Short Contact Protocols to Reduce Pain During Treatment of Actinic Keratoses With 10% ALA Gel Red-light Photodynamic Therapy (PDT)
Phase: PHASE2
Conditions: Actinic Keratosis
Sponsor: Case Comprehensive Cancer Center



C A S E 4 6 2 3   
  
  
  
 
Pa ge 2    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
 
W o b ur n, M A 0 1 8 0 1 
 
S U P P LI E D A G E N T S  A N D D E VI C E S :    
  
  
 
( 1) A mel uz  g el, 1 0 % a mi n ole v uli nic aci d , a n F D A -a p pr o ve d dr u g; 
  
 
( 2) B F - R h o d o L E D® , a n F D A -a p pr o ve d li g ht s o urce 
  
  
  
 
 
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 3    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
Title:     S h ort c o ntact pr ot oc ols t o re d uce p ai n d uri n g treat me nt of acti nic kerat oses wit h 1 0 % A L A 
gel -re d li g ht p h ot o d y na mic t hera p y ( P D T) 
 
 
 
Pri nci p al I n vesti g at or: E d war d V. M a yti n, M. D. P h. D. 
 
 
 
 
 
P RI N CI P A L I N V E S TI G A T O R SI G N A T U R E:  
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
  
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 4    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
S U M M A R Y O F C H A N G E S  
 
 
Pr ot oc ol 
D ate  
Secti o n  
C h a n ge  
 
 
I nitial I R B a p pr o v al 
 
 
 
 
 
 
 
 
 
 
 
 
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 5    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
S T U D Y S C H E M A  
 
 
Ti m eli ne of pr oce d ures f or p atie nts e nr olle d i n t he st u d y. 
 
 
 
 
 
 
 
VI SI T 1  
P D T  
tre at m e nt 
sessi o n # 1  
VI SI T 2  
P h ot o s of 
s ki n 
re d ness  
VI SI T 3  
P D T 
tre at m e nt 
sessi o n # 2  
VI SI T 4  
 
Fi n al lesi o n 
c o u nts  
Sc he d ule d visit:  
Pr oce d ure: ↓ 
D a y 1  
D a y 3 ± 1  
d a y  
Wee k 8  
± 1 wee k  
M o nt h  3- 6  
Si g n i nf or me d c o nse nt   
X 
 
 
 
E xa mi ne patie nt, mar k eac h lesi o n 
wit h a pe n, a n d  c o u nt t he lesi o ns 
X 
 
X 
 X 
Ta ke p h ot o gra p hs i n pr ofessi o nal 
st u di o (fr o ntal vie w a n d si de vie ws) t o 
d oc u me nt i nfla m mati o n.  
X 
X 
 
 
Ta ke p h ot o gra p hs usi n g cli nic i P h o ne 
ca mera t o d oc u me nt lesi o n c o u nts 
( pe n-mar ks)  
X 
 
X 
X 
A p pl y t o pical A L A gel  a n d  i nc u bate 
f or 1 0, 2 0, or 6 0 mi n pri or t o t ur ni n g 
o n t he li g ht s o urce (as per assi g ne d 
st u d y ar ms A, B, or C, res pecti vel y) 
X 
 
X 
 
Ill u mi nate wit h re d li g ht f or 2 0, 1 0, or 
1 0 mi n (as per assi g ne d st u d y ar ms A, 
B, or C, res pecti vel y)  
X 
 
X 
 
Rec or d patie nt -re p orte d pai n le vel 
( V A S) 
X 
 
X 
 
Gi ve t he patie nt a q uesti o n naire  t o fill 
o ut  at h o me (t o descri be si de-effects 
o n eac h of t he 6 da ys p ost -P D T ) 
X 
 
X 
 
Pr o vi de patie nt wit h a hat, s u nscree n 
a n d aftercare i nstr ucti o ns 
X 
 
X 
 
Patie nt satisfacti o n s ur ve y  
 
 
 
X 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 6    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
 
P R O T O C O L S U M M A R Y  
 
Pr ot oc ol N u m ber/ Title  
S h ort c o nt act pr ot oc ols t o re d uce p ai n d uri n g tre at me nt of 
acti nic ker at oses wit h  1 0 %  A L A gel  re d-li g ht p h ot o dy n a mic 
t her a py ( P D T) 
St u d y P hase  
I n v esti gat or-i nitiate d st u d y  
Brief Bac k gr o u n d/ Rati o n ale  
 
 
 
A mel uz  1 0 %  A L A  gel  is  a  t o pical  F D A -a p pr o ve d 
p h ot ose nsitizer t hat is use d i n c o m bi nati o n wit h re d li g ht 
(B F - R h o d o L E D®  u nit, a n F D A -a p pr o ve d d e vice) t o treat 
acti nic  kerat oses .  R e d  li g ht  ill u mi nati o n  is  t y picall y  
a d mi nistere d  after a 3- h o ur i nc u bati o n wit h t he A L A gel , a n d 
is ass ociate d wit h a n u n desira ble si de effect, sti n gi n g pai n. 
T he pr o p ose d  cli nical st u d y will test t he h y p ot hesis  t hat o ne 
or m ore s h orter i nc u bati o n re gi me ns ca n  pr o vi de e xcelle nt 
treat me nt efficac y w hile re d uci n g or eli mi nati n g  t he pai n t hat 
is t y picall y e x perie nce d b y patie nts wit h  t he c o n ve nti o nal 3-
h o ur re gi me n. 
Pri mar y O bjecti ve  
Pri mar y E n d p oi nt(s)  
    Efficac y  
    Pai n  
 
Sec o n dar y O bj ecti ve(s)  
Sec o n dar y E n d p oi nt(s)  
    Patie nt satisfacti o n . 
    A E pr ofile / Safet y 
E x pl orat or y O bjecti ve(s)  
 
 
C orrelati ve O bjecti ve(s)  
 
N o ne  
Sa m ple Size  
3 0 partici pa nts  
Disease sites/ C o n diti o ns  
Acti nic K erat osis 
I nter ve nti o ns 
Sta n dar d P D T usi n g t o pical a mi n ole v uli nate  (1 0 % A L A 
gel ) f oll o we d b y re d li g ht ( F D A-a p pr o v e d pr ot oc ol) f or 
acti nic kerat osis.  
 
 
 
  
  
  
  
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 7    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
A B B R E VI A TI O N S  
 
 
 
 
C C C C  Case C o m pre he nsi ve Ca ncer Ce nter  
C R F  
Case Re p ort F or m  
C R U  
Cli nical Researc h U nit  
D S T C  
Data Safet y  a n d T o xicit y  C o m mittee  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
I C F 
I nf or me d C o nse nt F or m 
I R B 
I nstit uti o nal Re vie w B oar d 
P R M C  Pr ot oc ol Re vie w a n d M o nit ori n g C o m mittee  
S O C  
Sta n dar d of Car e  
C C F  
Cle vela n d Cli nic F o u n dati o n  
U H  
U ni versit y H os pitals  
A K  
Acti nic Ker at osis  
A L A  
A mi n ole v uli nic aci d  
P pI X  
Pr ot o p or p h yri n I X  

C A S E 4 6 2 3   
  
  
  
 
Pa ge 8    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
T A B L E O F C O N T E N T S  
 
0. 0  
S C H E M A ( S u m m ar y Di a gr a m) 
 
1. 0  
I N T R O D U C TI O N   
 
1. 1  
Bac k gr o u n d a n d Si g ni fica nce   
1. 2  
Scie ntific rati o nale f or t he pr o p ose d st u d y 
1. 3  
Rati o nale f or t he e x p eri me ntal desi g n  
 
2. 0 
O B J E C TI V E S  
2. 1 
Pri mar y O bjecti ve  
 
2. 2  
Sec o n dar y O bj ecti ve(s)  
 
3. 0 
S T U D Y D E SI G N  
3. 1  
St u d y desi g n pr ot oc ol 
3. 2  
N u m ber of s u bjects 
3. 3 
Re place me nt of s u bjects  
3. 4  
E x pecte d d ur ati o n of s u bject partici pati o n  
 
4. 0  
S U B J E C T  S E L E C TI O N  
4. 1 
I n cl usi o n Criteria 
4. 2  
E xcl usi o n Criteria  
4. 3  
I n cl usi o n of W o me n a n d Mi n orities  
 
5. 0 
R E GI S T R A TI O N  
5. 1 
Recr uit me nt  
5. 2  
C o nse nt 
5. 3  
Ra n d o mizati o n  
  
 
6. 0  
T R E A T M E N T P L A N  
6. 1 
O verall des cri pti ve narrati ve  
6. 2  
D urati o n of T hera p y 
6. 3  
D urati o n of F oll o w U p 
 
7. 0 
D O S E D E L A Y S / D O S E M O DI FI C A TI O N S  
 
8. 0 
A D V E R S E E V E N T S A N D P O T E N TI A L RI S K S  
  
8. 1 
A d verse E v e nts a n d P ote ntial Ris k List  
  
8. 1. 1 A mel uz  
  
8. 1. 2 P h ot o d y na mic T her a p y 
8. 2 
Defi niti o ns  
  
8. 2. 1 A d verse E v e nts 
  
8. 2. 2 Si g nifica nce of a n A d verse E v e nt 
  
8. 2. 3 Seri o us A d verse E v e nts 
  
8. 2. 4 E x pecte d ness  
  
8. 2. 5 Attri b uti o n 
8. 3  
Re p orti n g Pr oce d ures f or All A d verse E v e nts 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 9    
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
 
8. 4  
Seri o us A d verse E v e nt Re p orti n g Pr oce d ures 
  
 
8. 5 
Data Safet y T o xi cit y C o m mittee    
 
9. 0 
P H A R M A C E U TI C A L I N F O R M A TI O N  
9. 1  
I n v esti gati o nal A ge nt (s)  
 
9. 2 
C o m mercial A ge nt (s) 
 
1 0. 0 
E X P L O R A T O R Y/ C O R R E L A TI V E   
 
 
1 1. 0 
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
 
 
1 2. 0 
M E A S U R E M E N T O F E F F E C T   
 
1 3. 0 
R E C O R D S T O B E K E P T/ R E G U L A T O R Y C O N SI D E R A TI O N S  
  
 
 
1 4. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 4. 1  
Pri mar y q uesti o ns t o be teste d  
 
1 4. 2 
Sa m ple size calc ul ati o ns  
1 4. 3 
Esti mate of accr ual r ate  
 
 
 
R E F E R E N C E S  
 
  
 
A P P E N DI C E S   
1. 0  
S pecificati o ns f or A m el uz  
2. 0  
S pecificati o ns f or t he B F - R h o d o L E D® re d li g ht s o urce 
3. 0  
P ost- P D T Si de Effects J o ur nal  
4. 0  
Patie nt Satisfacti o n Q uesti o n naire  
  
 
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 0     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
1. 0 
I ntr o d ucti o n 
 
1. 1 
B ac k gr o u n d a n d Si g nific a nce  
Acti nic kerat oses ( A K), are d ys plastic preca n cer o us lesi o ns of t he s ki n wit h  p ote ntial t o de vel o p 
i nt o s q ua m o us cell carci n o ma. A Ks are e xtre m el y c o m m o n a n d  are t y picall y o bser ve d i n s u n-
da ma ge d s ki n  of Ca ucasi a n i n di vi d uals . It is i m p orta nt t o treat A Ks b eca use of t h e p ossi bilit y t hat 
2- 5 % of t he m ma y e v ol v e i nt o s q ua m o us cell carci n o ma ( S C C). Pr o gressi o n of A K t o S C C is e ve n 
hi g her i n i m m u n os u p presse d patie nts, e. g. or ga n tra ns pla ntati o n  reci pie nts. A m o n gst c urre nt l y 
a vaila ble treat me nts f or wi des prea d A K t hat i n cl u de s ur gical (cr y ot h era p y, scal pel e x cisi o n) a n d 
me dici nal  a p pr oac h es  ( t o pical  5-fl u or o uracil,  i mi q ui m o d,  dicl ofe nac  crea m)  a p pr oac h es,  a  
relati vel y ne w m o dalit y calle d ph ot o d y na mic t hera p y ( P D T) has se veral disti nct a d va nta ges  [1 ]. 
P D T is a met h o d i n w hic h a t o pical dr u g s uc h as a mi n ole v uli nic ac id ( A L A) or met h yl -A L A is 
a p plie d t o A K lesi o ns, w here it is ta ke n u p selecti vel y b y preca n cer cells  [2 ]. Wit hi n t he cells, A L A 
is c o n verte d i nt o a p h ot ose nsitizer ( pr ot o p or p h yri n I X, P pI X) wit hi n mit oc h o n dria, w here u p o n a 
str o n g visi ble li g ht is use d t o acti vate t he P pI X, tri g geri n g p h ot oc he mical reacti o ns s uc h as t he 
ge nerati o n of r eacti ve o x y ge n s pecies t hat kill t he preca n cer cells. P D T e x cels as a m o dalit y t o 
treat wi des prea d ar eas of fiel d ca n ceri zati o n, a n d it has t he a d diti o nal a d v a nta ges of mi ni mal d o w n 
ti me  a n d  ra pi d  rec o ver y,  lac k  of  scarri n g,  lac k  of  pi g me ntar y  c ha n ges,  a n d  re peat a bilit y [3 ]. 
H o we ver, a  li miti n g fact or wit h  all c urre nt v ersi o ns of a mi n ole v uli nate -b ase d P D T is sti n gi n g p ai n 
t hat patie nts ofte n ha ve t o e n d ure d uri n g ill u mi nati o n  [4 ].  T his pai n is pr o p orti o nal t o t he a m o u nt 
of t he tar get p h ot ose nsitizer ( P pI X) t hat is prese nt i n t he s ki n pri or t o t he start of ill u mi nati o n. Pai n 
is a fre q ue nt occ urre n ce i n patie nts w h o recei ve P D T wit h sta n d ar d pr ot oc ols c urre ntl y a p pr o v e d 
b y t he F D A, all of w hic h re q uire d a n A L A i nc u bati o n peri o d of ma n y h o urs, i.e., 1 4 -1 8 hr wit h 
Le v ula n Kerastic k ( 2 0 % A L A), 3 hr wit h Met vi xia ( 1 6 % met h yl -A L A), a n d 3 hr f or A mel uz ( 1 0 % 
A L A na n oe m ulsi o n). Met vi xia a n d A mel uz, als o re q uire t hat a n occl usi ve dressi n g be  a p plie d t o 
e n ha nce pe netr ati o n . Met vi xia is n o l o n ger a vaila ble i n t he  U S, lea vi n g A mel uz  a n d Le v ula n as 
t he o nl y t w o via ble o pti o ns f or der mat ol o gists pr o vi di n g P D T  i n t he U nite d States. A mel uz has 
ge nerat e d si g nifica nt i nterest d ue its pr o perties as li pi d - base d na n oe m ulsi o n t hat e x hi bits s u peri or 
u pta ke i nt o A K lesi o ns [5 ]. 
 
T o date, t he pr o bl e m of P D T treat me nt -ass ociate d pai n has bec o me a seri o us i m pe di me nt t o t he 
f ull i m ple me ntati o n a n d acce pta nce of P D T b y t he ge neral p o p ulati o n of der mat ol o g y patie nts. 
St ories a b o ut pai nf ul e x perie nces d uri n g P D T are s hare d o nli ne or b y w or d of m o ut h, a n d te n d t o 
ge nerat e f ear a n d r el ucta nce t o u n der g o P D T. A n ot her iss ue is lac k of c o n ve nie nce . Tra diti o nal 
P D T ca n re q uire ma n y h o urs of w aiti n g ti me i n t he office, w hic h te n ds t o disc o ura ge p atie nts a n d 
p h ysicia ns fr o m e m br aci n g P D T as e nt h usiasticall y as t he y s h o ul d, gi ve n its p ote ntial be nefits. A 
t hir d iss ue is t he re q uire me nt f or occl usi o n w he n usi n g A mel uz a n d re d li g ht. W hile t he latter 
pr ot oc ol was ori gi nall y desi g ne d t o ac hie ve ma xi mal A K cleara n ce f or a s mall n u m ber of A K i n a 
defi ne d ar ea, it is n ot i deal f or br oa d fiel d treat me nt of A K a b o ve t he nec k, partic ularl y o n t he face 
w here o ccl usi ve dr essi n gs are ver y i nc o n ve nie nt. 
 
1. 2 
Scie ntific r ati o n ale f or t he pr o p ose d st u d y  
 
T he pr o p ose d pil ot st u d y will si m ulta ne o usl y a d dress t he 3 c urre nt dra w bac ks of P D T usi n g 
A mel uz  a n d r e d li g ht, w hic h ar e: ( 1) pai n d uri n g ill u mi nati o n, ( 2) le n gt h y i nc u bati o n peri o ds, a n d 
( 3) t he i nc o n ve ni e nce of plastic wra p occl usi o n.   
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 1     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
T he r ati o nale f or t his st u d y is base d u p o n rece nt fi n di n gs a n d o bser v ati o ns fr o m a n ot her versi o n 
of P D T tec h n ol o g y f or acti nic kerat osis, na mel y, 5-A L A ( Le v ula n) a n d bl ue li g ht, i n w hic h a s h ort -
i nc u bati o n re gi me n was de vel o pe d a n d s h o w n t o pr o vi de e xcelle nt effi cac y w hile ge nerati n g 
mi ni mal pai n d uri n g ill u mi nati o n [6, 7 ]. T he pri nci ple e x pl oite d b y t h ose st u dies is t hat c o n v ersi o n 
of  A L A  t o  P pI X  be gi ns  as  s o o n  as  A L A  is  a p plie d  t o  t he  lesi o ns  [8 ]. T h us  P pI X  ca n  be  
p h ot oacti vate d, e v e n at l o w le vels, b y ill u mi nati o n wit h bl ue or re d li g ht, t here b y   d estr o yi n g 
mit oc h o n dria  a n d  tri g geri n g  a  s o me w hat  dela ye d  yet  hi g hl y  effecti ve  i nfla m mat or y -
i m m u n ol o gical res p o nse t o eli mi nate t he l esi o ns [9 ]. Pre vi o usl y, i n de v el o pi n g a ‘ p ai nless bl ue li g ht 
pr ot oc ol’, o ur gr o u p c o m pare d t w o Le v ula n/ bl ue li g ht pr ot oc ols i n a bilateral c o m parati ve f or mat 
(eac h patie nt ser vi n g as his/ her o w n c o ntr ol).  O n o ne si de, A K lesi o ns were treate d usi n g t he 
s h ortest dr u g i nc u bati o n ti me t hat was k n o w n t o pr o d uce si g nifica nt lesi o n cleara nce ( 1 h A L A 
i nc u bati o n), f oll o we d b y ill u mi nati o n f or 1 6 mi n 4 0 sec (as i n t he sta n dar d F D A-a p pr o ve d bl ue 
li g ht pr ot oc ol). T his pr o d uce d a p ai n le vel, o n a vera ge, ~ 5 o n a 1-1 0 vis ual -a nalo g scale. O n t he 
c o ntralateral si de of t he f ace, A K lesi o ns were treate d wit h i m me diate (si m ulta ne o us) ill u mi nati o n, 
i n w hic h 2 0 % A L A s ol uti o n was a p plie d a n d t he n bl ue li g ht was s h o ne f or eit her 3 0 mi n, 4 5 mi n, 
or 6 0 mi n.  I n all t hree of t hese ti me d c o h orts, patie nts re p orte d ver y l o w pai n le vels ( ~ 1 o ut of 
1 0), a n d yet t he y d e vel o pe d er yt he m a a n d lesi o n cleara nce rates at 3 m o nt h t hat were si m ilar 
(statisticall y  n o n-i nferi or)  t o  t he  ‘tra diti o nal’  1  hr  A L A  i nc u bati o n  peri o d  [7 ].  T his  st u d y  
de m o nstrate d t hat g o o d tr eat me nt efficac y ca n still be o btai ne d e v e n w h e n pai n is mi ni mize d usi n g 
a n A L A s h ort- c o ntact a p pr oac h.  
 
I n t he c urre nt st u d y, we will see k t o tra nslate t he fi n di n gs o bser ve d wit h 5-A L A/ bl ue li g ht (a b o ve), 
i nt o a re gi me n wit h 1 0 % A L A gel a n d re d li g ht, a n d assess its feasi bilit y. 
 
 
1. 3.  
 R ati o n ale f or t he e x peri m e nt al desi g n.  
 
T he  e x peri me ntal  strate g y  is t o  e xa mi ne  s h ort-c o ntact  A mel uz/re d  li g ht  pr ot oc ols  i n  a  well -
esta blis he d P D T cli nic, t o e x pl ore p ai n re d u cti o n a n d treat me nt efficac y usi n g a n F D A -a p pr o ve d 
P D T dr u g ( A mel uz) a n d li g ht s o urce ( B F - R h o d o L E D® re d li g ht pa nel) u n d er c o n diti o ns t hat ha v e 
bee n  m o difie d  t o  be  s u b-ma xi mal  ( i.e.,  usi n g s h orter t ha n  us ual  dr u g- i nc u bati o n  ti mes).  O ur 
h y p ot hesis is t hat patie nt c o mf ort will be greatl y  i m pr o ve d, yet a n acce pta ble treat me nt efficac y 
will be mai ntai ne d. We pla n t o  i n vite patie nts w h o are alrea d y sc he d ul e d t o u n der g o P D T  treat me nt 
i n Dr. Ma yti n’s cli nic f or acti nic ker at oses of t he face t o partici pate i n t he st u d y.   
 
T he  f oll o wi n g  scie ntific  q uesti o ns will  be  aske d  a n d  a d dresse d  i n  a  m a n ner  c o nsiste nt  wit h 
scie ntific pri nci ples as well as pr actic al c o nsi der ati o ns.   
 
( 1) Will t he a p plicati o n of t he na n o e m ulsi o n (1 0 % A L A g el ), i n t he a bs e nce of o ccl usi o n, still 
ac hie ve si g nifica nt i nfla m mati o n a n d lesi o n cleara nce?  
( 2) Will s h orte ne d i nc u bati o n ti mes of A mel uz still ac hie ve si g nifica nt i nfla m mati o n a n d lesi o n 
clear a nce?  
( 3) Will t he ne w test r e gi me ns ac hie ve re d u ce d pai n d uri n g ill u mi nati o n? 
( 4) Will t he ne w test r e gi me ns be safe? 
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 2     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
C o nsi der ati o n  a n d disc ussi o n a b o ut  t he r ati o n ale f or h o w we devel o pe d  t he pr o p ose d  s h ort-
c o nt act pr ot oc ols, i n rel ati o n t o e ac h scie ntific q uesti o n, is pr ovi de d bel o w : 
 
( 1) Will t he na n oe m ulsi o n ( A L A gel ) still w or k i n t he a bse nce of occl usi o n?  
A ns wer:  Beca us e t he 1 0 % A L A gel  has m u c h better pe netrati o n t ha n 5 -A L A/ Kerastic k t hat w as 
s h o w n t o w or k wit h o ut occl usi o n, it see ms hi g hl y li kel y t hat 1 0 % A L A gel will pe netrate lesi o ns 
a n d acc u m ulate s uffici e nt P pI X e v e n i n t he a bse n ce of occl usi o n.  
 
( 2) Will s h ort 1 0 % A L A gel  i nc u bati o n ti mes still ac hie ve si g nifica nt i nfla m mati o n a n d lesi o n 
clear a nce ? 
A ns wer:  For c o m pari n g t he efficac y of  1 0 % A L A -gel -re d li g ht treat me nt, t he be n c h mar k is t he 3-
hr  i nc u bati o n  re gi me n  a p pr o ve d  b y  t he  F D A,  w hic h  uses  1 0 % A L A  gel  ( u n der  occl usi o n),  
f oll o we d b y 8 mi n ( 3 7 J/ c m 2) of r e d li g ht [1 0, 1 1 ]. H o we ver, we ca n als o p oi nt t o a st u d y b y Nest or 
et al. t hat c o m pare d A m el uz a n d Le v ula n directl y, a n d s h o we d e q ui vale nt A K lesi o n cleara n ce 
w he n  eac h a g e nt was a p plie d f or 1 h o ur ( wit h o ut occl usi o n) f oll o we d b y  a sta n d ar d 1 0 0 0 sec 
e x p os ure t o bl ue li g ht [1 2 ]. T h ose res ults i n dicate t hat s h ort 1 0 % A L A gel  i nc u bati o n ti mes wit h o ut 
occl usi o n ca n still ac hie ve si g nifica nt i nfla m mati o n a n d lesi o n cleara nce.  T o de vel o p t his i dea 
f urt her f or 1 0 % A L A  gel a n d r e d li g ht , we ha ve e xtra p olate d fr o m a n ot her st u d y usi n g bl ue li g ht 
P D T, o ur cli nical trial  [7 ] i n w hic h t he d urati o n of bl ue li g ht ill u mi nati o n was drasticall y s h orte n e d  
b ut yet ac hie v e d  s ur prisi n g efficac y. T h at  w or k  i n v ol ve d se veral differe nt st u d y ar ms. I n o ne ar m, 
t he ori gi nal 1 4 -1 8 hr 2 0 % A L A s ol uti o n  i nc u bati o n, was  s h orte ne d t o 1 hr A L A i nc u bati o n 
f oll o we d b y a sta n dar d 1 6 mi n 4 0 sec bl ue li g ht ill u mi nati o n. Base d u p o n t h ose res ults, we belie ve 
t hat t he A mel uz i nc u bati o n ti me ca n be re d uce d fr o m 3 hr t o 1 hr, f oll o we d b y a sta n dar d 1 0 mi n 
( 3 7 J/c m 2) of re d li g ht t o ac hie ve a reas o n a ble t hera pe utic effect. I n a differe nt  st u d y ar m fr o m 
Ka w et al, t he 2 0 % A L A  s ol uti o n i nc u bati o n ti me was s h ortene d t o zer o, i.e., A L A was a p plie d 
a n d t he n bl ue li g ht was t ur ne d o n f or 3 0 mi n utes t o pr o vi de  a si m ulta ne o us  i nc u bati o n/ill u mi nati o n. 
Pai n was mi ni mize d, yet t he a m o u nt of A K lesi o n cleara n ce ac hie ve d b y t he si m ulta ne o us re gi me n 
was  re mar k a bl y si milar (statisticall y n o n-i nferi or) t o A K cleara nce  see n  after   t he  1-h o ur A L A 
i nc u bati o n re gi me n. F or t he re d li g ht pr ot oc ol pr o p ose d here , we will c h o ose a  t otal A mel uz 
i nc u bati o n ti me of 3 0 mi n, a n d perf or m si m ulta ne o us  i nc u bati o n/ill u mi nati o n usi n g t w o sli g ht 
variati o ns. I n R e gi m e n A, t here will be a 1 0 mi n A L A i nc u bati o n ti me f oll o we d b y 2 0 mi n ( 7 5 
J/c m 2) of re d li g ht. R e gi m e n B  will ha ve a 2 0 mi n i nc u bati o n ti me f oll o w e d b y 1 0 mi n ( 3 7 J/c m 2) 
of re d li g ht. As a t hir d ar m (c o ntr ol), Re gi me n C  will ha ve a 1 hr  i nc u bati o n f oll o we d b y 1 0 mi n 
( 3 7 J/c m 2) of re d li g ht, w hic h is c o m para ble t o t he ar m of t h e Ka w  st u d y t hat use d 1 hr i nc u bati o n 
f oll o we d b y ~ 1 6 mi n ( 1 0 J/c m 2) of bl ue li g ht. B y m o deli n g o ur test c o n diti o ns after Ka w et al [7 ], 
we e x pect t o o bser ve  o ut c o mes si milar t o t hat st u d y  (i.e., e q ui vale nt i nfla m mati o n, e q ui vale nt A K  
lesi o n cleara n ce rat es,  a n d  re d uce d pai n ). T he  bi ol o gical  rati o nale  f or  si m ulta ne o us  A L A  
i nc u bati o n/ill u mi nati o n is t hat P pI X  is c o nti n u o usl y pr o d uce d a n d c o ns u me d, t here b y  pr o d uci n g 
t hera pe utic eff ects o ver a wi de ra n ge a n d wit h a wi de safet y mar gi n. 
 
( 3) Will t he ne w test r e gi me n ac hie v e re d u ce d pai n d uri n g ill u mi nati o n? 
A ns wer:  T he li keli h o o d is e xtre mel y hi g h t hat t h e test re gi me n ( or at least re gi me n s A a n d B) will 
be nearl y pai nless. T here is n o w s u bsta ntial e vi de nce i n t he literat ure, s h o wi n g t hat if visi ble li g ht 
is deli vere d c o nti n u o usl y w hile P pI X le v els are l o w , t he n P pI X d o es n ot  b uil d u p t o hi g h e n o u g h 
le vels wit hi n pre -ca ncer cells t o tri g ger pai n. I nstea d, t he P pI X is  acti vate d a n d destr o ye d as s o o n 
as it  is  pr o d uce d.  Wit h o ut  hi g h  P pI X  c o nce ntrati o ns  i n  pre-ca n cer  cells,  t here  is  n o  P pI X  

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 3     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
c o nce ntr ati o n  gra die nt  a n d  t heref or e  n o  P pI X  l ea ka g e  fr o m  e pit helial  pre -ca ncer  cells  i nt o  
nei g h b ori n g ner ve e n di n gs. T he latter is t he mai n ca use of p ai n d uri n g tra diti o nal P D T [1 3 ].  
 
( 4) Will t he ne w test r e gi me n be saf e ? 
A ns wer:  Yes, b eca us e all test c o n diti o ns ( dr u g c o nce ntrati o n, dr u g i n c u bati o n ti me, ill u mi nati o n 
ti me) are eit her at or bel o w t he F D A-a p pr o ve d le v els f or A mel uz paire d wit h t he  B F - R h o d o L E D® 
re d li g ht s o urce. 
 
T he p ossi ble be nefit of t his st u d y will be t he de m o nstrati o n of s u g gesti ve e vi de nce f or a ne w A L A-
P D T  re gi me n  usi n g A m el uz/re d li g ht  f or  acti ni c kerat osis,  t hat  pr o vi des a  t hera pe utic res ult 
e q ui vale nt t o c urr e nt re gi me n s, yet mi ni mizes t he  pai n t hat patie nts m ust e n d ure.  
 
 
2. 0  
O B J E C TI V E S  
 
2. 1   
Pri m ar y O bjecti ve  
• T o de m o nstrate t h at a s h ort -c o ntact P D T pr ot o c ol wit h A mel uz a n d re d li g ht ge nerates less 
pai n d uri n g ill u mi nati o n t ha n t he sta n dar d F D A -a p pr o ve d pr ot oc ol c urre ntl y use d . 
• T o test t he h y p ot hesis t hat a s h ort -c o ntact P D T pr ot oc ol wit h A mel uz a n d re d li g ht will 
pr o d uce lesi o n cleara nce o utc o mes t hat are statisticall y n o n -i nferi or t o t he tra diti o nal, pai nf ul 
pr ot oc ol. 
2. 2  
Sec o n d ar y O bjecti ve(s)  
• T o test t he h y p ot hesis t hat a s h ort-c o ntact P D T pr ot oc ol wit h A mel uz a n d re d li g ht will 
ge nerat e a n i nfla m mat or y res p o nse. 
• T o test t he h y p ot hesis t hat a s h ort-c o ntact P D T pr ot oc ol wit h A mel uz a n d re d li g ht will be 
better t olerate d a n d pr o vi de hi g her patie nt satisfacti o n t ha n t he c urre ntl y practice d pr ot o c ol. 
 
 
3. 0 
S T U D Y D E SI G N  
 
3. 1  
St u d y p r ot oc ol descri pti o n  
T he o bje cti ve of t his st u d y is t o test t hree ne w  P D T re gi me ns f or acti nic kerat oses ( A K) of t he face 
t hat pr o mise t o greatl y re d uce t he pai n n or mall y ass ociate d wit h t he pr oce d ure. T he ne w re gi me ns, 
calle d A, B, a n d C, res pecti vel y, will use  a p h ot ose nsitizer ( a mi n ole v uli nic aci d , 1 0 % A L A gel , 
A mel uz ® ) a n d a n acti vati n g re d li g ht ill u mi nati o n s o urce (B F - R h o d o L E D® re d li g ht pa n el, 6 3 5 
n m) fr o m Bi ofr o nter a , I nc. B ot h A L A gel  a n d t he 6 3 5 n m li g ht s o urce fr o m Bi ofr o ntera are 
c urre ntl y F D A -a p pr o v e d f or br oa d -area P D T treat me nt of A K. T he a p pr o ve d F D A treat me nt 
(sta n dar d re gi me n) s pecifies t hat A L A gel b e a p plie d t o picall y a n d left o n f or 3 h o urs, f oll o we d 
b y e x p os ure t o re d li g ht f or 1 0 mi n utes. Here, t h e ti mi n g f or t o pical A L A  gel  i nc u bati o n will b e 
s h orte ne d,  t o  test  t he  h y p ot hesis  t hat  pai n  e x perie nce d  d uri n g  re d  li g ht  ill u mi nati o n  ca n  be  
si g nifica ntl y  re d uce d  w hile  still  preser vi n g  t he  efficac y  of  t he  pr oced ure  i n  ter ms  of  lesi o n  
clear a nce ( pai n a n d efficac y ar e pri mar y e n d p oi nts ). Safet y a n d patie nt satisfacti o n will als o be 
assesse d (sec o n dar y e n d p oi nts). Ti mi n g f or t he 3 re gi me ns will be as f oll o ws: A , A L A gel f or 1 0 
mi n, t he n re d li g ht f or 2 0 mi n w hile A L A gel  is left i nc u bati n g. B , A L A gel f or 2 0 mi n, t he n re d 
li g ht f or 1 0 mi n w hile A L A gel  is left i nc u bati n g.  C , A L A gel f or 6 0 mi n, t he n re d li g ht f or 1 0 
mi n. We h y p ot hesize t hat eac h of t he ne w re gi me ns  will ca use si g nifica ntl y less pai n t ha n t he 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 4     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
c urre nt sta n dar d re gi me n f or A L A gel /re d li g ht P D T, a n d t hat a lesi o n cleara nce res p o nse will be 
ac hie ve d t h at is si milar (i.e., statisticall y n o n -i nferi or) t o t he sta n dar d treat me nt re gi me n.  
 
3. 2 
N u m ber of s u bjects  
A t otal of 3 0 patie nts will be nee de d t o c o m plete t he st u d y. 
 
3. 3 
Re pl ace m e nt of s u bjects  
If a st u d y s u bject wit h dra ws f or a n y reas o n, u p t o 3 m o nt hs  after t he start of t his st u d y, t he n a ne w 
s u bject ca n be recr uite d i n his/ her place. 
 
3. 4   
E x pecte d d ur ati o n of t her a p y, a n d d ur ati o n of s u bject p artici p ati o n 
T he t otal d urati o n of t he s u bject partici pati o n i n t his st u d y will be a p pr o xi matel y 4 m o nt hs a n d 
will  i ncl u de  3 - 4 cli nic  visits  a n d  a  scree ni n g  pr oce d ure  (eit her  i n  pers o n  or via  tele p h o ne 
i nter vie w).  
 
 
4. 0 
P A TI E N T S E L E C TI O N  
 
4. 1  
I ncl usi o n Criteri a  
 
Males or fe males, m ust be at least 1 8 years of a ge, wit h  a mi ni m u m of 1 0 acti nic kerat oses lesi o ns 
o n t he f ace. A t otal of 1 0  s u bjects will be e nr oll e d f or eac h of t he st u d y ar ms A, B, a n d C. T he 
st u d y will be c o n d ucte d at t he Cle vela n d Cli nic. 
 
  
4. 1. 2  Fe m ale s u bjects m ust n ot bec o me pre g n a nt d uri n g t he st u d y  
 
T he effects of 5 -a mi n ole v uli nic aci d ( A m el uz ®)  o n t he h u ma n fet us are u n k n o w n.  F or 
t his reas o n, w o me n of c hil d-beari n g p ote ntial m ust a gree t o use c o ntrace pti o n . H o wever, 
it s h o ul d be n ote d t h at t h e v ast m aj ority of p atie nts wit h c hr o nic s u n-i n d uce d A K lesi o ns 
are bey o n d t he a ge of m e n o p a use . S h o ul d a w o m a n bec o m e pre g n a nt or s us pect t hat s he 
is pre g na nt w hile s he is partici pati n g i n t his st u d y, s he s h o ul d i nf or m t he treati n g p h ysicia n 
i m me diatel y. 
 
4. 1. 3 
S u bjects m ust be a ble t o u n derst a n d a n d willi n g t o si g n a writte n i nf or me d c o nse nt 
d oc u m e nt . 
 
4. 2  
E xcl usi o n Criteri a  
4. 2. 1  Pre g na nt or n ursi n g. 
4. 2. 2  Usi n g a n y t o pical treat m e nt o n t heir A Ks; m ust st o p at least o ne m o nt h pri or. 
4. 2. 3  C urre ntl y u n der g oi n g treat me nt f or ot her ca ncers wit h me dical or ra di ati o n t hera p y. 
4. 2. 4  Patie nts wit h a k n o w n h y perse nsiti vit y t o 5-a mi n ole v uli nic aci d or a n y c o m p o ne nt of t he 
st u d y material. 
4. 2. 5  Patie nts wit h hist or y of a p h ot ose nsiti vit y disease, s uc h as p or p h yria c uta nea tar da. 
 
4. 3  
I ncl usi o n of W o m e n, C hil dre n, a n d Mi n orities   
Me n a n d w o me n at least 1 8 years of a ge of a n y et h nic gr o u p are eli gi ble f or t his trial, as 
l o n g as t he y f ulfill t he eli gi bilit y criteria.  

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 5     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
5. 0 
R E GI S T R A TI O N  
 
5. 1   
Recr uit m e nt  
T his st u d y will be i ntr o d uce d t o patie nts w h o meet eli gi bilit y criteria d uri n g t heir r o uti ne P D T 
visits a n d will eit her be pr o vi de d a c o p y of t he c o nse nt f or m t o ta ke h o me a n d re vie w  or gi ve 
per missi o n t o be c o nt act e d f or m ore i nf or mati o n re gar di n g t h e st u d y. If t h e st u d y c o or di n at or is 
a vaila ble, t he y will briefl y meet wit h t he patie nt t o pr o vi de c o p y of i nf or me d c o nse nt f or m a n d 
e x plai n st u d y desi g n, a n d t he patie nt will be i nstr ucte d t o re vi e w c o ns e nt f or m a n d call st u d y 
c o or di nat or wit h a n y q uesti o ns a n d/ or if t he y w o ul d li ke t o m o ve f or war d wit h partici pati o n. If t he 
st u d y c o or di nat or is n ot a vaila ble t o meet wit h t h e patie nt d uri n g t h eir r o uti ne visit, t he y will be 
n otifie d a n d will call t he patie nt t o e x plai n t he st u d y , a n d will als o se n d a c o p y of t he c o nse nt f or m 
via mail or e mail t o t he patie nt t o re vie w. If t he st u d y is n ot i ntr o d uce d t o t he patie nt, b ut t he y are 
eli gi ble, t he st u d y c o or di nat or ca n se n d a c o p y of o ur recr uit me nt letter t o patie nt via mail or 
M y C hart t o be  f oll o we d u p b y  a p h o ne call. Recr uit me nt will als o be ai de d b y I R B -a p pr o ve d 
a d vertise me nts p oste d i n t he Der mat ol o g y waiti n g r o o m or ot her a p pr o ve d l ocati o ns.   
 
5. 2   
C o nse nt:    
 
O n ce t he p atie nt re vie ws t he c o p y of t he c o nse nt f or m t hat was pr o vi de d b y t he st u d y c o or di nat or, 
eit her i n p ers o n or via m ail or e m ail a n d t he patie nt e x presses i nterest i n p artici pati n g he/s he will 
be sc he d ule d f or t he first st u d y visit.  O nce t he patie nt arri ves i n cli nic, t he st u d y will be e x plai ne d 
o nce  a gai n,  al o n g  wit h  t he  c ha nce  t o  as k  a d diti o nal  q uesti o ns, a n d  if  t he  patie nt  i n dicates 
c o nti n ui n g willi n g ness  t he n he/s he will si g n t he c o nse nt f or m a n d be c o nsi dere d e nr olle d.  
 
5. 3  
R a n d o miz ati o n :  
  
 
U p o n e nr oll me nt, eac h  patie nt will be t o assi g ne d  t o o ne of t he t hree treat m e nt re gi me ns ( A, B, or 
C) usi n g a bl oc k -r a n d o mizati o n sc he me t hat will be ge nerate d b y st aff i n t he Researc h  P har m ac y  
(I n vesti gati o nal Dr u g Ser vice) of t he Cle vel a n d Cli nic; t his assi g n me nt will i ns ure a n  e q ual  
distri b uti o n of st u d y patie nts acr oss  t he 3 gr o u ps. 
 
 
6. 0  T R E A T M E N T P L A N  
 
6. 1.   O ver all descri pti ve n arr ati ve  
At t he first visit ( Visit # 1) ( Da y 1), i nf or me d c o nse nt will be o btai ne d bef ore starti n g a n y st u d y 
pr oce d ur es. A K lesi o ns will be c o u nte d b y Dr. M a yti n a n d his pers o nall y-s u per vise d C C L C M 
me dical st u de nt resear c h er usi n g cli nical criteria t hat i ncl u de pres e nce of a visi ble lesi o n wit h 
er yt he ma ( pi n k or re d), prese nce of scale, a n d a gritt y c o nsiste nc y b y feel ( pal pati o n). Eac h 
i de ntifie d lesi o n will be mar ke d wit h a blac k pe n. All t he mar ke d lesi o ns will t he n be c o u nte d.  
As a bac k - u p, t he patie nt’s face will be p h ot o gra p he d wit h all t he pe n-mar ks i n place, f or lat er 
i n de pe n de nt c o nfir mati o n of lesi o ns c o u nts. 
 
P h ot o gra p hs will be ta ke n  t w o wa ys.  First, d oc u me nt ati o n of t he pe n-mar ke d lesi o ns o n t he face  
will be ta ke n usi n g C C F i -P h o nes t hat are r o uti nel y use d i n o ur cli nic; t he se di gital p h ot o gra p hs 
will  be tra nsferre d a n d st ore d directl y i n eac h st u d y patie nt ’s electr o ni c ( E pic)  rec or d.  

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 6     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
Sec o n d, f or p h ot o gra p hi c d oc u me ntati o n  of i nfla m mati o n , t he patie nt will als o be p h ot o gra p he d 
b y a pr ofessi o nal p h ot o gra p her  usi n g sta n dar dize d li g hti n g a n d m ulti ple vie ws t o d oc u me nt t he 
de gree of i nfla m mati o n at baseli ne .  
T he s ki n will be de greas e d wit h a n alc o h ol wi pe , lesi o ns ge ntl y a bra de d wit h fi ne sa n d pa per, a n d 
a t hi n la yer of A L A g el  ( A mel uz®) will be a p plie d t o t he e ntire face. N o o ccl usi ve dressi n g will 
be use d. F or p atie nts i n gr o u p A , t he A L A g el  will be left o n f or 1 0 mi n, a n d t he n p ositi o ne d i n 
fr o nt of t he r e d li g ht a n d e x p ose d f or 2 0 mi n; t his is a ( 1 0 + 2 0) re gi me n. P atie nts i n gr o u p  B  a n d 
gr o u p C  will recei ve a ( 2 0 + 1 0) re gi me n or ( 6 0 + 1 0) re gi me n, res pecti vel y. 
Pai n  will be assesse d b y as ki n g t he patie nt t o rate t heir percei ve d p ai n le vel o n a n 1 1 -p oi nt V A S 
scale ( 0 = n o pai n, 1 0 = i nt olera ble pai n). Patie nts will be as ke d t o re p ort t heir V A S  sc ore at 1 
mi n ute  after re d li g ht be gi ns, a n d at t he  5 mi n ute  mar k  ( w h e n t he R h o d o L E D bee ps). T he y will be 
as ke d f or a fi nal V A S  sc ore i m me diatel y after t he li g ht is t ur ne d off. 
T o assess s i de eff ects, patie nts will recei ve a 6- d a y q uesti o n naire t o rec or d t heir si de-effects dail y 
d uri n g t he c o mi n g wee k, a n d w hic h as ks t he m t o c o nfir m t hat t he y c o m pletel y a v oi de d a n y s u n 
e x p os ure  d uri n g  t he  first  t w o  da ys  after P D T . Patie nts  will  als o  recei ve a sta n dar d s et  of  
i nstr ucti o ns f or h o me aft ercare t hat i ncl u des A q ua p h or e m ollie nt, a t o pical ster o i d if necessar y f or 
c o mf ort, a n d i nstr ucti o ns t o wear s u nscree n a n d a v oi d s u nli g ht f or 4 8 hr.  
 
At t he sec o n d visit  ( Visit # 2)  ( Da y 3 ± 1 da y), t he patie nt will be p h ot o gra p he d b y o ur pr ofessi o nal 
p h ot o gra p her  usi n g  sta n dar dize d  li g hti n g  a n d  m ulti ple  vie ws,  t o  d o c u me nt  t he  d e gree  of  
i nfla m mati o n at 3 da ys after re d li g ht P D T.  
 
At t he t hir d visit  ( Visit # 3)  (Wee k 8  ± 1 wee k), lesi o ns will a gai n be mar ke d  a n d c o u nte d.  
P h ot o gra p hs will be ta ke n usi n g C C F i P h o nes t hat are r o uti nel y use d t o d oc u me nt t he mar ke d 
lesi o ns o n t he f ace. T hes e di gital p h ot o gra p hs will be tra nsferre d a n d st ore d directl y i n eac h st u d y 
patie nt’s electr o ni c ( E pic) rec or d.   
If a n y re mai ni n g lesi o ns are i de ntifie d, t he s ki n will be de grease d wit h a n alc o h ol wi pe, lesi o ns 
ge ntl y a bra d e d wit h fi ne sa n d pa per, a n d a t hi n la y er of A L A g el ( A mel uz ®)  will be a p plie d t o t h e 
e ntire face. N o o ccl usi ve dressi n g will be use d. F or patie nts i n gr o u p A , t he A L A gel will be left 
o n f or 1 0 mi n, a n d t he n p ositi o ne d i n fr o nt of t he re d li g ht a n d e x p ose d f or 2 0 mi n; t his is a ( 1 0 + 
2 0) re gi me n. Patie nts i n gr o u p B  a n d gr o u p C  will recei ve a ( 2 0 + 1 0) re gi me n or ( 6 0 + 1 0) re gi me n, 
res pecti vel y. 
Pai n  will be assesse d b y as ki n g t he patie nt t o rate t heir percei ve d p ai n le vel o n a n 1 1 -p oi nt V A S 
scale ( 0 = n o pai n, 1 0 = i nt olera ble pai n). Patie nts will be as ke d t o re p ort t heir V A S sc ore at 1 
mi n ute after re d li g ht be gi ns, a n d at t he 5 mi n ute mar k ( w h e n t he  R h o d o L E D bee ps). T he y will be 
as ke d f or a fi nal V A S sc ore i m me diatel y after t he li g ht is t ur ne d off.  
T o assess s i de eff ects, patie nts will recei ve a 6- d a y q uesti o n naire t o rec or d t heir si de-effects dail y 
d uri n g t he c o mi n g wee k. T he y will als o recei ve a sta n dar d set of i nstr ucti o ns f or h o me aftercare 
t hat i ncl u des A q ua p h or e m ollie nt, a t o pical ster oi d if necessar y f or c o mf ort, a n d i nstr ucti o ns t o 
wear s u ns cree n a n d a v oi d s u nli g ht f or 4 8 hr. 
 
T he f o urt h (fi n al) visit ( Visit # 4) will oc c ur at 3- 6 m o nt hs after Visit 1, f or fi nal lesi o n c o u nts, 
p h ot o gra p hs usi n g de part me nt i P h o ne, a n d a d mi nistrati o n of a patie nt satisfacti o n q uesti o n naire . 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 7     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
 
( See secti o n 1 1. 0 f or m ore det ails a b o ut t he Visit C ale n d ar) 
 
6. 2  
D ur ati o n of T her a p y 
Eac h  P D T t h era p y sessi o n  (Visit  1 a n d Visit 3) will last f or n o m ore t h a n 2  h o urs, de pe n di n g u p o n 
w hic h ar m of t he st u d y t he patie nt is i n.  
 
6. 3  
D ur ati o n of F oll o w U p  
Patie nts  will be f oll o we d u ntil t he e n d of Visit 4 , w hic h m ust occ ur wit hi n a f oll o w-u p wi n d o w of 
3- 6 m o nt hs after Visit 1 . T h us t he ma xi m u m d urati o n of F/ U is 6 m o nt hs. 
 
 
7. 0   
D O SI N G D E L A Y S / D O S E M O DI FI C A TI O N S :  n/a 
 
 
8. 0 
A D V E R S E E V E N T S: LI S T A N D R E P O R TI N G R E Q UI R E M E N T S  
T he f oll o wi n g is a list of A Es a n d t he re p orti n g re q uire me nts ass ociate d wit h o bser ve d A Es.  
 
T he cli nical c o urs e of eac h e ve nt will be f oll o we d u ntil res ol uti o n, sta bilizati o n, or u ntil it has bee n 
deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he ca use. Seri o us a d verse e ve nts t hat 
are still o n g oi n g at t he e n d of t he st u d y peri o d wil l necessitate f oll o w-u p t o deter mi ne t h e fi nal 
o utc o me. A n y seri o us a d verse e ve nt t hat occ urs after t he st u d y peri o d a n d is c o nsi dere d t o be 
p ossi bl y  relate d  t o  t he  st u d y  treat me nt  or  st u d y  partici pati o n  will  be  rec or d e d  a n d  re p orte d  
i m me diatel y. 
 
8. 1  
A d verse E ve nts a n d P ot e nti al Ris ks  
 
8. 1. 1 
A mel uz ®  
A mi n ole v u li nic aci d (A L A ) is a n at ural c o m p o n e nt f o u n d i n all cells i n t he h u ma n b o d y. A mel uz 
is 1 0 % A L A s us p e n de d i n a li pi d-base d n a n oe m ulsi o n. T he a p plicati o n of A L A is n ot ass oci ate d 
wit h a n y ris ks or si de eff ects. 
 
8. 1. 2  P h ot o dy n a mic T her a py  
W he n A L A is c o n verte d i nt o P pI X  i n t u m or cells, a n d ill u mi nate d wit h li g ht, t he f oll o wi n g si g ns 
a n d s y m pt o ms are k n o w n t o occ ur as p art of t he t hera pe utic res p o nse:  
(i)  
Sti n gi n g a n d/ or b ur ni n g se nsati o n:  > 5 0 % 
(ii) 
Er yt he ma (l ocalize d r e d n ess): 3 5 %  
(iii) 
E de ma, l ocalize d: > 3 5 %  
(i v)  
Peeli n g, tra nsie nt: < 5 0 % 
( v) 
Blister f or mati o n:  rare  
 
8. 1. 3  P h ot o dy n a mic T her a py res p o nse ( wit h l oc al c ut a ne o us effects):   
T he c o nstellati o n of tra nsie nt l ocal s y m pt o ms of sti n gi n g a n d/ or b ur ni n g, itc hi n g, er yt he ma a n d 
e de ma as a r es ult of t o pical a p plicati o n of A L A f oll o we d b y ill u mi nati o n wit h re d li g ht has bee n 
o bser ve d i n cli nical st u dies ; f or e xa m ple see ref [1 4 ]. Sti n gi n g a n d/ or b ur ni n g s u bsi de s bet wee n 1 
mi n a n d 2 4 h o urs after t he li g ht is t ur ne d off, a n d a p pears q u alitati vel y si milar t o t h at percei ve d b y 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 8     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
patie nts wit h er yt hr o p oi etic pr ot o p or p h yria u p o n e x p os ure t o s u nli g ht. T here is n o clear dr u g d os e 
or li g ht d ose de pe n de nt c ha n ge i n t he i nci de n ce or se verit y of sti n gi n g a n d/ or b ur ni n g. 
 
8. 1. 4  E xtr a- c ut a ne o us  a dverse e x perie nces re p orte d:   
I n pre v i o us st u dies, n o n o n-c uta ne o us a d vers e e ve nts were f o u n d t o be c o nsiste ntl y ass ociate d wit h 
A mel uz  a p plicati o n f oll o we d b y re d li g ht e x p os ure. N o cli nicall y si g nifica nt patter ns of cli nical 
la b orat or y c h a n ges w ere o bser ve d f or sta n dar d ser u m c he mical or h e mat ol o gic para met ers i n a n y 
of t he c o ntr olle d cli nical trials.   
 
8. 1. 5  S afety i n pre g n a ncy:   
N o car ci n o ge nicit y testi n g has bee n carrie d o ut usi n g A L A. N o e vi de nce of m uta ge nic effects was 
see n i n f o ur st u dies c o n d ucte d wit h A L A t o e val uate t his p ote ntial. N o assess me nt of effects of 
A L A o n fertilit y has bee n perf or m e d i n la b orat or y a ni mals. It is  u n k n o w n w hat effec ts s yste mic 
e x p os ure t o A L A mi g ht ha ve o n fertilit y or re pr o d u cti ve f u ncti o n.  T heref ore, A mel uz  is c o nsi dere d 
as Pre g na nc y C ate g or y C.  
 
8. 2 
Defi niti o ns  
 
8. 2. 1 
A dverse Eve nts    
 
A n  a d verse  e ve nt  ( A E)  is  a n y  u nf a v ora bl e  or  u ni nte n de d  e ve nt,  p h ysical  or  ps yc h ol o gical,  
ass ociate d wit h a researc h st u d y, w hic h ca uses har m or i nj ur y t o a researc h partici pa nt as a res ult 
of t he partici p a nt’s i n v ol ve me nt i n a researc h st u d y. T he e ve nt ca n i ncl u d e a b n or ma l la b orat or y 
fi n di n gs, s y m pt o ms, or disease ass oci ate d wit h t h e researc h st u d y. T he e v e nt d oes n ot necess aril y 
ha ve t o ha ve a ca usal r elati o ns hi p wit h t he researc h, a n y ris k ass ociate d wit h t he researc h, t he 
researc h i nter v e nti o n, or t he researc h assess me nts.  
 
A d verse e ve nts ma y b e t h e res ult of : (a) t h e i nter ve nti o ns a n d i nteracti o ns us e d i n t he researc h; ( b) 
t he  c ollecti o n  of  i de ntifia ble  pri vate  i nf or mati o n  i n  t he  researc h;  (c) a n  u n derl yi n g  disease,  
dis or der, or c o n diti o n of t he s u bject; a n d/ or ( d) ot her circ u msta n ces u nrelate d t o t he researc h or 
a n y u n derl yi n g disease, dis or der, or c o n diti o n of t h e s u bject. I n g e neral, a d v erse e ve nts t hat are at 
least partiall y t he res ult of (a) or ( b) w o ul d be c o nsi dere d rel ate d t o t he researc h, w h ereas a d vers e 
e vents s olel y relate d t o (c) or ( d) w o ul d b e c o nsi dere d u nrel ate d t o t he res earc h.  
 
E xter n al  a dverse  eve nts  are  a d v erse  e ve nts  e x p erie nce d  b y  s u bjects  e nr olle d  i n  m ultice nter  
cli nical  trials  at  sites  ot her  t ha n  t he  site(s)  o ver  w hic h  t he  I nstit uti o nal  Re vie w  B oar d  has  
j uris dicti o n.  
I nter n al a dverse eve nts are a d vers e e v e nts e x perie nce d b y s u bjects e nr oll e d at t he site(s) u n der 
t he I R B’s j uris dicti o n f or eit her m ultice nter or si n gle-ce nter res earc h pr ojects.  
 
8. 2. 2   T he si g nific a nce of a n a d verse e v e nt is use d t o descri be t he patie nt/e ve nt o utc o me or acti o n 
criteria ass ociate d wit h e ve nts t hat p ose a t hreat t o a patie nt’s life or f u ncti o ni n g (i.e., m o derat e, 
se vere or life t hreate ni n g).  Base d o n t he N ati o nal Ca ncer I nstit ute G ui deli nes f or t h e Ca ncer 
T h era p y E v al uati o n Pr o gra m, se verit y ca n be d efi ne d b y t he f oll o wi n g gra des of e ve nts: 
  
 
Gr a des 1 are mil d a d verse e ve nts. ( e. g., mi n or e v e nt re q uiri n g n o s pecific me dical i nter ve nti o n; 
as y m pt o matic la b orat or y fi n di n gs o nl y; mar gi nal cli nical rele va n ce)  

C A S E 4 6 2 3   
  
  
  
 
Pa ge 1 9     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
 
Gr a des 2 are m o der ate a d verse e v e nts (e. g., mi ni mal i nter ve nti o n; l ocal i nter ve nti o n; n o n -i n vasi ve 
i nter ve nti o n; tra nsf usi o n; electi ve i nter ve nti o nal ra di ol o gical pr oce d ure; t hera pe utic e n d os c o p y or 
o perati o n). 
 
Gr a des  3  ar e  se v ere  a n d  u n desira ble  a d vers e  e ve nts  (e. g.,  si g nifica nt  s y m pt o ms  re q uiri n g  
h os pitalizati o n  or  i n vasi ve  i nter ve nti o n;  tra nsf usi o n;  electi ve  i nter v e nti o nal  ra di ol o gical  
pr oce d ur e; t hera p e utic e n d osc o p y or o perati o n). 
 
Gr a des  4  are  life  t hreate ni n g  or  disa bli n g  a d verse  e v e nts  (e. g.,  c o m plicate d  b y  ac ute,  life -
t hreate ni n g meta b olic or car di o vas c ular c o m plicati o ns s uc h as circ ul at or y fail ure, he m orr ha g e, 
se psis; life– t hreate ni n g p h ysi ol o gic c o nse q ue nces; nee d f or i nte nsi ve care or e mer ge nt i n vasi ve 
pr oce d ur e; e mer g e nt i nter ve nti o nal ra di ol o gical pr oce d ure, t h era p e utic e n d osc o p y or o perati o n). 
 
Gr a des 5 are fatal a d verse e ve nts res ulti n g i n deat h.     
 
8. 2. 3   Seri o us A dverse Eve nts   
A seri o us a dverse eve nt ( S A E) is a n y a d v erse e x p erie nce occ urri n g at a n y d ose t hat res ults i n a n y 
of t he f oll o wi n g o utc o mes:  
•  Res ults i n de at h.   
•  Is a lif e-t hre ate ni n g a d verse e x p erie n ce.  T he ter m life -t hreat e ni n g i n t he defi niti o n of 
seri o us refers t o a n a d verse e ve nt i n w hic h t he s u bject was at ris k of deat h at t he ti me of t he 
e ve nt.  It d oes n ot r ef er t o a n a d v erse e ve nt w hic h h y p ot heticall y mi g ht ha ve ca us e d deat h 
if it were m ore s e ver e.  
•  Re q uires i n p atie nt  h os pit aliz ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit aliz ati o n.   A n y  
a d verse  e ve nt  lea di n g  t o  h os pitalizati o n  or  pr ol o n gati o n  of  h os pitalizati o n  will  be  
c o nsi dere d as Seri o us, U N L E S S at least o ne of t h e f oll o wi n g e x pect ati o ns is met:  
o  T he a d missi o n res ults i n a h os pital sta y of less t ha n 1 2 h o urs O R  
o  T he a d missi o n is pr e -pla n ne d (i.e., electi ve or sc h e d ule d s ur g er y arra n ge d pri or 
t o t he start of t he st u d y) O R 
o  T he  a d missi o n  is  n ot  ass ociate d  wit h  a n  a d verse  e ve nt  (e. g.,  s ocial  
h os pitalizati o n f or p ur p oses of res pite care.  
H o we ver it s h o ul d be n ote d t hat i n vasi ve treat me nt d uri n g a n y h os pitalizati o n ma y f ulfill 
t he criteria of “ me di call y i m p orta nt” a n d as s uc h ma y be re p orta ble as a seri o us a d verse 
e ve nt  de p e n da nt  o n  cli nical  j u d g me nt.   I n  a d diti o n  w here  l ocal  re g ul at or y  a ut h orities 
s pecificall y r e q uire a m ore stri n ge nt defi niti o n, t he l ocal re g ul ati o n ta kes prece d e nt.  
•  Res ults i n persiste nt or si g nific a nt dis a bility/i nc a p acity .  T h e d efi niti o n of disa bilit y is a 
s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life’s f u n cti o ns. 
•  Is a c o n ge nit al a n o m aly/ birt h defect .  
•  Is a n i m p ort a nt me dic al eve nt.  I m p ort a nt me dical e ve nts t hat ma y n ot res ult deat h, be life-
t hreate ni n g, or re q uir e h os pitalizati o n ma y be c o nsi dere d a seri o us a d v erse e x perie n ce 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he p atie nt or s u bject 
a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n 
t his defi niti o n.  E xa m ples of s uc h me di cal e v e nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt  i n a n e mer ge nc y r o o m  or at  h o me, bl o o d disease or dis or ders, or 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 0     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e. 
 
8. 2. 4 
E x pecte d ness  
A d verse E v e nts ca n b e E x pecte d or U n e x pecte d.  
 
A n e x pecte d a dverse eve nt  is a n e ve nt pre vi o usl y k n o w n or a ntici pate d t o res ult fr o m partici pati o n 
i n t he researc h st u d y or a n y u n derl yi n g disease, dis or der, or c o n diti o n of t he s u bject. T he e ve nt is 
us uall y liste d i n t he I n vesti gat or Br oc h ure, c o nse nt f or m or res earc h pr ot oc ol.  
 
A n u ne x pecte d a dverse eve nt  is a n a d verse e ve nt n ot pre vi o usl y k n o w n or a ntici pate d t o res ult 
fr o m t he res ear c h st u d y or a n y u n derl yi n g diseas e, dis or der, or c o n diti o n of t he s u bject.  
 
8. 2. 5 
Attri b uti o n  
Attri b uti o n is t he relati o ns hi p bet wee n a n a d v ers e e ve nt or seri o us a d v erse e ve nt a n d t he st u d y 
dr u g.  Attri b uti o n will be assi g ne d as f oll o ws: 
 
•  Defi nite – T he A E is clearl y relate d  t o t he st u d y dr u g. 
•  Pr o ba ble – T he A E is li k el y relate d t o t he st u d y dr u g. 
•  P ossi ble – T he A E ma y be relate d  t o t he st u d y dr u g. 
•  U nli kel y – T he A E is d o u btf ull y relate d t o t he st u d y dr u g. 
•  U nrelate d – T h e A E is cl earl y N O T relate d  t o t he st u d y dr u g. 
 
8. 3  
Re p orti n g Pr oce d ures f or All A d verse E ve nts  
All  partici pati n g  i n vesti gat ors  will  assess  t he  occ urre nce  of  A Es  t hr o u g h o ut  t he  s u bject’s  
partici pati o n i n t he st u d y. T he cli nical c o urs e of eac h e ve nt will be f oll o we d u ntil res ol uti o n, 
sta bilizati o n, or u ntil it has bee n deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he 
ca use.   
 
T he i n vesti gat or is r es p o nsi ble f or e ns uri n g t hat all a d verse e v e nts o bser v e d b y t he i n vesti gat or or 
re p orte d b y t he s u bject w hic h occ ur after t he s u bject has si g ne d t he i nf or me d c o nse nt are f ull y 
rec or d e d i n t he s u bject’s case re p ort f or m, s u bject’s me dical rec or ds, a n d/ or a n y ot her i nstit uti o nal 
re q uire me nt. S o urce d oc u me ntati o n m ust be a vaila ble t o s u p p ort all a d vers e e ve nts.  
 
A la b orat or y test a b n or m alit y c o nsi dere d cli nicall y rele va nt (e. g., ca usi n g t he s u bject t o wit h dra w 
fr o m t he st u d y), re q uiri n g treat me nt or ca usi n g a p p are nt cli nical ma nifestati o ns, or j u d ge d rele v a nt 
b y t he i n vesti gat or, s h o ul d be re p ort e d as a n a d verse e ve nt.   
 
T he i n vesti gat or will pr o vi de t he f oll o wi n g f or all a d verse e ve nts: 
•  Descri pti o n of t he e v e nt 
•  Date of o nset a n d res ol uti o n 
•  Gra de of t o xicit y  
•  Attri b uti o n of relate d ness t o t he i n vesti gati o nal a ge nt 
•  Acti o n ta ke n as a res ult of t he e ve nt  
•  O utc o me of e v e nt  
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 1     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
I n t his st u d y, descri pti o ns a n d gra di n g scales f o u n d i n t he N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E) versi o n 4. 0 a vaila ble at htt p://cte p.ca ncer. g o v  will be utilize d f or A E 
re p orti n g.  
 
I n v esti gati ve sites will re p ort a d verse e ve nts t o t heir res pecti ve I R B acc or di n g t o t he l ocal I R B’s 
p olicies a n d pr oce d ures i n re p orti n g a d verse e v e nts. 
 
8. 4  
Seri o us A d verse E ve nt Re p orti n g Pr oce d ures  
Seri o us a d vers e e v e nts t hat occ ur be gi n ni n g wit h t he si g ni n g of t he i nf or me d c o nse nt, d uri n g 
treat me nt, or wit hi n 3 0 d a ys of t he last d ose of treat me nt m ust be re p orte d t o t he C C F Pri nci pal 
I n v esti gat or.   
 
Re p orts of all seri o us a d v erse e v e nts (i ncl u di n g f oll o w- u p i nf or mati o n) will be s u b mitte d t o t he 
C C F I R B per t h e g ui deli nes l ocate d i n t he C C F I R B Sta n dar d O perati n g Pr oce d ures u n der I R B-
6 0 i n ma n ual. C o pies of eac h r e p ort a n d d o c u me ntati o n of I R B n otificati o n a n d res p o nse will be 
file d i n t he re g ulat or y bi n der. 
T he f oll o wi n g f o ur t y pes of e ve nts will be re p orte d t o t he Cle vela n d Cli nic I R B:  
1.  A d verse e ve nts w hic h ar e seri o us, u ne x p ecte d, a n d relate d or p ossi bl y rel ate d t o 
partici pati o n i n t he resear c h.  
2.  Seri o us a d verse e ve nts t h at are e x pect e d i n s o me s u bjects, b ut are d eter mi n e d t o be 
occ urri n g at a si g nifica ntl y hi g her fre q u e nc y or s e verit y t ha n e x pecte d.  
3.  Ot her u ne x pecte d a d v ers e e ve nts, re gar dless of se verit y, t hat ma y alter I R B a nal ysis 
of t he ris k vers us p ote nti al be nefit of t he researc h a n d, as a res ult, warra nt 
c o nsi derati o n of s u bsta nti ve c ha n ges i n t he researc h pr ot oc ol or i nf or m e d c o nse nt 
pr ocess/ d oc u me nt.  
4.  U na ntici pate d Pr o ble ms  i n v ol vi n g ris ks t o s u bjects or ot hers or a n y s eri o us or 
c o nti n ui n g n o nc o m plia nce wit h t his p olic y or t he re q uire me nts or det er mi nati o ns of 
t he I R B. 
 
T he  st u d y  tea m  will  n otif y  Bi ofr o ntera  of  a n y  seri o us  a d verse  e ve nts  via  e mail  t o  
 wit hi n 2 4 h o urs of st u d y tea m a ware ness.  
 
 
9. 0  
P H A R M A C E U TI C A L I N F O R M A TI O N     
 
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h t he c o m mercial a ge nts a d mi nistere d 
i n t his st u d y ca n be f o u n d i n Secti o n 8. 0.  
   
 
9. 1. A mel uz ® : T he f oll o wi n g i nf or mati o n a b o ut A mel uz ®  is cite d fr o m t he pac k a ge i nsert: 
 
C he mic al N a m e:      
5- a mi n ole v uli nic aci d ( A L A)  
 
Ot her N a m es:         
delt a -a mi n ole v uli nic aci d  
 
Cl assific ati o n:           
T o pical a ge nt  
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 2     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
M olec ul ar F or m ul a:   T he c he mical na me f or A L A H Cl is 5 -a mi n o- 4- o x o pe nta n oic aci d 
h y dr oc hl ori de ( M W = 1 6 7. 5 9). T he str uct ural f or m ula is re prese nt e d bel o w: 
 
 
 
M o de of Acti o n:       
P h ot oacti vati o n f oll o wi n g t o pical a p plicati o n of A M E L U Z occ urs 
w he n a mi n ole v uli nic aci d ( pr o dr u g) is meta b olize d t o 
pr ot o p or p h yri n I X ( P pI X), a p h ot oacti ve c o m p o u n d w hic h 
acc u m ulates i n t he s ki n. W he n e x p ose d t o re d li g ht of a s uita ble 
wa vele n gt h a n d e ner g y, P pI X is acti vate d res ulti n g i n a n e xcite d 
state of p or p h yri n m olec ules. I n t h e pres e nce of o x y ge n, reacti ve 
o x y ge n s pecies are f or me d w hic h ca uses d a ma ge t o cell ular 
c o m p o ne nts, a n d e ve nt u all y destr o ys t he cells. A M E L U Z 
p h ot o d y na mic t hera p y of A K lesi o ns utilizes p h ot oacti vati o n of 
t o picall y a p plie d A M E L U Z res ulti n g fr o m B F - R h o d o L E D® 
ill u mi nati o n, w hic h pr o vi des a re d li g ht of narr o w s pectr u m a n d a 
li g ht d ose of a p pr o xi matel y 3 7 J/c m2.  
 
Met a b olis m:    
A L A is c o n vert e d t o P pI X wit hi n mit oc h o n dria. P pI X is t he n 
destr o ye d u p o n ill u mi nati o n wit h t he i nci de nt li g ht (see a b o v e).  
 
Pr o d uct descri pti o n : A M E L U Z (a mi n ole v uli nic aci d h y dr oc hl ori d e) t o pical gel, 1 0 % is a n o n-
sterile w hite-t o- yell o wis h gel. T he gel f or m ulati o n c o ntai ns a na n oe m ulsi o n.  
A mi n ole v uli nic aci d, a p or p h yri n prec urs or, is a w hite t o off- w hite cr ystalli ne s oli d. It is rea dil y 
s ol u ble i n water, met ha n ol, a n d di met h ylf or ma mi de. Its c he mical na me is 5-a mi n o- 4- o x o-
pe nta n oic aci d h y dr oc hl ori de, m olec ular wei g ht is 1 6 7. 5 9 a n d m olec ula r f or m ula is 
C 5 H 9 N O 3∙H Cl.  
 
Eac h gra m of A M E L U Z c o ntai ns 1 0 0 m g of a mi n ole v uli nic aci d h y dr oc hl ori de (e q ui vale nt t o 7 8 
m g a mi n ole v uli nic aci d) as t he acti ve i n gre die nt a n d t he f oll o wi n g i nacti ve i n gre die nts: xa nt ha n 
g u m,  s o y bea n  p h os p hati d ylc h oli ne,  p ol ys or bate  8 0,  me di u m -c hai n  tri gl yceri des,  is o pr o p yl  
alc o h ol,  di basic  s o di u m  p h os p hate,  m o n o b asic  s o di u m  p h os p hate,  pr o p yle ne  gl yc ol,  s o di u m  
be nz oate a n d p urifie d water.  
 
Pr o d uct  S u p pl y : A M E L U Z  gel  is  s u p plie d  i n  a n  al u mi n u m  t u be  wit h  a  w hite,  hi g h  de nsit y 
p ol yet h yle ne ( H D P E) scre w ca p. Eac h t u be c o ntai ns 2 g of gel.  
 
St or a ge re q uire m e nts  a n d st a bilit y: A M E L U Z has a s helf -life of 2 4 m o nt hs a n d s h o ul d be 
st ored i n a refri ger at or, 2° C – 8° C ( 3 6° F – 4 6° F). E xc ursi o ns per mitte d t o 1 5° C – 3 0° C ( 5 9° F – 
8 6° F).  
After o pe ni n g, A M E L U Z ca n be st or e d f or u p t o 1 2 wee ks i n a refri g erat or at 2° C – 8° C ( 3 6° F – 
4 6° F) if t he t u be is ti g htl y cl ose d.  
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 3     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
R o ute of a d mi nistr ati o n:   A M E L U Z ®  will be a p plie d t o picall y t o t he s ki n, as directe d b y t he 
ma n ufact ur er. S pecificall y, u si n g gl o ve pr otecte d fi n gerti ps or a s p at ula, A M E L U Z gel will be 
a p plie d usi n g s ufficie nt a m o u nt of g el t o c o v er t he e ntire treat me nt area  wit h 1 m m t hic k ness , 
i ncl u di n g a p pr o xi matel y 5 m m of t he s urr o u n di n g s ki n. A p plicati o n area s h o ul d n ot e xcee d 2 0 
c m 2 a n d n o m ore t ha n 2 gra ms of A M E L U Z ( o n e t u be) s h o ul d be use d at o ne ti me. T he gel ca n 
be a p plie d t o h ealt h y s ki n ar o u n d t he lesi o ns. A p plicati o n  near m u c o us m e m bra nes s u c h as t h e 
e yes, n ostrils, m o ut h, a n d ears ( kee p a dista n ce of 1 c m fr o m t h ese areas)  s h o ul d be a v oi de d. T he 
st u d y  s u bject  will  be  a d vise d  t o  a v oi d  s u nli g ht  u ntil  he/s he  will  ret ur n t o  t he  cli nic  f or  t he  
ill u mi nati o n p hase of t he treat me nt. 
 
Dr u g Pr oc ure m e nt: A M E L U Z ® will be s u p plie d b y Bi ofr o ntera , i n t he a m o u nt of o ne t u be of 
A M E L U Z ®  gel per st u d y patie nt. 
Dr u g  Acc o u nt a bilit y:  T he  i n vesti gat or  or  desi g nate d  st u d y  pers o n nel  are  res p o nsi ble  f or  
mai ntai ni n g acc ur ate dis p e nsi n g rec or ds of t he st u d y dr u g.   All st u d y dr u gs m ust be acc o u nte d f or, 
i ncl u di n g st u d y dr u g acci de ntall y or deli beratel y destr o ye d.  U n der n o circ u msta nces will  t he 
i n vesti gat or all o w t he i n vesti gati o nal dr u g t o b e use d ot her t ha n as direct e d b y t he pr ot oc ol.  If 
a p pr o priate,  dr u g st or a g e, dr u g dis pe nsi n g, a n d  dr u g acc o u nta bilit y ma y be dele g ate d t o t he 
p har mac y s ecti o n of t he i n vesti gati ve si te.   
 
Dr u g Destr ucti o n:   A M E L U Z ® ca n b e st ore d f or 1 2 wee ks i n a refri gerat or at 2° C – 8° C ( 3 6° F – 
4 6° F) if t he t u be is ti g htl y cl ose d  
 
 
9. 2. Li g ht S o urces f or P D T  
 
B F - R h o d o L E D® la m ps are re d li g ht s o urces wit h a narr o w s p ectr u m ar o u n d 6 3 5 n m t hat deli ver 
a li g ht d ose of a p pr o xi matel y 3 7 J/c m 2 wit hi n 1 0 mi n utes. P D T usi n g A M E L U Z ® i n c o m bi nati o n 
wit h B F - R h o d o L E D® la m p is i n dicate d f or lesi o n-directe d a n d fi el d -direct e d treat me nt of acti nic 
kerat oses ( A Ks) of mil d -t o-m o derate se v erit y o n t he face a n d s cal p.  
1 0. 0 
C O R R E L A TI V E / S P E CI A L S T U DI E S :  
St u d y patie nts will be  i de ntifie d o nl y b y patie nt St u d y I D n u m ber , a n d t heir data st ore d i n a 
pass w or d- e n cr y pte d R E D Ca p data bas e accessi bl e o nl y be me m bers of t h e st u d y tea m.  
 
Pri v ac y a n d c o nfi de nti alit y : Me dical i nf or mati o n gat here d i n t his st u d y will be li mite d t o w hat 
is rec or de d i n t he r o uti ne cli nical P D T treat me nt n ote, al o n g wit h a n y st u d y-relate d n otes e ntere d 
i nt o t he electr o nic me dical rec or d ( E PI C). Patie nts m ust c o nse nt t o ha ve p h ot o gra p hs ta ke n of t heir 
facial lesi o ns at eac h visit, usi n g a sta n dar d d e part me ntal p h ot o gra p hic c o nse nt. C o nse nt t o all o w 
use of t h ose i ma ges i n me dical p u blicati o ns or pres e ntati o ns t hat res ult fr o m t he st u d y is v ol u ntar y , 
as t he patie nt will i n dicate i n a c hec k b o x. 
 
1 1. 0  
S T U D Y P A R A M E T E R S A N D D E T AI L E D S T U D Y C A L E N D A R  
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 4     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
Details of 1 0 % A L A a p plicati o n a n d re d li g ht treat me nt  were des cri be d  i n detail u n der Secti o n 
6. 0, “ Tr eat me nt Pla n ”. T he ti mi n g of visits is  s u m marize d bel o w a n d i n secti o n 1 1. 5  (“ Cal e n dar”).   
 
1 1. 1 
P D T tre at m e nt ( Visit 1 ) 
All A K lesi o ns ar e meas ure d cli nicall y a n d p h ot o gra p he d. T he cli nicia n a p plies 1 0 % A L A 
gel t o e ntire face, wit h o ut occl usi o n, a n d all o ws it t o i nc u bate if f or eit her 1 0 mi n, 2 0 mi n, 
or 6 0 mi n, de p e n di n g u p o n t he st u d y ar m assi g n me nt. T he p atie nt will t he n be e x p ose d t o 
re d li g ht (B F - R h o d o L E D® de vice) f or eit her  1 0 mi n or 2 0 mi n, as p er t h e assi g ne d st u d y 
ar m. 
 
1 1. 2 
P ost -tre at m e nt assess m e nt of si de-effects ( Visit 2)  
T he patie nt will ret ur n at da y 3 ( ± 1 da y)  f or facial p h ot o gra p hs t o d oc u me nt t heir  er yt he ma 
reacti o n. T h e y will als o be as ke d a b o ut t heir si de-effects, a n d i ns ure t hat t he y k n o w t o fill 
o ut t he si de-eff ects q uesti o n naire d uri n g t he 6 da ys p ost- P D T.  
 
1 1. 3 
P D T tre at m e nt ( Visit 3)  
T his will occ ur 8 w ee ks ( ± 1 wee k) after Visit 1. All A K lesi o ns will be meas ur e d cli nicall y 
a n d p h ot o gra p he d a n d if a n y re mai n, t he n t he s a me P D T treat me nt re gi me n use d at Visit 1 
will be e m pl o ye d a gai n h ere f or a sec o n d r o u n d of treat me nt. 
 
1 1. 4 
Fi n al o bser v ati o n ( Visit 4)  
T his will occ ur 3 - 6 m o nt hs after Visit 1. The s u bj ect will ret ur n f or fi nal s ki n e xa m, lesi o n 
c o u nts, a n d p h ot o gr a p h y.  A patie nt satisfacti o n q u esti o n naire will als o b e a d mi nistere d at 
t his visit. T he  lar ge sc he d uli n g visit wi n d o w is desi g ne d t o  ma xi mize t he li kel i h o o d of 
patie nt c o m plia nce , si nce  ma n y patie nts wit h A K are retirees w h o  s p e n d ma n y m o nt hs 
tra veli n g a n d s pe n d t heir wi nters i n war mer cli mat es  far fr o m Cle vela n d . 
 
1 1. 5 
St u d y C ale n d ar  
 
C A L E N D A R.   Ti meli ne of pr oce d ures f or p atie nts e nr olle d i n t he st u d y.  
 
 
VI SI T 1  
P D T  
tre at m e nt 
sessi o n # 1 
VI SI T 2  
P h ot os of  
s ki n 
re d ness  
VI SI T 3  
P D T 
tre at m e nt 
sessi o n # 2 
VI SI T 4  
 
Fi n al lesi o n 
c o u nts  
Sc he d ule d visit:  
Pr oce d ure: ↓ 
D a y 1  
D a y 3 ± 1 
d a y  
Wee k 8 ± 1  
wee k  
M o nt h 3 - 6  
Si g n i nf or me d c o nse nt   
X 
 
 
 
E xa mi ne patie nt, mar k eac h lesi o n 
wit h a pe n, a n d  c o u nt t he lesi o ns 
X 
 
X 
X  
Ta ke p h ot o gra p hs i n o ur pr ofessi o nal 
st u di o (fr o ntal vie w a n d si de vie ws) t o 
d oc u me nt i nfla m mati o n.  
X 
X 
 
 
Ta ke p h ot o gra p hs usi n g cli nic i P h o ne 
ca mera t o d oc u me nt lesi o n c o u nts 
( pe n-mar ks)  
X 
 
X 
X 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 5     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
 
 
1 2. 0  
M E A S U R E M E N T O F E F F E C T  
E n d p oi nts t o be e val uate d are as f oll o ws: Pai n re p orte d b y t he patie nts d uri n g ill u mi nati o n will 
be meas ur e d o n a s u bjecti ve 1 1- p oi nt vis ual- a nal o g scale ( V A S). Treat me nt res p o nse will be 
e val uate d b y cli nical e xa m a n d f oll o w- u p p h ot o gra p hs at t he t w o f oll o w- u p visits.  
E n d p oi nts will be:  
1 2. 1 
Pai n d uri n g ill u mi nati o n ( V A S scale 0- 1 0) at 1 mi n, 5 mi n, a n d 1 0 mi n 
1 2. 2 
1 0 0 % lesi o n clear a nce rates  
1 2. 3 
7 5 % lesi o n clear a nce rat es  
1 2. 4 
Vis ual differ e nces o bs er v e d i n t he bef ore- a n d -aft er p h ot os 
1 2. 5  
S u bject satisfacti o n q uesti o n naire 
1 2. 6 
A d verse E v e nts - Patie nts’ si de effects l o g ( 6 da ys p ost- P D T) a n d I n vesti gat or assess me nt. 
 
Re gar di n g lesi o ns cleara nce r ates (ite ms 1 2. 2 a n d 1 2. 3), t he fi nal efficac y o utc o me will be defi ne d 
as t he lesi o n c o u nts after t w o treat me nts, a n d t h ese fi nal c o u nts are w h at t he esti mate d e nr olle d 
sa m ple sizes ar e base d o n.  Lesi o n stat us after 1 P D T treat me nt will als o be a nal yze d, b ut n ot 
c o nsi dere d i n t he a nal yses of n o ni nferi orit y. 
 
 
1 3. 0 
R E C O R D S T O B E K E P T / R E G U L A T O R Y C O N SI D E R A TI O N S  
A d verse e ve nt lists, g ui deli nes, a n d i nstr ucti o ns f or A E re p orti n g ca n b e f o u n d i n Secti o n 8. 0 
( A d vers e E ve nts: List a n d Re p orti n g Re q uire me nts). 
 
1 3. 1 
D at a Re p orti n g  
T he O n C ore Data b ase will be utilize d, as re q uire d b y t he Cas e C o m pre he nsi ve Ca n cer 
Ce nter, t o pr o vi de d ata c ollecti o n f or b ot h accr u al e ntr y a n d trial data m a na ge me nt.   O n C ore 
is  a  Cli nical  Trials  Ma na ge me nt  S yste m  h o use d  o n  sec ure  ser v ers  mai ntai ne d  at  Case 
Wester n Res er ve U ni versit y.   O n C ore pr o perl y us e d is c o m plia nt wit h Title 2 1 C F R Part 1 1.  
A p pl y t o pical A L A gel a n d  i nc u bate 
f or 1 0, 2 0, or 6 0 mi n pri or t o t ur ni n g 
o n t he li g ht s o urce (as per assi g ne d 
st u d y ar ms A, B, or C, res pecti vel y) 
X 
 
X 
 
Ill u mi nate wit h re d li g ht f or 2 0, 1 0, or 
1 0 mi n (as per assi g ne d st u d y ar ms A, 
B, or C, res pecti vel y)  
X 
 
X 
 
Rec or d patie nt -re p orte d pai n le vel 
( V A S) 
X 
 
X 
 
Gi ve t he patie nt a q uesti o n naire t o fill 
o ut at h o me (t o descri be si de -effects 
o n eac h of t he 6 da ys p ost -P D T)  
X 
 
X 
 
Pr o vi de patie nt wit h a hat, s u nscree n 
a n d aftercare i nstr ucti o ns 
X 
 
X 
 
Patie nt satisfacti o n q uesti o n naire  
 
 
 
X 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 7     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
d oc u me nts t o deter mi ne w het her t hes e acti vities were c o n d ucte d, a n d d at a were rec or de d, 
a nal yse d, a n d acc uratel y re p orte d acc or di n g t o t h e pr ot oc ol, G o o d Cli nical Practice ( G C P), 
g ui deli nes of t he I nter n ati o nal C o nfere nce o n Har m o nizati o n (I C H), a n d a n y a p plica ble 
re g ulat or y r e q uire me nts.   
 
1 3. 2. 6 D at a S afety a n d M o nit ori n g Pl a n  
T his pr ot oc ol will a d here t o t he p olicies of t he Cas e C o m pre he nsi ve Ca n cer Ce nter Data 
a n d Safet y M o nit ori n g Pla n i n acc or da nce wit h N CI re g ulati o ns.  
 
1 4. 0     S T A TI S TI C A L C O N SI D E R A TI O N S  
 
1 4. 1 
Pri m ar y o bjecti ve:  
We wis h t o e val uat e t w o pri mar y e n d p oi nts, w hic h test t he f oll o wi n g h y p ot heses: 
 
Q uesti o n 1: 
Pai n is si g nifica ntl y re d uce d i n eac h of t he 3 s h ort P D T re gi me ns as c o m pare d t o 
t he sta n dar d r e gi me n.  
Q uesti o n 2: 
Cli nical e fficac y ( A K l esi o n cleara n ce) after eac h of t he 3 s h ort P D T re gi m e ns is 
statisticall y n o differe nt t ha n (is n o n- i nferi or t o) t he sta n dar d re gi me n. 
 
1 4. 2 
S a m ple size esti m ates : 
 
Alt h o u g h t here are t w o pri mar y e n d p oi nts, we ha ve p o were d t he st u d y base d u p o n t he sec o n d 
e n d p oi nt (efficac y) beca use t he first e n d p oi nt is alrea d y e xtre mel y li kel y t o pr o vi de acce pta ble 
res ults as a n a ntici pat e d o utc o me .  O ur reas o ni n g is as f oll o ws:  
 
F or Q u esti o n 1, e val uati n g  f or differe nces i n pai n , we will c o m pare t h e res ults fr o m o ur  st u d y 
patie nts t o p u blis he d res ults fr o m cli nical trials t hat use d A L A 3 hr i nc u b ati o n wit h occl usi o n 
a n d re d li g ht [5 ]. I n t h ose st u dies, o n a n 1 1-p oi nt V A S scale t he mea n p ai n s e nsati o n w he n usi n g 
t he acti ve dr u g w as 5. 5 [ 9 5 % c o nfi de n ce i nter v al ( CI) 4. 7 – 6. 2] d uri n g t he first P D T, a n d 5. 8 
( 9 5 % CI 4. 7 – 6. 9) d uri n g t he sec o n d P D T. W h e n usi n g  place b o, t he mea n pai n se nsati o n was 0. 9 
( 9 5 % CI 0. 3 – 1. 6) a n d 0. 3 ( 9 5 % CI 0 – 0. 6), res pecti vel y.  I n o ur st u d y, for esti mati n g w hat pai n 
le vel we mi g ht e x pect i n eac h t he t w o s h ort- d urati o n pr ot oc ols (re gi me ns A a n d B), t he o nl y 
esti mates a vaila ble are t h e V A S pai n val ues re p ort e d wit h a si milar s h ort- d urati o n pr ot oc ols 
usi n g Le v ula n a n d bl ue li g ht [7 ] i n w hic h t he mea n pai n se nsati o n was 0. 5 2 ( 9 5 % CI 0 – 1. 0 9). 
Base d o n t his, we f ull y e x pect t hat t he pai n re d ucti o n wit h re gi me ns A a n d B will be s u bsta ntial 
a n d cli nicall y mea ni n gf ul, re gar dl ess of t he sa m ple size. 
 
F or Q u esti o n 2, we  wa nt t o test f or n o n-i nferi orit y bet wee n o ur P D T re gi me n(s) a n d , t he ori gi nal 
3- hr i nc u bati o n wit h occl usi o n + 1 0 mi n re d li g ht re gi me n use d f or F D A a p pr o val  [5, 1 0 ]. F or t his 
p ur p ose, we will d o t he c o m paris o ns usi n g o ur re gi me n C, i n w hic h patie nts recei v e a 1 h o ur 
i nc u bati o n wit h o ut occl usi o n + 1 0 mi n re d li g ht. I n t he ori gi nal cli nical trial of A mel uz  a n d re d 
li g ht, A K cleara n ce rates were re p orte d t o b e 7 8 ± 1 5 % after 1 P D T treat me nt ( mea n ± S D, n = 
3 1 patie nts ) [1 5 ]. T o c o me u p wit h a n esti mate of w hat mi g ht ha p pe n wit h a s h orter re d li g ht 
re gi me n, we cite t he st u d y b y Nest or et al 2 0 1 9 w hic h re prese nts a reas o na ble s urr o gate f or o ur 
pr o p ose d s h ort ( 1- hr ) r e d li g ht re gi me n [1 2 ]. I n t hat st u d y, A mel uz was i nc u bate d f or 1 hr wit h o ut 
occl usi o n a n d t he n ill u mi nate d wit h bl ue li g ht ; t he A K cleara nce rate o n t he face i n 2 0 p atie nts 
usi n g A mel uz was  5 2. 3 % after 1 P D T treat me nt, a n d 9 7. 1 % after 2 P D T treat me nts. Nest or et al  

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 8     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
als o e xa mi ne d  t he A K cl eara n ce rate i n a n ot her 2 0 patie nts usi n g Le v ula n, w hic h was 5 7. 7% 
after 1 P D T tr eat me nt, a n d  9 4. 9% after 2 P D T treat me nts.  T he 1- treatm e nt A K cleara nce rate 
( 5 7. 7 %) r ese m bles a pre vi o us st u d y t hat we perf or me d wit h Le v ula n a n d a 1 hr i nc u bati o n ( Ka w 
et al), yiel di n g a n A K cleara nce  o n t he face of 6 1 % after 1 P D T treat me nt . T his s u g gests t hat 
res p o nses after bl ue li g ht or re d li g ht are v er y si milar. T heref ore, will use t he varia n ce f or t he 1 
hr i nc u bati o n gr o u p i n t he bl ue li g ht st u d y ( Ka w et al) w hic h was  6 1% ±  3 0 %  ( mea n ± SD ; n = 8 
patie nts ) [7 ]. U nf ort u natel y, t he Nest or 2 0 1 9 st u d y di d n ot pr o vi de a n y varia nce val ues  f or t heir 
re d li g ht data. Ho we v er, ot her A mel uz st u dies i n t he literat ure [1 5 ] re p ort a t y pical sta n dar d 
de viati o n ( S D) i n t he ra n ge of 2 5-3 0 % f or t he mea n A K cleara n ce rate, s o we will u se 3 0 % as t he 
S D val ue f or o ur p atie nts i n t his calc ulati o n. 
    T h us we wis h t o  c o m p are t he A K cleara n ce rates f or t he f oll o wi n g t w o c o n diti o ns, f or 
statistical n o n-i nferi orit y: 
 
Gr o u p 1  (l o n g 3 h o urs; c o ntr ol gr o u p):  7 8 ± 1 5 %  ( mea n ± S D, n = 3 1 pati e nts) 
Gr o u p 2  (s h ort 1 h o urs; e x peri me ntal  gr o u p): 6 1% ± 3 0 %  ( w hat p o w er will 1 0 patie nts gi ve us?) 
 
Statistical calc ulati o n of sa m ple size  ( Dr. B o H u, P h. D):  F or t he n o n-i nferi orit y desi g n, n = 1 0 
patie nts per gr o u p will ha ve 8 0 % p o wer t o c o m pare eac h i nter ve nti o n wit h t he c o ntr ol gr o u p, 
ass u mi n g a n o n-i nferi orit y mar gi n of 2 5 % cleara n ce rat e, a tr u e differe nce of 1 0 % a n d a st a n dar d 
de viati o n of 1 3 % (t w o-si de d al p ha = 0. 0 5). 
 
 
1 4. 3 
Esti m ate of t he accr u al r ate:   
 
Dr. Ma yti n treats ~ 3 - 4 p atie nts wit h A K lesi o ns o n t he ar ms or le gs  per wee k, usi n g re d li g ht 
P D T .  O nce t he I R B pr ot oc ol is a p pr o ve d, w e a nti ci pate t hat we s h o ul d be a ble t o recr uit o ne 
patie nt per  wee k , or ~ 3-4 patie nts/ m o nt h, wit h e nr oll me nt c o m plet i o n i n ~ 5 m o nt hs a n d f ull 
st u d y c o m pleti o n wit hi n o ne year.  
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 2 9     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
R E F E R E N C E S  
 
1.  
Ma yti n, E. V. a n d C. B. Warre n, P h ot o d y n a mic T her a py , i n M ayti n E V, W arre n C B. 
P h ot o dy n a mic t her a py. P ost T W, e d. U p T o D ate. W alt h a m, M A: U p T o D at e I nc. 
htt p:// w w w. u pt o date.c o m . Accesse d S e pte m b er 3 0, 2 0 2 2. 2 0 1 8. 
2.  
A na n d, S., et al., Bi o m o d ulat or y a p pr oac hes t o p h ot o d y na mic t hera p y f or s oli d t u m ors . 
C a ncer Lett , 2 0 1 2. 3 2 6 ( 1): p. 8- 1 6. 
3.  
Braat he n, L. R., et al., G ui deli nes o n t he use of p h ot o d y na mic t hera p y f or n o n mela n o ma 
s ki n ca ncer: a n i nter nati o nal c o nse ns us. I nter nati o nal S ociet y f or P h ot o d y na mic T hera p y 
i n Der mat ol o g y, 2 0 0 5. J A m Ac a d Der m at ol , 2 0 0 7. 5 6 ( 1): p. 1 2 5- 4 3. 
4.  
Warr e n, C. B., et al., Pai n ass ociate d wit h a mi n ole v uli nic aci d- p h ot o d y na mic t hera p y of 
s ki n disease. J A m A c a d Der m at ol , 2 0 0 9. 6 1 ( 6): p. 1 0 3 3- 4 3. 
5. 
Rei n h ol d U. et al. A ra n d o mize d, d o u ble- bli n d, p hase III, m ultice ntre st u d y t o e val uate 
t he safet y a n d effi cac y of B F- 2 0 0 A L A ( A mel uz) vs. place b o i n t he fiel d-directe d 
treat me nt of mil d-t o- m o derate acti nic kerat osis wit h p h ot o d y na mic t hera p y ( P D T) w he n 
usi n g t he B F- R h o d o L E D la m p. Br J Der mat ol. 2 0 1 6; 1 7 5( 4): 6 9 6- 7 0 5.  
6.  
B ull oc k, T. A., et al., Si g nifica nt i m pr o ve me nt of facial acti nic kerat oses after bl ue li g ht 
p h ot o d y na mi c t hera p y wit h oral vita mi n D pretreat me nt: A n i nter ve nti o nal c o h ort-
c o ntr olle d trial . J A m A c a d Der m at ol , 2 0 2 2. 8 7 ( 1): p. 8 0- 8 6. 
7.  
Ka w, U., et al., A re gi me n t o mi ni mize pai n d uri n g bl ue li g ht p h ot o d y na mic t hera p y of 
acti nic ker at oses: Bilater all y c o ntr olle d, ra n d o mize d trial of si m ulta ne o us v ers us 
c o n ve nti o nal ill u mi nati o n . J A m Ac a d D er m at ol , 2 0 2 0. 8 2 ( 4): p. 8 6 2- 8 6 8. 
8.  
Warr e n, C. B., et al., N o ni n vasi ve fl u oresce nce m o nit ori n g of pr ot o p or p h yri n I X 
pr o d ucti o n a n d cli nical o utc o mes i n acti nic kerat oses f oll o wi n g s h ort-c o ntact a p plicati o n 
of 5 -a mi n ole v uli nate. J Bi o me d O pt , 2 0 1 0. 1 5 ( 5): p. 0 5 1 6 0 7. 
9.  
A na n d, S., et al., Pai nless P h ot o d y na mic T hera p y Tri g gers I n nat e a n d A d a pti ve I m m u ne 
Res p o nses i n a M uri ne M o del of U V-i n d uce d S q ua m o us S ki n Pre- ca ncer. P h ot oc he m 
P h ot o bi ol , 2 0 2 1. 9 7 ( 3): p. 6 0 7- 6 1 7. 
1 0.  
Dirsc h ka, T., et al., P h ot o d y na mic t hera p y wit h B F- 2 0 0 A L A f or t he treat me nt of acti nic 
kerat osis: res ults of a m ultice ntre, ra n d o mize d, o bser ver- bli n d p hase III st u d y i n 
c o m paris o n wit h a re gist ere d met h yl- 5- a mi n olae v uli nate crea m a n d place b o . Br J 
Der m at ol , 2 0 1 2. 1 6 6 ( 1): p. 1 3 7- 4 6. 
1 1.  
Dirsc h ka, T., et al., L o n g-ter m ( 6 a n d 1 2 m o nt hs) f oll o w- u p of t w o pr os pecti ve, 
ra n d o mize d, c o ntr olle d p hase III trials of p h ot o d y na mic t hera p y wit h B F- 2 0 0 A L A a n d 
met h yl a mi n olae v uli nate f or t he treat me nt of acti ni c kerat osis . Br J Der m at ol , 2 0 1 3. 
1 6 8 ( 4): p. 8 2 5- 3 6. 
1 2.  
Nest or, M. S., et al., Safet y a n d Efficac y of A mi n ole v uli nic Aci d 1 0 % T o pical Gel vers us 
A mi n ole v uli nic Aci d 2 0 % T o pical S ol uti o n F oll o we d b y Bl ue-li g ht P h ot o d y na mic 
T hera p y f or t he Tr eat me nt of Acti nic Kerat osis o n t he Face a n d Scal p: A Ra n d o mize d, 
D o u ble- bli n d St u d y . J Cli n Aest het Der m at ol , 2 0 1 9. 1 2 ( 3): p. 3 2- 3 8. 
1 3.  
Ba bes, A., et al., P h ot ose nsitizati o n i n P or p h yrias a n d P h ot o d y na mic T hera p y I n v ol v es 
T R P A 1 a n d T R P V 1 . J Ne ur osci , 2 0 1 6. 3 6 ( 1 9): p. 5 2 6 4- 7 8. 
1 4.  
Ma yti n, E. V., et al., 5- Fl u or o uracil E n ha n ces Pr ot o p or p h yri n I X A cc u m ulati o n a n d 
Lesi o n Cleara n ce d uri n g P h ot o d y na mic T hera p y of Acti nic Kerat oses: A M ec ha nis m-
Base d Cli nical Trial . Cli n C a ncer Res , 2 0 1 8. 2 4 ( 1 3): p. 3 0 2 6- 3 0 3 5. 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 3 0     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
1 5.  
Szei mies, R. M., et al., P h ot o d y na mic t hera p y wit h B F- 2 0 0 A L A f or t he treat me nt of 
acti nic ker at osis: res ults of a pr os pecti ve, ra n d o mi ze d, d o u ble- bli n d, place b o-c o ntr olle d 
p hase III st u d y . Br J Der m at ol , 2 0 1 0. 1 6 3 ( 2): p. 3 8 6- 9 4. 
 
 
 

C A S E 4 6 2 3   
  
  
  
 
Pa ge 3 1     
  
 
Versi o n date:  06/ 0 5 / 2 0 2 3 
 
 
 
A p pe n di x 1: S pecific ati o ns f or A m el uz ®  
See A p pe n de d P D F A mel uz ® U S -PI  
 
A p pe n di x 2: S pecific ati o ns f or B F -R h o d o L E D ® re d -li g ht s o urce  
See A p pe n de d P D F f or B F - R h o d o L E D ® L a m p M a n u al