 7 -1 0 m m of distr acti o n, 2 = 

gr e at er t h a n 1 0 m m of distr acti o n). C o nj u ncti v oc h al asis will b e gr a d e d as a bs e nt or pr es e nt i n e ac h ar e a of 
t h e l o w er e y eli d (t e m p or al, c e ntr al, n as al) b as e d o n t h e o blit er ati o n of t h e t e ar fil m b y c o nj u ncti v a e i n t h e 
r e gi o n of i nt er est. T h e d e gr e e of e y eli d v asc ul arit y will b e sc or e d o n a sc al e of 0 t o 3 ( 0 = n o n e; 1 = mil d; 
2 = m o d er at e; 3 =s e v er e) as will t h e d e gr e e of i nf eri or e y eli d m ei b o mi a n orific e pl u g gi n g ( 0 = n o n e; 1 =l ess 
t h a n 1 / 3 li d i n v ol v e me nt; 2 = b et w e e n 1 / 3 a n d 2 / 3 li d i n v ol v e m e nt; 3 gr e at er t h a n 2 / 3 li d i n v ol v e m e nt).  
T h e pr es e nc e of fi br osis, p a pill ar y, or f ollic ul ar c o nj u ncti v al c h a n g es will b e d et er mi n e d as a bs e nt or 
pr es e nt.  
 
(*) Sc hir m er stri ps  will b e pl ac e d i n t h e o ut er 1 / 3 of t h e l o w er c o nj u ncti v a e a n d t h e l e n gt h of w etti n g aft er 
5 mi n ut es will b e r ec or d e d i n e ac h e y e. N o a n est h esi a will b e us e d pri or t o Sc hir m er stri p pl ac e m e nt.   
 
(*) M ei b u m q u alit y will b e r at e d o n a sc al e of 0 t o 4 ( 0 =cl e ar; 1 =cl o u d y; 2 = gr a n ul ar; 3 =t o ot h p ast e; 4 = n o 
m ei b u m e xtr act e d).
1 0 3   
 
(*) C o nf o Sc a n 4 ( Ni d e k T ec h n ol o gi es Srl, P a d o v a, It al y):  E x a mi n ati o n will b e c arri e d o ut usi n g t h e 4 0 X l e ns 
of t h e C o nf osc a n 4.  B ef or e t h e e x a mi n ati o n, a dr o p of t o pic al a n est h etic 0. 5 % pr o p ar ac ai n e h y dr oc hl ori d e 
( Alc o n, U S A) will b e us e d t o a n est h etiz e b ot h e y es. A dr o p of G e nt e al g el ( 0. 3 % H y pr o m ell os e, Alc o n 
L a b or at ori es, I nc., U S A) will b e a p pli e d o nt o t h e l e ns ti p. T h e p ati e nt will b e s e at e d i n fr o nt of t h e 
micr osc o p e wit h c hi n r est a n d f or e h e a d s u p p ort i n pl ac e a n d as k e d t o fi x at e t h e e x a mi n e d e y e t o t h e li g ht 
i nsi d e t h e l e ns. T h e j o y stic k will m o v e t h e l e ns t o w ar d t h e e y e u ntil t h e g el c o nt acts t h e c or n e a.  T h e d e vic e 
al erts t h e o p er at or w h e n t h e str o m a a p p e ars o n t h e m o nit or, aft er t h at, a b utt o n is pr ess e d t o i niti at e 
r ec or di n g. T h e d e vic e a ut o m atic all y c o m pl ets t h e ali g n m e nt a n d ac q uir es s e v er al c or n e al sc a ns at a s p e e d 
of 2 5 fr a m es p er s ec o n d, o bt ai ni n g 3 5 0 i m a g es p er sc a n, e v er y 3 u m f or t h e a nt eri or m o d e sc a n. E ac h i m a g e 
r e pr es e nt e d a c or o n al s ecti o n of 4 6 0 X 3 4 5 u m ( 1 5 8, 7 0 0 u m 2 ) wit h a mi ni m u m a xi al st e p of 1 u m, 
m a g nific ati o n of X 5 0 0, a n d l at er al r es ol uti o n of 0. 6 u m / pi x el. T w o g o o d q u alit y i m a g es of t h e s u b -b as al 
n er v e pl e x us will b e s el ect e d a n d r u n t hr o u g h t h e C or n e al N er v e A n al ysis t o ol ( Ni d e k T ec h n ol o gi es Srl, 
P a d o v a, It al y), a n e w n er v e a n al ysis s oft w ar e pr o gr a m. T h e crit eri a of s el ecti o n will b e ( 1) b est f oc us e d 
i m a g e wit h ( 2) g o o d c o ntr ast a n d ( 3) t h e c o m pl et e i m a g e i n t h e s a m e l a y er. A ut o m at e d a n al ysis p erf or m e d 
b y t his s oft w ar e t o ol will b e a u g m e nt e d wit h m a n u al r efi n e m e nt t o i m pr o v e t h e a n al ysis acc ur ac y. M a n u al 
r efi n e m e nt will b e p erf or m e d o n a st e p-b y -st e p b asis b y s el ecti n g or tr aci n g r e q uir e d p ar a m et ers, w hic h 
r e m ai n u n d et ect e d b y a ut o m atic a n al ysis. A v ari a bl e a m o u nt of r efi n e m e nt is n e e d e d d e p e n di n g o n t h e 
q u alit y of t h e i m a g e. T h e 9 p ar a m et ers c a pt ur e d i ncl u d e: 1 - N er v e fi b ers l e n gt h ( N F L) w as d efi n e d as t h e 
t ot al l e n gt h of t h e n er v e fi b ers (i n micr o m et ers) p er fr a m e ( u m /fr a m e). 2-N er v e fi b ers l e n gt h d e nsit y 
( N F L D) w as d efi n e d as t h e t ot al l e n gt h of t h e n er v e fi b ers (i n micr o m et ers) i n t his l a y er di vi d e d b y t h e ar e a 
of t h e fr a m e ( μ m / m m 2 ). 3- N u m b er of tr u n ks ( d efi n e d as t h e t ot al n u m b er of m ai n n er v es i n o n e i m a g e). 4 - 
N u m b er of br a nc h es ( d efi n e d as t h e t ot al n u m b er of n er v e br a nc h es i n o n e i m a g e). 5 - N u m b er of fi b ers 
( d efi n e d as t h e t ot al n u m b er of n er v e fi b ers, i ncl u di n g n er v e tr u n ks a n d br a nc h es, i n o n e i m a g e). 6 - 
N u m b er of bif urc ati o ns ( d efi n e d as t h e t ot al n u m b er of n er v e bif urc ati o ns i n o n e i m a g e). 7 - N u m b er of 
b e a di n gs ( d efi n e d as t h e t ot al n u m b er of w ell -d efi n e d h y p er -r efl ecti v e p oi nts i n all i d e ntifi e d m ai n n er v es 
(tr u n ks) i n o n e i m a g e). 8- B e a di n g d e nsit y ( d efi n e d as t h e t ot al n u m b er of n er v e b e a di n gs i n o n e i m a g e 
di vi d e d b y t h e t ot al l e n gt h of n er v e tr u n ks i n milli m et er ( b e a di n gs / m m)). 9 - NI D E K N er v e fi b ers t ort u osit y 
( a u nit-l ess m e as ur e t h at r e pr es e nts t h e d e gr e e of c ur v at ur e of n er v e fi b ers). T h e a v er a g e ti m e f or m a n u al 
o pti mi z ati o n a n d a n al ysis of e ac h i m a g e is 3. 5 ( + / - 0. 5) mi n ut es.   
 
C ut a n e o u s Q S T:  Dr. F eli x h as 2 0 y e ars of e x p eri e nc e utili zi n g Q S T m et h o ds f or ass essi n g 
s o m at os e ns or y f u ncti o n i n a v ari et y of p ati e nt gr o u ps a n d h e alt h y, c o ntr ol s u bj ects . Pr eli mi n ar y d at a : O n e 
pr e vi o us gr o u p utili z e d Q S T i n D E a n d f o u n d t h at s u bj ects wit h D E h a d l o w er h e at p ai n t hr es h ol ds a n d 
t ol er a nc e l e v els ( hi g h er p ai n s e nsiti vit y) o n t h e f or e ar m.7 2   T h es e  d at a s u g g est t h at D E s u bj ects as a gr o u p 
h a v e i ncr e as e d s e nsiti vit y t o t h er m al sti m uli i n a n ar e a r e m ot e fr o m t h e e y e. I n o ur pr ot oc ol, w e t est a sit e 
(f or e h e a d) t o l o o k f or r ec e pti v e fi el d e x p a nsi o n (s ec o n d ar y h y p er al g esi a), as f or e h e a d pri m ar y n er v es 

c on v er g e i nt o t h e tri g e mi n al g a n gli o n wit h c or n e al n er v es, as w ell as a r e m ot e sit e (f or e ar m 5 1 , 7 3 , 7 4 ) w h er e 
a b n or m aliti es of s e ns or y f u ncti o n s u g g est t h e p ot e nti al f or c e ntr al (t h al a m us a n d c ort e x) s yst e m 
i n v ol v e m ent. W e als o a p pl y t esti n g pr ot oc ols t h o u g ht t o b e m or e s p ecific f or c e ntr al s e nsitiz ati o n 
(t e m p or al s u m m ati o n ( T S)) a n d d esc e n di n g i n hi biti o n of p ai n (c o n diti o ns p ai n m o d ul ati o n ( C P M)). 
S p ecific all y, p ers o ns wit h c ert ai n c hr o nic p ai n c o n diti o ns h a v e b e e n s h o w n t o e x pr ess gr e at er s u m m ati o n 
of p ai n d u e t o r e p etiti v e pr es e nt ati o ns of a n o xi o us sti m ul us 7 5 , 7 6   a n d m ut e d d esc e n di n g p ai n m o d ul ati o n7 7 , 
c o m p ar e d t o t h os e wit h o ut c hr o nic p ai n. T esti n g : M ec h a nic al p ai n t hr es h ol ds ( M P T) : A st a n d ar d s et of pi n 
pric k sti m ul at ors   ( U N C -C h a p el Hill, Bi o m e dic al E n gi n e eri n g C or e) will b e us e d t o m e as ur e m ec h a nic al 
p ai n t hr es h ol ds. T his s p eci aliz e d s et c o nsists of 7 gr a d e d m o n ofil a m e nts, wit h a r a n g e of pr ess ur es 
b et w e e n 8 a n d 5 1 2 m N, wit h s m o ot h ti p g e o m etr y t h at is c o nsist e nt acr oss all 7 fil a m e nts a n d d o es n ot 
p e n etr at e  s ki n. E ac h s u bj ect will b e i nstr uct e d t o r es p o n d t o e ac h t est as t o w h et h er or n ot t h e sti m ul us f elt 
p ai nf ul t o t h e m. O n e ac h tri al, t h e pi n pric k sti m ul at or is a p pli e d p er p e n dic ul ar t o t h e t est sit e o n t h e s ki n 
a n d h el d i n pl ac e f or ~ 1 s ec. T w o sti m ul us s eri es will b e p erf or m e d at e ac h sit e acc or di n g t o t h e m et h o d of 
li mits.7 8  M P T  will b e d efi n e d as t h e arit h m etic m e a n of t h e v al u es o bt ai n e d o n asc e n di n g a n d d esc e n di n g 
sti m ul us s eri es. T e m p or al s u m m ati o n :  T e m p or al s u m m ati o n will b e m e as ur e d o nl y at t h e f or e ar m t est sit e. 
Usi n g t h e 2 5 6 m N pi n pric k sti m ul at or, w e will first pr es e nt a si n gl e sti m ul us o n t h e f or e ar m a n d as k t h e 
s u bj ect t o r at e t h e i nt e nsit y a n d u n pl e as a nt n ess of t h e p ai n g e n er at e d. T h e n w e will pr es e nt a tr ai n of 1 0 
sti m uli ( o n e s ec o n d “ o n”, o n e s ec o n d “ off”) a n d as k t h e s u bj ect t o r at e t h e p e a k p ai n i nt e nsit y a n d 
u n pl e as a nt n ess. M e as ur es of T S will b e o bt ai n e d b y s u btr acti n g t h e r ati n g of t h e first sti m ul us fr o m t h e 
p e a k p ai n. C o n diti o n e d p ai n m o d ul ati o n : Aft er t h e b as eli n e t e m p or al s u m m ati o n pr ot oc ol ( d escri b e d 
a b o v e) is p erf or m e d o n t h e ri g ht f or e ar m, a n o xi o us “c o n d iti o ni n g” sti m ul us is pr es e nt e d t o t h e l eft h a n d 
(i m m ersi o n i n a c ol d w at er b at h f or 6 0 s ec), t h e n a s ec o n d s et of m e as ur es of pi n pric k t e m p or al 
s u m m ati o n is p erf or m e d. T h e m a g nit u d e of c o n diti o n e d p ai n m o d ul ati o n is c alc ul at e d b y s u btr acti n g 
r ati n gs of pai n d uri n g b as eli n e t e m p or al s u m m ati o n fr o m r ati n gs of p ai n d uri n g t e m p or al s u m m ati o n 
pr oc e d ur es p erf or m e d aft er t h e c o n diti o ni n g sti m ul us. L o w er r ati n gs f or p ost - c o m p ar e d t o pr e-
c o n diti o ni n g r ati n gs i n dic at e gr e at er d esc e n di n g m o d ul ati o n of p ai n. N o r e d u cti o n, n or a n i ncr e as e, i n p ai n 
r ati n gs s u g g ests d ysf u ncti o n wit hi n t h e d esc e n di n g tr ac ks of t h e s yst e m. 7 9   
 
A s s e s s e d c o -m o r bi diti e s : M a n y f act ors, b esi d es g a b a p e nti oi d us e, c a n aff ect D E s y m pt o ms i ncl u di n g 
m e dic ati o n us e ( pr escri pti o n a n d o v er t h e c o u nt er) a n d c o -m or bi diti es ( d e pr essi o n). As s uc h, w e will 
ri g or o usl y c oll ect i nf or m ati o n o n v ari a bl es of i nt er est a n d i n s ec o n d ar y m ulti v a ri a bl e a n al ys es, e v al u at e t h e 
i m p act of t h es e c o-m or bi diti es o n D E s y m pt o ms a n d oc ul ar p ai n aft er L A SI K. C o -m or bi diti es t o b e c oll ect e d 
i ncl u d e ( a) oc ul ar a n d s yst e mic m e dic ati o ns; ( b) oc ul ar a n d s yst e mic c o-m or bi diti es ( di a b et es, 
h y p ert e nsi o n); (c) n o n -oc ul ar p ai n vi a a p ai n hist or y q u esti o n n air e; ( d) d e pr essi o n a n d a n xi et y vi a  t h e 
P ati e nt H e alt h Q u esti o n n air e ( P H Q -9) a n d t h e S C L -9 0 R; a n d ( e) Q o L vi a t h e S F -1 2 h e alt h s ur v e y ( p h ysic al 
a n d m e nt al c o m p o n e nts).   
 
D at a a n d S p e ci m e n B a n ki n g *  
( 1) Bl o o d s a m pl es wi ll b e st or e d a n d g e n o mic D N A ( g D N A) is ol at e d a n d g e n ot y p e d at H uss m a n I nstit ut e of 
H u m a n G e n o mics ( HI H G), Bi or e p osit or y a n d G e n ot y pi n g C or es : 1 5 0 1 N W 1 0t h A v e n u e B R B 4 5 0 . Mi a mi, F L 
3 3 1 3 6 . All bl o o d s a m pl es will b e st or e d i n a d e-i d e ntifi e d f as hi o n wit h a u ni q u e i d e ntifi er. W e pl a n o n 
st ori n g t h e bl o o d s o t h at w e c a n l at er a n al yz e w hic h g e n etic p ol y m or p his ms ass oci at e d wit h p ersist e nt p ost 
o p s y m pt o ms.  
( 2) T e ar s a m pl es  will b e st or e d i n a -8 0 oC fr e e z er i n a d e -i d e ntifi e d f as hi o n i n t h e Mc K ni g ht Visi o n 
R es e arc h C e nt er, n e xt d o or t o t h e B asc o m P al m er E y e I nstit ut e  l oc at e d at 1 6 3 8 N W 1 9t h A v e, Fl o or 7. 
Mi a mi, F L 3 3 1 3 6 . T h e y will l at er b e us e d t o q u a ntif y pr ot ei ns a n d li pi ds ( e. g. i nfl a m m at or y m e di at ors) t h at 
pr e dict p ersist e nt p ost o p p ai n.  
 

D at a M a n a g e m e nt*  
O r g a ni z ati o n al St r u ct u r e: St u d y acti viti es will b e c e nt er e d at B P EI r efr acti v e cli nic l oc at e d o n t h e 3 r d 
fl o or a n d a d mi nistr ati v e acti viti es will t a k e pl ac e i n r o o m 2 7 5 o n t h e 2n d  fl o or of t h e s a m e b uil di n g.  Dr. 
G al or, t h e PI, will h a v e r es p o nsi bilit y o v er all as p ects of t h e st u d y. Dr. G al or will w or k cl os el y wit h Dr. L e vitt 
wit h e xt e nsi v e e x p eri e nc e wit h t h e d esi g n a n d e x ec uti o n of P h as e 1 - 4 cli nic al tri als i n ac a d e mi a a n d 
i n d ustr y a n d Willi a m F e u er, a bi ost atistici a n wit h d ec a d es of e x p eri e nc e i n t h e desi g n a n d c o n d uct of 
o p ht h al mic cli nic al tri als.   
R a n d o mi z ati o n: Eli gi bl e i n di vi d u als will b e r a n d o ml y assi g n e d, i n a r ati o as cl os e as p ossi bl e t o 1: 1, t o 
eit h er t h e c o ntr ol or t h e tr e at m e nt gr o u p acc or di n g t o t h e r a n d o miz ati o n sc h e d ul e pr e p ar e d b y t h e 
b i ost atistici a n ( Mr. F e u er). A v ari a bl e ( n = 2 or n = 4) bl oc k e d r a n d o mi z ati o n list f or tr e at m e nt assi g n m e nts 
will b e c o nstr uct e d t o e ns ur e t h at tr e at m e nt assi g n m e nts ar e b al a nc e d aft er, at m ost 4 p ati e nts. O nc e 
pr e p ar e d, a c o p y of t h e r a n d o mi z ati o n sc h e d ul e will b e gi v e n t o t h e B P EI p h ar m acist w h o will b e i n c h ar g e 
of dis p e nsi n g t h e st u d y c a ps ul es t o e ac h p artici p a nt acc or di n g t o t h e gr o u p t o w hic h t h e p artici p a nt w as 
assi g n e d. T h e p h ar m acist will b e i n cl os e c o m m u nic ati o n wit h t h e bi ost atistici a n w h o will d e al  wit h a n y 
iss u es r e g ar di n g t h e r a n d o mi z ati o n sc h e d ul e. 
St ati sti c al a n al y si s:  St atistic al a n al ys es will b e p erf or m e d usi n g S P S S 2 1. 0. B ef or e t h e i m pl e m e nt ati o n 
of a n y st atistic al t ests, w e will us e d escri pti v e st atistics t o ass ess t h e distri b uti o n al pr o p erti es of t h e 
diff er e nt v ari a bl es a n d t h eir i nt err el ati o ns hi ps, as w ell as t o d et er mi n e missi n g d at a a n d t o d et ect o utli ers. 
Tr a nsf or m ati o ns will b e us e d f or v ari a bl es wit h s k e w e d distri b uti o ns b ef or e t h eir i ncl usi o n i n a n al ys es t h at 
r e q uir e n or m alit y or a p pr o xi m at e n or m alit y. If n or m alit y c a n n ot b e ac hi e v e d, t h e n n o n p ar a m etric 
t ec h ni q u es will b e us e d. T h e a m o u nt of missi n g d at a will b e mi ni miz e d t hr o u g h ri g or o us d at a q u alit y 
c o ntr ol pr oc e d ur es i m pl e m e nt e d fr o m t h e st art of t h e st u d y. B ut, as is t h e us u al c as e i n cli nic al st u di es, 
missi n g d at a m a y occ ur. W h e n e v er a p pr o pri at e, missi n g d at a will b e i m p ut e d usi n g m e a n -b as e d or 
r e gr essi o n-b as e d i m p ut ati o n pr oc e d ur es. All a n al ys es will b e p erf or m e d o n a n i nt e nt -t o-tr e at b asis, i. e., f or 
p ur p os es of st atistic al a n al ys es, all p artici p a nts will b e c o nsi d er e d i n t h e gr o u p t o w hic h t h e y w er e 
ori gi n all y r a n d o mi z e d. All st atistic al t ests will b e t w o -si d e d t ests, c o n d uct e d at a n o mi n al 5 % l e v el of 
si g nific a nc e. St u d y p artici p a nts will b e r a n d o mi z e d t o t w o gr o u ps, “c o ntr ol” a n d tr e at m e nt, a n d o utc o m e 
v ari a bl es as w ell as p ot e nti al c o nf o u n d ers will b e  asc ert ai n e d at b as eli n e ( 0 m o nt hs) a n d at 3 a n d 6 
m o nt hs. T h e pri nci p al st atistic al a n al ysis f or t his st u d y will b e a fr e q u e nc y c o m p aris o n of D E s y m pt o ms 
( D E Q 5 ≥6; or mil d t o s e v er e) b et w e e n t h e t w o gr o u ps ( Fis h er e x act or C hi s q u ar e m et h o d ol o g y) at 6 
m o nt hs. S ec o n d ar y a n al ys es will i ncl u d e t h e eff ect of m e dic ati o n o n s ec o n d ar y e n d -p oi nts i ncl u di n g 
m e as ur es of t e ar a n d s o m at os e ns or y f u ncti o n (tri g e mi n al a n d dist al sit es). M ulti -v ari a bl e a n al ys es will b e 
c o n d uct e d t o c o nsi d er t h e c o ntri b uti o n of d e m o gr a p hics , b as eli n e e x a mi n ati o n fi n di n gs, a n d L A SI K 
tr e at m e nt p ar a m et ers. W e will us e t his st u d y t o ass e m bl e t h e t e a m, d e m o nstr at e t h e pr ot oc ol is f u ncti o ni n g 
a n d est a blis h if t h er e is a n y tr e n d, all of w hic h ar e n e e d e d i n or d er t o s u b mit a c o m p etiti v e U -t y p e NI H 
p r o p os al f or a l ar g er, m ulti-c e nt er e d R C T t h at will r e plic at e a n d e xt e n d o ur pr o gr a m.  
P o w e r c o n si d e r ati o n s : P u blis h e d d at a s u g g est t h at u p w ar ds of 5 5 % of p ati e nts will e x p eri e nc e 
p ersist e nt D E s y m pt o ms at 6 m o nt hs. A R C T wit h pr e g a b ali n d osi n g b ef or e a n d f or 2 w e e ks aft er s ur g er y, 
si mil ar t o o ur pr o p os e d pr ot oc ol, d e m o nstr at e d a 1 0 0 % r es p o ns e r at e i n p ati e nts u n d er g oi n g t ot al k n e e 
art hr o pl ast y ( T K A). 3 5  Usi n g t h e Fis h er’s e x act t est t o c o m p ar e o ur pr o p os e d gr o u ps ( 3 0 p ati e nts i n e ac h 
gr o u p), a  0 % fr e q u e nc y of P P P at 6 m os. ( as i n t h e T K A p a p er) 3 5  i n t h e tr e at m e nt gr o u p a n d a 5 5 % 
fr e q u e nc y of P P P i n t h e pl ac e b o gr o u p w o ul d yi el d a hi g hl y si g nific a nt p v al u e of < 0. 0 0 0 1. Ass u mi n g a 
tr e at m e nt r es p o ns e of 4 4 % ( 2 4 % fr e q u e nc y of P P P at 6 m os.) i n t h e tr e at m e nt gr o u p a n d a 5 5 % fr e q u e nc y 
of P P P i n t h e pl ac e b o gr o u p, w e w o ul d still h a v e t h e p o w er t o s h o w a si g nific a nt diff er e nc e b et w e e n gr o u ps 
( P = 0. 0 4 2). T h e i m p o rt a nc e of o u r fi rst -of - a-ki n d f e asi bilit y st u d y of p e ri o p e r ati v e p r e g a b ali n c a n n ot 
b e o v e rst at e d. Fr o m t his gr o u n d br e a ki n g st u d y w e s h o ul d h a v e s uffici e nt e pi d e mi ol o gic a n d s y m pt o m -
r es p o ns e d at a t o d esi g n a n d c o n d uct a l ar g e w ell- c o ntr oll e d w ell-p o w er e d m ultic e nt er R C T of pr e g a b ali n 
f or t h e pr e v e nti o n of p ersist e nt D E aft er L A SI K.  T h e t a bl e b el o w gi v es n ec ess ar y s a m pl e si z es f or a r a n g e of 
tr e at m e nt effic aci es, 7 5 % t o 9 5 %, at b ot h 8 0 % a n d 9 0 % p o w er ass u mi n g a n al ysis wit h t h e Fis h er e x act t est 

a n d a n al p h a err or of 0. 0 5. If t h e tr e at m e nt is 7 5 % eff ecti v e a s a m pl e of 3 0 p er gr o u p w o ul d pr o vi d e 8 0 % 
p o w er.  
 
 
  
 Pl ac e b o c o ntr ol gr o u p i nci d e nc e  
5 5 %  
  
Eff ecti v e n ess of tr e at m e nt  
  
7 5 %  
8 5 %  
9 0 %  
9 5 %  
E x p ect e d I nci d e nc e i n acti v el y tr e at e d gr o u p  
1 4 %  
8 %  
6 %  
3 %  
S a m pl e si z e p er gr o u p f or 8 0 % p o w er  
2 5  
1 8  
1 7  
1 5  
S a m pl e si z e p er gr o u p f or 9 0 % p o w er  
3 1  
2 2  
2 0  
1 8  
 
R a n d o mi z ati o n:  Eli gi bl e i n di vi d u als will b e r a n d o ml y assi g n e d, i n a r ati o as cl os e as p ossi bl e  t o 1: 1, t o 
eit h er t h e c o ntr ol or t h e tr e at m e nt gr o u p acc or di n g t o t h e r a n d o miz ati o n sc h e d ul e pr e p ar e d b y t h e 
bi ost atistici a n ( Mr. F e u er). A v ari a bl e ( n = 2 or n = 4) bl oc k e d r a n d o mi z ati o n list f or tr e at m e nt assi g n m e nts 
will b e c o nstr uct e d t o e ns ur e t h at tr e at m e nt assi g n m e nts ar e b al a nc e d aft er, at m ost 4 p ati e nts. O nc e 
pr e p ar e d, a c o p y of t h e r a n d o mi z ati o n sc h e d ul e will b e gi v e n t o t h e B P EI p h ar m acist w h o will b e i n c h ar g e 
of dis p e nsi n g t h e st u d y c a ps ul es t o e ac h p artici p a nt acc or di n g t o t h e gr o u p t o w hic h t h e  p artici p a nt w as 
assi g n e d. T h e p h ar m acist will b e i n cl os e c o m m u nic ati o n wit h t h e bi ost atistici a n w h o will d e al wit h a n y 
iss u es r e g ar di n g t h e r a n d o mi z ati o n sc h e d ul e. 
D at a m a n a g e m e nt : A l o g will be cr e at e d t o tr ac k all d at a c oll ecti o n acti viti es. T h e l o g will s p ecif y d at a ar e t o 
b e c oll ect e d f or e ac h p artici p a nt as w ell as t h e ex p ect e d a n d act u al d at es of c oll ecti o n. R e p orts of c o m pl ete d 
ass ess me nts will be g e n er at e d t o pl a n r e q uir e m e nt s f or p artici p a nt f oll o w-u p. U n d er t h e st u d y Bi ost atistici a n’s 
s u p er visi o n, st aff will b e tr ai n e d i n n ec ess ar y acti viti es r el at e d t o d at a c oll ecti o n, m a n a g e m e nt a n d q u alit y 
c o ntr ol.  All s o urc e d at a will b e st or e d i n a s ec ur e d l oc ati o n. I n a d diti o n, w e wil l w or k wit h a d at a m a n a g er t o 
cr e at e a d at a c oll ecti o n s he et i n R E D C A P. All d at a will b e i n p utt e d i nt o R E D C A P.  All of t h e r es e arc h st aff will 
h a v e u p d at e d tr ai ni n g, a ut h oriz ati o n of acc ess, all el ectr o nic d oc u m e nts (i e R E D C A P S) will b e p ass w or d 
pr ot ect e d a n d o nl y t h os e a ut h ori z e d  will b e a bl e t o e nt er a n d s e e t h e d at a. I n a d diti o n, o nl y t h e s o urc e 
d oc u m e nts will h a v e t h e p ati e nt i d e ntifi er. All d at a i n R E D C A P S will b e st or e d wit h a u ni q u e i d e ntifi er a n d 
n ot wit h p ati e nt i d e ntif yi n g i nf or m ati o n.  
 
D escri b e a n y pr oc e d ur es t h at will b e us e d f or q u alit y c o ntr ol of c oll ect e d d at a: T h e st u d y c o or di n at or will 
p ut all t h e d at a i n R E D C A P S w hic h will b e b uilt wit h q u alit y c o ntr ol m e as ur es (i e n ot b ei n g a bl e t o p ut i n a 
v al u e t h at is n ot p ossi bl e). I n a d diti o n, ot h er st u d y m e m b ers will p erf or m p eri o dic q u alit y c o ntr ol c h ec ks 
o n 1 0 % of t h e d at a t o e ns ur e g o o d q u alit y. W e will als o e v al u at e d at a q u alit y o n a m o nt hl y b asis b y 
e x a mi ni n g d escri pti v es of all t h e d at a c oll ect e d.  
 
- W h at i nf or m ati o n will b e i ncl u d e d i n t h at d at a  or ass oci at e d wit h t h e s p eci m e ns? O nl y a u ni q u e i d e ntifi er 
will b e st or e d wit h t h e s p eci m e ns.  
- W h er e a n d h o w d at a or s p eci m e ns will b e st or e d? S o urc e d at a will b e st or e d i n l oc k e d c a bi n et of st u d y 
c o or di n at or. El ectr o nic, d e -i d e ntifi e d d at a will b e st or e d o n R E D C A P S 
- H o w l o n g t h e d at a or s p eci m e ns will b e st or e d? D at a f or 2 0 y e ars. S p eci m e ns u ntil t h e y ar e us e d.  
- W h o will h a v e acc ess t o t h e d at a or s p eci m e ns? O nl y t h os e list e d o n t h e I R B pr ot oc ol i ncl u di n g 
c oi n v esti g at ors, st atistici a n, st u d y c o or d i n at or, a n d PI. 
- W h o is r es p o nsi bl e f or r ec ei pt or tr a ns missi o n of t h e d at a or s p eci m e ns? St u d y c o or di n at or a n d PI will b e 
r es p o nsi bl e. 
- H o w d at a a n d s p eci m e ns will b e tr a ns p ort e d? D at a el ectr o nic all y. All s p eci m e ns will b e h o us e d l oc all y at 
U M. 

 
 
 
P r o vi si o n s t o M o nit o r t h e D at a t o E n s u r e t h e S af et y of S u bj e ct s*  
Ri s k s t o H u m a n S u bj e ct s  H u m a n S u bj e cts I n v ol v e m e nt, C h a r act e risti cs, a n d D esi g n   
Pr o p os e d i n v ol v e m e nt of h u m a n s u bj ects:   P ati e nts will b e pr os p ecti v el y r ecr uit e d fr o m B asc o m P al m er E y e 
I nstit ut e ( B P EI)).   
 
D escri pti o n a n d j ustific ati o n of t h e c h ar act eristics of t h e s u bj ect p o p ul ati o n : A t ot al of 5 0 p ati e nts will b e 
r ecr uit e d i nt o t h e pr o p os e d st u d y b as e d o n t h e p erf or m e d p o w er c alc ul ati o n.  As w e pl a n t o r ecr uit 
p ati e nts fr o m Mi a mi -D a d e c o u nt y h os pit als, w e a ntici p at e t h at t h e r aci al / et h nic c h ar act eristics of t h e 
s u bj ect p o p ul ati o n will r efl ect t h e d e m o gr a p hics of Mi a mi -D a d e C o u nt y . 
 
D escri pti o n a n d j ustific ati o n t h e s a m pli n g :  As t his st u d y p os es mi ni m al ris k t o t h e p ati e nt, f urt h er t esti n g 
will occ ur o n t h e s a m e d a y as si g ni n g of t h e i nf or m e d c o ns e nt.  T h e r es e arc h pr oc e d ur es i ncl u d e 
q u esti o n n air es a n d oc ul ar s urf ac e e v al u ati o n ( 3 ti m es), t e ar s a m pl e c oll ecti o n a n d a n al ysis ( 3 ti m es), a n d 
g e n etic a n al ysis ( o n e ti m e).  
 
R ecr uit me nt M et h o ds:  All eli gi bl e p ati e nts w h o pl a n o n u n d er g oi n g L A SI K s e e n at t h e B asc o m P al m er E y e 
Cli nic will b e off er e d r ecr uit m e nt i nt o t h e st u d y.  T h e st u d y c o or di n at ors will e x pl ai n t h e st u d y g o als, t h e 
re q uir e d e v al u ati o ns, t h e n ec ess ar y f oll o w u p, a n d t h e p ot e nti al ris ks.  S u bj ects will b e as k e d f or t h eir 
v ol u nt ar y p artici p ati o n a n d if t h e y a gr e e, a d e q u at e ti m e will b e gi v e n t o r e a d a n d r e vi e w t h e i nf or m e d 
c o ns e nt.  A n I R B - a p pr o v e d s t u d y fl y er will b e pl ac e d i n a n 8. 5 x 1 1 fl y er h ol d er wit hi n s e v er al e x a m r o o ms 
i n t h e L asi k Visi o n C e nt er as w ell as t h e w aiti n g r o o m.  
 
S o u rc es of M at e ri als   
R es e arc h m at eri al :   I nf or m ati o n o bt ai n e d i n t h e c o urs e of t h e st u d y will i ncl u d e: d e m o gr a p hic i nf or m ati o n, 
p ast oc ul ar a n d m e dic al hist or y, a n d us e of m e dic ati o ns. S e v er al q u esti o n n air es will b e a d mi nist er e d w hic h 
will c oll ect i nf or m ati o n o n pr es e nc e of D E s y m pt o ms, oc ul ar p ai n, a n d c o- m or bi diti es ( d e pr essi o n, P T S D) .  
T esti n g will i ncl u d e c ut a n e o us s e nsiti vit y m e as u r e m e nts; P ati e nt t e ars a n d bl o o d will b e c oll ect e d f or l at er 
a n al ysis.  E ac h p ati e nt will b e assi g n e d a u ni q u e i d e ntifi er a n d s a m pl es will b e st or e d a n d a n al y z e d wit h t h e 
u ni q u e i d e ntifi er i nf or m ati o n o nl y.    T h e m e dic al d at a o bt ai n e d fr o m p artici p a nts wi ll i ncl u d e d e m o gr a p hic 
i nf or m ati o n, m e dic al a n d s ur gic al hist or y, a n d m e dic ati o n i nf or m ati o n.  D at a will b e c oll ect e d o n p a p er a n d 
c o n v ert e d t o a n el ectr o nic f or m ( R E D C A P S ).  T h e d oc u m e nt will n ot i ncl u d e i n di vi d u all y i d e ntifi a bl e 
pri v at e i nf or m ati o n a n d w ill i d e ntif y p ati e nts usi n g t h eir u ni q u e i d e ntifi er.  A s e p ar at e d oc u m e nt will li n k 
e ac h u ni q u e i d e ntifi er t o a p ati e nt.   All el ectr o nic a n d p a p er d at a will b e st or e d i n t h e l oc k e d offic es of t h e 
st u d y c o or di n at or.  O nl y t h e pri nci p al i n v esti g at ors a n d st u d y c o or di n at ors will h a v e acc ess t o i n di vi d u all y 
i d e ntifi a bl e pri v at e i nf or m ati o n.   
 
 
 
P ot e nti al Ris ks   
D uri n g t h e st u d y, t h e y will b e as k e d t o fill o ut a q u esti o n n air e t h at as ks q u esti o ns a b o ut d e pr essi o n, 
a n xi et y, a n d p ai n. If t h es e q u esti o ns b ec o m e t o o distr essf ul f or t h e s u bj ect t o c o m pl et e, a n d t h e y d o n ot 
wis h t o t a k e p art i n t his p orti o n of t h e st u d y, t h e y will n ot b e a bl e t o p artici p at e i n t his st u d y.  
All s u bj ects will u n d er g o D E t esti n g i ncl u di n g os m ol arit y m e as ur e m e nt, slit l a m p e x a mi n ati o n, S c hir m er’s 
t esti n g, M M P 9 m e as ur e m e nt usi n g I nfl a m m a dr y, a n d t e ar c oll ecti o n.  T h es e t ests p os e n o si g nific a nt ris ks t o 
t h e p ati e nt.  All p ati e nts will u n d er g o c ut a n e o us s e nsiti vit y m e as ur e m e nts.  T h er e is n o ris k of d a m a g e t o 
t h e e y e or  s ki n wit h s e nsiti vit y t esti n g.  All p ati e nts will als o b e as k e d t o pr o vi d e a bl o o d s a m pl e f or g e n etic 

a n al ysis.  T h e ris ks ass oci at e d wit h t h e bl o o d dr a w ar e mi ni m al a n d i ncl u d e p ai n, h e m at o m a f or m ati o n, a n d 
i n r ar e c as es, i nf ecti o n.  As i n all st u di es, t h er e is a ris k t h at n o n -a ut h ori z e d i n di vi d u als will g ai n acc ess t o 
p ati e nt i nf or m ati o n.  W e will miti g at e t his ris k b y k e e pi n g all s e nsiti v e i nf or m ati o n b e hi n d l oc k e d d o ors 
a n d p ass w or d pr ot ect e d, wit h o nl y a ut h ori z e d us ers h a vi n g acc ess.  All st u d y r el at e d  pr oc e d ur es ar e b ei n g 
d o n e f or r es e arc h p ur p os es o nl y. All pr oc e d ur es ar e t h e b est a v ail a bl e t o st u d y t h e r es e arc h q u esti o ns.  
 
 
P ot e nti al Dr u g Si d e Eff ects : 
 
T h e m ost c o m m o n si d e eff ects of pr e g a b ali n i ncl u d e:  
•  
Tir e d n ess  
•  
Di zzi n ess  
•  
H e a d ac h e  
•  
Dr y m o ut h  
•  
N a us e a  or v o miti n g  
•  
C o nsti p ati o n  
•  
G as or bl o ati n g  
•  
'' Hi g h'' or el e v at e d m o o d 
•  
S w elli n g of t h e ar ms, h a n ds, f e et, a n kl es, or l o w er l e gs  
•  
B ac k p ai n  
 
 
I nt e r a cti o n s: 
 
Dr u g i nt er acti o ns m a y c h a n g e h o w y o ur m e dic ati o ns w or k or i ncr e as e y o ur ris k f or s eri o us si d e eff ects. 
T his d oc u m e nt d o es n ot c o nt ai n all p ossi bl e dr u g i nt er acti o ns. K e e p a list of all t h e pr o d ucts y o u us e 
(i ncl u di n g pr escri pti o n / n o n pr escri pti o n dr u gs a n d h er b al pr o d ucts) a n d s h ar e it wit h y o ur d oct or a n d 
p h ar m acist. D o n ot st art, st o p, or c h a n g e t h e d os a g e  of a n y m e dici n es wit h o ut y o ur d oct or's a p pr o v al.  
A s m all n u m b er of p e o pl e w h o t a k e a ntic o n v uls a nts f or a n y c o n diti o n (s uc h as s eiz ur e, bi p ol ar dis or d er, 
p ai n) m a y e x p eri e nc e d e pr essi o n, s uici d al t h o u g hts / att e m pts, or ot h er m e nt al / m o o d pr o bl e ms. T ell y o ur 
d oct or ri g ht a w a y if y o u or y o ur f a mil y /c ar e gi v er n otic e a n y u n us u al /s u d d e n c h a n g es i n y o ur m o o d, 
t h o u g hts, or b e h a vi or i ncl u di n g si g ns of d e pr essi o n, s uici d al t h o u g hts / att e m pts, t h o u g hts a b o ut h ar mi n g 
y o urs elf.  
A v er y s eri o us all er gic r e acti o n t o t his dr u g is r ar e. H o w e v er, g et m e dic al h el p ri g ht a w a y if y o u n otic e a n y 
s y m pt o ms of a s eri o us all er gic r e acti o n, i ncl u di n g: r as h, itc hi n g /s w elli n g ( es p eci all y of t h e 
f ac e /t o n g u e /t hr o at), s e v er e di zzi n ess, tr o u bl e br e at hi n g. 
 
 
A d e q u ac y of P r ot e cti o n a g ai nst  Ris ks  
T h e st u d y c o or di n at or will e x pl ai n t h e st u d y g o als, t h e r e q uir e d t esti n g, a n d t h e p ot e nti al ris ks.  O nl y s u bj ects 
wit h t h e m e nt al c a p acit y t o u n d erst a n d t h e st u d y a n d t h e i nf or m e d c o ns e nt pr oc ess will b e r ecr uit e d.  
S u bj ects will b e as k e d f or t h eir v ol u nt ar y p artici p ati o n a n d if t h e y a gr e e, a d e q u at e ti m e will b e gi v e n t o r e a d 
a n d r e vi e w t h e i nf or m e d c o ns e nt.  T h e pri nci p al i n v esti g at ors will b e a v ail a bl e t o a ns w er a n y f urt h er 
q u esti o ns.  T h e st u d y c o or di n at or will d oc u m e nt t h at t h e c o ns e nt w as pr o p erl y o bt ai n e d.  
 
P r ot ecti o n a g ai nst  Ris k:  P ati e nts will b e ass ur e d t h at r ef us al t o p artici p at e i n t h e st u d y will i n n o w a y 
c o m pr o mis e t h e c ar e t h e y r ec ei v e.  Wit h r e g ar ds t o d at a pr ot ecti o n, all d at a will b e d e -i d e ntifi e d t o pr ot ect 
p ati e nt pri v ac y.    
 

P ot e nti al B e n efit of t h e P r o p os e d R es e a rc h t o t h e S u bj e ct a n d Ot h e rs:   T his pr oj ect h as t h e p ot e nti al t o 
dir ectl y b e n efit t h e s u bj ect as t h e us e of pr e g a b ali n m a y d ecr e as e t h e fr e q u e nc y a n d s e v erit y of dr y e y e 
s y m pt o ms aft er L A SI K. 
 
I m p ort a n c e of t h e K n o wl e d g e t o b e g ai n e d :  I m p ort a nt k n o wl e d g e will b e g ai n e d fr o m t h e st u d y as its 
fi n di n gs will i m pr o v e o ur u n d erst a n di n g of p ersist e nt dr y e y e s y m pt o ms aft er L A SI K a n d t h eir p ot e nti al 
r e d ucti o n. 
 
D at a a n d S af et y M o nit o ri n g . T h e r es e arc h t e a m will m e et o n a w e e kl y b asis t o r e vi e w st u d y crit eri a, 
r ecr uit m e nt, s af et y, a n d d at a i nt e grit y iss u es. T h e pri nci p al i n v esti g at ors will h a v e t h e o v er all 
r es p o nsi bilit y of e ns uri n g p ati e nt s af el y a n d acc ur ac y of d at a b ut will h a v e a f ull t i m e st u d y c o or di n at or t o 
h el p wit h t h es e e n d e a v ors. T h e st u d y c o or di n at or will r e vi e w all st u d y d oc u m e nts pri or t o t h e p ati e nt 
l e a vi n g t o mi ni miz e t h e ris k of missi n g d at a.  T h e d at a b as e will b e r e vi e w e d b y t h e PIs o n a w e e kl y b asis t o 
e ns ur e t h at all i nf o r m ati o n is c oll ect e d a n d st or e d a p pr o pri at el y.  T h e fi n al d at a r e g ar di n g effic ac y  will o nl y 
b e a v ail a bl e aft er all s u bj ects c o m pl et e t h e st u d y as t h e i n v esti g at or a n d st u d y c o or di n at or will b e m as k e d 
t o t h e dr u g r a n d o mi z ati o n. S p ecific all y, aft er t h e t w o w e e ks of t h er a p y, a p h o n e s ur v e y will b e c o n d uct e d t o 
ass ess si d e eff ects i n all p ati e nts. I n p ers o n si d e eff ect c h ec ks will als o b e d o n e at t h e 3 a n d 6 m o nt h visit 
alt h o u g h n o acti v e dr u g ( or pl ac e b o) will b e us e d b e y o n d t h e i niti al 2 w e e k p eri o d. T h er e wi ll b e t w o l e v els 
of s af et y m o nit ori n g d uri n g t h e c o urs e of t h e cli nic al tri al t h at ar e c o m m e ns ur at e wit h ris k b as e d o n t h e 
n at ur e, si z e a n d c o m pl e xit y of t his tri al. O ur pr ot oc ol utili z es pr e g a b ali n f or a n e w i n dic ati o n c o nsist e nt 
wit h a p pr o v e d i n dic ati o ns  t o tr e at p ersist e nt n e ur o p at hic p ai n at t h e s a m e d os e a n d r o ut e of 
a d mi nistr ati o n. T h er ef or e, o ur S af et y M o nit ori n g Pl a n will i ncl u d e: 1) o n g oi n g ti m el y e v al u ati o ns b y t h e 
cli nic al tri al t e a m, a n d 2) i nstit uti o n al o v ersi g ht b y t h e U ni v ersit y of Mi a mi I nst it uti o n al R e vi e w B o ar d 
(I R B). All A Es will b e r ec or d e d i n p artici p a nts’ m e dic al r ec or ds. A Es will b e gr a d e d a n d attri b uti o n 
assi g n e d. T h e st u d y t ec h nici a ns, c o or di n at ors a n d PI will m e et w e e kl y t o r e vi e w t h e pr o gr ess of t h e st u d y, 
i ncl u di n g all A Es. E x p ecte d pr ot oc ol -r el at e d A Es ( e. g. di z zi n ess  a n d g astr oi nt esti n al u ps et) will b e r e p ort e d 
t o t h e I R B d uri n g a n n u al o n g oi n g r e vi e ws. U n e x p ect e d a n d s e v er e a d v ers e e v e nts ( S A E) i ncl u d e 
h os pit ali z ati o n, lif e -t hr e at e ni n g c o n diti o n, p er m a n e nt or s u bst a nti al dis a bilit y, t est-dr u g o v er d os e, f alls, 
a n y i m p ort a nt m e dic al e v e nt, a n d d e at h will b e r e p ort e d t o t h e I R B i n a n e x p e dit e d f as hi o n. T h e PI will 
e ns ur e acc ur at e d oc u m e nt ati o n a n d i n v esti g ati o n a n d f oll o w -u p of all p ossi bl e st u d y -r el at e d a d v ers e 
e v e nts. T h e c u m ul ati v e i nci d e nc e of a d v ers e e v e nts ( A Es) will b e r ec or d e d o v er t h e 6 -m o nt h p eri o d.  
 
Wit h d r a w al of S u bj e ct s*  
S u bj ects m a y wit h dr a w fr o m t h e st u d y at a n y ti m e p oi nt. D at a alr e a d y c oll ect e d will b e i ncl u d e d f or t h e 
s ec o n d ar y e n d p oi nt a n al ysis, if p er mitt e d b y t h e p ati e nt.  
 
V ul n e r a bl e P o p ul ati o n s : N / A 
 
M ulti -Sit e R e s e a r c h : 
If t his is a m ulti-sit e st u d y w h er e y o u ar e t h e l e a d i n v esti g at or, d escri b e t h e pr oc ess es t o e ns ur e 
c o m m u nic ati o n a m o n g sit es, s uc h as:  
O nc e Mi a mi I R B a p pr o v es t h e pr ot oc ol /I C F, w e will s h ar e all d oc u m e nt ati o n wit h t h e S a n Di e g o sit e. T h e y 
will b e r es p o nsi bl e f or o bt ai ni n g t h eir o w n I R B a p pr o v al. W e will  h a v e m o nt hl y c alls wit h S a n Di e g o t o 
disc uss st u d y r el at e d iss u es a n d m e et i n p ers o n t wic e a y e ar at o p ht h al m ol o g y m e eti n gs.  
T h e s a m e s af et y c h ec ks t h at will b e i m pl e m e nt e d i n Mi a mi will als o b e c arri e d o ut b y t h e S a n Di e g o sit e.  
 
T h e s u bj ect’s i d e ntit y a n d r ec or ds will b e k e pt as c o nfi d e nti al as p ossi bl e as r e q uir e d b y l a w a n d 
will n ot b e  m a d e p u blicl y a v ail a bl e.   E xc e pt as r e q uir e d b y l a w, s u bj ects will n ot b e i d e ntifi e d o n a n y 
st u d y f or m b y n a m e, S oci al S ec urit y n u m b er, a d dr ess, t el e p h o n e n u m b er, or a n y ot h er dir ect 

p ers o n al i d e ntifi er.   I nst e a d, t h e y will b e assi g n e d a s u bj ect e nr oll m e nt I D.  T h e st u d y d oct or will 
k e e p a list t h at m atc h es p artici p a nt i d e ntific ati o n n u m b ers t o p artici p a nt n a m es a n d will o nl y s h ar e 
t h e f oll o wi n g i nf or m ati o n wit h t h e S a n Di e g o sit e: a g e, g e n d er, r ac e, c urr e nt m e dic ati o ns, a n d 
m e dic al hist or y.   It is p ossi ble t h at t his ot h er i nf or m ati o n c o ul d b e us e d t o i d e ntif y t h e s u bj ect e v e n 
t h o u g h t h eir n a m es d o n ot a p p e ar. 
M e dic al i nf or m ati o n c oll ect e d d uri n g t his st u d y a n d t h e r es ults of a n y t est or pr oc e d ur e t h at m a y 
aff ect t h e m e dic al c ar e of t h e s u bj ect m a y b e i ncl u d e d i n t h eir m e dic al r ec or d. T h e i nf or m ati o n 
i ncl u d e d i n t h eir m e dic al r ec or d will b e a v ail a bl e t o h e alt h c ar e pr o vi d ers a n d a ut h ori z e d p ers o ns 
i ncl u di n g t h e s u bj ect’s i ns ur a nc e c o m p a n y. 
D uri n g t h eir p artici p ati o n i n t his st u d y, t h e y will h a v e acc ess t o t h eir m e dic al r ec or ds a n d a n y st u d y 
i nf or m ati o n t h at is p art of t h at r ec or d.   
 
T h e r es ults of t his r es e arc h m a y b e pr es e nt e d at sci e ntific or m e dic al m e eti n gs or p u blis h e d i n sci e ntific 
j o ur n als.  I n t his c as e, t h e s u bj ect’s i d e ntit y will n ot b e m a d e k n o w n. 
 
C o m m u nit y -B a s e d P a rti ci p at o r y R e s e a r c h  
N / A  
 
S h a ri n g of R e s ult s wit h S u bj e ct s*  
O nc e t h e d at a is a n al y z e d a n d t h e p a p er writt e n, w e will m ail e ac h s u bj ect a l ett er e x pl ai ni n g t h e st u d y 
fi n di n gs a n d t h a n ki n g t h e m f or t h eir p artici p ati o n i n t h e st u d y. 
 
S etti n g  
All s u bj ects will b e  i d e ntifie d a n d r ecr uit e d wit hi n  r efr acti v e s ur g er y scr e e ni n g cli nics at B asc o m  P al m er E y e 
I nstit ut e.: 
 
R e s o u r c e s A v ail a bl e  
All st u d y p ers o n n el will h a v e all t h eir CI TI c o urs es c o m pl et e d. T h e st u d y c o or di n at or will w or k wit h t h e 
I R B t o e ns ur e c o m pli a nc e wit h all  r e g ul at or y r es p o nsi biliti es. 
A p pr o xi m at el y 9 0 0 r efr acti v e pr oc e d ur es ar e p erf or m e d at B P EI p er y e ar, a n d a p pr o xi m at el y 8 0 % of t h os e 
ar e L A SI K pr oc e d ur es. M ost s u bj ects w h o pl a n t o u n d er g o L A SI K w o ul d q u alif y f or e nr oll m e nt i n t his st u d y.  
5 0 % of m y ti m e at t h e Uni v ersit y of Mi a mi will b e d e v ot e d t o p erf or mi n g t his cli nic al tri al.  
F aciliti es t o b e us e d:  B P EI h as all f aciliti es r e q uir e d t o p erf or m L A SI K ( S o ni a Y o o, Willi a m C ul b erts o n), 
r a n d o mi z e p ati e nts t o pl ac e b o / dr u g ( Bill F e u er), pr e p ar e a n d dis p e ns e t h e m e dic ati o ns t o t h e p ati e nts 
( S er afi n G o nz al e z), p erf or m a n oc ul ar s urf ac e e x a mi n ati o n ( C ar m e n P er e z Bl a nc o ; b ac k u p: Ai l e n G uti err e z), 
a n d c ut a n e o us s e nsiti vit y t esti n g ( Eli z a b et h F eli x ; b ac k u p: Ail e n G uti err e z ). 
B asc o m P al m er E y e I nstit ut e h as a Cli nic al R es e arc h U nit wit h r es o urc es a n d e x p ertis e i n c arr yi n g o ut 
r es e arc h, i ncl u di n g a ntici p ati n g or u n a ntici p at e d m e dic al or  ps yc h ol o gic al iss u es t h at m a y aris e.  
All p ers o n n el will b e CI TI c ertifi e d, all will u n d er g o tr ai ni n g b y Dr. G al or pri or t o i niti ati o n of t h e st u d y, a n d 
w e e kl y m e eti n gs will b e h el d t o e ns ur e a d h er e nc e t o t h e pr ot oc ol a n d r es e arc h pr oc e d ur es.  
 
P ri o r A p p r o v al s  
N o n e  
 
R e c r uit m e nt M et h o d s  
P ati e nts will b e as k e d t o p artici p at e if t h e y ar e d e e m e d a c a n di d at e f or L A SI K b y Dr. C ar m e n P er e z Bl a nc o 
a n d if t h e y pl a n t o h a v e t h eir L A SI K d o n e at B P EI.  

P ati e nts c o mi n g f or a r efr acti v e s ur g er y e v al u ati o n at B P EI.  
D escri b e  t h e m et h o ds t h at will b e us e d t o i d e ntif y p ot e nti al s u bj ects. Dr. P er ez -Bl a nc o will scr e e n t h e 
p ati e nts f or t h eir a p pr o pri at e n ess f or L A SI K ( as p art of cli nic al c ar e) a n d als o f or p ot e nti al e nr oll m e nt i n 
t h e st u d y. 
D escri b e t h e a m o u nt a n d ti mi n g of a n y p a y m e nts t o s u bj ects. S u bj ects will b e gi v e n $ 5 0  f or p artici p ati n g i n 
t h e first visit, $ 2 5  f or t h e 3 m o nt h visit a n d $ 5 0  o n t h e l ast visit (t ot al $ 1 2 5 ). 
 
L o c al N u m b e r of S u bj e ct s  
6 0  
 
C o nfi d e nti alit y  
•  
All s o urc e d oc u m e nts will b e st or e d i n t h e offic e of t h e st u d y c o or di n at or i n a l oc k e d c a bi n et. I n 
a d diti o n, all el ectr o nic i nf or m ati o n will b e st or e d o n R E D C A P i n a d e -i d e ntifi e d f as hi o n. 
•  
D at a a n d s p eci m e ns will b e st or e d l oc all y f or 1 0 y e ars.  
•  
O nl y a p pr o v e d st u d y p e rs o n n el (PI, st u d y -c o or di n at or, d at a m a n a g er, a n d st atistici a n) will h a v e 
acc ess t o t h e d at a a n d s p eci m e ns l oc all y.  
 
P r o vi si o n s t o P r ot e ct t h e P ri v a c y I nt e r e st s of S u bj e ct s  
 
T h e s u bj ect’s a ut h ori z ati o n f or us e of t h eir p ers o n al h e alt h i nf or m ati o n d o es n ot e x pir e.  T his i nf or m ati o n 
m a y b e m ai nt ai n e d i n a r es e arc h r e p osit or y ( d at a b as e) a n d m a y b e us e d as d escri b e d i n t his d oc u m e nt f or 
a n y a n d all st u d y /r es e arc h -r el at e d p ur p os es.  R es ults of all t ests a n d pr oc e d ur es d o n e s ol el y f or t his 
r es e arc h st u d y a n d n ot as p art of t h eir r e g ul ar c ar e will b e i ncl u d e d as p art of t h eir m e dic al r ec or ds. T h e 
H u m a n S u bj ects R es e arc h Offic e I nstit uti o n al R e vi e w B o ar d ( U M I R B) is a c o m mitt e e w h os e j o b it is t o 
pr ot ect t h e s af et y a n d pri v ac y of r es e arc h p artici p a nts a n d r es ults of all t ests a n d pr oc e d ur es d o n e s ol el y 
f or t his r es e arc h st u d y t h at ar e n ot p art of t h eir r e g ul ar c ar e, will b e i ncl u d e d as p art of t h eir m e dic al 
r ec or ds. 
 
P RI V A C Y A N D C O N FI D E N TI A LI T Y   
S u bj ects’ i d e ntit y a n d r ec or ds will b e k e pt as c o nfi d e nti al as p ossi bl e as r e q uir e d b y l a w a n d will n ot b e m a d e 
p u blicl y a v ail a bl e.  E xc e pt as r e q uir e d b y l a w, t h e y will n ot b e i d e ntifi e d o n a n y st u d y f or m b y n a m e, S oci al 
S ec urit y n u m b er, a d dr ess, t el e p h o n e n u m b er, or a n y ot h er dir ect p ers o n al i d e ntifi er.  I nst e a d, t h e y will b e 
assi g n e d a p artici p a nt i d e ntific ati o n n u m b er.  T h e st u d y d oct or will k e e p a list t h at m atc h es p artici p a nt 
i d e ntific ati o n n u m b ers t o p artici p a nt n a m es.  H o w e v er, t h e st u d y for ms will c o nt ai n ot h er i nf or m ati o n a b o ut 
t h e s u bj ect, s uc h as a g e, s e x, a n d m e dic al hist or y.  It is p ossi bl e t h at t his ot h er i nf or m ati o n c o ul d b e us e d t o 
i d e ntif y t h e m e v e n t h o u g h t h eir n a m e d o es n ot a p p e ar. 
M e dic al i nf or m ati o n c oll ect e d d uri n g t his st u d y  a n d t h e r es ults of a n y t est or pr oc e d ur e t h at m a y aff ect t h eir 
m e dic al c ar e m a y b e i ncl u d e d i n t h eir m e dic al r ec or d. T h e i nf or m ati o n i ncl u d e d i n t h eir m e dic al r ec or d will 
b e a v ail a bl e t o h e alt h c ar e pr o vi d ers a n d a ut h ori z e d p ers o ns i ncl u di n g t h eir i ns ur a n c e c o m p a n y.  
T h e r es ults of t his r es e arc h m a y b e pr es e nt e d at sci e ntific or m e dic al m e eti n gs or p u blis h e d i n sci e ntific 
j o ur n als.  I n t his c as e, t h eir i d e ntit y will n ot b e m a d e k n o w n. 
Ot h er gr o u ps m a y n e e d t o l o o k at t h eir m e dic al r ec or ds a n d st u d y f or ms t o  m a k e s ur e t h at t h e i nf or m ati o n 
is c orr ect a n d t o e v al u at e t h e c o n d uct of t his r es e arc h st u d y.  T h es e i ncl u d e t h e f oll o wi n g: 
 
U ni v ersit y of Mi a mi’s H u m a n S u bj ects R es e arc h Offic e t h at r e vi e w e d t his st u d y  
 
R e g ul at or y a g e nci es i n t h e U nit e d St at es, s uc h as t h e  F o o d a n d Dr u g A d mi nistr ati o n, D e p art m e nt of 
H e alt h a n d H u m a n S er vic es a n d t h e Offic e f or H u m a n R es e arc h Pr ot ecti o ns  

 
R e g ul at or y a g e nci es fr o m ot h er c o u ntri es w h er e t his r es e arc h st u d y is als o b ei n g c o n d uct e d  
 
C o m p e n s ati o n f o r R e s e ar c h -R el at e d I nj u r y  
S u bj ec ts will b e gi v e n $ 5 0  f or p artici p ati n g i n t h e first visit, $ 2 5  f or t h e 3 m o nt h visit a n d $ 5 0  o n t h e l ast 
visit (t ot al $ 1 2 5 ). 
 
E c o n o mi c B u r d e n t o  Su bj e ct s 
T a ki n g ti m e a w a y fr o m w or k t o c o m pl et e 3 st u d y visits.  
 
C o n s e nt P r o c e s s  
T h e  c o ns e nt pr oc ess  will t a k e pl ac e  at  B P EI r efr acti v e e v al u ati o n cli nic . Aft er t h e scr e e ni n g visit f or 
r efr acti v e s ur g er y, if t h e p ati e nt is i nt er est e d , t h e y m a y b e c o ns e nt e d t h at s a m e d a y or o n t h e d a y t h at t h e y 
c o m e f or t h eir b as eli n e oc ul ar s urf ac e e x a mi n ati o n. T h e st u d y c o or di n at o r will e x pl ai n all p arts of t h e 
c o ns e nt pr oc ess a n d will d oc u m e nt t h e pr oc ess i n a d diti o n t o t h e c o ns e nt its elf. T h e s u bj ect will h a v e 
a d e q u at e ti m e t o r e a d t h e c o ns e nt a n d h a v e all q u esti o ns a ns w er e d. W e will a bi d e b y  t h e S O P: I nf or m e d 
C o ns e nt Pr oc ess f or  R es e arc h ( H R P -0 9 0) . 
 
 
S u bj e ct s  w h o a r e n ot y et a d ult s  (i nf a nt s, c hil d r e n , t e e n a g e r s): N / A  
 
C o g niti v el y I m p ai r e d A d ult s : N / A  
 
A d ult s U n a bl e t o C o n s e nt : N / A  
 
P r o c e s s t o D o c u m e nt C o n s e nt i n W riti n g  
W e will f oll o w t h e S O P: Writt e n D oc u m e nt ati o n of C o ns e nt ( H R P-0 9 1) . 
 
D r u g s o r D e vi c e s  
St u d y dr u g will b e accr u e d, st or e d, a n d c o m p o u n d e d at R es e arc h P h ar m ac y f or t his st u d y O N L Y. C o ntr oll e d 
s u bst a nc es will b e st or e d i n a d esi g n at e d l oc k e d c a bi n et. St or a g e t e m p er at ur e will b e m o nit or e d 
c o nti n u o usl y f or a n y p ossi b l e e xc ursi o ns. St u d y dr u gs f or ot h er st u di es will N O T b e us e d f or t his st u d y a n d 
vic e v ers a. St u d y dr u g pr e p ar ati o n a n d dis p e nsi n g will b e d o n e b y s ol el y b y u n bli n d e d p h ar m acists at t h e 
R es e arc h P h ar m ac y wit h t ec h nic al assist a nc e fr o m p h ar m ac y t ec h nici a ns.