A Randomized, Multi-center, Evaluator-blinded Study to Evaluate the Efficacy and Safety of Restylane Defyne Compared to Restylane for Correction of Moderate to Severe Nasolabial Folds
Phase: NA
Conditions: Nasolabial Folds in Chinese Population
Sponsor: Galderma R&D

Pa ge 1 of 9 5
A r a n d o mize d, m ulti -ce nter, e v al u at o r-bli n de d st u d y t o e v al u ate t he 
effic ac y a n d s afet y of Rest yl a ne Def y ne c o m p are d t o Rest yl a ne f or
c orrecti o n of m o der ate t o se vere n as ol a bi al f ol ds.
St u d y pr o d ucts :
Rest y la neDef y ne ™
Rest y la ne
Cli nical trial n u m ber ( C T N):
4 3 C H 1 5 0 8
C o or di nati n g I n vesti gat or(s):
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 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 t he 
cli nical st u d y descri be d herei n. 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
P P D

Pa ge 2 of 9 5
S u m m ar y of C h a n ges i n Cli nic al St u d y Pr ot oc ol 4 3 C H 1 5 0 8 fr o m v ersi o n 
4. 0 t o versi o n 5. 0.
T he c ha n ges, i ncl u di n g rati o nale, are descri be d i n t he ta ble bel o w . A d de d te xt is writte n i n 
b ol d a n d delete d te xt is writte n as stri ket hr o u g h.
Secti o n i n t he cli nic al 
st u d y pr ot oc ol
R ati o n ale f or 
c h a n ges
Desc ri pti o n of c h a n ges
I n vesti gat ors a n d St u d y 
A d mi nistrati ve Str uct ure
A N D
S p o ns or Si g nat ures
C ha n ge of Me dical 
ex pert
C ha n ge of Cli nical 
pr oject ma na ger
Si g ne d A gree me nt of t he 
Cli nical St u d y  Pr ot oc ol
A refere nce t o t he 
Rest y la ne Def yne I B 
was a d de d.
T he C S P, t he cli nical trial a gree me nt 
( C T A), a n d t he a d diti o nal i nf or mati o n 
gi ve n i n t he I n vesti g at or’s Br oc h ure 
(I B) a n d I nstr ucti o ns f or Use (I F U) f or 
Rest y la ne Def yne as well as t he I F U f or
a n d Rest y la ne will ser ve as a basis f or 
c o-o perati o n i n t his st u d y .
A b bre viati o ns a n d 
Defi niti o ns of Ter ms
I B a d de d
I n vesti gat or’s Br oc h ure (I B) a d de d
Secti o ns 2. 7
A refere nce t o t he 
Rest y la ne Def yne I B 
was a d de d.
Detaile d i nf or mati o n o n re p orte d A Es 
rele va nt f or Rest yla ne Def yne a n d 
Rest y la ne is pr o vi de d i n t he I nstr ucti o n 
f or Use (I F U) as well as i n t he I B f or 
Rest yl a ne Def y ne .
Secti o ns 6. 1
is a vaila ble i n t he I B a n d t he i nstr ucti o ns 
f or use (I F U) ) ( A p pe n di x 2).
Secti o ns 8. 4. 8
Refer t o t he Rest yl a ne Def yne I B a n d
E U I F U ( A p pe n di x 2) a n d as well as t he 
Rest y la ne C hi na I F U ( A p pe n di x 3).
A p pe n di x 3 I nstr ucti o n 
f or Use Restyl a ne C hi na
Ne w versi o n 
a p pr o ve d b y C F D A
Versi o n 8. 0 of t he I nstr ucti o ns f or Use 
Rest y la ne C hi na ( E xtracts fr o m Q M S -
5 6 0 2) has bee n i ncl u de d i n A p pe n di x 3. 
V ersi o n 6. 0 of t he I nstr ucti o n f or Use has 
bee n re m o ve d.
I n vesti gat ors Br oc h ure 
(I B)
U p dates re q uire d:
Yes 
   N o 
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)
U p dates re q uire d:
Yes 
   N o 
Electr o nic Case Re p ort 
F or m (e C R F)
U p dates re q uire d:
Yes 
   N o 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
P P D
P P D

Pa ge 3 of 9 5
S u m m ar y of C h a n ges i n Cli nic al St u d y Pr ot oc ol 4 3 C H 1 5 0 8
fr o m v ersi o n 
3. 0 t o versi o n 4. 0.
T he c ha n ges, i ncl u di n g rati o nale, are descri be d i n t he ta ble bel o w . A d de d te xt is writte n i n 
b ol d a n d delete d te xt is writte n as stri ket hr o u g h.
Secti o n i n t he cli nic al 
st u d y pr ot oc ol
R ati o n ale f or c h a n ges
Desc ri pti o n of c h a n ges
I n vesti gat ors a nd St u d y  
A d mi nistrati ve Str uct ure
C ha n ge of r ole 
descri pti o n
St u d y  direct or Cli nic al P r oject 
M a n a ger
C ha n ge of Cli nical 
pr oject ma na ger
S p o ns or Si g nat ures
C ha n ge of r ole 
descri pti o n
St u d y  direct or Cli nic al P r oject 
M a n a ger
C ha n ge of Cli nical 
pr oject ma na ger
8. 4. 5 
Re p orti n g 
of 
seri o us a d verse e ve nts
C F D A G C P Or der N o 
2 5 re g ulati o n
I n ad diti o n, acc or di n g t o n ati o n al 
re g ul ati o n,
the I nvesti gat or s h o ul d
re p ort a n y S A E
e ve nt
usi n g 
t he 
C F D A 
S A E 
f or m 
t o
t he 
a d mi nistr ati ve 
de p art me nt 
of 
me dic al 
de vice cli nic al tri als, w h o 
will 
re p ort
wit hi n 
2 4 
h o urs 
of 
a ware ness t o t he:

F o o d a n d Dr u g A d mi nistr ati o n 
( F D A) of pr o vi nce, a ut o n o m o us 
re gi o n, or m u nici p alit y w here t he 
site is l oc ate d C F D A a n d rele va nt
Pr o vi ncial
re g ulat or y 
a ut h orit y 
( R A) 
acc or di n g 
t o 
l ocal 
re g ulati o ns. 

C o m missi o n 
of 
He alt h 
a n d 
F a mil y 
Pl a n ni n g of pr o vi nce or 
a ut o n o m o us 
re gi o n 
or 
m u nici p alit y 
w here 
t he site is 
l oc ate d

Res p o nsi ble I E C
A 
c o p y of t he i nitial C F D A S A E 
re p ort s h o ul d be se nt t o S p o ns or b y  e-
mail or fa x a n d o ne c o p y sh o ul d be 
ke pt at t he st u d y site. C o ntact details 
t o C F D A 
a n d eac h pr o vi ncial R A
l oc al F D A 
a n d 
C o m missi o n 
of 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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P P D

Pa ge 4 of 9 5
He alt h 
a n d 
F a mil y 
Pl a n ni n g 
of 
pr o vi nce or a ut o n o m o us re gi o n or 
m u nici p alit y 
w here
t he 
site 
is 
l oc ate d s h o ul d be a vaila ble at t he 
st u d y sites.
T he
I n vesti gat or
s hall als o re p ort 
S A Es 
t o t he res p o nsi ble I E C i n 
acc or da nce wit h 
l ocal re q uire me nts.
T he I nvesti gat or is res p o nsi ble f or 
c o nfir mi n g t he re p orti n g pr oce d ures 
a p plica ble at his/ her I E C re gar di n g 
S A Es 
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 pecific c o ntact details t o 
eac h I E C s h o ul d be a vaila ble at t he 
st u d y sites.
F oll o w - u p 
i nf or mati o 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 ossi ble 
a n d re p orte d i m me diatel y but n ot later 
t ha n 2 4 h o urs 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  
acti vities, 
m u st 
be 
d oc u me nte d b y  the I n vesti gat or. A n y 
f oll o w- u p 
i nf or mati o n 
s h o ul d 
be 
re p orte d b y  the I n vesti gat or i n t he 
e C R F 
or 
fa xe d/e-maile d 
t o 
t he 
S p o ns or if t here are diffic ulties i n 
accessi n g t he e C R F 
s yste m. T he 
I n vesti gat or s h o ul d als o se n d a f oll o w-
u p re p ort
vi a 
t he a d mi nistr ati ve 
de p art me nt 
of 
me d ic al 
de vice 
cli nic al tri als t o t he l oc al F D A, l oc al 
C o m missi o n of He alt h a n d F a mil y 
Pl a n ni n g, C F D A, pr o vi ncial R A, a n d 
I E C 
i n 
acc or da nce 
wit h 
l ocal 
re g ulati o ns.
T he 
I n vesti gat or will 
ass ure 
c o m plete ness 
of 
t he S A E 
inf or mati o n 
a n d 
t he 
s u p p orti n g 
d oc u me ntati o n. A c o p y of t he f ull y 
c o m plete d S A E
a n d C F D A
S A E
for m s s h o ul d be ke pt at t he site.
T he S p o ns or is i n a d diti o n t o t he 
I n vesti gat or res p o nsi ble f or re p orti n g 
relate d 
all 
S A E 
a n d 
de vice 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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Pa ge 5 of 9 5
deficie ncies wit h t he li keli h o o d of 
S A E, wit hi n 5 b usi ness d a ys u p o n 
bei n g i nf or me d t o t he S h a n g h ai 
M u nici p al 
F o o d 
a n d 
Dr u g 
A d mi nistr ati o n 
a n d 
S h a n g h ai 
M u nici p al 
C o m missi o n 
of He alt h 
a n d 
F a mil y 
Pl a n ni n g. 
S p o ns or 
s h o ul d als o n otif y ot her cli nic al tri al 
i nstit uti o ns 
a n d 
i n vesti g at ors 
p artici p ati n g 
i n t he st u d y, w h o 
pr o m ptl y s h o ul d re p ort t o t heir 
l oc al 
I R B/I E C.t o 
t he 
C F D A 
acc or di n g t o nati o nal re g ulati o ns .
8. 4. 7 Pre g na nc y
Clarificati o n t o 
re p orti n g pr oce d ure
A 
pre g na nc y
c o nfir me d d uri n g 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 p re g na nc y re p ort 
for m i n t he e C R F wit hi n 2 4 h o urs 
after t he I n vesti g at or’s a w are ness
i m me diatel y up o n ac k n o wle d ge a n d 
c o ntact 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. 4. 5 . T he re p ort ca n be pr os pecti ve or 
retr os pecti ve. 
F oll o w -u p 
s hall 
be 
c o n d ucte 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. 
If o utc o me i nf or m ati o n bec o mes 
a v ail a ble after st u d y c o m pleti o n, t he 
I n vesti g at or s h all c o m plete a h ar d 
c o p y of t he pre g n a nc y re p ort f or m 
a n d f or w ar d t o t he S p o ns or . 
Cases t hat le d t o f oetal distress, f oetal 
deat h or a c o n ge nital a b n or malit y or 
birt h defect are t o b e re gar de d as 
S A Es a n d s hall be re p orte d o n t he 
ex p os ure i n uter o re p ort f or m t o t he 
S p o ns or i m me diatel y but n o later t ha n 
2 4 
h o urs 
after 
t he I nvesti gat ors 
a ware ness
i n 
acc or d a nce 
wit h 
Secti o n 8. 4. 5 . T hese e ve 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 na nc y  that are relate d 
t o t he pre g na nt w o ma n a n d f ulfils a n y 
seri o us criteria, s uc h as pre-ecla m psia 
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. 
Electi 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 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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Pa ge 6 of 9 5
A E s.
A 
c o p y of 
t he f ull y c o m plete d 
pre g n a nc y f or m a n d e x p os ure i n 
uter o f or m s h o ul d be ke pt at t he 
site.
I n vesti gat ors 
Br oc h ure 
(I B)
U p dates re q uire d:
Yes 
   N o 
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)
U p dates re q uire d:
Yes 
   N o 
Electr o nic Case 
Re p ort 
F or m (e C R F)
U p dates re q uire d:
Yes 
   N o 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 7 of 9 5
I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct ure
C o or di nati n g I nvesti 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 1 8 4 7 4 9 0 0 0
Facsi mile:
+ 4 6 1 8 4 7 4 9 0 0 1
Me dical e x pert:
Cli nical Pr oject Ma na ger :
St u d y  statisticia n:
F urt her details o n all partici 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.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
P P D
P P D

Pa ge 8 of 9 5
S p o ns or Si g n at ures
T he C S P is electr o nicall y si g ne d i n t he d oc u me nt ma na ge me nt s yste m wit hi n t he Q- Me d
A B 
q ualit y  ma na ge me nt sys te m b y  t he re prese ntati ves liste d bel o w.
Q- Me d
A B
Electr o nicall y si g ne d i n t he d oc u me nt
ma na ge me nt s ys te m wit hi n Q-Me d q ualit y  
ma na ge me nt s ys te m
S p o ns or’s Me dic al E x pert ,  
Q-Me d
A B
Electr o nicall y si g ne d i n t he d oc u me nt 
ma na ge me nt s ys te m wit hi n Q-Me d q ualit y  
ma na ge me nt s ys te m
Cli nic al Pr oject M a n a ger ,  
Q-Me d
A B
Electr o nicall y si g ne d i n t he d oc u me nt 
ma na ge me nt s ys te m wit hi n Q-Me d q ualit y  
ma na ge me nt s ys te m
St atistici a n, 
Q- Me d
A B
Electr o nicall y si g ne d i n t he d oc u me nt 
ma na ge me nt s ys te m wit hi n Q-Me d q ualit y  
ma na ge me nt s ys te m
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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P P D
P P D
P P D
P P D

Pa ge 9 of 9 5
Si g ne d A gree me nt of t he Cli nic al St u d y Pr ot oc ol
C T N :
4 3 C H 1 5 0 8
Title of t he C S P :
A ra n d o mize d, m ulti -ce nter, e val uat or- bli n de d st u d y to e val uate t he 
efficac y an d safet y of Rest y la ne Def y ne c o m pare d t o Rest y la ne f or 
c orrecti o n of m o derate t o se vere nas ola bial f ol ds.
I, t he u n dersi g ne d, ha ve rea d a n d u n dersta n d t he C S P
s pecifie d a b o ve, a n d a gree o n t he 
c o nte nts. T he C S P , t he c li nical trial agree me nt ( C T A), a n d t he a d diti o nal i nf or mati o n gi ve n 
i n t he I nvesti gat or’s Br oc h ure (IB) a n d I nstr ucti o ns f or Use (IF U ) f or Rest y la ne Def y ne as 
well as t he I F U f or Rest yla n e will ser ve as a basis f or c o- o perati o n i n t his st u d y.
Pri nci p al I n vesti g at or
Pri nte d na me 
Si g nat ure
Date
St u d y site
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 1 0 of 9 5
S y n o psis
Title of st u d y:
A
ran d o m ize d, m u lti-c e nter, e valu ator - blin d e d st ud y t o e v aluate t he e fficac y 
a n d safet y of Re st yla ne De f y ne c o m pare d t o
Restyl a ne f or c o rrecti o n of
m o d erate t o sev ere nas o lab ial f ol ds.
Cli nic al Tri al N u m ber:
4 3 C H 1 5 0 8
C o u n tries i n v ol ve d, 
n u m b er o f sites/co u n tr y,
n u m b er o f su b jects:
T he st u d y wi ll be c o n d ucte d at a p pr o xi matel y 5 sites l ocate d i n C hi na. T he 
ai m is t o i ncl u de a p pr o xi matel y 1 7 5 s u bjects treate d wit h Rest yla ne Def y ne i n 
o ne nas ola bial f ol d ( N L F) a n d Rest yla ne i n t he o p p osite N L F, as ra n d o ml y
assi g ne d.
C o or di n ati n g I n vest i g at or:
Pri m ar y effic ac y o bjecti ve 
a n d e n d p oi nt:
T he pri mar y o bjecti ve is t o e val uate t he efficac y of Rest yla ne Def y ne 
c o m pare d t o Rest yla ne i n c orrecti o n of N L Fs b y  co m pari n g res p o nse rates 
base d o n t he Wri n kle 
Se verit y Rati n g Scale ( W S R S), as assesse d b y t he 
Bli n de d e val uat or , at 6 m o nt hs after last treat me nt.
A res p o nse rate is defi ne d as perce nta ge of  su bjects wit h at least o ne gra de
(≥1) i m pr o ve me nt o n t he W S R S. 
T he n o n- i nferi orit y of Rest yla ne Def y ne 
vers us Rest yla ne will be s h o w n if t he t w o-si de d 9 5 % c o nfi de nce i nter val of 
t heir differe nce at 6 m o n t hs after last treat me nt e xcl u des a n i nferi orit y of 1 5 % 
or m ore.
S afet y o bjecti ves a n d 
e n d p oi nts:
T he safet y o bjecti ves are:

T o e val uate t he safet y of Rest yla ne Def y ne a n d Rest yla ne d uri n g t he 
w h ole st u d y b y c ollecti n g A d verse E ve nts ( A Es).
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
P P D
C CI
C CI

Pa ge 1 1 of 9 5
St u d y Desi g n:
T his is a ra n d o mize d, m ulti -ce nter, e val uat or -bli n de d st u d y i n C hi na t o 
e val uate t he efficac y a n d safet y of Rest yla ne 
Def y ne 
( E mer vel Dee p) 
c o m pare d t o Rest yla ne i n c orrecti o n of m o derate t o se vere N L Fs.
Writte n i nf or me d c o nse nt will be o btai ne d bef ore a n y st u d y relate d pr oce d ure 
is perf or me d. S u bjects will be scree ne d f or eli gi bilit y wit hi n 2 1 da ys pri or t o 
st u d y ra n d o mizati o n o n Da y 1. S u bse q ue nt t o scree ni n g eli gi ble s u bjects will 
be e nr olle d i n t he st u d y.
I niti al Tre at me nt
Eac h s u bject will recei ve a n i nitial treat me nt o n Da y 1 wit h Rest yla ne Def y ne 
i n o ne N L F a n d Rest yla ne i n t he o p p osite N L F, as ra n d o ml y assi g ne d. T he 
first i njecti o n will al wa ys b e gi ve n i n t he ri g ht N L F. 
 
 
 
 
I n
or der t o e val uate t he pai n of i njecti o n se parate d fr o m t he pai n of t he nee dle 
i nserti o n al o ne, a pa use of 3 t o 5 sec o n d is re q uire d after i nserti o n of t he 
nee dle bef ore starti n g i njecti o n. As pirati o n s h o ul d be perf or me d pri or t o 
i njecti o n i n or der t o a v oi d accide ntal i ntra vasc ular i njecti o n. F or i nitial 
treat me nt, it is rec o m me n de d n ot t o use m o re t ha n 1. 5 m L f or eac h N L F. T he 
i njecti o n pr oce d ure f or t he t w o N L Fs will be sta n dar dize d as far as p ossi ble i n 
ter ms of v ol u me, ti me f or i njecti o n, a n d i njecti o n tec h niq ue, a n d will be 
rec or de d i n t he e C R F.
T he ai m of t he treat me nt is t o ac hie ve o pti m al aest hetic i m pr o ve me nt, defi ne d 
as at least o ne (≥1) gra de i m pr o ve me nt fr o m baseli ne o n t he W S R S, 
as 
assesse d b y t he b li n de d e val uat or.
T o uc h -U p Tre at m e nt
A t o uc h- u p treat me nt ma y b e perf or me d 4 we e ks after t he i nitial treat me nt if 
o pti mal aest hetic i mpr o ve me nt has n ot bee n o btai ne d, i.e., s u bjects w h o di d 
n ot i mpr o ve at least o ne (≥1) gra de i n W S R S 
(i n o ne or b ot h N L Fs, as 
assesse d b y  the b li n de d e val uat or). T o pical or l ocal a nest hetic or ot her pai n -
relie vi n g me dicati o n, i ncl u di n g ice, ma y be use d bef ore a n d after t o uc h- u p 
treat me nt. T o uc h - u p treat me nt will n ot be perf or me d if t here are o n g oi n g 
treat me nt relate d A E s or if o pti m al aest hetic i m pr o ve me nt of b ot h N L Fs is 
alread y ac hie ve d. T he t o uc h -u p treat me nt is o pti o nal a n d re q uires t he s u bject’s 
ver bal c o nse nt. If a t o uc h- u p is perf or me d it is prefera bl y perf or me d i n b ot h 
N L Fs a n d it is rec o m me n de d n ot t o use m o re t ha n 0. 5 m L f or eac h N L F. It is 
of o ut m ost i mp orta nce t o e ns ure t hat t he s u bject recei ves t he sa me pr o d uct as 
i nitial treat me nt i n res pecti ve N L F.
E v al u ati o n of effic ac y
T h e b li n de d e val uat or will e val uate t he wri n kle se verit y ( baseli ne val ue) usi n g 
t he W S R S. 
T he W S R S 
will be c o m plete d 
 b y  th e 
b li n de d e val uat or f or efficac y assess me nt.
T he s u bjects will be p h ot o gra p he d at baseli ne ( bef ore treat me nt) a n d at eac h 
f oll o w- u p visit (bef ore treat me nt, w he n a p plica ble) t o d oc u me nt c o n diti o n at 
baseli ne, 
 a n d t o d oc u me nt A Es i n t he treate d area.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI
C CI

Pa ge 1 2 of 9 5
E v al u ati o n of s afet y
I nf or mati o n re gar di n g A Es will be c ollecte d c o nti n u o usl y d uri n g t he st u d y. 
Sc he d u le d visits:
S cr e e ni n g
Da y -2 1 t o Da y 1
Baseli ne (i nitial treat me nt)
Da y 1
F oll o w- u p a n d T o u c h -u p 
treat me nt
Wee k 4 ( Da y 2 9 )
F oll o w- u p
W ee k 4 , Mo nt h s 3, 6, a n d 9
(after last treat me nt)
F oll o w- u p/ Fi nal visit
M o nt h 1 2 (after last treat me nt)
I nclusi o n cri teri a:
T he s u bject m ust meet t he f oll o w i n g criteria t o be eli gi ble f or t he st u d y:
1.
Si g ne d a n d date d i nf or me d c o nse nt t o partici pate i n t he st u d y .
2.
Me n or w o m e n a ge d 1 8 years of a ge or ol der of C hi nese ori gi n .
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 ures bel o w t he le vel of t he l o wer or bital ri m 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, nee dli n g, 
facelift, ra di ofre q ue nc y etc.).
4.
I nte nt t o u n der g o c orrecti o n of b ot h N L Fs wit h a wri n kle se verit y i n 
W S R S of eit her 3 o n b ot h si des or 4 o n b ot h si des, as assesse d b y t he 
bli n de d e val uat or.
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 y perse nsiti vit y 
t o a n y 
i njecta ble 
h yal ur o nic aci d ( H A) gel.
2.
K n o w n/ pre vi o us aller g y or h y perse nsiti vit y t o l ocal a nest hetics, e. g.,
li d ocai ne or ot her a mi de-t ype a nest hetics.
3.
Hist or y of se vere or m ulti ple aller gies ma nifeste d b y a na p h yla xis .
4.
Pre vi o us 
tiss ue 
re vitalizati o n treat me nt wit h 
laser or 
li g ht, 
mes ot hera p y, 
ra di ofre q ue nc y, c he mical peeli n g , or der ma brasi o n 
bel o w  the le vel of t he l o wer or bital ri m wit hi n 6 m o nt hs bef ore 
treat me nt.
5.
Pre vi o u s s ur ger y (i ncl u di n g aest hetic facial s ur gical t hera p y or 
li p os ucti o n) or tatt o o i n t he area t o be treate d.
6.
Pre vi o us 
tiss ue a u g me ntati o n t hera p y or 
c o nt o uri n g wit h 
a n y 
per ma ne nt 
( n o n-bi o de gra da ble) 
or 
se mi-p er m a ne nt 
facial tiss ue 
a u g me ntati o n t hera p y or a ut ol o g o us fat or p er m a ne nt i mpla nt bel o w 
t he le vel of t he l o wer or bital ri m.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI

Pa ge 1 3 of 9 5
7.
Pre vi o us use of a n y h yal ur o nic aci d 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 
l o wer or bital ri m wit hi n 1 2 m o nt hs bef ore treat me nt.
8.
Pre vi o us use of ne ur ot o xi ns bel o w  the le vel of t he l o wer or bital ri m 
(cr o w's feet li ne is acce pta ble) wit hi n 1 2 m o nt hs bef ore treat me nt.
9.
Hist or y of  ra diati o n or c a ncer o us or pre-ca ncer o us lesi o ns (e. g., acti nic 
kerat osis) i n t he area t o be treate d.
1 0.
Scars or def or mities, acti ve s ki n disease, i nfla m mati o n or relate d 
c o n diti o ns s uc h as i nfecti o n, peri oral der matitis, se b orr heic der matitis, 
ecze ma, r osacea, ac ne, ps oriasis , a n d her pes z oster near or i n t he area 
t o be treate d.
1 1.
S u bjects wi t h de ntal or oral stat us o n vis ual i ns pecti o n t hat i n t he 
o pi ni o n of t he I n vesti gat or w o ul d ma ke t he s u bject u ns uita ble f or 
i ncl usi o n, or S u bjects wit h de ntal, oral or si n us s ur ger y wit hi n past 1 2 
m o nt hs pri or t o t he treat me nt visit or pla n ne d s ur ger y, i ncl u di n g de ntal 
i mpla nts, d uri n g t he st u d y peri o d.
1 2.
O n g oi n g i nfecti o n i n m o ut h or de ntals .
1 3.
C hr o nic i nfecti o n i n hea d a n d nec k re gi o n .
1 4.
Hist or y of or acti ve a ut oi m m u ne disease or c o n necti ve tiss ue diseases 
s uc h 
as 
s yste mic 
l u p us 
eryt he mat os us, 
r he u mat oi d 
art hritis, 
p ol y m y ositis, der mat o m y ositis, or l ocalize d or s yste mic scler o der ma.
1 5.
Te n de nc y t o f or m kel oi ds, h y pertr o p hic scars, or a n y ot her heali n g 
dis or der.
1 6.
Hist or y of blee di n g dis or ders or treat me nt wit h 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 or ot her n o n- ster oi d a nti-
i nfla m mat or y dr u g s (N S AI Ds ), O m e ga -3, or vita mi n E wit hi n 2 wee ks 
bef ore treat me nt .
1 7.
Treat me nt 
wit h 
c he mot 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 di es), s yste mic or 
t o pical (facial) c ortic oster oi ds wit hi n 
3 m o nt hs bef ore treat me nt 
(i n hale d c ortic oi ds are all o we d) .
1 8.
C o nc o mita nt treat me nt wit h t o pical (facial) reti n oi ds wit hi n 3 m o nt hs 
or s yste mic reti n oi ds wit hi n 6 m o nt hs bef ore treat me nt.
1 9.
A n y me dical c o n diti o n t hat i n t he o pi ni o n of  the I n vesti gat or w o ul d 
ma ke t he s u bject u ns uita ble f or i ncl usi o n (e. g., p or p h yria , a c hr o nic, 
rela psi n g, or here ditar y disease t hat ma y affect t he ge neral c o n diti o n or 
ma y 
re q uire fre q ue nt me dical 
treat me nt, a n y ab n or mal scree ni n g 
la b orat or y val ue or E C G, or ps yc hiatric dis or ders).
2 0.
Ot her c o n diti o n pre ve nti n g t he s u bject fr o m e nteri n g t he st u d y i n t he 
I n vesti gat or's o pi ni o n, e. g., s u bjects n ot li kel y t o a v oi d ot her facial 
c os metic treat me nts, s u bjects a ntici pate d t o be u nreli a ble, u na vaila ble 
or i nca pa ble of u n dersta n di n g t he st u d y assess me nts , or ha vi n g 
u nrealistic e x pectati o ns of t he treat me nt res ult.
2 1.
W o m e n w h o are pre g na n t or breast fee di n g, or w o me n of c hil d beari n g 
p ote ntial w h o are n ot practici n g a de q uate c o ntrace pti o n or pla n ni n g t o 
bec o me pre g na nt d uri n g t he st u d y peri o d.
2 2.
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 mpl o yees, or cl ose relati ves of 
e mpl o y ees at t he S p o ns or C o m pa n y.
2 3.
Partici pati o n i n an y ot her cli nical st u d y wit hi n 
3 0 da ys bef ore 
treat me nt.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 1 4 of 9 5
I n vesti g ati o n al pr o d uct, 
d ose a n d m o de of 
a d m i nist r ati o n:
Rest yla ne Def y ne ( wit h li d ocai ne) c o nsists of sta bilize d h yal ur o nic aci d of n o n-
a ni mal ori gi n at a c o nce ntrati o n of 2 0 m g/ m L i n p h os p hate b uffere d sali ne wit h 
li d ocai ne h y dr oc hl ori de 3 m g/ m L. T he st u d y pr o d uct is s u p plie d i n sterile 1 m L 
s yri n ges. A 2 7 G × ½” u ltra-t hi n wall nee dle will be use d f or i njecti o n.
T he treati n g I n vesti gat or will c hec k t he ra n d o mizati o n vi a t he e C R F s yste m f or 
st u d y pr o d uct, i.e,. t he N L F o n o ne si de of t he face will be ra n d o ml y assi g ne d t o 
treat me nt wit h Rest yla ne Def y ne a n d t he o p p osite N L F t o treat me nt wit h 
Rest yla ne.
Rest yla ne Def y ne s h o ul d be i njecte d i nt o t he mi d t o dee p der mis of t he facial 
s ki n i n t he N L F. T he i njecti o n pr oce d ure s h o ul d strictl y f oll o w the r ules of 
ase ptic s ur gical tec h ni q ue (refer t o t he Rest yla ne Def y ne I nstr ucti o ns F or Use 
f or details).
F or i nitial treat me nt, it is rec o m me n de d n ot t o use m o re t ha n 1. 5 m L f or eac h 
N L F. F or t o uc h u p treat me nt, it is rec o m me n de d n ot t o use m o re t ha n 0. 5 m L 
f or eac h N L F.
T he li near t hrea di n g tec h ni q ue ca n be use d t o caref ull y lift u p t he wri n kle. T h e 
i njecti o n tec h ni q ue s h o ul d be t he sa me f or b ot h si des of  the face in a n y o n e 
s u bject t o li mit varia bilit y d ue t o tec h ni q ue. S ufficie nt a m o u nts of pr o d uct 
s h o ul d be i njecte d t o f ull y c orrect t he defect. Defects s h o ul d be f ull y c orrecte d, 
b ut n ot o verc orrecte d
Rest yla ne Def y ne is a p pr o ve d u n der t he bra n d na me E mer vel Dee p Li d ocai ne 
i n se veral c o u ntries.
Refere nce t her a p y, d ose 
a n d m o de of 
a d m i nist r ati o n
Rest yla ne ( wit h o ut li d ocai ne) c o nsists of sta bilize d h yal ur o nic aci d of n o n -
a ni mal ori gi n at a c o nce ntrati o n of 2 0 m g/ m L, i n p h os p hate b uffere d sali ne. T he 
st u d y pr o d uct is s u p plie d i n sterile 1 m L s yri n ges. A 3 0 G × ½” nee dle will b e 
use d f or i njecti o n.
Res t ylane s h o ul d be i njecte d i nt o t he mi d d le pa rt of t he der mis lay er o f t he 
facial s ki n i n t he N L F. T he i nj ectio n pr o ce d u re s h o ul d strictl y f oll o w r ules o f 
ase ptic s urg ical tec hni q u e (refer t o t he R est ylane I n str uctio n s F o r Use f o r 
det ails).
F or i nitial treat me nt, it is rec o m me n de d n ot t o use m o re t ha n 1. 5 m L f or eac h 
N L F. F or t o uc h u p treat me nt, it is rec o m me n de d n ot t o use m o re t ha n 0. 5 m L 
f or eac h N L F.
T he li near t hrea di n g tec h ni q ue ca n be use d t o caref ull y lift u p t he wri n kle. T h e 
i njecti o n tec h ni q ue s h o ul d be t he sa me f or b ot h si des of  the face i n a n y o n e 
s u bject t o li mit varia bilit y d ue t o tec h ni q ue. S ufficie nt a m o u nts of pr o d uct 
s h o ul d be i njecte d t o f ull y c orrect t he defect. Defects s h o ul d be f ull y c orrecte d, 
b ut n ot o verc orrecte d
D ur ati o n of tre at me nt 
a n d f oll o w -u p:
F oll o w i n g scree ni n g a n d treat me nt (i nitial a n d o pti o nal 4- wee k t o uc h-u p) t here 
is a f oll o w- u p peri o d of 1 2 m o nt hs i nclu di n g f oll o w- u p visits at 4 we e ks (± 3 
da ys), 3 m o nt hs ( ± 7 da ys), 6 m o nt hs ( ± 7 da ys), 9 m o nt hs ( ± 2 we e ks) a n d 1 2 
m o nt hs ( ± 2 we e ks).
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI

Pa ge 1 5 of 9 5
Effic ac y Assess me nt:
N L F se verit y Assess me nt:
T he Wri n kle 
Se verit y Rati n g Scale ( W S R S) is a vali date d p h ot o gra p h -base d 
o utc o me i nstr u me nt t hat is desi g ne d s pecificall y f or q ua ntif yi n g facial f ol ds. 
Sc ori n g of f ol d se verit y is base d o n vis ual assess me nt of t he le n gt h a n d 
a p pare nt de pt h of t he N L F at a certai n ti me-p oi nt a n d t he res ult is n ot base d o n 
a c o m paris o n t o t he baseli ne or pre -treat me nt a p peara nce. Eac h sc ore i n t he 
W S R S is e xe m plifie d b y a p h ot o gra p h of N L Fs.
At scree ni n g, baseli ne a n d each f oll o w up visit, t he W S R S will be use d b y  the 
bli n de d e val uat or f or N L F se verit y assess me nt.
Wri n kle Se verit y Rati n g Scale ( W S R S):
Gr a d e
Des cripti o n
1
A b se nt: N o v isib le f ol d; c o ntin u o u s sk i n line
2  
M ild: S h all o w b u t visib le f ol d w it h a slig h t i nd e ntati o n; min o r 
facial feat ure
I mp lant
is e x pecte d
t o pr o d u ce a slig h t i m pro v e me nt
i n 
ap p earan ce
3
M o de rate: M o d eratel y d eep f ol d s; clear facial fea t ure v isib le at 
n or m al a p p earan ce b ut n o t w he n stretc he d.
E x celle nt c o rrectio n i s ex p ect e d fr o m i njecta ble i m pla nt
4
Se ver e: V er y l o n g a n d de e p f ol d; pr o mi ne nt faci al feat ure; less 
t ha n 2- m m v isib le f ol d w h e n stretc he d
S i g nificant i m pr o ve m e nt is e x p ecte d fr o m i njecta ble im p lant
5
E x tre me: E xtre mel y dee p a n d l o n g f ol d; detr i me ntal t o facial 
ap p earan ce; 2- t o 4- m m V- s ha p e d fo l d w he n st retc he d. 
U n li kel y t o ha ve satisfac t or y c orrectio n wit h i nj e cta ble i m plan t 
al one
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI

Pa ge 1 6 of 9 5
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI

Pa ge 1 7 of 9 5
S a fet y Assess me n t:
Eac h s u bject will be q uesti o ne d a b o ut A Es at eac h cli nical visit f oll o wi n g t he 
scree ni n g visit. T he q uesti o n as ke d will be “Si nce y o ur last cli nical visit ha ve 
y o u ha d a n y healt h pr o ble m s ? ” I nf or mati o n o n A Es ca n als o be o btai ne d fr o m 
si g ns a n d s y mpt o m s detecte d d uri n g eac h e xa mi nati o n, o bser vati o ns b y t he 
st u d y pers o n nel,
la b orat or y tests, or s p o nta ne o us re p orts fr o m 
t he s u bjects.
St atistic al Met h o ds:
Pri m ar y a n al ysis
N o n -i nferi orit y testi n g f or Rest yla ne Def y ne relati ve t o Rest yla ne will be base d 
o n t he 9 5 % c o nfi de nce i nter val a p pr oac h wit h a n o n -i nferi orit y mar gi n of 1 5 %. 
T he c o nfi de nce i nter val will b e c o nstr ucte d f or t he differe nce ( Rest yla ne mi n u s 
Rest yla ne Def y ne) i n res p o nse rates at t he 6 m o nt h f oll o w-u p v isit.
N o n -i nferi orit y will be declare d if t he 2- si de d 9 5 % i nter val is f ull y bel o w  15 % 
(i.e., t he u p per b o u n d of  the i nter val is less t ha n 1 5 %) i n b ot h t he F A S a n d P P 
p o p ulati o ns.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pa ge 1 8 of 9 5
S afet y
 
A d verse e ve nt i nci de nces will b e 
s u m marize d b y Me d D R A s yste m or ga n class ( S O C) a n d preferre d ter m ( P T).
S a m ple size
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
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Pa ge 1 9 of 9 5
A b bre vi ati o ns a n d Defi niti o ns of Ter ms
A E
A d verse eve nt 
Bli n de d 
e val uat or
A n 
eval uat or res p o nsi ble f or i n de pe n de nt e val uati o n of treat me nt 
res ult(s). T he eval uat or m ust 
be bli n de d t o t he treat me nt a n d n ot
i n v ol ve d i n t he treat me nt of t he s u bject.
C F D A
C hi na F o o d a n d Dr u g A d mi nistrati o n
C o or di n ati n g 
I n vesti gat or
I n vesti gat or w h o is a p p oi nte d b y  the S p o ns or t o c o or di nate w or k i n a 
m ultice nter st u d y
C R O
C o ntract researc h o r ga nizati o n
C S P
Cli nical st u d y  pr ot oc ol
C T A
Cli nical trial agree 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 bilit y , relia bilit y, safet y or perf or ma nce (i ncl u des m alf u ncti o ns, use 
err ors , a n d i na de q uate la belli n g)
D M P
Data m a na ge me nt p la n
e C R F
Electr o nic c ase re p ort for m
F A S
F ull A nal ys is Set
G
Ga u ge
G C P
G o o d cli nical practice
H A
H y al ur o nic a ci d
I B
I n vesti gat or’s Br oc h ure
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 ni zati o n
I E C
I n de pe n de nt et hics co m mittee
I F U
I nstr ucti o ns f or u se
I n vesti gati o nal 
pr o d uct
Me dical 
de vice bei n g assesse d f or safety or perf or ma nce i n a st u d y. 
“ I n vesti gati o nal pr o d uct” is t he sa me as “st u d y de vice”, “i n vesti gati o nal 
de vice” , or ” i n vesti gati o nal me dical de vice”.
I nstit uti o n
A n y  pu 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 nvesti gat or ( PI) or ot her q ualifie d pers o n , i.e., s u b-
in vesti gat or , desi g nate d a n d s u per vise d b y  th e PI 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
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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Pa ge 2 0 of 9 5
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.
I S O
I nter nati o nal Or ga nizati o n f or Sta n dar dizati o n
Me d D R A
Me dical d icti o nar y f or re g ulat or y acti vities
N L F
Nas ola bial fol d
N S AI D
N o n -ster oi dal a nti-i nfla m mat or y dr u gs
PI
Pri nci pal I n vesti gat or; q ualifie d pers o n res p o nsi ble f or c o n d ucti n g t he 
st u d y at a st u d y site
P P
Per p r ot oc ol
P T
Preferre d ter m
R A
Re g ulat or y  a ut h orit y
Refere nce 
pr o d uct
Me dical de vice, t hera p y (e. g. acti ve c o ntr ol), place b o or n o treat me nt, 
use d i n t he refere nce gr o u p i n a st u d y
S A E
Seri o us a d verse eve nt
S A P
Statistical A nal y sis Pla n
S D V
S o urce data verificati o n
S -H C G
Ser u m h u ma n ch ori o nic g o na d otr o pi n
S O C
S y ste m o r 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 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 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 uct s
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 treat me nt t o be perf or me d 4 wee ks ± 3 da y s after i nitial 
treat me nt if o pti mal aest hetic i m pr o ve me nt was n ot o btai ne d , i.e.,
s u bjects w h o di d n ot i m pr o ve ≥1 gra de o n W S R S i n o ne or b ot h N L Fs, 
(as assesse d by t he bli n de d e val uat or).
U- H C G
Uri nar y  hu ma n ch ori o nic g o na d otr o pi n
W H O
W orl d Healt h Or ga nizati o n
W S R S
Wri n kle se verit y  rati n g scale
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
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C CI

Pa ge 2 1 of 9 5
T a ble of C o nte nts
I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct ure ............................................................................ 7
Si g ne d A gree me nt of t he Cli nic al St u d y Pr ot oc ol .............................................................................. 9
S y n o psis ................................................................................................................................................ 1 0
A b bre vi ati o ns a n d Defi niti o ns of Ter ms ........................................................................................... 1 9
T a ble of C o nte nts ................................................................................................................................ 2 1
List of T a bles ....................................................................................................................................... 2 5
List of Fi g ures ...................................................................................................................................... 2 5
List of A p pe n dices ............................................................................................................................... 2 5
1
E T HI C A L C O N SI D E R A TI O N S ............................................................................................ 2 6
1. 1
St ate me nt of et hic al c o m pli a nce ......................................................................................... 2 6
1. 2
A p plic ati o n t o i n de pe n de nt et hics c o m mittee a n d/ or re g ul at or y a ut h orities ................. 2 6
2
B A C K G R O U N D I N F O R M A TI O N ........................................................................................ 2 6
2. 1
I n dic ati o n a n d p o p ul ati o n descri pti o n............................................................................... 2 6
2. 2
I n vesti g ati o n al pr o d uct descri pti o n ................................................................................... 2 6
2. 3
Refere nce pr o d uct descri pti o n ........................................................................................... 2 7
2. 4
Pre vi o us e x perie nce ............................................................................................................. 2 7
2. 4. 1
N o ncli nic al d oc u me nt ati o n ............................................................................................ 2 7
2. 4. 2
Cli nic al d oc u me nt ati o n .................................................................................................. 2 8
2. 5
St u d y r ati o n ale ..................................................................................................................... 2 9
2. 6
J ustific ati o n f or t he desi g n of t he st u d y ............................................................................. 2 9
2. 7
Ris ks a n d be nefits ................................................................................................................ 3 0
3
O B J E C TI V E( S) A N D E N D P OI N T( S) .................................................................................... 3 1
3. 1
O bjecti ves a n d e n d p oi nts .................................................................................................... 3 1
3. 1. 1
Pri m ar y o bjecti ve a n d e n d p oi nt .................................................................................... 3 1
3. 1. 3
S afet y O bjecti ves ............................................................................................................ 3 1
4
D E SI G N O F T H E S T U D Y ...................................................................................................... 3 2
4. 1
Ge ner al o utli ne ..................................................................................................................... 3 2
4. 2
N u m ber of s u bjects .............................................................................................................. 3 3
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
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Pa ge 2 2 of 9 5
4. 3
D u r ati o n of s u bject p artici p ati o n ....................................................................................... 3 3
4. 4
R a n d o miz ati o n a n d bli n di n g .............................................................................................. 3 4
4. 4. 1
R a n d o miz ati o n ................................................................................................................ 3 4
4. 4. 2
Bli n di n g ........................................................................................................................... 3 4
4. 4. 3
E mer ge nc y u n bli n di n g ................................................................................................... 3 4
4. 5
Me dic al hist or y
.................................................................................................................... 3 5
4. 6
C o nc o mit a nt me dic ati o ns, tre at me nts, a n d pr oce d ures ................................................... 3 5
4. 7
Sc he d ule of e ve nts ................................................................................................................ 3 6
4. 8
Vi sits ..................................................................................................................................... 3 8
4. 8. 1
Scree ni n g ( D a y -2 1 t o D a y 1) ......................................................................................... 3 8
4. 8. 2
B aseli ne Visit - I niti al tre at me nt ( D a y 1)...................................................................... 3 8
4. 8. 3
Wee k 4 f oll o w -u p after i niti al tre at me nt ( D a y 2 9 3 d a ys) / O pti o n al 
t o uc h-u p ........................................................................................................................... 3 9
4. 8. 4
Wee k 4 f oll o w -u p after t o uc h -u p tre at me nt - o nl y f or s u bjects w h o 
recei ve d t o uc h-u p tre at me nt ( 4 wee ks 3 d a ys) .......................................................... 4 0
4. 8. 5
M o nt h 3 ( ± 7 d a ys), 6 ( ± 7 d a ys), a n d 9 ( ± 2 wee ks) f oll o w -u p ....................................... 4 0
4. 8. 6
M o nt h 1 2 ( ± 2 wee ks) f oll o w -u p/ Fi n al visit or E arl y ter mi n ati o n .............................. 4 1
5
S U B J E C T S ................................................................................................................................ 4 1
5. 1
S u bject i nf or m ati o n a n d i nf or me d c o nse nt ....................................................................... 4 1
5. 2
I ncl usi o n criteri a.................................................................................................................. 4 2
5. 3
E xcl usi o n criteri a ................................................................................................................. 4 2
5. 4
Scree ni n g a n d s u bject n u m bers .......................................................................................... 4 4
5. 5
Wit h dr a w al of s u bjects
....................................................................................................... 4 4
6
S T U D Y P R O D U C T S ................................................................................................................ 4 5
6. 1
I n vesti gati o n al pr o d uct ....................................................................................................... 4 5
6. 2
Refere nce pr o d uct ............................................................................................................... 4 5
6. 3
A d diti o n al pr o d ucts a n d m ateri al ...................................................................................... 4 6
6. 4
P ac k a gi n g, l a belli n g, a n d st or a ge ....................................................................................... 4 6
6. 5
Pr o d uct acc o u nt a bilit y ........................................................................................................ 4 6
6. 6
Tre at me nt ............................................................................................................................. 4 7
6. 6. 1
Tre at me nt pr oce d ure ..................................................................................................... 4 7
6. 6. 2
Tre at me nt re gi me n ( d ose a n d i nter v al) ........................................................................ 4 8
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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Pa ge 2 3 of 9 5
6. 6. 3 
P ost- tre at me nt c are ........................................................................................................ 4 8
6. 6. 4 
P ost- tri al pr o visi o ns ....................................................................................................... 4 9
6. 6. 5
Electr o nic c ase re p ort f or m rec or di n gs ........................................................................ 4 9
6. 6. 6
Tre at me nt c o m pli a nce .................................................................................................... 4 9
7
E F FI C A C Y A S S E S S M E N T S .................................................................................................. 4 9
7. 1
Ge ner al i nf or m ati o n ............................................................................................................ 4 9
7. 2
Wri n kle se verit y r ati n g sc ale
.............................................................................................. 5 0
7. 5
P h ot o gr a p h y ......................................................................................................................... 5 2
8
S A F E T Y A S S E S S M E N T S ....................................................................................................... 5 2
8. 2
L a b or at or y assess me nts ...................................................................................................... 5 3
8. 3
E C G -scree ni n g..................................................................................................................... 5 3
8. 4
A d verse e ve nts ..................................................................................................................... 5 4
8. 4. 1
Defi niti o n of a n a d verse e ve nt ....................................................................................... 5 4
8. 4. 2
Defi niti o n of a seri o us a d verse e ve nt ............................................................................ 5 4
8. 4. 3
Rec or di n g i nstr ucti o ns ................................................................................................... 5 4
8. 4. 4
Re p orti n g of a d verse e ve nts ........................................................................................... 5 6
8. 4. 5
Re p orti n g of seri o us a d verse e ve nts .............................................................................. 5 6
8. 4. 6
F oll o w -u p of u nres ol ve d e ve nts after ter mi n ati o n of t he st u d y .................................. 5 7
8. 4. 7 
Pre g n a nc y........................................................................................................................ 5 8
8. 4. 8
A ntici p ate d a d verse e ve nts ............................................................................................ 5 8
8. 5
De vice deficie ncies ............................................................................................................... 5 8
8. 5. 1
Defi niti o n of a de vice deficie nc y .................................................................................... 5 8
8. 5. 2
Rec or di n g i nstr ucti o ns ................................................................................................... 5 9
8. 5. 3
Re p orti n g of de vice deficie ncies .................................................................................... 5 9
8. 6
D at a s afet y m o nit ori n g b o ar d ( N ot A p plic a ble) ............................................................... 5 9
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 ......................................................................... 5 9
9. 1
D at a m a n a ge me nt ................................................................................................................ 5 9
9. 2
Elec tr o nic c ase re p ort f or ms............................................................................................... 6 0
9. 2. 1
D at a e ntr y ........................................................................................................................ 6 0
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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Pa ge 2 4 of 9 5
9. 2. 2
T he q uer y pr ocess ........................................................................................................... 6 0
9. 2. 3
User i de ntific ati o n .......................................................................................................... 6 1
9. 2. 4
A u dit tr ail ........................................................................................................................ 6 1
9. 3
S o urce d oc u me nts ................................................................................................................ 6 1
9. 4
Rec or d kee pi n g a n d access t o s o urce d at a ......................................................................... 6 2
9. 5
D oc u me nt a n d d at a rete nti o n ............................................................................................. 6 2
1 0
S T A TI S TI C A L M E T H O D S .................................................................................................... 6 2
1 0. 1
Ge ner al ................................................................................................................................. 6 2
1 0. 2
A n al ysis p o p ul ati o ns ............................................................................................................ 6 3
1 0. 3
De m o gr a p hics, b aseli ne assess me nts, a n d s u bject c h ar acteristics .................................. 6 3
1 0. 4
Effic ac y a n al ysis ................................................................................................................... 6 3
1 0. 4. 1
Pri m ar y a n al ysis ............................................................................................................. 6 3
1 0. 4. 2
Sec o n d ar y a n al ysis ......................................................................................................... 6 4
1 0. 5
S afet y a n al ysis ...................................................................................................................... 6 4
1 0. 6
H a n dli n g of missi n g d at a .................................................................................................... 6 4
1 0. 7
I nteri m a n al ysis ( N ot A p plic a ble) ...................................................................................... 6 4
1 0. 8
D at a m o nit ori n g c o m mittee ( N ot A p plic a ble) ................................................................... 6 5
1 0. 9
Wit h dr a w als a n d de vi ati o ns
............................................................................................... 6 5
1 0. 1 0
S a m ple size ........................................................................................................................... 6 5
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 ................................................................................ 6 5
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 ...................................................... 6 6
1 2. 1
Q u alit y c o ntr ol ..................................................................................................................... 6 6
1 2. 2
Q u alit y ass ur a nce ................................................................................................................ 6 6
1 2. 3
C h a n ges t o t he cli nic al st u d y pr ot oc ol ............................................................................... 6 7
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 .................................................. 6 7
1 4
P U B LI C A TI O N P O LI C Y ........................................................................................................ 6 7
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 ........................................................... 6 8
1 6
R E F E R E N C E S ......................................................................................................................... 6 9
A P P E N DI C E S ..................................................................................................................................... 7 0
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
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Pri nt date:
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Pa ge 2 5 of 9 5
List of T a bles
Ta ble 1.
Sc he d ule of e ve nts ............................................................................................................ 3 6
Ta ble 2.
Wri n kle se verit y rati n g scale ............................................................................................ 5 0
List of Fi g ures
Fi g ure 1.
Fl o w c hart: St u d y visits .................................................................................................... 3 3
List of A p pe n dices
A p pe n di x 1 Declarati o n of Helsi n ki ....................................................................................................... 1
A p pe n di x 2 I nstr ucti o ns f or Use Rest yla ne Def y ne............................................................................... 1
A p pe n di x 3 I nstr ucti o n f or Use Rest yla ne C hi na................................................................................... 1
A p pe n di x 4 P h ot o g ui de f or Wri n kle Se verit y Rati n g Scale ( W S R S) ................................................... 1
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI

Pa ge 2 6 of 9 5
1 
E T HI C A L C O N SI D E R A TI O N S
1. 1
St ate me nt of et hic al c o m pli a nce
T he st u d y s hall be c o n d ucte d i n c o m plia nce wit h t he cli nical trial agree me nt ( C T A), t he 
cli nical st u d y pr ot oc ol ( CS P) , g o o d cli nical p ractice ( G C P), a n d a p plica ble re gi o nal or 
nati o nal re g ulati o ns. T he i nter nati o nal sta n dar d f or cli nical st u d y of me dical de vices f or 
h u ma n s u bjects, I SO 1 4 1 5 5 : 2 0 1 1 s hall be f oll o we d. T he
Inter nati o nal C o nfere nce 
o n 
Har m o nizati o n
(IC H ) gui deli ne f or G C P ( E 6) s hall be f oll o we d as a p plica ble f or me dical 
de vice . T h e st u d y s hall be c o n d ucte d i n acc or da nce wit h t he et hical pri nci ples t hat ha ve t heir 
ori gi n i n t he Declarati o n of Helsi n ki ( A p pe n di x 1 ).
1. 2
A p plic ati o n t o i n de pe n de nt et hics co m mittee a n d/ or re g ul at or y a ut h orities
It is t he res p o nsi bilit y of t he P ri nci pal I n vesti gat or ( PI) t o o btai n a p pr o val of t he 
C S P /C S P a me n d me nt (s) fr o m t he in de pe n de nt et hics co 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 fa v ora ble o pi ni o n fr o m t he I E C has bee n o btai ne d. T he PI  shall file 
all c orres p o n de nce wit h t he I E C i n t he I nvesti gat or file a n d co pies of I E C a p pr o vals s hall be 
f or war de d t o t he S p o ns or. A n y  ad diti o nal re q uire me nts i m p ose d b y  the I EC or re g ulat or y 
aut h orities (R A ) s hall be f oll o we d. 
T he c ollecti o n, access t o, pr ocessi 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 ca rrie 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.
2
B A C K G R O U N D I N F O R M A TI 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 D ef y ne is a n i njecta ble filler use d f or facial tiss ue a u g me ntati o n a n d, i n t his st u d y,
i nte n de d f or t he c orrecti o n of m o derate t o se vere nas ola bial f ol ds ( N L Fs) i n su bjects o ver t he 
a ge of 1 8.
2. 2
I n vesti g ati o n al pr o d uct descri pti o n
A m o n g t he differe nt materials u se d as ra w materials i n der mal 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 vi v o a n d herei nafter referre d t o as H A, is t he 
m ost fre q ue ntly use d 1. H yal ur o nic aci d is a nat urall y  occ urri n g p ol ys acc hari de f o u n d i n all 
verte brates a n d i n s o me bacteria 1 ,2. The c he mical str uct ure is ver y  si m ple wit h re peati n g 
disacc hari de u nits of gl uc ur o nic aci d a n d N- acet yl gl uc osa mi ne . As t he che mical str uct 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.
T o mi ni mize t he ris k f or c o nta mi nati o n, t he H A use d i n t he ma n ufact ure of Gal der ma ’s H A
gels is of n o n- a ni mal s o urce, bi os y nt hesize d fr o m Stre pt oc occ us s pecies of bacteria. D uri n g 
ma n ufact uri n g, cr oss-li n ks are i ntr o d uce d bet wee n t he H A c hai ns t o o btai n a gel net w or k a n d 
as a res ult t he d urati o n of t he gel i n t he b o d y  is se veral m o nt hs, as c o m pare d t o o nl y a fe w 
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da y s f or a s ol uti o n of nati ve H A.
T he H A g el is i ns ol u ble i n water a n d or ga nic s ol ve nts;
h o we ver, t he gel is hi g hl y  hy d r o p hilic a n d s wells i n wate r. H yal ur o nic aci d base d fillers 
t ypicall y e x hi bit better bi oc o m pati bilit y  an d fe wer a d verse reacti o ns t ha n fillers base d o n 
ot her materials.
T he gel, w he n i njecte d, acts b y  increasi n g t he tiss ue v ol u me, t here b y 
i m pr o vi n g tiss ue str uct ure a n d s u p p ort. T he gel is gra d uall y de gra de d o ver ti me a n d 
e ve nt uall y t he c orrecti o n ma de will s u bsi de.
Rest y la ne Def y n 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
c o ntai ni n g a c o nce ntrati o n of 2 0 m g H A per m L i n a p h y si ol o gical b uffer s yste m. Li d ocai ne 
h y dr oc hl ori de ( 3 m g / m L) 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 treatme nt. W he n t he gel is injecte d a n d t he tiss ue e x pa n ds s o me pai n ca n 
be e x perie nce d a n d it is t heref ore desira ble t o ha ve a l ocal a nest hetic effect at t he site of 
i njecti o n.
Rest y la ne Def yne has bee n re g ulat or y cleare d u n der t he bra n d na me E mer vel Dee p L i d ocai ne 
i n m ore t ha n 5 0 c o u ntries fr o m m ost c o nti ne nts of t he w orl d i ncl u di n g t he E ur o pe, N ort h 
A merica ( o nly Ca na da ), Lati n A merica, A ustralia, a n d Asia . T he i nte n de d use, i n t he re gi o n
of ori gi n ( E ur o pe), is facial tiss ue a u g me ntati o n f or t he c orrecti o n of se vere wri n kles or to 
re defi ne t he s ha pe of t he face (c hee k b o nes, tear tr o u g hs, or li ps). T he re g ulat or y cleare d
i nte n de d use differs bet wee n differe nt c o u ntries. 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 osal la yer of 
t he li ps, s u bc utis, or s u pra peri ostic z o ne. 
T he gel i n Rest yl a ne Def yne is , as all t he E mer vel filler pr o d ucts, pr o d uce d usi n g t he O pti mal 
Bala nce Tec h n ol o g y  ( O B T) pr ocess.
2. 3
Refere nce pr o d uct descri pti o n
T he refere nce pr o d uct i n t he st u d y is Rest yl a ne, a n ot her H A -base d der mal filler. T he H A 
c o nte nt i n Rest yl a ne is 2 0 m g/ m L i n a p h y si ol o gical b uffer s yste m, h o we ver, Rest yl a ne d oes 
n ot c o ntai n a n y li d ocai ne as c o m pare d t o Rest yl a ne Def yn e , t he i n vesti gati o nal pr o d uct of t he 
st u d y. Rest y la ne is pr o d uce d usi n g t he N A S H A ™tec h n ol o g y pr o d uci n g a gel c o ntai ni n g 
sta bilize d n o n-a ni mal H A gel .
Rest y la ne was C E -mar ke d i n E ur o pe i n 1 9 9 6 a n d is n o w re g ulat or y cleare d i n m ore t ha n 
8 0 c o u ntries i ncl u di n g t he U S a n d i n se veral Asia n c o u ntries. I n 2 0 0 8, Rest y la ne recei ve d 
mar keti n g re gistrati o n i n C hi na
as a me dical de vice t o be use d f or facial der mal tiss ue 
a u g me ntati o n t o c orrect m o derate t o se vere N L Fs.
2. 4
Pre vi o us ex perie nce
2. 4. 1
N o nc li nic al d oc u me nt a ti o n
Pr o d ucts ma n ufact ure d usi n g t he O B T pr ocess ha ve bee n teste d a n d meet all bi oc o m pati bilit y  
re q uire me nts s pecifie d i n t he i nter nati o nal sta n dar d I S O 1 0 9 9 3: 1 ( Bi ol o gical E val uati o n of 
Me dical De vices ; i.e., ha vi n g n o t o xic or i nj uri o us effects o n t he h u ma n b o d y )3 ,4; it is neit her 
c yt ot o xic n or ge n ot o xic, a n d it d oes n ot gi ve rise t o ac ute t o xicit y, p y r o ge nicity, s ki n 
irritati o n, or dela y e d se nsitizati o n. 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
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I n in vi v o a ni mal st u dies, t he O B T pr o d ucts de m o nstrate d g o o d filler l o n ge vity, si milar or 
s u peri or t o c o m parat or pr o d ucts, a n d all pr o d ucts
were 
well 
t olerate d wit h 
mi ni mal 
micr osc o pic i nfla m mati o n sc ores sec o n dar y  t o li mite d tiss ue dist ur ba nce.
2. 4. 2
Cli nic al d oc u me nt ati o n
Rest y la ne D ef y ne has bee n e val uate d i n a 1- ye ar, ra n d o mize d, e val uat or-bli n de d, acti ve-
c o ntr olle d, m ulti -ce nter, s plit-face c o m paris o n U S st u d y of t he t w o H A fillers Rest y la ne 
Def y ne a n d J u véder m Ultra Pl us wit h t he o bjecti ve t o c o m pare efficac y a n d safety 5.
O ne h u n dre d si xt y-t w o ( 1 6 2) s u bjects wit h m o de rate t o se vere N L Fs were treate d wit h 
Rest y la ne Def yne i n o ne N L F a n d J u vé der m Ultra Pl us i n t he ot her.
T he pri mar y  efficac y anal y sis i n t he i nte nt-t o-treat p o p ulati o n at Wee k 2 4 s h o we d a mea n 
c ha n ge fr o m baseli ne of - 1. 1 i n wri n kle se verit y rati n g scale (W S R S ) sc ore f or b ot h 
Rest y la ne Def y ne a n d J u vé der m Ultra Pl us. N o n -i nferi ority of Rest yl a ne Def y ne c o m pare d 
wit h J u vé der m Ultra Pl us was de m o nstrate d. F or mea n c ha n ge fr o m baseli ne i n W S R S sc ore, 
Rest y la ne Def y ne a n d J u vé der m Ultra Pl us were cli nicall y co m para ble at all-ti me p oi nts u p 
t o Wee k 4 8.
T he be nefit of pre -i nc or p orate d li d ocai ne i n Rest y la ne Def y ne was o bser ve d i m me diately at 
t he ti me of i njecti o n a n d u p t o 1 h o ur p ost-i njecti o n.
Rest y la ne D ef y ne s h o we d a fa v ora ble safet y pr ofile i n s u bjects wit h m o derate t o se vere 
wri n kles a n d f ol ds, a n d was c o m para ble t o J u vé der m Ultra Pl us. T he perce nta ge of s u bjects 
wit h a d verse e ve nts (A Es ) after treat me nt wit h Rest y la ne Def yne was si milar t o t he 
perce nta ge of s u bjects wit h A Es after treat me nt wit h J u vé der m Ult ra Pl us. T he A Es t hat were 
assesse d b y  the I n vesti gat ors as pr o d uct -relate d were m ostl y mil d i n i nte nsit y. M ost of t he 
A Es relate d t o st u d y pr o d ucts were ass ociate d wit h treat me nt si de (ri g ht or left) a n d t he 
distri b uti o n bet wee n t he t w o treate d si des was si milar. T he m ost c o m m o n A Es relate d t o 
st u d y pr o d ucts were i njecti o n site s welli n g a n d i njecti o n site er yt he ma. T w o s u bjects ha d A Es 
wit h 
ca usal relati o ns hi p t o st u d y pr o d ucts, aller gic c o ntact der matitis a n d i nterstitial 
gra n ul o mat o us der matitis, res pecti vely t hat le d t o st u d y disc o nti n uati o n. I n t he t w o s u bjects, 
t he A E was re p orte d f or b ot h si des of t he face, i.e., f or b ot h pr o d ucts . B ot h e ve nts res ol ve d 
wit h o ut se q uelae.
A n ot her ra n d o mize d, e val uat or- bli n de d st u d y i n E ur o pe c o m pari n g E mer vel Dee p (i de ntical 
t o Rest y la ne Def y ne b ut wit h o ut 
li d ocai ne) wit h 
Rest y la ne Perla ne
i n 8 6 s u bjects, 
de m o nstrate d si milar safet y bet wee n t he der mal fillers a n d a s u peri or, al beit of li mite d 
cli nical rele va nce, efficac y of E mer vel Dee p after N L F c orrecti o n 6.
Rest y la ne was re gistere d i n C hi na 2 0 0 8 as a me dical de vice f or facial tiss ue a u g me ntati o n t o 
c orrect m o derate t o se vere N L Fs.
Rest y la ne has bee n e xte nsi vel y eval uate d w orl d wi de
i n 
cli nical st u dies7- 2 1 a n d has als o bee n pr o ve n safe a n d efficaci o us i n a cli nical trial i n a 
C hi nese st u d y po p ulati o n 1 8. T h e st u d y was perf or me d i n C hi na a n d t he ai m was t o st u d y the 
safety a n d efficac y of Rest y la ne f or facial tiss ue a u g me ntati o n (i.e., N L Fs; n = 8 6). E fficac y 
was sustai ne d wit h a si g nifica nt i m pr o ve me nt fr o m baseli ne at all-ti me p oi nts u p t o t he last 
o bser vati o n at 6 m o nt hs p ost -treat me nt. T he st u d y als o s h o we d t hat Rest y la ne was well 
t olerate d a n d n o s yste mic reacti o ns or ot her safet y co ncer ns were raise d. S o me transie nt 
a ntici pate d p ost-i njecti o n reacti o ns were re p orte d, ge nerally of mil d i nte nsit y. T hese reacti o ns 
res ol ve d s p o nta ne o usl y wit h o ut nee d of s pecific treat me nt. T he res ults fr o m t he st u d y 
de m o nstrate d t hat Rest y la ne is, at least, as efficaci o us i n a C hi n ese st u d y po p ulati o n as i n a 
Title  
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4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
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Pa ge 2 9 of 9 5
U S st u d y  p o p ulati o n 1 2, 1 3, 1 5 a n d t hat t he fre q ue nc y of A Es relate d t o treat me nt was si milar i n a 
C hi nese st u d y  p o p ulati o n as i n U S st u d y p o p ulati o n 1 2, 1 3, 1 5.
2. 5
St u d y rati o n ale
Rest y la ne has bee n pr o ve n t o be safe a n d efficaci o us in a cli nical trial i n a C hi nese st u d y 
p o p ulati o n 1 8. B y  co m paris o n, Rest y la ne i n a C hi nese st u d y po p ulati o n was at least as 
efficaci o us as i n a U S 
st u d y po p ulati o n a n d wit h 
si milar safety as i n a U S 
st u d y 
p o p ulati o n 1 2, 1 3, 1 5. T he efficac y a n d safet y of Rest yla ne Def yne f or c orrecti o n of t he N L Fs i n a 
C hi nese p o p ulati o n has n ot yet bee n e val uate d. T his st u d y will pr o vi de d oc u me ntati o n o n t he 
efficac y a n d safet y of Rest y la ne D ef y ne f or facial a u g me ntati o n, t o c orrect N L Fs
i n a 
C hi nese p o p ulati o n. T he d oc u me n tati o n will be use d t o s u p p ort re gistrati o n of t he pr o d uct i n 
C hi na.
T his st u d y ai ms t o e val uate t he efficac y an d safety of Rest y la ne Def y ne c o m pare d t o 
Rest y la ne f or c orrecti o n of N L Fs i n a C hi nese p o p ulati o n. T his st u d y  will f oll o w t he s u bjects 
f or 1 2 mo nt hs.
2. 6
J ustific ati o n f or t he d esi g n of t he st u d y
T he p ur p ose of t he st u d y is t o e val uate t he efficac y of Rest yl a ne Def y ne c o m pare d t o 
Rest y la ne i n c orrecti o n of N L Fs b y  eval uati o n of wri n kle se verit y res p o nse rates at 6 m o nt hs 
after last treat me nt.
 
Safet y i nf or mati o n will be c ollecte d 
 
 b y  collecti n g A Es
t hr o u g h o ut t he 1 2 m o nt h st u d y
peri o d . T he st u d y will be use d as cli nical d oc u me ntati o n f or re gistrati o n of Rest y la ne Def y ne 
i n C hi na.
A s plit-face desi g n, w here eac h patie nt recei ves o ne treat me nt i n o n e N L F a n d a n ot her 
treat me nt i n t he o p p osite N L F, is t he sta n dar d desi g n t o e val uate t he efficac y an d safet y of 
der mal filler c o m pare d t o a n ot her 1 0. T he e val uati o n will be carrie d o ut b y a bli n de d e val uat or 
t o e na ble u n biase d assess me nts of t he W S R S 
 
.
T he rati o nale f or c h o osi n g a pri mar y  efficac y e n d p oi nt of 6 m o nt hs is t hat t his is i n li ne wit h 
t he pre vi o usl y  co n d ucte d ra n d o mize d st u dies carrie d o ut wit h E mer vel Dee p
/ Rest y la ne 
Def y ne, w hic h ha ve pr o ve n t o ge nerat e relia ble res ults. Si x m o nt hs efficac y data is i n li ne 
wit h C hi na F o o d a n d Dr u g A d mi nistra ti o n ( C F D A) re q uire me nts f or i njecta ble facial fillers 
of s o di u m h y al ur o nate.
T he 5- gra de vali date d W S R S t o ol2 2 has bee n use d i n t he ot her st u dies wit h acce pta ble i nter-
a n d i ntra-rater c orrelati o n. T he scale is vali date d a n d it is acce pte d b y  US F D A f or 
re gistrati o n st u dies.
 
 
 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI
C CI

Pa ge 3 0 of 9 5
2. 7
Ris k s a n d be nefits
B y  J an uar y  20 1 6, Rest yl a ne is re g ulat or y cleare d i n m ore t ha n 8 0 c o u ntries i ncl u di n g t he U S 
a n d C hi na , a n d Rest y la ne Def y ne, re g ulat or y cleare d u n der t he b ra n d na me E mer vel Dee p 
Li d ocai n, i n m ore t ha n 5 0 c o u ntries . B ot h pr o d ucts are c o nsi dere d safe a n d effecti ve f or 
facial der mal tiss ue a u g me ntati o n t o c orrect N L Fs .
Rest y la ne a n d Rest yl a ne Def y ne, as all ot her i njecta ble me dical de vices, ha ve t he p ote ntial t o 
ca use c o m plicati o ns. M ost e ve nts are relate d t o t he i njecte d v ol u me a n d i njecti o n tec h ni q ue, 
t h o u g h s o me c o ul d be ass ociate d wit h pr o perties or c o nstit utes of t he gel itself. After t he 
i njecti o n of Rest yla ne Def y ne a n d Rest y la ne, 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 nc l u de br uisi n g, er yt he ma, s welli n g, pai n, te n der ness, or itc hi n g 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 d a y s after i njecti o n i nt o t he 
s ki n. T he i nte nsit y a n d d urati o n of t hese e ve nts are us uall y co nsi dere d t olera ble b y  a maj orit y 
of s u bjects. T he st u d y pr o d ucts will be a d mi nistere d i n acc or da nce wit h t he i nstr ucti o ns i n 
Secti o n 6. 6. 1.
T he pri mar y  pote ntial be nefit of t he st u d y is a percei ve d i m pr o ve me nt i n t he vis ual 
a p peara nce of t he face, s pecifically t he N L Fs. H o we ver, th ere is a ris k t hat t he s u bject will 
n ot gai n t he f ull aest hetic c orrecti o n of N L F s. T here is als o a ris k f or de vel o p me nt of 
pal pa ble l u m ps or dis p lace me nt of t he i njecte d g el . I nfla m mati o n or i nfecti o n ha ve bee n 
re p orte d i n a fe w cases after H A filler treat me nt. T here m a y  be ris k of 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 o r. Detaile d 
i nf or mati o n o n re p orte d A Es 
rele va nt f or Rest y la ne Def y ne a n d 
Rest y la ne is pr o vi de d i n t he I nstr ucti o n f or Use (I F U) as well as i n t he I B f or Rest yl a ne 
Def y ne.
Li d ocai ne ca 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.
T he fre q ue nc y of p ost mar ket A E re p orti n g is base d o n t he n u m ber of u nits s ol d. T he 
re p orti n g fre q ue nc y of A Es assesse d as relate d t o Rest y la ne a n d Rest y la ne Def yne are 
ra n gi n g fr o m sel d o m (a p pr o xi matel y 1/ 1 0 0 0 – 1/ 1 0 0 0 0 e ve nts per s ol d u nit) t o rare/ is olate d 
cases (i.e., < 1/ 1 0 0 0 0 0 e ve nts per s ol d u nit).
T he ris ks relate d t o H A fil ler i njecti o ns f or c orrecti o n of wri n kles a n d f ol ds ha ve bee n j u d ge d
t o be l o w, base d o n n o ncli nical data ( Secti o n 2. 4. 1 ), e x perie nce fr o m cli nical st u dies 
( Secti o n 2. 4. 2 ) a n d p ost -mar keti n g data . Gi ve n
t he a ntici pate d l o w le vel of tra nsien t a n d
accep tab le A Es
i n 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
R est y l a n e D ef y n e a n d R est y l a n e f or c orr e cti o ns of N L Fs a p pears t o o ffer a cli nical
be nefit at reas o na ble ris k.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
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Pa ge 3 1 of 9 5
3
O B J E C TI V E ( S) A N D E N D P OI N T( S )
3. 1
O bjecti ves a n d e n d p oi nts
3. 1. 1
Pri m ar y o bjecti ve a n d e n d p oi nt
T he pri mar y  objecti ve of t he st u d y is t o e val uate t he efficac y of Rest yl a ne Def y ne c o m pare d 
t o Rest y la ne i n c orrecti o n of N L Fs b y  co m pari n g res p o nse rates base d o n t he W S R S, 
as 
assesse d b y t he bli n de d e val uat or , at 6 m o nt hs after last treat me nt.
A res p o nse rate is defi ne d as perce nta ge of s u bjects wit h at least 1 gra de i m pr o ve me nt o n t he 
W S R S. T he n o n- i nferi orit y of Rest y la ne Def y ne vers us Rest yl a ne will be s h o w n if t he t w o-
si de d 9 5 % c o nfi de nce i nter val of t heir differe nce at 6 m o nt hs after last treat me nt e xcl u des a n 
i nferi orit y of 1 5 % or m ore.
3. 1. 3
S afet y O bjecti ves
T he safety o bjecti ves a n d e n d p oi nts are:

T o e val uate t he safety of Rest y la ne Def y ne a n d Rest y la ne d uri n g t he w h ole st u d y by 
c ollecti n g A Es.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI

Pa ge 3 2 of 9 5
4
D E SI G N O F T H E S T U D Y
4. 1
Ge ner al o utli ne
T his is a ra n d o mize d, m ulti -ce nter, e val uat or-bli n de d st u d y in C hi na t o e val uate t he efficac y 
a n d safet y pr ofile ass ociate d wit h c orrecti o n of m o derate t o se vere nas ola bial f ol ds usi n g
Rest y la ne Def y ne ( wit h li d ocai ne) c o m pare d t o Rest y la ne ( wit h o ut li d ocai ne). Bli n di n g will 
be acc o m plis he d b y a bli n de d e val uat or , t o w h o m ra n d o mizati o n a n d treat me nt are c o nceale d, 
t o e val uate t he wri n kle se verit y scale. T he treati n g In vesti gat or will n ot be bli n de d.
Writte n i nf or me d c o nse nt will be o btai ne d bef ore a n y st u d y relate d pr oce d ure is perf or me d. 
S u bjects will be scree ne d f or eli gi bilit y wit hi n 2 1 d a y s pri or t o st u d y ra n d o mizati o n o n 
D a y 1. S u bse q ue nt t o scree ni n g , eli gi ble s u bjects will be e nr olle d i n t o t he st u d y. 
Eac h s u bject will recei ve a n i nitial treat me nt o n Da y  1 ( baseli ne) wit h Rest y la ne Def y ne i n 
o ne N L F a n d Rest yl a ne i n t he o p p osite N L F, as ra n d oml y assi g ne d. T he first i njecti o n will 
al wa ys start i n t he ri g ht N L F. 
 
 
 
A n o pti o nal sec o n d treat me nt (t o uc h- u p) will be offere d 4 wee ks after t he i nitial treat me nt if 
o pti mal aest hetic i m pr o ve me nt is n ot ac hie ve d, i.e., i n s u bjects w h o di d n ot i m pr o ve ≥1 gra de 
i n W S R S i n o ne or b ot h N L Fs as assesse d b y t he b li n de d e val uat or. 
Rest y la ne Def y ne s h o ul d be i njecte d i nt o t he mi d t o dee p der mis an d Rest y la ne s h o ul d be 
i njecte d i nt o t he mi d dle part of t he der mis la yer of t he facial s ki n i n t he N L F. F or i nitial 
i njecti o ns, it is rec o m me n de d n ot t o use m ore t ha n 1. 5 m L
f or eac h N L F a n d for t o uc h-u p 
i njecti o n it is rec o m me n de d n ot t o use m ore t ha n 0. 5 m L
f or eac h N L F. A d mi nistrati o n of 
Rest y la ne D ef y ne a n d Rest y la ne will be perf or me d b y t he treati n g I n vesti gat or acc or di n g a 
sta n dar dize d pr oce d ure descri be d i n S ecti o n 6. 6 .
After t he treat me nt visits (i nitial a n d o pti o nal ) t here is a f oll o w-u p peri o d of 1 2 m o nt hs . 
F oll o w -u p visits are sc he d ule d at 4 wee ks ( ±3 da ys), 3 m o nt hs ( ± 7 da y s), 6 m o nt hs ( ± 7 da y s), 
9 m o nt hs ( ± 2 wee ks) , a n d 1 2 m o nt hs ( ± 2 wee ks)
after t he last treat me nt f or efficac y an d 
safety assess me nts ( Fi g ure 1 ).
T he ai m of t he treat me nt is t o ac hie ve o pti mal aest hetic i m pr o ve me nt, defi ne d as at least o ne
(≥1 ) gra de i m pr o ve me nt fr o m baseli ne o n t he W S R S, as assesse d b y  the bli n de d e val uat or.
T he bli n de d e val uat or will e val uate t he wri n kle se verit y usi n g W S R S at baseli ne a n d at eac h 
f oll o w-u p visit f or efficac y assess me nt.
 
T he s u bjects will be 
p h ot o gra p he d bef ore treat me nt at t he baseli ne visit a n d at t he o pti o nal t o uc h- u p treat me nt
visit as well as at eac h f oll o w- u p visit . T he p h ot o gra p hs will be use d t o d oc u me nt c o n diti o n 
at baseli ne, 
 a n d t o d oc u me nt A E s i n 
t he treate d area.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI
C CI

Pa ge 3 3 of 9 5
Fi g ure 1.
Fl o w c h art: St u d y visits
I nf or mati o n re gar di n g A Es will be c ollecte d c o nti n u o usl y t hr o u g h o ut t he st u d y fr o m t he 
si g nat ure of I C F at t he scree ni n g visit. D e vice deficie nc y  i nf or mati o n will be c ollecte d after 
eac h treat me nt.
4. 2
N u m ber of s u bjects
T he st u d y will be perf or me d at a p pr o xi matel y 5 sites i n C hi na a n d a p pr o xi matel y 1 7 5
s u bjects will be ra n d o mize d a n d treate d. A p pr o xi matel y 3 0 t o 4 0 s u bjects are esti mate d t o be 
e nr olle d per site.
4. 3
D ur ati o n of s u bject p artici p ati o n
S u bjects will be scree ne d f or eli gi bilit y wit hi n 2 1 da y s pri or t o st u d y ra n d o m izati o n o n t he 
baseli ne visit ( D a y 1). T he st u d y su bjects will be treate d at t he baseli ne visit a n d t hereafter 
f oll o we d f or 1 2 m o nt hs fr o m t he last treat me nt visit at eit her t he i nitial ( Da y 1) or t he 
I nf or me d C o nse nt & Scree ni n g
Ra n d o mizati o n
Treat me nt wit h Rest yl a ne Def y ne i n o ne N L F a n d 
Rest yl a ne i n t he o p p osite N L F , as ra n d o mly assi g ne d. 
Treat me nt will al wa ys start i n t he ri g ht N L F.
4 we e ks f oll o w- u p after i nitial treat me nt: O pti mal c orrecti o n ?
Yes
N o
T o uc h -u p treat me nt
M o nt h 3, 6 a n d 9 f oll o w -u p
4 we e ks after t o uc h -u p
M o nt h 1 2 f oll o w -u p/fi nal visit
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI

Pa ge 3 4 of 9 5
o pti o nal t o uc h- u p ( Da y 29) treat me nt visit . A s u bject w ill be i n v ol ve d i n t he st u d y for u p t o
1 4. 5 m o nt hs.
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 ber 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 bli n di n g
4. 4. 1
R a n d o miz ati o n
Eac h s u bject will be ra n d o mize d t o o ne of t w o treat ment se q ue nces; eit her Rest y la ne Def y ne 
i n t he s u bject’s ri g ht N L F f oll o we d b y  Rest yl a ne i n t he s u bject’s left N L F, or Rest y la ne i n
t he s u bject’s ri g ht N L F f oll o we d b y  Rest yla ne Def y n e i n t he s u bject’s left N L F. Treat me nt
will al wa ys start i n t he s u bject’s ri g ht N L F. T he ra n d o mizati o n will be stratifie d b y  site a n d 
t he ra n d o mizati o n list will be c o m p uter ge nerate d u n der t he s u per visi o n of a desi g nate d 
statisticia n.
Eac h s u bject will be assi g ne d a s u bject n u m ber as t he y arri ve f or t he treat me nt visit. 
Ra n d o mizati o n will be assi g ne d via t he electr o nic case re p ort f or m (e C R F) s yste m w he n all 
i ncl usi o n criteria a n d e xcl usi o n criteria ha ve bee n verifie d . At t he ti me of ra n d o mizati o n, t he
s u bject’s i nitials, date, s u bject n u m ber, treat me nt se q ue nce, a n d t he si g nat ure of t he 
I n vesti gat or m ust be d oc u me nte d i n a ra n d o mizati o n l o g. All treat me nt i nf or mati o n will be 
ke pt b y  t he treati n g In vesti gat or d uri n g t he stu d y  n ot t o be discl ose d t o t he b li n de d e val uat or.
4. 4. 2
Bli n di n g
D ue t o t he differe nces in t h e p h y sical c haracteristics ( visc osit y) of t he st u d y pr o d ucts a n d t he 
differe nce i n s yri n ge desi g n a n d material
(size o f s yri n ge a n d plastic vs glass s yri n ge), it is 
n ot p ossi ble t o tr ul y  d o u ble-bli n d t he st u d y, a n d t he treat me nt assi g n me nt ca n n ot be o bsc ure d 
fr o m t he treati n g In vesti gat or.
Beca use t he met h o d of a d mi nistrati o n is si milar, t he treat me nt ca n b e mas ke d fr o m t he 
s u bjects b y  si m pl y pre ve nti n g t he m fr o m vie wi n g t he s yri n ges d uri n g a d mi nistrati o n of t he 
st u d y pr o d ucts . T his will be d o ne b y placi n g a n o pa q ue dra pe or patc h o ver t he s u bject’s e yes 
d uri n g t he i njecti o n pr oce d ure.
T he bli n de d e val uat or s hall n ot be all o we d t o retrie ve st u d y s u p plies or t o be prese nt d uri n g 
o pe ni n g of t he st u d y s u p plies or i njecti o ns. T he treati n g In vesti gat or is n ot all o we d t o disc uss 
treat me nts wit h t he bli n de d e val uat or or t he s u bjects. All d oc u me nts wit h i nf or mati o n o n 
st u d y pr o d ucts s h all be ke pt i n a se parate bi n der n ot a vaila ble t o t he bli n de d e val uat or. T he 
bli n de d e val uat or s h o ul d n ot ha ve a ccess t o e C R F pa ges wit h st u d y  pr o d uct i nf or mati o n.
T he S p o ns or a n d t he S p o ns or ’s re prese ntati ve at t he site s hall n ot be bli n de d d uri n g t he st u d y.
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 u n bli n de d.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 3 5 of 9 5
4. 5
Me dic al h ist or y
Hist or y  of sur gical e ve nts a n d me dical 
c o n diti o ns t hat are j u d ge d as rele va nt b y  th e 
I n vesti gat or s hall be d oc u me nte d i n t he e C R F usi n g m e dical ter mi n ol o g y.
4. 6
C o nc o mit a nt me dic ati o n s, tre at me nts, a n d pr oce d ure s
E xce pt 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 ures m a y  be 
utilize d w he n t he PI  or his/ her a ut h orize d desi g nee c o nsi ders it me dicall y  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 nistere d d uri n g t he st u d y is t o be rec or de d i n t he e C R F. T he ge neric na me 
or t he tra de 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 n d pr oce d ures are restricte d or pr o h i bite d d uri n g t he
st u d y:

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 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 s h o ul d n ot be use d wit hi n 
t w o ( 2) wee ks bef ore treat me nt t o a v oi d i ncrease d br uisi ng or blee di n g at i njecti o n sites.

Li d ocai ne s h o ul d be use d wit h ca uti o n i n p atie nts recei vi n g ot her l ocal a nest hetics or 
a ge nts str uct urall y relate d t o a mi de-t ype l ocal a nest hetics e. g., certai n a nti-arr h yt h mics, 
si nce t he sys te mic t o xic effects ca n be a d diti ve. 

C o nc o mita nt 
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, 
im 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) is pr o hi bite d.

L o n g ter m c o nc o mita nt treat me nt wit h s yste mic or t o pical (facial) c ortic oster oi ds is 
pr o hi bite d (i n hale d c ortic oi ds are all o we d). C ortic oster oi ds s h o ul d be use d wit h ca uti o n 
a n d s h o ul d be a dj u d ge d as necessar y b y t he I n vesti gat or.

Use of s ys te mic or t o pical (facial) reti n oic aci d is pr o hi bite d.

Pr oce d ures i n v ol vi n g a n acti ve der ma l res p o nse i n t he face bel o w t he l o wer or bital ri m 
(e. g., tiss ue a u g me nti n g t hera py, c o nt o uri n g or re vitalizati o n treat me nt wit h per ma ne nt or 
n o n- per ma ne nt fillers, per ma ne nt i m pla nt, mes ot hera p y, ra di ofre q ue nc y, fat-i njecti o n, 
ne ur ot o xi n, laser or li g ht treat me nt, c he mical peeli n g , or der ma brasi o n) are pr o hi bit e d.

Pla n ne d s ur ger y incl u di n g aest hetic facial s ur gical t hera p y or facial li p os ucti o n, si n us 
s ur ger y or de ntal r o ot s ur ger y, or tatt o o i n t he area t o be treate d is pr o hi bite d.

Partici pati o n i n a n y  ot her cli nical st u d y is pr o hi bite d.
If a s u bject has use d an y  of t he a b o ve pr o hi bite d me dicati o ns or perf or me d a n y of t he a b o ve 
pr o hi bite d pr oce d ures a pr ot oc ol de viati o n s h o ul d be d oc u me nte d a n d t he s u bject s h o ul d, f or 
safety reas o ns, c o nti 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.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI

Pa ge 3 6 of 9 5
4. 7
Sc he d ule of e ve nts
T a ble 1. Sc he d ule of e ve nts
Acti vit y
S cre e n in g a
B a sel in e a
I niti al
tre a t me n t
W e e k 4 fo llo w -u p
a ft er Ini ti al
tre a t me n t/ 
O pti o n a l To u c h-
u p tre a t me n tb
W e e k 4 fo llo w -u p
a ft er to u c h-u p
(f or su b j ects w ho 
r ecei v e d t o u c h-
u p)
M o n t h 3 , 6
a n d 9
f ollo w-
u p
M o n t h 1 2 fol lo w -
u p / Fi n al vi sit
/E arl y
t er min a ti o n
D a y -2 1 t o 1
D a y 1
D a y 2 9
4 w e e ks (± 3 d a ys)
aft e r i niti al 
tr e at m e nt
4 w e e ks
(± 3 d a ys)
aft er to u c h-u p
3, 6 m o n th s (± 7 d a ys)
a n d
9 m o nt hs ( ± 2 w e e ks)
aft er l ast tr e atm e nt c
1 2 m o n th s
( ± 2 we e ks)
aft er l ast tr e atm e nt c
In fo rm e d co n s e nt
X
D e m o g r ap h y
X
M e d ic al histo ry & co n c urre n t
d is e as es
X
X
C o n co m it a nt
m e d ica tio n /p ro ce d u r es
X
X
X
X
X
X
V it al sig n s
X
H e m at ol o g y
X
S er u m c h e mistr y + Pr e g n a nc y
T ests ( S -H C G)
X
X
E C G
X
P r e gn a n cy te st ( U-H C G)
X d ,e
X d ,e
In clu sio n a n d Excl us io n criteri a
X
X
R a n d o m iza tio n
X
P h o to g r ap h y
X f
X f
X
X
X
Tr e a tm e nt
X
X b
W S R S
(b li n d e d e v al u at or)
X
X g
X e
X
X
X
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
Versi o n :
Effecti ve  date:
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI

Pa ge 3 7 of 9 5
Acti vit y
S cre e n in g a
B a sel in e a
I niti al
tre a t me n t
W e e k 4
fo llo w -u p
a ft er Ini ti al
tre a t me n t/ 
O pti o n a l To u c h-
u p tre a t me n tb
W e e k 4 fo llo w -u p 
a ft er to u c h-u p 
(f or su b j ects w ho 
r ecei v e d t o u c h-
u p)
M o n t h 3 , 6
a n d 9
f ollo w-
u p
M o n t h 1 2 fol lo w -
U p / Fi n al vi sit 
/E arl y
t er min a ti o n
D a y -2 1 t o 1
D a y 1
D a y 2 9
4 w e e ks (± 3 d a ys)
aft e r i niti al 
tr e at m e nt
4 w e e ks
(± 3 d a ys)
aft er to u c h-u p
3, 6 m o n th s (± 7 d a ys)
a n d 9
m o nt hs ( ± 2 w e e ks)
aft er l ast tr e atm e n t c
1 2 m o n th s
( ± 2 we e ks)
aft er l ast tr e atm e nt c
D e v ic e d efici e nc ies
X
X h
Ass es sm e nt o f A d v er se E v e n ts
X
X
X
X
X
St u d y te rm in at io n
X
a)
Scr e e n i ng v isit a n d b as eli n e v isit c a n b e c o m bi n e d t o o n e visit, iff easi b l e.
b)
T o uc h -u p tr e at m e nt m a y b e p erf or m e d f or s u bj ects w h o di d n ot i m pr ov e ≥1 gr a d e i n W S R S (i n o n e or b ot h NL Fs, as ass ess e d b y t h e b li n d e d e v al u at or ). T o uc h -u p 
tr e at m e nt will n ot b e p erf or m e d wit h o ut t h e s u bj ect’s v er b al c o ns e nt, if t h er e ar e o n g oi n g tr e at m e nt-r el at e d A Es or if o pti m al a est h etic i m pr o v e m e nt of b ot h NL Fs 
is alr e a d y ac hi e v e d.
c)
L ast tr e at m e nt is eit h er t h e i niti al tr e at m e nt or t h e t o uc h -u p tr e at me nt.
d)
A uri n e p r e g n a nc y t est s h o ul d b e p erf or m e d at t h e b as eli n e visit , b ef or e tr e at m e nt, if t h e scr e e ni n g visit a n d t h e first pr e g n a nc y t est w as p erf or m e d 2 w e e ks 
b ef or e t h e b as eli n e visit. A uri n e pr e g n a nc y t est s h o ul d b e p erf or m e d b ef or e tr e at m e nt at t h e w e e k 4 f oll o w -u p visit if t o uc h -u p is p erf or m e d.
e)
Pr i ort o tre a t me nt, if tre a t me nt is p er f or me d.
f)
O nl y pr e -tr e at m e nt
g)
T o o bt ai n a b as eli n e v al u e , pri or t o tr e at m e nt
h)
O nl y t o s u bj ect t h at r ec ei v e t h e o pti o n al t o uc h-u p tr e at m e nt
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
Versi o n :
Effecti ve  date:
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI

Pa ge 3 8 of 9 5
4. 8
Visits
4. 8. 1
Scree ni n g ( D a y - 2 1 t o D a y 1)
St u d y  su bject will be i nf or me d a b o ut t he st u d y an d t he ris ks a n d be nefits of partici pati n g. 
I nf or mati o n will be gi ve n , b ot h ver ball y  an d i n writi n g , a n d t he I nf or me d C o nse nt F or m 
(IC F) will be si g ne d a n d date d b y  the s u bject a n d t he I nvesti gat or bef ore perf or mi n g a n y 
st u d y relate d pr oce d ures. I ncl usi o n a n d e xcl usi o n criteria will be c hec ke d a n d de m o gra p hic 
data , rele va nt me dical hist or y as well as rele va nt o n g oi n g me dicati o n will be c ollecte d b y  the 
I n vesti gat or. Scree ni n g la b orat or y tests a n d E C G will be perf or me d i n acc or da nce t o 
S ecti o ns 8. 2 a n d 8. 3 t o verif y  excl usi o n criteria 1 9 . T he bli n de d e val uat or will ma ke a li ve 
assess me nt t o e val uate t he wri n kle se verity usi n g t he W S R S t o verif y  i ncl usi o n criteria 4 .
C ollecti o n of A E will start w he n t he I C F has bee n si g ne d b y  t he s u bject.

O btai n I nf or me d c o nse nt

O btai n de m o gra p hic data (i nitials, date of birt h, ge n der, a n d et h nic ori gi n)

I nter vie w f or me dical hist or y a n d c o nc urre nt diseases

I nter vie w f or c o nc o mita nt me dicati o ns a n d pr oce d ures

P erf or m ser u m p re g na nc y test f or all w o me n of c hil d beari n g p ote ntial

Scree ni n g la b orat or y  assess me nts (he mat ol o g y a n d ser u m c he mistr y)

E C G

Assess W S R S
(b y  bli n de d e val uat or ) t o verif y i ncl usi o n criteria 4

Assess eli gi bilit y (incl usi o n a n d e xcl usi o n criteria )
If t he s u bject meets all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria a baseli ne 
visit will be perf or me d i m me diatel y or sc he d ule d wit hi n t he ne xt 2 1 da y s.
4. 8. 2
B aseli ne Visit - I niti al tre at me nt ( D a y 1)
T he baseli ne visit ca n be perf or me d i n direct c o nnecti o n wit h t he scree ni n g visit or at t he 
latest 2 1 da y s after t he scree ni n g visit.
If t he scree ni n g a n d baseli ne vis its are se parate d, t he i ncl usi o n a n d e xcl usi o n criteria will be 
re-c hec ke d a n d if a n y c ha n ges ha ve occ urre d i n t he healt h s tat us, c o nc o mita nt me dicati o n a n d
pr oce d ures will be assesse d bef ore t he s u bject ca n be i ncl u de d i n t he st u d y . 
F urt her, vital si g ns will be assesse d, sta n dar dize d p re-treat me nt p h ot o gra p h will be ta ke n as 
descri be d i n Secti o n 7. 5 , a n d a pre g na nc y  test ( U-H C G) will be perf or me d i n w o me n of 
c hil d beari n g p ote ntial. Bef ore treat me nt, the b li n de d e val uat or will ma ke a li ve assess me nt t o 
e val uate t he wri n kle se verit y o n W S R S t o o btai n a baseli ne val ue .

I nter vie w f or me dical hist o ry a n d c o nc urre nt diseases

I nter vie w f or co nc o m ita nt m e dicati o ns a n d treat me nts

V ital si g ns ( p ulse rate, bl o o d press ure, res pirat or y rate, a n d a xillar y te m perat ure)
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 3 9 of 9 5

P erf or m uri ne p re g na nc y test f or all w o me n of c hil d beari n g p ote ntial (if 2 wee ks si nce 
t he pre g na nc y test perf or me d at t he scree ni n g visit)

Assess W S R S t o o btai n a baseli ne val ue ( by bli n de d e val uat or )

C o nfir m eli gi bilit y  criteria
F or eac h eli gi ble s u bject, o ne N L F will be ra n d oml y assi gne d t o treat me nt wit h Rest y la ne
Def y ne ( wit h li d ocai ne) a n d t he o p p osite N L F 
t o treat me nt wit h 
Rest y la ne ( wit h o ut 
li d ocai ne). Treat me nt will be a d mi nistere d acc or di n g t o t he i nstr ucti o ns i n S ecti o n 6. 6 . A n y 
de vice deficie ncies or A Es si nce last visit, d uri n g or after t he treat me nt will be re p orte d. 

R a n d o mize t he s u bject a n d arra n ge f or bli n di n g of t he s u bject

O btai n a pre -treat me nt p h ot o gra p h ( baseli ne)

Perf or m treat me nt i n t he ri g ht N L F acc or di n g t o ra n d o mizati o n ( Secti o n 6. 6 )

Perf or m treat me nt i n t he left N L F acc or di n g t o ra n d o mizati o n ( Secti o n 6. 6 )

I nter vie w f or A E si nce last visit a n d eval uate t he s u bject f or p ost -treat me nt A Es

E val uate de vice deficie ncies
4. 8. 3
Wee k 4
f oll o w- up after i niti al tre at me nt ( D a y 2 9 3 d a ys ) / O pti o n al t o uc h-u p
A foll o w - u p visit will ta ke place 4 wee ks ( D 2 9 3 da y s) after t he i nitial treat ment. A n 
o pti o nal t o uc h- u p treat me nt ma y  be perf or me d if o pti mal aest hetic i m pr o ve me nt was n ot 
o btai ne d .
S ta n dardize d p h ot o gra p hs will be ta ke n, W S R S will be c o m plete d b y  th e bli n de d e val uat or,
 
 a n y AEs si nce t he i nitial 
treat me nt or c ha n ge i n me dicati o ns use d will be re p orte d. 

Assess W S R S
( b y bli n de d e val uat or)

O btai n p h ot o gra p h s

I nter vie w f or co nc o m ita nt m e dicati o ns a n d treat me nts

I nter vie w f or A E
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI
C CI
C CI
C CI

Pa ge 4 0 of 9 5
A t o uc h -u p treat me nt ma y  be perf or me d at t his visit if o pti mal aest hetic i m pr o ve me nt was n ot 
o btai n e d, i.e., s u bjects w h o di d n ot i m pr o ve ≥1 gr a de o n W S R S 
i n o ne or b ot h N L Fs as 
assesse d b y  the bli n de d e val uat or. T he to uc h -u p treat me nt will n ot be perf or me d wit h o ut t he 
s u bject’s ver bal c o nse nt, if t here are o n g oi n g treat me nt-relate d A Es , or if o pti mal aest hetic 
im pr o ve me nt is alrea d y ac hie ve d. 
A pre g na nc y  test ( U-H C G) will be perf or me d i n w o me n of c hil d beari n g p ote ntial bef ore t he 
t o uc h- u p treat me nt (descri be d i n Secti o n 6. 6) . De vice deficie ncies a n d A Es i n c o n necti o n t o 
t he treat me nt will be re p orte d.
 
 
A sec o n d 4- wee k f oll o w 
u p visit s h o ul d be sc he d ule d.

P erf or m uri ne p re g na nc y test f or all w o me n of c hil d beari n g p ote ntial

Perf or m t reat me nt (as i nitiall y ra n d o mize d, start i njecti o n i n t he ri g ht N L F)

E val uate t he s u bject f or p ost -treat me nt A Es

E val uate de vice deficie ncies
4. 8. 4
Wee k 4
f oll o w-u p after t o uc h - u p tre at me nt - o nl y f or s u bjects w h o recei ve d 
t o uc h- u p tre at me nt ( 4 wee ks 3 d a ys)
A f oll o w- u p assess me nt will be perf or me d 4 wee ks after t he t o uc h-u p treat me nt visit. 
Sta n dar dize d p h ot o gra p hs will be ta ke n. W S R S will be c o m plete d b y  the bli n de d e val uat or
 
a n y A Es si nce last visit
or c ha n ge i n me dicati o ns use d will be re p orte d. 

Assess W S R S ( b y  bli n de d e val uat or)

O btai n p h ot o gra p h s

I nter vie w f or c o nc o mita nt me dicati o ns a n d treat me nts 

I nter vie w f or A E
4. 8. 5
M o nt h 3
( ± 7 d a ys), 6 ( ± 7 d a ys), a n d 9 ( ± 2 wee ks) f oll o w-u p
F oll o w -u p visits will be perf or me d 3 m o nt hs
± 7 da y s, 6 m o nt hs ± 7 d a y s, a n d 9 m o nt hs ± 2 
wee ks after last treat me nt. Sta n dar dize d p h ot o gra p hs will be ta ke n. W S R S will be c o m plete d 
b y  the bli n de d e val uat or 
 
. A n y A Es si nce last visit or c ha n ge i n me dicati o ns use d 
will be re p orte d.

Assess W S R S ( b y  bli n de d e val uat or)
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI
C CI
C CI

Pa ge 4 1 of 9 5

O btai n p h ot o gra p hs 

I nter vie w f or c o nc o mita nt me dicati o ns a n d treat me nts 

I nter vie w f or A E
4. 8. 6
M o nt h 1 2
( ± 2 wee ks) f oll o w-u p / Fi n al visit or E arl y ter mi n ati o n
A fi nal f oll o w-u p visit will be perf or me d 1 2 m o nt hs ± 2 wee ks after t he last treat me nt visit. I n 
t he case of s u bject wit h dra wal bet wee n re g ular visits ( Secti o n 5. 5 ) t he s u bject s h o ul d, w he n
p ossi ble, be sc he d ule d f or an earl y ter mi nati o n visit .
Sta n dar dize d p h ot o gra p hs will be ta ke n. W S R S will be c o m plete d b y  the bli n de d e val uat or 
. A n y  AEs si nce 
last visit or c ha n ge i n me dicati o ns use d will be re p orte d. A fi nal pre g na nc y  test ( U- H C G) will 
be perf or me d i n w o me n of c hil d beari n g p ote ntial.

P erf or m ser u m p re g na nc y test f or all w o me n of c hil d beari n g p ote ntial

L a b orat or y assess me nts (ser u m c he mistr y)

Assess W S R S ( b y  bli n de d e val uat or)

O btai n p h ot o gra p hs

I nter vie w f or c o nc o mita nt me dicati o ns a n d treat me nts 

I nter vie w f or A E
5
S U B J E C T 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 EC a p pr o ve d su bject inf or mati o n
a n d I CF a n d it m ust n ot 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 a n d a p pr o val 
fr o m t he a p plica ble I E C.
It is t he res p 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 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 decisi o n t o partici pate t hr o u g h o ut t he st u d y. T he i nf or mati o n s h o ul d 
be gi ve n t o t he s u bject pri or t o i ncl usi o n i n t he st u d y a n d s h o ul d e. g., e x plai n t he p ur p ose a n d 
pr oce d ures 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 ve d, a n d t he o pi ni o n of t he I EC . T he s u bject shall be i nf or me d t hat t he partici pati o n is 
c o nfi de ntial a n d v ol u ntar 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 t he st u d y at a n y 
ti me, wit h o ut a n y effect o n 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 clearl y 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 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI

Pa ge 4 2 of 9 5
u n dersta n d t he i nf or me d c o nse nt f or m 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 nf or me d c o nse nt f or m s hall be pers o nall y si g ne d 
a n d date d b y  the s u bject a n d t he PI  or his/her a ut h orize d desi g nee res p o nsi ble f or c o n d ucti n g 
t he i nf or me d c o nse nt pr ocess. 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 c o u ntries o utsi de C hi na . T he data will n ot 
c o ntai n a n y i nf or mati o n t hat ca n be use d t o i de ntif y t he 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 yz e d a n d st ore d i n a data base b y  the 
S p o ns or a n d its re prese ntati ves i n or 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 gra p hs, b ut t heir na mes will n ot be discl ose d.
All si g ne d I CF s hall be file d i n t he I n vesti gat or file. T he su bject s hall be pr o vi de d a c o p y of 
t he si g ne d a n d date d inf or me d co nse nt f or m a n d a n y  ot her writte n inf or mati o n.
T he I nves ti gat or s hall e ns ure t hat i m p orta nt ne w 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 eli gi ble f or t he st u d y:
1.
Si g ne d a n d date d i nf or me d c o nse nt t o partici pate i n t he st u d y .
2.
Me n or w o me n a ge d 1 8 y ears of a ge or ol der of C hi nese ori gi n .
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 ures 
bel o w t he le vel of t he l o wer or bital ri m 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, nee dli n g, facelift, ra di ofre q ue nc y  etc.).
4.
I nte nt t o u n der g o c orrecti o n of b ot h N L Fs wit h a wri n kle se verity i n W S R S of eit her 3 
o n b ot h si des or 4 o n b ot h si des, as assesse d b y t he b li n de d e val uat or.
5. 3
E xcl usi o n criteri a
T he pr ese 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 njecta ble H A gel.
2.
K n o w n/ pre vi o us aller g y  or h yperse nsiti vit y  t o l ocal a nest hetics, e. g., li d ocai ne or ot her 
a mi de-t ype a nest hetics.
3.
Hist or y  of se vere or m ulti ple aller gies ma nifeste d b y a na p h yla xis.
4.
Pre vi o us tiss ue re vitalizati o n treat me nt wit h laser or li g ht, mes ot hera p y , 
ra di ofre q ue nc y, c he mical peeli n g, or der ma brasi o n bel o w t he le vel of t he l o wer or bital 
ri m wit hi n 6 m o nt hs bef ore treat me nt.
5.
Pre vi o us s ur ger y  (i ncl u di n g aest hetic facial s ur gical t hera py or li p os ucti o n) or tatt o o i n 
t he area t o be treate d.
6.
Pre vi o us tiss ue a u g me ntati o n t hera p y  or c o nt o uri n g wit h a n y per ma ne nt ( n o n-
bi o de gra da ble) or se mi -per ma ne nt facial tiss ue a u g me ntati o n t hera p y or a ut ol o g o us fat 
or per ma ne nt i m pla nt bel o w t he le vel of t he l o wer or bital ri m.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 4 3 of 9 5
7.
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 l o wer or bital ri m wit hi n 1 2 m o nt hs bef ore 
treat me nt.
8. 
Pre vi o us use of ne ur ot o xi ns bel o w t he le vel of t he l o wer or bital ri m (cr o w's feet li ne is 
acce pta ble) wit hi n 1 2 m o nt hs bef ore treat me nt .
9.
Hist or y  of ra diati o n or ca ncer o us or pre-ca ncer o us lesi o ns (e. g., acti nic kerat osis) i n t he 
area t o be treate d.
1 0.
Scars or def or mities, acti ve s ki n disease, i nf la m mati o n or relate d c o n diti o ns s uc h as 
i nfecti o n, peri oral der matitis, se b orr heic der matitis, ecze ma, r osacea, ac ne, ps oriasis,
a n d her pes z oster near or i n t he a rea t o be treate d.
1 1.
S u bjects wit h de ntal or oral stat us o n vis ual i ns pecti o n t hat i n t he o pi ni o n of t he 
I n vesti gat or w o ul d ma ke t he s u bject u ns uita ble f or i ncl usi o n, or S u bjects wit h de ntal, 
oral or si n us s ur ger y  wit hi n past 1 2 m o nt hs pri or t o t he treat me nt visit or pla n ne d 
s ur ger y, i ncl u di n g de ntal i m pla nts, d uri n g t he st u d y peri o d.
1 2.
O n g oi n g i nfecti o n i n m o ut h or de ntals .
1 3.
C hr o nic i nfecti o n i n hea d a n d nec k re gi o n .
1 4.
Hist or y  of or acti ve a ut oi m m u ne disease or c o n necti ve tiss ue diseases s uc h as s yste mic 
l u p us eryt he mat os us, r he u mat oi d art hritis, p ol y m y ositis, der mat o m y ositis, or l ocalize d 
or s y ste mic scler o der ma.
1 5.
Te n de nc y t o f or m kel oi ds, h y pertr o p hic scars, or a n y ot her heali n g dis or der.
1 6.
Hist or y  of blee di n g dis or ders or treat me nt wit h 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 or ot her n o n-ster oi d 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 2 wee ks bef ore treat me nt .
1 7.
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 di es), s yste mic or t o pical (facial) c ortic oster oi ds wit hi n 3 
m o nt hs bef ore treat me nt (i n hale d c ortic oi ds are all o we d) .
1 8.
C o nc o mita nt treat me nt wit h t o pical (facial) reti n oi ds wit hi n 3 m o nt hs or s y ste mic 
reti n oi ds wit hi n 6 m o nt hs bef ore treat me nt.
1 9.
A n y  me dical co n diti o n t hat i n t he o pi ni o n of t he I n vesti gat or w o ul d ma ke t he s u bject 
u ns uita ble f or i ncl usi o n ( e. g., p or p h y ria, a c hr o nic, rela psi n g or here ditar y disease t hat 
ma y  affect t he ge neral c o n diti o n or ma y re q uire fre q ue nt me dical treat me nt, a n y 
a b n or mal scree ni n g la b orat or y val ue or E C G, or ps yc hiatric dis or ders).
2 0.
Ot her c o n diti o n pre ve nti n g t he s u bject fr o m e nteri n g t he st u d y i n t he I n vesti gat or's 
o pi ni o n, e. g. , s u bjects n ot li kel y t o a v oi d ot her facial c os metic treat me nts, s u bjects 
a ntici pate d t o be u nrelia b le, u na vaila ble or i nca pa ble of u n dersta n di n g t he st u d y 
assess me nts , or ha vi n g u nrealistic e x pectati o ns of t he treat me nt res ult.
2 1.
W o me n w h o are pre g na nt or breast fee di n g, or w o me n of c hil d beari n g p ote ntial w h o 
are n ot practici n g a de q uate c o ntrace pti o n or pla n ni n g t o bec o me pre g na nt d uri n g t he 
st u d y peri o d.
2 2.
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 .
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 4 4 of 9 5
2 3.
Partici pati o n i n a n y  ot her cli nical st u d y wit hi n 3 0 da y s bef ore treat me nt.
5. 4
Scree ni n g a n d s u bject n u m bers
Eac h s u bject w h o has si g ne d t he I CF will be assi g ne d a scree ni n g n u m ber a n d s hall be liste d 
o n a su bject scree ni n g a n d incl usi o n l o g. Eac h scree ne d s u bject will be assi g ne d a scree ni n g 
n u m ber c o nsisti n g of “ S” a n d t he site n u m ber f oll o we d b y  a c o nsec uti ve n u m ber starti n g wit h 
0 1 at eac h site, e. g., S 1 0 1, S 1 0 2. T he scree ni n g n u m ber s hall be liste d o n a s u bject scree ni n g 
a n d i ncl usi o n l o g.
A “scree ni n g fail ure” is defi ne d as a s u bject w h o d oes n ot f ulfil t he eli gi bilit y criteria. F or 
scree ni n g fail ures, t he e C R F scree ni n g visit s hall be c o m plete d t o a n e xte nt t hat ma kes it 
clear w hic h assess me nts ha ve bee n ma de a n d t he reas o n w h y t he s u bject di d n ot f ulfil t he 
eli gi bilit y criteria. T he reas o n f or e xcl u di n g a s u bject fr o m e nteri n g t he st u d y s hall als o be 
s pecifie d i n t he su bject scree ni n g a n d incl usi o n lo g. 
W he n t he I n vesti gat or has c o nfir me d t hat all i ncl usi o n criteria a n d n o e xcl usi o n criteria are 
met , eac h e nr olle d s u bject will be assi g ne d a s u bject n u m ber b y  the e C R F c o nsisti n g of t he 
site n u m ber f oll o we d by a c o nsec uti ve n u m ber starti n g wit h 0 1 at eac h site, e. g., 1 0 1, 1 0 2 etc.
T he s u bject n u m ber, s u bject na me , a n d ot her i nf or mati o n s ufficie nt t o li n k t he e C R F t o t he 
me dical rec or ds (e. g., nati o nal i de ntificati o n n u m ber, c hart n u m ber, etc.) s hall be rec or de d o n 
a su bject i de ntificati o n list. T he s u bject i de ntificati o n list s hall o nl y  be a vaila ble at t he site, 
b ot h t hr o u g h o ut a n d after t he st u d y. 
5. 5
Wit h dr a w al of su bjects
Eac h s u bject s hall be a d vise d i n t he i nf or me d c o nse nt f or m t hat he/s he has t he ri g ht t o 
wit h dra w fr o m t he st u d y at a n y ti me, f or a n y reas o n, wit h o ut prej u dice. S u bjects ma y  als o be 
disc o nti n ue d fr o m t his st u d y if t he I n vesti gat or deter mi nes t hat it is i n t he s u bject’s best 
i nterest t o d o s o, a n d ma y be wit h dra w n at t he I n vesti gat or's discreti o n at a n y ti me.
T he wit h dra wal crite ria are:

Me dic al re as o ns : If t he s u bject s uffers fr o m a me dical c o n diti o n t hat i n t he j u d g me nt of 
t he I n vesti gat or ma kes it me dicall y  necessar y to wit h dra w t he s u bject. T he s pecific 
rati o nale f or In 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 u bject re q uest : I ncl u des c o nse nt wit h dra wal, s u bject rel ocati o n, sc he d ule c o nflicts. A 
s u bject 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 d y at t he re q uest of t heir le gall y a ut h orize d
re prese ntati ve at a ny 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 n ot 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 s u 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, or c o nfir m wit h t w o d oc u me nte d p h o ne calls a n d a certifie d letter ( deli ver y 
recei pt re q ueste d) wit h o ut a ns wer, bef ore declari n g t he s u bject l ost t o f oll o w - u p.

Ot her : T his cate g or y is t o be use d f or a s u bject w h o disc o n ti n ues d ue t o a reas o n ot her 
t han as s pecifie d i n t he pre -defi ne d cate g ories a b o ve, e. g., fail ure t o 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 ol-s pecifie d e val uati o ns.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 4 5 of 9 5
T he reas o n a n d date f or wit h dra wal s hall be d oc u me nte d i n t he e C R F. W he n p ossi ble, a n 
e x pla nat or y co m me nt s hall be a d de d i n t he st u d y  ter mi nati o n m o d ule/ pa ges t o f urt her e x plai n 
t he reas o n f or wit h dra wal. If wit h dra wal of a s u bject occ urs d uri n g a re g ular st u d y visit, t he 
e C R F f or t hat s pecific visit s hall be c o m plete d as far as p ossi ble t o get her wit h t he st u d y 
ter mi nati o n e C R F m o d ule
a n d a fi nal pre g na nc y test ( U-H C G) will
be d o ne i n w o me n of 
c hil d beari n g p ote ntial.
If wit h dra wal of a s u bject occ urs bet wee n re g ular st u d y visits t he s u bject s h o ul d, w he n
p ossi ble (irres pecti ve of t he reas o n f or wit h dra wal) , be sc he d ule d f or a ter mi nati o n visit . I n 
t hese cases the e C R F f or earl y ter mi nati o n visit s h o ul d be c o m plete d.
If a s u bject is wit h dra w n fr o m t he st u d y, all data c ollecte d u ntil t he ti me of wit h dra wal will 
be use d i n t he a nal ys es.
A wit h dra w n or disc o nti n ue d s u bject m ust n ot be re place d or re -e ntere d i nt o t he st u d y.
If a n A E w hic h, acc or di n g t o t he I n vesti gat or’s assess me nt, is relate d t o t he use of a n y of t he 
st u d y p r o d ucts a n d is still o n g oi n g at t he ti me of t he wit h dra wal please refer t o S ecti o n 8. 4. 6 .
6
S T U D Y P R O D U C T S
T he ter m “st u d y pr o d uct s” refers t o Rest y la ne Def y n e a n d Rest y la ne. B ot h Rest y la ne Def y ne
a n d Rest yla ne will be s u p plie d b y t he S p o ns or.
6. 1
I n vesti g ati o n al pr o d uct
Rest y la ne D ef y ne (wit h li d ocai ne) is a sterilize d i njecta ble gel c o nsisti n g of sta bilize d H A of 
n o n- a ni mal ori gi n wit h t he a d diti o n of 3 m g
li d ocai ne h y dr oc h l ori de per m L . T he pr o d uct 
c o ntai ns 2 0 m g / m L H A i n a p h y si ol o gical p h os p hate b uffer s yste m. T he gel is tra ns pare nt 
a n d c ol orless. T he pr o d uct is s u p plie d i n a prefille d plastic s yri n ge wit h a l uer-l oc k fitti n g. 
T w o 2 7 G × ½ ”
ultra -t hi n wal l nee dles are pac ke d t o get her wit h eac h Rest y la ne Def y ne 
s yri n ge. T he s yri n ge, c o ntai ni n g 1 m L  gel, is la bele d a n d pac ka ge d i n a blister . T he 
i n vesti gati o nal pr o d uct is f or si n gle use o nly.
C o m mercial Rest y la ne D ef y ne pr o d uce d f or t he E U mar ket will be pr o vi de d t o t he sites a n d 
d etaile d pr o d uct i nf or mati o n is a vaila ble i n t he I B a n d t he i nstr ucti o ns f or use (I F U)
(A p pe n di x 2 ).
6. 2
Refere nce pr o d uct
Rest y la ne is a sterilize d i njecta ble gel c o nsisti n g of sta bilize d H A of n o n-a ni mal ori gi n wit h a 
c o nce ntrati o n of 2 0 m g/ m L i n p h os p hate b uffere d sali ne. T he gel is tra ns pare nt a n d c ol orless. 
T he pr o d uct is s u p plie d i n si n gle use glass s yri n ge wit h a l uer-loc k fitti n g. Tw o 3 0 G × ½”
nee dles are pac ke d t o get her wit h eac h Rest yl a ne. T he s yri n ge, c o ntai ni n g 1 m L  gel, is
la bele d a n d pac ka ge d i n a blister . T he pr o d uct is f or si n gle use o nl y .
T he refere nce pr o d uct is c o m mercial pr o d uct i nte n de d f or t he C hi nese mar k et. A n I F U is 
i ncl u de d i n t he cart o n a n d als o a vaila ble i n A p pe n di x 3 .
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 4 6 of 9 5
6. 3
A d diti o n al pr o d ucts a n d m ateri al
Rest y la ne Def y n e a n d Rest yla ne, pre -pac ke d i n blister wit h t w o nee dles , will be s u p plie d b y  
t he S p o ns or.
A n y  ot her a d diti o nal pr o d ucts re q uire d f or t he st u d y, e. g., t o pical or l ocal a naest hetic, pai n 
relief, a n d a de q uate me dical e q ui p me nt i n case of cli nical e mer ge nc y will be s u p plie d b y  the 
I n vesti gat or.
6. 4
P ac k a gi n g, l a belli n g, a n d st or a ge
Rest y la ne D ef y ne ( wit h li d ocai ne) a n d Rest yl a ne ( wit h o ut li d ocai ne) are ma n ufact ure d b y  
Q- Me d A B, U p psala, S we de n , w h o will s u p pl y the st u d y pr o d ucts. Rest y la ne Def y ne, t he 
i n vesti gati o nal pr o d uct , is C E -mar ke d , i.e., c o m mercial pr o d uct i nte n de d f or t he E U -mar ket.
T he refere nce pr o d uct , Rest y la ne, is c o m mercial pr o d uct i nte n de d f or t he C hi nese mar ket. 
C o m mercial
Rest y la ne Def y ne i nte n de d f or t he E U mar ket
a n d c o m mercial Rest yl a ne
i nte n de d f or t he C hi nese mar ket will be use d i n t he st u d y.
T he s y ri n ges are labelle d wit h na me of t he pr o d uct a n d t he na me of t he ma n ufact urer ( Q -Me d 
A B) . T he s yri n ges i n its blister are pac ke d i n a cart o n. T he cart o n will be la belle d i n l ocal 
la n g ua ge, s pecif yi n g t he S p o ns or na me, pr ot oc ol n u m ber, l ot n u m ber, e x pir y  date a n d t hat t he 
pr o d uct is t o be use d f or cli nical st u d ies e xcl usi vel y.
T he st u d y pr o d ucts s h o ul d be st ore d at a te m perat ure u p t o 2 5 oC a n d pr otecte d fr o m s u nli g ht 
a n d freezi n g. O pe ne d s yri n ges s h o ul d n ot be re-use d . T he e x pir y date is i n dicate d o n 
pac ka ge.
6. 5
Pr o d uct acc o u nt a bilit y
T he st u d y pr o d uct s will be release d t o t he PI or his/ her a ut h orize d desi g nee after st u d y 
a p pr o vals ha ve bee n recei ve d fr o m t he I E C a n d ot her rele va nt a ut h orities/i nstit uti o ns, as 
a p plica ble, a n d t he C T A ha s bee n si g ne d b y  all parties.
T he PI m ust e ns ure t hat t he st u d y pr o d uct s are ke pt i n a sec ure l ocati o n, wit h access li mite d 
t o t h ose a ut h ori z e d b y  t he PI .
T he st u d y pr o d ucts 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 bilit y rec or ds, i.e., d oc u me ntati o n of t he p h y sical 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 st u 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 t he pr o d uct n a me, date recei ve d, l ot n u m ber , 
e x pirati o n date , a n d a m o u nt recei ve d. I n ad diti o n, dis pe nsi n g l o gs s hall be mai ntai ne d 
i ncl u di n g t he pr o d uct na me , dis pe nse date, t he n u m ber of s yri n ges use d/ a m o u nt dis pe nse d, 
t he s u bject recei vi n g st u d y pr o d uct , a n d n u m ber of s yri n ges left i n st oc k at t he site. A l o g f or 
acc o u nta bilit y pr oce d ure is pr o vi de d b y t he S p o ns or.
W he n t he st u 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 or a t hir d-part y  ve n d or f or destr ucti o n o r be destr o y e d l ocall y at t he 
site, wit h pr o per d oc u me ntati o n, after a gree me nt 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 S ecti o n 8. 5. 3 .
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 4 7 of 9 5
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 s hall be 
acc o u nte d f or a n 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 n use d material a n d t he ass ociate d risks i ncl u di n g 
i nfecti o ns acc or di n g t o sta n dar d pr oce d ures at t he site. Dis p osal 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. T he st u d y pr o d ucts 
m ust n ot be use d o utsi de t he st u d y. 
6. 6
Tre at me nt
6. 6. 1
Tre at me nt p r oce d ure 
T he s u bjects will
be i nf or me d a b o ut t he i n dicati o ns, e x pecte d res ult, preca uti o ns , a n d 
p ote ntial A E s.
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 nt cr oss-i nfecti o ns s h o ul d be o bser ve d at all ti mes i ncl udi n g t he use of 
dis p osa ble gl o ves d uri n g t he i njecti o n pr oce d ure . T he s u bject s h o ul d n ot wear ma ke - u p o n
t he da y  of treat me nt, if ma ke - u p was alrea d y a p plie d t his m ust be c o m pletel y re m o ve d pri or
t o a ny i njecti o n . T he treat me nt site s h o ul d be t h or o u g hly clea ne d at least t wice wit h a s uita ble 
a ntise ptic s ol uti o n.
T he treati n g I n vesti gat or will c o nfir m ra n d o mizati o n vi a t he e C R F s yste m f or st u d y pro d uct s
i.e., t he N L F o n o ne si de of t he face will be ra n d oml y assi g ne d t o treat me nt wit h Rest y la ne 
Def y ne a n d t he o p p osite N L F t o treat me nt wit h Rest y la ne. Treat me nt will al wa ys start i n t he 
s u bject’s ri g ht N L F. Rest y la ne D ef y ne s h o ul d be i njecte d i nt o t he mi d t o dee p der mis of t he 
facial s ki n i n t he N L F a n d Rest y la ne s h o ul d be i njecte d i nt o t he mi d dle part o f t he der mis 
la yer of t he facial s ki n i n t he N L F.
T he treati n g I n vesti gat or s h o ul d kee p t he s u bject bli n d t o t he treat me nt b y placi n g a n o pa q ue 
dra pe or patc h o ver t he s u bject's e yes d uri n g t he ti me t hat t he i njecti o ns are a d mi nistere d. T he 
details re gar din g ra n d o mizati o n a n d bli n di n g of s u bjects a n d bli n de d e val uat or are i n
S ecti o n 4. 4 . 
T o a v oi d brea ka ge of t he nee dle, n o atte m pt t o be n d or ot her wise ma ni p ulate t he nee dle
bef ore or d uri n g treat me nt is rec o m me n de d. Bef ore i njecti n g, t he air s h o ul d be re m o ve d b y  
pressi n g t he r o d caref ull y until a s mall dr o plet is visi ble at t he ti p of t he nee dle. As pirati o n 
pri or t o i njecti o n i n or der t o a v oi d acci de ntal i ntra vasc ular i njecti o n is rec o m me n de d. T he 
li near t hrea di n g tec h ni q ue ca n be use d t o caref ully lift u p t he wri n kle. T he i n jecti o n tec h ni q ue 
s h o ul d be t he sa me f or b ot h si des of t he face i n a n y o ne s u bject t o li mit varia bilit y  due t o 
tec h ni q ue. B ot h pr o d ucts s h o ul d be i njecte d sl o wl y while p ulli n g t he nee dle bac k war ds. 
I njecti o n s h o ul d st o p j ust bef ore t he nee dle is p ulle d o ut fr o m t he s ki n t o pre ve nt material 
fr o m lea ki n g o ut fr o m t he i njecti o n site. E xcessi ve press ure m ust n ot be a p plie d at a n y ti me 
d uri n g i njecti o n. If resista nce is e nc o u ntere d t he nee dle s h o ul d be partiall y  wit h dra w n a n d 
re p ositi o ne d or f ull y wit h dra w n a n d c hec ke d f or f u ncti o n. Se parate sterile nee dles s h o ul d be 
use d f or eac h N L F.
T he i njecti o n sites ma y  be ge ntl y  massa ge d
 
 by t he t reati n g I n vesti gat or t o c o nf or m t he c o nt o ur of t he s urr o u n di n g tiss ue.
At t he i nitial treat me nt v isit ( Da y 1) s u bjects s h o ul d assess t he pai n e x perie nce d d uri n g 
treat me nt. 
 
I n or der t o be a ble t o 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI

Pa ge 4 8 of 9 5
e val uate t he pai n of i njecti o n, se parate d fr o m t he pai n of t he nee dle i nserti o n al o ne, a pa use 
of 3 t o 5 sec o n d is re q uire d after i nserti o n of t he nee dle bef ore starti n g t he i njecti o n. B ot h 
pr o d ucts s h o ul d be i njecte d sl o wl y as i njecti o n pace c o ul d affect t he pai n e x perie nce d; t he 
ti me re q uire d f or eac h i njecti o n will be rec or de d i n t he e C R F.
 
 
 
 
 
T he i njecti o n pr oce d ure f or t he t w o N L Fs will be sta n dar dize d as far as p ossi ble i n ter ms of 
v ol u me, ti me re q uire d f or i njecti o n, de pt h of i njecti o n, a n d i njecti o n tec h ni q ue a n d will be 
rec or de d i n t he e C R F.
6. 6. 2
Tre at me nt re gi me n ( dose a n d inter v al )
T he rec o m me n de d ma xi m u m v ol u me f or eac h N L F at t he i nitial treat me nt a n d t he t o uc h-u p 
treat me nt c o m bi ne d is 2. 0 m L gel .
6. 6. 2. 1 I niti al tre at me nt
F or i nitial i njecti o n, it is rec o m me n de d n ot t o use m ore t ha n 1. 5 m L f or eac h N L F. T he ai m 
of t he treat me nt is t o ac hie ve o pti mal c orrecti o n of eac h N L F , de fects s h o ul d be f ully 
c orrecte d b ut n ot o verc orrecte d .
 
 
6. 6. 2. 2 T o uc h -u p tre at me nt
A t o uc h- u p treat me nt m a y  be perf or me d f o ur wee ks after t he i nitial treat me nt if o pti mal 
c orrecti o n has n ot bee n ac hie ve d , as assesse d b y  the bli n de d val uat or . If a t o uc h- u p is 
perf or me d it s h o ul d prefera bl y be perf or me d i n b ot h N L Fs. F or s u bse q ue nt t o uc h-u p 
treat me nt, it is rec o m me n de d n ot t o use m ore t ha n 0. 5 m L
f or eac h N L F. It is of o ut m ost 
i m p orta nce t hat t he s u bject recei ves t he sa me pr o d uct as recei ve d at t he i nitial treat me nt i n 
res pecti ve N L F. 
T o pical or l ocal a nest hetic or ot her pai n -relie vi n g me dicati o n, i ncl u di n g ice, m a y
be use d 
bef ore a n d after t o uc h -u p treat me nt.
T o uc h - u p will n ot be perf or me d wit h o ut t he s u bject’s ver bal c o nse nt , if t here are o n g oi n g 
treat me nt-relate d A Es, or if o pti mal aest hetic i m pr o ve me nt is alrea d y ac hie ve d.
6. 6. 3
P ost -tre at me nt c are
Ice i n a p pr o priate pac ka gi n g “ice -pac k” ca n be a p plie d o n t he treat me nt site f or a s h ort peri o d 
t o re d uce s welli n g a n d disc o mf ort.
 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
C CI
C CI
C CI

Pa ge 4 9 of 9 5
After t he i njecti o n, 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 br uisi n g, er yt he ma , s welli n g, pai n, te n der ness, a n d itc hi n g at t he i m pla nt site. 
T y picall y  res ol uti o n is s p o nta neo us wit hi n a fe w d a y s. 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, stea m bat hs, etc.) or e xtre me c ol d least u ntil a n y 
i nitial s welli n g a n d er yt he ma has res ol ve d. I n or der t o pre ve nt i nfecti o ns, t he s u bject s h o ul d 
a v oi d t o uc hi n g t he treate d area a n d n o crea ms or c os metics s h o ul d be a p plie d bef ore t he s ki n 
has heale d c o m pletel y.
6. 6. 4
P ost -tri al p r o visi o ns
After t he st u d y is fi nalize d S p o ns or will n ot s u p pl y an y  more treat me nts t o t he s u bjects, e ve n 
if t he res ult d oes n ot persist.
6. 6. 5
Electr o nic case re p ort f or m rec or di n gs
T he f oll o wi n g details of t he i njecti o n at i nitial treat me nt a n d t o uc h-u p, if a p plica ble, are t o be 
rec or de d i n t he e C R F:

Date f or a d mi nistrati o n

Ti me re q uire d f or eac h i njecti o n , o nl y rec or de d at t he i nitial treat me n t visit

A d mi nistere d v ol u me per N L F (b y  scale o n syri n ge )

I njecti o n tec h ni q ue ( li near t hrea di n g or ot her )

De pt h of i njecti o n per N L F ( mi d der mis, dee p der mis , or ot her)

L ot n u m ber

P ost -treat me nt care ( massa ge, ice-pac k, or ot her )

L ocal a naest hetic use d at t o uc h- u p treat me nt (pr o d uct na me, v ol u me i njecte d/a m o u nt 
a p plie d , a n d c o nce ntrati o n )
I n a d diti o n, an y  tec h nical pr o ble ms (d e vice d eficie ncies) or cli nical c o m plicati o ns ( A Es)
ass ociate d wit h t he i njecti o n will be rec or de d i n t he e C R F. 
6. 6. 6
Tre at me nt c o m pli a nce
T he treat me nt is a n i m pla nt a d mi nistere d b y  the treati n g I n vesti gat or a n d t he details of t he 
a d mi nistrati o n are rec or de d i n t he e C R F. N o ot her meas ure me nts of treat me nt c o m plia nce 
will be ma de.
7 
E F FI C A C Y A S S E S S M E N T S
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 i ncl u de assess me nt of W S R S
2 2 ( Secti o n 7. 2 ), 
, a n d p h ot o gra p h y  (Secti o n 7. 5 ). A descri pti o n of t he
la b orat or y assess me nts is gi ve n i n Secti o n 8. 2 a n d t he E C G assess me nt i n Secti o n 8. 3 .
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
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Pa ge 5 0 of 9 5
Assess me nts will be perf or me d 
 t he bli n de d
e val uat or, as descri be d i n t he res pecti ve secti o n.
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 prefera bl y  the 
sa me i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o ns c o mpletes all c orres p o n di n g 
f oll o w-u p e val uati o ns.
7. 2
Wri n kle se verit y r ati n g sc ale
T he W S R S is a vali date d p h ot o gra p h -base d o utc o me i nstr u me nt t hat is desi g ne d s pecifically 
f or q ua ntif y i n g facial f ol ds (Ta ble 2 ). Sc ori n g of f ol d se verit y is base d o n vis ual assess me nt 
of t he le n gt h a n d a p pare nt de pt h of t he N L F at a certai n ti me-p oi nt a n d t he res ult is n ot base d 
o n a c o m paris o n t o t he baseli ne or pre -treat me nt a p peara nce. Eac h sc ore i n t he W S R S 
is 
e xe m plifie d b y a p h ot o gra p h of N L Fs 2 2 (A p pe n di x 4 ).
Li ve assess me nts will be perf or me d t hr o u g h -o ut t he st u d y.
T a ble 2. Wri n kle se verit y rati n g sc ale
Gr a de
Descri pti o n
1
A bse nt: N o visi ble f ol d; c o nti n u o us s ki n li ne .
2
Mil d:
S hall o w b ut visi ble f ol d wit h a sli g ht i n de ntati o n; mi n or facial feat ure .
I m pla nt is e x pecte d t o pr o d uce a sli g ht i m pr o ve me nt i n a p peara nce .
3
M o der ate:
M o deratel y dee p f ol ds; clear facial feat ure visi ble at n or mal a p peara nce b ut 
n ot w he n stretc he d. 
E xcelle nt c orrecti o n is e x pecte d fr o m i njecta ble i m pla nt .
4
Se vere: Ver y l o n g a n d dee p f ol d s; pr o mi ne nt facial feat ure; less t ha n 2-m m visi ble f ol d 
w he n stretc he d .
Si g nifica nt i m pr o ve me nt is e x pecte d fr o m i njecta ble i m pla nt .
5
E xtre me: E xtre mel y dee p a n d l o n g f ol ds; detri me ntal t o facial a p peara nce; 2- t o 4 -m m 
visi ble V- s ha pe d f ol d w he n stretc he d. 
U nli kel y t o ha ve satisfact or y c orrecti o n wit h i njecta ble i m pla nt al o ne .
T he bli n de d e val uat or will e val uate W S R S
at t he scree ni n g a n d baseli ne visit s t o verif y 
i ncl usi o n criteria 4 a n d f urt her e val uate t he W S R S bef ore t he i nitial treat me nt. T he W S R S 
will als o be assesse d b y  the bli n de d e val uat or at eac h f oll o w-u p visit ( 4 wee ks after i nitial 
treat me nt a n d t o uc h-u p, if a p plica ble, as well as 3, 6, 9, a n d 1 2 m o nt h after t he last treat me nt) 
f or efficac y assess me nt. At t he W ee k 4 f oll o w- u p visit after t he i nitial treat me nt, t he W S R S 
assess me nt will be use d f or treat me nt g ui da nce , e. g., t o deci de if t o uc h-u p treat me nt s h o ul d 
be perf or me d . A cli nical l y si g nifica nt i m pr o ve me nt is defi ne d as ≥1 gra de i m pr o ve me nt i n 
t he W S R S. 
Eac h N L F (ri g ht/left) will be e val uate d se paratel y,  t h us ge nerati n g t w o wri n kle se verity sc ore
res ults per s u bject. A s u bject s h o ul d prefera bl y be assesse d b y  the sa me bli n de d e val uat or
t hr o u g h o ut t he e ntire st u d y.
W he n treat me nt is a d mi nistere d at t he sa me visit as t he W S R S assess me nt, it is i m p orta nt t o 
asses wri n kle se verit y pri or t o i njecti o n . 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
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Pa ge 5 1 of 9 5
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI

Pa ge 5 2 of 9 5
7. 5
P h ot o gr a p h y
Di gital p h ot o gra p hs will be ta ke n of eac h s u bject pre -treat me nt at visits w he n treat me nt is 
perf or me d a n d at eac h f oll o w-u p visit. T he p h ot o gra p hs will be use d t o d oc u me nt c o n diti o n 
at baseli ne, 
 a n d t o d oc u me nt A Es i n t he treate d area. If necessar y , t he 
p h ot o s h o ul d be ta ke n w he n A Es occ ur. N ote t hat n o c o veri n g ma ke- u p s h o ul d be us e d o n t he
p h ot o gr ap hs. 
Eac h I n vesti gat or a n d ot her st u d y site pers o n nel desi g nate d t o ta ke p h ot o gra p hs, if a p plica ble, 
s hall be t h or o u g hly trai ne d i n t he e q ui p me nt a n d tec h ni q ues, a n d h o w t o u pl oa d p h ot o gra p hs 
t o t he sec ure d we b 
p ortal, if a p plica ble, bef ore
st u d y start. T he
s ame
p h ot o gra p hic 
e q ui p me nt a n d stan dar dize d setti n g m ust be use d at eac h vi sit (e. g., dis ta nce, li gh t, facial
p ositi o n a n d e x pre ssio n). F or f urt her details, please see t he i nstr ucti o n of i ma ge pr oce d ures 
i n t he p h ot o user g ui de
All p h ot o s s h o ul d be ta ke n fr o m a strai g ht fr o ntal vie w wit h f ull face fra me. T he s u bject s h all
ha ve a ne utral facial e x pressi o n.
Eac h p h ot o gra p h s h all be la belle d wit h t he s u bject i nitials, s u bject n u m ber, as well as t he visit
I D a n d visit date 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 ntialit y, t he 
p h ot o gra 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. 
8 
S A F E T Y A S S E S S M E N T S
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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Pa ge 5 3 of 9 5
8. 2
L a b or at or y a ssess me nts
B ot h t he he mat ol o g y  an d t he ser u m c he mistr y la b orat or y assess me nts i ncl u di n g S- H C G will 
be perf or me d at t he scree ni n g visit (Da y  - 2 1 t o D a y 1). Ser u m c he mistr y la b orat or y 
assess me nts a n d S -H C G will als o be perf or me d at t he M o nt h 
1 2 f oll o w- u p or E arl y 
ter mi nati o n visit :
La b orat or y  assess me nts:

He mat ol o g y : he m o gl o bi n , re d bl o o d cells, w hite bl o o d cells, differe ntial c o u nt a n d platelet 
c o u nt.

Ser u m c he mistr y: re nal f u ncti o n tests (creati ni ne a n d B U N) ; a n d li ver f u ncti o n tests 
(as partate a mi n o tra nsferase (A S A T), ala ni ne a mi n o tra nsferase ( A L A T) t otal bilir u bi n, 
direct bilir u bi n, a n d i n direct bilir u bi n).
T he res ults fr o m t he la b orat or y assess me nts at t he scree ni n g visit will be use d f or scree ni n g 
p ur p oses b y t he In vesti gat or . N o la b orat or y  res ults will be re p orte d i n t he e C R F, h o we ver, t he 
date s will be rec or de d i n t he e C R F.
A ser u m p re g na nc y test (S- H C G) i n w o me n of c hil d beari n g p ote ntial will be perf or me d at 
scree ni n g a n d at t he 1 2 m o nt h f oll o w -u p or earl y ter mi nati o n visit . A uri ne pre g na nc y  test ( U-
H C G) i n w o me n of c hil d bea ri n g p ote ntial will be perf or me d pri or t o t he baseli ne treat me nt , if 
t he scree ni n g ser u m pre g na nc y  test was d o ne 2 wee ks bef ore t he baseli ne visit , as well as
pri or t o t o uc h-u p treat me nt . T he p re g na nc y tests will be rec or de d i n t he e C R F.
Ot her la b orat or y test mi g ht be perf or me d at t he discreti o n of t he in vesti gat or. All la b orat or y 
assa ys will be perf or me d at a l ocal la b orat or y. Refere nce ra n ges will be s u p plie d b y  the 
la b orat or y an d use d b y  the I n vesti gat or t o assess t he la b orat or y data f or cli nical si g nifica nce 
a n d o ut of ra n ge pat h ol o gical c ha n ges. 
A n y  cli nical si g nifica nt a b n or mal la b orat or y val ues at t he 1 2 m o nt h f oll o w- u p or earl y 
ter mi nati o n visit will be re p orte d as A Es i n t he e C R F.
8. 3
E C G -scree ni n g
E C G will be ta ke n at t he scree ni n g v isit (D a y  - 2 1 t o D a y 1) a n d assesse d b y  t he In vesti gat or
f or cli nical si g nifica nce. T he r es ults of E C G will o nl y  be use d f or scree ni n g p ur p oses a n d will 
n ot be c ollecte d i n t he e C R F.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
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Pa ge 5 4 of 9 5
8. 4
A d verse eve nts
8. 4. 1
Defi niti o n of a n a d verse e ve nt
A n A E
is a n y unt o war d me dical 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 ncl u di n g a b n or mal la b orat or y fi n di n gs) i n s u bjects, users or ot her pers o n s2 3, 
w het her or n ot relate d t o t he st u d y pr o d uct . 
T his defi niti o n i ncl u des:

eve 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

eve nts relate d t o t he pr oce d ures i n v ol ve d
8. 4. 2
Defi niti o n of a s eri o us a d verse e ve nt
A seri o us a d verse eve nt ( S A E) is a n A E t hat:

le d t o deat h,

le d t o seri o us deteri orati o n i n t he healt h of t he s u bject, t hat eit her res ulte d i n

a life-t hreate ni n g2 4 ill ness or i nj ur y, or

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

i n-patie nt or pr ol o n ge d h os pitalizati o n 2 5, or

me dical 
or s ur gical i nter ve nti 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 t o a b o d y str uct ure or a b o d y f u ncti o n,

le d t o f oetal distress, f oetal deat h , or a c o n ge nital a b n or mal ity 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 ( Secti o n 8. 4. 4 ).
8. 4. 3
Rec or di n g i nstr ucti o ns
Eac h s u bject s h o ul d be q uesti o ne d a b o ut A E s at eac h st u d y visit f oll o wi n g t he scree ni n g visit.
T he q uesti o n as ke d s h o ul d be : ”Si nce y o ur last cli nical visit ha ve y o u ha d a n y healt h 
pr o ble ms ?”. Inf or mati o n o n A E s ca n als o be o btai ne d fr o m si g ns a n d s ym pt o ms detecte d 
d uri n g eac h e xa mi nati o n or fr o m a la b orat or y test, o bser v ati o ns ma de b y  the st u d y site
pers o n nel ,
 s p o nta ne o us re p orts fr o m t he s u bjects. 
W he n 
a n A E is relate d t o a d e vice d eficie nc y (refer t o Secti o n 8. 5 ), 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 eC 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 for m .
I n vesti gat ors, or ot her st u d y site pers o n nel, s hall rec or d all A E s i n t he eC R F , i ncl u di n g:

E ve nt ter m (rec or de d i n sta n dar d me dical ter mi n ol o g y a n d a v oi di n g a b bre viati o ns)
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI
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Pa ge 5 5 of 9 5

Descri pti o n of e ve nt a n d affecte d area (if a p plica ble)

Start date (first d a y  wit h s y m pt o ms)

St o p date (last d a y  wit h s ym pt o ms)

I nte nsity ( mil d, m o derate , or se vere acc or di n g t o defi niti o n i n S ecti o n 8. 4. 3. 1 )

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. 4. 3. 2 )

C a usal relati o ns hi p t o st u d y pr o d uct or st u d y pr o d uct i njecti o n pr oce d ure ( yes or n o)

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
ot her 
pr oce d ures/tests, s u bject wit h dra w n)

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 q uelae, 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 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 .
8. 4. 3. 1 I nte nsity
I nte nsity will be rec or de d for eac h re p orte d A E . T he f oll o wi n g defi niti o ns of i nte nsity are t o 
be use d:
Mil d :  
Aware ness of s y m pt o ms or si g ns, b ut easil y  t olerate d (acce pta ble)
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 pacit 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 cha 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 t hat d a y  
s hall be rec or de d .
8. 4. 3. 2 C a us al rel ati o ns hi p a n d seri o us ness
Eac h A E , seri o us as well as n o n- seri o us, s hall be assesse d b y  the treati n g 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 us ness ( Yes or N o) of t he e ve nt . 
A
t w o-p oi 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 p o nse t o eac h of t he f oll o wi n g q uesti o ns i n t he 
eC R F :

“ D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y  that 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  that t he e ve nt ma y  ha ve bee n 
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 relatio 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. 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
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Pa ge 5 6 of 9 5
8. 4. 4
Re p orti n g of a d verse eve nts 
A d verse e ve nt re p orti n g o n eac h s u bject s hall start after t he I CF has bee n si g ne d at t he 
scree ni n g visit . T he re p orti n g s hall c o nti n ue d uri n g eac h f oll o w- u p visit (i ncl u di n g 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 t o be re p orte d as a n A E i n t he eC R F .
8. 4. 5
Re p orti n g of seri o us a d verse eve nts
T he I n vesti gat or s h o ul d re p ort a n y S A E t o t he S p o ns or a n d rele va nt a ut h orities 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 he i nitial re p ort t o t he S p o ns or will be ma de i n t he e C R F s yste m. If t here are diffic ulties 
accessi n g t he e C R F, t he S A E re p ort c o ul d be se nt t o t he S p o ns or via e mail or fa x.
I n case of diffic ult y t o o btai n all t he re q uire d i nf or mati o n wit hi n 2 4 h o urs, a n i nitial re p ort 
ca n be s u b mitte d, wit h
t he f oll o wi 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:

Cli nical trial n u m ber ( C T N)

S u bject i de ntificati o n (a ge, ge n der, s u bject n u m ber)

A E descri pti o n

Date w he n A E occ urre d

Date w he n A E beca me seri o us

Na me of PI a n d ori gi nal re p ort er (if ot her t ha n t he PI )

Na me of st u d y pr o d uct 

Treat me nt s pecificati o n
S u p p orti n g d oc u me ntati o n t o be pr o vi de d wit h t he S A E re p ort:

C o nc o mita nt me dicati o n f or m/list

C o nc o mita nt pr oce d ure /treat me nt f or m/list

A E f or m/list

Me dical hist or y  f or 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:
c o m plai nts. 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 1 8 4 7 4 9 1 0 1
F or n o n- ur ge nt c o m ple me ntar y inf 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 o m ple me ntar y i nf or mati o n: 
Att n. C o m plai nts Q A
Se mi narie gata 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  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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5. 0
 
 
 
Pri nt date:
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Pa ge 5 7 of 9 5
I n a d diti o n, acc or di n g t o nati o nal re g ulati o n, the I n vesti gat or s h o ul d re p ort a n y S A E e ve nt
usi n g t he C F D A S A E f or m t o t he a d mi nistrati ve de part me nt of me dical de vice cli nical trials, 
w h o will re p ort wit hi n 2 4 h o urs of a w are ness t o t he:

F o o d a n d Dr u g A d mi nistrati o n
( F D A) of pr o vi nce, a ut o n o mo us re gi o n, or m u nici palit y  
w here t he site is l ocate d (l ocal F D A)

C o m missi o n of Healt h a n d Fa mil y Pla n ni n g of pr o vi nce or a ut o n o m o us re gi o n or 
m u nici p alit y w here t he site is l ocate d

Res p o nsi ble I E C
A c o p y of t he i nitial C F D A S A E re p ort s h o ul d be se nt t o S p o ns or b y  e-mail or fa x a n d o ne 
c o p y s h o ul d be ke pt at t he st u d y site. C o ntac t details t o l ocal F D A a n d C o m missi o n of Healt h 
a n d Fa mil y Pla n ni n g of pr o vi nce or a ut o n o m o us re gi o n or m u nici p alit y w here t he site is 
l ocate d s h o ul d be a vaila ble at t he s t u d y sites.
T he I n vesti gat or is res p o nsi ble f or c o nfir mi n g t he re p orti n g pr oce d ures a p plica ble at his/ her 
I E C re gar di n g S A Es 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 pecific c o ntact details t o eac h I E C s h o ul d be a vaila ble at t he st u d y sites.
F oll o w -u p i nf or mati o 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 ossi ble a n d re p orte d i m me diatel y but n ot later t ha n 2 4 h o urs 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 acti vities, m ust be d oc u me nte d b y  t h e In vesti gat or. 
A n y  foll o w - u p i nf or mati o n s h o ul d be re p orte d b y  the I n vesti gat or i n t he e C R F or fa xe d/e-
maile d t o t he S p o ns or if t here are diffic ulties i n accessi n g t he e C R F s yste m. T he I n vesti gat or
s h o ul d als o se n d a f oll o w- u p re p ort via t he a d mi nistrati ve de part me nt of me dical de vice 
cli nical trials t o t he l ocal F D A, l ocal C o m missi o n of Heal t h a n d Fa mil y  Pla n ni n g, a n d I E C i n 
acc or da nce wit h l ocal re g ulati o ns. T he I nvesti gat or will ass ure c o m plete ness of t he S A E 
i nf or mati o n a n d t he s u p p orti n g d oc u me ntati o n. A c o p y of t he f ull y c o m plete d S A E a n d 
C F D A S A E for m s s h o ul d be ke pt at t he site.
T he S p o ns or is i n a d diti o n t o t he I n vesti gat or res p o nsi ble f or re p orti n g all S A E a n d de vice 
deficie ncies wit h t he li keli h o o d of S A E, wit hi n 5 b usi ness d a y s u p o n bei n g i nf or me d t o t he 
S ha n g hai M u nici pal F o o d a n d Dr u g A d mi nistrati o n a n d S ha n g hai M u nici pal C o m missi o n of 
Healt h a n d Fa mil y  Pla n ni n g. S p o ns or s h o ul d als o n otif y  ot her cli nical trial i nstit uti o ns a n d 
i n vesti gat ors partici pati n g i n t he st u dy, w h o pr o m ptl y s h o ul d re p ort t o t heir l ocal I R B/I E C . 
8. 4. 6
F oll o w -u p of u nres ol ve d eve nts after t er mi n ati o n of t he st u d y
All
seri o us as well as n o n -seri o us A E s 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 en 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 ve nts s hall be f oll o we d- u p after t he last st u d y visit
u ntil res ol ve d, assesse d as c hr o nic or sta ble, or f or at least 3 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 o n t he A E f oll o w u p m o d ule i n t he eC R F .
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 5 8 of 9 5
8. 4. 7
Pre g n a nc y
Pre g na nc y i n itself is n ot re gar de d as a n A E .
If t here is a pre g na nc y  duri n g t he st u d y peri o d t he s u bject m ust be wit h dra w n fr o m a n y 
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 n g t he st u d y peri o d m ust be re p orte d b y t he I nvesti gat or o n a 
p re g na nc y re p ort for m i n t he e C R F wit hi n 2 4 h o urs after t he I n vesti gat or’s a ware ness. T he 
re p ort ca n be pr os pecti ve or retr os pecti ve. F oll o w - u p s hall be c o n d ucte 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. If o utc o me i nf or mati o n bec o mes a vaila ble after st u d y 
c o m pleti o n, t he I nvesti gat o r s hall c o m plete a har d c o p y of t he pre g na nc y re p ort f or m a n d 
f or war d t o t he S p o ns or. 
Cases t hat le d t o f oetal distress, f oetal deat h or a c o n ge nital a b n or malit y or birt h defect are t o 
be re gar de d as S A E s a n d s hall be re p orte d o n t he ex p os ure i n uter o re p ort f or m t o t he 
S p o ns or i m me diatel y but n o later t ha n 2 4 h o urs after t he I n vesti gat ors a ware ness i n 
acc or da nce wit h 
Secti o n 8. 4. 5 . T hese e ve 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 na nc y  that are relate d t o t he pre g na nt w o ma n 
a n d f ulfils a n y seri o us criteria, s uc h as pre -ecla m psia 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. Electi 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.
A c o p y of t he f ull y c o m plete d pre g na nc y  for m a n d e x p os ure i n uter o f or m s h o ul d be ke pt at 
t he site.
8. 4. 8
A ntici p ate d a d verse eve nts
After t he i njecti o n s o me c o m m o n i njecti o n-relate d reacti o ns mi g ht occ ur wit h b ot h pr o d ucts. 
T hese reacti o ns i ncl u de br uisi n g, er yt he ma, s welli n g, pai n, te n der ness a n d itc hi ng at t he 
i njecti o ns site. T ypicall y t hese reacti o ns start o n t he da y of treat me nt a n d res ol ve s p o nta ne o us 
wit hi n a fe w da y s after i njecti o n. T his is i n li ne wit h w hat has bee n o bser ve d i n t he C hi nese 
cli nical st u d y for Rest yl a ne a n d is als o c o nsiste nt wit h i nter nati o nal cli nical st u d y res ults f or 
Rest y la ne a n d Restyl a ne Def yne.
Refer t o t he Rest yl a ne D ef y ne I B a n d E U I F U (A p pe n di x 2 ) as well as t he Rest y la ne C hi na 
I F U (A p pe n di x 3 ).
8. 5
De vice deficie ncies
8. 5. 1
Defi niti o n of a d e 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 ura bilit y, relia bilit y, safet y2 6, or perf or ma nce.
N ote: De vice deficie ncies i ncl u de malf u ncti o ns, use err ors , a n d i na de q uate la belli n g.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 5 9 of 9 5
8. 5. 2
Rec or di n g i nstr ucti o ns
W he n a d e vice d eficie nc y is disc o vere d t he Cli nical St u d y  C o m plai nt F or m i n t he e C R F s hall
be c o m plete d b y  the I n vesti gat or. T he t ype of c o m plai nt s hall be descri be d a n d i nj ur y to t he 
s u bject, 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 plica ble. If a n 
i nj ur y has occ urre d, a n A E m o d ule or a n S A E for m s hall be c o m plete d f oll o wi n g i nstr ucti o ns 
i n S ecti o n 8. 4 . If n o S A E was e x perie nce d as a res ult of t he d e vice d eficie nc y t he I n vesti gat or
s hall assess w het her or n ot t he d e vice d eficie 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 bee 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 nate
T he S p o ns or will ma ke t he sa me assess me nt t he Cli nical St u d y  C o m plai nt F or m.
8. 5. 3
Re p orti n g of d e vice d eficie ncies
T he I n vesti gat or s hall c o m plete t he Cli nical St u d y  Co m plai nt F or m i n t he e C R F. A de vice 
deficie nc y  that le d t o a n S A E a n d a n y de vice deficie nc y  that c o ul d ha ve le d t o a n S A E s hall 
be re p orte d wit hi n 2 4 h o urs after t he I n vesti gat or’s a ware ness i n acc or da nce wit h Secti o n 
8. 4. 5 . I n or der t o f ulfil re g ulat or y re p orti n g re q uire me nts, all deficie ncies wit h t he st u d y
pr o d uct m ust be assesse d b y  bot h t he I n vesti gat or a n d t he S p o ns or t o deter mi ne if it c o ul d 
ha ve le d t o a n S A E .
If a n S A E has res ulte d fr o m a de vice deficie nc y  or if eit her t he I n vesti gat or or t he S p o ns or 
assesses t hat t he de vice deficie nc y  co ul d ha ve le d t o a n S A E t he e ve nt will be re p orte d i n 
acc or da nce wit h Re g ulat or y  re q uire me nts, as a p plica ble.
T he defici e nt st u d y pr o d uct s hall be ke pt , if a p plica ble, b y  the st u d y site u ntil t he Q ualit y 
Ass ura nce (Q A ) co m plai nts gr o u p has c o nfir me d w het her t he pr o d uct s hall be ret ur ne d t o 
S p o ns or f or f urt her st u d y or if it ca n be destr o ye d at t he st u d y site.
8. 6
D at a s afet y m o nit ori n g b o ar d ( N ot A p plic a ble)
N ot A p plica ble f or t his st u d y .
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
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 refers t o t he acti vities defi ne d t o ac hie ve safe r o uti nes t o 
e nter cli nical data i nf or mati o n i nt o a data base, efficie ntl y a n d a v oi di n g err ors. T he data 
ma na ge me nt 
r o uti ne i ncl u des
pr oce d ures f or ha n dli n g eC R Fs, 
data base set - u p a n d 
ma na ge me nt, 
data e ntr y an d verificati o n, data vali 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 pr 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 . Data vali dati o n will be perf or me d b y  c o m p uteri ze d l o gical c hec ks a n d ma n ual re vie w. 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9

Pa ge 6 0 of 9 5
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  for re g ulat or y acti vities (Me d D R A ) dicti o naries as s pecifie d i n t he 
D M P. S afet y data ( S A E a n d if a p plica ble A E of s pecial i nterest) i n t he cli nical data base will 
be rec o ncile d a gai nst t he data i n t he safet y data base.
W he 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 eC R Fs a n d e ntere d i n 
t he data base is as c orrect a n d c o m plete as p ossi ble, the cli nical data base will be l oc ke d. St u d y
data will be tra nsferre d t o S A S datasets w hic h t hereafter will be writ e- 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 e C R F is re q uired a n d s hall be c o m plete d electr o nicall y for eac h scree ne d s u bject 
(scree ni n g visit) a n d i ncl u de d s u bjects (s u bse q ue nt visits). 
T he e C R F i ncl u des pass w or d pr otecti o n a n d i nter nal q ualit y  chec ks, s uc h as a ut o matic ra n ge 
c hec ks, 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 site bef ore 
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  the 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 orize d st u d y 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 ys te m f or a n y s u bject.
T he st u d y data is t he s ole pr o pert y of t he S p o ns or a n d s hall n ot be ma de a vaila ble i n a n y f or m 
t o t hir d parties, e x ce pt f or a ut h orize d re prese ntati ves of a p pr o priate R 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 co p y  ( pr o vi de d b y t he ve n 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 of data s hall be s pecifie d i n a si g nat ure a n d dele gati o n lo g.
9. 2. 1
D at a e ntr y
All data s hall be e ntere d i n E n glis h. T he eC R Fs s h o ul d al wa ys 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 ossi ble d uri n g or after t he s u bject’s visit. F or ms t hat will be c o m plete d b y  the s u bject 
 s h o ul d be tra nslate d i nt o l ocal la n g ua ge. T he data will be 
tra nslate d a n d e ntere d i nt o t he e C R F i n E n glis h b y t he treati n g I n vesti gat or or dele gate d st u d y 
site pers o n nel . T he s u bject’s i de ntity 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 bjects m ust n ot be re gistere d i n t he e C R Fs or i n t he data base. T he 
I n vesti gat or m ust verif y  that all data e ntries i n t he e C R Fs are acc urate a n d c orrect. If s o me 
assess me nts are n ot d o ne, or if certai n i nf or mati o n is n ot a vaila ble, n ot ap plica ble or 
u n k n o w n, t he I nvesti gat or s hall
i n dicate t his i n t he e C R F. T he 
I nvesti gat or s hall
electr o nicall y si gn off t he st u d y data. B y  si gni n g, t he I n vesti gat or ta kes res p o nsi bilit y for t he 
acc urac 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 e C 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 n d c o nsiste nc y. 
Eac h e C R F s hall be c o m pare 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 orrecti o ns, a n d alterati o ns s hall be ma de 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
 2 0 1 7- 0 7- 0 5 0 6: 3 7
5. 0
 
 
 
Pri nt date:
 2 0 2 3- 0 4- 1 4 1 2: 4 9
C CI

Pa ge 6 1 of 9 5
b y  the PI or his/ her a ut h orize d desi g nee. T he m o nit or ca n n ot e nter data i n t he e C R Fs. O nce 
st u d y data ha ve bee n s u b mitte d t o t he ce ntral 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 n g 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 ti me a n d date will be l o g ge d. R oles a n d ri g hts of t he site 
pers o n nel res p o nsi ble f or e nteri n g st u d y data int o t he e C R F s hall be deter mi ne d i n a d va nce. 
If discre pa nt data is detecte d d uri n g re vie w of t he data, eit her b y  the S p o ns or or its 
re prese ntati ves, t he res p o nsi ble d ata m a na ger or m o nit or s hall raise a q uer y  in t he electr o nic 
data 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 s hall be 
res ol ve d i n t he s yste m b y  the PI  or his/ her a ut h orize d desi g nee . T he a p pr o priate st u d y 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 traile d b y  the 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 pers o n nel, ti me, a n d date is 
l o g ge d.
9. 2. 3
U ser i de ntific ati o n
T he eC R F rec or ds will be a ut o maticall y a p pe n de d wit h t he i de ntificati o n of t he creat or, b y  
mea ns of t heir u ni q ue UserI D. S pecifie d rec or ds s hall be electr o nicall y si gne d b y  the 
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 wle d ge me nt t hat t he data are 
acc urate. T his will 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 o n s hall be ma de i n acc or da nce wit h t he rele va nt 
s oft ware pr oce d ures. 
9. 2. 4
A u dit tr ail
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 bee n e ntere d, verifie d, a n d vali date d, t he data base 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 co nsi dere d a data e ntr y for m a n d d oes n ot c o nstit 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 u me nts use d 
b y  the 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 t he s u bject, t he i ncl usi o n a n d e x cl usi o n criteria, a n d all rec or ds c o veri n g t he 
s u bject’s partici pati o n i n t he st u d y. T h e y  incl u de la b orat or y notes, me m ora n da, material 
dis pe nsi n g rec or ds, s u bject files, etc.
T he PI  is res p o nsi ble f or mai ntai ni n g s o urce d oc u me nts. T hese s hall be ma de a vaila 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 
e C R F f or eac h s u bject 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 mitte d wit h t he eC R F, s uc h as p h ot o gra p hs , s hall be clearl y  i de ntifie d wit h 
t he C T N , s u bject n u m ber , a n d visit I D. 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 preser ve i n di vi d ual c o nfi de ntialit y.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
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9. 4
Rec or d kee pi n g a n d access t o s o urce d at a
T he PI /Instit uti o n s hall per mit st u d y-relate d m o nit ori n g, 
a u dits, I E C re vie w, a n d R A
i ns pecti o ns a n d s hall pr o vi de direct access t o t he s o urce 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 nf or mati o n t o li n k rec or ds, i.e., eC R F ,
me dical rec or ds, ori gi nal si g ne d i nf or me d c o nse nt f or ms a n d detaile 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  local 
le gislati o n a n d i nter nati o nal g ui deli nes. A n y tra nsfer of res p o nsi bilit y for st ora ge of t he 
rec or ds s hall be d oc u me nte d a n d t he 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  that 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 ( by t he use of writte n s u bject i nf or mati o n a n d si g ne d 
i nf or me d c o nse nt). T he data rec or de d i n t he eC R F s 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 b y  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 t he me dical rec or d. 
T he so urce d ata locati o n l o g s pecifies w hat data t hat s hall be a vaila ble i n t he me dical rec or d. 
T he so urce d ata locati o n l o g s hall als o s pecif y the data f or w hic h t he eC R F ser ves as t he 
s o urce. S uc h data o nl y nee d t o be rec or de d i n t he eC R F a n d are t ypicall y  ass ociate d wit h 
st u d y-s pecific pr oce d ures a n d n ot wit h n or mal cli nical care practice. F or t his t ype of st u d y
data t he I n vesti gat or w o ul d n ot be e x pecte d t o d u plicate t he i nf or mati o n i nt o t he me dical 
rec or d. 
9. 5
D oc u me nt a n d d at a rete nti o n
All rec or ds pertai 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 nf or me d c o nse nt 
f or ms, st u d y
pr o d uct 
acc o u nta 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 o n m ust be retai ne d after st u d y co m pleti o n acc or di n g t o nati o nal le gislati o n a n d 
t he C T A . S p o ns or will i nf or m t he sites as t o w he n t hese 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 ntal or pre mat ur e 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). Refer t o t he C T A.
After st u dy c o m pleti 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 t he PI’s res p o nsi bilit y t o i nf or m Q-Me d
A B i n writi n g i f 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 the d oc u me nts is tra nsferre d t o s o me o ne else.
1 0
S T A TI S TI C A L M E T H O D S
1 0. 1
Ge ner al
All statistical a nal ys es, i ncl u di n g s u m mar y ta bles a n d data listi n gs, will be perf or me d usi n g 
S A S ® . C o nfi de nce i nter vals a n d p- val ues will be t w o-si de d a n d perf or me d at a si g nifica nce
le vel of 5 %.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
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C o nti n u o us e n d p oi nts will be s u m marize d usi n g descri pti ve statistics, e. g., mea n, me dia n ,
sta n dar d de viati o n , mi n i m u m, a n d ma x i m u m val ues . Cate g orical e n d p oi nt s will be prese nte d 
i n fre q ue nc y ta bles wit h n u m ber a n d perce nta ge of o bser vati o ns f or eac h le vel.
A c o m pre he nsi ve Statistical A nal ys is Pla n ( S A P) wit h detaile d descri pti o n of all statistical 
a nal ys es will be writte n a n d fi nalize d pri or t o data base l oc k .
1 0. 2
A n al ysis p o p ul ati o ns
T he f oll o wi n g p o p ulati o ns will be defi ne d :

Safet y
I ncl u des all s u bjects w h o were i njecte d i n at least o ne N L F, 
base d o n t he as treate d pri nci ple.

F ull A nal ys is Set ( F A S)
I ncl u des all s u bjects w h o 
were 
i njecte d i n b ot h N L Fs. 
S u bjects 
are a nal yze d acc or di n g t o t he ra n d o mizati o n 
assi g n me nt.

Per pr ot oc ol ( P P)
I ncl u des all F A S s u bjects w h o c o m plete d t he M o nt h 6 f oll o w -
u p visit wit h o ut a n y  maj or de viati o ns.
T he F A S p o p ulati o n is t he pri mar y  po p ulati o n f or all efficac y anal y ses. If t here are a n y C S P 
de viati o ns c o nsi dere d t o ha ve s u bsta ntial i m pact o n t he efficac y outc o me at t he M o nt h
6 
foll o w - u p visit, a P P p o p ulati o n e xcl u di n g t h ose s u bjects will be defi ne d. A detaile d list 
c o ntai ni n g s uc h de viati o ns will be i ncl u de d i n t he S A P. As t his is a n o n- i nferi ority trial, n o n-
i nferi orit y will nee d t o be s h o w n i n b ot h F A S a n d P P a nal yses. Safet y  anal y sis 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 of s u bjects will be prese nte d i n ta bles a n d/ or fi g ures as a p pr o priate. T he 
n u m ber of scree ne d, treate 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. 3
De m o gr a p hics, b aseli ne assess me nts , a n 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  st u d y pr o d uct usi n g 
descri pti ve statistics .
1 0. 4
Effic ac y a n al ysis
1 0. 4. 1 Pri m ar y a n al ysis
N o n -i nferiorit y testi n g f or Rest y la ne Def y ne relati ve t o Rest y la ne will be base d o n t he 9 5 % 
c o nfi de nce i nter val a p pr oac h wit h a n o n- i nferi orit y mar gi n of 1 5 %. T he c o nfi de nce i nter val 
will be c o nstr ucte d f or t he differe nce ( Restyl a ne mi n us
Rest y la ne Def y ne) i n res p o nse rates 
at t he 6 m o nt h f oll o w- u p visit. N o n -i nferi orit y will be declare d if t he t w o-si de d 9 5 % i nter val 
is f ull y bel o w 1 5 %, i.e., t he u p per b o u n d of t he i nter val is less t ha n 1 5 % i n b ot h t he F A S a n d 
P P p o p ulati o ns.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
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1 0. 5
S afet y a n al ysis
All A Es will be c o de d acc or di n g t o Me d D R A. All a d verse e ve nts will be s u m marize d b y  
s yste m or ga n class ( S O C) a n d preferre d ter m ( P T). T he sa me s u m maries will be ge nerate d 
f or relate d A Es, se vere A Es, A Es lea di n g t o disc o nti n uati o n, a n d S A Es. F or relate d A Es, t he 
n u m ber of d a y s t o o nset a n d t he d urati o n of e ve nt will be s u m marize d b y  SO C a n d P T usi n g  
mea n, S D, mi n, ma x, a n d me dia n statistics.
1 0. 6
H a n d li n g of missi n g d at a
As t he st u d y desi g n is i ntra-i n di vi d ual, i n w hic h t he o utc o me of b ot h treat me nts t o be 
c o m pare d is a vaila ble o n eac h s u bject, it is e x pecte d t hat w he n a data is missi n g, it will be 
missi n g f or b ot h N L Fs i n m ost of t he cases. A maj orit y of t he de viati o ns fr o m t he pr ot oc ol 
ca n be e x pecte d t o affect b ot h N L Fs a n d e val uati o ns of t he sa me s u bject t he sa me wa y . 
F A S a nal ys es of W S R S will use m ulti ple i m p utati o n met h o d ( MIM) as t he pri mar y  met h o d 
f or i m p uti n g missi n g val ues. Rat her t ha n i m p utin g eac h missi n g o bser vati o n b y  a si n gle 
val ue, t his a p pr oac h re prese nts a ra n d o m sa m ple of t he missi n g val ues, a n d t heref ore 
acc o u nts f or t he pre dicti o n u ncertai nt y of t he u n k n o w n missi n g val ues.
Safet y  an d P P a nal ys es 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. 7
I nteri m a n al ysis ( N ot A p plic a ble)
N o i nteri m a nal ys is is pla n ne d.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
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Versi o n: 
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C CI
C CI

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1 0. 8
D at a m o nit ori n g c o m mittee ( N ot A p plic a ble)
N ot a p plica ble i n t his st u d y .
1 0. 9
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 vi 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, a n d last visit perf or me d.
S u bjects wit h C S P
de viati o ns will 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. De pe n di n g o n t he seri o us ness of t he de viati o n, s u bject mi g ht be e xcl u de d 
fr o m t he P P p o p ulati o n, w hic h s hall be d oc u me nte d pr i or t o data base l oc k .
1 0. 1 0 S a m ple size
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
T he st u d y shall f oll o w t he re q uire me nts as s pecifie d i n Pe o ple's Re p u blic of C hi na ( P R C)
Pr o visi o ns f or Cli nical Trials of Me dical 
De vices wit h res pect t o t he pr ocessi n g a n d 
pr otecti o n 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 oller, a n d t he Instit uti o n a n d PI will b ot h be c o nsi dere d d ata p r ocess ors.
All pr ocessi n g of p ers o nal d ata a n d p h ot os 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 a n d p h ot os . T he Instit uti o n a n d t he PI
are res p o nsi ble f or c o m pl yi n g wit h all re q uire me nts p urs ua nt t o nati o nal le gislati o n i n t he 
c o u ntr y in w hic h t he Instit uti o n a n d t he PI are l ocate d. T he S p o ns or will e ns ure t hat all 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
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C CI

Pa ge 6 6 of 9 5
re q uire me nts are c o m plie d wit h f or data pr ocessi n g, w hic h is carrie d o ut i n S we de n b y  the 
S p o ns or.
T he i nf or me d c o nse nt f or m s hall c o ntai n i nf or mati o n a b o ut w hat pers o nal data a n d p h ot os t o 
be c ollecte d i n t he st u d y a n d 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 ufficie nt t o e na ble all s u bjects t o gi ve t heir c o nse nt 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 d ata a n d p h ot os . S uc h i nf or mati o n i ncl u des 
i nf or mati o n re gar di ng t he p ur p oses of t he c ollecti o n, pr ocessi n g, data tra nsfer t o c o u ntries 
o utsi de C hi na, a n d t he le n gt h of ti me d uri n g w hic h pers o 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 p ers o nal d ata, a n d t he ri g ht t o c orrecti o n of i nc orrect 
i nf or mati o n. If a s u bject deci des t o disc o nti n ue t he st u d y pre mat urely , data c ollecte d bef ore 
wit h dra w of c o nse nt will be use d i n t he e val uati o n o f t he st u d y, h o we ver n o ne w data ma y  be 
c ollecte d. A ut h orize d re prese ntati ves fr o m t he S p o ns or, cli nical researc h or ga nizati o n ( C R O)
or a R 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 dical rec or ds a n d t he e C R F. Data a n d 
i nf or mati o n s hall be ha n dle d strictl y  c o nfi de ntial.
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
1 2. 1
Q u alit y c o ntr 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 h e Sp o ns or acc or di n g t o G C P g ui deli nes
t o verif y  that t he ri g hts a n d well-bei n g of t he s u bjects 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 bse q 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 re p orte d i n t he e C R F w hic h will be verifie d, disc usse d , a n d
c ollecte d b y  the m o nit or a n d a p pr o priate c orrecti ve a n d pre ve nti ve 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, 
safety or well -bei n g of t he s u bject or t he scie ntific i nte grit y of t he st u d y, i ncl u di n g t h ose 
w hic h 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 b y 
nati o nal re g ulati o ns. De viati 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 or me d as descri be d i n t he 
m o nit ori n g m a n ual.
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  the S p o ns or as well as i ns pecti o n 
b y  ap pr o priate R A . It is i m p orta nt t hat t he PI a n 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 ble 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 nstrates 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, date a n d place of birt h, ad dress a n d place of w or k, a n d s hall s h o w t he trai ni n g, 
a p p oi nt me nts a n d, f or t he PI , 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 t he PI
t o be res p o nsi ble f or t he st u d y. 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
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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 ved 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 o we d. All in 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 g nat 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 d y pr ot oc ol
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  de viati o n fr o m ,
or c ha n ges t o , t he C S P wit h o ut a gree me nt wit h t he S p o ns or a n d pri or re vie w a n d d oc u me n te d 
a p pr o val fr o m t he I E C, e xce pt w here necessar y  to 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 m ust be d oc u me nte d i n a writte n pr ot oc ol a me n dme nt . 
H o we ver, a d mi nistrati ve c ha n ges are t o be d oc u me nte d i n t he S p o ns or file wi t h o ut re q uiri n g 
a pr ot oc ol a me n d me nt.
1 3
FI N A N CI N G, IN D E M NI FI C A TI O N , A N D IN S U R A N C E
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 u bject 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 c o vere d b y  Gal der ma’s gl o bal 
ge neral lia bilit y pr o gra m. A n i ns ura nce certificate will be pr o vi de d u p o n re q uest. T he 
i nstit uti o n/ 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 d y acc or di n g t o t he C T A.
1 4
P U B LI C A TI O N P O LI C Y
T he PI ’s, Instit uti o n’s , a n d Q- Me d
A B ’s o bli gati o ns re gar di n g intellect ual p r o perty ri ghts,
co nfi de ntial it y, a n d p u blicati o n s are descri be d i n detail i n t he C T A.
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 nical 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 or of t he res ults of t his 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 ut h ors hi p will be base d o n 
( 1) s u 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 nter pretati 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 for i m 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 he d ; a n 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 hat 
q uesti o ns relate d t o t he acc urac y or i nte grit 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 d2 8.
C o n diti o ns 1, 2, 3, a n d 4 m ust all be met
i n or der t o b e 
desi 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 or k as pri mar y a ut h or.
Title  
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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
T he S p o ns or will s us pe n d or ter mi nate t he st u d y w he n s o i nstr ucte d b y  t he IE C or R 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 vali d scie ntific or 
a d mi nistrati ve reas o ns.
T he S p o ns or ma 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  su 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 or y  re q uire me nts.
I n t he e ve nt of pre mat ure ter mi nati o n, Q- Me d
A B will pr o vi de i nf or 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 u d y.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
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1 6
R E F E R E N C E S
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 mal 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. Classificati 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 he r B et al. C ha pter 3 4: H yal ur o nic aci ds. I n: Asc her B e d. I njecti o n Treat me nt i n C os metic 
S ur ger y. I nf or ma U K Lt d. 2 0 0 9.
5.
Gal der ma. A pi v otal U S A ra n d o mize d e val uat or - bli n de d, acti ve-c o ntr olle d, m ulti -ce nter, s plit-
face c o m paris o n st u d y of E mer vel ® Dee p
Li d ocai ne vers us J u ve der m ® Ultra Pl us i n t he 
treat me nt of m o derate 
t o se vere facial wri n kles a n d f ol ds. Cli nical I n vesti gati o na Re p ort: 
R D. 0 6. CI R. 1 8 1 5 6. 2 0 1 3 .
6.
Gal der ma. A p hase I V Eur o pea n ra n d o mize d, e val uat or - bli n de d, c o ntr olle d, m ulti -ce nter, i ntra-
i n di vi dual ri g ht-left c o m paris o n st u d y of E ve n or Dee p vers us Perla ne i n t he treat me nt of s oft 
tiss ue c o nt o ur def or mities. Cli nical I n vesti gati o nal Re p ort: R D. 0 3. S R E. 4 0 0 7 2. 2 0 1 1.
7.
Bra n dt F 1, Ba n k D, Cr oss S L , Weiss R . A li d ocai ne-c o ntai ni n g f or m ulati o n of lar ge-gel particle 
h yal ur o nic aci d alle viates pai n. Der mat ol S ur g. 2 0 1 0 N o v; 3 6 S u p pl 3: 1 8 7 6 - 8 5.
8.
Li n d q vist C, T vete n S, B o n de vi k B E a n d Fa grell D. A ra n d o mize d, e val uat or -bli n d, m ultice nter 
c o m paris o n of the efficac y a n d t olera bilit y of Li d ocai ne vers us Z y plast i n t he c orrecti o n of 
nas ola bial f ol ds. Plast Rec o nstr S ur g. 2 0 0 5 Ja n; 1 1 5( 1): 2 8 2 - 9.
9.
Carr ut hers A, Care y W, De L ore nzi C, Re mi n gt o n K, Sc hac hter D a n d Sa pra S. Ra n d o mize d, 
d o u ble -bli n d c o m paris o n of t he efficac y of 2 h yal ur o n ic aci d deri vati ves, rest yla ne Li d ocai ne a n d 
h ylaf or m, i n t he treat me nt of nas ola bial f ol ds. Der mat ol S ur g. 2 0 0 5 N o v;
3 1( 1 1 Pt 2): 1 5 9 1 -8; 
disc ussi o n 1 5 9 8.
1 0. C o he n J, Da ya n S, Bra n dt F, Nels o n D, A xf or d -Gatle y R, T heise n M a n d Nari ns R. S yste mic 
re vie w of cli nical trials of s mall- a n d lar ge-gel -particle h yal ur o nic aci d i njecta ble fillers f or 
aest hetic s oft tiss ue a u g me ntati o n. Der mat ol S ur g 2 0 1 3; 3 9: 2 0 5 - 2 3 1.
1 1. Nari ns R S, Bra n dt F, Le y de n J, L ore nc P Z, R u bi n M, S mit h S. A ra n d o mize d, d o u ble -bli n d, 
m ultice nter c o m paris o n of t he efficac y a n d t olera bilit y of Rest yla n e vers us Z y plast f or t he 
c orrecti o n of nas ola bial f ol ds. Der mat ol S ur g 2 0 0 3; 2 9: 5 8 8 - 9 5.
1 2. Ta yl or S C, B ur gess C M, Calle n der V D. Efficac y of Varia ble - Particle H yal ur o nic Aci d Der mal 
Fillers i n Patie nts wit h S ki n of C ol or: A Ra n d o mize d, E val uat or -Bli n de d C o m parati ve Trial. 
Der mat ol S ur g. 2 0 1 0 Ma y; 3 6 S u p pl 1: 7 4 1 - 7 4 9.
1 3. Ta yl or S C, B ur gess C M, Calle n der V D.  Safet y of n o na ni mal sta bilize d h yal ur o nic aci d der mal 
fillers i n patie nts wit h s ki n of c ol or: a ra n d o mize d, e val uat or - bli n de d c o m parati ve trial. Der mat ol 
S ur g. 2 0 0 9 Oct; 3 5 S u p pl 2: 1 6 5 3 - 1 6 6 0.
1 4. Gl o ga u R G, Ka ne M A. Effect of i njecti o n tec h ni q ues o n t he rate of l ocal A d verse E ve nts in 
patie nts i m pla nte d wit h n o na ni mal h yal ur o nic aci d gel der mal fillers. Der mat ol S ur g. 2 0 0 8 J u n; 3 4 
S u p pl 1: S 1 0 5 - 1 0 9. 
1 5. D o ver J S, R u bi n M G, B hatia A C. Re vie w of t he efficac y, d ura bilit y, a n d safet y data of t w o 
n o na ni mal sta bilize d h yal ur o nic aci d fillers fr om 
a pr os pecti ve, ra n d o mize d, c o m parati ve, 
m ultice nter st u d y. Der mat ol S ur g. 2 0 0 9 Fe b; 3 5 S u p pl 1: 3 2 2 -3 3 0; disc ussi o n 3 3 0 - 3 3 1.
1 6. Nari ns R S, Da ya n S H, Bra n dt F S, Bal d wi n E K. Persiste nce a n d i m pr o ve me nt of nas ola bial f ol d 
c orrecti o n wit h n o na ni mal -sta bilize d h y al ur o nic aci d 1 0 0, 0 0 0 gel particles/ m L filler o n t w o 
Title  
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Versi o n: 
Eff e cti v e
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Pa ge 7 0 of 9 5
retreat me nt sc he d ules: res ults u p t o 1 8 m o nt hs o n t w o retreat me nt sc he d ules. Der mat ol S ur g. 
2 0 0 8 J u n; 3 4 S u p pl 1: S 2 -8; disc ussi o n S 8.  
1 7. Nari ns R S, Bra n dt F S, Da ya n S H, H or nfel dt C S. Persiste nce of Nas ola bial F ol d C orrecti o n wit h a 
H yal ur o nic Aci d Der mal Filler wit h Retreat me nt: Res ults of a n 1 8- M o nt h 
E xte nsi o n St u d y. 
Der mat ol S ur g. 2 0 1 1 Ma y; 3 7( 5): 6 4 4 - 6 5 0.
1 8. Xia o qi n g Y, J u n X, C ha n gs he n g L, Y o n g g ua n g M, Wei L. A M ultice nter St u d y of t he Efficac y 
a n d Safet y of Rest yla ne i n t he Treat me nt of Nas ola bial F ol ds i n C hi na. Plastic a n d Rec o nstr ucti ve 
S ur ger y. 2 0 0 9 1 2 4( 5); 2 5 6e -2 5 7e.
1 9. He de n P, Fa grell D, Jer n bec k J, R yla n der R, Sa m uels o n U, Sell ma n G, Star k B. I njecti o n of 
sta bilize d h yal ur o nic aci d-base d gel of n o n- a ni mal ori gi n f or t he c orrecti o n of nas ola bial f ol ds: 
c o m paris o n wit h a n d wit h o ut li d ocai ne. Der mat ol S ur g. 2 0 1 0; 3 6: 7 7 5 - 7 8 1.
2 0. Weiss 
R, Ba n k D, Bra n dt F. Ra n d o mize d, d o u ble -bli n d, s plit-face st u d y of s mall-gel -particle 
h yal ur o nic aci d wit h a n d wit h o ut li d ocaine d uri n g c orrecti o n of nas ola bial f ol ds. Der mat ol S ur g 
2 0 1 0; 3 6: 7 5 0 – 7 5 7.
2 1. Ha milt o n R G, Str o b os J, A d ki ns o n N F Jr. I m m u n o ge nicit y st u dies of c os meticall y a d mi nistere d 
n o na ni mal -sta bilize d h yal ur o nic aci d particles. Der mat ol S ur g. 2 0 0 7 Dec; 3 3 S u p pl 2: S 1 7 6-8 5.
2 2. Da y DJ, Littler C M, S wift R W, G ottlie b S. T he wri n kle se verit y rati n g scale. A m J Cli n Der mat ol 
2 0 0 4; 5( 1): 4 9 - 5 2.
2 3. F or users or ot her pers o ns, t his defi niti o n is restricte d t o e ve nts relate d t o t he i n vesti gati o nal 
pr o d uct.
2 4. T he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o 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 deat h if it were m ore 
se vere. ( S o urce: I C H-E 2 A
cli nical safet y data 
ma na ge me nt : defi niti o ns a n d sta n dar ds f or e x pe dite d re p orti n g).
2 5. Pla n ne d h os pitalizati 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 healt 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).
2 6. I na de q uac y of d e vice safet y refers t o pr o perties of t he de vice w hic h c o ul d ha ve or ha ve le d t o a n 
A E.
2 7. Weiss R, Ba n k R, Bra n dt F. Ra n d o mize d, D o u ble -Bli n d, S plit -Face St u d y of S mall -Gel -Particle 
H yal ur o nic Aci d wit h a n d wit h o ut Li d ocai ne D uri n g C orrecti o n of Nas ola bial F o l ds, Der mat ol 
S ur g 2 0 1 0; 3 6: 7 5 0 – 7 5 9.
2 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 dical J o ur nal E dit ors (I C MJ E) ( htt p:// w w w.ic mje. or g).
A P P E N DI C E S
A p pe n di x 1
Declarati o n of Helsi n ki 
A p pe n di x 2
I nstr ucti o n f or Use Rest yla ne Def y n e
A p pe n di x 3
I nstr ucti o n f or Use Rest yla ne C hi na
A p pe n di x 4
P h ot o g ui de f or Wri n kle Se verit y  Rati n g Scale ( W S R S)
Title  
D o c i d  
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Eff e cti v e
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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 Helsi 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 neral Asse m bl y, H o n g K o n g, Se pte m ber 1 9 8 9
4 8t h W M A Ge neral 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 neral 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 Clarificati o n a d de d)
5 5t h W M A Ge neral Asse m bl y, T o k y o, Ja pa n, 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 ociati o n ( W M A) has de vel o pe d t he Declarati o n of 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 Declarati o n 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 t he 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 ved i n me dical researc h i n v ol vi n g h u ma n s u bjects t o a d o pt t hese 
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 bi n ds t he p h ysicia n wi t 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 i n 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 of  the 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, 
i ncl 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 base 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 pri m ar y pur p ose of me dical researc h i n v ol vi n g h u ma n s u bjects is t o u n dersta n d t he ca uses, 
de vel o p me nt a n d eff e cts of dis e as es a n d i mpr o ve pre ve nti ve, dia g n ostic a n d t hera pe 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 ntio ns m ust be e val uate d c o nti n uall y t hr o u g h researc h 
f or t heir safet y, effecti ve ness, efficie nc y, accessi bilit y a n d q ualit y.
7.
Me dical researc h is s u bject t o et hical sta n dar ds t hat pr o m ote a n d e ns ure res pect f or all h u m a n s u bjects 
a n d pr otect t heir healt h a n d ri g hts.
8.
W hile t he pri m ar y pur 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 di vi d ual researc h s u bjects.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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2 ( 5)
9.
It is t he d ut y of p h ysicia ns w h o are i n vol 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 t o self-deter mi nati o n, pri 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 res p o nsi bilit y f or t he pr otecti o n of researc h s u bjects m ust al wa ys rest w it h t he p h ysicia n or ot her healt h care 
pr ofessi o nals a n d ne ver 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 ysicia 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 in t heir o w n c o u ntries as well as a p plica ble i nter nati o nal n or ms a n d sta n dar ds. N o nati o nal 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  the pr otecti 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 be c o n d ucte d i n a ma n ner t hat mi ni mises p ossi ble har m t o t he e n vir o n me nt.
1 2.
Me dical researc h i n v ol vi n g h u ma n s u bjects m ust b e c o n d ucte d o nl y b y i n di vi d uals wit h t he a p 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 patie 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 priatel 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 derre prese nte d i n me dical 
researc h s h o ul d be pr o vi d e d a p pr o priate access t o 
partici pati o n i n researc h.
1 4.
P h ysicia ns w h o c o mbi ne me dical researc h wit h me dical care s h o ul d i n v ol ve t heir 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 he researc h st u d y will n ot a d versel 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 ns ure d.
Ris ks, B ur de ns a n d Be nefits
1 6.
I n me dical practice a n d i n me dical researc h, m ost 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 u bjects 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 m a n s u bjects m ust 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 di 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 t he m a n d t o ot her i n di vi d uals or gr o u ps affecte 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 mple 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 n v 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 of of  
defi niti ve o utc o mes, p h ysicia ns m ust assess w het her t o c o nti n ue, m o dif y or i m me diatel 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 ps 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 bei n g 
wr o n ge d or of i nc urri n g a d diti o nal har m.
All v ul nera ble gr o u ps a n d i n di vi d uals s h o ul d recei ve s pecificall y c o nsi dere d pr otecti o n.
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2 0.
Me d ical researc h wit h a v ul nera 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 orities of t his gr o u p a n d t he researc h ca n n ot be carrie d o ut i n a n o 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 ols
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 scie ntific pri nci ples, be 
base d o n a t h or o u g h k n o wl e d ge of t he scie ntific literat ure, 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 welfare of a ni mals use d f or researc h m ust be 
res pecte d.
2 2.
T he 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 ntai n a state me nt of t he et hical c o nsi 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 pri nci ples i n t his Declarati o n ha ve bee n ad dresse d. T he pr ot oc ol s h o ul d i ncl u de i nf or mati 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 n d 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 mpe 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 arra n ge me nts f or p ost-trial pr o visi o ns.
Rese arc h Et hics C o m mittees
2 3.
T he researc h pr ot oc ol m u st be s u b mitte d f or co 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 n de pe n de nt of t he researc her, t he s p o ns or a n d a n y ot her u n d ue i nfl ue nce a n d m us t be d ul y 
q ualifie d. It m ust ta ke i nt o c o nsi derati o n t he 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 we ll as a p plica ble i nter nati o nal n or ms a n d sta n dar ds b ut t hese m ust n ot be 
all o we 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 nf or mati o n a b o ut a n y serio us a d verse e ve nts. N o a me n d me nt t o t he 
pr ot oc ol ma y be ma de wit h o ut c o nsi 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 o m 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 nclusi 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 mati o n.
I nf or me d C o nse nt
2 5.
Partici pati o n b y i n di vi d uals ca pa ble of gi vi n g i nfor me d c o nse nt as s u bjects i n me dical researc h m u st be 
v ol u ntar y. Alt h o u g h it ma y be a p 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 n g i nf or me d c o nse nt ma y be e nr olle 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 o nse 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 of f u n di n g, a n y possi ble c o nflicts of  interest, 
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 ort 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 ote 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 the st u d y or t o wit h dra w  co nse nt t o partici pate at a n y 
ti me wit h o ut re prisal. S pecial atte nti o 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 well as t o t he met h o ds use d t o deli ver t he i nf or mati o n.
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After e ns uri n g t hat t he p ote 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 pr o priatel 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 me 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 presse 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 dical 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 utc o m e 
a n d res ults of t he st u d y.
2 7.
W he n see ki n g i nf or me d c o nse nt f or partici pati o n i n a researc 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 bject is i n a de pe n de nt relati o ns hi p w it h t he p h ysicia n or ma y c o nse nt u n der d uress. I n 
s uc 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 di vi d ual w h o is c o mpletel y 
i n de pe n de nt of t his relati o ns hi p.
2 8.
F or a p ote ntial researc 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 me d c o nse nt fr o m t he le gall y a ut h orise d re prese ntati ve. T hese i n di vi d uals m ust n ot be i ncl u de 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 researc h ca n n ot i nstea d be perf or me d wit h pers 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 ntial researc h s u bject w h o is dee m e 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 
asse nt t o decisi o ns a b o ut partici pati o n i n resea rc h, t he p h ysicia n m ust see k t hat asse 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 ysicall 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 nsci o us patie nts, ma y 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 nse 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 ysicia 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 wit 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 wi t h a c o n diti o n t hat re n ders t he m un a 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 mittee. C o nse nt t o re 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 he s u bject or a le gall y a ut h orise d re prese ntati ve.
3 1.
T he p h ysicia 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 u d y m ust ne ver 
a d versel y affect t he p atie nt -p h ysicia n relati o ns hi p.
3 2.
F or me dical researc h usi n g i de ntifia ble h u m a n material or data, s uc h as researc h o n material or data 
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 f or its c ollecti o n, st ora ge 
an d/ or re use. T here ma y be e xce pti o nal sit uati o ns w here c o nse nt w o ul d be i m p ossi ble or i m practica 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 b e 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 et 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 of a n e w  inter 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 use 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 scie ntificall y s o u n d me t h o d ol o gical reas o ns t he use of a n y i nter ve nti o n less 
effecti ve 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 deter mi ne t he efficac y 
or safet y of a n i nter ve nti o n
a n d t he patie 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 o n 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 of n ot recei vi n g t he 
best pr o ve n i nter ve nti o n.
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5 ( 5)
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 neficial 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 ults
3 5.
E ver y researc h st u d y i n v ol vi n g h u ma n s u bjects m ust be re gistere 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 ut h ors, 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 blicati 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 m a n s u bjects a n d are acc o u nta ble f or t he c o mplete ness a n d acc urac y of  their 
re p orts. All par ties s h o ul d a d here t o acce pte d g ui deli nes f or et hical re 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  fu n di 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 da nce 
wit 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 actice
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 or ot her k n o w n 
i nter ve nti o ns ha ve bee n i neffecti 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 prese ntati 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 healt h or alle viati n g s ufferi n g. T his i nter ve nti o n s h 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 n d efficac y. I n all cases, ne w  inf 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.
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A p pe n di x 2
I nstr ucti o ns f or Use Rest yl a ne Def y ne
( E xtract fr o m Q M S-8 6 6 2 versi o n 3. 0)
I N S T R U C 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 h y al 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
qs a d 1 m L
II.
D E S C RI P TI O N
Rest y la ne® De 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 y al ur o nic aci d wit h t he a d diti o n of li d ocai ne h y dr oc hl ori de 3 m g / mL . The gel is s u p plie d i n 
a prefille d plastic s yri n ge. T he c o nte nts of t he s yri n ge are sterilize d usi n g m oist heat. T he 
s yri n ge is pac ka ge d i n di vi d uall y in a blister, wit h t w o 2 7 G x ½” Ultra t hi n wall nee dles. T he 
nee dles ha ve bee n sterilize 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 ncl u des patie nt rec or d la bels t hat s h oul 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 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 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 osal la yer of t he li ps, s u bc utis or s u pra peri ostic 
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 u ri n g t he treat me nt.
T he pr o d uct is o nl y  inte n de d t o be use d b y  aut h orize d pers o n nel i n acc or da nce wit h l ocal 
le gislati o 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 ntact y o ur l ocal Gal der ma re prese ntati ve or Rest yla ne distri b ut or f or 
i nf or mati o n a b o ut trai ni n g o p p ort u nities.
I V.
M O D E O F A C TI O N
T he 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 me a n d lifti n g ca pacit y ori gi nate fr om t he a bilit y of cr oss-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 
Title  
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-
Patie nts prese nti n g wit h 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 treat 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 i nt 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 occlusi 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 patie nts w h 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 hyal 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.
VII.
P R E C A U TI O N S F O R U S E
Ge neral c o nsi derati o ns rele va nt t o i njecta ble me dical de vices
-
K n o wle d ge of t he a n at 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 
t o 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.
-
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 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 xercise d w he n treati n g areas wit h li mite d c ollateral 
circ ulati o n, d ue t o i ncrease d ris k of isc he mia.
-
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, t o a v oi d f or mati o n of 
pal pa ble l u m ps.
-
Patie nts wit h pre -e xisti n g pi g me nte d dar k l o wer e ye li d circles, t hi n s ki n a n d pre-
e xisti n g te n de nc y t o war d oe de ma f or mati 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 nts 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 pa tie nts wit h a te n de nc y t o f or m 
h y pertr o p hic scars 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 bcli nical 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 pir i n a n d 
n o nster oi dal a nti -i nfla m mat or y dr u gs ma y, 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 ble 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 ge i s da ma ge d. 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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3 ( 5)
-
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 derati 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 li d ocai ne is use d c o nc urre 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 ma nifesti n g as 
s ym pt o ms affecti n g t he ce ntral ner v o us s ys te m a n d car diac c o n d ucti o n.
-
Li d ocai ne s h o ul d be use d wit h ca uti o n i n patie nts recei vi n g o t her l ocal a naest hetics or 
a ge nts str uct urall y relate d t o a mi de -t ype l ocal a naest hetics e. g., certai n a nti -
arr h yt h mics, si nce t he s yste mic t o xic effects ca n be a d diti ve. 
-
Li d ocai ne s h o ul d be use d ca uti o usl y  i n patie nts wit h e pile ps y, i m paire d car diac 
c o n 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 perficially t his ma y res ult i n visi ble l u m ps a n d/ or 
bl uis 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, stea m 
bat hs, etc.) or e xtre me c ol d 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, c he mical peeli n g or a ny ot her pr oce d ure 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 risk of 
eliciti n g a n i nfla m mat 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 xi m u m d osa ge of 2 m L per treat me nt site is 
rec o m me n de d.
-
T his pr o d uct has n ot bee n teste d 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 njecti o n 
pr oce d ure a n d t o t he use of t his pr o d uct. 
T he f oll o wi n g p ost mar ket 
a d verse e ve nts ha ve bee n re p orte 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 yt he ma, h y perse nsiti vit y , i n d urati o n, i nfecti o n, i nfla m mati o n, 
isc he mia/ necr osis, mass, 
ne ur ol o gical s ym pt o ms 
s uc h as paraest hesia, pai n/te n der ness, 
pa p ules/ n o d ules, pr urit 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.
Ot her p ote ntial a d verse e ve nts t hat ha ve bee n re p orte d f oll o wi n g i njecti o n of h y al ur o nic aci d 
gels i n ge neral a n d m a y  occ ur w he n usi n g t he pr o d uct i ncl u de t he f oll o wi n 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.
I njecti o n relate d a d verse e ve nts s uc h as br uisi n g , er yt he ma, itc 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.
Vasc 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 njecta ble pr o d uct. T his m a 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  the bl o o d 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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4 ( 5)
vessels affecte d; or rarel y as isc he mic 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 orte d re gar di 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 res 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 m a y  occ ur, es peciall y in patie nts w h o ha d pri or 
r hi n o plasty.
S y m pt o ms of i nfla m mati o n at t he i m pla nt site c o m me nci n g eit her s h ortly after i njecti o n or 
after a dela y  of up t o se veral wee ks ha ve bee n re p orte d. I n case of u ne x plai ne d i nfla m mat or y 
reacti o ns i nfecti o ns s h o ul d be e xcl u de d a n d treate d if necessar y  si nce i na de q uately treate d 
i nfecti o ns ma y  pr o gress i nt o c o m plicati 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 treat me nt is n ot rec o m me n de d. I n case of  
persiste nt or rec urre nt i nfla m mat or y sy m pt o ms, c o nsi der re m o val of t he pr o d uct b y  
as pirati o n/ drai na ge, e xtr usi o n or e nz y m atic de gra dati o n ( use of h y al ur o ni dase has bee n 
descri 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 welli n g m a y  be re d uce d b y  usi n g e. g., N S AI D f or 2- 7
d a y s or
a s h ort c o urse of 
c ortic oster oi ds 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 orta 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 verse 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 nas ola bial f ol ds, 6 9. 8 % of s u bjects mai 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.
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 o ssi 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 yri n ge i n t he blister pac k. As a n alter nati 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/ca n n ula a n d s yri n ge:
-
use s ur gical gl o ves
-
u nscre 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 st o p per fr o m t he syri n ge
-
fir ml y scre w t he 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
Clea 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 njecti o n.
T o a v oi d brea ka ge of t he nee dle/ca n n ula, d o n ot atte m pt t o be n d or ot her wise ma ni p ulate it 
bef ore or d uri n g treat me nt.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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Pri nt date:
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5 ( 5)
Bef ore injecti n g t he pr o d uct, de press t he pl u n ger r o d caref 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 ula 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 nee dle of a p pr o priate size. 
As pirati o n is rec o m me n de d pri 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. Inject sl o wl y. D uri n g i njecti o n, kee p t he si de h ole of t he ca n n ula 
faci n g d o w n war ds, aw a y  fr o m t he s ki n s urface.
I nject t he gel by ge ntl y pressi n g d o w n o n t he pl u n ger r o d wit h t he 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 near t hrea di n g or cr oss -
hatc hi n g.
It is rec o m me n de d t o c ha 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, b ut 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 o n, t he w hite ne d 
area s h o ul d be massa ge d ge ntl y u n til it ret ur ns t o a n or mal c ol o ur.
Ge ntl y massa ge t he treate d area after i njecti o n.
T he s yri n ges a n d nee dles /ca n n ulas m ust be discar de d i m me diately 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 nal g ui d eli nes. T he 
pr o d uct s hall n ot be re use d d ue 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 pl y whe 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 vice s.
XI.
S H E L F LI F E A N D S T O R A G E
D o n ot use after t he e x pir y  date i n dicate d o n pac ka ge. 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.
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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1 ( 1 2)
A p pe n di x 3
I nstr ucti o n f or Use Rest yl a ne C hi n a
(E xtract fr o m Q M S-5 6 0 2 versi o n 8. 0)
Ple ase re a d t he I nstr ucti o n f or Use c aref ull y, a n d use t he pr o d uct acc or di n g t o t he 
i nstr ucti o n.
M o difie d S o di u m H y al ur o n ate Gel f or I njecti o n
I N S T R U C TI O N S F O R U S E
Na me
Tra de Na me:
瑞蓝
C hi nese Pr o n u nciati o n:
R ui L a n
Ge neric Na me:
M o difie d so di u m h yal ur o nate g el f or injecti o n
C hi nese Pr o n u nciati o n:
Z h u S he Y o n g Xi u S hi T o u Mi n g Z hi S ua n Na Ni n gJia o
M o del:
瑞蓝
2 （Rest y la ne）
S pecificati o n:  
0. 5 m L /s yri n ge; Article n u m ber 1 0 - 7 0 1 0 9
1 m L /s yri n ge; Article n u m ber 1 0 - 7 0 0 0 9
Re gistr ati o n Certific ate N u m ber f or I m p orte d Me dic al De vice 
C F D A(I) 2 0 1 4 3 6 4 0 8 7 2
Re gistr ati o n Pr o d uct St a n d ar d C o de N u m ber f or I mp orte d Me dic al De vice 
Y Z B/ S W E 8 1 2 0 - 2 0 1 3 “ M o difie d S o di u m H yal ur o nate Gel f or I njecti o n”
N ote! P lease i de ntif y ge n ui ne pr o d uct via p h o ne 4 0 0 6 5 0 1 0 5 3 or o n w w w.rest yl a ne.c o m.c n
a n d kee p t he s yri n ge la bel f or tracea bilit y pur p oses (see “ Pr o d uct Pac ka ge a n d Tracea bilit y 
I nf or mati o n” f or f urt her details).
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
Effecti ve dat e: 
 
Versi o n: 
Eff e cti v e
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2 ( 1 2)
C o m p ositi o n
M o difie d s o di u m h y al ur o n ate 
I ncl u de:
S o di u m h y al ur o nate
2 0 m g/ m L
P h os p h ate b uffere d s ali ne
I ncl u de:
S o di u m c hl ori de ( Na Cl)
9 m g/ m L
P otassi u m di h y dr o ge n p h os p hate ( K H 2P O 4)
0. 0 3 m g/ m L
Dis o di u m h y dr o ge n p h os p hate ( Na 2H P O 4 x 2 H 2O)
0. 1 4 m g/ m L
Water f or i njecti o n
a d 1 m L
Descri pti o n
瑞蓝
2 （Rest y la ne）
c o ntai ns a gel of m o difie d h y al ur o nic aci d of n o n- a ni mal ori gi n. 
H y al ur o nic aci d is nat urall y  occ urri n g a n d is a n i m p orta nt str uct ural ele me nt i n t he s ki n a n d 
i n s u bc uta ne o us a n d c o n necti ve tiss ues as well as i n t he s yn o vial tiss ue a n d j oi nt fl ui d. 
H y al uro nic aci d is meta b olize d a n d de gra de d nat urall y  b y t he b o d y. All ra w materials use d i n 
t he ma n ufact uri n g pr ocess are of n o n-a ni mal ori gi n.
瑞蓝2 （Rest y la ne）
is sterile, tra ns pare nt a n d visc o us m o difie d s o di u m h y al ur o nate gel f or 
i njecti o n s u p plie d i n a dis p osa ble glass s yri n ge wit h a l uer-l oc k fitti n g. T he c o nte nts of t he 
s yri n ge are sterile. 
T he ra n ge li mits f or gel particle size f or 瑞蓝2 (Rest y la ne) is bet wee n 0. 0 8 – 1 m m
f or 8 0 % 
of t he t otal v ol u me of gel particles. T he me dia n gel parti cle size is a b o ut 0. 4 m m. T he me dia n 
gel particle size is t he mi d dle size t hat se parates t he half of t he sa m ple c o ntai ni n g t he lar ger 
particles fr o m t he half c o ntai ni n g t he s maller particles. T he gel particles are meas ure d as 
s welle d gel particles.
M o de o f Acti o n
瑞蓝
2 （Rest y la ne）
is a der mal tiss ue filler use d t o rest ore t he s ki n c o nt o urs t o t he desire d 
le vel of c orrecti o n t hr o u g h a u g me ntati o n of facial s ki n.
瑞
蓝
2 （
Rest yl a ne ）
will de gra de gra d uall y  in t he b o d y , t ypicall y 6- 1 2 m o nt hs after 
i njecti o n. Wit h de gra dati o n t he filler effect will disa p pear. T he patie nts, w h o wa nt t o kee p t he 
filler effect, ca n recei ve f oll o w-u p i njecti o ns w he n t he filler effect bec o mes less visi ble or 
disa p pears .
T he filler effect re mai ns f or l o n ger t ha n 6 m o nt hs i n t he maj orit y  of patie nts as s h o w n i n t he 
C hi nese st u d y, w here patie nts were i njecte d wit h
瑞蓝
2 （Rest y la ne）
i n t he nas ola bial 
f ol ds. 
Title  
D o c i d  
4 3 C H 1 5 0 8 Cli nic al St u d y Pr ot oc ol
M A- 2 9 7 0 8
 
 
 
 
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Versi o n: 
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3 ( 1 2)
I n dic ati o ns
瑞蓝
2 （Rest y la ne）
is i nte n de d t o be use d f or facial tiss ue a u g me ntati o n b y  injecti o ns i nt o 
t he mi d der mis t o c orrect m o derate t o se vere nas ola bial f ol ds. 瑞蓝
2 （Rest y la ne）
s h o ul d 
be i njecte d i nt o t he mi d dle part of t he der mis la yer of t he facial s ki n. T he i njecti o n pr oce d ure 
s h o ul d strictl y f oll o w t he r ules of ase ptic s ur gical tec h ni q ue. T he pr o d uct s h o ul d o nl y be use d 
b y  d oct ors w h o ha ve a p pr o priate trai ni n g, a n d e x perie nce, a n d w h o are k n o wle d gea ble a b o ut 
t he a nat o my at a n d ar o u n d t he site of i njecti o n.
N ote! 
I njecti o ns of 瑞
蓝
2 （
Rest y la ne ）
m ust
o nl y  be d o ne b y  plastic s ur ge o ns, 
der mat ol o gist s a n d c os metic d oct ors at h os pitals a n d me dical plastic s ur ger y instit uti o ns 
officiall y a p pr o ve d b y  the state a d mi nistrati ve a ut h orities. T hese i nstit uti o ns i ncl u de cli nics 
f or me dical c os metic a n d plastic s ur ger y, me dical c os metic o ut patie nt de part me nts a nd plastic 
s ur ger y de part me nts i n ge neral h os pitals a n d s pecialize d h os pitals f or me dical c os metic a n d 
plastic s ur ger y, w hic h m ust ha ve o btai ne d a ” Me dical I nstit uti o n B usi ness Li ce nse”. D oct ors 
of t h ose i nstit uti o ns s h o ul d o nl y  use 瑞蓝2 （Rest y la ne）after bei n g trai ne d a n d certifie d b y  
t he after sales ser vice a ge nt of t he S we dis h c o m pa n y Q-Me d 
A B, Q- Me d 
I nter nati o nal 
Tra di n g ( S ha n g hai) C o., Lt d., a n d its a p p oi nte d a ge nts. After 
o btai ni n g t he trai ni n g 
certificate, t he d oct ors m ust strictl y foll o w t he i nstr ucti o ns i n t his d oc u me nt (Instr ucti o ns f or 
Use).
Pr o d uct P ac k a ge a n d Tr ace a bilit y I nf or m ati o n
T he fill v ol u me a n d n u m ber of nee dles i n t he pac ka ge are state d o n t he cart o n of 瑞蓝
2
(Rest y la ne). T he pac ka ge f or 瑞蓝
2 ( Rest y la ne) wit h fill v ol u me 0. 5 m L /s yri n ge c o ntai ns 
o ne glass s yri n ge wit h 0. 5 m L 瑞蓝
2 ( Rest yl a ne ) gel a n d o ne nee dle. T he pac ka ge f or 瑞蓝
2 ( Rest y la ne) wit h fill v ol u me 1 m L /s yri n ge c o ntai ns o ne glass s yri n ge wit h 1
m L 瑞蓝
2
(Rest y la ne) gel a n d t w o nee dle s. All nee dles are 3 0 G x ½ ″ a n d sterilize d b y  ga m ma 
irra diati o n.
T here is a stic ker (i ncl u di n g tracea bilit y bar c o de a n d sec urit y c o de c o vere d b y  wa x li ke i n k)
o n t he cart o n f or i de ntificati o n of ge n ui ne pr o d ucts. T he sec urity c o de will be visi ble after 
re m o vi n g t he wa x li ke i n k. Please i nstr uct t he patie nts t o re m o ve t he wa x li ke i n k a n d 
c o nfir m 
a 
ge n ui ne 
a n d 
a ut he ntic
pr o d uct 
via 
p h o ne 
4 0 0 
6 5 0 
1 0 5 3
or 
o n 
w w w.rest yl a ne.c o m.c n i n acc or da nce wit h
t he i nstr ucti o n o n t he cart o n. P lease gi ve t he 
sec urity c o de i n acc or da nce wit h t he i nstr ucti ons gi ve n o ver t he p h o ne or o n t he we bsite, a n d 
fill t he n u m ber wit h s uccessf ul i de ntificati o n i nt o t he P atie nt R ec or d acc or di n g t o t he 
re q uire me nt.
D o n ot use t he pr o d uct if t he i de ntificati o n c hec k s h o we d t hat it is n ot 瑞蓝
2 ( Rest y la ne) 
ma n ufact ure d
b y  Q- Me d A B, S we de n. If t he pr o d uct is a c o u nterfeit pr o d uct, p lease 
i m me diatel y c o ntact t he distri b ut ors or Q -Me d I nter nati o nal Tra di n g ( S ha n g hai) C o., Lt d., t he 
after sales ser vice a ge nt of t he S we dis h c o m pa n y Q-Me d A B .
T he s yri n ge fille d wit h 瑞蓝
2 ( Rest yl a ne) gel a n d t he s u p plie d nee dles are pac ke d i n a blister. 
O n eac h s yri n ge there is a peel -off la bel mar ke d wit h “
” . Tear off t he la bel a n d attac h 
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4 ( 1 2)
the wi de part (i ncl u di n g t he h ol o gra m, l ot n u m ber a n d i de ntificati o n c o de) t o t he Patie nt 
Rec or ds an d kee p it at t he cli nic t o e ns ure tracea bilit y of t he s yri n ge. T he narr o w part of t he 
la bel (i ncl u di n g t he i de ntificati o n c o de) m ust be attac he d t o t he d oc u me nt ke pt b y  t he patie nts 
t he msel ves (f or f urt her details please see t he re q uire me nt i n 瑞蓝
2 ( Rest y la ne) Patie nt 
C o nse nt F or m).
Please i nstr uct t he patie nts t o kee p t he cart o n of 瑞蓝
2 ( Rest yl a ne), or t o tear off t he part 
c o ntai ni n g h ol o gra m a n d pr o d uct l ot n u m ber a n d kee p it i n t he d oc u me nt ke pt b y  t he patie nts 
t he msel ves.
T he i de ntificati o n c o de a n d l ot n u m ber m ust be s u b mitte d b y  doct ors or patie nts w he n 
a d verse e ve nts are re p orte d, i n or der t o trace t he pr o d uct use d b y patie nts. 
Tre at me nt Pr oce d ure
T he d oct ors ha ve t o i nf or m t he patie nts a b o ut t he i n dicati o ns, e x pecte d res ult a n d d urati o n of 
filler effect, c o ntrai n dicati o ns, preca uti o ns, war ni n gs a n d p ote ntial a d verse e ve nts bef ore 
treat me nt. D oct ors s hall als o disc uss all p ote ntial ris ks of s oft tiss ue i njecti o n wit h t heir 
patie nts pri or t o treat me nt a n d e ns ure t hat patie nts are a ware of si g ns a n d s ym pt o ms of 
p ote ntial c o m plicati o ns. Bef ore t he treat me nt, t he patie nt’s s uita bilit y for t he treat me nt a n d 
t he nee d f or pai n relief s h o ul d be assesse d. F or o pti mal patie nt c o mf ort, t o pical or l ocal 
a naest hesia is rec o m me n de d. T he i njecti o n tec h ni q ue a n d t he a d mi nistere d q ua ntit y m a y  
var y . T he li near t hrea di n g tec h ni q ue ca n be use d t o caref ull y lift u p t he wri n kle, b ut s o me 
d oct ors prefer a series of p u nct ual i njecti o ns or a c o m bi nati o n of t he t w o. 瑞蓝2 ( Rest y la ne),
is a d mi nistere d usi n g a t hi n ga u ge nee dle ( 3 0 G x ½”) b y  injecti n g t he material i nt o t he 
der mis . 
D uri n g i njecti o n it is rec o m me n de d t hat t he e ye of t he nee dle s h o ul d face u p war ds. T he 
c o nt o ur of the nee dle s h o ul d be visi ble b ut n ot t he c ol o ur of it. A n i njecti o n t o o s u perficial 
ma y  gi ve bla nc hi n g effects a n d b u m ps o n t he treat me nt site. If t he o verl y i n g s ki n t ur ns a 
w hitis h c ol o ur ( bla nc hi n g), t he i njecti o n s h o ul d be st o p pe d i m me diatel y an d t he are a 
massa ge d u ntil it ret ur ns t o a n or mal c ol o ur. Bla nc hi n g m a y  re prese nt a vessel occl usi o n. If 
n or mal s ki n c ol ori n g d oes n ot ret ur n, d o n ot c o nti n ue wit h t he i njecti o n. 
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 nt cr oss-i nfecti o ns are t o be o bser ve d. Clea n t he treat me nt site t h or o u g hl y 
wit h s uita ble a ntise ptic s ol uti o n.  
T o a v oi d brea ka ge, d o n ot atte m pt t o be n d or ot her wise ma ni p ulate t he nee dle bef ore or 
d uri n g treat me nt.
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5 ( 1 2)
Bef ore i njecti n g, re m o ve t he air b y pressi n g t he r o d caref ull y u ntil a s mall dr o plet is visi ble at 
t he ti p of t he nee dle.
As pirati o n pri or t o i njecti o n is rec o m me n de d t o verif y t hat t he nee dle is n ot i ntra vasc ular. 
I nject 瑞蓝
2 （Rest y la ne）sl o wl y w hile p ulli n g t he nee dle bac k war ds. I njecti o n s h o ul d st o p 
j ust bef ore t he nee dle is p ulle d o ut fr o m t he s ki n t o pre ve nt material fr o m lea ki n g o ut fr o m 
t he i njecti o n site or e n di n g u p t o o s u perfic ially i n t he s ki n . 
D o n ot a p pl y excessi ve press ure t o t he s yri n ge at a n y ti me. Prese nce of scar tiss ue ma y 
i m pe de a d va nce me nt of t he nee dle. If resista nce is e nc o u ntere d t he nee dle s h o ul d be partiall y 
wit h dra w n a n d re p ositi o ne d or f ull y wit h dra w n a n d c hec ke d f or f u ncti o n.
It is rec o m me n de d t o c ha n ge nee dle f or eac h ne w treat me nt site.
If t here is pr o n o u nce d s ki n la xity, it is rec o m me n de d t hat 瑞蓝
2 （Rest yla ne ）
be i njecte d 
o n t w o or m ore se parate occasi o ns. 
T he c orrecti o n site s h o ul d be massa ge d 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. 
Ice i n a p pr o priate pac ka gi n g ca n be a p plie d o n t he treat me nt site f or a b o ut 1 5 mi n utes t o 
re d uce s welli n g a n d disc o mf ort. T his ca n be re peate d f or a n ot her 5- 1 5 mi n utes if s welli n g 
a n d disc o mf ort persist.  Beca use pr ol o n ge d e x p os ure t o c ol d te m perat ure at or bel o w 4 oC ca n 
lea d t o c ol d i nj ur y si milar t o fr ost bite, use of ice c o m press s h o ul d be ke pt t o as s h ort a ti me as 
p ossi ble. 
A d diti o nal i m pla ntati o ns of 瑞蓝
2 （Rest yl a ne ）
ma y  be necessar y  to ac hie ve t he desire d 
le vel of c orrecti o n if patie nts are n ot satisfie d wit h t he filler effect. 
N ote! T he ti me i nter val bet wee n t he i nitial i njecti o n a n d s u bse q ue nt t o uc h u p i njecti o n is at 
least 
4 wee ks. 
F or i nitial i njecti o ns, it is rec o m me n de d n ot t o use m ore t ha n 1. 5 m L f or eac h nas ola bial f ol d. 
F or s u bse q ue nt t o uc h u p i njecti o n, it is rec o m me n de d n ot t o use m ore t ha n 0. 5 m L f or eac h 
nas ola bial f ol d.
N ote! Defects s h o ul d be f ull y c orrecte d, b ut n ot o verc orrecte d at e ac h tre at me nt sessi o n .
N ote! T he c orrect i njecti o n tec h ni q ue is i m p ort a nt f or t he fi n al res ult of t he tre at me nt.
Please c o ns ult Q -Me d
I nter nati o nal Tra di n g ( S ha n g hai) C o., Lt d ., t he after sales ser vice a ge nt 
of t he S we dis h c o m pa n y Q-Me d 
A B, f or 
m ore details a b o ut tec h ni q ues a n d trai ni n g 
o p p ort u nities.
T he s yri n ge, t he nee dle a n d a n y gel t hat is u n use d a n d left i n t he s yri n ge m ust be discar 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 n use d material a n d t he ass ociate d ris ks i ncl u di n g i nfecti o ns. Dis p osal s h o ul d be 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 nal 
g ui deli nes .
Title  
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6 ( 1 2)
S T E RI L E N E E D L E

F o ll o w nati o nal, l ocal or i nstit uti o nal g ui deli nes f or use an d dis p osal of me dical s har p de vices. O btai n 
pr o m pt me dical atte nti o n if i nj ur y occ urs.

T o hel p a v oi d nee dle brea ka ge, d o n ot atte m pt t o strai g hte n a be nt nee dle. Discar d it a n d c o m plete t he 
pr oce d ure wit h a re place me nt nee dle.

D o n ot res hiel d use d nee dles . Reca p pi n g b y ha n d is a hazar d o us practice a n d s h o ul d be a v oi de d.

Discar d u ns hiel de d nee dles i n a p pr o ve d s har ps c ollect ors.
C o ntr ai n dic ati o ns
1 ．瑞蓝
2 （Rest y la ne）
is c o ntrai n dicate d f or patie nts wit h se vere aller gies ma nifeste d b y  a 
hist or y  of a na p hyl a xis, or hist or y or prese nce of m ulti ple se vere aller gies.
2 ．D o n ot use i n patie nts wit h a hist or y  of h y perse nsiti vit y  to stre pt oc occal pr otei ns, as t he 
pr o d uct ma y  c o ntai n trace a m o u nts of s uc h material.
3 ．瑞蓝
2 （Rest y la ne）
s h o ul d n ot be use d i n t he f oll o wi n g sit uati o ns:
- Per ma ne nt i m pla nt or i m pla nt ot her t ha n h y al ur o nic aci d i n t he sa me area
- N o n - per ma ne nt i m pla nt place d i n t he sa me area d uri n g t he pre vi o us 6-1 2 m o nt hs
- If n o i nf or mati o n is a vaila ble o n t he t ype of i m pla nt
4 ．D o n ot use i n patie nts wit h blee di n g dis or ders or patie nts w h o are ta ki n g t hr o m b ol ytics or 
a ntic oa g ula nts.
5 ．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 treat me nt site .
W ar ni n gs
1 ．瑞蓝
2 （Rest yl a ne）
is o nl y  inte n de d f or use as a n i ntra der mal i m pla nt. T he pr o d uct 
s h o ul d n ot be use d f or breast site i njecti o ns.
2 ．D o n ot resterilize 瑞蓝
2 （Rest y la ne）. 
3 ．D o 
n ot i nject i ntra m usc ularly or
i ntra vasc ularl y. As pirati o n 
pri or t o i njecti o n is 
rec o m me n de d.
4 ．
U ni nte nti o nal i ntr o d ucti o n of s oft tiss ue fillers i nt o t he vasc ulat ure i n t he face m a y  lea d 
t o e m b olizati o n, occl usi o n of t he vessels, isc he mia, necr osis or i nfarcti o n at t he i m pla nt 
site or i n t he area s u p plie d b y  the bl o o d vessels affecte d. Rare b ut seri o us a d verse e ve nts 
i ncl u de te m p orar y or per ma ne nt visi o n i m pair me nt, bli n d ness, cere bral isc he mia or 
str o ke. St o p t he i njecti o n i m me diatel y if bla nc hi n g occ urs or if a patie nt c o m plai ns of 
u n us ual pai n or e x hibits a n y sy m pt o ms s u g gesti ve of i na d verte nt i ntra vasc ular i njecti o n. 
S uc h patie nts s h o ul d recei ve pr o m pt me dical e val uati o n a n d atte nti o n.
5 ．瑞蓝
2 ( Rest yla ne) s h o ul d n ot be mi x e d wit h ot her pr o d ucts bef ore i m pla ntati o n of t he 
de vice .
6 ．T he pr o d uct is f or si n gle use o nl y .
7 ．D o n ot use if pac ka ge is da ma ge d.
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7 ( 1 2)
Prec a uti o ns
1 ．N or mal preca uti o ns ass ociate d wit h i ntra der mal i njecti o ns m ust be o bser ve d. Li ke a n y 
s uc h pr oce d ure, t he i m pla ntati o n of 瑞蓝
2 （Rest y la ne）
is ass ociate d wit h a n i n here nt 
ris k of i nfecti o n. T he i njecti o n pr oce d ure s h o ul d strictl y foll o w t he r ules of ase ptic 
s ur gical tec h ni q ue.
2 ．Use wit h ca uti o n i n patie nts w h o are i m m u n os u p presse d.
3 ．S pecial ca uti o n s h o ul d be e xercise d w he n treati n g areas i n cl ose pr o xi mit y t o per ma ne nt 
i m pla nt.
4 ．S pecial ca uti o n is re q uire d t o 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. I n or der t o mi ni mize t he ris ks of p ote ntial c o m plicati o ns, 
i nject t he pr o d uct sl o wly a n d a p pl y t he least a m o u nt of press ure necessar y.
5 ．Patie nts w h o are usi n g s u bsta nces t hat ma y  affect platelet f u ncti o n, s uc h as as piri n a n d 
n o n- ster oi dal a nti-i nfla m mat or y dr u gs ma y, 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. 
6 ．I njecti on pr oce d ures ca n lea d t o reacti vati o n of late nt or s u bcli nical her pes viral 
i nfecti o ns.
7 ．If t he pr o d uct is i njecte d t o o s u perficially t his ma y res ult i n visi ble l u m ps a n d/ or bl uis h 
disc ol orati o n.
8 ．Wit h 
c uta ne o us c o nt o ur def or mities t he best res ults are o btai ne d if t he defect ca n be 
ma n uall y  stretc he d t o t he p oi nt w here it is eli mi nate d. Mar ke dl y i n d urate d defects ma y be 
diffic ult t o c orrect. T he de gree a n d d urati o n of t he c orrecti o n de pe n d o n t he c haracter of 
t he defect treate d, t he tiss ue stress at t he i m plant site, t he de pt h of t he i m pla nt i n t he tiss ue 
a n d t he i njecti o n tec h ni q ue. 
9 ．瑞蓝
2 （Rest y la ne）
s h o ul d n ot be use d f or patie nts wit h u nattai na ble e x pectati o ns.
1 0 ．
If laser treat me nt, c he mical peeli n g or a n y ot her pr oce d ure base d o n acti ve der mal 
res p o nse is c o nsi dere d after treat me nt wit h 瑞蓝
2 （Rest y la ne）,
t here is a t he oretical 
ris k of eliciti n g a n i nfla m mat or y reacti o n at t he i m pla nt site. T his als o a p plies if 瑞蓝
2
（
Rest y la ne）
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. It is rec om me n de d t hat a peri o d of 2 t o 4 wee ks ela pses bef ore a p pl yi n g 
differe nt treat me nt m o dalities or u ntil t he s ki n has heale d c o m pletel y.
1 1 ．
T he patie nt s h o ul d be i nf or me d t hat he or s he s h o ul d n ot e x p ose t he treate d area t o 
i nte nse heat (e. g. s olari u m, sa u na or e xcessi ve s u n e x p os ure), e xtre me c ol d, s ki n massa ge 
of t he treat me nt area or face mas k at least u ntil t he i nitial s welli n g a n d re d ness ha ve 
res ol ve d. 
1 2 ．
瑞蓝
2 （Rest y la ne）
has n ot bee n teste d i n pre g na nt or breastfee di n g w o me n or i n 
c hil dre n.
1 3 ．
Please kee p t he tracea bilit y inf or mati o n a n d i nstr uct t he patie nts t o i de ntif y ge n ui ne 
pr o d ucts.
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8 ( 1 2)
I nter acti o ns
Treat me nt wit h 瑞蓝
2 （Rest y la ne）
i n c o m bi nati o n wit h dr u gs or ot her me dical de vices , 
e xce pt f or ot her Rest y la ne pr o d ucts , has n ot bee n teste d. D o n ot use 瑞蓝
2 ( Rest y la ne) 
t o get her wit h a n y ot her i njecta ble i m pla nt, e xce pt f or ot her Rest yl a ne pr o d ucts.
A d verse e ve nts 
A ntici p ate d i njecti o n-rel ate d re acti o ns
After t he i njecti o n of 瑞蓝
2 （Rest y la ne）, s h ort li ve d i njecti o n-relate d reacti o ns are t o be 
e x pecte d. T hese reacti o ns i ncl u de o ne or m ore of t he f oll o wi n g: er 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 ypicall y  t hese reacti o ns start o n t he da y of 
treat me nt, last bet wee n 3 t o 7 da y s a n d res ol ve s p o nta ne o usl y, as o bser ve d i n t he C hi nese 
cli nical st u d y, w hic h is c o nsiste nt wit h i nter nati o nal res ults. 瑞蓝
2 （Rest y la ne）
ca n be 
pal pa ble i n s o me patie nts. 
P ost m ar keti n g a d verse e ve nt re p orti n g
T he f oll o wi n g p ost mar keti n g a d verse e ve nts ha ve bee n re p orte d ( n o n-e x ha usti ve list). T he 
fre q ue nc y of re p orti n g is base d o n t he n u m ber of esti mate d treat me nts perf or me d wit h 
Rest y la ne.
1/ 1 0 0 0 – 1/ 1 0 0 0 0
M ass/i n d urati o n, Swelli n g   wit h i m me diate o nset a n d o nset u p t o
se veral wee ks after treat me nt 
1/ 1 0 0 0 0 – 1/ 1 0 0 0 0 0
Atr o p h y/scarri n g, 
B r uisi n g/ he mat o ma,  
Disc ol orati o n/ 
h y per pi g me ntati o n , Er yt he ma, E xtr usi o n of de vice, H y perse nsiti vit y / 
a n gi oe de ma, Infecti o n
a n d 
a bscess
f or mati o n, Infla m mati o n, 
I njecti o n site reacti o ns i ncl u di n g b ur ni n g se nsati o n, e xf oliati o n, 
irritati o n, a n d war mt h, Isc hemia/ necr osis, N e ur ol o gical s ym pt o ms 
i ncl u di n g facial ner ve paral ys is, h y p oaest hesia, a n d paraest hesia,
N o n- der mat ol o gical e ve nts i ncl u di n g a n xiet y, dizzi ness, d y s p n oea, 
hea dac he, 
malaise, 
na usea, 
p y re xia, 
a n d 
si n usitis, 
O t her 
der mat ol o gical e ve nts i ncl u di ng al o pecia, c ha p pe d li ps, dr y  ski n, a n d 
s ki n wri n kli n g,
P ai n/te n der ness, P a p ules/ n o d ules , Pr urit us, S h ort 
d urati o n of effect, V is ual dist ur ba nce s i ncl u di n g bli n d ness , tra nsie nt 
bl urre d visi o n, e yeli d pt osis , i ncrease d lacri mati o n, a n d re d uce d 
vis ual ac uit y  
< 1/ 1 0 0 0 0 0
A c ne, Blisters / vesicles, Ca pillar y dis or ders i ncl u di n g tela n giectasia, 
Der matitis,  
D er mat op h yt os is,
D e vice 
disl ocati o n, 
Disc har ge/e xtra vasati o n, 
E nca ps ulati o n, 
G ra n ul o ma, 
M uscle 
t witc hi n g, Ras h, R eacti vati o n of her pes i nfecti o n, U rticaria
Title  
D o c i d  
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9 ( 1 2)
Vasc ular c o m pr o mise ma y  occ ur d ue t o a n u ni nte nti o nal 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 s oft tiss ue filler i n t he face. T his 
ma y  ma nifest as bla nc hi n g, disc ol orati o n s uc h as a d us k y  or retic ular a p peara nce of t he 
tiss ue, necr osis or ulcerati o n 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 rarely as isc he mic e ve nts i n ot her or ga ns d ue t o e m b olisati o n. Rare b ut seri o us 
cases of isc he mic e ve nts ass ociate d wit h te m p orar y or per ma ne nt visi o n i m pair me nt, 
bli n d ness, cere bral isc he mia or str o ke ha ve bee n re p orte d f oll o wi n g facial aest hetic 
treat me nts.
L ocalize d isc he mia/necr osis a n d scarri n g m a y occ ur after i njecti o n i n or near vessels. S pecial 
ca uti o n s h o ul d be ta ke n if t he patie nt has u n der g o ne a pri or s ur gical pr oce d ure i n t he pla n ne d 
treat me nt area.
S y m pt o ms of i nfla m mati o n at t he i m pla nt site c o m me nci 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 case of u ne x plai ne d i nfla m mat or y 
reacti o ns i nfecti o ns s h o ul d be e xcl u de d a n d treate d if necessar y  si nce i na de q uately treate d 
i nfecti o ns ma y  pr o gress i nt o c o m plicati 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 treat me nt is n ot rec o m me n de d.
T he pr ol o n ge d use of a n y me dicati o n, e. g., c ortic oster oi ds or a nti bi otics i n treat me nt of 
a d verse e ve nts has t o be caref ull y assesse d, si nce t his ma y carr y a ris k f or t he patie nt. I n case 
of persiste nt or rec urre nt i nfla m mat or y sy m pt o ms, c o nsi der re m o val of t he pr o d uct b y  
as pirati o n/ drai na ge, e xtr usi o n or e nz y m atic de gra dati o n ( use of h y al ur o ni dase has bee n 
descri 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 per f or me d, t he 
s welli n g m a y  be re d uce d b y  usi n g, e. g., N S AI D f or 2- 7 d a y s or a s h ort c o urse of 
c ortic oster oi ds 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.
P ost i nfla m mat or y pi g me ntati o n c ha n ges ha ve bee n o bser ve d i n cli nical st u dies i n pe o ple 
wit h dar k s ki n ( Fitz patric k T y pe I V-VI ).
F or patie nts w h o ha ve e x perie nce d cli nicall y si g nifica nt reacti o ns, 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 si g nifica nce of pre vi o us reacti o ns.
N o 
seri o us a d verse e ve nts were
re p orte d i n t he C hi nese cli nical st u d y wit h
瑞
蓝
2
（Rest y la ne）.
A d verse e ve nts m ust be re p orte d t o Q -Me d I nter nati o nal Tra di n g ( S ha n g hai) C o., Lt d., t he 
after sales ser vice a ge nt of t he S we dis h c o m pa n y Q- Me d A B .
Title  
D o c i d  
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1 0 ( 1 2)
St or a ge
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.
D ate of m a n uf act ure
T he date of ma n ufact ure is i n dicate d o n pac ka ge.
S helf life
T he s helf life of t he pr o d uct is 3 6 m o nt hs fr o m t he date of ma n ufact ure. T he e x pir y date is 
i n dicate d o n pac ka ge.
M a n uf act urer/ A p plic a nt
Na me:
Q- Me d A B
Re gistrati o n a d dress:
Se mi narie gata n 2 1, S E -7 5 2 2 8  U p psala, S we de n
Ma n ufact uri n g a d dress:
Se mi narie gata n 2 1, S E -7 5 2 2 8  U p psala, S we de n
Se mi narie gata n 3 1, S E -7 5 2 2 8  U p psala, S we de n
P h o ne:
+ 4 6 1 8 4 7 4 9 0 0 0
Fa x:
+ 4 6 1 8 4 7 4 9 0 0 1
Le g al A ge nt/ After S al es Ser vice A ge nt
Na me : 
Q- Me d I nter nati o nal Tra di n g ( S ha n g hai) C o., Lt d.
A d dress :
R o o m 2 0 1 7, N o. 1 Ji L o n g R oa d, Free Tra de Z o ne, 2 0 0 1 3 1, (S ha n g hai ),
C hi na
P h o ne :
0 2 1- 5 8 6 9 0 3 0 0
Fa x :
0 2 1- 5 8 6 9 0 3 0 0
Ot hers
F or m ore 
i nf or mati o n a b o ut t he pr o d uct, please c o ns ult Q -Me d 
I nter nati o nal Tra di n g 
( S ha n g hai) C o., Lt d., t he after sales ser vice a ge nt of t he S we dis h c o m pa n y Q- Me d A B, or 
visit t he we bsite bel o w:
w w w.rest yl a ne.c o m.c n
Rest y la ne, 瑞蓝, N A S H A a n d Gal der ma are tra de mar ks o w ne d by Nestlé S ki n Healt h S. A .
N ote! T he pr o d uct 瑞蓝
2 （Rest y la ne）
t o be s ol d i n C hi na m ust be s peciall y pac ke d b y  the 
S we dis h c o m pa n y Q -Me d 
A B acc or di n g t o t he re q uire me nt of C hi na
F o o d a n d Dr u g 
A d mi nistrati o n , P. R. C hi na . 瑞蓝
2 （Rest y la ne）
m ust o nl y  be p urc hase d t hr o u g h t he sales 
c ha n nels of t he S we dis h c o m pa n y Q -Me d A B.
Title  
D o c i d  
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1 1 ( 1 2)
Asse m bl y of Nee dle t o S yri n ge
F or safe use of 瑞蓝
2 (Rest y la ne) it is i m p orta nt t hat t he nee dle is pr o perl y  asse m ble d t o t he 
s yri n ge. I m pr o per asse m bl y ma y res ult i n se parati o n of t he nee dle a n d s yri n ge d uri n g 
i njecti o n.
H ol d fir ml y ar o u n d t he s yri n ge barrel wit h t he t h u m b a n d f orefi n ger. Gras p t he nee dle s hiel d
wit h t he ot her ha n d. T o facilitate pr o per faste ni n g, b ot h p us h a n d r ot ate t he m fir mly 
t o get her. See pict ure. Strict ase ptic tec h ni q ue m ust be f oll o we d . 
Title  
D o c i d  
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1 2 ( 1 2)
S y m b ols o n P ac k a ge
L ot N u m ber
Use b y
Sterile. T he c o nte nts of t he s yri n ge ha ve bee n sterilize d b y  usi n g 
m oist heat. 
Date of ma n ufact ure
D o n ot re -use
    Sterile. T he nee dles ha ve bee n sterilize d b y  usi n g irra diati o n.
First iss ue date: M arc h 2 0 0 9 
Re visi o n date: Se pte m ber 2 0 1 6
Title  
D o c i d  
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1 ( 3)
A p pe n di x 4
P h ot o g ui de f or Wri n kle Se verit y R ati n g Sc ale ( W S R S)
Gr a de 1: 
A bse nt: N o visi ble f ol d; c o nti n u o us s ki n li ne
Gr a de 2:
Mil d:
S hall o w b ut visi ble f ol d wit h a sli g ht i n de ntati o n; mi n or facial feat ure
I m pla nt is e x pecte d t o pr o d uce a sli g ht i m pr o ve me nt i n a p peara nce.
Title  
D o c i d  
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P P D
P P D

2 ( 3)
Gr a de 3:
M o der ate:
M o deratel y dee p f ol ds; 
Clear facial feat ure visi ble at n or mal a p pear a nce b ut n ot w he n stretc he d. 
E xcelle nt c orrecti o n is e x pecte d fr o m i njecta ble i m pla nt
Gr a de 4:
Se vere: Ver y l o n g a n d dee p f ol d; pr o mi ne nt facial feat ure;
Less t ha n 2- m m visi ble f ol d w he n stretc he d
Si g nifica nt i m pr o ve me nt is e x pecte d fr o m i njecta ble i m pla nt
Title  
D o c i d  
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P P D
P P D

3 ( 3)
Gr a de 5:
E xtre me: E xtre mel y dee p a n d l o n g f ol d;
Detri me ntal t o facial a p peara nce; 2 - t o 4-m m V -s ha pe d f ol d w he n stretc he d.
U nli kel y t o ha ve satisfact or y c orrecti o n wit h i njecta ble i m pla nt al o ne
Title  
D o c i d  
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Pri nt date:
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P P D

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
2 0 1 7- 0 7- 0 4 1 2: 5 0
J u stifi c ati o n
D o c u m e nt c o m pil e d b y
2 0 1 7- 0 7- 0 4 1 3: 0 9
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 1 7- 0 7- 0 5 0 5: 3 3
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 1 7- 0 7- 0 5 0 5: 3 4
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 1 7- 0 7- 0 5 0 6: 3 7
J u stifi c ati o n
A p pr o v e d b y O w n er
Title  
D o c i d  
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Pri nt date:
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P P D
P P D
P P D
P P D
P P D