A Randomized, Controlled, Single-blinded, Within-subject (Split-face), Multicenter, Prospective Clinical Study to Evaluate the Effectiveness and Safety of Using the Dermal Filler RHA®4 Injected With a Cannula or With a Sharp Needle for the Treatment of Moderate to Severe Nasolabial Folds
Phase: NA
Conditions: Wrinkle, Nasolabial Fold, Aging
Sponsor: Teoxane SA

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-2001 
CONFIDENTIAL 
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Page 1 of 67 
 
 
 
 
A randomized, controlled, single-blinded, within-subject (split-face), 
multicenter, prospective clinical study to evaluate the effectiveness and safety 
of using the dermal filler RHA®4 injected with a cannula or with a sharp 
needle for the treatment of moderate to severe nasolabial folds 
 
 
 
 
IDE Pivotal Study 
Protocol:  TEO-RHA-2001 
Version:  v.1.5 
Date:  06-May-2021 
 
Study Sponsor: 
TEOXANE SA 
Rue de Lyon 105 
CH - 1203 Genève, Switzerland 
+41 (0) 22.344.96.36 
 
US Sponsor: 
 Gloster Biomedical International 
 577 North Hope Ave 
Santa Barbara, California, USA 93110  
805.679.1258 
 
Clinical Research Organization:  
ethica CRO Inc. 
3551 St. Charles Blvd, Suite 501 
Kirkland, Quebec, Canada H9H 3C4 
866.384.4221 
 
 
 
Confidentiality Statement 
The information contained in this document is provided in confidence. It is understood 
that this information will not be disclosed to others without prior agreement with the 
Sponsor, except to other study personnel and to the extent necessary to obtain informed 
consent from participating subject. 
 

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PROTOCOL APPROVAL SIGNATURE PAGE 
 
The following individuals approve this version of Protocol TEO-RHA-2001. All changes to this 
version of the protocol must have a prior written approval and require an amendment or 
administrative letter. 
Accepted for the Sponsor – TEOXANE SA: 
 
 
_______________________________________________________________________   
Mathilde CHENET, Clinical Project Manager  
 
 
 
 
 
 
 
 
 
 
DATE 
 
 
 
_______________________________________________________________________   
Sandra CHENNOUFI, Clinical Development and Medical Affairs Director  
DATE 
 
 
 
_______________________________________________________________________   
Delphine DECONCHAT, QA/RA Director  
 
 
 
 
 
 
 
 
 
 
 
DATE 
 
 
 
 
 
Accepted for the Clinical Research Organization - ethica CRO Inc: 
 
 
_______________________________________________________________________   
Murray JENSEN, Managing Director  
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE 
 
 
 

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INVESTIGATOR SIGNATURE PAGE 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol. I will 
ensure that all subinvestigators and other investigation staff members have read and understand 
all aspects of the protocol. 
• Maintain all information supplied by TEOXANE SA in confidence and, when this 
information is submitted to an Institutional Review Board (IRB) or another group, it will be 
submitted with a designation that the material is confidential. 
• Cooperate fully with TEOXANE and ethica CRO during the investigation. I will adhere to all 
Food and Drug Administration (FDA), International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH), International Organization for 
Standardization (ISO) 14155, Good Clinical Practice (GCP), Declaration of Helsinki, and other 
applicable regulations and guidelines regarding clinical investigations during and after 
investigation completion. 
I have read this protocol in its entirety and I agree to all aspects. 
 
____________________________________________________________________________   
Principal Investigator (Print Name)  
 
Signature  
 
 
 
 
 
 
DATE 
 
 
 
 

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SYNOPSIS 
Protocol 
Version 
Version 1.5 
06-May-2021 
Investigational 
Device 
RHA®4 injected with a (25G x 2”) 
cannula into the NLF. The brand of 
cannula (i.e., Softfil, Dermasculpt, or 
TSK) used for injection is up to the 
discretion of the Treating Investigator 
(TI), 
providing 
the 
cannula 
is 
registered for use by the US FDA and 
that the cannula bore is 25G x 2” long. 
The injection technique is left to the 
discretion of the TI. 
Study Number 
TEO-RHA-2001 
Phase 
IDE Pivotal 
Control Device 
Approved RHA® 4 injected with the 
provided TSK 27G x ½” sharp needle. 
Indication 
Injection into the deep dermis to 
superficial subcutaneous tissue for 
the correction of moderate to severe 
dynamic facial wrinkles and folds. 
Study Sites 
Multicenter, 3 to 4 US sites 
Title 
A randomized, controlled, single-blinded, within-subject (split-face), multicenter, prospective 
clinical study to evaluate the effectiveness and safety of using the dermal filler RHA®4 injected 
with a cannula or with a sharp needle for the treatment of moderate to severe nasolabial folds. 
Sponsor 
TEOXANE SA, Rue de Lyon 105, CH - 1203 Geneva, Switzerland 
Study 
Duration 
12 to 16 weeks for each subject. 
Anticipated study length is ~24 
weeks (8W enrollment + up to 16W 
f/u), but may be extended depending 
on the COVID-19 public health 
emergency.  
Number of 
Subjects 
At least 50 subjects treated with 
cannula and sharp needle with at least 
20% of subjects presenting Fitzpatrick 
skin type IV to VI including 10% of 
subjects presenting Fitzpatrick skin 
type V and VI. 
Treatment 
Groups 
Each enrolled subject will receive injections of RHA®4 with a cannula into the nasolabial fold 
(NLF) of the left or right side of the face, and injections of the control device (sharp needle) into 
the contralateral NLF. 
Study Design 
This is a randomized, controlled, single-blinded, within-subject (split-face), multicenter, 
prospective study to investigate whether RHA®4 injected in NLFs with a cannula (25G x 2” long) 
is non-inferior to RHA®4 injected in NLFs with a sharp needle (27G x ½”) for the correction of 
moderate to severe NLFs as determined by the Blinded Live Evaluator (BLE) using the NLF-
WSRS (validated NLF Wrinkle Severity Rating Scale) at 12 weeks from last treatment. 
At screening, the Treating Investigator (TI) and Blinded Live Evaluator (BLE) will evaluate 
subjects’ NLF severity to confirm eligibility and to establish a pre-treatment score for assessing 
aesthetic improvement (i.e., moderate to severe bilateral nasolabial folds; grade 3 or 4 on the five-
point NLF-WSRS; symmetrical in terms of grade). BLE and TI must independently agree that the 
criterion is met; however, strict concordance of severity is not required. 
At Visit 1, RHA®4 injected with cannula will be administered in a random sequence (first or second 
injection) and side of the face (left or right NLF) and RHA®4 injected with a sharp needle will be 
administered to the other side. The TI will administer study devices and will be unblinded to 
treatment allocation. Blinded assessments of effectiveness will be conducted by the BLE (Blinded 
Live Evaluator). 
Subjects then attend Visit 2 (4 weeks following initial treatment) and will receive touch-up 
treatments (if necessary) using a needle or cannula as per the subject’s initial treatment assignment. 
Subjects receiving touch-up treatments at Visit 2 will attend Visit 2b (4 weeks following touch-up 
treatment); subject not receiving touch-up treatment will not attend Visit 2b. 

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Subjects will receive a safety follow-up call from the study site within 3-days of initial treatment, 
and if applicable, within 3 days of touch-up treatment. 
Before and 30 minutes after injection, as well as at each study visit, assessments of visual 
disturbances (i.e., Snellen visual acuity, confrontational visual field test, ocular motility) will be 
conducted.  
Subjects will then attend scheduled in-office study visits at 8 and 12 weeks following last treatment 
where safety and effectiveness assessments, including photography, AEs, visual assessments, 
device symmetry assessments, concomitant medications, NLF severity (NLF-WSRS), FACE-Q, 
GAIS and subject satisfaction, will be conducted. 
Subjects who present with an unresolved clinically significant device-related AE at the last study 
visit will attend an optional visit or phone-call follow-up (discretion of the TI) from the study staff 
within 4 weeks of last study visit. Follow-up of the clinically significant device-related AE will 
continue until the AE is resolved or the TI determines that additional follow-up is no longer 
necessary. 
Hypothesis 
RHA®4 injected in NLFs with a cannula is non-inferior to RHA®4 injected in the NLFs with a 
sharp needle for the correction of moderate to severe NLFs as determined by the NLF-WSRS 
(validated NLF Wrinkle Severity Rating Scale) at 12 weeks from last treatment. 
A change from Baseline in the NLF-WSRS of ≥1-grade will be considered clinically meaningful, 
and the non-inferiority margin for change in NLF-WSRS between needle and cannula will be 0.5 
grade. The formal hypothesis set to be tested is as follow: 
Ho:  µΔ(needle – cannula) > 0.5 
Ha:  µΔ(needle – cannula) < 0.5 
where µΔ(needle – cannula) represents the mean difference in change from Baseline between needle and 
cannula. 
Objectives 
1. Demonstrate the non-inferiority of RHA®4 injected in the NLFs with a cannula versus the 
control (RHA®4 injected in NLF with a sharp needle) at 12 weeks from last treatment for the 
correction of moderate to severe NLFs. Assessment of non-inferiority will be based on the 
change from Baseline in NLF-WSRS at 12 weeks as rated by the Blinded Live Evaluator 
(BLE) at each investigative site. 
2. Evaluate the safety of RHA®4 injected in NLF with a cannula versus the control up to 12 
weeks from last treatment. 
Inclusion 
Criteria 
1. Outpatient, male or female of any race, 22 years of age or older. 
2. Female subjects of childbearing potential must have a negative UPT at Visit 1 and practice a 
reliable method of contraception throughout the study. 
A female is considered of childbearing potential unless she is: 
- postmenopausal for at least 12 months prior to study treatment administration; 
- without a uterus and/or both ovaries; or 
- has been surgically sterile for at least 6 months prior to study treatment administration.  
Reliable methods of contraception are: 
- hormonal methods (contraceptive pill or implant) or intrauterine device in use >90 days prior to study 
treatment administration; 
- barrier methods such as diaphragm plus spermicide or condom plus spermicide in use at least 14 days 
prior to study treatment administration; or 
- vasectomized partner who has had a vasectomy at least 3 months prior to receiving treatment (or who 
has a confirmed ‘0’ sperm count).  
[Exception: Female subjects of childbearing potential who are not sexually active will not be required to practice a 
reliable method of contraception. These subjects may be enrolled at Investigator’s discretion if they are counseled 
to remain sexually inactive during the study or agree to use an approved method of contraception should they become 
sexually active and understand the possible risks in getting pregnant during the study.] 
3. Moderate to severe bilateral nasolabial folds (grade 3 or 4 on the five-point NLF-WSRS). BLE 
and TI must independently agree that the criterion is met; however, strict concordance of 
severity not required. [NOTE: BLE assessments will be used for the primary endpoint. If TI 

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and BLE do not agree on eligibility, or if their assessments differ by ≥2 grades, the subject 
will not be eligible, half-point grades will not be accepted]. 
4. Nasolabial folds of the same NLF-WSRS grade on the left and right sides of the face.  
5. Willing to abstain from facial aesthetic procedures/therapies that could interfere with the study 
evaluations (e.g., other fillers, botulinum toxin injections, laser or chemical resurfacing, facial 
plastic surgery, etc.) for the duration of the study (see Section 7.5.1 for prohibited/restricted 
medication/procedures). 
6. Able to follow study instructions and complete all required visits. 
7. Sign the IRB-approved ICF, Photographic Release Form, the Authorization for Use and 
release of Health and Research Study Information (HIPAA) form, and if applicable, the 
California Experimental Research Subject’s Bill of Rights prior to any study-related 
procedures being performed. 
Exclusion 
Criteria 
1. Known hypersensitivity or previous allergic reaction to any component of the study devices. 
2. Use of a prohibited treatment/procedure within time periods defined in Section 7.5.1. 
3. Known sensitivity to local anesthetics of the amide type, history of multiple severe allergies, 
or history of anaphylactic shock. 
4. Known susceptibility to keloid formation, hypertrophic scarring or clinically significant skin 
pigmentation disorders (TI discretion). 
5. Clinically significant active skin disease or infection in the NLF regions within 6 months prior 
to study entry (TI discretion). 
6. History of severe chronic systemic diseases, including but not limited to, poorly controlled 
diabetes mellitus (all types), congestive heart failure, severe liver disease, severe kidney 
disease, and others as judged by the TI. 
7. Abnormal visual tests (i.e., Snellen acuity test worse than 20/40 with corrections, if 
applicable), abnormal confrontational visual field test, and/or abnormal ocular motility test. 
8. History of active chronic debilitating systemic disease that, in the opinion of the investigator, 
would make the subject a poor candidate in the study. 
9. History of connective tissue disease. 
10. Malignancy (excluding non-melanoma skin cancer) within the past 5 years. 
11. History of skin cancer in the treatment area. 
12. Need for clinically significant (TI discretion) and continuous medical treatment within 2 
weeks prior to Visit 1. 
13. History or presence of condition or feature that may confound the interpretation of the results 
in the NLF areas, for example, tattoo, significant facial hair, scar, prior surgery in the area, 
potential for active disease or infection flare up such as herpes simplex. 
14. Herpes simplex lesion flare-ups greater than 6 per year. 
15. Elective, clinically significant facial procedures that may confound the interpretation of the 
results in the NLF area (TI discretion), prior to study enrollment. 
16. Has received botulinum toxin injections in the face below the orbital rim including crow’s feet 
(note: frontalis and glabellar treatment is permitted) within 6 months before randomization. 
17. Subjects with known prolonged bleeding times because of disease or anticoagulant medication 
(including warfarin or low-dose aspirin). If on a drug or supplement that prolongs bleeding 
times (e.g., non-steroidal anti-inflammatory, anticoagulant, high-dose vitamin E, fish oil, 
corticosteroids), wait 7 days or until bleeding times return to normal before injecting. (Note: 
low dose 81mg/day ASA is permitted). 
18. Medical or psychiatric conditions that may increase the risk associated with study participation 
or may interfere with the interpretation of study results or compliance of the subject and, in 
the judgment of the Investigator, would make the subject inappropriate for entry into this 
study. 
19. Clinically significant alcohol or drug abuse, or history of poor cooperation or unreliability. 

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20. Exposure to any other investigational drug/device within 90 days of entering the study or 
planning to participate in another investigation during the course of the study. 
21. Study staff or close relative to study staff (e.g., parents, children, siblings, or spouse) 
Device 
Administration 
Depth of injection: Study device will be administered into the deep dermis to the superficial 
subcutaneous tissue at the discretion of the TI. 
Injection technique: The injection technique (e.g., linear threading (retrograde or anterograde), 
cross hatching, fan like administration, multiple puncture) will be at the discretion of the TI and 
will be recorded in the eCRF. [NOTE: Cross-hatching is a “needle only” injection technique]  
Injection volume: The maximum volume per administration of a study device into a single NLF 
is 3.0 mL (max 3.0 mL for right side, and max 3.0 mL for left side) for a maximum volume of 6 
mL per session. 
Blinding 
Due to the visual and sensory differences between the cannula and sharp needle, it is not feasible 
to mask the TI or the subject. However, the BLE will be blinded to the treatment allocation. 
Furthermore, to ensure that the BLE remains masked and that all assessors remain unbiased when 
making their assessments, the BLE, TI and subject will not be allowed to refer to each other’s 
efficacy assessments. 
All subjects will be instructed to not discuss their study treatment, AEs, or CTRs with the BLE. 
Randomization 
A randomization algorithm will provide equal balancing for the side of the face and the order of 
injection (i.e., left or right / 1st or 2nd order). 
Visit 
Procedures 
The NLF-WSRS will be assessed by the BLE at Baseline (pre-injection) and 12 weeks following 
last treatment (initial or touch-up), and by the TI at Baseline (pre-injection) and at all follow-up 
visits (i.e., Weeks 4, 8 and 12 following last treatment). 
The GAIS will be assessed by the BLE at Week 12, and by the TI and subject at all follow-up 
visits. Subject satisfaction and FACE-Q will be assessed at all follow-up visits.  
Subject Safety Assessments will be conducted at all scheduled in-office study visits. Adverse 
Events (AEs) will be obtained from signs and symptoms reported by the subject in the 4-week 
post-treatment CTR diary or detected during phone and in-office follow-up visits. Diary CTR data 
will be counted and evaluated separately from AE data. CTRs that are recorded on the last day of 
diary will be automatically elevated to the status of AE. 
Symmetry will be assessed by the BLE at Baseline pre-injection and 12 weeks following last 
treatment, and by the TI and subjects at Baseline pre-injection and at all follow-up visits. 
Assessment of visual acuity/function will be assessed at Visit 1 (pre- and post-injection), Visit 2 
(pre-and post-touch-up if applicable) as well as at all other follow-up visits. 
Before initial treatment at Visit 1 and at each scheduled in-office follow-up visit, the Investigators 
will perform a live assessment of both the subjects’ left and right NLF using the NLF-WSRS as a 
guide for grading severity and 2D photography.  
Refer to the Study Summary Tables and the Study Schematic for a schedule of activities. 
Aesthetic 
Effectiveness 
Evaluations 
1. NLF-WSRS (BLE) at Baseline and 12 weeks following last treatment 
2. NLF-WSRS (TI) at Baseline, 4, 8 and 12 weeks following last treatment 
3. GAIS assessment (BLE) at 12 weeks following last treatment 
4. GAIS assessment (TI) at 4,8 and 12 weeks following last treatment 
5. GAIS assessment (Subject) at 4, 8 and 12 weeks following last treatment 
6. Patient Satisfaction (Subject) at 4, 8 and 12 weeks following last treatment 
7. FACE-Q at Baseline, 4, 8 and 12 weeks following last treatment 
8. Symmetry (BLE) at Baseline and 12 weeks following last treatment 
9. Symmetry (TI) at Baseline, 4, 8 and 12 weeks following last treatment 
10. Symmetry (Subject) at Baseline, 4, 8 and 12 weeks following last treatment 

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11. Number of treatment sessions to obtain optimal cosmetic result. 
12. Treatment volume to obtain optimal cosmetic result. 
Primary 
Effectiveness 
Endpoint 
The primary effectiveness endpoint will be aesthetic improvement from pre-injection as assessed 
by the NLF-WSRS (BLE) at 12 weeks (V4) following last treatment (initial or touch-up). The 
primary hypothesis is that RHA®4 used in conjunction with cannula is non-inferior to RHA®4 with 
sharp needle. An NLF-WSRS change from Baseline of >1 grade will be considered clinically 
significant. A non-inferiority margin of 0.5 grade difference in change from Baseline between 
cannula and needle will be used to test the primary hypothesis.  
In order to confirm assay sensitivity at 12 weeks, the proportion of responder of ≥1 grade point on 
the NLF-WSRS at 12 weeks for the group injected with a needle (control) is required to be ≥70% 
(when compared to pre-treatment). 
Secondary 
Effectiveness 
Endpoints 
Secondary effectiveness objectives are to evaluate the effectiveness of RHA®4  used in in 
conjunction with the use of a cannula (25G x 2”) for treatment of moderate to severe nasolabial 
folds using the following endpoints:  
1. NLF-WSRS (TI) change from Baseline at 4, 8 and 12 weeks following last treatment 
2. NLF-WSRS (BLE) responders (change from Baseline of ≥1-grade) at 12 weeks following last 
treatment 
3. NLF-WSRS (TI) responders at 4, 8 and 12 weeks following last treatment 
4. GAIS (BLE) “improved” or “much improved” at 12 weeks following last treatment 
5. GAIS (TI) “improved” or “much improved” at 4, 8 and 12 weeks following last treatment 
6. GAIS (Subject) “improved” or “much improved” at 4, 8 and 12 weeks following last treatment 
7. Satisfaction (Subject) of “satisfied” or “very satisfied” at 4, 8 and 12 weeks following last 
treatment 
8. FACE-Q change from Baseline at 4, 8 and 12 weeks following last treatment 
9. Number of treatment sessions to obtain optimal cosmetic result. 
10. Treatment volume to obtain optimal cosmetic result. 
11. Symmetry (BLE) at Baseline and 12 weeks following last treatment. 
12. Symmetry (TI) at Baseline, 4, 8 and 12 weeks following last treatment. 
13. Symmetry (Subject) at Baseline, 4, 8 and 12 weeks following last treatment. 
14. Ease of injection (initial injection) 
Safety 
Endpoints 
1. AEs across the duration of the study (incidence, intensity, and duration) 
2. AEs of Special Interest (AESI) across the duration of the study (i.e., visual disturbances such 
as loss of vision, blurriness, double vision, pain in or around the eyes, blindness, blind spot or 
shadow in the visual field, trouble moving eyes, ocular hypotonia, ptosis, etc.) 
3. Post-injection Common Treatment Response (4-week CTR diary; incidence, intensity, and 
duration) 
4. Visual assessments (Snellen visual acuity, confrontational visual field test, ocular motility) at 
Visit 1 (pre- and post-injection), Visit 2 (pre- and post-injection if Touch-up) as well as at all 
other follow-up visits 
5. Injection Site pain immediately after treatment, and at 5, 30, and 60 minutes post-treatment 
Statistical 
Methods 
Analysis Populations: The Intent-to-Treat (ITT) Population will consist of all subjects who were 
randomized. Subjects will be summarized and analyzed according to randomized treatment. 
The Per Protocol (PP) Population will consist of all study subjects who 1) met all 
inclusion/exclusion criteria, 2) successfully completed the study and 3) experienced no major 
protocol violations/deviations that could affect efficacy assessments. 
The Safety (SAFT) Population will consist of all study subjects who were randomized and received 
treatment with the study device. Subjects will be summarized and analyzed according to treatment 
received. 

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Primary Efficacy Endpoint: The primary endpoint of NLF-WSRS change from Baseline at 12 
weeks (BLE) will be analyzed in a non-inferiority statistical model using the PP Population with a 
0.5 margin for the difference between cannula and needle. Expressing the difference between 
treatment groups as the mean of change from Baseline in RHA®4 injected with needle minus mean 
change from Baseline in RHA®4 injected with cannula, the one-sided 97.5% confidence limit must 
be <0.5 to conclude non-inferiority. A paired t-test will be used to calculate the confidence interval. 
In order to confirm assay sensitivity at 12 weeks, the proportion of responders of ≥1-grade point 
on the NLF-WSRS at 12 weeks for the group injected with a needle (control) is required to be 
≥70% (when compared to pre-treatment).  
A sensitivity analysis will be done using the ITT population. Multiple imputation will be used for 
missing observations. Specifically, missing change from baseline in NLF-WSRS at 12 weeks will 
be imputed using the regression method with treatment group as the independent variable and with 
age and NLF-WSRS at earlier timepoints as covariates. 
Secondary Efficacy Endpoints: All statistical inference tests will be performed at the same 
significance level (α) of 0.05. For categorical and continuous variables, the two groups will be 
compared using two-sided parametric or non-parametric tests for paired data, as appropriate. For 
continuous variables, the Shapiro-Wilk test will be used to assess normality. If data are normally 
distributed, testing will be conducted using the Student t-test, while testing will be conducted with 
the Wilcoxon signed-rank test if not normally distributed. The ITT population will be used for 
summaries and comparisons. No imputation will be performed; analyses will utilize available data 
as observed. 
Safety Assessments will be summarized for the SAFT population using descriptive statistics: 
frequencies and percentages for categorical assessments, and means, variability, and ranges for 
continuous assessments. 
• 
AE type (i.e., preferred term) and frequency over the duration of the study. 
• 
AE intensity over the duration of the study, measured as incidence of severe AEs. 
• 
AE duration measured as days from AE start date to AE end date. 
• 
Post-injection Common Treatment Response from the 4-week patient CTR diary: incidence, 
severity, and duration will be described. 
• 
Visual assessments over the duration of the study (i.e., Snellen visual acuity, confrontational 
visual field test, ocular motility). 
• 
Injection Site pain immediately after treatment (i.e., 0 minutes), and at 5, 30 and 60 minutes 
post-treatment will be described. 
Other than subject-level AEs, safety assessments will be descriptively compared between RHA®4  
injected in NLF with a cannula and RHA®4  injected in NLF with a sharp needle. Descriptive 
comparisons between treatment groups will be limited to treatment-emergent AEs. 
Sample Size 
Assuming a mean difference of 0 between RHA®4 (Cannula) and RHA®4 (Needle), and assuming 
a SD of 0.75, non-inferiority for each device tested using a bilateral 97.5% CI and a non-inferiority 
upper bound of 0.5, a sample size of 38 subjects for each treatment group is required for 80% 
power to detect non-inferiority for RHA®4. As this is a split-face study, 38 subjects will provide a 
sample size of n=38 for each treatment group. 
Assuming a 20% drop-out rate, a minimum of 50 subjects (38 / 0.8 = 47.5) will be required. 
 
 
 
 

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TABLE 1.  STUDY SUMMARY TABLE 
Study Visits 
(1 week = 7 days) 
Visit 1 
Baseline 
scr, enroll, Tx 
Visit 1a 
Phone F/U  
3D post-Tx 
Visit 2 
4W post-Tx 
Includes optional 
T/U 
Visit 2a 
Phone F/U  
3D post-T/U 
Visit 2b  
4W post-T/U 
Visit only for subjects 
receiving T/U at V2 
Visit 3 
8W after 
last Tx* 
 
Visit 4 
12W after 
last Tx 
Unscheduled 
Visit** 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
UPT (if applicable) 
X 
 
If T/U 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
If T/U 
X 
X 
X 
X 
Randomization  
X 
 
 
 
 
 
 
 
Injection 
X 
 
If T/U 
 
 
 
 
 
Photography 
Pre- and 
Post-Tx 
 
X 
Pre-Tx / Post-
Tx if T/U 
 
X 
X 
X 
X 
Visual Assessments*** 
Pre- and 
Post-Tx 
 
Pre- and 
Post-Tx  
 
X 
X 
X 
X 
Provide 4-week CTR e-diary 
to subject 
X 
 
If T/U 
 
 
 
 
 
TI Assessments 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
If T/U 
X 
X 
X 
X 
NLF-WSRS  
Pre-Tx 
 
X 
Pre-Tx if T/U 
 
X 
X 
X 
 
GAIS  
 
 
X 
Pre-Tx if T/U 
 
X 
X 
X 
 
Symmetry 
Pre-Tx 
 
X 
Pre-Tx if T/U 
 
X 
X 
X 
X 
Ease of Injection 
X 
 
 
 
 
 
 
 
BLE Assessments 
 
 
 
 
 
 
 
 
NLF-WSRS 
Pre-Tx 
 
 
 
 
 
X 
 
GAIS 
 
 
 
 
 
 
X 
 
Symmetry 
Pre-Tx 
 
 
 
 
 
X 
 
Subject Assessments 
 
 
 
 
 
 
 
 
Injection site pain VAS 
(immediately after treatment of 
each side, and at 5,30 and 60 min) 
X 
 
If T/U 
 
 
 
 
 
FACE-Q 
Pre-Tx 
 
X 
Pre-Tx if T/U 
 
X 
X 
X 
X 
GAIS  
 
 
X 
Pre-Tx if T/U 
 
X 
X 
X 
 
Patient Satisfaction  
 
 
X 
Pre-Tx if T/U 
 
X 
X 
X 
 
Symmetry 
Pre-Tx 
 
X 
Pre-Tx if T/U 
 
X 
X 
X 
X 
Study Exit 
 
 
 
 
 
 
X 
 
BLE = Blinded Live Evaluator 
CTR = Common Treatment Response 
F/U = Follow-up 
GAIS = Global Aesthetic Improvement Scale 
NLF-WSRS = Nasolabial Fold Wrinkle Severity Rating Scale 
TI = Treating Investigator 
Tx = Treatment 
T/U = Touch-up injection 
UPT = Urine pregnancy test 
VAS = Visual Analogue Scale 
* 
Visit occurs 8 weeks after V1 if T/U NOT administered, or 8 weeks after V2 if T/U is administered 
**   In-office or phone F/U visit may occur at any time to assess AEs 
*** Snellen visual acuity, confrontational visual field test, ocular motility test. Post-tx assessments conducted 30 minutes following injection. 

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FIGURE 1.  STUDY SCHEMATIC 
  
 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ..................................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE ................................................................................................................... 3 
SYNOPSIS.................................................................................................................................................................... 4 
TABLE OF CONTENTS .......................................................................................................................................... 12 
CONTACT LIST ....................................................................................................................................................... 15 
ABBREVIATIONS .................................................................................................................................................... 16 
1 
INTRODUCTION ......................................................................................................................................... 17 
1.1 
Background .......................................................................................................................................... 17 
1.2 
Rationale for Study .............................................................................................................................. 18 
1.3 
Hypothesis ........................................................................................................................................... 18 
2 
STUDY OBJECTIVES ........................................................................................... Erreur ! Signet non défini. 
3 
COMPLIANCE STATEMENT ................................................................................................................... 20 
3.1 
Variations to the Protocol .................................................................................................................... 20 
3.2 
Investigational Sites ............................................................................................................................. 20 
3.3 
Training and Certification on the NLF Wrinkle Severity Rating Scale (NLF-WSRS) ........................ 20 
3.4 
Medical Monitor .................................................................................................................................. 21 
3.5 
Photography ......................................................................................................................................... 21 
4 
OVERVIEW OF STUDY DESIGN ............................................................................................................. 22 
4.1 
Study Design ........................................................................................................................................ 22 
4.2 
Study Design Rationale ....................................................................................................................... 22 
4.2.1 
Study Population ............................................................................................................................. 22 
4.2.2 
Primary Endpoint ............................................................................................................................ 23 
5 
STUDY POPULATION ................................................................................................................................ 24 
5.1 
Inclusion Criteria ................................................................................................................................. 24 
5.2 
Exclusion Criteria ................................................................................................................................ 24 
6 
TREATMENT ALLOCATION, RANDOMIZATION AND BLINDING ............................................... 26 
7 
DEVICE APPLICATION ............................................................................................................................. 27 
7.1 
Study Devices ...................................................................................................................................... 27 
7.2 
Injection of Study Devices ................................................................................................................... 27 
7.2.1 
Injection Depth ................................................................................................................................ 27 
7.2.2 
Injection Technique......................................................................................................................... 27 
7.2.3 
Supplementary Anesthesia .............................................................................................................. 28 
7.2.4 
Visual Assessments ......................................................................................................................... 28 
7.2.5 
Injection Sequence .......................................................................................................................... 29 
7.2.6 
Treatment Volume Allowance ........................................................................................................ 29 
7.3 
Labeling, Packaging and Storage ......................................................................................................... 29 
7.4 
Study Device Supply and Accountability ............................................................................................ 29 
7.4.1 
Other Study Supplies ...................................................................................................................... 30 
7.5 
Concomitant Medications and Procedures ........................................................................................... 30 
7.5.1 
Prohibited Treatment and Procedures ............................................................................................. 30 
8 
DATA COLLECTION .................................................................................................................................. 32 
8.1 
Electronic Case Report Form ............................................................................................................... 32 
8.2 
Subject Diaries and Questionnaires ..................................................................................................... 32 
8.3 
Photography ......................................................................................................................................... 32 
9 
STUDY EVALUATIONS ............................................................................................................................. 33 
9.1 
Informed Consent ................................................................................................................................ 33 
9.2 
Visit Procedures ................................................................................................................................... 33 
9.2.1 
Visit 1 (Screening / Enrolment / Treatment) ................................................................................... 33 
9.2.2 
Visit 1a Phone Follow-up (3 days post initial injection  1 day) .................................................... 33 
9.2.3 
Visit 2 (4 weeks from V1; ±3 days) ................................................................................................ 33 
9.2.4 
Visit 2a Phone Follow-up Phone (3 Days post-T/U injection  1 day) ........................................... 34 

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9.2.5 
Visit 2b (4 weeks post-T/U; ±3 days) ............................................................................................. 34 
9.2.6 
Visit 3 (8 weeks from last treatment; ±7 days) ............................................................................... 35 
9.2.7 
Visit 4 (12 weeks from last treatment; ±7 days) ............................................................................. 35 
9.2.8 
Unscheduled Visit ........................................................................................................................... 36 
9.3 
Efficacy ................................................................................................................................................ 36 
9.3.1 
Aesthetic Effectiveness Evaluations ............................................................................................... 36 
9.3.1.1 
Nasolabial Fold Wrinkle Severity Rating Scale .................................................................... 36 
9.3.1.2 
Global Aesthetic Improvement Scale .................................................................................... 36 
9.3.1.3 
Patient Satisfaction ................................................................................................................ 37 
9.3.1.4 
Treatment Volume ................................................................................................................. 37 
9.3.1.5 
Ease of Injection .................................................................................................................... 37 
9.3.1.6 
Symmetry .............................................................................................................................. 37 
9.3.1.7 
FACE-Q................................................................................................................................. 37 
9.4 
Safety ................................................................................................................................................... 38 
9.4.1 
Patient Common Treatment Response Diary .................................................................................. 38 
9.4.2 
3-Day Telephone Follow-up ........................................................................................................... 38 
9.4.3 
Vision Assessments......................................................................................................................... 39 
9.4.4 
Injection Site Pain ........................................................................................................................... 39 
9.4.5 
Pregnancy and Contraception ......................................................................................................... 40 
9.4.6 
Adverse Events ............................................................................................................................... 40 
9.4.6.1 
Definition of an Adverse Event ............................................................................................. 40 
9.4.7 
Adverse Events of Special Interest (AESI) ..................................................................................... 41 
9.4.8 
Vascular Occlusion Adverse Events ............................................................................................... 41 
9.4.9 
Serious Adverse Events (SAEs) and Unexpected Adverse Device Effects (UADEs) .................... 41 
9.4.10 
Causality Assessment ................................................................................................................. 42 
9.4.11 
Severity Assessment ................................................................................................................... 43 
9.4.12 
Device Malfunction .................................................................................................................... 43 
9.4.13 
Safety Reporting ......................................................................................................................... 43 
9.4.13.1 
All Adverse Events ................................................................................................................ 43 
9.4.13.2 
Serious Adverse Events (SAEs) and Unexpected Adverse Device Effects (UADEs) ........... 44 
9.4.13.3 
Adverse Events of Special Interest (AESI) Reporting ........................................................... 45 
9.4.13.4 
Device Malfunctions Reporting ............................................................................................. 45 
9.4.14 
MDR Reportable Events ............................................................................................................ 45 
9.4.14.1 
Pregnancy .............................................................................................................................. 46 
10 SUBJECT COMPLETION / WITHDRAWAL / STOPPING RULES .................................................... 47 
10.1 
Completion .......................................................................................................................................... 47 
10.2 
Withdrawal .......................................................................................................................................... 47 
10.3 
Stopping Rules ..................................................................................................................................... 47 
11 STATISTICAL METHODS ......................................................................................................................... 49 
11.1 
Primary Endpoint ................................................................................................................................. 49 
11.2 
Secondary Endpoints ........................................................................................................................... 49 
11.3 
Safety Endpoints .................................................................................................................................. 49 
11.4 
Analysis Populations............................................................................................................................ 50 
11.4.1 
Intent-to-Treat (ITT) Population ................................................................................................ 50 
11.4.2 
Per Protocol (PP) Population ...................................................................................................... 50 
11.4.3 
Safety (SAFT) Population .......................................................................................................... 50 
11.5 
Sample Size Considerations ................................................................................................................. 50 
11.6 
General Considerations ........................................................................................................................ 51 
11.7 
Effectiveness Analysis ......................................................................................................................... 52 
11.7.1 
Primary Endpoint ....................................................................................................................... 52 
11.7.2 
Secondary Endpoints .................................................................................................................. 52 
11.8 
Safety Analysis .................................................................................................................................... 52 
11.8.1 
Adverse Events (AEs) ................................................................................................................ 52 
11.8.2 
Injection Site Pain ...................................................................................................................... 53 
 

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12 ETHICAL ASPECTS .................................................................................................................................... 54 
12.1 
Informed Consent ................................................................................................................................ 54 
12.2 
Health Authorities and IRBs ................................................................................................................ 54 
12.3 
Confidentiality Regarding Study Subjects ........................................................................................... 54 
13 STUDY MANAGEMENT & ADMINISTRATION ................................................................................... 55 
13.1 
Protocol Amendments.......................................................................................................................... 55 
13.2 
Monitoring and Quality Assurance ...................................................................................................... 55 
13.2.1 
Information to Study Personnel .................................................................................................. 55 
13.2.2 
Study Monitoring ....................................................................................................................... 55 
13.2.3 
Audit and Inspection .................................................................................................................. 56 
13.3 
Protocol Deviations.............................................................................................................................. 56 
14 DATA HANDLING AND RECORD KEEPING ........................................................................................ 58 
14.1 
Source Data .......................................................................................................................................... 58 
14.2 
Case Report Form ................................................................................................................................ 59 
14.3 
Archiving of Study Documentation ..................................................................................................... 59 
15 FINANCING AND INSURANCE ................................................................................................................ 60 
16 REPORTING AND PUBLICATION OF RESULTS ................................................................................. 61 
17 REFERENCES .............................................................................................................................................. 62 
18 APPENDICES................................................................................................................................................ 63 
APPENDIX A: Adjustments of Visits and Assessments due to Public Health Emergency of COVID-19 ... 63 
APPENDIX B: Protocol Version History ........................................................................................................... 67 
 
 

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CONTACT LIST 
Medical Monitor 
Patrick Trevidic, MD 
7 rue de Sontay,  
–Paris 75116 - FRANCE 
Phone:  NA 
Fax:   
NA 
doc.patrick.trevidic@orange.fr 
 
Sponsor Clinical Program Manager 
Mathilde Chenet  
TEOXANE SA 
Rue de Lyon 105 
CH - 1203 Genève - SWITZERLAND 
Phone: 41 (0) 22.344.96.36 
Fax:  
41 (0) 22.340.29.33 
m.chenet@teoxane.com 
 
Sponsor US Legal Representant 
Catherine Gloster 
Gloster Biomedical International, LLC 
577 North Hope Ave 
Santa Barbara, CA 93110 - USA 
Phone: 805.679.1258 
Fax:  
805.682.1250 
c.gloster@GlosterBiomedical.com 
 
CRO Clinical Project Manager 
Tania Mete 
ethica CRO Inc. 
3551 St. Charles Blvd, Suite 501 
Kirkland, Quebec, H9H 3C4 - CANADA 
Phone: 514.337.0442 ext. 212 
Fax:  
514.336.1142 
tmete@ethicaCRO.com 
 
24-Hour Emergency Phone Number 
ethica CRO Inc.  
514.262.9398 
 
 
 
NOTE: Changes in the names, addresses or telephone numbers of these contacts will be considered 
administrative and will not require a protocol amendment before being implemented. 

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ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BL 
Baseline 
BLE 
Blinded Live Evaluator 
CFR 
U. S. Code of Federal Regulations 
CTR 
Common Treatment Response 
CRO 
Clinical Research Organization 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GAI 
Global Aesthetic Improvement 
HA 
Hyaluronic Acid 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NLF 
Nasolabial Fold 
OCR 
Optimal Cosmetic Result 
PI 
Principal Investigator (typically functions as the Treating Investigator) 
PMA 
Premarket Approval 
PP 
Per protocol 
RHA 
Resilient Hyaluronic Acid 
SAE 
Serious Adverse Event 
SAFT 
Safety 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SMMP 
Safety and Medical Monitoring Plan 
SOC 
System Organ Class 
TRAE 
Treatment Related Adverse Event 
UADE 
Unexpected Adverse Device Effects 
TI 
Treating Investigator (typically functions as the Principal Investigator) 
Tx 
Treatment 
UPT 
Urine Pregnancy Test 
WSRS 
Wrinkle Severity Rating Scale 
 
 

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1 
INTRODUCTION 
1.1 
Background 
Hyaluronic acid (HA) is a long-chain, repeated dimer, N-acetyl glucosamine and D-glucuronic 
acid polymer and is a major component of the extracellular matrix. HA is widely present in all 
animal species and does not differ from one species to another. Due to this extended compatibility, 
non-human HA can be used in humans without unacceptable adverse effects. Due to its natural 
viscoelastic and hydrogel properties, HA is widely used as matrix in tissue regeneration and 
particularly in dermal defect reconstruction. 
It was demonstrated that by chemically crosslinking the molecule, HA becomes resistant to 
degradation and its persistence in tissues is increased.1,2 This does not affect the carboxylic and N-
acetyl functions of the molecule and allows modification of the rheological and physical properties 
of HA while maintaining the biocompatibility of the basic polymer.3 
Dermal fillers in general, and hyaluronic acid (HA) fillers specifically, are aesthetic devices that 
are not used for the diagnosis or treatment of any specific disease state. Rather, they are used for 
the treatment of age-related wrinkles/folds and facial volume loss.  Specific use data are published 
on the American Society of Plastic Surgeons (ASPS) website.  Based on Teoxane’s knowledge of 
the aesthetic industry, it is likely that most HA dermal filler procedures are performed by 
dermatologists, aesthetic nurses, and/or physician assistants rather than by plastic surgeons. 
However, as use statistics are not available from the various dermatological societies, the data 
provided below are likely an underestimation of the total number of dermal filler procedures 
performed in the U.S.  It is not expected that the demographics of this indication would be 
substantially different from the ASPS data. 
The following data for 2019 were extracted from the ASPS website in August 2020 
(https://www.plasticsurgery.org/news/plastic-surgery-statistics): 
• 16.3 M cosmetic minimally invasive procedures, up 2% from previous year 
• 2.72 M procedures with any dermal filler, up 1% from previous year 
• 2.16 M procedures with HA, up 1% from previous year 
• 36% of all HA filler procedures were in patients ≥ 55 years old 
• 3% of all HA filler procedures were in males 
While data are not available from ASPS regarding race or ethnic-specific subgroups, data from 
various HA dermal fillers clinical trials indicate that the majority of subjects are Caucasian 
females.  Historically, approximately 20-25% of subjects enrolled in dermal filler studies have 
been Fitzpatrick skin types IV-VI (as per FDA requirements for minimum enrollment of darker 
skin type subjects in these studies). As such, the percentage of darker skin types treated in dermal 
filler studies is not necessarily representative of real world experience for patients seeking many 
dermal filler aesthetic procedures/indications. 
RHA4 dermal filler is a device containing colorless, biodegradable, sterile, biocompatible, 
crosslinked HA of non-animal origin (i.e., bacterial fermentation using Streptococcus 
zooepidemicus). Crosslinking is performed using 1,4-butanediol diglycidyl ether (BDDE) to form 
a gel. RHA4 contains 0.3% w/w of lidocaine hydrochloride, a drug substance widely used for its 
anesthetic properties (i.e., it blocks the origin and transmission of nervous influx at the point of 
injection by stabilizing the neuronal membrane).  

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RHA4 is intended for injection into the deep dermis to superficial subcutaneous tissue of the face 
to correct moderate to severe dynamic facial wrinkles and folds, such as NLFs. RHA4 has 
received PMA approval for this indication per P170002 in October 2017. 
1.2 
Rationale for Study 
While RHA4 (injected with a sharp needle) has been approved by the FDA for the treatment of 
NLFs, the use of a cannula for injecting RHA4 has not yet been approved by the FDA. 
In the current study, RHA4 injected with a sharp needle is being compared to RHA4 injected 
with a cannula in a non-inferiority pivotal study designed to support a PMA application (FDA) for 
using a cannula for the injection of RHA4. The clinical results using RHA®4 will also be 
applicable to approved products for the same indication: RHA®2 and RHA®3. Effectively RHA®4 
is representative and the worst case of the full range of products, RHA®2, RHA®3 and RHA®4 in 
terms of raw material and manufacturing processes, level of crosslinking, injection depth, pain at 
time of injection, needle and cannula dimensions and responder rates at the primary endpoint.  
1.3 
Hypothesis 
RHA®4 injected in NLFs with a cannula is non-inferior to RHA®4 injected in the NLFs with a 
sharp needle for the correction of moderate to severe NLFs as determined by the NLF-WSRS 
(validated NLF Wrinkle Severity Rating Scale) at 12 weeks from last treatment. 
A change from Baseline in the NLF-WSRS of ≥1-grade will be considered clinically meaningful, 
and the non-inferiority margin for change in NLF-WSRS will be 0.5 grade between needle and 
cannula. The formal hypothesis set to be tested is as follows: 
Ho:  µΔ(needle – cannula) > 0.5 
Ha:  µΔ(needle – cannula) < 0.5 
where µΔ(needle – cannula) represents the mean difference in change from Baseline between needle and 
cannula. 
 
 
 
 

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2 
STUDY OBJECTIVES 
The study is designed to achieve the following objectives: 
1. Demonstrate the non-inferiority of RHA®4 injected in the NLFs with a cannula versus the 
control (RHA®4 injected in NLF with a sharp needle) at 12 weeks from last treatment for the 
correction of moderate to severe NLFs. Assessment of non-inferiority will be based on the 
change from Baseline in NLF-WSRS at 12 weeks as rated by the Blinded Live Evaluator (BLE) 
at each investigative site. 
2. Evaluate the safety of RHA®4 injected in NLF with a cannula versus the control up to 12 weeks 
from last treatment. 

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3 
COMPLIANCE STATEMENT 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) and Good Clinical Practice (GCP), the Declaration of Helsinki, and the 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312). In addition, the study will be conducted 
in compliance with all applicable laws and regulatory requirements relevant to the use of new 
medical devices in the United States. 
The sites’ Principal Investigator (also referred to as the Treating Investigator [TI], both terms are 
used interchangeably) is responsible for ensuring the privacy, safety and welfare of the subjects 
during and after the study, and must ensure that personnel are trained and immediately available 
in case of a medical emergency. The TI must be familiar with the background and requirements of 
the study and with the properties of the study device as described in the Investigator’s Brochure 
and package inserts. The Principal Investigator at each site has the overall responsibility for the 
conduct and administration of the study at their site, and for contact with study site management, 
and local authorities. ethica CRO will facilitate and manage all interactions between the site and 
the IRB.  
3.1 
Variations to the Protocol 
No changes from the final approved (signed) protocol will be initiated without the prior approval 
of the FDA and the IRB except 1) when necessary to eliminate immediate hazards to the subjects 
or when the change involves only logistics or administration, or 2) minor administrative or 
typographical corrections. The sites’ Principal Investigators and the Sponsor must sign any 
protocol amendments. 
3.2 
Investigational Sites 
Three (3) to Four (4) U.S. investigational sites will participate in this study. Each site will obtain 
written approval from a Central IRB prior to recruitment and enrollment of any subject into the 
study. Any changes to the study procedures must be made with the mutual agreement of the 
Principal Investigator and the Sponsor, documented in an amendment to the protocol, and 
approved by the reviewing IRB.  
Each site will have one TI who will be responsible for administering all study treatments, assessing 
safety, and conducting subject assessments, and a BLE who will conduct live NLF-WSRS, 
symmetry and GAIS assessments at selected visits. TIs and BLEs will be specialists in the fields 
of cosmetic dermatology or plastic surgery and will have extensive experience with dermal fillers. 
The TI will function as the site’s Principal Investigator. Additionally, each site will have a study 
coordinator. 
If a site has 2 or more BLEs, the site will ensure that the same BLE performs assessments for a 
given subject. 
Each site will have identified a local eye specialist (i.e., ophthalmologist) who will examine 
subjects immediately in case of ophthalmic symptoms following any injection or during follow-
up visits. 
3.3 
Training and Certification on the NLF Wrinkle Severity Rating Scale (NLF-WSRS) 
The study will use a validated 5-grade photonumeric scale measuring the severity of NLFs. All 
assessors (i.e., TI and BLE) will be certified on the use of the NLF-WSRS. Specifically, all 

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assessors will be trained on the scale then tested using a photo booklet with a broad range of NLF 
severities. An assessor will be considered certified once his/her percentage of agreement with the 
true values is ≥80%. 
3.4 
Medical Monitor 
A Medical Monitor will provide safety oversight for this clinical study. The Medical Monitor, in 
consultation with the Sponsor’s team, will review and evaluate AEs/SAEs/UADEs/AESIs on a 
regular basis, review safety reports, and will provide consultation and recommendations with 
regard to inclusion/exclusion criteria, concomitant medications/treatments, and subject 
discontinuations. The Medical Monitor will follow the Safety Management Plan and report the 
trends of AEs, and address specifically SAE, UADE, AESI with the Sponsor. 
3.5 
Photography 
Set-up of photographic equipment, as well as training and quality control processes, will be 
provided and will be managed by a dedicated professional third party (i.e., Canfield Scientific 
Inc.). 

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4 
OVERVIEW OF STUDY DESIGN 
4.1 
Study Design 
This is a randomized, controlled, single-blinded, within-subject (split-face), multicenter, 
prospective study to investigate whether RHA®4 injected in NLFs with a cannula (25G x 2” long) 
is non-inferior to RHA®4 injected in NLFs with a sharp needle (27G x ½”) for the correction of 
moderate to severe NLFs as determined by the Blinded Live Evaluator (BLE) using the NLF-
WSRS (validated NLF Wrinkle Severity Rating Scale) at 12 weeks following last treatment (i.e., 
initial or touch-up). 
At screening, the Treating Investigator (TI) and Blinded Live Evaluator (BLE) will evaluate 
subjects’ NLF severity to confirm eligibility and to establish a pre-treatment score for assessing 
aesthetic improvement (i.e., moderate to severe bilateral nasolabial folds; grade 3 or 4 on the five-
point NLF-WSRS; symmetrical in terms of grade). BLE and TI must independently agree that the 
criterion is met; however, strict concordance of severity is not required. 
At Visit 1, RHA®4 injected with cannula will be administered in a random sequence (first or 
second injection) and side of the face (left or right NLF) and RHA®4 injected with a sharp needle 
will be administered to the other side. The TI will administer study devices and will be unblinded 
to treatment allocation. Blinded assessments of effectiveness will be conducted by the BLE 
(Blinded Live Evaluator). 
Subjects then attend Visit 2 (4 weeks following initial treatment) and will receive touch-up 
treatments (if necessary) using a needle or cannula as per the subject’s initial treatment assignment. 
Subjects receiving touch-up treatments at Visit 2 will attend Visit 2b (4 weeks following touch-up 
treatment); subjects not receiving touch-up treatment will not attend Visit 2b. 
Subjects will receive a safety follow-up call from the study site within 3-days of initial treatment, 
and if applicable, within 3 days of touch-up treatment. 
Before and 30 minutes after injection, as well as at each study visit, assessments of visual 
disturbances (i.e., Snellen visual acuity, confrontational visual field test, ocular motility) will be 
conducted. 
Subjects will then attend scheduled in-office study visits at 8 and 12 weeks following last treatment 
where safety and effectiveness assessments, including photography, AEs, visual assessments, 
device symmetry assessments, concomitant medications, NLF severity (NLF-WSRS), FACE-Q, 
GAIS and subject satisfaction, will be conducted. 
Subjects who present with an unresolved clinically significant device-related AE at the last study 
visit will attend an optional visit or phone-call follow-up (discretion of the TI) from the study staff 
within 4 weeks of last study visit. Follow-up of the clinically significant device-related AE will 
continue until the AE is resolved or the TI determines that additional follow-up is no longer 
necessary. 
4.2 
Study Design Rationale 
4.2.1 
Study Population 
At least 50 subjects will be enrolled and receive study treatment. The study population includes 
female and male subjects who are 22 years old. Additionally, enrolment will be comprised of at 
least 20% of subjects (i.e., 10 subjects) presenting with Fitzpatrick Skin Types IV-VI including at 
least 10% of subjects (i.e., 5 subjects) with Fitzpatrick Skin Type V and VI (at least two subjects 
of each Fitzpatrick Skin Type V and VI will be enrolled). See Section 5 for a full description of 

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the inclusion and exclusion criteria. 
4.2.2 
Primary Endpoint 
The primary effectiveness endpoint will be aesthetic improvement from pre-injection as assessed 
by the NLF-WSRS (BLE) at 12 weeks (V4) following last treatment (initial or touch-up). The 
primary hypothesis is that RHA®4 used in conjunction with cannula is non-inferior to RHA®4 with 
sharp needle. An NLF-WSRS change from Baseline of >1-grade will be considered clinically 
significant. A non-inferiority margin of 0.5 grade difference in change from Baseline between 
cannula and needle will be used to test the primary hypothesis.  
In order to confirm assay sensitivity at 12 weeks, the proportion of responders of ≥1-grade point 
on the NLF-WSRS at 12 weeks for the group injected with a needle (control) is required to be 
≥70% (when compared to pre-treatment).  

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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
1. Outpatient, male or female of any race, 22 years of age or older. 
2. Female subjects of childbearing potential must have a negative UPT at Visit 1 and practice a 
reliable method of contraception throughout the study. 
A female is considered of childbearing potential unless she is: 
- postmenopausal for at least 12 months prior to study treatment administration; 
- without a uterus and/or both ovaries; or 
- has been surgically sterile for at least 6 months prior to study treatment administration.  
Reliable methods of contraception are: 
- hormonal methods (contraceptive pill or implant) or intrauterine device in use >90 days prior to study 
treatment administration; 
- barrier methods such as diaphragm plus spermicide or condom plus spermicide in use at least 14 days 
prior to study treatment administration; or 
- vasectomized partner who has had a vasectomy at least 3 months prior to receiving treatment (or who 
has a confirmed ‘0’ sperm count).  
[Exception: Female subjects of childbearing potential who are not sexually active will not be required to practice 
a reliable method of contraception. These subjects may be enrolled at Investigator’s discretion if they are 
counseled to remain sexually inactive during the study or agree to use an approved method of contraception 
should they become sexually active and understand the possible risks in getting pregnant during the study.] 
3. Moderate to severe bilateral nasolabial folds (grade 3 or 4 on the five-point NLF-WSRS. BLE 
and TI must independently agree that the criterion is met; however, strict concordance of 
severity is not required. [NOTE: BLE assessments will be used for the primary endpoint. If TI 
and BLE do not agree on eligibility, or if their assessments differ by ≥2 grades, the subject will 
not be eligible, half-point grades will not be accepted] 
4. Nasolabial folds of the same NLF-WSRS grade on the left and right sides of the face. 
5. Willing to abstain from facial aesthetic procedures/therapies that could interfere with the study 
evaluations (e.g., other fillers, botulinum toxin injections, laser or chemical resurfacing, facial 
plastic surgery, etc.) for the duration of the study (see Section 7.5.1 for prohibited/restricted 
medication/procedures). 
6. Able to follow study instructions and complete all required visits. 
7. Sign the IRB-approved ICF, Photographic Release Form, the Authorization for Use and release 
of Health and Research Study Information (HIPAA) form, and if applicable the California 
Experimental Research Subject’s Bill of Rights prior to any study-related procedures being 
performed. 
5.2 
Exclusion Criteria 
1. Known hypersensitivity or previous allergic reaction to any component of the study devices. 
2. Use of a prohibited treatment/procedure within time periods defined in Section 7.5.1. 
3. Known sensitivity to local anesthetics of the amide type, history of multiple severe allergies, 
or history of anaphylactic shock. 
4. Known susceptibility to keloid formation, hypertrophic scarring or clinically significant skin 
pigmentation disorders (TI discretion). 

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5. Clinically significant active skin disease or infection in the NLF regions within 6 months prior 
to study entry (TI discretion). 
6. History of severe chronic systemic diseases, including but not limited to, poorly controlled 
diabetes mellitus (all types), congestive heart failure, severe liver disease, severe kidney 
disease, and others as judged by the TI. 
7. Abnormal visual tests (i.e., Snellen acuity test worse than 20/40 with corrections, if applicable), 
abnormal confrontational visual field test, and/or abnormal ocular motility test. 
8. History of active chronic debilitating systemic disease that, in the opinion of the investigator, 
would make the subject a poor candidate in the study. 
9. History of connective tissue disease. 
10. Malignancy (excluding non-melanoma skin cancer) within the past 5 years. 
11. History of skin cancer in the treatment area. 
12. Need for clinically significant (TI discretion) and continuous medical treatment within 2 weeks 
prior to Visit 1. 
13. History or presence of condition or feature that may confound the interpretation of the results 
in the NLF areas, for example, tattoo, significant facial hair, scar, prior surgery in the area, 
potential for active disease or infection flare up such as herpes simplex. 
14. Herpes simplex lesion flare-ups greater than 6 per year. 
15. Elective, clinically significant facial procedures that may confound the interpretation of the 
results in the NLF area (TI discretion), prior to study enrollment. 
16. Has received botulinum toxin injections in the face below the orbital rim including crow’s feet 
(note: frontalis and glabellar treatment is permitted) within 6 months before randomization. 
17. Subjects with known prolonged bleeding times because of disease or anticoagulant medication 
(including warfarin or low-dose aspirin). If on a drug or supplement that prolongs bleeding 
times (e.g., non-steroidal anti-inflammatory, anticoagulant, high-dose vitamin E, fish oil, 
corticosteroids), wait 7 days or until bleeding times return to normal before injecting. (Note: 
low dose 81mg/day ASA is permitted). 
18. Medical or psychiatric conditions that may increase the risk associated with study participation 
or may interfere with the interpretation of study results or compliance of the subject and, in the 
judgment of the Investigator, would make the subject inappropriate for entry into this study. 
19. Clinically significant alcohol or drug abuse, or history of poor cooperation or unreliability. 
20. Exposure to any other investigational drug/device within 90 days of entering the study or 
planning to participate in another investigation during the course of the study. 
21. Study staff or close relative to study staff (e.g., parents, children, siblings, or spouse). 

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6 
TREATMENT ALLOCATION, RANDOMIZATION AND BLINDING 
All subjects who are randomized will receive a 3-digit subject number, starting at 001. Subject 
numbers will be assigned in ascending order and will be coupled with the site identification number 
for unique identification of each subject. The subject number will be used to identify the subject 
throughout the study. Subjects withdrawn from the study will retain their subject number; new 
subjects will be allocated a new subject number. Screen Failures will be entered in the eCRF. 
Upon qualifying for treatment, subjects will be randomized for the side of the face and the order 
of injection of study devices (i.e., left or right / 1st or 2nd order). 
Subjects will be considered “enrolled” at the time of consent, and will be considered “enrolled and 
randomized” at the time of randomization. The required sample size is based on “enrolled and 
randomized” subjects. If an enrolled subject withdraws from the study prior to being randomized, 
he/she may be replaced. 
Due to the visual and sensory differences between the cannula and sharp needle, it is not feasible 
to mask the TI or the subject. However, the BLE will be blinded to the treatment allocation. 
Furthermore, to ensure that the BLE remains masked and that all assessors remain unbiased when 
making their assessments, the BLE, TI and subject will not be allowed to refer to each other’s 
efficacy assessments. All subjects will be instructed to not discuss their study treatment, AEs, or 
CTRs with the BLE. 
The TI with the support of its study staff will secure the treatment allocation and any other record 
of study treatment from potential discovery by the BLE. Any instance where the blind is opened 
to the BLE will be documented in writing. 
 
 
 

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7 
DEVICE APPLICATION 
7.1 
Study Devices 
RHA® 4: A sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel 
implant. It consists of crosslinked hyaluronic acid produced by fermentation of Streptococcus 
zooepidemicus, formulated to a concentration of 23 mg/g and 0.3% w/w lidocaine in a physiologic 
buffer. It is supplied in individual treatment syringes with 27G ½ inch disposable sterile needles. 
For additional information, please refer to TEO-RHA-2001 Investigator’s Brochure. 
Cannulas for Injection: The brand of cannula (i.e., Softfil, Dermasculpt, or TSK) used for 
injection is up to the discretion of the Treating Investigator (TI), providing the cannula is 
registered for use by the US FDA and that the cannula bore is 25G x 2” long.  
The cannulas will not be part of the RHA® 4 package and labeling. The cannulas will be provided 
to the TI separately and labelled for the clinical study purposes. The cannulas will be made 
available in their original packaging with a TEOXANE SA sticker on it, which will include the 
study reference. 
The cannulas will be used for RHA® 4 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 will be supplied sterile and together with the cannulas in 
their packaging. The choice of the brand of the cannula used for RHA® 4 administration is left to 
the TI’s discretion and the cannula selected will be recorded into the eCRF . 
7.2 
Injection of Study Devices 
At Visit 1, each randomized subject will receive injections of  RHA4 injected with cannula into 
the NLF of the left or right side of the face, and injections of the control device (i.e. RHA4 
injected with a sharp needle) into the contralateral NLF. 
At Visit 2, if deemed necessary by the TI, subjects will receive touch-up treatments at 4 weeks 
following the initial treatment. If both NLFs require touch-up, both will be treated. If only one 
NLF requires touch-up, only that one NLF will be treated. Touch-up will be injected with the same 
method as initial treatment assigned to the side of the treated NLF (needle or cannula). The type 
of cannula used for Visit 1 injections must be used for the Visit 2 touch-up injections. 
If a touch-up injection is not administered, the scheduling of subsequent study visits will be based 
on Visit 1 (i.e., from the last study treatment). If a touch-up injection is administered, the 
scheduling of subsequent study visits will be based on Visit 2. 
The subject will be instructed to avoid touching the treated area for 6 hours after treatment, after 
which the area can be washed gently with soap and water. Subjects should be advised not to wear 
make-up 12 hours after injection.  
7.2.1 
Injection Depth 
Study devices will be administered into the deep dermis to superficial subcutaneous tissue, at the 
discretion of the TI; however, the depth of injection will be the same on both sides. 
7.2.2 
Injection Technique 
The injection technique (e.g., linear threading (retrograde or anterograde), cross hatching, fan like 
administration, multiple puncture, etc.) will be at the discretion of the TI. Technique(s) used for 

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each side will be recorded in the eCRF. [NOTE: Cross hatching is a “needle only” injection 
technique]. 
Devices will be injected using the needle that is provided within the standard packaging of the 
device on the left or right side of the face. The TI is not permitted to use a needle of different 
gauge, length or brand. On the contralateral side, devices will be injected using a small cannula 
(25G x 2” long; Softfil, Dermasculpt, or TSK brand cannulas). 
7.2.3 
Supplementary Anesthesia 
RHA4 contains lidocaine. Additional anesthesia is prohibited (e.g., EMLA, dental blocks, ice, 
etc.). Ice may be used at the discretion of the TI for post-injection treatment for pain or discomfort, 
but only after all injection pain assessments for both sides of the face have been completed (i.e., at 
60 minutes post-injection). 
Use of ice will be recorded as a concomitant treatment on the Concomitant Treatment eCRF. 
7.2.4 
Visual Assessments 
The subject will undergo three visual assessment tests to detect rare and unintentional injection 
into a blood vessel. Subjects must be instructed to wear the same corrective eyewear (if applicable) 
at each visit. 
Each site will have identified a local eye specialist (i.e., ophthalmologist) who will examine 
subjects immediately in case of ophthalmic symptoms after an injection or during follow-up visits. 
The following assessments will be performed at each visit at the study site by the TI, or an 
appropriately trained study coordinator, nurse practitioner, or physician assistant: 
• Snellen visual acuity 
• Confrontational visual fields tests 
• Ocular motility 
These visual assessments will be performed: 
• Prior to initial treatment (to serve as Baseline) 
• 30 minutes post-injection  
• Visit 2 (before and 30 minutes after touch-up treatment if applicable) 
• Visits 2b, 3 and 4  
• Unscheduled visit  
Only subjects with vision acuity of 20/40 or better, and normal peripheral vision and ocular 
motility will be included. Should any of the vision assessments suddenly worsen after the injection 
of the filler, the TI must examine the subject to exclude vascular injection and contact an eye 
specialist if necessary.  
At any time during the study, if the vision assessments show a change from Baseline defined as 
either one of the following:  
• Snellen acuity test: any change of 1 line or more  
• Confrontational visual field test: change to peripheral vision  
• Ocular motility: change to ocular motility  

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The assessment will be considered abnormal (and clinically significant) and the subject will be 
evaluated by an eye specialist to evaluate if the result is related to a vascular injection of the dermal 
filler or not. 
If the referral to the eye specialist confirms that the subject had the filler injected into a blood 
vessel, the subject will be withdrawn and the need of stopping the study will be reviewed. 
7.2.5 
Injection Sequence 
Upon qualifying for treatment, subjects will be randomized for the side of the face and the order 
of injection using cannula or needle (i.e., left or right / 1st or 2nd order). 
The sequence of injections will be performed as follows: 
1. Inject right (or left) NLF then immediately commence pain assessments; 
2. Inject left (or right) NLF then immediately commence pain assessments. 
7.2.6 
Treatment Volume Allowance 
The maximum volume per administration of a study device into a single NLF is 3.0 mL (max 3.0 
mL for right side, and max 3.0 mL for left side) for a maximum volume of 6 mL per session. 
7.3 
Labeling, Packaging and Storage 
Supplies of RHA4 will be provided to the sites in bulk (i.e., individual kits per subject will not 
be provided). External packaging (carton) will be labeled with study information (i.e., study 
number, study Sponsor, name and address of TEOXANE, quantity, “CAUTION: Investigational 
device. Limited by US Federal law to investigational use”, etc.). There may be one or two blisters 
inside each carton. Each blister will contain one syringe and two needles. Each blister is unique to 
a subject and must not be used for more than one subject. The Tyvek lid on the blister will include:  
• Study number: TEO-RHA-2001 
• IDE number: e.g., G200323 
• Name and address of the Sponsor/Manufacturer (i.e., TEOXANE S.A.) 
• Quantity of syringes (n=1) 
• Quantity of 27G ½ inch needles (n=2) 
• Batch number and Manufacturing date 
• Expiry date 
• The CAUTION statement mentioned above 
The Investigator Brochure will provide all relevant contraindications, hazards, adverse effects, 
warnings and precautions. 
The study device is to be stored at room temperature (2C to 25C) in a secure restricted area. 
It is the responsibility of the TI to verify that a device is within its expiry date before being used. 
7.4 
Study Device Supply and Accountability 
The study Sponsor will ensure that participating sites are provided with a sufficient supply of study 
devices and cannulas for all treatments. It is forbidden to use a study device for purposes other 
than defined in this protocol. Syringes are single use and must not be shared between subjects. 
Study devices must be kept in a locked area with access restricted to designated study personnel. 
The Principal Investigator or designee will inventory and acknowledge receipt of all study device 
shipments, and ensure that the integrity of study devices is not jeopardized prior to use.  

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Accurate accountability records will be maintained that include batch numbers, quantities 
received/returned/destroyed, as well as dates and volumes administered, and the site monitor will 
be provided access to the study devices and records for periodic review. 
Unused syringes and cannulas will be returned to the Sponsor at the end of the study unless other 
arrangements are agreed upon in writing. Used syringes and cannulas will be destroyed as per 
each site’s standard procedures. 
7.4.1 
Other Study Supplies 
Supplies that are unique to the study will be provided by ethica CRO (e.g., UPTs, photographic 
equipment, source document worksheets, etc.). The site is responsible for routine supplies related 
to pre-/post-injection care (e.g., alcohol wipes, gauze, etc.). 
7.5 
Concomitant Medications and Procedures 
All treatment/procedures received by the subject within 30 days prior to the Baseline visit and 
throughout the treatment period, including the name of the treatment/procedure, must be recorded 
in the eCRF with end dates, if applicable. Use of prohibited treatment/procedures must be recorded 
in the eCRF up to the extent of the prohibited time period indicated above. Furthermore, previous 
use of facial aesthetic treatment/procedures must be recorded for up to 1 year prior to the Baseline 
visit. 
In the event such prohibited therapies are administered during the study period, the Medical 
Monitor will be contacted to discuss the details of the event. Subject participation will not 
automatically be discontinued. At a minimum, the event will be documented by the site staff as a 
protocol deviation, as instructed by the Medical Monitor. Depending upon the nature of the 
prohibited therapy and the timing relative to the determination of the primary endpoint, the 
Medical Monitor may make a decision to discontinue the subject. 
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. If the permissibility of a specific medication/treatment is 
in question, the Medical Monitor should be contacted before the prohibited medication/treatment 
is administered. 
7.5.1 
Prohibited Treatment and Procedures 
Subjects must not undergo any type of facial or cosmetic procedure below the orbital rim, including 
but not limited to dental, plastic or reconstructive surgery; non-ablative procedures; botulinum 
toxin injections; laser resurfacing; dermabrasion; lipo-injection; or chemical peel at any time 
during this study. Other necessary therapies that will not interfere with the response to treatment 
may be provided to the subject at the discretion of the TI. 
The following medications/procedures have either restrictions for usage, or are prohibited during 
the course of the study and appropriate washout periods noted below must be respected: 
Dermal fillers used below the orbital rim: 
• 
Bioresorbable fillers (e.g., HA, collagen, autologous fat, etc.) 
≥12 months 
• 
Permanent fillers (e.g., PMMA, polyacrylamide, silicon, etc.) or semi-
permanent fillers (e.g., polylactic acid, calcium hydroxylaptite, 
hydroxyethylmethacrylate, etc.). 
Any previous use prohibited 

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Procedures below the orbital rim (including crow’s feet): 
• 
Botulinum toxin injections  
• 
Clinically significant oral or maxillofacial surgery that may interfere with 
study 
assessments 
or 
procedures 
(e.g., 
craniofacial 
surgery, 
reconstructive therapy, implants, dentoalveolar surgery, etc.). 
≥6 months 
≥12 months 
Investigational drugs/devices: 
• 
Exposure to any other investigational drug/device 
≥90 days 
Other medications: 
• 
Exposure to a drug or supplement that prolongs bleeding times (e.g., non-
steroidal anti-inflammatory, anticoagulant, high-dose Vitamin E, St. 
John’s Wort, fish oil, corticosteroids) 
• 
Additional anesthesia during injections is prohibited (e.g., EMLA, dental 
blocks, ice, etc.). Ice may be used at the discretion of the TI for post-
injection treatment for pain or discomfort, but only after all injection pain 
assessments for both sides of the mouth have been completed (i.e., at 60 
minutes post-injection). 
≥7 days before treatment and 
≥7 days after treatment 
The subject will be instructed to avoid touching the treated area for 6 hours after treatment, after 
which the area can be washed gently with soap and water. Additionally, subjects should be advised 
to not use make-up below the infraorbital rim prior to study visits, or during the 12 hours following 
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.  

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8 
DATA COLLECTION 
8.1 
Electronic Case Report Form 
Treatment and follow-up of subjects will be recorded in a 21 CFR part 11 compliant eCRF. Data 
will be first recorded into the medical record and study specific source document worksheets prior 
to entry into the eCRF. The study coordinator will refer to these worksheets in conjunction with 
the medical record in order to complete data entry into the eCRF. 
In order to review and electronically sign the eCRF, the TI and BLE will each have an individual 
login password that will allow them to view only the data that they have generated. The TI and 
BLE must ensure that they electronically sign for completed eCRFs on a timely basis. 
8.2 
Subject Diaries and Questionnaires 
Subjects will record Common Treatment Responses (CTRs) for 4 weeks post-injection using 
electronic diaries. 
The electronic CTR diary will also record the occurrence of any visual 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, etc.). Subjects will be instructed to 
report immediately such events to the investigational site or to their health care practitioner. 
Subjects will complete paper-based questionnaires, and data recorded by the subjects will be 
entered in the eCRF by the study coordinator. 
If a subject is unable to complete an electronic CTR diary, a paper diary will be provided. 
8.3 
Photography 
Calibrated photographs will be taken at Visit 1 (pre- and post-injection) and at Visits 2 (pre- and 
post-injection if touch/up), 2b, 3, and 4, and at any unscheduled visits according to a standardized 
protocol incorporating appropriate quality control processes (i.e., Canfield Scientific Inc.).  
The photographs 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. 

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9 
STUDY EVALUATIONS 
9.1 
Informed Consent 
The TI (or designate) will explain the benefits and risks of study participation to each subject. 
Written informed consent must be obtained prior to any study related procedure. 
9.2 
Visit Procedures 
9.2.1 
Visit 1 (Screening / Enrolment / Treatment) 
Procedures that can be completed up to 14 days before V1 are indicated by “+” 
• Written informed consent+ 
• UPT (if female subject of childbearing potential) + 
• Inclusion / exclusion criteria+ 
• Medical history and demographics+ 
• Concomitant medications/treatments+ 
• Visual assessment by trained evaluator (pre-injection and 30 minutes post-injection) 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
• Randomization to study treatment (i.e., left side/right side; 1st/2nd order) 
• Photography (pre- and post-injection) 
• Injection of study devices 
• TI Assessments 
- 
NLF-WSRS (pre-injection) 
- 
Symmetry (pre-injection) 
• BLE Assessments 
- 
NLF-WSRS (pre-injection) 
- 
Symmetry (pre-injection) 
• Subject Assessments 
- 
Symmetry (pre-injection) 
- 
FACE-Q (pre-injection) 
- 
Injection site pain VAS (immediately after injection of each NLF and 5, 30 and 60 minutes post-
injection of each side) 
• CTR Diary  
- 
Train subject on proper use and completion  
- 
Train subject in recognizing potentially rare events of injection into the vascular system (as 
described in the CTR diary), and to contact their doctor immediately if an event is suspected 
• Adverse Event evaluation 
9.2.2 
Visit 1a Phone Follow-up (3 days post initial injection  1 day) 
• CTR diary review 
• Concomitant medications/treatments review 
• AE review 
9.2.3 
Visit 2 (4 weeks from V1; ±3 days) 
• Concomitant medications/treatments 
• Adverse Event evaluation (including CTR Diary review) 

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• Photography (if T/U, taken pre-treatment) 
• Visual assessment by trained evaluator (if T/U, done pre-treatment) 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
• TI Assessments 
- 
NLF-WSRS (if T/U, done pre-treatment) 
- 
GAIS (if T/U, done pre-treatment) 
- 
Symmetry (if T/U, done pre-treatment) 
• Subject Assessments 
- 
GAIS (if T/U, done pre-treatment) 
- 
Patient Satisfaction (if T/U, done pre-treatment) 
- 
Symmetry (if T/U, done pre-treatment) 
- 
FACE-Q (if T/U, done pre-treatment) 
• Touch-up Injections (TI discretion) 
- 
If T/U administered: 
▪ 
UPT (if female of childbearing potential) 
▪ 
Injection site pain VAS (immediately after injection of each NLF and 5, 30 and 60 minutes 
post-injection of each side) 
▪ 
Photography (post-injection) 
▪ 
Visual assessment by trained evaluator (30 minutes post-injections) 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
▪ 
CTR Diary 
- 
Train subject on proper use and completion 
- 
Train subject in recognizing potentially rare events of injection into the vascular system 
(as described in the CTR diary), and to contact their doctor immediately if an event is 
suspected 
▪ 
Subject attends phone follow-up and Visit 2b 
9.2.4 
Visit 2a Phone Follow-up Phone (3 Days post-T/U injection  1 day) 
• CTR diary review 
• Concomitant medications/treatments review 
• AE review 
9.2.5 
Visit 2b (4 weeks post-T/U; ±3 days) 
Visit only for subjects receiving T/U at V2 
• Concomitant medications/treatments 
• Adverse Event evaluation (including CTR Diary review) 
• Photography 
• Visual assessment by trained evaluator 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
• TI Assessments 
- 
NLF-WSRS 
- 
GAIS 
- 
Symmetry 
 

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• Subject Assessments 
- 
GAIS 
- 
Patient Satisfaction 
- 
Symmetry 
- 
FACE-Q 
9.2.6 
Visit 3 (8 weeks from last treatment; ±7 days) 
• Concomitant medications/treatments 
• Adverse Event evaluation 
• Photography  
• Visual assessment by trained evaluator 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
• TI Assessments 
- 
NLF-WSRS 
- 
GAIS 
- 
Symmetry 
• Subject Assessments 
- 
GAIS 
- 
Patient Satisfaction 
- 
Symmetry 
- 
FACE-Q 
9.2.7 
Visit 4 (12 weeks from last treatment; ±7 days) 
• Concomitant medications/treatments 
• Adverse Event evaluation 
• Photography  
• Visual assessment by trained evaluator 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
• TI Assessments 
- 
NLF-WSRS 
- 
GAIS 
- 
Symmetry 
• BLE Assessments 
- 
NLF-WSRS 
- 
GAIS 
- 
Symmetry 
• Subject Assessments 
- 
GAIS 
- 
Patient Satisfaction 
- 
Symmetry 
- 
FACE-Q 
• Study Exit 
- 
If a device related and  clinically significant AE(s) is ongoing at V4, TI determines if action should 
be taken and may schedule a clinic visit to verify resolution. 

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9.2.8 
Unscheduled Visit  
An unscheduled in-office or phone call visit may occur at any time during the study to assess 
adverse events, or to assess ongoing unresolved device-related adverse events after study exit. 
• Concomitant medications/treatments 
• AE Review 
• Photography  
• Symmetry (TI and Subject) 
• FACE-Q (subject) 
• Visual assessment by trained evaluator 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
9.3 
Efficacy 
9.3.1 
Aesthetic Effectiveness Evaluations 
9.3.1.1 
Nasolabial Fold Wrinkle Severity Rating Scale 
The NLF-WSRS will be assessed at rest by the TI and BLE using the validated 5-grade WSRS 
photo-numeric scale and text as detailed in Table 2 below: 
Table 2.  Nasolabial Fold Wrinkle Severity Rating Scale (NLF-WSRS) 
Category 
Grade 
Description 
Absent 
1 
No nasolabial fold – Continuous skin line 
Mild 
2 
Shallow, but visible fold – Slight indentation 
Moderate 
3 
Moderately deep nasolabial fold – Clear facial feature visible 
Severe 
4 
Very deep nasolabial fold – Prominent 3-dimensional feature 
Extreme 
5 
Extremely deep and long nasolabial fold – Skin redundancy 
Left and right sides assessed individually. To qualify for the study, subjects must have NLF-WSRS 
grades of 3 or 4 (at rest as determined by the TI and BLE; symmetrical in terms of grade). Half-
point grades will not be accepted. 
9.3.1.2 
Global Aesthetic Improvement Scale 
GAIS will be assessed by the TI, BLE and the subject using the Visit 1 pre-injection photograph 
and the subjective 5-grade scale as detailed in Table 3 below. Left side and right side will be 
assessed individually. Subjects will be instructed: “Compare your pre-injection photograph to the 
photograph provided to you and rate the degree of aesthetic improvement by using the following 
scale”. The TI and BLE will complete the assessment using the same pre-injection photograph 
(photograph will be labeled with “left side” and “right side"). 
Table 3.  Global Aesthetic Improvement Scale 
Grade 
Description 
1 
Much improved 
2 
Improved 
3 
No change 
4 
Worse 
5 
Much worse 

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9.3.1.3 
Patient Satisfaction 
Patient Satisfaction will be assessed by the subject using the following subjective 5-grade scale as 
detailed in Table 4 below. Left side and right side will be assessed individually. Subject will be 
instructed: “Rate your level of satisfaction with the effect of study treatment on your nasolabial 
folds by using the following scale”: 
Table 4.  Patient Satisfaction Scale 
Grade 
Description 
1 
Very satisfied 
2 
Satisfied 
3 
Neither satisfied nor dissatisfied 
4 
Dissatisfied 
5 
Very dissatisfied 
9.3.1.4 
Treatment Volume 
The total volume injected in each NLF to achieve OCR will be collected for each method of device 
injection (needle or cannula). Treatment volume will be measured to an accuracy of 0.1 mL. 
9.3.1.5 
Ease of Injection 
Ease of injection when using the cannula and the needle will be assessed by the TI after the initial 
injection as per the following: 
Score 
Description 
1 
Very difficult 
2 
Difficult 
3 
Neither difficult nor easy 
4 
Easy 
5 
Very Easy 
9.3.1.6 
Symmetry 
NLF symmetry will be assessed by the TI, BLE, and subject for right and left NLF by answering 
the question “Are the NLFs symmetric or asymmetric?” (answer = symmetric or asymmetric 
answer). If asymmetric, the asymmetry will be further assessed as mild, moderate or severe. 
9.3.1.7 
FACE-Q 
Subjects will complete the Nasolabial Fold domain of the FACE-Q, once for the left side NLF and 
once for the right side NLF. The subject will be instructed as follows: “These questions ask about 
how you look right now. For each question, circle only one answer. With your nasolabial folds in 
mind (the deep lines that run downward from the sides of your nose), in the past week, how much 
have you been bothered by:”, and will provide response as per Table 5 below: 
Table 5.  FACE-Q – NLF Domain 
Not at All 
A Little 
Moderately 
Extremely 
a.  How deep your nasolabial fold are? 
1 
2 
3 
4 
b. How your nasolabial folds look when your face is relaxed (still)? 
1 
2 
3 
4 
c.  How old your nasolabial folds make you look? 
1 
2 
3 
4 
d.  How your nasolabial folds look when you smile? 
1 
2 
3 
4 
e. How your nasolabial folds look compared with other people your age? 
1 
2 
3 
4 

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9.4 
Safety 
Safety will be evaluated through a 4-week patient Common Treatment Response (CTR) diary that 
captures post-injection signs/symptoms, measures of injection site pain and AE reporting based on 
phone follow-ups and clinic visits. Safety assessment will also include visual assessment tests 
performed at Visit 1 (before and 30 minutes post-injection, including referral to an eye specialist 
[i.e., ophthalmologist] if a visual disturbance is noted post injection), Visit 2 (before and 30 
minutes post-touch-up injection), and at Visits 2b, 3 and 4 (or unscheduled visit). 
9.4.1 
Patient Common Treatment Response Diary 
The study coordinator will provide subjects with instructions for daily recording of his/her 
observations of the CTRs of the study treatments into an electronic diary for the first 4 weeks after 
each treatment. The diary will be activated after treatment and will be discussed during the 3-day 
post-injection telephone follow-up. Subjects should complete the diary at approximately the same 
time each day (i.e., AM or PM).  
The subject diary will capture the following CTRs that typically occur following the injection of a 
dermal filler; specifically, redness, pain, tenderness, firmness, swelling, lumps/bumps, bruising, 
itching, discoloration, and “other”. The CTR diary will include a detailed glossary describing all 
signs/symptoms listed in the diary. Subjects will record the presence and the severity of each 
observed sign/symptom as: none, mild, moderate, or severe. 
In addition, the CTR diary will capture the occurrence of the following AEs*:  
• Visual Disturbance (loss of vision, blurriness, double vision, pain in or around the eye, 
blindness, blind spots, shadow in visual field, problems moving eyes) 
• Skin changing color around eyelids 
• Crusty or scabby skin around eyelids 
• Headache 
• Fever 
• Dizziness 
• Confusion 
• Weakness/numbness in arms or legs 
• Changes to consciousness or alertness 
• Difficulty speaking/speech impairment 
• Face droop 
• Changes to chewing and drinking 
• Chest discomfort with irregular heartbeat 
• Sensitivity to hot/cold liquids and foods 
* The CTR diary will instruct subjects as follows: “If you experience any of these events, contact 
your study doctor. If you are unable to reach the study doctor, immediately seek medical attention.” 
9.4.2 
3-Day Telephone Follow-up 
The subject will be contacted by telephone by the investigational site approximately 3 days 
following study injections and will be queried regarding health status and AEs. Information 
gathered will be documented in the progress notes and upon confirmation at the next clinic visit, 
data will be entered into the eCRF. The investigational site must attempt at least twice to contact 
the subject. All failed attempts will also be documented in the study notes. 

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9.4.3 
Vision Assessments 
Subjects will undergo three vision assessment tests to detect rare and unintentional injection into 
a blood vessel. The following assessments will be performed by the TI, or an appropriately trained 
study coordinator, nurse practitioner, or physician assistant: 
Snellen visual 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 one 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. 
Confrontational visual fields tests: If applicable, the TI or designee will ask the subject to remove 
his/her hat or anything that could interfere with their 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 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. 
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 
9.4.4 
Injection Site Pain 
Injection pain will be self-assessed by the subject using a Visual Analog Scale (VAS) Pain Scale 
Ruler (see figure 2 below). Each NLF will be assessed individually. The VAS Pain Scale Ruler 
has two sides. Using the side that shows faces and is labeled “Pain Assessment Tool”, subjects 
will move the slider to the location that represents their level of pain. The site will use the other 
side of the ruler to determine the VAS score (expressed in units of mm). 
Figure 2.  VAS Ruler 
 
Injection Site Pain during injection will be assessed immediately after each NLF injection and at 
5, 30 and 60 minutes post-injection of each side. The occurrence of injection site pain is not to be 
considered an AE unless it is in excess to that typically observed following injection of a dermal 
filler (as determined by the TI). 
 

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9.4.5 
Pregnancy and Contraception 
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 by using effective birth control methods (e.g., oral contraceptive, condom, IUD, 
injectable contraceptive, diaphragm or vasectomized partner). Male subjects have no contraceptive 
restrictions. 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. 
Pregnancies will be recorded using the Pregnancy Form and will not be considered as an AE.  
9.4.6 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship to 
the study device(s) will be recorded in the eCRF. Subjects will be questioned for the occurrence 
of any new or worsening signs or symptoms at each visit by the following methods: 
• Information volunteered by the subject 
• Open ended and non-leading questions such as: Have you had any health problems since 
your last visit? 
• Observation by the investigational team, other care providers or relatives 
9.4.6.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject administered the study device and which 
may, but does not necessarily, have a causal relationship with the device. An AE can therefore be 
any unfavorable or unintended sign (for example an abnormal laboratory finding), symptom or 
disease temporally associated with the use the study device, whether or not considered related to 
that device. 
AEs may include, but are not limited to, subjective or objective symptoms spontaneously offered 
by the subject, solicited via the diary and subject interviews, uncovered by review of concomitant 
medications or therapies, and/or observed by the study site staff. The TI will determine the 
description (sign, symptom, or diagnosis), onset, resolution, seriousness, severity, cause and action 
taken for any event.  
CTRs will not be considered AEs unless the duration and/or severity exceed what is typically 
observed following injection of a dermal filler, and are clinically significant as determined by the 
TI. CTRs will be reviewed by TI to ensure that CTRs are elevated to the status of an AE as 
appropriate, and will determine AE severity and the relationship to the study devices. CTRs that 
are present on day 28 of the diary (or on the last recorded day of the diary) will by default be 
elevated to the status of an AE, regardless of TI assessment. 
If a subject completes ≥75% of the diary (i.e., ≥21 days) the diary will be processed as if it were 
fully completed and a CTR recorded on the last day of the diary will be considered as an AE. 
However, if a subject completes 20 days of the diary or less, the consideration whether any CTR 

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presents at the last recorded day of the diary is to be elevated to an AE will be as per the judgement 
of the TI. 
Disease signs and symptoms that existed prior to the study injections are not considered AEs. 
Recurring symptoms associated with pre-existing conditions are not considered AEs unless they 
have a clinically significant increase in severity and/or frequency, as determined by the TI. 
Clinically significant abnormal laboratory tests (if applicable) must be recorded as an AE. 
Changes resulting from normal growth and/or development occurring at a physiologically 
appropriate time that do not vary significantly from the frequency or severity expected, for 
example, the onset of menses or menopause, are not to be considered AEs. 
9.4.7 
Adverse Events of Special Interest (AESI) 
AESI are defined as any new visual 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. 
9.4.8 
Vascular Occlusion Adverse Events  
When vascular occlusion involves vessels of the eye, the event should be handled as a medical 
emergency. The injection should be stopped at once and the patient should be transferred to a 
previously identified eye specialist (i.e., ophthalmologist).  
Symptoms may include unilateral vision loss, ocular pain, headache, nausea/vomiting, lack of 
extraocular movement, ptosis, and exotropia (one or both eyes deviate outward).  
Treatment varies from observation to digital massage, intraocular pressure-lowering agents such 
as acetazolamide and mannitol, IV methylprednisolone, oral corticosteroids, oxygen and carbon 
dioxide therapy, antibiotics, mechanical and chemical thrombolysis, anterior chamber 
paracentesis, or anticoagulants. 
9.4.9 
Serious Adverse Events (SAEs) and Unexpected Adverse Device Effects (UADEs) 
A SAE is defined as any unfavorable medical occurrence that meets any of the following:  
1. Results in death. 
2. Is life-threatening: “Life-threatening” refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event, which hypothetically might have 
caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization: Planned and 
routine hospital admissions for pre-existing conditions are not considered SAEs and do not 
require reporting as an AE unless the condition has worsened beyond what would reasonably 
be expected for that subject. If a subject experiences an additional AE that prolongs a pre-
planned hospitalization this is considered to be an SAE and should be reported as an SAE. 
Pre-planned admissions must be recorded in the subject’s source documentation.  
4. Results in persistent or significant disability/incapacity. 
5. Is a congenital anomaly or birth defect resulting from a pregnancy that occurred during the 
study. 

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6. Is an important medical event: Important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above should usually be considered 
serious. 
A UADE is defined as any device-related AE that meets any of the following: 
1. Is not identified in nature, severity or frequency in current literature on the product. 
2. Is life threatening, even if temporary in nature. 
3. Results in permanent impairment of a body function or permanent damage to a body structure. 
4. Necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure. 
5. Any device malfunction that would be likely to cause or contribute to a death or serious injury 
if the malfunction were to recur. 
9.4.10 
Causality Assessment 
The TI’s assessment of an AE’s relationship to the study device is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event will be reported. The TI will assign 
the causality assessment according to his/her clinical experience and the subject’s description of 
the event. The Sponsor will be responsible for the final causality judgment. The causal relationship 
should be classified according to the following criteria (not all variables need to be present to be 
indicative of relationship to the device): 
Definitely related: 
• The temporal sequence of AE onset relative to injection of study device is reasonable. 
• The AE is more likely explained by the study device or procedure than by another cause. 
• The AE shows a pattern consistent with previous knowledge of the study device. 
Probably related: 
• The temporal sequence of AE onset relative to injection of study device is reasonable. 
• The AE is more likely explained by the study device or procedure than by another cause. 
Possibly related: 
• The temporal sequence of AE onset relative to injection of study device is reasonable. 
• The AE could have been due to another equally likely cause. 
Probably not related: 
• There is another more likely cause of the AE. 
Definitely not related: 
• The temporal sequence of AE onset relative to injection of study device is not reasonable. 
• There is another obvious cause of the AE. 

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9.4.11 
Severity Assessment 
For events reported on the AE eCRF, the TI will determine the severity classification based on 
his/her clinical experience and by using the following definitions of severity (note: a “severe” AE 
is not the same as a SAE): 
• Mild: Symptoms are barely noticeable or do not make the subject uncomfortable. The AE 
does not influence performance or functioning. Prescription drugs are not ordinarily needed 
for relief of symptom(s). 
• Moderate: Symptoms are of sufficient severity to make the subject uncomfortable. 
Performance of daily activities is influenced. Treatment of symptom(s) with prescription 
drugs or therapies may be needed. 
• Severe: Symptoms are of sufficient severity to cause the subject severe discomfort. 
Performance of daily activities is compromised. Treatment for symptom(s) with prescription 
drugs or therapies may be needed. 
The maximal severity for the AE will be recorded, even if the AE presented as being less severe 
at some point during the event.  
9.4.12 
Device Malfunction 
Device malfunction is a failure of the device to perform in accordance with its intended purpose 
when used in accordance with the IFU/IB or protocol. A device malfunction may or may not be 
associated with an AE. If it is, the AE or UADE should be reported separately. 
For any event involving suspicion of device malfunction, the sponsor request that the TI return the 
study or the control device (when possible) for further evaluation. 
9.4.13 
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 any of the following events: 
• SAEs, including death reports and UADEs, AESIs – using the SAE/UADE/AESI Report 
form 
• Device malfunctions – using the Device Malfunction Report Form 
• Pregnancies– using the Pregnancy 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 by e-mail to: medical@teoxane.com 
9.4.13.1 All Adverse Events 
All AEs, whether serious or not, will be recorded from the time of informed consent until the last 
study visit, or until 30 days following the last study treatment. The TI will assess all AEs and 

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record details of seriousness, severity, duration, and action taken with study device, and 
relationship to the study device. 
If an AE occurs, the first concern will be the safety of the study participants. All Device Related 
AEs occurring after study device administration will be followed until the event has resolved or 
stabilized or until follow-up is no longer possible or the TI deems it unnecessary. 
The Sponsor is responsible for reporting AEs to the relevant governing authorities in the time 
frame applicable according to international and local law. 
9.4.13.2 Serious Adverse Events (SAEs) and Unexpected Adverse Device Effects (UADEs) 
All SAEs and UADEs that occur after the time of informed consent through 7 days after subject 
completion of the study, or within 4 weeks following the last study treatment, must be reported to 
TEOXANE within 24 hours of awareness. Initial reports must be made by contacting TEOXANE 
as per the following: Complete the SAE/UADE/AESI Report Form and submit by email to 
medical@teoxane.com. It is the site’s responsibility to perform the following: 
• Obtain and maintain all pertinent medical records, information, and medical judgments from 
colleagues who assisted in the treatment and follow-up of the subject. 
• Provide TEOXANE with a complete, written case history, including copies of supporting 
reports (e.g., progress notes, laboratory reports) and a statement as to whether the event was 
or was not related to the use of the study device. 
• With the assistance of ethica CRO, notify the governing IRB of the SAE or UADE in 
accordance with the requirements of SAE reporting stipulated by the governing IRB. 
Serious Adverse Event Reporting 
The TI will report SAEs on the (S)AE report form within 24 hours of awareness and complete the 
eCRF within 48 hours of awareness. TEOXANE will handle the SAE report according to the 
process described in the SMMP. 
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor or designee 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. 
Should the SAE fulfill the criteria of an MDR reportable event (for RHA®4 injected with the needle 
only as it is FDA approved), TEOXANE will provide further information to the TI within 7 
working days of receipt of the SAE report form to allow the TI to report the event to the reviewing 
IRB as applicable. 
Unanticipated Adverse Device Effect Reporting 
The TI will report UADEs on the SAE/UADE report form within 24 hours of awareness and 
complete the eCRF within 48 hours of awareness. 
TEOXANE will handle the UADE report according to the process described in the SMMP, 
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 will provide further information to the TI within 

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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. 
Study Hold Due to UADEs 
If the Medical Monitor determines that an UADE(s) presents an unreasonable risk to subjects, the 
Sponsor shall put on hold all investigation or parts of investigations presenting that risk as soon as 
possible. The study hold shall occur no later than 5 working days after the Sponsor makes this 
determination and not later than 15 working days after the Sponsor first received notice of the 
effect. The Sponsor will not resume an on hold investigation without IRB and FDA approval. 
9.4.13.3 Adverse Events of Special Interest (AESI) Reporting 
All AESIs 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 will handle the AESI 
report according to the process described in the SMMP. 
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 and the study medical monitor. Follow-up actions will be 
decided on case-by-case basis and documented. 
TEOXANE will handle the AESI report according to the process described in the SMMP, 
including evaluation of the AESI and reporting of the AESI to the FDA, all reviewing IRBs, and 
participating TIs within 10 working days of awareness. 
As the AESI are considered as reportable event to the FDA, TEOXANE will provide further 
information to the TI within 7 working days of receipt of the AESI report form to allow the TI to 
report the event to the reviewing IRB as applicable.  
9.4.13.4 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 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 
the eCRF within 7 calendar days of awareness. 
TEOXANE will handle the device malfunction report according to process described in the 
SMMP. 
Should the malfunction fulfill the criteria of a reportable event, TEOXANE will provide further 
information to the TI within 7 working days of receipt of the device malfunction report form to 
allow the TI to report it to the reviewing IRB as applicable. 
9.4.14 
MDR Reportable Events 
MDR reportable events are events that reasonably suggest that a marketed device (RHA®4 injected 

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with a needle) may have caused or contributed to a death or serious injury, or has malfunctioned 
and the malfunction of the device or a similar device that they market would be likely to cause or 
contribute to a death or serious injury if the malfunction were to recur. The Sponsor will review 
all reported SAEs, UADEs and AESIs in order to determine if they are MDR reportable events. 
Upon Sponsor confirmation that an MDR reportable event has occurred, the Sponsor will report 
the event to the FDA as per 21 CFR 803.10, 21 CFR 803.50, and/or 21 CFR 803.53. 
9.4.14.1 Pregnancy 
The TI must report pregnancy to TEOXANE within 48 hours of learning of it using the specific 
pregnancy 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 postpartum 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 28 calendar days 
after the initial notification and approximately 28 calendar days postpartum. 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 postpartum follow-up is expected, the TI will notify 
TEOXANE 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). 

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10 SUBJECT COMPLETION / WITHDRAWAL / STOPPING RULES 
10.1 
Completion 
A subject will be considered to have completed the study if he or she has completed all the 
assessments or has experienced an event that precludes further participation in the study. 
10.2 
Withdrawal 
A subject will be withdrawn from the study for any of the following reasons: 
- Lost to follow-up; 
- Withdrawal of consent; 
- The Principal Investigator believes that for safety reasons (e.g., AE, concurrent illness) that 
it is in the best interests of the subject to be withdrawn from study participation; 
- The subject’s attending physician requests that the subject be withdrawn from the study; 
- The Principal Investigator or the Sponsor, for any reason, stops the study or stops the 
subject’s participation in the study. 
Protocol deviations will not lead to automatic withdrawal unless they indicate a significant risk to 
the subject’s safety. All major protocol deviations must be discussed promptly with the Medical 
Monitor. 
A subject may be withdrawn from the study, in consultation with the Medical Monitor, for any of 
the following reasons: 
- Lack of compliance to study procedures; 
- A major protocol deviation or violation; 
- Poor visit attendance. 
Should a subject decide to withdraw after administration of a study device(s), or should the 
Principal Investigator decide to withdraw the subject, the Principal Investigator (or designate) will 
complete and report the observations up to the time of withdrawal. 
All subjects who are withdrawn from the study will be requested to come in to complete their next 
scheduled clinic visit. The next scheduled visit may be brought forward to facilitate this. A 
complete evaluation at the time of the subject’s withdrawal should be made. Additionally, subjects 
who withdraw from the study will be requested to allow continued safety monitoring, either via 
telephone interviews or clinic visits, whichever is more appropriate. 
The reason and date of withdrawal must be noted on the eCRF. If the reason for withdrawal is an 
AE or an abnormal laboratory test result, monitoring will continue until resolution or until an 
appropriate medical judgment concerning the cause or importance has been made. The specific 
event or test result(s) must be recorded on the eCRF. 
10.3 
Stopping Rules 
In the case of the following SAE occurring, patient enrollment and treatment of subjects at that 
site will be suspended until a root-cause investigation (including the Medical Monitor 
consultation), is performed: 
• Anaphylactic reactions or severe allergic reactions 
• Vascular embolic event leading to skin necrosis 

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• Change in vision due to injection of the filler into a blood vessel (as defined in the AESI 
section), if confirmed and judged clinically significant by the eye specialist (i.e., 
ophthalmologist) 
• Stroke 
• Cerebral ischemia or cerebral hemorrhage leading to stroke, skin necrosis, and damage to 
underlying facial structures 
Administration of hyaluronidase should be considered for any device related SAE(s) reported and 
should be recorded on the eCRF of the subject as concomitant treatment. 
If the cause of the event was anticipated (e.g., the Investigator did not properly follow the study 
protocol), the study site may resume after appropriate corrective actions have been successfully 
implemented (e.g., retraining of the TI or change of the TI). 
If the cause of the event was unanticipated (UADE), the TI will follow the procedure as noted in 
Section 9.4.13.2. The entire study must be immediately suspended, and subject enrolment and/or 
treatment will be stopped. The study enrolment will remain on-hold until the event can be properly 
characterized and an appropriate treatment strategy to avoid this unanticipated event be devised. 
The subjects already enrolled will continue to be followed for safety and efficacy assessments. 
The study may resume if the underlying problem can be addressed and the safety of subjects can 
be ensured. The IRB(s) will be notified if the study is stopped, and permission to resume the study 
will be obtained from the FDA and IRB prior to restarting as described in Section 9.4.13.2. 
 

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11 STATISTICAL METHODS 
11.1 
Primary Endpoint 
The primary effectiveness endpoint will be aesthetic improvement from pre-injection as assessed 
by the NLF-WSRS (BLE) at 12 weeks (V4) following last treatment. The effectiveness of RHA®4 
will be demonstrated if RHA®4 used in conjunction with cannula is statistically non-inferior to 
RHA®4 with sharp needle as assessed by the BLE at 12 weeks after the last treatment. 
In order to confirm assay sensitivity at 12 weeks, the proportion of responders of ≥1-grade point 
on the NLF-WSRS at 12 weeks for the group injected with a needle (control) is required to be 
≥70% (when compared to pre-treatment).  
11.2 
Secondary Endpoints 
The following secondary effectiveness endpoints will be explored: 
1) NLF-WSRS (BLE) responders (change from Baseline of ≥1-grade) at 12 weeks following last 
treatment. 
2) NLF-WSRS (TI) change from Baseline at 4, 8 and 12 weeks following last treatment. 
3) NLF-WSRS (TI) responders at 4, 8 and 12 weeks following last treatment. 
4) GAIS (BLE) “improved” or “much improved” at 12 weeks following last treatment.  
5) GAIS (TI) “improved” or “much improved” at 4, 8 and 12 weeks following last treatment.  
6) GAIS (Subject) “improved” or “much improved” at 4, 8 and 12 weeks following last treatment 
7) Satisfaction (Subject) of “satisfied” or “very satisfied” at 4, 8 and 12 weeks 
8) FACE-Q (Subject) change from Baseline at 4, 8 and 12 weeks following last treatment 
9) Symmetry (BLE) at Baseline and 12 weeks following last treatment 
10) Symmetry (TI) at Baseline and 4, 8 and 12 weeks following last treatment 
11) Symmetry (Subject) at Baseline and 4, 8 and 12 weeks following last treatment.  
12) Number of treatment sessions to obtain optimal cosmetic result. 
13) Treatment volume to obtain optimal cosmetic result. 
14) Ease of injection (initial injection). 
11.3 
Safety Endpoints 
The following safety endpoints will be explored: 
1) AEs across the duration of the study (incidence, intensity, and duration). 
2) AEs of Special Interest (AESI) across the duration of the study (i.e., visual disturbances such 
as loss of vision, blurriness, double vision, pain in or around the eyes, blindness, blind spot or 
shadow in the visual field, trouble moving eyes, ocular hypotonia, ptosis, etc.). 
3) Post-injection Common Treatment Response (4-week CTR diary; incidence, intensity, and 
duration). 
4) Visual assessments (Snellen visual acuity, confrontational visual field test, ocular motility) at 
Visit 1 (pre- and post-injection), Visit 2 (pre- and post-injection [if Touch-Up]) as well as at 
all other follow-up visits. 
5) Injection Site pain immediately after treatment, and at 5, 30, and 60 minutes post-treatment. 

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11.4 
Analysis Populations 
Three subject analysis populations are defined: Intent-to-Treat (ITT) Population, Per Protocol (PP) 
Population, and Safety (SAFT) Population. All analysis populations will be defined and 
determined prior to database closure and unblinding for the final analysis.  
11.4.1 
Intent-to-Treat (ITT) Population 
The ITT Population will consist of all subjects who were randomized. The ITT principle will be 
followed in that subjects will be analyzed according to the treatment assigned as per the 
randomization schedule. Furthermore, all subjects in the ITT Population will be included in the 
analysis, regardless of availability of data at the time point of interest. The ITT Population will be 
the primary population used for effectiveness analyses of secondary efficacy endpoints. 
11.4.2 
Per Protocol (PP) Population 
The PP Population will consist of all study subjects who 1) met all inclusion/exclusion criteria, 2) 
successfully completed the study and 3) experienced no major protocol violations/deviations that 
could affect efficacy assessments. The decision whether a protocol violation/deviation is relevant 
for the exclusion of subjects from the PP Population will be made in a data review meeting prior 
to breaking the study blind. The PP Population will be the primary population used for 
effectiveness analyses of the primary efficacy endpoint. Major protocol deviations that will result 
in a subject being excluded from the PP population are as follows: 
a) Failure to meet all inclusion and exclusion criteria as defined in the study protocol; 
b) Missing NLF-WSRS score (BLE) at Visit 1; 
c) Missing NLF-WSRS (BLE) at Visit 4 (Week 12); 
d) Visit 4 (Week 12) occurring outside a window of 84±14 days* from the last study treatment 
(i.e., Visit 1 or Visit 2); 
e) Study treatment not received at Visit 1; 
f) Missed Visit 2 (i.e., no opportunity for the subject to receive touch-up treatment); 
g) Study device injection volume that exceeds 6.0 mL per injection session (right NLF + left 
NLF), 3.0 mL right side, or 3.0 mL left side. 
* The study protocol stipulated a window of 84±7 days; however, to be considered a major protocol deviation that 
affects the PP population, the visit must occur outside a window of ±14 days. 
11.4.3 
Safety (SAFT) Population 
The SAFT Population will consist of all study subjects who were randomized and received 
treatment with the study device. The SAFT Population will be the primary population used for 
effectiveness analyses of the safety outcomes. 
11.5 
Sample Size Considerations 
In a previous NLF split-face study that compared RHA®4 and Perlane-L® (NCT02253147) in 120 
subjects, and that used the same validated NLF-WSRS Scale as being utilized in the current study, 
the mean (SD) change from Baseline in NLF-WSRS score at 24-weeks post-treatment (BLE 
assessment) was -1.34 (0.57) for RHA®4  and -1.16 (0.62) for Perlane-L®. The mean difference 
(RHA®4 minus Perlane-L®) in change from Baseline in NLF-WSRS scoring at 24-weeks post-
treatment was -0.18 with a 95% CI of -0.29 to -0.07; from this, we can estimate that the SD of the 
difference was 0.61. 

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While it can be assumed that these data from NCT02253147 can be applied for NLF-WSRS 
assessments (BLE) at 12-weeks in the current study, to conservatively accommodate the difference 
in observation periods, the SD of the difference will be set to 0.75. 
Assuming a mean difference of 0 between RHA®4 (Cannula) and RHA®4 (Needle), and assuming 
a SD of 0.75, non-inferiority for each device tested using a bilateral 97.5% CI and a non-inferiority 
upper bound of 0.5, a sample size of 38 subjects for each treatment group is required for 80% 
power to detect non-inferiority for RHA®4. As this is a split-face study, 38 subjects will provide a 
sample size of n=38 for each treatment group. 
Assuming a 20% drop-out rate, a minimum of 50 subjects (38 / 0.8 = 47.5) will be required. 
11.6 
General Considerations 
Data will be listed by treatment group and subject number. Safety and efficacy data will be 
summarized by treatment group. Descriptive statistics will consist of mean, standard deviation, 
minimum/maximum for continuous variables, and frequency and percent for discrete variables. 
A full description of the statistical methods planned for this study will be provided in the Statistical 
Analysis Plan (SAP). The SAP will be finalized and approved by the study Sponsor prior to the 
last subject’s last visit. All programs for data output and analyses will be written in SAS version 
9.4 or higher (SAS Institute, Inc., Cary, NC). 
Missing Values 
There will be no missing values for the primary effectiveness endpoint analysis as the PP 
population will be employed. For the ITT analysis of the primary effectiveness endpoint, multiple 
imputation will be used for missing observations. Specifically, missing change from baseline in 
NLF-WSRS at 12 weeks will be imputed using the regression method with treatment group as the 
independent variable and with age and NLF-WSRS at earlier timepoints as covariates. Number of 
imputations will equal the percentage of subjects with missing data, rounded up to an integer. 
Results will be combined using the Rubin method (Rubin DB. Multiple Imputation for 
Nonresponse in Surveys. New York: John Wiley & Sons, 1987). 
No imputation will be performed for secondary effectiveness endpoints or safety outcomes; 
analyses will utilize available data as observed. 
Discontinuation and Drop-Outs 
Dropouts will not be replaced. All available data from dropouts will be included in analyses using 
the ITT population. Subject disposition will summarize the number of subjects enrolled in the 
study, subjects who discontinued from the study and reasons for discontinuation. 
Interim Analysis 
There will be no interim effectiveness analysis. 
Poolability of Investigative Sites: To assess site poolability for the test of the primary null 
hypothesis that the mean difference in NLF-WSRS change from baseline between needle and 
cannula is 0, “difference” will be analyzed as the dependent variable in an ANOVA with “site” as 
the categorical independent variable. If “site” is not significant at the 0.20 level, a paired t-test (or 
Wilcoxon signed rank test) will be used to test the null hypothesis. If “site” is significant at the 
0.20 level, a random effects general linear model will be used, with “site” as a random effect and 
no fixed effects; in this model, the test of the intercept is the test of the null hypothesis. 

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Impact of COVID-19 
Any material disruption to the study due to COVID-19 will be addressed, as appropriate, in post-
hoc sentivity anslyses. 
11.7 
Effectiveness Analysis 
11.7.1 
Primary Endpoint 
The primary endpoint of NLF-WSRS change from Baseline at 12 weeks as rated by the BLE will 
be analyzed in a non-inferiority statistical model using the PP population with a 0.5 margin for the 
difference between cannula and needle. A sensitivity analsyis will be done using the ITT 
population. Expressing the difference between treatment groups as the mean of change from 
Baseline in RHA®4 injected with needle minus change from Baseline in RHA®4 injected with 
cannula, the one-sided 97.5% confidence limit must be < 0.5 to conclude non-inferiority. A paired 
t-test will be used to calculate the confidence interval to account for dependence. The formal 
hypothesis set to be tested is: 
Ho:  µΔ(needle – cannula) > 0.5 
Ha:  µΔ(needle – cannula) < 0.5 
where µΔ(needle – cannula) represents the mean difference in change from Baseline between needle and 
cannula. 
In order to confirm assay sensitivity at 12 weeks, the proportion of responders of ≥1-grade point 
on the NLF-WSRS at 12 weeks for the group injected with a needle (control) is required to be 
≥70% (when compared to pre-treatment). 
Based on past experience, change from Baseline is expected to be normally distributed. However, 
if the normality assumption for the paired t-test is not met based on the Shapiro-Wilk test, a 
normalizing data transformation will be applied and confidence intervals will then be back-
transformed to assess non-inferiority. 
11.7.2 
Secondary Endpoints 
All statistical inference tests will be performed at the same significance level (α) of 0.05. For 
categorical and continuous variables, the two groups will be compared using two-sided parametric 
or non-parametric tests for paired data, as appropriate. For continuous variables, the Shapiro-Wilk 
test will be used to assess normality. If data appear normally distributed, testing will be conducted 
using the Student t-test, while testing will be conducted with the Wilcoxon signed-rank test if not 
normally distributed. 
11.8 
Safety Analysis 
The SAFT Population will be used to summarize the safety of the study devices and will consist 
of all treated subjects. The primary safety analysis is the calculation of the incidence of CTRs and 
adverse events in the study period. Point estimates for all CTRs, AEs and SAEs will be presented 
and two-sided exact 95% confidence intervals will be calculated for the overall incidence of AEs 
and SAEs. Tables will be generated which summarize AEs by investigator assessments of both 
relationship to treatment and severity. 
11.8.1 
Adverse Events (AEs) 
Safety outcomes will be incidence rate of AEs, including UADEs, types of AEs and their severity 
and relationship to study treatment. 

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AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
These events, irrespective of relationship to study medication, will be summarized by MedDRA 
system organ class (SOC) and MedDRA preferred term (PT). The number of subjects reporting an 
AE, the number of AEs, and percentages of subjects in each category will be summarized. AEs by 
severity and relationship to study will be summarized in a similar way. Serious AEs will be 
summarized separately. Specifically, the following AE incidence tables will be provided: 
• All and possibly* related AEs sorted by SOC 
• All and possibly* related AEs sorted by decreasing frequency 
• SAEs: All and possibly* related SAEs sorted by seriousness criterion 
• SAEs: All and possibly* related SAEs sorted by SOC 
• UADEs: All and possibly* related UADEs sorted by SOC 
• Death: All and possibly* related deaths sorted by SOC 
* definitely probably, possibly 
Incidence rates with two-sided exact 95% confidence intervals will be calculated for the overall 
incidence of AEs and SAEs 
Statistical analysis will also be performed to evaluate the potential impact of the injection 
technique on the AE incidence rates. 
11.8.2 
Injection Site Pain 
Injection site pain, as measured using a 100 mm VAS, at each post-treatment time point (i.e., 
immediately after injection and 5, 30 and 60 minutes) will be summarized using descriptive 
statistics (mean, standard deviation, minimum and maximum). 
 

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12 ETHICAL ASPECTS 
12.1 
Informed Consent 
This study will be conducted in compliance with 21 CFR Part 50 for informed consent. Written 
informed consent will be obtained from each subject before any procedures or assessments are 
done and after the aims, methods, anticipated benefits, and potential hazards are explained. It will 
also be explained to the subject that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment. 
Written and/or oral information about the study in a language understandable by the subject will 
be given to all subjects. The information provided must include an adequate explanation of the 
aims, methods, anticipated benefits, potential hazards, compensation and/or honoraria, and 
insurance arrangements in force. 
The subject’s willingness to participate in the study will be documented in writing on a consent 
form, which will be signed by the subject with the date and time of that signature indicated. The 
site will keep the original consent forms and copies will be given to the subjects. 
See also Section 9.1.  
12.2 
Health Authorities and IRBs 
The Principal Investigator will ensure that the conduct of the study conforms to the Declaration of 
Helsinki, the Belmont Report, and with national laws and regulations for clinical research.  
Before starting this study, the protocol will be submitted to the FDA and central IRB for evaluation. 
As required, the study will not start before the IRB and the FDA give approval. 
12.3 
Confidentiality Regarding Study Subjects 
The Principal Investigator must assure that the privacy of the subjects, including their personal 
identity and all personal medical information, will be maintained at all times. In eCRFs and other 
documents submitted to the Sponsor, subjects will not be identified by their names, but by an 
identification code (e.g., subject or screen number).  
The site monitor, properly authorized persons on behalf of the Sponsor’s quality assurance unit, 
or competent authorities may scrutinize personal medical information for the purpose of verifying 
data recorded on the eCRF. Personal medical information will always be treated as confidential, 
according to local privacy regulations. 

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13 STUDY MANAGEMENT & ADMINISTRATION 
13.1 
Protocol Amendments 
No amendments to the protocol will be implemented without the prior written consent of the 
Sponsor. Should an amendment be necessary, the reviewing IRB and FDA may require review 
and approval prior to its implementation. 
13.2 
Monitoring and Quality Assurance 
13.2.1 
Information to Study Personnel 
The Principal Investigator, with the assistance of ethica CRO, is responsible for ensuring that all 
study personnel are qualified for their designated roles and for providing information about the 
study to all staff members involved in the study or in any element of subject management, both 
before starting the practical performance of the study and during the course of the study (e.g., when 
new staff become involved). 
The ethica CRO site monitor is responsible for initiating the site, conducting interim monitoring 
visits, ensuring site compliance with the protocol and closing out the site at the end of the study. 
Additional information available during the study should be given as agreed upon, either by the 
Principal Investigator or the site monitor, and always when new staff members become involved 
in the study. 
13.2.2 
Study Monitoring 
ethica CRO clinical monitors will conduct approximately 2-3 on-site or remote interim monitoring 
visits at each study site in order to ensure compliance to the protocol, applicable regulations, and 
ICH-GCP, and to ensure safety of the subjects and maintenance of adequate and accurate clinical 
records. A dedicated close-out visit will also be conducted at each site. 
Monitoring functions will be performed in compliance with GCP and the study specific Monitoring 
Plan. The Principal Investigator agrees to allow the site monitors, and other authorized Sponsor 
personnel, access to the clinical supplies, the investigational agent dispensing and storage area, 
subject medical records, laboratory data, and other source documentation of the study subjects. 
Source Document worksheets for all subjects and eCRFs will be reviewed in detail by the site 
monitor to ensure data integrity. If errors or omissions are found in the course of a data audit, or if 
clarification of data is required, the eCRFs and/or worksheets in question will be corrected by the 
study coordinator and confirmed/signed for by the TI or BLE, as appropriate. Data clarification or 
query forms may be generated for omissions or clarifications, to be completed and returned to the 
site monitor. 
The dates of monitoring visits will be recorded by the site monitor in a sign-in log to be kept at the 
site. The Sponsor expects that, during monitoring visits, the study coordinator and Principal 
Investigator will be available, the source documentation will be available, and a suitable 
environment for on-site visits will be provided for review of study-related documents. 
The TI and assisting staff must agree to cooperate with the site monitor to resolve any problems, 
errors, or possible misunderstandings concerning any data discrepancies detected in the course of 
these monitoring visits. 
As part of the supervision of the study progress other Sponsor personnel may accompany the site 
monitor on visits to the study site. 

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13.2.3 
Audit and Inspection 
According to ICH Guidelines on GCP, the Sponsor (or its designate) may audit the investigational 
site to compare raw data, source data, and associated records with the interim (if applicable) or 
final report of the study to assure that data have been accurately reported. 
The Principal Investigator must accept that regulatory authorities may conduct an inspection to 
verify compliance of the study with GCP. The Principal Investigator should notify the Sponsor 
and ethica CRO no later than 24 hours upon notification of being audited by the FDA or IRB. 
13.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, GCP, or Manual of 
Procedures requirements. The noncompliance may be either on the part of the subject, the Principal 
Investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly. It is the responsibility of the site to use continuous vigilance 
to identify and promptly report deviations to ethica CRO.  
All deviations from the protocol must be addressed in study subject source documents. A 
completed copy of the ethica CRO Protocol Deviation Form must be maintained in the regulatory 
file, as well as in the subject’s source document. Protocol deviations must be sent to the IRB per 
its guidelines. 
The protocol must be rigorously adhered to; however, exceptions will be made in emergency 
situations when the protection, safety, and well-being of the subject requires immediate 
intervention based on the judgment of an Investigator.  
Protocol deviations are termed as Major or Minor, as defined below: 
• Minor Protocol Deviation: any difference or departure in the conduct of a study from the 
criteria and/or procedures prescribed in the IRB approved protocol which does not affect 
the participant’s rights, safety, welfare, and/or the integrity of the study and resultant data.  
deviations may result from action or inaction of the participant, investigator or staff.  
1. Deviation has no substantive effect on the risks to research participants; 
2. Deviation has no substantive effect on the value of the data collected (i.e., the 
deviation does not confound the scientific analysis of the results); 
3. Deviation did not result from willful or knowing misconduct on the part of the 
investigator(s) and; 
4. The deviation did not result in or require any substantive action to be taken or result 
in any change to the subject’s condition or status (i.e., did not affect the subject’s 
participation in any way, did not result in a change to the subject’s emotional or 
clinical condition, did not cause an adverse experience or require a change to the 
clinical care of the subject, etc.) 
• Major Protocol Deviation: Any difference or departure from the criteria and/or 
procedures prescribed in the IRB approved protocol that affects the participant’s rights, 
safety, welfare, increases the risk/benefit ratio, or compromises the integrity of the study’s 
data. 
1. Deviation resulted in or required a substantive action to be taken or resulted in a 
change to the subject’s condition or status; 

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2. Deviation has harmed or posed a significant risk of substantive harm to research 
participants; 
3. Deviation has damaged the scientific integrity of the data collected for the study; 
4. Deviation is evidence of willful or knowing misconduct on the part of the 
investigator(s); 
5. Deviation involves serious or continuing noncompliance with federal, state or local 
research regulations; 
6. There have been repeated minor protocol deviations from the same 
investigator/research staff; 
7. There has been a failure to follow action ordered to correct minor protocol deviations. 
Protocol deviations that will result in a subject being excluded from the Per-Protocol population 
are detailed in protocol Section 11.4.2. 
 

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14 DATA HANDLING AND RECORD KEEPING 
14.1 
Source Data  
The site is required to maintain adequate and accurate medical records designed to record all 
observations and other data pertinent to the study for each study subject. Source documentation is 
generally considered to be the document on which the information or data point was first recorded. 
Source documentation may include a subject’s medical records, hospital charts, clinic charts, and 
the site’s study files as well as the results of diagnostic tests such as X-rays, laboratory tests, and 
electrocardiograms. 
Source Document Worksheets will be prepared by ethica CRO Inc. for this purpose and serve as 
part of the source record for a subject's study-related data. The Source Document Worksheets will 
allow for the collection of the following information and allow for verification of subject identity 
throughout the study: 
a. Subject’s name; 
b. Subject’s contact information; 
c. The date that the subject entered the study and the subject number assigned; 
d. The study title and/or the protocol number of the study and the Sponsor’s name; 
e. A statement of the ICF process and the date that informed consent, HIPAA and California 
Experimental Research Subject’s Bill of Rights (if applicable) were signed; 
f. Records of previous and current dermatological treatments and/or therapies; 
g. Dates of all subject visits; 
h. NLF-WSRS, GAIS, FACE-Q, Satisfaction assessments, Symmetry, and pain at time of 
injection (and at 5, 30 and 60 minutes after injection); 
i. 4-week patient CTR diaries; 
j. Study device injection volumes and injection techniques; 
k. All prescription and non-prescription concurrent medications, therapies, and treatments (up 
to 30 days prior to enrollment through the final study visit) and any changes to the list of 
medications; 
l. Visual assessments 
m. Occurrence and status of any AEs; 
n. The date the subject exited the study, and a notation as to whether the subject completed the 
study or reason for discontinuation; 
o. The results of urine pregnancy testing, if performed. 
Pertinent records related to the study (e.g., the subject’s medical chart) will be made available to 
the Sponsor representative on request with due precaution to protect the privacy of the subject. If 
applicable (i.e., SAE reporting), personal identifying information (except subject initials) will be 
redacted on any photocopies of relevant medical records and replaced with the unique subject 
number before submission to the Sponsor. The TI will protect the confidentiality of all subjects’ 
records within applicable federal, state and local laws. 
A subject identification code list will be maintained in order to allow unambiguous identification 
of each subject included in the study. This list should contain the subject’s full name, date of birth, 
dates of participation and identification number as per local regulations. 

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The Principal Investigator must agree to supply all details to Sponsor auditor(s) and/or regulatory 
authorities, ensuring the data is held confidentially at the site after completion of the study. A note 
will be made in the hospital or clinical medical records, if appropriate, that the subject is 
participating in a clinical study. 
The eCRF and subjects’ medical records will be reviewed by ethica CRO, representatives from 
TEOXANE SA, the IRB, and/or the FDA to the extent permitted by regulations. 
14.2 
Case Report Form 
In this study the case report form will be an eCRF. The study coordinator must complete the eCRF 
for each subject within a timely manner of the visit occurring. 
The site monitor will review the completed eCRF for accuracy, completeness and consistency with 
source documentation (i.e., medical records, source document worksheets, etc.). The site monitor 
will submit requests for correction/clarification of data (e.g., queries) to the study coordinator 
when inconsistencies are identified during monitoring and source data verification or during the 
edit check process.  
All corrections and alterations of eCRF data must be made by the study coordinator in a timely 
manner and according to the instructions provided. Completed eCRFs for each visit (i.e., those 
reviewed by ethica CRO and with no remaining queries) should then be reviewed and 
electronically signed by the TI. In order to review and electronically sign the eCRF, the TI will 
each have his/her own login that will allow them to view only the data that they have generated. 
A full audit trail detailing corrections and alterations made to the eCRF will be maintained. 
Upon study completion, a softcopy of the eCRF for each subject will be provided to the site. 
14.3 
Archiving of Study Documentation 
Essential documents are any records that demonstrate the compliance of the subject, Investigators, 
Sponsor, and site monitor with the study protocol, with standards of GCP, and with all applicable 
regulatory requirements. Essential documents (including but not limited to study-related 
correspondence (including emails), subject records, subject privacy documentation, records of the 
distribution and use of study devices, and copies of eCRFs should be retained and available for 
audit by the Sponsor’s auditor and regulatory authorities until at least 2 years after the latest among 
the following scenarios: completion or termination of the study, the last approval of a marketing 
application, no pending or contemplated marketing applications, or formal discontinuation of 
clinical development of RHA4. These documents should be retained for a longer period, however, 
if mandated by the applicable regulatory requirements, by conditions imposed by the IRB, or by 
an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Principal 
Investigator when these documents no longer need to be retained.  
The Sponsor must be notified in writing if the Principal Investigator chooses to store the records 
at a different physical address than the site address or if the Principal Investigator wishes to 
relinquish ownership of the data so that mutually agreed-upon arrangements can be made for 
transfer of ownership to a suitably qualified, responsible person. 

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15 FINANCING AND INSURANCE 
A separate financial agreement (Clinical Trial Agreement) will be made between the Sponsor and 
the Principal Investigator at each site. 
The study is covered under a TEOXANE SA liability insurance policy. The certificate of insurance 
will be provided upon request. 

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16 REPORTING AND PUBLICATION OF RESULTS 
TEOXANE SA, as the Sponsor, has a proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation among multiple Principal Investigators and sites and 
TEOXANE SA personnel. Authorship will be established prior to the writing of the manuscript. 
As this study involves multiple sites, no individual publications will be allowed prior to completion 
of the final report of the multicenter study except as agreed with TEOXANE SA. 
All information, including but not limited to information regarding RHA4 or the Sponsor’s 
operations supplied by the Sponsor to the Principal Investigator and not previously published, 
along with any data generated as a result of this study are considered confidential and remain the 
sole property of the Sponsor. The Principal Investigator agrees to maintain this information in 
confidence, and will use the information only to perform the study. 
The Sponsor or its designee is responsible for preparing a clinical study report. 
The Sponsor or its designee is responsible for publicly registering this study on 
http://www.clinicaltrials.gov/ prior to initiating enrolment. 
 
 

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17 REFERENCES 
 
1. Weiss C, et al. The role of Na-hylan in reducing postsurgical tendon adhesions. Bull Hosp Jt 
Dis Orthop Inst. 1986, Vol. 46, 1, pp. 9-15. 
2. Weiss C, et al. The role of Na-hylan in reducing postsurgical tendon adhesions: Part 2. Bull 
Hosp Jt Dis Orthop Inst. 1987, Vol. 47, 1, pp. 31-39. 
3. Balaz EA, et al. Biocompatible viscoelastic gel slurries, their preparation and use. 0 466 300 A2 
European, 1992. 

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18 APPENDICES 
APPENDIX A: ADJUSTMENTS OF VISITS AND ASSESSMENTS DUE TO 
PUBLIC HEALTH EMERGENCY OF COVID-19 
1. General Guidance 
Subject safety and preserving the integrity of the data are of the highest priority. Any federal, state 
and local rules, guidances, 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), Clinical Project Manager (CPM), 
and IRB, as applicable. All protocol deviations which occur as a result of COVID-19 disruptions 
(including remote visits), will be differentiated from other deviations and must be documented on 
the appropriate reporting forms/source document, and clearly annotated “protocol deviations due 
to COVID-19 illness/restrictions/etc.”. 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. 
The TI is responsible for ensuring subjects’ safety and for monitoring all active subjects per 
protocol. TI must ensure that study subjects are kept informed of changes to the study and 
monitoring plans that could impact them. 
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 to the standard of care. 
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. 
2. Adjustment of Study Visits 
Telemedicine is understood as a possible solution due to COVID-19 disruption and it is not 
mandatory; if the situation allows it, study visits should be done in person. 
On-site Study Visit: If the local situation allows for conduct of on-site study visits, the TI and 
study personnel must take all necessary steps/precautionary measures at the site to minimize or 
eliminate immediate hazards of viral transmission within and/or outside the clinical site premises.  
Before any research activities occur on-site, both subjects and research staff should be screened 
for symptoms or risk of COVID-19 infection. Subjects should be pre-screened by phone before 
their on-site study visit. 
If the local situation only allows for completion of some study procedures, the TI will prioritize 
the research activities that absolutely require an in-person visit in order to maintain the viability 
and integrity of the research (e.g., device injections, injection pain VAS, BLE assessments). The 
TI may consider conducting the other assessments (e.g., medical history review, subject 

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questionnaires) using telemedicine to minimize subject time on site and risk of exposure at the site. 
However, all efforts should be made to conduct all assessments at the scheduled visits, if possible. 
Remote Study Visit: If the local situation does not allow for an on-site study visit to be conducted 
or if a subject does not wish to come to the study site, a remote study visit may be conducted via 
video conferencing in lieu of an on-site visit. Phone call may also be used to perform some 
assessments if a subject has no video conferencing capabilities. 
To preserve the primary endpoint, the mandatory in-clinic visits are Visit 1 (Baseline), Visit 2 
(touch-up), and Visit 4 (Week 12). 
The TI or study personnel who will conduct remote visits must be trained on how to conduct real-
time video conferencing visits. Also, procedures should be put in place to maintain the subject’s 
privacy, as would be done for a clinical visit: 
• 
Before the scheduled date of the visit: 
o The site personnel should determine if the subject can accommodate for video 
conferencing (e.g., internet access, PC, smartphone, video conference apps, etc.). 
o The TI or site personnel conducting the remote visit should obtain the subject’s verbal 
consent before proceeding with the visit and document it in the source document. The 
TI or personnel should also explain to the subject how the visit will be conducted. 
o The site personnel should send all required study material to conduct the visit to the 
subject (e.g., study questionnaires, UPTs, etc.). 
o A test call may also be completed with the subject prior to the appointment. 
• 
On the day of the scheduled visit:  
o Both the investigator/site delegate and the subject should confirm their respective 
identities with one another before engaging in a real-time video conference visit. For 
example, the site personnel will state their name and role and the subject may be 
identified by using two subject identifiers (e.g., name and date of birth) and a photo 
ID. 
o The date and time of the real-time video interaction, the location of the subject, and 
the location of the TI or site personnel conducting the remote visit should be 
documented in the source document. 
o Remote collection of data by TI or delegate will be conducted as described in section 
3 below. 
3. Adjustment of Study Assessments  
Informed consent: The following process will be followed for consenting a prospective subject 
remotely: 
• Each subject will be provided with a copy of the IRB-approved consent form to aid in the 
consent discussion before the consent process begins. The consent form may be provided 
to a prospective subject by mail or e-mail.  
• The TI and/or site delegate will participate in the consent process via video conference. All 
parties must introduce themselves and their role in the consenting process.  

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• The consent form provided to the subject will be reviewed in detail and the subject will be 
invited to ask any questions and to have them addressed by the study team.   
• If the subject is interested in joining the research study, the subject will be asked to sign 
the consent document. The personnel conducting the consent process must verify that the 
subject physically signed the consent document by viewing via video conference and then 
obtain a photo or scanned copy of the signed consent form before proceeding with study 
assessments. 
• In order to obtain the required signatures from the TI and person conducting the consent 
process on the same day, the site will either sign a separate copy of the informed consent 
form or ask the subject to send a copy of the signed ICF by e-mail.  
• The site should ensure to obtain all signature pages from the subject and to document the 
consent process in the source document. The site should also file in the source document 
all signed components as one combined document and provide a copy to the subject.  
Inclusion/exclusion criteria: The list of inclusion/exclusion criteria will be reviewed via video 
conference or phone call with the subject to confirm that they are eligible for the study. Data will 
be documented in the source documents and eCRF. 
For potential subjects in a high-risk population for COVID-19 (e.g., 60 years old and older, with 
comorbidities such as diabetes, cardiovascular disease, respiratory system issues, etc.), deferring 
participation should be considered to minimize risks of exposure. 
UPT (if applicable): UPTs cannot be conducted remotely.  
Demographics: Demographic information will be collected via video conference or phone call 
from the subject at the remote screening visit and will be documented in the source documents and 
eCRF. 
Medical and surgical history / Concomitant medications: Medical history and concomitant 
medications will be reviewed via video conference or  phone call at each remote visit and reported 
in the source documents and eCRF. 
Photography: Standardized photographs can be performed by the subject using a specific 
Canfield tool for visits not associated with the primary outcome (i.e., Visits 2, 2b, and 3). 
Randomization: Randomization is performed before initial treatment. Therefore, subjects will be 
required to present themselves at the clinic for randomization.  
Injection: Injections of study devices cannot be administered remotely. Therefore, subjects will 
be required to present themselves at the clinic for study treatments: 
• Initial Treatment (Visit 1): In order to participate in this study, subjects must agree to 
travel to the clinic to receive their initial treatment with the study devices. 
• Optional Touch-Up Treatment (Visit 2): If the TI deems a touch-up appropriate, subjects 
must agree to travel to the clinic to receive their touch-up treatment with the study devices. 

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Adverse Events: AEs will be reviewed remotely via video conference or phone call with the 
subject at each remote study visit. Any AE/SAE (including suspected / confirmed COVID-19 
cases) elicited by a subject during a remote visit / phone call must be immediately captured, and 
all attempts should be done to capture the necessary clinical and medical information. Reporting 
of AEs and SAEs to the Sponsor and IRB should follow the protocol procedure and IRB 
requirements. 
Vision Assessments: Vision assessments cannot be performed remotely. However an ophthalmic 
follow-up questionnaire completed by the TI. Any abnormal vision related symptoms or signs 
noted in the questionnaire require IMMEDIATE and EMERGENT referral to the designated on-
call ophthalmologist. The results are documented in the source documents and eCRF 
TI Assessments (NLF-WSRS, GAIS, and Symmetry): All TI assessments may be conducted 
remotely via video conference with the subject and results documented in the source documents 
and eCRF. 
BLE Assessments (NLF-WSRS, GAIS, and Symmetry): The primary effectiveness endpoint 
will be aesthetic improvement from pre-injection as assessed by the NLF-WSRS (BLE) at Visit 4. 
As such, the BLE assessment of the NLF-WSRS at Visit 1 and Visit 4 cannot be conducted 
remotely. Therefore, subjects will be asked to travel to the clinic at those visits in order for the 
BLE to perform a live NLF-WSRS assessment. GAIS and Symmetry BLE assessments may be 
conducted remotely via video conference with the subject and results documented in the source 
documents and eCRF. 
Subject Assessments (FACE-Q, GAIS, Patient Satisfaction, Symmetry): All subject 
assessments will be contained in a single questionnaire booklet that will be sent by email to the 
subject for completion at each remote visit. In order to perform the GAIS, the subject’s baseline 
photo will also be provided by email. The subject will be asked to mail or e-mail the completed 
questionnaire booklets to the site after each remote visit. 
Provide 4-week CTR e-diary to subject: After each treatment, the study coordinator will activate 
the e-diary and train the subject on proper use and completion. Training may be done on-site or 
remotely per subject’s preference. The subject will complete the e-diary over the next 4 weeks. 
 
 
 

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APPENDIX B: PROTOCOL VERSION HISTORY 
Version and Date 
Description 
v.1.0; 05-Nov-2020 
Initial protocol 
v.1.1; 02-Dec-2020 
Modifications made in response to FDA G200323-Interactive Deficiency 
(December 1, 2020) 
v.1.2; 08-Dec-2020 
Modifications made in response to FDA G200323-Interactive Deficiency 
(December 8, 2020) 
v.1.3; 14-Jan-2021 
Modifications made in response to FDA G200323-IDE Approval Letter 
(December 11, 2020) Additional Recommendations and Considerations 
v.1.4; 05-Mar-2021 
Modifications made in response to FDA S001-G200323-IDE Letter 
(February 18, 2021) Additional Recommendations and Considerations 
Contact List (pg 15): Change of Medical Monitor to Dr. Patrick 
Trevidic. 
Section 7.5.1 Prohibited Treatment and Procedures: Prohibition 
regarding use of ice post-injection extended to 60 minutes (up from 30 
minutes). 
Section 9.2.1 Visit 1: Indicted procedures that can be omplete up to 14 
days before V1. 
v.1.5; 06-May-2021 
Modifications made in response to FDA S001-G200323-IDE Letter 
(April 21, 2021), Additional Recommendations and Considerations, 
Study Design Consideration #1: Multiple Imputation Analysis: 
Synopsis, Statistical Methods, Primary Endpoint, 3rd paragraph: For 
multiple imputation, age and NLF-WSRS at earlier timepoints are added 
as covariates. 
Section 11.6 General Considerations, Missing Values: For multiple 
imputation, age and NLF-WSRS at earlier timepoints are added as 
covariates.