Clinical trial NCT02701764
Conditions: Dry Eye
Keywords: laser-assisted in situ keratomileusis dry eye symptoms LASIK prevention
Sponsor: University of Miami
Start date: 2016-07-26; Completion date: 2018-12-01
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Can Lyrica (Pregabalin) help prevent severe Dry Eye post LASIK surgery?

Detailed description:
Dry eye symptoms can occur after LASIK surgery. They generally get better with time but in some patients, they can persist. The investigators believe that in some individuals, dry eye symptoms after LASIK persist because the nerves in the cornea become hypersensitive. The investigators wish to study if a medication, called pregabalin, can protect corneal nerves at the time of LASIK surgery and decrease the frequency and severity of dry eye symptoms 6 months after surgery. This medication has been used in a similar way to reduce the frequency of uncomfortable sensations after other surgeries (knee, abdomen) but has never been studied in LASIK surgery.

Arms: arm 1: Pregabalin 150 mg twice a day starting 1 day prior to LASIK and continuing for 14 days total. arm 2: Placebo pill twice a day starting 1 day prior to LASIK and continuing for 14 days total.
Interventions: intervention 1: Pregabalin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
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.