Micropulse for Suppression of Diabetic Macular Edema
Phase: NA
Conditions: Diabetic Macular Edema
Sponsor: University of California, Davis

P R O T O C O L TI T L E: Micr o p ulse f or s u p pressi o n of dia betic mac ular e de ma   
“ P U L S E S T U D Y” 
 
 
Pa ge 1 of 1 1 
Pr ot oc ol Versi o n Date: 0 6 Oct 2 0 2 1  
 
Re vis e d: A u g ust 1 5, 2 0 1 4  
1)  
Pr ot oc ol Title 
m icr oP U lse Laser f or S u p pressi o n of  dia betic mac ular E de ma ( P U L S E St u d y) 
N C T 0 3 5 1 9 5 8 1  
 
2)  
A ut h or of Pr ot o c ol 
X   U C D a vis Res e arc her  
 
 Rese arc her f r o m ot her i nstit uti o n  
 Pri v ate S p o ns or 
 C o o per ati ve Gr o u p 
X   Ot her: U C D Resi de nt  
 
3)  
I R B Re vie w Hist or y  
N o ne 
4)  
O bjecti ves  
T he p ur p ose of t his st u d y is t o a nal yze t he effect of s u bt hres h ol d micr op ulse di o de 
laser i n t he treat me nt of ce ntral -i n v ol vi n g dia betic mac ular e d e ma i n e y es wit h g o o d 
vis ual ac uit y defi ne d as 2 0/ 3 2 or better  o n E T D R S testi n g, c o m pare d t o o bs er vati o n al o ne 
(s ha m treat me nt).  
We h y p ot hesize t h at e yes treate d wit h s u bt hres h ol d micr o p ulse di o de laser will 
de m o nstrate eit her a si g nifica nt i m pr o ve me nt or st a bilizati o n of vis ual ac uit y  at 1 2 a n d 2 4 
m o nt hs, or a si g nifica nt dela y i n visi o n l oss t o 2 0/ 4 0 or w orse, re q uiri n g i nitiati o n of a nti-
vasc ular e n d ot helial gr o wt h fact or ( a nti- V E G F) t hera p y . 
5)  
B ac k gr o u n d 
Dia betic reti n o pat h y is o ne of t he m ost c o m m o n c o m plicati o ns of dia betes a n d dia betic 
mac ular e d e ma ( D M E) is o ne of t he m ost c o m m o n ca uses of visi o n l oss i n dia betes. 1 Vari o us 
treat me nt strate gies f or dia betic mac ular e de m a i ncl u de f ocal or gri d laser, a nti- vasc ular 
e n d ot helial gr o wt h fact or (a nti- V E G F ), a n d c ortic oster oi d treat me nts.1, 2  T he Earl y Treat me nt of 
Dia betic Reti n o pat h y  St u d y (E T D R S ) i n t he 1 9 8 0s a n d 1 9 9 0s, w hic h i ncl u d e d patie nts wit h 
m o derate t o se v ere n o n- pr oliferati ve  dia b etic reti n o pat h y ( N P D R ) or mil d pr oliferati ve dia b etic 
reti n o pat h y (P D R ), re v eale d t hat f ocal p h ot oc o a g ulati o n is effecti ve i n re d u ci n g t he ris k of 
m o derate visi o n l oss fro m D M E b y 5 0 %. 3, 4  F ocal laser was als o s h o w n t o be m ore effecti ve wit h 
fe wer si de effects t ha n i ntra oc ular ster oi ds s uc h as tria mci n ol o ne acet o ni de i n t he treat me nt of 
D M E i n e yes wit h vis ual ac uit y of 2 0/ 4 0 or w ors e, ma ki n g f ocal laser a be n ch mar k a g ai nst 
w hic h ot her treat me nts w ere c o m p are d .5  Res ults of t he Dia betic Reti n o pat h y Cli nical Researc h 
net w or k ( D R C R. net) Pr ot oc ol- I esta blis he d a n e w be nc h mar k a n d re v eale d t hat i n e yes wit h 
D M E a n d  vis ual ac uit y of 2 0/ 3 2 or w orse, i ntra vitreal a nti- V E G F t hera p y usi n g ra ni biz u ma b 
wit h pr o m pt or deferre d f ocal laser was s u peri or t o f ocal laser al o ne. 6 M ore rece ntl y, t he RI D E 
a n d RI S E st u dies r e veal e d t hat i n e yes wit h vis ual ac uit y of 2 0/ 4 0 or w ors e, patie nts treate d wit h 
ra ni biz u ma b ha d 1 5 or m ore letters of vis ual ac uit y gai n c o m pare d t o s h a m i njecti o ns.7  C urre nt 
treat me nt g ui deli nes f or D M E are lar gel y deri ve d fr o m D R C R net w or k Pr ot oc ol T, w hic h has 
a d dresse d t he relati ve efficac y  of v ari o us a nti- V E G F a g e nts i n i m pr o vi n g vis ual ac uit y , a n d 
decreasi n g ce ntr al f o veal t hic k ness 8, 9.  H o we ver, all maj or cli nical trials i n ma na ge me nt of D M E 

P R O T O C O L TI T L E: Micr o p ulse f or s u p pressi o n of dia betic mac ular e de ma   
“ P U L S E S T U D Y” 
 
 
Pa ge 2 of 1 1 
Pr ot oc ol Versi o n Date: 0 6 Oct 2 0 2 1  
 
Re vis e d: A u g ust 1 5, 2 0 1 4  
ha ve o nl y a d dr esse d e y es wit h vis ual ac uit y of 2 0/ 3 2 or w orse. T o d ate, t here are n o c o nse ns us 
o n t he best treat me nt a p pr oac h f or ce nt er -i n v ol vi n g D M E wit h g o o d vis ual ac uit y ( 2 0/ 2 5 or 
better). T he D R C R. net Pr ot oc ol V is a n o n g oi n g ra n d o mize d c o ntr olle d st u d y t o deter mi ne if 
pr o m pt a nti- V E G F t hera p y ca n pres er ve visi o n i n e yes wit h D M E a n d g o o d vis ual ac uit y of 
2 0/ 2 5 or better. W hile t his st u d y has n ot yet bee n c o m plete d, i ntra vitreal a nti- V E G F t hera p y is 
n ot wit h o ut ris k, s o me of w hic h i ncl u de e n d o p ht h al mitis, ele vate d i ntra oc ular press ure, a n d 
s yste mic vasc ular e ve nts. We h y p ot hesize t h at earl y ma na ge me nt of D M E wit h g o o d vis ual 
ac uit y req uir es treat me nt wit h a less i n vasi ve strate g y.  
A rece nt l y-de vel o p e d  treat me nt f or D M E is s u bt hres h ol d micr o p ulse laser ( S M L). I n 
c o ntrast t o f ocal las er, S M L deli vers laser e ner g y i n a “c h o p pe d ” fas hi o n all o wi n g t he tiss ue t o 
c o ol bet wee n p ulses t o eli mi nate t her mal i nj ur y t o t he reti na1 0.  Pre vi o us st u dies ha ve s h o w n t he 
s u peri orit y of S M L t o c o n ve nti o nal f ocal/ gri d laser p h ot oc oa g ulati o n i n i m pr o vi n g vis ual 
ac uit y. 2, 1 1 , 1 5  I n e yes u n d er g oi n g a nti- V E G F t hera p y f or D M E, S M L ma y re d uce t he fre q u e nc y of 
i njecti o ns. U nli ke tra diti o nal “f ocal” laser t hera p y w hic h are ass ociate d wit h mac ular scarri n g 
a n d c h or oi dal ne o v asc ularizati o n, S M L are n ot ass ociate d wit h a n y of t hes e c o m plicati o ns, e ve n 
after m ulti ple treat me nts . W hile s o me p h ysicia ns e m pl o y S M L f or treat me nt of D M E i n e yes 
wit h g o o d vis ual ac uit y, d ue t o t he safet y of t his l aser, t here are n o c l ear e vi de nce s u p p orti n g 
t heir use. He n ce, t her e r e mai ns n o c o nse ns us f or sta n dar d of care f or w h et h er o bser v ati o n, a nti-
V E G F i njecti o n, f ocal/ gri d laser, or S M L s h o ul d be use d f or e yes wit h vis u al ac uit y of 2 0/ 2 5 or 
better. As m ost patie nts wit h g o o d vis ual ac uit y are rel u cta nt t o u n der g o a n i ntra oc ular i njecti o n 
w hic h has greater ris ks ass ociate d s uc h as e n d o p ht hal mitis, vitre o us he m orr ha ge, or reti nal 
detac h me nt, w e see k t o assess t he p ote ntial be nefit of S M L laser al o ne vs. o bser vati o n (s ha m) i n 
t his selecti o n of e yes i n preser vi n g visi o n a n d a n at o m y. 
T he E T D R S st u d y e m pl o ye d bi o micr osc o p y, f u n d us p h ot o gra p h y, a n d fl u orescei n 
a n gi o gra p h y as t he sta n d ar d  m o dalities  f or ass essi n g t he prese n ce a n d e xte nt of D M E. 3 Si nce t hat 
ti me, ne wer met h o ds are a vaila ble t o c haracterize D M E i ncl u di n g o ptical c o here nce t o m o gra p h y 
(O C T ), f u nd us a ut ofl u or esce nce ( F A F), a n d O C T a n gi o gra p h y ( O C T- A) .1 2 Si milarl y , w hile 
vis ual ac uit y testi n g ha s bee n t he m ost c o m m o n met h o d f or f u ncti o nal ass ess me nt, ne wer 
met h o ds s uc h as micr o peri metr y are b ei n g utilize d t o e val uate  a n d q u a ntif y f u ncti o nal o utc o me 
b y mea ns of r eti nal se nsi vit y. 1 2, 1 3 T he e val uati o n of reti nal se nsiti vit y is d o ne t hr o u g h vis ual fiel d 
testi n g.  H o we ver, tr a diti o nal vis ual fiel d tests are n ot se nsiti ve e n o u g h t o i de ntif y s mall 
sc ot o mas, es peciall y w h e n fi xati o n is altere d b y m ac ular e de ma.  Micr o peri metr y is a vis ual fiel d 
test t hat has a f u n d us trac ki n g s yste m all o wi n g it t o o verc o me fi xati o n i nsta bilit y.  F urt her m ore, 
the sti m ul us use d t o assess reti nal se nsiti vit y is pr ojecte d i n t he i de ntical reti nal area d uri n g t he 
i nitial a n d s u bse q ue nt e x a mi nati o ns, t here b y all o wi n g i de ntificati o n of s mall s c ot o mas a n d 
ecce ntric fi xati o n.  T his is critical i n preser vi n g fi xati o n w he n treati n g t he mac ular e d e ma wit h 
p h ot oc oa g ulati o n 1 2 
Micr o peri metr y h as gai n e d rece nt p o p ularit y i n assessi n g f u ncti o nal i m pair me nt i n patie nts 
wit h D M E , all o wi n g a c orrelati o n bet w ee n  reti nal m or p h ol o g y ( mac ular t hi c k ness) a n d reti nal 
se nsiti vit y.1 2, 1 4 F or e xa m ple, Ver ma et al ha ve s h o w n decrease d reti nal se nsiti vit y c orrelati n g 
wit h decrease d f o v eal t hic k ness i n i n di vi d uals wit h dia betes wit h o ut dia betic reti n o pat h y.1 3  
Ot hers ha ve s h o w n i m pr o ve d reti nal se nsiti vit y i n e yes wit h D M E aft er  S M L treat me nt  w he n 
assesse d b y micr o p eri metr y .1 5  T hese st u dies u n dersc ore t he i m p ort a nce of micr o peri metr y i n 
q ua ntif yi n g vis ual f u ncti o n i n e yes wit h D M E, partic ularl y i n e yes wit h g o o d vis ual ac uit y w here 
a n i m pr o ve me nt i n vis ual ac uit y ma y n ot be rea dil y discer na ble.   

P R O T O C O L TI T L E: Micr o p ulse f or s u p pressi o n of dia betic mac ular e de ma   
“ P U L S E S T U D Y” 
 
 
Pa ge 3 of 1 1 
Pr ot oc ol Versi o n Date: 0 6 Oct 2 0 2 1  
 
Re vis e d: A u g ust 1 5, 2 0 1 4  
O ur g oal i n t his st u d y is t o assess t he effect of s u bt hres h ol d micr op ulse d i o d e laser i n e y es 
wit h D M E a n d g o o d vis ual ac uit y defi ne d b y visi o n of 2 0/ 3 2 or better  bas e d o n E T D R S testi n g.  
We h y p ot hesize t h at s u bt hres h ol d micr op ulse d i o d e laser will si g nifica ntl y i m pr o ve vis ual 
ac uit y, reti nal a n at o m y, a n d reti nal se nsiti vity o n micr o peri metr y , a n d als o pre ve nt visi o n l oss b y 
dela y i n g t he nee d f or a nti- V E G F t h era p y c o m pare d t o o bser vati o n al o ne.  
 
6)  
Incl usi o n a n d E xcl usi o n Criteri a  
S u bjects will be r ecr uite d fr o m patie nts see n at t he U C Da vis E ye Ce nter reti na 
cli nic w h o are willi n g a n d eli gi ble t o partici pate b ase d o n o ur i ncl usi o n crit eria. 
I ncl usi o n Criteri a: 
1.  A ge > = 1 8 y ears  
2.  T y pe 1 or t y pe 2 dia b etes mellit us  
3.  Cli nical e vi de nce of ce nt er -i n v ol ve d D M E c o nfir me d o n O C T, a n d defi ne d b y O C T 
Ce ntral S u bfiel d ( C S F) t hic k ness at t he ti me of ra n d o mizati o n b y t he f oll o wi n g: 
a. Zeiss Cirr us:  2 7 5 μ i n w o me n, a n d  2 9 0 μ i n me n  
b.  Hei del ber g S pectralis:  2 9 0 μ i n w o me n, a n d  3 0 5 μ i n me n  
4.  Best c orrecte d vis ual ac uit y of 2 0/ 3 2 or better o n E T D R S testi n g  
 
E xcl usi o n Criteri a:  
1.  Mac ular e de ma fr o m ca uses ot her t ha n D M E  
2.  A n oc ular c o n diti o n is prese nt s uc h t hat i n t he o pi ni o n of t he i n vesti gat or, vis ual ac uit y 
w o ul d n ot i m pr o ve fr o m res ol uti o n of mac ular e de ma (i.e/f o veal atr o p h y, pi g me nt 
a b n or malities, de nse har d e x u dates) 
3.  A n oc ular c o n diti o n is prese nt ot her t ha n D M E w hic h ma y c o ntri b ute t o mac ular e de ma 
(i.e/ vei n occl usi o n, E R M, u veitis, R P, etc …). 
4.  Cataract t hat i n t he o pi ni o n of t he i n vesti gat or ma y alter vis ual ac uit y t hr o u g h o ut t he 
c o urse of t he st u d y 
5.  Hist or y of pri or laser or ot her s ur gical, i ntra vitreal, or peri b ul bar treat me nt f or D M E i n 
t he st u d y e ye wit hi n t he pri or 6 m o nt hs. 
6.  M ore t ha n 4 pri or i ntra o c ular i njecti o ns f or treat me nt of D M E at a n y ti me  
7.  M ore t ha n 1 pri or f ocal/ gri d mac ular p h ot oc o a g ulati o n sessi o n f or treat me nt of D M E at 
a n y ti me  
8.  Hist or y of t o pical ster oi d or N S AI D treat me nt wit hi n 3 0 da ys pri or t o ra n d o mizati o n 
9.  Hist or y of P R P wit hi n 4 m o nt hs pri or t o ra n d o mizati o n or a ntici pate d nee d f or P R P i n t he 
6 m o nt hs f oll o wi n g ra n d o mizati o n. 
1 0.  A n y hist or y of vitrect o m y. 
1 1.  Hist or y of maj or oc ular s ur ger y (cataract e xtracti o n, scleral b uc kl e, a n y i ntra oc ular 
s ur ger y, etc.) wit hi n pri or 4 m o nt hs or a ntici pate d wit hi n t he ne xt 6 m o nt hs f oll o wi n g 
ra n d o mizati o n 
1 2.  Hist or y of Y A G ca ps ul ot o m y perf or me d wit hi n 2 m o nt hs pri or t o ra n d o mizati o n. 
1 3.  A p ha kia 
1 4.  E xa m e vi de nce of e xter n al oc ular i nfecti o n, i ncl u di n g c o nj u ncti vitis, c halazi o n, or 
si g nifica nt ble p haritis 

P R O T O C O L TI T L E: Micr o p ulse f or s u p pressi o n of dia betic mac ular e de ma   
“ P U L S E S T U D Y” 
 
 
Pa ge 4 of 1 1 
Pr ot oc ol Versi o n Date: 0 6 Oct 2 0 2 1  
 
Re vis e d: A u g ust 1 5, 2 0 1 4  
7)  
St u d y Ti m eli nes  
•  T he d urati o n of a n i n di vi d ual s u bje ct’s partici p ati o n i n t he st u d y will be t w o 
years  w hic h will i ncl u de at least 1 0 t otal visits at vari o us ti me p oi nts i ncl u di n g 
o n t he da y of e nr oll me nt, f oll o we d b y 1, 3, 6, 9, a n d 1 2, 1 5, 1 8, 2 1, 2 4 m o nt hs 
after t he d a y of e nr oll me nt  
•  T he d urati o n a ntici pate d t o e nr oll all st u d y s u bjects is 1 year  
•  T he esti mate d date f or t h e i n vesti gat ors t o c o m plete t his st u d y  is Dece m ber  
2 0 2 3 
•  3 6 e yes will be e nr olle d base d o n p o wer cal c ulati o ns f or 8 0 % p o wer ass u mi n g 
at least 4 0 % of e y es m o nit ore d b y o bser vati o n al o ne will e x perie n ce visi o n 
l oss t o 2 0/ 4 0 or w orse, a n d t hat S M L treat me nt will re d uce t hat val ue t o 1 5 %, 
usi n g a 2: 1 rati o f or ra n d o mizati o n ( 2 treat me nt : 1 o bser vati o n (s ha m)). T he 
E T D R S st u d y s h o we d t hat a m o n g e yes wit h g o o d vis ual ac uit y ( 2 0/ 2 5 or 
better), 4 0 % will e x perie nce a vis ual ac uit y decrease b y 5 letters or m ore. We 
ass u me a hi g her rate a m o n g e yes wit h 2 0/ 3 2 or better. 
8)  
St u d y E n d p oi nts  
Pri mar y o utc o me: 
•  Pr o p orti o n of p atie nts wit h visi o n l oss t o 2 0/ 4 0 or w orse o n E T D R S testi n g 
o n t w o visits ≤2 8 da ys a part at 1 2 a n d 2 4 m o nt hs. 
•  Mea n ti me t o visi o n l oss t o 2 0/ 4 0 or w orse o n E T D R S testi n g o n t w o visits 
≤2 8 da ys a part  
Se c o n dar y O ut c o mes:  
•  Mea n c ha n g e i n vis ual ac uit y , l o w l u mi na nce vis ual ac uit y a n d c o ntrast 
se nsiti vit y at 3, 6, 9, 1 2, 1 5, 1 8, 2 1, a n d 2 4 m o nt hs fr o m baseli ne 
•  Mea n c ha n g e i n ce ntral mac ular  t hic k ness ( CM T ) o n O C T at 3, 6, 9, 1 2, 1 5, 
1 8, 2 1, a n d 2 4 m o nt hs fr o m baseli ne 
•  Mea n c ha n g e i n reti nal s e nsiti vit y assesse d b y micr o peri metr y at 3, 6, 9, 1 2 , 
1 5, 1 8, 2 1, a n d 2 4 m o nt hs fr o m baseli ne 
•  Perce nta g e of s u bjects wit h vis ual ac uit y  l oss (i ncl u di n g l o w l u mi na nce 
vis ual ac uit y a n d c o ntr ast se nsiti vit y) of ≥ 5 letters at 1 2 a n d 2 4 m o nt hs  
•  Perce nta g e of s u bjects wit h at least 1 0 a n d 1 5 letter gai n or l oss at 1 2 a n d 2 4 
m o nt hs  
•  Vis ual ac uit y ar ea u n der t he c ur ve at 1 2 a n d 2 4 m o nt hs  
•  N u m ber of S M L treat me nts recei ve d at 1 2 a n d 2 4 m o nt hs  
•  N u m ber of a nti- V E G F tr eat me nts recei ve d at  1 2 a n d 2 4 m o nt hs 
•  A ny s afety c o n cer ns d oc u me nte d d uri n g t he st u dy 

P R O T O C O L TI T L E: Micr o p ulse f or s u p pressi o n of dia betic mac ular e de ma   
“ P U L S E S T U D Y” 
 
 
Pa ge 5 of 1 1 
Pr ot oc ol Versi o n Date: 0 6 Oct 2 0 2 1  
 
Re vis e d: A u g ust 1 5, 2 0 1 4  
9)  
Pr oce d ures I n v ol ve d  
T his is a ra n d o mize d, c o ntr olle d cli nical trial c o m pari n g s u bt hres h ol d micr o p ulse 
laser vers us s h a m laser tr eat me nt f or e yes wit h dia betic mac ular e de ma wit h g o o d vis ual 
ac uit y of 2 0/ 3 2 or better. After si g ni n g writte n c o nse nt a n d e nr olli n g i n t he st u d y, patie nts 
will be ra n d o mize d t o r ecei ve eit her s u bt hres h ol d micr o p ulse laser treat me nt or n o 
treat me nt (s ha m). Ra n d o mizati o n will occ ur as a rati o of 2: 1 a n d will ta ke place d uri n g 
t he cli nic visit. A bl oc k ra n d o mizati o n sc he me will be create d bef ore t he st u d y be gi ns t o 
e ns ure a p pr o priate tr eat m e nt all ocati o n a m o n g t he t w o gr o u ps.  At t he ti me of 
ra n d o mizati o n, o nl y o ne e ye will be ra n d o mize d t o eit her t he treat me nt or o bser vati o n.  If 
b ot h e yes meet t he i ncl usi o n criteria, o ne e ye ( w orse e ye) will be assi g ne d t o t he 
treat me nt gr o u p a n d t h e f ell o w e ye t o t he s ha m treat me nt gr o u p.  S u bjects selecte d f or t he 
st u d y will t he n u n der g o a c o m plete o p ht hal mic e x a mi nati o n, i ncl u di n g meas ure me nts of 
best c orrecte d vis ual ac uit y, l o w l u mi na nce vis ual ac uit y, c o ntrast se nsiti vit y ( usi n g 
E T D R S t esti n g wit h  a mas ke d c o or di n at or), i ntra oc ular press ure, slit la m p e xa m 
i ncl u di n g d oc u me ntati o n of le ns stat us, a n d dilate d f u n d usc o pic e x a m wit h sta n dar d 
dilati n g a ge nts use d at t he U C Da vis E ye Ce nter. S u bjects will t he n u n der g o baseli ne 
i ma gi n g wit h S D - O C T a n d f u n d us a ut ofl u ores ce n ce ( F A F) usi n g t he S pectralis 
O C T + S L O  i nstr u me nt ( Hei del ber g E n gi n eeri n g, Hei del ber g, G er ma n y) a n d O pt os ( O pt os 
I n c.). T he O pt os i ma gi n g s yste m will o nl y be use d as a bac k u p t o t he Hei d el ber g, as w ell 
as micr o peri metr y t esti n g  usi n g Ni de k M P- 1 i nstr u me nt ( Pa d o va, Ital y). B ot h t he use of 
O C T , F A F, a n d micr o p eri metr y testi n g are  wit hi n t he sta n dar d of care f or t he 
ma na ge me nt of D M E .  
F or O C T  a n d F A F, a l u bricati n g artificial tear dr o p ma y be use d o n s u bjects wit h 
dr y e yes t o e n h a nce i ma g e q ualit y as is r o uti nel y d o ne. Eac h e ye will ha ve 3-4 i ma ges 
acq uire d, w hi c h will ta ke a p pr o xi matel y 3 0- 4 5 sec o n ds f or eac h e ye. O C T i ma gi n g m ust 
i ncl u de at least o ne hi g h res ol uti o n sca n acr oss t he f o vea, a n d ce ntral mac ular t hic k ness 
meas ure d as deter mi ne d usi n g t he O C T i nstr u me nt's al g orit h m.  F A F i ma gi n g m ust 
i ncl u de t he e ntire mac ular re gi o n t hr o u g h w hic h t h e micr o p ulse laser treat m e nt will be 
a p plie d. 
F or micr o p eri metr y, a  b uilt -i n f u n d us ca mera is us e d t o f oc us o n t he patie nt’s reti na 
a n d f u n d us trac ki n g e ns ures fi xati o n sta bilit y.  As t he patie nt percei ves t he sti m ul us, t he y 
press a tri g ger w hi c h is t he n rec or de d si milar t o ot her wi del y use d peri metr y tests  
( H u m p hre y vis ual fiel d t est). Testi n g will ta ke a p pr o xi matel y 3 - 4 mi n utes per e ye.   
Q ualifie d o p ht hal mic pers o n nel ( p h ysicia ns, certifie d o p ht hal mic tec h nicia ns, a n d 
certifie d o p ht hal mic p h ot o gra p hers) u n der a st u d y pers o n nel s u per visi o n will a d mi nister 
all e ye dr o ps, perf or m t h e o p ht hal mic e xa m, a n d ca pt ure i ma g es o n t he S pectralis O C T 
a n d M P-1 micr o peri meter .  
T he s u bjects i n t he treat me nt ar m will be treate d o n t he da y of ra n d o mizati o n b y 
S M L p h ot oc oa g ulati o n usi n g t he Iri de x I Q 5 7 7 las er u nit wit h T x Cell sca n ni n g laser 
deli ver y s yste m. Treat me nt will i n v ol ve t he f oll o wi n g ste ps:  

P R O T O C O L TI T L E: Micr o p ulse f or s u p pressi o n of dia betic mac ular e de ma   
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Pa ge 6 of 1 1 
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Re vis e d: A u g ust 1 5, 2 0 1 4  
1.  
C o nfir m t he patie nt’s i de ntit y a n d e ye t o be treate d usi n g a sta n dar d pre- pr oce d ure 
ti me- o ut. C o nfir m t he patie nt’s e ye is dilate d a n d c o mf orta bl y p ost ure d at t h e 
slitla m p f or treat me nt. 
2.  
E ns ure t he laser ai mi n g bea m is i n f oc us o n t he reti nal s urface.  
3.  
C o nfir m t he I Q 5 7 7 laser s yste m is i n C W treat me nt m o de usi n g t he laser’s Preset 
f u ncti o n. Usi n g a c o ntact le ns wit h a n a p pr o xi mat e 1 x laser ma g nifi cati o n f or 
mac ular las er treat me nt ( e. g. V ol k Area Ce ntralis ® ) a n d a 2 0 0 μ m s p ot, perf or m t he 
test s p ot i n c o nti n u o us wa ve ( C W) m o d e wit h a 2 0 0 ms d urati o n i n t he mi ni mall y 
e de mat o us mac ula > 2 D D fr o m f o veal ce nter.  
4.  
Start at 5 0 m W a n d titrate p o wer u p war ds i n 1 0 m W i ncre me nts – m o vi n g t o a ne w 
area eac h ti me – u ntil a barel y visi ble tiss ue reacti o n is see n. If a reacti o n is e vi de nt 
wit h 5 0 m W, d o n ot i ncrease t he p o w er. N ot e t he t hres h ol d p o wer. 
5.  
S witc h t he laser t o Micr o P ulse m o de at 5 % d ut y c ycle usi n g t he laser’s Preset 
f u ncti o n a n d a dj ust t he p o wer t o 4 ti mes t he p o wer ac hie v e d i n t he C W pre -
treat me nt test s p ot. 
6.  
Deli ver a si n gle s p ot o utsi de t he mac ula t o c o nfir m laser s yste m is i n Micr o P ulse 
m o de.  
7.  
A dj ust t he T x Cell Sca n ni n g Deli ver y S yste m t o a 7 x 7 gri d wit h zer o-s p ot s paci n g. 
8.  
Deli ver hi g h- de nsit y a p pl icati o ns as i n dicate d i n FI G U R E  1: t hree 7 x 7 gri ds a b o ve 
a n d bel o w t he f o v ea ( 2 5 0 μ m fr o m its ce nter ) a n d o ne 7 x 7 gri d at eac h si de 
(te m p oral a n d n asal) of t he f o vea ( 2 5 0 μ m fr o m its ce nter ); if e de ma is prese nt 
o utsi de t his area, treat it t o o.  
FI G U R E  1 
 
 
 
 
 
 
 
 
 
 
 
 
 
T x Cell 7 x 7 gri d patter n ( 4 9 s p ots)  
8 pa nels of 7 x 7 gri ds 
a p plie d t o s urr o u n d 
f o ve ola. A p pr o xi matel y 
2 5 0 µ m ra di us fr o m t he 
a nat o mical f o ve ola, 
esti mate d o n O C T.  

P R O T O C O L TI T L E: Micr o p ulse f or s u p pressi o n of dia betic mac ular e de ma   
“ P U L S E S T U D Y” 
 
 
Pa ge 7 of 1 1 
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Re vis e d: A u g ust 1 5, 2 0 1 4  
9.  
C o nfir m t hat t he patie nt ca n detect at least fi n ger -c o u nti n g visi o n after laser 
pr oce d ur e. 
T h ose i n t he s ha m treat m e nt ar m will u n der g o t he sa me set u p pr oce d ures as 
descri be d a b o ve, h o w e ver, n o act ual las er treat me nt will occ ur. S u bjects will t he n ret ur n 
t o t he cli nic f or re p eat o p ht hal mic e xa m, O C T  i ma gi n g, a n d micr o peri metr y  at 1 m o nt h, 3 
m o nt h, 6 m o nt h, 9 m o nt h, 1 2 m o nt h, 1 5 m o nt h, 1 8 m o nt h, 2 1 m o nt h a n d 2 4 m o nt h ti me 
p oi nts, w hic h is si milar i n fre q ue n c y as sta n d ar d of care. Patie nts i n t he treat me nt ar m are 
eli gi ble f or re p eat S M L laser at a n y s u bse q ue nt visit if t here is a n y decli ne i n visi o n ( 1 or 
m ore E T D R S li nes) or w orse ni n g i n e de ma ( > 1 0 % i ncrease), at t he discreti o n of t he 
treati n g p h ysicia n. If visi o n decli nes t o 2 0/ 4 0 or w orse at a n y st u d y visit, patie nts i n t he 
treat me nt ar m will u n der g o re peat tr eat me nt wit h S M L laser, w hile t h ose i n t he s ha m ar m 
will u n der g o re peat s ha m laser.  
If t he patie nt de m o nstr ate d 2 0/ 4 0 or w orse E T D R S vis ual ac uit y at a n y st u d y visit, 
he or s he will be r e q uire d t o ret ur n wit hi n 2 8 da ys f or re p eat E T D R S vis ual ac uit y 
testi n g, o p ht hal mic e xa m, O C T i ma gi n g, a n d micr o peri metr y. If t h e patie nt de m o nstrate d 
2 0/ 4 0 or w orse E T D R S vis ual ac uit y at t his re peat visit, t he n t he patie nt will ha ve 
reac h e d st u d y e n d p oi nt a n d be c o nsi dere d treat me nt fail ure. At t hat visit, patie nts ma y be 
gi ve n a n y c o m bi nati o n of i ntra vitreal a nti-V E G F i njecti o n ( preferre d bas e d o n D R C R. net 
pr ot oc ol I a n d pr ot oc ol T ), f ocal/ gri d las er, re peat S M L treat me nt, or i ntra vitreal ster oi d 
i njecti o n, base d o n t he discreti o n of t he i n vesti gat or. After st u d y e n d p oi nt ( vis ual ac uit y 
l oss t o 2 0/ 4 0 or w orse), p atie nts ma y be treate d o n a m o nt hl y, pr o re nata ( P R N), or 
"treat-a n d- e xte n d" basis base d o n t he i n di vi d ual i n vesti gat or's prefere n ce. Patie nts are 
still re q uire d t o c o nti n ue wit h st u d y visits, b ut a n y a d diti o nal visits or treat me nts, 
alt h o u g h still d oc u me nte d, will be c o nsi dere d off-st u d y.  
All data will be a nal yze d i n acc or d a nce t o t he “i nte nti o n -t o-treat” pri nci ple.  
1 0)  D at a a n d S peci m e n B a n ki n g  
All data will be st ore d o n sec ure d n et w or k dri v es at U C Da vis a n d i nf or mati o n 
pr o perl y de- i d e ntifie d (see bel o w).  
1 1)  D at a M a n a ge m e nt a n d C o nfi de nti alit y  
Ca pt ure d O C T i ma ges a n d micr o peri metr y re p orts will be a nal yze d b y t h e U C 
Da vis Rea di n g Ce nter i n a mas ke d f as hi o n. Data a nal ysis will be perf or me d by st u dy 
st aff, a n d sta n dar d statistical met h o ds will be use d i n t he a nal ysis of data c ollecte d.  
S u bjects will be de -i de ntifie d via t he use of a se p arate sec ure d oc u m e nt c orrelati n g 
s u bjects’ U C Da vis me di cal rec or d n u m bers wit h a st u d y I D assi g ne d f or t he s ole p ur p ose 
of t his st u d y. Rec or de d d ata will be st ore d i n a p ass w or d pr otect e d e xcel file. O nl y t he 
i n vesti gat ors will ha ve access t o t hese files.  All st u d y pers o n nel will be Bi o me dical a n d 
G C P CI TI certifie d a n d will be mai ntai ne d b y t he researc h c o or di nati n g staff.  
1 2)  Pr o visi o ns t o M o nit or t he D at a t o E ns ure t he S afet y of S u bjects  
  
St u d y data will be a nal yze d wit h t he assista nce of a C T S C bi o statisticia n t o deter mi ne if 
a n y safet y c o ncer ns e xist i n res pect t o diseas e pr o gressi o n bet wee n t he treat me nt ar m a n d t he 
s ha m ar m.  A nal ysis will be perf or me d at t he ti me p oi nt w he n 1 2- m o nt h f oll o w- u p data has b ee n 

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Re vis e d: A u g ust 1 5, 2 0 1 4  
ac q uire d fr o m at least 1 0 e yes ra n d o mize d t o eac h gr o u p (laser treat me nt a n d s ha m).  A s u m mar y 
of t he fi n di n gs will be pr e pare d a n d utilize d t o det er mi ne if c h a n ges i n st u d y c o n d uct or st u d y 
ter mi nati o n is necessar y. 
 
1 3)  Wit h dr a w al of S u bjects  
A n y patie nt wis hi n g t o wit h dra w fr o m t he st u d y at a n y ti me d uri n g t he st u d y will be 
a ble t o d o s o.  T he y w o ul d ret ur n t o o ur cli nic as t he y n or mall y w o ul d f or f ut ure care, 
h o we ver a n y data o btai n e d fr o m f ut ur e t heir visit will n ot be i ncl u de d i n t he st u d y. 
1 4)  Ris ks t o S u bjects  
F or t he o p ht hal mic e x a mi nati o n, O C T i ma gi n g, a n d micr o peri metr y, t here are n o 
k n o w n ris ks t o t he s u bject be y o n d w hat is n or mal f or sta n dar d o c ular e xa mi nati o n a n d 
testi n g use d i n r o uti ne patie nt visits at t he U C Da vis E ye Ce nter. T he li mits f or safe 
oc ular e x p os ure t o laser li g ht ha ve bee n w ell esta blis he d a n d are d o c u me nte d b y t he 
A merica n N ati o nal Sta n dar ds I nstit ute, A N SI Z 1 3 6. 1- 2 0 0 7. T he m ost c o ns er vati ve A N SI 
sta n dar d f or m a xi m u m per missi ble e x p os ure, M P E, f or 8 7 0 nm li g ht is 7 5 0 m W ass u mi n g 
f ull p u pil i ntra bea m vie wi n g ( 7 m m p u pil a pert ure) f or l o n g e x p os ure ti mes ( u p t o 8 
h o urs). E x p os ure i n o ur st u d y pr ot oc ol will n ot e xcee d t his well- esta blis he d li mit. T he 
S pectralis S D - O C T u nit has a b uilt-i n ti mer t hat pre ve nts t he u nit fr o m i ma gi n g f or m ore 
t ha n 5 mi n utes c u m ulati vel y d uri n g a si n gle patie nt e nc o u nter, ma ki n g it effecti vel y 
i m p ossi ble t o e x p ose t he patie nt t o u nacce pt a ble le vels of li g ht.   
T he ris ks ass ociate d wit h t he use of s u bt hres h ol d micr o p ulse di o de laser are m uc h re d u ce d 
c o m pare d t o t he sta n d ar d c o nti n u o us wa ve laser w hic h is use d i n t he treat m e nt of reti nal e d e ma 
wit h vis ual ac uit y t hat is e q ual t o or w ors e t ha n 2 0/ 4 0 o n t he S nelle n c hart. Sta n dar d c o nti n u o us 
wa ve f o cal laser treat me nts are ass oci ate d wit h ris ks i ncl u di n g earl y a n d late vis ual l oss 
a g gra vati o n of m ac ular e de ma ( M E) s u b-reti nal fi br osis, c h or oi dal ne o vas c ularizati o n, vis ual 
fiel d l oss, l oss of c ol or visi o n, meta m or p h o psia, a n d pr o gressi ve e x p a nsi o n of t he laser s cars i nt o 
t he f o vea1 6. H o we ver, t h e use of t he s u bt hres h ol d micr o p ulse di o de laser li mits t hese sta n dar d 
ris k fact ors b y utilizi n g l o wer e n er g y i nte nsit y a n d its “c h o p pe d” deli ver y met h o d.1 7 M ulti ple 
st u dies ha ve  de m o nstrat e d t he saf et y of s u bt hres h ol d micr o p ulse laser c o m pare d t o sta n dar d 
c o nti n u o us wa ve laser i n t he treat me nt of mac ular e de ma usi n g vari o us i ma g i n g m o dalities.  
T here h a ve bee n n o detecta ble c ha n g es n ote d i n e y es treate d wit h s u bt hres h ol d micr o p ulse di o de 
laser o n O C T, fl u or escei n a n gi o gra p h y ( F A) or f u n d us a ut ofl u oresce nce ( F A F).1 5, 1 7, 1 8 T his has 
als o bee n c orr o b or ate d b y hist ol o gic st u dies i n w hic h S M L was n ote d t o treat tiss ue wit h o ut 
da ma ge t o t he ne ur ose ns or y reti na. 1 0  Ot hers ha ve als o de m o nstrate d re peat a bilit y of S M L 
treat me nt wit h o ut detecta ble str uct ural or f u n cti o nal da ma ge1 6, 1 7, 1 9.  I n a pr os pecti ve ra n d o mize d 
cli nical trial, V uj ose vic et al. c o m pare d t he s afet y of S M L  vers us m o difie d E T D R S gree n laser 
p h ot oc oa g ulati o n. T he y ha ve s h o w n t hat reti nal se nsiti vit y i ncrease d, a n d f u n d us 
a ut ofl u oresce nce i ma gi n g re veal e d n o c ha n g es at o ne year f oll o w u p i n e yes wit h D M E e ve n 
after r etreat me nt wit h S M L, w hereas  t h ose treate d wit h sta n dar d c o nti n u o us wa ve laser re v eale d 
areas of h y per a ut ofl u ores ce nce a n d decrease d reti nal se nsiti vit y. T he mea n n u m ber of treat me nts 
was 2. 0 3 ± 0. 7 5 i n t he S M L gr o u p. 1 5 M ore o ver, L uttr ull et al. ha ve s h o w n t h at 1 5 o ut of 3 9 e yes 
wit h D M E a n d vis ual ac uit y better t ha n 2 0/ 4 0 treat e d wit h S M L  re q uire d retreat me nt, yet n o 

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Re vis e d: A u g ust 1 5, 2 0 1 4  
e vi de nce of laser eff ect or i nj ur y was n ote d t o t he  reti nal pi g me nt e pit heli u m ( R P E) or 
ne ur ose ns or y reti na b y a n y i ma gi n g m o dalit y i ncl u di n g i nfrare d f u n d us p h ot o gra p h y, re d- free 
f u n d us p h ot o gra p h y, f u n d us a ut ofl u oresce nce, fl u orescei n a n gi o gra p h y, or S D -O C T at a n y ti me 
i n a n y e ye p ost o per ati vel y, ot her t ha n re d u cti o n i n t he reti nal t hic k ness.2 0 T hese st u dies 
u n dersc or e t he saf et y of micr o p ulse laser e ve n i n t he setti n g of t heir re p etiti ve use.   
Micr o p ulse laser f or t he treat me nt of D M E i n pre g na nc y has bee n f o u n d t o be a safe o pti o n. 
M ulti ple st u dies a n d pa pers ha ve i n cl u de d t he use of laser i n pre g na nt w o me n. First -li ne 
treat me nts f or D M E i n pr e g na nc y are a n d s h o ul d re mai n bl o o d gl uc ose c o ntr ol a n d laser. ²¹   
T o date, t her e is n o sta n dar d of care re g ar di n g treat me nt of mac ular e de ma i n e yes wit h 
vis ual ac uit y of 2 0/ 3 2 or better; t h us t here is n o ass ociate d ris k f or t h ose p atie nts ra n d o mize d t o 
t he s ha m treat me nt gr o u p u nless vis ual ac uit y dr o ps t o 2 0/ 4 0 or w orse. Patie nts i n t he s ha m 
treat me nt ar m of t h e st u d y will be m o nit ore d o n r o uti ne f oll o w u p visits a n d treate d i n 
acc or d a nce wit h sta n dar d practice g ui d eli nes if necessar y.  
 
1 5)  P ote nti al Be nefits t o S u bjects  
T he  pr o p ose d st u d y ma y directl y be nefit its partici pa nts  if S M L i n dee d re d u ces ris k of 
visi o n l oss i n patie nts wit h D M E a n d g o o d vis ual ac uit y. 
 
1 6)  M ulti -Site Rese a rc h  
T his is a si n gle -site st u d y 
 
1 7)  C o m m u nit y -B ase d P artici p at or y Rese a rc h  
T his is n ot a c o m m u nit y -base d partici p at or y res earc h.  
1 8)  S h ari n g of Res ults wit h S u bjects  
Res ults of t he st u d y relate d t o i n di vi d ual s u bjects will be s hare d u p o n t heir re q uest.  
C ollecti ve st u d y res ults ca n be s har e d wit h st u d y s u bjects h o we ver wit h de- i de ntifie d data 
o nl y, s uc h t hat n o ne of t h e partici pa nts ca n be i de ntifie d. 
1 9)  Pri or A p pr o v als 
N o ne 
2 0)  Pr o visi o ns t o Pr otect t h e Pri v ac y I nterests of S u bjects  
All s u bjects retai n t he ri g ht t o i nteract wit h a n y me m ber of t he m e dical a n d n o n -
me dical tea m.  Patie nts ma y elect t o o nl y i nteract wit h t he i n vesti gat ors of t he st u d y.  
St u d y staff will be a vaila ble d uri n g t he e xa mi nati o n at all ti mes t o a d dress a n y of t he 
q uesti o ns or c o ncer ns t hat t he st u d y s u bjects ma y ha ve.  T he d ata o btai ne d d uri n g t he 
c o urse of t he st u d y will b e st ore d o n pass w or d pr otecte d files a n d accessi ble o nl y t o t he 
researc h i n vesti gat ors a p pr o ve d o n t he st u d y 
2 1)  C o m pe ns ati o n f or Rese arc h -Rel ate d I nj ur y  
T he resear c h d oes n ot i n v ol ve m ore t ha n mi ni mal ris k t o s u bjects 

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Re vis e d: A u g ust 1 5, 2 0 1 4  
2 2)  Ec o n o mic B ur de n t o S u bjects  
Partici pati o n i n t he st u d y d oes n ot i nc ur a n y a d diti o nal c osts t o t he st u d y s u bjects.  
T he c ost of t he m icr o p uls e laser tr eat me nts a n d S D -O C T are all part of sta n dar d of care 
f or patie nts wit h reti nal e de ma, w hic h will be c h ar ge d t o s u bjects as part of t heir me dical 
care. If r e peat i ma gi n g is nee de d b e y o n d w hat is c o nsi dere d sta n dar d of care, it will be 
c o vere d b y t h e st u d y.  T h ose recei vi n g t he “s ha m” treat me nt will n ot be bille d f or a l aser 
treat me nt. 
2 3)  Dr u gs or De vices  
T his resear c h st u d y d oes n ot i n v ol ve i n vesti gati o nal dr u gs or de vices . T he e ye 
dr o ps, Hei del ber g S pectr alis S D- O C T de vice, a n d t he I Q 5 7 7 laser de vice, wit h 
c o nti n u o us-wa ve a n d Micr o P ulse treat me nt m o des,  are all use d i n sta n d ar d of care.  
1.  
M ura ka mi, T. & Y os hi m ura, N. Dia b etic Mac ul ar E de ma. 2 0 1 3,  5 0 5 – 5 1 0 ( 2 0 1 3). 
2.  
Fazel, F., Ba g h eri, M., G ola bc hi, K. & Ja ha n ba ni Ar da ka ni, H. C o m paris o n of 
s u bt hres h ol d di o de laser micr o p ulse t hera p y v ers us c o n ve nti o nal p h ot oc oa g ulati o n laser 
t hera p y as pri mar y treat me nt of dia betic mac ul ar e de ma. J. C urr. O p ht h al m ol.  2 8,  2 0 6 –
2 1 1 ( 2 0 1 6). 
3.  
Earl y Treat me nt Dia betic Reti n o pat h y St u d y Researc h Gr o u p. P h ot oc oa g ul ati o n f or 
dia betic mac ular e de m a. Earl y Treat me nt Dia betic Reti n o pat h y St u d y re p ort n u m ber 1. 
Earl y Treat me nt Dia betic Reti n o pat h y St u d y researc h gr o u p. Arc h. O p ht h al m ol. ( C hic a g o, 
Ill.  1 9 6 0) 1 0 3,  1 7 9 6 – 8 0 6 ( 1 9 8 5). 
4.  
Gr o u p, E. T. D. R. S. R. Earl y p h ot oc oa g ulati o n f or dia betic reti n o pat h y. E T D R S re p ort 
n u m ber 9. Earl y Tr eat me nt Dia betic Reti n o pat h y St u d y Researc h Gr o u p. O p ht h al m ol o gy  
9 8,  7 6 6 – 8 5 ( 1 9 9 1). 
5. 
Dia betic Reti n o pat h y Cli nical Researc h Net w or k. A ra n d o mize d tri al c o m p ari n g 
i ntra vitreal tria mci n ol o ne acet o ni de a n d f ocal/ gri d p h ot oc oa g ulati o n f or dia betic mac ular 
e de ma. O p ht h al m ol o gy  1 1 5,  1 4 4 7 – 9, 1 4 4 9 – 1 0 ( 2 0 0 8). 
6. 
Dia betic Reti n o pat h y Cli nical Researc h Net w or k et al. Ra n d o mize d trial e val uati n g 
ra ni biz u ma b pl us pr o m pt or deferre d l aser or tria mci n ol o ne pl us pr o m pt laser f or dia betic 
mac ular e d e ma. O p ht h al m ol o gy  1 1 7,  1 0 6 4 – 1 0 7 7.e 3 5 ( 2 0 1 0). 
7.  
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Pa ge 1 1 of 1 1 
Pr ot oc ol Versi o n Date: 0 6 Oct 2 0 2 1  
 
Re vis e d: A u g ust 1 5, 2 0 1 4  
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