A Controlled, Randomized, Double-blinded, Between-subject, Multicenter, Prospective Clinical Study to Evaluate Safety and Effectiveness of RHA® 3 Versus Restylane-L® for Lip Augmentation
Conditions: Lip Augmentation, Lip
Sponsor: Teoxane SA

n
TEOXANE
1. TITLE PAGE
A Controlled, Randomized, Double-blinded, Between-subject, Multicenter,
Prospective Clinical S
to Evaluate Safety and Effectiveness of RHA@ 3
versus
for Lip Augmentation
Clinical Investigation Plan
RHA@ 3
I
G200102
Pivotal
Lip Augmentation
Controlled, randomized, double-blinded, multicenter, prospective
I
Original Protocol Version 1.0, l3-Mar-2020
Amended Protocol Version l, 
22-MaF2021
INVESTIGATIONAL PRODUCT
CLINICAL INVESTIGATION
PLAN NUMBER:
INVESTIGATIONAL DEVICE
EXEMPTION NUMBER:
DEVELOPMENT PHASE:
INDICATION:
METHODOLOGY:
PROTOCOL VERSION:
PROTOCOL DATE:
AMENDMENT 5 DATE:
PROTOCOL WRITTEN BY:
SPONSOR:
TEOXANE
RuedeLyon 105
cH - 1203
Switzerland
SPONSOR CONTACT PERSON
UNITED STATES SPONSOR:
This clinical investigation will be conducted in accordance with International Organization for Standardization
(ISO) 14155, Good Clinical Practice (GCP), and applicable regulatory requirements, including the archiving of
essential documents. All unpublished information contained in this document is the confidential property of
TEOXANE and may not be disclosed to parties not associated with the clinical investigation or used for any pwpose
without prior written consent of TEOXANE.
AD-PR-37.01 15-Apr-2016
Page 1 of132

r
Clinical Investigation Plan
APPROVAL SIGNATURES
CLINICAL INVESTIGATION
PLAN NUMBER:
I
A Controlled, Randomized, Double-blinded, Between-subject,
Confidential
CLINICAL INVESTIGATION
PLAN TITLE:
Multicenter, Prospective Clinical
to Evaluate
and
Effectiveness of RHA@ 3 versus
Augmentation
for Lip
I, the undersigned, have read this clinical investigation plan and confirm that, to the best of my
knowledge, it accurately describes the planned conduct of the investigation.
SIGNATURE 
DATE
r
Clinical Program Manager
r
Clinical Development and Medical Affairs Director
I
-
Page 2 of 132

I
Clinical Investisation Platt E
SIGNATURE
Confidential
DATE
-
Page 3 of 132

I
Clinical Investigation Plan
AMENDED PROTOCOL
Revision history:
TITLE:
CLINICAL INVESTIGATION
PLANNUMBER:
PROTOCOL VERSION:
ORIGINAL PROTOCOL DATE
AMENDMENT I DATE:
AMENDMENT 2 DATE:
AMENDMENT 3 DATE:
AMENDMENT 4 DATE:
AMENDMENT 5 DATE:
Confidential
A Controlled, Randomized, Double-blinded, Befween-subject,
Multicenter, Prospective Clinical Study to Evaluate Safety and
Effectiveness orRHR@ 3 versus I 
for Lip
Augmentation
r
I
Original Protocol Version 1.0, l3-Mar-2020
Amended Protocol Version a, 22-Mar-2021
The following are the amended protocol and appendices, including all revisions specified in the
REASONS FOR AMENDMENT and SUMMARY OF AMENDED SECTIONS.
Page 4 of 132

I
Clinical Investisation Plu.t E
Confidential
2. CLINICAL INVESTIGATION PLAN SUMMARY
2.1. Summary
RHAO 3
-
RHA@ 3 injectable gel is intended to be used for injection in the vermillion body,
vermillion border, and oral commissures to achieve lip augmentation and lip
fullness in subjects aged.22 or older
Pivotal
A Controlled, Randomized, Double-blinded, Between-subject, Multicenter,
Prospective Clinical Study to Evaluate Safety and Effectiveness of RHAo 3 versus
I 
lut Lr-u Auv'rcttalru'
TEOXANE SA, Rue de Lyon 105, CH - 1203 Geneva, Switzerland
The purpose ofthe clinical investigation is to evaluate the safety and effectiveness
ornire! 3 when compared to I 
to add volume and fullness to the lips
l2 weeks after the last treatment (initial or touch-up)
a
a
Primary Effectiveness Obj ective :
o To assess the effectiveness (non-inferiority) of RHAe 3 versus
I 
on adding volume and fullness to the lips in subjects seeking
lip augmentation, 12 weeks after the last treatment (initial or touch-up)
Secondary Effectiveness Objective:
o To assess the effectiveness of RHA& 3 versus I 
on adding
volume and fullness to the lips in subjects seeking lip augmentation up to
52 weeks
oToassesstheresponderrateofRHAo3u.''u'fafterlip
augmentation up to 52 weeks
o To assess the subject satisfaction and patient-reported outcome of the
aesthetic procedure (FACE-Q) with RHA. 3 versui I 
after lip
augmentation up to 52 weeks
o To assess the Global Aesthetic Improvement Scale (GAfS) of RHAE' 3
u..rnr f 
after lip augmentation up to 52 weeks
II.IVESTIGATIONAL
PRODUCTNAME
CLINICAL
IIWESTIGATION PLAN
(crP)NT.JMBER
CONTROL DEVICE
NAME
INDICATION FOR USE
DEVELOPMENT PHASE
TITLE OF
INVESTIGATION
MANUFACTURER/
SPONSOR
CLINICAL
INVESTIGATION
PURPOSE
OBJECTIVES
Page 5 of 132

I
Clinical Investigation Plan
Confidential
INVESTIGATION
DESIGN
CLIMCAL
INVESTIGATION PLAN
(cIP)NL]MBER
INVESTIGATIONAL
PRODUCTNAME
This is a multicenter, double-blinded, randomized, prospective, controlled clinical
study to identify whether RHAo 3 is non-inferio. to I 
for lip
augmentation at Week 12 after the last treatment (initial or touch-up)"
The treating investigator (TI) will evaluate the subject's lip fullness using the live
validated 5-grade Teoxane Lip Fuliness Scale (TLFS grade 1 to 5) ar Screening
(Visit 1, 0 Week) for eligibility of the subject for the study.
The blinded live evaluator (BLE) will evaluate the subjec's lip fullness using the
TLFS at Screening (Visit 1,0 Week) to confirm eligibility and to establish a
score for assessment of effectiveness. This will be done
Enrolled subjects will be rancomly assigned in a 3:1 ratio to eitherthe RHA.i)3 or
th. f 
rrearment gronp. Subl."ts will be blinded to the study treatment.
The TI will administer the frllers, and if necessary, subjects will receive a touch-up
treatment 4 weeks after the initial treatment to optimize the results. If the touch-up
treatment is administered, tlre subject will be asked to come to the site for an
additional t islt f 
4 weeks after the touch-up injecrion.
Subjects will be followed for 52 weeks after their last treatment (initial treatment or
touch-up), at which point, the;r will be offered retreatmenr with RHA, 3, regardless
of their original treatment, provided that the TI deems the treatment to be
appropriate and the subject a3rees. Reasons for not administering the retreatment
will be documented. The subject will then be followed for an additional 4 weeks
before exiting the shrdy. If dre subject or the TI declines rerreatmenr, this visit
\I 
JZ wEstrs arlsr L'c lz-sr rrcarment; wlr De consloered tne srudy txlt vrslt.
For subjacts with retreatmen! the Exit visit will Ue at f 
4 weeks after the
retreatment.
of the TI.
Safety Objective:
o To assess the safety of RHAo 3 in subjects after lip augmentation
a
3
-
Page 6 of 132

I
Clinical Investigation Plutr I
Confidential
3
The TI will conduct safety and effectiveness evaluations at each
will occur at 4 weeks after the initial and
treatment
and 52 weeks
after the last treatment, and 4 weeks
weeks after the last
which
36 weeks
after retreatment or until all treatment-related ongoing adverse events (AEs) have
resolved or resolved with sequelae as per TI judgment or if follow-up is no longer
possible.
A follow-up telephone call for safety will be performed 3 days after each treatment
fll 
initial, touch-ui, and retreatment, respectively). Subjects will
..p".t th.i. *.."" 
treatment responses (CTRs) in a subject diary forl days after
each injection. The diary will also include a list of selected AEs
associated with
of dermal fillers for
ects to
Subjects who had entered the study under earlier versions ofthe CIP (version I
and earlier) and who do not agree with the extension of their participation in the
study as per CIP version 5.0, to 52 weeks after last injection, will be allowed to
continue with the visits as originally planned. They will exit the stuOy ut fiO
ff i};li.;i:;l,Ti:1';tHl;:.;Ti.T[:f, "TJi,IiZ#:,'-1i",;J
retreatment. Further details are described in the CIP.
A BLE will conduct assessments of effectiveness during the study, inciuding
assessment of the primary endpoint An
The BLE will conduct effectiveness evaluations at
weeks after the last heatment),
weeks after the
last treatment), and
weeks after the retreatment, if applicable)
The eft-ectiveness of RHABr 3 will be demonstrated if the change fiom Baseline for
subjects treated with RHAD 3 is statistically non-inferior to the change from
Baseline for subjects treated with I 
at l2 weeks after the last treatment
as assessed by the BLE using the TLFS. The difference in the TLFS change from
Baseline to 12 weeks will be used to establish non-inferiority.
A change in the TLFS >1 grade compared to pretreatment will be considered
clinically meaningful.
TLFS change from Baseline assessed:
o By the BLE at Visit 4 and each visit at the study site afterwards
Responder rate calculated using TLFS assessed:
o By the BLE at Visit 4 and each visit at the study site afterwards
a
a
INVESTIGATIONAL
PRODUCTNAME
CLINICAL
INVESTIGATION PLAN
(crP)NT.JMBER
PRIMARY
EFFECTIVENESS
ENDPOINT
SECONDARY
EFFECTIVENESS
ENDPOINTS
PageT ofl32

I
Clinical Investigation Pl^. I
Confidential
SAFETY ENDPOINT
CLINICAL
I}N/ESTIGATION PLAN
(crP)NLJMBER
IIVVESTIGATIONAL
PRODUCTNAME
o Adverse Events
. 
Post-injection CTR from the subject's lday diary
a
A responder will be defined as a subject who has a >1 grade improvement on
the TLFS.
o
Subject satisfaction using the Subject Satisfaction Scale at each visit at the
study site starting at Visit 2
FACE-Q scores for each module (satisfaction with lips and satisfaction with
e
outcome
assessed
the su
ect at each visit at the
site
a
GAIS as assessed:
o By the BLE starting at Visit 4 and each visit at the study site afterwards
a
RHA@ 3
-
Page 8 of 132

I
Clinical Investisation Plu.t I
Confidential
The primary endpoint of the study is the difference in the TLFS change from
Baseline to I 2 weeks after the last day of treatment between subjects treated with
KnA J anu tnoss r.rsalcu wltr I
-III
I
-
3
RHA
INVESTIGATIONAL
PRODUCTNAME
CLINICAL
INVESTIGATION PLAN
(CIP)NUMBER
SAMPLE SIZE
Page 9 of 132

I
Clinical Investigation Plan
Confidential
ELIGIBILITY CRITERIA
STUDY CENTERS AND
LOCATION
CLINICAL
INVESTIGATION PLAN
(crP)NUMBER
INVESTI6ATIONAL
PRODUCTNAME
Inclusion Criteria:
A potential subject will be included in the study if he/she meers all of the following
inclusion criteria:
l. Outpatient, male or female of any race,22 years of age or older.
2. Subject, if female, is not pregnant, not breastfeeding, and either not of
childbearing potential (defined as postmenopausal for at least I year or
surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or
hysterectomy]) or must have a negative urine pregnancy test (UpT) at Visit I
and prior to each injectior and must agree to practice I of the following
medically acceptable methods of birth control throughout the study:
3. Subject seeking lip augmentation (realistic and achievable as per TI opinion).
RHA@3
-
Page 10 of 132

I
Clinical Investigation Plu.t I
Confidential
RTIA@ 3
6. Able to follow study instructions and complete all required visits.
'7. Sign the institutional review board-approved informed consent form,
photographic release form, and the authorization for use and release ofhealth
and research study information (Health Insurance Portability ar.rd
Accountability Act) form and, if applicable, the Califomia Experimental
Research Subject's Bill of Rights prior to any study-related procedures being
performed.
Exclusion Criteria:
A potential subject will be excluded from the study if he/she meets any of the
fol lowing exclusion criteria:
1. Known hypersensitivity or previous allergic reaction to any component of the
study or the control device.
2. Known sensitivity to local anesthetics of the amide fype, including known or
suspected lidocaine hypersensitivity, history of multiple severe allergies, or
history of anaphylactic shock.
3. An outbreak of herpes labialis within 4 weeks of randomization or 4 or more
outbreaks in the 12 months prior to random'ization.
4. History of severe chronic systemic diseases, including but not limited to, poorly
controlled diabetes mellitus (all types), congestive heart failure, severe liver
disease, severe kidney disease, and others asjudged by the TI.
6. Has an active inflammation, infection, cancerous or precancerous lesion, or
unhealed wound on the lips, in the area of the mouth, or the area around the
mouth.
INVESTIGATIONAL
PRODUCTNAME
CLIMCAL
INVESTIGATION PLAN
(CIP)NUMBER
Page 11 of132

Confidential
Clinical Investigation Plan
CLINICAL
I},IVESTIGATION PLAN
(crP) NUMBER
II.N/ESTIGATIONAL
PRODUCTNAME
8. Need for clinically significant (TI discretion) and continuous medical treatment
within 2 weeks prior to randomization.
RHAO 3
-
Page 12 of 132

I
Clinical Investigation Ptun E
Confidential
RTIA@ 3
18. Medical or psychiatric conditions that may increase the risk associated with
study participation or may interfere with the interpretation of study results or
compliance of the subject and, in the judgment of the TI, would make the
subject unsuitable for entry into this study).
21. Clinically significant alcohol or drug abuse or history ofpoor cooperation or
unreliability.
23.
Individual study
The minimum and maximum anticipated duration of
subject participation are 52
The anticipated duration for
subjects who were enrolled under CIP version
or earlier and who do not agree
to the extension of their participation in the srudy as per CIP version 5.0 will be a
-
The TLFS change from Baseline of subjects treated with RHA'o 3 will be
statistically non-inferior to the change from Baseline of subjects treated with
I 
for the assessment of lip augmentation and fullness as determined by
theBLEusingtheTLFSatWeekl2afterthelasttreatment._
-
INVESTICATTONAL
PRODUCTNAME
CLIMCAL
INr'ESTIGATION PLAN
(CIP)NIjMBER
STUDY DURATION
HYPOTHESIS
-
Page 13 of132

I
Clinical Investigation Plan
Confidential
SAFETY EVALUATIONS
EFFECTIVENESS
EVALUATION
CLINICAL
INVESTIGATION PLAN
(cIP)NUMBER
INVESTIGATIONAL
PRODUCTNAME
r 
Adverse Events
. 
posr-injection crRf
-
--
TLFS - a live validated 5-point scale for assessing lip fullness
Global Aesthetic Improvement Scale (GAIS) - a subjective, balanced, 5-point
scale assessing aesthetic improvement
FACE-Q scales - validated subject-reported outcome measure, assessed at each
study visit by the subject. The following modules will be used in the study:
o Satisfaction with lips: This scale measures the appearance of the upper and
lower lips with items that ask about size, shape, and fuilness, as well as
how the lips suit the face and how nice the lips look when smiling
o Satisfaction with outcome: This scale measures a subject's satisfaction
with the result of their most recent procedure
Subject Satisfaction Scale - a subjective, balanced, 5-point scale assessing
subject satisfaction with snrdy treatment
a
a
o
a
o
RIIA@ 3
Page 14 of 732

I
clinical Investigation Ptun I
Confidential
a
All data will be recorded in an electronic case report form (eCRF).
Quantitative data will be described by their mean, SD, and median, and extreme
values. The 95% CI will also be produced when relevant.
Qualitative data will be described by their number and percentage.
The following analysis populations will be used:
. 
Screening: All subjects who provide informed consent and demographic and/or
Baseline screening assessment results, regardless of the subject's
randomization and treatment status in the investigation.
. 
Safety: AII subiects who receive at least I treatment with RHAo3 or
I
. 
Modified intent-to-treat (mITT) analysis set will be used for the efficacy
analysis. The mITT set is based on the conventional ITT:
]er-protocol (PP): All subjects in the mITT population
Primary Effectiveness Analysis :
Non-inferiority analys is (ma in ana lysis) :
To demonstrate non-inferiority of RHAo 3 compared to I 
at l2 weeks
after the last treatment, the difference in the TLFS
deviations
who receive treatment
or clinical investi
and do not have
between Baseline
and 12 weeks will then be tested between
J
RHA
PRODUCTNAME
TIONAL
CLIMCAL
INVESTIGATION PLAN
(crP)Nr.,MBER
STATISTICAL METHODS
AND ANALYSIS
SUMMARY
Page 15 of 132

Confidential
Clinical Investigation Plan
CLIMCAL
IT{VESTIGATION PLAN
(crP)NUMBER
INVESTIGATIONAL
PRODUCTNAME
For each product, summary statistics (mean. minimum, maximum. SD, and 95% CI
of the mean) for the above-mentioned parameters will be provided/presented for
each study visit.
For endpoints with qualitative results, frequencies and percenrages will be
calculated and presented for each study visit.
RHA
J
-
Page 16 of 132

I
Clinical Investigation Piut E
Confidential
RHAO 3
Safetv Analysis:
The TI, through questioning and observations, will report all AEs, their severity and
relationship to the srudy device.
INVESTIGATIONAL
PRODUCTNAME
CLIMCAI
INVESTIGATION PLAN
(crP)NT.JMBER
Page 77 of 132

I
Clinical Investigation Plan
Confidential
BLINDING
TREATMENT GROUPS
DEVICE TREATMENT
CLINICAT
IT.MSTIGATION PLAN
(crP)NUMBER
INVESTIGATIONAL
PRODUCTNAME
The BLE and subj ects will be blinded to treatment allocation. Furthermore, to
ensure that they remain masked and unbiased when making their assessments
throughout the study, the BLE, TI, and subjects will not be allowed to refer to each
other's effectiveness assessments.
All subjects will be instructed to not discuss their study treatment, AEs, or CTRs
with the BLE.
Subjects will be randomly assigned (3:1 ratio) to 1 of the foliowing groups:
. 
RHA6) 3
.I
Injection area: The TI will inject each device into the vermillion body, vermillion
border, and oral commissures as needed to achieve optimal aesthetic outcome.
Amount of filler to be administered: Up to 1 .5 mL per lip (upper and lower) at each
treatment (initial, touch-up, and retreatment).
All AEs will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) dictionary. All AEs reported during the study will be described by
system organ class and preferred term. The number and percentage of subjects
experiencing at least I AE that are device related
adverse device
will be
-
RHA@ 3
-
Page 18 of 132

Conlidential
Clinical Investigation PlunI
I
T
I
II
I
I
I
T
I
T
I
T
I
I
I
T
II
T
T
I
I
T
I
I
I
I
I
T
I
I
I
-
I
I
-
I
I
I
T
TI
I
-
I
T
I
I
T
T
-
I
T
T
-
I
II
II
I
II
II
II
I
-
I
I
I
I
I
IrII
III
IIrI
IIII
IIII
E
II
IIII
IIII
III
II I
I
II
I
-
I
I
Page l9 of 132

I
Clinical Investigation Plan
Confidential
I
T
T
I
I
T
I
I
I
II
I
I
I
I
I
I
I
I
T
I
I
I
-
I
I
I
I
I
I
T
t
I
I
I
I
I
I
I
I
I
I
I
I
I
I
T
I
I
t
T
I
I
I
I
I
I
I
T
I
r
I
T
I
I
I
r
I
I
I
-
I
t
T
I
I
Page 20 of 132

Confidential
Clinical Investigation ptunl
Page2l ofl32

I
Clinical Investigation Plan
Confidential
Table2-2
I
I
I
I
II
I
II I
III
IIII
IrIr
IIIr
IrIr
II
I
III
I
II
III
II
II
I
I
I
II
II
II
I
I
I
II
II
II
I
-
II
I
I
T
I
T
I
I
I
-
tI
I
I
I
I
I
I
I
I
I
T
I
I
I
I
I
r
I
I
I
I
I
I
II
I
I
r
T
I
I
I
I
I
T
-
II
I
I
I
I
I
I
T
T
t
I
I
I
I
-
Ir
I
I
I
T
Page 22 of 132

Conlidential
Clinical
PlanI
-
I
I
I
I
I
I
I
I
I
I
I
T
I
I
I
I
I
I
I
I
I
I
I
t
I
I
I
I
I
I
I
I
I
T
I
T
I
I
I
I
I
I
I
I
I
T
I
I
I
T
I
I
I
I
I
I
I
T
I
I
I
I
I
I
I
Page23 of 132

I
Clinical Investigation Plan
Confidential
Page 24 of 132

I
Clinical Investieation Plun E
Confidential
3. TABLE OF CONTENTS
1. TITLE PAGE.........
AMENDED PROTOCOL ................
2. CLINICAL INVESTIGATION PLAN SIIMMARY.
2.1. Summary
3. TABLEOFCONTENTS
IIII
INTRODUCTION TO THE CLINICAL INVESTIGATION ...
5.1. Background
5.2. Study Device Name .......
5.3. Current Indication Statement...
I
5.
5.4
5.5
6.3.
6.4.
Intended Purpose Statement...
Investigational Product Description
5.5.1. Delivery System and Implantation ..
5.5.2. Nonclinical Testing
5.5.3. Previous Clinical Experience......
5.5.3.1. RHA@ 3 EU Pilot Study..
......35
......35
6.
5.5.3.2. RHA@ 3 US Pivotal Study (IDE ref G140028) 
..................36
5.5.3.3. RHA@ Postmarketing Data 
..........36
5.6. Control Device 
...........37
I 
Injection of RHA@: orl 
...............37
5.8. Justification for the Clinical Investigation................. 
........... 3 t
5.8.1. Justification for the Clinical lnvestigation Design 
......38
CLINICAL INVESTIGATION PURPOSE, OBJECTTVES, AND ENDPOTNTS................39
6.1. Clinical Investigation Purpose... 
.....39
6.2. Objectives.. 
......'....'....'.39
6.2.1. Primary Effectiveness Objective ............. 
...................39
6.2.2. Secondary Effectiveness Objective 
.'.....'.39
..39
6.2.4. Safety Objective
.39
Hypothesis 
.................- 42
Risks and Anticipated Adverse Device Effects........ 
......-------.42
6.4.1. fusksAssociatedWithAllSkinInjectionProcedures.....................................A2
6.4.2. Risks Associated With the Anesthetic Agent (Lidocaine) or Other Allergens .42
Page 25 of 132

r
Confidential
C111ical Investigation Plan
6.4.3. fusks That Are Typically Associated with RHA@ 3, I 
and HA
Dermal Fillers in General
7. CLINICAL INVESTIGATION DESIGN.......
7.2
7.3
7.4
.43
.43
.45
48
48
49
49
.50
8
Clinical Investigation Enrollment .................
Clinical Investigation Sites........
Sel ection of Clinical Investigation Subj ect Population ..
7.4.1. Inclusion Criteria
7 .4.2. Exclusion Criteria.................
INVESTIGATION PROCEDURES ...........
8.1. Procedures by Visit
8.1.1. Visit 1 (0 Week)
8.1.2. Visit I gelephone Call, +3 Days After the Initial Treatment)
8.1.3. Visit | 1+ Weeks After the Initial Treatment).............
IrI
8.1.7.rr
Visit | @rimary Endpoint, 12 Weeks After the Last Treatment)
8.2. Assessments.........................
8.2. l. Safety Variables.......
Common Treatment Response..
Urine Pregnancy Test
..55
..56
..57
..58
..58
..58
..59
60
60
.61
..62
62
..64
.63
Ir
8.2.1.1.
8.2.r.2.rr
-
Page 26 of 132

I
Clinical Investisation Platt E
Confidential
8.2.1.5.
I
Adverse Events...
68
68
68
69
69
8.2.2.r
8.2.2.2
8.2.2.3
8.2.2.4
Teoxane Lip Fullness Scale......
Subject Satisfaction
Global Aesthetic Improvement.
FACE-Q
IIIII
9. CLINICAL INVESTIGATION TREATMENT AND FOLLOW-UP........
Subject Informed Consent......
Randomization..............
BlindingAJnblinding Clinical Investigation Plan.
9.3.L General Blinding
9.3.2. Blinded Procedures................
1
I
7
7
72
9.1
9.2
9.3
9.4
9.5
9.6
9.3.3. Unblinding Procedures
Pretreatment Procedures and Tests....
Baseline Evaluations and Data Collection
Clinical lnvestigational Product Treatment.........
9.6.1. Study Device
9.6.2. Control Device ..
9.6.3
Injection of RHA@ : or I......
.76
.76
76
77
.77
,.78
..78
..78
..78
.79
.79
..80
.80
..80
II I
10. ADVERSE EVENTS
I 0. l. Definitions..................,
10.1 .1. Adverse Events
Page27 ofl32

r
Clinical Investigation Plan
ll
12
Confidential
I0.l.2.Adverse Device Effects
I 0. 1.6. Device Malfunction .........
10.2. Evaluation and Assessment.........
10.2.1. Relationship to Device ....
I 0.3. Safety Reporting...
INVESTIGATOR AND SPONSOR RESPONSIBILITIES
I 2. l. Investigator Responsibilities ............
12.1.1. Deviations From Clinical Investigation plan .
12. I .2. Maintaining Records
..80
..8 I
..8 I
..8 I
.81
..82
84
.85
10.3.4. Device Malfunctions Reporting 
..............g6
10.4. Pregnancy............... 
..... g6
10.5. Data Monitoring Committee 
.......... g6
10.6. Clinical Events Committee. 
........... g7
STATISTICAL METHODS.............. 
.......88
I 1 .1 . Analysis Populations ............... 
........ gg
I 1.2. Sample Size Determination............... 
................. gg
I 1.3. Subjects and Demographics .............. 
................. 90
I 1.3 .2. Clinical Investigation Plan Deviations
..90
..90
..90
I1.4. Effectiveness Analyses.... 
.............. 9l
1 1.5. Safety Analyses 
.......... 93
II 
.........s4
IT
94
................85
.................85
... -..-. -. -..'-- --- -- -.94
.......9s
......9s
.......96
.......96
.......97
l2.l.4.Prohibition of Promotion................. 
........97
12.2. SponsorResponsibilities 
................ 9g
I2.2.l.General Duties 
....................9g
98
If 
......ee
12.2.4. Changes in the Clinical Invesrigation PIan...... 
............9g
Page 28 of 132

I
Clinical Investieation Pt* I
Confidential
I 3. 1. Data Management..........................
1 3.2. Confidentiality of Data.......
13.3. Source Documents.
13.4. Electronic Case Report Forms.......
13.5. Record Retention...
1 3.6. Clinical Data Monitoring Procedures....
14. ETHICS AND REGULATORY COMPLIANCE..
14.1. Conduct of the Clinical Investigation............
14.2. Conflict of Interest..................
1 4.3. Institutional Review Board/Competent Authority Approval
14.4. Clinical lnvestigation Informed Consent Approval
I 4.5. Subj ect Identifi cation and Confidentialify ..............
100
100
r00
101
101
102
102
103
103
103
103
103
t04
104
104
105
105
105
105
105
II
14.8. Insurance ...............
14.9. Site Audit Plan..
l4.9.l.Internal Audits by Sponsor or Sponsor's Designee....
14.9.2.External Audits
14.10. 
Investigational ProductTraceability
14.ll. 
Public Domain Access to the Clinical Investigation..
15. GENERAL CONSIDERATIONS
I 5. 1 . Discontinuation of the Investigation
II
17. ATTACHMENTS...
17.1. Investigator's Agreement .
IIII
18.2. Appendix 8.....
18.3. Appendix C.....
................. 105
.................. 106
................. 106
................. 106
.................. 107
.................. 109
................. 109
.................. 1 10
.. ... .... ..... ... I I 1
..... 114
.....115
......rt7
......1 18
Page29 of 132

I
Clinical Investigation Plan
Confidential
-
Page 30 of 132

I
Clinical Investigation Plutr I
Confidential
IIIIIIII
TIIIIIIIIIII
TII
IIIIIIITIIII
I
-
Page 31 of 132

I
Clinical Investigation Plan
Confidential
r
IIIII
I
-
Page 32 of 132

I
clinical Investisation Pt* I
Confidential
5. INTRODUCTION TO THE CLINICAL IIWESTIGATION
5.1. Background
Lips belong to the key features of the face, which together with eyes, nose, and cheek bones, are
associated with youth and attractiveness. The shape and fullness of lips are influenced by many
factors, including skeletal structure and subcutaneous fat distributions that can dramatically change
their appearance over time.l In recent decades, a greater cultural value on youth and health,
together with improved techniques, have resulted in an increase in cosmetic procedures.
Surgical and cosmetic techniques can change the appearance of the lips in several ways, whether
to enlarge, reduce, or reconstruct after trauma or surgical resection. Lip augmentation procedure
is one of the most sought-after procedures because it aims to return the youthful appearance and it
is also able to improve the shape and fullness of the lips to make them more attractive based on
the current fashion trends. Lip augmentation procedures usually include the implantation of
additional material, either biologic or synthetic, into the lips, which can be injected, introduced by
a threading technique, or by an open surgical approach.2
According to the statistics of the American Society of Plastic Surgeons for 2018,3 the number of
lip augmentation (other than injectable materials) procedures increased since 2000 by 660/o to a
total of 30,859 procedures in 2018. Even more significant is the use of soft tissue fillers in general,
which were the second most frequent cosmetic minimally invasive procedure in 2018, with more
than 2.6 million procedures performed during the year. Only botulinum toxin type A injection,
with more than7.4 million applications in 2018, was more frequent.3
Many fillers are used in cosmetic srugery, and they are generally registered as medical devices. A
specific place can be reserved for autologous fat injections that may or may not use treatment kits
intended for this purpose. Such kits are considered medical devices that need United States (US)
Food and Drug Administration (FDA) clearance before commercialization. The duration of the fat
injection effects varies greatly based on the graft survival. Harvested and prepared adipose grafts
need to be injected with substantial overcorrection due to expected resorption, which can Yary
between 30 to 50/o and is generally unpredictable.a
The effect of external fillers can be temporary, semipermanent, or permanent. The US FDA had
only approved one permanent filler as of the end of year 2019 - polymethylmethacrylate beads
suspended in bovine collagen with the addition of lidocaine.5 It is sold under the brand name
BellaFill@ (Suneva Medical; previously known as ArteFill@); however, it is contraindicated for use
in lip augmentation.6
Semipermanent fillers approved by the FDA include calcium hydroxylapatite sold as Radiesse@
(Merz Aesthetics), which is expected to last approximately l8 months, and poly-L-lactic acid sold
as Sculptra@ Aesthetic (Galderma), which is expected to last about 2 years. Neither of these
products have been approved by the FDA for injection into the lips nor are they recommended for
injection into the lips as per their respective instructions for use 0FU).7'8
Temporary fillers include collagen and hyaluronic acid (HA) products. Several collagen fillers
were approved by the FDA,5 namely Evolence@ Collagen Filler (Colbar Lifescience),
CosmoDermrM (Inamed), CosmoPlastrM (Inamed), Fibrel@ (Serono), Zlplast@ (Collagen Corp),
and Zyderm@ lAllergan); however, all these products have been discontinued by their
manufacturers in the US market.e
-
Page 33 of 132

I
Conlidential
Clinical Investigation Plan
Currently, the only fillers approved by the FDA for lip augmentation are those made with HA.
These include Restylane@ (Galderma), Restylane@ Silk (Galderma), Restylane-L@ (Galderma),
Juvederm Volbella@ XC (Atlergan) and Juvederm@ Ultra XC (Allergan).
Hyaluronic Acid (HA), also known as hyaluronan, is a long-chain, repeated dimer, of N-acefyl
glucosamine and D-glucuronic acid polymer and it is the most abundant glycosaminoglycan found
in the human dermis. It is a ubiquitous component of all mammalian connective tissues and is
responsible for giving skin its volume while also binding collagen and elastin fibers into a
supportive matrix that gives skin its structure. Due to this extended compatibilify, HA can be used
in humans without unacceptable adverse effects. The HA molecule (or hyaluronan) is a major
component of the extracellular matrix. Due to its natural viscoelastic and hydrogel properties,
hyaluronan is widely used as matrix in tissue regeneration and particularly in dermal defect
reconstruction. Used as a dermal filler, HA has a long track record of safefy data.
The persistence of HA in the tissues and its resistance to degradation can be obtained by chemical
crosslinking. This does not affect the 2 specific functions of the molecule (carboxylic andN-acetyl
functions) and allows modification of the rheological and physical properties of the HA, while
maintaining the biocompatibility of the basic polymer.r0
5.2. Study Device Name
RHA@ 3.
5.3. Current Indication Statement
The study device under clinical investigation has been FDA approved for injection into the mid-
to-deep dermis for the correction of moderate to severe dynamic facial wrinkles and folds, such as
nasolabial folds (lt{LFs), in adults aged 22 years or older.s This study is investigating another
indication.
5.4. Intended Purpose Statement
RHA@ 3 injectable gel is intended to be used for injection in the vermillion body, vermillion border,
and oral commissures to achieve lip augmentation and lip fullness in subjects 22 years or older.
5.5. Investigational ProductDescription
The device under clinical investigation is RHA@ 3 manufactured by TEOXANE 94.10'rt
-
Page 34 of 132

I
Clinical Investigation Ptut't I
Confidential
I
5.5.1. Delivery System and Implantation
RHA@ 3 is supplied in individual blisters containing a I mL treatment syringe with two 27 G x 1/2"
needles. The content ofthe syringe is sterile and nonpyrogenic. It should not be resterilized or used
if the package is opened or damaged.
5.5.2. NonclinicalTesting
RHA@ 3 has been already approved by the FDA for another indication, it is considered
biocompatible and details on nonclinical testing are
in the
Io IFU rr and the S
ofS
and Effectiveness Datalz for RHA@ 3
5.5.3. Previous ClinicalExperience
Details on previous clinical experiences are provided in the IB 1o. pg4o 3.to'tt
5.5.3.1. RHAo 3 EU Pilot Study
This study was a quantitative and comparative safety and effectiveness analysis of RHA@ 2,
RHA@ 3, and RHA@ 4 injectable dermal fillers in moderate and severe nasolabial folds treatment
versus Conformit6 Europ6enne (CE)-marked comparators. It included 90 subjects with 2 visible
Page 35 of 132

I
Clinical Investigation Plun I
Confidential
moderate or severe bilateral symmetrical nasolabial folds. Of these, 30 subjects were included in
a group receiving either RHA@ 3 or Juvederm@ Ultra 4 (Allergan). The products were injected in
nasolabial folds, one different product in each fold, in a split-face design. No significant difference
was observed between the effects of tested medical devices and comparators, at any time point
except after 18 months, where there was better improvement with RHA@ 2, RHAo 3, and RHA@ 4.
The safety of RHA@ 2, RHA@ 3, and RHA@ 4 was shown to be as good and equivalent to the
comparators.lo,ll
5.5.3.2. RHA@ 3 US Pivotal Study (IDE ref c140028)
This was a controlled, randomized, double-blinded, within-subject, multicenter, prospective
clinical sfudy of TEOSYAL@ RHA 2 and TEOSYAL@ RHA 3 versus Juvederm@ Ultra XC in the
treatment of moderate to severe nasolabial folds. TEOSYAL@ RHA 2 and TEOSYAL@ RHA 3 are
the respective names of RHA@2, RHAo3, on the European Union market. A total of 174 subjects
with moderate to severe bilaterally symmetrical aging defects in the nasolabial folds were
randomized. The study was a split-face design with I nasolabial fold treated with the
investigational product and the other nasolabial fold with the control device; 74 subjects were
allocated to each treatment cohort, 26 subjects were untreated controls. Results showed non-
inferiority of RHA@ 2 and RHA@ 3 compared to Juvederm@. Common Treatment Responses (CTR)
and adverse events (AEs) were recorded and analyzed. For each category of CTR recorded in the
diary (e.g., bruising, firmness, etc.), the proportion of subjects experiencing at least 1 CTR of each
category was similar between treatment groups of each treatment cohort. Additionally, for the
majority of CTRs experienced, the maximal severity experienced was "Mild" or "Moderate." For
some CTRs, such as lumps/bumps and firmness, while the overall proportion of subjects with
events recorded in their diary was similar, the proportion of subjects with events recorded on the
last day of the diary was greater in the RHA@ treatment groups compared to the Juvedermo
treatment groups. By default, this led to comparatively higher rates of AEs associated with these
CTRs in the TEOSYAL@ RHA treatment groups. Importantly, virrually all treatment-related AEs
were based on subjects' CTR diary entries, indicating that virhrally all treatment-related AEs were
typical (and expected) signs and symptoms observed after injection of a HA dermal filler.
A total of 27 subjects (36.0%;95o/o confidence interval lCIl 130.5, 41.51) in the RHAo 3 group and
26 subjects (34.7%; 95% Cl 129.2, 40.21) in the Juvederm@ treatment group reported at least
I treatment-related AE, respectively. No serious AEs (SAEs) or unanticipated adverse device
effects (UADEs) were reported in the TEOSYAL@ RHA 3/Juvederm@ cohort. The proporrion of
subjects experiencing at least 1 treatment-related AE was lower in subjects with Fitzpatrick skin
type IV-VI. In subjects with Fitzpatrick skin type I-III, treatment-related AEs were noted in
2l (47.7%) and 19 (43,2%) subjects in the TEOSYAL@ RHA 3 and Juvederm@ treatment groups,
respectively. In subjects of Fitzpatrick skin type IV-VI, treatment-related AEs were noted in
6 (19.4%) and 7 (22.6%) subjects in the TEOSYAL@ RHA 3 and Juvederm@ treatment groups,
respectively. l o'l I
5.5.3.3. RHA@ Postmarketing Data
The following adverse events were reported as part of postmarketing surveillance on the use of
RHA@ 3 outside the US. These adverse events are listed in order of privalence: lumps and bumps,
firmness, unsatisfactory results, granuloma, implant migration papule, scarring, and anaphylactic
reaction.
-
Page36 of 132

I
Clinical Investisation Plun I
Confidential
5.6. Control Device
The control device is
I 
is a gel of HA generated by Streptococcus species of bacteria, chemically
crosslinked with 1,4-butanediol diglycidyl ether (BDDE), stabilized and suspended in phosphate
buffered saline at pH : 7 and concentration of 20 mg/ml with 0.3% lidocaine.
I 
is indicated for mid-to-deep dermal implantation for the correction of
moderate-to-Severefacialwrinklesandfoldi,suchu'nu.olubiu1rotas'fisalso
indicated for submucosal implantation for lip augmentation in subjects over the age of 2l years.
I 
should be used according to its IFU.r3
lnjection 
of RIrA@ s or I
Injection area: The TI will inject each device into the vermillion body, vermillion border, and oral
commissures, as needed to achieve optimal aesthetic outcome.
Amount of filler to be administered: Up to 1.5 mL per lip (upper and lower) at each treatment
(initial, touch-up, and retreatment).
The information about the injection technique, area of injection, and the amount of filler will be
collected in the eCRF.
5.8. Justification for the Clinical Investigation
ln the US, RHA@ 3 is FDA approved for injection into the mid-to-deep dermis for the correction
of moderate to severe dynamic facial wrinkles and folds, such as NLFs, in adults Z2years or older.
Assuming a similar volumizing effect, the purpose of this study is to inject RHAo 3 into the lips
toachieve1ipaugmentationanddemonstratethatitisnon-inferio'iofforthis
indication in iubjects aged}Zyears or older. The goal is to show that treatment with RHA@ 3 will
result in added volume and fullness to the lips 12 weeks after the last treatment.
Expected risks include those associated with all skin injection procedures, such as injection
pinpoint bleeding, pain, lightheadedness or fainting, nausea, and/or feeling flushed. Further risks
are associated with the use of anesthetic agents, namely allergic reactions. Risks associated with
the use of the RHA@ 3 are expected to be similar to those associated with other HA dermal fillers.
In summary, the expected potential risks and benefits are generally similar to those observed with
other HA dermal fillers.
-
Page37 ofl32

r
Clinical Investigation Plan
Confidential
5.8.1. Justification for the Clinical Investigation Design
The study is designed to evaluate RIIA@ 3 in
procedures prospectively and to
compare its safety and effectiveness to that of
The study design was selected to
minimize bias by randomization and blinding of subjects and of the Blinded Live Evaluator (BLE),
whose assessment will be used for the
analysis. The comparison of the safety
and effectiveness of the RHA@ 3 and
fillers will be done between
ects and will
include subjects from multiple sites
-
Page 38 of 132

I
Clinical Investisation Plutr I
Confidential
6.1. Clinical Investigation Purpose
The purpose of this clinical investigation is to evaluate the safety and effectiveness of RHA@ 3
*t.r, "o-pared to I 
to'add volume and fullness to ihe lips 12 weeks after the last
treatment (initial or touch-up)
6. CLINICAL IINfESTIGATTON PURPOSE, OBJECTMS, AND ENDPOINTS
6.2. Objectives
Objectives are summarized and mapped to the endpoints in Table 6-l
6.2.1. Primary Effectiveness Objective
To assess the effectiveness (non-inferiority) of RHA@ 3 versus I 
on adding volume
and fullness to the lips in subjects seeking lip augmentation, L2 weeks after the last treatment
(initial or touch-up).
6.2.2. SecondaryEffectiveness Objective
o To assess the effectiveness of RHA@ 3 versus I 
on adding volume and fullness
to the lips in subjects seeking lip augmentation up to 52 weeks
o To assess the responder rate of RHA@ 3 versus I 
after lip augmentation up to
52 weeks
To assess the subj ect satisfaction and
outcome of the aesthetic procedure
augmentation up to 52 weeks
(FACE-Q) with RHA@ 3 versus
after lip
ToassesstheGloba1AestheticImprovementScale(GAIS)ofRHA@3,,",..,.f
after lip augmentation up to 52 weeks
6.2.4. SafetyObjective
o To assess the safety of RHA@ 3 in subjects after lip augmentation
o
a
Page 39 of 132

I
Clinical Investigation Plan
Confidential
Table 6-1 
Objectives Mapped to Endpoints
a
To assess the GAIS of RHAo 3 versus
f 
drrEl ru ausrr.llralr,n u.o
to 52 weeks
a
To assess the subject satisfaction and
patient-reported outcome of the
aesthetic procedure (FACE-Q) with
RHA@ 3 .'"r.nr f 
after lip
augmentation up to 52 weeks
To assess the responder rate of RHAo 3
't ersus I 
after lip
augmentation up to 52 weeks
a
a
To assess the effectiveness of RHA6 3
u".srsl 
on adding volume
and fullness to the lips in subjects
seeking lip augmentation up to 52 weeks
S econdary effectiveness
a
To assess the effectiveness (non-
inferiority) of RHA@ 3 versus
I 
on adding volume and
fullness to the lips in subjects seeking
lip augmentation, 12 weeks after the last
treatment (initial or touch-up)
Primary effectiveness
Objectives
GAIS as assessed:
o By the BLE starting at Visit 4 and each visit at the study
site afterwards
o
a
Subject satisfaction using the Subject Satisfaction Scale at
each visit at the study site starting at Visit 2
FACE-Q scores for each module (satisfaction with lips and
satisfaction with outcome) assessed by the subject at each
visit at the study site
Responder rate calculated using TLFS assessed:
o By the BLE at Visit 4 and each visit ar the study site
afterwards
a
A responder will be defined as a subject who has a >1 -grade
improvement on the TLFS
TLFS change from Baseline assessed:
o By the BLE at Visit 4 and each visit at the study site
afterwards
o
a
The effectiveness of RHA@ 3 will be demonstrated if the
change from Baseline for subjects treated with RI{Ae 3 is
statistically non-inferior to the change from Baseline for
subjects treated with I 
at l2 weeks after the last
treatrnent as assessed by the BLE using the TLFS. The
difference in the TLFS change from Baseline to 12 weeks
will be used to establish non-inferiority
a
a
Endpoints
-
Page 40 of 132

I
Clinical Investisation Plun I
Confidential
I
-
a
a
Adverse events
Post-injection CTR
Endpoints
I
Safety
To assess the safety of R[IA@ 3 in
subjects after lip augmentation
I
-
Objectives
Page 41 of 132

Confidential
Clinical Investigation Plan
6.3. Hypothesis
The TLFS change from Baseline of subjects treated with RHA@ 3 will be statistically non-inferior
to the change from Baseline of subjects treated *ith I 
for the assessment of lip
augmentation and fullness as
treatment (initial or touch-up).
determined
the BLE
the TLFS at Week 12 after the last
6.4. Risks and Anticipated Adverse Device Effects
The safety of the study devices has not been established during pregnancy or in breast feeding
females.
The following risks have been associated with the use of HA dermal fillers in general, not just
RHA@ 3. There are various lypes of risks associated with the injection of a HA dermal filler on the
face or into the lips:
o Risks associated with all skin injection procedures
. Risks associated with the anesthetic agent (lidocaine) or other allergens
o Risks that are typically associated with RHA' 3,I 
and HA dermal fillers in
general
o Other risks that are not typical but have been reported in the literature
6.4.1. Risks Associated With All Skin Injection Procedures
The following are risks associated with all skin injection procedures:
. lnfection
o Bleeding
o Blistering
o Bruising (ecchymosis)
o Increased bleeding or bruising at the injection site if using medications that reduce the
ability to clot (such as aspirin, ibuprofen [e.g., Motrin@ or Advil@], vitamin E and
prescription anticoagulants)
o Pain at and around the injection site that could induce lightheadedness or fainting
6.4.2. Risks Associated With the Anesthetic Agent (Lidocaine) or Other Allergens
Subjects with known history of allergy to lidocaine or Gram-positive bacterial proteins should not
receive any injection as both sfudy devices contain them and they risk anaphylactic shock.
Reported anaphylactic shocks are very rare.
The concentration of lidocaine is low and the risk of other types of allergic reactions is low. Those
allergic reactions may include skin rash, redness, itching, hives, burning, stinging, swelling,
tenderness, and temporary loss of skin color.
-
Page 42 of 732

I
Confidential
Clinical Investigation Pt*I
6.4.3. Risks That Are Typically Associated with RHA@ 3,I 
and HA Dermal
Fillers in General
The following have been associated with the use of HA dermal fillers. Although RHAo 3 has
shown some differences compared to some of the HA dermal fillers currently available, they are
expected to share a similar safety profile. The following risks are anticipated adverse device events
when using a HA dermal filler:
. There are common treatment reactions such as: redness (erythema), inflammation, pain,
tenderness, firmness (induration), swelling, lumps/bumps, bruising (ecchymosis), edema,
itching, discoloration/hyperpi gmentation.
. 
Other, less frequent risks have also been reported such as paresthesia, rash, telangiectasia,
dermatitis, scarring, scab, peeling/shedding, urticaria, abscess formation, papules, blister,
product migration, nausea, headache, reactivation of herpes, malaise, hlpersensitivity,lack
of effect.
I
III
Page 43 of 132

I
Clinical Investigation PIan
Confidential
For further and most recent information about RHA@ 3, refer to the most recent version of the IB
and the IFU.
-
Page 44 of 732

I
Clinical Investisation Plutt I
Confidential
7. CLINICAL INVESTIGATION DESIGN
This is a multicenter, double-blinded, randomized, prospective, controlled clinical study to identiff
whether RHA@ 3 is non-inferior to I 
for lip augmentation at Week 12 after the last
treatment (initial or touch-up).
The TI will evaluate the subject's lip fullness using the live validated 5-grade Teoxane Lip Fullness
Scale (TLFS grade 1 to 5) at Screening (Visit 1, 0 Week) for eligibility of the subject for the study.
The BLE will evaluate the subject's lip fullness using the TLFS at Screening (Visit l, 0 Week) to
confirm eligibility and to establish a pretreatment score for assessment of effectiveness. This will
be done independently of the TI. If the assessments of the TI and the BLE are the same or differ
exactly by 1 point of the scale, the difference will be considered acceptable. The TI and the BLE
need to agree on eligibility criteria of the subject (lip fullness grade I to 3). If the subject is eligible,
the BLE's assessment will be used for the primary endpoint. If the TI and the BLE do not agree
on eligibility, or if their assessments differ by 2 points or more of the scale, the subject will not be
eligible.
Enro1ledsubjectswillberandomlyassignedina3:lratiotoeithertheRHA@3orthef
treatment group. Subjects will be blinded to the study treatment. The TI will administer the fillers,
and if necessary, subjects will receive a touch-up treatment 4 weeks after the initial treatment to
optimize the results. If the touc!_qp_1ggel@ent is administered, the subject will be asked to come
to the site for an additional visit I4 
weeks after the touch-up injection.
Subjects will be followed for 52 weeks after their last treatment (initial treatment or touch-up), at
which point they will be offered retreatment with RHA@ 3, regardless of their original treatment,
provided that the TI deems the treatment to be appropriate and the subject agrees. Reasons for not
administering the retreatment will be documented. The subject will then be followed for an
additional 4 weeks before exiting the study. If the subject or the TI declines retreatment, this visit
(I52 
weeks after the last tregLmenlfyill be considered the study Exit visit. For subjects with
,Fu-ment, the Exit visit will u. I4 
weeks after the retreatment.
The TI will conduct safety and effectiveness evaluations at each study visit, which will occur at
4 weeks after the initial and
treatment
ects with
I 
12 weeks
36 weeks
and 52 weeks
after
the last freatment, and 4 weeks
after retreatment or until all treatment-related ongoing
AEs have resolved or resolved with sequelae as per TI judgment or if follow-up is no longer
possible.
A follow-up telephone call for safety will be performed at 3 days after each treatment (I
I 
initial, touch-up, and retreatment, respectively). Subjects will report their CTRs in a
subject diary for I Aays after each injection. The diary will also include a list of selected AEs
potentially associated with injection ofiermal fillers foriubjects to report if applicable I
Page 45 of 132

I
Clinical Investigation Plan
Confidential
Subjects who had entered the study under earlier versions of the CIP (version I 
and earlier) and
who do not agree with the extension of their participation in the study, to 52 weeks after last
treatment, will be allowed to continue with the visits as originally planned (see Table 2-2). They
i1ffi 'llii;T3i#-.,ii#:*:ff ryxl'*:"1ru:ffi;'ff lH
after retreatment.
A BLE will conduct assessments of effectiveness during the study, including assessment of the
pnmary
at Visit 4
12 weeks after the last treatment
The BLE will conduct effectiveness
evaluations
-
Page 46 of 132

I
Clinical Investisation Plut't I
Figure 7-1 Investigation Design
Confidential
Page 41 of 732

I
Clinical Investigation Plan
Confidential
7.2. Clinical Investigation Enrollment
This study will enroll at least 200 subjects and a maximum of 202 subjects. Subjects must have lip
fullness of
I to 3 on the TLFS
from I to
and desire at least I
of correction.
Eligible subjects will be randomly assigned in a 3:l ratio to either the RHAo : orI
group.
The TI will not be b
while the BLE and
ects will be blinded to treatment allocation
All evaluations
the BLE will be
from the
Furthermore, to ensure that they remain masked and unbiased when making their assessments
throughout the study, the BLE, TI, and the subject will not be allowed to refer to each other's
effectiveness assessments.
Page 48 of 132

I
Clinical Investisation Platr I
Confidential
7.3. Clinical Investigation Sites
The clinical
is to be conducted at 7 to 10 investi
sites in the US
7.4. Selection of Clinical Investigation Subject Population
Subjects who seek lip augmentation are possible candidates for the clinical investigation and will
be screened for eligibility based on the inclusion and exclusion criteria below.
Vulnerable Subjects:
Part 2l CFVccP/International Organization for Standardization (ISO) regulations, and IRBs
stipulate that additional protections should be included for individuals who are deemed vulnerable:
. 
Prisoners
. 
Pregnant women and fetuses
. Children
-
Page 49 of 732

I
Clinical Investigation Plan
Confidential
o Cognitively impaired persons and adult subjects who cannot consent for themselves, in
which case, a legally authorized representative would provide consent
Individuals who are deemed vulnerable are excluded from the clinical investigation.
7.4.1. InclusionCriteria
A potential subject will be included in the study if he/she meets all of the following inclusion
criteria:
1. Outpatient, male or female of any race, 22 years of age or older.
2. Subject, if female, is not pregnant, not breastfeeding, and either not of childbearing
potential (defined as postmenopausal for at least I year or surgically sterile fbilateral tubal
ligation, bilateral oophorectomy, or hysterectomy]) or must have a negative urine
pregnancy test (UPT) at Visit 1 and prior to each injection and must agree to practice 1 of
the following medically acceptable methods of birth control throughout the study:
3. Subject seeking lip augmentation (realistic and achievable as per TI opinion)
4.
6. Able to follow study instructions and complete all required visits.
7. Sign the institutional review board-approved informed consent form, photographic release
form, and the authorization for use and release of health and research study information
(Health Insurance Portability and Accountability Act) form and, if applicable, the
California Experimental Research Subject's Bill of Rights prior to any study-related
procedures being performed.
-
Page 50 of 132

I
Clinical Investigation Plun I
Confidential
7.4.2. ExclusionCriteria
A potential subject will be excluded from the study if he/she meets any of the following exclusion
criteria:
l. Known hypersensitivity or previous allergic reaction to any component of the study or the
control device.
2. Known sensitivity to local anesthetics of the amide type including known or suspected
lidocaine hypersensitivity, history of multiple severe allergies, or history of anaphylactic
shock.
3. An outbreak of herpes labialis within 4 weeks of randomization or 4 or more outbreaks in
lhe 12 months prior to randomization.
4. History of severe chronic systemic diseases, including but not limited to, poorly controlled
diabetes mellitus (all types), congestive heart failure, severe liver disease, severe kidney
disease, and others asjudged by the TI.
6. Has an active inflammation, infection, cancerous or precancerous lesion, or unhealed
wound on the lips, in the area of the mouth, or the area around the mouth.
8. Need for clinically significant (TI discretion) and continuous medical treatment within
2 weeks prior to randomization.
-
Page 51 of132

I
Confidential
Clinical Investigation PlanI
18. Medical or psychiatric conditions that may increase the risk associated with study
participation or may interfere with the interpretation of study results or compliance of the
subject and, in the judgment of the TI, would make the subject unsuitable for entry into
this study).
21. Clinically significant alcohol or drug abuse or history of poor cooperation or unreliability
Page 52 of 132

I
Clinical Investisation Plutt I
Confidential
Page 53 of 132

r
Clinical Investigation Plan
Confidential
E
Page 54 of 132

I
Clinical Investisation Ptun I
Confidential
8. INVESTIGATION PROCEDURES
8.1. Procedures by Visit
Subjects must provide written informed consent before any study-related procedures are initiated,
including the cessation of prohibited concomitant therapy.
8.1.1. Visit 1 (0 Week)
Visit 1 is the first day of the study, 0 Week for all subjects.
Eligible subjects seeking lip augmentation will be screened for the study.
The screening procedures will include the following assessments:
1. Obtain written informed consent
2. Collect demographic information
3. Record medical history, including current therapies (e.g., prescription and nonprescription
medications) and previous surgeries
4. Collect prior and concomitant medications
5. UPT for women of childbearing potential
7. Both the TI and the BLE perform the TLFS assessment to assess eligibility
8. Assess inclusion/exclusion criteria
Signature of the written informed consent, collection of demographics, medical/surgical history,
and prior/concomitant medication and washout of prohibited medications (see Section 9.4) may
be performed up to 7 days before Visit 1. In any case, signature of the written informed consent
must precede all study-related procedures.
-
Page 55 of 132

r
Clinical Investigation Plan
Con{idential
Subsequently, the subject will be randomly assigned to RHA@ 3 orIgroup; 
fordetails
see Section 9.2.
The TI will administer the allocated filler maintaining the blinding described in Section 9.3 and
according to the IB and Section 9.6.
8.1.2. Visit | 
(Telephone Call, +3 Days After the Inifial Treatment)
Visit I 
is a telephone call 3 days after the initial treatment (3 days, 0 Week from the last
treatment) for all subjects.
The TI or
will collect information about
AEs
Page 56 of 132

I
Clinical Investigation Ptun I
Confidential
8.1.3. Visit | (4 Weeks After the Initiat Treatment)
Visit I is performed at the site 4 weeks + 3 days after the initial treatment.
If deemed necessary by the TI, an optional touch-up treatment can be administered at this visit.
The touch-up treatmeni will be performed either with RHA@ : ot I 
depending on the
treatment allocation at Visit 1.
Page 57 of 132

I
Clinical Investigation Plan
Confidential
-
Page 58 of 132

I
clinical Investisation Plutr E
Confidential
8.1.7. Visit | (Primary Endpoint, 12 Weeks After the Last Treatment)
Visit I is at the site and will be scheduled 12 weeks after the last treatment (initial or touch-
The assessments
at this visit will be used for the primary endpoint evaluation. B
I 
the following assessments will be performed at Visit l:
J
TLFS
GAIS
BLE
a.
b.
-
Page 59 of 132

I
Clinical Investigation Plan
Confidential
-
Page 60 of 132

I
Clinical Investigation Ptun I
Confidential
Page 61 of 132

I
Clinical Investigation Plan
Confidential
-
Page 62 of 132

I
Clinical Investisation Plutt I
Confidential
Page 63 of 132

I
Clinical Investigation Plan
Confidential
-
Page 64 of 132

I
Clinical Investisation Ptun I
8.2. Assessments
8.2.1. SafetyVariables
Confidential
assessments will include the evaluation of AEs
8.2.1.1. Common TreatmentResponse
will receive a diary booklet and instructions for
treatments for the first
The subject
CTRs ofthe
his/her observations of the
Page 65 of 132

I
Clinical Investigation Plan
Confidential
8.2.1.2. Urine Pregnancy Test
A UPT for women of childbearing potential only will be conducted at the site prior to each
application of the filler (Section 2.2).
Page 66 of 132

I
Clinical Investigation Plutt I
Confidential
Page 67 of 132

Confidential
Clinical Investigation Plan
8.2.1.5. AdverseEvents
The definition and management of AEs, and any special considerations for AEs, are provided in
Section 10.
-
Page 68 of 132

I
clinical Investisation Ptun I
Confidential
8.2.2.1. Teoxane Lip Fullness Scale
Lip fullness will be assessed by the TI and the BLE at time points in the schedule of events
(Section 2.2) using the 5-point TLFS provided in Appendix B.
For eligibility purposes only: if the TI and BLE assessment differ by exactly 1 point on the TLFS,
this is considered acceptable. If their assessment differs by more than I point, the subject will not
be eligible.
8.2.2.2. Subject Satisfaction
ect satisfaction will be measured
a5
balanced subjective t.ul" I
subject will be instructed to "Rate your
level of satisfaction with the effect of study treatment on yorr lip fullness by using the following
scale" using the scale in Table 8-1.
Table 8-1 
Subject Satisfaction Scale
Description
Very satisfied
I
I
Very dissatisfied
Grade
1
2
J
4
5
8.2.2.3. Global Aesthetic Improvement
Global aesthetic improvement assessment will be performed by the I
time
in the schedule of events
GAIS
The
-
Page 69 of 132

r
Clinical Investigation Plan
Conlidential
Table 8-2 
Global Aesthetic Improvement Scale
5
4
tJ
2
1
Grade
Much worse
Worse
No change
Improved
Much improved
Description
8.2.2.4. FACE-Q
The validated subject-reported outcome measure FACE-Q scalerT will be assessed as in the
schedule of events (Section 2.2). Selected modules from the scale will be used for the purpose of
this study:
o Satisfaction with lips: This scale measures the appearance of the lips with items that ask
about size, shape, and fullness, as well as how the lips suit the face and how nice the lips
look when smiling.
Satisfaction with outcome: This scale measures a subject's satisfaction with the result of
his/her most recent procedure.
a
Page 70 of 132

I
Clinical Investigation
Confidential
PtunI
-
Page7l ofl32

I
Confidential
Clinical
Plan
-
Page 72 of 132

I
Clinicat Investigation
Confidential
PtunI
Page 73 of 132

I
Clinical Investigation Plan
Confidential
-
Page 74 of 132

I
Clinical Investieation Plan E
Confidential
9. CLINICAL II\I!'ESTIGATION TREATMENT AND FOLLOW.UP
9.1. Subject Informed Consent
All suitable candidates being considered for enrollment in the clinical investigation will meet with
the TI or designee and have the investigation explained in detail. This will include, but will not be
limited to, the potential risks and benefits of participation. Each subject will be provided with a
written copy of the informed consent in a language he/she can comprehend and will be given ample
opporhrnity to read and pose questions he/she may have about the investigation. If, after review,
the subject agrees to participate, he/she will sign the ICF. If the subject subsequently fails to meet
eligibility criteria, he/she will be considered a screen failure and will not receive treatment with
the study device or the control device under the clinical investigation. The TI should, with the
subject's consent, inform the subject's primary physician about his/her participation in the clinical
study.
Information regarding changes in the clinical investigation or new information obtained that could
significantly affect a subject's future health and/or medical care must be provided to all subjects
in written format. Subjects should be asked to reaffirm their continuing informed consent.
Failure to obtain signed informed consent prior to the use of the study device constitutes a major
CIP violation and noncompliance with 2l CFR$ 50.20 and/or ISO 14155. If informed consent is
not obtained, the subject's participation will be terminated, and his/her data will not be used. The
TI will provide a written report to the sponsor indicating the failure to obtain signed informed
consent within the reporting timelines required by the central IRB and other local/national laws.
The sponsor or designee will then inform the appropriate agencies/committees according to
applicable national regulations.
9.2. Randomization
The randomization schedule will be computer generated using a permuted block algorithm and
randomly allocate the investigational product in a 3:1 ratio.
-
Page75 of 132

I
Clinical Investigation Plan
Confidential
9.3. Blinding/Unblinding Clinical Investigation Plan
9.3.1. GeneralBlinding
The TI, unblinded to treatment allocation, will be asked to minimize the number of people who
will have treatment allocation information or who will have
form of access to such
information.
The BLE, all the subjects, and study personnel not involved with the site (e.g., data management,
medical monitor) will be blinded to treatment assignment.
9.3.2. BlindedProcedures
Investigators and research staff will make concerted efforts to withhold all information regarding
the assigned treatment from the subject (including family, friends, or caregivers). Subjects will be
required to wear an eye mask while the TI or designee is preparing the filler and during the
mJectlon.
All evaluations
the BLE will be
from the
Furthermore, to ensure that they remain blinded and unbiased when making their assessments
during the study, the BLE, TI, and the subject will not be allowed to discuss each other's study
assessments.
9.3.3. UnblindingProcedures
Unblinding in case of medical emergency is not applicable since the TI, who is in charge of safety
follow-up of subjects, will be aware of the treatment administered.
Overall unblinding will take place at the end of the study only after database lock has occurred.
9.4. Pretreatment Procedures and Tests
The procedures and tests to be performed prior to randomization are described for Visit 1 (0 Week).
-
Page 76 of 132

I
Clinical Investigation Plun I
Confidential
9.5. Baseline Evaluations and Data Collection
All of the data collected at Visit I (0 Week) prior to randomization will be defined as Baseline for
the purpose of the study and further analysis.
All evaluations performed by the BLE will be considered as Baseline for the purpose of the primary
endpoint analysis.
9.6. Clinical Investigational Product Treatment
The TI will inject the filler (the study dwice or the control device) in all subjects at the initial
treatment (Visit l). Four weeks later [, 
the TI will decide whether touch-up treatment is
necessary to achieve OCR. If yes, the same filler that was injected during the initial treatment will
be administered as touch-up treatment.
Page77 ofl32

I
Clinical Investigation Plun I
Confidential
9.6.1. Study Device
The study device is RHA@ 3 I 
Please see Section 5.5 and the IBr0 for fuither
information.
9.6.2. Control Device
will be used as the active treatment control for the initial treatment and
!91rch-uptreatment,ifapp1icable,insubjectsrandomlyassignedtofgoup,I
I is approved for use in lip augmentation in the US and will be used according to the IFU.r3
9.6.3. Injection of RHAo3 or f
lnjection area: The TI will inject each device into the vermillion body, vermillion border, and oral
commissures, as needed to achieve optimal aesthetic outcome.
Amount of filler to be adm inicfered Up to 1.5 mL per lip (upper and lower) at each treatment
(initial, touch-up, and retreatment).
Information about injection technique, area, and amount of filler will be collected in the eCRF
Page 78 of 132

I
Clinical Investisation Ptun I
Confidential
-
Page79 ofl32

I
Ctinical Investigation Plan
Confidential
10. ADVERSE EVENTS
Subjects will be monitored carefully during the investigation for
events
events include the
adverse device effects
ADEs
All events will be reported and documented on the appropriate eCRF (AE report). Adverse event
information will be recorded in the eCRF Adverse Event Form.
All observations and clinical findings, including the nature, seriousness, severity, and relationship
to the study or to the control device and/or the procedure, will be assessed by the TI and
documented on the eCRF. Documentation will also include a detailed description of the event,
treatments rendered in response to the event, and outcomes of the treatment.
Assessment and reporting of safefy events will follow all national and local laws and requirements
for the conduct of clinical studies, including ISo 14155 and US 2l cFR 812.150.
10.1. Definifions
10.1.1. Adverse Events
An AE is any untoward medical occurrence, unintended disease or injury, or any untoward clinical
signs (including an abnormal laboratory finding) in subjects, users, or other persons, whether or
not related to the study device, the control device, or the study procedures.
10.1.2. Adverse Device Effects
An ADE is any adverse event related to the use of the study device, the control device, or the study
procedures. This definition includes adverse events resulting from insufficient or inadequate
instructions for use, deployment, implantation, installation, or operation, or any malfunction of the
study or the control device. This definition also includes any event resulting from use error or from
intentional misuse of the study or the control device.
Page 80 of 132

I
Clinical Investigation Ptutt I
Confidential
10.1.6. Device Malfunction
Device malfunction is a failure of the device to perform in accordance with its intended purpose
when used in accordance with the IFU/IB or CIP. A device malfunction may or may not be
associated with an AE. If it is, the AE or ADE should be reported separately.
10.2. Evaluation and Assessment
For the purposes of this investigation, any untoward medical occurrence, unintended disease or
injury, or any untoward clinical signs that occurs in a subject after randomization is considered an
AE, regardless of the investigation group to which the subject is assigned.
Any medical conditions, problems, signs, symptoms, and findings that occur prior to
randomization are to be reported as pre-existing conditions. Such conditions should be documented
and reported on the medical history eCRF as a pre-existing condition. If a pre-existing condition
worsens after randomization (frequency increases and/or severity grade increases), it should be
documented as an AE.
Page 81 of 132

I
Clinical Investigation Plan
Confidential
I
r
II
I
10.2.1. Relationship to Device
For each AE identified in the investigation, the TI or designee must assess its relationship to the
sludy and the control device and/or to the procedure. The TI must determine whether there is a
reasonable possibility that these caused or contributed to an AE.
-
Page 82 of 732

I
Clinical Investigation Pl* I
Confidential
-
-
Page 83 of 132

I
Clinical Investigation Ptun f
Confidential
10.3. Safety Reporting
It is the TI's responsibilify to oversee the safety of the investigation at his/her site. This safety
monitoring will include careful assessment by the TI and appropriate reporting of all safety events
as noted previously.
The site should follow all applicable governance, including FDA regulations, FDA guidance, and
IRB requirements for notification of all types of AEs.
-
Page 84 of 132

I
Clinical Investigation Ptutt I
Confidential
-
Page 85 of 132

I
Clinical Investigation Plan
Confidential
10.3.4. Device Malfunctions Reporting
Device malfunctions will be reported using the Device malfunction form and supply information
relevant to the event.
10.4. Pregnancy
All women of childbearing potential who participate in the study should be counseled on the need
to practice adequate birth control and on the importance of avoiding pregnancy during study
participation. Women should be instructed to contact the TI or study staff immediately if
pregnancy occurs or is suspected.
Pregnancy testing will be conducted prior to administration of the study or the control device on
every woman of childbearing potential. A woman who is found to be pregnant at Visit I will be
excluded from the study and considered to be a screen failure.
A woman who becomes pregnant during the study after the first injection will not receive fuither
injections and will be followed for safety purposes. The assessments scheduled for the Exit visit
are required to be performed as soon as possible after learning of the pregnancy.
The TI must report the pregnan.y to I 
within 48 hows of learning of it using the specific
pregnancy form and send it to the same e-mail address as for SAE reporting.
10.5. Data Monitoring Committee
Not applicable.
-
Page 86 of 132

I
Clinical Investigation Plun I
10.6. Clinical Events Committee
Not applicable.
Confidential
-
Page87 ofl32

I
Clinical Investigation Plan
Confidential
11. STATISTICAL METHODS
This section presents a summary of the planned statistical analyses. A statistical analysis plan
(SAP) that describes the details of the analyses to be conducted will be written prior to database
lock. The SAP will be submitted to the FDA during the course of the study.
11.1. Analysis Populations
The following 4 analysis populations are planned for this investigation:
o Screening: All subjects who provide informed consent and demographic and/or Baseline
screening assessment results, regardless of the subject's randomization and treatment status
in the investigation.
o Safety: All subjects who receive at least 1 treatment with RHAo : ot I
r Modified intent-to-treat (mITT) analysis set will be used for efficacy analysis. The mITT
set is based on the conventional ITT:
]er-protocol (PP): All subj ects in the mITT
who receive treatment and do not
have
ma or CIP deviations.
-
Page 88 of 132

I
Clinical Investisation Pt* I
Confidential
11.2. Sample Size Determination
The primary endpoint of the study is the difference in the TLFS change from Baselineto 12 weeks
after the last day of treatment between subjects treated with RHA@ 3 and those treated with
I
III
Page 89 of 132

I
Clinical Investigation Plan
Confidential
11.3. Subjects and Demographics
11.3.2. Clinical Investigation Plan Deviations
A CIP deviation is any noncompliance with the clinical investigation CIP or lnternational Council
for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCp
requirements. The noncompliance may be either on the part of the subject, the TI, or study site
staff. Corrective actions are to be developed by the site and implemented promptly.
It is the responsibility of the site TI to report any CIP deviations after identification. All deviations
must be addressed in study source documents and reported ro the sponsor. Clinical investigation
plan deviations must be sent to the reviewing IRBs as per local regulations. The site TI is
responsible for knowing and adhering to the reviewing IRB requirements. Further details about
the handling of CIP deviations will be included in the CIP deviation guidance plan.
-
Page 90 of 1 32

I
Clinical Investigation Pt* I
Demographic variables will include
will be collected
and
Information on race and
Confidential
I 1.4. Effectiveness Analyses
Effectiveness
es will be
primarily on mITT analysis set.
The primary
compared to
then be tested befween
analysis will be performed as
I 
ar l- \\ceKs arrcr
to demonstrate non-inferiority of RHA@ 3
the difference in the
3 minus
-
Page 91 of 132

I
Clinical Investigation Ptun I
Confidential
Secondary Effectiveness Analysis :
will be of
ve nature.
For the parameters hereafter:
. TLFS: Jerg
o Responder rate based on TLFS
o GAIS:INrN,I
. FACE-Q scores for each module: Subject (after data standardization, as detailed in SAP)
. 
Subject satisfaction score: Subject (quantitative scores and categories as described in SAP)
For each product, summary statistics (mean, minimum, maximum, SD, and 95% CI of the mean)
for the above-mentioned parameters will be provided/presented for each study visit.
For endpoints with qualitative results, frequencies and percentages will be calculated and presented
for each study visit.
Page 92 of 132

I
Clinical Investisation Plu.t I
Confidential
11.5. Safety Analyses
The TI, through questioning and observations, will report all AEs, their severity and relationship
to the study device.
All AEs will be coded using MedDRA. All AEs reported during the study will be described by
system organ class and preferred term. The number and
who
least I AE that are device related ADEs will be
Page 93 of 132

I
Clinical Investigation Plan
Confidential
Page 94 of 132

I
Clinical Investigation Ptutr I
Confidential
12. INVESTIGATOR AND SPONSOR RESPONSIBILITIES
Steps to ensure the accuracy and reliability of data include the selection of qualified TIs and
appropriate investigation sites, review of CIP procedures with the TI and associated personnel
before the investigation, periodic monitoring visits, and meticulous data management.
12.1. Investigator Responsibilities
The TI is responsible for the conduct of the investigation at the site. Prior to shipment of the first
study device and first procedure, the TI must do the following:
o Read and understand the CIP
. 
Sign and complete the lnvestigator's Agreement
o Provide an accurate financial disclosure and file an update annually and I year after the
completion of the investigation
o Ensure appropriate IRB and institutional approvals are in place prior to completing any
portion of the informed consent process or permitting subject panicipation
e Complete and file a fully executed clinical trial agreement between sponsor or sponsor's
designee, TI, and institution (as applicable)
. Provide assurance of completed training on the study device and procedures being studied
under the CIP
r Handle and store the RHA@ : una I 
as per the cIP and their respective IFU
and IB
-
Page 95 of 132

I
Clinical Investigation Plun I
Confidential
l2.l.l. Deviations From Clinical Investigation Plan
A CIP deviation is defined as an event where the TI or site personnel deviate from the CIP or
investigation procedures. It is the TI's responsibility to ensure that there are no deviations from
the CIP.
A TI may deviate from the CIP without prior written approval from the sponsor or sponsor's
designee in cases of medical emergencies to protect the life or physical well-being of a subject in
an emergency. In that event, the TI is required to noti$ the sponsor and the applicable IRB as soon
as possible, but no later than 5 working days after the emergency occurred, of the deviation from
the CIP.
12.1.2. Maintaining Records
The TI will maintain the following accurate, complete, and current records relating to the TI's
participadon in an investigation:
o Correspondence with another TI, an IRB, the sponsor, a monitor, or the FDA.
Records of each su
ect's case history and exposure to the study or control device,
a
Page 96 of 132

I
Clinical Investigation Ptutt I
Confidential
12.1.4. Prohibition of Promotion
The IDE regulations prohibit the promotion of any investigational device. Even though the
investigational devices in this investigation have market clearance, they are being investigated in
this investigation for a new application. Therefore, no TI (or any pe6on acting on behalf of a TI)
may promote the investigational use or represent that the device is safe or effective for the purposes
for which it is being investigated, or imply safety or effectiveness (or lack thereof) by discussing
individual site experiences in any forum.
Page97 ofl32

I
Clinical Investigation Plutt I
Confidential
Prohibition of promotion does not apply to promotion of the clinical investigation by the sponsor
to facilitate recruitment.
12.2. Sponsor Responsibilities
12.2.1. General Duties
The sponsor has the overall responsibility for the conduct of the investigation, including assurance
that the investigation satisfies the regulatory requirements of the appropriate regulatory agencies,
ensuring IRB
and
that informed
consent is obtained.
Page 98 of 132

I
Clinical Investigation Plut I
Confidential
12.2.4. Changes in the Clinical Investigation Plan
The sponsor will obtain FDA approval for any change to the CIP that may affect the scientific
soundness of the investigation or the rights, safety, and/or welfare of the subjects.
Page 99 of 132

I
Clinical Investigation Plun I
of the image
tracked in a
for other purposes such as publication or
release lo
The
ect's decision will be
Confidential
13.1. Data Management
The standard
records will be followed
GCP
The Tliinstitution will permit direct access to source data and documents for investigation-related
monitoring, audits, IRB reviews, event adjudication, and regulatory inspections to be performed.
The TI will obtain, as part of the informed consent process, permission for authorized sponsor
employees, investigation monitors, or regulatory authorities to review, in confidence, records that
identiff subjects in this investigation.
13.2. Conlidentiality of Data
Information about investigation subjects will be kept confidential and managed according to the
requirements and regulations of the local and national governing bodies.
All data and information collected during this investigation will be considered confidential by the
sponsor and their delegates. All data used in the analysis and summary of this investigation will
be anonymous and without reference to specific subject names. Access to subject files will be
limited to authorized personnel of the sponsor and sponsor's designee, the TI, clinical site research
staff, and authorized regulatory authorities. Authorized regulatory personnel have the right to
inspect and copy all records pertinent to this investigation.
The photography will include the subject's face. Should photograph(s) of a subject's face be used
for potential publication, promotions or other purposes, it must only include parts of the face that
are necessary to illustrate or document the effect of the dermal filler used as per this study. The
subject will need to sign a specific photography release form to speciff whether he/she allows use
-
Page 100 of 132

I
Clinical Investigation Ptun I
Confidential
13.3. Source Documents
Source data is all information, original records (and certified copies of original records) of clinical
findings, observations, or other activities in a clinical investigation necessary for the reconstruction
and evaluation of the investigation. Source data are contained in source documents (original
records or certified copies). Examples of these original documents and data records include, but
are not limited to, the following: medical records, clinical and office charts, laboratory notes,
memoranda, subjects' diaries or evaluation checklists, recorded data from automated instruments,
copies or transcriptions certified after verification as being accurate and complete, microfiches,
photographic negatives, microfilm or magnetic media, X-rays, subject files, and records kept at
the pharmacy and at the laboratories involved in the clinical investigation.
13.4. Electronic Case Report Forms
This investigation will use an eCRF as the primary data collection instrument and will record data
by electronic capture. All data requested on the eCRF must be entered. All missing data must be
explained. If an entry on the eCRF is left blank because the procedure was not done or the question
was not asked, a query will be generated for the site data entry staff. If any entry error has been
made, correct and enter the correct data in the eCRF. All such changes are recorded in the audit
and queries report. All electronic data capture systems must be 2l CFR Part 1l and/or
ISO 14155-compliant.
The eCRFs contain confidential material. Specific instructions to complete the eCRFs will be
provided to the TI and other site personnel, as appropriate. The TIs or designees are responsible
for reporting clinical investigation-requested information in the eCRFs.
Page 101 ofl32

I
Confidential
Clinical Investigation Plan
13.5. Record Retention
The TI will retain investigation essential documents for a minimum of 2 years after the date a
marketing application is approved for the device for the indication for which it is being
investigated, or 2years after formal closure of the investigation, whichever is longer. These
documents must be retained for a longer period if required by an agreement with the sponsor or
sponsor's designee or defined by local or national regulations. The sponsor or sponsor's designee
will inform the Tl/institution as to when these documents no longer need to be retained. All clinical
sites will maintain all records pertaining to this investigation for a minimum of 2 years after the
investigation is discontinued. The sponsor or sponsor's designee will notify the clinical sites of the
date of discontinuation.
13.6. Clinical Data Monitoring Procedures
Clinical research associates will conduct site visits at the investigation facilities to monitor the
investigation in compliance with the CIP, SOPs, GCP, ISO 14155, and the clinical monitoring plan
(CMP). Monitoring visits will occur as defined in the CMP and/or as required to conduct the
investigation. The clinical investigation center agrees to allow these monitors and other authorized
- 
iluutrss ru lr'un'a,un anu cllnrcal supplles relateo to [ne lnvesrl-qa.ron.
CRAs will verify data entered into the eCRFs against hospital records or other source documents
to ensure accuracy and completeness of the eCRFs for each subject. Treating investigators and
their staff agree to assist the monitors in their activities. Requests may be made to review subject
charts by the sponsor or sponsor's designee so that CIP adherence and source documentation can
be verified.
Page 102 of 132

I
Clinical Investisation Plan I
Confidential
14. ETHICS AND REGULATORY COMPLIAIICE
14.1. Conduct of the Clinical Investigation
Conduct of the clinical investigation will follow
I,
as well as CFR/ISO 14155, the Declaration of Helsinki, ICH Harmonized Tripartite
Guideline for GCP, and other national and local laws. Each TI must sign and date the Investigator's
Agreement prior to the start of this investigation. With the signature, the TI agrees to perform all
investigation procedures according to the governing local and national regulations, and the CIP.
14.2. Conflict of Interest
The FDA reviews the financial interests of TIs (or subinvestigators and their spouses and/or
dependent children) in an IDE investigation. If the FDA believes that the financial interests of any
TI raises a serious question about the integrity of the data, the FDA may take any action it deems
necessary to ensure the reliability of the data, including the following:
o Initiating agency audits of the data derived from the TI in question
o Requesting that the applicant submit further analyses of data, e.g., to evaluate the effect of
the TI's data on the overall investigation outcome
. 
Requesting that the applicant conduct additional independent studies to confirm the results
of the questioned investigation
Therefore, any TI (or subinvestigator), their spouses, and/or dependent children who has a
potential conflict of interest with this investigation (patent ownership, royalties, or financial gain
greater than the minimum allowable by their institution, etc.) must have the conflict evaluated by
the sponsor. If a financial interest appears to exist, a management plan should be generated to
minimize bias and must be approved by the investigation sponsor prior to participation in this
investigation.
14.3. Institutional Review Board/Competent Authority Approval
A properly constituted, valid IRB must review and approve the CIP, the ICF, and related subject
information and recruitment materials before the start of the investigation. It is the responsibility
of the TI to obtain approval of the CIP from the institution's IRB and to keep the IRB informed of
any SAEs and amendments to the CIP. Additional requirements imposed by the IRB or other
regulatory authority will be followed if appropriate. A11 correspondence with the IRB should be
filed by the TI and copies sent to the sponsor or sponsor's designee(s).
14.4. Clinical Investigation Informed Consent Approval
Informed consent will be obtained in writing and documented before a subject is enrolled in the
clinical investigation in accordance with the principles of informed consent according to the
Declaration of Helsinki, GCP, 2l CFR Part 50, the Medical Devices Directive 93l42lEEC, and
ISO 14155.
It is the responsibility of the TI to ensure that written informed consent is obtained from the subject
(or legally acceptable representative) before any activity or procedure is undertaken that is not part
of routine care. Information obtained during the conduct of the clinical investigation that may
impact the subject informed consent may require revisions to the ICF. If so, revisions and
-
Page 103 of 132

I
Clinical Investigation Plan
Confidential
reapprovals of such changes by the appropriate regulating authorify are required. Documentation
of the current versions of the ICF will be documented in the clinical trial master file.
14.5. Subject Identification and Confidentiality
Subject identification and confidentiality will be ensured according to the terms and definitions in
2l CFR Parts 50, 56 and 812/ISO14155. This includes, but is not limited to, the following:
o Subjects will be identified on all eCRFs and source documents by a unique identification
reference that may include the subjects' initials
o Electronic case report forms are confidential documents and will only be made available
to the sponsor or sponsor's designee, the TI, the biostatistician, and if requested, to advisory
committees and regulatory authorities (including FDA)
o Data will be stored and analyzed by computer following national regulations for handling
of computerized data
Eachinvestigationcenterwillmaintain(anonymou.totralistidentifyingallsubjects
entered into the investigation. The list will be maintained as part of the investigation file.
This investigation will be conducted according to the US FDA standards of GCP (FDA Title 2l
CFRs Part I l, 50, 54,56 and 812), ISO 14155, the Declaration of Helsinki, and the ICH guidelines.
This investigation is to be conducted according to and other applicable national, state, and local
government regulations and institutional research policies and procedures.
Should photograph(s) of a subject's face be used for potential publication, promotions, or other
purposes, it must only include parts of the face that are necessary to illustrate or document the
effect of the dermal filler used as per this study. The subject will be asked whether helshe agrees
to use hislher photographs for use outside the study, such as publication or promotion using a
separate photography release form. Hisftrer decision will be stored at the site in a separate
photography release log.
-
Page 104 of 132

I
Clinical Investigation Plu.r I
Confidential
14.8. Insurance
The sponsor will maintain insurance coverage for this investigation. Pertinent information
regarding the coverage will be made available to the site upon request.
14.9. Site Audit Plan
Participation as a TI in this investigation implies acceptance of potential inspection by government
regulatory authorities, and applicable compliance and quality assurance offices. The TI and/or
designee must be available to respond to reasonable requests and queries made by authorized
regulatory representatives during the audit process. The TI must provide the sponsor or sponsor's
designee with copies of all correspondence that may affect the review of the current investigation
or his/her qualification as a TI in clinical studies conducted by the sponsor.
14.9.1. Internal Audits by Sponsor or Sponsor's Designee
In accordance with local and national regulations and the sponsor's or sponsor's designee's SOPs,
the sponsor or sponsor's designee may request access to all investigation records, including source
documents, for inspection. The TI will ensure the capability for inspections of applicable
investigation-related facilities (e.g., catheterization laboratory, surgery suite, diagnostic
laboratory, etc).
Internal quality assurance audits will be conducted at selected investigation sites during the
investigation. Selection of sites to undergo auditing will be determined by the sponsor per a
pre-established audit plan.
14.9.2. External Audits
Regulatory agencies may also request to inspect investigation sites. The TI or designee is required
to report to the sponsor or sponsor's designee as soon as possible after receiving a request from a
regulatory authority to perform an inspection. The TI agrees to allow inspectors from regulatory
agencies to review records and to assist the inspectors in their duties, ifrequested.
14.10. Investigational Product Traceability
Investigational products will be stored at each site according to the respective IFU and IB and
records will be kept to document product storage and management; sponsor-provided unique
identification numbers and labeling identiffing them as IDE products will be clearly visible. All
sites will maintain a device accountability log that will match subjects to a particular study device
by a unique manufacturer number. At the conclusion of the investigation, all study and control
devices will be returned to the sponsor.
l4.II. 
Public Domain Access to the Clinical Investigation
A description of this clinical investigation will be available on http://www.ClinicalTrials.gov, as
required by US law. Information regarding public access will be presented in the ICF, as required
by US law.
-
Page 105 of 132

I
Confidential
Clinical Investigation Plan
15. GENERAL CONSIDERATIONS
15.1. Discontinuation of the Investigation
Discontinuation of individual subjects is described in Section 9.7
Page 106 of 132

I
clinical Investigation Ptun E
Confidential
Page 107 of 132

I
Clinical Investigation Plan
Confidential
Page 108 of 132

Clinical
PlutrI
17. ATTACHMENTS
17.1. Investigator's Agreement
CLINICAL INVESTIGATION
PLAN NUMBER:
CLINICAL INVESTIGATION
PLAN TITLE:
AMENDED CLINICAL
INVESTIGATION PLAN
I have read this clinical
outlined herein.
Treating Investigator:
Printed Name:
Signature
Date:
Confidential
A 
Controlled, Randomized, Double-blinded,
Between-subject, Multicenter, Prospective Clinical Study to
Evaluate Safery and Effectiveness of RHA@ 3 versus
I 
lul r-lu r1.ulalll'lrldlrull
22-Mar-2021
and
to conduct this clinical
Page 109 of 132

Confidential
Clinical Investigation Plan
Page l10ofl32

I
Clinical Investigation Ptun E
Confidential
-
Pagel1lofl32

I
Clinical Investigation Plan
Confidential
-
Page ll2 of 132

I
Clinical Investisation Plun I
Confidential
-
Page I 13 of 132

I
Clinical Investigation Ptun I
18.2. Appendix B
Confidential
-
Page 114 of 132

I
Clinical Investigation Ptun I
18.3. Appendix C
Confidential
Page 1 15 of 132

r
Clinical Investigation Plan
Confidential
-
Page I 16 of 132

I
Clinical Investigation Plu" I
Confidential
-
Page 177 of 132

I
Clinical Investigation PIan
Confidential
I
I
T
TtIIII
I
I
rIr
-
I
II
II
IIIIIII
T
I
I
II
I
II
I
IIrI
I
TIIIIII
I
IIr
T
ItII
I
TIIIIII
I
I
II
I
II
TI
IIIII
TII
I
I
I
II
I
I
I
I
I
II
II
I
I
I
I
I Ir
II
IIr
I
I
TII
II
T
TII
TI
I
I
I II
I
I
I r
-
Page118of132

I
Clinical Investigation Plun I
Confidential
I
I
-
Page I 19 of 132

I
Clinical Investigation Plun I
Confidential
Page 120 of 132

I
Clinical Investigation Plutt I
I
Confidential
Page 721 of 732

I
Clinical Investigation Plan
Conlidential
Page 122 of 132

I
Ctinical Investigation Plut't I
I 
I
Confidential
Page 123 of 132

I
Clinical Investigation Plun I
Confidential
-
Page 124 of 132

I
Clinical Investigation Plut I
Confidential
Page 125 of 132

I
Clinical Investigation Ptun I
Confidential
-
Page 126 of 132

I
Clinical Investigation Plutr I
Confidential
Page 727 of 732

I
Clinical Investigation Plun I
Confidential
r
Page 128 of 132

I
Clinical Investigation Ptun I
Confidential
Page 129 of 132

I
Clinical Investigation Plan
Confidential
Page 130 of 132

I
Clinical Investigation Ptun I
Confidential
Page 131 of132

I
Clinical Investigation Ptun I
Confidential
Page 132 of 132