A Randomized, Evaluator-Blinded Study to Evaluate Facial Harmony and Subject Satisfaction Using Restylane Defyne in a Stepwise Treatment Approach
Phase: NA
Conditions: Lower Face Folds and Lines
Sponsor: Galderma R&D

M A -4 2 2 4 8. d oc
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A R a n d o mize d, E v al u at or -Bli n de d St u d y t o E v al u ate F aci al H ar m o n y 
a n d S u bject S atisf acti o n Usi n g Rest yl a ne Def y ne i n a Ste p wise Tre at me nt 
A p pr o ac h
St u d y pr o d ucts :
Rest y la ne ® Def y n e ™
Cli nical trial n u m ber ( C T N) : 
0 5 D F 1 9 1 0
S p o ns or:
Q- Me d A B
Se mi n arie gata n 2 1
S E -7 5 2 2 8 U p psala, S we de n
Tele p h o ne: 
+ 4 6 1 8 4 7 4 9 0 0 0
Facsi mile: 
+ 4 6 1 8 4 7 4 9 0 0 1
C o nfi de nti alit y St ate me nt
T his st u d y pr ot oc ol c o ntai ns c o nfi de ntial i nf or mati o n bel o n gi n g t o Q -Me d A B. E xce pt as 
ma y  be ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese materials, yo u a gree 
t o h ol d s uc h i nf or mati o n i n c o nfi de nce a n d neit her discl ose it t o a n y t hir d parties (e xce pt 
w here re q uire d b y a p plica ble la w) n or use it f or a n y ot her p ur p ose t ha n i n relati o n t o th e 
cli nical st u d y descri be d herei n. 
Title  
D o c i d  
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Effecti ve dat e: 
 
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I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct ure
F urt her details o n all partic i pati n g I n vesti gat ors a n d t he c o m plete a d mi nistrati ve str uct ure of 
t he st u d y are f o u n d i n t he st u d y files. N ote t hat a d mi nistrati ve c ha n ges are t o be d oc u me nte d i n 
t he st u d y files wit h o ut re q uiri n g a cli nical st u d y pr ot oc ol ( C S P) a me n d me nt.
C o or di nati n g I n vesti gat or:
S p o ns or:
Q- Me d A B
Se mi narie gata n 2 1
S E - 7 5 2 2 8 U p psala, S we de n
Tele p h o ne: 
+ 4 6 ( 0) 1 8 4 7 4 9 0 0 0
Se ni or Me dical E x pert:
 
Cli nical Pr oject Ma na ger :
Statisticia n:
Title  
D o c i d  
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P P D
P P D
P P D
P P D
P P D
P P D
P P D

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S y n o psis
Cl inic al S t u d y Title:
A Ra n d o mize d, E val uat or -Bli n de d St u d y t o E val uate Facial Har m o n y 
a n d S u bject Satisfacti o n Usi n g Rest yla ne Def y ne i n a Ste p wise 
Treat me nt A p pr oac h
Cli nic al Tr i al N u m ber: 0 5 D F 1 9 1 0
Re gi o n(s) / 
C o u ntr y(ies) I n v ol ve d 
a n d Pl a n ne d N u m ber 
of  St u d y Si tes:
Re gi o n/ C o u ntr y(ies): S o ut h A merica a n d E ur o pe
N o. of St u d y Ce ntres : 2 - 4
T ot al N u m ber of 
S u bjects ( Pl a n ne d): 
A p pr o xi matel y 6 0 s u bjects will be e nr olle d ( of w hic h at least 2 0 males ).
Cli nic al St u d y Desi g n:
T his is a 1 2- wee k, ra n d o mize d, m ul ti-ce ntr e, e val uat or-bli n de d, o n -
la bel, p ost-mar ket st u d y.
A p pr o xi matel y 6 0 s u bjects ( of w hic h at least 2 0 males) will be e nr olle d 
a n d ra n d o mize d i nt o t w o gr o u ps. Stratificati o n f or site a n d ge n der will 
be perf or me d. B ot h gr o u ps will be ste p wise treate d i n t he c hin a n d
nas ola bial f ol ds ( N L F) /mari o nette li nes ( M L) . O ne gr o u p will start 
treat me nt i n c hi n (at baseli ne), f oll o we d b y treat me nt i n N L Fs a n d M Ls
at wee k 3. T he ot her gr o u p will start treat me nt i n N L F s a n d M Ls
at 
baseli ne, f o ll o we d b y treat me nt i n c hin at w ee k 3. T he t w o gr o u ps are 
referre d t o as d o w n-u p a n d t o p -d o w n, res pecti vel y.
A n o pti o na l t o uc h-u p will be pr o vi de d at w ee k 6 f or all s u bjects a n d 
treat me nt areas t hat ha ve n ot o btai ne d o pti mal aest hetic i m pr o ve me nt as 
a gree d bet wee n s u bject a n d I n v esti gat or. S u bjects will be f oll o we d u ntil 
w ee k 9.
St u d y assess me nts, s uc h as q uesti o n naires, m ust be c o m plete d bef ore 
treat me nt if i njecti o n is pla n ne d at t he visit (a p plica ble f or baseli ne, 
wee k 3 a n d wee k 6 [if t o uc h -u p will be perf or me d]) .
Cli nic al St u d y 
D ur a ti o n:
First s u bject first visit t o last s u bject last visit will be a p pr o xi matel y 2 4 
wee ks: 
 
1 2 wee ks e nr ol me nt
 
3 wee ks scree ni n g 
 
9 wee k f oll o w u p
Effecti ve ness 
O bjecti ves a n d 
E n d p oi nts:  
O bjecti ve
T o e val uate aest hetic i m pr o ve me nt after treat me nt i n c h i n a n d 
N L F s/M L s, res pecti vel y, a n d i n c o m bi nati o n.
E n d p oi nt
 a n d Treati n g I n vesti gat or assess me nt usi n g t he Gl o bal 
Aest hetic I m pr o ve me nt S cale ( G AI S) at wee k 3, 6 a n d 9.
Title  
D o c i d  
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Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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O bjecti ve
T o e val uate nat ural ness of t he treat me nt res ult 
 
. 
E n d p oi nt
Assesse d b y   
 a n d Treati n g I n vesti gat or usi n g directe d 
q uesti o ns at w ee k 3, 6 a n d 9.
O bjecti ve
T o e val uate s u bject satisfacti o n treati n g c hi n vers us treati n g N L Fs / M Ls, 
res pecti vel y, a n d i n c o m bi nati o n.
E n d p oi nt
S u bject assess me nt usi n g s u bject satisfacti o n q uesti o n naire a n d 
 at baseli ne, w ee k 3, 6 a n d 9.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
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Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI
C CI
C CI

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S afet y O bjecti ves a n d 
E n d p oi nts:
T o e val uate A d verse E v e nts ( A Es) c ollecte d t hr o u g h o ut t he st u d y.
De vice deficie ncies will be assesse d at treat me nt visits.
I ncl usi o n Criteri a:
1.
S u bjects willi n g t o c o m pl y wit h t he re q uire me nts of t he st u d y 
a n d pr o vi di n g a si g ne d writte n i nf or me d c o nse nt.
2.
S u bjects willi n g 
t o u n der g o a u g me ntati o n a n d c orrecti o n 
t hera p y i n t he st u die d i n dicati o ns
3.
S u bjects w illi n g t o a bstai n fr o m a n y ot her facial plastic s ur gical 
or c os metic pr oce d ures f or t he d urati o n of t he st u d y (e. g., laser 
or c he mical res urfaci n g, facelift, etc.).
4.
A d ult males or n o n -pre g na nt, n o n- breastfee di n g fe males a n d 
w o me n of n o n -c hil d beari n g p ote n tial o ver t he a ge of 2 1.
 
Uri nar y pre g na nc y test m ust be ne gati ve f or fe males of 
c hil d beari n g p ote ntial at scree ni n g a n d all i njecti o n 
visits.
 
Defi niti o n of n o n -c hil d beari n g p ote ntial:
W o me n of n o n- c hil d beari n g p ote ntial are defi ne d as t h ose w h o 
ha ve n o ut er us, li gati o n of t he fall o pia n t u bes, or per ma ne nt 
cessati o n of o varia n f u ncti o n d ue t o o varia n fail ure or s ur gical 
re m o val of t he o varies. P ost me n o pa usal w o me n 
m ust 
be 
a me n orr heic f or at least 1 2 m o nt hs t o be c o nsi dere d of n o n -
c hil d beari n g p ote ntial.
5.
If t he s u bject is a fe male of c hil d beari n g p ote ntial, s he a grees t o 
use a n acce pta ble f or m of effecti ve birt h c o ntr ol f or t he d urati o n 
of t he st u d y a n d is willi n g t o ta ke a uri ne p re g na nc y test at t he 
scree ni n g/e nr ol me nt visit a n d pri or t o treat me nt. Acce pta b le 
f or ms of effecti ve birt h c o ntr ol i ncl u de:

Barrier met h o ds of c o ntrace pti o n: C o n d o m or Occl usi ve 
ca p ( dia p hra g m or cer vical ca ps) wit h 
s per mici dal 
f oa m/ gel/fil m/crea m/s u p p ositor y;

Bilateral t u bal li gati o n;

C o m bi ne d  
oral  
c o ntrace pti ves  
(oestr o ge n 
a n d 
Title  
D o c i d  
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pr o g ester o ne), i mpla nte d or i njecta ble c o ntrace pti ves o n a 
sta ble d ose f or at least 2 8 da ys pri or t o Da y 1;

H or m o nal or c o p per i ntra uteri ne de vice (I U D) i nserte d at 
least 2 8 da ys pri or t o Da y 1;

Vasect o mize d 
part ner f or at least 3 m o nt hs 
pri or t o 
scree ni n g;

S trict absti ne nce (at least o ne m o nt h pri or t o baseli ne a n d 
a grees t o c o nti n ue f or t he d urati o n of t he st u d y or use 
acce pta ble f or m of birt h c o ntr ol).
E xcl usi o n Criteri a:
1.
K n o w n/ pre vi o us aller g y or h y perse nsiti vit y t o a n y i njecta ble 
h yal ur o nic aci d ( H A) gel or t o gra m-p ositi ve bacterial pr otei ns. 
2.
Hist or y of aller g y or h y perse nsiti vit y t o li d ocai ne or ot her 
a mi de -t y pe a naest hetics , or t o pical a naest hetics or ner ve 
bl oc ki n g a ge nts (if s uc h pr o d ucts are i nte n de d t o be use d f or 
t hat s u bject).
3.
Pre vi o us or pre se nt m u lti ple aller gies or se vere aller gies, s uc h 
as ma nifeste d b y a na p h yla xis or a n gi oe de ma, or fa mil y hist or y 
of t hese c o n diti o ns.
4.
Pre vi o us use of a n y per ma ne nt ( n o n-bi o de gra d a ble) treat me nt, 
lifti n g t hrea ds, per ma ne nt i m pla nts or a ut ol o g o us fat bel o w t he 
le vel of t he h oriz o ntal li ne fr o m t he l o wer or bital ri m.
5.
Pre vi o us use of a n y se mi-per m a ne nt treat me nt (e. g., calci u m 
h y dr o x yla patite or P ol y - L-Lactic aci d) bel o w t he le vel of t he 
h oriz o ntal li ne fr o m t he l o wer or bital ri m wit hi n 2 4 m o nt hs of 
t he baseli ne visit.
6.
Pre vi o us use of a n y H A base d or c olla ge n base d bi o de gra da ble 
facial tiss ue a u g me ntati o n t hera p y bel o w t he le vel of t he 
h oriz o ntal li ne fr o m t he l o wer or bital ri m wit hi n 1 2 m o nt hs
of 
t he baseli ne visit.
7.
Hist or y of ot her facial treat me nt/ pr oce d ure i n t he pr e vi o us 
6 m o nt hs t hat i n t he Treati n g I nvesti gat or’s o pi ni o n, w o ul d 
i nterfere wit h t he st u d y i njecti o ns a n d/ or st u d y assess me nts or 
e x p oses t he s u bject t o u n d ue ris k b y st u d y partici pati o n, e. g.:

R es urfaci n g (laser, p h ot o m o d ulati o n, 
i nte nse p ulse d 
li g ht [IP L] ra di o fre q ue nc y, de r ma brasi o n, nee dli n g, 
c he mical peel or ot her a blati ve/ n o n -a blati ve pr oce d ures 
(s uc h as ultras o u n d a n d cr y ot hera p y)) 

M es ot hera p y 

Li p ol ytic i njectio ns
(e. g. de o x yc h olic aci d or ot her 
li p ol ytic s u bsta nces)

B ot uli n u m 
t o xi n i njecti o ns b el o w t he le vel of t he 
h oriz o ntal li ne fr o m t he l o wer or bital ri m 
8.
Pre vi o us facial s ur ger y, wit hi n 1 2 m o nt hs, bel o w t he le vel of 
t he h oriz o ntal li ne fr o m t he l o wer or bit al ri m.
Title  
D o c i d  
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Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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9.
Hist or y of ca ncer or pre vi o us ra diati o n near or o n t he area t o be 
treate d.
1 0. Pres e nce of a n y disease or lesi o ns near or o n t he area t o be 
treate d, e. g.:

I nfla m mati o n, acti ve or c hr o nic i nfecti o n (e. g., i n m o ut h, 
hea d a n d nec k re gi o n)

P eri oral der mati tis, acti ve her pes si m ple x or her pes 
z oster lesi o ns, or o ut brea k wit hi n 4 wee ks fr o m baseli ne,
or hist or y of f o ur o ut brea ks , or m ore,
d uri n g t he last 
year.

Scars or def or mities

Ca ncer, or preca ncer s uc h as acti nic kerat osis or acti nic 
c heilitis
1 1. Prese nce of tatt o o, pierci n g, bear d or facial hair, w hic h, i n t he 
Treati n g I n vesti gat or’s o pi ni o n, w o ul d i nterfere wit h t he st u d y 
i njecti o ns a n d/ or st u d y assess me nt.
1 2. Prese nce of a de ntal, oral, or facial c o n diti o n w hic h, i n t he 
Treati n g I n vesti gat or’s o pi ni o n, w o ul d i nterfere wit h t he st u d y 
i njecti o ns a n d/ or st u d y assess me nt, e. g. has de nt ures or a n y 
d e vice c o veri n g all or part of t he u p per palate, a n d/ or se vere 
mal occl usi o n or de nt ofacial or ma xill ofacial def or mities. 
1 3. A n u n derl yi n g k n o w n disease, a s ur gical or me dic al c o n diti o n 
t hat w o ul d 
e x p ose t he s u bject t o u n d ue ris k, e. g. acti ve 
he patiti s, a ut oi mm u ne disease, hist or y of blee di n g dis or ders, 
c o n necti ve tiss ue diseases s uc h as r he u mat oi d art hritis, s yste mic 
l u p us 
er yt he mat os us, 
p ol y m y ositis, 
der mat o m y ositis, 
or 
scler o der ma.
1 4. Use 
of c o nc o mita nt me dicati o n 
t hat ha ve t he p ote ntial t o 
pr ol o n g ble edi n g ti mes s uc h as a ntic oa g ula nts or i n hi bit ors of 
platelet a g gre gati o n (e. g. as piri n [e xce pt l o w d ose as piri n] or 
ot her n o n- ster oi dal a nti-i nfla m mat or y dr u gs [ N S AI Ds], O me ga 
3 or Vita mi n E), wit hi n 1 4 da ys pri or t o i njecti o n. O me ga 3 a n d 
Vita mi n 
E 
are acce pta ble o nl y as part of a sta n dar d 
m ulti vita mi n f or m ulati o n. 
1 5. Treat me nt 
wit h 
c he m ot hera p y, i m m u n os u p pressi ve a ge nts, 
i m m u n o m o d ulat or y t hera p y (e. g. m o n ocl o nal  
a nti b o dies), 
s yste mic c ortic osteri o ds (i n hale d c ortic oster oi ds are all o we d) 
wit hi n 3 m o nt hs pri o r t o Baseli ne visit. 
1 6. Use of t o pical facial c ortic oster oi ds or prescri pti o n reti n oi ds 
( bel o w t he le vel of t he h oriz o ntal li ne fr o m t he l o wer or bital 
ri m) wit hi n 1 m o nt h of t he B aseli ne visit or s yste mic reti n oi d 
treat me nt wit hi n 6 m o nt hs of t he Baseli ne v isit.
1 7. Pres e nce of a n y c o n diti o n, w hic h i n t he o pi ni o n of t he Treati n g 
I nvesti gat or ma kes t he s u bject u na ble t o c o m plete t he st u d y per 
pr ot oc ol, e. g. 

S u bjects n ot li kel y t o a v oi d ot her pr o hi bite d facial 
c os metic treat me nts 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
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Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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
S u bjects n ot li kel y t o c o m plete the st u d y beca use of 
ot her c o m mit me nts

S u bjects 
a ntici pate d t o be 
u na vaila ble 
f or visits, 
i nca pa ble 
of  
u n dersta n di n g  
t he 
i n vesti gati o nal 
assess me nts or 
ha vi n g 
u nrealistic 
e x pectati o ns of 
treat me nt res ult

S u bjects w h o ha ve a c o nc o mita nt c o n diti o n (e. g. ac ute
viral or bacterial i nfecti o n wit h fe ver) t hat mi g ht c o nf use 
or c o nf o u n d st u d y treat me nts or assess me nts
1 8. Partici pati o n i n a n y i nter ve nti o nal cli nical st u d y wit hi n 3 0 da ys 
of scr ee ni n g.
1 9. St u d y site pers o n nel, cl ose relati ves of t he st u d y site pers o n nel 
(e. g., pare nts, c hil dre n, si bli n gs, or s p o use), e m pl o yees, or cl ose 
relati ves of e m pl o yees at t he S p o ns or C o m pa n y.
I n vesti g ati o n al 
Pr o d uct:
Rest yla ne Def y ne 
Cr oss -li n ke d h yal ur o nic aci d 2 0 m g/ m L
Li d ocai ne h y dr oc hl ori de 3 m g/ m L
P h os p hate b uffere d sali ne p H 7 q s a d 1 m L
T he s yri n ge is pac ka ge d wit h t w o 2 7 Ga u ge ( G) x ½ ″ Ultra-T hi n Wall 
( U T W) nee dles.
At eac h treat me nt sessi o n, a ma xi m u m of 2 m L per treat me nt site is 
rec o m me n de d per E u r o pea n U ni o n (E U ) la bel.
De pe n di n g o n t he area t o be treate d a n d t he tiss ue s u p p ort, t he pr o d uct 
s h o ul d be i njecte d i n t he mi d t o dee p der mis, s u bc utis or s u pra peri ostic 
z o ne. 
Tre at me nt re gi me n:
S u bjects ra n d o mize d t o d o w n - u p treat me nt ( n= 3 0 of w hic h at least 1 0 
males):
B aseli ne - T he c hi n a n d s urr o u n di n g area t o be treate d wit h u p t o 2 m L 
of Rest yla ne Def y ne per treat me nt site wit h a ma xi m u m of 4 m L i n 
t otal.
Wee k 3
– N L F s a n d M Ls
t o be treate d wit h u p t o 2 m L/li ne per N L F 
a n d u p t o 2 m L per M L
of Rest yl a ne Def y ne
Wee k 6
- O pti o nal t o uc h -u p i n a n y of t he treate d areas t hat ha ve n o t
o btai ne d o pti mal aest hetic i m pr o ve me nt. U p t o 2 m L per facial half is 
rec o m me n de d f or N L F a n d M Ls , a n d a t otal of 2 m L i n t he c hi n a n d 
s urr o u n di n g area.
S u bjects ra n d o mize d t o t o p-d o w n treat me nt ( n = 3 0 of w hic h at least 1 0 
males):
B aseli ne – N L F s a n d M Ls t o be trea te d wit h u p t o 2 m L per N L F a n d 
u p t o 2 m L per M L
of Rest yla ne Def y ne
Wee k 3
– T he c hi n a n d s urr o u n di n g area t o be treate d wit h u p t o 2 m L 
of Rest yla ne Def y ne per treat me nt site, wit h a ma xi m u m of 4 m L i n 
t otal. 
Wee k 6
– O pti o nal t o uc h -u p i n a n y of t he tr eate d areas t hat ha ve n ot 
o btai ne d o pti mal aest hetic i m pr o ve me nt. U p t o 2 m L per facial half is 
rec o m me n de d f or N L F a n d M L , a n d a t otal of 2 m L i n t he c hi n a n d 
s urr o u n di n g area.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
9( 5 5 )
S ufficie nt a m o u nt of st u d y pr o d uct s h o ul d be i njecte d t o ac hie ve 
o pti mal c orre cti o n as a gree d bet wee n t he Treati n g I n vesti gat or a n d 
. T he met h o d of i njecti o n is at t he discreti o n of t he Treati n g 
I nvesti gat or .
Bli n de d E v al u ati o n:
St atistic al Met h o d:
S a m ple Size:
T he sa m ple size of a p pr o xi matel y 6 0 s u bjects ( 3 0 per treat me nt gr o u p) 
is n ot base d o n a statistical calc ulati o n. T he selecte d n u mber of s u bjects 
is re gar de d as s ufficie nt f or a n e val uati o n of effecti ve ness an d safet y of 
t he t w o treat me nt a p pr oac hes w he n treati n g t he c hi n, N L Fs a n d M Ls 
wit h Rest yla ne Def y ne.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
1 0 (5 5 )
A b bre vi ati o ns a n d Defi niti o ns of Te r ms
A b bre vi ati o n / Ter m 
Defi niti o n
A E
A d verse e ve nt 
C A
C o m pete nt A ut h orit y
C E
Fre nc h: C o nf or mité E ur o pée n ne
C F R
C o de of F e d eral R e g ulati o ns
C o or di nati n g I n vesti gat or 
I n vesti gat or w h o is a p p oi nte d b y t he S p o ns or t o c o or di nate 
w or k i n a m ultice nt re st u d y
C R O
C o ntract researc h or ga nizati o n
C S P
Cli nical st u d y  pr ot oc ol
C T A
Cli nical trial a gree me nt
C T N
Cli nical trial n u m ber
C V
C urric ul u m vitae
De vice d eficie nc y 
I na de q uac y of a me dical de vice wit h res pect t o its i de ntit y, 
q ualit y , d ura bility, relia bilit y , safety or perf or ma nce (i ncl u des 
m alfu ncti o ns, use err ors , a n d i na de q uate la belli n g)
D M P
Data ma na ge me nt pla n
e C RF
Electr o n ic case re p ort f or m
E U
E ur o pea n U ni o n
G
Ga u ge
G AI S
Gl o bal aest hetic i m pr o ve me nt scale
G C P
G o o d cli nical practice
G D P R
Ge neral Data Pr otecti o n Re g ulati o n
H A
H y al uro nic aci d
I CF
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o nfere nce o n Har m o nis ati o n
I E C
I n de pe n de nt et hics c o m mittee
I F U
I nstr ucti o ns f or use
I UD
I ntra uteri ne de vice
I nstit uti o n
A n y  p u blic or pri vate e ntit y or a ge nc y or me dical or de ntal 
facilit y w here a cli nical st u d y is c o n d ucte d.
I n vesti gat or
T he Pri nci pal I n vesti gat or ( PI ) or ot her q ualifie d pers o n , i.e. 
s u b-I n vesti gat or, desi g nate d a n d s u per vise d by t he P I at a st u d y 
site t o perf or m critical st u d y-relate d pr oce d ures or t o ma ke 
i m p orta nt st u d y-relate d decisi o ns as s pecifie d o n t he si g nat ure 
a n d dele gati o n l o g
I n vesti gat or file 
Esse ntial d oc u me nts relati n g t o a cli nical st u d y  as defi ne d i n 
a p plica ble G C P g ui da nce d oc u me nt a n d mai ntai ne d b y  t he 
I n vesti gat or.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
1 1 (5 5 )
A b bre vi ati o n / Ter m 
Defi niti o n
I PL
I nte nse P ulse d Li ght
I P R
I n de pe n dent P h ot o gra p hic Re vie wer
I S O
I nter nati o nal Or ga nizati o n f or Sta n dar dizati o n
M D R
M I TT
Me dical De vices Re g ulati o n
M o difie d i nte nt i o n-t o-treat
M L
Mari o nette li nes
Me d D R A
Me dical dicti o nar y  f or re g ulat or y acti vities
N L F
Nas ola bial f ol d
N S AI D
N o n -ster oi dal a nti-i nfla m mat or y dr u g
O B T
O pti mal Bala nce Tec h n ol o g y
PI
Pri nci pal I n vesti g at or; q ualifie d pers o n res p o nsible f or 
c o n d ucti n g t he st u d y at a st u d y site
P T
Preferre d ter m
S A E
Seri o us a d verse e ve nt
S D V
S o urce data verificati o n
S O C
S y ste m or ga n class
S p o ns or file
Esse ntial d oc u me nts relati n g t o a cli nical st u d y  as defi ne d i n 
a pp lica ble GC P g ui da nce d oc u me nt an d mai ntai ne d b y  t he 
S p o ns or.
St u d y  files
T he I n vesti gat or file a n d t he S p o ns or file
St u d y  pr o d ucts
T he i n vesti gati o nal pr o d uct a n d t he refere nce pr o d uct u n der 
st u d y
St u d y  site
I nstit uti o n or site w here t he st u d y is carrie d o ut
T o uc h - u p
Re peate d i njec ti o n t o be perf or me d after treat me nt, if necessar y 
t o ac hie ve o pti mal c orrecti o n 
U- H C G
Uri nar y  h u ma n c h ori o nic g o na d otr o pi n
U T W
Ultra -T hi n Wall
W H O
W orl d Healt h Or ga nizati o n
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
1 2 (5 5 )
T a ble of C o nte nts
I N V E S TI G A T O R S A N D S TU D Y A D MI NI S T R A TI V E S T R U C T U R E
2
S Y N O P SI S
3
A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
1 0
LI S T O F T A B L E S
1 5
LI S T O F FI G U R E S
1 5
LI S T O F A P P E N DI C E S
1 5
1. 
E T HI C A L C O N SI D E R A TI O N S
1 6
1. 1 
State me nt of et hical c o m plia nce
1 6
1. 2 
A p plica ti o n t o i n de pe n de nt et hics c o m mittee
1 6
2. 
B A C K G R O U N D I N F O R M A TI O N
1 7
2. 1 
I n dicati o n a n d p o p ulati o n descri pti o n
1 7
2. 2 
St u d y Pr o d uct Pr ofile
1 7
2. 2. 1 
I nvesti g ati o n al pr o d uct descri pti o n
1 7
2. 3 
St u d y rati o nale a n d j ustificati o n f or desi g n
1 8
2. 4 
Ris ks a n d be nefits
1 8
3. 
O B J E C TI V E( S) A N D E N D P OI N T( S)
1 9
3. 1 
O bjecti ves a n d e n d p oi nts
1 9
3. 1. 1 
Effective ness o bjectiv es a n d e n d p oi nts
1 9
3. 1. 2 
S afety o bjective a n d e n d p oi nts
2 0
4. 
D E SI G N O F T H E S T U D Y
2 0
4. 1 
Ge neral o utli ne
2 0
4. 2 
N u m ber of s u bjects
2 1
4. 3 
D urati o n of s u bject partici pati o n
2 1
4. 4 
Ra n d o mizati o n a n d bli n di n g
2 1
4. 4. 1 
R a n d o miz ati o n
2 1
4. 4. 2 
Bli n di n g
2 2
4. 4. 3 
E mer ge ncy u n bli n di n g
2 2
4. 5 
Me dical hist or y
2 2
4. 6 
Pri or a n d c o nc o mita nt t hera pies
2 2
4. 6. 1 
Rec or di n g
2 3
4. 7 
Sc he d ule of E ve nts
2 4
4. 8 
Visits
2 5
4. 8. 1 
Visit 1: Scree ni n g Visit
2 5
4. 8. 2 
Visit 2: B aseli ne Visit ( First I njecti o n)
2 5
4. 8. 3 
Visi t 3: 3- Week Visit ( Sec o n d I njecti o n)
2 5
4. 8. 4 
Visit 4: 6 -Week Visit ( O pti o n al T o uc h -u p)
2 6
4. 8. 5 
Visit 5: 9 -Week Visit ( E n d of St u dy)
2 6
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
1 3 (5 5 )
4. 9 
De m o gra p hics a n d ba seli ne assess me nts
2 7
5. 
S U B J E C T S
2 8
5. 1 
S u bject i nf or mati o n a n d i nf or me d c o nse nt
2 8
5. 2 
I ncl usi o n criteria
2 8
5. 3 
E xcl usi o n criteria
2 9
5. 4 
S u bject n u m ber
3 1
5. 5 
Wit h dra wal of s u bjects
3 1
6. 
S T U D Y P R O D U C T S
3 3
6. 1 
I nvesti gati o nal pr o d uct
3 3
6. 2 
A d diti o nal pr o d ucts a n d ma terials
3 3
6. 3 
Pac ka gi n g, la belli n g, a n d st ora ge
3 3
6. 3. 1 
I nvesti g ati o nal pr o d uct
3 3
6. 4 
Pr o d uct acc o u nta bilit y
3 3
6. 5 
Treat me nt
3 4
6. 5. 1 
Tre at me nt pr oce d ure
3 4
6. 5. 2 
Tre at me nt re gi me n ( d ose a n d i nterv al)
3 4
6. 5. 3 
P ost -treat me nt c are
3 5
6. 5. 4 
P ost -tri al pr ovisi o ns
3 5
6. 5. 5 
Electr o nic c ase re p ort f or m rec or di n gs
3 5
6. 5. 6 
Tre at me nt c o m pli a nce
3 6
7. 
E F FI C A C Y A S S E S S M E N T S
3 7
7. 1 
Ge neral i nf or mati o n
3 7
7. 2 
2 D P h ot o g ra p h y
3 7
7. 3 
Gl o bal Aest hetic I m pr o ve me nt Scale ( G AI S)
3 8
7. 4 
Nat ural ness, 
3 8
3 8
7. 6 
S u bject Satisfacti o n Q uesti o n naire
3 9
3 9
3 9
3 9
8. 
S A F E T Y A S S E S S M E N T S
3 9
8. 1 
A d verse e ve nts
3 9
8. 1. 1 
Defi niti o n of a n a dverse eve nt ( Me dic al Devices Re g ul ati o n ( M D R) article 2( 5 7))
3 9
8. 1. 2 
Defi niti o n of a seri o us a dverse eve nt ( M D R article 2( 5 8))
3 9
8. 1. 3 
Rec or di n g i nstr ucti o ns
4 0
8. 1. 4 
Re p orti n g of a dverse eve nts
4 2
8. 1. 5 
Re p orti n g of seri o us a dverse eve nts
4 3
8. 1. 6 
F oll o w -u p of u nres olve d eve nts o n g oi n g at ter mi n ati o n of t he st u dy
4 4
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
1 4 (5 5 )
8. 1. 7 
Re p orti n g a n d f oll o w -u p of eve nts occ urri n g after s u bject ter mi n ati o n of t he st u dy
4 4
8. 1. 8 
Pre g n a ncy
4 4
8. 1. 9 
A ntici p ate d a dverse eve nts
4 5
8. 2 
De vice deficie ncies
4 5
8. 2. 1 
Defi niti o n of a device deficie ncy
4 5
8. 2. 2 
Rec or di n g i nstr ucti o ns
4 5
8. 2. 3 
Re p orti n g of device de ficie ncies
4 5
9. 
D A T A H A N D LI N G A N D M A N A G E M E N T
4 6
9. 1 
Data ma na ge me nt
4 6
9. 2 
Electr o nic case re p ort f or ms
4 6
9. 2. 1 
D at a e ntry
4 7
9. 2. 2 
T he q uery pr ocess
4 7
9. 2. 3 
User i de ntific ati o n
4 7
9. 2. 4 
A u dit tr ail
4 7
9. 3 
S o urce d oc u me nts
4 7
9. 4 
Rec or d kee pi n g a n d access t o s o urce data
4 8
9. 5 
D oc u me nt a n d data rete nti o n
4 8
1 0. 
S T A TI S TI C A L M E T H O D S
4 9
1 0. 1 
A nal ysis p o p ulati o ns
4 9
1 0. 2 
De m o gra p hics, baseli ne assess me nts, a n d s u bject c haracteristics
4 9
1 0. 3 
Efficac y a nal ysis
4 9
1 0. 4 
S afet y a nal ysis
5 0
1 0. 5 
Ha n dli n g of missi n g data
5 0
1 0. 6 
I nteri m a nal ysis
5 0
1 0. 7 
Wit h dra wals a n d de viati o ns
5 0
1 0. 8 
Sa m ple size
5 0
1 1. 
P R O T E C TI O N O F P E R S O N A L D A T A
5 0
1 2. 
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
5 1
1 2. 1 
Q ualit y c o ntr ol
5 1
1 2. 2 
Q ualit y ass ura nce
5 1
1 2. 3 
C ha n ges t o t he cli nical st u d y pr ot oc ol
5 2
1 2. 3. 1 
A me n d me nts
5 2
1 2. 3. 2 
Devi ati o ns
5 2
1 3. 
FI N A N CI N G, I N D E M NI FI C A TI O N, A N D I N S U R A N C E
5 2
1 4. 
P U B LI C A TI O N P O LI C Y
5 2
1 5. 
S U S P E N SI O N O R P R E M A T U R E T E R MI N A TI O N
5 3
1 6. 
S U M M A R Y O F C H A N G E S
5 3
1 7. 
R E F E R E N C E S
5 5
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
1 5 (5 5 )
List of Ta bles
Ta ble 1. 
Sc he d ule of e ve nts ............................................................................................... 2 4
Ta ble 2. 
Fitz patric k S k i n T ypes ( F S T) ............................................................................... 2 7
Ta ble 3. 
Gl o bal Aest hetic I m p r ove me nt Scale ( G AI S) ..................................................... 3 8
List of Fi g ur es
Fi g ure 1 
St u d y  Flo w C hart ................................................................................................. 2 1
List of A p pe n dices
A p pe n di x 1 
Decl ar ati o n of Helsi n ki .................................................................................... 1
A p pe n di x 2 
I n vesti g at or Si g n at ure P a ge ............................................................................ 1
A p pe n di x 3 
I nstr ucti o ns f or Use – Rest yl a ne Def y ne ( Versi o n 3. 0, Effecti ve d ate: 2 0 1 5-
1 2- 1 5) 
1
A p pe n di x 4 
Gl o b al Aest hetic I m pr o ve me nt Sc ale ( G AI S) ................................................ 1
A p pe n di x 5 
N at ur al ness, 
 
 (I n vesti g at or’s q uesti o n n aire) ................................................................................ 1
....................1
.................... 1
.................... 1
A p pe n di x 9 
S u bject s atisf acti o n q uesti o n n aire .................................................................. 1
1
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
1 6 (5 5 )
1.
Et hic a l C o nsi der ati o ns
1. 1 
St ate me nt of ethic al c o m pli a nce
T he stu d y  shall be c o n d ucte d i n c o m plia nce wit h t he cli nical trial a gree me nt ( C T A), C S P, 
g o o d cli nical practice ( G C P), a n d a p plica ble re gi o nal or nati o nal re g ulatio ns. T he st u d y shall 
be c o n d ucte d i n acc or dance wit h t he et hical pri nci ple s t hat ha ve t heir or i gi n i n t he 
Declarati o n of Helsi n ki ( 1 9 6 4, a n d its a me n d me nts i n f orce at t he i nitiati o n of t he st u d y) 
(A p pe n di x 1 ).
T he st u d y s hall f oll o w t he i nternati o nal sta n dar d f or cli nic al st u d y of me dical de vices f or 
h u ma n s u bjects, I nter nati o nal Or ga nizati o n f or Sta n dar dizati o n (I SO) 1 4 1 5 5 : 2 0 1 1, a n d t he 
I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) g ui deli ne f or G C P E 6 ( R 2) as a pplica ble 
f or me dical de vice.
1. 2 
A p plic ati o n t o i n de pe n de nt et hics co m mittee
It is t he resp o nsi bilit y  of t he Pri ncipal I n vesti gat or ( PI) t o o btai n a p pr o val of t he C S P
a me n dme nt (s) fr o m t he i n de pe n de nt et hics c o m mittee (I E C). T he st u d y s hall n ot be gi n u ntil 
t he re q uire d fav o ura ble o pi ni o n fr o m t he I E C has bee n o btaine d. T he PI s hall file all 
c orres p o n de nce wit h t he I E C i n t he I n vesti gat or file a n d co pies of I E C a p pr o vals s hal l be 
f or war de d t o t he S p o ns or. A n y a d diti o nal re q uire me nts i m p ose d b y t he I EC s hall be 
foll o we d.
As t he st u d y pr o d uct is C E -mar ke d f or t he i nte nde d use , a p plicati o n f or a p pr ova l fr o m 
c o m pete nt a ut h or it y (C A ) is n ot re q uire d.
T he c ollecti o n, access t o, pr oc essi n g, a n d tra nsfer of pr otecte d healt h i nf or mati o n or se nsiti ve 
pers o nal data s hall be carrie d o ut i n acc or da nce wit h a p plica ble r ules a n d re g ulati o ns (see 
f urt her i nf or mati on i n secti o n 1 1).
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
1 7 (5 5 )
2.
B ac k gr o u n d I nf or m ati o n
2. 1 
I n dic ati o n a n d p o p ul ati o n descri pti o n
Rest y la ne Def yn e is i nte n de d t o a u g me nt t he v ol u me of facial tiss ues. It is rec o m me n de d t o 
be use d f or c orrecti o n of se vere wri n kles, or t o re define facial feat ures. De pe n di n g o n t he 
area t o be treate d a n d t he tiss ue s u p p ort, t h e pr o d uct s h o ul d be i njecte d i n t he mi d t o dee p 
der mis, s u bc utis or s u pra peri ostic z o ne. Li d ocai ne i s a d de d t o t he for m ulati o n t o di mi nis h t he 
p ai n res ulti n g fr o m t he i njectio n d uri n g t he treat m e nt.
I n t his st u dy, t he i n vesti gati o nal pr o d ucts will be use d f or ste p wise treat me nt of t he c hi n a n d 
nas ola bial f ol ds ( N L F)/mari o nette li nes ( M L) wit h i n t he a p pr ove d i n dicati o n.
A p pr o xi matel y  6 0 s u bjects, meeti n g all i ncl usi o n/e xcl usi o n c riteria, will be enr oll e d t o t he 
st u d y.
2. 2 
St u d y Pr o d uct Pr ofile
2. 2. 1 I n vesti gati o nal pr o d uct descri pti o n
A m o n g t he differe nt materials use d as ra w materials i n fillers, s o di u m h y al ur o nate, als o 
de n ote d h yal ur o nic aci d w he n f o u n d i n viv o a n d herei nafter referre d to as H A, is t he m o st 
fre q ue ntl y use d 1. H A is a nat urall y occ urri n g p ol ysacc hari de f o u n d i n all verte brates a n d i n 
s o me bacteria. H A bas e d fillers t ypic all y e x hi bit better bi oc o m pati bilit y a n d fe wer a d verse 
reacti o ns t ha n fillers ma de fr o m ot her materials1 , 2.
T he c he mical str uct ure of H A i s ver y si m ple wit h re peati n g disacc hari de u nits of gl uc u r o nic 
aci d a n d N-acet yl gl uc osami ne. As t he c he mica l struct ure of H A is i de ntical i n all s pecies a n d 
tiss ues, it is n o n-aller ge nic.
Rest y la ne Def yn e is a sterile, bi o de gra da ble, tra ns pare nt gel of n o n -a ni mal cr oss -li n ke d H A
2 0 m g/ m L  wit h t he a d diti o n of li d ocai ne h y dr oc hl ori de 3 m g/ m L. T he gel is s u p plie d i n a 
pr efille d plastic s yri n ge. T he c o n te nts of t he syri n ge ar e sterilize d usi n g m oist heat. T he 
s yri n ge is pac ka ge d i ndi vi d uall y  i n a blister, wit h t w o 2 7 G x ½” Ultra T hi n Wall ( U T W)
nee dles. T he nee dles ha ve bee n ster ilize d usi n g irra diati o n. Rest yla ne Def y ne was C E-
mar ke d 2 0 1 0 wit h t he pre vi o us na me E mer vel ® Dee p Li d ocai ne. Rest y la ne Def yne is a 
pr o d uct w h ose f u ncti o nal c o m p o ne nt, cr oss -li n ke d H A, is o btai ne d b y usi n g t he 
.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI

M A -4 2 2 4 8. d oc
1 8 (5 5 )
2. 2. 1. 2 Cli nic al d oc u me nt ati o n
T he first i njecta ble O B T gel pr o d uct was C E - mar ke d i n E ur o pe i n 2 0 0 9. Se veral st u dies h a v e 
bee n c o n d ucte d t o ass ess t he safet y a n d efficac y of O B T pr o d ucts i n t he treat m e nt of e. g. 
c hee ks, N L Fs , a n d li ps 6- 1 0.
2. 3 
St u d y rati o n ale a n d j ustific at i o n f or desi g n
T his st u d y ai ms to d oc u me nt t he res ults of a ste p wise treat me nt a n d deter mi ne if a n y of t he 
t w o a p pr oac hes t o be use d i n t his st u d y, d o w n -u p a n d t o p -d o w n, affect s t he st u die d
e n d p oi nts. Res ul ts fr o m t he st u d y will be t he basis f or f ut ure treat me nt g ui deli nes use d b y 
aest hetic healt h care practiti o ners w he n i njecti n g Rest yla ne Def yne i n t he c hi n, N L F a n d M L .
A p pr o xi matel y 6 0 s u bjects ( of w hic h at least 2 0 males) wi ll be e nr olle d a n d ra n d o mize d i nt o 
t w o gr o u ps wit h diff ere nt treat me nt sc he d ules. C o m paris o n bet wee n t he t w o gr o u ps will hel p 
t o deter mi ne if t he differe nt treat me nt a p pr oac hes affects t he o utc o me, s uc h as s u bject 
satisfacti o n.
2. 4 
Ris k s a n d be nefits
After t he i njecti o n of t he st u d y pr o d ucts, s o me c o m m o n i njecti o n-relate d reacti o ns mi g ht 
occ ur. T hese reacti o ns i ncl u de e r yt he ma, s welli n g, pai n, itc hi n g, br uisi n g or te n der ness at t he 
i m pla nt site. T y picall y, res ol uti o n is s p o nta ne o us wit hi n a fe w da ys after i njecti o n.
T here is a ris k t hat t he s u bject will n ot ga i n t he f ull aest hetic c orrecti o n of t he treate d areas. 
T here i s als o a ris k f or de vel o p me nt of pal pa ble H A l u m ps or dis place me nt of t he i njecte d 
H A. I nfla m mati o n or i nfecti o n has bee n re p orte d i n a fe w case s after treat me nt. T here ma y be 
ris k of br uisi n g an d/ or da ma gi n g b o d y str uct ures s uc h as ner ves or bl o o d vessels c o n necte d t o 
t he i njecti o n site, h o we ver t hese ris ks are mi n or.
F oll o wi n g facial aest he tic treat me nts is olate d rare cases ha ve bee n re p orte d re gar di n g 
isc he mic e ve nts affecti ng t he e y e lea di n g t o vis ual l oss, a n d t he brai n res ulti n g i n cere bral 
i nfarcti o n. Detaile d i nf or mati o n o n re p orte d a d verse e ve nts ( A E ) rele va nt f or t he st u d y 
pr o d uct is pr o vi de d i n t he i nstr ucti o ns f or use (I F U).
Li d ocai ne c a n i n rare cases gi ve aller gic reacti o ns, a n d t heref ore s u bjects wit h k n o w n aller g y 
or h y perse nsiti vit y  t o l ocal a naest hetics s h o ul d n ot be i ncl u de d i n t he st u d y.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI

M A -4 2 2 4 8. d oc
1 9 (5 5 )
Gi ve n t he a ntici pate d l o w le vel of tra nsien t a n d accep table A Es in c o n necti o n wit h t he 
i njecti o n, t he ris k- be nefit assess me nt of t he use of t h e st u dy pr o d u cts f or l o w er f a c e
a u g m e nt ati o n offers a p ote ntial cli nical be nefit , s uc h as s u bject rate d i m pr o ve me nt of 
attracti ve ness a n d satisfacti o n, at reas o na ble ris k.
3.
O bjecti ve (s) a n d E n d p oi nt (s)
3. 1 
O bject i ves a n d e n d p oi nts
3. 1. 1 Effecti ve ne ss o bjecti ves a n d e n d p oi n ts
O bjecti ve
 
E n d p oi nt
 a n d Treati ng I n vesti gat or assess me nt us i n g t he Gl o bal Aest hetic I m pr o ve me nt 
S cale at w ee k 3, 6 a nd 9.
O bjecti ve
T o e val ua te nat ural ness of t he treat me nt res ult 
 
.
E n d p oi nt
Assesse d b y   
 a n d Treati n g I n vesti gat or u si n g directed q uesti o ns at w ee k 3, 6 a n d 9.
O bjecti ve
T o e val uate s u bje ct satisfacti o n treati n g c hi n vers us treati n g N L F/ M L , res pectivel y , a n d i n 
c o m bi nati o n.
E n d p oi nt
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
2 0 (5 5 )
S u bject assess me nt usi n g s u bject satisfacti o n q uesti o n naire a n d  
 at baseli ne, 
w ee k 3, 6 a n d 9.
3. 1. 2 Safet y  o bject i ve a n d e n d p oi nts
O bjecti ve:
T o e val uate A Es c ollecte d t hr o u g h o ut t he st u d y
E n d p oi n t
I nci de nce, i nte nsit y, d urati o n a n d o nset of A Es c ollecte d fr o m i njecti o n of st u dy 
pr o d uct t o patie nt wit h dra wal or e n d of st u d y ( visit 5).
4.
D esig n of t he St u d y
4. 1 
Ge ner al o utl i ne
T his is a 1 2- wee k, ra n d o mize d , male-fe male a n d site stratifie d, e val uat or-bli n d e d, m ulti-
ce ntre st u d y t o e val uate t he effecti ve ness a n d safet y of Restyl a ne Def yne w he n usi n g t w o 
differe nt i njecti o n a p pr oac hes, ste p wise d o w n - u p vs. t o p-d o w n , w he n treatin g t he l o wer face.
A p pr o xi ma tel y 6 0 s u bjects re q uiri n g a u gme ntati o n a n d c orrecti o n t hera p y i n t he c hi n, N L F s
a n d M L s f ulfilli n g all eli gi bilit y criteria will be e nr olle d i n t he st u d y. T he s u bjects will be 
ra n d o mize d t o o ne of t wo treat me nt gr o u ps, t he firs t treat me nt gr o u p will receive i njecti o ns i n 
t he c hi n area at baseli ne a n d i n t he N L Fs a n d M L s at t he visit 3 (wee k 3) , t he sec o n d gr o u p 
wil l u n der g o t he sa me treat me nt b ut i n re verse or der. T he t w o gr o u ps are referre d t o as d o w n-
u p a n d t o p -d o w n. Male -fe male stratificati o n will be a pplie d i n t he ra n d o mizati o n a n d the ai m 
is t o ra n d omize 1 0 male s u bjects t o eac h gr o u p.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI

M A -4 2 2 4 8. d oc
2 1 (5 5 )
Si x wee ks after t he sec o n d treat me nt, at visit 4, a n o pti o nal t o uc h-u p will be a d mi nistere d t o 
s u bjects t hat ha ve n ot o btai ne d o pti mal aest hetic i m pr o ve me nt as a gree d b et wee n s u bject a n d 
I n vesti gat or.
T he s u bject will ret urn t o t he cli nic f or a fi nal f oll o w- u p visit ( visit 5) 9 w ee ks after t he first 
treat me nt.
All efficac y  st u d y assess me nts will be perf or me d bef ore treat me nt a nd safet y  will be
f oll o we d by A E a n d de vice d eficie nc y re p orti n g t hr o u g h o ut the st u d y.
T he I n vesti gat or will assess, G l o bal A est hetic Im pr o ve me nt S cale (G AI S ), 
n at ural ness/
, 
 –
a n d safet y.
T h e su bject assess me nts i ncl u de, 
 
s ubject satisfacti o n q ues ti o n naire.
.
Fi g ure 1 
St u d y Fl o w C h art
Vi sit 1
Vi sit 2
Vi sit 3
Vi si t 4
Vi sit 5
S cr e e ni n g
B a s eli n e
D a y 1
W e e k 3
2 1 ± 3 d a y s 
fr o m vi sit 2
W e e k 6
4 2 ± 3 d a y s 
fr o m vi sit 2
W e e k 9
6 3 ± 5 d a y s 
fr o m vi sit 2
E n d of St u d y
R a n d o mi z ati o n
Tr e at m e nt of 
c h i n or N L F + 
M L
S e c o n d   
tr e at m e nt of 
u ntr e at e d c hi n 
or N L F + M L
O pti o n al t o u c h-
u p
4. 2 
N u m ber of s u bjects
A p pr o xi matel y  6 0 s u bjects, of w hic h at least 2 0 males, wil l be e nr olled at 2- 3 st u d y  sites i n 
S o ut h A merica a n d E u r o pe. T he d urati o n of t he e nr ol me nt peri o d is e x pe cte d t o be ar o u n d 1 2 
wee ks .
4. 3 
D ur ati o n of s u bject p artici p ati o n
T he t otal d urati o n of t he st u d y is e x pecte d t o last a p pr o xi matel y 2 4 wee ks ( 6 m o nt hs) , or u ntil 
6 0 s u bjects ha ve bee n s uccessf ull y treate d. A s ubject will be i n v ol ve d i n t he stu d y  f or 9 – 1 2 
wee ks .
E n d of st u d y  is w he n e nr ol me nt has reac he d t he tar get n u m b er of s u bjects a n d all s u bjects 
ha ve c o m plete d t he last st u d y  visit.
4. 4 
R a n d o miz ati o n a n d b li n di n g
4. 4. 1 Ra n d o mizati o n
A p pr o x i matel y 6 0 s u bjects will be ra n d o mize d i n a  
rati o t o either d o w n - u p or t o p-d o w n
treat me nt a p pr oac hes . Bef ore starti n g t he st u d y, a c o m p uter ge nerate d ra n d o mizati o n list will 
be pre pare d u n der t he s u per visi o n of a desi g nate d statisticia n fr o m t he S p o ns or. T he 
ra n d o mizati o n list will be stratifie d by site a n d g e nder . Ra n d o mizati o n n u m b ers will be 
all ocate d i n asce n di n g se q ue ntial or der wit hi n eac h strata . Ra n d o mizati o n will be perf or me d 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
2 2 (5 5 )
usi n g a n I nteracti ve Res p o nse S y ste m b y assi g ni n g each s u bject t o t he t w o treat me nt gr o u ps
acc or di n g t o t he ra n d o mizati o n list.
4. 4. 2 B li n di n g
T he I P R wi ll revie w bli n de d pairs of p h ot o gra p hs fr o m pre a n d p ost treat me nt. N o 
i nf or mati o n re gar di n g treat me nt gr o u p or visit will be a vaila ble t o t he p h ot o gra p hic re vie wer. 
T he p h ot o gra p hs will be c o de d a n d a se pa rate ke y, n ot a vaila ble t o t he IP R, will be use d t o 
pai r t he I P R e val uati o ns t o t he c orrect s u bject a n d visit.
4. 4. 3 E mer ge nc y  u n bli n di n g
N ot a p plica ble as t he treat i n g I n vesti gat or is n ot bli n de d t o treat m e nt.
4. 5 
Me dic al
h ist or y
Hist or y of rele va nt s ur gical e ve nts a n d me dical c o n diti o ns s h o ul d b e d oc u me nte d (i ncl u di n g
a n y pri or der mat ol o gical pr oce d ures or i m pla nts) i n t he electr o nic case re p ort f or ms (e C R F)
usi n g me dical ter mi n ol o g y.
4. 6 
Pri or a n d c o nc o mit a nt t her a pies
E xce p t as n ote d bel o w, c o nc o mita nt me dicati o ns or ot her treat me nts or pr oce d ure s m a y  be 
utilise d w h e n t he PI or his/ her a ut h orise d desi g nee c o nsi ders it me dically necessar y. 
I nf or mati o n re gar di n g a n y use of c o nc o mita nt me dicati o ns, i ncl u di n g o ver-t he-c o u nter 
me dicati o ns a d mi ni stere d d uri n g t he st u dy are t o be rec or de d i n t he e C R F. T he ge neric na me 
or t h e trade na me of all c o nc o mita nt me dicati o n or a descri pti o n of t he pr oce d ure a n d t he 
reas o n f or its use s hall be d oc u me nte d i n t he e C R F.
T he f oll o wi n g m e dicati o ns , treat me nts,a nd pr oce d ures are restricte d or pr o hi bite d d uri n g t he
st u d y:

Use of c o nc o mita nt me di cati o n t hat ha ve t he p ote ntial t o pr ol o n g blee di n g ti mes s uc h 
as a ntic oa g ula nts or i n hi bit ors of platelet a g gre gati o n (e. g. as piri n [e xce pt l o w d ose 
as piri n] or ot her n o n- ster oi dal a nti-i nfla m mat or y dru gs [ N S AI Ds], O me ga 3 or 
Vita m i n E),  wit hi n 1 4 da ys  pri or t o i njecti o n. O me ga 3 a n d Vita mi n E are acce pta ble 
o n l y as part of a sta n dar d m ulti vita mi n f or m ulati o n.

Treat me nt wit h c he m ot hera p y, i m m u n os u p pressi ve a g e nts, i m m u n o m o d u lat or y 
t hera py (e. g. m o n ocl o nal a nti b o dies,) ; sys te mic c ortic oster oi ds (i n haled 
c ortic oster oi ds are all o we d) wit hi n 3 m o nt hs pri or t o i njecti o n visits ( visit 2, 3 a n d 4).
 
Li d ocai ne s h o ul d be use d wit h ca uti o n i n s u bjects recei v i n g ot her l ocal a naest hetics
or a ge nts str uct urall y  relate d t o a mi de-t ype a naest hetics , e. g. certai n a ntiarr h yth mics, 
as t he s yste mic t o xic effects ca n be a d diti ve.

Pr o ce d ures i n v ol vi n g a n acti ve der mal res p o nse i n t he facial area i ncl u di n g t he li ps 
(e. g. tiss ue a u g menti n g t hera p y, c o nt o uri n g or re vitalisati o n treat me nt wit h per ma ne nt 
or n o n- per ma ne nt fillers, mes o t hera py, fat -i njecti o n, ne ur ot o xi n (bel o w t he le vel of t h e 
h oriz o ntal li ne fr o m t he l o wer or bital ri m ), laser or li g ht treat me nt, c he mical peeli ng or 
der ma br asi o n) are pr o hi bite d.

Facial s ur ger y  i ncl u di n g li p os ucti o n, i nserti o n of pe r ma ne nt i m pla nts in t he facial 
area, pla n ne d si n us s ur ger y or de ntal r o ot s ur gery, or tatt o o i n t he treat me nt area are 
pr o hi bite d.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
2 3 (5 5 )

Use of t o pical facial c ortic oster oi ds or prescri p ti o n reti n oi ds or s yste mic reti n oi d 
treat me nt near or i n t he treat me nt area are pr o hi bite d.
Pa rticipati o n i n a n y  ot her cli nical st u d y is pr o hi bite d.
If a s ubject recei ves pr o hi bite d t hera p y  d uri n g t he st u d y, a pr ot oc ol de viati o n s h o ul d be 
d oc u me nte d. T he s u bject s hall c o n ti n ue i n t he st u d y f or t he sc he d ule d f oll o w-u p visits u nless
ot her wise i nstr uc te d by t he S p o ns or.
4. 6. 1 Rec or di n g
Pri or a n d c o nc o mita nt t hera pies are t o be rec or de d i n t he e C R F a n d re vie we d, a n d u p date d if 
nee de d, at eac h visit.
A n y  ne w c o nc o mitant t hera p y or m o dificati o n of a n e xisti n g t h era p y ma y be li n ke d t o a n A E. 
A c orres p o n di n g A E f or m m ust be c o m plete d t o acc o u nt f or t he c ha n ge i n t hera p y, e x ce pt i n 
s o me cases s uc h as t hera p y use d f or pr o p hyl a xis, d ose m o dificati o n f or a c hr o nic c o n diti o n.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
2 4 (5 5 )
4. 7 
Sc he d ule of E ve nts
T a ble 1. 
Sc he d ule of e ve nts
Vis it 1 
Visit 2 
Visit 3 
Visit 4 
V isit 5
Scree ni n g 1
Base li ne/
Da y  1
( wit hi n 3 
wee ks 
after 
scree ni n g)
Wee k 3
( 2 1 ± 3 
da ys fr o m 
visit 2)
Wee k 6
( 4 2 ± 3 
da ys fr o m 
visit 2)
Wee k 9
( 6 3 5
da ys fr o m 
vis it 2)
I nf orme d C o nse nt
X 
( X)2
De m o gra p hic Data i ncl u di n g, Fitz patric k s ki n t y pe, 
me dical hist or y & c o nc urr e nt diseases, pre vi o us 
facial treat me nts/ pr oce d ures
X 
( X)2
Wei g ht a n d hei g ht
X 
( X)2
X 3
I ncl usi o n / E xcl usi o n Criteria
X   
X
C o nc o mita nt M e dicati o n/ P r oce d ures 
X   
X   
X   
X   
X
Uri ne Pre g na nc y Test
X   
X   
X 4
P h ot o gra p h y 2 D
X   
X   
X   
X
Ra n d o mizati o n
X
Treat me nt 5
X   
X   
X 6
A d verse E ve nts 7
X   
X   
X   
X
I n vesti gator Assess me nt
G AI S
X   
X   
X
Nat ural ness/ 
 ar o u n d t he c hi n/
X 8
X 8
X   
X
S u bject Assess me n t
1)
T he scree ni n g visit a n d bas eli ne visit ( visit 2) ma y be perf or me d o n t he sa me da y
2)
Scree ni n g visit assess me nts s h o uld be perf or me d o n t he sa me d a y as t he baseli ne visit if n o se parate scree ni n g visit ha s bee n 
c o m plete d
3)
Wei g ht o nl y
4)
If t o uc h-u p treat me nt is pla n ne d
5)
Treat me nt t o be perf or me d after all assess me nts ha ve bee n c o m plete d.
6)
O pti o nal t o uc h -u p i njecti o n 
7)
A E re p orti n g peri o d starts at t he baseli ne visit after ra n d o mizati o n
8)
O nl y a p plica ble q uesti o ns
9)
1 0)
Assess me nts t o be perf or me d after e n d of st u d y
1 1)
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
2 5 (5 5 )
4. 8 
V isits
4. 8. 1 Visit 1 : Scree ni n g Visit
T he scre e ni n g visit a n d baseli ne visit ( v isit 2) ma y be perf or me d o n the sa me da y . T he
f oll o wi n g acti vities a n d scree ni n g assess me nts will be perf or me d wit hi n t hree wee ks pri or t o
baseli ne.

I nf or me d C o nsent

De m o gra p hic Data i ncl u di n g , Fitz patric k s ki n ty p e, me dical his t or y & c o nc urre nt 
diseases, pre vi o us facial treat me nts/ pr oce d ures , see secti o n 4. 9.

Wei g ht a n d hei g ht

I ncl usi o n / E xclusi o n Criteria

C o nc o mita nt M e dicati o n/ Pr oce d u res
4. 8. 2 Visit 2: Bas eli ne Visit ( First Injec tio n) 
I ncl u de scree ni n g visit assess me nts if scree ni n g a n d baseli ne is perf or me d o n t he sa me da y .

I ncl usi o n / E xcl usi o n Criteria

C o nc o mita nt Me dicati o n/ Pr oce d ures 

Uri ne Pre g na nc y  Test

P h ot o gra p h y 2 D 

Ra n d o mizati o n

Treat me nt (t o be perf or me d after efficacy assess me nts)

A d ver se E ve nts
I n vesti gat or assess me nts

S u bject assess me nts


S u bject satisfacti o n q uesti o n naire (o nl y a p plica bl e q uesti o ns)
4. 8. 3 Visit 3: 3 -Wee k V isit ( Sec o n d I njectio n)

C o nc o mita nt Me dicati o n/ Pr oce d ures 

Uri ne Pre g na nc y  Test

P h ot o gra p h y 2 D

Treat me nt (t o be perf or me d after efficac y assess me nts)

A d verse E ve nts
I n vesti gat or assess me nts

G AI S
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI

M A -4 2 2 4 8. d oc
2 6 (5 5 )

Na t ural ness/
( o nl y 
a p plica ble q uesti o ns)

S u bject as sess me nts

S u bject satisfacti o n Q uesti o n naire
4. 8. 4 Visit 4: 6 -Wee k Visit ( O pti o nal T o uc h- u p)

C o nc o mita n t Me dicati o n/ Pr oce d ures

Uri ne Pre g na nc y  Test (if t o uc h-u p tre at me nt is pla n ne d)

P h ot o gra p h y 2 D

T o uc h - u p treat me nt (t o be perf or me d after efficac y assess me nts)

A d verse E ve nts
I n vesti gat or assess me nt

G AI S

Nat ural ness/ 
 ar o u n d t he c hi n/im pr o ve me nt i n the s u b me ntal area

S u bject assess me nt

S u bject satisfacti o n Q uesti o n naire
4. 8. 5 Visit 5: 9 -Wee k Visit ( E n d of St u d y )

Wei g h t

C o nc o mita nt Me dicati o n/ Pr oce d ures 

P h ot o gra p h y 2 D 

A d ve rse E ve nts
I n vesti gat or assess me nts

G AI S

Nat ural ness/

S u bject assess me nts
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
2 7 (5 5 )

S u bject sati sfacti o n Q uesti o n naire
4. 9 
De m o gr a p h ics a n d b aseli ne assessme nts

Date of birt h

Ge n der

C hil d beari n g p ote ntial

Race a n d e t h nic ori gi n
o
Et h nicit y : His pa nic or Lati n o, N ot His pa nic or Lati n o
o
Race: A merica n I ndia n /Alas ka n Nati ve , Asia n , Blac k , Nati ve Ha waiia n or 
ot her Pacific Isla n der , W hite , ot her

Fitz patric k s ki n t y pe ( F S T), see Ta ble 2 bel o w.
T a ble 2. 
Fitz p atric k S ki n T y pes ( F S T) *
S ki n t y pe 
S ki n c ol or
S ki n c h ar acteristics
I 
W hite; ver y f air; re d or bl o n d hair; bl ue e yes; 
frec kles
Al wa ys b ur ns , ne ver ta ns
II 
W hite; fair; red or bl o n d hair; b l ue, hazel or gree n 
e yes
Us uall y b ur ns, ta ns wit h diffic ult y
III 
Crea m w hite; fair wit h a n y e ye or hair c ol or ; ver y 
c o m m o n
S o m eti mes mil d b ur n, gra d uall y ta ns
I V 
Br o w n; t y pical Me diterra nea n Ca ucasia n s ki n 
Rarel y b ur ns, ta ns wit h ease
V 
Dar k br o w n; Mi d d le Easter n s ki n t y pes
Ver y  rarel y b ur ns, ta ns ver y easil y
VI 
Blac k
Ne ver b ur ns, ta ns ver y easil y
F S T is a s ki n classificati o n s yste m t hat cate g orize s differe nt s ki n c ol ors, a n d t heir reacti o ns t o ultra vi o let 
li g ht.†
                                                
* htt ps:// w w w. ver y well .c o m/fitz patric k-classificati o n-scale-1 0 6 9 2 2 6
† Fitz patric k T. B. ( 1 9 8 8). T he vali dit y a n d practicalit y of s u n -reacti ve s ki n t y pes I t hr o u g h VI. Arc h. Der mat ol. 1 24, 8 6 9 –
8 7 1 .
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI

M A -4 2 2 4 8. d oc
2 8 (5 5 )
5.
S u bject s
5. 1 
S u bject i nf or m ati o n a n d i nf or me d c o nse nt
T he PI  or his/ her a ut h orize d desi g nee m ust al wa ys use t he I E C-a p pr o ve d s u bject i nf or mati o n
a n d i nf or me d c o nse nt f or m (IC F) a n d it m ust n o t be c ha n ge d wit h o ut pri or disc ussi o n wit h 
t he S p o ns or an d a p pr o val fr o m t he a p plica bl e I E C.
It is t he resp o nsi bilit y  of t he PI or his/ her a ut h orize d desi g nee t o gi ve eac h s u bject pri or t o 
i ncl usi o n i n t he st u d y, f ull a n d a de q uate ver bal a n d writte n i nf or mati o n re gar di n g all as pects 
of t he cli nical st u d y t hat are rele va nt t o t he su bject’s d ecisi o n t o partici pate t hr o u g h o ut t he 
st u d y, e. g. e x plai n t he p ur p ose a n d pr oce d ur es of t he st u d y, t he d urati o n a n d n u m ber of 
e x pecte d partici pa nts, p ossi ble ris ks i n v ol v e d, a n d t he o pi ni o n of t he IE C . T he s u bject s hall
be i nf or me d t hat t he partici pati o n i s c o nfi de ntial a n d v ol u nt ar y a n d t hat t he s u bject has t he 
ri g ht t o wit h dra w fr o m the st u d y at a n y ti me, wit h o ut a n y c o nse q ue nces t o his/ her f ut ure 
me dical care, treat me nt or be nefits t o w hic h t he s u bject is ot her wise e ntitle d. T he 
i nf or m ati o n s hall be pr o v i de d i n a la n g ua ge clearly a n d f ull y u n der sta n da ble t o t he s u bject.
T he s u bject s hall be gi ve n s ufficie nt ti me t o rea d a n d u n dersta n d t he I CF a n d t o c o nsi der 
partici pati o n i n t he st u d y. Bef ore a n y st u d y-relate d acti vities are perf or me d , t he I CF s hall be 
pe rso nall y si g ne d a n d date d b y  t he s u bject a n d t he PI  or dele gate d I n vesti gat or. T he c o nse nt 
i ncl u des i nf or mati o n t hat data will be c ollecte d, rec or de d, pr ocesse d , a n d ma y be tra nsferre d 
t o b ot h E U a nd n o n- E U c o u ntries. T he data will n ot c o ntai n a n y i nf or mat i on t hat ca n be use d
t o ide ntif y  a ny s u bject .
P h ot o gra p hs c ollecte d d uri n g t he st u d y  will be a nal yse d a n d st ore d i n a data base b y t he 
S p o ns or a n d its re prese ntati ves i n o r der t o e val uate t he effect of t he treat me nt i n t he st u d y. 
T he s u bjects will be rec o g niza ble o n t he p h ot o g ra p hs, b ut t heir na mes will n ot be discl ose d.
All si g ne d I CFs s hall be file d i n t he I n vesti gat or file. T he s u bject s hall be pr o vi de d wit h a
c o p y of t he si g ne d a n d date d I C F a n d an y  ot her writte n i nf or mati o n.
T he I n vesti gat or s hall e ns u re t hat i m p orta nt new i nf or mati o n is pr o vi de d t o ne w a n d e xisti n g 
su bjects t hr o u g h o ut t he st u d y.
5. 2 
I ncl usi o n criteri a
T he s u bjects m ust meet t he f oll o wi n g criteria t o be e li gi ble f or t he st u d y:
1.
S u bje cts willi n g t o c o m pl y wit h t he re q uire me nts of t he st u d y  an d pr o vi di n g a si g ne d 
wri tte n i nf or me d c o nse nt.
2.
S u bjects willi n g t o u n der g o a u g me n tati o n a n d c orrecti o n t hera py i n t he st u die d 
i n dicati o ns
3.
S u bjects willi n g t o a bstai n fr o m a n y ot her facial plastic s ur gical or c os metic 
pr oce d ur es f or t he d urati o n of t he st u d y (e. g., laser or che mic al res urfaci n g, facelift, 
etc.).
4.
A d ult males or n o n -pre g n a nt, n o n-breastfee di n g fe males a n d w o me n of n o n -c hil d 
beari n g p ote ntial o ver t he a ge of 2 1.
 
Uri nar y pre g na nc y  test must be ne gati ve f or fe males of c hil d beari n g p ote ntial at 
scree ni n g a n d all i nj ecti on visits.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
2 9 (5 5 )
Defi niti o n of n o n -c hil d beari n g p ote ntial: W o me n of n o n -c hil d beari n g p ote ntial are 
defi ne d as t h ose w h o ha ve n o uter us, li gati o n of t he fall o pia n t u bes, or per ma nent 
cessati o n of o varia n f u nc ti o n d ue t o o varia n fail ure or sur gical re m o val of t he o varies. 
P ost me n o pa usal w o me n m ust be a me n orr heic f or at least 1 2 m o nt hs t o be c o nsi dere d 
of n o n -c hil d bea ri n g p ote ntial.
5.
If t he s u bject is a fe male of c hil d beari n g p ote ntial, s he a grees t o use a n acce pta ble 
f or m of effecti ve birt h c o ntr ol f or t he d ura ti o n of t he st u d y  a n d is willi n g t o ta ke a 
uri ne pre g na nc y  test at t he scree ni n g/e nr ol me nt visit a n d pri or t o treat me nt.
Acce pta ble f or ms of effecti ve birt h c o ntr ol i ncl u de:
 
Barr ier met h o ds of c o ntrace pti o n: C o n d o m or Occl usi ve ca p ( diap h ra g m or 
cer vical ca ps) wit h s per mici dal f oa m/ gel/fil m/crea m/s u p p osit or y ;
 
Bilater al t u bal li gati o n;
 
C o m bi ne d oral c o ntrace pti ves (estr o ge ns a n d pr o gester o ne), i m pla nte d or 
i njecta ble c o ntrace pti ves o n a sta ble d ose f or at lea st 2 8 da ys pri or t o Da y 1;
 
H or m o nal or c o p per i ntr a uteri ne de vice (I U D) i nserte d at least 2 8 da ys pri or t o 
Da y  1;
 
Vasect o mize d part ner f or at least 3 m o nt hs pr i or t o scree ni n g;
 
Strict a bsti ne nce (at least o ne m o nt h pri or t o baseli ne a n d a grees t o c o nti n ue f or 
t he d urati o n of t he st u dy o r use acce pta ble for m o f birt h c o ntr ol).
5. 3 
E xcl usi o n criteri a
T he prese nce of a n y of t he f oll o wi n g e xcl usi o n criteria will e xcl u de a s u bject fr o m e nr ol me nt 
i n t he st u d y:
1. 
K n o w n/ pre vi o us aller g y  or h yperse nsiti vit y  t o a ny i nject a ble H A gel or t o gra m-
p ositi v e bacterial pr otei ns .
2. 
His t or y of aller g y  or hy p erse nsiti vit y t o li d ocai ne or ot her a mi de-t ype a naest hetics, or 
t o pical a naest hetics or ner ve bl oc ki n g a ge nts (if s uc h pr o d ucts are i nte n de d t o be use d
f or t hat s u bject).
3.
Pre vi o us or prese nt m ulti ple aller gies o r se vere aller gies, s uch as ma nifeste d b y  
a na p h yl a xis or a n gi oe de ma, or fa mil y h ist or y of t hese c o n diti o ns.
4.
Pre vi o us use of a n y per ma ne nt ( n o n -bi o de gra da ble) treat me nt, lifti n g t hrea ds, 
per ma ne nt i m pla nts or a ut ol o g o us fat bel o w t he le vel of t he h oriz o nt al li ne fr o m t he 
l o wer or bital ri m.
5.
Pre vi o us use of a n y se mi -per ma ne nt treat me nt ( e. g., calci u m h ydr o x yl a patite or P ol y-
L- Lactic a ci d) bel o w t he le vel of t he h oriz o ntal l i ne fr o m t he l o wer or bital ri m wit hi n 
2 4 m o nt hs of t he baseli ne visit.
6.
Pre vi o us use of an y  H A base d or c olla ge n base d bi o de gra da ble facial tiss ue 
a u g me ntati o n t hera p y b el o w t he le vel of t he h oriz o ntal li ne fr o m t he lo wer or bital ri m 
wit hi n 1 2 m o nt hs of t he baseli ne visit .
7.
Hist or y  of ot her facial treat me nt/ pr oce d ure i n t he pre vi o us 6 m o nt hs t hat i n t he 
Treati n g I n vesti gat or’s o pi ni o n, w o ul d i nterfere wit h t he st u d y i njecti o ns a n d/ or st u d y 
assess me nts or e x p oses t he s u b ject t o u n d ue ris k b y st u d y partici pati on, e. g.:
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
3 0 (5 5 )

R es urfaci n g (laser, p h ot o m o d ulati o n, i nte nse p ulse d li g ht [I P L ] ra di o 
fre q uen c y, der ma brasi o n, n ee dlin g, c he mical peel or ot her a blati ve/ n o n -
a blati ve pr oce d ures (s uc h as ultras o u n d a n d cr yot hera p y) )

M es ot hera py

Li p ol yt ic i njecti o ns  (e. g. de o x yc holic aci d or ot her li p ol y tic s u bsta nces)

B ot uli n u m t o xi n i njecti o ns bel o w t he le vel of the h oriz o ntal li ne fr o m t he 
l o wer or bital ri m
8.
Pre vi o us facial s ur ger y , wit hi n 1 2 m o nt hs, bel o w t he le vel of t he h oriz o ntal li ne fr o m 
t he l o wer or bital ri m.
9.
Hist or y  of ca ncer or pre vi o us ra diati o n near or o n t he area t o be tr eate d.
1 0. Prese nce of a n y disease o r lesi o ns near or o n t h e area t o be treate d, e. g.:

I nfla m mati o n, acti ve or c hr o nic i nfecti o n (e. g., i n m o ut h,  hea d a n d nec k 
re gi o n)

P eri oral der matitis, acti ve her pes si m ple x or her pes z oster lesi o ns, or 
o ut brea k wit hi n 4 w ee ks fr o m baseli ne, or hist or y o f f o ur o ut brea ks, or 
m o re, d uri n g t he last year

Scars or def or mities

Ca ncer, or preca ncer s uc h as acti nic kerat osis or acti nic c heilitis
1 1. Prese nce of tatt o o, pierci n g, b ear d or facial hair, w hic h, i n t he Treati n g I n vesti gat or’s 
o pi ni o n, w o ul d i nterfere wi t h t he st u d y i njectio ns a n d/ or st u d y  assess me nt.
1 2. Prese nce of a de ntal, oral, or fa cial c o n diti o n w hic h, i n t he Treati n g I n vesti gat or’s 
o pi ni o n, w o ul d i nterfere wit h t he s t u d y i njecti o ns a n d/ or st u d y assess me nt, e. g. has 
de nt ur es or a n y de vice c o veri n g all or part of t he u p per pala te, a n d/ or se vere 
mal occl usi o n or de nt ofacial or ma xill of acial def or mities.
1 3. A n u n derl yi n g k n o w n disease, a s ur gical or me dical c o n diti o n t hat w o u l d e x p ose t he 
s u bject t o u n due ris k, e. g. acti ve he patit is, a ut oi m m u ne disease, hist ory of blee di n g 
dis or d ers, c o n necti ve tiss ue diseases s uc h as r he u mat oi d art hritis, s yste mic l u p us 
er yt he mat os us, p ol y m y ositis, der m at o m yositis, or scler o der ma.
1 4. Use of c o nc o mita nt me dicati o n t hat ha ve t he p ote ntial t o pr ol o n g blee di n g ti mes s uc h 
as a ntic oa g u lants or i n hi bit ors of pl atelet a g gre gati o n (e. g. as piri n [e xce pt l o w d ose 
as piri n] or ot her N S AI Ds, O me ga 3 or Vita mi n E), wit hi n 1 4 da y s pri or t o i njecti o n. 
O me ga 3 a n d Vita mi n E are acce pta ble o n l y as part of a sta n dar d m ulti vita mi n 
f or m ulati o n.
1 5. Treat me nt wit h c he m ot hera p y , i m mu n os u p pressi ve a ge nts, i m m u n o m o d ulat or y  
t hera py (e. g. m o n ocl o nal a nti b o dies,), s y ste mic c ortic osteri o ds (i n hale d 
c ortic oster oi ds are all o we d) wit hi n 3 m o nt hs pri or t o Baseli ne visit.
1 6. Use of t o pical fac ial c ortic oster oi ds or prescript i o n reti n oi ds ( belo w t h e le vel of t he 
h oriz o ntal li ne fr o m t he l o wer or bital ri m ) wit hi n 1 m o nt h of t he Baseli ne visit or 
s yste mic reti n oi d treat me nt wit hi n 6 m o nt hs of t he Baseli ne visit.
1 7. Prese nc e of a n y c o n diti o n, w hic h i n t he o pi ni o n of t he Treati n g In v esti gat or ma kes t h e 
s u bject u na ble t o c o m plete t he st u d y per pr ot oc ol, e. g. 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
3 1 (5 5 )

S u b jects n ot li kel y t o a v oi d ot her pr o hi bite d facial c os metic treat me nts

S u bjects n ot li kel y t o c o m plete t he st u d y because of ot her c o m mit me nts

S u b jects a ntici pate d t o be u na vailable f or visits, i n ca pa ble of u n dersta n di n g 
t he i n vesti gati o nal assess me nts or havi n g u nrealistic e x pectati o ns of 
treat me nt res ult

S u bjects w h o ha ve a c o nc o mita nt c o n dit i o n (e. g. ac ute viral or bacterial 
i nfecti o n wit h fe ver) t hat mi g ht c o nf use or c o nf o u nd st u d y treat me nts or 
assess me nts
1 8. Partici pati o n i n a n y  i nter ve nti o nal cli nical st ud y  wit hi n 3 0 da ys of scree ni n g.
1 9. St u d y  site pers on nel, cl ose relati ves of t he st u d y  site pers o n nel (e. g., pare nts, c h il dre n, 
si bli n gs, or s p o use), e m pl o yees, or cl ose relati ve s of e m pl o y ees at t he S p ons or 
C o m pa n y .
5. 4 
S u bject n u m ber
Eac h s u bject w h o has si g ne d t he I C F will be assi g ne d a s u bject n u m ber T he s u bject n u m bers 
will be all ocate d i n asce n di n g or der wit hi n eac h ce ntre. T he reas o n f or e xcl u di n g a 
c o nse nti n g s u bject fr o m e nte rin g t he st u d y  s h o uld be s pecifie d i n eac h case. A scree n fail ure 
s h o ul d n ot be re-e ntere d i n t he st u d y.
F or t he d urati o n of t he c li nical st u d y, eac h s u bject will be i de ntifie d usi n g t he s u bject n u mber 
f or all d oc u me ntati o n a nd disc ussi o n.
5. 5 
Wit h dr a w al of s ubj ects
A n i n vesti gat or ma y deci de t o disc o nti n ue a s u bject fr o m t he cli nical st u d y f or safet y reas o ns.
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  s h oul d be e x plai ne d t o t he 
s u bject b y t he cli nical st u d y pers o n nel, a ny s u bject is free t o disc o nti n ue partic i patio n i n t his 
cli nical st u 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 o se 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 n al t hera p y w he n cl i nicall y i n dicate d. 
W he n a s u bject d oes n ot c o m plete t he cli n ical st u d y, he/s he will be f ull y assesse d, if s uc h 
assess me nt is p ossi ble. T he pr oce d ure s desi g nate d f or t he earl y ter mi nati o n visit s h o ul d be 
co m plete d f or all s u bjects disc o n ti n ui n g t he cli nical stu d y  a n d t he a p pr o priate e C R F s h o ul d 
be c o m plete d.
All dis c o nti n uati o ns a n d t he reas o n f or disc o nti n uati o n are t o be d oc u me nte d b y t he 
i n vesti gat or o n t he E xit f or m.
F or disc o nti n uati o n d ue t o a n d A E, t he A d verse E ve nt f or m is t o be co m plete d. T he 
i n vesti gat or s h o ul d als o e ns ure t hat t he s u bject recei ves s uita ble t hera py f or t he A E.
A s u bject w h o has bee n ra n d o mize d a n d assi g ne d a kit n u m ber/ra n d o mi zati o n n u m ber ca n n ot 
be re pl ace d b y a n ot her s u bject if h e/s he disc o nti n ues t he cli nica l st u d y f or a n y reaso n. 
A d diti o nal s u bjects c o ul d be e nr olle d (ra n d o mize d/assi g ne d t o treat me nt) i n or der t o attai n 
t he n u m ber of e val ua ble s u bjects.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
3 2 (5 5 )
Pre g na ncies occ urri n g d uri n g t he scree ni n g peri o d are c o nsi dere d as scree ni n g fail ures; t he y  
s h o ul d be recor de d as s uc h i n t he e C R F a n d n o pre g na nc y f or m is t o be c o m plete d. 
I n case of a pre g na nc y  occ urri n g after t he baseli ne visit, f oll o w t he pr oce d ures descri be d i n 
secti o n 8. 1. 8 . T he s u bject ma y re mai n i n t he st ud y , b ut n o i n vasi ve pr oce d ure s h o ul d be 
c o n d ucte d.
T he S p o ns or ma y  als o deci de t o pre mat urel y ter mi nate or s us pe n d a s u bject’s par tici pati o n i n 
t he cli nical st u d y.
P ote nt ial reas o ns f or disc o nti n uati o n are defi ne d bel o w:
T he w it h dra wal criteria are:

Me dic a l re as o ns : If t he s ubject s uffers fr o m a me dical c o n diti o n t hat i n t he j u d ge me nt 
o f t he I n vesti gat or ma kes it me dicall y necessar y t o wit h dra w t he s u bject. T he s pecific 
rati o nale f or I n vesti gat or-i nitiate d wit h dra wal of a s u bject f or me dical reas o ns s hall 
d oc u me nt t he s pecific c o n diti o n f or wit h dra wi n g t he s u bject.

S afet y re as o ns : If a su bject s uffers a n A E, w hic h i n t he j u d g me nt of t he I nvesti gat or or 
t he S p o ns or prese nts a n u nacce pta ble c o nse q ue nce or ris k t o t he s u bject.

Wit h dr a w al of i nf or me d c o nse nt: A s ubject ca n wit h dra w t heir c o nse nt t o partici pate 
i n t he st u d y at t heir o w n re q uest or be wit h dra w n fr o m partici pati o n i n t he st u dy at t he 
re q uest of t heir le gally a ut h or ise d re prese ntati ve at a n y ti me f or a n y reas o n.

L ost t o f oll o w-u p: If a s u bject d oes not ret ur n f or a sc he d ule d visit, reas o na ble eff ort 
s hall be ma de t o c o ntact t hat su bject, e. g. call t hree ti mes at differe nt h o urs a n d lea ve 
messa ges if a p plica ble bef ore declari n g t he s u bject l ost t o f oll o w- u p.

Ot her: E xa m ple s of ot her reas o ns f or wit h drawa l ma y be fail ure to c o m pl y wit h 
pr ot oc ol re q uire me nts or t o c o m plete t he pr ot oc o l-s pecifie d e val uati o ns.
If reas o n f or disc o nti nuati o n is “ wit h dra wal b y  s u bject” or “ other”, t he s u bject will be 
q u esti o ne d t o r ule o ut t he p os si bilit y of a n A E. If t he A E le d t o disc o nti n uati on t he n “a d verse 
e ve nt” s h o ul d be c h ose n as t he reas o n f or disc o nti n uati o n, rat her t ha n “ wit h dra wal b y  
s u bject” or “ ot her”.
If a n A E w hic h, acc or di n g to t he I n vesti gat or’s assess m e nt, is relate d t o t he use o f a ny of t he 
st u d y pr o d ucts a nd is still o n g oi n g at t he ti me of t he wit h dra wal, t he I n vesti gat or s hall f oll o w-
u p t he s u bject u ntil t he A E res ol ves, is assesse d b y  t he In vesti gat or t o be “c hr o nic” or 
“sta ble” or f or at least 3 m ont hs.
S u bjects w h o ha ve rece i ve d pr o hi bite d c o nc o mita nt medi cati o ns or t hera pi es s ho ul d be 
f oll o we d acc or di n g t o pr ot oc ol.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
3 3 (5 5 )
6.
St u d y Pr o d ucts
T he ter m “ st u d y pr o d uct” refers t o Rest yl a ne Def yn e.
6. 1 
I n vesti g ati o n al pr o d uct
Rest y la neD e f yne is a sterile, bi o de gra da ble, tra ns pare nt gel of n o n -a ni mal cr oss -li n ke d
H A wit h t he a d diti o n of li d oc ai ne h y dr oc hl ori de 3 m g/ m L . T he gel is s u p plie d i n a prefille d
plastic s y ri n ge. T he syri n ge c o ntai ns 1 m L gel. T he i n vesti gati o nal pr o d uct is f or si n g le use 
o nl y .
6. 2 
A d diti o n al pr o d ucts a n d m ateri al s
T he st u d y site will pr o vi de pre g na nc y  tests ( uri nar y h u ma n c h orio nic g o na d otr o pi n; U -H C G) 
a n d nee dles as nee de d .
L ocal a n aest hesia (t o pical or i nfiltrati o n) ma y  be use d at t he discreti o n of t he treati n g 
I n vesti gat or bef ore t he treat me nt. If use d, t he a naest hesia s hall be s u p plie d b y t he st u d y site. 
T y pe of a naest h esia, pr o d uct na me, a n d q ua ntit y  use d m ust be rec or de d i n t he e C R F.
T he I n vesti gat or s hall pr o vi de a de q uate e q ui pm e nt i n case of e mer ge nc y.
T he s p o ns o r will pr o vi de p h ot o e q ui p ment as a gree d w he n nee de d.
6. 3 
P a c k a gi n g, l a belli n g, a n d st or a ge
6. 3. 1 I n vesti gati o nal pr o d uct
Sta n dar d c o m merciall y  a vaila ble pr o d ucts will be use d.
In a d diti o n t o t he sta n dar d la belli n g of t he de vic e, a st u d y-s pecific la bel will be attache d t o 
t he b o x c o ntai ni n g stu d y  s pecific i nf or mati o n i n a d diti o n t o a p plica ble l ocal l a belli n g 
re q uire me nts.
T h e i n vesti gati o nal pr o d ucts s yri n ges s hall be st ore d i n t heir ori gi nal pac ka gi n g at a 
te m perat ure u p t o 2 5°C pr otecte d fr o m s u nli g ht a n d freezi n g. O pe ne d pac ka ges or partiall y 
use d de vices s hall n ot be re use d. T he e x pir y date is i n dicate d o n pac ka ge.
D etaile d pr o d uct i nf or mati o n is pr o vi de d i n t he I F Us, w hic h is deli vere d wit h eac h st u d y 
pr o d uct .
6. 4 
Pr o d uct acc o u n t a bilit y
T he st u d y pr o d ucts will be release d t o t he PI or his/ her aut h orize d desi g nee after st ud y  
a p pr o vals ha ve bee n recei ve d fr o m t he I E C, t he C T A h as bee n si g ne d b y al l parties, site 
i nitiati o n visit has bee n perf or me d a n d all esse ntial d oc u me nts are i n place .
T he PI  m ust e ns ure t hat t he st ud y pr o d ucts are ke pt i n a se c ure l ocati o n, wit h access l i mite d 
t o t h ose a ut h orize d b y  t he PI.
T he st u d y pr o d uct s m ust be tracea ble fr o m t he ma n ufact urer(s) t o t heir use i n s u bjects u ntil 
ret ur n or dis p osal. It is t heref ore i m p orta nt t hat t he PI mai ntai ns acc urate pr o d uct 
acc o u nta bili t y rec or ds, i.e. d oc u me ntatio n of t he p h ysical l ocati o n of all st u d y pr o d ucts,
deli veries , a n d ret ur n of st u d y pr o d ucts bet wee n t he S p o ns or a n d t he PI, a n d d oc u me ntati o n 
of a d mi nistrati o n of pr o d uct t o t he s u bject. A s hi p pi n g rec or d s hall be ke pt of all stu d y
pr o d ucts recei ve d fr o m t he S p o ns or; i ncl u di n g pr o d uct na me , date recei ve d, batc h or l o t
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
3 4 (5 5 )
n u m ber, e x pirati o n date , a n d a m o u nt recei ve d. I n a d diti o n, dis pe nsi n g l o gs s hall be 
mai ntai ne d i n cl u di n g t he pr o d uct na me, batc h n u m ber, e x pir y date, dis pe nse date, t he n u m ber 
of s y ri n ges use d, t he s u bject recei vi n g i n vesti gati o nal pr o d uct, an d n u m ber of s y ri n ges left i n 
st oc k at t he site.
W he n t he stu d y is c o m plete d, all u n use d or e x pire d st u d y pr o d uct at eac h st u d y site s hall be 
ret ur ne d t o t he S p o ns or f or destr u cti o n or be destr o y e d l ocall y at t he site, wit h pr o per 
d oc u m e ntati o n, after a gree ment wit h t he S p o ns or. A n y  malf u ncti o ni n g st u d y  pr o d ucts s hall 
be re p orte d as descri be d i n secti o n 8. 2. 3.
Pr o d ucts deli beratel y or acci de ntall y destr o ye d d uri n g s hi p me nt or at a st u d y site shall be 
acc o u nte d f or an d d oc u me nte d. Use d s yri n ges, dis p osa ble nee dle , a n d a n y o pe ne d u n use d 
material m ust be dis car de d i m me diatel y after t he treat me nt sessi o n a n d m ust n ot be re use d 
d ue t o ris k f or c o nta mi nati o n of t he u nuse d material a n d t he ass ociat e d ris ks i ncl u di n g 
infect i o ns acc or di n g t o sta n dar d pr oce d ures at t he site. Dis p os al of hazar d o us material, i.e. 
s yri n ges a n d nee dles m ust c o nf or m t o a p plica ble la ws a n d re g ulati o ns.
All st u d y  pr o d uct(s) se nt t o t he PI will be acc o u nte d f or a n d n o u na ut h or ize d use is per mitted.
6. 5 
Tr e at me nt
6. 5. 1 Treat me nt pr oce d ure 
Bef ore treat me nt t he s u bject will be i nf or me d a b o ut t he p ote ntial ris ks i n v ol ve d wit h t he 
treat me nt a n d w he n t o c o ntact t he I n vesti gat or i n case of e mer gi n g s y m pt o ms.
T he i n vesti gati o nal pr o d uct is reser ve d f or use b y d oct ors w h o ha ve bee n trai ne d i n t he 
a p pr o priate i njecti o n tec h ni q ues.
I njecti o n pr oce d ures are ass ociate d wit h a ris k of i nfecti o n. Ase ptic tec h ni q ue a n d sta n dar d 
practice t o pre ve n t cr oss-i nfecti o ns s h o ul d be o bser ve d at all ti mes i ncl u di n g t he use of 
dis p os a ble gl o ves d uri n g t he i njecti o n pr oce d ure . All traces of ma ke - u p s h o ul d be re m o ve d 
pri or t o a n y i njecti o n . T he treat me nt site s h o ul d be clea ne d wit h a s uita ble a ntise ptic s ol uti o n
(e xte n d at least fi ve c m ar o u n d t he i njecti o n site) .
I njecti o n tec h ni q ue
T h e i njecti o n tec h ni q ue is i mp orta nt f or t he aest hetic effect of t he treatm e nt . T he i njecti o n 
tec h ni q ue is at t he discreti o n of t he treati n g In vesti gat o r. T he sa me pre d o mi na nt i njecti o n 
tec h ni q ue s h o ul d be use d f or all s u bjects per site t o li mit varia bilit y d ue t o tec h ni q ue.
6. 5. 2 Treat me nt re gi me n (d ose a n d i nter val)
D o w n - u p
Baseli ne - T he c hi n a n d s urr o u n di n g area t o be treate d wit h u p t o 2 m L of Rest yla ne Def yne 
per treat me nt site wit h a ma xi m u m of 4 m L  i n t otal.
Wee k 3 – N L Fs/ M Ls t o be treate d wit h u p t o 2 m L/l i ne per N L F a n d u p t o 2 m L per M L
of 
Rest y la ne Def yn e .
Wee k 6 - O pti o nal t o uc h -u p i n a n y  of t he treate d areas that ha ve n ot o btai ne d o pti mal 
aest hetic i m pr o ve me nt. U p t o 2 m L per facial half is rec o m me n de d f or N L F a n d M L
i n 
c o m bi nati o n , an d a t otal of 2 m L i n the c hi n a n d s urr o u n di n g area.
S ufficie nt a m o u nt of st u d y pr o d uct s h o ul d be i njecte d t o ac hie ve o pti mal c or recti o n as a gree d 
bet wee n t he Treati n g I n vesti gat or a n d s u bject.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
3 5 (5 5 )
T o p -d o w n
Baseli ne - N L F a n d M L
t o be treate d wit h u p t o 2 m L p er N L F a n d u p t o 2 m L  per M L
of 
Rest y la ne Def yne.
Wee k 3 – T he c hi n a n d s urr o u n d i n g area t o be treate d wit h u p t o 2 m L of Rest ylane Def y ne 
per treat me nt site wit h a ma x i m u m of 4 m L i n t otal.
Wee k 6 - O pti o nal t o uc h-u p i n a n y of t he treate d areas t hat ha v e n ot o btai ne d o pti m al 
aest hetic i m pr o ve me nt. U p t o 2 m L per facial half is rec o m me n de d f or N L F a n d M L
i n 
c o m bi nati o n, a n d a t otal of 2 m L  i n t he c hi n a n d s urr o u n di n g area.
S ufficie nt a m o u nt of st u d y pr o d uct s h o ul d be i njecte d t o ac hie ve o pti mal c orrecti o n as a gree d 
bet wee n t he Tr eati n g I n vesti gat or a n d s u bject.
A t otal of u p t o 1 2 m L o f st u d y pr o d uct is t o be i njecte d at t he treat me nt visits ( visit 2 a n d 3) 
a n d u p t o 6 m L d uri n g t he o pti o nal t o uc h - up at visit 4.
6. 5. 3 P ost -treat me nt care
T he i njecte d sites c o ul d b e ge ntl y m o ul de d b y t he treati n g I n vesti gat or t o c o nf or m t o t he 
c o nt o ur of t he s urr o u n di n g tiss ues. T o pical c o oli n g ma y  be a p plied t o re d uce i nitial s welli n g
a n d br uisin g. After t he i njecti o n, s o m e c o m m o n i njecti o n-relate d reacti o ns mi g ht occ ur. 
T hese re acti o ns i ncl u de er ythe ma, s welli n g, pai n, itc hi n g, br uisi n g or te n der ness at t he 
im pla nt site. T y picall y, res ol uti o n is s p o nta ne o us wit hi n o ne wee k after i njecti o n i nt o t he s ki n.
T he s u bject m ust a v oi d e x p osi n g t he treate d ar ea t o heat (s u n bat hi n g, sa u na , stea m bat hs, 
etc.) or e xtre me c ol d u ntil a n y  si g ns of i nitial s welli n g a n d re d ness ha ve disa p peare d .
6. 5. 4 P ost -trial p r o visi o ns
I n time t he i m pla nt will be de gra de d i n t he b o d y  a n d a d diti o nal treat me nts will be necessar y  
t o mai ntai n t he aest hetic res ult. Aft er t he st u d y is fi nalise d Q- Me d
A B will n ot s u p pl y  a ny 
m ore treat me nts t o t he s u bj ects, b ut t he i n vesti gati o nal pr o d ucts are c o m merciall y a vaila ble if 
t he s u bjects w o ul d li ke t o ha ve a d diti o nal treat me nts.
6. 5. 5 Electr o nic c ase re p o rt f or m rec or di n gs
T he treat me nt is a gel i njecte d b y  the I n vesti gat or a n d t he f oll o wi n g details of t he i njecti o n 
are t o be rec or de d i n t he e C R F:

L ocal a naest hetic use d ( pr o d uct na me, a m o u nt a p plie d, a p plicati o n date, a n d 
c o nce ntrati o n)

Date f or a d mi nistra ti o n

A d mi nistere d v ol u me

I njectio n tec h ni q ue, see list bel o w.

De pt h of i njecti o n

Area of i njecti o n

P ost -treat me nt care (e. g. m o ul di n g, ice-pac k )

Use of nee dle

Si ze of nee dle
I n a d diti o n, a n y tec h nical pr o ble ms ( de vice deficie nci es) or cli nical c o m plicati o n s ass ociate d 
wit h t he i njecti o n will be rec or de d i n t he eC R F .
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
3 6 (5 5 )
I njecti o n tec h ni q ue t o be rec or de d i n s o urce data a n d t he e C R F‡:

A nte gra de li near t hrea di n g : als o calle d p us h-a hea d tec h ni q ue as s o me pr o d uct is 
p us he d a hea d of t he n ee dle. O nce t he nee dle is i n place, t he pr o d uct is i njecte d a hea d 
w hile i nsert i n g the nee dle i n t he tiss ue.

Retr o gra de li near t hrea di n g : t he nee dle is t hrea de d i nt o t he tiss ue at t he a p pr o p riate 
de pt h, a n d t he pr o d uct i n i njecte d as a strai g ht li ne o n wit h dra wal of t he nee dle

Serial p u nct ure : n u mer o us s mall nee dle i nserti o ns t o deliver a s mall a m o u nt of t he 
pr o d uct, re peate d al o n g a li ne or re gi o ns of t he tiss ues

Micr o -b ol us: s mall ali q u ots of t he pr o d uct is i njecte d al o n g a li ne or re gi o ns of t he 
tiss ues

F a n ni n g: a n u m ber of li near threa ds t o s prea d t he pr o d uct o ve r a wi der area

Cr o ss- hatc hi n g: c o m bi nes m ulti ple i njecti o ns of li near t hrea di n g t hat crisscr oss at 
ri g ht a n gle t o pr o vi de v ol u me i n a s q uare s ha pe

Ot her : at t he c h oice of t he treati n g I n vesti gat or
6. 5. 6 Treat me nt c o m plia nce
Treat me nt c o m plia nce is f ulfille d i f t he treati n g I n vesti gator has i njecte d s ufficie nt a m o u nt of 
st u d y pr o d uct t o ac hie ve o pti mal c orrecti o n. A n y de viati o ns t o t he tr eat me nt pr oce d ure s hall 
be rec or de d i n t he d e viati o n l o g a n d mi g ht be reas o n t o cate g orize t he treat me nt as n ot 
c o m plia nt.
                                                
‡ Va n Eij k T, Bra u m M., A n o vel met h o d t o i nject h yal ur o nic aci d: t he fer n patter n tec h ni q ue. J Dr u gs Der m 
2 0 0 7; 6: 8.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

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7.
E ffic ac y A ssess me nts
7. 1 
Ge ner al i nf or m ati o n
T he met h o ds f or c ollecti n g efficac y  data incl u de 2 D p h ot o gra p h y (secti o n 7. 2 ), G AI S 
(secti o n 7. 3 ), nat ural ness/
(7. 4) ,   
 
, s u bject satisfacti o n q uesti o n naire ( 7. 6), 
 
. Assess me nts wil l be perf or me d 
b y  t he s u bjects, t he I n vesti gat or,
 as s h o w n i n t he sc he d ule of e ve nts 
(secti o n 4. 7).
A t treat me nt visits, all assess me nts m ust be perf or me d bef ore st u d y treat me nt is a d mi nistere d.
T o a v oi d i nter -o bser ver varia bilit y , e ver y eff ort s h o ul d be ma de t o e ns ure t hat t he sa me 
i n di vi d ual w h o ma de t he i nitial scree ni n g or baseline deter mi nati o ns c o m pletes al l 
c orres p o n di n g f oll o w- u p e val uati o ns.
7. 2 
2 D P h ot o gr a p h y
P h ot o gra p hs s hall be ta ke n p ri or t o t he i njecti o ns of t he i n vesti gati o nal pr o d uct w he n 
a p plica ble a nd at f oll o w - u p visits i n or der t o d oc u me nt treat me nt effect.
N ote t hat n o c o veri n g ma ke- u p s hall be us e d o n t he p h ot o gr ap h s.
At visits w here i njecti o ns are perf or me d, t he p h ot o gra p hs shall be ta ke n pri or t o t he i njecti o ns
a n d s h o ul d i ncl u de a fr o nt, 4 5°- fro nt lateral , a n d pr ofile pict ure.
I nstr ucti ons f or p h ot o gra p h y are pr o vi de d i n a se parate p h ot o gra p h y ma n ual. Eac h 
p h ot o gr a p h shall be la belle d wit h t he s u bject n u m ber, a n d t he visit n u m ber at w hic h t he 
p h ot o gra p h was ta ke n. I n or der t o mai ntai n c o nfi de nti alit y, t he p h ot ogra p hs m ust n ot i ncl u de 
a n y i nf or mati o n t hat ma y re veal t he s u bject’s i de ntit y. T he p hot o gra p hs s h o ul d be use d i n t he 
assess me nt of G AI S, 
 a n d t o d oc u me nt 
A Es. T he p h ot o gra p hs s hall be p rese nte d o n a c om p uter m o nit or ( prefera bl y t he sa me 
m o nit or t hr o u g h o ut t he st u d y ).
P h ot o gra p hs s hall b e ta ke n at t he ti me p oi nt s i n dicate d i n t he sc he d ule of e ve nts (secti o n 4. 7 ).
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
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Versi o n: 
Eff e cti v e
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7. 3 
Gl o b al Aest hetic I m pr o ve me nt Sc ale ( G AI S)
T h e G AI S is a q u alitati ve 5 -gr a d e d s c ale e val uat i n g a est h eti c i m pr o v e m e nt (T a bl e 3 ).
W hil e G AI S is n eit h er a n o bj e cti v e m e as ur e m e nt t o ol n or a v ali d at e d t o ol, G AI S 
i m pr o v e m e nt h as b e e n c o m m o nl y a c c e pt e d b y t h e m e di cal c o m m u nit y i n E ur o p e a n d t h e 
U nit e d St at es as cli ni c al m e a ni n gf ul s cal e t o ass ess visi bl e a est h eti c res ults. T he G AIS c a n 
b e us e d n ot o nl y  b y t h e I n v esti g at or, b ut is als o a us ef ul to ol f or 
.
T a ble 3. Gl o b al Aest hetic I m pr o ve me nt Sc ale ( G AI S)
R ati n g (f or t he   
) 
Descri pti o n (f or t he I n vesti g at or a n d 
)
Ver y  m uc h i m pr o ve d 
O pti mal c os metic res ult f or t he s u bject.
M uc h i m pr o ve d
Mar ke d i m pr o ve me nt i n a p peara nce fr o m  t he ori gi nal c o n diti o n, b ut 
n ot c o m pletel y o pti mal f or t his s u bject.
I mpr o ve d
O b vi o u s i m pr o ve me nt i n a p peara nce fr o m t he ori gi nal c o n diti o n.
N o c ha n ge
T he a p peara nce is esse ntiall y t he sa me as t he ori gi nal c o n diti o n.
W orse
T he a p peara nce is w orse t ha n t he ori gi nal c o n diti o n.
S o urce: A da pte d fr o m Nari ns et al. 2 0 0 3 1 1.
T he  
a n d I n vesti gat or s hall, i nd e pe n de ntl y of eac h o t her, r at e t h e l o w er f a c e f or 
a est h eti c c h a n g e b y  c o m p ari n g t h e a p p e ar a n c e at f ollo w -u p a gai nst a p h ot o gra p h ta ke n 
b ef or e tr e at m e nt . T he p h ot o gra p hs s hall be prese nte d o n a c o m p uter m o nit or ( prefera bl y  t he 
sa me m o nit or t hr o u g ho ut t he st u d y ). T he I n vesti gat or will perf or m a live as sess me nt 
 
. T he f oll o wi n g q uesti o n will be as ke d: ” H o w w o ul d y o u 
descri be t he s u bject’s/  
 aest hetic a p pe ar a nce of t he l o wer f ace , i.e. t he tre ate d are a, 
c o m p are d t o t he p h ot o gr a p hs t a ke n bef ore tr e a t me nt ?” T h e  
 s h all r at e 
a c c or di n g t o t h e l eft c ol u m n i n T a bl e 3 a n d t h e I n vesti gat or s hall rate acc or di n g t o t he 
ri g ht c ol u m n i n T a bl e 3 , t he sc ores f or   
 a n d In vesti gat or rati n g are c o m p ara ble.
A cli nical l y sig nifica nt i m pr o ve me nt is defi ne d as a sc ore of i m pr o ve d; m uc h i m pr o ve d; or 
ver y  m uc h i m pr o ve d. T he G AI S assess me nts s hall as far as p ossi ble be p erf or me d b y t he 
sa me I n vestigat or t hr o u g h o ut t he st u d y .
7. 4 
N at ur al ness ,
B ot h t he I n vesti gat or a n d 
will a ns wer t he q uesti o ns re gar di n g nat ural ness , 
 
acc or di n g t o A p pe n di x 5 (I n vesti gat or’s
q uesti o n naire) a n d A p pe n di x 6
 res pecti vel y. 
 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
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7. 6 
S u bject S atisf acti o n Q uesti o n n aire
T he s u bjects will assess s u bject satisfacti o n, 
 
res ult at visit 2 – 5 ( baseli ne, w ee k 3, 6 a n d 9), bef ore treat m e nt wit h st u d y pr o d uct, whe n 
a p plica ble (A p pe n di x 9 ). Q uesti o n 1, 2 , 3 a n d 6 will be re m o ve d fr o m t he baseli ne 
q uesti o n naire an d q uesti o n 2 fr o m wee k 3 .
8.
S afet y A ssess me nts
8. 1 
A d ve rse e ve nts
8. 1. 1 Defi niti o n of a n a d verse e ve nt ( Me dical De vices Re g ulati o n ( M D R) articl e 2( 5 7))
A n A E is a ny u nt o war d me d ical occ urre nce , u ni nte n de d disease or i nj ur y , or u nt o war d 
cli nical si g ns (i nc l u di ng a b n or mal la b orat or y  fin d i n gs) i n s u bjects, users or ot h er pers o ns §, i n
the c o nte xt of a cli nical i n vesti gati o n, w het her or n ot relate d t o t he i n vesti gati o nal de vice. 
T his defi niti o n i ncl u des:
a)
e ve nts relate d t o t he i n vesti gati o nal pr o d uct or t he refere nce pr o d uct
b)
e ve nts relate d t o t he pr oce d ures i n v ol ve d
c)
e ve nts t hat are a ntici pate d as well as u na ntici pat e d
8. 1. 2 Defi niti o n of a seri o us ad v erse e ve nt ( M D R articl e 2( 5 8))
A seri o us a d verse e ve nt (S A E) is a ny A E t hat:
a)
le d t o deat h,
b)
le d t o seri o us deter i orati o n i n t he healt h of t he s u bject, t hat eit her res ulte d i n
1.
a life-t hreate ni n g* * ill ness or i nj ur y, or
                                                
§ F or u sers or ot her pers o ns, t his defi niti o n is restricte d t o e ve nts rela te d t o t he i n vesti gati o nal pr o d uct .
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
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M A -4 2 2 4 8. d oc
4 0 (5 5 )
2.
a per ma ne nt i m pair me nt of a b o d y str uct ure or b o d y f u ncti o n , or
3.
h os pitalizati o n or pr o l o n ge d h os pitalizati o n † †, or
4.
me dical or s ur gical i n ter venti o n t o pre ve nt life-t hreate ni n g ill ness or i nj ur y  or 
per ma ne nt i m pair me nt to a b o d y  str uct ure or a b o d y f u ncti o n,
5.
chr o nic diseas e
c)
le d t o fetal distress, fetal deat h , or a c o n ge nital p h ysical or me n tal i m pair m e nt or birt h 
defect
I n cases of d o u bt , w het her a n A E f ulfils a seri o us criteri o n or n ot , t here s h o ul d be a 
pre dis p ositi o n t o re p ort as a S A E rat her t ha n n ot re p ort as s uc h (see secti o n 8. 1. 4 ).
8. 1. 3 Rec or di n g i nstr ucti ons
Eac h s u bject s h o ul d be q uest i o ne d a b o ut A E s at eac h st u d y visit f oll o wi n g si g ni n g of 
i nf or me d c o nse nt. T he q uesti o n as ke d s h o ul d be: ” Si nce y o ur last c li nical visit; ha ve y o u ha d 
a n y healt h pr o ble ms?”. Inf or m ati o n o n A E s ca n als o be o btai ne d fr o m si g ns a nd s y m pt o ms 
detecte d d uri n g ea c h e xa mi nati o n or fr o m a la b orat or y test , o bser vati o ns ma de b y  t he st u d y
site pers o n nel , s u bject diaries, or s p o nta ne o us rep orts fr o m t he s u bjects or t heir relati ves .
W he n a n A E is relate d t o a d e vice d eficie nc y (refer t o sectio n 8. 2), i ncl u di n g tec h nical de vice 
malf u ncti o n, t he A E s hall be rec or de d o n t he A E f or m/ m o d ule i n t he e C R F a n d t he tec h nical 
c o m plai nt s hall be re p orte d se paratel y o n t he cli nical st u d y c o m plai nt f or m e C R F.
I n vesti gat ors, or ot her st u d y site pers o n ne l, s hall rec or d all A E s i n t he eC R F , i ncl u di n g:
a)
E ve nt ter m (rec or de d i n sta n dar d me dical ter mi n olo g y  a n d a v oi di n g a b bre viati o ns)
b)
A ffecte d area
c)
Start date ( first d a y  wit h s ym pt o ms )
d)
St o p date (last d a y  wit h sy m pt o ms)
e)
I nte nsity ( mil d , m o derate , or se vere acc or di n g t o defi niti o n i n secti o n 8. 1. 3. 1)
f)
Seri o us ness (seri o us or n ot seri o us, acc or di n g t o defi niti o n i n secti o n 8. 1. 3. 2)
g)
C a usal relati o ns hi p t o st u dy pr o d uct or st u d y pr o d u ct i njecti o n pr oce d ure ( yes or n o)
h)
Acti o n ta ke n ( n o ne, me dicati o n treat me nt, n o n- p har mac ol o gical treat me nt, or o t her 
pr oce d ures/tests, s u bject wit h dra w n)
i)
O utc o me of t he A E (o n g oi n g, rec o vere d, rec o vere d wit h se quelae, deat h , chr o nic / 
sta ble, n ot rec o vere d at t he e n d of t he st u d y)
T he A E f or m/ m o d ule i n t he e C R F m ust be si g ne d a n d date d b y  t he In vesti gat or .
                                                                                                                                                       
* * T he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers to a n e ve nt i n w hic h t he patie nt was at ris k of 
deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve ca use d dea t h if it 
were m ore se vere. ( S o urce: I C H-E 2 A cli nic al s af et y d at a m a n a g e m e nt : defi niti o ns a n d sta n dar ds f or 
e x pe dite d re p orti n g ).
† † Pla n ne d h os pital izati o n f or a pre-e xisti n g c o n diti o n, or a pr oce d ure re q uire d b y t he C S P, wit h o ut seri o us 
deteri orati o n i n he alt h, is n ot c o nsi dere d a S A E. ( S o urce: I S O 1 4 1 5 5: 2 0 1 1).
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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M A -4 2 2 4 8. d oc
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8. 1. 3. 1 I nte nsity
I nte nsity will be rec or de d f or eac h re p orte d A E. T he f oll o wi n g defi niti o ns of i nte nsit y are t o 
be use d:
Mil d :   
Aware nes s of sy m pt o ms or si g ns, b u t easil y t olerate d (accepta bl e)
M o der ate:
E n o u g h disc o mf ort t o i nterfere wit h us ual acti vit y  ( dist ur bi n g)
Se vere:
Inca p acit y t o w or k or t o d o us ual acti vit y ( u nacce pta ble)
If t he i nte nsit y c ha n ges wit hi n o ne da y, t he ma xi m u m i nte nsit y of t he A E d uri n g that da y  
s hall be rec or de d.
8. 1. 3. 2 C a us al rel ati o ns hi p a n d seri o us ness
Eac h A E s hall be assesse d b y  t he In vesti gat or f or ca usal relati o ns hi p wit h t he st u d y pr o d uct
a n d its us e (t he i njecti o n pr oce d ure) a n d f or seri o usness (Yes or N o) of t he e ve nt .
A t w o- poi nt scale ( Yes or N o res p o nse) s hall be use d f or t he ca usalit y assess me nts . T he 
I n vesti gat ors s hall be as ke d t o i n dicate a res po n se t o eac h of t he f oll o wi n g q uesti o ns i n t he 
e C RF :

“ D o y o u c o nsi der t hat t here is a reas o na ble p ossi bi lit y t hat t he e ve nt ma y ha ve bee n 
ca use d b y t he st u d y p r o d uct? ”, a n d

“ D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y  t hat t he e ve nt ma y ha ve been 
ca use d b y t he st u d y pr o d uct i njecti o n pr oce d ure?”
If a ny of t hese q uesti o ns is a ns were d Yes, t he A E is c o nsi dere d relate d .
Eac h A E will als o be assesse d f or ca usal relati o ns hi p a n d seri o us ness b y t he S p o ns or , i n or der 
t o f ulfil re g ulat or y re q uire me nts.
I n a d diti o n, eac h S A E will be classifie d b y b ot h t he I n vesti gat or a n d t h e S p o ns or se paratel y,
acc or di n g t o f our d iffere nt le vels of ca usalit y:
1.
N ot rel ate d – R elati o ns hi p t o t he de vice, c o m parat or or pr oce dures ca n b e e xcl u de d
w he n:

the e ve nt has n o te m p oral relati o ns hi p wit h t he use of t he i n vesti gati o nal d e vice,
or t he pr oce d ures relate d t o t he i n vesti gati o nal de vice;

the seri o us a d verse e v e nt d oes n ot f oll o w a k n o w n res p o nse patter n t o t he me dical
de vice (if t h e res p o nse p atter n is pre vi o usl y k n o w n) a n d is bi ol o gicall y
im p la usi ble;

the disc o nti n u ati on o f me dical de vice a p plicati o n or t he re du cti o n o f t he le vel of
acti vati on /e x p os ure – w he n cli nicall y feasi ble – a n d rei ntr od u cti on o f its use ( or
i ncreas e of t h e le v el of acti vati o n/e x p os ure), d o n ot i m pact o n t he seri o us a d v erse
e ve nt;

th e e ve nt i nv o l ves a b o d y-site o r a n or ga n t hat ca n no t be affecte d b y t he d e vice or
p r oce du re;

t he seri ou s a d verse e v e nt ca n be attri b ute d t o a n ot her ca us e (e. g. a n u n derl yi n g or
co nc urre n t ill ness/cli nical c on d iti o n, a n effect of a n ot her de vice, dr u g, treat me nt
o r ot her ris k fact ors);
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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2. 0
 
 
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4 2 (5 5 )

the e ve nt d oes n ot de p e n d o n a false res ult gi v e n b y t he i n vesti gati o nal de vice
use d f or dia g n osis, w he n a p plica ble;
In or der t o esta blis h th e no n -relate d n ess, n ot all t he criteri a liste d a b o ve mi g ht be met
at t he sa me ti me, de pe n di n g o n t he t y pe of de vice/ pr oce d ures a n d t he s eri o us a d verse
eve nt.
2.
P ossi ble – T h e relati on s hi p wit h t he use of t he i n vesti gati o nal de vice or c o m parat or, 
or t he relati o ns hi p wit h pr oce d ures, is wea k b ut ca n n ot be r ule d o ut co m pletel y .
Alter nati ve ca uses are als o p ossi ble (e. g. a n u n derl yi n g or c o nc urre nt ill ness/ cli nical
c o n diti o n or/a n d a n effect of a n ot her de vice, dr u g or treat me nt). Cases w here
relate d ness ca n n ot be assesse d, or n o i nf or mati o n has bee n o btai ne d s h o ul d also be
classifie d as p ossi ble.
3.
P r o b a ble – T he rela ti o ns hi p wit h t he use of t he i n vesti gatio nal de vice or c o m parat or,
or t he rela ti o nshi p wit h pr oce d ures, see ms rele va nt a n d/ or t he e ve nt ca n n ot be
reas o na bly e x plai ne d b y a n ot her ca use.
4.
C a us al rel ati o ns hi p – the seri o us a d verse e ve nt is ass ociate d wit h t he i n v esti gati o nal
de vice, c o m p arat or or wit h pr oce d ures be y o n d reas o na ble d o u bt, w he n:

t he e ve nt is a k n o w n si de effect of t he pr o d uct cate g or y t he de vice bel o n gs t o or of
si milar de vices a n d pr oce dures;

t he e ve nt has a te m p oral relati o ns hi p wit h i n vesti gati o nal de vice use/a p plicati o n or
pr oce d ure s;

t he e ve nt i n v ol ves a b o dy- site or or ga n t hat
o
t he i n vesti gati o nal de vi ce or pr oce d ures are a p plie d t o;
o
the i n vesti gati o nal de vi ce or pr oce d ures ha v e a n effect o n;

t he seri o us a d verse e ve nt f oll o ws a k n o w n res p o nse patter n t o t he me dical de vic e
(if t he res p o nse patter n is pre vi o usl y k n o w n);

the di sc o nti n uati o n of me dical de vice a p plicati o n ( or re d ucti o n of t he le vel of
acti vati o n/ e x p os ure) a n d rei ntr o d ucti o n of its use ( or i ncrease of t he le vel of
acti vati o n/e x p os ur e), i m pact o n t he seri o us a d verse e ve nt ( w he n clinicall y
feasi ble);

ot her p oss i ble ca uses (e. g. a n u n derl yi n g or c o nc urre nt ill ness/ cli nical c o n diti o n
or/a n d a n effect of a n ot her de vice, dr u g or treat me nt) h a ve bee n a de q uatel y r ule d
o ut;

har m t o t he s u bje ct is d ue t o err or i n use;

the e ve nt de p e n ds o n a false res ult gi ve n by t he i n vesti gati o nal de vice use d f or
dia g n osis, w he n a p plica ble;
I n or der t o est a blis h t he relate d ness, n ot all t he criteria liste d a b o ve mi g ht b e met at
th e sa me ti me, de p e nd i n g on t h e t y pe of de vice/pr oce d ures a n d t he seri o us a d verse
ev e nt.
8. 1. 4 R e p orti n g of a d verse e ve nts
A d verse e ve nt re p orti n g o n eac h s u bject s hall start at baseli ne ( visit 2 ) after t he s u bject has 
bee n ra n d o mize d . T he re p orti n g s hall c o nti nue d uri n g eac h f oll o w - u p visit (i ncl u di n g 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
4 3 (5 5 )
tele p h o ne c o ntacts a n d e xtra visits bet wee n pla n ne d visits ) u ntil t he last sc he d ule d visit i n t he 
st u d y.
All A E s, n o n-seri o us as well as seri o us, are to be re p orte d as a n A E i n t he e C R F.
8. 1. 5 Re p orti n g of seri o us a d verse e ve nts
T he I n vesti gat or s hall re p ort a n y S A E t o t he Sp o n s or or via S p o ns or’s re prese nta ti ve, 
i m me di atel y b ut n ot l ater t h a n 2 4 h o urs of a w are ness of t he e ve nt . T his i nitial re p ort ca n 
be m a de via fa x or e-mail or s u b mitte d via t he e C R F.
I n case of diffic ult y t o o btai n all t he req uire d i nf or mati o n wit hi n 2 4 h o u rs, a n i nitial re p ort 
ca n be s ub mitte d , wit h t he foll o w i n g i nf or mati o n as a mi ni m u m, irres pecti ve of w het her 
s o me of it is re gar de d as preli mi nar y :

S u bject i de ntificati o n (a ge, ge nder, i nitials, s u bject n u m ber)

A d verse e ve nt des cri pti o n

Date w he n A E occ urr e d

Na me of PI

Na me of st u d y pr o d uct
F oll o w -u p i nf o r matio n a n d data missi n g i n t he i nitial S A E re p orti n g s hall be gat here d as s o o n 
as p o ssi ble a n d re p orte d t o t he S p o ns or’s re prese n tati ve i m me diatel y b ut n ot later t ha n 2 4 
h o u rs of a ware ness of t he ne w data . C o m plete a n d a de q uate i nf or mati o n o n eac h S A E is 
re q uire d. All atte m pts t o o btai n t his i nf or mati o n, i ncl u di n g dates f or f oll o w-u p ac tivities, 
m ust be d oc u me nte d b y t he I n vesti gat or.
S u p p orti n g d oc u me ntati o n t o be pr o vi de d w it h t he S A E re p ort:

C o nc o mita nt t hera pies f or m/list

A E f or m/list

Me dical hist or y  for m /list

A n y  ot her rele va nt s u p p orti n g d oc u me ntati o n (e. g. h os pital n otes, deat h certificate, 
a ut o ps y re p orts etc.)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
E -m ail f or S A E re p orti n g: 
safety. q -me d @ gal der ma.c o m
F a x n u m ber f or S A E re p orti n g: 
+ 4 6 ( 0) 1 8 4 7 4 9 1 7 5
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
F or n o n u r ge nt c o m ple me ntar y i nf or mati o n n ot p ossi ble t o se n d b y e-mail or fa x, please use 
s urface mail .
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
S urf ace m ail f or pr o vi di n g 
Q -Me d A B 
c om ple me ntar y  i nf or mati o n: 
Att n. Safet y  - Me dica l Affairs
Se mi narie gat a n 2 1 
S E -7 5 2 2 8 U P P S A L A, S we de n
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
4 4 (5 5 )
T he S A E f or m m ust be si g ne d a n d date d by t he I nvesti gat or . If t he initial 2 4- h o ur S A E re p ort 
d oes n ot c o ntai n f ull i nf or mati o n or if it is ma de wit h o ut usi n g t he S A E for m t he f ull y 
c o m plete d a n d si g ne d S A E for m s hall be e- maile d or fa xe d t o t he S p o ns or. A c o p y of t he 
f ull y c om p lete d S A E f or m s hall be ke pt at t he site.
I n a d diti o n, t he PI s hall re p ort S A Es t o t he res p o nsi ble I EC wit h o ut u n d ue dela y. T he PI is
res p o nsi ble f or c hec ki n g w hat re p ortin g pr oce d ures are a p plica ble f or his/ her I E C re gar di n g 
S A Es a n d fi nal re p ort of t he o utc o me of t he st u d y a n d t o c o m pl y wit h s uc h re p orti n g 
pr oce d ures d uri n g t he st u d y peri o d.
T he S p o ns or is res p o nsi ble f or re p orti n g t o t he C A , if a p plicable a n d acc or di n g t o nat i o nal 
re g ulati o ns. F or all S A Es w hic h i n dicate a n i m mi ne nt ris k of deat h, serio u s i nj ur y, or seri o us 
ill ness a n d t hat re q uires pr o m pt re me dial acti o n f or ot her s u bjects, use rs or ot her pers o ns or a 
ne w fi n di n g t o it: i m me diatel y, b ut n ot later t ha n 2 cale ndar da y s after a ware ness b y Sp o ns or .
F or a descri pti o n of t he pr oce d ure re gar di n g e mer ge nc y u n bli n di n g, see secti o n 4. 4. 3.
8. 1. 6 F oll o w -u p of u nres ol ve d e ve nts o n g oi n g at te r mi nati o n of t he stu d y
All seri o us as well as n o n-seri o us A Es wit h a ca usal relati o ns hi p t o t he st u d y pr o d uct or 
treat me nt pr oce d ure a n d o n g oi n g at st u d y  e n d, s hall be f oll o we d u p after t he s u bject's 
partici pati o n i n t he st u d y is o ver. S uc h e vents s hall be f oll o we d-u p after t he last st u d y visit 
u nt il res ol ve d, assesse d as c hr o nic or sta ble, or f or t hree m o nt hs. Fi nal o utc o me after t he e n d 
of t he st u d y  s hall be re p orte d on A E f oll o w u p f or m.
8. 1. 7 Re p orti n g a n d f oll o w - u p of e ve nts occ urri n g after s u bje ct ter mi natio n of t he st u d y
All A E s wit h a ca usal relati o ns hi p t o t he st u d y pr o d ucts or treat me nt pr oce d ure t hat t he 
I n vesti gat or beco m es a ware of, seri o us as well as n o n -seri o us, wit h o nset after t he st u d y  
ter mi nati o n (s u bject’s last st u d y visit) s hall be re p orte d t o t he S p o ns or. T he re p ort s h o ul d as a 
m i ni m um i ncl u de t he i nf or mati o n descri be d i n secti o n 8. 1. 3. T he re p ort ca n be se nt via fa x or 
e-mail acc or di n g t o c o ntact details s pecifie d i n secti o n 8. 1. 5 . T he e ve nts s hall t hereafter be
f oll o we d- u p u ntil res ol ve d or c o nsi dere d c hr o nic or sta ble, or f or at least t hree m o nt hs. Fi nal 
o utc o mes s hall be re p orte d .
8. 1. 8 Pre g na nc y
Pre g na nc y  itself is n ot re gar de d as a n A E .
If t here is a pre g na nc y d uri n g t he st u d y peri o d t he s ubject m ust be wit h d ra w n fr o m a ny 
f oll o wi n g st u d y treat me nt, b ut s h o ul d c o nti n ue t o be f oll o we d wit hi n t he st u d y a n d t he 
o utc o me of pre g na nc y  m ust be re p orte d e ve n if t he deli ver y occ urs after st u d y c o m pleti o n.
A pre g na nc y c o nfir me d d uri ng t he st u d y peri o d m ust be re p orte d b y t he I n vesti gat or o n a 
pre g na nc y re p ort f or m i m me diatel y u p o n ac k n o wle d ge be s u b mit ted t o t he S p o ns or
acc or di n g t o c o ntact details s pecifie d i n secti o n 8. 1. 5 . T he re p ort ca n be pr os pecti ve or 
retr os pecti ve. Foll o w -u p s hall be c o n d uc te d t o o btai n o utc o me i nf or mati o n o n all pr os pecti ve 
re p orts.
Cases t hat le d to fetal distress, fetal deat h or a c o n ge nital ab n or malit y  or birt h defect are t o be 
re gar ded as S A E s a n d s hall be re p orte d o n t he e x p osure i n uter o re p ort f or m t o t he S p o ns or 
i m me diatel y b ut n o later t ha n 2 4 h o urs after t he I n vesti gat ors a ware ness. T hese eve nts s hall 
be ha n dle d as S A E s d uri n g data pr ocessi n g. Ot her c o m plicati o ns d uri n g t he pre g n a nc y t hat 
are relate d t o t he pre g na nt w o ma n a n d f ulfils a n y s eri o us criteria, s uc h as pre-ecla m psia
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
4 5 (5 5 )
re q uiri n g h os pitalizati o n , s hall be re p orte d a n d ha n dle d as S A Es. E lecti ve a b orti o ns wit h o ut 
c o m plicati o ns s hall n ot be re p orte d as A E s.
8. 1. 9 A ntici pate d a d verse e vents
I nf or mati o n re gar di n g a ntici pate d A Es f or Rest yl a ne Def y n e is i ncl u de d i n t he IF U.
8. 2 
De vice deficie ncies
8. 2. 1 Defi niti o n of a de vice deficie nc y
A de vice deficie nc y  is defi ne d as a n i na de q uac y  of a me dical de vice wit h res pect t o its 
i de ntit y, q ualit y, d urabili t y, relia bilit y, safet y‡ ‡, or perf or ma nce .
N ote: De vice defi cie ncies i ncl u de ma lf u ncti o ns, use err ors, a n d i na de q uate la belli n g.
8. 2. 2 Rec or di n g i nstr ucti o ns
W he n a de v ice deficie nc y is disc o vere d, Part A of t he clinical st u d y  c o m plai nt f or m s hall be 
c o m pleted b y t he I n vesti gat or. T he ty pe of c o m plai nt s hall be descri be d a n d i nj ur y t o t he 
s u bject or user or u ni nte n de d e x p os ure t o st u d y pr o d uct s hall be re p orte d as a p plic a ble. If a n 
i nj ur y has occ urre d, a n A E m o d ule o r a n S A E f or m s hall be c o m plete d as a p pl ica ble (refer t o 
secti o n 8. 1 ). If n o S A E was e x perie nce d as a res ult of t he de vice deficie nc y  t he I nvesti gat or 
s hall assess w h et her or n ot t he de vice deficie nc y  c o ul d ha ve le d t o a n S A E if:

S uita ble acti o n ha d n ot b ee n ta ke n,

I nter ve nti o n ha d n ot bee n ma de or ,

Circ u msta nces ha d bee n less f ort u nat e
I n Part B of t he cli nical st u d y c o m plai nt f or m t he S p o ns or will ma ke t he sa me assess me nt.
8. 2. 3 Re p orti n g of de vice deficie ncies
T he In vesti gat or s hall se n d t he c o m plete d cli nical stu d y  c o m plai nt f or m t o t he S po ns or .
E- m a il f or de vice deficie ncies re p orti n g: 
c o m plai nts. q-me d @ gal der ma.c o m
F a x n u m ber f or de vice deficie ncies re p orti n g: 
+ 4 6 1 8 4 7 4 9 1 0 1
A de vice deficie nc y  t hat le d t o a S A E a n d a n y de vice deficie nc y t hat c o ul d ha ve l e d t o a S A E 
s hall be re p orte d t o t he S p o ns or wit hi n 2 4 h o ur s after t he I n vestigat or ’s a ware ness (f or 
c o ntact i nf or mati o n, see secti o n 8. 1. 5).
If t he I n vesti gat or or t he S p o ns or as sesses t hat t he de vice deficie nc y  c o ul d ha ve le d t o a S A E 
t he S p o ns or is resp o nsi ble f or re p orti n g t he de vi ce deficie nc y t o C A a n d t he PI is res p o nsi ble 
f or re p orti n g it t o t he I E C.
                                                
‡ ‡ I na de q uac y of de vice safet y refers t o pr o perties of t he de vic e w hic h c o ul d ha ve or ha ve le d t o a n A E.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
4 6 (5 5 )
T he deficie nt st u d y  pr o d uct shall be ke pt b y t he st u d y site u ntil t he S p o ns or has c o nfir me d 
w het her t he pr o d uct s hall be r et ur ne d t o S p o ns or f or f urt h er st u d y or if it ca n be destr oye d at 
t he st u d y site.
9.
D at a H a n dli n g a n d M a n a ge me nt 
9. 1 
D at a m a n a ge me nt
Data ma na ge me nt base d o n G C P refe rs t o t he acti vities defi ne d t o ac hie ve safe r outi nes t o 
e nter cli nical data i nf or mati o n i n t o a data base, efficie ntl y  a n d av oi di n g err o rs. T he data 
ma na ge me nt r o uti ne i ncl u d es proce d ures f or data base set -u p a n d ma na ge me nt, data e ntr y  a n d 
verificati o n, data v ali dati o n, a n d d oc u me ntati o n of t he perf or me d acti vities i ncl u di n g 
i nf or mati o n of discre pa ncies i n t he pr ocess. T he data ma na ge me nt p r ocess will be descri be d 
i n detail i n t he d ata m a na ge me nt p la n ( D M P).
T he data base, t he data e ntr y  scree ns a n d pr o gra m will be desi g ne d i n acc or da nce wit h t he 
C S P a n d the C R F te m plate. Data vali dati o n will be perf or me d b y c o m p uterize d l o gical 
chec ks a n d ma n ual re vie w. Dr u gs a n d e ve nts will be c o de d i n acc or da nce wit h W orl d Healt h 
Or ga nizati o n ( W H O ) Dr u g a n d me dical dicti o nar y f or re g ulat or y acti vities (Me d D R A )
dicti o nari es as s pecifie d i n t he D M P. S A E i nf or mati o n i n the cli nical data base will be
rec o ncile d a gai nst t he data i n t he safety data bas e.
W h e n all eff orts ha ve bee n ma de t o e ns ure t hat t he data rec or de d i n t he e C R Fs a n d e ntere d i n 
t he data base is as c orrect a n d c o mplete as p ossi ble, t he cli nical data base wil l be l oc ke d. St u d y
data will be tra nsferre d t o S A S datasets, w h ic h t hereafter will be w rite-pr otecte d. Statistical 
a nal ys es will be ge nerate d i n S A S usi n g data fr o m t he l oc ke d datasets.
9. 2 
Electr o nic c ase re p ort f or ms
A n electr o nic data ca pt ure a p plicati o n , c o m plia nt wit h re g ulat or y re q uire me nts f or s oft ware 
vali dati o n c o m pl yi n g wit h U S F D A 2 1 C F R 1 1 will be use d t o c ollect, m o dif y, mai ntai n, 
arc hi ve, retrie ve, a n d tra ns mit st u d y data. A n eC R F is re q uire d a n d s hall b e c o m plete d 
electr o nicall y f or eac h scree ne d s u bject (scree ni n g visit) a n d enr olle d s u bj ects (s u bse q ue nt 
vi sits).
T he e C R F i nc l u des pass w or d pr otecti o n a n d i nter nal q ualit y  c hec ks, s uc h as a ut o matic ra n ge 
c hecks , t o i de ntif y data t hat a p pear i nc o nsiste nt, i nc o m plete, or i nacc urate. St u d y data s hall 
be e ntere d directl y  fr o m t he s o urce d oc u me nts, w hic h are t o be defi ne d at eac h sit e before 
i ncl usi o n of t he first s u bject.
A ut h orize d st u d y site pers o n nel desi g nate d b y t he PI s hall c o m plete data c ollecti o n. 
A p pr o priate trai ni n g a n d sec urit y meas ures s hall be c o m plete d wit h all a ut h orized
i n vesti gati o n site pers o n nel pri or t o t he st u d y bei n g i nitiate d a n d a n y data bei n g e ntere d i nt o 
t he s yste m f or a n y s u bject.
T he st ud y data is t he s ole pr o perty of t he S p o ns or a n d s hall n ot be ma de a vaila ble i n a ny f or m 
t o t hird parties, e xce pt f or a ut h orize d re presentati ves of a p pr o pr iate C A , wit h o ut writte n
per missi o n fr o m t he S p o ns or. At t he e n d of t he st u d y, electr o nic data are ke pt at t he S p o ns or 
a n d a c o p y ( pr o vi de d b y t he ven d or) at t he st u d y site as part of t he I n vesti gat or file.
A n y  dele gati o n of c ollecti o n o f data s hall be s pe cifie d a n d rec or de d .
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
4 7 (5 5 )
9. 2. 1 Dat a e ntr y
All data s hall be e ntere d i n E n glis h. T he e C R Fs s h o ul d al wa y s reflect t he latest o bser vati o ns 
o n t he s u bjects partici pati n g i n t he st u d y. T heref ore, t he e C R Fs s hall be c o m plete d as s o o n as 
p oss i ble d uri n g or after t he s u bject’s visit. T he s u bj ect’s i de ntit y m ust al wa ys re mai n 
c o nfi de ntial, i.e. t he na me a n d a d dress of t he s u bj ects m ust n ot be re gistere d i n t he e C R Fs or 
in t he data base. T he I n vesti gat or m ust verif y t hat all data e ntries i n t he e CR Fs are acc u rate 
a n d c orrect. If s o me assess me nts are not d o ne, or if certai n i nf or mati o n is n ot a vaila ble, n ot 
a p plica ble or u n k n o w n , t he I n vesti gat or s hall i n dicate t his i n t he eC R F. T he I n vesti gat or s hall
electr o nicall y si gn off t he st u d y data. B y  si g nin g, t he I n ve sti gat or ta kes res po nsi bilit y  f or t he 
acc ur ac y, c o m plete ness, a n d le gi bilit y of t he data re p orte d t o t he S p o ns or i n t he eC R F.
9. 2. 2 T he q uer y  pr ocess
T he m o nit or s hall re vie w t he e C R Fs a n d e val uate t he m f or c o m plete ness a nd c o nsiste nc y . 
Eac h e C R F s hall be c o m par e d wit h t he res pecti ve s o urce d oc u me nts t o e ns ure t hat t here are 
n o discre pa ncies bet wee n critical data. All e ntries, c or recti o ns, a n d alterati o ns s hall be ma de 
b y  t he PI or his/ her a ut h orize d desi g nee. T he m o nit or c a n n ot e nter data i n t he e C R F s. O nce 
st u dy data ha ve bee n s u b mitte d t o t he ce nt ral ser ver via t he e C R F, c orrecti o ns t o t he data 
fiel ds will be a u dit traile d, mea ni ng t hat t he reas o n f or c ha n ge, t he na me of t he pers o n w h o 
ma de t he c ha n ge, t o get her wit h t i me a n d date will be l o g ge d. R ol es a n d ri g ht s of t he site 
pers o n nel res p o nsi ble f o r e nteri n g st u d y data i nt o t he e C R F s hall be deter mi ne d i n a d va nce. 
If discre pa nt d ata is detecte d d uri n g re vie w of t he data, eit her b y t he S p o ns or or b y its
re prese ntati ves, t he res p o nsi ble d ata ma na ger or m o nit or s hall raise a q uer y i n t he electr o nic 
dat a ca pt ure a p plicati o n. T he q uer y  s hall state t he q uesti o n or data t o be c ha n ge d a n d shall be 
res ol ve d i n t he sys te m b y t he PI  or his/ her a ut h orize d desi g nee . T he a p pr o priate st u dy site 
pers o n nel s hall a ns wer t he q ueries i n t he e C R F. T his will be a u dit trai le d by t he electr o nic 
data ca pt ure a p plicati o n mea ni n g t hat t he na me of st u d y site pe rs o n nel, ti me, a n d date is 
l o g ge d.
9. 2. 3 U ser i de ntificati o n
Electr o nic C R F rec or ds will be a ut o mat icall y a p pe n de d wit h t he i dentificati o n of t he creat or, 
b y  mea ns of t heir u ni q ue Us erI D. S pecifie d rec or ds s hall be electr o nicall y si g ne d by t he 
I n vesti gat or t o d oc u me nt his/ her re vie w of t he data a n d ac k n o wl e d ge me nt t hat t he data are 
acc urate. T his wi ll be facilitate d b y mea ns of t he I n vesti gat or’s u ni q ue UserI D a n d pass w or d; 
date a n d ti me sta m ps will be a d de d a ut o maticall y at ti me of electr o nic si g nat ure. If a n e ntr y 
i n a n e C R F re q uires c ha n ge, t he c orrecti on s hall be ma de i n acc or da nce wit h t he rele v a nt 
s oft ware pr oce d ures.
9. 2. 4 A u dit trail
All c ha n ges will be f ull y rec or de d i n a pr otecte d a u dit trail a n d a reas o n f or t he c ha n ge s hall 
be state d . O nce all data ha ve be e n e ntere d, verifie d, a n d vali date d, t he data ba se will be 
l oc ke d.
9. 3 
S o urce d oc u me nts
T he eC R F is esse ntiall y c o nsi dere d a dat a e ntr y f or m a n d d oes n ot c o nst it ute t he ori gi nal ( or 
s o urce) me dical rec or ds u nless ot her wise s pecifie d. S o urce d oc u me nts are all d oc ume nts use d 
b y  t he I n vesti gat or or h os pital t hat relate t o t he s u bject’s me dical hist or y , t hat verifies t he 
e xiste nce of the s u bject, t he i ncl usi o n a n d excl usi o n criteria, a n d all rec or ds c o veri n g t he 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
4 8 (5 5 )
s u bject’s partici pati o n i n t he st u d y. T he y i ncl u de la bor at or y n otes, me m ora n da, material 
dis pe nsi n g r ec or ds, s u bject files, etc.
T he PI  is res p o nsi ble f or mai ntai ni n g a de q uate an d acc urate s o urce d oc u me nts. S o urce data 
s h o ul d b e attri b uta ble, le gi ble, c o nte m p ora ne o us, ori gi nal, acc urate, a n d c o m plete. C ha n ges
t o s o urce data s h o ul d be tracea ble, s h o ul d n ot o bsc ure t he ori gi nal e ntr y an d s h o ul d be 
e x plai ne d if necessar y .
T hese s hall be ma de a v aila ble f or i ns pecti o n b y t he m o nit or at eac h m o nit ori n g visit. T he 
I n vesti gat or m ust s u b mit a c o m plete d eC R F f or eac h s u bj ect f or w h o m si g ne d inf or me d 
co nse nt has bee n c ollecte d. All s u p p orti ve d oc u me ntati o n s u b mitt e d wit h t he e C R F, s uc h as 
lab orat or y  or h os pital rec or ds, shall be clearl y i de ntifi e d wit h t he C T N a n d s u bject n u m ber. 
A n y  pers o nal i nf or mati o n, i ncl u di n g na me, s hall be re m o ve d or re n dere d ille gi ble t o prese r ve 
i n di vi d ual c o nfi de ntialit y.
9. 4 
Rec or d kee pi n g a n d access t o s o urce d at a
T he PI /I nstit uti o n s hall per mit stu d y -relate d m o nit ori n g, a u dits, I EC re vie w, a n d C A
i ns pecti o ns a n d s hall pr o vi de direct access t o t he s ource data/ me dical rec or d i ncl u di n g t he 
i de ntit y of all partici pati n g s u bjects (s ufficie nt i nfor mati o n t o li n k rec or ds, i. e. e C R F, me d ical 
rec or ds, ori ginal si g ne d I C F a n d detai le d rec or ds of st u d y pr o d uct acc o u nta bilit y ). T he 
rec or ds s hall be retai ne d b y the PI as re q uire d b y l ocal le gislati o n a n d i n ter nati o nal 
g ui deli nes. A n y tra nsfer of res po nsi bilit y  f or st ora ge of t he rec or ds s hall be d oc u me nte d a n d 
the S p o ns or s hall be i nf or me d i n writi n g.
T he S p o ns or s hall verif y  t hat eac h s u bject has c o nse nte d i n writi n g t o direct access t o t he 
ori gi nal me dical rec or d/s o urce data ( b y t he use of writte n su bje ct i nf or mati o n a n d si g ne d 
i nf or me d c o nsent). T he data rec or de d i n t he e C R Fs will be c hec ke d f or c o nsiste nc y wit h t he 
s o urce d oc u me nts/ me dical rec or d by t he m o nit or d uri n g m o nit ori n g (s o urce data verificati o n;
S D V). I n or der t o be a ble t o perf or m S D V, i nf or mati o n a b o ut eac h s u bject’s partici pati o n i n 
t he st u d y has t o be detaile d i n the me dical rec or d or ot her rele va nt s o urce .
9. 5 
D oc u me nt a n d d at a rete nti o n
All rec or ds p ertai ni n g t o t he c o n d uct of t he st u d y, i ncl u di n g si g ne d e C R Fs, I CF, st u d y
pr o d uct acc o u nt a bilit y rec or ds, s o urce d oc u me nts, a n d ot her st u d y d oc u me nt ati on m ust be 
retai ne d f or 1 5 years after st u d y c o m pleti o n or l o n ger if re q uire d b y  nati o nal le gislati o n. 
S p o ns or will i nf or m t he site(s) as t o w he n t hes e d oc u me nts n o l o n ger nee ds t o be retai ne d. 
Meas ures s hall be ta ke n t o pre ve nt acci de nta l or pre mat ure destr ucti o n of t hese d oc u me nts
(e. g. pr otecti o n a gai nst da ma ge a n d u na ut h orize d access, prefera bl y b y  st ora ge i n a fire pr o of
ca bi net).
After st u d y c o m ple ti o n a n d data base l oc k, a sec urit y seale d C D wit h electr o nic st u d y  data 
s hall be pr o vi de d b y  t he e C R F ve n d or f or arc hi vi n g.
It is the PI’s res p o nsi bilit y  t o i nf or m t he S p o ns or i n writi n g if t he I n vesti gat or file is m o ve d 
or if t he res p o nsi bilit y  f or t he d oc u me nts is tra nsferre d t o s o me o ne else .
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
4 9 (5 5 )
1 0. St at istic al Met h o ds
1 0. 1
A n al ysis p o p ul at i o ns
T he f ol l o wi n g p o p ulati o ns will be defi ne d:

Sa fet y
I ncl u des all s u bjects w h o were i njecte d wit h st u d y 
pr o d uct.

M o difie d
I nte nti on- t o-
treat ( MI T T)
I ncl u des all treat me nt c o m plia nt s u bjects, i.e. s u bjects 
treate d at b ot h base li ne a n d 3 wee ks.
All effic a c y a nal yses will be base d o n t he M I T T p o p ulati o n. Safe t y a nal ys is is perf or me d 
base d o n t he safet y p o p ulati o n set.
T he dis p ositi o n o f s u bjects will be prese nte d i n ta bles a n d/ or fi gures as a p pr o priate. T he 
n u m ber of scree ned, t reate d, c o m plete d, a n d wit h dra w n s u bjects will be prese nte d , as well as 
n u m ber of s u bjects i n eac h a nal ys is p o p ulati o n set.
1 0. 2
De m o gr a p hics, b aseli ne assess me nts , an d s u bject c h ar acteristics
De m o gra p hic e n d p oi nt s a n d s u bject c haracteristics will be prese nte d b y  i n vesti gati o nal 
pr o d uct u si n g descri pti ve statistics.
1 0. 3
Ef fic ac y a n al ysis
All a nal ys es will be perf or me d b y  treat me nt gr o u p a n d i n t otal.
T he G AI S assess me nt wi ll be prese nte d i n fre q ue nc y ta bles at eac h f ol l o w-u p visit a n d f or 
eac h e val uat or separate l y ( 
/I n vesti gat or). I n a dditi o n, t he pr o p orti o n of i m pr o ve d 
s u bjects (assesse d as ver y m uc h i m pr o ve d, m uc h i m pr o ve d or i m pr o ve d) will be prese nte d 
t o get her
.
T he s u bject satisfacti o n q uesti o n naire assess ments will be prese nte d i n fre q ue nc y  ta bles at 
each a p plica ble visit. F or t he q uesti o ns w h ere t he a ns wer is gi ve n usi n g a n a gree m e nt scale 
t he n u m ber a n d perce nta ge of s u bjects a greei n g ( Defi nitel y a gree/ S o me w hat agree) t o t he 
assess me nt will als o be prese nt e d.
T he e val uati o n of nat ural ness , 
w ill be 
prese nte d i n fre q ue nc y ta bles at eac h f oll o w-u p visit a n d f or eac h e val uat or separatel y  
(  
/I n vesti gat or).
 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI
C CI
C CI
C CI
C CI
C CI

M A -4 2 2 4 8. d oc
5 0 (5 5 )
1 0. 4
S afet y a n al ysis
A d verse e ve nts will be s u m marise d i n fre q ue nc y  ta bles b y st u d y pr o d uct, c o ntai ni n g n u m ber 
of s u bjects w it h n o A Es, n u m ber of s u bjects wit h at least o ne A E, a n d n u m ber of e ve nts, 
s u b di vi de d b y relate d/ u nrelate d, seri o us/ n o n-seri o us. All A Es will be s u mmarise d a n d liste d 
b y  sys te m or ga n class ( S O C) an d preferre d ter m ( P T) assi g ne d usi n g Me d D R A. F urt her m ore, 
A Es will be s u m maris e d b y ca usalit y, a n d b ot h relate d a n d u nrelate d e ve nts will be 
s u m marise d se parately b y  ma xi m u m i nte nsit y. F or relate d A Es, i.e. A Es j u d ge d b y t he 
I n vesti gat or or S p o ns or t o be relate d t o t he st u d y pr o d uct a n d/ or st u d y pr o d uct i njecti o n 
pr oce d ure , t he n u m ber of da y s t o o nset a n d t he d urati o n of t he e ve nt will be s u m marise d b y 
P T.
1 0. 5
H a n dli n g of missi n g d at a
St u d y  data will be prese nte d base d o n o bser ve d cases, i.e. n o i m p utati o n of missi n g val ues 
will be perf or me d.
1 0. 6
I nterim a n al ysis
Si nce t hi s is a n o pe n st u d y, a vaila ble data ma y be a nalys e d pri or t o st u d y c o m pleti o n.
1 0. 7
Wit h dr a w als a n d de vi ati o ns
All wit h dra w n s u bjects will be liste d i n di v i d uall y, i ncl u di n g at least s u bject n u m ber, date a n d 
reas o n f or wit h dra wal, an d last vis it perf or me d.
S u bjec ts wit h C S P de viati o ns w ill be liste d in di vi d uall y , i ncl u di n g s u bject n u m ber a n d 
o bser ve d de viati o n.
D e viati o ns fr o m t he statistical pla n will be d oc u me nte d i n t he statistical re p ort or t he Cli nic al 
St u d y  Re p ort.
1 0. 8
S a m ple size
T he sa m ple size of a p pr o xi mately 6 0 s u bjects ( 3 0 per treat me nt gr o u p) is n ot base d o n a 
statistical calc ulati o n. T he selecte d n u m ber of s u bjects is re gar de d as s ufficie nt f or a n 
eval uati o n of effecti ve ness a n d safet y of t he t w o treat me nt a p pr oac hes w he n treati n g t he c hi n ,
N L Fs a n d M L s wit h Rest yla ne Def yn e.
1 1. Pr otecti o n of pers o n al d at a
T he st u d y s hall i ncl u de c ollecti o n a n d pr ocessi n g of pers o nal d ata as s pecifie d i n t he 
Re g ulati o n ( E U) 2 0 1 6/ 6 7 9 ( Ge neral Data Pr otecti o n Re g ulati on, G D P R) o n t he pr otecti o n of
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
C CI

M A -4 2 2 4 8. d oc
5 1 (5 5 )
i n di vi d uals wit h re gar d t o t he pr ocessi n g of pers o nal data. F or t he p ur p oses of t he st u d y, 
S p o ns or will be c o nsi dere d t he d ata co ntr ol ler, a n d I nstit uti o n a n d PI will b ot h be c o n si dere d 
d ata p r ocess ors.
All pr ocessi n g of pe rs onal d ata m ust be carrie d o ut i n acc or da nce wit h nati o nal le gislati o n 
c o ncer ni n g t he pr otecti o n of p ers o nal d ata. T he I nstit uti o n a n d t he PI  are res p o nsi ble f or 
c om p l yi n g wit h all re q uire me nts p urs ua nt t o natio nal le gislati o n i n t he c o u ntr y  i n w hic h t he 
I nstit uti o n a n d t he PI  are l ocate d. T he S p ons or will e ns ure t ha t all re q uire me nts are co m plie d 
wit h f or data pr ocessi n g.
T he I CF s hall c o ntai n i nf or mati o n a b o ut w hat p ers o nal data t o be c ollecte d i n t he st u d y a nd 
t hat t his will be ke pt c o nfi de ntial . T he pr o vi de d i nf or mati o n s hall be s uff icie nt t o ena ble all 
s u bjects to gi ve t heir c o nse n t n ot o nl y  t o t he partici pati o n i n t he st u d y, b ut als o t o t he 
pr ocessi n g of p ers o nal data. S uc h i nf or mati o n i ncl u des i nf or mati o n re gar di n g t he p ur p oses of 
t he c ollecti n g, pr o cessi n g, data tra nsfer t o c o u ntries n ot ha vi n g sa me hi g h le vel of sec urit y f or 
pr ocessi n g of pers o nal data t ha n S we de n a n d E U, a n d t he le n gt h of ti me d uri n g w hic h 
pe rso nal data will be st ore d . T he s u bject s hall ha ve t he ri g ht of access t o st ore d pers o nal d ata,
a n d t he ri g ht t o c orrecti o n of i nc orre ct i nf or mati o n. If a s u bject deci des t o ter mi nate t he st u dy 
pre mat urel y , data c ollecte d bef ore wit h dra wal of c o nse nt will be u se d i n t he e val uati o n of t he 
st u d y, h o we ver n o ne w data m a y  be c ollecte d. A ut h orize d re prese ntati ves fr o m t he S p o ns or, 
c ontract researc h or ga nizati o n ( CR O) or a C A ma y  visit t he st u d y site t o perf or m 
a u dits/i ns pecti o ns, i ncl u di n g s o urce data verificati o n, i.e. c o m pari n g data i n t he s u bjects’ 
me dic al rec or ds a n d t he e C R F. Data a n d i nf or mati o n sh all be ha n dle d strictl y  c o nfi dential.
1 2. Q u alit y C o ntr ol a n d Q u al it y A ss ur a nce
1 2. 1
Q u ali t y c ontr ol
O n -site mo nit ori n g of t he st u d y will be arra n ge d b y  t he Sp o ns or or dele g ate d part y acc or di n g 
t o G C P g ui deli nes t o verif y t hat t he ri g hts a n d well-bei n g of t he s u bj ects are pr otecte d, t he 
re p orte d data are acc urate, c o m plete, verifia ble fr o m s o urce d oc u me nts, a n d t hat t he c o n d uct 
of t he st u d y c o m plies wit h t he a p pr o ve d C S P , s u bseq ue nt a me n d me nt(s), G C P a n d t he 
a p plica ble re g ulat or y re q uire me nts.
A n y  C S P de viati o n s hall be d oc u me nte d a p pr o priatel y , verifie d, disc usse d , a n d c ollecte d by 
t he m o nit or a n d ap pr o priate acti o ns will be ta ke n . T he PI is res p o nsi ble f or pr o m ptl y  
re p orti ng a n y  de viati o ns fr o m t he C S P t hat affects t he ri g hts, safet y or well -bei n g of t he 
s u bject or t he scie ntific i nte grity of t h e st u d y, i ncl u di n g t h ose t hat occ ur u n der e mer ge nc y 
circ u msta nces, t o t he S p o ns or as well as t he I E C if re q uire d by nati o nal re g ulati o n s.
De viati o ns will be re vie we d t o deter mi n e t he nee d t o a me n d t he C S P or t o ter mi nate t he 
st u d y.
1 2. 2
Q u alit y ass ur a nce
T he st u d y  site m a y  be s u bject t o q ualit y ass ura nce a u dit b y  t he S p o ns or as well as i ns pecti o n 
b y  a p pr o priate C A . It is i m p orta nt t hat t he PI an d ot her rele va nt st u d y  site pers o n nel are 
a vaila ble d uri n g t he m o nit ori n g visits, p ossi b le a u dits, a n d i ns pecti o ns, a n d t hat s ufficie nt 
ti me is de v ote d t o t he m o nit ori n g pr ocess.
Eac h partici pati n g me m ber of t he st u d y site tea m s hall pr o vi de a c urric ul u m vitae ( C V) or 
e q ui vale nt t hat de m o nstrate s t heir q ualificati o ns t o c o n d uct t he st u d y. T he C V s hall gi ve 
na me, a d dress a n d place o f w or k, a n d s hall s h o w t he trai ni n g, a p p oint me n ts a n d, f or t he PI, 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
5 2 (5 5 )
a n y ot her i nf or mati o n t hat will c o nfir m t he s uita bilit y of the PI t o be res p o nsi ble f or t he 
st u d y.
It is t he res p o nsi bilit y of t he PI t o e ns ure t hat all pers o n nel i n v ol ve d i n t he st u d y  are f ully 
i nf or me d of all rele va nt as pects of t he st u d y, i ncl u di n g detaile d k n o wle d ge of a n d trai ni n g i n 
all pr oce d ures t o be f oll owe d. All I n vesti gat ors a n d ot her res p o nsi ble pers o ns s hall be liste d 
t o get her wit h t heir f u ncti o n i n t he st u d y o n t he si gnat ure a n d dele gati o n l o g.
1 2. 3
C h a n ges t o t he cli nic al st u dy pr ot oc ol
1 2. 3. 1 
A me n d me nts
T he PI  a n d ot her site pers o n nel i n v ol ve d i n t he st u d y m ust n ot i m ple me nt a n y c ha n ges t o t he 
C S P wi t h o ut a gree me nt wit h t he S p o ns or a n d pri or re view a n d d oc u me nte d a p pr o val fr o m 
the I E C a n d C A , if a p plica ble, exce pt w here necessa r y t o eli mi nate a n i m me diate hazar d t o 
t he s u bjects. All c ha n ges t o t he fi nal C S P mus t be d oc u me nte d i n a date d a n d versi o n 
c ontr olle d writte n pr ot oc ol a me n d me nt. F or n o n -s u bsta ntial c ha n ges n ot affecti n g the ri g ht s, 
safety a n d well -bei n g of t he s u bjects o r n ot relate d t o t he cli nical o bjecti ves or e n d p oi nts, a 
si m ple n otificati o n t o t he IE C a n d C A , if a p plica ble, ca n be s ufficient.
1 2. 3. 2 
De viati o ns
T he PI  is n ot all o we d t o de viate fr o m t he C S P. H o we ver, u n der e mer ge nc y circ u msta nces, 
de viati o ns fr o m t he C S P t o pr ote ct t he ri g hts, safet y a n d well-bei n g of t he s u bjects ma y  
pr ocee d wit h o ut pri or a p pr o val of t he S p o ns or a n d t he I E C a n d C A . S uc h de viati o ns s h o ul d 
be d oc u me nte d a n d re p or te d t o t he I E C a n d C A as s o o n as p ossi bl e. A n y C S P de viati o n s hall 
be re p orte d i n t he de viati o n l o g, w hic h will be verifie d, disc usse d, a n d c ollecte d b y  t he 
m o nit or a nd a p pr o priate acti o ns will be ta ke n. De vi ati o ns will be re vie we d t o deter mi ne t he 
nee d t o a me n d t he C S P or t o ter mi nate t he st u d y . Ha n dli n g of C S P de viati o ns will be 
perf o r me d as descri be d i n t he m o nit ori n g ma n ual. T he PI  is res p o nsi ble f or pr o m ptl y 
re p orti n g a ny de viati o ns fr o m t he C S P t hat affe cts t he ri g hts, safet y or well -bei n g of t he 
s u bject or t he scie ntific i nte grit y of t he s t u d y, i ncl u di n g t h ose whic h occ ur u n der e mer ge n c y 
circ u msta nces, t o t he S p o ns or ( wit hi n 2 4 hrs f oll o wi n g detecti o n) as well a s t he IE C if 
re q uire d.
1 3. Fi n a nci n g, In de m nifi c ati o n, a n d Ins ur a nce
T he C T A o utli nes t he c o m pe nsati o n a n d pa y me nt ter ms of t he st u d y. T he C T A m ust be 
si g ne d bef ore t he first s ubject is scree ne d i n t he st u d y. If t here are differe nces bet wee n t he 
C T A a n d t he C S P re gar di n g certai n ri g hts a n d o bli gati o ns, t he C T A is t he pre vaili n g 
d oc u me nt. Q- Me d
A B ’s o bli gati o ns i n t his cli nical st u d y are co vere d b y Gal der ma’s gl o bal 
ge neral lia bil it y pr o gra m. An i ns ura nce certificate will be pr o vi de d u p o n re q uest. T he 
I nstit uti on/ PI is o bli gate d t o mai ntai n i ns ura nce c o vera ge f or t heir o bli gati o ns i n t he cli nical 
st u dy acc or di n g t o t he C T A.
1 4. P u blic at i o n P oli c y
T he PI ’s, I nstit uti on’s , a n d Q-Me d
A B ’s o bli gati o ns re gar di n g i ntellect ual pr o perty r i ghts,
c o nfi de ntialit y, a n d p u blicati o n s are descri be d i n detail i n t he C T A.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
5 3 (5 5 )
T he ai m is t o s u b mit t he res ults of t his st u d y  f or p u blicati o n i n t he p u blic data base 
Cli ni cal Trials. g o v a n d t o a me dical j o ur nal f or a first j oi nt p u blicati o n of t he res ults. 
E ver y o ne w h o is t o be liste d as a n a uth o r of t he res ults of t h is m ulti ce nter st u d y s hall ha ve 
ma de a s u bsta ntial, direct, i ntellect ual c o ntri b uti o n t o t he w or k. A u t h ors hi p will be base d o n 
( 1) su bsta ntial c o ntri b uti o ns t o t he c o nce pti o n or desi g n of t he w or k; or t he ac q uisiti o n, 
a nal ys is, or i nterpretati o n of data f or t he w or k; a n d ( 2) drafti n g t he w or k or re visi n g it 
criticall y f or im p orta nt i ntellect ual c o nte nt; a n d ( 3 ) fi nal a p pr o val of t he versi o n t o be 
p u blis h e d; an d ( 4) a gree me nt t o be acc o u nta ble f or all as pects of t he w or k i n e ns uri n g t ha t 
q uesti o ns relate d t o t he acc urac y  or i ntegrit y of a n y part of t he w or k are a p pr o priatel y 
i n vesti gate d a n d res ol ve d§ §. C o n diti o ns 1, 2, 3, a n d 4 m ust all be met i n or der t o be 
de si g nate d as a ut h or. T h ose w h o d o n ot meet all f o ur criteria will be ac k n o wle d ge d. A m o n g 
t he a ut h ors t hat f ulfil t he a b o ve me nti o ne d criteria, o ne a ut h or will be a p p oi nte d b y  
Q- Me d
A B t o ta ke pri mar y res p o nsi bilit y f or t he o verall w o r k as pri mar y a ut h or.
1 5. S u s pe nsi o n or Pre m at ure Te r mi n ati o n
T he S p o ns or will s us pe n d or ter mi nate t he stu d y w he n s o i nstr ucte d b y t he IE C or C A , or if it 
is j u d ge d t hat t he s u bjects are s u bjecte d t o u nreas o na ble ris ks, or f or v ali d scie ntific or 
a d mi nistrati ve reas o ns , or f or b usi n ess reas o ns .
T he S p o ns or m a y  als o deci de t o cl ose a si n gle st u d y site d ue t o u nsatisfact or y s u bject 
e nr ol me nt or n o n-c o m plia nce wit h t he C S P , G C P, or a p plica ble re g ulat o r y re q uire me nts.
I n t he e ve nt of pre mat u re ter mi nati o n, Q-Me d
A B will pr o vi de i nf o r mati o n o n t he ha n dli n g 
of c urre ntl y  e nr olle d s u bjects w h o ha ve n ot c o m plete d t he st ud y .
1 6. S u m m ar y of C h a n ges
Secti o n i n t he cli nic al
st u d y pr ot oc ol
R ati o n al f or c h a n ges
Descri pti o n of c h a n ges
T hr o u g h o ut t he
pr ot oc ol
A d mi nistrati ve a n d e dit orial
cha n ges
C orrecti o n of s pelli n g mista kes
an d c ha n ge of a d dress t o
in vesti gati o nal site
8. 1 .1
Defi niti o n of a n 
a d verse e ve nt
M D R article
2( 5 7)
T h e defi niti o n of a n a d verse 
e ve nt has bee n u p date d
acc or di n g t o
M D R article 
2( 5 7)
8. 1. 2
Defi niti o n of a 
seri o us a d verse e ve nt
M D R article 2( 5 8)
T h e defi niti o n of a seri o us
a d verse e ve nt h as b ee n u p date d
acc or di n g t o
M D R article 
2( 5 8)
                                                
§ § Defi ni n g t he r ole of a ut h ors a n d c o ntri b ut ors, c o m pile d b y t he I nter nati o nal C o m mittee of Me d ical J o ur nal 
E dit ors (I C MJ E) ( htt p:// w w w.ic mje. or g).
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
5 4 (5 5 )
Secti o n i n t he cli nic al
st u d y pr ot oc ol
R ati o n al f or c h a n ges
Descri pti o n of c h a n ges
8. 1. 3. 2 Ca us al 
relati o ns hi p a n d 
seri o us ness
M D R article 2( 5 8)
T h e defi niti o n of a seri o us
a d verse e ve nt has b ee n u p date d
acc or di n g t o
M D R article 
2( 5 8) to i ncl u de f o ur differe nt 
le vels of ca usalit y
A p pe n di x 3
I nstr ucti o ns f or Use 
I n c orrect I F U i n versi o n 1. 0 of
the C S P
N O T E: T he i nc orrect I F U was
re place d i n a n i nter me diate
versi o n of t he C S P bet wee n
versi o n 1. 0 a n d 2. 0. T his
i nter me diate C S P versi o n has
bee n use d f or all s u b missi o ns
to E Cs a n d C As. T he I F U ca n
be re place d wit h o ut c ha n gi n g
the C S P versi o n as state d i n
A p pe n di x 3 ( pa ge 1), t he
cha n ge w as t heref ore n ot
co nsi dere d t o re q uire a C S P
versi o n u p date.
I nstr ucti o ns f or Use –
Restyl a ne Defy ne ( Versi o n 4. 0,  
Effective d ate: 2 0 1 9 - 1 2-0 9)
w as re place d b y:
I nstr ucti o ns f or Use –
Restyl a ne Defy ne ( Versi o n 3. 0, 
Effec tive d ate: 2 0 1 5-1 2- 1 5)
A p pe n di x 4
Gl o bal Aest hetic 
I m pr o ve me nt Scale 
( G AI S)
I n c orrect G AI S ta bl e a n d
instr ucti o n
A p pe n di x 4 was u p date d t o
m atc h secti o n 7. 3 i n t he C S P
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

M A -4 2 2 4 8. d oc
5 5 (5 5 )
1 7. R efere nces
1. 
M o n heit G D, C ole ma n K M. H yal ur o nic aci d fillers. Der mat ol 2 0 0 6 Ma y -J u n; 1 9 ( 3): 1 4 1-5 0.
2. 
G ol d M. T he scie nce a n d art of h yal ur o nic aci d der m al filler use i n est hetic a p plicati o ns. J C os met Der mat ol 2 0 0 9 
Dec; 8( 4): 3 0 1 -7.
3. 
P o ns -G uira u d A. Classi ficati o n des pr o d uits de c o m ble me nt dis p o nsi ble e n Fra nce. A n n Der mat ol Ve ner ol 
2 0 0 8; 1 3 5: I S 2 7 - 3 4.
4. 
Asc her B et al. C ha pter 3 4: H yal ur o nic aci ds. I n: Asc he r B e d. I njecti o n T reat me nt i n C os metic S ur ger y. I nf or ma 
U K Lt d. 2 0 0 9.
5. 
Asc her B, Ba yerl C, Br u n P, Kes tem o nt P, Rza n y B, P o ncet M, et al. Efficac y a n d safet y of  a ne w h yal ur o nic aci d 
der mal filler i n t he treat me nt of se vere n as ola bial li nes - 6-m o nt h i nter i m res ults of a ra nd o miz e d, e val uat or- bli n de d, 
i ntra-i n di vi d ual c o m paris o n st u d y. J C os met Der mat ol. 20 1 1 J u n; 1 0( 2): 9 4 – 8.
6. 
Rza n y B, Ba yerl C, B o d o k h I, B oi nea u D, Dirsc h ka T, Q ueille -R o ussel C , et al. Efficac y a n d safet y of a ne w 
h yal ur o nic aci d der mal filler i n t he treat me nt of m o derate nas ola bial f ol ds: 6- m o nt h i nteri m res ults of a ra n d o mize d, 
e val uat or- b lin de d, i ntra -i n di vi d ual c o m paris o n st u d y. J C os met Laser T her. 2 0 1 1 J u n; 1 3( 3): 1 0 7– 1 2.
7. 
Ca rtier H et al. Peri oral rej u ve natio n wit h a ra n ge of c ust o mize d h yal ur o nic aci d fillers: efficac y a n d safet y o ver si x 
m o nt hs wit h a s pecific f oc us o n t he li ps. J Dr u gs Der mat ol 2 0 1 2; 1 1( 1)(s u p pl): 1 7- 2 6.
8. 
Keste m o nt, P et al. S ustai ne d efficac y a n d hi g h patie nt satisfacti o n after c hee k e n ha nce me nt wit h a ne w h y al ur o nic 
aci d der mal filler. J Dr u gs D er mat ol 2 0 1 2. 1 1, s 9 - 1 6.
9. 
Rza n y, B., et al. F ull -face rej u ve nati o n usi n g a ra n ge o f h y al ur o nic aci d fillers: efficac y, safet y, a n d patie nt 
satisfacti o n o ver 6 m o nt hs. Der mat ol. S ur g 2 0 1 2a. 3 8, 1 1 5 3 - 1 1 6 1.
1 0. 
Se g ura S et al. A c o m plete ra nge of h yal ur o nic aci d filler wit h disti ncti ve p h ysical pr o perties s pecificall y desi g ne d 
f or o pti mal tissue a da ptati o ns. J Dr u gs Der mat ol 2 0 1 2; 1 1( 1)(s u p pl): 5 -8.
1 1. 
Nari ns R S, Bra n dt F, Le y de n J, L o re nc Z P, R u bi n M, S mit h S. A ra nd o mize d, d o u ble -bli n d, m ultice n ter c o m paris o n 
of the efficac y a n d t olera bilit y of Rest yla ne vers us Z y plast f or t he c orrecti o n of nas o labial f ol ds. Der mat ol S ur g 
2 9; 6: 2 0 0 3.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

1( 5)
A p pe n di x 1 
Decl ar ati o n of Helsi n ki
W M A Decl ar ati o n of
H elsi n ki - Et hic al Pri nci ples f or Me dic al
Rese arc h I n v ol vi n g 
H u m a n S u bjects
A d o pte d b y t he 1 8t h W M A Ge neral Asse m bl y, Helsi n ki, Fi nla n d, J u ne 1 9 6 4
a n d a me n de d b y t he:
2 9t h W M A Ge neral Asse m bl y, T o k y o, Ja pa n, Oct o ber 1 9 7 5
3 5t h W M A Ge neral Asse m bl y, Ve nice, Ital y, Oct o ber 1 9 8 3
4 1st W M A Ge ne ral Assem bl y, H o n g K o n g, Se pte m ber 1 9 8 9
4 8t h W M A G e nera l Asse m bl y, S o merset West, Re p u blic of S o ut h Africa, Oct o ber 1 9 9 6
5 2 n d W M A Ge n eral Asse m bl y, E di n b ur g h, Sc otla n d, Oct o ber 2 0 0 0
5 3r d W M A Ge neral Asse m bl y, Was hi n gt o n D C, U S A, Oct o ber 2 0 0 2 ( N ote of Clar ificati on a d de d)
5 5t h W M A Ge ner al Asse m bl y, T o k y o, Ja pan, Oct o ber 2 0 0 4 ( N ote of Clarificati o n a d de d)
5 9t h W M A Ge neral Asse m bl y, Se o ul , Re p u blic of K orea, Oct o ber 2 0 0 8
6 4t h W M A Ge neral Asse m bl y, F ortaleza, Brazil, Oct o ber 2 0 1 3
Pre a m ble
1. T he W orl d Me dical Ass ocia ti o n ( W M A) has de vel o ped t he Declarati o n o f Helsi n ki as a state me nt of et hical 
pri nci ples f or me dical researc h i n v ol vi n g h u ma n s u bjects, i ncl u di n g researc h o n i de ntifia ble h u ma n material 
a n d data.
T he Declarat i on is i nte n de d t o be rea d as a w h ole a n d eac h of its c o nstit ue nt para gra p hs s h o ul d be a p plie d 
wit h c o nsi derati o n of all ot her rele va nt para gra p hs.
2. C o nsiste nt wit h the ma n date of t he W M A, t he Declarati o n is a d dresse d pri maril y t o p h ysicia ns. T he W M A 
e nc o ura ges ot hers w h o are i n v ol ve d i n me dica l researc h i n v ol vi n g h uma n s u bjects t o a d o pt t h ese pri nci ples.
Ge ner al Pri nci ples
3. T he Declarati o n of Ge ne va of t he W M A b i nds t he p h ysicia n wit h t he w or ds, “ T he healt h of m y patie nt will 
be m y first c o nsi derati o n ,” a n d t he I nter nati o nal C o de of Me dical
Et hics declares t hat, “ A p h ysicia n s hall act 
in t he patie nt's best i nterest w he n pr o vi di n g me dical care.”
4. It is t he d ut y o f t he p h ysicia n t o pr o m ote a n d safe g uar d t he healt h, well-bei n g a n d ri g hts of patie nts,
incl u di n g t h ose w h o are i n v ol ve d i n me dical researc h. T he p h ysicia n's k n o wle d ge a n d c o nscie nce are 
de dicate d t o t he f ulfil me nt of t his d ut y.
5. Me dical pr o gress is b ase d o n researc h t hat ulti matel y m ust i ncl u de st u dies i n v ol vi n g h u ma n s u bjects.
6. T he p rimar y p ur p ose of me dical researc h i n v ol vin g h u ma n s u bjects is t o u n dersta n d t he ca u ses, de vel o p me nt 
a n d effects of diseases a n d i m pr o ve pre ve nti ve, dia g n ostic a n d t he rape utic i nter ve nti o ns ( met h o ds, 
pr oce d ures a n d treat me nts). E ve n t he best pr o ve n i nter ve nt i o ns m ust be e val uate d c o nti n uall y t hr o ug h 
researc h f or t heir safet y, effecti ve nes s, efficie nc y, accessi bilit y a n d q ualit y.
7. Me dical researc h is s u bject t o et hica l sta n dar ds t hat pr o m ote a n d e ns ure res pect f or all h u ma n s u bjects a n d 
pr otect t heir heal t h a n d ri g hts.
8. W hile t he pri ma r y p ur p ose of me dical researc h is t o ge nerate ne w k n o wle d ge, t his g oal ca n ne ver ta ke 
prece de nce o ver t he ri g hts a n d i nterests of i n d i vi d ual researc h s u bjects.
9.
It is t he d ut y of p h ysicia ns w h o are i n v ol ve d i n me dical researc h t o pr otect t he life, healt h, di g nit y, i nte grit y, 
ri g ht to self -deter mi nati o n, pr i vac y, a n d c o nfi de ntialit y of pers o nal i nf or mati o n of researc h s u bjects. T he 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

2( 5)
resp o nsi bilit y f or t he pr otecti o n of researc h s u bjects m ust al wa ys rest wit h t he p h ysicia n o r ot her healt h care 
pr ofessi o nal s a n d never wit h t he researc h s u bjects, e ve n t h o u g h t he y ha ve gi ve n c o nse nt.
1 0. P h y sicia ns m ust c o nsi der t he et hical, le gal a n d re g ulat or y n or ms a n d sta n dar ds f or researc h i n v ol vi n g h u ma n 
s u bjects i n t heir o w n c o u ntries as we ll as a p plica ble i nter nati o nal n or ms a n d sta n dar ds. N o nati o n al or 
i nter nati o nal et hical, le gal or re g ulat or y re q uire me nt s h o ul d re d uce or eli mi nate a n y of t he pr o tecti o ns f or 
researc h s u bjects set f ort h i n t his Declarati o n.
1 1. Me dical researc h s h o ul d
b e c o n d ucte d i n a ma n ner t hat mi ni mises possi ble har m t o t he e n v ir o n me nt.
1 2. Me dic al researc h i n v ol vi n g h u ma n s u bjects m ust be c o n d ucte d o nl y b y i n di vi d uals wit h t he ap pr o priate 
et hics a n d scie ntific e d ucati o n, trai ni n g a n d q ualificati o ns. Researc h o n pa tie nts or healt h y v ol u nteers 
re q uires t he s u per visi o n of a c o m pete nt a n d a p pr o priate l y q ualifie d p h ysicia n or ot her healt h care 
pr ofessi o nal.
1 3. Gr o u ps t hat are u n der represe nte d i n me dical researc h s h o ul d be pr o vi de d a p pr o priate access t o partici pati o n 
i n researc h.
1 4. P h y sicia ns w h o c o m bi ne me dical researc h wit h me dic al care s h o ul d i n v o l ve their patie nts i n researc h o nl y t o 
t he e xte nt t hat t his is j ustifie d b y its p ote ntial pre ve nti ve, dia g n ostic or t hera pe utic val ue a n d if t he p h ysicia n 
has g o o d reas o n t o belie ve t hat partici pati o n i n t h e researc h st u d y will n ot a d ver sel y affect t he healt h of t he 
patie nts w h o ser ve as researc h s u bjects.
1 5. A p pr o priate c o m pe nsati o n a n d treat me nt f or s u bjects w h o are har me d as a res ult of partici pati n g i n researc h 
m ust be e n s ure d.
Ris ks, B ur de ns a n d Be nefi ts
1 6. I n me dical practice a nd i n m e dical resear c h, most i nter ve nti o ns i n v ol ve ris ks a n d b ur de ns.
Me dical researc h i n v ol vi n g h u ma n s ubjects ma y o nl y be c o n d ucte d if t he i m p orta nce of t he o bjecti ve 
o ut wei g hs t he ris ks a n d b ur de ns t o t he researc h s u bjects.
1 7. All me dical researc h i n v ol vi n g h u ma n s u bjects m u st be prece de d b y caref ul assess me nt of pre dicta ble ris ks 
a n d b ur de ns t o t he i n d i vi d uals a n d gr o u ps i n v ol ve d i n t he researc h i n c o m paris o n wit h f oreseea ble be nefits 
t o the m a n d t o ot her i n di vi d uals or gr o u ps aff ecte d b y t he c o n diti o n u n der i n vesti gati o n .
Meas ures t o mi ni mise t he ris ks m ust be i m ple me nte d. T he ris ks m ust be c o nti n u o usl y m o nit ore d, assesse d 
a n d d oc u me nte d b y t he researc her.
1 8. P h y sicia ns ma y n ot be i nv ol ve d i n a researc h st u d y i n v ol vi n g h u m a n s u bjects u nless t he y are c o nfi de nt t hat
t he ris ks ha ve bee n a de q uatel y assesse d a n d ca n be satisfact oril y ma na ge d.
W he n t he ris ks are f o u n d t o o ut w ei g h t he p ote ntial be nefits or w he n t here is c o ncl usi ve pr o o f of defi niti ve 
o utc o mes, p h ysic ia ns m ust assess w het her t o c o nti n ue, m o dif y or i mme dia tel y st o p t he st u d y.
V ul ner a ble Gr o u ps a n d I n di vi d u als
1 9. S o me gr o u p s a n d i n di vi d uals are partic ularl y v ul nera ble a n d ma y ha ve a n i ncrease d li keli h o o d of b ein g 
wr o n ge d or of i nc urri n g a d diti o nal ha r m.
All v ul nera ble gr o u ps a n d i n di vi d uals s h o uld recei ve s pecificall y c o nsi dere d pr otecti o n.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9

3( 5)
2 0. Me dical researc h wit h a v ul n era ble gr o u p is o nl y j ustifie d if t he researc h is res p o nsi ve t o t he healt h nee ds or 
pri or ities of t his gr o u p a n d t he researc h ca n n o t be carrie d o ut i n a no n -v ul nera ble gr o u p . I n a d diti o n, t his 
gr o u p s h o ul d sta n d t o be nefit fr o m t he k n o wle d ge, practices or i nter ve nti o ns t hat res ult fr o m t he researc h.
Scie ntific Re q uire me nts a n d Rese arc h Pr ot oc o ls
2 1. Me dical researc h i n v ol vi n g
h u ma n s u bjects m ust c o nf or m t o ge nerall y acce pte d scientific pri nci ples, be 
base d o n a t h or o u g h k n o wle d ge of t he scie ntific literat u re, ot her rele va nt s o urces of i nf or mati o n, a n d 
a de q uate la b orat or y a n d, as a p pr o priate, a ni mal e x peri me ntati o n. T he w elfare of a ni m als use d f or researc h 
m ust be res pecte d.
2 2. T h e desi g n a n d perf or ma nce of eac h researc h st u d y i n v ol vi n g h u ma n s u bjects m ust be clearl y descri be d a n d 
j ustifie d i n a researc h pr ot oc ol.
T he pr ot oc ol s h o ul d c o nta i n a state me nt of t he et hical c o ns i derati o ns i n v ol ve d a n d s h o ul d i n dicate h o w t he 
pr i nci ples i n t his Declarati o n ha ve bee n a d dresse d. T he pr ot oc ol s h o ul d i ncl u de i nf orma ti o n re gar di n g 
f u n di n g, s p o ns ors, i nstit uti o nal affiliati o ns, p ote ntial c o nflicts of i nterest, i nce nti ves f or s u bjects a nd 
i nf or mati o n re gar di n g pr o visi o ns f or treati n g a n d/ or c o m pe nsati n g s u bjects w h o are har me d as a 
c o nse q ue nce of partici pati o n i n t he researc h st u d y.
I n cli nical trials, t he pr ot oc ol m ust als o descri be a p pr o priate arran g e me nts f or p ost -trial pr o visi o ns.
Rese ar c h Et hics C o m mittees
2 3 . T he researc h pr ot oc ol m ust be s u b mitte d f or c o nsi derati o n, c o m me nt, g ui da nce a n d a p pr o val t o t he 
c o ncer ne d researc h et hics c o m mittee bef ore t he st u d y be gi ns. T his c o m mittee m ust be tra ns pare nt i n its 
f u ncti o ni n g, m ust be i nde pe n de n t of t he researc her, t he s p o ns or a n d a n y o t her u n d ue i nfl ue nce a n d m ust be 
d ul y q ualifie d. It m ust ta ke i nt o c o nsi derati o n t h e la ws a n d re g ulati o ns of t he c o u ntr y or c o u ntries i n w hic h 
t he researc h is t o be perf or me d as well as a p plica ble i nter nati o nal n or ms a n d sta n dar ds b ut t h ese m ust n ot be 
allo w e d t o re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h s u bjects set f ort h i n t his Declarati o n.
T he c o m mittee m ust ha ve t he ri g ht t o m o nit or o n g oi n g st u dies. T he researc her m ust pr o vi de m o nit ori n g 
i nf or mati o n t o t he c o m mittee, es peciall y i nfor m ati o n a b o ut a n y seri o us A E s. N o a me n d me nt t o t he pr ot oc ol 
ma y be ma de w it h o ut c ons i derati o n a n d a p pr o val b y t he c o m mittee. After t he e n d of t he st u d y, t he 
researc hers m ust s u b mit a fi nal re p ort t o t he c om mittee c o ntai ni n g a s u m mar y of t he st u d y’s fi n di n gs a n d 
c o ncl usi o ns.
Pri v ac y a n d C o nfi de nti alit y
2 4. E ver y preca uti o n m ust be ta ke n t o pr otect t he pri vac y of researc h s u bjects a n d t he c o nfi de ntialit y of t heir 
pers o nal i nf or m ati o n.
I nf or me d C o nse nt
2 5. Partici p ati o n b y i n di vi d uals ca pa ble of gi vi n g i nf or m e d c o nse nt as s u bjects i n me dical researc h m ust be 
v ol u ntar y. Alt h o u g h it ma y be ap pr o priate t o c o ns ult fa mil y me m bers or c o m m u nit y lea ders, n o i n di vi d ual 
ca pa ble of gi vi ng i nf or me d c o nse nt ma y be e nr oll e d i n a researc h st u d y u nless he or s he freel y a gr ees.
2 6. I n me dical researc h i n v ol vi n g h u ma n s u bjects ca pa ble of gi vi n g i nf or me d c ons e nt, eac h p ote ntial s u bject 
m ust be a de q uatel y i nf or me d of t he ai ms, met h o ds, s o urces o f f u n di n g, a n y p ossi ble c o nflicts of i nter est, 
i nstit uti o nal affiliati o ns of t he researc her, t he a ntici pate d be nefits a n d p ote ntial ris ks of t he st u d y a n d t he 
disc o mf o rt it ma y e ntail, p ost-st u d y pr o visi o ns a n d a n y ot her rele va nt as pects of t he st u d y. T he p o te ntial 
s u bject m ust be i nf or me d of t he ri g ht t o ref use t o partici pate i n t he st u dy or t o wit h dra w c o nse nt t o 
partici pate at a n y ti me wit h o ut re prisal. S pecial atte n tio n s h o ul d be gi ve n t o t he s pecific i nf or mati o n nee ds of 
i n di vi d ual p ote ntial s u bjects as we ll as t o t he met h o ds use d t o deli ver the i nf or mati o n.
Title  
D o c i d  
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M A- 4 2 2 4 8
 
 
 
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A fter e ns uri n g t hat t he pote ntial s u bject has u n derst o o d t he i nf or mati o n, t he p h ysicia n or a n ot her 
a p pro p riatel y q ualifie d i n di vi d ual m ust t he n see k t he p ote ntial s u bject’s freel y-gi ve n i nf or m e d c o nse nt, 
prefera bl y i n writi n g. If t he c o nse nt ca n n ot be e x pre sse d i n writi n g, t he n o n -writte n c o nse nt m ust be f or mall y 
d oc u me nte d a n d wit nesse d.
All me d ical researc h s u bjects s h o ul d be gi ve n t he o pti o n of bei n g i nf or me d a b o ut t he ge neral o ut c o me a n d 
res ults of t he st u d y.
2 7. W he n se e ki n g i nf or me d c o nse nt f or partici pati o n in a r esearc h st u d y t he p h ysicia n m ust be partic ularl y 
ca uti o us if t he p ote ntial s u b j ect is i n a de pe n de nt relati o ns hi p wit h t he p h ysicia n or ma y c o nse nt u n der 
d uress. I n s u c h sit uati o ns t he i nf or me d c o nse nt m ust be s o u g ht b y a n a p pr o priatel y q ualifie d i n divi d ua l w h o 
is c o m pletel y i n de pe n de nt of t his relati o ns hi p.
2 8. F or a p ote ntial rese arc h s u bject w h o is i nca pa ble of gi vi n g i nf or me d c o nse nt, t he p h ysicia n m ust see k 
i nf or med c o nse nt fr o m t he le gall y a ut h ori se d re prese ntati ve. T hese i n di v i d uals m ust n ot be i ncl ude d i n a 
researc h st u d y t hat has n o li keli h o o d of be nefit f or t he m u nless it is i nte n de d t o pr o m ote t he healt h of t he 
gr o u p re prese nte d b y t he p ote ntial s u bject, t he r esearc h ca n n ot i nstea d be perf or me d wit h p ers o ns ca pa ble of 
pr o vi di n g i nf or me d c o nse nt, a n d t he researc h e ntails o nl y mi ni mal ris k a n d mi ni mal b ur de n.
2 9. W he n a p ote n tial researc h s u bject w h o is dee me d i nca pa ble of gi vi n g i nf or me d c o nse nt is a ble t o gi ve as se nt 
t o decisi o ns a b o ut partici pati o n i n researc h, t he p h ysician m ust see k t hat as se nt i n a d diti o n t o t he c o nse nt of 
t he le gall y a ut h orise d re prese ntati ve. T he p ote ntial s u bject’s disse nt s h o ul d be res pecte d.
3 0. Researc h i n v ol vi n g s u bjects w h o are p h ysi call y or me ntall y i nca pa ble of gi vi n g c o nse nt, f or e xa m ple, 
u nc o n sci o us patie nts, may be d o ne o nl y if t he p h ysical or me ntal c o n diti o n t hat pre ve nts gi vi n g i nf or me d 
c o ns e nt is a necessar y c haracteristic of t he researc h gr o u p. I n s uc h circ u msta nces t he p h y sicia n m ust see k 
i nf or me d c o nse nt fr o m t he le gall y a ut h orise d re prese ntati ve. If n o s uc h re prese ntati ve is a vaila ble a n d if t he 
researc h ca n n ot be dela ye d, t he st u d y ma y pr ocee d w it h o ut i nf or me d c o nse nt pr o vi de d t hat t he s pecific 
reas o ns f or i n v ol vi n g s u bjects wit h a c o n diti o n t hat re n ders t he m u na ble t o gi ve i nf or me d c o nse nt ha ve bee n 
state d i n t he researc h pr ot oc ol a n d t he st u d y has bee n a p pr o ve d b y a researc h et hics c o m mi ttee. C o nse nt t o 
r e mai n i n t he researc h m ust be o btai ne d as s o o n as p ossi ble fr o m t h e s u bject or a le gall y a ut h orise d 
re prese ntati ve.
3 1. T he p h ysici a n m ust f ull y i nf or m t he patie nt w hic h as pects of t heir care are relate d t o t he researc h. T he 
ref usal of a patie nt t o partici pate i n a st u d y or t he patie nt’s decisi o n t o wit h dra w fr o m t he st ud y m ust ne ver 
a d versel y affect t he patie nt -p h ysicia n relati o ns hi p .
3 2. F or me dical r esear c h usi n g i de ntifia ble h u ma n material or data, s uc h as researc h o n material or da ta 
c o ntai ne d i n bi o ba n ks or si milar re p osit ories, p h ysicia ns m ust see k i nf or me d c o nse nt for its c ollecti o n, 
st ora ge a n d/ or re use. T here ma y be e xce pti o n al sit uati o ns w here c o nse nt w o ul d be i m p ossi ble or 
i mpractica ble t o o btai n f or s uc h researc h. I n s uc h sit uati o ns t he researc h ma y be d o ne o nl y after 
c o nsi derati o n a n d a p pr o val of a researc h e t hics c o m mittee.
Use of Pl ace b o
3 3 . T he be nefits, ris ks, b ur de ns a n d effecti ve ness o f a ne w i nter ve nti o n m ust be teste d a gai nst t h ose of t he best 
pr o ve n i nter ve nti o n(s ), e xce pt i n t he f oll o wi n g circ u msta nces:
W here n o pr o ve n i nter ve nti o n e xists, t he us e of place b o, or n o i nter ve nti o n , is acce pta ble; or
W here
f or c o m pelli n g a n d scientificall y s o u n d met h o d ol o gical reas o ns t he use of a n y i nter ve nti o n less 
effec tive t ha n t he best pr o ve n o ne, t he use of place b o, or n o i nter ve nti o n is necessar y t o det er mi ne t he 
efficac y or safet y of a n i nter v e nti o n
a n d t he p atie nts w h o recei ve a n y i nter ve nti o n less effecti ve t ha n t he best pr o ve n o ne, place b o, or n o 
i nter ve nti on will n ot be s u bject t o a d diti o nal ris ks of seri o us or irre versi ble har m as a res ult o f n ot recei vi n g 
t he best pr o ve n i nter ve ntio n.
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E xtre me care m ust be ta ke n t o a v oi d a b use of t his o pti o n.
P ost -Tri al Pr o visi o ns
3 4. I n a d va nce of a cli nical trial, s p o ns ors, researc hers a n d h ost c o u ntr y g o ver n me nts s h o ul d ma ke pr o visi o ns 
f or p ost-trial access f or all partici pa nts w h o still nee d a n i nter ve nti o n i de ntifie d as be neficia l i n t he trial. T his 
i nf or mati o n m ust als o be discl ose d t o partici pa nts d uri n g t he i nf or me d c o nse nt pr ocess.
Rese arc h Re gistr ati o n a n d P u blic ati o n a n d Disse mi n ati o n of Res u lts
3 5. E ver y researc h st u d y i n v ol vi n g h u m a n s u bjects m ust be re g istere d i n a p u blicl y accessi ble data base bef ore 
recr uit me nt of t he first s u bject.
3 6. Researc hers, a u t hors, s p o ns ors, e dit ors a n d p u blis hers all ha ve et hical o bli gati o ns wit h re gar d t o t he 
p u b licati o n a n d disse mi nati o n of t he res ults of researc h. Researc hers ha ve a d ut y t o ma ke p u blicl y a vaila ble 
t he res ults of t heir researc h o n h u ma n s u bjects a n d are acco u nta ble f or t he c o m plete ness a n d acc urac y of 
t heir re p orts. All parties s h o ul d a d here t o acce pte d g ui deli nes f or et hical r e p orti n g. Ne gati ve a n d 
i nc o ncl usi ve as well as p ositi ve res ults m ust be p u blis he d or ot her wise ma de p u blicl y a vaila ble. S o urces of 
f un d i n g, i nstit uti o nal affiliati o ns a n d c o nflicts of i nterest m ust be declare d i n t he p u blicati o n. Re p orts of 
researc h n ot i n acc or dance w it h t he pri nci ples of t his Declarati o n s h o ul d n ot be acce pte d f or p u blicati o n.
U n pr o ve n I nter ve nti o ns i n Cli nic al Pr acti ce
3 7. I n t he treat me nt of a n i n di vi d ual patie nt, w here pr o ve n i nter ve nti o ns d o n ot e xist o r ot her k n o w n 
i nter ve nti o ns ha ve bee n i n effecti ve, t he p h ysicia n, after see ki n g e x pert a d vice, wit h i nf or me d c o nse nt fr o m 
t he patie nt or a le gall y a ut h orise d re present ati ve, ma y use a n u n pr o ve n i nter ve nti o n if i n t he p h ysicia n's 
j u d ge me nt it offers h o pe of sa vi n g life, re-esta blis hi n g he alt h or alle viati n g s ufferi n g. T his i nter ve nti o n 
sh o ul d s u bse q ue ntl y be ma de t he o bject of researc h, desi g ne d t o e val uate its safet y a nd efficac y. I n all cases, 
ne w i nf or mati o n m ust be rec or de d a n d, w here a p pr o priate, ma de p u blicl y a vaila ble.
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
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Versi o n: 
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A p pe n di x 2 
I n vesti g at or Si g n at u re P a ge
Si g ne d A gree me n t of t he Cli nic al St u d y Pr ot oc ol
C T N:
0 5 D F 1 9 1 0
Title of t he C S P: 
A Ra n d o mize d, E val uat or -Bli n de d St u d y t o E val uate Facial Har m o n y a n d 
S u bject Satisfacti o n Usi n g Rest yla ne Def y ne i n a Ste p w ise Treat me nt 
A p pr oac h
We, t he u n dersi g ne d, ha ve rea d a n d u n de rsta n d t he C S P s pecified a b o ve, a n d a gree o n t he 
c o nte nts. T he C S P, t he cli nical trial a gree me nt ( C T A) an d t he a d diti o nal i nf or mati o n gi ve n i n 
t he i nstr ucti o ns f or use (I F U) will ser ve as a b a sis f or c o-o perati o n i n t his st u d y.
P ri nci p al I n vesti g at or
Pri nte d na me 
Si g n at ure
Date
St u d y site
Title  
D o c i d  
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N ote: Ne w versi o ns of t he I F U mi g ht be release d d uri n g t he tr ial. T hese 
c ha n ges will n ot res ult i n pr ot oc ol a me n d me nts a n d t he I n vesti g at ors will be 
i nf or me d of t he u p dates t hr o u g h ot her mea ns.  
A p pe n di x 3 
I nstr ucti o ns f or Use – Rest yl a ne Def y ne ( Ver sio n 3. 0, Effecti ve d ate: 2 0 1 5-
1 2- 1 5)
T a ble of c o nte nts
1 
I N T R O D UC TI O N
1
2 
P U R P O S E
1
3 
S C O P E
1
4 
R E Q UI R E M E N T S F O R A P P R O V A L
1
5 
R E S U L T S
2
6 
C O N C L U SI O N
9
1. I ntr o d ucti o n
T his re p ort c o m pile s t he i nf or mati o n gi ve n i n t he I nstr ucti o ns f or Use f or Rest y la ne®
De f yne ™. T he i nf or mati o n is writte n i n 2 2 la n g uages:
E n glis h, B ul garia n, Cr oatia n, Czec h, Da nis h, D utc h, Fi n nis h, Fre nc h, Ge r ma n, Gree k, 
H u n gar ia n, Italia n, N or we gia n, P olis h, P ort u g uese, Ru ma nia n, R ussia n, Ser bia n, Sl o va k, 
S pa nis h , S we dis h a n d T ur kis h. (Ar ticle N o. 9 0- 9 8 0 0 3 )
T he article n u m ber a n d ver si o n of t he I nstr ucti o ns f or Use t o get her wit h t he re visi o n date 
e x presse d b y m o nt h a n d year , an d t h e C E mar ki n g wit h De kra N otifi e d B o d y n u m ber, s hall 
be i nserte d i n t he pri nte d I nstr ucti o ns f or Use. 
2. P ur p ose
T he p ur p ose of t he I nstr ucti o ns f or Use is t o e ns ure t hat t he user gets t he i nf or mati o n ne e de d 
t o ha n dle t he de vice safel y.
3. Sc o pe
T he I nstr uc ti o ns f or Use is s u p plie d wit h Rest yl a ne De f yn e , 1 ml i n E U.
4. Re q uire me nts f or a p pr o v al
T he c o nte nts of t he I nstr ucti o ns f or Use m ust be i n acc or da nce wit h Me dical De vice 
Directi ve, C o u ncil Directi ve 9 3/ 4 2/ E E C, S S -E N 1 0 4 1 a n d I S O 1 5 2 2 3.
R ele va nt parts fr o m S u m ma r y of Pr o d uct C haracteristics f or me dici nal pr o d ucts c o ntai ni n g 
li d ocai ne s h o ul d be i ncl u de d.
Title  
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5. Res ults
Fr o nt pa ge :
Rest y la ne® (l o g oty pe)
D E F Y N E ™
T H E E mer ve l® C O L L E C TI O N
I njecta ble Gel wit h Li d ocai ne
I nf or mati o n pa ges ( E n glis h presente d bel o w):
I N S T R UC TI O N S F O R U S E ( E N)
I. 
C O M P O SI TI O N
Cr oss -li n ke d hyal ur o n ic aci d
2 0 m g/ m L
Li d ocai ne h y dr oc hl ori de
3 m g/ m L
P h os p hate b uffere d sali ne p H 7
qs a d 1 m L
II. 
D E S C RI P TI O N
Rest y la ne® D e f yne ™is a sterile, bi od e gra da ble, tra ns pare nt gel of n on- a ni mal cr oss -li n ke d 
h y alur o nic aci d wit h t he a d diti on of l i d ocai ne h y dr oc hl ori de 3 m g/ m L. T he gel is s u p plie d i n 
a prefille d plasti c s yri n ge. T he c o nte nts of t he syri n ge are steri lize d usi n g m oist heat. T he 
s yri n ge is pac k a ge d i n di vi d uall y i n a blister, wit h t w o 2 7 G x ½” Ultra t h i n wall nee dles. T he 
nee dles ha ve bee n ste rilize d usi n g irra diati o n. T he pr o d uct is f or si n gle use o nl y . T o e ns ure 
tracea bilit y the pac ka ge i nc l u des patie nt rec or d la bels t hat s h o ul d be attac he d t o patie nt 
rec or ds.
III. 
I N T E N D E D U S E
T he pr o d uct is i nte nde d t o a u g me nt t he v ol u me of facial tiss ues. It is rec o m me n de d t o be 
use d f or c orrecti o n of se vere wri n kles , or t o re defi ne t he s ha pe of t he li ps, c hee ks or tear
tr o u g hs. De pe n di n g o n t he area t o be treate d a n d t he tiss ue s u p p ort, t he pr o d uct s h o ul d be 
i njecte d i n t he mi d t o dee p der mis, s u b m uc osa l la yer of t he li ps, s u bc utis or s u pra peri ost ic 
Title  
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z o ne. Li d ocai ne is a d de d t o t he f or m ulati o n t o di mi nis h t he pai n res ulti n g fr o m t he i njecti o n 
d uri n g t he treat me nt.
T he pr o d uct is o nl y  i nte n de d to be use d b y a ut h or ize d pers o n nel i n acc or da nce wit h l ocal 
le gislatio n, trai ne d i n t he a p pr o priate i njecti o n tec h ni q ues . Bef ore t he first treat me nt sessi o n, 
it is rec o m me n de d t o c o n tact yo ur l ocal Gal der ma re prese ntati ve or Rest yl a ne distri b ut or f or 
i nf or mati o n a b o ut trai ni ng o p p or t u nities.
I V. 
M O D E O F A C TI O N
T h e pr o d uct a d ds v ol u me t o t he tiss ue t here by rest ori n g t he s ki n c o nt o urs of t he face t o t he 
desire d le vel . T he v ol u m e a n d lifti ng ca pacit y  ori gi nate fr o m t he a bilit y of cross -li n ke d
h y al ur o nic aci d t o bi n d water.
V. 
C O N T R AI N DI C A TI O N S 

P atie nts prese nt i n g with k n o w n aller g y t o h yal ur o nic aci d filler or a mi de l ocal 
a naest hetics

Patie nts prese nti n g wit h p or p h y ria
VI. 
W A R NI N G S

D o n ot use w here t here is acti ve disease, s uc h as i nfla m mati o n, i nfecti o n or t u m o urs, 
i n or near t he i nte n de d tre at me nt site.

D o n ot i nject i ntra vasc ularl y. As f or ot her i njecta ble me dical de vices, i na d verte nt 
i njecti o n int o or ne xt t o bl o o d vessels c o ul d p ote ntiall y lea d t o vasc ular occl usi o n or 
c o m pressi o n, isc he mia a n d necr osis. 

D o n ot use i n patie nts wit h blee di n g dis or ders or i n pa tie nts wh o are ta ki n g
t hr o m b ol ytics or a ntic oa g ula nts.

D o n ot i nject t his pr o d uct i nt o a n area w here a n i m pla nt ot her t ha n h y al ur o nic aci d has 
bee n place d.

D o n ot resterilize.

D o n ot mi x wit h ot her pr o d ucts.
Title  
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VII. 
P R E C A U TI O N S F O R U S E
Ge ner al c o nsi derati o ns rel e va nt t o i njecta ble me dical de vices

K n o wl e d ge of t he a nat o m y of treat me nt site a n d s pecial ca uti o n are re q uire d i n or der 
to a v oi d perf orati o n or c o m pressi o n of vessels, ner ves a n d ot her v ul nera ble str uct ures.

Injecti o n pr oce d ure s are ass ociate d wit h a ris k of i nfe cti o n. Ase ptic tec h ni q ue a n d 
sta n dar d practice t o pre ve nt cr oss-i nfecti o ns are t o be o bser ve d.

S pecial ca uti o n s h o ul d be e xerc ise d w he n treati n g areas wit h li mite d c ollateral 
circ ulati o n, d ue t o i ncreas e d ris k of isc he mi a.

S pecial ca uti o n s h o ul d be e xercise d i n treati n g facial areas wit h li mite d s oft tiss ue 
s u p p ort or s oft tiss ue c o ver, s uc h as t he peri or bital area, to a v oi d f or m ati o n of 
pal pa ble l u m ps.

Patie nts wit h pre -existi n g pi g me nte d dar k l o wer e ye li d circles, t hi n s ki n an d pre -
e xisti n g te n den c y  t o war d o e de ma f ormati o n are n ot s uita ble ca n di dates f or treat me nt 
of t he l o wer peri or bital re gi o n.

Patie nts usi n g i m m u n os u p pressa n ts are n ot s uita ble ca n di dates f or treat me nt.

S pecial ca uti o n s h o ul d be e xercise d i n treati n g patie n ts wit h a te n de nc y t o f or m 
h y pertr o p hic sc ars or a n y ot her heali n g dis or ders .

I njecti o n pr oce d ures ca n lea d t o reacti vati o n of late nt or s u bclinical her pes viral 
i nfecti o ns.

Patie nts w h o are usi n g s u bsta nces t hat affect platelet f u ncti o n, s uc h as as piri n a n d 
n o nster oi dal a nti -i nfla m mat or y dr u gs may, as wit h a n y i njecti o n, e x perie nce i ncrease d 
br uisi n g or blee di n g at i njecti o n sites.

Patie nts wit h u nattai na bl e e x pectati o ns are n ot s uita ble ca n di dates f or treat me nt.

D o n ot use t he pr o d uct if t he pac ka g e is dama ge d. 

D o n ot use t he pr o d uct if t he c o nte nts of t he s yri n ge are cl o u d y.
S pecific c o nsi derati o ns rele va nt t o t he use of t his pr o d uct

C o nsi der ati o ns s h o ul d be gi ve n t o t he t otal d ose of li d ocai ne a d mi nistere d if de ntal 
bl oc k or t o pical a d mi nistrati o n of l i d ocai ne is use d c o ncurre ntl y . Hi g h d oses of 
li d ocai ne ( m ore t ha n 4 0 0 m g) ca n ca use ac ute t o xic reacti o ns manifesti n g as 
s ym pt o ms affecti n g t he ce ntral nerv o us s ys te m a n d car diac c o n d ucti o n.
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
Li d ocai n e s h o ul d be use d wit h ca uti o n i n patie nts recei vi n g ot her l ocal a naest hetics or 
a ge nts str uct urally relate d t o a mi de-t ype l ocal a naest hetics e. g., certai n a nti -
arr h y t h mics, si nce t he syste mic t o xic ef fects ca n be a d diti ve. 

Li d ocai ne s h o ul d be use d ca uti o u sl y i n patie nts wit h e pile ps y, im paire d car diac 
c on d ucti o n, se verel y i m paire d he patic f u ncti o n or se vere re nal d ys f u ncti o n.

If t he pr o d uct is i njecte d t o o s u perficiall y t his ma y res ult i n visi ble l u m ps a n d/ or 
bl u is h disc ol orati o n.

T he patie nt m ust a v oi d e x p osi n g t he treate d area t o heat (s u n bat hi n g, sa u na, steam 
bat hs, etc.) or e xt re me c old u ntil a n y  si g ns of l ocal i nfla m mati o n ha ve disa p peare d.

If laser treat me nt, che mical peeli n g or a n y  ot her pr oce dure base d o n acti ve der mal 
res p o nse is perf or me d after treat me nt wit h t his pr o d uct t here is a t he oretical ris k of
eliciti n g a n i nfla m m at or y reacti o n at t he i m pla nt site. T his als o a p plies if t he pr o d uct 
is a d mi nistere d bef ore t he s ki n has heale d c o m pletel y after s uc h a pr oce d ure.

At eac h treat me nt sessi o n a ma x i m u m d osa ge of 2 mL per treat me n t site is 
rec o m me nde d.

T h is pr o d uct has n ot bee n tested i n pre g na nt or breastfee di n g w o me n .

D o n ot use i n c hil dre n.
VIII. 
A D V E R S E E V E N T S
Patie nts m ust be i nf or me d of t he p ote ntial ris ks a n d a d verse e ve nts relate d t o t he i njectio n 
pr oce d ure a n d t o t he use of this pr o d uct. 
T he f oll o wi n g p ost mar ket a d vers e e ve nts ha ve bee n re p o rte d ( n o n-e x ha usti ve list): 
a n gi oe de ma, atr o p h y/ scari n g, blisters, br uisi n g, ca pillar y dis or ders s uc h as tela n giectasia, 
der matitis, disc ol orati o n, er y t he ma, h y perse nsiti vit y, i n d urati o n, i nfecti o n, i nfla mmati o n, 
isc he mia/ necr osis, mass, ne u r ol o gical sy m pt o ms s uc h as paraest hesia, pai n/te n der ness, 
pa p ules/ n o d ules, pr ur it us, reacti vati o n of her pes i nfecti o n, s h ort d urati o n of effect, s welli n g 
a n d urticaria.
O t her p ote ntial a d verse e ve nts t hat ha ve bee n re p orte d f oll owi n g i njecti o n of h yal ur o ni c aci d 
gels i n ge neral a n d ma y  occ ur w he n usi n g t he pr o d uct i ncl u de t he f oll o win g: a bscess, ac ne, 
de vice disl ocati o n , fist ula, gra n ul o ma, ras h a n d vis ual dist ur ba nce.
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I njecti o n relate d a d verse e ve nts s u c h as br uisi n g, er yt he ma, i tc hi n g, s welli n g, pai n a n d 
te n der ness ge nerall y res ol ve s p o nta ne o usl y wit hi n o ne wee k after i njecti o n.
Vas c ular c o m pr o mise ma y occ ur d ue t o a n i na d verte nt i ntra vasc ular i njecti o n or as a res ult of 
vasc ular c o m pressi o n ass ociate d wit h i m pla ntati o n of a n y i n jecta ble pr o d uct. This ma y  
ma nifest as isc he mia or necr osis at t he i m pla nt site or i n t he area s u p plie d b y t he bl o o d 
vessels affecte d; or rarel y as isc he mi c e ve nts i n ot her or ga ns d ue t o e m b olisati o n. F oll o wi n g 
facial aest hetic treat me nts is olate d rare cases ha ve bee n re p ort e d re gardi n g isc he mic e ve nts 
affecti n g t he e ye lea di n g t o vis ual l oss, a n d t he brai n re s ulti n g i n cere bral i nfarcti o n. After
i njecti o ns of t he n ose isc he mia/ necr osis ma y  occ ur, es peciall y i n patie nts w h o ha d pri or 
r hi n o plast y.
S y m pt o ms o f i nfla m mati o n at t he i m plant site c o m me nc i n g eit her s h ortly after i njecti o n or 
after a dela y of u p t o se veral wee ks ha ve bee n re p orte d. I n cas e of u ne x plai ne d i nfla m mat or y 
reacti o ns i nfecti o ns s h oul d be e xcl u de d a n d treate d if n ecessar y si nce i nade q uatel y treate d 
i nfecti o ns m a y  pr ogress i nt o c o m p licati o ns s uc h as a bscess f or mati o n. Treat me nt usi n g o nl y 
oral c ortic oster oi ds wit h o ut c o nc urre nt a nti bi otic trea t me nt is n ot rec o m me n de d. I n case of 
persi ste nt or rec urre nt i nfla m mat or y s ym pt o ms, c o nsi der re m o val of t he pr o d uct b y  
as pirati on/ drai na ge, e xt r usi o n or e nz ymatic de gra dati o n ( use of h y al ur o ni dase has bee n 
d escri be d i n scie ntific p u blicati o ns). Bef ore a n y re m o val pr oce d ure is perf or me d, t he 
s wellin g ma y  be re d uce d b y usi n g e. g. N S AI D f or 2 -7 da y s or a s h o rt c o urse of 
c orticoster oi d s f or less t ha n 7 da y s, i n or der t o m ore easily pal pate a n y re mai ni n g pr o d uct.
F or patie nts w h o ha ve e x perie nce d me dicall y i m p or ta nt a d verse e ve nts, a decisi o n f or 
retreat me nt s h o ul d ta ke i nt o c o nsi derati o n t he ca use a n d se verit y of pre vi o us reacti o ns.
F or re p orti n g a d ve rse e ve nts c o ntact y o ur l ocal Gal der ma re prese ntati ve or distri b ut or f or t his 
pr o d uct.
I X. 
P E R F O R M A N C E
I n a ra n d o mize d c o ntr olle d m ultice nter st u d y wit h Rest y la ne De f yn e f or c orrecti o n of 
m o derate t o se vere n as ola bial f ol ds, 6 9. 8 % of s ubjects m ai ntai ne d a cli nicall y  si g nifica nt 
i m pr o ve me nt at 4 8 wee ks after treat me nt.
Title  
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X. 
T R E A T M E N T P R O C E D U R E
I nf or m t he patie nt a b o ut t he preca uti o ns t o be ta ke n , t he e x pecte d res ult a n d t he p ossi ble 
a d verse e ve nts .
It is i m p orta nt t o use a sterile, a p pr o priate nee dle or bl u nt ca n n ula. S uita ble nee dles ( 2 7 G x
½” Ultra t hi n wall) are s u p plie d wit h t he s y ri n ge i n t he blister pac k. As a n alter nat i ve, a bl u nt 
t hi n walle d ca n n ula wit h a rec o m me n de d size of 2 7 G ca n be use d.
Asse m bli n g t he nee dle/c a n n ula a n d s yri n ge:

use s ur g ical gl o ves

u n scre w t he pr otecti ve ca p fr o m t he st o p per

caref ull y re m o ve t he sto p per fr o m t he s yri n ge

fir ml y scre w the nee dle/ca n n ula wit h its s hiel d o nt o t he ti p of t he s yri n ge

re m o ve t he s hiel d j ust bef ore i njecti o n
C lea nse t he area t o be treate d wit h a n a ntise ptic a n d all o w it t o dr y  bef ore i njectio n.
T o a v oi d brea ka ge of t he nee d le/ca n n ula, d o n ot atte m pt t o be n d or ot her wise m a ni p ulate it 
bef ore or d uri n g treat me nt.
Bef ore i njecti n g t he pr o d uct, de press t he pl u n ger r o d care f ull y u ntil a s mall dr o plet is visi ble 
at t he ti p of t he nee dle/ca n n ula .
Ali g n t he be vel of t he nee dle b y  tur ni n g t he s yri n ge o n its a xis. If a bl u nt ca n n ul a is use d, a n 
e ntr y p oi nt is ma de i n t he s ki n, f or e xa m ple wit h a s har p ne e dle of a p pr o pria te size. 
As pirati o n is rec o m me n de d p ri or t o i njecti o n i n or der t o re d uce t he ris k of i na d verte nt 
i njecti o n i nt o a bl o o d vessel. I nject sl o wl y. D uri n g i njecti o n, keep t he si de h ole of t he ca n n ula 
faci n g d o w nwar ds, a wa y  fr o m t he s ki n s urface.
I nject t he gel b y  ge ntl y pressi n g d o w n o n t he pl u n ger r o d wit h t h e t h u m b or pal m of t he ha n d.
C h o ose fr o m a variet y of i njecti o n tec h ni q ues, i.e. serial p u nct ure, li ne ar t hrea di n g or cr oss -
hatc hi n g.
It is rec o m me n de d t o cha n ge nee dle/ca n n ula f or eac h ne w treat me nt site.
Defects s h o ul d be f ull y c orrecte d, but n ot o verc orrecte d, at eac h treat me nt sessi o n.
If " bla nc hi n g" of t he s ki n is o bser ve d as a res ult of o ver -s u perficial i njecti on, t he w hite ne d 
area s h o ul d be massa ge d ge ntl y u ntil it ret ur ns t o a n or ma l c ol ou r.
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Ge ntl y massa ge t he treate d area after i njectio n.
T he s y rin ges a n d nee dles /ca n n ulas m ust be discar de d i m me diatel y  after use i n acc or da nce 
wit h acce pte d me dical practice a n d a p plica ble nati o nal, l ocal or i nstit uti o n al g ui deli nes. T he 
pr o d uct s hall n ot be re use d d u e t o ris k f or c o nta mi nati o n of u n use d material a n d t he 
ass ociate d ris k i ncl u di n g i nfecti o n.
Sta n dar d preca uti o ns a p p l y w he n ha n dli n g t he nee dles. Nee dles s h o ul d be dis p ose d i n a 
c o ntai ner de dicate d f or s har p de vices.
XI. 
S H E L F LI F E A N D S T O R A G E
D o n ot use afte r t he e x pir y date i n dicate d o n pac ka g e. St ore u p t o 2 5° C. Pr otect fr o m freezi n g 
a n d s u nli g ht .
XII. 
M A N U F A C T U R E R
Q- Me d A B , Se mi narie gata n 2 1, S E-7 5 2 2 8 U p psala , S we de n
P h o ne + 4 6( 0) 1 8 4 7 4 9 0 0 0, Fa x + 4 6( 0) 1 8 4 7 4 9 0 0 1
w w w. q -me d.c o m, e -mail: i nf o. q- me d @ gal der ma.c o m
Rest y la ne, E mer vel a n d Gal der ma are tra de mar ks of Nestlé S ki n Healt h S. A.
Last pa ges
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M a n uf act urer
of t he nee dles i n t he blister p ac k: ( o nl y i n E n glis h)
G A L D E R M A (l o g ot ype)
6. C o ncl usi o n
T he c o nte nts of t he I nstr ucti o ns f or Use are i n acc or da nce wit h Me dical De vice Directi ve,
C o u ncil Directi ve 9 3/ 4 2/ E E C, S S -E N 1 0 4 1 a n d I S O 1 5 2 2 3.
S u m mar y  of Pr o d uct C haracteristics f or me dici nal pro d ucts c o ntai ni n g l i d ocai ne have bee n
e valuate d a n d rele va nt parts ha ve bee n i ncl u de d.
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1( 1)
A p pe n di x 4 
Gl o b al Aest hetic I m pr o ve me nt Sc ale (G AI S )
T he 5 -gra de d G AI S will be use d t o li ve assess t he aest hetic i m pr o ve me nt of t he treat me nt area b y t he 
Treati n g I n vesti gat or a n d   
, b y c o m pari n g t o a p h ot o gr a p h ta ke n at t he ba seli ne visit bef ore 
t he first treat me nt.
T he Treati n g I nvesti gat or a n d  
will, i n de pe n de ntl y of eac h ot her, res p o n d t o t he q uesti o n: 
“ H o w w o ul d y o u descri be t he s u bject’s/ 
aest hetic a p peara nce of t he l o wer face, i.e. t he treate d
area, c o m pare d t o t he p h ot o gra p h s ta ke n bef ore treat me nt?” b y usi n g t he res pecti ve cate g orical scale 
bel o w. 
Gl o b al A est hetic I m pr o ve me nt Sc ale
R ati n g (
) 
Descri pti o n (f or t he I n vesti g at or a n d  
)
Ver y  m uc h i m pr o ve d 
O pti mal c os metic r es ult f or t he s u bject.
M uc h i m pr o ve d
Mar ke d i m pr o ve me nt i n a p peara nce fr o m t he ori gi nal c o n diti o n, b ut 
n ot c o m pletel y o pti mal f or t his s u bject.
I mpr o ve d
O b vi o us i m pr o ve me nt i n a p peara nce fr o m t he ori gi nal c o n diti o n.
N o c ha n ge
T he a p peara nce is es se ntiall y t he sa me as t he origi nal c o n di ti o n.
W orse
T he a p peara nce is w orse t ha n t he ori gi na l c o n diti o n.
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N at ur al ness, 
 
 (I n vesti g at or’s q uesti o n n aire)
N at ur al ness
T he I n vesti gat or will assess nat ural n ess of t he treat me nt r es ult base d o n re vie w of baseli ne 
p h ot o gra p hs a n d li ve assess me n t b y i n dicati o n h o w m uc h t he y a gree or disa gree t o t he 
state me nt: “ T he treatme nt res ults are nat ural l o o ki n g”
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A p pe n di x 9 
S u bjec t s atisf acti o n q uesti o n n aire 
1 
M y  first treat me nt i m pr o ve d m y a p peara nce
2 
C o m pare d t o m y  first treat me nt, treati n g b ot h areas i n c o m bi nati o n i m pr o ve d m y  
a p peara nce
3 
I a m satisfie d wit h t he c o nt o ur of m y l o wer face after treat me nt 
4 
I am satis fie d wit h t he s ha pe of my c hi n
5 
I a m satisfie d wit h h o w well defi ne d m y c hi n l o o ks
6 
I feel m ore attractive after tr eat me nt
7 
I feel c o mf orta ble bei n g p h ot o gra p he d
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Si g n p a g e: 1 of 1
S I G N A T U R E S PA G E
D at e
Si g n e d b y
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J u stifi c ati o n 
A p pr o v e d b y T e c h ni c al E x p ert
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J u stifi c ati o n 
A p pr o v e d b y T e c h ni c al E x p ert
2 0 2 0- 0 9- 2 4 0 6: 5 2
J u stifi c ati o n 
A p pr o v e d b y Pr oj e ct M a n a g er
2 0 2 0- 0 9- 2 4 0 9: 1 6
J u stifi c ati o n 
A p pr o v e d b y T e c h ni c al E x p ert
2 0 2 0- 1 0- 0 2 1 1: 1 0
J u stifi c ati o n 
A p pr o v e d b y 
Title  
D o c i d  
0 5 D F 1 9 1 0 Cli nic al St u d y Pr ot oc ol
M A- 4 2 2 4 8
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 2 0- 1 0- 0 2 1 1: 1 0
2. 0
 
 
Pri nt date:
 2 0 2 2- 1 0- 2 8 0 9: 1 9
P P D
P P D
P P D
P P D
P P D
P P D