A Randomized, Blinded Evaluator, No-treatment Control, Multicenter, Prospective Clinical Study of RHA® Redensity Eye for the Treatment of Moderate to Severe Tissue Volume Deficiencies in the Infraorbital Regions
Phase: NA
Conditions: Infra-orbital Hollows, Tear-trough Deformity, Wrinkle
Sponsor: Teoxane SA



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APPROVAL SIGNATURES 
CLINICAL INVESTIGATION 
PLAN NUMBER: 
TEO-RHA-1902 
CLINICAL INVESTIGATION 
PLAN TITLE: 
A Randomized, Blinded Evaluator, No-treatment Control, 
Multicenter, Prospective Clinical Study of RHA® 1 for the 
Treatment of Moderate to Severe Tissue Volume Deficiencies 
in the Infraorbital Regions 
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 
 
 
 
 
 
 
 
Sonia Frappier 
Head of Clinical Development Market Expansion 
TEOXANE SA 
 
 
 
 
 
 
Aurelie Feroyard 
Regulatory Affairs Director 
TEOXANE SA 
 
 
 
 
 
 
 
 
 
Laure Dalodier 
Senior Clinical Project Manager 
TEOXANE SA 
 
 
 
 
 

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SIGNATURE 
 
DATE 
 
 
 
 
Marlis Sarkany, MD 
Senior Medical Director 
Premier Research 
 
 
 
 
 
 
 
 
Charlotte Tucker 
Manager, Biostatistics 
Premier Research 
 
 
 
 
 

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AMENDED PROTOCOL 
Revision history: 
TITLE: 
A Randomized, Blinded Evaluator, No-treatment Control, 
Multicenter, Prospective Clinical Study of RHA® 1 for the 
Treatment of Moderate to Severe Tissue Volume Deficiencies in 
the Infraorbital Regions 
CLINICAL INVESTIGATION 
PLAN NUMBER: 
TEO-RHA-1902 
PROTOCOL VERSION: 
11.0 
ORIGINAL PROTOCOL DATE: 
Original Protocol Version 1.0, 22-June-2020  
AMENDMENT 1 DATE: 
Amended Protocol Version 2.0, 30-July-2020 
AMENDMENT 2 DATE:  
Amended Protocol Version 2.1, 06-August-2020 
AMENDMENT 3 DATE: 
Amended Protocol Version 2.2, 06-August-2020 
AMENDMENT 4 DATE: 
Amended Protocol Version 3.0, 23-September-2020 
AMENDMENT 5 DATE: 
Amended Protocol Version 3.1, 29-October-2020 
AMENDMENT 6 DATE: 
Amended Protocol Version 4.0, 17-March-2021 
AMENDMENT 7 DATE: 
Amended Protocol Version 4.1, 02-June-2021 
AMENDMENT 8 DATE: 
Amended Protocol Version 5.0, 20-July-2021 
AMENDMENT 9 DATE: 
Amended Protocol Version 6.1, 18-November-2021 
AMENDMENT 10 DATE: 
Amended Protocol Version 7.0, 16-May-2022 
AMENDMENT 11 DATE: 
Amended Protocol Version 7.1, 10-October-2022 
AMENDMENT 12 DATE:  
Amended Protocol Version 8.0, 25-January-2023 
AMENDMENT 13 DATE: 
Amended Protocol Version 9.0, 19-September-2023 
AMENDMENT 14 DATE: 
Amended Protocol Version 10.0, 24-January-2024 
AMENDMENT 15 DATE: 
Amended Protocol Version 11.0, 04-March-2024 
AMENDMENT 16 DATE: 
Amended Protocol Version 12.0, 24-April-2024 
 
The following are the amended protocol version 12.0 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 
INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
TITLE OF 
INVESTIGATION 
A Randomized, Blinded Evaluator, No-treatment Control, Multicenter, Prospective 
Clinical Study of RHA® 1 for the Treatment of Moderate to Severe Tissue Volume 
Deficiencies in the Infraorbital Regions 
MANUFACTURER/ 
SPONSOR 
TEOXANE SA, Rue de Lyon 105, CH – 1203 Geneva, Switzerland 
DEVELOPMENT PHASE: 
Pivotal 
CONTROL DEVICE 
NAME 
No treatment 
INDICATION FOR USE 
RHA® 1 is intended to be used for correction of moderate to severe tissue volume 
deficiencies in the infraorbital regions 
CLINICAL 
INVESTIGATION 
PURPOSE 
The purpose of the study is to evaluate the safety and effectiveness of RHA® 1 for 
the correction of moderate to severe tissue volume deficiencies in the infraorbital 
regions 
TREATMENT GROUPS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study (Stage 1 and Stage 2) plans to enroll around 256 subjects (maximum 
259); ≥20% of subjects with Fitzpatrick skin types IV-VI, including 10% of subjects 
presenting with Fitzpatrick skin types V/VI (at least 3% of type V and 3% of type 
VI) with a maximum of 259 subjects. A 3:1 ratio between the RHA® 1 group and 
the No-treatment control group is planned for the overall study enrollment (Stage 1 
and Stage 2 combined). 
It will be a staged study: 
Stage 1 will enroll approximately 58 subjects who will be randomly assigned 
(approximately 6:1 ratio) to the following groups: 
• 
RHA® 1 group – approximately 50 subjects 
• 
Untreated control group – approximately 8 subjects 
Subjects receiving RHA® 1 will be further divided by the method of administration 
(i.e., injection with a needle or a cannula), which will be defined for each site before 
the beginning of the study. Depending on the site, subjects will receive RHA® 1 
either with a needle (RHA® 1 needle subgroup) or by a cannula (RHA® 1 cannula 
subgroup). Site selection will aim to achieve 1:1 distribution between the 
subgroups. Every attempt will be made to enroll approximately 10 subjects with 
Fitzpatrick skin types IV-VI during Stage 1. The enrollment in Stage 2 will be 
adjusted as needed to achieve the overall goal. 
Safety data of all treated Stage 1 subjects up to 24 weeks after the initial treatment 
will be submitted for review as investigational device exemption (IDE) supplement 
to G200191 to request approval to expand the study for Stage 2. 
Stage 2 will commence after the United States (US) Food and Drug Administration 
(FDA) reviews the Stage 1 safety data and gives approval to expand enrollment of 
the study per the updated protocol for Stage 2. The proposed study design for 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
Stage 2 is presented thereafter (Note: it may be revised and submitted for review 
with Stage 1 safety data review). 
Remaining subjects: approximately 198 (maximum 201) subjects will be randomly 
assigned at Screening to 1 of the following groups: 
• 
RHA® 1 group – approximately 136 subjects 
• 
No-treatment control group – approximately 62 subjects 
Subjects receiving RHA® 1 will be further divided by the method of administration 
(i.e., injection with a needle or a cannula), which will be defined for each site before 
the beginning of the study. Depending on the site, subjects will receive RHA® 1 
either with a needle (RHA® 1 needle subgroup) or by a cannula (RHA® 1 cannula 
subgroup). Site selection will aim to achieve 1:1 distribution between the 
subgroups, approximately 100 subjects in each subgroup. 
A total of 248 subjects in the safety study population will be able to detect any 
adverse event (AE) in the subpopulation of subjects with Fitzpatrick skin type IVVI 
with an incidence rate of at least 2.5% (and any AE with an incidence rate of at least 
0.5% in the overall population). At least 248 subjects will be enrolled in the safety 
study population to maintain sufficient power for the safety and effectiveness 
analysis. Including the 8 subjects randomized in the Untreated control group to 
avoid any BLE bias, the study will not enroll more than 259 subjects. 
STUDY CENTERS AND 
LOCATION 
Up to 4 investigative sites in the US will participate in Stage 1 and up to 12 
investigative sites in the United States will participate in Stage 2 of this study. 
STUDY DURATION 
Individual study participation: The minimum and maximum anticipated duration of 
subject participation are 3 to 19 months (12 to 76 weeks), respectively. 
Overall study duration: with the staged enrollment and extended follow-up time 
after retreatment, the anticipated study length is approximately 32 months (nearly 
3 years), including enrollment, which is expected to take approximately 8 weeks 
for Stage 1 and then another 14 weeks after receiving FDA approval to continue to 
Stage 2 but may be extended depending on the public health emergency due to 
Coronavirus disease 2019 (COVID-19). 
Due to the staged enrolment which will be described in the “investigation design” 
section, the overall enrolment will take at least 8 additional months before it may 
resume only upon FDA approval after Stage 1. It is understood that the entire study 
duration will consequently be increased due to the recruitment halt and time for 
FDA review. 
OBJECTIVES 
• 
Primary effectiveness objective: 
o 
To assess the effectiveness of RHA® 1 (as judged by clinicians and 
subjects) for the correction of moderate to severe tissue volume 
deficiencies in the infraorbital regions at 12 weeks after the initial 
treatment. 
 
 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
• 
Secondary effectiveness objectives: 
o 
To assess the effectiveness of RHA® 1 for the correction of moderate to 
severe tissue volume deficiencies in the infraorbital regions up to 52 weeks 
after initial treatment and 12 weeks after retreatment. 
• 
Safety Objective: 
o 
To assess the safety of RHA® 1 in subjects treated for the correction of 
moderate to severe tissue volume deficiencies in the infraorbital regions 
up to 52 weeks after initial treatment and 12 weeks after retreatment. 
o 
To demonstrate that safety of RHA® 1 is not impacted by the method of 
administration (injected with a needle or a cannula). 
• 
Exploratory objective: 
o 
To evaluate the Tyndall effect after treatment with RHA® 1 in the 
infraorbital regions. 
DEVICE TREATMENT 
Method of administration will be either with a 30G ½″ needle (included with the 
product) or a 25G 1½″ cannula (TSK [STERiGLIDETM] or SoftFil® Precision). 
Injection area and depth: RHA® 1 is injected from the sub-dermis to the periosteum 
in the infraorbital hollow. 
Amount of filler to be administered: Up to 1.0 mL per eye at each treatment 
(max: 2.0 mL per treatment). 
Information about the method of administration, injection technique, depth of 
injection (sub-dermis or supraperiosteum), and the amount of filler will be collected 
in the electronic case report form (eCRF). Injection Guidelines will be available to 
the Treating Investigator (TI) prior to his/her first subject visit. 
INVESTIGATION 
DESIGN 
Enrollment 
This is a multicenter, blinded evaluator, randomized, prospective, no-treatment 
control clinical study to identify whether RHA® 1 is superior to no treatment for the 
correction of moderate to severe tissue volume deficiencies in the infraorbital 
regions. The study (Stage 1 and Stage 2 combined) will include at least 20% of 
subjects with Fitzpatrick skin types IV-VI: including minimum of 10% subjects 
presenting with Fitzpatrick skin types V or VI, of which ≥3% will have Fitzpatrick 
skin type V (≥8 subjects) and ≥3% will have Fitzpatrick skin type VI (≥8 subjects). 
Every attempt will be made to enroll approximately 10 subjects with Fitzpatrick 
skin types IV-VI during Stage 1. The enrollment in Stage 2 will be adjusted as 
needed to achieve the overall goal. 
The TI and the Blinded Live Evaluator (BLE) will evaluate the subject’s infraorbital 
hollows independently of each other using the Teoxane Infraorbital Hollows Scale 
(TIOHS) at Screening (Visit 1) for eligibility. If the assessments of the TI and the 
BLE are the same or differ exactly by 1 point on the scale, the difference will be 
considered acceptable. The TI and the BLE must agree that the subject meets the 
inclusion criterion number 4 (TIOHS grade 2 or 3). Bilateral symmetry is not 
required. 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 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
or if their assessments differ by 2 points or more on the scale, the subject will not 
be eligible. 
As requested by the US FDA enrollment for G200191 will be staged. 
 
Stage 1 
During Stage 1, approximately 58 subjects will be enrolled and randomly assigned 
(approximately 6:1 ratio) to RHA® 1 group or to Untreated control group. Subjects 
in the Untreated control group are enrolled to keep the BLE blinded to the study 
treatment and the randomization ratio during Stage 1. Depending on the site, RHA® 
1 will be administered with a 30G ½″ needle (RHA® 1 needle subgroup) or with a 
25G 1 ½″ cannula (RHA® 1 cannula subgroup). Site selection will aim to achieve 
approximately 1:1 distribution between the subgroups. After approximately 
58 subjects are enrolled, recruitment will be halted. 
Subjects enrolled in Stage 1 in the RHA® 1 group will follow the usual schedule 
(Phase 1a and Phase 2) without interruption. In the meantime, safety data from the 
first 24 weeks of the RHA® 1 group will be submitted to the FDA as an IDE 
supplement for an interim safety review. Upon receiving approval to expand 
enrollment from the FDA per the updated submitted study protocol, the enrollment 
will resume for Stage 2. 
Untreated control group 
Subjects randomly assigned to the Untreated control group in Stage 1 will receive 
no treatment. As they are enrolled in order to keep the BLE blinded up to the 
primary endpoint, their visits and assessments will be reduced; they will come to 
the site only at the initial visit and 12 weeks (Visit 5) after randomization, which 
will become their Exit Visit. During the visits they will be assessed by the BLE and 
the subject assessments will not be applicable. The TI assessments will consist of 
screening assessments to assess eligibility (including TIOHS), photography, and 
AE collection. 
Stage 2 
Stage 2 will include approximately 198 (maximum 201) additional subjects. 
Subjects enrolled during Stage 2 will be randomly assigned at Screening (Visit 1) 
to receive RHA® 1 or to receive no treatment (No-treatment control group). Subjects 
receiving RHA® 1 will be further divided by the method of administration (i.e., 
injection with a needle or a cannula), which will be defined for each site before the 
study begins. Depending on the site, RHA® 1 will be administered with a 30G ½″ 
needle (RHA® 1 needle subgroup) or with a 25G 1 ½″ cannula (RHA® 1 cannula 
subgroup). Site selection will aim to achieve approximately 1:1 distribution 
between the subgroups. The BLE will be blinded to the study groups (RHA® 1 
group or No-treatment control group). 
Phase 1a: Up to 12 weeks after the initial treatment for the RHA® 1 group or after 
randomization for the No-treatment control group; primary endpoint 
Subjects who will be randomly assigned to the RHA® 1 group at Screening during 
Stage 1 or Stage 2 will receive their injection at Visit 1. The TI or designee will call 
subjects 72 hours post-treatment (Visit 1 Call). Subjects will come to the site 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
2 weeks (Visit 2), 4 weeks (Visit 3), 8 weeks (Visit 4), and 12 weeks (Visit 5, 
primary endpoint) after the initial treatment. Afterwards, subjects will proceed 
directly to Phase 2. Phase 1b is not applicable for subjects randomly assigned to the 
RHA® 1 group. 
Subjects randomly assigned to the No-treatment control group (Stage 2) at 
Screening will receive no treatment in Phase 1a of the study. They will come to the 
site 2 weeks (Visit 2), 4 weeks (Visit 3), 8 weeks (Visit 4), and 12 weeks (Visit 5, 
primary endpoint) after randomization. After completing all assessments for 
Visit 5, subjects will immediately begin Phase 1b (Visit 1b is on the same day as 
Visit 5) and will receive their initial treatment with RHA® 1. 
Subjects randomly assigned to the Untreated control group (Stage 1) at Screening 
will receive no treatment. They will come to the site 12 weeks after randomization 
(Visit 5, data from this group is not applicable for primary endpoint), which will 
become their Exit Visit. 
Phase 1b: after the primary endpoint assessment up to 12 weeks after the initial 
treatment for the No-treatment control group 
Phase 1b is only applicable to subjects initially randomly assigned to the 
No-treatment control group. Once all evaluations applicable for Visit 5 are 
completed, subjects will proceed directly to Visit 1b (on the same day). Evaluations 
completed at Visit 5 will be used for Visit 1b and will become the new Baseline for 
Phase 1b. 
Subjects will receive their initial treatment with RHA® 1 at Visit 1b. 
Subjects will follow the same schedule as those initially randomly assigned to the 
RHA® 1 group: RHA® 1 will be administered on the same day (Visit 1b). The TI or 
designee will call the subject 72 hours post-treatment (Visit 1b Call). Subjects will 
come to the site 2 weeks (Visit 2b), 4 weeks (Visit 3b), 8 weeks (Visit 4b), and 
12 weeks (Visit 5b) after their initial treatment. Afterwards, subjects will proceed 
to Phase 2. 
Phase 2 and Exit Visit: 12 weeks after the initial treatment up to the end of the study 
for the RHA® 1 group and the No-treatment control group 
Phase 2 will occur 12 weeks after receiving initial treatment with RHA® 1 for 
subjects in the RHA® 1 group (Stage 1 and Stage 2) and the No-treatment control 
group (after Phase 1b). 
All these subjects will come to the site 24 weeks (Visit 6), 36 weeks (Visit 7), and 
52 weeks (Visit 8) after their initial treatment. All subjects will be followed for 
52 weeks after their initial treatment with RHA® 1. 
Subjects will be offered retreatment at Visit 8 (52 weeks after their initial 
treatment). Retreatment will be administered if the TI deems it to be appropriate 
and the subject agrees. If the subject does not receive retreatment, Visit 8 (52 weeks 
after initial treatment) will become the Exit visit. 
If the subject receives retreatment at Visit 8, the TI or designee will call him or her 
after 72 hours (Visit 8 Call). The subjects will come to the site 2 weeks (Visit 9; 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
safety only), 4 weeks (Visit 10), and 12 weeks (Visit 11) after retreatment for 
follow-up and safety assessments. Visit 11 will be the Exit Visit. 
Assessments throughout the study: RHA® 1 group (Stage 1 and Stage 2) and 
No-treatment control group 
The TI will conduct safety and effectiveness evaluations according to the schedule 
of events until the Exit Visit (Visit 8 or 11). Subjects with an ongoing adverse 
device effect (ADE) will be followed until the event(s) has resolved or resolved 
with sequelae, or deemed no longer necessary as per TI judgment, or if follow-up 
is no longer possible. 
Subjects will report their Common Treatment Responses (CTRs) in a subject diary 
for 30 days after any injection (initial or retreatment). 
The BLE will conduct assessments of effectiveness at all visits starting at Visit 5 
(12 weeks after randomization). The primary endpoint assessment will be at Visit 5 
(12 weeks after randomization) only. The primary endpoint will include data from 
subjects assigned to the RHA® 1 group (Stage 1 and Stage 2) and the No-treatment 
control group before receiving initial injection.  
BLINDING 
The BLE will be blinded to allocation to groups (RHA® 1 group, Untreated control 
group, No-treatment control group) and to randomization ratio. Furthermore, to 
ensure that they remain blinded 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. 
PRIMARY 
EFFECTIVENESS 
ENDPOINT 
The primary endpoint will be the responder rate after 12 weeks. The effectiveness 
of RHA® 1 will be demonstrated if: 
• 
The responder rate for subjects treated with RHA® 1 (Stage 1 and Stage 2) 
is statistically superior to the responder rate for subjects of the 
No-treatment control group 12 weeks (Visit 5) after randomization as 
assessed by the BLE using the live-validated TIOHS. Specifically, the 
primary hypothesis is: 
Ho: Δ = 0 
Ha: Δ > 0 
where Δ = RHA1 response rate minus No-treatment control response rate. 
Response rate is defined as number of responders divided by number of 
subjects in the analysis population for the given treatment group. 
Additionally, the following 2 conditions must be met: 
• 
The responder rate for RHA® 1 is ≥70% 
• 
The difference between the responder rate for subjects treated with RHA® 1 
and the No-treatment control group is ≥50% 
A responder will be defined as a subject with ≥1-grade improvement in each of the 
eyes on the TIOHS as assessed by the BLE before initial treatment and 12 weeks 
after the initial treatment (Visit 5). Improvement of the right eye and the left eye 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
will be assessed individually (one eye at a time). A responder will be defined when 
the right eye improves by ≥1-grade and when the left eye improves by ≥1 grade. 
The co-primary endpoint will be the change from Baseline in selected questions of 
the FACE-Q Appraisal of lower eyelids domain score (converted to a 0-100 scale – 
Rasch conversion) at 12 weeks. The effectiveness of RHA® 1 will be demonstrated 
if the modified FACE-Q Appearance of lower eyelids change from Baseline score 
for subjects treated with RHA® 1 is statistically superior (by at least 12 points) to 
the subjects of the No-treatment control group 12 weeks (Visit 5) after 
randomization (including subjects who received RHA® 1 during Stage 1). 
Specifically, the co-primary hypothesis is: 
Ho: Δ = 0 
Ha: Δ > 0 
where Δ = RHA1 change from Baseline minus No-treatment control change from 
Baseline. 
Additionally, the following 2 conditions must be met: 
• 
The mean change from Baseline of the modified FACE-Q “Appraisal of 
lower eyelids” raw score for RHA® 1 is ≥ 3 
• 
The difference between the modified FACE-Q “Appraisal of lower 
eyelids” change from Baseline for subjects treated with RHA® 1 and the 
No-treatment control group is ≥12. 
Only the following questions will be considered for the co-primary endpoint: 
• 
Question “d”: How noticeable the lines under your eyes are? 
• 
Question “e”: Crepey (wrinkled) skin under your eyes? 
• 
Question “f”: How old the area under your eyes makes you look? 
• 
Question “g”: How tired the area under your eyes makes you look? 
Only data from Phase 1a (Stage 1 and Stage 2) will be taken into account. Data from 
subjects randomly assigned to the No-treatment control group after treatment 
received in the Phase 1b will not be pooled for the primary endpoint analysis. 
Superiority will be declared if: 
• 
the lower bound of 2-sided 95% confidence interval for the responder rate 
for RHA® 1 is at least 70%, and 
• 
the lower bound of 2-sided 95% confidence interval for the difference in 
the responder rate between subjects treated with RHA® 1 and the 
No-treatment control group is at least 50%, and 
• 
the lower bound of 2-sided 95% confidence interval for the modified 
FACE-Q “Appraisal of lower eyelids” raw score for RHA® 1 is at least 3, 
and 
• 
the lower bound of 2-sided 95% confidence interval for the difference in 
mean change from Baseline of the modified FACE-Q between RHA® 1 
treated group and the No-treatment control group is at least 12 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
SECONDARY 
EFFECTIVENESS 
ENDPOINTS 
The secondary endpoints will consist of the following: 
• 
Proportion of subjects with both eyes with ≥1-grade improvement on the 
TIOHS as assessed: 
o 
By the BLE at each site visit starting from Visit 5 (12 weeks after 
randomization/initial treatment) = rate of responders at the given time 
point 
o 
By the TI at each site visit starting from Visit 2 (2 weeks after 
randomization/initial treatment) 
o 
By the Independent Panel Review (IPR) at Baseline and Visit 5 (12 weeks 
after randomization/initial treatment) 
• 
Proportion of subjects with both eyes and with one eye with ≥1-grade, 
≥2-grade, ≥3-grade improvement on the TIOHS as assessed: 
o 
By the BLE at each site visit starting from Visit 5 (12 weeks after 
randomization/initial treatment) 
o 
By the TI at each site visit starting from Visit 2 (2 weeks after 
randomization/initial treatment) 
o 
By the IPR at Baseline and Visit 5 (12 weeks after randomization/initial 
treatment) 
• 
Proportion of subjects who were “improved” or “much improved” using the 
Global Aesthetic Improvement Scale (GAIS) 
o 
By the BLE at each site visit starting from Visit 5 (12 weeks after 
randomization/initial treatment) 
o 
By the TI at each site visit starting from Visit 3 (4 weeks after 
randomization/initial treatment) 
o 
By the subject at each site visit from Visit 3 (4 weeks after 
randomization/initial treatment) 
• 
Proportion of subjects “satisfied” or “very satisfied” with the effect of the study 
treatment, using the Subject satisfaction scale as assessed by the subject at each 
site visit from Visit 3/Visit 3b (4 weeks after initial treatment) 
• 
FACE-Q assessment by the subject through the Appraisal of lower eyelids (all 
questions) scale of the FACE-Q at each site visit starting from Baseline (except 
for Visit 2) 
• 
Periorbital Subject Assessment Questionnaire (PSAQ) assessment by the 
subject 
o 
Only part A at Baseline (Visit 1/Visit 1b before initial treatment) 
o 
Parts A and B without question 12 at each site visit starting from 
Visit 3/Visit 3b (after initial treatment) 
o 
Parts A and B including question 12 on the Exit visit 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
• 
Total volume of RHA® 1 per eye and per treatment session to obtain Optimal 
Cosmetic Result (OCR) 
• 
Proportion (%) of subjects retreated 
SAFETY ENDPOINTS 
The safety endpoints: 
• 
Adverse events with a focus on treatment related AEs (ADEs) based on the TI 
assessment, and AEs reported from the CTR diary from randomization 
• 
Assessment of blink and closure test and visual disturbances through functional 
assessments 30 minutes after injection and at each visit: Snellen visual acuity, 
confrontational visual field test, ocular motility; any vision disturbances and 
stroke or stroke-like symptoms will be understood as an Adverse Event of 
Special Interest (AESI) 
• 
Assessment of neurological functions such as subject’s mental status, motor 
function, sensory function, reflexes, coordination, and cranial nerve functions 
in case of visual disturbances or signs/symptoms of visual disturbances; any 
abnormal neurological results will be considered as an SAE 
• 
Post-injection CTR, including visual disturbances, through 30-day subject CTR 
diary 
• 
Assessment of injection site pain immediately after injection is completed (both 
eyes), at 5 minutes, 15 minutes, and 30 minutes after injection on a visual 
analog scale (VAS) (0-100 mm) 
• 
Assessment of safety comparison between subjects with Fitzpatrick skin 
types I-III and IV-VI throughout the study 
• 
Assessment of safety comparison between subjects receiving RHA® 1 
treatment with a needle and a cannula 
EXPLORATORY 
ENDPOINT 
Exploratory endpoint includes Tyndall effect assessment by the TI at all site visits 
after initial treatment (Visit 1/Visit 1b)  
ELIGIBILITY CRITERIA 
Inclusion Criteria: 
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 1 year or 
surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy]); or must have a negative urine pregnancy test 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: 
a. 
Hormonal methods, such as oral, implantable, injectable, or transdermal 
contraceptives for a minimum of 1 full cycle (based on the subject’s 
typical menstrual cycle period) before randomization 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
b. Total abstinence from sexual intercourse since the last menses before 
randomization 
c. 
Intrauterine device 
d. Double-barrier method (condoms, sponge, diaphragm, with spermicidal 
jellies, or cream) 
3. Subject is seeking treatment of moderate to severe tissue volume deficiencies 
in the infraorbital region (realistic and achievable as per TI opinion) 
4. Has a grade of 2 to 3 (moderate to severe) on the TIOHS for both eyes 
Note: If the assessments of the TI and the BLE are the same or differ exactly 
by 1 point on the scale, the difference will be considered acceptable. The TI 
and the BLE need to agree that the subject meets the eligibility criterion 
(TIOHS grade 2 or 3). Bilateral symmetry is not required. If the subject is 
eligible, the BLE’s assessment will be used for the Baseline 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 on the scale, the subject will not be 
eligible. 
5. Able to follow study instructions and complete all required visits 
6. Willing to 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 
Exclusion Criteria: 
A potential subject will be excluded from the study if he/she meets any of the 
following exclusion criteria: 
1. Known hypersensitivity or previous allergic reaction to any component of the 
study device, including local anesthetics of the amide type (e.g., mepivacaine, 
lidocaine), including known or suspected lidocaine hypersensitivity, or allergy 
to Gram-positive bacterial proteins 
2. Known history of multiple severe allergies, or history of anaphylactic shock 
3. Subjects who have either at least one of the following assessments during the 
vision tests: Snellen acuity test worse than 20/40 (with corrections, if 
applicable); abnormal confrontational visual field test; abnormal ocular 
motility test 
4. Prior lower eyelid surgery, including orbital or midface surgery, or has a 
permanent implant or graft in the midfacial region that could interfere with 
effectiveness assessments or plans to have it during the study 
5. Is planning to undergo during the study or has undergone any type of facial, 
plastic, nonablative, or reconstructive surgery (e.g., blepharoplasty, face lift, or 
rhinoplasty) within 6 months before randomization. Subject is also excluded if 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
residual swelling is present or complete healing has not occurred within at least 
6 months of the treatment received. 
6. Is planning to undergo during the study or has been injected in the treated area 
or upper part of the face (above the lower orbital rim) with: 
a. 
Semi-permanent 
dermal 
filler 
(e.g., 
calcium 
hydroxylapatite, 
poly-L-lactic acid) ≤24 months before randomization 
b. Bioresorbable facial dermal filler (hyaluronic acid, collagen, or 
autologous fat) ≤12 months before randomization 
c. 
Botulinum toxin injection ≤ 6 months before randomization 
d. Permanent filler injection (e.g., polymethylmethacrylate, silicone) at any 
time in the past 
7. Is planning to undergo during the study or has been subjected to procedures in 
the periorbital or malar region ≤6 months before randomization using: 
a. 
Laser/light therapies (e.g., cutaneous laser, intense pulse light, 
photodynamic therapy, or photomodulation treatment) 
b. Neuromodulator injections 
c. 
Mesotherapy 
d. Radiofrequency 
e. 
Dermabrasion 
f. 
Chemical procedures, such as peels (trunk and extremities permitted) 
g. Prescription-strength topical retinoids 
h. Other ablative or nonablative procedures 
8. Has an orbital fat prolapse that might be linked to high weight variability (loss 
or gain), excessive lower eyelid skin laxity, ectropion, entropion, or 
previously/currently 
treated 
with 
fat 
injections 
≤12 months 
before 
randomization 
9. Has triangular malar mounds or fluid bags 
10. Known 
susceptibility 
to 
keloid 
formation, 
hypertrophic 
scars, 
hyperpigmentation, or compromised healing that would compromise the 
effectiveness outcome 
11. Ongoing cutaneous infection at the site of injection at randomization 
12. Any significant concomitant skin disease or ocular condition that may interfere 
with the study assessments as judged by the TI 
13. Compromised immunity, including but not limited to, poorly controlled 
diabetes mellitus (all types), autoimmune disease, or treatment with systemic 
corticosteroids, standard immunosuppressants, or biologics that may increase 
the risk of infection as judged by the TI 
14. Subjects with known prolonged bleeding times because of disease or taking 
any products known to increase coagulation time (including but not limited to 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
warfarin, low-dose aspirin, vitamin E, fish oil, nonsteroidal anti-inflammatory 
drugs, as judged by the TI) ≤1 week before randomization 
15. Has received any investigational product, including medical devices, within 
90 days prior to randomization or is planning to participate in another 
investigation during the course of the study 
16. 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 
17. Clinically significant alcohol or drug abuse or history of poor cooperation or 
unreliability as judged by the TI 
18. Has eye tattoos, scars, lumps, or severe asymmetry that would interfere with 
visualization of the eye region for the effectiveness assessments as per TI 
discretion 
19. Study staff or close relative to study staff (e.g., parents, children, siblings, or 
spouse) 
ASSESSMENTS 
• 
TIOHS: A live-validated 5-point scale (from grade 0 to 4) for assessing 
infraorbital hollows depression as assessed by TI and BLE 
• 
GAIS: A subjective, balanced, 5-point scale assessing aesthetic improvement 
as assessed by the subject, TI, and BLE 
• 
FACE-Q scale: Validated Subject-Reported Outcome Measure, assessed at 
each study visit by the subject using the Appraisal of lower eyelids scale 
• 
Subject satisfaction scale: A subjective, balanced, 5-point scale assessing 
subject satisfaction with study treatment 
• 
Treatment volume: The total injected volume of RHA® 1 per eye and per 
treatment session injected to obtain OCR 
• 
PSAQ: A subjective, balanced, 7-point questionnaire assessing aesthetic 
improvement and satisfaction by the subject 
• 
Tyndall effect assessment by TI at each site visit after initial treatment 
(Visit 1/Visit 1b) 
• 
Adverse events: with the focus on AEs related to treatment (ADEs), 
Unanticipated Adverse Device Effects (UADEs), serious AEs (SAEs), AESIs, 
AEs from CTRs, causality, and severity as per TI assessment 
• 
Vision assessment and blink and closure tests: Assessment by TI of blink and 
closure function and vision disturbances through functional assessments: 
Snellen visual acuity, confrontational visual field test, ocular motility 
• 
Basic neurological examination by TI in case of visual disturbances or 
signs/symptoms of visual disturbances: assessment of the subject’s mental 
status, motor function, sensory function, reflexes, coordination, and cranial 
nerve functions 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
• 
Post-injection CTRs: through 30-day subject CTR diary, which also includes 
vision disturbances 
• 
Assessment by the subject of injection site pain immediately after injection, at 
5 minutes, 15 minutes, and 30 minutes after injection on a VAS (0 – 100 mm) 
STATISTICAL METHODS 
AND ANALYSIS 
SUMMARY 
All data will be recorded in eCRFs. 
The following 4 analysis populations are planned for this investigation: 
• 
Screening population: All subjects who provide informed consent and 
demographic and/or Baseline Screening assessment results, regardless of their 
randomization and treatment status in the investigation. The untreated control 
group will only be included in the Screening population as they will not receive 
RHA® 1 treatment throughout the clinical study 
• 
Safety population (SAFT): All subjects who are assigned to either the RHA® 1 
group or the No-treatment control group and complete Visit 1 
• 
Intent-to-Treat population (ITT): All subjects who are assigned to either the 
RHA® 1 group (from Stage 1 and Stage 2) or the No-treatment control group 
and complete Visit 1. Subjects will be analyzed according to their initially 
assigned arm assignment, regardless of whether or not they received RHA® 1 
• 
Per-Protocol population (PP): All subjects in the ITT population who 
completed up to Visit 5 (primary endpoint visit at 12 weeks) with no major CIP 
deviations that could affect effectiveness assessments. The sponsor will 
identify major CIP deviations per Protocol Deviation Guidance Plan (PDGP) 
prior to the database lock. 
Analysis of the primary effectiveness endpoints will be based on the ITT population 
and will be repeated for the PP population. Analysis of the secondary effectiveness 
endpoints will be based on the ITT population. TIOHS responder rate as assessed 
by BLE secondary analyses will be repeated for the PP population. 
Before the primary analysis is performed, a poolability analysis will be conducted 
for sites and needle/cannula subgroups by: 
• 
Comparison for the Baseline TIOHS values by sites and by needle/cannula 
subgroups (by means of analysis of covariance [ANCOVA] or relevant non-
parametric test e.g., Mann–Whitney–Wilcoxon) 
• 
Comparison of rate of responders at Visit 5 by sites and by needle/cannula 
subgroups based on TIOHS for each treatment arm (by means of Chi-squared 
test) 
• 
Comparison of the modified FACE-Q “Appraisal of lower eyelids” with only 
the last 4 question score converted to a 0-100 scale by Rasch-conversion by 
sites and by needle/cannula subgroups for each treatment arm at Visit 5 (by 
means of ANCOVA or relevant non-parametric test e.g., Mann–Whitney–
Wilcoxon) 
For the ITT analysis of the primary effectiveness endpoint, multiple imputations 
will be used for missing observations. Specifically, missing change from Baseline 
in TIOHS at 12 weeks will be imputed using the regression method with treatment 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
group as the independent variable, TIOHS change from Baseline as the dependent 
variable, and age, sex, Fitzpatrick skin type (I-III / IV-VI) and TIOHS at Baseline 
(BLE) as covariates. One data will be imputed per eye. 
The following sensitivity analysis of the primary endpoint will be performed 
(further described in the statistical analysis plan): 
• 
Mean imputation approach 
• 
Baseline observation carried forward if >5% of missing data 
• 
All missing as success, half missing as success and worst-case imputations 
• 
The main analysis will be repeated for the IPR data 
One primary analysis will be performed: 
• 
The RHA® 1 group vs. the No-treatment control group 
Primary Effectiveness Analysis: 
The rate of responders 12 weeks after randomization in the RHA® 1 group (Stage 1 
and Stage 2) will be compared with the rate of responders in the No-treatment 
control group using an independent testing based on a 2-group, 1-sided, Fisher’s 
exact statistic test. To achieve superiority, the observed p-value must be ≤0.025. 
Additionally, to be able to declare superiority: 
• 
At least 70% of the subjects treated with RHA® 1 must be responders 
• 
The difference between the responder rate for subjects treated with RHA® 1 
and the No-treatment control group must be ≥50% points 
The co-primary endpoint, change from Baseline in modified FACE-Q Appearance 
of lower eyelids score (converted to a 0-100 scale using Rasch conversion) at 12 
weeks, will be evaluated. 
Only the following questions will be considered for the co-primary endpoint: 
• 
Question “d”: How noticeable the lines under your eyes are? 
• 
Question “e”: Crepey (wrinkled) skin under your eyes? 
• 
Question “f”: How old the area under your eyes makes you look? 
• 
Question “g”: How tired the area under your eyes makes you look? 
The modified FACE-Q Appearance of lower eyelids change from Baseline score 
for subjects treated with RHA® 1 (Stage 1 and Stage 2) will be compared with 
FACE-Q Appearance of lower eyelids for subjects of the No-treatment control 
group at 12 weeks (Visit 5) after randomization using t-test or non-parametric 
equivalent like Wilcoxon rank-sum test. 
Superiority will be declared if: 
• 
the lower bound of 2-sided 95% confidence interval for the responder rate 
for RHA® 1 is at least 70%, and 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
• 
the lower bound of 2-sided 95% confidence interval for the difference in 
the responder rate between subjects treated with RHA® 1 and the 
No-treatment control group is at least 50%, and 
• 
the lower bound of 2-sided 95% confidence interval for the modified 
FACE-Q “Appraisal of lower eyelids” raw score for RHA® 1 is at least 3, 
and 
• 
the lower bound of 2-sided 95% confidence interval for the difference in 
mean change from Baseline of the modified FACE-Q between RHA® 1 
treated group and the No-treatment control group is at least 12 
Overall superiority can be declared if all superiority criteria are met both for primary 
and co-primary endpoints. 
Subgroup analyzes for the following primary efficacy variables are planned: 
• 
Modified FACE-Q change from Baseline Rasch converted score will be 
summarized for each Fitzpatrick skin type (I-III, IV-VI, and V/VI), volume 
injected (≤1mL / 1mL-≤1.5mL / >1.5mL), age group (22-≤median age of the 
ITT population / >median age of the ITT population ), sex, ethnicity (Hispanic 
or Latino / Not Hispanic or Latino), site, and method of administration 
(needle/cannula) categories 
• 
Responder rates of treatment arms will be summarized for Fitzpatrick skin type 
subgroups (I-III, IV-VI, and V/VI), volume injected (≤1mL / 1mL-≤1.5mL / 
>1.5mL), age group (22-≤median age of the ITT population / >median age of 
the ITT population ), sex, ethnicity (Hispanic or Latino / Not Hispanic or 
Latino), site, and method of administration (needle/cannula) categories 
These analyses will be performed on the ITT population and based on the data after 
applying the multiple imputation method from primary analysis. 
Secondary Effectiveness Analysis: 
No imputation will be performed for secondary (or pooled secondary) effectiveness 
endpoints, or safety outcomes; all analyses will utilize available data as observed. 
For each treatment group, descriptive summary statistics (mean, minimum, 
maximum, standard deviation [SD], and 95% confidence interval [CI] of the mean) 
and change from Baseline (absolute and relative) will be presented by study visit. 
Baseline is defined as the measurement preceding the initial treatment. For the 
No-treatment control group, Baseline is defined as the last measurement at Visit 5 
(12 weeks after randomization) before continuing to Phase 1b. 
For endpoints with qualitative results, frequencies and percentages will be 
calculated and presented for each visit by treatment group. 
A Fisher’s exact test will be used to compare proportions at each time point between 
the RHA® 1 group (Stage 1 and 2 subjects) and the No-treatment control group in 
Phase 1a. 
For the TIOHS, ≥1-grade, ≥2-grade, or ≥3-grade improvement (for one eye and for 
both eyes) frequencies will be tabulated for individual eyes and subjects. 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
For the FACE-Q, the answers to all questions of the scale will be pooled and data 
will be transformed and adapted to a scale of 100 units (i.e., worst/lowest score = 0; 
best/highest score = 100) as per FACE-Q user manual. The highest score will reflect 
positive outcome. 
For the PSAQ, absolute and relative frequencies will be presented for each question 
and category in a summary data table. 
For the GAIS (all evaluators), proportions of “improved” and “much improved” 
will be presented, along with the number of subjects and 95% CI of the proportion 
at each applicable study visit. 
For subject satisfaction, proportions of “satisfied” and “very satisfied” will be 
presented, along with the number of subjects and 95% CI of the proportion at each 
applicable study visit. 
The total volume per treatment session to obtain the OCR, and volume injected, 
will also be described in statistical summaries (mean, SD, median, quartiles, 
minimum, and maximum). The volume will be presented per eye and for both eyes. 
The percentage of subjects receiving retreatment and total volume from that session 
will be summarized. 
The assessment of the Tyndall effect will be tabulated in a frequency table 
presenting relative and absolute frequencies. 
Additionally, secondary endpoints will be presented for the following subgroups at 
Visit 1/V1b, Visit 5/V5b, Visit 6 and Visit 8: 
• 
Fitzpatrick skin type V/VI 
• 
Age groups (22-≤median age of the ITT population / >median age of the 
ITT population) 
• 
Sex (Male / Female) 
Safety Analyses: 
The CTR for 30 days after injection will be tabulated by severity and duration 
categories (0 to 3 days, 3 to 7 days, 7 to 14 days, 14 to 21 days, and 21 to 30 days), 
and by Fitzpatrick skin type subgroups (I-III, IV-VI, and V/VI). 
The CTR incidence rates will be presented by treatment groups (RHA® 1 needle 
and cannula subgroups separately, and pooled RHA® 1 needle and cannula 
subgroups). CTRs present on the last day of the diary will be automatically reported 
as AEs. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 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 1 AE that are treatment related (ADE) will be presented. For subjects treated 
with RHA® 1, the percentages of subjects who experience at least one ADE will be 
compared between Fitzpatrick skin type subgroups (I-III and IV-VI), age groups, 
sex, ethnicity, administration method and volume injected, using a Fisher exact test. 
Further analyses will be performed for the AEs and ADEs as described in the 
statistical analysis plan. For UADEs and AESIs, which are less frequent, 

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INVESTIGATIONAL 
PRODUCT NAME 
RHA® 1 
CLINICAL 
INVESTIGATION PLAN 
(CIP) NUMBER 
TEO-RHA-1902 
information will be provided in separate listings. Individual listings of all AE data 
will also be given (i.e., by MedDRA system organ class, duration, and method of 
administration). 
Assessment of injection site pain immediately after injection, at 5, 15, and 
30 minutes after injection (0-100 mm VAS) will be described with summary 
statistics (mean, minimum, maximum, median, SD, and 95% CI). 
A statistical analysis plan that will describe the details of the analyses to be 
conducted and all statistical assumptions will be written and approved prior to 
database lock. 
As requested by the US FDA enrollment for G200191 will be staged. Stage 1 will 
enroll approximately 58 subjects who will be randomly assigned to receive 
treatment (RHA® 1 will be injected with a needle or a cannula in an approximate 
1:1 ratio) or who will be in Untreated control group. Enrollment will ensure to 
include some subjects from each Fitzpatrick skin type of groups IV, V, and VI. 
After at least 58 subjects are enrolled, the recruitment will be halted. Stage 1 treated 
subjects will be followed for 24 weeks to gather safety data for an IDE supplement 
to support expanding study enrollment. The IDE supplement will be provided to the 
FDA for an interim safety review. Upon receiving approval from the FDA to expand 
the study enrollment, the enrollment will resume. 
For the interim safety review (after Stage 1), complete descriptive safety analysis 
will be performed, including tabulations of CTR, AE/AESI/SAE/ADE/UADE, and 
injection site pain described for the final analysis. Additionally, CTR and AE 
incidence rates (overall and by MedDRA system organ class and preferred term) 
will be summarized by injection depth. 
One additional interim analysis will be performed during Stage 2 after all subjects 
complete Visit 5. The database will be cleaned and locked after Visit 5 for the 
efficacy data collected before Visit 5. The primary and efficacy endpoints will be 
analyzed based on the locked data collected until Visit 5. Safety data will be also 
reported based on these data. After the data is captured from the database, the study 
will continue as planned to collect data for further evaluations.  

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2.2. Schedule of Events 
Table 2-1 
Phase 1a and 1b 
 
Phase 1a 
RHA® 1 group, Untreated control group, and 
No-treatment control group  
Phase 1b 
No-treatment control group after receiving 
RHA® 1 
Phase 2 
See 
Table 
2-2 
  
Baseline 
 
 
 
 
Primary 
endpoint 
 
 
 
 
 
 
 
Weeks/days post randomization 
or initial treatment 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W ±3d 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W 
±3d 
Visit 
V1a 
V1 
Call 
V2 
V3 
V4 
V5b 
V1b 
V1b 
Call 
V2b 
V3b 
V4b 
V5b 
RHA® 1 group (Stage 1 and Stage 2 subjects), Untreated control group (Stage 1), 
No-treatment control group (Stage 2) 
 
See 
Table 
2-2 
 
 
Written informed consent a 
X 
 
 
 
 
 
Demographics a 
X 
 
 
 
 
 
Medical/surgical/ophthalmologic 
history a 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria a 
X 
 
 
 
 
 
Randomization a 
X 
 
 
 
 
 
UPT a, c 
X 
 
 
 
 
 
Vision assessment, blink and 
closure test a, d 
X 
 
 
 
 
 
RHA® 1 group (needle and cannula subgroups) (Stage 1 and Stage 2 subjects) 
Not applicable for the RHA® 1 group 
Prior and concomitant 
medications a 
X 
X 
X 
X 
X 
X 
 
Injection of RHA® 1 
X 
 
 
 
 
 
Hand out 30-day CTR diary 
after 
 
 
 
 
 
30-day CTR diary retrieval and 
review 
 
 
 
X 
 
 
TI Assessments 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 

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Phase 1a 
RHA® 1 group, Untreated control group, and 
No-treatment control group  
Phase 1b 
No-treatment control group after receiving 
RHA® 1 
Phase 2 
See 
Table 
2-2 
  
Baseline 
 
 
 
 
Primary 
endpoint 
 
 
 
 
 
 
 
Weeks/days post randomization 
or initial treatment 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W ±3d 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W 
±3d 
Visit 
V1a 
V1 
Call 
V2 
V3 
V4 
V5b 
V1b 
V1b 
Call 
V2b 
V3b 
V4b 
V5b 
Photography 
before/ 
after 
 
X 
X 
X 
X 
Tyndall effect assessment  
after 
 
X 
X 
X 
X 
Vision assessment, blink and 
closure testd 
before/ 
after 
 
X 
X 
X 
X 
See 
Table 
2-2 
GAIS  
 
 
 
X 
X 
X 
TIOHS 
before 
 
X 
X 
X 
X 
BLE Assessments 
 
 
 
 
 
 
GAIS 
 
 
 
 
 
X 
TIOHS 
before 
 
 
 
 
X 
Subject Assessments 
 
 
 
 
 
 
Pain VAS  
after 
 
 
 
 
 
FACE-Q 
before 
 
 
X 
X 
X 
GAIS 
 
 
 
X 
X 
X 
PSAQ 
X (part A 
only) 
 
 
X  
X  
X 
Subject satisfaction 
 
 
 
X 
X 
X 
Untreated control group (Stage 1 only)b 
Not applicable for the Untreated control groupb 
TI Assessments 
 
 
 
 
 
 
 
Adverse events 
X 
 
 
 
 
X 
Photography 
X 
 
 
 
 
X 
TIOHS 
Xa 
 
 
 
 
 

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Phase 1a 
RHA® 1 group, Untreated control group, and 
No-treatment control group  
Phase 1b 
No-treatment control group after receiving 
RHA® 1 
Phase 2 
See 
Table 
2-2 
  
Baseline 
 
 
 
 
Primary 
endpoint 
 
 
 
 
 
 
 
Weeks/days post randomization 
or initial treatment 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W ±3d 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W 
±3d 
Visit 
V1a 
V1 
Call 
V2 
V3 
V4 
V5b 
V1b 
V1b 
Call 
V2b 
V3b 
V4b 
V5b 
BLE Assessments 
 
 
 
 
 
 
 
See 
Table 
2-2 
GAIS 
 
 
 
 
 
X 
TIOHS 
X 
 
 
 
 
X 
No-treatment control group (Stage 2 only) 
UPTc 
 
 
before 
 
 
 
 
 
Injection of RHA® 1 
 
X 
 
 
 
 
 
Hand out 30-day CTR diary 
 
after 
 
 
 
 
 
30-day CTR diary retrieval and 
review 
 
 
 
 
X 
 
 
TI Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications a 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
after 
X 
X 
X 
X 
X 
Photography 
X 
X 
X 
X 
X 
after 
 
X 
X 
X 
X 
Tyndall effect assessment  
 
 
 
 
 
after 
 
X 
X 
X 
X 
Vision assessment, blink and 
closure testd 
 
 
 
 
 
before/ 
after 
 
X 
X 
X 
X 
GAIS  
 
 
X 
X 
X 
 
 
 
X 
X 
X 
TIOHS 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
BLE Assessments 
 
 
 
 
 
 
 
 
 
 
 
GAIS 
 
 
 
 
X 
 
 
 
 
 
X 
TIOHS 
X 
 
 
 
 
X 
 
 
 
 
 
X 

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Phase 1a 
RHA® 1 group, Untreated control group, and 
No-treatment control group  
Phase 1b 
No-treatment control group after receiving 
RHA® 1 
Phase 2 
See 
Table 
2-2 
  
Baseline 
 
 
 
 
Primary 
endpoint 
 
 
 
 
 
 
 
Weeks/days post randomization 
or initial treatment 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W ±3d 
0W 
3d 
±2d 
2W 
±3d 
4W 
±3d 
8W 
±3d 
12W 
±3d 
Visit 
V1a 
V1 
Call 
V2 
V3 
V4 
V5b 
V1b 
V1b 
Call 
V2b 
V3b 
V4b 
V5b 
Subject Assessments 
 
 
 
 
 
 
 
 
 
 
 
Pain VAS  
 
 
 
 
 
after 
 
 
 
 
 
FACE-Q 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
GAIS 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
PSAQ 
 
 
X 
X 
 
X (part 
A only) 
 
 
X 
X 
X 
Subject satisfaction 
 
 
X 
X 
 
 
 
 
X 
X 
X 
Abbreviations: BLE = Blinded Live Evaluator; CTR = Common Treatment Response; d = day; GAIS = Global Aesthetic Improvement Scale; PSAQ = Periorbital 
Subject Assessment Questionnaire; TI = Treating Investigator; TIOHS = Teoxane Infraorbital Hollows Scale; UPT = urine pregnancy test; V = visit; VAS = visual 
analog scale; W = week. 
Footnotes: 
a. 
Procedures performed at Visit 1 prior to randomization (or initial injection) represent Screening. Written informed consent must precede all 
study-related procedures. Demographics, medical/surgical/ophthalmologic history, prior and concomitant medication data collection, and UPT need to 
be performed prior to first injection to assess eligibility and are part of screening procedures performed at Visit 1. Eligible subjects are then randomly 
assigned to groups and all other study procedures are performed as Baseline after randomization. 
b. Subject randomly assigned to the Untreated control group will exit the study 12 weeks after randomization (Visit 5). 
c. 
Women of childbearing potential must have a negative UPT at Visit 1 and prior to each injection and must practice a reliable method of contraception 
throughout the study. 
d. Vision assessments include Snellen visual acuity, confrontational visual field test, and ocular motility test. In addition, in case of visual disturbances, a 
basic neurological examination must be performed. 
 
 

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Table 2-2 
Phase 2 
Phase 2 (Stage 1 and Stage 2 subjects) 
 
 
 
Retreatmenta 
Weeks/days after the initial treatment or 
retreatment 
24W 
±7d 
36W 
±7d 
52W ±7d 
3d ±2d 
from Re-
Txa 
2W from 
Re-Tx ±3da 
4W from Re-
Tx ±3da 
12W from 
Re-Tx ±7da 
Visits 
 
 
V6 
V7 
V8a 
V8 
Re-Txa 
V8 Calla 
V9a 
V10 
V11a 
Untreated control group 
Not applicable for subjects in the Untreated control group 
RHA® 1 group after completing Phase 1a and No-treatment control group after completing Phase 1b (See Table 2-1) 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
UPTb 
 
 
 
before 
 
 
 
 
Injection of RHA® 1 
 
 
 
X 
 
 
 
 
Hand out 30-day CTR diary 
 
 
 
after 
 
 
 
 
30-day CTR diary retrieval and review 
 
 
 
 
 
 
X 
 
TI Assessments 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Photography 
X 
X 
X 
after 
 
 
X 
X 
Tyndall effect assessment  
X 
X 
X 
after 
 
X 
X 
X 
Vision assessment, blink and closure testc 
X 
X 
X 
before/ after 
 
X 
X 
X 
GAIS  
X 
X 
X 
 
 
 
X 
X 
TIOHS 
X 
X 
X 
 
 
 
X 
X 
BLE Assessments 
 
 
 
 
 
 
 
 
GAIS 
X 
X 
X 
 
 
 
X 
X 
TIOHS 
X 
X 
X 
 
 
 
X 
X 
Subject Assessments 
 
 
 
 
 
 
 
 
Pain VAS  
 
 
 
after 
 
 
 
 
FACE-Q 
X 
X 
X 
 
 
 
X 
X 

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Phase 2 (Stage 1 and Stage 2 subjects) 
 
 
 
Retreatmenta 
Weeks/days after the initial treatment or 
retreatment 
24W 
±7d 
36W 
±7d 
52W ±7d 
3d ±2d 
from Re-
Txa 
2W from 
Re-Tx ±3da 
4W from Re-
Tx ±3da 
12W from 
Re-Tx ±7da 
Visits 
 
 
V6 
V7 
V8a 
V8 
Re-Txa 
V8 Calla 
V9a 
V10 
V11a 
GAIS 
X 
X 
X 
 
 
 
X 
X 
PSAQ 
X 
X 
X 
 
 
 
X 
X 
Subject satisfaction 
X 
X 
X 
 
 
 
X 
X 
Abbreviations: BLE = Blinded Live Evaluator; CTR = Common Treatment Response; d = day; GAIS = Global Aesthetic Improvement Scale; PSAQ = Periorbital 
Subject Assessment Questionnaire; Re-Tx = Retreatment; TI = treating investigator; TIOHS = Teoxane Infraorbital Hollows Scale; UPT = urine pregnancy test; 
V = visit; VAS = visual analog scale; W = week. 
Footnotes: 
a. 
Subjects will be offered retreatment at Visit 8 (52 weeks after their initial treatment). Retreatment will be administered if the TI deems it to be 
appropriate and the subject agrees. If the subject does not receive retreatment, the Visit 8 (52 weeks after initial treatment) will become the Exit Visit. If 
the subject receives retreatment at Visit 8, a telephone call visit will be performed 72 hours after retreatment (Visit 8 Call). The subject will come to the 
site for Visit 9 (2 weeks after retreatment) and Visit 10 (4 weeks after retreatment) followed by the final visit 12 weeks after retreatment (Visit 11). 
Afterwards the subject will exit the study. 
b. Women of childbearing potential must have a negative UPT prior to each injection and must practice a reliable method of contraception throughout the 
study. 
c. 
Vision assessments include Snellen visual acuity, confrontational visual field test, and ocular motility test. In addition, in case of visual disturbances, a 
basic neurological examination must be performed. 
 
 

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3. TABLE OF CONTENTS 
1. 
TITLE PAGE ............................................................................................................................1 
2. 
CLINICAL INVESTIGATION PLAN SUMMARY ...............................................................5 
2.1. 
Summary .....................................................................................................................5 
2.2. 
Schedule of Events ....................................................................................................22 
3. 
TABLE OF CONTENTS .......................................................................................................28 
3.1. 
List of Tables ............................................................................................................33 
3.2. 
List of Figures ...........................................................................................................33 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................34 
5. 
INTRODUCTION TO THE CLINICAL INVESTIGATION ...............................................36 
5.1. 
Background ...............................................................................................................36 
5.2. 
Study Device Name ..................................................................................................36 
5.3. 
Intended Purpose Statement ......................................................................................36 
5.4. 
Investigational Product Description ..........................................................................37 
5.4.1. Delivery System and Implantation ....................................................................38 
5.4.2. Nonclinical Testing and Previous Clinical Experience .....................................38 
5.4.3. Injection of RHA® 1 ..........................................................................................38 
5.5. 
Justification for the Clinical Investigation ................................................................38 
5.6. 
Justification for the Clinical Investigation Design....................................................39 
6. 
CLINICAL INVESTIGATION PURPOSE, OBJECTIVES, AND ENDPOINTS ................40 
6.1. 
Clinical Investigation Purpose ..................................................................................40 
6.2. 
Objectives and Endpoints .........................................................................................40 
6.2.1. Primary Effectiveness Objective .......................................................................40 
6.2.2. Secondary Effectiveness Objectives .................................................................40 
6.2.3. Safety Objective ................................................................................................40 
6.2.4. Exploratory Objective .......................................................................................40 
6.3. 
Hypothesis.................................................................................................................45 
6.4. 
Risks and Anticipated Adverse Device Effects ........................................................46 
6.4.1. Risks Associated With All Skin Injection Procedures ......................................46 
6.4.2. Risks Associated With the Anesthetic Agent (Lidocaine) or Other Allergens .46 
6.4.3. Risks That Are Typically Associated With RHA® 1 and HA Dermal Fillers in 
General ..............................................................................................................46 
6.4.4. Other Risks ........................................................................................................47 
7. 
CLINICAL INVESTIGATION DESIGN ..............................................................................49 
7.1. 
Clinical Investigation Duration .................................................................................55 
7.2. 
Clinical Investigation Enrollment .............................................................................55 
7.3. 
Clinical Investigation Sites .......................................................................................57 
7.4. 
Selection of Clinical Investigation Subject Population ............................................57 

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7.4.1. Inclusion Criteria ...............................................................................................58 
7.4.2. Exclusion Criteria ..............................................................................................58 
7.4.3. Subject Withdrawal or Discontinuation ............................................................60 
8. 
INVESTIGATION PROCEDURES ......................................................................................62 
8.1. 
Procedures by Visit (Stage 1 and Stage 2) ................................................................62 
8.1.1. Phase 1a .............................................................................................................62 
8.1.1.1. 
Visit 1 (Screening/Randomization/Baseline/Initial Treatment) ............62 
8.1.1.2. 
Visit 1 Call (+3 Days After the Initial Treatment) ................................63 
8.1.1.3. 
Visit 2 (2 Weeks After the Initial Treatment or Randomization) .........64 
8.1.1.4. 
Visit 3 (4 Weeks After the Initial Treatment or Randomization) .........64 
8.1.1.5. 
Visit 4 (8 Weeks After the Initial Treatment or Randomization) .........65 
8.1.1.6. 
Visit 5 (Primary Endpoint; 12 Weeks After the Initial Treatment or 
Randomization) ...................................................................................65 
8.1.2. Phase 1b (Subjects From Stage 2 Only) ............................................................66 
8.1.2.1. 
Visit 1b (12 Weeks After the Randomization) ......................................66 
8.1.2.2. 
Visit 1b Call (+3 Days After the Initial Treatment at Visit 1b) ............67 
8.1.2.3. 
Visit 2b (2 Weeks After the Initial Treatment or Randomization) .......67 
8.1.2.4. 
Visit 3b (4 Weeks After the Initial Treatment at Visit 1b), Visit 4b 
(8 Weeks After the Initial Treatment at Visit 1b), and Visit 5b 
(12 Weeks After the Initial Treatment at Visit 1b) .............................67 
8.1.3. Phase 2 ...............................................................................................................68 
8.1.3.1. 
Visit 6 (24 Weeks After Randomization/the Initial Treatment) and 
Visit 7 (36 Weeks After the Initial Treatment) ...................................68 
8.1.3.2. 
Visit 8 (52 Weeks After the Initial Treatment; Exit Visit for Subjects 
Without Retreatment) ..........................................................................69 
8.1.3.3. 
Visit 8 Call (+3 Days After the Retreatment) .......................................70 
8.1.3.4. 
Visit 9 (2 Weeks After the Retreatment)...............................................70 
8.1.3.5. 
Visit 10 (4 Weeks After the Retreatment).............................................70 
8.1.3.6. 
Visit 11 (12 Weeks After the Retreatment; Exit Visit for Subjects Who 
Received Retreatment) ........................................................................71 
8.2. 
Assessments ..............................................................................................................71 
8.2.1. Urine Pregnancy Test ........................................................................................71 
8.2.2. Safety Assessments ...........................................................................................72 
8.2.2.1. 
Common Treatment Response ..............................................................72 
8.2.2.2. 
Blink and Closure Tests ........................................................................73 
8.2.2.3. 
Vision Assessments ...............................................................................73 
8.2.2.4. 
Basic Neurological Examination ..........................................................75 
8.2.2.5. 
Adverse Events......................................................................................75 
8.2.2.6. 
Injection Site Pain .................................................................................75 

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8.2.3. Effectiveness Assessments ................................................................................76 
8.2.3.1. 
Teoxane Infraorbital Hollow Scale .......................................................76 
8.2.3.2. 
Subject Satisfaction ...............................................................................76 
8.2.3.3. 
Global Aesthetic Improvement .............................................................77 
8.2.3.4. 
FACE-Q ................................................................................................77 
8.2.3.5. 
Periorbital Subject Assessment Questionnaire......................................78 
8.2.3.6. 
Treatment Volume for Optimal Cosmetic Results ................................78 
8.2.3.7. 
Tyndall Effect Assessment ....................................................................78 
8.2.3.8. 
Photography ..........................................................................................79 
8.3. 
Adjustments of Visits and Assessments Due to Public Health Emergency of 
Coronavirus Disease 2019 ........................................................................................79 
8.3.1. General Guidance ..............................................................................................79 
8.3.2. Adjustment of Visit 1 ........................................................................................80 
8.3.3. Adjustment of Visits 5/1b, 8, and the Exit Visit ...............................................80 
8.3.4. Adjustment of Visits 2, 2b, 3, 3b, 4, 4b, 5b, 6, 7, 9, and 10 ..............................81 
8.3.5. Other Adjustments .............................................................................................82 
9. 
CLINICAL INVESTIGATION TREATMENT AND FOLLOW-UP ...................................83 
9.1. 
Subject Informed Consent.........................................................................................83 
9.2. 
Randomization ..........................................................................................................83 
9.3. 
Blinding/Unblinding Clinical Investigation Plan......................................................84 
9.3.1. General Blinding ...............................................................................................84 
9.3.2. Blinded Procedures ............................................................................................84 
9.3.3. Unblinding Procedures ......................................................................................85 
9.4. 
Pre-treatment Procedures and Tests ..........................................................................85 
9.5. 
Baseline Evaluations and Data Collection ................................................................85 
9.6. 
Prohibited Medications .............................................................................................86 
9.7. 
Clinical Investigational Product Treatment ..............................................................86 
9.7.1. Study Device .....................................................................................................86 
9.7.2. Control Device ..................................................................................................86 
9.7.3. Injection of RHA® 1 ..........................................................................................87 
9.7.4. Post-treatment Procedures .................................................................................87 
9.8. 
Stopping Rules ..........................................................................................................87 
9.9. 
Withdrawal of Food and Drug Administration Approval .........................................88 
10. ADVERSE EVENTS..............................................................................................................89 
10.1. 
Definitions.................................................................................................................89 
10.1.1. Adverse Events ..................................................................................................89 
10.1.2. Adverse Device Effects .....................................................................................89 
10.1.3. Serious Adverse Events .....................................................................................89 

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10.1.4. Unanticipated Adverse Device Effects ..............................................................90 
10.1.5. Adverse Events of Special Interest ....................................................................90 
10.1.6. Device Malfunction ...........................................................................................90 
10.2. 
Evaluation and Assessment.......................................................................................90 
10.2.1. Relationship to Device ......................................................................................91 
10.3. 
Safety Reporting .......................................................................................................93 
10.3.1. Serious Adverse Event Reporting .....................................................................94 
10.3.2. Unanticipated Adverse Device Effect Reporting ..............................................94 
10.3.3. Adverse Events of Special Interest Reporting ...................................................94 
10.3.4. Device Malfunctions Reporting ........................................................................95 
10.4. 
Pregnancy ..................................................................................................................95 
10.5. 
Data Monitoring Committee .....................................................................................96 
10.6. 
Clinical Events Committee .......................................................................................96 
11. STATISTICAL METHODS ...................................................................................................97 
11.1. 
Analysis Populations .................................................................................................97 
11.2. 
Sample Size Determination.......................................................................................98 
11.3. 
Subjects and Demographics ......................................................................................99 
11.3.1. Disposition and Withdrawals ............................................................................99 
11.3.2. Clinical Investigation Plan Deviations ..............................................................99 
11.3.3. Demographics and Other Baseline Characteristics ...........................................99 
11.4. 
Effectiveness Analyses .............................................................................................99 
11.5. 
Safety Analyses .......................................................................................................102 
11.6. 
Other Analyses ........................................................................................................104 
11.7. 
Interim Analyses .....................................................................................................104 
11.8. 
Independent Panel Review ......................................................................................105 
12. INVESTIGATOR AND SPONSOR RESPONSIBILITIES ................................................106 
12.1. 
Investigator Responsibilities ...................................................................................106 
12.1.1. Deviations From Clinical Investigation Plan ..................................................107 
12.1.2. Maintaining Records .......................................................................................107 
12.1.3. Submitting Reports ..........................................................................................108 
12.1.4. Prohibition of Promotion .................................................................................108 
12.2. 
Sponsor Responsibilities .........................................................................................109 
12.2.1. General Duties .................................................................................................109 
12.2.2. Selection of Investigators ................................................................................109 
12.2.3. Training ...........................................................................................................110 
12.2.4. Changes in the Clinical Investigation Plan ......................................................110 
13. DATA QUALITY ASSURANCE ........................................................................................111 
13.1. 
Data Management ...................................................................................................111 

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13.2. 
Confidentiality of Data ...........................................................................................111 
13.3. 
Source Documents ..................................................................................................112 
13.4. 
Electronic Case Report Forms ................................................................................112 
13.5. 
Record Retention ....................................................................................................113 
13.6. 
Clinical Data Monitoring Procedures .....................................................................113 
14. REVIEW OF THE TI SITE FILE ETHICS AND REGULATORY COMPLIANCE ........114 
14.1. 
Conduct of the Clinical Investigation .....................................................................114 
14.2. 
Conflict of Interest ..................................................................................................114 
14.3. 
Institutional Review Board/Competent Authority Approval ..................................114 
14.4. 
Clinical Investigation Informed Consent Approval ................................................114 
14.5. 
Subject Identification and Confidentiality ..............................................................115 
14.6. 
Site Qualification Visits ..........................................................................................115 
14.7. 
Site Initiation Visits ................................................................................................115 
14.8. 
Insurance .................................................................................................................116 
14.9. 
Site Audit Plan ........................................................................................................116 
14.9.1. Internal Audits by Sponsor or Sponsor’s Designee .........................................116 
14.9.2. External Audits ................................................................................................116 
14.10. Investigational Product Traceability .......................................................................116 
14.11. Public Domain Access to the Clinical Investigation...............................................116 
15. GENERAL CONSIDERATIONS ........................................................................................117 
15.1. 
Discontinuation of the Investigation .......................................................................117 
15.2. 
Use of Information and Publications ......................................................................117 
16. REFERENCES .....................................................................................................................118 
17. ATTACHMENTS .................................................................................................................119 
17.1. 
Investigator’s Agreement ........................................................................................119 
18. APPENDICES ......................................................................................................................120 
18.1. 
Appendix A .............................................................................................................121 
18.2. 
Appendix B .............................................................................................................124 
18.3. 
Appendix C .............................................................................................................125 
18.4. 
Appendix D .............................................................................................................126 
18.5. 
Appendix E .............................................................................................................127 
REASONS FOR AMENDMENT ...............................................................................................128 
SUMMARY OF AMENDED SECTIONS ..................................................................................129 
 

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3.1. List of Tables 
Table 2-1 
Phase 1a and 1b ........................................................................................................22 
Table 2-2 
Phase 2 ......................................................................................................................26 
Table 6-1  
Objectives Mapped to Endpoints ..............................................................................41 
Table 8-1  
Subject Satisfaction Scale .........................................................................................77 
Table 8-2  
Global Aesthetic Improvement Scale .......................................................................77 
Table 8-3 
FACE-Q scale ...........................................................................................................78 
Table 10-1 Adverse Event Severity Scale ...................................................................................91 
Table 10-2 Adverse Event Relationships ....................................................................................92 
 
3.2. List of Figures 
Figure 7-1 
Stages 1 and 2 of the Enrollment ..............................................................................52 
Figure 7-2 
Investigation Design (Stage 1) .................................................................................53 
Figure 7-3 
Investigation Design (Stage 2) .................................................................................54 
 

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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
analysis of covariance 
BDDE 
1,4-butanediol diglycidyl ether 
BLE 
Blinded Live Evaluator 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIP 
Clinical Investigation Plan 
CMP 
Clinical Monitoring Plan 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CTR 
Common Treatment Response 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good Clinical Practice 
HA 
Hyaluronic Acid 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IDE 
Investigational Device Exemption 
IPR 
Independent Panel Review 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NaHA 
sodium hyaluronate 
OCR 
Optimal Cosmetic Result 
PP 
Per-Protocol 
PSAQ 
Periorbital Subject Assessment Questionnaire 
SAE 
Serious Adverse Event 
SAFT 
Safety Population 

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ABBREVIATION 
EXPLANATION 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SMP 
Safety Management Plan 
SOP 
Standard Operating Procedure 
TI 
Treating Investigator 
TIOHS 
Teoxane Infraorbital Hollows Scale 
UADE 
Unanticipated Adverse Device Effect 
UPT 
Urine Pregnancy Test 
US 
United States 
VAS 
Visual Analog Scale 
WHO-DD 
World Health Organization Drug Dictionary 

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5. INTRODUCTION TO THE CLINICAL INVESTIGATION 
5.1. Background 
The eyes represent a key feature of the face. Their color, shape, surrounding area, and their 
expressivity immediately draw our attention. The effects of aging are particularly visible in the 
periorbital area due to delicate periorbital skin and subcutaneous tissue. Over the past decade, this 
area has become an area of choice for facial rejuvenation. According to a cross-sectional research 
survey, aesthetically oriented women consider infraorbital grooves as one of the most troublesome 
areas of the face.1 
Grooves in the infraorbital region include the tear trough deformities (located between the 
palpebral and orbital parts of the orbicularis oculi), the nasojugal grooves (inferior border of the 
orbicularis oculi), and the palpebromalar grooves (overlying the inferomedial orbital rim). Several 
factors such as the herniation of intraorbital fat, the atrophy of the skin and subcutaneous fat, the 
contraction of the orbital part of the orbicularis oculi muscle or squinting, and the malar bone 
resorption may cause the grooves. Relatively broad depressions in the infraorbital area, referred to 
as infraorbital hollows, may occur with or without grooves and in some cases, if the soft tissue 
atrophies inferior to the arcus marginalis, the hollow can manifest as a groove and may require 
treatment.2,3 
Treatment in the infraorbital region includes surgical and nonsurgical methods. Nonsurgical 
methods include injection of one’s own harvested fat tissue or injection of soft tissue fillers. Soft 
tissue fillers used in cosmetic surgery are generally registered as medical devices. There are 
various types of fillers and their effect can be permanent (e.g., polymethylmethacrylate), 
semi-permanent (e.g., calcium hydroxylapatite, poly-L-lactic acid), or temporary (e.g., collagen, 
hyaluronic acid).4 To date, there is no medical device approved by the US Food and Drug 
Administration (FDA) for injection into the periorbital area and treatment of infraorbital hollows; 
the use of soft tissue fillers is currently off-label in that area. 
Hyaluronic acid (HA), 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 properties of the HA, 
while maintaining the biocompatibility of the basic polymer.5 The injection of a HA gel dermal 
fillers, as a minimally invasive procedure, is becoming the method of choice for the treatment of 
the infraorbital hollows. This clinical investigation will evaluate the use of the HA dermal filler 
RHA® 1 for the treatment of the infraorbital area. 
5.2. Study Device Name 
RHA® 1. RHA® stands for Resilient Hyaluronic Acid. 
5.3. Intended Purpose Statement 
RHA® 1 is intended to be used for the correction of moderate to severe tissue volume deficiencies 
in the infraorbital hollows in subjects 22 years old or older. 

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5.4. Investigational Product Description 
The device under clinical investigation is RHA® 1 manufactured by TEOXANE SA. 
RHA® 1 is a viscoelastic, sterile, nonpyrogenic, clear, colorless, homogenous, and biodegradable 
gel implant. It is formulated with sodium hyaluronate (NaHA) at a concentration of 15 mg/g 
obtained from bacterial fermentation using the Streptococcus equi bacterial strained, crosslinked 
with 1,4-butanediol diglycidyl ether (BDDE) and reconstituted in a physiological buffer (pH 7.3). 
RHA® 1 also contains 0.3% lidocaine hydrochloride to reduce pain on injection. 
The current shelf life is 36 months from the manufacturing date. 
The investigational product must be stored at room temperature from 2°C/35.6°F, up to 25°C/77°F 
throughout the clinical investigation period. 
Further information about the study device handling may be found in the Investigational Product 
Guidelines provided to the Treating Investigator (TI). 
Each 1.0 mL volume syringe of RHA® 1 is provided in a polycarbonate blister sealed with a Tyvek 
lid. For the sites selected to be “needle” sites, the blister will include in each package 2 sterile 
Terumo Thin Wall needles 30G x ½″. For the sites selected to be “cannula” sites, the blister will 
not include needles. 
Labeling 
The labeling on the Tyvek lid includes: 
• Study number: TEO-RHA-1902 
• Investigational Device Exemption (IDE) number: G200191 
• Name and address of the Sponsor/Manufacturer (i.e., TEOXANE SA) 
• Quantity of syringes (n=1) 
• For the sites selected to be “needle” sites: Quantity of 30G ½″ needles (n=2) 
• For the sites selected to be “cannula” sites: Quantity of 30G ½″ needles (n=0) 
• Batch number and manufacturing date 
• Expiration date (36 months from manufacturing date) 
• Statement: “CAUTION: Investigational device. Limited by Federal (or United States) law to 
investigational use.” 
Composition 
Crosslinked HA 
 
15 mg/mL 
Lidocaine hydrochloride 
3 mg 
Phosphate buffer pH 7.3 
quantitat sufficient per 1 mL 
Cannula 
The cannula will not be part of the RHA® 1 package and labeling; cannulas will be provided to the 
TI separately for the clinical study purposes. The cannulas will be made available in their original 
packaging with a TEOXANE SA’s sticker on it, which will include the study reference. 

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The following types of cannulas will be supplied upon TI’s preference, 25G 1 ½″ from: 
• TSK (STERiGLIDETM) 
• SoftFil® Precision 
The cannulas will be used for RHA® 1 administration, which will be initiated by an entry point 
made manually with the sharp “pre-hole needle” (also called the “puncture needle”) so that the 
cannula (attached to the syringe) may be carefully inserted and maneuvered until the desired tissue 
plane is reached. The pre-hole needles of appropriate gauge for each cannula will be supplied 
sterile and together with the cannulas in their packaging. The choice of the cannula used for 
RHA® 1 administration is left to the TI’s discretion. 
5.4.1. Delivery System and Implantation 
RHA® 1 is supplied in individual blister packages containing a 1 mL treatment syringe with two 
30G x ½″ needles (only for the sites selected to be “needle” sites). The contents of the syringe are 
sterile and nonpyrogenic. They should not be resterilized or used if the blister package has been 
opened or damaged. 
The needle/cannula needs to be assembled to the syringe as per the Investigator Brochure (IB)5 
and the Injection Guidelines6 provided to the TI. When using a cannula, the entry point for the 
blunt tip cannula is made by inserting manually (and removing) the corresponding sharp “pre-hole 
needle”. Before injecting, the needle/cannula needs to be primed by carefully pressing the syringe 
plunger until a small droplet of the gel is visible at the tip of the needle or cannula. 
The filler needs to be injected according to the Injection Guidelines6 provided to the TI. 
5.4.2. Nonclinical Testing and Previous Clinical Experience 
All information regarding the nonclinical testing and the previous clinical experience with RHA® 1 
is included in the current IB.5 
5.4.3. Injection of RHA® 1 
Injection area and depth: RHA® 1 is injected from the sub-dermis to the periosteum in the 
infraorbital hollow. 
Amount of filler to be administered: Up to 1.0 mL per eye at each treatment (max: 2.0 mL per 
treatment). 
Information about the method of administration, injection technique, depth of injection 
(sub-dermis or supraperiosteum), and the amount of filler will be collected in the electronic case 
report form (eCRF). Injection Guidelines6 will be available to the TI prior to his/her first subject 
visit. 
5.5. Justification for the Clinical Investigation 
RHA® 1 is an investigational device, which has not yet been approved by the FDA. It has been 
assessed for the perioral lines indication in a previous clinical investigation conducted by 
TEOXANE SA, which has been completed and shortly submitted to the FDA. 
The purpose of this study is to inject RHA® 1 into the infraorbital regions to achieve volume 
correction in the infraorbital area and to demonstrate that it is superior to no treatment in subjects 

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aged 22 years and older to support a premarketing authorization application to US FDA for 
RHA® 1. 
To date, one dermal filler, Juvederm Volbella® XCs has been approved by the US FDA for use in 
the infraorbital regions. The options for treatment of this area are the already-approved dermal 
filler, surgery, injection of one’s own fat tissue, or to off-label use of the medical devices marketed 
for different indications. Data about the effectiveness and/or safety are available from Nikolis et al, 
retrospective studies and case reports. The majority of the risks from RHA® 1 are expected to be 
similar to those associated with other HA dermal fillers used as off-label treatment in the 
infraorbital regions (see Section 6.4). These include risks associated with all skin injection 
procedures, with the use of anesthetic agents, or with the use the RHA® 1. In the light of the 
potential risks and benefits, a prospective clinical study of RHA® 1 HA dermal filler to assess the 
effectiveness and safety of the RHA® 1 in the infraorbital area is justified. 
5.6. Justification for the Clinical Investigation Design 
The study is designed to prospectively evaluate RHA® 1 in the treatment of tissue volume 
deficiencies in the infraorbital regions and show that it is superior to no treatment. The study design 
was selected to minimize bias by using subject randomization and blinding of the independent 
evaluator (Blinded Live Evaluator [BLE]), whose assessment will be used for the primary endpoint 
analysis. The comparison of the safety and effectiveness of RHA® 1 against no treatment will be 
done between subjects and will include subjects from multiple sites, with special attention to 
inclusion of subjects with Fitzpatrick skin types IV-VI. 
 

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6. CLINICAL INVESTIGATION PURPOSE, OBJECTIVES, AND ENDPOINTS 
6.1. Clinical Investigation Purpose 
The purpose of the study is to evaluate the safety and effectiveness of RHA® 1 for the correction 
of moderate to severe tissue volume deficiencies in the infraorbital regions. 
6.2. Objectives and Endpoints 
Objectives mapped to endpoints are displayed in Table 6-1. 
6.2.1. Primary Effectiveness Objective 
To assess the effectiveness of RHA® 1 (as judged by clinicians and subjects) for the correction of 
moderate to severe tissue volume deficiencies in the infraorbital regions at 12 weeks after the 
initial treatment. 
6.2.2. Secondary Effectiveness Objectives 
To assess the effectiveness of RHA® 1 for the correction of moderate to severe tissue volume 
deficiencies in the infraorbital regions up to 52 weeks after initial treatment and 12 weeks after 
retreatment. 
6.2.3. Safety Objective 
• To assess the safety of RHA® 1 in subjects treated for the correction of moderate to severe 
tissue volume deficiencies in the infraorbital regions up to 52 weeks after initial treatment and 
12 weeks after retreatment 
• To demonstrate that safety of RHA® 1 is not impacted by the method of administration 
(injected with a needle or a cannula) 
6.2.4. Exploratory Objective 
To evaluate the Tyndall effect after treatment with RHA® 1 in the infraorbital regions.

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Table 6-1  
Objectives Mapped to Endpoints 
Objectives 
Endpoints  
Primary effectiveness 
To assess the effectiveness of RHA® 1 (as judged by clinicians and 
subjects) for the correction of moderate to severe tissue volume 
deficiencies in the infraorbital regions at 12 weeks after the initial 
treatment 
The primary endpoint will be the responder rate after 12 weeks. 
The effectiveness of RHA® 1 will be demonstrated if: 
• 
The responder rate for subjects treated with RHA® 1 (Stage 1 and Stage 2) is 
statistically superior to the responder rate for subjects of the No-treatment 
control group 12 weeks (Visit 5) after randomization as assessed by the BLE 
using the live-validated TIOHS 
Additionally, the following 2 conditions must be met: 
• 
The responder rate for RHA® 1 is ≥70% 
• 
The difference between the responder rate for subjects treated with RHA® 1 
and the No-treatment control group is ≥50% 
A responder will be defined as a subject with a ≥1-grade improvement in both 
eyes on the TIOHS as assessed by the BLE before initial treatment and 12 weeks 
after the initial treatment (Visit 5). 
The co-primary endpoint will be the change from Baseline in the modified 
FACE-Q Appraisal of lower eyelids domain score (converted to a 0-100 scale – 
Rasch conversion) at 12 weeks. The effectiveness of RHA® 1 will be demonstrated 
if the modified FACE-Q Appearance of lower eyelids change from Baseline score 
for subjects treated with RHA® 1 is statistically superior (by at least 12 points) to 
the subjects of the No-treatment control group 12 weeks (Visit 5) after 
randomization (including subjects who received RHA® 1 during Stage 1). 
Additionally, the following 2 conditions must be met: 
• 
The mean change from Baseline of the modified FACE-Q “Appraisal of 
lower eyelids” raw score for RHA® 1 is ≥ 3 
• 
The difference between the modified FACE-Q “Appraisal of lower 
eyelids” change from Baseline for subjects treated with RHA® 1 and the 
No-treatment control group is ≥12 

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Objectives 
Endpoints  
Only the following questions will be considered for the co-primary endpoint: 
• 
Question “d”: How noticeable the lines under your eyes are? 
• 
Question “e”: Crepey (wrinkled) skin under your eyes? 
• 
Question “f”: How old the area under your eyes makes you look? 
• 
Question “g”: How tired the area under your eyes makes you look? 
Only data from the Phase 1a will be taken into account. Data from subjects 
randomly assigned to the No-treatment control group after treatment received in 
the Phase 1b will not be pooled for the primary endpoint analysis. 
Superiority will be declared if: 
• 
the lower bound of 2-sided 95% confidence interval for the responder rate 
for RHA® 1 is at least 70%, and 
• 
the lower bound of 2-sided 95% confidence interval for the difference in 
the responder rate between subjects treated with RHA® 1 and the 
No-treatment control group is at least 50%, and 
• 
the lower bound of 2-sided 95% confidence interval for the modified 
FACE-Q “Appraisal of lower eyelids” raw score for RHA® 1 is at least 
3, and 
• 
the lower bound of 2-sided 95% confidence interval for the difference in 
mean change from Baseline of the modified FACE-Q between RHA® 1 
treated group and the No-treatment control group is at least 12 
Secondary effectiveness  
To assess the effectiveness of RHA® 1 for the correction of moderate to 
severe tissue volume deficiencies in the infraorbital regions up to 
52 weeks after initial treatment and 12 weeks after retreatment 
The secondary endpoints will consist of the following: 
• 
Proportion of subjects with both eyes with ≥1-grade improvement on the 
TIOHS as assessed: 
o 
By the BLE at each site visit starting from Visit 5 (12 weeks after 
randomization/ initial treatment) = rate of responders at the given time 
point 
o 
By the TI at each site visit starting from Visit 2 (2 weeks after 
randomization/ initial treatment) 
o 
By the IPR at Baseline and Visit 5 (12 weeks after randomization/initial 
treatment) 

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Objectives 
Endpoints  
• 
Proportion of subjects with both eyes and with one eye with ≥1-grade, 
≥2-grade, ≥3-grade improvement on the TIOHS as assessed: 
o 
By the BLE at each site visit starting from Visit 5 (12 weeks after 
randomization/ initial treatment) 
o 
By the TI at each site visit starting from Visit 2 (2 weeks after 
randomization/ initial treatment) 
o 
By the IPR at Baseline and Visit 5 (12 weeks after randomization/initial 
treatment) 
• 
Proportion of subjects who were “improved” or “much improved” using the 
Global Aesthetic Improvement Scale (GAIS) as assessed: 
o 
By the BLE at each site visit starting from Visit 5 (12 weeks after 
randomization/ initial treatment) 
o 
By the TI at each site visit starting from Visit 3 (4 weeks after 
randomization/ initial treatment) 
o 
By the subject at each site visit from Visit 3 (4 weeks after randomization/ 
initial treatment) 
• 
Proportion of subjects “satisfied” or “very satisfied” with the effect of the 
study treatment, using the Subject satisfaction scale as assessed by the subject 
at each site visit from Visit 3/Visit 3b (4 weeks after initial treatment) 
• 
FACE-Q assessment by the subject through the Appraisal of lower eyelids (all 
questions) scale of the FACE-Q at each site visit starting from Baseline 
(except for Visit 2) 
• 
Periorbital Subject Assessment Questionnaire (PSAQ) assessment by the 
subject 
o 
Only part A at Baseline (Visit 1/Visit 1b) before initial treatment 
o 
Parts A and B without question 12 at each site visit starting from Visit 
3/Visit 3b (after initial treatment) 
o 
Parts A and B including question 12 at the Exit visit 
• 
Total volume of RHA® 1 per eye and per treatment session to obtain Optimal 
Cosmetic Result (OCR) 
• 
Proportion (%) of subjects retreated  
Safety 

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Objectives 
Endpoints  
• 
To assess the safety of RHA® 1 in subjects treated for the correction 
of moderate to severe tissue volume deficiencies in the infraorbital 
regions up to 52 weeks after initial treatment and 12 weeks after 
retreatment 
• 
To demonstrate that safety of RHA® 1 is not impacted by the method 
of administration (injected with a needle or a cannula) 
 
 
 
  
The safety endpoints include: 
• 
Adverse events, with a focus on treatment related AEs based on the TI 
assessment, and AEs reported from the CTR diary, from randomization 
• 
Assessment of blink and closure test and visual disturbances through 
functional assessments 30 minutes after injection and at each visit: Snellen 
visual acuity, confrontational visual field test, ocular motility; any vision 
disturbances and stroke or stroke-like symptoms will be understood as 
Adverse Event of Special Interest (AESI) 
• 
Assessment of neurological functions such as subject’s mental status, motor 
function, sensory function, reflexes, coordination, and cranial nerve functions 
in case of visual disturbances or signs/symptoms of visual disturbances; any 
abnormal neurological results will be considered as an SAE 
• 
Post-injection CTR, including visual disturbances, through 30-day subject 
CTR diary 
• 
Assessment of injection site pain immediately after injection is completed 
(both eyes), at 5 minutes 15 minutes, and 30 minutes after injection on a visual 
analog scale (VAS) (0-100 mm) 
• 
Assessment of safety comparison between subjects with Fitzpatrick skin 
types I-III and IV-VI throughout the study 
• 
Assessment of safety comparison between subjects receiving RHA® 1 
treatment with a needle and a cannula 
Exploratory 
To evaluate the Tyndall effect after treatment with RHA® 1 in the 
infraorbital hollows 
Exploratory endpoint includes Tyndall effect assessment by the TI at all site 
visits after injection from Visit 1/Visit 1b. 
Abbreviations: AE = adverse event; AESI = Adverse Event of Special Interest; BLE = Blinded Live Evaluator; CTR = common treatment responses, GAIS = Global 
Aesthetic Improvement Scale; IPR = Independent Panel Review; OCR = optimal cosmetic result; PSAQ = Periorbital Subject Assessment Questionnaire; 
TI = Treating Investigator; TIOHS = Teoxane Infraorbital Hollows Scale; VAS = visual analog scale

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6.3. Hypothesis 
The RHA® 1 group will be superior to the No-treatment control group for the correction of volume 
deficiencies in the infraorbital regions as determined by the Teoxane Infraorbital Hollows Scale 
(TIOHS – 5-point scale from grade 0 to 4) at 12 weeks after the initial treatment or randomization 
(for the No-treatment control group). An improvement in the TIOHS of ≥1 grade compared to pre-
treatment for both eyes will be considered clinically meaningful. Specifically, the primary 
hypothesis is: 
Ho: Δ = 0 
Ha: Δ > 0 
where Δ = RHA1 response rate minus No-treatment control response rate. Response rate is defined 
as number of responders divided by number of subjects in the analysis population for the given 
treatment group. 
Additionally, the following 2 conditions must be met: 
• The responder rate for RHA® 1 is ≥70% 
• The difference between the responder rate for subjects treated with RHA® 1 and the 
No-treatment control group is ≥50% 
Additionally, the change from Baseline in selected questions of the FACE-Q Appraisal of lower 
eyelids domain score (converted to a 0-100 scale – Rasch conversion) at 12 weeks for subjects 
treated with RHA® 1 will be statistically superior (by at least 12 points) to the subjects of the 
No-treatment control group. Specifically, the co-primary hypothesis is: 
Ho: Δ = 0 
Ha: Δ > 0 
where Δ = RHA1 change from Baseline minus No-treatment control change from Baseline. 
Additionally, the following 2 conditions must be met: 
• 
The mean change from Baseline of the modified FACE-Q “Appraisal of lower eyelids” 
raw score for RHA® 1 is ≥ 3 
• 
The difference between the modified FACE-Q “Appraisal of lower eyelids” change from 
Baseline for subjects treated with RHA® 1 and the No-treatment control group is ≥12 
Superiority will be declared if: 
• the lower bound of 2-sided 95% confidence interval for the responder rate for RHA® 1 is 
at least 70%, and 
• the lower bound of 2-sided 95% confidence interval for the difference in the responder 
rate between subjects treated with RHA® 1 and the No-treatment control group is at least 
50%, and 
• the lower bound of 2-sided 95% confidence interval for the modified FACE-Q “Appraisal 
of lower eyelids” raw score for RHA® 1 is at least 3, and 
• the lower bound of 2-sided 95% confidence interval for the difference in mean change 
from Baseline of the modified FACE-Q between RHA® 1 treated group and the 
No-treatment control group is at least 12 

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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® 1. There are various types of risks associated with the injection of a HA dermal filler in the 
infraorbital region: 
• Risks associated with all skin injection procedures 
• Risks associated with the anesthetic agent (lidocaine) or other allergens 
• Risks that are typically associated with RHA® 1 and HA dermal fillers in general 
• 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: 
• Infection 
• Bleeding 
• Blistering 
• Bruising 
• 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, fish oil, and prescription 
anticoagulants) 
• 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 since both study devices contain them and they risk anaphylactic shock. 
Reported anaphylactic shocks are very rare. 
The concentration of lidocaine in RHA® 1 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. 
6.4.3. Risks That Are Typically Associated With RHA® 1 and HA Dermal Fillers in General 
The following risks are anticipated adverse device events when using a HA dermal filler: 
• Common Treatment Responses (CTRs): 
o Redness (erythema) 
o Pain 
o Tenderness 
o Firmness (induration) 

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o Swelling 
o Lumps/Bumps 
o Bruising 
o Itching 
o Discoloration (hyperpigmentation) 
• Other common reactions such as inflammation or edema 
• 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 
6.4.4. Other Risks 
Other risks that may not be typical but have been reported in the literature related to injection of 
HA filler into the infraorbital areas are presented below. While rare, the following risks are to be 
considered: 
• Granuloma 
• Fever 
• Dizziness 
• Chest discomfort with irregular heartbeat 
• Herpes simplex 
• Angioedema 
• Flu-like symptoms 
• Dyspnea 
• Implant displacement 
• Long-lasting edema 
While the actual frequency is unknown, one of the rare risks of dermal fillers is the unintentional 
injection into a blood vessel that may lead to potential Serious Adverse Events (SAEs) such as: 
• Vascular compromise: embolization, occlusion of the vessels, ischemia, or infarction 
• Stroke or stroke-like symptoms, such as confusion, weakness/numbness in the arms or legs, 
changes to consciousness or alertness, difficulty speaking/speech impairment, or facial 
drooping 
• Vision disturbances (including, but not limited to any loss of vision, blurriness, double vision, 
pain in or around the eye, blindness, blind spot or shadow in the visual field, trouble moving 
eyes, skin color changes around the eyelids, etc.) 
• Skin necrosis 

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• Cerebral ischemia or cerebral hemorrhage leading to stroke, skin necrosis, and damage to 
underlying facial structures 
In the case of accidental injection into a vessel or if a subject exhibits any of the symptoms listed 
above, the injection should be stopped immediately. Subjects should receive immediate medical 
attention and possibly evaluation by a retina specialist or ophthalmologist should an intravascular 
injection occur that presents with vision disturbances (see Section 8.2.2.3). 
Treatment varies from observation to hyaluronidase administration (significant amount, at least 
200 IU, repeating cycles 3 to 4 times if no improvement of the zone is observed after 60 minutes), 
warm compress (lasting 5 to 10 minutes every 30 to 60 minutes), digital massage, topical 
nitroglycerin, intravenous or oral corticosteroids, hyperbaric oxygen therapy, antibiotics, and 
anticoagulants. In case of occlusion of the branches of the ophthalmic artery, intraocular 
pressure-lowering agents such as acetazolamide or mannitol can be administered, or an anterior 
chamber paracentesis can be performed.8 
For further information on the management of vascular compromise or visual disturbance, please 
refer to the Injection Guidelines.6 For most recent information about RHA® 1, refer to the most 
recent version of the IB.5 
 

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7. CLINICAL INVESTIGATION DESIGN 
Enrollment 
This is a multicenter, blinded evaluator, randomized, prospective, no-treatment control clinical 
study to identify whether RHA® 1 is superior to no treatment for the correction of moderate to 
severe tissue volume deficiencies in the infraorbital regions. The study (Stage 1 and Stage 2 
combined) will include at least 20% of subjects with Fitzpatrick skin types IV-VI: including a 
minimum of 10% of subjects presenting with Fitzpatrick skin types V or VI, of which ≥3% will 
have Fitzpatrick skin type V (≥8 subjects) and ≥3% will have Fitzpatrick skin type VI 
(≥8 subjects). Every attempt will be made to enroll approximately 10 subjects with Fitzpatrick skin 
types IV-VI during Stage 1. The enrollment in Stage 2 will be adjusted as needed to achieve the 
overall goal. 
The TI and the BLE will evaluate the subject’s infraorbital hollows independently of each other 
using the TIOHS at Screening (Visit 1) for eligibility. If the assessments of the TI and the BLE are 
the same or differ exactly by 1 point on the scale, the difference will be considered acceptable. The 
TI and the BLE must agree that the subject meets the inclusion criterion number 4 (TIOHS grade 2 
or 3). Bilateral symmetry is not required. 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 2 points or more on the scale, the subject will not be eligible. 
As requested by the US FDA enrollment for G200191 will be staged. 
Stage 1 
During Stage 1, approximately 58 subjects will be enrolled and randomly assigned (approximately 
6:1 ratio) to RHA® 1 group or to Untreated control group. Subjects in the Untreated control group 
are enrolled to keep the BLE blinded to the study treatment during Stage 1. The BLE will be kept 
unaware of the randomization ratio. Depending on the site, RHA® 1 will be administered with a 
30G ½″ needle (RHA® 1 needle subgroup) or with a 25G 1 ½″ cannula (RHA® 1 cannula 
subgroup). Site selection will aim to achieve approximately 1:1 distribution between the 
subgroups. After approximately 58 subjects are enrolled, recruitment will be halted. 
Subjects enrolled in Stage 1 in the RHA® 1 group will follow the usual schedule (Phase 1a and 
Phase 2) without interruption. In the meantime, safety data from the first 24 weeks of the RHA® 1 
group will be submitted to the FDA as an IDE supplement for an interim safety review. Upon 
receiving approval to expand enrollment from the FDA per the updated submitted study protocol, 
the enrollment will resume for Stage 2. 
Untreated control group 
Subjects randomly assigned to the Untreated control group will receive no treatment. As they are 
enrolled in order to keep the BLE blinded, their visits and assessments will be reduced; they will 
come to the site only at the initial visit and 12 weeks after randomization (Visit 5). Visit 5 will 
become their Exit Visit. During the visits they will be assessed by the BLE and the subject 
assessments will not be applicable. The TI assessments will consist of screening assessments to 
assess eligibility (including TIOHS), photography, and AE collection. 
Stage 2 
Stage 2 will include approximately 198 (maximum 201) additional subjects. Subjects enrolled 
during Stage 2 will be randomly assigned at Screening (Visit 1) to receive RHA® 1 or to receive 

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no treatment (No-treatment control group). Subjects receiving RHA® 1 will be further divided by 
the method of administration (i.e., injection with a needle or a cannula), which will be defined for 
each site before the study begins. Depending on the site, RHA® 1 will be administered with a 30G 
½″ needle (RHA® 1 needle subgroup) or with a 25G 1 ½″ cannula (RHA® 1 cannula subgroup). 
Site selection will aim to achieve approximately 1:1 distribution between the subgroups. The BLE 
will be blinded to the study groups (RHA® 1 group or No-treatment control group). 
Phase 1a: Up to 12 weeks after the initial treatment for the RHA® 1 group or after 
randomization for the No-treatment control group; primary endpoint 
Subjects who will be randomly assigned to the RHA® 1 group at Screening during Stage 1 or 
Stage 2 will receive their injection at Visit 1. The TI or designee will call subjects 72 hours post-
treatment (Visit 1 Call). Subjects will come to the site 2 weeks (Visit 2), 4 weeks (Visit 3), 8 weeks 
(Visit 4), and 12 weeks (Visit 5, primary endpoint) after the initial treatment. Afterwards, subjects 
will proceed directly to Phase 2. Phase 1b is not applicable for subjects randomly assigned to the 
RHA® 1 group. 
Subjects randomly assigned to the No-treatment control group (Stage 2) at Screening will receive 
no treatment in Phase 1a of the study. They will come to the site 2 weeks (Visit 2), 4 weeks 
(Visit 3), 8 weeks (Visit 4), and 12 weeks (Visit 5, primary endpoint) after randomization. After 
completing all assessments for Visit 5, subjects will immediately begin Phase 1b (Visit 1b is on 
the same day as Visit 5) and will receive their initial treatment with RHA® 1. 
Subjects randomly assigned to the Untreated control group (Stage 1) at Screening will receive no 
treatment. They will come to the site 12 weeks after randomization (Visit 5), which will become 
their Exit Visit. 
Phase 1b: after the primary endpoint assessment up to 12 weeks after the initial treatment 
for the No-treatment control group 
Phase 1b is only applicable to subjects initially randomly assigned to the No-treatment control 
group. Once all evaluations applicable for Visit 5 are completed, subjects will proceed directly to 
Visit 1b (on the same day). Evaluations completed at Visit 5 will be used for Visit 1b and will 
become the new Baseline for Phase 1b. 
Subjects will receive their initial treatment with RHA® 1 at Visit 1b. 
Subjects will follow the same schedule as those initially randomly assigned to the RHA® 1 group: 
RHA® 1 will be administered on the same day (Visit 1b). The TI or designee will call the subject 
72 hours post-treatment (Visit 1b Call). Subjects will come to the site 2 weeks (Visit 2b), 4 weeks 
(Visit 3b), 8 weeks (Visit 4b), and 12 weeks (Visit 5b) after their initial treatment. Afterwards, 
subjects will proceed to Phase 2. 
Phase 2 and Exit Visit: 12 weeks after the initial treatment up to the end of the study for the 
RHA® 1 group and the No-treatment control group 
Phase 2 will occur 12 weeks after receiving initial treatment with RHA® 1 for subjects in the 
RHA® 1 group (Stage 1 and Stage 2) and the No-treatment control group (after Phase 1b). 
All these subjects will come to the site 24 weeks (Visit 6), 36 weeks (Visit 7), and 52 weeks 
(Visit 8) after their initial treatment. All subjects will be followed for 52 weeks after their initial 
treatment with RHA® 1. 

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Subjects will be offered retreatment at Visit 8 (52 weeks after their initial treatment). Retreatment 
will be administered if the TI deems it to be appropriate and the subject agrees. If the subject does 
not receive retreatment, Visit 8 (52 weeks after initial treatment) will become the Exit Visit. 
If the subject receives retreatment at Visit 8, the TI or designee will call him or her after 72 hours 
(Visit 8 Call). The subjects will come to the site 2 weeks (Visit 9; safety only), 4 weeks (Visit 10), 
and 12 weeks (Visit 11) after retreatment for follow-up and safety assessments. Visit 11 will be 
the Exit Visit. 
Assessments throughout the study: RHA® 1 group (Stage 1 and Stage 2) and No-treatment 
control group 
The TI will conduct safety and effectiveness evaluations according to the schedule of events until 
the Exit Visit (Visit 8 or 11). Subjects with an ongoing adverse device effect (ADE) will be 
followed until the event(s) has resolved or resolved with sequelae, or deemed no longer necessary 
as per TI judgment, or if follow-up is no longer possible. 
Subjects will report their Common Treatment Responses (CTRs) in a subject diary for 30 days 
after any injection (initial or retreatment). 
The BLE will conduct assessments of effectiveness at all visits starting at Visit 5 (12 weeks after 
randomization). The primary endpoint assessment will be at Visit 5 (12 weeks after randomization) 
only. The primary endpoint will include data from subjects assigned to the RHA® 1 group (Stage 1 
and Stage 2) and the No-treatment control group before receiving initial injection. Data from 
subjects randomly assigned to the Untreated control group and to the No-treatment control group 
after they receive treatment in Phase 1b will not be considered for the primary endpoint. 
See Table 2-1, Table 2-2, Figure 7-1, Figure 7-2, and Figure 7-3. 
 

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7.1. Clinical Investigation Duration 
Individual study participation: The minimum and maximum anticipated duration of subject 
participation will be 3 to 19 months, respectively. 
Overall study duration: the original anticipated study length was approximately 22 months, 
including enrollment. However, since the study now includes staged enrollment with an interim 
safety data review by the FDA at 24 weeks after initial treatment of the first 50 subjects enrolled 
to the RHA® 1 group and a longer duration of follow-up after repeat treatment, the study is 
expected to last nearly 32 months (almost 3 years). Enrollment for Stage 1 is expected to take 
approximately 8 weeks, and when allowed to expand the study to Stage 2, an additional 14 weeks. 
However, this timing may also be extended depending on the public health emergency due to 
Coronavirus disease 2019 (COVID-19). 
With the IDE supplement to present the interim safety data of the first 50 treated subjects after 
24 weeks of follow-up (RHA® 1 group Stage 1), TEOXANE SA has provided an updated clinical 
investigation plan (CIP) for Stage 2 (CIP version 6.0). The purpose of the supplement has been to 
receive FDA approval to expand enrollment and continue the pivotal study. 
7.2. Clinical Investigation Enrollment 
Overall, this study will enroll approximately 256 subjects and a maximum of 259 subjects. 
Subjects must have grade of 2 to 3 on the TIOHS (ranging from 0 to 4) and desire at least 1 point 
of correction. Overall, at least 20% of the subjects must be of Fitzpatrick skin types IV-VI 
(50 subjects): including a minimum of 10% of subjects presenting with Fitzpatrick skin types V or 
VI of which ≥3% of Fitzpatrick skin type V (at least 8 subjects) and ≥3% of Fitzpatrick skin type V 
(at least 8 subjects). Every attempt will be made to enroll approximately 10 subjects with 
Fitzpatrick skin types IV-VI during Stage 1. The enrollment in Stage 2 will be adjusted as needed 
to achieve the overall goal. A 3:1 ratio between the RHA® 1 group and the No-treatment control 
group is planned for the overall study enrollment (Stage 1 and Stage 2 combined). 
The study will have staged enrollment as requested by the FDA. 
• Stage 1 will enroll approximately 58 subjects who will be randomly assigned (approximately 
6:1 ratio) to the following groups: 
o RHA® 1 group – approximately 50 subjects 
o Untreated control group – approximately 8 subjects 
Subjects receiving RHA® 1 will be further divided by the method of administration 
(i.e., injection with a needle or a cannula), which will be defined for each site before the 
beginning of the study. Depending on the site, subjects will receive RHA® 1 either with a 
needle (RHA® 1 needle subgroup) or by a cannula (RHA® 1 cannula subgroup). Site selection 
will aim to achieve 1:1 distribution between the subgroups. 
Safety data of all treated Stage 1 subjects up to 24 weeks after the initial treatment will be 
submitted for review as investigational device exemption (IDE) supplement to G200191 to 
request approval to expand the study for Stage 2. 
• Stage 2 will commence after the US FDA reviews the Stage 1 safety data and gives approval 
to expand enrollment of the study per the updated protocol for Stage 2. The proposed study 

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design for Stage 2 is presented thereafter (Note: it may be revised and submitted for review 
with Stage 1 safety data review). 
Remaining subjects: approximately 198 subjects (maximum 201) will be randomly assigned 
at Screening to 1 of the following groups: 
o RHA® 1 group – approximately 136 subjects 
o No-treatment control group – approximately 62 subjects 
Subjects receiving RHA® 1 will be further divided by the method of administration 
(i.e., injection with a needle or a cannula), which will be defined for each site before the 
beginning of the study. Depending on the site, subjects will receive RHA® 1 either with a 
needle (RHA® 1 needle subgroup) or by a cannula (RHA® 1 cannula subgroup). Site selection 
will aim to achieve 1:1 distribution between the subgroups, approximately 100 subjects in each 
subgroup. 
Data for the primary endpoint analysis 12 weeks after initial treatment will include the subjects 
from Stage 1 (aside from the Untreated control group) and Stage 2. The results of the effectiveness 
at the primary endpoint of Stage 1 and Stage 2 will be compared. 
The TI and the subject will not be blinded, while the BLE will be blinded to randomization to the 
RHA® 1 group, Untreated control group, or the No-treatment control group. In Stage 1, the BLE 
will not be made aware of the randomization ratio. All evaluations performed by the BLE will be 
performed completely 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. The BLE must have a separate eCRF account that will not allow them to access any 
data about the subject. 
Furthermore, to ensure that they remain blinded 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. All subjects will be instructed to not discuss their study treatment, AEs, 
or CTRs with the BLE. 
Subjects who do not meet all of the inclusion criteria or meet any of the exclusion criteria will not 
be enrolled. 
As subjects in the Untreated control group of Stage 1 will have no direct benefit from participating 
in the study, to facilitate subject recruitment, compliance, and retention, the subjects in the 
Untreated control group will be offered treatment of their nasolabial folds with injection of 
RHA®2, RHA® 3, or RHA® 4 (approved in the US) free of charge within 1 month of their study 
Exit Visit. The subjects will be informed of this option and the conditions that need to be met to 
be eligible for this complimentary treatment before entering the study. 
All these conditions need to be met: 
• The subject was randomly assigned to the Untreated control group 
• During the study, the subject was compliant with all the study procedures and instructions as 
judged by the TI 
• The subject attended all the study visits as scheduled for the subject. If the subject was 
withdrawn from the study prematurely by the TI’s or sponsor’s decision, the eligibility of the 

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subject for this complimentary treatment will be decided individually by the TI and will require 
approval from the sponsor 
• The subject wishes to receive treatment of their nasolabial folds with an injection of RHA® 2, 
RHA® 3, or RHA® 4 
7.3. Clinical Investigation Sites 
The clinical study is to be conducted at up to 4 investigational sites in the US during Stage 1 and 
up to 12 investigational sites in the US during Stage 2. Each site is anticipated to screen a sufficient 
number of subjects to enroll around 15 subjects during Stage 1 and around 20 subjects during 
Stage 2. A study site with a high recruitment rate may be allowed to recruit up to 30 subjects if 
other sites have slow enrollment or if a site is more able to enroll subjects with Fitzpatrick skin 
type IV, V, or VI. Nevertheless, a minimum of 12 subjects enrolled will be requested for each site. 
A site will use one method of administration for all its subjects (a needle or a cannula). 
Sites who enroll subjects for Stage 1 may have reached their total enrollment quota and may or 
may not participate in Stage 2 enrollment. 
7.4. Selection of Clinical Investigation Subject Population 
Subjects who seek correction of tissue volume deficiencies in the infraorbital area are possible 
candidates for the clinical investigation and will be screened for eligibility based on the following 
inclusion and exclusion criteria. 
Subjects enrolled in this investigation may be recruited from a variety of pathways, including each 
TI’s general subject population, and individuals seeking correction of tissue volume deficiencies 
in the infraorbital region referred to the TI. The TI will be allowed to advertise the clinical 
investigation, but the advertisement will first need to be approved by TEOXANE SA and by the 
applicable institutional review board (IRB). Efforts will be made to recruit at least 50 (20%) 
subjects with Fitzpatrick skin types IV-VI including minimum of 10% subjects presenting with 
Fitzpatrick skin types V or VI, of which ≥3% will have Fitzpatrick skin type V (at least 8 subjects) 
and ≥3% will have Fitzpatrick skin type VI (at least 8 subjects). Every attempt will be made to 
enroll approximately 10 subjects with Fitzpatrick skin types IV-VI during Stage 1. The enrollment 
in Stage 2 will be adjusted as needed to achieve the overall goal. 
Vulnerable subjects: 
Part 21 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: 
• Prisoners 
• Pregnant women and fetuses 
• Children 
• 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. 

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7.4.1. Inclusion Criteria 
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 1 year or surgically sterile [bilateral 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: 
a. Hormonal methods, such as oral, implantable, injectable, or transdermal contraceptives for 
a minimum of 1 full cycle (based on the subject’s typical menstrual cycle period) before 
randomization 
b. Total abstinence from sexual intercourse since the last menses before randomization 
c. Intrauterine device 
d. Double-barrier method (condoms, sponge, diaphragm, with spermicidal jellies, or cream) 
3. Subject is seeking treatment of volume deficiencies in the infraorbital regions (realistic and 
achievable as per TI opinion) 
4. Has a grade of 2 to 3 (moderate to severe) on the TIOHS for both eyes 
Note: If the assessments of the TI and the BLE are the same or differ exactly by 1 point on the 
scale, the difference will be considered acceptable. The TI and the BLE need to agree that the 
subject meets the eligibility criterion (TIOHS grade 2 or 3). Bilateral symmetry is not required. 
If the subject is eligible, the BLE’s assessment will be used for the Baseline 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 on the scale, the subject will not be eligible 
5. Able to follow study instructions and complete all required visits 
6. Willing to 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 
7.4.2. Exclusion Criteria 
A potential subject will be excluded from the study if he/she meets any of the following exclusion 
criteria: 
1. Known hypersensitivity or previous allergic reaction to any component of the study device, 
including local anesthetics of the amide type (e.g., mepivacaine, lidocaine), including known 
or suspected lidocaine hypersensitivity, or allergy to Gram-positive bacterial proteins 
2. Known history of multiple severe allergies, or history of anaphylactic shock 
3. Subjects who have either at least one of the following assessments during the vision tests: 
Snellen acuity test worse than 20/40 (with corrections, if applicable); abnormal confrontational 
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4. Prior lower eyelid surgery, including orbital or midface surgery, or has a permanent implant or 
graft in the midfacial region that could interfere with effectiveness assessments or plans to 
have it during the study 
5. Is planning to undergo during the study or has undergone any type of facial, plastic, 
nonablative, or reconstructive surgery (e.g., blepharoplasty, face lift, or rhinoplasty) within 
6 months before randomization. Subject is also excluded if residual swelling is present or 
complete healing has not occurred within at least 6 months of the treatment received 
6. Is planning to undergo during the study or has been injected in the treated area or upper part 
of the face (above the lower orbital rim) with: 
a. Semi-permanent dermal filler (e.g., calcium hydroxylapatite, poly L-lactic acid) 
≤24 months before randomization 
b. Bioresorbable facial dermal filler (hyaluronic acid, collagen, or autologous fat) ≤12 months 
before randomization 
c. Botulinum toxin injection ≤6 months before randomization 
d. Permanent filler injection (e.g., polymethylmethacrylate, silicone) at any time in the past 
7. Is planning to undergo during the study or has been subjected to procedures in the periorbital 
or malar region ≤6 months before randomization using: 
a. laser/light therapies (e.g., cutaneous laser, intense pulse light, photodynamic therapy, or 
photomodulation treatment) 
b. neuromodulator injections 
c. mesotherapy 
d. radiofrequency 
e. dermabrasion 
f. chemical procedures, such as peels (trunk and extremities permitted) 
g. prescription-strength topical retinoids 
h. other ablative or nonablative procedures 
8. Has an orbital fat prolapse that might be linked to high weight variability (loss or gain), 
excessive lower eyelid skin laxity, ectropion, entropion, or previously/currently treated with 
fat injections ≤12 months before randomization 
9. Has triangular malar mounds or fluid bags 
10. Known susceptibility to keloid formation, hypertrophic scars, hyperpigmentation, or 
compromised healing that would compromise the effectiveness outcome 
11. Ongoing cutaneous infection at the site of injection at randomization 
12. Any significant concomitant skin disease or ocular condition that may interfere with the study 
assessments as judged by the TI 
13. Compromised immunity, including but not limited to, poorly controlled diabetes mellitus (all 
types), autoimmune disease, or treatment with systemic corticosteroids, standard 
immunosuppressants, or biologics that may increase the risk of infection as judged by the TI 

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14. Subjects with known prolonged bleeding times because of disease or taking any products 
known to increase coagulation time (including but not limited to warfarin, low-dose aspirin, 
vitamin E, fish oil, nonsteroidal anti-inflammatory drugs, as judged by the TI) ≤1 week before 
randomization 
15. Has received any investigational product, including medical devices, within 90 days prior to 
randomization or is planning to participate in another investigation during the course of the 
study 
16. 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 
17. Clinically significant alcohol or drug abuse or history of poor cooperation or unreliability as 
judged by the TI 
18. Has eye tattoos, scars, lumps, or severe asymmetry that would interfere with visualization of 
the eye region for the effectiveness assessments as per TI discretion 
19. Study staff or close relative to study staff (e.g., parents, children, siblings, or spouse) 
7.4.3. Subject Withdrawal or Discontinuation 
Whenever possible, the TI should make every reasonable attempt to keep subjects in the 
investigation until the completion of the required Exit Visit. However, all subjects are free to 
withdraw from participation in this investigation at any time, for any reason, and without prejudice 
to their future medical care by the physician or at the institution/site. 
Factors leading to discontinuation from the clinical investigation may include the following: 
• A subject or legal representative withdrawal: Consent may be withdrawn at any time for any 
reason or no reason at all. Withdrawal should not affect the subject’s relationship with the 
physician, and no penalty or loss of benefits (if any) should occur. Every effort should be made 
by the research investigation staff to obtain the reason for the withdrawal of consent. 
• Investigator withdrawal: A TI may withdraw a subject from the clinical investigation at any 
time due to lack of therapeutic effect, intolerance of the device, unexpected safety events, 
intercurrent illness, major and/or repeated CIP deviations, administrative reasons, or any other 
reason that, in the TI’s opinion, is necessary to protect the subject’s safety and welfare. Subjects 
withdrawn from the clinical investigation after any device treatments may remain in the 
investigation for follow-up provided it is not detrimental to their health and safety (e.g., subject 
withdrawn after initial treatment, may continue with the assessments until Exit Visit). 
• Lost to follow-up: Lost to follow-up is defined as the inability to obtain a response from the 
subject or legal representative on 3 separate occasions separated each by at least 1 day, 
e.g., after failure to attend a visit. These contacts may be telephone calls or emails to the 
subject. However, at least 1 effort using a certified letter should be attempted to the last known 
address. All the attempts need to be documented in the source documentation. The 
investigational site must attempt to contact subjects who fail to attend scheduled visits by 
telephone or other means to exclude the possibility of an AE being the cause of withdrawal. 
Should this be the cause, the AE must be documented, reported, and followed as described in 
Section 10. 

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• Missing 2 consecutive visits: If a subject completely misses 2 consecutive visits without any 
justified reason as deemed by the TI and TEOXANE SA, the subject may be withdrawn from 
the clinical investigation and encouraged to come to the Exit visit, if possible. 
• The sponsor reserves the right to request the withdrawal of a subject due to CIP deviations or 
other reasons. 
• Subject is unable to continue in the study due to COVID-19 public health emergency, see 
Section 8.3 for details. 
• Stopping further administration of the study device: For any individual subject, further 
administration of the study device may be stopped and administration of hyaluronidase be 
considered if device-related SAE(s) or severe ADE are reported, including, but not limited to: 
o Anaphylactic reactions or severe allergic reactions 
o Signs of vascular injection, i.e., intense pain and blanching in the treated and adjacent areas, 
vision disturbances 
If hyaluronidase is used, this needs to be recorded in the eCRF as concomitant treatment. 
If study device administration is stopped during Visit 1 or Visit 1b before all intended treatment 
is administered, the subject will be withdrawn from the study and followed up for safety 
reasons according to the TI’s judgment and the site’s standard. 
If the aforementioned events occur after the administration of the study device was completed 
as intended on Visit 1 or Visit 1b, the subject may continue as per TI’s discretion with all visits 
as planned until Visit 8, which will become the Exit visit; retreatment will not be applicable. 
This will not be considered as withdrawal/discontinuation. 
• Declined retreatment at Visit 8 will not be considered as withdrawal/discontinuation if the 
subject completes all evaluations during Visit 8, which will become the Exit visit for that 
subject. However, the reason for declining retreatment needs to be documented as described 
in Section 9.7. 
Whenever the subject withdraws from the study or is withdrawn from the investigation by the TI, 
he/she or legal representative must be informed that all data collected up to the point of withdrawal 
will be maintained in the investigation files, the data management system, and included in any 
analyses, as appropriate. If a subject is withdrawn before investigation completion, the reason for 
withdrawal and date of discontinuation will be entered on the appropriate eCRF and as much 
obtainable follow-up data should be entered into the database as possible. Whenever possible and 
reasonable, the evaluations that were to be conducted at the completion of the investigation should 
be performed at the time of premature discontinuation. 
Criteria for stopping the entire clinical investigation are described in Section 9.8. 

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8. INVESTIGATION PROCEDURES 
8.1. Procedures by Visit (Stage 1 and Stage 2) 
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. Separate informed consents will be used 
for Stage 1 and Stage 2. 
For the timing of study assessments and procedures, refer to the schedule of events (Table 2-1, 
Table 2-2). The expected duration of each visit at the study site is about 2 hours; the expected 
duration of the telephone call is about 5 minutes. Throughout the study, every reasonable effort 
should be made by study personnel to follow the timing of assessments and procedures in the 
schedule of events for each subject. If a subject misses a study visit for any reason, the visit should 
be rescheduled as soon as possible. 
The study consists of a maximum of 19 visits, of which 15 visits are at the study site and 2 visits 
are telephone follow-ups after treatment. There is no separate Screening Phase; Screening will be 
performed at Visit 1. 
All procedures listed to be done by the TI can be done by the TI’s designee as per the delegation 
log at the study site, with the exception of the injection of the filler, AE collection, TIOHS, Global 
Aesthetic Improvement Scale (GAIS), and Tyndall effect assessments. 
8.1.1. Phase 1a 
Phase 1a is applicable for subjects in the RHA® 1 group (Stage 1 and Stage 2) and the No-treatment 
control group. Visit 1 and Visit 5 from Phase 1a are applicable for subjects in the Untreated control 
group. 
8.1.1.1. Visit 1 (Screening/Randomization/Baseline/Initial Treatment) 
Visit 1 is the first day of the study. Eligible subjects seeking treatment of volume deficiencies in 
the infraorbital regions will be screened for the study. 
The Screening procedures will include the following assessments: 
1. Obtain written informed consent (as applicable for Stage 1 or Stage 2) 
2. Collect demographic information 
3. Record medical history, including ophthalmologic history 
4. Collect prior and concomitant therapies (e.g., prescription and nonprescription medications) 
and previous surgeries 
5. UPT for women of childbearing potential 
6. Vision assessments, blink and closure tests 
7. Both the TI and the BLE perform the TIOHS assessment to assess eligibility and to establish 
the Baseline for future evaluations 
8. Assess inclusion/exclusion criteria 
If the subject is deemed eligible, the TI or designee will photograph the subject’s eyes. 

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Subsequently, the subject will be randomly assigned to the RHA® 1 group or the Untreated control 
group (Stage 1)/the No-treatment group (Stage 2); for details see Section 9.2. 
The Baseline procedures (after randomization, before injection) will include the following 
assessments: 
1. RHA® 1 group 
a. Part A of the Periorbital Subject Assessment Questionnaire (PSAQ) 
b. FACE-Q 
2. No-treatment control group 
a. FACE-Q 
3. Untreated control 
a. Not applicable 
If the subject is randomly assigned to the Untreated control group (Stage 1), the Visit 1 procedures 
will be considered completed with randomization. If the subject is randomly assigned to the 
No-treatment control group (Stage 2), the Visit 1 procedures will be considered completed after 
the Baseline procedures. 
If the subject is randomly assigned to RHA® 1 group, the TI will administer the filler according to 
the IB, Injection Guidelines, and Section 9.6. Depending on the site, the TI will use either only a 
needle or only a cannula. 
After the injection, the following assessments will be performed (no BLE assessments): 
1. TI: 
a. AEs 
b. Vision assessments, blink and closure tests 
c. Tyndall effect 
d. Photograph subject’s periorbital area 
2. Subject 
a. Pain assessment (visual analog scale [VAS]) immediately after the injection is completed 
(both eyes) and at 5, 15, and 30 minutes after injection 
At the end of the study visit, the TI or designee will hand out the 30-day CTR diary to the subject. 
8.1.1.2. Visit 1 Call (+3 Days After the Initial Treatment) 
Visit 1 Call is a telephone call 3 ± 2 days after the initial treatment and is applicable for subjects 
treated with RHA® 1 at Visit 1. It is not applicable for subjects randomly assigned to the Untreated 
control group or the No-treatment control group. 
The TI or designee will collect information about potential AEs and changes in concomitant 
medication and remind the subject to complete the 30-day CTR diary. The TI or designee will 
attempt to reach the subject at least 3 times during that day. 

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8.1.1.3. Visit 2 (2 Weeks After the Initial Treatment or Randomization) 
Visit 2 is performed at the site 2 weeks ± 3 days after the randomization and is applicable for 
subjects in the RHA® 1 group (Stage 1 and Stage 2) and No-treatment control group; it is not 
applicable for subjects in the Untreated control group. 
At the beginning of Visit 2, the TI or designee will review the CTR diary from Visit 1 (subjects in 
the RHA® 1 group only). 
The following assessments will be performed by the TI at Visit 2: 
a. AEs 
b. Vision assessments, blink and closure tests (RHA® 1 group only) 
c. Concomitant medications 
d. TIOHS 
e. Tyndall effect (RHA® 1 group only) 
f. Photograph subject’s periorbital area 
8.1.1.4. Visit 3 (4 Weeks After the Initial Treatment or Randomization) 
Visit 3 is performed at the site 4 weeks ± 3 days after the randomization and is applicable for 
subjects in the RHA® 1 group (Stage 1 and Stage 2) and No-treatment control group; it is not 
applicable for subjects in the Untreated control group. 
At the beginning of Visit 3, the TI or designee will collect and review the CTR diary from Visit 1 
(subjects in the RHA® 1 group only). 
The following assessments will be performed at Visit 3: 
1. TI: 
a. AEs 
b. Vision assessments, blink and closure tests (RHA® 1 group only) 
c. Concomitant medications 
d. TIOHS 
e. GAIS 
f. Tyndall effect (RHA® 1 group only) 
g. Photograph subject’s periorbital area 
2. Subject: 
a. FACE-Q 
b. GAIS 
c. PSAQ (RHA® 1 group only, parts A and B without question 12) 
d. Subject satisfaction (RHA® 1 group only) 

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8.1.1.5. Visit 4 (8 Weeks After the Initial Treatment or Randomization) 
Visit 4 is performed at the site 8 weeks ± 3 days after the randomization and is applicable for 
subjects in the RHA® 1 group (Stage 1 and Stage 2) and No-treatment control group; it is not 
applicable for subjects in the Untreated control group. 
The following assessments will be performed at Visit 4: 
1. TI: 
a. AEs 
b. Vision assessments, blink and closure tests (RHA® 1 group only) 
c. Concomitant medications 
d. TIOHS 
e. GAIS 
f. Tyndall effect (RHA® 1 group only) 
g. Photograph subject’s periorbital area 
2. Subject: 
a. FACE-Q 
b. GAIS 
c. PSAQ (RHA® 1 group only, parts A and B without question 12) 
d. Subject satisfaction (RHA® 1 group only) 
8.1.1.6. Visit 5 (Primary Endpoint; 12 Weeks After the Initial Treatment or Randomization) 
Visit 5 is performed at the site 12 weeks ± 3 days after the randomization and is applicable for all 
subjects (including subjects in the Untreated control group). Data from subjects in the RHA® 1 
group and the No-treatment control group from Visit 5 will be used for the primary endpoint 
assessment (data from subjects in the Untreated control group will not be used for the primary 
endpoint assessment). 
The following assessments will be performed at Visit 5: 
1. TI: 
a. AEs 
b. Vision assessments, blink and closure tests (RHA® 1 group only) 
c. Concomitant medications (not applicable for the Untreated control group) 
d. TIOHS (not applicable for the Untreated control group) 
e. GAIS (not applicable for the Untreated control group) 
f. Tyndall effect (RHA® 1 group only) 
g. Photograph subject’s periorbital area 

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2. BLE: 
a. GAIS 
b. TIOHS 
3. Subject (not applicable for the Untreated control group): 
a. FACE-Q 
b. GAIS 
c. PSAQ (RHA® 1 group only, parts A and B without question 12) 
d. Subject satisfaction (RHA® 1 group only) 
After Visit 5, subjects initially assigned to the RHA® 1 group (from Stage 1 or Stage 2) group will 
proceed directly to Phase 2. Subjects initially randomly assigned to the No-treatment control group 
will proceed to Phase 1b. 
Visit 5 will be the Exit visit for subjects randomly assigned to the Untreated control group. After 
exiting the study, subjects assigned to the Untreated control group will be offered treatment of 
their nasolabial folds with injection of RHA® 2, RHA® 3, or RHA® 4 (approved in the US) free of 
charge within 1 month of their study Exit visit (see Section 7.2). 
8.1.2. Phase 1b (Subjects From Stage 2 Only) 
Phase 1b is applicable only for subjects initially randomly assigned to the No-treatment control 
group. 
8.1.2.1. Visit 1b (12 Weeks After the Randomization) 
Visit 1b will occur on the same day as Visit 5. Results from these assessments at Visit 5 will be 
used as the new Baseline and used for pre-treatment assessments of Visit 1b (refer to schedule of 
events in Section 2.2). 
The subjects will be asked to complete the part A of the PSAQ. 
A UPT will be performed prior to injection in all females of childbearing potential. Vision 
assessments and blink and closure tests will be performed prior to injection in all subjects. 
Afterwards, the TI will administer the filler according to the IB, Injection Guidelines, and 
Section 9.6. Depending on the site, the TI will use only a needle or only a cannula. 
After the injection, the following assessments will be performed (no BLE assessments): 
1. TI: 
a. AEs 
b. Vision assessments, blink and closure tests 
c. Tyndall effect 
d. Photograph subject’s periorbital area 
2. Subject 
a. Pain assessment (VAS) immediately after the injection is completed (both eyes) and at 5, 
15, and 30 minutes after injection 

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At the end of the study visit, the TI or designee will hand out the 30-day CTR diary to the subject. 
8.1.2.2. Visit 1b Call (+3 Days After the Initial Treatment at Visit 1b) 
Visit 1b Call is a telephone call 3 ± 2 days after the initial treatment and is applicable for all 
subjects treated with RHA® 1 at Visit 1b. 
The TI or designee will collect information about potential AEs and changes in concomitant 
medication and remind the subject to complete the 30-day CTR diary. The TI or designee will 
attempt to reach the subject at least 3 times during that day. 
8.1.2.3. Visit 2b (2 Weeks After the Initial Treatment or Randomization) 
Visit 2b is performed at the site 2 weeks ± 3 days after the initial treatment and is applicable for 
all subjects treated with RHA® 1 at Visit 1b. 
At the beginning of Visit 2b, the TI or designee will review the CTR diary from Visit 1b. 
The following assessments will be performed by the TI at Visit 2b: 
a. AEs 
b. Vision assessments, blink and closure tests 
c. Concomitant medications 
d. TIOHS 
e. Tyndall effect 
f. Photograph subject’s periorbital area 
8.1.2.4. Visit 3b (4 Weeks After the Initial Treatment at Visit 1b), Visit 4b (8 Weeks After 
the Initial Treatment at Visit 1b), and Visit 5b (12 Weeks After the Initial Treatment 
at Visit 1b) 
Visit 3b is performed at the site 4 weeks ± 3 days after the initial treatment at Visit 1b. At the 
beginning of Visit 3b, the TI or designee will collect and review the CTR diary from Visit 1b. 
Visit 4b is performed at the site 8 weeks ± 3 days after the initial treatment at Visit 1b. 
Visit 5b is performed at the site 12 weeks ± 3 days after the initial treatment at Visit 1b. Data from 
Visit 5 are not applicable for the primary endpoint assessment. 
The following assessments will be performed at Visit 3b, Visit 4b, and Visit 5b: 
1. TI: 
a. AEs 
b. Concomitant medications 
c. Vision assessments, blink and closure tests 
d. TIOHS 
e. GAIS 
f. Tyndall effect 
g. Photograph subject’s periorbital area 

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2. BLE: 
a. GAIS (Visit 5b only) 
b. TIOHS (Visit 5b only) 
3. Subject: 
a. FACE-Q 
b. GAIS 
c. PSAQ (parts A and B without question 12) 
d. Subject satisfaction 
After completing Visit 5b, subjects will proceed to Phase 2. 
8.1.3. Phase 2 
Phase 2 is applicable for all subjects randomly assigned to the RHA® 1 group (Stage 1 and Stage 2) 
and for subjects randomly assigned to the No-treatment control group after completing Phase 1b 
(Visit 5b). It is not applicable for subjects in the Untreated control group. 
8.1.3.1. Visit 6 (24 Weeks After Randomization/the Initial Treatment) and Visit 7 (36 Weeks 
After the Initial Treatment) 
Visit 6 is performed at the site 24 weeks ± 7 days after the subject’s initial treatment (RHA® 1 
group and No-treatment control group after Phase 1b) and is applicable for all subjects. 
Visit 7 is performed at the site 36 weeks ± 7 days after the subject’s initial treatment and is 
applicable for subjects in the RHA® 1 group (Stage 1 and Stage 2) and in the No-treatment control 
group. 
The following assessments will be performed at Visits 6 and 7: 
1. TI: 
a. AEs 
b. Vision assessments, blink and closure tests 
c. Concomitant medications 
d. TIOHS 
e. GAIS 
f. Tyndall effect 
g. Photograph subject’s periorbital area 
2. BLE: 
a. GAIS 
b. TIOHS 
3. Subject: 
a. FACE-Q 
b. GAIS 
c. PSAQ (parts A and B without question 12) 
d. Subject satisfaction 

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8.1.3.2. Visit 8 (52 Weeks After the Initial Treatment; Exit Visit for Subjects Without 
Retreatment) 
Visit 8 is performed at the site 52 weeks ± 7 days after the subject’s initial treatment and is 
applicable for subjects in the RHA® 1 group (Stage 1 and Stage 2) and in the No-treatment control 
group. 
The following assessments will be performed at Visit 8: 
1. TI: 
a. AEs 
b. Concomitant medications 
c. TIOHS 
d. GAIS 
e. Tyndall effect 
f. Photograph subject’s periorbital area 
2. BLE: 
a. GAIS 
b. TIOHS 
3. Subject: 
a. FACE-Q 
b. GAIS 
c. PSAQ (parts A and B, including question 12 if this visit is the Exit visit) 
d. Subject satisfaction 
After the assessments are completed, retreatment with RHA® 1 will be offered to all subjects, if 
the TI deems it to be appropriate and the subject agrees. The reason for not receiving retreatment 
will be documented (see Section 9.7). 
For subjects who do not receive retreatment, Visit 8 will be the Exit visit. Subjects with an ongoing 
ADE(s) will be followed until the event(s) has resolved or resolved with sequelae, or deemed no 
longer necessary as per TI judgment, or if follow-up is no longer possible 
If the subject and TI agree that the subject will receive retreatment, prior to administration of the 
filler, the subject will undergo vision assessments, blink and closure tests, and a UPT, if she is a 
woman of childbearing potential 
Afterwards, the TI will administer retreatment with RHA® 1 (applicable for subjects with 
retreatment) according to the IB, Injection Guidelines, and the details described in Section 9.6. 
Depending on the site, the TI will use only a needle or only a cannula. 
After the injection, if applicable, the following assessments will be performed (no BLE 
assessments): 
a) TI: 
a. AEs 
b. Vision assessments, blink and closure tests 
c. Tyndall effect 

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d. Photograph subject’s periorbital area 
b) Subject 
a. Pain assessment (VAS) immediately after the injection is completed (both eyes) and at 5, 
15, and 30 minutes after injection 
At the end of the study visit, the TI or designee will hand out the 30-day CTR diary to the subject. 
8.1.3.3. Visit 8 Call (+3 Days After the Retreatment) 
Visit 8 Call is a telephone call 3 ± 2 days after the retreatment for subjects who received 
retreatment. 
The TI or designee will contact the subject to collect information about potential AEs and changes 
in concomitant medication and remind the subject to complete the 30-day CTR diary. The TI or 
designee will attempt to reach the subject at least 3 times during that day. 
8.1.3.4. Visit 9 (2 Weeks After the Retreatment) 
Visit 9 is performed at the site 2 weeks ± 3 days after the retreatment for subjects who received 
retreatment. 
The TI or designee will remind the subject to complete the 30-day CTR diary. 
The following assessments will be performed at Visit 9: 
1. TI: 
a. 
AEs 
b. 
Vision assessments, blink and closure tests 
c. 
Concomitant medications 
d. 
Tyndall effect 
8.1.3.5. Visit 10 (4 Weeks After the Retreatment) 
Visit 10 is performed at the site 4 weeks ±3 days after retreatment for subjects who received 
retreatment. 
At the beginning of the visit, the TI or designee will collect and review the 30-day CTR diary the 
subject started completing after the retreatment. 
The following assessments will then be performed at Visit 10: 
1. TI: 
a. 
AEs 
b. 
Vision assessments, blink and closure tests 
c. 
Concomitant medications 
d. 
TIOHS 
e. 
GAIS 
f. 
Tyndall effect 
g. 
Photograph subject’s periorbital area 

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2. BLE: 
a. 
GAIS 
b. 
TIOHS 
3. Subject: 
a. 
FACE-Q 
b. 
GAIS 
c. 
PSAQ (parts A and B, including question 12 if this visit is the Exit visit) 
d. 
Subject satisfaction 
8.1.3.6. Visit 11 (12 Weeks After the Retreatment; Exit Visit for Subjects Who Received 
Retreatment) 
Visit 11 is applicable only for subjects who received retreatment at Visit 8 and will take place 
12 weeks after retreatment. The allowed visit window is ±7 days. 
The following assessments will then be performed at Visit 11: 
1. TI: 
a. AEs 
b. Vision assessments, blink and closure tests 
c. Concomitant medications 
d. TIOHS 
e. GAIS 
f. Tyndall effect 
g. Photograph subject’s periorbital area 
2. BLE: 
a. GAIS 
b. TIOHS 
3. Subject: 
a. FACE-Q 
b. GAIS 
c. PSAQ (parts A and B, including question 12 if this visit is the Exit visit) 
d. Subject satisfaction 
 
Visit 11 will be the Exit Visit for subjects who received retreatment. Subjects with an ongoing 
ADE(s) will be followed until the event(s) has resolved or resolved with sequelae, or deemed no 
longer necessary as per TI judgment, or if follow-up is no longer possible. 
8.2. Assessments 
8.2.1. Urine Pregnancy Test 
A UPT for women of childbearing potential will be conducted at the site at Screening and prior to 
each application of the filler (Section 2.2). 

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If the test result is positive at Screening prior to randomization, the subject will be considered a 
screen failure. If the test is positive at any time during the study after the randomization, the subject 
will be withdrawn from the study and followed per Section 10.4. A confirmatory serum test is not 
required. 
8.2.2. Safety Assessments 
Safety assessments will include the evaluation of AEs, post-injection CTR 30-day subject diary, 
vision assessments, basic neurological examination in case of visual disturbances or 
signs/symptoms of visual disturbances, blink and closure tests, and injection site pain assessment. 
8.2.2.1. Common Treatment Response 
The subject will receive a diary booklet and instructions for recording his/her observations of the 
CTRs of the study treatments for the first 30 days after each treatment, starting from the day of the 
injection. The diary will be dispensed after each treatment. Subjects should complete the diary at 
approximately the same time each day (i.e., am or pm). The diary will be discussed during the 
telephone call visit (Visit 1 Call, Visit 1b Call, and Visit 8 Call) to assess potential AEs. The diaries 
will be collected at the next site visit. When scheduling the visit 4 weeks after the injection (Visit 3, 
Visit 3b, Visit 10), every effort should be made to allow completion of the 30-day diary. 
The subject diary (Appendix A) will include a glossary with descriptions for the CTRs that the 
subject may experience after receiving dermal filler injection and explanation of the severity levels 
applicable for the CTRs. 
The subject will assess the severity as follows: 
• Mild – Symptom barely noticeable and does not cause discomfort. No influence on 
performance or functioning. Treatment of symptom is not needed. 
• Moderate – Symptom very noticeable and/or causes discomfort. Performance of daily activities 
is influenced. Treatment of symptoms may be needed. 
• Severe – Symptom causes severe discomfort. Performance of daily activities is compromised. 
Treatment of symptom is needed. 
The diary will include the following CTRs: redness, pain, tenderness, firmness, swelling, 
lumps/bumps, bruising, itching, and discoloration. Subjects will record the presence and the 
severity of each observed sign/symptom as none, mild, moderate, or severe. Events from this 
checklist should be reviewed and assessed by the TI. If the TI considers them to be AEs (if their 
duration and/or severity exceed what is typically observed following injection of a dermal filler), 
they should be recorded as such. In such case, the TI is to use his/her clinical judgment in 
determining the severity of the AE (see Section 10 for details), the TI will not rely on the subject’s 
individual opinion of severity. 
If the subject completes at least 23 days of the diary (>75%), the diary will be processed as if it 
were fully completed. In such case, CTRs that are present on the last day of the diary entry will be 
automatically considered as AEs, recorded in the eCRF, and followed up as such. If the subject 
completes 22 days of the diary or fewer, the consideration whether any of the CTRs present at the 
last recorded day of the diary is to be recorded as AE will be left to the TI’s judgment. 

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An option on the subject diary will be provided to report “other” event if the subject experiences 
a sign/symptom that is not listed. Signs/symptoms included on this field (“other”) will be 
automatically regarded as AEs, unless they refer to an event included in the CTR list, and must be 
recorded as such by the TI or designee (see Section 10 for details). If the event is included in the 
CTR list, it will be treated as such. 
Additionally, the 30-day subject diary will include a check box for subjects to identify potential 
AEs from a predefined list of events of interest after dermal filler injections, namely: vision 
disturbances, headache, fever, dizziness, confusion, face droop, sensitivity to hot/cold liquids and 
foods, weakness or numbness in arms or legs, changes to chewing and drinking, chest discomfort 
with irregular heartbeat, changes to consciousness or alertness, difficulty speaking/ speech 
impairment, skin changing color around the eyelids, crusty or scabby skin on the face. All of these 
events will be regarded as AEs and must be recorded as such by the TI or designee (see Section 10 
for details). Moreover, the subject will be instructed and reminded after each injection that any 
occurrence of these events should be brought to the site’s attention immediately and if necessary, 
the subject should seek immediate medical attention. 
8.2.2.2. Blink and Closure Tests 
For the blink test, 30 minutes after injection the TI or designee will ask the subject to blink his/her 
eyes rapidly several times and observe the blink to make sure that there is full contact between the 
upper eyelid and the lower eyelid. Each eye will be examined independently. An abnormal blink 
test would be the inability to blink. 
For the eye closure test, 30 minutes after injection the TI or designee will ask the subject to close 
his/her eyes and observe for complete closure with full contact between the upper eyelid and the 
lower eyelid. Each eye will be examined independently. An abnormal closure test occurs if the 
subject is not able to fully close his/her eyes. 
Abnormal result of the blink and/or the closure test will be recorded in the eCRF, root cause should 
be investigated, and possible treatments determined after examination of the subject. If a 
blink/abnormal closure test is accompanied by any visual disturbances or pain, the subject should 
be immediately referred to a retinal specialist or ophthalmologist. In addition, to exclude 
neurological complication/disorder, the TI must perform basic neurological examination and 
immediately transfer the subject to the closest emergency room or to call 911 in case of any 
abnormal findings (see Section 8.2.2.4). For further information refer to the applicable study-
specific Visual Assessments User Manual.7 
8.2.2.3. Vision Assessments 
Subjects will undergo 3 vision assessments 30 minutes after injection to detect rare and 
unintentional injection of the filler into a blood vessel – Snellen vision acuity, confrontational 
visual test field, and ocular motility. 
Subjects should be instructed to wear the same corrective eyewear (if applicable) at each visit; use 
of glasses/contact lenses will be recorded in the eCRF. 
Prior to the start of the study, each site will have identified a local eye specialist (ophthalmologist 
or retina specialist) who will examine subjects immediately in case of ophthalmic symptoms after 
an injection or during follow-up visits. 

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The TI or designee will perform vision assessments at each visit after the treatment start (Visit 1/ 
Visit 1b) as well as before and after each injection during treatment visits as indicated in the 
schedule of events (Section 2.2). 
Only subjects with vision acuity of 20/40 or better (with correction, if applicable), normal 
peripheral vision, and normal ocular motility will be enrolled in the study. Should any of the vision 
assessments suddenly worsen after the injection of the study device, the TI must examine the 
subject to exclude vascular injection and immediately contact an eye specialist if necessary. In 
addition, to exclude neurological complication/disorder, the TI must perform basic neurological 
examination and immediately transfer the subject to the closest emergency room or to call 911 
in case of any abnormal findings (see Section 8.2.2.4). 
As a guide, the TI may use a provided questionnaire to assess the urgency of the potential changes; 
the provided questionnaire does not replace the TI’s medical judgment on assessing each subject 
individually, it should be understood as a tool to help the TI in his/her exam. 
If the visual assessments after the injection show a change from assessments performed before the 
injection defined as either one of the following: 
• Snellen acuity test: any worsening of 1 line or more 
• Confrontational visual test field: change to peripheral vision 
• Ocular motility: change to ocular motility 
All subjects with abnormal vision assessments and without neurological complication/disorder 
will be immediately referred to an eye specialist to determine if the vision change is related to a 
vascular injection of the dermal filler or not. The eye specialist will also provide their opinion on 
whether the change is clinically significant (requires any further follow-up or treatment as per 
clinician’s judgment). 
If the referral to the eye specialist confirms that the subject had the filler injected into a blood 
vessel, the subject will be withdrawn as per Section 7.4.3 and the need of stopping the study will 
be reviewed as per Section 9.8. 
8.2.2.3.1. Snellen Vision Acuity 
The TI or designee will use the provided chart and place it on a wall or an easel at a distance 
defined on the chart. If the subject normally wears eyeglasses or contact lenses, he/she will be 
asked to use them during testing. The subject will cover 1 eye with his/her hand without pressing 
on it, and the TI or designee will ask the subject to read the letters out loud from the largest to the 
smallest and then repeat with the other eye. The TI or designee will record the visual acuity for 
each eye in the eCRF.9 For further information, refer to the applicable study-specific Visual 
Assessments User Manual.7 
8.2.2.3.2. Confrontational Visual Test Field 
If applicable, the TI or designee will ask the subject to remove his/her hat or anything that could 
interfere with his/her peripheral vision and then sit approximately 1 m away and directly in front 
of the subject. If possible, the TI or designee will adjust the seat to be at eye level with the subject. 
The subject will be asked to gently cover his/her left eye with the left hand and to fix his/her gaze 

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directly on the TI’s left eye throughout the test. The TI or designee will then close his/her right 
eye and maintain fixation on the subject’s eye. The TI or designee will then raise his/her left hand 
and hold up 1, 2, or 5 fingers consequently in the inferior temporal edge, inferior nasal edge, 
superior temporal edge, and superior nasal edge of the TI’s visual quadrant. The test will be then 
repeated with the other eye and ability to distinguish the numbers by the subject in each quadrant 
will be noted.10 For further information, refer to the applicable study-specific Visual Assessments 
User Manual.7 
8.2.2.3.3. Ocular Motility 
The TI or designee will first assess the eye alignment of the subject in primary gaze and then will 
ask him/her to move the eyes in an “H” pattern using a finger or a light. The TI or designee will 
then assess and note the ability of the eyes to move in all directions.11 
For further information, refer to the applicable study-specific Visual Assessments User Manual.7 
8.2.2.4. Basic Neurological Examination 
If there is any visual disturbance identified following the 3 vision assessments (Snellen visual 
acuity, confrontational visual test field, and ocular motility) or if there are signs/symptoms of 
visual disturbances, a basic neurological examination must be performed immediately. 
This neurological examination will last about 10 minutes. Please refer to the applicable 
study-specific Neurological Examination Instructions12 for detailed procedure to perform this 
examination. 
The result of neurological examination will be recorded in the eCRF. Any abnormal finding would 
require urgent transfer of the subject to the closest emergency room or to call 911. 
Only if the subject is showing clear signs of a neurological disorder, judged by the TI, the 
neurological examination does not need to be performed and the subject must be urgently 
transferred to the closest emergency room or 911 must be called immediately. 
In all these instances, the event will be considered an SAE. 
8.2.2.5. Adverse Events 
The definition and management of adverse events (AEs), and any special considerations for AEs, 
are provided in Section 10. 
8.2.2.6. Injection Site Pain 
Prior to treatment, the subject should be assessed for appropriate anesthetic treatment for managing 
comfort (e.g., topical anesthetic, local, or nerve block). Information about the use of any anesthetic 
treatment, including nonpharmacological methods such as ice pack, will be collected as 
concomitant treatment in the eCRF. If any anesthetic is indicated after the injection, efforts should 
be made to apply those only after the pain assessment 5 minutes after the injection has been 
performed (see Section 9.4 for further information). 
Pain at the site of injection will be assessed by the subject after the injection is completed (both 
eyes) as per the schedule of events (Section 2.2) immediately after the injection, 5 minutes, 

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15 minutes, and 30 minutes after the injection. The subject will use a VAS plastic ruler with a 
100 mm long line with the left end representing “no pain” and the right end representing 
“unbearable pain” and a slider. The subject will be asked to mark the location on the line with the 
slider that represents his/her level of pain. The distance along the line from the “no pain” end to 
the marked location will be expressed in units of millimeters. 
Since injection site pain is typical after administration of a filler, the occurrence of injection site 
pain will only be considered an AE if it is more intense/severe or lasts longer than during injection, 
or to that typically observed following injection of a filler, as determined by the TI’s clinical 
judgment. In such case, the TI is expected to follow-up on the pain appropriately to exclude 
vascular injection or other complications as potential underlying causes of the unusual pain. 
8.2.3. Effectiveness Assessments 
Effectiveness will be assessed by the TI, BLE, and subject as per the schedule of events 
(Section 2.2). 
8.2.3.1. Teoxane Infraorbital Hollow Scale 
Infraorbital hollows will be assessed by the TI and the BLE at time points in the schedule of events 
(Section 2.2) using the live-validated 5-point TIOHS provided in Appendix B. 
For eligibility purposes only: If the assessments of the TI and the BLE are the same or differ 
exactly by 1 point on the scale, the difference will be considered acceptable. The TI and the BLE 
need to agree that the subject meets the eligibility criterion (TIOHS grade 2 or 3). Bilateral 
symmetry is not required. If the subject is eligible, the BLE’s assessment will be used for the 
Baseline 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 on the scale, the subject will not be eligible. 
8.2.3.2. Subject Satisfaction 
Subject satisfaction will be measured by using a 5-point balanced subjective scale at time points 
in the schedule of events (Section 2.2). 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” 
using the scale in Table 8-1. 

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Table 8-1  
Subject Satisfaction Scale 
Grade 
Description 
1 
Very satisfied 
2 
Satisfied 
3 
Neither satisfied nor dissatisfied 
4 
Dissatisfied 
5 
Very dissatisfied 
8.2.3.3. Global Aesthetic Improvement 
Global aesthetic improvement assessment will be performed by the TI, BLE, and the subjects at 
time points in the schedule of events (Section 2.2) using a 5-grade GAIS (Table 8-2). During the 
assessment, the pre-injection photograph will be provided; the scale will be used to compare the 
Baseline photograph of the eyes to the current appearance of the eyes and to rate the degree of 
aesthetic improvement. The subject will be instructed to use a mirror to compare his/her face to 
the photograph provided and to rate the degree of aesthetic improvement using the scale. 
Table 8-2  
Global Aesthetic Improvement Scale 
Grade 
Description 
1 
Much improved 
2 
Improved 
3 
No change 
4 
Worse 
5 
Much worse 
8.2.3.4. FACE-Q 
The validated subject-reported outcome measure FACE-Q scale13 will be assessed as in the 
schedule of events (Section 2.2). Only one selected scale from the FACE-Q will be used for the 
purpose of this study – Appraisal of Lower Eyelids. This scale measures the appearance of the area 
under the eyes with items that ask about the bags and wrinkled skin located in this area, as well as 
how tired or old these features make someone look. This scale is provided in Appendix C. 
The 4 questions identified with the check mark will be used as the co-primary endpoint. The 
secondary endpoint will use all 7 questions. 
The subjects will be asked the following (Table 8-3): With the area under your eyes in mind, in 
the past week, how much have you been bothered by: 

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Table 8-3 
FACE-Q scale 
Co-primary 
endpoint 
Question 
Not at all A little 
Moderately Extremely 
N/A 
Excess fat under your eyes? 
1 
2 
3 
4 
N/A 
Excess skin under your eyes? 
1 
2 
3 
4 
N/A 
Puffiness under your eyes? 
1 
2 
3 
4 
√ 
How noticeable the lines 
under your eyes are? 
1 
2 
3 
4 
√ 
Crepey (wrinkle) skin under 
your eyes? 
1 
2 
3 
4 
√ 
How old the area under your 
eyes makes you look? 
1 
2 
3 
4 
√ 
How tired the area under 
your eyes makes you look? 
1 
2 
3 
4 
8.2.3.5. Periorbital Subject Assessment Questionnaire 
Subjects will complete the PSAQ at time points in the schedule of events (Section 2.2). The PSAQ 
consists of 2 parts of total 12 questions: part A with the first 5 questions, part B with the remaining 
7 questions. At Baseline before initial injection (Visit 1/Visit 1b), the subject will complete only 
part A of PSAQ. At each site visit starting after initial injection starting from Visit 3/Visit 3b, the 
subject will complete both parts of the PSAQ with the exception of question 12. Both parts of the 
PSAQ including the question 12 will be assessed at the Exit visit (Visit 8 or Visit 11). 
The subject will select whether he/she agrees or disagrees with statements in the questionnaire 
using 7-grade scale: 1 – Strongly disagree, 2 – Disagree, 3 – Somewhat disagree 4 – Neither agree 
nor disagree, 5 – Somewhat agree, 6 – Agree, 7 – Strongly agree. 
During the part B assessment, the pre-injection photograph will be provided if requested by the 
subject; the scale may be used to compare the Baseline photograph of the eyes to the current 
appearance of the eyes and to rate the degree of aesthetic improvement. The subject will be 
instructed to use a mirror to compare his/her face to the photograph provided as needed. The 
questionnaire is provided in Appendix D. 
8.2.3.6. Treatment Volume for Optimal Cosmetic Results 
The total volume of RHA® 1 per treatment session and per eye to obtain an Optimal Cosmetic 
Result (OCR) as judged by the TI will be measured to an accuracy of 0.1 mL. 
8.2.3.7. Tyndall Effect Assessment 
Injections applied too superficially can lead to bluish discoloration under the skin called the 
Tyndall effect, which is caused by blue light spectrum scattered by the colloid particles. To assess 
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The TI will then inspect the area under the eye for a bluish discoloration (blue like water in a 
swimming pool). Each eye will be assessed independently. 
For further information, refer to the applicable study-specific Visual Assessments User Manual.7 
8.2.3.8. Photography 
Calibrated photographs will be taken at each study visit (and if applicable, before and after study 
treatment), according to a standardized protocol incorporating appropriate quality control 
processes. The TI or designee will take a digital photograph of the subject’s eyes (upper face, 
above the orbital rim) at time points defined in the schedule of events (Section 2.2) using 
equipment provided by Canfield Scientific (third party of TEOXANE SA). The photograph taken 
by the TI or designee will include the whole face and cropped as necessary after the images are 
transferred. The TI will be trained prior to Screening of first subject at the site. 
The subject will be asked to sign a separate photography release form to specify whether he/she 
allows other uses of the photographs (e.g., publications, promotion). The subject’s decision will 
be then tracked in a separate photography release log kept at the site. 
Site staff need to make sure subject confidentiality is not jeopardized at any time; this includes but 
is not limited to: 
• Ensuring images are deleted from memory storage after the images are transferred 
• Ensuring images that include a subject’s lower face is cropped and the originals are deleted 
• Not leaving the camera unattended with the subject 
• Using only equipment provided by TEOXANE SA and not any personal device, such as smart 
phone 
• Adhering to the manual provided 
8.3. Adjustments of Visits and Assessments Due to Public Health Emergency of 
Coronavirus Disease 2019 
8.3.1. General Guidance 
Subject safety and preserving the integrity of the data are of the highest priority. Any local rules, 
guidance, or laws shall be followed. Study visits and procedures should be followed per-protocol 
whenever possible. Any specific changes in study conduct that deviate from the protocol should 
be communicated to the sponsor via reporting to the site’s Clinical Research Associate (CRA) and 
IRB, as applicable. All CIP deviations which occur as a result of COVID-19 disruptions, will be 
differentiated from other deviations. If the subject is unable or unwilling to come to the site due to 
COVID-19, the TI needs to ask for the reasons and document them in the source documents. 
Should a subject develop any symptoms that could be related to COVID-19 or any other acute 
infection disease, the subject will be instructed to: 
• Contact the TI as soon as possible 
• Contact their general physician to be examined and determine the course of action according 
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The TI or designee will follow-up with the subject as needed but at least within 72 hours of 
awareness to obtain an update on the subject’s health and to obtain information on whether 
COVID-19 has been diagnosed or not. If the subject has been diagnosed with COVID-19, the event 
will be reported as an AE. 
Injections of RHA® 1 can only be done on the site, in person. 
8.3.2. Adjustment of Visit 1 
It is necessary for all subjects to come to Visit 1 in person; otherwise, the subject will not be 
enrolled. The BLE needs to be present at Visit 1. To decrease the time the subject needs to spend 
at the site during the COVID-19 public health emergency situation, if possible, the TI or designee 
is encouraged to send the informed consent form (ICF) to the subject in advance and schedule 
a telephone call to answer the subject’s questions, if any. However, the ICF must be signed in 
person at the site and the signature of the ICF must precede all other study-related procedures. The 
subject will be encouraged to bring the relevant medical records and list of concomitant 
medications that could help shorten the time of the visit. 
8.3.3. Adjustment of Visits 5/1b, 8, and the Exit Visit 
Following Visits 5/1b, 8, and the Exit Visit (8 or 11), it is critical to make every possible effort to 
have the subject return to the site in the allowed time window. Only if it is not possible for the visit 
to be scheduled within the allowed window can those visits be scheduled within an additional +14 
days to the initially permitted window. This will not be considered a CIP deviation. The BLE needs 
to be present at these visits. 
Additionally: 
• To decrease the time the subject needs to spend at the site, the TI or designee is encouraged to 
send the paper FACE-Q and PSAQ to the subject in advance and ask him/her to complete it 
within 3 days of the visit or on the day of the visit before coming to the site. The TI or designee 
is also encouraged to perform a remote telemedicine visit or telephone call up to 3 days before 
the scheduled visit to obtain the subject’s answers to the GAIS and the Subject satisfaction 
scale or to answer any questions the subject may have to the FACE-Q or PSAQ. The UPT must 
be performed at the site before the injection for females of childbearing potential. However, if 
a subject thinks she might be pregnant, she will be encouraged to perform a home UPT and 
inform the TI immediately in case of a positive result in order to reschedule the upcoming visit 
(but no treatment shall occur until the end of the study). 
• Visit 5 (primary endpoint, on the same day as Visit 1b for subjects randomly assigned to the 
No-treatment control group). If the subject cannot come to the site even within the extended 
window, the subject will not be withdrawn from the study and will keep having subsequent 
visits as planned. 
• Visit 8 (Retreatment/Exit Visit). If the subject cannot come to the site even within the extended 
window, they will not receive retreatment and will have the Exit Visit performed (see below). 
If the only reason for not receiving retreatment is the situation caused by COVID-19, the TI 
will report it as such. If the reason for no retreatment is different, the TI is to report the 
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• Exit visit. If the subject cannot come to the site even within the extended window, he/she will 
have the Exit visit performed remotely. If the subject has no ongoing AEs at the time of the 
remote Exit visit, he/she will exit the study. If the subject has any ongoing AEs during the 
remote Exit visit, if the remote Exit visit is not possible or sufficient in TI’s opinion, or if the 
TI deems it necessary, the subject will come to the site for the Exit visit as soon as it is possible. 
This will be considered as CIP deviation. If the subject has both a remote Exit visit and an 
onsite Exit visit, the remote visit will be recorded as an Unscheduled visit in the eCRF and the 
last visit (onsite visit) will be recorded as the Exit visit in the eCRF. 
8.3.4. Adjustment of Visits 2, 2b, 3, 3b, 4, 4b, 5b, 6, 7, 9, and 10 
For Visits 2, 2b, 3, 3b, 4, 4b, 5b, 6, 7, 9, and 10, it is important to make every possible effort to 
have the subject return to the site in the allowed time window. If it is not possible due to the 
COVID-19 disruptions, these visits can be performed remotely via telemedicine. Telemedicine is 
understood as a possible solution due to COVID-19 disruption and it is not mandatory; if the 
situation allows it, visits should be done in person. The TI will decide the exact way the remote 
visit will be conducted but he/she should adhere to these basic rules: 
• If possible and applicable, the subject should send a scanned copy of the CTR diary to the TI 
a day before or in the morning of the scheduled remote visit and afterwards send a hard copy 
to the site. If not possible, the TI should ask detailed questions about the entries in the CTR 
diary during the remote visit. Afterwards, the subject should send the hard copy to the site and 
upon receipt, if the TI deems it necessary the TI should follow-up with the subject remotely or 
at the site during an Unscheduled visit. 
• All questionnaires may be sent by mail to the subject’s home address in advance. In such case, 
the subject should be encouraged to send a scanned copy of the completed questionnaires 
within 3 days of the scheduled remote visit to the TI before sending the hard copy to the site. 
• If possible, the subject should follow the guidance from Canfield to create standardized 
photographs on the day of the visit and use the Canfield web service to send them. 
• In case of remote visits, the BLE and TI effectiveness assessments will be performed with the 
help of the standardized photographs made by the subject to enable comparison with the 
Baseline and other visits. 
• Tyndall assessment should not be performed remotely; in case of a remote visit, this assessment 
will be considered missing. 
• Vision assessment and blink and closure test scheduled to be performed onsite, before and after 
injection, at the injection visits must be done onsite as scheduled. For all other visits, if the 
subject cannot come to the site, the TI will ask the subject questions related to his/her vision, 
and in case of any concerns or abnormal findings, the TI will refer the subject to an eye 
specialist. 
If the subject is not able to have the Visits 2, 2b, 3, 3b, 4, 4b, 5b, 6, 7, 9, and 10 performed either 
in person or remotely, the visit will be considered missed and a CIP deviation will be recorded. If 
the subject misses 2 first consecutive visits without any justified reason as deemed by the TI and 
TEOXANE SA, the data of this subject will be excluded from per-protocol population analyses 
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8.3.5. Other Adjustments 
Telephone call visits (Visit 2 Call, Visit 2b Call, and Visit 8 Call) will be performed as planned. 
Any other situations that may emerge due to the COVID-19 emergency that could not have been 
foreseen or are for other reasons not covered within the protocol, will be discussed and decided on 
a case-by-case basis with the sponsor and the study medical monitor. If deemed necessary, 
additional guidance will be provided to the site. 
 
 

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9. CLINICAL INVESTIGATION 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. Separate ICFs for Stage 1 and Stage 2 
will be provided. 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 opportunity 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 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 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 using a permuted block algorithm and 
randomly allocate the investigational product in a 6:1 ratio for Stage 1. 
In Stage 1 of the study, out of the 58 subjects enrolled, 50 subjects will receive RHA® 1 treatment 
and 8 subjects will receive no treatment. Then recruitment will be halted. An IDE supplement will 
be submitted to the FDA for interim safety review (with the safety data over 24 weeks of the 
50 treated subjects). Subjects enrolled to the RHA® 1 group from Stage 1 will continue to follow 
all the visits of RHA® 1 treatment group for 52 weeks without interruption, at which point they 
will be offered retreatment. If applicable, subjects will then be followed for an additional 12 weeks 
after retreatment. The Untreated control group will be followed for 12 weeks (Visit 5) at which 
point they will exit the study. 
Upon receiving approval of the supplement from the FDA to expand enrollment, enrollment will 
resume with subjects enrolled in a randomized manner for Stage 2 of the study. 
Randomization numbers will be assigned sequentially as subjects are entered into the study. 
The randomization will be stratified by site. 
Needle and cannula subgroups are intended to be determined at the site level: the method of 
administration of RHA® 1 (i.e., injection with a needle or a cannula) will be defined for each site 
at the beginning of the study. All subjects enrolled at a site using needle will have RHA® 1 injected 
with a needle (RHA® 1 needle subgroup). All subjects enrolled at a site using cannula will have 

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RHA® 1 injected with a cannula (RHA® 1 cannula subgroup). The sites will be selected with an 
aim to achieve 1:1 distribution of subjects between the subgroups. This will be applicable during 
Stage 1 and Stage 2 enrollment. 
Inclusion of subjects with Fitzpatrick skin type IV-VI and V/VI will be monitored centrally, and 
handled outside the randomization scheme. Overall, at least 20% of the enrolled subjects will have 
Fitzpatrick skin types IV-VI (50 subjects) with at least 10% of the enrolled subjects with 
Fitzpatrick skin types V or VI, of which at least 3% will have Fitzpatrick skin type V (≥8 subjects) 
and at least 3% will have Fitzpatrick skin type VI (≥8 subjects). 
Subjects enrolled during Stage 1 will also include subjects with Fitzpatrick skin type IV to VI. The 
above percentage are for the aggregate subjects from Stage 1 and Stage 2. During Stage 1, 
enrollment will ensure that at least 2 to 3 subjects of each Fitzpatrick skin type IV, V, and VI are 
enrolled. 
The randomization schedule will be prepared by Premier Research before the start of the study. 
No one involved in the study performance (and especially the BLE), with the exception of the TI 
and study site personnel, will have access to the randomization schedule before official unblinding 
of treatment assignment. No subject will be enrolled into this study more than once. 
If consent has been obtained but the subject does not meet the entry criteria, he/she will be 
considered a screen failure and will not be enrolled. 
9.3. Blinding/Unblinding Clinical Investigation Plan 
9.3.1. General Blinding 
The TI, unblinded to allocation to groups, will be asked to minimize the number of people who 
will have the allocation information or who will have any form of access to such information. 
Access will only be given to personnel who must have it, e.g., to administer the filler, call the 
subjects, or schedule visits. 
The BLE and study personnel not involved with the site (e.g., data management, medical monitor) 
will be blinded to assignment to groups and, if possible, to subgroups. To keep the BLE blinded 
during Stage 1, the BLE will not be provided with the CIP for the Stage 1, and approximately 
8 additional subjects will be enrolled to the Untreated control group and will be evaluated by the 
BLE. 
Subjects will not be blinded. 
9.3.2. Blinded Procedures 
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 him/her access to any 
subject data. 
Furthermore, to ensure that the BLE remains blinded and unbiased when making his/her 
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. 

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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. 
TEOXANE SA personnel responsible for safety reporting will have separate access to the 
allocation to groups for the purpose of preparing and distributing safety reports as applicable. 
9.4. Pre-treatment Procedures and Tests 
The procedures and tests to be performed prior to randomization are described for Visit 1 
(Section 8.1.1.1). 
The subject must not take medications or supplements that thin the blood 1 week before the 
injection (e.g., aspirin, nonsteroidal anti-inflammatory medications, St. John’s Wort, fish oil, or 
high doses of vitamin E supplements, upon TI’s judgment) since these agents may increase 
bruising and bleeding at the injection site.5 
The subject will be asked whether he/she previously had facial cold sores; the TI will consider the 
need for administering acyclovir or valacyclovir as per the standard of care. Administration of 
these medications will be recorded in the eCRF as prior/concomitant therapy. 
Prior to treatment, study staff should ensure that the subject is receiving the appropriate anesthetic 
to manage comfort (e.g., topical anesthetic, local, or nerve block). Information about anesthetic 
treatment, including nonpharmacological methods such as ice pack, will be collected as 
concomitant therapies. 
Makeup should be completely removed. The subject’s face should then be washed with soap and 
water and dried with a clean towel. Cleanse the area to be treated with antiseptic solution suitable 
for the periorbital area. Gloves are mandatory while injecting the filler. 
Before injecting the filler, prime the needle or cannula by carefully pressing the syringe plunger 
until a small droplet of the gel is visible at the tip of the needle or cannula. If a cannula (blunt tip) 
is used for RHA® 1 administration, the injection will be initiated preceded by creating an entry 
point made manually with by the sharp “pre-hole needle” so that the cannula may be carefully 
inserted and maneuvered until the desired tissue plane is reached. 
Please follow the IB and the Injection Guidelines for further details. 
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 purpose 
of the primary endpoint. Visit 5/Visit 1b data will become a new Baseline for subjects initially 
randomly assigned to the No-treatment control group for analyses that pool data from 
Visits 1b – 5b. 
Baseline data will include demographic variables, i.e., age, sex, height, and weight. Information 
on race and ethnicity will be collected for any eventual analysis of response differences in the 
study device in accordance with local regulatory requirements. Baseline subject characteristics 
will include medical history findings, UPT results, and prior and concomitant medications. 
All evaluations performed by the BLE will be considered as Baseline for the purpose of the primary 
endpoint analysis and other applicable analyses. 

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9.6. Prohibited Medications 
Subjects must not take medications or supplements that thin the blood 1 week before and 1 week 
after the injection (e.g., aspirin, nonsteroidal anti-inflammatory medications, St. John’s Wort, fish 
oil, or high doses of vitamin E supplements, upon TI’s discretion) since these agents may increase 
bruising and bleeding at the injection site.5 
As with all transcutaneous procedures, dermal filler implantation carries a risk of infection. 
Therefore, standard immunosuppressant, systemic corticosteroids and biologics are prohibited. 
9.7. Clinical Investigational Product Treatment 
The TI will inject RHA® 1 either at Visit 1 (for subjects randomly assigned to RHA® 1 group 
during Stage 1 or Stage 2) or at Visit 1b (subjects initially randomly assigned to No-treatment 
control group from Stage 2). 
At Visit 8, all subjects will be offered RHA® 1 dermal filler as retreatment. The TI and/or the 
subject can decline the retreatment. In such cases, the reasons for declining will be documented as 
per one of the following: 
• SAE related (possibly, probably, related) to RHA® 1 at any time 
• Retreatment is not recommended according to the TI due to an ADE the subject had (TI’s 
judgment) 
• Retreatment not required aesthetically according to the TI (aesthetic result still optimal) 
• Retreatment not required aesthetically according to subject (aesthetic result still optimal) 
• Subject declines retreatment because initial injection was too painful 
• Subject declines retreatment due to an AE related to previous treatment 
• Subject declines retreatment because subject is satisfied (even if the results are no longer 
optimal) 
• Subject declines retreatment because subject did not like the treatment effect 
• Subjects declines retreatment because subject no longer wants to attend the next safety visits 
• Subject declines for another reason: document the reason 
• Retreatment is not possible due to COVID-19 public health emergency 
• Subject is in quarantine due to COVID-19 
• Subject has been diagnosed with COVID-19 that has not resolved in time for retreatment 
9.7.1. Study Device 
The study device is RHA® 1 (TEOXANE SA). Please see Section 5.4 and the IB5 for further 
information. 
9.7.2. Control Device 
Not applicable. The control group will receive no treatment at Visit 1. 

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9.7.3. Injection of RHA® 1 
Method of administration will be either with a 30G ½″ needle (included with the product) or a 
25G ½″ cannula (SoftFil® Precision or TSK [STERiGLIDETM]). Method of administration will be 
based on the site. 
Injection area and depth: RHA® 1 is injected from the sub-dermis to the periosteum in the 
infraorbital hollow. 
Amount of filler to be administered: Up to 1.0 mL per eye at each treatment (max: 2.0 mL per 
treatment). 
Information about the method of administration, injection technique, depth of injection 
(sub-dermis or supraperiosteum), and the amount of filler will be collected in the eCRF. Injection 
Guidelines will be available to the TI prior to his/her first subject visit. 
9.7.4. Post-treatment Procedures 
After the injection, an ice pack may be applied to the injected area to reduce swelling; efforts 
should be made to apply it after the 5-minute pain assessments have been performed. Usage of 
ice-pack needs to be recorded as concomitant treatment in the eCRF. 
The subject will be instructed to avoid touching the treated area for 6 hours after treatment. After 
that, the area can be washed gently with soap and water. Subjects should be advised not to wear 
makeup 12 hours after injection. The subject will be instructed to avoid exposing the treated area 
to excessive sun, ultraviolet lamp, and extreme temperatures (e.g., cold weather, sauna) at least 
within the first 24 hours after the injection, or until the initial swelling and redness have resolved. 
Exposure to any of the above may cause or exacerbate and/or extend the duration of the temporary 
redness, swelling, and/or itching at the treatment site. The subject will be instructed not to fly or 
exercise within the first 24 hours after injection. The subject will also be instructed to avoid taking 
medications or supplements that thin the blood (e.g., aspirin, nonsteroidal anti-inflammatory 
medications, St. John’s Wort, fish oil, or high doses of vitamin E supplements) for 1 week after 
the injection. 
9.8. Stopping Rules 
Individual subject withdrawal or discontinuation is discussed in Section 7.4.3. This section 
discusses the criteria for stopping the entire clinical investigation. 
Safety will be monitored throughout the study by the study-appointed medical monitor in 
accordance with the safety management plan (SMP). Based on ongoing monitoring, the study may 
be stopped if the TEOXANE SA medical monitor suspects that the risks outweigh the potential 
benefits. 
If any of the following (S)AEs occur, subject enrollment and treatment of subjects at that site will 
be suspended until a root cause investigation (including the medical monitor consultation) is 
performed: 
• Adverse Event of Special Interest (AESI) as defined in Section 10.1.5 if confirmed and judged 
clinically significant by the eye specialist (ophthalmologist or retina specialist) 
• Vascular embolic event leading to skin necrosis 
• Stroke 

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If the cause of the event was anticipated (e.g., the TI did not properly follow the investigation plan 
and Injection Guidelines), the study may resume after appropriate corrective actions have been 
successfully implemented (e.g., retraining of the TI or a change in TI). 
If the cause of the event was unanticipated, the entire investigation must be suspended 
immediately, and subject enrollment and/or treatment will be stopped. The study will remain 
on hold until the event can be properly characterized and an appropriate treatment strategy can be 
developed to avoid this unanticipated event. 
9.9. Withdrawal of Food and Drug Administration Approval 
The sponsor will notify the central IRBs and participating TIs of any withdrawal of FDA approval 
of the investigation within 5 working days after receipt of such notice. 

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10. ADVERSE EVENTS 
Subjects will be monitored carefully during the investigation for possible safety events. Safety 
events include the CTRs, AEs, ADEs, SAEs, Unanticipated Adverse Device Effects (UADEs), 
AESIs and/or device malfunctions. The CTRs that do not fulfill the criteria for AEs as described 
in Section 8.2.2.1 will be recorded on a separate eCRF page and followed as discussed in Section 
8.2.2.1. 
All events will be reported and documented on the appropriate eCRF; AE information will be 
recorded in the eCRF Adverse Event Form. 
Serious AEs, AESIs, device malfunctions, and UADEs need to be reported by the TI or designee 
to TEOXANE SA within 24 hours as per Section 10.3 and recorded in the eCRF within 48 hours 
of awareness by the study team. 
Non-serious AEs will be recorded within 7 calendar days of awareness. All AEs, ADEs, AESIs, 
SAEs, and UADEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
All observations and clinical findings, including the nature, seriousness, severity, and relationship 
to the study 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 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. 
Handling of safety events in this clinical investigation will follow the protocol-specific SMP and 
TEOXANE SA standard operating procedures (SOPs) for safety reporting and device safety 
vigilance. 
Additionally, AEs will be reviewed regularly by the study medical monitor. 
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 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, or the study procedures. This 
definition includes AEs resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the study device. This definition also 
includes any event resulting from use error or from intentional misuse of the study device. 
10.1.3. Serious Adverse Events 
Serious AEs are a subset of AEs. 
An SAE means any AE that led to any of the following: 
• Death 

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• Serious deterioration in health of the subject, users, or other persons as defined by one or 
more of the following: 
o 
A life-threatening illness or injury 
o 
A permanent impairment of a body structure or a body function, including chronic 
diseases 
o 
Inpatient or prolonged hospitalization 
o 
Medical or surgical intervention to prevent life-threatening illness or injury, or permanent 
impairment to a body structure or a body function 
• Fetal distress, fetal death, or a congenital abnormality or birth defect including physical or 
mental impairment 
Planned inpatient hospitalization for a pre-existing condition or a procedure required by the CIP 
without a serious deterioration in health is not considered an SAE. 
Responsibilities and timelines for reporting of SAEs are outlined in Section 10.3. 
10.1.4. Unanticipated Adverse Device Effects 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or death 
caused by, or associated with, the device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the protocol or the IB, or any other 
unanticipated serious problem associated with the device that relates to the rights, safety, or welfare 
of subjects. 
10.1.5. Adverse Events of Special Interest 
Any new vision disturbances, including, but not limited to, any loss of vision, blurriness, double 
vision, pain in or around the eye, blindness, blind spot or shadow in the visual field, trouble moving 
eyes, ocular hypotonia, ptosis, etc. that occurs after any administration of the filler will be 
considered an AESI. In addition, stroke or stroke-like symptoms, such as confusion, 
weakness/numbness in the arms or legs, changes to consciousness or alertness, difficulty 
speaking/speech impairment, or facial drooping, will be considered an AESI.14,15 
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 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. 
For any event involving suspicion of device malfunction, the sponsor may request that the TI return 
the study device (when possible) for further evaluation. 
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 

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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. 
As with any procedure or treatment, there are known possible risks and complications. With the 
study device, all risks may not be known for the proposed indication. A list of anticipated AEs is 
found in the IB. 
At each evaluation after enrollment, the TI will determine whether an AE has occurred. The AE, 
date of onset, seriousness, severity, duration, treatment, outcome, and relationship to the study 
procedure and the study device will be recorded on the AE eCRF. All AEs will be assessed by a 
physician and monitored until they are adequately resolved, stabilized, or the subject has 
completed the investigation. 
The terms “severe” and “serious” are not interchangeable. The term “severity” refers to the 
intensity of a specific event and how it affects the whole subject. The term “seriousness” serves as 
a guide for defining regulatory reporting obligations. An event can be severe (such as severe pain 
that limits self-care), but it may not always fulfill the criteria for SAE (see Section 10.1.3), 
e.g., leading to hospitalization. An event can be mild in severity (such as mild dyspnea) but may 
fulfill the SAE criteria in that particular subject (e.g., subject is hospitalized for observation of new 
mild dyspnea). Severity and seriousness should be assessed independently of each other. 
The scale in Table 10-1 provides the definitions that will be used to determine the severity of each 
AE. Note that the scale defines severity based on how the event affects the subject. For example, 
a subject can have a large bruise, which on its own may be regarded as “severe”, but with respect 
to the subject’s overall well-being it would be better characterized as “moderate”. 
Table 10-1 
Adverse Event Severity Scale 
Severity 
Description 
Mild 
Event does not interfere with the subject’s activities of daily living, is transient, 
and resolves without medical intervention/therapy required. 
Moderate 
Event interferes with the subject’s activities of daily living, causing discomfort 
(some assistance may be needed) but poses no significant or permanent risk of 
harm to the subject. No or minimal medical intervention/therapy is required. 
Severe 
Event causes severe discomfort with marked limitation in the subject’s activities 
of daily living and some assistance usually is required. Medical 
intervention/therapy usually is required; sometimes invasive therapeutic 
intervention is needed. 
10.2.1. Relationship to Device 
For each AE identified in the investigation, the TI or designee must assess its relationship to the 
study device and/or to the procedure. The TI must determine whether there is a reasonable 
possibility that these caused or contributed to an AE. 
If an AE occurs after randomization but before the first dose of the study device, the relationship 
to the study device and/or the injection will be “not applicable”. However, such AEs still needs to 
be recorded. 

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The relationship assessment, based on clinical judgment, often relies on the following categories: 
• A temporal relationship between the event and application of the study device 
• A plausible biological mechanism for the study device to cause the AE 
• Another possible etiology for the AE 
• Previous reports of similar AEs associated with the study device or other devices in the same 
class 
• Recurrence of the AE after reapplication of the same study device or conversion to another 
device, if applicable 
The definitions in Table 10-2 will be used to determine the relationship of each event to the study 
device. 
Table 10-2 
Adverse Event Relationships 
Not applicable 
The event happened to a subject who has not (yet) received treatment with 
the study device 
Not related  
(to establish the 
non-relatedness, 
not all criteria 
listed might be 
met at the same 
time)  
• The event has no temporal relationship with the use of the device or 
the procedures 
• The event does not follow a known response pattern to the device (if 
the response pattern is previously known) and is biologically 
implausible 
• The discontinuation of device application or the reduction of the level 
of activation/exposure, when clinically feasible, and reintroduction of 
its use (or increase of the level of activation/exposure), do not impact 
on the event 
• The event involves a body site or an organ not expected to be affected 
by the device or procedure 
• The event can be attributed to another cause (e.g., an underlying or 
concurrent illness/clinical condition, an effect of another device, drug, 
treatment or other risk factors) 
• The event does not depend on a false result given by the device used, 
when applicable 
• Harms to the subject are not clearly due to use error 
Unlikely related 
The relationship with the use of the device seems not relevant and/or the 
event can be reasonably explained by another cause, but additional 
information may be obtained.  
Possibly related 
The relationship with the use of the device is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g., an underlying or 
concurrent illness/clinical condition and/or an effect of another device, 
drug, or treatment). Cases where relatedness cannot be assessed or no 
information has been obtained should also be classified as possible.  

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Probably related The relationship with the use of the device seems relevant and/or the event 
cannot reasonably explained by another cause, but additional information 
may be obtained.  
Causal 
relationship  
(to establish the 
relatedness, not 
all criteria listed 
above might be 
met at the same 
time) 
The event is associated with the device or with procedures beyond 
reasonable doubt when: 
• The event is a known side effect of the product category the device 
belongs to or of similar devices and procedures 
• The event has a temporal relationship with device use/application or 
procedures 
• The event involves a body site or organ that the device or procedures 
are applied to or have an effect on 
• The event follows a known response pattern to the device (if the 
response pattern is previously known) 
• The discontinuation of device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the 
level of activation/exposure), impact on the event (when clinically 
feasible) 
• Other possible causes (e.g., an underlying or concurrent illness/clinical 
condition and/or an effect of another device, drug or treatment) have 
been adequately ruled out 
• Harm to the subject is due to error in use 
 
The TI or designee must review and verify the completed AE form for accuracy and completeness. 
He/she will also make the final assessment of the relationship between the device/procedure and 
the AE. When possible, the TI should designate at least 1 other investigation physician who can 
perform the assessment of AE/ADE/SAE/UADE/AESI so as to provide uninterrupted coverage of 
monitoring of AEs that require expedited reporting. 
10.3. Safety Reporting 
It is the 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 governance, including FDA regulations, FDA guidance, and 
IRB requirements for notification of all types of AEs. 
The TI or designee must report to TEOXANE SA any of the following events: 
• SAEs, including death reports and UADEs, AESIs, see Sections 10.3.1, 10.3.2, and 10.3.3 – 
using the SAE/UADE/AESI Report Form 
• Device malfunctions, see Section 10.3.4 – using the Device Malfunction Report Form 

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• Pregnancies, see Section 10.4 – using the Pregnancy Report Form 
• New findings/updates in relation to already reported events 
These events must be reported immediately but no later than within 24 hours of first becoming 
aware of them by completing, signing, and dating the applicable form, verifying the accuracy of 
the information recorded in the form with the source documents and the eCRF, and sending the 
applicable form to TEOXANE SA by e-mail to: 
medical@teoxane.com 
The TI should not disclose the information about the treatment allocation on the form. This is to 
prevent unnecessary unblinding of TEOXANE SA or Premier Research study personnel reviewing 
the report. The report will be prepared in a blinded manner. TEOXANE SA personnel responsible 
for further safety reporting will have the ability to access the information about the treatment 
allocation and proceed with the preparation and submitting the report as applicable. Further details 
on reporting procedures are described in the SMP and in Appendix E. 
10.3.1. Serious Adverse Event Reporting 
The TI will report SAEs on the SAE/UADE/AESI Report Form within 24 hours of awareness and 
complete the eCRF within 48 hours of awareness. 
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor or designee via the same contact details in Section 10.3 as soon as possible, together 
with the following information, at a minimum: initial report, AE, date of occurrence, subject 
identification, study ID, and site number; this will allow the follow-up information to be linked to 
the initial SAE report. Specific information may be requested by opening queries in the eCRF or 
via e-mail communication. 
TEOXANE SA will handle the SAE report according to the process described in the SMP. 
10.3.2. Unanticipated Adverse Device Effect Reporting 
The TI will report UADEs on the SAE/UADE/AESI Report Form within 24 hours of awareness 
and complete the eCRF within 48 hours of awareness. 
TEOXANE SA will handle the UADE report according to the process described in the SMP, 
including evaluation of the UADE and reporting of the UADE to the FDA, all reviewing IRBs, 
and participating TIs within 10 working days of awareness. 
Since a UADE is a reportable event, TEOXANE SA will provide further information to the TI 
within 7 working days of receipt of the UADE report to allow the TI to report the event to the 
reviewing IRB as soon as possible, but in no event later than 10 working days after the TI first 
learns of the event. The TI must adhere to all reporting requirements for his/her IRB as applicable. 
10.3.3. Adverse Events of Special Interest Reporting 
All AESIs (see Section 10.1.5) need to be reported within 24 hours of awareness using the 
SAE/UADE/AESI Report Form and recorded in the eCRF within 48 hours of awareness. 
TEOXANE SA will handle the AESI report according to the process described in the SMP, 
including evaluation of the AESI and reporting of the AESI to the FDA, all reviewing IRBs, and 

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participating TIs within 10 working days of awareness for all AESI (whether related or not to the 
study device or procedure). 
The report must include depth of injection, injection volume, symptoms that were observed, time 
to onset, time to resolution, and any intervention(s) that were implemented. All AESIs will be 
evaluated carefully by TEOXANE SA and the study medical monitor. Follow-up actions will be 
decided on case-by-case basis and documented. 
10.3.4. Device Malfunctions Reporting 
Device malfunctions will be reported using the Device Malfunction Report Form and supply 
information relevant to the event. 
If a device malfunction results in an AE/SAE/UADE/AESI, it needs to be reported as such. 
If a device malfunction does not result in an AE/SAE/UADE/AESI but according to the TI may 
have caused or contributed to death or serious injury, or would likely cause or contribute to death 
or serious injury if the malfunction was to recur, he/she will complete the device malfunction form 
within 24 hours of awareness and record it in the eCRF within 48 hours of awareness. 
If a device malfunction does not fulfill any of the aforementioned criteria, the TI will record it in 
eCRF within 7 calendar days of awareness. 
TEOXANE SA will handle the device malfunction report forms according to process described in 
the SMP. 
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 device on every woman 
of childbearing potential. A woman who is found to be pregnant at Visit 1 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 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 pregnancy to TEOXANE SA within 48 hours of learning of it using the 
specific Pregnancy Report Form and send it to the same e-mail address as for SAE reporting. 
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion due to a 
congenital abnormality, or a complication of pregnancy or a congenital abnormality diagnosed at 
any time during the pregnancy or post-partum are considered SAEs and must be reported as such. 
An elective abortion of a normal pregnancy without complications is not considered an SAE. 
Every effort should be made to gather information regarding the pregnancy outcome and condition 
of the infant. It is the responsibility of the TI to obtain this information within 30 calendar days 
after the initial notification and approximately 30 calendar days post-partum. The need for safety 
follow-up until birth will not hold up the study database lock. If the study is completed and/or the 
study database is locked before the post-partum follow-up is expected, the TI will notify 

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TEOXANE SA of the outcome of the pregnancy only via e-mail: medical@teoxane.com and the 
pregnancy notification will be processed accordingly outside the eCRF. 
In addition to the above, if the TI determines that the pregnancy meets seriousness criteria, it must 
be reported also as an SAE (in addition to reporting the pregnancy itself). 
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 statistical analysis plan 
(SAP) that will describe the details of the analyses to be conducted and all statistical assumptions 
will be written and approved prior to database lock. 
Unless otherwise indicated, all testing of statistical significance will be 1-sided, and a difference 
resulting in a p-value of ≤0.05 will be considered statistically significant. 
Primarily parametric tests are planned to be used. In case assumptions for a statistical test are not 
fulfilled, appropriate non-parametric test will be used. 
Descriptive summary statistics will be provided for the following variables. For continuous 
variables, these statistics will typically include the number of subjects, mean, standard deviation 
(SD), median, minimum, maximum, and for some parameters, and 95% confidence interval (CI). 
For categorical variables, these statistics will typically include the number and percentage of 
subjects in each category. 
11.1. Analysis Populations 
The following 4 analysis populations are planned for this investigation: 
• Screening population: All subjects who provide informed consent and demographic and/or 
Baseline Screening assessment results, regardless of their randomization and treatment status 
in the investigation. The untreated control group will only be included in the Screening 
population as they will not receive RHA® 1 treatment throughout the clinical study. 
• Safety population (SAFT): All subjects who are assigned to either the RHA® 1 group or the 
No-treatment control group and complete Visit 1 (from Stage 1 and Stage 2). 
• Intent-to-Treat population (ITT): All subjects who are randomly assigned to either the RHA® 1 
group (from Stage 1 and Stage 2) or the No-treatment control group and complete Visit 1. 
Subjects will be analyzed according to their initial arm assignment regardless of whether or not 
they received RHA® 1. 
• Per-Protocol population (PP): All subjects in the ITT population who completed up to Visit 5 
(primary endpoint visit at 12 weeks) with no major CIP deviations that could affect 
effectiveness assessments. The sponsor will identify major CIP deviations prior to the database 
lock. 
Analysis of the primary effectiveness endpoints will be based on the ITT population and will be 
repeated for the PP population. Analysis of the secondary effectiveness endpoints will be based on 
the ITT population. TIOHS responder rate as assessed by BLE secondary analyses will be repeated 
for the PP population. 
Inclusion of subjects in the analysis populations will be determined prior to database lock. 
If a subject is randomly assigned incorrectly or is treated with the device when assigned to the 
No-treatment control group before Visit 1b, analyses of the ITT population will be based on the 
assigned treatment, whereas all other analyses will be based on the actual treatment. 
If a subject misses 2 consecutive visits without any justified reason or if the subject missed the 
primary endpoint visit, the subject will be included in the SAFT population for safety evaluation 
and will not be included in the PP populations for effectiveness analysis. 

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11.2. Sample Size Determination 
Originally, this study planned to enroll at least 148 subjects (≥20% of subjects with Fitzpatrick 
skin types IV-VI, including 10% subjects presenting with Fitzpatrick skin types V/VI). 
The estimated responder rate (a subject with a ≥1-grade improvement in both eyes on the TIOHS 
as assessed by the BLE before initial treatment and 12 weeks after the initial treatment [Visit 5]) 
for subjects treated with RHA® 1 is set at 70%. The first level risk error alpha will be set to 2.5%. 
A co-primary endpoint was introduced in the study with additional superiority testing for change 
from baseline the modified (only a few selected questions) FACE-Q Appraisal of lower eyelids 
domain scores (Rasch transformation values, 0-100 scale) at week 12 (Visit 5). A superiority 
margin of 12 points was selected that is estimated to reflect an effect size of 0.5. 
To detect an AE rate of 4% in the subpopulation of subjects with Fitzpatrick skin types IV-VI 
(minimum 20% of the global study population), the number of subjects to be enrolled is as follows: 
AE incidence rate: 4% 
끫롨끫롨% =
100
௡×0.2  ↔݊=
500
஺ா% ↔݊=
500
4  
n overall population: 125 
With an estimated 15% drop-out rate throughout the entire study, a minimum total sample of 
148 subjects (125 / 0.85~148) are required to detect a sufficient AE rate. The subpopulation of 
subjects with Fitzpatrick skin type IV to VI is at least 30; this includes at least 15 subjects with 
Fitzpatrick skin type IV and at least 15 subjects with Fitzpatrick skin type V/VI. 
Using an unbalanced 3:1 ratio, a sample size of a minimum of 171 subjects in the treatment group 
(of which 85 to 86 in each of cannula and needle group), and a minimum of 57 subjects in the 
control group, altogether 228 subjects 
• will provide a >99.9% power for a 1-sided 2-group Fisher’s exact test at the 2.5% significance 
level to demonstrate statistical superiority of the treatment group over the control group, 
assuming a rate of responders in the treatment group of 70% and a rate of responders in the 
No-treatment control group of 20%. 
• will provide >90% power for a 1-sided t test at 2.5 significance level to demonstrate statistical 
superiority of the treatment group over the control group, assuming a superiority margin of 
12 points, standard deviation of 24 points and 50 points as mean difference. 
In response to request of the US FDA, the overall sample size will be increased to 
256 (approximately 256 subjects and maximum 259 subjects), with 8 subjects randomized in the 
Untreated control group to minimize the bias of the BLE during Stage 1 of the study. It will be 
divided as follows: 
• Stage 1 enrollment: approximately 58 subjects 
• Stage 2 enrollment: approximately 198 additional subjects 
A total of 248 subjects in the safety study population (the 8 subjects randomized in the Untreated 
control group will not receive RHA® 1 treatment during the course of the study and will not be 
included in the SAFT) will be able to detect any AE in the subpopulation of subjects with 
Fitzpatrick skin type IV-VI with an incidence rate of at least 2.5% (and any AE with an incidence 

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rate of at least 0.5% in the overall population). Around 248 subjects will be enrolled in the safety 
study population to maintain sufficient power for the safety analysis. Including the 8 subjects 
randomized in the Untreated control group, the study will not enroll more than 259 subjects. 
11.3. Subjects and Demographics 
11.3.1. Disposition and Withdrawals 
The numbers of subjects screened, randomly assigned, completing, and withdrawing, along with 
the reasons for withdrawal, will be tabulated overall and by treatment group. 
The numbers of subjects completing the initial treatment and additional visits will be tabulated 
overall and by treatment group. 
The number of subjects in each analysis population will be reported. 
The Screening population will be used for disposition tabulations only. 
11.3.2. Clinical Investigation Plan Deviations 
A CIP deviation is any noncompliance with the clinical investigation CIP or The 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 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. 
11.3.3. Demographics and Other Baseline Characteristics 
These analyses will be conducted for SAFT, ITT, and PP analysis populations. 
Demographic variables will include age, sex, height, and weight. Information on race and ethnicity 
will be collected for any eventual analysis of differences in response to the study device or the 
control device, in accordance with local regulatory requirements. 
Baseline subject characteristics will include medical history findings and UPT results. 
Fitzpatrick skin type frequencies will be tabulated. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary (WHO-DD) anatomical therapeutic chemical classes and preferred names. 
11.4. Effectiveness Analyses 
Effectiveness analyses will be performed primarily on ITT analysis set. A sensitivity analysis will 
be performed on PP analysis set. 
Before the primary analysis is performed, a poolability analysis will be conducted for sites and 
needle/cannula subgroups by: 

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1. Comparison for the Baseline TIOHS values by sites and by needle/cannula subgroups (by 
means of analysis of covariance [ANCOVA] or relevant non-parametric test e.g.,  
Mann–Whitney–Wilcoxon) 
2. Comparison of rate of responders at Visit 5 by sites and by needle/cannula subgroups based on 
TIOHS for each treatment arm (by means of Chi-squared test) 
3. Comparison of the modified FACE-Q “Appraisal of lower eyelids” with the last 4 questions 
scores converted to a 0-100 scale by Rasch-conversion by sites and by needle/cannula 
subgroups for each treatment arm at Visit 5 (by means of ANCOVA or relevant non-parametric 
test e.g., Mann–Whitney–Wilcoxon) 
For the ITT analysis of the primary effectiveness endpoint, multiple imputations will be used for 
missing observations. Specifically, missing change from Baseline in TIOHS at 12 weeks will be 
imputed using the regression method with treatment group as the independent variable, TIOHS 
change from Baseline as the dependent variable, and age, sex, Fitzpatrick skin type (I-III / IV-VI) 
and TIOHS at Baseline (BLE) as covariates. One data will be imputed per eye. 
Sensitivity analysis of the primary endpoint will be performed (further described in the SAP): 
• Mean imputation approach 
• Baseline observation carried forward if >5% of missing data 
• All missing as success, half missing as success and worst-case imputations 
• The main analysis will be repeated for the IPR data 
One primary analysis will be performed: 
• The RHA® 1 group vs. the No-treatment control group 
Primary effectiveness analysis: The rate of responders 12 weeks after randomization in RHA® 1 
group (Stage 1 and Stage 2) will be compared with the rate of responders in the No-treatment 
control group using an independent testing based on a 2-group, 1-sided, Fisher’s exact statistic 
test. To achieve superiority, the observed p-value must be ≤0.025. 
Additionally, to be able to declare superiority: 
• At least 70% of the subjects treated with RHA® 1 must be responders 
• The difference between the responder rate for subjects treated with RHA® 1 and the 
No-treatment control group must be ≥50% points 
The co-primary endpoint, change from Baseline in the modified FACE-Q Appearance of lower 
eyelids score (converted to a 0-100 scale using Rasch conversion) at 12 weeks will be evaluated. 
Only the following questions will be considered for the co-primary endpoint: 
• Question “d”: How noticeable the lines under your eyes are? 
• Question “e”: Crepey (wrinkled) skin under your eyes? 
• Question “f”: How old the area under your eyes makes you look? 
• Question “g”: How tired the area under your eyes makes you look? 

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The modified FACE-Q Appearance of lower eyelids change from Baseline score for subjects 
treated with RHA® 1 (Stage 1 and Stage 2) will be compared with FACE-Q Appearance of lower 
eyelids for subjects of the No-treatment control group at 12 weeks (Visit 5) after randomization 
using t test or non-parametric equivalent like Wilcoxon rank-sum test. 
Superiority will be declared if: 
• the lower bound of 2-sided 95% confidence interval for the responder rate for RHA® 1 is 
at least 70%, and 
• the lower bound of 2-sided 95% confidence interval for the difference in the responder rate 
between subjects treated with RHA® 1 and the No-treatment control group is at least 50%, 
and 
• the lower bound of 2-sided 95% confidence interval for the modified FACE-Q “Appraisal 
of lower eyelids” raw score for RHA® 1 is at least 3, and 
• the lower bound of 2-sided 95% confidence interval for the difference in mean change from 
Baseline of the modified FACE-Q between RHA® 1 treated group and the No-treatment 
control group is at least 12 
Only data from Phase 1a (Stage 1 and Stage 2) will be taken into account. Data from subjects 
randomly assigned to the No-treatment control group after treatment received in the Phase 1b will 
not be pooled for the primary endpoint analysis. 
Overall superiority can be declared if all superiority criteria are met both for primary and co-
primary endpoints. 
Subgroup analyzes for the following primary efficacy variables are planned: 
The following additional subgroup analyses are planned on the ITT population and based on the 
data after applying the multiple imputation method from primary analysis: 
• Modified FACE-Q change from Baseline Rasch converted score will be summarized for 
each Fitzpatrick skin type (I-III, IV-VI, and V/VI), volume injected (≤1mL / 1mL-≤1.5mL 
/ >1.5mL), age group (22-≤median age of the ITT population / >median age of the ITT 
population ), sex, ethnicity (Hispanic or Latino / Not Hispanic or Latino), site, and method 
of administration (needle/cannula) categories 
• Responder rates of treatment arms will be summarized for each Fitzpatrick skin type (I-III, 
IV-VI, and V/VI), volume injected (≤1mL / 1mL-≤1.5mL / >1.5mL), age group (22-
≤median age of the ITT population / >median age of the ITT population ), sex, ethnicity 
(Hispanic or Latino / Not Hispanic or Latino), site, and method of administration 
(needle/cannula) categories 
Secondary effectiveness analysis: 
No imputation will be performed for secondary (or pooled secondary) effectiveness endpoints, or 
safety outcomes; all analyses will utilize available data as observed. 
For each treatment group, descriptive summary statistics (mean, minimum, maximum, SD, and 
95% CI of the mean) and change from Baseline (absolute and relative) will be presented by study 
visit. Baseline is defined as the measurement preceding the initial treatment. For the No-treatment 

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control group, Baseline is defined as the last measurement at Visit 5 (12 weeks after 
randomization) before continuing to Phase 1b. 
For endpoints with qualitative results, frequencies and percentages will be calculated and presented 
for each visit by treatment group. 
The secondary endpoints will be analyzed at each applicable visit using 2 levels of analysis: 
• Analysis from Visit 1 to Visit 5 (12 weeks after randomization) comparing subjects from the 
RHA® 1 group to the No-treatment control group 
• Analysis from Visit 1/Visit 1b to Visit 11 with all subjects pooled together 
Additionally, secondary endpoints will be presented for the following subgroups at Visit 1/1b, 
Visit 5/5b, Visit 6 and Visit 8: 
• Fitzpatrick skin type V/VI 
• Age groups (22-≤median age of the ITT population / >median age of the ITT population) 
• Sex (Male / Female) 
RHA® 1 results will be presented as follows: 
RHA® 1 results will be presented with cannula and needle subgroups combined. 
A Fisher’s exact test will be used to compare proportions at each time point between the RHA® 1 
group and the No-treatment control group in Phase 1a 
For the TIOHS, ≥1-grade, ≥2 grade, ≥3-grade improvement (for one eye and for both eyes) 
frequencies will be tabulated, for individual eyes and subjects. 
For the FACE-Q, the answers to all questions of the scale will be pooled and data will be 
transformed and adapted to a scale of 100 units (i.e., worst/lowest score = 0; best/highest 
score = 100) as per FACE-Q user manual. The highest score will reflect positive outcome. 
For the PSAQ, absolute and relative frequencies will be presented for each question and category 
in a summary data table. 
For the GAIS (all evaluators), proportions of “improved” and “much improved” will be presented, 
along with the number of subjects and 95% CI of the proportion at each applicable study visit. 
For subject satisfaction, proportions of “satisfied” and “very satisfied” will be presented, along 
with the number of subjects and 95% CI of the proportion at each applicable study visit. 
The total volume per treatment session to obtain the OCR, and volume injected will also be 
described in statistical summaries (mean, SD, median, quartiles, minimum, and maximum). The 
volume will be presented per eye and for both eyes. 
The percentage of subjects receiving retreatment and total volume from that session will be 
summarized. 
The assessment of the Tyndall effect will be tabulated in a frequency table presenting relative and 
absolute frequencies. 
11.5. Safety Analyses 
A first safety analysis will be performed for subjects enrolled during Stage 1 to the RHA® 1 group 
from Visit 1 to Visit 6 (24 weeks after Baseline). This will be used as the interim safety analysis 

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to be submitted to the FDA before being able to expand enrollment. The safety analysis will 
include comparison between needle and cannula subgroups, as well as analysis of safety for 
subjects who received injection into the mid-dermis (see Section 11.7). 
All safety endpoints (Stage 1 and Stage 2) will be analyzed at each applicable visit using 3 levels 
of analysis: 
• Analysis from Visit 1 to Visit 5 (12 weeks after randomization) comparing subjects from the 
RHA® 1 group to the No-treatment control group 
• Analysis from the RHA® 1 group from Visit 1 to Visit 5 (12 weeks after initial treatment) 
comparing results from the No-treatment control group after receiving treatment (Visit 1b to 
Visit 5b, 12 weeks after initial treatment) 
• Analysis from Visit 1/Visit 1b to Visit 11 with all subjects pooled together 
RHA® 1 results will be presented as follows: 
• RHA® 1 group (cannula and needle subgroups combined) 
• RHA® 1 needle subgroup 
• RHA® 1 cannula subgroup 
The CTR for 30 days after injection will be tabulated by severity and by duration categories 
(0 to 3 days, 3 to 7 days, 7 to 14 days, 14 to 21 days, and 21 to 30 days), and by Fitzpatrick skin 
type subgroups (I-III, IV-VI, and V/VI). 
The CTR incidence rates will be presented by treatment groups (RHA® 1 needle and cannula 
subgroups separately, and pooled RHA® 1 needle and cannula subgroups). 
An individual data listing of all CTR data will also be given. 
The CTRs will not be considered AEs unless the duration and/or severity exceed what is typically 
observed following injection of dermal filler, and are clinically significant as determined by the 
TI. The CTRs will be reviewed by the TI to ensure that CTRs are elevated to the status of an AE 
as appropriate and to determine AE severity and the relationship to the study device. 
The CTRs present on the last day of the diary will automatically be elevated to an AE. 
The 30-day diary will not only capture CTRs but also capture the occurrence of certain AEs of 
concerns for dermal filler injections. Those will be classified as AEs. Any observation documented 
under “Other” in the 30-day diary will also be automatically considered an AE, unless the reaction 
refers to an item on the CTR list. 
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 percentage of subjects experiencing at 
least 1 AE that are treatment related (ADE) will be presented. 
The ADEs will also be tabulated by severity and causal relationship to RHA® 1 as judged by the 
TI, by duration categories, and by source of the AE. The sources of the AE will be specified as: 
“identified by the TI”; “CTR on last day of diary” (present on the last day of the diary or considered 
to be an AE by the TI); “AE from the CTR (pre-defined events)” (events included in the diary with 

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checkboxes); “‘Other’ in the CTR diary” (unless they are CTRs). The ADEs will also be tabulated 
by severity, duration, and Fitzpatrick skin type subgroups (I-III, IV-VI, and V/VI). 
The incidence rates of the ADEs will be presented for Fitzpatrick skin type subgroups (I-III, IV-VI, 
and V/VI), overall and by system organ class and preferred term. 
For the subjects treated with RHA® 1, the percentages of subjects who experience at least one ADE 
will be compared between Fitzpatrick skin type subgroups (I-III and IV-VI), age groups, sex, 
ethnicity, administration method and volume injected, using a Fisher exact test. 
Further analyses will be performed for the AEs and ADEs as described in the SAP. For UADEs 
and AESIs, which are less frequent, information will be provided in separate listings. 
The CTR and AE incidence rates (overall and by SOC, PT) will be summarized by injection depth 
(supraperiosteum and sub-dermis). 
Individual listings of all AE data will also be given (i.e., by MedDRA system organ class, duration, 
and method of administration). 
Assessment of injection site pain immediately after injection, at 5 minutes, 15 minutes, and 
30 minutes after injection (0-100 mm VAS) will be described with summary statistics (mean, 
minimum, maximum, SD, and 95% CI). 
11.6. Other Analyses 
All data captured in the eCRF will be displayed in by subject listings. 
11.7. Interim Analyses 
As requested by the US Food and Drug Administration, enrollment will be staged. Stage 1 
enrollment will include 50 subjects to be treated with RHA® 1 and 8 subjects in the Untreated 
control group. Once those subjects have been enrolled, recruitment will be halted. Safety data 
obtained after following Stage 1 treated subjects for 24 weeks will be submitted to the FDA with 
an IDE supplement for an interim safety review to determine if enrollment may be expanded. The 
IDE supplement will include an updated protocol. Upon receiving approval of the supplement from 
the FDA to continue with the study, enrollment will resume. Stage 1 subjects will complete their 
30-day CTR diary and will come to the site 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks 
after their initial treatment. While safety data are being reviewed, Stage 1 subjects will continue in 
the study per the schedule of events for the RHA® 1 group up to 52 weeks for retreatment, and 
then for an additional 12 weeks after retreatment (if applicable). 
For this safety review (after Stage 1), complete descriptive safety analysis will be performed, 
including the same tabulations of CTR, AE/SAE/ADE/UADE, and injection site pain as described 
for the final analysis. Data will also be analyzed per the administration method (needle or cannula). 
Additionally, a logistic regression model will be used to detect correlation of Fitzpatrick skin type 
and AE, ADE, SAE, or UADE occurrence. 
The CTR and AE incidence rates (overall and by SOC, PT) will be summarized by injection depth 
(supraperiosteum and sub-dermis) for the interim safety review. 
One additional interim analysis will be performed during Stage 2 after all subjects complete Visit 5 
(primary endpoint visit). The database will be cleaned and locked after Visit 5 for the efficacy data 
collected before Visit 5. The primary and efficacy endpoints will be analyzed based on the locked 

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data collected until Visit 5. Safety data will be also reported based on these data. After the data is 
captured from the database, the study will continue as planned to collect data for further 
evaluations. 
Primary endpoint analysis and results provided until Visit 5 will be considered as final and will 
not be updated at the time of the final analysis. 
11.8. Independent Panel Review 
Three independent experts, who will not be TIs, BLEs, or otherwise part of the study staff in this 
clinical investigation, will be identified and appointed as the Independent Panel Review (IPR). The 
IPR will be trained and certified on the conduct of the TIOHS assessment as described in 
Section 12.2.3. The IPR will not be examining the subjects directly (live evaluation), the IPR will 
be presented with photographs of the subjects taken on Visit 1 (Baseline for the primary endpoint) 
and on Visit 5 (primary endpoint) presented one at a time in a randomized order and will assess 
the TIOHS grade. 
 

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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: 
• Read and understand the CIP 
• Sign and complete the Investigator’s Agreement (see attachment 17.1) 
• Provide an accurate financial disclosure and file an update annually and 1 year after the 
completion of the investigation 
• Ensure appropriate IRB and institutional approvals are in place prior to completing any 
portion of the informed consent process or permitting subject participation 
• 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 
• Handle and store the RHA® 1 as per the CIP and IB 
In addition, each TI must have written approval by the sponsor or sponsor’s designee to either use 
the study device being studied under this CIP and/or perform the procedure being studied. 
Throughout the course of the investigation, it is the TI’s responsibility to ensure that the 
investigation is conducted according to the signed Investigator’s Agreement, the CIP, all 
applicable national and local regulations, and the respective IRB requirements, specifically the 
following: 
• Protecting the rights, safety, and welfare of subjects under the TI’s care 
• Controlling device under investigation 
• Ensuring that informed consent is obtained from each subject in accordance with applicable 
national regulations and guidance 
Under no circumstances may a TI provide the study device for use to any person who has not 
received training for use from the sponsor or sponsor’s designee. 
Upon completion or termination of a clinical investigation or the TI’s part of an investigation, or 
at the sponsor’s request, a TI will return to the sponsor the used devices, any remaining supply of 
the study device or otherwise control the study device as the sponsor directs. 

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12.1.1. 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 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. 
Except in such an emergency, prior approval by the sponsor is required for changes in/or deviations 
from the CIP. Additionally, if these changes or deviations may affect the scientific soundness of 
the plan or the rights, safety, or welfare of human subjects, prior review and documented 
approval/favorable opinion from the IRB and FDA is also required. Approval of IRB and FDA is 
not needed when the change involves only logistical or administrative aspects of the trial, 
e.g., change in monitor or change or telephone number. 
Prior approval is generally not expected in situations where unforeseen circumstances are beyond 
the TI’s control (e.g., the subject was not available for a scheduled follow-up office visit or has 
moved without providing a forwarding address). These events, although outside the TI’s control, 
are still required to be reported on the appropriate CIP deviation eCRF to ensure that all deviations 
from the standard subject population are adequately documented and reported. The TI will inform 
the sponsor or sponsor’s designee of all deviations and inform the reviewing IRB of all CIP 
deviations as per the IRB requirements for this investigation. 
If the sponsor or sponsor’s designee becomes aware that a TI is not complying with any part of the 
CIP, including the signed Investigator’s Agreement, the CIP, or any conditions of approval 
imposed by the reviewing IRB, the sponsor or sponsor’s designee will immediately secure 
compliance, may suspend the TI’s participation (including enrollment at the site), and may 
discontinue shipments/use of the study device to the TI until compliance is achieved and 
guaranteed. The sponsor may terminate a TI’s participation in the investigation at its discretion. 
12.1.2. Maintaining Records 
The TI will maintain the following accurate, complete, and current records relating to the TI’s 
participation in an investigation: 
• Correspondence with another TI, an IRB, the sponsor, a monitor, or the FDA 
• Records of each subject’s case history and exposure to the study device, including the 
following: 
o Documents evidencing informed consent and any use of the study device by the TI without 
informed consent 
o Any written concurrence of a licensed physician and a brief description of the 
circumstances justifying the failure to obtain informed consent 
o All relevant observations, including records concerning AEs at least possibly related to the 
study device (whether anticipated or not) 

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o Information and data on the condition of each subject upon entering and during the course 
of the investigation, including information about relevant previous medical history and the 
results of all diagnostic tests 
o A record of the exposure of each subject to the study device, including the date and time 
of each use, and any other therapy 
o Records on communication or attempted communication with the subject, e.g., phone calls, 
attempts to reach the subject, etc. 
• The CIP, with documents showing the dates of and reasons for each deviation from the CIP 
• Any other records that the FDA requires to be maintained by regulation or by specific 
requirement for a category of investigations or a particular investigation 
12.1.3. Submitting Reports 
As described in Section 10.3, the TI will be expected to report SAEs, AESIs, UADEs, device 
malfunctions, and pregnancies to TEOXANE SA within 24 hours of awareness. If the event fulfills 
the criteria of a reportable event, TEOXANE SA will provide further information to the TI for the 
report within 7 working days after receipt to be included as applicable. 
In compliance with FDA, each TI will be required to prepare and submit complete, accurate, and 
timely reports to the sponsor or sponsor’s designee and the IRB. These reports may include the 
following: 
• Any UADE occurring during an investigation (no later than 10 working days after the TI first 
learns of the effect) 
• Any deviation from the investigation plan made to protect the life or physical well-being of a 
subject in an emergency (as soon as possible but no later than 5 working days after the 
emergency occurs). Except in emergency situations, a CIP deviation requires prior sponsor 
approval and if the deviation may affect the scientific soundness of the plan or the rights, safety, 
or welfare of subjects, prior FDA and IRB approval are required 
• Any use of the study device without obtaining informed consent (due within 5 working days 
after such use) 
• Any further information requested by the FDA and IRB about any aspect of the investigation 
The TI will provide in writing any withdrawal of IRB approval of the investigation or a TI within 
5 working days of such action. 
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 RHA® 1 device 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. 
Prohibition of promotion does not apply to promotion of the clinical investigation by the sponsor 
to facilitate recruitment. 

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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 approvals, selecting TIs, ensuring proper monitoring, and ensuring that informed 
consent is obtained. The sponsor has selected Premier Research as its clinical research organization 
(CRO) and will ensure oversight of the CRO according to US regulations. The sponsor will provide 
all information necessary to conduct the investigation, including the CIP, and any reports of prior 
investigations as appropriate. During the conduct of the clinical investigation, updates in 
information that may impact the clinical investigation will be made available to all appropriate 
national and local regulatory authorities. 
12.2.2. Selection of Investigators 
The sponsor will select TIs qualified by training and experience. Sites will be selected based upon 
a site assessment, appropriate facilities, clinical experience, and the qualifications of the TI. 
Investigators will be evaluated by the sponsor based on the following: 
• A curriculum vitae, or other statement of TI’s relevant training and experience, including 
type of experience with the intended procedure and clinical research, specifically 
o Education and experience in infraorbital hollows injections 
o Whether the TI has an adequate subject population to meet requirements of the 
investigation 
• Whether the TI has adequate time to be personally involved in the conduct of the investigation 
and adequate research staff and resources to support it 
• Whether the TI’s investigation center is associated with an IRB that satisfies all applicable 
regulatory requirements 
• Whether a TI was involved in an investigation or other research that was terminated (an 
explanation of the circumstances that led to the termination should be provided) 
Prior to site initiation, each TI must also submit: 
• A certificate of human subjects protection training (if required by reviewing IRB) 
• A completed financial disclosure form (and annually up to 1 year after the completion of the 
investigation) 
• A signed Investigator’s Agreement indicating a TI’s commitment to the following: 
o Conduct the investigation in accordance with the agreement, the CIP, CFR Parts 50, 56, 
and 812, and any conditions of approval imposed by the IRB or the FDA 
o Supervise all testing of the study device involving human subjects at their site 
o Ensure that the requirements for informed consent are met per 21 CFR Part 50/ISO14155 
o Conduct the investigation according to the CIP 
The sponsor reserves the right to apply additional criteria to site and/or TI selection. 

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12.2.3. Training 
The sponsor or sponsor’s designee will provide training on the study device prior to enrolling any 
subjects. Training may consist of a review of the IB and Injection Guidelines, hands-on training 
on the study device, presentations, literature, etc. and may be a part of a full training during an 
Investigator’s meeting. The training program will be standardized and will be documented. The 
study will use a live-validated 5-grade photonumeric scale (TIOHS). All assessors (TIs, BLEs, and 
IPR) will be qualified on the use of the TIOHS. Specifically, all assessors will be trained on the 
scale then tested using a photo booklet with a broad range of infraorbital hollow grades and 
ethnicities. An assessor will be considered qualified once his/her percentage of agreement with the 
true values is ≥80%. Additional training will include a review of the CIP, the regulations for 
medical device investigations, and general investigation logistics required to complete the 
investigation. 
Training of appropriate clinical investigation personnel will be the responsibility of the sponsor or 
sponsor’s designee. To ensure uniform data collection and CIP compliance, the sponsor or 
sponsor’s designee will review the CIP (including the ICF), techniques for identification of eligible 
subjects, instructions on data collection, methods for scheduling follow-up visits in the window, 
etc. Detailed feedback regarding completion of the eCRFs, investigation requirements, and CIP 
compliance will be provided by the sponsor, Premier Research, and/or its investigation monitors, 
as appropriate. 
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. 
Approved CIP amendments will be provided to the TIs by the sponsor or sponsor’s designee prior 
to implementing the amendment. The TI will be responsible for notifying the reviewing IRB of 
the CIP amendment (administrative changes) or obtaining IRB approval of the CIP amendment 
(changes in subject care of safety), according to the instructions provided with the CIP amendment. 
The IRB acknowledgment/approval of the CIP amendment must be documented in writing prior 
to implementation of the CIP amendment. Copies of this documentation must be provided to the 
sponsor or sponsor’s designee. 
 

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13. DATA QUALITY ASSURANCE 
Premier Research (as CRO) will oversee a database for this investigation in accordance with 
regulatory data integrity requirements, the data management plan (DMP), and Premier 
Research/sponsor SOPs. Data collected on the eCRFs will be entered into the database. Data will 
be reviewed for accuracy and completeness by Premier Research during all onsite and remote 
monitoring visits and throughout the data management process. Any discrepancies will be resolved 
with the TI or designee, as appropriate. Access to the database will be limited to appropriate trained 
personnel in order to preserve data integrity. 
13.1. Data Management 
The standard procedures for handling and processing records will be followed per GCP and 
Premier Research SOPs. A comprehensive DMP will be developed prior to the start of the clinical 
investigation. 
For the duration of the investigation, the TI and his/her delegates will maintain complete and 
accurate documentation, including but not limited to, medical records, investigation progress 
notes, laboratory reports, signed subject ICFs, device accountability logs, correspondence with the 
reviewing IRB, correspondence with the sponsor or sponsor’s designee and investigation monitor, 
AE reports, and information regarding subject discontinuation or completion of the investigation. 
The TI/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 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 specify whether he/she allows use 
of the image for other purposes such as publication or promotion. The subject’s decision will be 
tracked in a site-specific photography release log. Only the Canfield camera set up provided by 
TEOXANE SA can be used to take the photographs. 

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13.3. Source Documents 
Source data are 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. 
Regulations require that the TI maintain information in the subject’s medical records that 
corroborate data collected for the investigation. To comply with these regulatory requirements, at 
a minimum, the following is a list of information that should be maintained. 
• Medical history/general physical condition of the subject before involvement in the 
investigation of a sufficient nature to verify the CIP eligibility criteria 
• Dated and signed investigation/progress notes on the date of entry into the investigation 
documenting the following: 
o The general health of the subject 
o The discussion of the investigation risks and benefits with the subject 
o Completion of the informed consent process 
o A statement the subject reviewed and signed the subject ICF 
• Dated and signed notes from each subject visit to support all data recorded on the eCRFs 
• Adverse events reported and their continuation or resolution at each visit, including 
supporting documents such as discharge summaries, laboratory results, and noninvasive 
testing reports 
• Notes regarding CIP-required and prescription medications taken during the investigation 
(including start and stop dates, if known) 
• Subject’s general health and medical condition upon completion of or withdrawal from the 
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 21 CFR Part 11 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. 

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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 
investigated, 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 TI/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 
TEOXANE SA personnel access to information and clinical supplies related to the investigation. 
The 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. 
Monitoring visits will be performed at regular intervals according to the CMP throughout the 
course of the investigation to ensure compliance with the CIP. Monitoring activities may include, 
but are not limited to, the following: 
• Evaluation of subject Screening and selection methods 
• Verification of signed ICFs for each subject 
• Verification of source documentation against completed eCRFs for each subject 
• Assurance that required investigation reports, including reports to the applicable IRB, are 
generated in a timely manner 
• Monitoring of safety events, including SAEs, UADEs, AESIs, AEs, ADEs 
• Monitoring of device malfunctions irrespective of associated safety events 
• Review of accountability records reconciliation (device and cannula) 
• Review of CIP deviations 
• Overall investigation compliance 

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14. REVIEW OF THE TI SITE FILE ETHICS AND REGULATORY COMPLIANCE 
14.1. Conduct of the Clinical Investigation 
Conduct of the clinical investigation will follow SOPs from TEOXANE SA and Premier Research 
(CRO), 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: 
• Initiating agency audits of the data derived from the TI in question 
• 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), his/her spouse, 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. 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 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, 21 CFR Part 50, the Medical Devices Directive 93/42/EEC, 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 

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reapprovals of such changes by the appropriate regulating authority 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 
21 CFR Parts 50, 56 and 812/ISO14155. This includes, but is not limited to, the following: 
• Subjects will be identified on all eCRFs and source documents by a unique identification 
reference that may include the subjects’ initials 
• 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) 
• Data will be stored and analyzed by computer following national regulations for handling of 
computerized data 
Each investigation center will maintain (anonymous to TEOXANE SA) a list identifying all 
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 
CFR Parts 11, 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. 
During the study photography of subject’s face will be taken repeatedly. This photography may 
include the subject’s lower face; however, the image will be cropped using appropriate software. 
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 he/she agrees 
to use his/her photographs for use outside the study, such as publication or promotion using a 
separate photography release form. His/her decision will be stored at the site in a separate 
photography release log. 
14.6. Site Qualification Visits 
A site qualification visit will be performed to evaluate site facilities, TI qualifications, and site 
knowledge of GCP guidelines. The visit may be performed also by a telephone call. Premier 
Research’s SOP for site qualification visits will be followed and a report filed with the sponsor or 
sponsor’s designee prior to the submission of the clinical investigation to the site IRB. 
14.7. Site Initiation Visits 
As available, investigation personnel will participate in a site initiation visit that follows Premier 
Research’s SOP. Training will be provided to all applicable personnel not able to attend the site 
initiation visit. Components of this initiation visit may include the following: 
• Introduction of the investigation design, including the treatment and follow-up 
• Product training to all end-users 
• Electronic case report form completion training 

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• Safety reporting instructions 
• Training on the regulations governing human research 
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 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, if requested. 
14.10. 
Investigational Product Traceability 
Investigational product 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 number and 
labeling identifying it as IDE product 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 devices will be returned to the sponsor. 
Further information may be found in the Investigational Product Guidelines that will be provided 
to the participating sites. 
14.11. 
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. 

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15. GENERAL CONSIDERATIONS 
15.1. Discontinuation of the Investigation 
Discontinuation of individual subjects is described in Section 7.4.3. 
The investigation as whole may be suspended or discontinued early if there is an observation of 
SAEs or UADEs presenting an unreasonable risk to the investigation participants, inadequate 
subject enrollment, or determination that no statistically significant result can be obtained. 
The sponsor may terminate TI and site participation in the investigation if there is evidence of a 
TI’s failure to maintain adequate clinical standards, or evidence of a TI or staff’s failure to comply 
with the CIP. 
Notification of suspension or termination of the investigation will occur no later than 5 working 
days after the sponsor makes the determination. In the event of investigation suspension or 
termination, the sponsor or sponsor’s designee will send a report outlining the circumstances to 
the reviewing IRB, the appropriate regulatory agencies, and to all participating TIs. Any 
suspension or termination may not be reinitiated without prior approval of the IRB and sponsor. 
TEOXANE SA reserves the right to discontinue this investigation for safety or administrative 
reasons at any time. 
15.2. Use of Information and Publications 
All information concerning the study device, TEOXANE SA operations, patent applications, 
manufacturing processes, and basic scientific data supplied by sponsor or Premier Research to the 
TI and not previously published are considered confidential and remain the sole property of 
TEOXANE SA. This includes all investigation materials, eCRF forms, and worksheets. 
The information developed in this investigation may be used by TEOXANE SA as support for a 
premarket approval filing and in connection with the continued development and post-market 
approval of the study device. Any publication or other public presentation of study device data 
resulting from this investigation will require prior review and written approval of TEOXANE SA. 
None of the results, in whole or in part, of the investigation carried out under this CIP, nor any of 
the information provided by the sponsor for the purposes of performing the investigation, will be 
published or passed on to any third party without the consent of TEOXANE SA. Any TI involved 
with this investigation is obligated to provide the sponsor with complete test results and all data 
derived from the investigation. 

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16. REFERENCES 
1. 
Narurkar, V., Shamban, A., Sissins, P., Stonehouse, A., Gallagher, C. Facial treatment 
preferences in aesthetically aware women. Dermatologic Surgery. 2015;41(Suppl1):S153-
S160. 
2. 
Mendelson, B. C., Hartley, W., Scott, M., McNab, A., Granzow, J. W. Age-related changes 
of the orbit and midcheek and the implications for facial rejuvenation. Aesthetic plastic 
surgery. 2007;31(5):419-423. 
3. 
Lee, J. H., Hong, G. Definitions of groove and hollowness of the infraorbital region and 
clinical treatment using soft-tissue filler. Archives of plastic surgery. 2018;45(3):214. 
4. 
Fallacara A, Manfredini S, Durini E, Vertuani S. Hyaluronic acid fillers in soft tissue 
regeneration. Facial Plastic Surgery. 2017;33(1):87-96. 
5. 
TEOXANE SA. Investigator’s Brochure for Study TEO-RHA-1902, TEOXANE SA, 
Edition 1.0, Release date 17-Jun-2020. 
6. 
TEOXANE SA. Injection Guidelines, Protocol Number: TEO-RHA-1902, TEOXANE SA, 
Version Number 1.0, Release date 17-Jun-2020. 
7. 
TEOXANE SA. TEO-RHA-1902 Study, Visual Assessment User Manual, Edition 1.0, 
Release date 17-Jun-2020. 
8. 
DeLorenzi C. Complications of Injectable Fillers, Part 2: Vascular Complications. Aesthet 
Surg J. 2014;34(4):584-600. 
9. 
Stevens S. Test distance vision using a Snellen chart. Community Eye Health. 2007;20(63):52. 
10. Pollock, SC. Confrontation Visual Fields: A Concise Guide for Ophthalmologists in Training. 
https://aupo.org/system/files/resources/2019-04/Confrontation%20Visual%20Fields%20--
%20A%20Guide%20for%20Ophthalmologists%20in%20Training.pdf 
Updated 
25-Apr-
2019. Accessed 13-May-2020. 
11. Peterson E. The Motility Exam. http://morancore.utah.edu/basic-ophthalmology-review/the-
motility-exam/ Updated 2016. Accessed 13-May-2020. 
12. TEOXANE SA. Neurological Examination Instructions, Protocol Number: TEO-RHA-1902, 
Version Number 2.0, Release date 23-Dec-2021. 
13. Klassen AF, Cano SJ, Schwitzer JA, Scott AM, Pusic AL. FACE-Q scales for health-related 
quality of life, early life impact, satisfaction with outcomes, and decision to have treatment: 
development and validation. Plast Reconstr Surg. 2015;135(2):375-86. 
14. FDA Executive Summary General Issues Panel Meeting on Dermal Fillers, Prepared for the 
Meeting of the General and Plastic Surgery Devices Advisory Panel, Release date 
23-Mar-2021. 
15. Beleznay K, Carruthers JDA, Humphrey S, Carruthers A, Jones D. Update on Avoiding and 
Treating Blindness From Fillers: A Recent Review of the World Literature. Aesthet Surg J. 
2019;39(6):662-74. 

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17. ATTACHMENTS 
17.1. Investigator’s Agreement 
CLINICAL INVESTIGATION 
PLAN NUMBER: 
TEO-RHA-1902 
CLINICAL INVESTIGATION 
PLAN TITLE: 
A Randomized, Blinded Evaluator, No-treatment Control, 
Multicenter, Prospective Clinical Study of RHA® 1 for the 
Treatment of Moderate to Severe Tissue Volume 
Deficiencies in the Infraorbital Regions 
FINAL CLINICAL 
INVESTIGATION PLAN: 
Version 12.0, 24-Apr-2024 
 
I have read this clinical investigation plan and agree to conduct this clinical investigation as 
outlined herein. I will ensure that all subinvestigators and other investigation staff members have 
read and understand all aspects of this clinical investigation plan. I agree to cooperate fully with 
TEOXANE SA and Premier Research during the investigation. I will adhere to all FDA, ICH, ISO 
14155, GCP, Declaration of Helsinki, and other applicable regulations and guidelines regarding 
clinical investigations during and after investigation completion. 
Treating Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 

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18. APPENDICES 
18.1. Appendix A – Common Treatment Response 
18.2. Appendix B – Teoxane Infraorbital Hollow Scale 
18.3. Appendix C – FACE-Q 
18.4. Appendix D – Periorbital Subject Assessment Questionnaire 
18.5. Appendix E – Adverse Events Reporting – What If? 
 
 

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18.1. Appendix A 
 

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18.3. Appendix C 
FACE-QTM - APPRAISAL OF LOWER EYELIDS 
 
For each question, circle only one answer. With the area under your eyes in mind, in the past 
week, how much have you been bothered by: 
 
 
Not at all 
A little 
Moderately 
Extremely 
a. Excess fat under your eyes? 
1 
2 
3 
4 
b. Excess skin under your eyes? 
1 
2 
3 
4 
c. Puffiness under your eyes? 
1 
2 
3 
4 
d. How noticeable the lines under your eyes 
are? 
1 
2 
3 
4 
e. Crepey (wrinkled) skin under your eyes? 
1 
2 
3 
4 
f. How old the area under your eyes makes 
you look? 
1 
2 
3 
4 
g. How tired the area under your eyes makes 
you look?  
1 
2 
3 
4 
Copyright©2013 Memorial Sloan Kettering Cancer Center, New York, USA. All rights reserved. 
 
The FACE-Q, authored by Drs. Andrea Pusic, Anne Klassen and Stefan Cano, is the copyright of Memorial Sloan 
Kettering Cancer Center (Copyright ©2013, Memorial Sloan Kettering Cancer Center). The FACE-Q has been 
provided under license from Memorial Sloan Kettering Cancer Center and must not be copied, distributed or used 
in any way without the prior written consent of Memorial Sloan Kettering Cancer Center. 
 
Note to Investigators: This scale can be used independently of the other scales. 
 
 
 

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18.4. Appendix D 
 
 
 

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18.5. Appendix E 
 

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REASONS FOR AMENDMENT 
The reasons for amendment summarize all changes in version 12.0 as compared to final 
version 11.0: 
1. Resolution of a discrepancy on superiority test so that the observed p-values must be ≤0.025 
instead of ≤0.05 to reject the null hypothesis 

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SUMMARY OF AMENDED SECTIONS 
Summary of amended sections summarizes all changes as compared to final version 11.0. 
All insertions are indicated by bold, deletions are indicated by strikethrough, underlined are 
sections that were bold in the original text. 
The synopsis was updated to reflect the changes in the protocol. 
Section 2.1 
 
Summary 
Primary Effectiveness Analysis: 
The rate of responders 12 weeks after randomization in the RHA® 1 
group (Stage 1 and Stage 2) will be compared with the rate of responders 
in the No-treatment control group using an independent testing based on 
a 2-group, 1-sided, Fisher’s exact statistic test. To achieve superiority, 
the observed p-value must be ≤0.025. 
Section 11.4 
Effectiveness analysis 
The rate of responders 12 weeks after randomization in RHA® 1 group 
(Stage 1 and Stage 2) will be compared with the rate of responders in 
the No-treatment control group using an independent testing based on a 
2-group, 21-sided, Fisher’s exact statistic test. To achieve superiority, 
the observed p-value must be ≤0.025.