A Randomized, Blinded Evaluator, Multicenter, Prospective, Between-subjects Clinical Study to Evaluate Safety and Effectiveness of RHA®4 for the Treatment of Midface Volume Deficiency
Conditions: Cheek Augmentation, Correction of Age-related Midface Contour Deficiencies
Sponsor: Teoxane SA

1,
TTOXANF
A Prospective, Randomized, Blinded Evaluator, Multicenter,
Between-subj ects Clinical S
to Evaluate S
and Effectiveness of
RHA@ 4 versus
for Treatment of Midface
Volume Deficiency
Clinical Investigation Plan
INVESTIGATIONAL PRODUCT:
CLTNICAL TNVESTIGATION
PLAN NUMBER:
INVESTIGATIONAL DEVICE
EXEMPTION NUMBER:
DEVELOPMENT PHASE:
INDICATION:
METHODOLOGY:
RHA@ 4
c210086
I. TITLE PAGE
PROTOCOL VERSION:
PROTOCOL DATE:
INITIAL PROTOCOL:
PROTOCOL WRITTEN BY
Pivotal
Treatment of midface volume deficiency
Controlled, randomized, blinded evaluator, multicenter, between
subjects, prospective
I
l2-Jul-2023
Original Protocol Version 1.0, 08-Mar-2021
SPONSOR
TEOXANE SA
Rue de Lyon 105
cH- t203
Switzerland
SPONSOR CONTACT PERSON
L]NITED 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 All unpublished information contained in this document is the confidential property of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 SA and may not be disclosed to parties not associated
purpose without prior written consent of TEOXANE SA'
with the clinical investigation or used for any
AD-PR-37.01 15-Apr-2016
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APPROVAL SIGNATURES
CLINICAL INVESTIGATION
PLAN NUMBER:
CLINICAL INVESTIGATION
PLAN TITLE:
A Prospective, Randomized, Blinded Evaluator, Multicenter,
Between-subjects Clinical Stud
to Evaluate S
and
Effectiveness of RHA@ 4 versus
XC for Treatment of Midface Volume Deficiency
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
Sr Clinical Project Manager
Clinical Program Manager
Clinical Development and Medical Affairs Director
Regulatory Affairs Director
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SIGNATURE
DATE
Biostatistician
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AMENDED PROTOCOL
Revision history:
TITLE:
CLINICAL INVESTIGATION
PLAN NUMBER:
PROTOCOL VERSION:
ORIGINAL PROTOCOL DATE:
AMENDMENT 1 DATE:
AMENDMENT 2 DATE:
AMENDMENT 3 DATE:
AMENDMENT 4 DATE:
AMENDMENT 4.I DATE:
AMENDMENT 5 DATE:
AMENDMENT 5.1 DATE
AMENDMENT 5.2 DATE
AMENDMENT 6 DATE:
AMENDMENT 7 DATE:
AMENDMENT 8 DATE:
A Prospective, Randomized, Blinded Evaluator, Multicenter,
Between-subject Clinical Study
Effectiveness of RHA@ 4 versus
for Treatment of Midface Volume Deficiency
T
Original Protocol Version 1.0, 08-Mar-2021
Amended Protocol Version l, 
tZ-lul-ZOZZ
to Evaluate
and
The following are the amended protocol and appendices, including all revisions specified in the
REASONS FOR AMENDMENT and SUMMARY OF AMENDED SECTIONS.
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2. CLINICAL INVESTIGATION PLAN SUMMARY
2.1. Summary
I}.T\IESTIGATIONAL
PRODUCTNAME
RHA@4
CLIMCAL
INVESTIGATION PLAN
(CIP)NI.JMBER
TITLE OF
INVESTIGATION
A Prospective, Randomized, Blinded Evaluator, Multicenter, Between-subjects
and Ellectiveness of RHAo 4 versus
Clinical Stud
to Evaluate
for Treatment of Midface Volume Deficiency
SPONSOR/
MANUFACTURER
TEOXANE SA, Rue de Lyon 105, CH -1203 Geneva, Switzerland
DEVELOPMENT PHASE
Pivotal
CONTROL DEVICE
NAME
INDICATION FOR USE
RHA@4 (further referred to as "RHA4") injectable gel is intended to be used for
injection into the subcutaneous to supraperiosteal layers for cheek augmentation
and/or correction of age-related midface contour deficiencies in subjects aged 22 ot
older.
CLINICAL
INVESTIGATION
PURPOSE
The purpose ofthe clinical investigation is to evaluate the safety and effectiveness
of nife+ when compared to f 
in the treatment of midface volume deficiency.
TREATMENTGROUPS
This study plans to enroll at least 200 subjects (>20% of subjects with Fitzpatrick
skin types IV-VI, including 10% of subjects with types v/VI with at least 5 subjects
with type V and 5 subjects with type VI) with a maximum of 210 subjects. At least
10% of subjects will be male.
subjects will be randomly assigned (3:l ratio) at Screening to the following groups:
r 
RHA4 group - approximately 150 subjects
. I-approximately 
5o subjects
STLIDY CENTERS AND
LOCATION
8to10
ve sites in the United States
will
STUDYDURATION
Individual study
The minimum and maximum anticipated duration of
su
are 52 and 7l weeks, resPectivelY
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I}.I\rESTIGATIONAL
PRODUCT NAME
RTIA@ 4
CLIMCAL
INVESTIGATIONPLAN
(crP) NTTMBER
OBJECTIVES
a
Primary effectiveness objective :
o To assess the effectiveness of RHA4 ue.sur ! 
on adding volume in
the midface region in subjects seeking treatment of midface volume
deficiency 8 weeks after the last treatment (initial or touch-up)
Secondary effectiveness objectives:
o To assess the effectiveness of RHA4 ue..ur ! 
on adding volume in
the midface region in subjects seeking treatment of midface volume
deficiency up to 52 weeks after last treatment and, 12 weeks after
retreatment
a
a
Safety objective:
o To assess the safety of R[IA4 versus I 
in subjects undergoing
treatment of midface volume deficiency up to 52 weeks after last treatment
and 12 weeks after retreatment
o
DEVICE TREATMENT
The Treating Investigator
RHA4 administration and
Briefly:
Injection depth
(TI) is recommended to follow the iniection euideline lor
I 
rrs' uu'urs lur usc,,"r'or! 
rn-recuon.
Study and control devices (RHA4 ana ! 
will be injected in the subcutaneous
and/or supraperiosteal layers.
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INVESfiGATIONAL
PRODUCT NAME
RHA@4
CLIMCAL
INVESTIGATION PLAI.I
(crP)NUMBER
In-iection area
The TEOXANE SA midface treatment area will focus on the anteromedial and
lateral malar regions. A schematic of the treatment area is delimited using the
triangle below. Its base line is parallel to the nasolabial fold (at least 0.4" [1 cm]
lateral to the fold), the superior side ofthe triangle is a line from the superior part
of the nasal alar crease to the superior root of the helix of the ear and the inferior
side of the triangle is a line running from the lateral oral commissure to the superior
root ofthe helix ofthe ear.
Amount of device to administer:
The maximum volume per administration of RHA+ ana ! 
into the midface
area is 6.0 mL per treatment session (total for both sides of the face, i.e., 3.0 mL
maximum per side).
INVESTIGATION
DESIGN
Enrollment
This is a prospective, randomized, controlled, blinded evaluator, multicenter,
between suijects clinical study to identify whether RHA4 is non-inferio. to f
for treatment of midface volume deficiency 8 weeks after the last treatment (initial
or touch-up).
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INVESTIGATIONAL
PRODUCTNAME
RHA@4
CLIMCAL
INVESTIGATIONPLAN
(CIP)NTJMBER
The Blinded Live Evaluator (BLE) will evaluate the subject's midface as a whole
using the TMVDS at
to confirm
This will be done
of the TI.
Subjects who are eligible to participate
will be enrolled and
randomly assigned in a 3:1 ratio at Visit I to receive RHA4 orI
Administration and evaluation
At visit 1, continuous eligibility will be assessed. All evaluations performed at
Visit 1 before the injection will be considered for the Baseline.
The TI will inject the device at Visit l.
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INVESTIGATIONAL
PRODUCTNAME
RHA@4
CLIMCAL
INVESTIGATION PLAN
(crP)Nr.,MBER
Administration of
will follow the IFU, the TI can use an FDA-approved
needle and/or cannula as per their choice at each injection. Administration method
and injection technique at each injection will be recorded.
RHA4 can be injected with a needle and/or with a cannula; this will be left to the
choice of the TI at each injection. Administration method and injection technique
at each injection will be recorded.
If necessary, subjects will receive a touch-up treatment to optimize the results 4
weeks after the initial treatment with the same product that they received at Visit 1.
The TI will conduct
and effectiveness evaluations at each study visit
weeks after the initial or touch-
treatment
Additionally, the TI or designee will call the sub
3
after each treatment to
ask questions about their health status and AEs
and will conduct
safety evaluations 2 weeks after each treatment sesslon
Ail subjects, regardless of whether they received RHA4 or I 
at Visit 1 and
regardless of whether
received touch
treatment or
be offered a
Retreatment
retreatment with RHA4
will be administered if the TI deems it
and if the sub
The su
will then be followed for 12 weeks after
before exiting the study or until all
retreatment
treatment-related adverse events (AEs) have resolved or until the TI determines that
follow-up is no longer necessary. Subjects not receiving retreatment will exit the
study f 
(52 weeks after the last treatment).
Subjects will report their common treatment responses (CTRs) in a subject diary
for 30 days after each injection. The diary will also include a list of selected AEs
that are potentially associated with dermal filler injections, and subjects who
experience such AEs will be required to
them to the TI or seek
medical attention if
them.
The TI will follow up on the subject until the Exit visit I 
or until all
treatment-related ongoing AEs have resolved or until the TI determines that
follow-up is no longer necessary.
BLE assessments
The BLE will conduct assessments of effectiveness
primary endpoint, and all visits
If the
ect receives retreatment, the BLE will conduct additional
assessments
In case of premature termination, the BLE will
also conduct the assessment at the Exit visit.
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INVESTIGATIONAL
PRODUCTNAME
4
CLINICAL
IWESTTGATIONPI-AN
(crP)NUMBER
-
For further details on procedures and timing of the events please refer to the
Schedule of Events table.
BLINDING
The BLE will be blinded to allocation to groups (RHA4 group
Furthermore, to ensure that they remain blinded and unbiased
or
group)
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.
ASSESSMENTS
TMVDS: A validated proprietary 5-point scale
the volume deficit in the midface region
assesslng
a
Global Aesthetic Improvement Scale (GAIS): A balanced, 5-point scale
assessing aesthetic improvement
FACE-Q scale (satisfaction with cheeks): A subject-reported outcome measure,
assessed by the subject using the satisfaction with cheeks scale. This
assessment will be performed at rest and when smiling.
Subject satisfaction scale: A balanced, 5-point scale assessing subject
satisfaction with study treatment
a
a
Adverse Events: with the focus on AEs related to treatment (ADEs),
Unanticipated Adverse Device Effects (UADEs), Serious AEs (SAEs),
Adverse Events of Special Interest (AESIs), AEs from CTRs, causality,
duration, and severity as per TI assessment
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TNVESTIGATIONAL
PRODUCTNAME
RHA@4
CLIMCAL
INVESTIGATIONPLAN
(crP)NLTMBER
a
Post-injection CTRs: through 30-day subject CTR diary, which also includes
vision disturbances
a
ELIGIBILITY CRITERIA
A potential subject will be enrolled in the study if the subject meets all of the
following inclusion criteria:
1 . Is outpatient, male or female of any race, 22 years of age or older
2. If female, is not pregnant, not breastfeeding, and either not of chiidbearing
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 I and prior to each injection
and must agree to practice 1 of the following medically acceptable methods of
birth control throughout the study:
3. Seeks treatment of midface volume deficiency (realistic and achievable as per
TI opinion)
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II\ryESTIGATIONAL
PRODUCTNAME
RIIA@4
CLIMCAL
INVESTIGATIONPLAN
(crP)NUMBER
7. Is able to follow study instructions and complete all required visits
8. Is willing to sign the institutional review board-approved ICF, 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.
Exclusion Criteria I:
A potential subject will be excluded from the study ifthe subject meets any ofthe
following exclusion criteria:
2. Has known hypersensitivity or previous allergic reaction to any component of
the study or the control device
3. Has 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
4. Has known susceptibility to keloid formation, hypertrophic scarring, or
clinically significant skin pigmentation disorders as judged by the TI
5. Has a 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 that are likely to interfere with
the measured parameters or to put the subjects to an undue risk as judged by
the TI
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INVESTIGATIONAL
PRODUCTNAT{E
RTIA@ 4
CLIMCAL
INVESTIGATION PLAN
(crP)NT.JMBER
-
1 5. Has medical or psychiatric conditions that may increase the risk associated with
results or
or
interfere with the
of
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INVESTIGATIONAL
PRODUCTNAME
RHA@4
CLINICAL
INVESTIGATION PLAN
(crP)NUMBER
compliance of
into this study,
the subject and would make the subject inappropriate for entry
as judged by the TI
16. Has clinically significant alcohol or drug abuse, or history ofpoor cooperation
or unreliability, as judged by the TI
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INVESTIGATIONAL
PRODUCTNAME
RHA@4
CLINICAL
INVESTIGATION PLAN
(crP)NUMBER
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IN\'ESTIGATIONAL
PRODUCTNAME
RHAO4
CLIMCAL
INVESTIGATION PLA}.I
(crP)NTJMBER
t2.
PRIMARY
EFFECTIVENESS
ENDPOINT
The effecti VCNCSS of RHA4 wiil be demonstrated if the change from Baseline for
subj ects treated with RHA4 is statistically non-inlerior to
**,,,,f 
o \\eeKs aTler tnc rast
the change from Baseline
for subjects treated
treatment (at Visit -t) as
assessed by the BLE using the TMVDS. Non-inferiority margin is set as 0.5.
A change in the TMVDS >1 grade compared to pretreatment will be considered
clinically meaningful.
SECONDARY
EFFECTIVENESS
ENDPOINTS
a
TMVDS change from Baseline assessed
GV 
the BLE at each visit
a
Responder rate for TMVDS (>1 grade improvement on the TMVDS compared
to Baseline):
ISv 
the BLE at each vrsrt
a
GAIS as assessed:
Dy 
the BLE at each visit
rF
scores assessed
the
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INVESTIGATIONAL
PRODUCTNAME
4
CLIMCAL
INVESTIGATION PLA}.I
(crP)NUMBER
satisfaction assessed by the subject
SAFETY ENDPOINTS
a
Adverse events with a focus on treatment-related AEs based on the TI
assessment, and AEs reported from the CTR diary
Post-injection CTR, including vision disturbances, through 30-day subject
CTR diary
a
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INVESTIGATIONAL
PRODUCTNAME
RHA@4
CLINICAL
INVESTIGATION PLAN
(crP)NUMBER
SAMPLE SIZE
a
STATISTICAL METHODS
AND ANALYSIS
SUMMARY
All data will be recorded in an electronic case report form
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IT.I\IESTIGATIONAL
PRODUCTNAME
RHA@4
CLIMCAL
INVESTIGATION PLAN
(CIP)NIJMBER
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I}I'fESTIGATIONAL
PRODUCTNAME
RHA@4
CLINICAL
INVESTIGATION PLAN
(crP)NUMBER
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3. TABLE OF CONTENTS
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i g a,t!9 L Plan
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IIIIIIIr
TIIIIrIIIIrIIItI
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TIIIIII
TIIIIII
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5. INTRODUCTION TO THE CLINICAL INVESTIGATION
5.1. Background
The cheeks or midface area represent a key feature of the face, and together with the eyes, nose,
and lips, are associated with youth and attractiveness. The shape and fullness of the cheeks are
influenced by a multitude of internal and environmental factors that can dramatically change the
cheek's appearance over time.l In recent years, a greater cultural value on youth and healthilong
with improved techniques have resulted in an increase in cosmetic procedures, and the cheeks have
become an area of choice for facial rejuvenation.
Loss of subcutaneous fullness is one of the key factors that contributes to the aging of the cheeks.l
With age, depletion of subcutaneous fullness in the malar prominence and progressive buccal
hollowing causes suboptimal facial proportion, while the loss of infraorbital subcutaneous tissue
gives rise to more prominent orbicularis oculi and results in'ocrow's feet" (rhytids). In addition,
ptotic cheek fat can descend over time to form nasolabial folds (NLFs), resulting in a cheek
concavity that is further highlighted by gradually reduction of malar fullness.
The cheek is the facial injection site that can benefit the most from rejuvenation.2 Treatment in the
midface includes surgical (such as cheek implants) and nonsurgical procedures (such as injection
of soft tissue fillers).3 Injection of such fillers for facial volume restoration and contour
enhancement has shown to be a favorable treatment as the procedure can be performed quickly,
cause little down time, and yield a high rate of patient satisfaction.2 Soft tissue fillers are most
frequently used in the form of hyaluronic acid (HA) and in general were the second most frequently
used medical devices for minimally invasive cosmetic procedures in2019.a Fillers consisting of
HA that are
the United States (US) Food and Drug Administration (FDA) include
Juv6derm@
and Restylane@ Lyft for cheek augmentation.s
Hyaluronic acid, also known as hyaluronan, is the most abundant glycosaminoglycan found in the
human dermis. Used as a dermal filler, HA has a long record of data confirming its safe use. The
persistence of HA in the tissues and its resistance to degradation can be obtained by chemical
crosslinking, which allows modification of the rheological and physical propertier of th" HA,
while maintaining the biocompatibility of the basic polymer.6 The injection of an HA gel dermal
fillers, as a minimally invasive procedure, has been the method of choice for the augmentation and
enhancement of the cheeks. This clinical investigation will evaluate the use of the FiA dermal filler
RHA4 for the treatment of midface volume deficiency.
5.2. Study Device Name
RHA@ 4 (further only "RHA4"). RHA stands for Resilient Hyaluronic Acid.
5.3. Intended Purpose Statement
RHA4 is intended to be used for cheek augmentation and/or correction of age-related midface
contour deficiencies in subjects aged22 years or older.
5.4. InvestigationalProductDescription
The device under clinical investigation is RHA4 manufactured by TEOXANE SA.7
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5.4.1. Delivery System and Implantation
RHA4 is supplied in individual blister packages containing a 1.2 mL treatment syringe with two
27G yz" needles. The contents of the syringe are sterile and non-pyrogenic. They should not be
resterilized or used if the blister package has been opened or damaged.
5.4.2. Nonclinical Testing and Previous Clinical Experience
All information regarding- preclinical testing and previous clinical experience with RHA4 is
included in the current IB.6
5.5. Control Device
The control device is
I 
is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, homogenous gel
implant. It consists of HA produced by Streptococcus equi speciesof bacteria, which is crosslinked
with BDDE. It is formulated to a concentration of 20 mg/ml and, 0.3Yo w/w lidocaine in a
physiologic buffer.
I 
is indicated for deep (subcutaneous and/or supraperiosteal) injection for cheek
augmentation to correct age-related volume deficit in the midface in adults over the age of 21.
I 
should be used according to its IFU.8
5.6. Injection of RHA4 o.I
The TI is recommended to follow the injection guideline for RHA4 administration and I
IFU8 for I 
injection. Briefly:
Ini
deoth: Study and control devices (RHA4 und tr 
will be injected in the
subcutaneous and/or supraperiosteal layers.
Administration method: For RHA4, the needle that could be used is the one
in the box
(27G y2" needle [TSK]) and/or the cannula
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Ilriection area: The TEOXANE SA midface treatment area will focus on the anteromedial and
lateral malar regions. A schematic of the treatment area is delimited using the following triangle
(Figure 5-1): its base line is parallel to the nasolabial fold (at least 0.4" [1 cm] lateral to the fold),
the superior side ofthe triangle is a line from the superiorpart of the nasal alar crease to the superior
root olthe helix of the ear and the inferior side of the triangle is a line running from the lateral oral
commissure to the superior root of the helix of the ear.
Treatment of nasolabial folds, temples, pre-auricular and periorbital regions are prohibited.
Figure 5-1: Midface Treatment Area
Amount of device to administer: The maximum volume per administration of the RHA4 and
.0mLpertreatmentsession(totalforbothsidesoftheface,i.e.,
3.0 mL maximum per side).
5.7. Justification for the Clinical Investigation
h the US, RHA4 is FDA-approved for injection into the deep dermis to superficial subcutaneous
tissue for the correction of moderate to severe dynamic facial wrinkles and folds, such as NLFs,
in adults 22yearcor older. Assuming a similar volumizing effect, the purpose of this investigation
is to inject RHA4 into the subcutaneous and/or supraperiosteal for cheek augmentation and/or
correcti,on of age-related midface contour deficiencies. Assuming a similar volumizing effect, the
investigation is also designed to demonstrate that RHA4 it i."-i"i"tio, to j 
for this
indication in subjects aged22 years or older. The goal is to show that treatment with RHA4 will
result in added volume to the cheeks 8 weeks after the last treatment.
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5.7.1. Justification for the Clinical Investigation Design
The investigation is designed to prospectively evaluate RHA4 in treatment of midface volume
deficiency, and to compare its safety and effectiveness to that ofl. 
The clinical investigation
design was selected to minimize bias by using subject .undo-irution and blinding of tn"
independent evaluator (Blinded Live Evaluator [BLE]), whose assessments will be used for the
primary and
endpoint analyses. The comparison of the safety and effectiveness of
RHA4
will be done between su
ects and will include sub ects from mul
sites.
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6. CLINICAL INVESTIGATION PURPOSE, OBJECTIVES, AI\D EI\DPOINTS
6.1. 
ClinicallnvestigationPurpose
The purpose of this clinical investigation is to evaluate the safety and effectiveness of RHA4 when
"o-purid 
to I 
for the treatment of midface volume deficiency.
6.2.
6.2.1.
a
6.2.2.
6.2.3.
a
Objectives
Primary Effectiveness Obj ective
To assess the effectiveness of RHA4 versus I 
on adding volume in the midface
region in subjects seeking treatment of midface volume deficiency 8 weeks after the last
treatment (initial or touch-up) (Table 6-1)
Secondary Effectiveness Obj ective
To assess the effectiveness of RHA4 versus I 
on adding volume in the midface
region in subjects seeking treatment of midface volume deficiency up to 52 weeks after
last treatment and 12 weeks after retreatment
Safety Objective
To assess the safety of RHA4 versus I 
in subjects undergoing treatment of midface
volume deficiency to 52 weeks after last treatment and 12 weeks after retreatment
a
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Table 6-1: Objectives Mapped to Endpoints
Objectives
Endpoints
Primary effectiveness
To assess the effectiveness of RHA4
ue.rur f 
on adding volume in the
midface region in subjects seeking
treatment of midface volume deficiency
8 weeks after the last treatment (initial or
touch-up)
The effectiveness of RHA4 will be demonstrated if the
change from Baseline for subjects treated with RHA4 is
statistically non-inferior to the change from Baseline for
subjects treated witn ! 
8 weels after the last
treatment (at Visit 3) as assessed by the BLE using the
TMVDS. Non-inferiority margin is set as 0.5.
A change in the TMVDS >l grade compared to
a
pretreatment will be considered clinical ly meaningful.
Secondary effectivenessu
To assess the effectiveness of RHA4
u"r.us f 
on adding volume in the
midface region in subjects seeking
treatment of midface volume deficiency
up to 52 weeks after last treatment and 12
weeks after retreatment
TMVDS change from Baseline assessed
the BLE at each visit
a
Responder rate for TMVDS (21 grade improvement on the
TMVDS compared to Baseline):
the BLE at each visit
GAIS as assessed:
I,'v 
rne ELr, ar eacn vrsrt
I
scores assessed
the sub
at each visit
-
ect satisfaction assessed
at each visit!
a
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o
Safety
Adverse events with a focus on treatment-related AEs based
on the TI assessment, and AEs reported from the CTR diary
a
ection
To assess the safetv of RHA4 versus
I 
ln suoJects unoergolng lrcatrtl€trt
of midface volume deficiency to 52 weeks
after last treatment and 12 weeks after
retreatment
a
I
6.3. Hypothesis
The RHA4 group will be non-inferior to the I
for the treatment of midface volume
deficiency as determined by the TMVDS (5-point scale
treatment (initial or touch-up).
8 weeks after the last
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A change in the TMVDS >1 grade compared to pretreatment will be considered clinically
meaningful.
6.4. Risks and Anticipated Adverse Device Effects
The safety of the study and control devices has not been established during pregnancy or in
breastfeeding females.
The following risks have been associated with the use of HA dermal fillers in general, not just
RHA4. There are various types of risks associated with the injection of an HA dermal filler on the
face:
o Risks associated with all skin injection procedures
o Risks associated with the anesthetic agent (lidocaine) or other allergens
o Risks that are typically associated with RHA4, f, 
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:
o Infection
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 study and control 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,
tendemess, and temporary loss of skin color.
6.4,3. Risks That Are Typicatly Associated with RHA4,I, 
and HA Dermal Fi[ers
in General
The following have been associated with the use of HA dermal fillers. Although RHA4 has shown
some differences compared to some of the HA dermal fillers currently available, they are expected
to share a similar safety profile.6'e The following risks are anticipated adverse device events when
using an HA dermal filler:
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There are common treatment reactions such as: redness (erythema), inflammation, pain,
tendemess, firmness (induration), swelling, lumps/bumps, bruising (ecchymosis), edema,
itching, discoloratiorVhyperpigmentation.
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, hypersensitivity, lack
of effect, injection site inflammation, injection site abscess, injection site cellulitis, gingival
pain, and acne cyst.
a
o
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For further and most recent information about RHA4, refer to the most recent version of the 186
and the IFU.7
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7. CLINICAL INVESTIGATION DESIGN
Enrollment
This is a prospective, randomized, controlled, blindeA ""ut"ut-, 
multicenter, between subjects
clinical study to identify whether RHA4 is non-inferiot to I 
for treatment of midface volume
deficiency 8 weeks after the last treatment (initial or touch-up)'
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before
Administration and evaluation
At Visit 1, continuous eligibility will be assessed. All evaluations performed at Visit 1 before the
injection will be considered for the Baseline.
The TI will inject the device at Visit 1.
Administration of f 
will follow the
the TI can use an FDA-
needle and/or
cannula as
their choice at each injection.
If necessary, subjects will receive a touch-up treatment to optimize the results 4 weeks after the
initial treatment with the same product that
received at Visit 1. The TI will conduct safety and
effectiveness evaluations at each
visit
after the initial
or touch-up treatment
l. eOOitionally, the
after retreatment
TI or designee will call the
ects 3 days after each treatment to ask
and will conduct safety evaluations
questions about their health status and
2 weeks after each treatment session
All subjects, regardless of whether they received RHA4 or f 
at Visit I and regardless of
whether they received touch-up treatment or not, will be offered a retreatment with RHA4
(52 weeks after the last
Retreatment will be administered if the TI deems it
and if the
The subject will then be followed for 12 weeks
exiting the study or until all treatment-related
adverse events (AEs) have resolved or until the TI determines that follow-up is no longer
necessary. Subjects not receiving retreatment will exit the rtody I52 
weeks after the last
treatment).
Subjects will report their common treatment responses (CTRs) in a subject diary for 30 days after
each injection. The diary will also include a list of selected AEs that are potentially associated with
dermal filler injections, and subjects who experience such AEs will be required to immediately
report them to the TI or seek medical attention if they
them. All efforts should be made
to allow
by the TI or designee to schedule the
vrsrts
of the CTR
The TI will follow up on the subject until rhe Exit visit
or until all treatment-related
ve resolved or until the TI determines that follow-up is no longer necessary.
ongoing AEs ha
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BLE assessments
The BLE will conduct assessments of effectiveness
all visits
receives retreatment, the BLE will conduct additional assessments
premature termination, the BLE will also conduct the assessment at the Exit visit.
Ifthe subject
In case of
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Figure 7-1: Investigation Design
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7.1. ClinicallnvestigationDuration
Individual study parlicipation: The minimum and maximum
ated duration of su
ect
participation arc 52 and 7 I weeks, respectively
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7.2. ClinicallnvestigationEnrollment
to enroll at least 200
with a maximum of 2I0 subjects.
Subjects will be randomly assigned (3:1 ratio) at Screening to 1 of the following groups:
o RHA4 group -approximately 150 subjects
. I 
group - approximately 50 subjects
The TI and the subject will not be blinded, while the BLE will be blinded to allocation to groups
(RHA4 group or I 
group). All evaluations performed by the BLE will be conducted
completely separately from the TI, and the BLE must not have any access to subject documents,
.""oid., notes, or any other sources of information that might indicate the allocated treatment. The
BLE must have a separate eCRF account that will not allow him/her to access any data about the
subject.
Subjects who do not meet all inclusion criteria or meet any of the exclusion criteria will not be
enrolled.
7.3. Clinical Investigation Sites
The clinical
is to be conducted at 8 to 10
sites in the US
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7.4. 
Selection of Clinical Investigation Subject population
Subjects who seek treatment of midface volume deficiency are possible candidates for the clinical
investigation and will be screened for eligibility based on the inclusion and exclusion criteria
below.
V
subiects
Part 2I Code of Federal Regulations (CFR)/Good Clinical Practice (GCP)/International
Organization for Standardization (ISO) regulations, and IRBs stipulate that additional protections
should be included for individuals who are deemed vulnerable:
o Prisoners
o Pregnant women and fetuses
o Children
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 enrolled to the main study if the subject meets all of the following
inclusion criteria:
L Is outpatient, male or female of any race,22 years of age or older
2. If female, is not pregnant, not breastfeeding, and either not of childbearing potential
(defined as postmenopausal for at least 1 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:
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3. Seeks treatment of midface volume deficiency (realistic and achievable as per TI opinion)
7. Is able to follow study instructions and complete all required visits
8. Is willing to sign the IRB-approved ICF, photographic release form, and the authorization
for use and release of health and research study information (Health lnsurance 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.
7.4.2. ExclusionCriteria
A potential subject will be excluded from the main study if the subject meets any of the following
exclusion criteria:
2. Has known hypersensitivity or previous allergic reaction to any component of the study or
the control device
3. Has 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
4. Has known susceptibility to keloid formation, hypertrophic scarring, or clinically
significant skin pigmentation disorders as judged by the TI
5. Has a 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 that are likely to interfere with the measured parameters or to
put the subjects to an undue risk as judged by the TI
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15. Has 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 would make the subject inappropriate for entry into this study, as judged by the
TI
16. Has clinically significant alcohol or drug abuse, or history of poor cooperation or
urneliability, as judged by the TI
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8. INVESTIGATIONPROCEDURES
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 0 (Week up to -3)
Visit 0 is the
visit.
The screening procedures will include the following assessments:
l. 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. Measure height, weight, calculate body mass index (BMD
5. Collect prior and concomitant medications
6. Perform the TMVDS assessment (both the TI and the BLE)
lAssess inclusion/exclusion criteria
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Sub
8.1.2. Visit I (Week 0)
Visit 1 is the first day of the study, Week 0 for all subjects.
ects who are eligible
at Visit 0
will have following assessments performed before the injection:
a.
UPT for female subjects of childbearing potential
TMVDS (does not need to be repeated if visit 0 is on the same day as visit 1)
Review continuous eligibility
Photography of the subject's midface area
a.
TMVDS (does not need to be repeated if Visit 0 is on the same day as visit 1)
3. Subject
IencE-e 
questionnaire
All these assessments represent Baseline
1. TI
2. BLE
c.
d.
e.
The TI will administer the allocated filler
the
described in Section 9.3 and
to the IB IFUs and Section 9.7.
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8.1.3. Visit | 
(Telephone Call, +3 Days After the Initial Treatment)
Visit I 
is a telephone call 3 r 2 days after the initial treatment (3 days from the last treatment)
for all subjects.
The TI or
will collect information about
tial AEs
-visit
Visit 18 is performed at the site 2 weeks t 3 days after the initial treatment.
The TI or designee will collect information about potential AEs, review the partially completed
30-day CTR diary and perform vision assessments.
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8.1.9. Visit | (Primary Endpoint, 8 Weeks After the Last Treatment)
Visit I is at the site and will be scheduled 8 weeks +3 days after the last treatment, either initial or
touch-up. The assessments performed at this visit will be used for the primary endpoint evaluation.
2, BLE
a. 
TMVDS
d. 
GAIS
3. Subject:
trecE-Q questionnaire
b. 
GAIS
c. 
Subject satisfaction
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8.2.
8.2.1.
Assessments
Urine Pregnancy Test
A UPT for women of childbearing potential only will be conducted at the site prior to each
application of the filler (Section2.2).
8.2.2.
Safety Assessments
assessments will include the evaluation of
8.2.2.1. Adverse Events
The definition and management of AEs, and any special considerations for AEs, are provided in
Section 10.
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8.2.2.4. Common Treatment Response
will receive a
booklet and instructions for
treatments
The subject
CTRs of the
their observations of the
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8.2.3.1. Teoxane Midface Volume Deficit Scale
Midface volume deficiency will be assessed by the TI and the BLE at time points in the Schedule
of Events
the 5
int TMVDS
B.
For eligibility purposes only: if the TI and BLE assessment differ
on the
TMVDS this is considered
If the subject is eligible, the BLE's assessment will
be used for the Baseline of the primary endpoint. If the TI and the BLE do not agree on eligibility,
or if their assessments differ by more than 1 point of the scale, the subject will not be eligible.
8.2.3.2. Global Aesthetic Improvement
Global aesthetic improvement assessment will be assessed by the l, BLE, and subjects at trme
in the Schedule of Events
Section 2
a5-
GAIS
able 8-1
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Table 8-1: Global Aesthetic Improvement Scale
Grade
Description
I
Much improved
2
Improved
J
No change
4
Worse
5
Much worse
8.2.3.3. FACE-Q
The subject-reported outcome measure FACE-Q scalels will be assessed as in the Schedule of
Events (Section 2.2). Only one selected scale (satisfaction with cheeks scale) from the FACE-Q
will be used for the purpose of this study. This scale measures the appearance of the midface area
with items that ask about the symmetry, smoothness, attractiveness, contours and youthful fullness
of the cheeks. The subject will be asked to complete FACE-Q questionnaire at rest and when
smiling This scale is provided in Appendix C.
8.2.3.4. Subject Satisfaction
satisfaction will be measured by using a 5-point balanced scale
The subject will be instructed to "Rate your level of satisfaction
with the effect of study treatment in the treated area by using the following scale" (provided in
Table 8-2),
Table 8-2:
Subject Satisfaction Scale
Grade
Description
I
Very satisfied
2
I
J
4
I
5
Very dissatisfied
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9. CLINICAL INVESTIGATION TREATMENT AND FOLLOW.UP
9.1. Subject Informed Consent
while the enrollment for the main study is ongoing, the following will apply:
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
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 they can
comprehend and will be given ample opportunity to read and pose questions they may have about
the
after
the sub ect
to
will
the ICF
If the subject subsequently fails to meet eligibility criteria for the main study, they will be
considered a screen failure and will not receive treatment with the stud
device or the control
device under the clinical
I
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 deviation and noncompliance with 21 CFR Parts 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 usmg
block
allocate the
in a 3:1 ratio
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9.3. Blinding/UnblindingClinicallnvestigationPlan
9.3.1. General Blinding
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
The BLE and study personnel not involved with the site (e.g., data management, medical monitor)
will be blinded to treatment assignment.
9.3.2. BlindedProcedures
All evaluations performed by the BLE will be performed separately from the TI. The BLE must
not have any access to subject documents, records, notes, or any other sources of information that
might indicate the allocated treatment (such as the randomization schedule or the randomization
ratio). The BLE must also have a separate eCRF account that will not allow them access to any
subject data.
Furthermore, to ensure that the BLE remains blinded and unbiased when making their assessments
during the study, the BLE, the TI, and the subject will not be allowed to discuss each other's study
assessments. All subjects will be instructed to not discuss their study treatment, AEs, or CTRs with
the BLE.
9.3.3. Unblinding Procedures
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
(Section 8.1.1).
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9.5. 
Baseline Evaluations and Data Collection
All of the data collected at Visit 1 prior to randomization will be defined as Baseline for the pu{pose
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.
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9.7. ClinicallnvestigationalProductTreatment
The TI will inject the filler (RHA4 ot I) 
in all subjects at the initial treatment (Visit 1). Four
weeks later (Visit 2), the TI will decide whether touch-up treatment is necessary to achieve OCR.
If necessary, the same filler that was injected during the initial treatment will be administered as
touch-up treatment.
9.7.1. Study Device
The study device is RHA4
information.
Please see Section 5.4 and the 186 for further
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9.7.2. Control Device
will be used as the active treatment control for the initial treatment and
touch-up treatment, if applicable, in subjects randomized to I 
treatment.
deep (subcutaneous and/or supraperiosteal) injection for cheek
in the US and will be used according to the IFU.8
9.7.3. Injection of RIIA4 o.I
The TI is recommended to follow the injection guideline for RHA4 administration and f
IFU8 forl 
injection.
For administration of I, 
the TI can use a US FDA-approved needle and/or cannula as per
the IFU (i.e., needle 27G y2", needle 25G l" and cannula25G lyr").Injection technique and
administration method (needle and/or cannula) at each injection will be recorded.
RHA4 can be injected with a needle, and/or with a cannula; this will be left to the choice of the TI
at each injection. k{ection technique and administration method (needle and/or cannula) at each
injection will be recorded.
In
depth: study and control devices (RHA4 u.rd tr 
will be injected in the
subcutaneous and/or supraperiosteal layers.
Injection area: The TEOXANE SA midface treatment area will focus on the anteromedial and
lateral malar regions. A schematic of the treatment area is delimited using the following triangle
(Figure 9-l): its base line is parallel to the nasolabial fold (at least 0.4" [1 cm] lateral to ihe fold;,
the superior side ofthe triangle is a line from the superiorpart ofthe nasafalar "i"u." 
to the superior
root of the helix of the ear and the inferior side of the triangle is a line running from the lateral oral
commissure to the superior root of the helix of the ear.
Treatment of nasolabial folds, temples, pre-auricular and periorbital regions are prohibited.
Figure 9-1: Midface Treatment Area
Amount of device to administer: The maximum volume per administration of RHA4 u.rd I
into the midface area is 6.0 mL per treatment session (total for both sides of the fa"", i.e., 3.0 r.r1-
maximum per side).
for
-
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10. ADVERSE EVENTS
Subjects will be monitored carefully
the in
events.
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 conffol device and/or the procedure, will be assessed by the TI or designee
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 safety events will follow all national and local laws and requirements
for the conduct of clinical studies, including ISO 14155 and US 21 CFR 812.150.
10.1. Definitions
10.1.1. Adverse Events
An AE is 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 and whether anticipated
or unanticipated.
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 AEs resulting from insufficient or inadequate IFUs,
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.
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10.1.6. DeviceMalfunction
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 rnuy no1 b"
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
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AE, regardless of the investigation group to which the subject is assigned;
I
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.
10.2.1. Relationship to Device
For each AE identified in the investigation, the TI or designee must assess its relationship to the
study 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.
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If an AE occurs after randomizationbut before the first dose of the study device, the relationship
to the study device and/or the injection will be considered "not applicable". However, such AEs
still need to be recorded.
The relationship assessment, based on clinical judgment, often relies on the following categories:
o A temporal relationship between the event and application of the study or the control device
' 
A plausible biological mechanism for the study or the control device to cause the AE
lAnother possible etiology I
I
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10.3. Safety Reporting
It is TI's responsibility 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 govemance, including FDA regulations, FDA guidance, and
IRB requirements for notification of all types of AEs.
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10.3.4. DeviceMalfunctionsReporting
Device malfunctions will be reporled using the Device Malfunction Report Form and supply
information relevant to the event.
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10.4. Pregnancy
All female subjects 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. Female subjects of childbearing potential 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 female subject of childbearing potential. A subject who is found to be pregnant at Visit 1
will be excluded from the study and considered to be a screen failure for the main study.
A subject who becomes pregnant during the study after the first injection will not receive further
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 
safety representative within 48 hours of learning
of it using the specific Pregnancy Report Form and send it to the same email address as for SAE
reporting.
10.5. Data Monitoring Committee
Not applicable.
10.6. Clinical Events Committee
Not applicable.
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11. STATISTICAL METHODS
This section presents a summary of the planned statistical analyses. A SAP that describes the
details of the analyses to be conducted as well as all statistical assumptions will be written and
approved prior to database lock.
11.1. AnalysisPopulations
The following 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.
r Safety: All subjects who receive at least I treatment with RHA4 or I
o Intent-to-treat (ITT): All subjects who are randomly assigned to either the RHA4 group or
th" I 
control group.
o Per-protocol (PP): All subjects in the ITT population who receive treatment and do not
have any major CIP deviations. The sponsor will identify major CIP deviations prior to
database lock.
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11.2.
This
Sample Size Determination
will randomize at least 200 sub
with a maximum of 210 subjects.
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11.3. Subjects and Demographics
11.3.2. Clinical Investigation Plan Deviations
A CIP deviation is any noncompliance with the clinical investigation CIP or International 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 to 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.
Demo
variables will include
11.4. EffectivenessAnalyses
Primary effectiveness analysis will be based on the PP
the US FDA
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ll.4.l. Primary Effectiveness Analysis
The orimarv analvsts
comparec,o I 
u,
will be performed as follows: to demonstrate non-inferiority of RHA4
8 weeks after the last treatment, the difference inthe TMVDS
between Baseline and 8 weeks will then be tested between
4 minus
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11.4.2. SecondaryEffectivenessAnalysis
Teoxane Midface Volume Deficit Scale change from Baseline (I BLE.l):
Summary statistics (mean, minimum, maximum, SD, and 95% Cl of the mean,
Baseline) will be
for each
visit for TMVDS
overall
treatment
arln
Responder rate for TMVDS il. BLE. l):
Number and proportion of
with95% CI of
rate will be calculated for
each visit
treatment arm
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Global Aesthetic Improvement Scale (I BLE. f):
Frequencies and proportion of subjects with GAIS score categories and rates of GAIS responders
(who have improved or much improved score) along with 95Yo CIs will be presented by treatment
arTn.
FACE-O scores:
Subj ect satisfaction score :
Subject satisfaction
for satisfiedlvery satisfied response will be
tabulated for each visit
11.5. Safety Analyses
and
All AEs will be coded using the MedDRA dictionary. All AEs
described by system organ class (SOC) and preferred term (PT).
the stud will be
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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
o Sign and complete the Investigator's Agreement (see Attachment l7.r)
o Provide an accurate financial disclosure and file an update annually and 1 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 participation
o Complete and file a fully executed clinical trial agreement between sponsor or sponsor's
designee, TI, and institution (as applicable)
o Provide assurance of completed training on the study device and procedures being studied
under the CIP
o Handle and store the RHA4 uttd I 
as per the CIP and their respective IFUs and IBs
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.
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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 notify 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. MaintainingRecords
The TI will maintain the following accurate, complete, and current records relating to the TI's
participation in an investigation:
o Correspondence with another TI, an IRB, the sponsor, a monitor, or the FDA
of each
ect's case history and exposure to the study or control device,
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12.1.4. Prohibition of Promotion
The IDE regulations prohibit the promotion of any investigational device. Therefore, no TI (or any
person acting on behalf of a TI) may promote the investigational use or represent that the device
is safe or effective for the pu{poses for which it is being investigated, or imply safety or
effectiveness (or lack thereof) by discussing individual site experiences in any forum.
Prohibition of promotion does not apply to promotion of the clinical investigation by the sponsor
to facilitate recruitment
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12.2. SponsorResponsibilities
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,
ensunng IRB approv
and
that informed
consent is obtained.
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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.
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13.1. Data Management
The standard
records will be followed
GCP
The Tl/institution 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
identify subjects in this investigation.
13.2. Confidentiality 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 photographs 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 specify whether they allow use of
other purposes such as publication
The
ect's decision will be
release lo
the image for
tracked in a si
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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.r.""r.ury 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 verif,rcation 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 ur" ,""oid"d in the audit
and queries report. All electronic data capture systems must be 21 CFR part ll 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 disignees are responsible
for reporting clinical investigation-requested information in the ecMs.
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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
investigaied, or 2 years 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 TVinstitution 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 I4I55,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
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personnel access to information and clinical supplies related to the investigation.
ftr" Cner *ill 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.
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14. ETHICS AND REGULATORY COMPLIANCE
t4.1.
Conduct
Conduct of the Clinical Investigation
of the clinical investigation will follow
r,
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 goveming local and national regulations, and the clp
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 raise serious questions 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
o Requesting that the applicant conduct additional independent studies to confirm the results
of the questioned investigation
Therefore, any TI (or subinvestigator), his/her spouses, and/or dependent children who has a
potential conflict of interest with this investigation (e.g., patent ownership, royalties, or financial
gain greater than the minimum allowable by their institution) must have the conflict evaluated by
the sponsor. If a financial interest appears to exist, a management plan should be generated tb
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 ICFs, and related subject
information and recruitment materials before the start of the investigation. It is the responsiUitity
of the TI to obtain approval of the CIP from the institution's IRB and to keep the IRB informed of
any UADE as per IRB requirements and SMP. Additional requirements imposed by the IRB or
other regulatory authority will be followed if appropriate. All 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 fnformed 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, 21 CFR Part 50, the Medical Devices Directive 93l42lqiC, and
rso 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 pan
of routine care. Information obtained during the conduct of the clinical investigation that may
impact the subject informed consent may require revisions to the ICFs. If so, revisions and
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reapprovals of such changes by the appropriate regulating authority are required. Documentation
of the current versions of the ICFs 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(anonymoustoDalistidentifyingal1
subjects 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 21
CFRs Part I l, 50,54,56 and 812), ISO l4I55,the Declaration of Helsinki, and the ICH guidelines'
This investigation is to be conducted according to and other applicable national, state, and local
govemment regulations and institutional research policies and procedures.
Should photograph(s) of a subject's face be used for potential publication, promotions, or other
pu{poses, 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 they agree to
use their photographs for use outside the study, such as publication or promotion using a separate
photography release form. Their decision will be stored at the site in a separate photography release
log.
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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 inveitigation
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).
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. ExternalAudits
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 IB and records will be kept to
document product storage and management; sponsor-provided unique identification numbers and
labeling identifying 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 either returned
to the sponsor or to the central pharmacy or destroyed at site level if the appropriate site SOp are
in place.
14.11. Public Domain Access to the Clinical Investigation
A description of this clinical investigation will be available on htp://www.ClinicalTrials.gov, as
required by US law. Information regarding public access will be presented in the ICF, as required
by US law.
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15. GENERAL CONSIDERATIONS
15.1. Discontinuation of the Investigation
Discontinuation of individual subjects is described in Section 7.4'5.
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17. ATTACHMENTS
17.1. Investigator'sAgreement
CLINICAL INVESTIGATION
PLAN NUMBER:
CLINICAL INVESTIGATION
PLAN TITLE:
AMENDED CLINICAL
INVESTIGATION PLAN
I have read this CIP and
to conduct this clinical
Treating Investigator:
Printed Name:
Signature:
Date
A Prospective, Randomized, Blinded Evaluator, Multicenter,
Between-subjects Clinical Study to Evaluate S
and
Effectiveness of RHA@ 4 versus
for Treatment of Midface Volume
Deficiency
I 
t2-Iut-2023
as outlined herein.
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