Protocol Title: A Randomized, Multicenter, Evaluator-blind, Controlled Study to Evaluate the Safety and Effectiveness of JUVÉDERM VOLITE™ XC Injectable Gel for the Improvement in Cheek Skin Smoothness
Phase: NA
Conditions: Skin Smoothness of the Cheeks
Sponsor: Allergan

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
1 
Title Page 
Protocol Title: A Randomized, Multicenter, Evaluator-blind, Controlled Study to Evaluate 
the Safety and Effectiveness of JUVÉDERM VOLITE™ XC Injectable Gel for the 
Improvement in Cheek Skin Smoothness 
Protocol Number: 1867-701-008 Amendment 3 
Brief Protocol Title: JUVÉDERM VOLITE™ XC for cheek skin smoothness 
Product: JUVÉDERM VOLITE™ XC injectable gel 
Development Phase: IDE 
Sponsor Name and Legal Registered Address:  
Allergan  
2525 Dupont Drive 
Irvine, CA 92612 
Manufacturer: Allergan 
Regulatory Agency Identifying Number(s): IDE G180064 
Emergency Telephone Number: 
Refer to the Study Contacts page 
SAE Reporting Email/Fax Number: 
LC-Medical_Safety@Allergan.com or  
Fax +1-877-605-4524 or 
Back-up Fax +1-714-796-9567 
Names and contact information of sponsor study personnel are provided in the supplementary 
Study Contacts page.   
NCT03728309

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
2 
Sponsor Signatory and Investigator Signatory: 
Sponsor signature is provided on the last page of the protocol. The investigator signature page 
will be provided as a stand-alone document. The investigator is to retain the original in the site 
study files and return a copy to the sponsor for archiving in the trial master file. 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
3 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3 
see last page for approval date 
Amendment 2 
3-July-2019 
Amendment 1 
28-February-2019 
Original Protocol 
19-September-2018 
 
Amendment 3 (November 2019) 
Overall Rationale for the Amendment: 
To allow for more complete follow-up of ISRs and SAEs. 
Section No. and Name 
Description of Change 
Brief Rationale 
8.1 Withdrawal from the Study, 9.4 Safety 
Assessments 
Added that ongoing ISRs will be 
followed until resolved or follow-up is 
no longer possible 
To better characterize 
safety profile 
9.5 Adverse Events 
Clarified that SAEs be followed until 
follow-up is no longer possible 
To better characterize 
safety profile 
 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
Title Pa
Protocol 
Table of 
List of T
List of F
 
Syn
1.
 
Sch
2.
 
Intr
3.
 
3.1
 
3.2
 
3.3
 
3.4
 
Obj
4.
 
4.1
 
4.2
 
Stu
5.
 
5.1
 
5.2
 
5.3
 
5.4
 
5.5
 
Stu
6.
 
6.1
 
6.2
 
6.3
 
6.4
 
Tre
7.
 
7.1
ENTIAL  
RM VOLIT
N-T-01-04 Prot
ge ................
Amendmen
Contents ....
ables ...........
igures .........
opsis ...........
edule of Act
oduction ......
Study Ra
Backgro
Device D
Benefit/
ectives and 
Study Ob
Clinical 
dy Design ....
Overall 
Subject a
End of St
Scientific
Justificat
dy Populatio
Inclusion 
Exclusio
Lifestyle 
Screen F
atments .......
Treatmen
E™ XC 
ocol Template 
...................
t Summary o
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ivities .........
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tionale ........
und ..............
escription ...
Risk Assessm
Endpoints ...
jectives and 
Hypotheses .
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Design .........
nd Study Co
udy Definiti
 Rationale fo
ion for Devic
n .................
Criteria .....
n Criteria ....
Restrictions
ailures .........
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ts Administe
(Device) v1.0
Table
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of Changes T
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ment ..............
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Endpoints ..
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ompletion.....
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for Study De
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
7.2
 
7.3
 
7.4
 
7.5
 
7.6
 
Dis
8.
 
8.1
 
8.2
 
Stu
9.
 
9.1
 
9.2
 
9.3
 
9.4
 
9.5
 
9.6
 Stat
10.
ENTIAL  
RM VOLIT
N-T-01-04 Prot
7.1.1 
7.1.2 
7.1.3 
7.1.4 
Treatmen
Retreatm
Concomi
7.3.1 
7.3.2 
Method 
Blinding/
Preparati
continuation
Withdra
Lost to F
dy Assessme
Demogra
Treatmen
Effective
9.3.1 
9.3.2 
9.3.3 
Safety A
Adverse 
9.5.1 
9.5.2 
9.5.3 
9.5.4 
9.5.5 
9.5.6 
9.5.7 
Laborato
istical Consi
E™ XC 
ocol Template 
Instructions 
Washout Int
Run-In Med
Study Suppl
t Modificati
ent Criteria .
tant Therapy
Prohibited T
Permitted Tr
of Treatment 
Masking ....
on/Handling
/Withdrawal
wal from the 
ollow-Up ....
nts and Proc
phics and Ba
t Administra
ness Assessm
Primary Effe
Secondary E
Other Effect
ssessments ..
Events ........
Time Period
Information 
Method of D
Follow-up o
Regulatory R
Adverse Eve
Pregnancy ..
Medical Dev
ry Testing ...
derations ....
(Device) v1.0
for Use and
tervals ..........
dications and
lies ..............
on ...............
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y ...................
Treatments ...
reatments ....
Assignment
....................
g/Storage/Ac
l Criteria ......
Study ..........
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cedures ........
aseline Char
ation Assessm
ments ...........
fectiveness M
Effectiveness
tiveness Mea
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d and Freque
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of AEs/ADEs
Reporting R
ents of Spec
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ency for Coll
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Requirement
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867-701-008
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
10.1
10.2
10.3
 Ref
11.
 App
12.
12.1
12.2
12.3
ENTIAL  
RM VOLIT
N-T-01-04 Prot
 Sample S
 Populatio
 Statistica
10.3.1 
10.3.2 
10.3.3 
10.3.4 
erences ........
endices ......
 Appendi
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Regulato
Financial 
Informed 
Informed 
Data Pro
Publicati
Dissemin
Data Qua
Source D
Study an
Complia
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Follow-u
AE Defi
Adverse 
AE of Spe
Events 
Events N
SAE Def
Serious 
Unantici
Assessm
Relations
Procedur
E™ XC 
ocol Template 
ize Determin
ns for Analy
l Analyses ..
Effectivenes
Safety Analy
Other Analy
Interim Ana
...................
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x 1: Abbrevia
x 2: Study Go
ry and Ethica
Disclosure .
Consent Pro
Consent and
tection.........
on Policy ....
ation of Clin
lity Assuran
ocuments ...
d Site Closur
nce with Prot
x 3: Adverse 
p, and Repo
nition ...........
Device Effec
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ot Meeting t
inition.........
Adverse Devi
pated Advers
ent of Severi
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es for Repor
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nation ..........
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lyses ...........
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ations and Tr
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the AE/ADE
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rademarks ..
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finitions an
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ent 3
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ing, 
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
12.4
12.5
12.6
12.7
 
Table 2-
Table 2-
Table 2-
Table 2-
Table 9-
Table 9-
Table 9-
Table 9-
 
Figure 5
Figure 7
Figure 9
Figure 9
 
ENTIAL  
RM VOLIT
N-T-01-04 Prot
Procedur
 Appendi
Evaluati
Definitio
Docume
Device D
 Appendi
 Appendi
 Appendi
1 
Scree
2 
Treat
3 
Contr
4 
Contr
1 
Aller
2 
Aller
3 
Glob
4 
Safet
-1 
Stud
-1 
Allo
-1 
Asses
-2 
Asses
E™ XC 
ocol Template 
es for Repor
x 4: Medical 
ng, Follow-up
ns of a Medi
nting Medica
eficiency ....
x 5: Standard
x 6: Study Ta
x 7: Protocol
ning Visit Pr
ment Group 
ol Group Pro
ol Group Pro
gan Cheek S
gan Fine Lin
al Aesthetic I
y Data Colle
y Design ......
wable Treatm
sment Area 
sment Area 
(Device) v1.0
ting an SAE
Device Inci
p, and Repor
ical Device I
al Device Inc
....................
d Discontinu
abular Summ
l Amendmen
List
rocedures:  A
Procedures .
ocedures (N
ocedures (D
moothness S
nes Scale ......
Improvemen
ecting and Re
List 
....................
ment Area .....
for the Aller
for the Aller
7 
E or SADE ..
idents: Defin
rting ...........
Incident ......
cidents ........
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uation Criter
mary ............
nt History ....
t of Tables
All Subjects 
...................
No-Treatmen
elayed Trea
Scale ..........
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nt Scale .......
eporting Gu
of Figur
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rgan Cheek S
rgan Fine Li
Protocol 1
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idelines ......
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867-701-008
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8 Amendme
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ent 3
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.... 39 
.... 20 
.... 25 
.... 33 
.... 34 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
1.
Protocol 
1867-70
Safety a
Smoothn
STUDY 
STUDY 
NUMBE
randomi
TEST P
JUVÉD
multiple 
to exceed
both che
DURAT
6 months
1 month 
optional 
OBJEC
VOLITE 
KEY E
• 
Pri
• 
Se
• 
Se
• 
Sa
A
OVERA
• 
Ra
• 
Si
• 
Tr
ach
2, 
fol
• 
Co
the
tre
6 
ENTIAL  
RM VOLIT
N-T-01-04 Prot
Syn
Title and Nu
1-008 Amend
nd Effectivenes
ess 
PHASE:  ID
SITES:  Up t
R OF SUBJE
zed at a 2:1 rat
RODUCT, D
ERM VOLITE 
microdepot inj
d a total of 4 m
eks. Needle le
ION OF STU
 of follow-up, 
for screening 
treatment. 
TIVES:  The 
XC injectable 
NDPOINTS:   
mary:  ACSS 
condary:  Cha
condary:  AFL
fety:  FACE-
Es, Snellen vis
LL STUDY 
ndomized, co
ngle-blind:  EI
eatment group 
hieve optimal 
4, and 6 after l
lowed at Day 
ntrol group su
en either exit t
atment period. 
after last treat
E™ XC 
ocol Template 
opsis 
mber:   
ment 3: A Rand
ss of JUVÉDER
E 
o 20 US centers
CTS:  Up to 2
io to treatment 
EVICE VOLU
XC injectable 
ections across 
L for both chee
ngth selection, 
DY:  Treatme
and 4 months 
and 1 month of 
objective of this
gel for the imp
responder statu
nge from baseli
S responder sta
Q Recovery Ear
ual acuity, conf
DESIGN:    
ntrolled, paralle
s are blinded; T
subjects receiv
correction.  Fol
ast treatment. S
3 and Months 1
bjects are follo
he study or rece
Follow-up vis
ment. Subjects e
(Device) v1.0
domized, Multi
RM VOLITE™
s 
263 subjects wi
group and con
UME, AND MO
gel will be adm
both cheeks. A
eks. At optiona
total injection 
ent group:  up 
of follow-up a
f follow-up; up 
s study is to ev
provement in c
us at Month 1
ine to Month 1
atus at Month 
rly Life Impact
frontation visu
el-design 
TIs and subject
ve initial treatm
llow-up visits a
Subjects exit th
1 and 4 after re
owed for 1 mon
eive optional tr
its are 3 days a
exit the study a
8 
center, Evalu
™ XC Injectabl
ill be enrolled,
ntrol group 
ODE OF AD
ministered usi
At initial and r
al touch-up pro
volume, and i
to 1 month fo
fter optional r
to 1 month for
valuate the saf
cheek skin sm
 on FACE-Q 
1 
t questionnaire
ual fields, and 
ts are not blind
ment and option
are 3 days after
he study at M
epeat treatment
nth after rando
reatment (initi
after each trea
at Month 6. 
Protocol 1
ator-blind, Co
e Gel for the I
and approxim
MINISTRAT
ng a 32 G 1/2” 
epeat (if perfo
ocedure, volum
njection spaci
r screening, up
epeat treatment
r treatment and
ety and effecti
oothness. 
Satisfaction w
, procedural p
ocular motility 
ded  
nal touch-up tr
r each treatme
onth 6 or receiv
t. 
mization (no-tr
al and touch-up
tment (safety 
867-701-008
ntrolled Study t
mprovement in
ately 210 subje
ION: 
or a 32 G 3/16
rmed) treatmen
me is not to exc
ng will be deter
 to 1 month for
t. Control gro
d 6 months of f
veness of JUVÉ
ith Skin questio
ain, ISRs from 
 
reatment at 30 
nt (safety only
ve repeat treatm
reatment contr
p, if needed) in
only) and at Mo
8 Amendme
to Evaluate the
n Cheek Skin 
ects will be 
6” needle in 
nts, volume is n
ceed 2 mL for 
rmined by the T
r treatment, 
up:  up to 
follow-up after
ÉDERM 
onnaire 
30-day e-diari
days if needed
) and at Month
ment and are 
rol period) and 
n the delayed 
onths 1, 2, 4, an
 
ent 3
e 
not 
TI. 
r 
ies, 
d to 
hs 1, 
nd 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
9 
DIAGNOSIS AND CRITERIA FOR INCLUSION/EXCLUSION:   
Adults seeking improvement in cheek skin smoothness 
INCLUSION: 
1. Age 22 or over and in good general health 
2. Has an ACSS score of 2 for both cheeks or 3 for both cheeks on the 5-point Allergan cheek smoothness 
photonumeric scale (range: 0 to 4), as judged live by the EI 
OR 
has Fitzpatrick skin phototype V or VI and has an ACSS score of 1, 2, or 3 on both cheeks (the cheeks do 
not need to have the same score), as judged live by the EI (Fitzpatrick V/VI safety cohort) 
3. Has a FACE-Q Satisfaction with Skin Questionnaire sum score of 39 or less (sum score of 39 is 
equivalent to Rasch-transformed score of 69) unless enrolled as part of the Fitzpatrick V/VI safety cohort 
4. Ability to follow study instructions and likely to complete all required visits 
5. Written informed consent and data privacy consent have been obtained 
EXCLUSION: 
1. Requires more than 6 mL of product for optimal correction of both cheeks based on the TI’s clinical 
judgment 
2. Has undergone tissue augmentation with dermal fillers including HA, calcium hydroxylapatite, 
autologous fat, mesotherapy, or other cosmetic procedures (eg, face-lift, laser, photomodulation, intense 
pulsed light, radiofrequency, dermabrasion, chemical peel, or other ablative procedures) in the face within 
12 months before screening or is planning to undergo any such treatment during the study 
3. Has received any crosslinked HA filler in any anatomic area within 12 months of screening 
4. Has undergone treatment with botulinum toxin in the cheek area (including crow’s feet) within 6 months 
of screening or is planning to undergo such treatment during the study 
5. Has ever received semipermanent fillers or permanent facial implants (eg, poly-L-lactic acid, 
polymethylmethacrylate, silicone, expanded polytetrafluoroethylene) anywhere in the face or is planning 
to be implanted with any of these products at any time during the study 
6. Has facial tattoos, piercings, pigmentation, hair (ie, beard, mustache), or past trauma that would interfere 
with the visualization of the face for the effectiveness assessments 
7. Has undergone a dental procedure within 6 weeks before treatment or plans to undergo a dental procedure 
(other than prophylaxis or dental fillings) during the course of the study 
8. Has a tendency to develop hypertrophic scarring 
9. Has a history of allergy to lidocaine, HA products, and/or to gram-positive bacterial proteins as HA is 
produced by Streptococcus-type bacteria, or is planning to undergo desensitization therapy during the 
term of the study 
10. Has a history of anaphylactic shock 
11. Has current cutaneous inflammatory or infectious processes (eg, acne, herpes), abscess, an unhealed 
wound, or a cancerous or precancerous lesion on the face (injection may be delayed to allow subjects with 
a history of recurrent oral herpes to take prophylactic antiviral/herpes medication for 2 days) 
12. Is on an ongoing regimen of anticoagulation therapy (eg, warfarin) or is known to have a coagulation 
disorder 
13. Is on an ongoing regimen of medications (eg, aspirin, ibuprofen) or other substances (eg, herbal 
supplements with garlic, ginkgo biloba, or ginseng) known to increase coagulation time within 10 days of 
undergoing study device injection (study device injection may be delayed as necessary to accommodate 
this 10-day washout period) 
14. Has active autoimmune disease 
15. Has received any investigational product within 30 days before enrollment or is planning to participate in 
another investigation during the course of this study 
16. Has begun using any over-the-counter or prescription, oral or topical, anti-wrinkle products on the face 
within 30 days before enrollment or is planning to begin using such products during the study (subjects 
who have been on a regimen of such products for at least 30 days are eligible for the study if they intend 
to continue their regimen throughout the study) 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
10 
17. Females who are pregnant, nursing, or planning a pregnancy during the study 
18. Is an employee (or a relative of an employee) of the PI/TI/EI/site, Allergan, or representative of Allergan 
19. Has a condition or is in a situation which, in the TI’s opinion, may put the subject at significant risk, may 
confound the study results, or may interfere significantly with the subject’s participation in the study 
STATISTICAL METHODS: 
Sample Size Calculation: 
A sample size of 112 subjects in the treatment group and 56 subjects in the control group will provide 
99.9% power to detect a difference of at least 40% in the responder rates on ACSS between the groups, based on 
a 2-sided Fisher’s exact test at the 5% level. The treatment group is assumed to have at least an 80% responder 
rate at Month 1, and the control group is assumed to have at most a 40% responder rate. The assumptions of 
responder rates are estimated from Allergan study V12-001.  
At least 135 subjects with a baseline AFLS score of 2 on both cheeks or 3 on both cheeks are expected to enroll. 
The number of subjects with baseline AFLS score of 0, 1, or 4 on either cheek, or 2 on one cheek and 3 on the 
other cheek is not expected to exceed 75. Assuming at least 65% of subjects will have baseline AFLS score of 
2 on both cheeks or 3 on both cheeks, 72 subjects in treatment group and 36 subjects in control group will 
provide 94.4% power to detect a difference of at least 35% in the responder rates on AFLS between the 
treatment groups, based on a 2-sided Fisher’s exact test at the 5% level. The treatment group is assumed to have 
at least an 80% responder rate at Month 1, and the control group is assumed to have at most a 45% responder 
rate. The assumptions of responder rates are estimated from Allergan study V12-001.  
Accounting for subject attrition of 20% during the study, 210 subjects will be randomized at a 2:1 ratio to 
treatment group and control group. Randomization will be within each study site. 
Assuming 119 subjects from the treatment group and 28 subjects from the control group will be treated, a total 
of 147 treated subjects will provide 95% power to detect an AE related to treatment with an incidence rate of 2% 
in the population using a 1-sided exact binomial test at the 2.5% level. The safety calculation used an inequality 
test for 1 proportion. 
Effectiveness: 
The primary effectiveness measure is the EI’s assessment of cheek skin smoothness using the ACSS. The 
primary effectiveness analysis is the ACSS responder rate at Month 1. A responder is defined as a subject who 
shows at least a 1-point improvement from baseline on the ACSS on both cheeks. The responder rate and 
corresponding 95% confidence interval will be summarized. A 2-sided, Fisher’s exact test at the 5% level will be 
used to test whether the ACSS responder rate at Month 1 in the treatment group is significantly greater than that 
in the control group at Month 1 in the control period. The primary effectiveness endpoint will be met if the 
responder rate for the treatment group is statistically greater than that for the control group at Month 1. 
The secondary effectiveness variables are 1) subject responses on the FACE-Q Satisfaction with Skin 
questionnaire, and 2) EI’s assessment of fine lines on the cheeks on the AFLS. The secondary effectiveness 
analyses include change from baseline in FACE-Q scale score at Month 1 and the AFLS responder rate at 
Month 1. The responses to the 12 FACE-Q items will be summed and converted to a scale score that ranges 
from 0 to 100 (higher score indicates more satisfaction) using the algorithm developed by the FACE-Q scale 
developers. An AFLS responder is defined as a subject who shows at least a 1-point improvement from baseline 
on the AFLS scale on both cheeks. The AFLS responder rate will be analyzed in the same manner as the ACSS 
responder rate. Only subjects with baseline AFLS score of 2 on both cheeks or 3 on both cheeks will be included 
in the analysis. 
Safety: 
AEs will be summarized by primary system organ class, preferred term, and severity. Treatment-related AEs, 
AEs leading to discontinuation, serious adverse events, and deaths will be listed or tabulated. ISRs will be 
summarized using descriptive statistics, by symptom, maximum reported severity, and duration for initial, 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
11 
touch-up, and repeat treatments, separately. Frequency distributions or descriptive summaries of procedural pain 
and results of FACE-Q Recovery Early Life Impact questionnaire will be provided. Snellen visual acuity, 
confrontation visual fields, and ocular motility assessments performed by the TI (or designee) will be 
summarized descriptively. 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
4.2
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s if 
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h 
on 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
Figure 5-1 
 
5.2
A maxi
randomi
based on
enrolled 
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5.3
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
initial tre
obtained,
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treatmen
treatmen
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ore 
the 
-lift, 
l 
s 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
22 
3. Has received any crosslinked HA filler in any anatomic area within 12 months of 
screening 
4. Has undergone treatment with botulinum toxin in the cheek area (including crow’s feet) 
within 6 months of screening or is planning to undergo such treatment during the study 
5. Has ever received semipermanent fillers or permanent facial implants (eg, poly-L-lactic 
acid, polymethylmethacrylate, silicone, expanded polytetrafluoroethylene) anywhere in 
the face or is planning to be implanted with any of these products at any time during the 
study 
6. Has facial tattoos, piercings, pigmentation, hair (ie, beard, mustache), or past trauma that 
would interfere with the visualization of the face for the effectiveness assessments 
7. Has undergone a dental procedure within 6 weeks before treatment or plans to undergo a 
dental procedure (other than prophylaxis or dental fillings) during the course of the study 
8. Has a tendency to develop hypertrophic scarring 
9. Has a history of allergy to lidocaine, HA products, and/or to gram-positive bacterial 
proteins as HA is produced by Streptococcus-type bacteria, or is planning to undergo 
desensitization therapy during the term of the study 
10. Has a history of anaphylactic shock 
11. Has current cutaneous inflammatory or infectious processes (eg, acne, herpes), abscess, 
an unhealed wound, or a cancerous or precancerous lesion on the face (injection may be 
delayed to allow subjects with a history of recurrent oral herpes to take prophylactic 
antiviral/herpes medication for 2 days) 
12. Is on an ongoing regimen of anticoagulation therapy (eg, warfarin) or is known to have a 
coagulation disorder 
13. Is on an ongoing regimen of medications (eg, aspirin, ibuprofen) or other substances 
(eg, herbal supplements with garlic, ginkgo biloba, or ginseng) known to increase 
coagulation time within 10 days of undergoing study device injection (study device 
injection may be delayed as necessary to accommodate this 10-day washout period) 
14. Has active autoimmune disease 
15. Has received any investigational product within 30 days before enrollment or is planning 
to participate in another investigation during the course of this study 
16. Has begun using any over-the-counter or prescription, oral or topical, anti-wrinkle 
products on the face within 30 days before enrollment or is planning to begin using such 
products during the study (subjects who have been on a regimen of such products for at 
least 30 days are eligible for the study if they intend to continue their regimen throughout 
the study) 
17. Females who are pregnant, nursing, or planning a pregnancy during the study 
18. Is an employee (or a relative of an employee) of the PI/EI/TI/site, Allergan, or 
representative of Allergan 
19. Has a condition or is in a situation which, in the TI’s opinion, may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject’s participation in the study 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
6.3
Within t
the treat
avoid sha
consum
or receiv
study tre
tempora
 
6.4
Screen f
subsequ
ensure tr
Reportin
Minimal 
failure, e
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be rescr
informat
 
7.
Study tre
medical 
ENTIAL  
RM VOLIT
N-T-01-04 Prot
Life
he first 12 h
ment area. 
aving in the 
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Scre
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criteria for p
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23 
 recommen
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ts will be ad
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at the injecti
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d to respon
screen failu
participation
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to a study su
Protocol 1
ded that sub
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vised not to 
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on sites. 
articipate in 
en failure inf
meet the C
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867-701-008
jects not app
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any of these
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lacebo, or 
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to 
una, 
ny 
e not 
f 
ies. 
n 
not 
ol. 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
7.1
Study T
Formul
Concent
Route of 
Packagi
 
Manufa
Number 
Volume 
 
7.1.1 
The TIs m
practicin
surgery. 
JUVÉD
techniqu
the edge 
cheek (s
volume, 
volume 
Topical 
TI. After 
ENTIAL  
RM VOLIT
N-T-01-04 Prot
Trea
reatment Na
ation 
ration 
f Administrati
ng and Labeli
cturer 
and Timing 
Per Treatme
Inst
must be exp
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t intradermal
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24 
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JUV
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microdepot i
DERM VOLITE
Each kit will c
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/2”), specifical
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Pr
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by Federal (or 
Use 
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Protocol 1
ÉDERM VOLIT
Injectable g
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ontain 1 or m
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3/16” needles 
on label, such a
syringe packag
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Kit# VVVV
Lot# VVVV
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United States) 
as directed per 
ergan Industrie
ch-up 
peat treatment
to 4 mL 
eatment: up to 
ment: up to 4 
tration 
on of HA in
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ection to re
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867-701-008
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caine (w/w gel
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ge and the oute
1-008 
V 
VV 
onal Device. 
law to Investig
protocol 
e, SAS 
(treatment gro
2 mL 
mL 
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cosmetic/rec
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mL for touch-
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ent area with
8 Amendme
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multiple 
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 and be 
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preauricular
l injection 
he maximum
-up treatmen
directed by 
h soap and w
 
ent 3
n 
rch to 
r 
m 
nt.  
the 
water, 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
7.1.3 
 Run
2 days bef
30 days be
 
7.1.4 
The spo
for subje
responsi
(eg, anti
sensitivi
and inter
 
7.2
Retrea
A subjec
in the op
EI-rated 
been ach
desired. 
 
7.3
The use 
procedu
reason f
7.3.1 
During th
• 
• 
a
ENTIAL  
RM VOLIT
N-T-01-04 Prot
Run
-in Intervals 
ore treatment 
efore enrollme
Stu
nsor will pro
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ble for routi
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ty of at least 
net connect
Trea
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Con
of concomit
res or therap
or the treatm
Pro
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Receive inje
Undergo tiss
utologous f
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tment Mo
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TI and is ag
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comitant T
ant medicati
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ent. 
hibited Tre
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ctable anesth
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at, mesothera
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ations and
rophylactic her
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Over-the-counte
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hesia during 
ation with de
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26 
d Admini
Me
rpes treatment 
ons 
er or prescriptio
subjects who w
3/16” needle
d subject qu
vice adminis
hesia, ice pa
chorionic go
completion
n 
optimal corr
y both subj
e determinat
are eligible t
tion or over
the subject’s
t not:  
study treat
ermal fillers 
r cosmetic p
Protocol 1
stration 
dication  
for subjects w
on, oral or top
will use such pr
es, digital i
uestionnaires
stration and 
cks, urine p
onadotropin
. 
rection has 
ect and TI. T
ion of whet
to receive r
-the-counter
s eCRF at ea
ment 
including H
rocedures (e
867-701-008
with a history of
ical, anti-wrink
roducts during 
maging equip
s. The invest
follow-up v
regnancy tes
), blood pres
not been achi
The TI will h
her optimal c
epeat treatme
r, as well as c
ach visit alon
A, calcium h
g, face-lift, l
8 Amendme
f recurrent 
kle products 
the study 
pment, mirro
igational site
visits 
st kits (with 
ssure cuff, sc
ieved at Day
ave access to
correction ha
ent at Month
concomitant
ng with the 
hydroxylapa
laser, 
 
ent 3
ors 
e is 
cale, 
y 30 
o the 
as 
h 6 if 
t 
atite, 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
27 
photomodulation, intense pulsed light, radiofrequency, dermabrasion, chemical peel, or 
other ablative procedures) in the face 
• Undergo treatment with botulinum toxin in the cheek area (including crow’s feet) 
• Undergo treatment with semipermanent fillers or permanent facial implants 
(eg, poly-L-lactic acid, polymethylmethacrylate, silicone, expanded 
polytetrafluoroethylene) anywhere in the face 
• Undergo a dental procedure (other than prophylaxis or dental fillings) 
• Be on a regimen of medications (eg, aspirin, ibuprofen) or other substances (eg, herbal 
supplements with garlic, ginkgo biloba, or ginseng) known to increase coagulation time 
for 3 days after each study treatment 
• Receive any other investigational product 
• Use any over-the-counter or prescription, oral or topical, anti-wrinkle products on the 
face that were not a stable regimen for at least 30 days prior to study enrollment 
• The use of hyaluronidase for aesthetic purposes is not permitted. If hyaluronidase is used, 
the subject will be followed for safety only from that point on. 
The decision to administer a prohibited medication/treatment during the study period is done 
with the safety of the study subject as the primary consideration. When possible, sponsor is to be 
notified before the prohibited medication/treatment is administered.  
7.3.2 
Permitted Treatments 
Any medication/treatment or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the subject is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
• Indication 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the TI.  
It is recommended that the sponsor (or designee) be contacted if there are any questions 
regarding concomitant or prior therapy or the permissibility of a specific medication/treatment. 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
Topical 
limited to
If subjec
products 
enrollme
 
7.4
Prior to 
that will 
Random
to treat
will be c
and dire
not be re
 
7.5
The EIs 
The PIs/
secure t
assessm
treatmen
 
7.6
1. 
d
2. 
a
e
l
3. 
r
r
4. F
p
ENTIAL  
RM VOLIT
N-T-01-04 Prot
anesthesia 
o the treatm
ts are on a r
on the face,
nt, and subj
Met
initiation of 
be recorded 
ization/Initi
ment group o
entrally ran
ctions for th
placed. 
Blin
will be blin
TIs, study c
he randomiza
ents) from p
t assignmen
Pre
The PI or de
maintained d
iscrepancie
Only subject
dminister st
nvironment
abeled stora
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urther guid
rovided in t
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may be used d
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 the regimen
ect must con
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study treatm
on the appro
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ding/Mask
ded to treatm
oordinators, 
ation and oth
otential disco
ts with or in 
paration/H
signee must c
uring transit 
s are reported
s enrolled in 
udy treatmen
ally controlle
ge condition
delegated de
n, and record
lude subject 
ance and info
he Study Site
(Device) v1.0
during treatm
ly. 
ver-the-coun
n must have 
ntinue with th
eatment As
ment, each co
opriate eCRF
t visit), eligib
oup. Random
ng an IWRS
 be provided
king 
ment and will
and subjects
her records (
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the presenc
Handling/S
confirm appr
and pre-trea
d and resolv
the study m
nt. All study 
ed, and mon
s with acces
signee) is re
d maintenanc
ID number, 
ormation for
e Binder.  
28 
ment accord
nter or presc
been stable
he regimen 
ssignment
onsented subj
F.  At the ti
ble subjects 
mization will 
. Before the 
d to each site
l not be pres
s will not be 
eg, records o
e blinded EI
e of the EIs
Storage/Ac
ropriate te
atment stora
ed before u
may receive 
treatments m
itored (autom
ss limited to 
esponsible f
ce (ie, receip
device seri
r the final dis
Protocol 1
ing to routin
ription, oral 
for at least 3
throughout 
t and Allo
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me of rando
will be ran
be within e
study is ini
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blinded to 
of study trea
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. 
ccountabil
mperature co
ge for all stu
se of the stu
study treatm
must be stor
mated) area 
the PI/TI a
or study treat
pt, reconcili
al or lot num
sposition of 
867-701-008
ne practice, b
or topical, a
30 days prior
the study. 
cation Rat
assigned a s
mization (ie,
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ach study sit
tiated, the lo
ts are withdra
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treatment, an
atments and p
ll not discus
lity 
nditions hav
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dy treatment
ent, and only
red in a secur
in accordanc
nd authorized
tment accou
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mber, and date
unused stud
8 Amendme
but it must be
anti-wrinkle 
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
5. 
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9.5.6. 
29 
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ll be 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
In additio
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867-701-008
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as 
he 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
• 
e
n
• I
f
 
9.
• 
r
• 
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b
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N-T-01-04 Prot
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31 
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ll be docum
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867-701-008
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ts at 
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le of 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
• I
e
F
s
• P
b
p
d
 
9.1
Subject 
race, hei
medical/
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9.2
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9.3
9.3.1 
The pri
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867-701-008
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fined 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
35 
 
9.3.3 
Other Effectiveness Measures 
Other effectiveness measures include: 
• Subject responses on the validated FACE-Q Appraisal of Lines-Overall questionnaire 
(Klassen 2016; 10 items scored in the same manner as the first secondary effectiveness 
measure) 
• Subject assessment of the natural look of the cheek skin on an 11-point scale ranging 
from 0 (unnatural looking) to 10 (natural looking) 
• Subject assessment of the natural feel of the cheek skin on an 11-point scale ranging from 
0 (unnatural feeling) to 10 (natural feeling) 
• Subject assessment of the global aesthetic improvement of the cheek skin on the 5-point 
GAIS (Table 9-3) 
Table 9-3 
Global Aesthetic Improvement Scale 
Score 
Grade 
2 
Much Improved 
1 
Improved 
0 
No Change 
-1 
Worse 
-2 
Much Worse 
• Skin hydration measured by MoistureMeter® D instrument (Delfin Technologies) on the 
zygoma at the upper cheek, at the point where a vertical line from the lateral canthus 
intersects with the most prominent portion of the zygoma  
MoistureMeter® D instrument generates a high-frequency electromagnetic wave that penetrates 
perpendicularly into the skin. The resulting reflected wave is recorded, and the dielectric 
constant obtained is proportional to the quantity of fluids in the cutaneous area studied. 
Depending on the captor chosen, it is thus possible to measure the water content at different 
depths of the dermis and hypodermis. In this study, we will use the XS5 probe (depth of effective 
measurement: 0.5 mm) to measure the water content in the dermis. Prior to initiating enrollment, 
the EIs will be trained in the use of the MoistureMeter® D. 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
9.4
Safety 
• S
(
• S
f
• S
e
s
• 
• 
• S
• 
• 
The subj
with HA 
• 
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• 
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RM VOLIT
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ubject asses
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tarting on th
AEs from TI 
Monitoring o
nellen visu
Confrontatio
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dermal fille
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ain after inj
Tenderness t
irmness 
welling 
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Discoloratio
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ude: 
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f concomita
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nal visual fie
ity assessmen
afety e-diary
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s 
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validated FA
scored in the
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worst pain im
e presence an
r up to 30 da
atment 
and inquiry
nt medicatio
essed by the 
elds assessed
nts assessed
y will list the
and will incl
ss or bruising
36 
ACE-Q Reco
e same man
n at initial t
maginable) 
nd severity 
ays after tre
at scheduled
ons and conc
TI (or desi
d by the TI (o
d by the TI (
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lude space to
g) 
Protocol 1
overy Early 
ner as the fir
reatment on 
of ISRs, reco
atment (initi
d follow-up 
current proc
gnee) 
or designee
or designee)
ISRs that ha
o include oth
867-701-008
Life Impact 
rst secondary
an 11-point 
orded in the 
al, touch-up,
visits 
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) 
ve been repo
her symptom
8 Amendme
questionnai
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scale rangin
subject’s da
, and repeat)
orted previou
ms: 
 
ent 3
re 
ess 
ng 
ily 
) 
usly 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
The subj
S
Subjects 
and the 
diary wi
longer p
the resp
e-diaries
 
9.5
AEs will
baseline 
question 
AEs and 
and exa
abnorma
The defi
The PI/
that mee
followin
or that c
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includin
the first 
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of these 
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None 
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onses on the 
. 
Adv
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such as “H
changes in 
mination wil
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TI and any d
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concern will
TI and the re
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afety e-diary
None or
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perform
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ts 
ut the study 
querying for 
any changes
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vestigationa
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ition is consi
37 
e following 
ble. 
little, if any, 
ities. 
some discom
great disco
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ay 3 and Day
s as an AE. 
CRF and tra
the e-diarie
o ensure a c
beginning w
AEs by ask
s to your co
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priate. All re
ented on the 
E/SADE are p
for detecting
I or SAE/S
d related to 
study (see Se
will be mon
and relation
dy subjects.
r each subje
whatever is n
al DFU. If s
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idered stabl
Protocol 1
severities for
discomfort 
mfort leadin
mfort leading
y 30/Month 
ISRs that ar
cked to resol
s for the en
onsistent re
with signing 
ing each su
ndition sinc
e to be upd
portable AE
appropriate 
provided in 
g, documen
ADE and rem
the study tre
ection 8). 
itored and re
nship to stu
ct closely, an
ecessary to 
ubjects have 
tinue to be 
e by the PI/
867-701-008
r ISRs to be 
leading to li
g to some eff
g to comprom
1 visits for r
e ongoing at 
lution or unti
tire diary per
cording betw
of the ICF. A
bject a genera
e your last vi
ated. Directed
s and clinica
 eCRF. 
Appendix 12
ting, and rec
main respons
eatment or st
eported on an
dy treatment.
nd, if a comp
treat the subj
any ongoing
followed up u
TI, or follow
8 Amendme
recorded: 
ttle, if any, 
fect on daily
mised 
review by the
the end of th
il follow-up 
riod are to en
ween eCRF a
At each post
al, non-direc
isit?” Previo
d questionin
ally significa
2.3. 
cording even
ible for 
tudy procedu
n AE eCRF, 
. If AEs occu
plication occ
ject.  Additio
g treatment-
until resoluti
w-up is no lon
 
ent 3
y 
e TI, 
he 
is no 
nter 
and 
-
cted 
us 
ng 
ant 
nts 
ures, 
ur, 
curs, 
onal 
ion 
nger 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
38 
possible. After the final visit, the subject will resume receiving the standard medical care 
according to the standard care of the clinic. 
The following is a list of known potential AEs: 
• Redness, swelling, or a rash, which may be associated with itching, pain on pressure, 
after the injection 
• Pain at injection site 
• Bruising 
• Lump/bump/mass or nodule at the injection site 
• Discoloration of the injection site 
• Rare cases of allergy, severe sensitivity, localized inflammation and abscesses 
• Very occasionally, delayed side effects can occur many months after the treatment. These 
side effects may appear as red lumps showing up underneath the skin, or intermittent 
episodes of swelling. 
• In rare circumstances, facial fillers have been injected into blood vessels causing 
blockage and embolization which can result in skin necrosis, ulceration, or vision 
changes. Risks to vision include complete blindness, partial blindness, blurred vision, 
double vision, loss of peripheral vision, loss of a portion of the visual field or anterior 
segment ischemia (characterized by decreased vision and pain). These effects can be 
temporary or permanent but are rare. 
• Swelling or edema around the eye following an injection can result in a temporary 
decrease of vision. 
• In rare circumstances, facial fillers have been associated with granulomas, which are 
small inflammatory nodules under the skin. 
Unforeseeable risks or results are also a possibility. The risk of developing a serious 
complication is small. If a complication occurs, subjects will be advised to contact the TI who 
will use his/her medical judgment to do whatever is necessary to treat the subject. In the event of 
vision loss, the subject must also be referred to a retinal specialist for evaluation and appropriate 
care. 
9.5.1 
Time Period and Frequency for Collecting AE/ADE and 
SAE/SADE Information 
All SAEs/SADEs from the signing of the ICF until the last follow-up visit will be collected at the 
timepoints specified in the schedule of activities (Section 2), and as observed or reported 
spontaneously by study subjects. 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
39 
All AEs/ADEs from the signing of the ICF until the last follow-up visit will be collected at the 
timepoints specified in the schedule of activities (Section 2), and as observed or reported 
spontaneously by study subjects. 
Medical occurrences that begin before the start of study treatment but after obtaining IC will be 
recorded in the AE section of the eCRF and will be considered pretreatment AEs. 
All SAEs/SADEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix 12.3. The PI/TI will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
PIs/TIs are not obligated to actively seek AE or SAE information in former study subjects. 
However, if the PI/TI learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the PI/TI must promptly notify the sponsor. 
Safety data collection and reporting guidelines are summarized in Table 9-4. The method of 
recording, evaluating, and assessing causality of AEs/ADEs and SAEs/SADEs and the 
procedures for completing and transmitting SAE/SADE reports are provided in Appendix 12.3. 
Table 9-4 
Safety Data Collecting and Reporting Guidelines 
AE Type 
Reporting to Sponsor (upon awareness) 
Start 
Collection 
End 
Collection 
AE, ADE 
Record on AE eCRF for review by the Monitor 
Immediately 
after ICF 
signed 
Last subject 
visit 
AESI 
Record on appropriate eCRF & report via fax/email to 
sponsor within 24 hours of awareness 
Immediately 
after ICF 
signed 
Last subject 
visit 
SAE, SADE 
Record on SAE form & report via fax/email to sponsor 
within 24 hours of awareness 
Immediately 
after ICF 
signed 
Last subject 
visit 
Medical device 
incident 
Record on the appropriate form & report via fax/email to 
sponsor within 24 hours of awareness 
Immediately 
after ICF 
signed 
Last subject 
visit 
Device deficiency 
Record on the appropriate form & report via fax/email to 
sponsor within 24 hours of awareness 
Immediately 
after ICF 
signed 
Last subject 
visit 
 
9.5.2 
Method of Detecting AEs/ADEs and SAEs/SADEs 
Care will be taken not to introduce bias when detecting AEs/ADEs and/or SAEs/SADEs. Open-
ended and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
40 
9.5.3 
Follow-up of AEs/ADEs and SAEs/SADEs 
After the initial report, the PI/TI is required to proactively follow each subject at subsequent 
visits/contacts. All AEs/ADEs/SAEs/SADEs and AESIs as defined in Section 9.5.5 will be 
followed until resolution, stabilization, until the event is otherwise explained, or the subject is 
lost to follow-up (as defined in Section 8.2). For subjects who complete the study with an 
ongoing treatment-related AE or withdraw from the study with an ongoing treatment-related AE, 
the PI/TI will attempt to follow the subject until the AE has been resolved or follow-up is no 
longer possible. The PI/TI will ask for the subject’s permission to follow his/her status/condition 
outside the study. 
The PI/TI is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Allergan Medical Safety 
Physician to elucidate the nature and/or causality of the AE/ADE or SAE/SADE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.  
If a subject dies during participation in the study, the PI/TI will provide the Allergan Medical 
Safety Physician with a copy of any postmortem findings including histopathology.  
New or updated information will be recorded on the originally completed eCRF.  
The PI/TI will submit any updated SAE/SADE data to the sponsor within 24 hours of receipt of 
the information. 
9.5.4 
Regulatory Reporting Requirements for SAEs and SADEs 
• Prompt notification by the PI to the sponsor of an SAE/SADE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a 
study treatment under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs, and PIs.  
• A PI who receives an investigator safety report describing a SAE/SADE or other specific 
safety information (eg, summary or listing of SAEs/SADEs) from the sponsor will review 
and then file it and will notify the IRB, if appropriate according to local requirements. 
9.5.5 
Adverse Events of Special Interest 
An AESI is defined as any vision-related AE. See Section 9.5.1 for procedures for reporting an 
AESI. 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
41 
9.5.6 
Pregnancy 
If a female becomes pregnant during the study, the PI/TI (or designee) will notify the sponsor 
immediately after the pregnancy is confirmed. The PI/TI shall (1) instruct the subject to notify 
her physician of the presence of the investigational device and (2) follow the pregnancy to term 
or termination. Best practices are to be followed in order to ensure the welfare of the subject and 
the fetus. The Allergan Medical Safety Physician will contact the PI/TI to obtain information 
about the pregnancy outcome. The subject will continue to be followed, and the pregnancy will 
be documented as a protocol deviation. 
Pregnancy by itself will not be considered an AE or SAE.  Hospitalization for a normal delivery 
or elective abortion of a normal fetus does not constitute an SAE. However, the occurrence of an 
adverse pregnancy outcome for the mother or child may constitute an AE or SAE, and these are 
to be reported as described in Appendix 12.3. 
9.5.7 
Medical Device Incidents (Including Malfunctions) 
Incidents fulfilling the definition of an AE/ADE/SAE/SADE will follow the processes outlined 
in Section 9.5.3 and Appendix 12.3. 
In order to fulfill regulatory reporting obligations worldwide, the PI is responsible for the 
detection and documentation of events meeting the definitions of incident, malfunction, or 
deficiency that occur during the study with such devices.  
The definition of a medical device incident and a device deficiency can be found in 
Appendix 12.4. 
9.5.7.1 
Time Period for Detecting Medical Device Incidents  
• Medical device incidents, deficiencies, or malfunctions of the device that result in an 
incident will be detected, documented, and reported during all periods of the study in 
which the medical device is used.  
• If the PI (or designee) learns of any incident at any time after a subject has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the PI (or designee) will promptly notify the 
sponsor.  
• The method of documenting medical device incidents is provided in Appendix 12.4, and 
reporting information is provided in Section 9.5.7.3. 

 
 
Approval Date: 
 
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CONFID
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GRD-CL
9.5.7.2 
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
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Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
45 
• Change from baseline in subject responses to FACE-Q Appraisal of Lines-Overall 
questionnaire  
• Subject assessment of the natural look of the cheek skin on an 11-point scale ranging 
from 0 (unnatural looking) to 10 (natural looking) 
• Subject assessment of the natural feel of the cheek skin on an 11-point scale ranging from 
0 (unnatural feeling) to 10 (natural feeling) 
• Subject assessment of the global aesthetic improvement of the cheek skin on the 5-point 
GAIS 
• Change from baseline in cheek skin hydration measurements obtained via the 
MoistureMeter® D instrument 
Exploratory effectiveness endpoint: 
• Composite responder status responder status on ACSS and FACE-Q Satisfaction with 
Skin questionnaire 
Effectiveness analyses other than those for primary and secondary endpoints will be defined in 
the SAP. 
10.3.1.2 
Primary Endpoint Analysis 
The primary effectiveness variable is the EI’s assessment of cheek skin smoothness on the 
ACSS. The primary effectiveness analysis is the ACSS responder rate at Month 1. A responder is 
defined as a subject who shows at least a 1-point improvement from baseline on the ACSS scale 
on both cheeks. The responder rate and corresponding 95% confidence interval will be 
summarized. A 2-sided, Fisher’s exact test at the 5% level will be used to test whether the ACSS 
responder rate at Month 1 in the treatment group is significantly greater than that in the control 
group at Month 1 in the control period.  
The primary effectiveness analysis will test for superiority of JUVÉDERM VOLITE XC 
treatment group over no treatment in the difference in ACSS responder rate based on the EI’s 
assessment at Month 1. Month 1 refers to 1 month after the last treatment (initial or touch-up) for 
subjects in the JUVÉDERM VOLITE XC treatment group and 1 month after randomization for 
subjects in the no-treatment control group. 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
46 
The null hypothesis is that the responder rate for the JUVÉDERM VOLITE XC treatment group 
is equal to the responder rate for the no-treatment control group. The alternative hypothesis is 
that the responder rates are not equal for the treatment group and the no-treatment control group. 
These hypotheses are stated as: 
Ηo: Pv – Pc = 0 
Ηa: Pv – Pc > 0 or Pv – Pc < 0 
where Pv and Pc denote the responder rates for the JUVÉDERM VOLITE XC group at Month 1 
after last treatment (initial or touch-up) and for the no-treatment control group at Month 1 after 
randomization, respectively. Two-sided Fisher’s exact test with 5% significance level will be 
used to compare treatment effects between JUVÉDERM VOLITE XC and the no-treatment 
control group. If the 2-sided p-value is less than 0.05 and the responder rate is greater for 
JUVÉDERM VOLITE XC than for the no-treatment control group, then JUVÉDERM 
VOLITE XC will be considered superior to the no-treatment control group. 
For primary analysis, subjects with missing data at the primary timepoint (ie, Month 1) will be 
analyzed as non-responders. Details will be described in the SAP. 
10.3.1.3 
Secondary Endpoint Analysis 
The first secondary effectiveness variable is subject responses on the FACE-Q Satisfaction with 
Skin questionnaire. The responses to the 12 items will be summed and converted to a scale score 
that ranges from 0 to 100 (higher score indicates more satisfaction) using the algorithm 
developed by the FACE-Q scale developers. The secondary effectiveness analysis is mean 
change from baseline in FACE-Q scale score at Month 1.  
The other secondary effectiveness variable is the EI’s assessment of fine lines on the cheeks on 
the AFLS. The AFLS responder rate at Month 1 will be analyzed in the same manner as the 
ACSS responder rate. Only subjects with baseline AFLS score of 2 on both cheeks or 3 on both 
cheeks will be included in the analysis. 
10.3.2 
Safety Analyses 
The following safety categories will be summarized as appropriate for the safety population and 
will be fully defined in the SAP. 
• FACE-Q Recovery Early Life Impact questionnaire 
• Subject assessment of procedural pain 
• ISRs 
• AEs 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
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47 
• Snellen visual acuity, confrontational visual fields, and ocular motility assessments 
FACE-Q Recovery Early Life Impact questionnaire and procedural pain will be summarized by 
frequency distributions or descriptive statistics. 
ISRs reported by subjects will be summarized using descriptive statistics, by symptom, 
maximum reported severity, and duration for initial, touch-up, and repeat treatments, separately. 
Incidence of AEs will be summarized by primary system organ class, preferred term, and 
severity. Additionally, a summary will be tabulated by onset, duration, severity, action taken, 
relationship to treatment, and outcome.  The summary will include incidence rate as well as total 
number of events. 
Treatment-related AEs, SAEs, AEs leading to study discontinuations, and deaths will be listed or 
tabulated. All pre-treatment AEs will be listed but not summarized. 
Snellen visual acuity, confrontational visual fields, and ocular motility assessments will be 
summarized descriptively. 
10.3.3 
Other Analyses 
10.3.3.1 
Demographics and Baseline Characteristics Analyses 
Subject demographics, baseline characteristics, and height and weight will be summarized with 
descriptive statistics. Urine pregnancy test results and vital signs will be listed but not 
summarized. 
10.3.3.2 
Treatment Administration Analyses 
Treatment characteristics will be summarized with descriptive statistics for anesthesia usage, 
needle length, injection volume, injection spacing, and injection plane. 
10.3.3.3 
Subgroup Analyses 
Analysis of the primary effectiveness endpoint, ACSS responder status at Month 1, will be done 
descriptively for the following subgroups:  
• Baseline ACSS score:  2 versus 3 
• Fitzpatrick skin phototype:  I/II, III/IV, and V/VI 
• Volume injected:  < median versus > median 
The median total volume injected (initial plus touch-up) for both cheeks is used for this analysis. 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
48 
10.3.4 
Interim Analyses 
No interim analysis is planned for this study. After the first 30 treated subjects complete 1-month 
follow-up, a safety update including descriptions of AEs and associated treatment parameters for 
these subjects will be provided to the FDA. An analysis of the primary and secondary endpoints 
may be conducted once all subjects have passed the primary timepoint (Month 1). If such an 
analysis is conducted, the details of the analysis will be described a priori in other study 
documents. 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
11.
Guidanc
Develop
https://w
Klassen A
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life impact, s
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JA, Scott AM
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49 
come Measu
December 20
nces/ucm193
SB, Carruthe
skin, lips, a
dures. JAM
M, Pusic A
with outcom
Surg. 2015
Protocol 1
ures: Use in 
09.  
3282.pdf.  
rs A, Carrut
nd facial rh
A Dermatol.
L.  FACE-Q 
mes, and dec
;135:375-38
867-701-008
Medical Pro
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. 2016;152:4
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Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
12.
 
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Definition 
2-dimensional
Allergan Cheek
adverse device 
adverse event 
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Allergan Fine L
Clinical Data In
directions for u
electronic case 
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Food and Drug
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Investigational 
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8 Amendme
 
ent 3

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
12.2
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RM VOLIT
N-T-01-04 Prot
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51 
ernance 
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er 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
52 
Informed Consent Process 
• The PI or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study.  
• Subjects must be informed that their participation is voluntary. Subjects will be required 
to sign a statement of IC that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, HIPAA requirements, where applicable, and the IRB or study center.  
• The medical record must include a statement that written IC was obtained before the 
subject was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the IC must also sign the ICF. 
• Subjects must be re-consented to the most current version of the ICF during their 
participation in the study.  
• A copy of the ICF must be provided to the subject.  
Informed Consent and Subject Privacy 
The purpose, procedures, risks, benefits, and alternatives to study participation will be discussed 
with each potential subject. The subject must also give Authorization for Use and Release of 
Health and Research Study Information and other written documentation in accordance with the 
relevant country and local privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment. 
The PI or his/her authorized designee conducts the IC discussion and will document in the 
subject’s medical records the acquisition of IC and the subject’s agreement or refusal to notify 
his/her primary care physician about the study. The IC shall include all aspects of the study that 
are relevant to the subject’s decision to participate throughout the study. The IC process is to 
avoid any coercion or undue influence on, or inducement of, the subject to participate.  The 
subject is to personally sign and date the IC. The PI will retain the original copy of the signed 
form, and the subject will receive a copy. Upon signing the IC form, the subject is considered to 
be enrolled in the study and receives a subject number that will be used on all documentation for 
the subject throughout the study. Subject numbers will be assigned in ascending order, and 
numbers will not be omitted or reused. The subject number is coupled with the site identification 
number for unique identification of each subject. The PI (or designee) is to ensure important new 
information is provided to new or existing subjects throughout the study.  
Data Protection 
• Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
53 
• The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.  
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
Publication Policy 
• The sponsor has proprietary interest in this study. Authorship and manuscript composition 
will reflect joint cooperation between multiple investigators and sites and sponsor 
personnel. Authorship will be established prior to the writing of the manuscript. As this 
study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with the sponsor. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.  
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  
Dissemination of Clinical Study Data 
• Study data and information may be published in nonpromotional, peer-reviewed 
publications either by or on behalf of the sponsor. 
• Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required. 
• Study data will be posted on www.clinicaltrials.gov as required.  
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The PI 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• The PI must maintain accurate documentation (source data) that supports the information 
entered in the CRF. 
• The PI must permit study-related monitoring, audits, IRB review, and regulatory agency 
inspections and provide direct access to source data documents. 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
54 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the PI for 2 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may 
be transferred to another location or party without written notification to the sponsor. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the PI’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The PI may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in Section 4.0 of ICH E6, Good 
Clinical Practice: Consolidated Guidance and must follow ALCOA (ie, records must be 
attributable, legible, contemporaneous, original, and accurate). 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The PI may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or PI may include but are not limited 
to: 
• Failure of the PI to comply with the protocol, the requirements of the IRB or local health 
authorities, the sponsor’s procedures, or GCP guidelines 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
55 
• Inadequate recruitment of subjects by the PI 
• Discontinuation of further study treatment development 
• 
If a vascular embolic AE leading to skin necrosis, vision loss, or stroke occurs, all 
treatments at the investigational site will be suspended while the circumstances of the 
event are investigated. If the event is confirmed to be a vascular embolic event and 
related to JUVÉDERM VOLITE XC treatment, Allergan will suspend any further 
enrollment and treatments at the investigational site while performing a root cause 
analysis. If the AE is a result of deviation from the injection procedure, the TI may be 
retrained and allowed to continue enrolling subjects. If the event is not a result of 
deviation from the injection procedure, all enrollment and treatments at all investigational 
sites will be halted until the event can be characterized, and a strategy to avoid further 
AEs can be developed. 
Per ISO 14155, if a study is prematurely terminated or suspended due to safety issues, the 
sponsor shall inform all PIs and the regulatory authorities of the termination or suspension and 
the reason(s) for the termination or suspension. The IRB is also to be informed promptly and 
provided the reason(s) for the termination or suspension by the sponsor or by the PI, as specified 
by the applicable regulatory requirements. If a premature termination or suspension occurs, the 
sponsor shall remain responsible for providing resources to fulfill the protocol obligations and 
existing agreements for follow-up of subjects enrolled in the study, and each PI or authorized 
designee shall promptly inform enrolled subjects, if applicable. 
Compliance with Protocol 
The PI is responsible for compliance with the protocol at the investigational site. A representative 
of the sponsor will make frequent contact with the PI and his/her research staff and will conduct 
regular monitoring visits at the site to review subject and device accountability records for 
compliance with the protocol. Any protocol deviations will be discussed with the PI upon 
identification. The use of the data collected for the subject will be discussed to determine if the 
data are to be included in the analysis. The PI will enter data that may be excluded from analysis 
as defined by the protocol deviation specifications. All protocol deviations will be reported to the 
IRB according to the IRB’s reporting requirements. 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
12.3
AE Defi
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Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
57 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• New condition detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of a concomitant 
medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses are to be 
reported regardless of sequelae. 
• Lack of effectiveness or failure of expected medical device results per se will not be 
reported as an AE or SAE. Such instances will be captured in the effectiveness 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from lack 
of effectiveness will be reported as AE or SAE if they fulfill the definition of an AE or 
SAE. 
Events Not Meeting the AE/ADE Definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
SAE Definition 
An SAE is defined in accordance with ISO 14155 as an AE that: 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either resulted in 
1. A life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or 
4. medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
58 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered an SAE. 
All cancers that occur during a study are considered SAEs and will be documented and reported 
per Appendix 12.3. 
 
Serious Adverse Device Effect 
An SADE is defined in accordance with ISO 14155 as “an adverse device effect that has resulted 
in any of the consequences characteristic of a serious adverse event.” 
Unanticipated Adverse Device Effect  
A UADE is defined in accordance with 21 CFR 812.3 as “any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects.” 
Assessment of Severity 
Severity is a clinical determination of the intensity of an AE. The severity assessment for a 
clinical AE is to be completed using the following definitions as guidelines: 
Mild 
A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
An event is defined as serious when it meets at least one of the predefined outcomes as described 
in the definition of an SAE/SADE, NOT when it is rated as severe. 
Relationship to Treatment 
Relationship to treatment refers to a determination of the relationship (if any) between an AE and 
the device or treatment procedure. A causal relationship is present if the PI determines that there 
is a reasonable possibility that the AE may have been caused by the device or is associated with 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
59 
the procedure, such as an event that can be attributed to other products, surgical techniques, or 
medications required specifically for the procedure. Relationship to the device or procedure must 
be determined by the PI and cannot be delegated to other study staff. 
• Recording AEs/ADEs and/or SAEs/SADEs When an AE/ADE or SAE/SADE occurs, it 
is the responsibility of the PI to review all documentation (eg, hospital progress notes, 
laboratory reports, and diagnostics reports) related to the event. 
• The PI will then record all relevant AE/ADE or SAE/SADE information in the CRF. 
• It is not acceptable for the PI to send photocopies of the subject’s medical records to the 
Allergan Medical Safety Physician in lieu of completion of the AE/ADE/SAE/SADE 
eCRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Allergan Medical Safety Physician. In this case, all subject identifiers, with the 
exception of the subject number, will be redacted on the copies of the medical records 
before submission to the Allergan Medical Safety Physician. 
• The PI will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the event. 
Procedures for Reporting an AE or ADE 
All AEs/ADEs occurring during the study period (beginning with signing ICF) are to be recorded 
on the appropriate CRF. For any treatment-related AE/ADE that is ongoing at the exit, the PI/TI 
will attempt to follow the subject until the AE/ADE has been resolved or follow-up is no longer 
possible. 
AEs/ADEs that start after the study follow-up period has ended will be considered outside the 
scope of the study but will be captured.  
Procedures for Reporting an SAE or SADE 
All SAEs and SADEs occurring during the study period (beginning with signing ICF) are to be 
immediately reported to a sponsor representative at a fax number/email address listed on the 
cover page and recorded on the appropriate CRFs. All subjects with an SAE/SADE must be 
followed up and the outcomes reported. The PI is to supply the sponsor and the IRB with any 
additional requested information (eg, hospital discharge summary, autopsy reports, and terminal 
medical reports). The sponsor will evaluate all SADEs and determine and document in writing 
whether they meet the definition of UADE. These shall be reported to all participating PIs, the 
regulatory authorities, and IRBs as required by national regulations. 
In the event of an SAE/SADE, the PI must: 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
60 
• Notify the sponsor immediately by fax/email using the SAE/SADE reporting forms. For 
the SAE/SADE fax number/email address, see the front page of the protocol. 
• Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject. 
• Provide the sponsor with a complete, written case history which includes a statement as to 
whether the event was or was not related to the use of the investigational device. 
• Promptly inform the governing IRB of the event, if it is treatment-related. For other SAEs, 
notify the governing IRB as required by the IRB, local regulations, and the governing 
health authorities. 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
12.4
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Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
63 
Device Deficiency 
A device deficiency is defined in accordance with ISO 14155 as “inadequacy of a medical device 
with respect to its identity, quality, durability, reliability, safety, or performance.” Device 
deficiencies include malfunctions, use errors, and inadequate labeling. 
If a device deficiency occurs, the PI/TI or designee will notify the sponsor using the fax number 
or email on the front page of the protocol. Device deficiencies shall be documented throughout 
the study and appropriately managed by the sponsor. The sponsor shall review all device 
deficiencies and determine and document in writing whether they could have led to an SADE. 
These shall be reported to the regulatory authorities and IRBs as required by national regulations. 
 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
12.5
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867-701-008
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ent 3

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
12.6
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informati
 
 
 
 
 
 
 
 
 
 
 
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Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
66 
Treatments 
Investigational Therapy or 
Treatment 
JUVÉDERM VOLITE™ XC Injectable Gel 
 
Intervention Type 
Device 
 
Pharmacological Class of Invest. 
Therapy 
N/A 
 
Dose per Administration 
Up to 4 mL (initial and repeat); up to 2 mL 
(touch-up)
 
Dose Units 
mL 
 
Treatment Frequency 
Initial, touch-up, and repeat (treatment group 
only) treatments 
 
Route of Administration 
Injection 
 
Current Therapy or Treatment 
N/A 
 
Added on to Existing Treatments 
No 
 
Control Type 
No-treatment control 
 
Comparative Treatment Name 
None 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
 
Planned Number of Arms 
2 
 
Study is Randomized 
Yes 
 
Randomization Quotient 
2:1 
 
Study Blinding/Masking Schema 
Single blind 
 
Stratification Factor 
None 
 
Adaptive Design 
No 
 
Study Stop Rules 
Yes 
 
 
 

 
 
Approval Date: 
 
25-Nov-2019
CONFID
JUVÉDE
 
GRD-CL
 
12.7
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867-701-008
mendment is
hort. 
Brief
To ensure ade
subjects with F
phototypes V 
To ensure ade
subjects with F
phototypes V 
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subjects with F
phototypes V 
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subjects with F
phototypes V 
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nd 

 
 
Approval Date: 
 
25-Nov-2019
 
CONFIDENTIAL  
Protocol 1867-701-008 Amendment 3
JUVÉDERM VOLITE™ XC 
 
GRD-CLN-T-01-04 Protocol Template (Device) v1.0 
68 
Procedures 
timing of procedures
Table 2-4 Control Group 
Procedures 
Clarified the order of procedures and removed 
skin hydration assessment at initial treatment for 
control group since it is already assessed at 
Month 1 in no-treatment period 
To clarify the order and 
timing of procedures and 
remove redundant 
assessment 
9. Study Assessments and 
Procedures 
Clarified that ACSS and FACE-Q are only to be 
performed on day of randomization if 
randomization occurs on a different day than 
screening 
To clarify procedures 
9.3.1 Primary Effectiveness 
Measure 
Added detail about ACSS features 
To better describe the 
primary effectiveness 
measure 
9.5.1 Time Period and 
Frequency for Collecting 
AE/ADE and SAE/SADE 
Information 
Revised 1 sentence to align with current protocol 
template 
To align with current 
protocol template 
12.3 Appendix 3: Adverse 
Events 
Deleted 1 sentence to align with current protocol 
template 
To align with current 
protocol template