Clinical trial NCT04269395
Conditions: Keratosis, Actinic
Sponsor: Galderma R&D
Start date: 2020-04-07; Completion date: 2021-09-01
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose for this study is to assess recurrence of Actinic Keratosis in participants achieving complete response treated in earlier study.

Detailed description:
This is a double-blind, multicenter, long-term follow-up study. The primary purpose of this study is to assess recurrence of Actinic Keratosis in participants treated with Methyl aminolevulinate hydrochloride (MAL) 16.8 percent (%) cream (CD06809-41) or vehicle cream in the treatment of thin and moderately thick, non-hyperkeratotic, non-pigmented actinic keratosis of the face and scalp when using daylight photodynamic therapy (DL-PDT), for participants achieving complete response of treated lesions at Final Visit in Study RD.06.SPR.112199 (NCT04085367).

Arms: arm 1: Participants who completed the study RD.06.SPR.112199 (NCT04085367) and achieved complete response of all treated lesions at the final visit of the active cream group, will continue for long-term follow-up to evaluate recurrence of AKs in this study. arm 2: Participants who completed the study RD.06.SPR.112199 (NCT04085367) and achieved complete response of all treated lesions at the final visit in the vehicle cream group, will continue for long-term follow-up to evaluate recurrence of AKs in this study.
Interventions: intervention 1: MAL Cream intervention 2: Vehicle cream
Intervention descriptions: intervention 1: No intervention will be administered as a part of this study. Participants who received MAL cream in RD.06.SPR.112199 study will be rolled over in the study. intervention 2: No intervention will be administered as a part of this study. Participants who received vehicle cream in RD.06.SPR.112199 study and achieved complete response, will be rolled over in the study.

Protocol documents:
Prot_000.pdf: 
C LI NI C A L S T U D Y P R O T O C O L
A d o u ble -bli n d, m ultice nter, l o n g -ter m f oll o w-u p st u dy t o assess rec urre nce of Acti nic 
Ker at osis i n s u bjects tre ate d wit h Met hyl a mi n olev uli n ate hy dr oc hl ori de ( M A L) 1 6. 8 % cre a m 
( C D 0 6 8 0 9-4 1) or ve hicle cre a m i n t he tre at me nt of t hi n a n d m o der ately t hic k, n o n-
hy per ker at otic, n o n- pi g me nte d acti nic ker at osis of t he f ace a n d sc al p w he n usi n g d ayli g ht 
p h ot o dy n a mic t her a py ( D L- P D T), f or s u bjects ac hievi n g c o m plete res p o nse of tre ate d lesi o ns 
at Fi n al Visit i n St u dy R D. 0 6. S P R. 1 1 2 1 9 9
P r ot oc ol N u m ber: 
R D. 0 6. S P R. 1 1 5 2 3 0
E u dr a C T N u m ber:
N ot A p plica ble
:
I n vesti g ati o n al Pr o d uct:
N o ne
I N D N u m ber:
P h ase:
3
S p o ns or:
Gal der ma R esearc h & D e vel o p me nt , L LC
1 4 5 0 1 N ort h Free wa y
F ort W ort h, T X 7 6 1 7 7
C o ntr act Rese arc h Or g a niz ati o n:
Pr ot oc ol D ate :
0 7 J A N 2 0 2 1
Pr ot oc ol Versi o n :
Versi o n 3. 0 A me n d me nt 2
C O N FI D E N TI A L
T his d oc u me nt c o nt ai ns c o nfi de nti al, pr o priet ar y i nf or m ati o n, a n d m a y n ot be re pr o d uce d 
or c o m m u nic ate d t o a t hir d p art y wit h o ut t he writte n per missi o n of G al der m a R & D, L L C.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI
P P D
P P D
P P D


 
              
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 3 of 4 4
C O N FI D E N TI A L
2
S T U D Y P E R S O N N E L C O N T A C T S
G al der m a Rese arc h & Devel o p me nt, L L C Pers o n nel
Na me:
Title:
Se ni or Me dical E x pert
A d dress:
Gal der ma Researc h & De vel o p me nt, L L C
1 4 5 0 1 N ort h Free wa y
F ort W ort h, T X 7 6 1 7 7
U nite d States
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
P P D
P P D


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 4 of 4 4
C O N FI D E N TI A L
3
S Y N O P SI S
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Title: A d o u ble -bli n d, m ultice nter, l o n g -ter m f oll o w-u p st u d y t o assess rec urre nce of Acti nic Kerat osis i n s u bjects 
treate d wit h Met h yl a mi n ole v uli nate h y dr oc hl ori de ( M A L) 1 6. 8 % crea m ( C D 0 6 8 0 9-4 1) or ve hicle crea m i n t he 
treat me nt of t hi n a n d m o deratel y t hic k, n on- h y per kerat otic, n o n -pi g me nte d acti nic kerat osis of t he face a n d scal p 
w he n usi n g da yli g ht p h ot o d y na mic t hera p y ( D L -P D T), f or s u bjects ac hie vi n g c o m plete res p o nse of treate d lesi o ns at 
Fi nal Visit i n S t u d y R D. 0 6. S P R. 1 1 2 1 9 9
I n vesti g ati o n al Pr o d uct: n o ne
I N D N u m ber:
St u d y Ce nters: A p pr o xi matel y 6 0 st u d y ce nters are pla n ne d i n t he U nite d States
P h ase: 3
O bjecti ves:
Pri m ar y o bjecti ve : T he pri mar y o bjecti ve of t his st u d y is t o assess rec urre nce of  lesi o ns treate d i n R D. 0 6. S P R. 1 1 2 1 9 9
f or t h ose s u bjects w h o ac hie ve d C o m plete Res p o nse ( C R) of treate d A K lesi o ns. T h e y  will be offere d t he o p p ort u nit y 
t o partici pate i n t his 9-m o nt h l o n g -ter m f oll o w-u p st u d y (i.e., 5 2 wee ks after t he last D L - P D T), c o nti n ui n g t he d o u ble-
bli n d c o n d uct of t his st u d y .
S ec o n d ar y o bjecti ve : T he sec o n dar y o bjecti ve of t his st u d y is t o e val uate t he l o n g-ter m safet y of M A L D L -P D T a n d 
ve hicle crea m D L -P D T f or 5 2 w ee ks after t he last D L -P D T f or t h ose s u bjects w h o ac hie ve d C o m plete Res p o nse 
( C R) of treate d A K lesi o ns i n st u d y R D. 0 6. S P R. 1 1 2 1 9 9
St u d y Desi g n: T his is a d o u ble -bli n d, m ultice nter, parallel gr o u p, ve hicle -c o ntr olle d l o n g -t er m f oll o w-u p st u d y t o 
e val uate rec urre nce of A Ks i n s u bjects w h o c o m plete d st u d y R D. 0 6. S P R. 1 1 2 1 9 9. O nl y t h ose s u bjects w h o ac hie ve d 
C R of treate d A K lesi o ns at t he Fi nal Visit (1 2 w ee ks after t he last D L -P D T sessi o n) will be offere d t he o p p ort u nit y 
t o c o nti n ue t o be f oll o we d i n t he c urre nt st u d y f or 9 m o nt hs t o assess rec urre nce. After o btai ni n g i nf or me d c o nse nt 
f or t his f oll o w-u p st u d y, t he s u bjec ts will ret ur n at Wee ks 1 4 a n d 4 0, w hic h c orres p o n d t o 2 6 a n d 5 2 wee ks after t he 
last D L -P D T sessi o n, res pecti vel y t o assess t he lesi o ns treate d i n t he pre vi o us st u d y f or rec urre nce of A K.
Rec urre nce will be deter mi ne d b y rea p peara nce of t h ose lesi o ns c o m p letel y cleare d b y 2 D L-P D T sessi o ns, i.e., 
s u bjects w h ose lesi o ns are e val uate d t o be n o n-C R at t he visits i n t his st u d y will be dee me d t o ha ve rec urre nce. If t he 
perce nta ge of s u bjects mai ntai ni n g c o m plete res p o nse w o ul d be 6 0 % at Visit 3 ( 5 2 w ee ks after t he last D L -P D T), 
4 0 % of s u bjects w o ul d ha ve e x perie nce d rec urre nce (s u bject rec urre nce res p o nse). T he sa me calc ulati o n will be d o ne 
f or lesi o n c o m plete res p o nse, t o assess t he lesi o n rec urre nce. T here w ill be a tele p h o ne c hec k -i n wit h t he s u bjects b y 
t he cli nical site at Wee k 4 0 t o hel p retai n t he s u bject’s partici pati o n f or t he e ntire d urati o n of t he st u d y.
 
 
N u m ber of S u bjects: 
A p pr o xi matel y 1 1 1 s u bjects fr o m t he M A L crea m ar m a n d 1 9 s u bjects fr o m t he ve hicle crea m ar m fr o m t he pre vi o us 
st u d y are e x pecte d t o e nr oll i n t he f oll o w-u p st u d y. 
T re at me nt:
Neit her i n vesti gati o nal pr o d uct n or i nter ve nti o n will be part of t his st u d y.
St u d y D ur ati o n:
T he e x pecte d d urati o n f or eac h s u bject’s par tici pati o n i n t he st u d y will be a p pr o xi matel y 4 0 wee ks fr o m t he c o mpleti o n 
of st u d y R D. 0 6. S P R. 1 1 2 1 9 9 .
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 5 of 4 4
C O N FI D E N TI A L
S t u d y P o p ul ati o n:
T he st u d y p o p ulati o n will c o nsist of a d ult male a n d fe male s u bjects wit h cli nicall y c o nfir me d mil d t o m o derate acti nic 
kerat osis o n t he face a n d bal di n g scal p, w h o ha ve c o mplete d st u d y R D. 0 6. S P R. 1 1 2 1 9 9 wit h a C o m plete Res p o nse at 
Fi nal Visit of t hat st u d y, mea ni n g t h ose s u bjects, w h o se treate d A Ks were all clear e d at 1 2 we e ks after t he last D L -
P D T sessi o n.
I ncl usi o n Criteri a: T o be eli gi ble f or st u d y e ntr y, s u bjects m ust satisf y all of t he f oll o wi n g i ncl usi o n criteria :
1.
S u bjects w h o ha ve partici pate d i n st u d y R D. 0 6. S P R. 1 1 2 1 9 9 a n d ha ve ac hie ve d a c o m plete res p o nse at t he Fi nal 
Visit of t hat st u d y, defi ne d as c o m plete cleara nce of all treate d lesi o ns at 1 2 wee ks after t he last D L -P D T
2.
Writte n I nf or me d C o nse nt bef ore a n y assess me nt relate d t o t he L T F U st u d y is perf or me d
3.
Willi n g a n d ca pa ble of c o m pl yi n g wit h re q uire me nts of t he pr ot oc ol
E xcl usi o n Criteri a : S u bjects will be e xcl u de d fr o m t he st u d y if 1 or m ore of t he f oll o wi n g e xc l usi o n criteria are 
a p plica ble :
1.
S u bjects, w h o de vel o p or e x perie nce a c o n diti o n t hat m y c o m pr o mise s u bject safet y or c o m plia nce, i nterfere wit h 
e val uati o n or precl u de c o mpleti o n of t he st u d y. I n partic ular, t hese c o n diti o ns i ncl u de, b ut are n ot li mite d t o
mali g na nc y or ot her life t hreate ni n g diseases.
2.
Perti ne nt n o n -c o mplia nce wit h 
t he c o n diti o ns f or t his st u d y or i nstr ucti o ns b y  the i n vesti gat or d uri n g 
R D. 0 6. S P R. 1 1 2 1 9 9
Pri m ar y E n d p oi nt :

S u bject rec urre nce, defi ne d as t he pr o p orti o n of s u bjects wit h rec urre nce of a n y (≥1) cleare d treate d A K lesi o ns 
at Visit 3, 5 2 wee ks after t he last D L -P D T treat me nt .
Sec o n d ar y E n d p oi nt s:

S u bject rec urre nce, defi ne d as t he pr o p orti o n of s u bjects w it h rec urre nce of a n y (≥1) cleare d treate d A K lesi o ns 
at Visit 2 , 2 6 we e ks after t he last D L -P D T treat me nt ;

Lesi o n rec urre nce, defi ne d as t he perce nt rec urre nce of cleare d treate d lesi o ns at Visits 2 a n d 3, 2 6 a n d 5 2 w ee ks 
after t he last D L -P D T treat me nt .
T he rec urre nce res ults will be c o n ve ye d i n t he o p p osite se nse of cleara nce, i.e., t h ose s u bjects or lesi o ns t hat are n ot 
C R at Visits 2 a n d 3 w ill be dee me d t o ha ve rec urre nce.
S afet y Assess me nts :
T he f oll o w i n g safet y assess me nts are pla n ne d acc or di n g t o t he sc he d ule of a ssess me nts (see T a ble 1 ):

A d verse e ve nts ( A Es), Treat me nt -e mer ge nt A Es ( T E A Es) , a n d seri o us A Es ( S A Es)
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 6 of 4 4
C O N FI D E N TI A L
St atistic al A n al ysis :
Pri nci p al St atistic al Met h o d
P o p ul ati o ns: T he safet y p o p ulati o n will c o nsist of all e nr olle d s u bjects a n d w ill be use d f or all t he efficac y a n d safet y 
a nal yses.
P ri m ary E n d p oi nt : T he pr o p orti o n of s u bjects w it h rec urre nce of a n y (≥1) cleare d treate d A K lesi o ns at 5 2 w ee ks 
after t he last D L -P D T w ill be s u m marize d usi n g ta bles of fre q ue nc y. All s u bjects i n t he safet y p o p ula ti o n wit h 
missi n g data will be classifie d as n o n -res p o n ders re gar dless of treat me nt all ocati o n. S u m maries b y treat me nt gr o u p 
will be prese nte d f or b ot h t he i m p ute d data a n d t he o bser ve d cases .
 
Sec o n d ary E n d p oi nts: T he pr o p orti o n of s u bjects wit h rec urre nce of a n y ( ≥1) cleare d treate d A K lesi o ns at 2 6 w ee ks 
after t he last D L -P D T w ill be s u m marize d usi n g ta bles of fre q ue nc y. All s u bjects i n t he safet y p o p ulati o n wit h 
missi n g data will be classifie d as n o n -res p o n ders re gar dless of treat me nt all ocati o n. S u m maries b y treat me nt gr o u p 
will be prese nte d f or b ot h t he i m p ute d data a n d t he o bser ve d cases .
 
T he perce nt rec urre nce of cleare d treate d A K lesi o ns at 2 6 a n d 5 2 w ee ks after t he last D L -P D T treat me nt will be 
s u m marize d usi n g descri pti ve statistics. M issi n g c o u nts of cleare d treate d A K lesi o ns f or s u bjects i n t he safet y 
p o p ulati o n will be i m p ute d ass u mi n g t hat all baseli ne A K lesi o ns ha d rec urre d re gar dless of treat me nt all ocati o n.
S u m maries b y treat me nt gr o u p w ill be prese nte d f or b ot h t he i m p ute d data a n d t he o bser ve d cases.
 
S a m ple Size : T here is n o f or mal h y p ot hesis t o be teste d. T he n u m ber of 1 0 0 c o m pleters i n t he M A L crea m ar m is 
dee me d s ufficie nt f or t he descri pti ve p ur p oses of t his st u d y.
F i g ure 1 : St u d y Sc he m a ( S y n o psis)
T C =tele p h o ne c all
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI
C CI
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 7 of 4 4
C O N FI D E N TI A L
4
T A B L E O F C O N T E N T S
1
P R O T O C O L A P P R O V A L SI G N A T U R E S .............................................................. 2
2
S T U D Y P E R S O N N E L C O N T A C T S ......................................................................... 3
3
S Y N O P SI S .................................................................................................................... 4
4
T A B L E O F C O N T E N T S ............................................................................................ 7
T A B L E O F FI G U R E S ................................................................................................................... 9
T A B L E O F T A B L E S ..................................................................................................................... 9
5 
LI S T O F A B B R E VI A TI O N S................................................................................... 1 0
6
I N T R O D U C TI O N ..................................................................................................... 1 1
6. 1
B ac k gr o u n d & R ati o n ale .......................................................................................... 1 1
7
S T U D Y O B J E C TI V E S & E N D P OI N T S ................................................................. 1 4
7. 1
Pri m ar y O bjecti ve ..................................................................................................... 1 4
7. 2
Sec o n d ar y O bjecti ve .................................................................................................. 1 4
7. 3
Pri m ar y E n d p oi nt ...................................................................................................... 1 4
7. 4
Sec o n d ar y E n d p oi nts ................................................................................................. 1 4
7. 5
S afet y Assess me nts ..................................................................................................... 1 4
7. 6
Ot her Assess me nts ..................................................................................................... 1 4
8
I N V E S TI G A TI O N A L P L A N ................................................................................... 1 5
8. 1
O ver all St u d y Desi g n a n d Pl a n ................................................................................. 1 5
St u d y  Sc he ma .............................................................................................................. 1 6
Sc he d ule of Assess me nts ........................................................................................... 1 7
8. 2  
Disc ussi o n of St u d y Desi g n ....................................................................................... 2 0
St u d y  Desi g n................................................................................................................ 2 0
8. 3
Selecti o n of t he St u d y P o p ul ati o n ............................................................................. 2 0
N u m ber of Pla n ne d S u bjects ....................................................................................... 2 0
I ncl usi o n Criteria......................................................................................................... 2 0
E x cl usi o n Criteria........................................................................................................ 2 1
Re m o val of S u bjects Fr o m Assess me nts..................................................................... 2 1
Met h o d of C o nti n ui n g alrea d y Ra n d o mize d S u bject fr o m Pre vi o us st u d y ................. 2 2
Bli n di n g....................................................................................................................... 2 2
Pri or a n d C o nc o mita nt T hera p y................................................................................... 2 2
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 8 of 4 4
C O N FI D E N TI A L
8. 4
D ur ati o n of S u bject P artici p ati o n............................................................................ 2 4
Earl y Ter mi nati o n Visit ............................................................................................... 2 4
8. 5
U nsc he d ule d Visit ...................................................................................................... 2 4
9
S T U D Y A S S E S S M E N T S .......................................................................................... 2 5
9. 1
Effic ac y Assess me nts ................................................................................................. 2 5
Lesi o n Res p o nse.......................................................................................................... 2 5
9. 2
S afet y Assess me nts ..................................................................................................... 2 6
9. 2. 1. 1
Seri o us A d verse E ve nts ............................................................................................... 2 8
9. 2. 1. 2
A d verse E ve nts of S pecial I nterest ( A E SIs) ................................................................ 2 9
9. 2. 1. 3
Pr oce d ure f or Re p orti n g a Seri o us A d verse E ve nt ...................................................... 2 9
9. 2. 1. 4
Pr oce d ure f or Re p orti n g Pre g na ncies .......................................................................... 3 0
9. 2. 1. 5  
U ne x pecte d A d verse Reacti o ns................................................................................... 3 1
Pre ga nc y  Testi n g ......................................................................................................... 3 1
............................................................................... 3 2
1 0 
S T A TI S TI C A L M E T H O D S..................................................................................... 3 3
1 0. 1
St atistic al a n d A n al ytic al Pl a ns ................................................................................ 3 3
Data sets or P o p ulati o ns A nal y ze d .............................................................................. 3 3
1 0. 1. 1. 1
I nte nt-t o-Treat P o p ulati o n ........................................................................................... 3 3
1 0. 1. 1. 2
Safet y  P o p ulati o n......................................................................................................... 3 3
1 0. 1. 1. 3
Per Pr ot oc ol P o p ulati o n ............................................................................................... 3 3
De m o gra p hic a n d Ot her Baseli ne C haracteristics .......................................................3 3
Efficac y  A nalys is......................................................................................................... 3 3
1 0. 1. 3. 1
Pri mar y  E n d p oi nt A nalys is.......................................................................................... 3 3
1 0. 1. 3. 2
Pri mar y  E n d p oi nt Se nsiti vit y A nalys is........................................................................ 3 4
1 0. 1. 3. 3
Sec o n dar y  E n d p oi nts A nal ysis .................................................................................... 3 4
1 0. 1. 3. 4
S u b gr o u p A nal y sis ....................................................................................................... 3 4
Safet y A nal ys is............................................................................................................ 3 4
1 0. 1. 4. 1  
A d verse E ve nts ............................................................................................................ 3 4
I nteri m A nalys es .......................................................................................................... 3 4
Ha n dli n g of Missi n g Data............................................................................................ 3 5
1 0. 2
Deter mi n ati o n of S a m ple Size................................................................................... 3 6
1 0. 3 
Pr ot oc ol De vi ati o ns.................................................................................................... 3 6
1 1
Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L ....................................... 3 7
1 1. 1
A u dit a n d I ns pecti o n ................................................................................................. 3 7
1 1. 2
M o n it ori n g.................................................................................................................. 3 7
1 1. 3
Pers o n nel Tr ai ni n g .................................................................................................... 3 7
1 1. 4
D at a M a n a ge me nt ...................................................................................................... 3 7
 
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G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 9 of 4 4
C O N FI D E N TI A L
1 1. 5
Cli nic a l St u d y C o n d uct ............................................................................................. 3 8
1 1. 6
A m e n d me nts ............................................................................................................... 3 8
1 1. 7
Q u alit y M a n a ge me nt a n d Ris k E v al u ati o n ............................................................. 3 8
1 2
E T HI C S ...................................................................................................................... 3 9
1 2. 1
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d............................ 3 9
1 2. 2
Re g ul at or y A ut h orities .............................................................................................. 3 9
1 2. 3
Et hic al C o n d uct of t he St u d y .................................................................................... 3 9
1 2. 4
I nf or me d C o nse nt ...................................................................................................... 3 9
1 2. 5
S u bject C o nfi de nti alit y .............................................................................................. 4 0
1 3
R E P O R TI N G A N D P U B LI C A TI O N, I N C L U DI N G A R C HI VI N G .................... 4 1
1 4
R E F E R E N C E S .......................................................................................................... 4 2
I N V E S TI G A T O R SI G N A T UR E P A G E .................................................................................... 4 4
T A B L E O F FI G U R E S
Fi g ure 1: St u d y  Sc he ma ( S yn o psis) ................................................................................................. 6
Fi g ure 2: St u d y  Sc he ma.................................................................................................................. 1 6
T A B L E O F T A B L E S
Ta ble 1: Sc he d ule of Assess me nts .................................................................................................. 1 7
Ta ble 2: F or bi d de n Treat me nts i n Treat me nt Area........................................................................ 2 3
Ta ble 3: Lesi o n Se verit y Gra de Scale ............................................................................................ 2 5
Ta ble 4: Lesi o n Res p o nse ............................................................................................................... 2 5
................................................................................................... 3 6
 
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G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 0 of 4 4
C O N FI D E N TI A L
5
LI S T O F A B B R E VI A TI O N S
A E
A d ve rse E ve nt
A K
Acti nic kerat osis
B C C
Basal cell carci n o ma
B L
Baseli ne
CI
C o nfi de nce i nter val
C R
C o m plete res p o nse
C R O
C o ntract researc h or ga nizati o n
C S
Cli nicall y si g nifica nt
c-P D T
C o n ve nti o nal P D T
D L
Da yli g ht
e CR F
Electr o nic C ase R e p ort F or m
E D C
Electr o nic data ca pt ure
E T
Earl y ter mi nati o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F S T
Fitz patric k S ki n T y pe
G C P
G o o d Cli nical Practice
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
I B
I nvesti gat or’s Br oc h ure
I C
I nf or me d C o nse nt
I C F
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or P har mace uticals 
f or H u ma n Use
I E C
In de pe n de nt E t hics C o m mittee
I R B
Instit uti o nal R e vie w B oar d
L T F U
L o n g -ter m f oll o w- u p
M A L
Met h yl a mi n ole vi n ulate h y dr oc hl ori de
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
N D A
Ne w dr u g a p plicati o n
P D T
P h ot o d y na mic T hera p y
P pI X
Pr ot o p or p h yri n I X
S A E
S eri o us a d verse e ve nt
S A P
S tatistical anal ysis p la n
S C C
S q ua m o us cell car ni n o ma
SI N 
S u bject i de ntificati o n n u m ber
S O C
S yste m Or ga n Class
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o n
T A
Treat me nt area
T E A E
T reat me nt-e mer ge nt ad verse eve nt
T M F
Trial Master File
U P T
U ri ne p re g na nc y test
U S
U nite d States
U V
Ultra vi olet
 
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0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 1 of 4 4
C O N FI D E N TI A L
6
I N T R O D U C TI O N
6. 1 
B ac k gr o u n d & R ati o n ale
Acti nic kerat osis ( A K) is a c o m m o n e pit helial n o n- i nfiltrati ve lesi o n ca use d b y pr ol o n ge d 
e x p os ure t o ultra vi olet ( U V) ra diati o n, w hic h da ma ges cell c y cle re g ulat ors a n d lea ds t o t he 
pr oliferati o n of e pi der mal kerati n oc y tes. A cti nic kerat oses are pre mali g na nt s ki n lesi o ns t hat are 
c haracteristicall y distri b ute d o n s u n -e x p ose d areas s uc h as face, bal d scal p, nec k, c hest, bac k of 
t he ha n ds, a n d f orear ms. I n di vi d uals ofte n prese nt wit h m ulti ple a cti nic kerat osis.
A cti nic kerat os is is a gl o bal c o n diti o n a n d it is t he sec o n d m ost fre q ue nt dia g n osis ma de b y 
der mat ol o gists i n t he U S ( U hle n ha ke 2 0 1 3 ) wit h pre vale nce bet wee n 1 1 % a n d 2 6 % 
(Salasc he 2 0 0 0 ). A cti nic kerat oses t he msel ves are dee me d n ot seri o us, b ut t he y  are ver y c o m m o n, 
hi g hl y wi des prea d , a n d rec urre nt. A cti nic kerat osis is c o nsi dere d t he earliest, cli nicall y 
rec o g niza ble ma nifestati o n of s q ua m o us cell carci n o ma ( S C C) t hat is ca pa ble of tra nsf or mi n g 
i nt o S C C (in sit u a n d i n vasi ve) ( Fel d ma n 2 0 1 1 p 2 0 1 ). Bet wee n 6 0-8 0 % of S C C cases be gi n as 
A K ( Fel d ma n 2 0 1 1 ). T he rate of pr o gressi o n of A K t o i n vasi ve S C C has bee n esti mate d t o be 
fr o m less t ha n 0. 0 2 5 % to 1 6 % per y ear (Wer ner 2 0 1 3 ). H o we ver, t here is n o relia ble wa y t o 
meas ure t his rate a n d pre dict w hic h lesi o ns will tra nsf or m, mea ni n g t hat it is necessar y  t o treat 
A K lesi o ns t o a v oi d pr o gressi o n.
T he eti ol o g y  of A K is m ultifact orial, a n d ris k fact ors i ncl u de i ncrease d a ge, male ge n der, a fair 
s ki n Fitz patric k s ki n t y pe, a n d e xte nsi ve o ut d o or acti vities (G ol d ber g 2 0 1 0 ). M ore o ver, A K is a n 
i n dicat or of c hr o nic ultra vi olet ( U V ) da ma ge a n d t h us , of i ncrease d ris k f or U V -relate d s ki n 
ca ncer. A re vie w of e pi de mi ol o gical st u dies s h o we d t hat t he pre vale nce a n d i nci de nce of A K are
hi g hl y varia ble acc or di n g t o t he p o p ulati o n st u die d, w orl d l ocati o n, a ge, a n d ge n der ( Fr ost 1 9 9 4 ). 
F or e xa m ple, pre vale nce rates near 6 0 % ha ve bee n re p orte d i n A ustralia, a n d e ve n u p t o 6 4 % i n 
w o me n a n d 8 3 % i n me n a ge d 6 0 t o 6 9 y ears ( Fr ost 1 9 9 8 ; Fr ost 2 0 0 0 ), i n c o ntrast t o t he 
pre vale nce rate re p orte d i n E n gla n d i n 2 0 0 0 of 1 5. 4 % i n me n a n d 5. 9 % i n w o me n ol der t ha n 4 0 
ye ars (Me m o n 2 0 0 0 ). T hese rates i ncrease d t o 3 4. 1 % a n d 1 8. 2 %, res pecti vel y, at 7 0 years of a ge, 
w he n pre vale nce wa s m ost str o n gly relate d t o 2 o bjecti ve si g ns of s u n e x p os ure, s olar elast osis 
a n d le nti gi nes. T he S o ut h Wales S ki n Ca ncer St u d y re p orte d a n A K pre vale nce of 2 3 % 
(Har ve y 1 9 9 6 ). St u dies i n t he U nite d States ha ve re p orte d pre vale nce rates of 5 5 % i n i n di vi d uals 
a ge d 6 5 t o 7 5 y ears wit h hi g h s u n e x p os ure, b ut o nl y  1 2 % t o 1 9 % i n t h ose wit h l o w s u n e x p os ure 
(E n gel 1 9 8 8 ).
Vari o us treat me nt o pti o ns are a vaila ble f or A K lesi o ns, i ncl u di n g destr ucti ve t hera pies s uc h as 
cr y os ur ger y  or e xcisi o nal s ur ger y, t o pical t hera pies s uc h as 5-fl u or o uracil, i mi q ui m o d, 
dicl ofe nac, i n ge n ol me b utate, a n d n o n- a p pr o ve d t o pical or or al reti n oi ds (G ol d 2 0 0 6 ; 
Fe ns ke 2 0 1 0 ). H o we ver, patie nt satisfacti o n wit h ma n y of t hese treat me nts, es pecially t he 
destr ucti ve t hera pies, ca n be affecte d b y c o nsi dera ble treat me nt disc o mf ort a n d resi d ual scarri n g. 
P h ot o d y na mic t hera p y  ( P D T) is a hi g hl y efficaci o us t hera p y rec o m me n de d as a first-li ne 
treat me nt f or i n di vi d ual, or m ulti ple a n d/ or c o nfl ue nt A K lesi o ns (de Ber ker 2 0 0 7 ; 
Braat he n 2 0 0 7 ). P h ot o d y na mic t hera p y has bee n ass ociate d wit h a better c os metic o utc o me t ha n 
ot h er treat me nts, a n d it ca n als o be use d t o treat m ulti ple A K le si o ns o ver lar ge areas 
(Le h ma n n 2 0 0 7 ; Si d or off 2 0 1 0 ).
 
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0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 2 of 4 4
C O N FI D E N TI A L
Met vi xia ® crea m 1 6 8 m g/ g ( met h yl  a mi n ole v uli nate) was a p pr o ve d i n t he U S A i n 2 0 0 8 ( N D A
0 2 1 4 1 5) i n c o m bi nati o n wit h L E D re d li g ht ill u mi nati o n usi n g t he A ktilite ® C L 1 2 8 la m p f or t he 
treat me nt of t hi n a n d m o derately t hic k, n o n -h y per kerat otic , a n d n o n -pi g me nte d A K of t he face 
a n d scal p (it was i nitiall y a p pr o ve d i n 2 0 0 4 wit h t he C u reli g ht la m p), a n d was mar kete d f or m ore 
t ha n 4 years u ntil it was wit h dra w n i n t he U nite d States i n 2 0 1 2 f or c o m mercial reas o ns. T he 
pr o d uct, use d i n c o m bi nati o n wit h re d li g ht ill u mi nati o n, is als o na me d Met vi x or Met vi xi a i n 
ot her c o u ntries w orl d wi de.
Gal der ma has de ve l o pe d a ne w treat me nt re gi me n f or t he face a n d scal p, i n w hic h nat ural 
da y li g ht ( D L) ma y re place t he pre vi o usly-a p pr o ve d re d li g ht as t he mea ns of acti vati n g t he P pI X 
f or me d after a p plicati o n of t he crea m d uri n g P D T.
Gi ve n t hat t he area t o be treate d is n o l o n ger li mite d b y  t he size or c o nfi g urati o n of t he la m p, t he 
D L - P D T pr oce d ure is si m plifie d c o m pare d t o c o n ve nti o nal P D T ( c-P D T ). In a d diti o n, 
si g nifica ntly less pai n is e x perie nce d d uri n g ill u mi nati o n as s h o w n i n 2 ra n d o mize d, P hase 3 
cli nical st u dies rece ntl y c o n d ucte d b y Gal der ma. T hese st u dies, perf or me d i n A ustralia ( N = 1 0 0) 
a n d E ur o pe ( N = 1 0 8), c o nfir me d t hat m et h yl  a mi n ole v uli nate h y dr oc hl ori de (M A L ) D L -P D T has 
si milar efficac y as M A L wit h c - P D T, lea ds t o fe wer relate d a d verse e ve nts, is nearl y pai nless ,
a n d m ore c o n ve nie nt f or s u bjects ( R u bel 2 0 1 4 , Lac o ur 2 0 1 5 ). It is k n o w n t hat t he use of t he re d 
la m p res ults i n disc o mf ort a n d pai n f or s u bjects, as all pr o d uce d P pI X is p h ot o bleac he d i n a s h ort 
peri o d of ti me. Wit h 2 h o urs of D L e x p os ure, P pI X will be c o nti n u o usl y  pr o d uce d at a ver y l o w 
le vel a n d i m me diately p h ot o blea c he d wit h n o or al m ost n o pai n.
T he use of D L -P D T , as o p p ose d t o t he use of bl ue or re d li g ht s o urces c-P D T , has ma n y be nefits. 
I n partic ular, t he use of D L will treat w h ole fiel ds of ca ncerizati o n t o tar get visi ble a n d 
s u bcli nical A K lesi o ns, a n d is n ot li mit e d t o cli nicall y a p pare nt lesi o ns. I n 2 0 1 5, a n E ur o pea n 
c o nse ns us o n D L-P D T ( M ort o n 2 0 1 5 p 1 ) rec o m me n de d D L-P D T as a first -li ne treat me nt o pti o n 
f or i m m u n oc o m pete nt patie nts wit h Gra de I (t hi n) or II ( m o deratel y t hic k) A Ks or fiel ds of 
acti nic da ma ge o n t he face a n d scal p, d ue t o its efficac y , t olera bilit y, a n d si m plicit y. M ore 
rece ntly, a str uct ure d E x pert C o nse ns us o n Acti nic Kerat osis has c o nfir me d D L -P D T as a 
val ua ble o pti o n f or s u bjects wit h m ulti ple A Ks i n s mall or lar ge fiel ds ( Calza vara -Pi nt o n, 2 0 1 7 ).
Met h y l a mi n ole v uli nate h y dr oc hl ori de is mar kete d u n der vari o us tra de na mes: Met vi x / Met vi xia 
/ Me x vi via 1 6 0 m g/ g or 1 6 8 m g/ g. T he pr o d ucts are i de ntical b ut are la belle d differe ntl y ,
de pe n di n g o n t he vari o us c o u ntr y  s pecific a p pr o vals. As of 3 0 J u ne 2 0 19 , t he pr o d uct is a p pr o ve d 
i n 3 9 c o u ntries f or t he treat me nt of A K, basal cell carci n o ma (B C C ), a n d B o we n’s disease 
(i n di vi d ual c o u ntr y a p pr o vals var y) wit h a re d la m p. As of 3 0 J u ne 2 0 1 9 , Met vi x® Crea m wit h 
D L  acti vati o n f or t he treat me nt of A K has bee n a p pr o ve d as a variati o n to t he c urre nt Met vi x 
A ktilite a ut h oriz ati o n i n E ur o pe a n d o utsi de E ur o pe ( Ar ge nti na, A ustralia, Ne w Zeala n d, 
Si n ga p ore, S witzerla n d, R ussia n Fe derati o n, C ol o m bia, Me xic o, Brazil, C osta Rica, Ve nez uela, 
C hile , a n d Ca na da). I n a d diti o n, Lu xera, L u xer m , a n d Lu me xia are ot her c o m mercial na mes f or 
t he sa me pr o d uct, w hic h is a p pr o ve d f or t he treat me nt of A Ks wit h da y li g ht o nl y, a p pr o ve d i n 
A ustria, Ger ma n y, Ital y, P ort u gal, S pai n, a n d S we de n.
 
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1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 3 of 4 4
C O N FI D E N TI A L
Gal der ma is de vel o pi n g M A L  D L-P D T i n t he U nite d S tates f or lesi o n treat me nt, b ut ma y  
c o nsi der fiel d treat me nt as a sec o n dar y  i n dicati o n f or life c ycle ma na ge me nt. T his st u d y  ser ves as 
a f oll o w-u p st u d y  t o R D. 0 6. S P R. 1 1 2 1 9 9 t o e val uate rec urre nces of lesi o ns t hat ac hie ve d C R i n 
b ot h M A L crea m D L-P D T a n d ve hicle crea m D L-P D T treate d gr o u ps.
 
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A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 4 of 4 4
C O N FI D E N TI A L
7
S T U D Y O B J E C TI V E S & E N D P OI N T S
7. 1
Pri m ar y O bjecti ve
T he pri mar y  objecti ve of t his st u d y is t o assess rec urre nce of A Ks treate d i n R D. 0 6. S P R. 1 1 2 1 9 9 
f or t h ose s u bjects w h o ac hie ve d C o m plete Res p o nse ( C R) of treate d A K lesi o ns. T he y  will be 
offere d t he o p p ort u nit y  to partici pate i n t his 9- m o nt h l o n g-ter m f oll o w-u p st u d y (i.e., 5 2 wee ks 
after t he last D L-P D T), c o nti n ui n g t he d o u ble- bli n d c o n d uct of t his st u d y . 
7. 2
Sec o n d ar y O bjecti ve
T he sec o n dar y  o bjecti ve of t his st u d y is t o e val uate t he l o n g-ter m safety of M A L  D L-P D T a n d 
ve hicle crea m D L -P D T f or 5 2 wee ks after t he last D L-P D T f or t h ose s u bjects w h o ac hie ve d 
C o m plete Res p o nse ( C R) of treate d A K lesi o ns i n st u d y  R D. 0 6. S P R. 1 1 2 1 9 9.
7. 3
Pri m ar y E n d p oi nt
•
T he pri mar y  efficac y e n d p oi nt is t he s u bject rec urre nce, defi ne d as t he pr o p orti o n of s u bjects 
wit h rec urre nce of a n y ( ≥1) cleare d treate d A K lesi o ns at Visit 3, 5 2 wee ks after t he last D L -
P D T treat me nt .
7. 4
Sec o n d ar y E n d p oi nts
•
Lesi o n rec urre nce, defi ne d as t h e perce nt rec urre nce of cleare d treate d lesi o ns at Visits 2 a n d 
3, 2 6 a n d 5 2 wee ks after t he last D L -P D T treat me nt .
•
S u bject rec urre nce, defi ne d as t he pr o p orti o n of s u bjects wit h rec urre nce of a n y  (≥1) cleare d 
treate d A K lesi o ns at Visit 2, 2 6 wee ks after t he last D L -P D T treat me nt .
7. 5 
S afet y Assess me nts
•
Assess safety, i ncl u di n g a d verse e ve nts ( A Es), Treat me nt -e mer ge nt A Es ( T E A Es), relate d t o 
t he st u d y dr u g a d mi nistered i n st u d y R D. 0 6. S P R. 1 1 2 1 9 9 a n d seri o us A Es ( S A Es)
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
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G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 5 of 4 4
C O N FI D E N TI A L
8
I N V E S TI G A TI O N A L P L A N
8. 1
O ver all St u d y Desi g n a n d Pl a n
T his is a d o u ble -bli n d, ve hicle -c o ntr olle d, m ultice nter, parallel- gr o u p l o n g-ter m f oll o w- u p st u d y to 
e val uate rec urre nce of A Ks i n s u bjects w h o c o m plete d st u d y RD. 0 6. S P R. 1 1 2 1 9 9.
O nl y  th ose 
s u bjects w h o ac hie ve d C R of treate d A K lesi o ns at t he Fi nal Visit of t hat st u d y  will be offere d t he 
o p p ort u nit y  t o c o nti n ue t o be f oll o we d i n t he c urre nt st u d y f or 9 m o nt hs t o assess rec urre nce.
I n this st u d y, t he res ults of D L-P D T wit h M A L  1 6.8 % crea m or a ve hicle crea m will be c o m pare d ; 
n o i nter ve nti o n occ urs i n t his st u d y . 
All s u bjects will pr o vi de writte n i nf or me d c o nse nt pri or t o a n y st u d y -relate d pr oce d ure.
A t otal of a p pr o xi matel y 1 3 0 s u bjects will
c o nti n ue fr o m t he st u d y RD. 0 6. S P R. 1 1 2 1 9 9 t o be 
f oll o we d f or a n ot her 4 0 wee ks , w hic h c orres p o n ds t o 5 2 wee ks after t he last D L -P D T. It is 
a ntici pate d t hat a p pr o xi matel y 1 1 1 s u bjects will c o nti n ue fr o m t he M A L  crea m ar m, a n d 1 9 
s u bjects will c o nti n ue fr o m t he ve hicle crea m arm. Bli n di n g will be mai ntai ne d t hr o u g h t his st u d y.
S u bjects will ha ve a c o m bi ne d visit w hic h i ncl u des t he fi nal visit f or t he R D. 0 6. S P R. 1 1 2 1 9 9 st u d y  
a n d t he i nitial visit f or t his st u d y. Data fr o m t he pre vi o us st u d y will be p ulle d i nt o t he data base f or 
t his st u d y. S u bjects will ret ur n t o t he st u d y ce nter f or a n ot her visit at Visit 2 ( Wee k 1 4, 2 6 wee ks 
after t he last D L -P D T treat me nt) f or efficac y an d safet y assess me nts. T he i n vesti gati ve site staff 
will c o ntact t he s u bject via tele p h o ne at Wee k 2 6 ( 3 8 wee ks after t he last D L -P D T treat me nt) t o 
deter mi ne if t he s u bject is e x perie nci n g a n y  treat me nt-relate d safety iss ues.
T he pri mar y  e n d p oi nt of t his st u d y occ urs at Visit 3; Fi nal V isit, Wee k 4 0 ( 5 2 wee ks after t he last 
D L -P D T visit ).
T he 4 pla n ne d i nteracti o ns are:
Visit 1
R oll o ver visit fr o m st u d y R D. 0 6. S P R. 1 1 2 1 9 9 ; c orres p o n ds t o Visit 6 i n t hat 
st u d y. O nly t h ose s u bjects w h o ac hie ve C R will be gi ve n t he o p p ort u nit y t o 
c o nti n ue i n t his l o n g-ter m f oll o w-u p st u d y . All assess me nts ca pt ure d are 
tra nsferre d t o t his st u d y 
Visit 2
Wee k 1 4 ( 2 6 wee ks after t he last D L -P D T treat me nt) - Efficac y a n d safet y 
assess me nts ; 
 
Tele p h o ne 
c hec k i n 
Wee k 2 6
( 3 8 wee ks after t he last D L -P D T treat me nt ) - Safet y assess me nts
Visit 3
Wee k
4 0 Fi nal Visit (5 2 wee ks after t he last D L -P D T treat me nt) - Efficac y 
a n d safety assess me nts; 
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 6 of 4 4
C O N FI D E N TI A L
St u d y Sc he m a
Fi g ure 2: St u d y Sc he m a
T C =tele p h o ne c all
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 7 of 4 4
C O N FI D E N TI A L
Sc he d ule of Assess me nts
T a ble 1 : Sc he d ule of Assess me nts
Vi sit
1
2
2 b a, b
3
4
4 b a, b
5 a, b
6 a, b
1 
2 ( 7)
T C
3 ( 8)
P ur p o s e
M e di c al 
hi st or y  
a n d l a b s
Fir st
D L -P D T
s e s si o n
If
r e q uir e d
F oll o w -u p
1 w e e k aft er
1 st D L -P D T
S e c o n d D L -
P D T
s e s si o n
If
r e q uir e
d
F oll o w -u p
1 w e e k aft er
2 n d D L -P D T
Fi n al
1 2 w e e k s 
aft er
l a st D L -P D T
Vi sit 6 i s 
Vi sit 1 of 
L T F U 
st u d y
2 6 w e e k s 
aft er l a st
D L -P D T
T el e p h o n e 
c all t o 
c h e c k o n 
s u bj e ct
Fi n al
5 2 w e e k s 
aft er l a st 
D L -P D T
W e e k
S cr e e ni n g
B a s eli n e
W e e k 2
W e e k 3
W e e k 1 4/ E T f
W e e k
1 4
W e e k 2 8
W e e k
2 6
W e e k 4 0
W e e k
4 0 / E T
W e e k 5 4
Vi sit wi n d o w
-1 4 t o -5
d a y s
0 t o + 1 4
d a y s
0 t o + 1 4
d a y s
-2 t o + 1 4
d a y s
-2 t o + 2 8
d a y s
+/ - 5 d a y s
+/ - 5 d a y s
+/ - 5 d a y s
L O N G -T E R M F O L L O W -U P S T U D Y
I nf or m e d C o n s e nt 
 
X
X
D e m o gr a p hi c s 
(i n cl u di n g F S T)
X
X
M e di c al Hi st or y
X
X
Pr e vi o u s 
T h er a pi e s/ Pr o c e d ur e s 
X
X
Vit al Si g n s/ P h y si c al 
E x a mi n ati o n
X
X
g →
X
I n cl u si o n/ E x cl u si o n 
Crit eri a
X
X
X →
X
H e m at ol o g y/ Bl o o d 
C h e mi str y/ U A/ E C G
X
X
Pr e g n a n c y T e st c
X
X
X
X
X
X →
X 
X
X
W e at h er a s s e s s m e nt
X
X
X
X
A K m a p pi n g + c o u nti n g 
+ gr a di n g d
X
X
X
X
X →
X 
X
X
S u n s cr e e n a p pli c ati o n
X
X
X
X
R D. 0 6. S P R. 1 1 5 2 3 0
R D. 0 6. S P R. 1 1 2 1 9 9
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 8 of 4 4
C O N FI D E N TI A L
Vi sit
1
2
2 b a, b
3
4
4 b a, b
5 a, b
6 a, b
1 
2 ( 7)
T C
3 ( 8)
P ur p o s e
M e di c al 
hi st or y  
a n d l a b s
Fir st
D L -P D T 
s e s si o n
If
r e q uir e d
F oll o w -u p
1 w e e k aft er
1 st D L -P D T
S e c o n d D L -
P D T
s e s si o n
If
r e q uir e
d
F oll o w -u p
1 w e e k aft er
2 n d D L -P D T
Fi n al
1 2 w e e k s 
aft er
l a st D L -P D T
Vi sit 6 i s 
Vi sit 1 of 
L T F U 
st u d y
2 6 w e e k s 
aft er l a st
D L -P D T
T el e p h o n e 
c all t o 
c h e c k o n 
s u bj e ct
Fi n al
5 2 w e e k s 
aft er l a st 
D L -P D T
W e e k
S cr e e ni n g
B a s eli n e
W e e k 2
W e e k 3
W e e k 1 4/ E T f
W e e k
1 4
W e e k 2 8
W e e k
2 6
W e e k 4 0
W e e k
4 0 / E T
W e e k 5 4
Vi sit wi n d o w
-1 4 t o -5 
d a y s
0 t o + 1 4
d a y s
0 t o + 1 4
d a y s
-2 t o + 1 4
d a y s
-2 t o + 2 8 
d a y s
+/ - 5 d a y s
+/ - 5 d a y s
+/ - 5 d a y s
L O N G -T E R M F O L L O W -U P S T U D Y
L e si o n d é bri d e m e nt 
a n d tr e at m e nt 
a p pli c ati o n
X
X
X
X
G e ol o c ali z e d S at ellit e 
d at a a n d e x p o s ur e ti m e 
X
X
X
X
St u d y dr u g( s) 
Di s p e n si n g ( D) a n d 
A c c o u nt a bilit y ( A)
X
X
X
X
S u bj e ct A s s e s s m e nt of 
P ai n
X
X
X
X
S u bj e ct S ki n A s p e ct 
A s s e s s m e nt d
X
S u bj e ct s ati sf a cti o n 
q u e sti o n n air e d
X
X
X d
S af et y Vi sit Q u e sti o n
X
X
A d v er s e E v e nt s e
X
X
X
X
X
X
X
X →
X
X
X
X
C o n c o mit a nt 
T h er a pi e s/ Pr o c e d ur e s d
X
X
X
X
X
X
X →
X 
X 
X 
X
S u bj e ct s wit h C o m pl et e 
R e s p o n s e e v al u ati o n 
a n d I C f or c o nti n u ati o n 
i nt o l o n g-t er m f oll o w-u p 
st u d y
X
E x it f or mf
X
X
Vi sit s 2 a n d 4 m a y b e d el a y e d f or u p t o 2 w e e k s i n c a s e of u n s uit a bl e w e at h er c o n diti o n s at r a n d o mi z ati o n/tr e at m e nt o ut s et; t h e s e vi sit s wil l b e Vi sit s 2 b a n d 4 b . 
T h e s e p o st p o n e m e nt s will b e a ut o m ati c all y a d d e d t o t h e ti m e of s c h e d ul e d Vi sit s 5 a n d 6
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 1 9 of 4 4
C O N FI D E N TI A L
If s u bj e ct s e x p eri en c e r ai n d uri n g t h e 2 h o ur s of d a yli g ht e x p o s ur e of eit h er D L -P D T vi sit, t h e y will b e i n str u ct e d t o g o i n d o or s at t h e i n v e sti g ati v e sit e a n d t h e st u d y 
dr u g will b e w a s h e d off. T h e tr e at m e nt will b e c o n si d er e d i n c o m pl et e a n d s h o ul d b e r e p e at e d at a mi ni m u m i nt er v al of 2 w e e k s. T h er e will b e o nl y  on e att e m pt at 
r etr e at m e nt of a n i n c o m pl et e tr e at m e nt. T h e s e vi sit s will b e Vi sit s 2 b a n d 4 b. If t h e att e m pt at r etr e at m e nt i s al s o i n c o m pl et e, t h e s u bj e ct will n ot b e e x cl u d e d fr o m 
t h e st u d y. Li k e wi s e, t h e s e r e p e at vi sit s will b e a d d e d t o t h e ti m e of s c h e d ul e d Vi sit s 5 a n d 6 . If a s u bj e ct h a s t w o i n c o m pl et e vi sit s i n a r o w, t h er s u bj e ct will c o nti n u e 
wit h a s s e s s m e nt i n t hi s st u d y. 
a)
O nl y f or f e m al e s of c hil d b e ari n g p ot e nti al, U P T at Vi sit s 1, 2, a n d 3 of t hi s st u d y 
b)
S h o ul d b e p erf or m e d e arli er if s u bj e ct di s c o nti n u e s b ef or e Vi sit 3 of t hi s st u d y
c)
A d v er s e E v e nt s h a v e t o b e c oll e ct e d fr o m t h e ti m e of t h e I nf or m e d C o n s e nt si g n at ur e
d)
E x it f or m s h o ul d b e c o m pl et e d aft er s u bj e ct d at a c oll e cti o n h a s b e e n c o m pl et e d f or s u bj e ct s i n t h e st u d y; F S T = Fit z p atri c k S ki n T y p e
e)
R e d arr o w s si g nif y t h at p erti n e nt d at a o bt ai n e d at Vi sit 6 of R D. 0 6. S P R. 1 1 2 1 9 9 will b e tr a n s cri b e d a s t hi s vi sit a s Vi sit 1 of R D. 0 6. S P R. 1 1 5 2 3 0
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 0 of 4 4
C O N FI D E N TI A L
8. 2
Disc ussi o n of St u d y Desi g n
St u d y Desi g n
T his st u d y will e val uate rec urre nce of A Ks treate d i n st u d y R D. 0 6. S P R. 1 1 2 1 9 9. I n t his st u d y, 
in vesti gat ors will re vie w t he c o n diti o n of lesi o ns map pe d a n d treate d i n t hat st u d y, o ver a 9-m o nt h 
f oll o w-u p. O nl y t h ose s u bjects w h o ac hie ve a C o m plete Res p o nse at t he Fi nal Visit fr o m t he 
ve hicle a n d acti ve crea m gr o u ps i n t hat st u d y, are eli gi ble t o c o nti n ue i n t his l o n g-ter m f oll o w- u p 
st u d y.
I n st u d y RD. 0 6. S P R. 1 1 2 1 9 9, a p pr o xi matel y 5 7 0 s u bjects wit h mil d t o m o derate acti nic kerat oses 
of t he face a n d scal p, meeti n g s pecific criteria, will recei ve 2 sessi o ns of D L -P D T, ra n d o mize d t o 
recei ve eit her M A L 1 6. 8 % crea m ( C D 0 6 8 0 9-4 1) or ve hicle crea m i n a 
 rati o. It is esti mate d t hat 
3 8 0 s u bjects w o ul d recei ve M A L  D L-P T a n d 1 9 0 s u bjects w o ul d recei ve ve hicle crea m D L -P D T 
at 2 treat me nt sessi o ns 2 t o 4 wee ks a part. T he e n d p oi nt of st u d y RD. 0 6. S P R. 1 1 2 1 9 9 occ urs at 
Visit 6, 1 2 wee ks after t he last D L -P D T treat me nt, w he n t he treate d A K lesi o ns are assesse d f or 
c o m plete res p o nse. T he s u bject c o m plete res p o nse, defi ne d as t he pr o p orti o n of s u bjects wit h 
c o m plete cleara nce of all A K lesi o ns treate d, will c o m pare M A L crea m wit h ve hicle crea m. I n t he 
p o weri n g of t he st u d y, t he ass u m pti o ns of a 4 5 % s u bject c o m plete res p o nse f or M A L  16. 8 % crea m 
( C D 0 6 8 0 9-4 1) a n d 1 5 % s u bject c o m plete res p o nse f or ve hicle crea m were use d. Beca use t here will 
be s u bjects e nr olli n g i n t he l o n g-ter m f oll o w- u p st u d y fr o m b ot h treat me nt ar ms, it is esse ntial t o 
kee p t he s u bjects a n d t he site pers o n nel bli n de d t o t he treat me nt, i n or der t o n ot bias t he e val uati o ns 
of rec urre nce sc he d ule d at Visits 2 a n d 3 of t his st u d y, occ urri n g 2 6 a n d 5 2 wee ks after t he last 
D L -P D T .
A p pr o xi matel y  1 3 0 s u bjects w h o c o m plete d t he st u d y RD. 0 6. S P R. 1 1 2 1 9 9 a n d ac hie ve c o m plete 
res p o nse of all treate d lesi o ns (esti mate d t o be 1 1 1 ra n d o mize d t o M A L  DL- P D T a n d 1 9
ra n d o mize d t o Ve hicle D L-P D T) will be e nr olle d i n t his st u d y  i n or der t o ha ve a p pr o xi matel y 1 0 0 
s u bjects ra n d o mize d t o M A L D L-P D T w h o c o m plete t he l o n g -ter m f oll o w- u p.
8. 3
Selecti o n of t he St u d y P o p ul ati o n
N u m ber of Pl a n ne d S u bjects
A p pr o xi matel y 1 3 0 s u bjects. 
Refer t o Secti o n 1 0. 2 f or t he statistical c o nsi derati o ns o n w hic h t he sa m ple size is base d .
I ncl usi o n C riteri a
T o be eli gi ble f or st u d y e ntr y , s u bjects m ust satisf y all of t he f oll o wi n g i ncl usi o n criteria:
1.
S u bjects w h o ha ve partici pate d i n st u d y  R D. 0 6. S P R. 1 1 2 1 9 9 a n d ha ve ac hie ve d a c o m plete 
res p o nse at Fi nal Visit of t hat st u d y, c o m plete cleara nce of treate d lesi o ns at 1 2 wee ks after 
t he last D L -P D T .
2.
Writte n I nf or me d C o nse nt bef ore a n y  assess me nt relate d t o t he L T F U st u d y is perf or me d.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 1 of 4 4
C O N FI D E N TI A L
3.
S u bject is willi n g a n d a ble t o c o m pl y wit h all of t he ti me c o m mit me nts a n d pr oce d ur al 
re q uire me nts of t he cli nical st u d y pr ot oc ol.
E xcl usi o n C riteri a
S u bjects will be e xcl u de d fr o m t he st u d y  if 1 or m ore of t he f oll o wi n g criteria are a p plica ble :
1.
S u bjects, w h o de vel o p or e x perie nce a c o n diti o n t hat ma y c o m pr o mise s u bject safet y or 
c o m plia nce, i nterfere wit h e val uati o n or precl u de c o m pleti o n of t he st u d y . I n partic ular, t hese 
c o n diti o ns i ncl u de, b ut are n ot li mite d t o mali g na nc y or ot her life t hreate ni n g diseases.
2.
Perti ne nt n o n- c o m plia nce wit h t he c o n diti o ns f or t his st u d y or i nstr ucti o ns b y t he i n vesti gat or 
d uri n g R D. 0 6. S P R. 1 1 2 1 9 9.
Re m o v al of S u bjects F r o m A ssess me nts
Alt h o u g h t he i m p orta nce of c o m pleti n g t he e ntire cli nical st u d y will be e x plai ne d t o t he s u bjects, 
a n y s u bject is free t o disc o nti n ue his/ her partici pati o n i n t he stu d y  at a n y ti me a n d f or w hate ver 
reas o n, s pecifie d or u ns pecifie d, a n d wit h o ut a n y prej u dice. N o c o nstrai nts are t o be i m p ose d o n 
t he s u bject, a n d w he n a p pr o priate, a s u bject ma y be treate d wit h ot her c o n ve nti o nal t hera p y w he n 
cli nicall y i n dicate d. I n vestigat ors or t he S p o ns or ca n als o wit h dra w s u bjects fr o m t he cli nical 
st u d y if dee me d t o be necessar y. Data c ollecte d u p t o t he ti me of s u bject re m o val will be use d.
Reas o ns f or disc o nti n ui n g t he st u d y i ncl u de:

WI T H D R A W A L B Y S U BJ E C T
S u bject re q uest (i.e., c o nse nt wit h dra wal)

P R O T O C O L  VI O L A TI O N
U se of no n- per mitte d c o nc urre nt t hera p y ( u nless disc usse d a n d a gree d u p o n wit h t he 
In vesti gat or a n d m e dical m o nit or) see Secti o n 8. 3. 7

N O N -C O M P LI A N C E WI T H S T U D Y S C H E D U L E

L O S T T O F O L L O W -U P

A D V E R S E E V E N T
Occ urre nce of A Es n ot c o m pati ble wit h t he c o nti n uati o n of s u bject partici pati o n i n t he st u d y, 
i n t he I n vesti gat or’s o pi ni o n, or u nacce pta ble t o t he s u bject t o c o nti n ue 

P H Y SI CI A N D E CI SI O N 

O T H E R
T he reas o n(s) f or wit h dra wal will be d oc u me nte d i n t he e C R F.
S u bjects w h o pre mat urel y disc o nti n u e t he st u d y will be e nc o ura ge d t o c o m plete t he 
Fi nal/ E T st u d y visit .
Reas o na ble eff orts will be ma de t o c o ntact s u bjects w h o are l ost t o f oll o w - u p. T hese eff orts m ust 
be d oc u me nte d i n t he s u bject’s file . 
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 2 of 4 4
C O N FI D E N TI A L
T he sp o ns or has t he ri g ht t o ter mi nate t he st u d y  at a n y ti me i n case of S A Es or if s pecial 
circ u msta nces c o ncer ni n g t he t he c o m pa n y itself occ ur . I n t his e ve nt, t he In vesti gat or(s) will be 
i nf or me d of t he reas o n f or st u d y ter mi nati o n.
Met h o d of C o nti n ui n g alre a d y R a n d o mize d S u bject fr o m Pre vi o us st u d y
O nce a SI N has bee n assi g ne d, t hat n u m ber m ust n ot be use d a gai n f or a n y ot her s u bject (e. g., 
w he n a s u bject is wit h dra w n fr o m t he st u d y, t hat s u bject’s SI N m ust n ot be re use d f or a n y ot her 
s u bject). S ee S ecti o n 9.
Bli n di n g
Al l atte m pts will be ma de t o kee p t he i n vesti gati ve site staff a n d s u bjects bli n de d t o t he st u d y 
treat me nt fr o m st u dy R D. 0 6. S P R. 1 1 2 1 9 9 t hr o u g h o ut t he st u d y. Me m bers of t he st u d y ce nter 
staff, i ncl u di n g t he pr oce d ure o perat or, will n ot ha ve access t o t he ra n d o mize d treat me nt 
assi g n me nt of s u bjects i n R D. 0 6. S P R. 1 1 2 1 9 9 . It w o ul d be e xtre mel y u nli kel y f or a sit uati o n t o 
occ ur i n w hic h t he bli n d w o ul d nee d t o be br o ke n d uri n g t his st u d y .  The In vesti gat or or s u b-
i n vesti gat or s h o ul d c o ns ult wit h t he me dical m o nit or a n d t he S p o ns or i n cases w here it be 
re q uire d t o brea k t he bli n d.  
W he n t he bli n di n g c o de is br o ke n, t he reas o n m ust be f ull y  d oc u me nte d. If t he c o de is br o ke n b y 
t he In vesti gat or, t he s u bject m ust be wit h dra w n fr o m t he st u d y. T he re p orti n g re q uire me nts f or 
u n bli n di n g are t he sa me f or re p orti n g a n S A E. See als o Secti o n 9. 2. 1. 3
T he ra n d o mizati o n c o de will re mai n bli n de d t o all st u d y  sites a n d st u d y tea m me m bers u ntil 
c o m pleti o n of t he st u d y a n d after t he st u d y data base has bee n l oc ke d. Initial treat me nt peri o d 
res ults will be a nalyz e d after all s u bjects ha ve eit her c o m plete d Visit 6 , or ha ve wit h dra w n or 
bee n disc o nti n ue d fr o m t he st u d y  bef ore Visit 6. H o we ver , pers o n nel fr o m s p o ns or, C R O, a n d 
i n vesti gati o nal sites directl y i n v ol ve d wit h t he o n g oi n g c o n d uct of t he st u d y will n ot ha ve access 
t o a n y i nf or mati o n t hat ma y lea d t o u n bli n di n g f or t he o n g oi n g rec urre nce e val uati o n d uri n g t he 
f oll o w- u p st u d y.
Pri or a n d C o nc o mit a nt T her a p y
C o nc o mita nt t hera pies / me dicati o ns are defi ne d as f oll o ws:

A n y  e xisti n g t hera pies o n g oi n g at t he ti me of t he scree ni n g visit,

A n y  c ha n ges t o e xisti n g t hera pies (s uc h as c ha n ges i n d ose, f or m ulati o n, or a p plicati o n 
fre q ue nc y) d uri n g t he c o urse of t he st u d y, or

A n y  ne w t hera pies recei ve d b y t he s u bject si nce t he scree ni n g visit 
T he f oll o wi n g 2 cate g ories are t o be c o nsi dere d f or pri or a n d c o nc o mita nt t hera pies: 

Dr u gs/ T hera pies i ncl u de b ut are n ot li mite d t o prescri pti o n, o ver-t he-c o u nter, birt h c o ntr ol 
pills/ patc hes/ h or m o nal de vices, vita mi ns, m oist urizers, s u n scree ns, her bal 
me dici nes/s u p ple me nts, a n d h o me o pat hic pre parati o ns.

Me dical a n d s ur gical pr oce d ures
(e. g., p h ot ot hera p y, e x o d o ntia). Pr oce d ures w h ose s ole 
p ur p ose is dia g n osis ( n o n -t hera pe utic) are n ot i ncl u de d.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 3 of 4 4
C O N FI D E N TI A L
Pri or a n d c o nc o mita nt t hera pies f or dr u gs/t hera pies or f or me dical/s ur gical pr oce d ures are t o be 
rec or de d i n t he a p pr o priate e C R F. 
C o nc o mita nt t hera pies are t o be rec or de d, re vie we d, a n d u p date d at eac h visit. 
A n y  ne w c o nc o mita nt t hera p y or m o dificati o n of a n e xisti n g t hera p y ma y be li n ke d t o a n A E. I n 
s uc h cases, a c orres p o n di n g A E f or m s h o ul d be c o m plete d t o acc o u nt f or t he ne w t hera p y or 
c ha n ge i n t hera p y, i n w hic h case t he me dicati o n will be li n ke d t o a n ite m i n t he s u bject’s me dical 
hist or y .
T he t hera pies liste d i n Ta ble 2 are c o nsi dere d pr o hi bite d i n t he treat me nt areas beca use t he y  m a y 
i nterfere wit h t he lesi o n assess me nt s.
T a ble 2 : F or bi d de n Tre at me nts i n Tre at me nt Are a
Tre at me nt(s)
T o pical: 5 -fl u or o uracil, dicl ofe nac, i mi q ui m o d, reti n oi ds, al p ha-h y dr o x y  aci d, salic ylic aci d 
oi nt me nt, i n ge n ol me b utate
S ur gical: elli ptical e xcisi o n, e xcisi o n a n d rec o nstr ucti ve s ur ger y , M o hs’ micr o gra p hic s ur ger y, 
c he mical peels/c he m os ur ger y , cr yos ur ger y , der ma brasi o n
P h ot o d y na mic t hera p y
Electr oc oa g ulati o n t hera p y
Ra di ot hera p y of t he s ki n
Laser t hera p y
I n vesti gati ve t hera pies f or acti nic kerat osis
S y ste mic reti n oi ds
I m m u n os u p pressi ve a ge nts s uc h as gl uc oc ortic oi ds, c yt ostatic a ge nts, a nti b o dies, dr u gs acti n g 
o n i m m u n o p hili ns, i nterfer o n, T N F bi n di n g pr otei ns, m y c o p he n olate m ofetil, or bi ol o gics 
I n case t he s u bject is usi n g t o pical t hera py liste d i n Ta ble 2 o n ot her area s t ha n o n t he 
d oc u me nte d lesi o ns, t he I nvesti gat or will re mi n d hi m/ her t o pa y strict atte nti o n t o n ot a p pl y a ny 
of t hese t hera pies o n t he treat me nt areas.
If pr o hi bite d t hera pies bec o me a necessar y treat me nt f or t he safety or best i nterest of t he s u bject,
t he me dical m o nit or s h o ul d be n otifie d t o disc uss p ossi ble alter nati ves pri or t o a d mi nistrati o n of a 
pr o hi bite d t hera p y. It is als o p ossi ble t hat t he use of pr o hi bite d thera pies ma y  res ult i n early 
ter mi nati o n of a s u bject.
If a s u bject recei ves pr o hi bite d t hera py d uri n g t he cli nical st u d y, t he me dical m o nit or s h o ul d be 
n otifie d t o disc uss t he si g nifica nce a n d t he m o dalities t o be use d f or t he su bject t o c o nti n ue i n t he 
cli nical st u d y.
 
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R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 4 of 4 4
C O N FI D E N TI A L
8. 4  
D ur ati o n of S u bject P artici p ati o n
T he e x pecte d d urati o n f or eac h s u bject’s partici pati o n i n t he st u d y will be a p pr o xi matel y 4 0 wee ks.
E arl y Ter mi n ati o n Visit
S u bjects ma y  disc o nti n ue fr o m t he st u d y at a n y ti me.
S u bjects w h o pre mat urel y disc o nti n ue fr o m t he st u d y  s h o ul d u n der g o fi nal st u d y assess me nts.
8. 5
U nsc he d ule d Visit
T he s u bject s h o ul d be re mi n de d t o a d here t o t he st u d y sc he d ule. U nsc he d ule d visits are defi ne d 
as visits occ urri n g o utsi de of t he visit wi n d o w.
Assess me nts t o be c o n d ucte d at t he u nsc he d ule d visit will de pe n d o n t he reas o n f or t he visit a n d 
will be c o n d ucte d at t he discreti o n of t he pri nci pal i n ves ti gat or. A n y of t he 
pr oce d ures/assess me nts liste d i n Secti o n 8. 1. 2 ma y be c o n d ucte d, b ut n ot all are re q uire d.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 5 of 4 4
C O N FI D E N TI A L
9
S T U D Y A S S E S S M E N T S
A writte n , si g ne d Inf or me d C o nse nt F or m (I C F) , a n d Healt h I ns ura nce P orta bilit y  a n d 
Acc o u nta bil it y Act ( HI PA A) a ut h orizati o n is re q uire d bef ore a n y st u d y- relate d pr oce d ures are 
perf or me d.
U p o n pr o visi o n of t he si g ne d I C F, eac h s u bject will be assi g ne d a u ni q ue differe nt SI N fr o m t he 
SI N i n pr ot oc ol R D. 0 6. S P R. 1 1 2 1 9 9 . F or t he d urati o n of t he cli nical st u d y, t he s u bject will be 
i de ntifie d usi n g t he ne w SI N i n all d oc u me ntati o n a n d disc ussi o n f or t his pr ot oc ol.
9. 1
Effic ac y Assess me nts
E val uati o ns are t o be perf or me d b y t he sa me I n vesti gat or f or a gi ve n s u bject t hr o u g h o ut the 
st u d y, w he ne ver p ossi ble. T he I n vesti gat or is t o re mai n bli n de d t o t he st u d y treat me nt fr o m st u dy 
R D. 0 6. S P R. 1 1 2 1 9 9 . 
Lesi o n Res p o nse
T he lesi o ns treate d i n t he pi v otal trial will be e val uate d f or re occ urre nce.  A n y lesi o ns t hat ha ve 
rec urre d will be e val uate d f or se verit y acc or di n g t o t he gra di n g scale i n Ta ble 3
T a ble 3: Lesi o n S e verit y G r a de S c ale
Gr a de
Se verit y
Descri pti o n
Gra de 1
Mil d
S li g htl y pal pa ble, better felt t ha n see n
Gra de 2
M o derate
M o deratel y t hic k, easil y felt a n d see n
Gra de 3
Se vere
V er y t hic k a n d/ or o b vi o us acti nic kerat oses
T he In vesti gat or will be as ke d at Visit s 2 a n d 3 / E T t o i de ntif y eac h lesi o n treate d pre vi o usl y, a n d 
t he lesi o n res p o nse as a C R or a n o n -C R, as descri be d i n Ta ble 4 .
T a ble 4 : Lesi o n R es p o nse
Res p o nse
Sc ore
Descri pti o n
C o m plete res p o nse ( C R)
1
C o m plete disa p peara nce of t he lesi o n, vis uall y  
a n d b y pal pati o n
N o n c o m plete re p o nse (n o n -C R)
0
N o n -c o m plete disa p peara nce of t he lesi o n
If all of t he treate d lesi o ns i n t he treat me nt area are assesse d t o be C R at Visits 2 a n d 3 of t his 
st u d y ( 26 a n d 5 2 wee ks after t he last D L -P D T sessi o n), t he s u bject will be assesse d a s a s u bject 
C R a n d will be dee me d t o ha ve n o rec urre nce. If a n y of t he treate d lesi o ns i n t he treat me nt area 
are assesse d t o be n o n-C R, t h ose lesi ons are rec urre nces; t he s u bject will be assesse d as a n o n -
c o m plete res p o n der or dee me d as a s u bject rec urre nce . 
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 6 of 4 4
C O N FI D E N TI A L
9. 2
S afet y Assess me nts
Safet y  assess me nts will be c o n d ucte d f or all s u bjects at Visit 1 ( u p o n si g ni n g of t he I C F) a n d at 
e ver y s u bse q ue nt visit.
A d verse e ve nts ( A Es), Treat me nt -e mer ge nt A Es ( T E A Es), relate d t o t he st u d y treat me nt i n st u d y 
R D. 0 6. S P R. 1 1 2 1 9 9 . a n d seri o us A Es ( S A Es) will be rec or de d d uri n g eac h visit, s h o ul d t he y 
occ ur.
A d verse E ve nt Defi niti o n
A n A E is defi ne d as a n y u nt o war d me dical occ urre nce i n a cli nical st u d y , i n w hic h a s u bject is 
a d mi nistere d a me dici nal pr o d uct t hat d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t his 
treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y  ass ociate d wit h t he use of a me dici nal  
pr o d uct, w het her or n ot it is relate d t o t he me dici nal pr o d uct . T his i ncl u des a n e xacer bati o n of 
pre -e xisti n g c o n diti o ns or e ve nts, i nterc urre nt ill nesses, dr u g i nteracti o n, or t he si g nifica nt 
w orse ni n g of t he i n dicati o n u n der i n vesti gati o n, t hat is n ot rec or de d else w here i n t he eC R F u n der 
s pecific efficac y assess me nts. 
N ote(s): 

A n y  ne w si g n or sy m pt o m re p orte d b y t he s u b ject t hat a p pears after acci de ntal or 
i nte nti o nal o ver d ose or mis use s h o ul d be re p orte d as a n A E.

W he ne ver p ossi ble, a dia g n osis s h o ul d be re p orte d o n t he A E f or m, i nstea d of si g ns, 
s ym pt o ms , or a b n or mal la b orat or y  val ues. 
Pre g na nc y  is n ot t o be c o nsi dered a n A E 

Eac h ne w e pis o de of a c hr o nic disease (e . g., ha y fe ver, aller g y) fr o m t he ti me t he I C F is 
si g ne d s h o ul d be re p orte d as a ne w A E.
T he In vesti gat or or desi g nee will re p ort all A Es t hat occ ur fr o m t he ti me t he I C F is si g ne d u ntil 
t he e n d of t he st u dy. T he s p o ns or/ C R O s h o ul d be i nf or me d if t he I n vesti gat or bec o mes a ware of 
a n y safety i nf or mati o n t hat a p pears t o be relate d t o t he st u d y treat me nt of st u d y 
R D. 0 6. S P R. 1 1 2 1 9 9 , e ve n after t he s u bject has c o m plete d t he cli nical st u d y.
At eac h p ost -e nr oll me nt visit, t he In vesti gat or ( or s u b-i n vesti gat or) will q uesti o n t he s u bject 
a b o ut hi s/ her e x perie nci n g of A Es , usi n g a n o pe n n o n -pers uasi ve q uesti o n t o elicit re p orti n g of 
A Es (f or e xa m ple, “ Ha ve yo u n otice d a n y  c ha n ge i n yo ur healt h si nce t he last visit?” ). Directe d 
q uesti o ni n g a n d e xa mi nati o n will t he n be perf or me d as a p pr o priate. 
A n y  A E occ urri n g d uri n g t he A E re p orti n g peri o d will be rec or de d i m me diatel y  i n t he s o urce 
d oc u me nt a n d descri be d o n t he A d verse E ve nt F or m (“ A E F or m”) al o n g wit h t he da te of o nset, 
seri o us ness, se verit y, relate d ness or ca usalit y a n d o utc o me, wit h o ut o mitti n g a n y re q ueste d a n d 
k n o w n i nf or mati o n. A d diti o nal i nf or mati o n will be re q ueste d u n der certai n circ u msta nces.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
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A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 7 of 4 4
C O N FI D E N TI A L
A d verse e ve nts assesse d as relate d t o t he st u d y treat me nt fr o m t he pre vi o us st u d y will be 
m o nit ore d u ntil t he y  ha ve res ol ve d or reac he d a sta ble c o n diti o n. Ot her A Es will be m o nit ore d 
u ntil t he last visit if t he y  ha ve n ot res ol ve d or reac he d a sta ble c o n diti o n. If n ot res ol ve d at ti me of 
L T F U st u d y c o m pleti o n, sites will c o nti n ue t o c o ntact patie nt o n a re g ular basis u ntil res ol ve d or 
sta ble.
T he In vesti gat or will o btai n a n d mai ntai n all perti ne nt me dical rec or ds i n t he s u bject’s files, 
i nf or mati o n a n d me dical j u d g me nt fr o m c ollea g ues w h o assiste d i n t he s u bject’s o versi g ht. If 
necessar y , t he In vesti gat or will c o ntact t he s u bject’s pers o nal p h ys icia n or h os pital staff t o o btai n 
f urt her details.
Assess me nt of Se verit y
Eac h A E will be assi g ne d a cate g or y  b y t he In vesti gat or as f oll o ws:
Mil d :  
An A E t hat is easil y  t olerate d b y t he s u bject, ca uses mi ni mal disc o mf ort, a n d d oes 
n ot i nterfere wit h e ver y d a y  acti vities.
M o derate :  
An A E t hat is s ufficie ntl y  disc o mf orti n g t o i nterfere wit h n or mal e ver yd a y  
acti vities; i nter ve nti o n ma y be nee de d.
Se vere :  
A n A E t hat pre ve nts n or mal e ver y d a y  acti vities; treat me nt or ot her i nter ve nti o n 
us uall y  nee de d.
If t here is a c ha n ge i n se verit y of a n A E, it m ust be rec or de d as a se parate e ve nt.
Assess me nt of C a us alit y
T he In vesti gat or will ha ve deter mi ne d t hat t here is a reas o na ble ca usal relati o ns hi p bet wee n t he 
occ urre nce of t he A E, a n d e x p os ure t o t he st u d y dr u g (i .e.,
M A L crea m or ve hicle crea m ) a n d/ or 
st u d y pr oce d ure (e. g., ill u mi nati o n, bl o o d sa m ple c ollecti o n) i n st u d y R D. 0 6.S P R. 1 1 2 1 9 9.
F or A Es arisi n g d u ri n g t his st u d y, me dical j u d g me nt s h o ul d be use d t o deter mi ne t he relati o ns hi p, 
c o nsi deri n g all rele va nt fact ors i ncl u di n g t he patter n of t he reacti o n, te m p oral relati o ns hi ps, 
rele va nt me dical hist or y, a n d c o nf o u n di n g fact ors s uc h as c o-me dicati o n or c o nc u rre nt diseases.
T he e x pressi o n “reas o na ble ca usal relati o ns hi p” is mea nt t o c o n ve y  i n ge neral t hat t here are facts 
or ar g u me nts t o s u g gest a ca usal relati o ns hi p (I C H E 2 A, Secti o n III A 1).
T he relati o ns hi p assess me nt f or a n A E is t o be c o m plete d usi n g t he f oll o wi n g defi niti o ns as a 
g ui deli ne f or all A Es occ urri n g d uri n g t his cli nical st u d y:
Re as o n a ble p ossi bilit y:
Acc or di n g t o t he re p orti n g In vesti gat or, t here is a reas o na ble p ossi bilit y  (i. e., s u g gesti ve e vi de nce 
or ar g u me nts) t hat t here is a ca usal relati o ns hi p irres pecti ve of t he d ose a d mi nistere d:

Bet wee n t he st u d y dr u g ( met h y l a mi n ole vi n ulate h ydr oc h oli de 1 6. 8 % crea m or ve hicle 
crea m) a n d t he A E, a n d/ or
 
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A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 2 8 of 4 4
C O N FI D E N TI A L

Bet wee n t he cli nical st u d y pr ot oc ol p r oce d ure (e. g., t o pical bac k gr o u n d t hera py , bl o o d 
sa m ple c ollecti o n) a n d t he A E
N o Re as o n a ble P ossi bilit y:
N o s u g gesti ve e vi de nce or ar g u me nts ca n be i de ntifie d re gar di n g a ca usal relati o ns hi p bet wee n 
t he st u d y dr u g or t he cli nical st u d y pr ot oc ol pr oce d ure a n d t he A E.
F oll o w -u p of A d verse E ve nts
All In vesti gat ors s h o ul d f oll o w - u p wit h s u bjects wit h relate d A Es u ntil t he e ve nt is res ol ve d or 
u ntil, i n t he o pi ni o n of t he I n vesti gat or, t he e ve nt is sta bilize d or deter mi ne d t o be c hr o nic. 
Details of A E res ol uti o n m ust be d oc u me nte d i n t he e C R F.
D oc u me nt ati o n a n d Re p orti n g of A d verse E ve nts
A d verse e ve nts s h o ul d be re p orte d a n d d oc u me nte d i n acc or da nce wit h t he pr oce d ures o utli ne d 
bel o w . All A Es occ urri n g d uri n g t he st u d y m ust be d oc u me nte d o n t he rele va nt e C R F pa ges . T he 
f oll o wi n g data s h o ul d be d oc u me nte d f or eac h A E:

D escri pti o n of t he s y m pt o m /e ve nt

Classificati o n of “seri o us” or “n ot seri o us ”

Se verit y

Date of first occ urre nce a n d dat e of res ol uti o n (if a p plica ble)

Ot her acti o n ta ke n

Ca usal relati o ns hi p

O utc o m e of e ve nt ( u n k n o w n, rec o vere d, n ot yet rec o vere d, rec o vere d wit h se q uelae, deat h 
[ wit h date a n d ca use re p orte d])
9. 2. 1. 1
Seri o u s A d verse E ve nts
A n S A E is a n y  u nt o war d me dical occ urre nce or effect t hat, at a n y d ose,

Res ults i n deat h.

Is life-t hreate ni n g (a n A E is life-t hreate ni n g if t he s u bject was at i m me diate ris k of deat h fr o m 
t he e ve nt as it occ urre d, i.e., it i ncl u des a reacti o n t hat mi g ht ha ve ca use d deat h if it ha d 
o cc urre d i n a m ore seri o us f or m).

Re q uires or pr ol o n gs i n patie nt h os pitalizati o n. ( C o m plicati o ns occ urri n g d uri n g 
h os pitalizati o n are A Es a n d S A Es , if t he y ca use pr ol o n gati o n of t he c urre nt h os pitalizati o n. 
I n patie nt h os pitalizati o n is c o nsi dere d t o ha ve occ urre d if t he s u bject has ha d t o sta y f or a 
ni g ht at t he h os pital. T he criteri o n f or pr ol o n ga ti o n of h os pitalizati o n is als o defi ne d as a n 
e xtra ni g ht at t he h os pital. H os pitalizati o n ma y  n ot c o nstit ute s ufficie nt gr o u n ds t o be 
c o nsi dere d as a n S A E , if it is s olel y f or t he p ur p ose of dia g n ostic tests [e ve n if relate d t o a n 
A E], electi ve h os pitaliz ati o n f or a n i nter ve nti o n t hat was alrea d y pla n ne d bef ore s u bject 
e nr oll me nt i n t he cli nical st u d y, a d missi o n t o a da y care facilit y, s ocial a d missi o n [e.g. , if t he 
s u bject has n o place t o slee p], or a d mi nistrati ve a d missi o n [e.g. , f or a ye arl y e xa mi nati o n]. 
 
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0 7 J A N 2 0 2 1
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C O N FI D E N TI A L
T he details of s uc h h os pitalizati o ns m ust be rec or de d o n t he me dical hist or y or p h ys ical 
e xa mi nati o n eC R F .)

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y. ( A n A E is i nca pacitati n g or disa bli n g 
if it res ults i n a s u bsta ntial a n d/ or per ma ne nt disr u pti o n of t he s u bject’s a bilit y  t o carry o ut 
n or mal life f u ncti o ns .)

Res ul ts i n a c o n ge nital a n o mal y/ birt h defect.

A n i m p orta nt me dical e ve nt t hat ma y  n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n, ma y  be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt, 
t he e ve nt ma y je o par dize t he safety of t he 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 1 of t he o utc o mes liste d a b o ve i n t his defi niti o n. E xa m ples of s uc h 
e ve nts are 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 f or aller gic br o nc h os pas m, 
bl o o d d y scrasia, or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n.
9. 2. 1. 2
A d verse E ve nts of S peci al I nterest ( A E SIs)
T here are n o A E SI s i n t his st u d y as t here is n o treat me nt or i nter ve nti o n.
9. 2. 1. 3
Pr oce d ure f or Re p orti n g a Seri o us A d verse E ve nt
F or a n y S A E occ urri n g d uri n g t he cli nical st u d y, re gar dless of w het her or n ot relate d t o t he st u d y 
dr u g a n d/ or pr oce d ure, t he In vesti gat or m ust:
1.
Ta ke pr o m pt a n d a p pr o priate me dical acti o n, if necessar y . T he safety of t he s u bject is t he 
first pri orit y.
2.
E ns ure t hat t he e ve nt is e val uate d as a n S A E. I mme diatel y n otif y ( wit hi n 2 4 h o urs of 
recei pt of t he e ve nt ) t he 
 Safety a n d P har mac o vi gila nce gr o u p of a n S A E 
re p ort, by e mail or fa x:
F a x N u m ber : 
S afet y e m ail: 
N ote : Im me diate S A E re p orti n g is re q uire d b y  t he In vesti gat or if it occ urs d uri n g t he cli nical 
st u d y, w het her or n ot t he e ve nt is c o nsi dere d t o be relate d t o t he i n vesti gati o nal pr o d uct.
T he de m o gra p hics, me dical hist or y , dr u gs/t hera pies, a n d me dical a n d s ur gical pr oce d ures f or ms 
m ust als o be a vaila ble f or re vie w i n t he eC R F, at t hat ti me.
3.
Se n d a n y  rele va nt i nf or mati o n or a n o n ymize d me dical rec or ds t o t he 
 Safety 
a n d P har mac o vi gila nce gr o u p (see c o ntact details a b o ve), wit hi n 2 4 h o urs of recei pt of t his 
rele va nt i nf or mati o n.
4.  
M o nit or a n d rec or d t he pr o gress of t he e ve nt u ntil it res ol ves or reac hes a sta ble c o n diti o n, 
wit h or wit h o ut se q uelae. F or all a d diti o nal f oll o w -u p e val uati o ns, c o m plete a n u p date d 
S A E re p ort wit hi n 2 4 h o urs of recei pt of t he u p date d i nf or mati o n.
5.  
O btai n a n d mai ntai n i n t he s u bject files all perti ne nt me dical rec or ds, i nf or mati o n, a n d 
me dical j u d g me nts fr o m c ollea g ues w h o partici pate i n t he treat m e nt a n d f oll o w -u p of t he 
 
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R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
P P D
P P D
P P D
P P D


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
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C O N FI D E N TI A L
s u bject. If necessar y, c o ntact t he s u bject’s pers o nal p h ysicia n or h os pital staff t o o btai n 
f urt her details.
6.
W he n t he o utc o me of t he e ve nt is k n o w n, c o m plete a n u p date d S A E re p ort, if a p pr o priate.
7.
Pr o m pt n otificati o n of S A Es b y  the In vesti gat or is esse ntial s o t hat le gal o bli gati o ns a n d 
et hical res p o nsi bilities t o war d t he safet y of s u bjects are met. T he S p o ns or has a le gal 
res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her re g ulat or y a ge ncies 
a b o ut t he safet y of a pr o d uct u n der cli nical i n vesti gati o n. T he S p o ns or or its dele gate (i . e., 
t he C R O) will c o m pl y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts relati n g t o safety 
re p orti n g t o re g ulat or y a ut h orities, Instit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics 
C o m mittee (I E C) a n d In vesti gat ors. I n vesti gat or safety re p orts are pre pare d f or S U S A Rs 
acc or di n g t o l ocal re g ulat or y re q uire me nts, a n d are f or war de d t o In vesti gat ors as necessar y.
A n In vesti gat or w h o recei ves a n In vesti gat or safet y  re p ort descri bi n g an S A E(s) or ot her s pecific 
safety i nf or mati o n (e . g., s u m mar y or listi n g of S A Es) fr o m t he S p o ns or or its dele gate (i .e., 
t he C R O) will file it acc or di n gl y (i .e., wit hi n t he Trial Master File [ T M F]), a n d will n otif y 
t he IR B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
8.
C o m pl y  wit h t he a p plica ble re g ulat or y re q uire me nt(s) relate d t o t he re p orti n g of S A Es t o 
t he IR B/I E C.
9. 2. 1. 4
Pr oce d ure f or Re p ort i n g Pre g n a ncies
A pre g na nc y  occ urri n g d uri n g t his cli nical st u d y, w here t he fet us w o ul d n ot ha ve bee n e x p ose d t o 
t he st u d y dr u g beca use of t he te m p oral ga p fr o m st u d y dr u g e x p os ure t o t he be gi n ni n g of t his 
st u d y ( 1 2 wee ks a n d > 7 half lifes) will be m o nit ore d n o net heless , i n or der t o e ns ure t he c o m plete 
c ollecti o n of safet y data. If a s u bject bec o mes pre g na nt, t he i n vesti gat or m ust:
1.
C o nti n ue t o f oll o w t he s u bject i n t he cli nical st u d y. T he s u bject will n ot be recei vi n g a n y 
i nter ve nti o n i n t his st u d y. 
2.
C o m plete as f ull y as p ossi ble t he Pre g na nc y  S ur veilla nce F or m – Part I : Hist or y a n d Start 
of Pre g na nc y . Se n d b y e mail or fa x al o n g wit h t he e xit f or m wit hi n 2 4 h o urs of recei pt of 
t he i nf or mati o n, t o t he 
 Safet y a n d P har mac o vi gila nce gr o u p. Refer t o 
Secti o n 9. 2. 1. 3 .
N ote: I mme diate pre g na nc y  re p orti n g is re q uire d b y t he In vesti gat or if it occ urs d uri n g t he 
cli nical st u d y.
3.
M o nit or a n d rec or d t he pr o gress of t he pre g na nc y  u ntil its o utc o me. C o ntact t he s u bject’s 
re g ular p hys icia n ( ge neral practiti o ner or g ynec ol o gist) or h os pital staff t o o btai n f urt her 
details , a n d as k f or re g ular f oll o w -u p i nf or mati o n.
4.
Pr o vi de tri -m o nt hl y  u p dates u ntil t he fi nal o utc o me of t he pre g na nc y , b y c o m pleti n g t he 
Pre g na nc y  S ur veilla nce F or m – Part II: C o urse a n d O utc o me of Pre g na nc y . F or all 
a d diti o nal f oll o w -u p e val uati o ns, se n d t he f or m b y e mail or fa x t o t he 
 Safety 
 
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A p pr o v e d
1. 0
P P D
P P D


G al der m a R & D 
 
0 7 J A N 2 0 2 1
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P a ge 3 1 of 4 4
C O N FI D E N TI A L
a n d P har mac o vi gi la nce gr o u p wit hi n 2 4 h o urs of recei pt of t he i nf or mati o n. If t he s u bject 
ca n n o l o n ger be reac he d (i .e., l ost t o f oll o w-u p), d oc u me ntati o n of t he 
n o n- res p o nse/c o ntact wit h 2 p h o ne calls a n d a letter (certifie d wit h ret ur n recei pt) is 
re q uire d.
5.
At t he o utc o me of t he pre g na nc y , c o m plete as f ull y as p ossi ble t he Pre g na nc y S ur veilla nce 
F or m – Part II: C o urse a n d O utc o me of Pre g na nc y . Pri nt a n d se n d t he f or m b y e mail or fa x 
t o t he 
 Safet y a n d P har mac o vi gila nce gr o u p wit hi n 2 4 h o urs of re cei pt of t he 
i nf or mati o n.
6.
If t he pre g na nc y lea ds t o a n a b orti o n (i.e., v ol u ntar y a b orti o n, s p o nta ne o us a b orti o n, or 
t hera pe utic a b orti o n), i n uter o deat h , or c o n ge nital a n o mal y , f oll o w t he pr oce d ure f or 
declarati o n of /re p orti n g a n S A E (see Secti o n 9. 2. 1. 3 ).
9. 2. 1. 5
U ne x pecte d A d verse Re acti o ns
A n u ne x pecte d a d verse reacti o n is a n y u nt o war d a n d u ni nte n de d res p o nse t hat is relate d t o t he 
a d mi nistrati o n of t he st u d y  dr u g at a n y d ose, t he nat ure or se verity of w hic h is n ot c o nsiste nt wit h 
t he a p plica ble pr o d uct i nf or mati o n (e. g., refere nce safety i nf or mati o n i n t he I B f or M A L 1 6. 8 % 
crea m , st u d y pr ot oc ol ).
T he S p o ns or or its dele gate ( i.e.,
) will c o m pl y wit h c o u ntr y-s pecific re g ulat or y 
re q uire me nts relati n g t o safet y re p orti n g t o re g ulat or y a ut h orities, I R B/I E C , a n d In vesti gat ors. 
I n vesti gat or safet y re p orts are pre pare d f or S U S A Rs acc or di n g t o l ocal re g ulat or y re q uire me nts 
a n d s p o ns or p olic y , a n d are f or war de d t o In vesti gat ors as necessar y .
A n In vesti gat or w h o r ecei ves a n In vesti gat or safet y  re p ort descri bi n g an S A E(s) or ot her s pecific 
safety i nf or mati o n (e . g., s u m mar y or listi n g of S A Es) fr o m t he S p o ns or or its dele gate ( i.e., 
) will file it acc or di n gl y (i.e., wit h t he T M F), a n d will n otif y t he IR B /IE C, if 
ap pr o priate , acc or di n g t o l ocal re q uire me nts.
Pre g a nc y Testi n g
All w o me n of c hil d beari n g p ote ntial will ha ve a uri ne pre g na nc y  test at V isit 1 a n d U P Ts at 
s u bse q ue nt visits at Visits 2 a n d 3, acc or di n g t o Secti o n 8. 1. 2 .
If t he res ult of a U P T is p ositi ve, it m ust be c o nfir me d wit h a ser u m pre g na nc y  test.
S u bjects wit h a p ositi ve ser u m pre g na nc y  test res ult at Visit 1 will be f oll o we d i n t his st u d y .
U ri ne pre g na nc y tests wit h a se nsiti vit y  < 2 5 I U/ L will be pr o vi ded t o t he st u d y ce nters f or use i n 
t he st u d y.
U ri ne pre g na nc y  tests will be perf or me d at t he st u d y ce nters, a n d all ot her sa m ples will be se nt t o 
t he ce ntral la b orat or y f or a nalys is.
 
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P P D
P P D


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C O N FI D E N TI A L
 
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A p pr o v e d
1. 0
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G al der m a R & D 
 
0 7 J A N 2 0 2 1
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C O N FI D E N TI A L
1 0
S T A TI S TI C A L M E T H O D S
A statistical anal y sis p la n ( S A P) will be de vel o pe d as a se parate d oc u me nt. T he S A P will c o ntai n 
detaile d a n d tec h nical descri pti o n s of s pecific data c o n ve nti o ns, calc ulati o ns , a n d statistical 
pr oce d ures f or e xec uti n g t he a nal yses t hat are s pecifie d i n t his S ecti o n 1 0 of t he cli nical st u d y 
pr ot oc ol .
1 0. 1
St atistic al a n d A n al ytic al P l a ns
D at a sets or P o p ul ati o ns A n al y ze d
1 0. 1. 1. 1
I nte nt-t o-Tre at P o p ul ati o n
N ot a p plica ble.
1 0. 1. 1. 2
S afet y P o p ul ati o n
T he safet y p o p ulati o n will c o nsist of all e nr olle d s u bjects a n d will be use d f or all t he effica c y a n d 
safety a nal yses.
1 0. 1. 1. 3
Per Pr ot oc ol P o p ul ati o n
N ot a p plica ble.
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
S u bject dis p ositi o n, de m o gra p hics, baseli ne c haracteristics, pre vi o us t h era pies, a n d c o nc o mita nt 
t hera pies b y  treat me nt will be s u m marize d b y descri pti ve statistics.
Effic ac y A n al ysis
B ot h pri mar y  a n d sec o n dar y e n d p oi nts will be e val uate d f or t he safety p o p ulati o n.
All efficac y  varia bles will be s u m marize d b y treat me nt at eac h visit.
T he cate g orical varia bles will be s u m marize d b y  fre q ue nc y an d perce nta ge f or eac h res p o nse 
cate g or y ( N, %). T he c o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics 
( n u m ber of o bser vati o ns, mea n, me dia n, mi ni m u m, ma xi m u m, a n d sta n dar d de viati o n ) f or t he 
data c ollecte d at eac h visit.
F urt her details o n efficac y  a n al yses will be pr o vi de d i n t he S A P.
1 0. 1. 3. 1
Pri m ar y E n d p oi nt A n al ysis
T he pr o p orti o n of s u bjects wit h rec urre nce of a n y (≥1) cleare d treate d A K lesi o ns at 5 2 wee ks 
after t he last D L -P D T will be s u m marize d usi n g ta bles of fre q ue nc y . All s u bjects i n t he safet y 
p o p ulati o n wit h missi n g data will be classifie d as n o n -res p o n ders re gar dless of treat me nt 
all ocati o n. S u m maries b y treat me nt gr o u p will be prese nte d f or b ot h t he i m p ute d data a n d t he 
o bser ve d cases .
 
 
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A p pr o v e d
1. 0
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 3 4 of 4 4
C O N FI D E N TI A L
 
1 0. 1. 3. 2
Pri m ar y E n d p oi nt Se nsiti vit y A n al ysis
N o se nsiti vit y  a nalys is is pla n ne d.
1 0. 1. 3. 3
Sec o n d ar y E n d p oi nts A n al ysis
T he pr o p orti o n of s u bjects wit h rec urre nce of a n y (≥1) cleare d treate d A K lesi o ns at 2 6 wee ks 
after t he last D L -P D T will be s u m marize d usi n g ta bles of fre q ue nc y . All s u bjects i n t he safety 
p o p ulati o n wit h missi n g data will be classifie d as n o n-res p o n ders re gar dless of treat me nt 
all ocati o n. S u m maries b y treat me nt gr o u p will be prese nte d f or b ot h t he i m p ute d data a n d t he 
o bser ve d cases .
 
 
T he perce nt rec urre nce of cleare d treate d A K lesi o ns at 2 6 a n d 5 2 wee ks after t he last D L -P D T 
treat me nt will be s u m marize d u si n g descri pti ve statistics. M issi n g c o u nts of cleare d treate d A K 
lesi o ns f or s u bjects i n t he safet y p o p ulati o n will be i m p ute d ass u mi n g t hat all baseli ne A K lesi o ns 
ha d rec urre d re gar dless of treat me nt all ocati o n. S u m maries b y  treat me nt gr o u p will be pres e nte d 
f or b ot h t he i m p ute d data a n d t he o bser ve d cases.
 
1 0. 1. 3. 4
S u b gr o u p A n al ysis
N o s u b gr o u p a nal ys is is pla n ne d.
S afet y A n al ysis
All safet y a nal ys es will be base d o n t he safet y p o p ulati o n.
S u m ma ries of all sa fety e n d p oi nts will be prese nte d.
1 0. 1. 4. 1
A d verse E ve nts
Treat me nt -e mer ge nt A Es , defi ne d as t h ose A Es occ urri n g after t he first a d mi nistrati o n of st u d y 
treat me nt u ntil t he last st u d y visit, fr o m st u d y RD. 0 6. S P R. 1 1 2 1 9 9 will be ta b ulate d i n fre q ue nc y 
ta bles b y  s yste m or ga n class a n d preferre d ter m base d o n t he Me dical Dicti o nar y  for Re g ulat or y 
Acti vities f or eac h st u d y p hase. A d diti o nal s u m mar y ta bles will be pr o vi de d f or S A Es, A Es relate d 
t o t he st u d y dr u g(s) (defi ne d as t he o nes wit h a reas o na ble p ossi bilit y  of ca usal relati o ns hi p wit h 
t he st u d y dr u g ), A Es relate d t o t he st u d y pr oce d ures ( defi ne d as t he o nes wit h a reas o na ble 
p ossi bilit y  of ca usal relati o ns hi p wit h t he st u d y pr oce d ures) , a n d A Es lea di n g t o treat me nt 
disc o nti n uati o n a n d st u d y wit h dra wal . F or a gi ve n A E, a s u bject will be c o u nte d o nce e ve n if he/s he 
has e x perie nce d m ulti ple e pis o des of t hat partic ular A E. 
I nteri m A n al yses
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI
C CI
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 3 5 of 4 4
C O N FI D E N TI A L
A n i nteri m a nalys is is pla n ne d of all a vaila ble data fr o m t his st u d y , R D. 0 6. S P R. 1 1 5 2 3 0, at t he 
ti me of re g ulat or y s u b missi o n f or mar keti n g a p pr o val f or M A L crea m. 
H a n dli n g of Missi n g D at a
F or t he pr o p orti o n of s u bjects wit h rec urre nce at 2 6 a n d 5 2 wee ks after t he last D L -P D T 
treat me nt, all s u bjects i n t he safety p o p ulati o n wit h missi n g data will be classifie d as n o n -
res p o n ders re gar dless of treat me nt all ocati o n.
F or t he rec urre nce of cleare d treat e d A K lesi o ns at 2 6 a n d 5 2 wee ks after t he last D L -P D T 
treat me nt, missi n g c o u nts of cleare d treate d A K lesi o ns f or s u bjects i n t he safety p o p ulati o n will 
be i m p ute d ass u mi n g t hat all baseli ne A K lesi o ns ha d rec urre d re gar dless of treat me nt all ocati o n.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 3 6 of 4 4
C O N FI D E N TI A L
1 0. 2
Dete r mi n ati o n of S a m ple S ize
T his l o n g-ter m f oll o w u p st u d y is pla n ne d t o gat her data a b o ut rec urre nces at ar o u n d t he 1 ye ar 
ti me p oi nt after t he D L-P D T treat me nts.
S u bjects w h o ac hie ve a c o m plete re s p o nse at Fi nal Visit of st u d y  R D. 0 6. S P R. 1 1 2 1 9 9 , 1 2 wee k s 
after t he last D L -P D T treat me nt, will be offere d t he o p p ort u nit y  t o be f oll o we d i n t his 9- m o nt h 
l o n g-ter m f oll o w-u p st u d y  t o ha ve treate d lesi o ns assesse d f or rec urre nce. T he sa m ple size 
calc ulati o n of st u d y  R D. 0 6. S P R. 1 1 2 1 9 9 was base d o n pr o vi di n g e n o u g h s u bjects t o e na ble t he 
detecti o n of a treat me nt differe nce i n t he pri mar y  e n d p oi nt of t hat st u d y a n d e ns uri n g 
a p pr o xi matel y 1 0 0 s u bjects ra n d o mize d t o M A L D L-P D T c o m plete t he l o n g -ter m f oll o w-u p 
st u d y.
A p pr o xi matel y  6 7 5 s u bjects are scree ne d f or a t otal of 5 7 0 s u bjects t o be ra n d o mize d ( 3 8 0 i n t he 
M A L  D L-P D T ar m a n d 1 9 0 i n t he ve hicle crea m D L -P D T ar m usi n g a  
 ra n d o mizati o n rati o)
i n t he st u d y R D. 0 6. S P R. 1 1 2 1 9 9 t o ha ve a p pr o xi matel y 1 0 0 s u bjects ra n d o mize d t o M A L  D L-
P D T c o m plete t his l o n g-ter m f oll o w-u p st u d y.
 
 
 
1 0. 3
Pr ot oc ol De vi ati o ns
Maj or de viati o ns are cate g orize d i nt o t he f oll o wi n g cate g ories:

Eli gi bilit y  de viati o ns (incl usi o n/ e xcl usi o n criteria)

N o nc o m plia nce wit h st u d y  pr oce d ures if t he c o nse q ue nce of n o nc o m plia nce w o ul d 
c o m pr o mise eit her t he s u bject’s safet y  a n d/ or t he st u d y i ntegrit y, pri mar y e n d p oi nt, a n d/ or is 
n ot i n li ne wit h G o o d Cli nical Practice (G C P )/IC H g ui deli nes

Use of p r o hi bite d c o nc o mita nt t hera pies
All pr ot oc ol de viati o ns will be i de ntifie d, e val uate d, a n d cl ose d bef ore t he res pecti ve data base 
l oc k (fi nal a nal ysis) a n d will be descri be d i n t he fi nal S A P a n d cli nical st u d y re p ort.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0
C CI
C CI
C CI


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 3 7 of 4 4
C O N FI D E N TI A L
1 1
Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L
1 1. 1
A u dit a n d I ns pecti o n
St u d y  ce nters a n d st u d y d oc u me ntati o n ma y  be s u bject t o Q ualit y Ass ura nce a u dit d uri n g t he 
c o urse of t he st u dy b y t he sp o ns or or i ts n o mi nate d re prese ntati ve. I n a d diti o n, i ns pecti o ns ma y 
be c o n d ucte d b y re g ulat or y a ut h orities at t heir discreti o n.
1 1. 2
M o nit ori n g
Data f or eac h s u bject will be rec or de d o n eC R F s. Data c ollecti o n m ust be c o m plete d f or eac h 
s u bject w h o si g ns a n I C F a n d is a d mi nistere d st u d y dr u g.
I n acc or da nce wit h curre nt G C P a n d I C H g ui deli nes, t he st u d y  m o nit or will carr y o ut s o urce 
d oc u me nt verificati o n at re g ular i nter vals t o e ns ure t hat t he data c ollecte d i n t he eC R F are 
acc urate a n d relia ble. 
T he In vesti gat or m ust per m it t he m o nit or, t he IE C /IR B , t he S p o ns or’s i nter nal a u dit ors, a n d 
re prese ntati ves fr o m re g ulat or y a ut h orities direct access t o all st u d y-relate d d oc u me nts a n d 
perti ne nt h os pital or me dical rec or ds f or c o nfir mati o n of data c o ntai ne d wit hi n t he e C R Fs.
1 1. 3
Pers o n nel Tr ai ni n g
St u d y  m o nit ors a n d all rele va nt pers o n nel will be trai ne d bef ore st u d y i nitiati o n o n t he sta n dar d 
o perati n g pr oce d ures t o be use d i n t his cli nical st u d y, t he pr ot oc ol, a n d all st u d y-s pecific 
pr oce d ures. Tea m or ga nizati o n, c o m m u nicati o n, a n d o perati o nal iss ues will als o be disc usse d a n d 
a gree d u p o n.
I n vesti gat ors, e val uat ors, a n d st u d y c o or di nat ors will be trai ne d at t he Site I nitiati o n Visit b y  t he 
site cli nical researc h ass ociate.
It is t he pri nci pal i n vesti gat or’s res p o nsi bilit y t o e nsure t hat a ll pers o n nel i n v ol ve d i n t he st u d y 
c o n d uct recei ve trai ni n g bef ore partici pati n g i n a n y  pr oce d ure a n d/ or e val uati o n. Eac h st u d y 
ce nter will ha ve a trai ni n g rec or d as part of t he site file a n d T M F .
1 1. 4
D at a M a n a ge me nt
T he desi g nate d C R O will be res p o n si ble f or acti vities ass ociate d wit h t he data ma na ge me nt of 
t his st u d y. T his will i ncl u de , b ut is n ot li mite d t o, setti n g u p a rele va nt data base a n d data tra nsfer 
mec ha nis ms, al o n g wit h a p pr o priate vali dati o n of data a n d res ol uti o n of q ueries . All data 
ma n a ge me nt acti vities will be detaile d i n t he data ma na ge me nt pla n. 
St u d y  ce nters will rec or d all st u d y i nf or mati o n i n a n a p pr o priate s o urce d oc u me nt. T he data wi ll 
t he n be e ntere d directl y  i nt o a n electr o nic data ca pt ure ( E D C) s yste m b y c o m pleti n g t he e C R F via 
a sec ure i nter net c o n necti o n. Data e ntere d i nt o t he eC R F m ust be verifia ble a gai nst s o urce 
d oc u me nts at t he st u d y  ce nter. A n y c ha n ges t o t he data e ntere d i nt o t he E D C s yste m will be 
rec or de d i n t he a u dit trail.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 3 8 of 4 4
C O N FI D E N TI A L
1 1. 5
Cli nic al St u d y C o n d uct
Wit h t he e xce pti o n
of a v oi di n g a n i m me diate ris k t o a s u bject, t he In vesti gat or s h o ul d n ot de viate 
fr o m t he cli nical st u d y pr ot oc ol or i m ple me nt a n y  c ha n ges wit h o ut writte n a p pr o val fr o m t he 
s p o ns or a n d pri or re vie w a n d d oc u me nte d a p pr o val/fa v ora ble o pi ni o n fr o m t he IR B/I E C of a 
pr ot oc ol a me n d me nt.
T he in vesti gat or s h o ul d d oc u me nt a n d e x plai n a n y de viati o n fr o m t he cli nical st u d y pr ot oc ol.
1 1. 6
A m e n d me nts
T he sp o ns or ma y  m o dif y t he cli nical st u d y pr ot oc ol at a n y  ti me f or et hical, me dical, or scie ntific 
reas o ns. A ny a me n d me nts will be ha n dle d acc or di n g t o a p plica ble l ocal re g ulati o ns.
1 1. 7
Q u alit y M a n a ge me nt a n d Ris k E v al u ati o n
Details will be pr o vi de d i n a se parate I nte grate d Q ualit y Ris k Ma na ge me nt Pla n.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 3 9 of 4 4
C O N FI D E N TI A L
1 2
E T HI C S
1 2. 1 
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d
Bef ore i nitiati o n of t he st u d y  at eac h st u d y ce nter, t he pr ot oc ol, t he I C F, ot her writte n material 
gi ve n t o t he s u bjects, a n d a n y  ot her rele va nt st u d y d oc u me ntati o n will be s u b mitte d t o t he 
a p pr o priate I E C/I RB. Writte n a p pr o val of t he st u d y  a n d all rele va nt st u d y i nf or mati o n m ust be 
o btai ne d bef ore t he st u d y ce nter ca n be i nitiate d . A n y  necessar y e xte nsi o ns or re ne wals of 
I E C/I R B a p pr o val m ust be o btai ne d f or c ha n ges t o t he st u d y s uc h as a me n d me nts t o t he pr ot oc ol, 
t he IC F or ot her st u d y  d oc u me ntati o n. T he writte n a p pr o val of t he I E C/IR B t o get her wit h t he 
a p pr o ve d I C F m ust be file d i n t he st u d y  files.
T he in vesti gat or will re p ort pr o m ptl y  t o t he I E C/I R B a n y ne w i nf or mati o n t hat ma y a d versel y 
affect t he safet y of t he s u bjects or t he c o n d uct of t he st u d y . T he n vesti gat or will s u b mit writte n 
s u m maries of t he st u d y stat us t o t he IE C/I R B as re q uire d . O n c o m pleti o n of t he st u d y , t he 
I E C/I R B will be n otifie d t hat t he st u d y has e n de d.
1 2. 2
Re g ul at or y A ut h orities
R ele va nt st u d y d oc u me ntati o n will be s u b mitte d t o t he re g ulat or y aut h orities of t he partici pati n g 
c o u ntries, acc or di n g t o l ocal/ nati o nal re q uire me nts, f or re vie w a n d a p pr o val bef ore t he be gi n ni n g 
of t he st u d y . O n c o m pleti o n of t he st u d y , t he re g ulat or y aut h orities will be n ot ifie d t hat t he st u d y 
has e n de d.
1 2. 3
Et hic al C o n d uct of t he St u d y
T he in vesti gat or(s) a n d all parties i n v ol ve d i n t his st u d y  s h o ul d c o n d uct t he st u d y i n a d here nce t o 
t he et hical pri nci ples base d o n t he Declarati o n of Helsi n ki, G C P, IC H g ui deli nes, a n d t he 
a p plica ble nati o nal a n d l ocal la ws a n d re g ula t or y re q uire me nts.
1 2. 4
I nf or me d C o nse nt
T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust be i n acc or da nce wit h a p plica ble re g ulat or y  
re q uire me nt(s) a n d m ust a d here t o G C P.
T he In vesti gat or is res p o nsi ble f or e ns uri n g t hat n o s u bject u n der g oes a n y  st u d y-relate d 
e xa mi nati o n or acti vit y bef ore t hat s u bject has gi ve n writte n i nf or me d c o nse nt t o partici pate i n 
t he st u d y.
T he In vesti gat or or desi g nate d pers o n nel will i nf or m t he s u bject of t he o bjecti ves, met h o ds, 
a ntici pate d be nefits a n d p ote ntial ris ks , a n d i nc o n ve ni e nces of t he st u d y. T he s u bject s h o ul d be 
gi ve n e ver y  o p p ort u nit y t o as k f or clarificati o n of a n y p oi nts s he/he d oes n ot u n dersta n d a n d, if 
necessar y , as k f or m ore i nf or mati o n. At t he e n d of t he i nter vie w, t he s u bject will be gi ve n a m ple 
ti me t o c o nsi der the st u d y . S u bjects will be re q uire d t o si g n a n d date t he I C F . After si g nat ures are 
o btai ne d, t he I C F will be ke pt a n d arc hi ve d b y t he in vesti gat or i n t he In vesti gat or’s st u d y  file. A 
si g ne d a n d date d c o py of t he s u bject I C F will be pr o vi de d t o t he s u bject or his/ her a ut h orize d 
re prese ntati ve.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 4 0 of 4 4
C O N FI D E N TI A L
It s h o ul d be e m p hasized t hat t he s u bject m a y ref use t o e nter t he st u d y or t o wit h dra w fr o m t he 
st u d y at a ny ti me, wit h o ut c o nse q ue nces f or t heir f urt her care or pe nalt y or l oss of be nefits , t o 
w hic h t he s u bject is ot he r wise e ntitle d. S u bjects w h o ref use t o gi ve or w h o wit h dra w writte n 
i nf or me d c o nse nt s h o ul d n ot be i ncl u de d or c o nti n ue i n t he st u d y.
If ne w i nf or mati o n bec o mes a vaila ble t hat ma y be rele va nt t o t he s u bject’s willi n g ness t o 
c o nti n ue partici pati o n i n t he st u d y , a ne w I C F will be a p pr o ve d b y t he I E C(s)/IR B(s) (a n d 
re g ulat or y aut h orities , if re q uire d). T he st u d y s u bjects will be i nf or me d a b o ut t his ne w 
i nf or mati o n a n d rec o nse nt will be o btai ne d.
1 2. 5
S u bject C o nfi de nti alit y
M o nit ors, a u dit ors, a n d ot her a ut h orize d age nts of t he S p o ns or a n d/ or its desi g nee, t he 
I E C(s)/IR B(s) a p pr o vi n g t his researc h, a n d t he U S F D A , as well as t hat of a n y ot her a p plica ble 
a ge nc y(ies), will be gra nte d direct access t o t he st u d y s u bjects’ ori gi nal me dical rec or ds f or 
verificati o n of cli nical st u d y pr oce d ures a n d/ or data, wit h o ut vi olati n g t he c o nfi de ntialit y  of t he 
s u bjects t o t he e xte nt per mitte d b y t he la w a n d re g ulati o ns. I n a ny prese ntati o ns of t he res ults of 
t his st u d y or i n p u blicati o ns, t he s u bjects’ i de ntities will re mai n c o nfi de ntial.
All pers o nal data c ollecte d a n d pr ocesse d f or t he p ur p oses of t his st u d y  s h o ul d be ma na ge d b y t he 
In vesti gat or a n d his/ her staff wit h a de q uate preca uti o ns t o e ns ure c o nfi de ntialit y  of t h ose data, 
a n d i n acc or da nce wit h t he a p plica ble nati o nal a n d/ or l ocal la ws a n d re g ulati o ns ( HI P A A f or t he 
U ni te d S tates) o n per s o nal data pr otecti o n.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 4 1 of 4 4
C O N FI D E N TI A L
1 3  
R E P O R TI N G A N D P U B LI C A TI O N, I N C L U DI N G A R C HI VI N G
Esse ntial d oc u me nts are t h ose d oc u me nts t hat i n di vi d uall y  a n d c ollecti vely per mit e val uati o n of 
t he st u d y a n d q ualit y of t he data pr o d uce d. After c o m pleti o n of t he st u d y (e n d of st u d y defi ne d as 
t he date of t he last visit of t he last s u bject), all d oc u me nts a n d data relati n g t o t he st u d y will be 
ke pt i n a n or derl y ma n ner b y  t he in vesti gat or i n a sec ure st u d y  file. T his file will be a vaila ble f or 
i ns pecti o n b y t he S p o ns or or its re prese ntati ves. Esse ntial d oc u me nts s h o ul d be retai ne d f or 
2 ye ars after t he fi nal mar keti n g a p pr o val i n a n I CH re gi o n or f or at least 2 ye ars si nce t he 
disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct. It is t he res p o nsi bilit y of 
t he S p o ns or t o i nf or m t he st u d y ce nter w he n t hese d oc u me nts n o l o n ger nee d t o be retai ne d . T he 
In vesti gat or m ust c o ntact t he s p o ns or bef ore destr o yi n g a ny st u d y- relate d d oc u me ntati o n. I n 
a d diti o n, all s u bject me dical rec or ds a n d ot her s o urce d oc u me ntati o n will be ke pt f or t he 
ma xi m u m ti me per mitte d b y t he h os pital, i nstit uti o n , or me dical practice.
T he S p o ns or m ust re vie w a n d a p pr o ve a n y res ults of t he st u d y or a bstracts f or pr ofessi o nal 
meeti n gs pre pare d b y t he In vesti gat or(s) . P u blis he d data m ust n ot c o m pr o mise t he o bjecti ves of 
t he st u d y. Data fr o m i n di vi d ual st u d y ce nters i n m ulti ce nter st u dies m ust n ot be p u blis he d 
se paratel y.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 4 2 of 4 4
C O N FI D E N TI A L
1 4  
R E F E R E N C E S
Braat he n L, Szei mies R- M, Basset -Se g ui n N, Biss o n nette R, F ole y  P, Pariser D 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. J 
A m Ac a d Der m at ol . 2 0 0 7; 5 6: 1 2 5 - 4 3.
Braat he n L R. Da y li g ht p h ot o d yna mic t hera p y i n pri vate practice i n S witzerla n d: gai n wit h o ut 
pai n. Act a Der m Ve nere ol . 2 0 1 2; 9 2( 6): 6 5 2 - 3.
Calza vara -Pi nt o n P G et al. Str uct ure d E x pert C o nse ns us o n Acti nic Kerat osis: Treat me nt 
Al g orit h m F oc usi n g o n Da y li g ht P D T. J C ut a n Me d S ur g 2 0 1 7; 2 1: 3 S - 1 6 S.
De Ber ker D, Mc Gre g or J M, H u g hes B R. G ui deli nes f or t he ma na ge me nt of acti nic kerat osis. Br 
J Der m at ol . 20 0 7 ; 1 5 6: 2 2 2 – 2 3 0.
E n gel et al . Healt h Effects of S u nli g ht E x p os ure i n t he U nite d States. Arc h Der m at o l. 1 9 8 8; 1 2 4: 
7 2 - 7 9.
Fel d ma n S R, Fleisc her A B Jr. P r o gressi o n of acti nic kerat osis t o s q ua m o us cell carci n o ma 
re visite d: cli nical a n d treat me nt i m plicati o ns. C utis . 2 0 1 1; 8 7( 4): 2 0 1 - 2 0 7.
Fe ns ke N A. Acti nic Kerat oses: Past, Prese nt a n d F ut ure . J Dr u gs Der m at ol . 2 0 1 0; 9( 5):s 4 5- s 4 9.
Fr ost C A . E pi de mi ol o g y  of solar kerat oses . Br J Der m at ol . 1 9 9 4; 1 3 1: 4 5 5 - 4 6 4.
Fr ost C A . T he pre vale nce a n d deter mi na nts of s olar kerat oses at a s u btr o pical latit u de 
( Q uee nsla n d, A ustralia). Br J Der m at ol . 1 9 9 8; 1 3 9: 1 0 3 3 - 1 0 3 9.
Fr ost C A et al. Hi g h I nci de nce a n d Re gressi o n Rates of S olar Kerat oses i n a Q uee nsla n d 
C o m m u nit y . J Invest Der m at ol . 2 0 0 0; 1 1 5( 8): 2 7 3 - 2 7 7.
G ol d M H . C urre nt treat me nts of acti nic kerat osis . J Dr u gs Der m at ol . 2 0 0 6; 5( 2): s 1 7 -s 2 5.
G ol d ber g D. Re vie w of acti nic kerat osis. Part I: eti ol o g y , e pi de mi ol o g y a n d cli nical prese ntati o n. 
J Dr u gs Der m at ol . 2 0 1 0; 9( 9): 1 1 2 5 - 3 2.
Har ve y  I. N o n - mela n o ma s ki n ca ncer a n d s olar kerat oses. I. Met h o ds a n d descri pti ve res ults of 
t he S o ut h Wales s ki n ca ncer st u dy. Br J C a ncer . 1 9 9 6; 7 4: 1 3 0 2 - 1 3 0 7.
Lac o ur J P, Ulric h C, Gila berte Y, V o n Fel bert V , Basset -Se g ui n N , Dre n o B, Girar d C, Re d o n d o 
P, Serra -G uille n C, S y n nersta d I, Tarste dt M, Tsia na kas A, Ve ne ma A W, Kelle ners- S meets N, 
A da ms ki H, Perez -Garcia B, Gerritse n MJ, Leclerc S, Kerr o uc he N, Szei mies R M. Da y li g ht 
p h ot o d y na mic t hera p y wit h met h y l ami n ole v uli nate crea m is effecti ve a n d nearl y pai nless i n 
treati n g acti nic kerat oses: a ra n d o mise d, i n vesti gat or-bli n de d, c o ntr olle d, p hase III st u d y  
t hr o u g h o ut E ur o pe. J E ur Ac a d Der m at ol Ve nere ol . 2 0 1 5; 2 9( 1 2): 2 3 4 2 - 8.
Le h ma n n P . Met h y l a mi n ole v uli nate- p hot o d y na mic t hera p y:  a re vie w of cli nical trials i n t he 
treat me nt of acti nic kerat oses a n d n o n mela n o ma s ki n ca ncer. Br J Der m at ol . 2 0 0 7; 1 5 6: 7 9 3 - 8 0 1.
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 4 3 of 4 4
C O N FI D E N TI A L
Me m o n A A . Pre vale nce of s olar da ma ge a n d acti nic kerat osis i n a Merse ysi de p o p ulati o n. Br J 
Der m at ol . 2 0 0 0 ; 1 4 2: 1 1 5 4- 1 1 5 9.
M ort o n C, W ulf H C, Szei mies R M, Gila berte Y, Basset- Se g ui n N, S ortiri o u et al. Practical 
a p pr oac h t o t he use of da yli g ht p h ot o d y na mic t hera p y  wit h t o pical met h yl a mi n ole v uli nate f or 
acti nic kerat osis: a E ur o pea n c o nse ns us. J E ur Aca d Der mat ol Ve nere ol. 2 0 1 5 Se p; 2 9( 9): 1 7 1 8 -
2 3 .
Salasc he S. E pi de mi ol o g y  of acti nic kerat osis a n d s q ua m o us cell carci n o ma. J A m A c a d 
Der m at ol . 2 0 0 0; 4 2: 4 - 7.
R u bel D M, S pel ma n L, M urrell D F, See J A, He witt D, F ole y  P, B osc C, Ker o b D, Kerr o uc he N, 
W ulf H C, S h u mac k S. Da y li g ht p h ot o d yna mic t hera p y wit h met h yl a mi n ole v uli nate crea m as a 
c o n ve nie nt, si milarl y effecti ve, nearly pai nless alter nati ve t o c o n ve nti o nal p h ot o d y na mic t hera p y 
i n acti nic kerat osis treat me nt: a ra n d o mize d c o ntr olle d trial. Br J Der m at ol. 2 0 1 4; 1 7 1( 5): 
1 1 6 4 - 7 1.
Si d or off A . Ta ki n g treat me nt decisi o ns i n n o n-mela n o ma s ki n ca ncer -t he place f or t o pical 
p h ot o d y na mic t hera p y ( P D T) . P h ot o di a g a n d P h o t o dy n T her. 2 0 1 0; 7: 2 4 - 3 2.
S pie wa k R . Patc h testi n g f or c o ntact aller g y a n d aller gic c o ntact der matitis . T he O pe n Aller gy
J o ur n al . 2 0 0 8; 1: 4 2 - 5 1.
U hle n ha ke E. O pti mal treat me nt of acti nic kerat osis. Cli n I nterv A gi n g . 2 0 1 3; 8: 2 9 - 3 5.
U S De part me nt of Healt h a n d H u ma n Ser vices. Healt h i ns ura nce p orta bilit y  a n d acc o u nta bilit y 
act of 1 9 9 6 ( P. L. 1 0 4-1 9 1) [ HI P A A]. htt p://as pe. h hs. g o v/a d m nsi m p/ pl 1 0 4 1 9 1. ht m . Effecti ve 
A u g ust 2 1, 1 9 9 6.
Wer ner R N . T he nat ural hist or y  of acti nic kerat osis: a s yste matic re vie w. Br J Der m at ol . 2 0 1 3; 
1 6 9: 5 0 2 - 5 1 8.
Wie gell S R, Hae ders dal M, P hili pse n P A, Eri kse n P, E n k C D, W ulf H C . C o nti n u o us acti vati o n 
of P pI X b y da y li g ht is effecti ve as a n d less pai nf ull t ha n c o n ve nti o nal p h ot o d yna mic t hera p y f or 
acti nic kerat osis; a ra n d o mize d, c o ntr olle d, si n gle-bli n de d st u d y . Br J Der m at ol . 2 0 0 8; 1 5 8: 7 4 0 -
7 4 6 .
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0


G al der m a R & D 
 
0 7 J A N 2 0 2 1
Pr ot oc ol N u m ber: R D. 0 6. S P R. 1 1 5 2 3 0
Versi o n 3. 0
P a ge 4 4 of 4 4
C O N FI D E N TI A L
I n vesti g at or Si g n at ure P a ge
Pr ot oc ol Title:
A 
d o u ble -bli n d, m ultice nter, 
l o n g-ter m f oll o w-u p st u d y to assess 
rec urre nce of Acti nic 
Kerat osis 
i n s u bjects treate d wit h 
Met h y l 
a mi n ole v uli nate h y dr oc hl ori de ( M A L) 1 6. 8 % crea m ( C D 0 6 8 0 9-4 1) or 
ve hicle crea m i n t he treat me nt of t hi n a n d 
m o deratel y t hic k, n o n-
h y per kerat otic, n o n- pi g me nte d acti nic kerat osis of t he face a n d scal p w he n 
usi n g d a y li g ht p h ot o d y na mic t hera p y (D L -P D T), f or s u bjects ac hie vi n g 
c o m plete 
res p o nse of 
treate d lesi o ns at 
Fi nal 
Visit i n 
S t u d y 
R D. 0 6. S P R. 1 1 2 1 9 9
Pr ot oc ol N u m ber:
R D. 0 6. S P R. 1 1 5 2 3 0
C o nfi de nti alit y a n d C urre nt G C P C o m pli a nce St ate me nt
I, t he u n dersi g ne d, ha ve re vie we d t his pr ot oc ol (a n d a me n d me nts), i ncl u di n g a p pe n dices, a n d I 
will c o n d uct t he st u d y  as descri be d i n c o m plia nce wit h t his pr ot oc ol (a n d a me n d me nts), G C P, 
a n d rele va nt I CH g ui deli nes.
O nce t he pr ot oc ol has bee n a p pr o ve d b y t he I E C/I R B, I will n ot m o dif y t his pr ot oc ol wit h o ut 
o btai ni n g pri or a p pr o val of Gal der ma Researc h & De vel o p me nt, L L C a n d of t he I E C/I RB. I will 
s u b mit t he pr ot oc ol a me n d me nts a n d/ or a n y I C F m o dificati o ns t o Gal der ma Researc h & 
De vel o p me nt, L L C a n d t he I E C/IR B, a n d a p pr o val will be o btai ne d bef ore a n y  a me n d me nt s are 
i m ple me nte d.
I u n dersta n d t hat all i nf or mati o n o btai ne d d uri n g t he c o n d uct of t he st u dy wit h re gar d t o t he 
s u bjects’ state of healt h will be re gar de d as c o nfi de ntial . N o s u bjects’ na mes will be discl ose d . 
All s u bjects will be i de ntifie d b y assi g ne d n u m bers o n all eC R F s, la b orat or y sa m ples, or s o urce 
d oc u me nts f or war de d t o t he s p o ns or. Cli nical i nf or mati o n ma y  be re vie we d b y t he s p o ns or or its 
a ge nts or re g ulat or y a ge ncies. A gree me nt m ust be o btai ne d fr o m t he s u bject bef ore discl os ure of 
s u bject i nf or mati o n t o a t hir d party.
I nf or mati o n de vel o pe d i n t his cli nical st u d y ma y be discl ose d b y Gal der ma Researc h & 
De vel o p me nt, L L C t o ot her cli nical i n vesti gat ors, re g ulat or y a ge ncies, or ot her healt h a ut h ority 
or g o ver n me nt a ge ncies as re q uire d.
I n vesti gat or Si g nat ure
Date
Pri nte d Na me
Title
I nstit uti o n
St u d y  Ce nter N u m ber
 
1 5- J a n- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 A m e n d m e nt 2 Pr ot o c ol V 3. 0 0 7 J A N 2 0 2 1 e U S
A p pr o v e d
1. 0

SAP_001.pdf: 
This document is confidential.
SAP Version: Final Version 2.0 
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020 
Filing requirements: TMF
Page 1 of 28 
Statistical Analysis Plan for Interventional Studies
Sponsor Name: Galderma Research & Development, LLC
Protocol Number: RD.06.SPR.115230
A double-blind, multicenter, long-term follow-up study to assess recurrence of Actinic Keratosis in 
subjects treated with Methyl aminolevulinate hydrochloride (MAL) 16.8% cream (CD06809-41) or 
vehicle cream in the treatment of thin and moderately thick, non-hyperkeratotic, non-pigmented 
actinic keratosis of the face and scalp when using daylight photodynamic therapy (DL-PDT), for 
subjects achieving complete response of treated lesions at Final Visit in Study RD.06.SPR.112199
Clinical Trial Phase: III
Protocol Version and Date: 3.0 Amendment 2 (07-Jan-2021)
Syneos Health Project Code: 7007743
Notice of Confidential and Proprietary Information:
The information contained in this document is confidential belonging to Galderma Research &
Development, LLC. Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an official of 
Galderma Research & Development, LLC. However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a national 
regulatory authority under the condition that they are requested to keep it confidential. In the event of an 
actual or suspected breach of this obligation, Syneos Health should be notified promptly.
 
              
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
S p o n s or: G al d er m a R e s e ar c h & D e v el o p m e nt, L L C; Pr ot o c ol N o.: R D. 0 6. S P R. 1 1 5 2 3 0 Pr ot o c ol V 3. 0
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n: Fi n al V er si o n 2. 0
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 1, Eff e cti v e D at e 0 3- M ar- 2 0 2 0
Fili n g r e q uir e m e nt s: T M F
P a g e 3 of 2 8
I c o nfir m t h at I h a v e r e vi e w e d t hi s d o c u m e nt a n d a gr e e wit h t h e c o nt e nt.
A p pr o v al s
S y n e o s H e alt h A p pr o v al
, Pri n ci p al Bi o st ati sti ci a n
N a m e, Titl e
L e a d Bi o st ati sti ci a n
Si g n at ur e
D at e ( D D- M m m- Y Y Y Y)
N a m e, Titl e
S e ni or R e vi e wi n g Bi o st ati sti ci a n
Si g n at ur e
D at e ( D D- M m m- Y Y Y Y)
G al d er m a  A p pr o v al
N a m e, Titl e
Pri n ci p al Bi o st ati sti ci a n
Si g n at ur e
D at e ( D D- M m m- Y Y Y Y)
              
2 9- S e p- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 S A P FI N A L 2. 0 2 7 S E P 2 0 2 1 Si g
A p pr o v e d
1. 0
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 4 of 28
Table of Contents
Revision History ............................................................................................................................................ 2
Approvals..................................................................................................................................................... 3
Glossary of Abbreviations ................................................................................................................... 6
Introduction.......................................................................................................................................... 7
Study Objectives ................................................................................................................................. 8
Study Design ....................................................................................................................................... 9
Efficacy and Safety Assessments ..................................................................................................... 14
Efficacy Endpoints............................................................................................................................. 15
Populations Analyzed........................................................................................................................ 15
Sample Size Consideration............................................................................................................... 16
Statistical Methods and Data Considerations ................................................................................... 17
              
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 5 of 28
Changes from the Protocol Analysis Plan......................................................................................... 26
Shells of Tables, Figures and Listings and Reporting Output (General Features) ........................... 27
Appendices........................................................................................................................................ 28
              
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 6 of 28
Glossary of Abbreviations
Abbreviation
Description
AE
Adverse Event 
AK
Actinic Keratosis 
ATC
Anatomical Therapeutic Chemical
CI 
Confidence Interval 
COVID-19
Coronavirus Disease 2019
CR
Complete Response 
CRO 
Contract Research Organization 
CSR
Clinical Study Report
DL-PDT
Daylight Photodynamic Therapy
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FST 
Fitzpatrick Skin Type 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IRC
Independent Review Committees
LTFU 
Long-term Follow-up
MAL 
Methyl Aminolevinulate Hydrochloride 
MedDRA 
Medical Dictionary for Regulatory Activities 
PDT 
Photodynamic Therapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TMF 
Trial Master File 
UPT 
Urine Pregnancy Test 
WHO
World Health Organization
              
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 7 of 28
Introduction
This Statistical Analysis Plan (SAP) is based on the study protocol final version 3.0 dated 07-JAN-2021.
This document describes all the analyses and reporting that will be required for a clinical report purpose 
and any resulting publications. This SAP has been developed prior to any examination of study data. The
analyses and reporting will be performed after the completion of study. Any post hoc, or unplanned, 
exploratory analyses performed, if included, will be clearly identified as such in the final Clinical Study 
Report (CSR).
              
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 8 of 28
Study Objectives
Primary Objective
The primary objective of this study is to assess recurrence of lesions treated in RD.06.SPR.112199 for 
subjects who achieved Complete Response (CR) of treated Actinic Keratosis (AK) lesions. They will be 
offered the opportunity to participate in this 9-month long-term follow-up study (i.e., 52 weeks after the last 
DL-PDT), continuing the double-blind conduct of this study.
Secondary Objective
The secondary objective of this study is to evaluate the long-term safety of MAL DL-PDT and vehicle cream 
DL-PDT for 52 weeks after the last DL-PDT for those subjects who achieved CR of treated AK lesions in 
study RD.06.SPR.112199.
              
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 9 of 28
Study Design
This is a double-blind, vehicle-controlled, multicenter, parallel-group long-term follow-up study to evaluate 
recurrence of AKs in subjects who completed study RD.06.SPR.112199. Only those subjects who achieved 
CR of treated AK lesions at the Final Visit of that study will be offered the opportunity to continue to be 
followed in the current study for 9 months to assess recurrence. 
In this study, the results of DL-PDT with MAL 16.8% cream or a vehicle cream will be compared; no 
intervention occurs in this study. 
All subjects will provide written informed consent prior to any study-related procedure. 
A total of approximately 130 subjects will continue from the study RD.06.SPR.112199 to be followed for 
another 40 weeks, which corresponds to 52 weeks after the last DL-PDT. It is anticipated that approximately 
111 subjects will continue from the MAL cream arm, and 19 subjects will continue from the vehicle cream 
arm. Blinding will be maintained throughout this study. 
Subjects will have a combined visit which includes the final visit for the RD.06.SPR.112199 study and the 
initial visit for this study. Data from the previous study will be pulled into the database for this study. Subjects 
will return to the study center for another visit at Visit 2 (26 weeks after the last DL-PDT) for efficacy and 
safety assessments. The investigative site staff will contact the subject via telephone at Week 26 to 
determine if the subject is experiencing any treatment-related safety issues. 
The primary endpoint of this study occurs at Visit 3; Final Visit, Week 40 (52 weeks after the last DL-PDT 
visit). 
Figure 1 - Study Schema 
              
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development  LLC; Protocol No : RD 06 SPR 115230 Protocol V3 0
This document is confidential.
SAP Version: Final Version 2.0 
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020 
Filing requirements: TMF
Page 13 of 28
e) Adverse Events have to be collected from the time of the Informed Consent signature 
f) Exit form should be completed after subject data collection has been completed for subjects in the study 
Red arrows signify that pertinent data obtained at Visit 6 of RD.06.SPR.112199 will be transcribed as this visit as Visit 1 of RD.06.SPR.115230.
 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 14 of 28
Efficacy and Safety Assessments
Efficacy Variables 
Lesion Response
The lesions treated in the pivotal trial will be evaluated for reoccurrence. Any lesions that have recurred will 
be evaluated for severity according to the grading scale in Table 2.
Table 2 - Lesion Severity Grade Scale
Grade 
Severity
Description
Grade 1
Mild
Slightly palpable, better felt than seen
Grade 2
Moderate
Moderately thick, easily felt and seen
Grade 3
Severe
Very thick and/or obvious actinic keratoses
The Investigator will be asked at Visits 2 (26 weeks after the last DL-PDT) and Visit 3/Final Visit (52 weeks 
after the last DL-PDT) to identify each lesion treated previously, and the lesion response as a CR or a non-
CR, as described in Table 3.
Table 3 - Lesion Response Score
Response
Score
Description
Complete response (CR)
1
Complete disappearance of the lesion, visually and by palpation
Non-complete response (non-CR)
0
Non-complete disappearance of the lesion
If all of the treated lesions in the treatment area are assessed to be CR at Visits 2 and 3 of this study (26 
and 52 weeks after the last DL-PDT session, respectively), the subject will be assessed as a subject CR
and will be deemed to have no recurrence. If any of the treated lesions in the treatment area are assessed 
to be non-CR, those lesions are recurrences; the subject will be assessed as a non-complete responder or 
deemed as a subject recurrence. 
Safety Variables
Safety assessments will be conducted for all subjects at Visit 1 (upon signing of the Informed Consent Form 
(ICF) and at every subsequent visit.
Adverse Events
Adverse events (AEs) will be recorded during each visit (Visits 1, 2 and 3) and during telephone call.
An AE is defined as any untoward medical occurrence in a clinical study, in which a subject is administered 
a medicinal product that does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or not it is 
related to the medicinal (investigational) product. This includes an exacerbation of pre-existing conditions 
or events, intercurrent illnesses, drug interaction, or the significant worsening of the indication under 
investigation, that is not recorded elsewhere in the eCRF under specific efficacy assessments.
Refer to the study protocol for further details about AEs definition and management.
              
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Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 15 of 28
Pregancy Testing
All women of childbearing potential will have a urine pregnancy test at Visits 1, 2 and 3.
If the result of a urine pregnancy test (UPT) is positive, it must be confirmed with a serum pregnancy test.  
Subjects with a positive serum pregnancy test result at Visit 1 will be followed in this study. Urine pregnancy 
tests with a sensitivity < 25 IU/L will be provided to the study centers for use in the study.  Urine pregnancy 
tests will be performed at the study centers, and all other samples will be sent to the central laboratory for 
analysis.
Efficacy Endpoints 
Primary Endpoint
The primary efficacy endpoint is the subject recurrence, defined as the proportion of subjects with 
recurrence of DQ\  FOHDUHG WUHDWHG $. OHVLRQV DW 9LVLW   ZHHNV DIWHU WKH ODVW '/-PDT treatment.
Secondary Endpoints
x
6XEMHFW UHFXUUHQFH GHILQHG DV WKH SURSRUWLRQ RI VXEMHFWV ZLWK UHFXUUHQFH RI DQ\  FOHDUHG WUHDWHG
AK lesions at Visit 2, 26 weeks after the last DL-PDT treatment.
x
Lesion recurrence, defined as the percent recurrence of cleared treated lesions at Visits 2 and 3, 26 
and 52 weeks after the last DL-PDT treatment.
Populations Analyzed
Intent-to-Treat Population
Not applicable.
Safety Population
The safety population will consist of all enrolled subjects and will be used for all the efficacy and safety 
analyses. Screen failures will not be included into the Safety Population.
Per Protocol Population
Not applicable.
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
S p o n s or: G al d er m a R e s e ar c h & D e v el o p m e nt, L L C; Pr ot o c ol N o.: R D. 0 6. S P R. 1 1 5 2 3 0 Pr ot o c ol V 3. 0
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n: Fi n al V er si o n 2. 0
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 1, Eff e cti v e D at e 0 3- M ar- 2 0 2 0
Fili n g r e q uir e m e nt s: T M F
P a g e 1 6 of 2 8
S a m pl e Si z e C o n si d er ati o n 
T hi s l o n g-t er m f oll o w u p st u d y i s pl a n n e d t o g at h er d at a a b o ut r e c urr e n c e s at ar o u n d t h e 1 y e ar ti m e p oi nt 
aft er t h e D L- P D T tr e at m e nt s.
S u bj e ct s w h o a c hi e v e a c o m pl et e r e s p o n s e at Fi n al Vi sit of st u d y R D. 0 6. S P R. 1 1 2 1 9 9, 1 2 w e e k s aft er t h e 
l a st D L- P D T tr e at m e nt, will b e off er e d t h e o p p ort u nit y t o b e f oll o w e d i n t hi s 9- m o nt h l o n g-t er m f oll o w- u p 
st u d y  t o  h a v e  tr e at e d  l e si o n s  a s s e s s e d  f or  r e c urr e n c e.  T h e  s a m pl e  si z e  c al c ul ati o n  of  st u d y  
R D. 0 6. S P R. 1 1 2 1 9 9  w a s  b a s e d  o n  pr o vi di n g  e n o u g h  s u bj e ct s  t o  e n a bl e  t h e  d et e cti o n  of  a  tr e at m e nt  
diff er e n c e i n t h e pri m ar y e n d p oi nt of t h at st u d y a n d e n s uri n g a p pr o xi m at el y 1 0 0 s u bj e ct s r a n d o mi z e d t o 
M A L D L- P D T c o m pl et e t h e l o n g-t er m f oll o w- u p st u d y.
A p pr o xi m at el y 6 7 5 s u bj e ct s ar e s cr e e n e d f or a t ot al of 5 7 0 s u bj e ct s t o b e r a n d o mi z e d ( 3 8 0 i n t h e M A L D L-
P D T  ar m  a n d  1 9 0  i n  t h e  v e hi cl e  cr e a m  D L- P D T  ar m  u si n g  a   
 r a n d o mi z ati o n  r ati o)  i n  t h e  st u d y  
R D. 0 6. S P R. 1 1 2 1 9 9 t o h a v e a p pr o xi m at el y 1 0 0 s u bj e ct s r a n d o mi z e d t o M A L D L- P D T c o m pl et e t hi s l o n g-
t er m f oll o w- u p st u d y.
 
 
 
              
2 9- S e p- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 S A P FI N A L 2. 0 2 7 S E P 2 0 2 1 Si g
A p pr o v e d
1. 0
C CI
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
S p o n s or: G al d er m a R e s e ar c h & D e v el o p m e nt, L L C; Pr ot o c ol N o.: R D. 0 6. S P R. 1 1 5 2 3 0 Pr ot o c ol V 3. 0
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n: Fi n al V er si o n 2. 0
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 1, Eff e cti v e D at e 0 3- M ar- 2 0 2 0
Fili n g r e q uir e m e nt s: T M F
P a g e 1 7 of 2 8
St ati sti c al M et h o d s a n d D at a C o n si d er ati o n s 
G e n er al C o n si d er ati o n s 
B a s eli n e
B a s eli n e a n al y si s vi sit i s b a s e d o n st u d y R D. 0 6. S P R. 1 1 2 1 9 9. F or st ati sti c al a n al y s e s p ur p o s e, b a s eli n e i s 
d efi n e d  a s  t h e  l a st  m e a s ur e m e nt  pri or  t o  t h e  fir st  D L- P D T  tr e at m e nt of  st u d y  R D. 0 6. S P R. 1 1 2 1 9 9
(r e g ar dl e s s of tr e at m e nt c o m pl eti o n st at u s).
              
2 9- S e p- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 S A P FI N A L 2. 0 2 7 S E P 2 0 2 1 Si g
A p pr o v e d
1. 0
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
S p o n s or: G al d er m a R e s e ar c h & D e v el o p m e nt, L L C; Pr ot o c ol N o.: R D. 0 6. S P R. 1 1 5 2 3 0 Pr ot o c ol V 3. 0
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n: Fi n al V er si o n 2. 0
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 1, Eff e cti v e D at e 0 3- M ar- 2 0 2 0
Fili n g r e q uir e m e nt s: T M F
P a g e 1 8 of 2 8
R ef er e n c e St art D at e a n d A n al y si s D a y
T h e fir st tr e at m e nt d at e of st u d y R D. 0 6. S P R. 1 1 2 1 9 9 will b e t h e r ef er e n c e st art d at e.
A n al y si s d a y will b e c al c ul at e d fr o m t h e fir st tr e at m e nt d at e of st u d y R D. 0 6. S P R. 1 1 2 1 9 9 a n d will b e u s e d 
t o s h o w st art/ e n d d a y of a s s e s s m e nt s, e v e nt s, t h er a pi e s or pr o c e d ur e s.
 
A n al y si s Vi sit s D efi niti o n
A n al y si s vi sit will b e c al c ul at e d a c c or di n g t o t h e f oll o wi n g t a bl e ( s e e T a bl e 5) t o s u m m ari z e t h e d at a b y 
pr o p er vi sit.
T a bl e 5 -  A n al y si s Vi sit s D efi niti o n
Cli ni c al
Vi sit 
A n al y si s
Vi sit 
A n al y si s
Vi sit
N u m b er
T ar g et
St u d y 
D a y
Vi sit
Wi n d o w
Vi sit  1  ( 1 2  w e e k s  
aft er t h e l a st D L- P D T)
W e e k 1 4 
1 1  
D a y of Vi sit 6 of st u d y 
R D. 0 6. S P R. 1 1 2 1 9 9
< = T ar g et St u d y D a y + 1 4 d a y s
Vi sit  2  ( 2 6  w e e k s  
aft er t h e l a st D L- P D T)
W e e k 2 8 
1 2  
D a y of l a st D L- P D T
+ 1 8 2 d a y s
> = T ar g et St u d y D a y - 2 1 d a y s
< = T ar g et St u d y D a y + 2 1 d a y s
T el e p h o n e
 C o nt a ct
( 3 8  w e e k s  aft er  t h e  
l a st D L- P D T) 
W e e k 4 0 
1 3  
D a y of l a st D L- P D T
+ 2 6 6 d a y s
> = T ar g et St u d y D a y - 2 1 d a y s
< = T ar g et St u d y D a y + 2 1 d a y s
Vi sit  3  ( 5 2  w e e k s  
aft er t h e l a st D L- P D T)
W e e k 5 4 
1 4  
D a y of l a st D L- P D T
+ 3 6 4 d a y s
> = T ar g et St u d y D a y - 2 8 d a y s
E arl y  t er mi n ati o n  vi sit  will  b e  m a n a g e d  a s  a  st a n d- al o n e  vi sit.  T h e  a s s e s s m e nt s  p erf or m e d  at  e arl y  
t er mi n ati o n vi sit will b e wi n d o w e d b a s e d o n t h e a n al y si s vi sit wi n d o w s.
U n s c h e d ul e d vi sit s will b e wi n d o w e d b a s e d o n t h e a n al y si s vi sit wi n d o w s.
If m ulti pl e a s s e s s m e nt s ar e p erf or m e d  wit hi n t h e s a m e wi n d o w, all a s s e s s m e nt s will b e li st e d a n d t h e o n e s
t a k e n cl o s e st t o t h e t ar g et st u d y d a y will b e u s e d f or t h e a n al y si s.
              
2 9- S e p- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 S A P FI N A L 2. 0 2 7 S E P 2 0 2 1 Si g
A p pr o v e d
1. 0
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
S p o n s or: G al d er m a R e s e ar c h & D e v el o p m e nt, L L C; Pr ot o c ol N o.: R D. 0 6. S P R. 1 1 5 2 3 0 Pr ot o c ol V 3. 0
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n: Fi n al V er si o n 2. 0
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 1, Eff e cti v e D at e 0 3- M ar- 2 0 2 0
Fili n g r e q uir e m e nt s: T M F
P a g e 1 9 of 2 8
Mi s si n g D at a M a n a g e m e nt 
F or t h e pr o p orti o n of s u bj e ct s wit h r e c urr e n c e at 2 6 a n d 5 2 w e e k s aft er t h e l a st  D L- P D T tr e at m e nt, all 
s u bj e ct s  i n  t h e  s af et y p o p ul ati o n  wit h  mi s si n g  d at a  will  b e  cl a s sifi e d  a s  n o n-r e s p o n d er s  r e g ar dl e s s  of  
tr e at m e nt all o c ati o n.
F or t h e r e c urr e n c e of cl e ar e d tr e at e d A K l e si o n s at 2 6 a n d 5 2 w e e k s aft er t h e l a st  D L- P D T tr e at m e nt,
mi s si n g c o u nt s of cl e ar e d tr e at e d A K l e si o n s f or s u bj e ct s i n t h e s af et y p o p ul ati o n will b e i m p ut e d a s s u mi n g 
t h at all b a s eli n e A K l e si o n s h a d r e c urr e d r e g ar dl e s s of tr e at m e nt all o c ati o n.
D e s cri pti v e St ati sti c s
F or  t h e  d e s cri pti v e st ati sti c s, u nl e s s  ot h er wi s e n ot e d, t h e c at e g ori c al  v ari a bl e s  will b e s u m m ari z e d  b y 
fr e q u e n c y  a n d  p er c e nt a g e  ( n,  %)  f or  e a c h  r e s p o n s e  c at e g or y,  
 
 
.
St ati sti c al T e st s a n d C o nfi d e n c e I nt er v al s
N o f or m al h y p ot h e si s t e st will b e p erf or m e d i n t hi s st u d y f or t h e pri m ar y a n d t h e s e c o n d ar y e n d p oi nt s. 
 
S oft w ar e V er si o n
All a n al y s e s will b e p erf or m e d u si n g S A S ® s oft w ar e V er si o n 9. 4 or hi g h er.
St u d y S u bj e ct s
Di s p o siti o n of S u bj e ct s
T h e n u m b er a n d p er c e nt a g e of s u bj e ct s ( n, %) will b e s u m m ari z e d b y tr e at m e nt gr o u p a n d o v er all ( all 
s u bj e ct s) f or t h e f oll o wi n g c at e g ori e s:
S u bj e ct s s cr e e n e d;
S u bj e ct s eli gi bl e;
              
2 9- S e p- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 S A P FI N A L 2. 0 2 7 S E P 2 0 2 1 Si g
A p pr o v e d
1. 0
C CI
C CI
C CI


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 20 of 28
x
Screen failures;

Reasons for screen failure;
x
Screen failures due to COVID-19;

Reasons for screen failure due to COVID-19;
x
Subjects enrolled;
x
Subjects enrolled who completed the study;
x
Subjects enrolled who discontinued the study;

Reasons for study discontinuation;
x
Subjects enrolled who discontinued the study due to COVID-19;

Reasons for study discontinuation due to COVID-19;
x
Subjects enrolled affected by COVID-19 related study disruptions;
x
Subjects enrolled affected by COVID-19 related study disruptions impacting efficacy;
x
Subjects enrolled affected by COVID-19 related study disruptions impacting safety.
All disposition data will be listed. A listing of all subjects affected by the COVID-19 related study disruptions
inclusive of the description of how the individual's participation was altered will be provided.
Demographic and Baseline Characteristics
Descriptive summaries of the following demographic data and baseline characteristics will be presented by 
treatment group and overall using the Safety population.
x
Age
x
Age group

  \HDUV ROG

40-64 years old

  \HDUV ROG
x
Sex

Male

Female
x
Ethnicity

Hispanic or Latino

Not Hispanic or Latino

Not Reported

Unknown
x
Race

White

Black or African American

Asian

American Indian or Alaska Native

Hawaiian Native or Other Pacific Islander

Other

Multiple
x
Fitzpatrick skin type

Type I

Type II

Type III
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 21 of 28

Type IV

Type V

Type VI
x
Number of baseline AK lesions of grade 1 and grade 2 and total number of baseline AK lesions
x
Classified number of baseline AK lesions

4-8 AK lesions

9-12 AK lesions
x
Baseline AK grade

Grade 1 (mild) AK

Grade 2 (moderate) AK
All demographic data and baseline characteristics will be listed.
Accounting of Subjects
Number and percentage (n, %) of subjects for each clinical visit and each analysis visit will be presented 
by treatment group and overall using the Safety Population.
Protocol Deviations
Potential major protocol deviations may include but are not limited to:
x
Eligibility deviations (inclusion/exclusion criteria);
x
Noncompliance with study procedures if the consequence of noncompliance would compromise either 
the subject’s safety and/or the study integrity, primary endpoint, and/or is not in line with Good Clinical 
Practice (GCP)/ICH guidelines;
x
Use of prohibited concomitant therapies;
x
Administrative error:

Accidental unblinding;

AK lesion counts and evaluation performed by a non-approved evaluator.
Major protocol deviations and major protocol deviations due to COVID-19 will be summarized using 
frequency and percentage (n, %) for each deviation coded term by treatment group and overall using the 
Safety Population. All protocol deviations will be listed.
Medical History, Prior and Concomitant Therapies and Procedures
For statistical analysis purposes, prior therapies/procedures are defined as those ending before the day of 
first treatment of study RD.06.SPR.112199; concomitant therapies/procedures are defined as those starting 
before the day of first treatment of study RD.06.SPR.112199 and ongoing on the day of first treatment and 
as those starting on the day of first treatment of study RD.06.SPR.112199 or after. Previous and 
concomitant therapies/medications will be coded using WHO Drug Dictionary (March 1, 2019, B3/C3 
format). Medical history and prior and concomitant medical/surgical procedures will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary (version 22.0).
A summary table will be provided for each of the following using Safety population by treatment group and 
overall:
x
Number and percentage (n, %) of subjects who had medical history by System Organ Class and
Preferred Term.
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
S p o n s or: G al d er m a R e s e ar c h & D e v el o p m e nt, L L C; Pr ot o c ol N o.: R D. 0 6. S P R. 1 1 5 2 3 0 Pr ot o c ol V 3. 0
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n: Fi n al V er si o n 2. 0
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 1, Eff e cti v e D at e 0 3- M ar- 2 0 2 0
Fili n g r e q uir e m e nt s: T M F
P a g e 2 2 of 2 8
N u m b er a n d p er c e nt a g e ( n, %) of s u bj e ct s w h o h a d pri or t h er a pi e s/ m e di c ati o n s b y A T C l e v el s 2, 3 a n d
Pr ef err e d T er m.
N u m b er a n d p er c e nt a g e ( n, %) of s u bj e ct s w h o h a d c o n c o mit a nt t h er a pi e s/ m e di c ati o n s b y A T C l e v el s 
2, 3 a n d Pr ef err e d T er m.
N u m b er a n d p er c e nt a g e ( n, %) of s u bj e ct s w h o h a d pri or m e di c al/ s ur gi c al pr o c e d ur e s b y S y st e m Or g a n 
Cl a s s a n d Pr ef err e d T er m.
N u m b er  a n d  p er c e nt a g e  ( n,  %)  of  s u bj e ct s  w h o  h a d  c o n c o mit a nt  m e di c al/ s ur gi c al  pr o c e d ur e s  b y  
S y st e m Or g a n  Cl a s s a n d Pr ef err e d T er m.
Li sti n g s  of  all  m e di c al  hi st or y,  pri or  a n d  c o n c o mit a nt  t h er a pi e s/ m e di c ati o n s  a n d  m e di c al/ s ur gi c al  
pr o c e d ur e s  will b e pr o vi d e d.
Vit al Si g n s
D e s cri pti v e  st ati sti c s  ( n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  fir st  a n d  t hir d  q u artil e,  mi n  a n d  m a x)  b y  
tr e at m e nt gr o u p a n d o v er all will b e pr e s e nt e d f or vit al si g n s at Vi sit 1 ( W e e k 1 4 a n al y si s vi sit, 1 2 w e e k s 
aft er t h e l a st D L- P D T).
N u m b er a n d p er c e nt a g e ( n, %) of s u bj e ct s wit h Cli ni c all y Si g nifi c a nt A b n or m al V al u e s ( a s i d e ntifi e d b y t h e 
I n v e sti g at or) will b e s u m m ari z e d b y tr e at m e nt gr o u p a n d o v er all at Vi sit 1 ( W e e k 1 4 a n al y si s vi sit, 1 2 w e e k s 
aft er t h e l a st D L- P D T).
A li sti n g of all vit al si g n s will b e pr o vi d e d.
P h y si c al E x a mi n ati o n
P h y si c al  e x a mi n ati o n  a s s e s s m e nt s  will  b e  s u m m ari z e d  i n  t er m s  of  n u m b er  a n d  p er c e nt a g e  ( n,  %)  of  
s u bj e ct s wit h ' n or m al', ' a b n or m al/ n ot cli ni c all y si g nifi c a nt' a n d ' a b n or m al/ cli ni c all y si g nifi c a nt' r e s ult s f or e a c h 
b o d y s y st e m.
S u m m ari e s will b e pr e s e nt e d b y tr e at m e nt gr o u p a n d o v er all at Vi sit 1 ( W e e k 1 4 a n al y si s vi sit, 1 2 w e e k s 
aft er t h e l a st D L- P D T).
A li sti n g of all p h y si c al e x a mi n ati o n a s s e s s m e nt s will b e pr o vi d e d.
St u d y D ur ati o n
F oll o w- u p st u d y d ur ati o n a n d pi v ot al a n d f oll o w- u p st u d y d ur ati o n of e a c h s u bj e ct will b e li st e d.
Effi c a c y A n al y si s
All effi c a c y a n al y s e s will b e b a s e d o n t h e S af et y p o p ul ati o n. S u bj e ct s will b e a n al y z e d a c c or di n g t o t h e 
tr e at m e nt t h e y w er e r a n d o mi z e d t o i n st u d y R D. 0 6. S P R. 1 1 2 1 9 9.
Pri m ar y s u m m ar y f or effi c a c y a n al y si s will b e b a s e d o n t h e S af et y p o p ul ati o n at Vi sit 3 ( W e e k 5 4 a n al y si s 
vi sit, 5 2 w e e k s aft er t h e l a st D L- P D T).
All effi c a c y d at a will b e li st e d.
              
2 9- S e p- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 S A P FI N A L 2. 0 2 7 S E P 2 0 2 1 Si g
A p pr o v e d
1. 0
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
S p o n s or: G al d er m a R e s e ar c h & D e v el o p m e nt, L L C; Pr ot o c ol N o.: R D. 0 6. S P R. 1 1 5 2 3 0 Pr ot o c ol V 3. 0
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n: Fi n al V er si o n 2. 0
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 1, Eff e cti v e D at e 0 3- M ar- 2 0 2 0
Fili n g r e q uir e m e nt s: T M F
P a g e 2 3 of 2 8
A n al y si s of t h e Pri m ar y E n d p oi nt
Vi sit 3 ( W e e k 5 4 
a n al y si s vi sit, 5 2 w e e k s aft er t h e l a st D L- P D T)  will b e s u m m ari z e d u si n g t a bl e s of fr e q u e n c y. All s u bj e ct s 
i n t h e s af et y p o p ul ati o n wit h mi s si n g d at a will b e cl a s sifi e d a s n o n-r e s p o n d er s r e g ar dl e s s of tr e at m e nt 
all o c ati o n. S u m m ari e s b y tr e at m e nt gr o u p will b e pr e s e nt e d f or b ot h t h e i m p ut e d d at a a n d t h e o b s er v e d 
c a s e s. 
 
 
 
S e n siti vit y A n al y s e s of Pri m ar y E n d p oi nt
N o s e n siti vit y a n al y si s i s pl a n n e d.
A n al y si s of S e c o n d ar y E n d p oi nt s
Vi sit 2 ( W e e k 2 8 
a n al y si s vi sit, 2 6 w e e k s aft er t h e l a st D L- P D T)  will b e s u m m ari z e d u si n g t a bl e s of fr e q u e n c y. All s u bj e ct s 
i n t h e s af et y p o p ul ati o n wit h mi s si n g d at a will b e cl a s sifi e d a s n o n-r e s p o n d er s r e g ar dl e s s of tr e at m e nt 
all o c ati o n. S u m m ari e s b y tr e at m e nt gr o u p will b e pr e s e nt e d f or b ot h t h e i m p ut e d d at a a n d t h e o b s er v e d 
c a s e s. 
 
I nt eri m A n al y s e s a n d D at a M o nit ori n g
A n i nt eri m a n al y si s i s pl a n n e d of all a v ail a bl e d at a fr o m t hi s st u d y, R D. 0 6. S P R. 1 1 5 2 3 0, at t h e ti m e of 
r e g ul at or y s u b mi s si o n f or m ar k eti n g a p pr o v al f or M A L cr e a m.
              
2 9- S e p- 2 0 2 1 0 0: 0 0: 0 0
R D. 0 6. S P R. 1 1 5 2 3 0 S A P FI N A L 2. 0 2 7 S E P 2 0 2 1 Si g
A p pr o v e d
1. 0
C CI
C CI
C CI
C CI


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 24 of 28
Examination of Subgroups
No subgroup analysis is planned.
Safety Analysis
All safety analyses will be based on the Safety population. Subjects will be analyzed according to the 
treatment they actually received in study RD.06.SPR.112199. Summaries of all safety endpoints will be 
presented.
Adverse Events Analysis
Treatment-emergent AEs are defined as those AEs occurring after the first administration of study treatment 
until the last study visit from study RD.06.SPR.112199 and as all AEs in this study RD.06.SPR.115230.
All treatment-emergent AEs will be listed in a by-subject listing which will include both the term reported on 
the eCRF (verbatim term) and the MedDRA System Organ Class and Preferred Term. Relative start and 
stop days will be included along with the actual onset and resolution dates.
If relationship is missing the closest relationship, i.e. “Related” will be imputed. If severity is missing the 
greatest severity, i.e. “Severe”, will be imputed.
A summary table of TEAEs will be provided for each of the following for the safety population by treatment 
group and overall:
x
Number and percentage (n, %) of subjects with any TEAE and frequency of TEAEs overall and by 
System Organ Class and Preferred Term;
x
Number and percentage (n, %) of subjects with any TEAE by closest relationship to study drug and 
frequency of TEAEs by closest relationship to study drug; 
x
Number and percentage (n, %) of subjects with any TEAE by closest relationship to study procedures 
and frequency of TEAEs by closest relationship to study procedures;
x
Number and percentage (n, %) of subjects with any TEAE related to the study drug and frequency 
of TEAEs related to the study drug by System Organ Class and Preferred Term; 
x
Number and percentage (n, %) of subjects with any TEAE related to the study procedures and 
frequency of TEAEs related to the study procedures by System Organ Class and Preferred Term;
x
Number and percentage (n, %) of subjects with any TEAE by greatest severity and frequency of 
TEAEs by greatest severity overall and by System Organ Class and Preferred Term;
x
Number and percentage (n, %) of subjects with any TEAE leading to study discontinuation and 
frequency of TEAEs leading to study discontinuation.
A summary table of serious TEAEs will be provided for each of the following in the safety population by 
treatment group and overall:
x
Number and percentage (n, %) of subjects with any Serious TEAE and frequency of Serious TEAEs 
overall and by System Organ Class and Preferred Term;
x
Number and percentage (n, %) of subjects with any Serious TEAE by closest relationship to study 
drug and frequency of Serious TEAEs by closest relationship to study drug; 
x
Number and percentage (n, %) of subjects with any Serious TEAE by closest relationship to study 
procedures and frequency of Serious TEAEs by closest relationship to study procedures;
x
Number and percentage (n, %) of subjects with any Serious TEAE related to the study drug and 
frequency of Serious TEAEs related to the study drug by System Organ Class and Preferred Term; 
x
Number and percentage (n, %) of subjects with any Serious TEAE related to the study procedures 
and frequency of Serious TEAEs related to the study procedures by System Organ Class and 
Preferred Term;
x
Number and percentage (n, %) of subjects with any Serious TEAE leading to study discontinuation 
and frequency of Serious TEAEs leading to study discontinuation;
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 25 of 28
x
Number and percentage (n, %) of subjects with any Serious TEAE leading to death and frequency 
of Serious TEAEs leading to death.
In order to evaluate the impact of COVID-19 on the safety of the subjects, a summary table of TEAEs and 
serious TEAEs will be provided for each of the following for the safety population by treatment group and 
overall:
x
Number and percentage (n, %) of subjects with any TEAE related to COVID-19 and frequency of 
TEAEs related to COVID-19 by System Organ Class and Preferred Term.
x
Number and percentage (n, %) of subjects with any Serious TEAE related to COVID-19 and 
frequency of Serious TEAEs related to COVID-19 by System Organ Class and Preferred Term.
Listings of all AEs leading to death, all serious AEs, all TEAEs leading to study discontinuation and all AEs 
due to COVID-19 will be provided.
Pregnancy Testing 
All women of childbearing potential will have a urine pregnancy test at Visit 1 (Week 14 analysis visit, 12 
weeks after the last DL-PDT), Visit 2 (Week 28 analysis visit, 26 weeks after the last DL-PDT) and Visit 3
(Week 54 analysis visit, 52 weeks after the last DL-PDT).
If the result of a UPT is positive, it must be confirmed with a serum pregnancy test. Subjects with a positive 
serum pregnancy test result at Visit 1 (Week 14 analysis visit, 12 weeks after the last DL-PDT) will be 
followed in this study.
A listing of all pregnancy test results will be provided.
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 26 of 28
Changes from the Protocol Analysis Plan
Any change from the protocol will be justified and fully documented.
If the blind review suggests changes to the principal features stated in the protocol, these have to be
documented in a protocol amendment. Otherwise, it will suffice to update the statistical analysis plan with 
the considerations suggested from the blind review.
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 27 of 28
Shells of Tables, Figures and Listings and Reporting Output (General 
Features) 
Tables, figures and listings will be generated using SAS® and will be displayed on A4 size paper with 
landscape orientation, 2 cm for top and bottom margins, 0.8 cm for left and right margins and 8pt Courier 
New font.
The header section will comprise the sponsor’s name, the protocol number, the delivery description, the 
TFL number, the TFL title, the population and the page number (Page X of Y). The footer section will include 
the TFL footnotes, the data extract date (if applicable), the date and time of the execution of the program, 
and the name of the program.
A clear, accurate and complete programming code will be developed to generate the statistical analyses, 
summary tables, figures and listings to be integrated in the report. Fluent use of precise titles and footnotes 
will be made to improve the understanding of summaries and document any assumption. Details of analysis 
specifications including but not limited to the SAS code will be documented on the shells.
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0


Statistical Analysis Plan for Interventional Studies
Sponsor: Galderma Research & Development, LLC; Protocol No.: RD.06.SPR.115230 Protocol V3.0
This document is confidential.
SAP Version: Final Version 2.0
Controlled Document ID: 3903A.01, Effective Date 03-Mar-2020
Filing requirements: TMF
Page 28 of 28
Appendices
Shells for Table, Figure and Listings
The final list of tables, figures and listings and their shells for the reporting of this study is available in a 
separate document that is developed and is finalized before database lock.
              
29-Sep-2021 00:00:00
RD.06.SPR.115230 SAP FINAL 2.0 27SEP2021 Sig
Approved
1.0