A Randomized, Controlled, Double-blinded, Within-subject (Split-face), Multicenter, Prospective Clinical Study to Compare the Level of Pain Using the Dermal Filler RHA® Redensity Formulated With Two Different Anesthetics in the Treatment of Perioral Rhytids
Phase: NA
Conditions: Aging, Pain
Sponsor: Teoxane SA

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 57 
     
 
 
A randomized, controlled, double-blinded, within-subject (split-face), 
multicenter, prospective clinical study to compare the level of pain using the 
dermal filler RHA® 1 formulated with two different anesthetics in the 
treatment of perioral rhytids 
 
 
 
IDE Pivotal Study 
Protocol:  TEO-RHA-1801 
Version:  v.1.5 
Date:  10-Sep-2019 
 
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. 
8555 Transcanada Hwy, Suite 201 
Montreal, Canada H4S 1Z6 
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. 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 57 
PROTOCOL APPROVAL SIGNATURE PAGE 
 
The following individuals approve this version of Protocol TEO-RHA-1801. 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 Operations Manager  
 
 
DATE 
 
 
 
_______________________________________________________________________   
Delphine DECONCHAT, QA/RA Director  
 
 
 
 
 
DATE 
 
 
 
 
 
Accepted for the Clinical Research Organization - ethica CRO Inc: 
 
 
_______________________________________________________________________   
Murray JENSEN, Managing Director  
 
 
 
 
 
 
 
DATE 
 
 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 57 
INVESTIGATOR SIGNATURE PAGE 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, good 
clinical practices and all applicable laws and regulations. 
• 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. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
 
Principal Investigator (Printed Name) 
 
Signature 
 
Date 
 
 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 57 
SYNOPSIS 
Protocol Version 
Version 1.5 
10-Sep-2019 
Investigational 
Device 
RHA® 1 with MEPIVACAINE 
(RHA® 1-M) 
Study Number 
TEO-RHA-1801 
Phase 
IDE Pivotal 
Control 
Device 
RHA® 1 with lidocaine 
(RHA® 1) 
Indication 
Injection in the dermis and 
superficial dermis of the face for 
correction of moderate to severe 
perioral rhytids 
Study Sites 
Multicenter, maximum 3 US sites 
Title 
A randomized, controlled, double-blinded, within-subject (split-face), multicenter, 
prospective clinical study to compare the level of pain using the dermal filler RHA® 1 
formulated with two different anesthetics in the treatment of perioral rhytids 
Sponsor 
TEOXANE SA, Rue de Lyon 105, CH - 1203 Geneva, Switzerland 
Study Duration 
Approximately 60 days 
Number of 
Subjects 
Maximum 30 subjects treated with 
RHA® 1 and RHA® 1-M with at least 
20% of subjects presenting Fitzpatrick 
skin type IV to VI including at least 
10% of subjects presenting Fitzpatrick 
skin type V to VI. 
Treatment Groups 
Each enrolled subject will receive injections of RHA® 1-M with MEPIVACAINEinto the 
perioral rhytids of the left or right side of the mouth, and injections of the control device (i.e., 
RHA® 1 with lidocaine) into the perioral rhytids of the contralateral side of the mouth. 
Study Design 
This is a randomized, controlled, double-blinded, within-subject (split-face), multicenter, 
prospective study to investigate whether RHA® 1-M with MEPIVACAINEis non-inferior to 
RHA® 1 with lidocaine in terms of injection site pain felt by the subject during injection. 
At screening, the Treating Investigator (TI) will evaluate subjects’ perioral rhytid severity 
(using the Perioral Rhytid Severity Rating Scale; PR-SRS) to confirm eligibility and to 
establish a pre-treatment score for assessing aesthetic improvement. 
At Visit 1, RHA® 1-M with MEPIVACAINEwill be administered in a random sequence (first 
or second injection) and side of the mouth (left or right) and RHA® 1 with lidocaine will be 
administered to the other side. Study subjects and the TI injecting study devices will be 
blinded. 
The perioral area will be divided into 4 quadrants (upper right, upper left, lower right, lower 
left). There will be a no-treatment zone of approximately 8 mm between the Cupid’s bow on 
the upper lip and the same distance on the lower lip area in order to be able to assess the 
difference of the anesthetic effect between the two products. If needed to improve cosmetic 
result, the lower perioral quadrants will be injected, but only after both upper quadrants have 
been injected. 
Immediately after injection of an upper perioral quadrant, subjects will rate injection site pain 
experienced during injection using a 100 mm Visual Analog Scale (VAS). Injection site pain 
in each side of the mouth will also be assessed at 15, 30, 45 and 60 minutes after the upper 
quadrant was injected. 
Additionally, subjects will assess anesthetic sensation on each side of the mouth every hour 
until normal sensation returns. 
Safety evaluation will consist of AE assessments, a 30-day CTR (Common Treatment 
Response) diary, assessments of visual disturbances (i.e., Snellen visual acuity, 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 5 of 57 
confrontational visual field test, ocular motility), assessment of lip function, and a follow-up 
call performed by the study site at 72 hours after injection. 
Subjects will attend Visit 2 (30 days post-injection) where efficacy and safety assessments 
will be conducted. Subjects who present with an unresolved clinically significant device 
related AE at Visit 2 will receive the optional follow-up phone call no later than 30 days after 
Visit 2. If the clinically significant AE remains unresolved, the Investigator will request that 
the subject to attend the optional in-clinic follow-up visit (i.e., Visit 3) within 5 working days. 
Follow-up of the clinically significant AE will continue until the AE is resolved or the TI 
determines that additional follow-up is not necessary. 
At study exit (i.e., Visit 2, optional follow-up phone call, or Visit 3), subjects will be offered 
treatment with a commercially available dermal filler approved for injection into the perioral 
rhytids if they present wrinkles/lines in the no-treatment zone.  
Hypothesis 
The anesthetic effect of RHA® 1-M with MEPIVACAINEwill be non-inferior to RHA® 1 
with lidocaine in terms of injection site pain felt by the subject during injection into the upper 
perioral rhytids assessed immediately after injection of each upper quadrant using a 100 mm 
Visual Analog Scale (VAS). 
Objectives 
Demonstrate the non-inferiority of RHA® 1-M with MEPIVACAINEversus the control 
(RHA® 1 with lidocaine) in terms of reducing pain during device injection into the upper 
perioral rhytids. Injection pain during injection will be based on the 100 mm Visual Analog 
Scale (VAS), as assessed by subjects immediately after injection of each upper perioral 
quadrant.  
Inclusion Criteria 
1. Outpatient, male or female of any race, 22 years of age or older. Female subjects of 
childbearing potential must have a negative UPT at Visit 1 and practice a reliable method 
of contraception throughout the study. 
2. Moderate to severe bilateral perioral rhytids (grade 2 or 3 on the four point PR-SRS).   
3. Perioral rhytids of the same PR-SRS grade on the left and right sides of the mouth.  
4. Willing to abstain from facial aesthetic procedures/therapies that could interfere with the 
study evaluations (e.g., other fillers, botulinum toxin injections [frontalis and glabella 
complex treatment allowed], laser or chemical resurfacing, etc.) for the duration of the 
study (see Section 7.5.1 for prohibited/restricted medication/procedures). 
5. Able to follow study instructions and complete all required visits. 
6. 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. Female subjects who are pregnant, breast-feeding, or of childbearing potential and not 
practicing reliable birth control. 
2. Known hypersensitivity or previous allergic reaction to any component of the study 
devices. 
3. Use of a prohibited treatment/procedure within time periods defined in Section 7.5.1. 
4. Known sensitivity to local anesthetics of the amide type, history of multiple severe 
allergies, or history of anaphylactic shock. 
5. Known susceptibility to keloid formation, hypertrophic scarring or clinically significant 
skin pigmentation disorders (TI discretion). 
6. Clinically significant active skin disease or infection in the perioral area within 6 months 
prior to study entry (TI discretion). 
7. History of active chronic debilitating systemic disease that, in the opinion of the 
investigator, would make the subject a poor candidate in the study. 
8. History of connective tissue disease. 
9. Malignancy (excluding non-melanoma skin cancer) within the past 5 years. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 6 of 57 
10. Need for clinically significant (TI discretion) and continuous medical treatment within 2 
weeks prior to Visit 1. 
11. History or presence of condition or feature that may confound the interpretation of the 
results in the perioral region, for example, tattoo, significant facial hair, acne scaring, 
prior surgery in the area, potential for active disease or infection flare up such as herpes 
simplex. 
12. Herpes simplex lesion flare-ups greater than 6 per year. 
13. History of skin cancer in the treatment area. 
14. Elective, clinically significant facial procedures that may confound the interpretation of 
the results in the perioral region (TI discretion), prior to study enrollment. 
15. Clinically active disease or infection in the perioral area or mouth (e.g., dental abscess). 
16. Subjects with known prolonged bleeding times because of disease or medication. 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 14 days or until 
bleeding times return to normal before injecting. (Note: low dose 81mg/day ASA is 
permitted). 
17. Medical or psychiatric conditions that may increase the risk associated with study 
participation or 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. 
18. Dentures or any device covering all or part of the upper palate, and/or severe 
malocclusion, dentofacial or maxillofacial deformities, or significant asymmetry of the 
perioral area (TI discretion). 
19. Subjects seeking lip augmentation. 
20. Exposure to any other investigational drug/device within 90 days of entering the study. 
21. Clinically significant alcohol or drug abuse, or history of poor cooperation or 
unreliability. 
Device 
Administration 
Depth of injection: Study device will be administered into the dermis, including the 
superficial dermis at the discretion of the TI. 
Injection technique: The injection technique (e.g., linear threading, cross hatching, fan like 
administration, multiple puncture) will be at the discretion of the TI, and will be recorded. 
The same injection techniques will be used on both sides of the mouth. 
Injection area: For the purposes of this study, the lip will be defined as the structures within 
the vermilion border. The focus of this study is to treat perioral rhytids, and there will be no 
augmentation of the lips, but the vermilion border may be treated to ensure a satisfactory 
result of the treatment of the perioral rhytids. 
Injection volume: The maximum volume per administration of a study device into the 
perioral rhytids (upper and lower) is 6.0 mL (max 3.0 mL for right side, and max 3.0 mL for 
left side). 
No Treatment Zone: To minimize potential overlap of anesthetic effects of each study 
device, left and right perioral areas will be separated by a “no treatment zone” defined as the 
area between philtral columns (approximately 8mm). Similarly, a no treatment zone of the 
lower perioral area will be defined as the ~8mm area directly below the upper perioral no 
treatment zone. 
Blinding 
This is a double-blinded study. Subjects and TI will be blinded to treatment allocation. 
Randomization 
A randomization algorithm will provide equal balancing for the side of the mouth and the 
order of injection of study devices (i.e., left or right / 1st or 2nd order). 
Visit Procedures 
Refer to the Study Summary Tables and the Study Schematic for a schedule of activities. 
Anesthetic 
Effectiveness 
• 
Injection Site Pain during injection in the upper perioral quadrants (primary endpoint) 
• 
Injection Site Pain at 15, 30, 45 and 60 minutes post-injection in each side of the mouth 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 7 of 57 
Evaluations 
• 
Duration of anesthetic effect (patient diary) in each side of the mouth 
Aesthetic 
Effectiveness 
Evaluations 
• 
PR-SRS change from Baseline at 30 days post-injection. 
• 
Responder rate for PR-SRS at 30 days post-injection. 
• 
FACE-Q assessment by subject at Visit 1 pre-injection and at 30 days post-injection. 
• 
GAIS assessment by investigator at Visit 1 post-injection and at 30 days post-injection. 
• 
GAIS assessment by subject at Visit 1 post-injection and at 30 days post-injection. 
• 
Patient Satisfaction assessment at Visit 1 post-injection and at 30 days post-injection. 
Safety Evaluations 
• 
Adverse Events. 
• 
Post-injection Common Treatment Response including visual disturbances (30-day 
patient CTR diary). 
• 
Assessments of lip function;  
o 
Lip function - a subject’s ability to suck liquid through a straw 
o 
Lip sensation - a subject’s ability to feel the change in sensation to touch  
o 
Lip movement - a subject’s ability to pronounce a preselected series of words 
• 
Assessment of visual disturbances (Snellen visual acuity, confrontational visual field test, 
ocular motility). 
Primary Endpoint 
Injection site pain felt during injection of the upper perioral quadrant assessed by the subject 
immediately following injection with RHA® 1-M with MEPIVACAINEcompared to the 
injection site pain felt during injection into the contralateral upper perioral quadrant assessed 
immediately following injection with RHA® 1 with lidocaine. 
Secondary 
Endpoints 
• Injection Site Pain in each side of the mouth at 15, 30, 45 and 60 minutes after injection in 
each upper perioral quadrant. 
• Duration of anesthetic effect in each side of the mouth commencing at the time of the final 
Injection Site Pain assessment. 
• Perioral Rhytid Severity Rating Scale (PR-SRS) of each side of the mouth at Visit 1 (pre- 
and post-injection) and at Visit 2. 
• FACE-Q assessment of each side of the mouth at Visit 1 (pre-injection) and at Visit 2. 
• Global aesthetic improvement (GAI) of each side of the mouth at Visit 1 (post-injection) 
and at Visit 2. 
• Patient Satisfaction for each side of the mouth at Visit 1 (post-injection) and at Visit 2. 
• Volume injected in each upper perioral quadrant. 
• Volume injected in each side of the mouth. 
Sample Size 
A minimum sample size of 10 subjects will provide >80% power at 5% significance level 
(one-sided) to detect a 10mm non-inferiority of the pain felt in the upper perioral quadrants 
during injection with RHA® 1-M with MEPIVACAINEcompared to pain felt during injection 
with RHA® 1 with lidocaine. 
Due to the small number of subjects needed according to this simulation and to the variability 
in human pain tolerance, the Sponsor increased the sample size of the study from 10 to 30. 
Statistical Methods 
The primary endpoint will be analyzed in a non-inferiority statistical model using the pain 
felt by the subject during injection of the upper perioral quadrants. A difference of 10mm 
between the two treatment groups will be used as the non-inferiority margin. 
If non-inferiority is achieved, the pain felt during injection by the subject will be analyzed in 
terms of superiority, specifically, to confirm if RHA® 1-M is superior to RHA® 1 for reducing 
pain. 
Statistical analysis of the primary endpoint will be performed using paired one-sided tests, 
with a significance level of 0.05, either parametric or non-parametric as appropriate. 
 
 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 8 of 57 
TABLE 1.  STUDY SUMMARY TABLE 
Study Visits 
V1 
scr, enroll, Tx 
F/U call 
72h post-Tx 
V2 
30d post-tx 
F/U call – Optional 
30d post-V2 
V3 – Optional 
Within 5d of F/U call 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
UPT (if applicable) 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
Randomization  
X 
 
 
 
 
Study treatment 
X 
 
 
 
 
Injection site pain VAS (immediately 
after Tx of the upper perioral quadrants and 
at 15, 30, 45 and 60 minutes post-Tx) 
X 
 
 
 
 
Photography 
 Pre- and Post-Tx 
 
X 
 
 
PR-SRS 
 Pre- and Post-Tx 
 
X 
 
 
FACE-Q 
Pre-Tx 
 
X 
 
 
GAI (TI) 
Post-Tx 
 
X 
 
 
GAI (subject) 
Post-Tx 
 
X 
 
 
Patient Satisfaction 
Post-Tx 
 
X 
 
 
CTR Diary 
X 
X 
X 
 
 
Duration of Anesthetic Effect diary 
X 
X 
 
 
 
Lip functionality 
Pre- and Post-Tx 
 
X 
 
 
Visual Assessments* 
Pre- and Post-Tx 
 
X 
 
X** 
Optional Treatment (no tx zone) 
 
 
X† 
X†† 
X† 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
 
CTR = Common Treatment Response 
F/U = Follow-up 
GAI = Global Aesthetic Improvement 
TI = Treating Investigator 
Tx = Treatment 
UPT = Urine pregnancy test 
VAS = Visual Analogue Scale 
PR-SRS = Perioral Rhytid Severity Rating Scale 
*  Snellen visual acuity, confrontational visual field test, ocular motility test 
** Only if unresolved AE is related to a suspected vascular event 
† Optional Treatment to be provided at study exit, either at Visit 2 or Visit 3 
†† If subject exits at optional F/U call, optional treatment to be provided within 1 
month following the call 
 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 9 of 57 
FIGURE 1.  STUDY SCHEMATIC 
  
 
 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 10 of 57 
TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ............................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE .............................................................................................................. 3 
SYNOPSIS .............................................................................................................................................................. 4 
TABLE OF CONTENTS ..................................................................................................................................... 10 
CONTACT LIST ................................................................................................................................................. 13 
ABBREVIATIONS .............................................................................................................................................. 14 
1 
INTRODUCTION ..................................................................................................................... 15 
1.1 
Background .......................................................................................................................................... 15 
1.2 
Rationale for Study .............................................................................................................................. 16 
1.3 
Hypothesis ........................................................................................................................................... 16 
2 
STUDY OBJECTIVE .................................................................................................................. 17 
3 
COMPLIANCE STATEMENT ..................................................................................................... 18 
3.1 
Variations to the Protocol .................................................................................................................... 18 
3.2 
Investigational Sites ............................................................................................................................. 18 
3.3 
Training and certification on the Perioral Rhytids Severity Rating Scale (PR-SRS) ........................... 18 
3.4 
Medical Monitor .................................................................................................................................. 19 
3.5 
Photography ......................................................................................................................................... 19 
4 
OVERVIEW OF STUDY DESIGN ................................................................................................ 20 
4.1 
Study Design ........................................................................................................................................ 20 
4.2 
Study Design Rationale ....................................................................................................................... 21 
4.2.1 
Study Population ............................................................................................................................. 21 
4.2.2 
Primary Endpoint ............................................................................................................................ 21 
5 
STUDY POPULATION .............................................................................................................. 22 
5.1 
Inclusion Criteria ................................................................................................................................. 22 
5.2 
Exclusion Criteria ................................................................................................................................ 22 
6 
TREATMENT ALLOCATION, RANDOMIZATION AND BLINDING ................................................. 24 
7 
DEVICE APPLICATION ............................................................................................................. 25 
7.1 
Study Devices ...................................................................................................................................... 25 
7.2 
Injection of Study Devices ................................................................................................................... 25 
7.2.1 
Injection Depth ................................................................................................................................ 25 
7.2.2 
Injection Technique......................................................................................................................... 25 
7.2.3 
Supplementary Anesthesia .............................................................................................................. 25 
7.2.4 
No Treatment Zone ......................................................................................................................... 26 
7.2.5 
Visual Assessment .......................................................................................................................... 27 
7.2.6 
Injection Sequence .......................................................................................................................... 27 
7.2.7 
Treatment Volume Allowance ........................................................................................................ 27 
7.3 
Labeling, Packaging and Storage ......................................................................................................... 27 
7.3.1 
Relabeling ....................................................................................................................................... 28 
7.4 
Study Device Supply and Accountability ............................................................................................ 28 
7.4.1 
Other Study Supplies ...................................................................................................................... 28 
7.5 
Concomitant Medications and Procedures ........................................................................................... 28 
7.5.1 
Prohibited Treatment and Procedures ............................................................................................. 28 
8 
DATA COLLECTION ................................................................................................................. 31 
8.1 
Electronic Case Report Form ............................................................................................................... 31 
8.2 
Subject Diaries ..................................................................................................................................... 31 
8.3 
Photography ......................................................................................................................................... 31 
9 
STUDY EVALUATIONS ............................................................................................................. 32 
9.1 
Informed Consent ................................................................................................................................ 32 
9.2 
Visit Procedures ................................................................................................................................... 32 
9.2.1 
Visit 1 (Screening / Enrolment / Treatment) ................................................................................... 32 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 11 of 57 
9.2.2 
Follow-up Phone Call (72 hours post-injection) ............................................................................. 32 
9.2.3 
Visit 2 (30 days from V1; ±3 days) ................................................................................................. 32 
9.2.4 
Follow-up Phone Call – Optional (no later than 30 days from V2) ................................................ 33 
9.2.5 
Visit 3 - Optional (Within 5 working days of the previous follow-up phone call).......................... 33 
9.3 
Effectiveness Variables ........................................................................................................................ 33 
9.3.1 
Anesthetic Effectiveness Variables ................................................................................................. 33 
9.3.1.1 
Injection Site Pain - Primary Effectiveness Variable ............................................................ 33 
9.3.1.2 
Duration of Anesthetic Effect ................................................................................................ 34 
9.3.2 
Aesthetic Effectiveness Variables ................................................................................................... 34 
9.3.2.1 
Perioral Rhytids Severity Rating Scale .................................................................................. 34 
9.3.2.2 
FACE-Q................................................................................................................................. 35 
9.3.2.3 
Global Aesthetic Improvement .............................................................................................. 35 
9.3.2.4 
Patient Satisfaction ................................................................................................................ 35 
9.3.2.5 
Treatment Volume ................................................................................................................. 35 
9.4 
Safety ................................................................................................................................................... 36 
9.4.1 
30-Day Patient Common Treatment Response Diary ..................................................................... 36 
9.4.2 
72-Hour Telephone Follow-up ........................................................................................................ 36 
9.4.3 
Lip Functionality ............................................................................................................................. 37 
9.4.4 
Visual Assessments ......................................................................................................................... 37 
9.4.5 
Pregnancy and Contraception ......................................................................................................... 37 
9.4.6 
Adverse Events ............................................................................................................................... 37 
9.4.6.1 
Definition of an Adverse Event ............................................................................................. 38 
9.4.7 
Vascular Occlusion Adverse Events ............................................................................................... 38 
9.4.8 
Serious Adverse Events (SAEs) and Unexpected Adverse Device Effects (UADEs) .................... 39 
9.4.9 
Causality Assessment ...................................................................................................................... 39 
9.4.10 
Severity Assessment ....................................................................................................................... 40 
9.4.11 
Adverse Event Reporting ................................................................................................................ 40 
9.4.11.1 
All Adverse Events ................................................................................................................ 40 
9.4.11.2 
Serious Adverse Events (SAEs) and Unexpected Adverse Device Effects (UADEs) ........... 40 
9.4.11.3 
Reporting of Adverse Events Associated with Visual Disturbances ..................................... 41 
9.4.11.4 
Pregnancy .............................................................................................................................. 41 
10 SUBJECT COMPLETION / WITHDRAWAL / STOPPING RULES .................................................... 43 
10.1 
Completion .......................................................................................................................................... 43 
10.2 
Withdrawal .......................................................................................................................................... 43 
10.3 
Stopping Rules ..................................................................................................................................... 43 
11 STATISTICAL METHODS .......................................................................................................... 45 
11.1 
Primary Endpoint ................................................................................................................................. 45 
11.2 
Secondary Endpoints ........................................................................................................................... 45 
11.3 
Safety Endpoints .................................................................................................................................. 46 
11.4 
Analysis Populations............................................................................................................................ 46 
11.4.1 
Intent-to-Treat (ITT) Population ..................................................................................................... 46 
11.4.2 
Per Protocol (PP) Population .......................................................................................................... 46 
11.4.3 
Safety (SAFT) Population ............................................................................................................... 46 
11.5 
Sample Size Considerations ................................................................................................................. 46 
11.6 
General Considerations ........................................................................................................................ 47 
11.7 
Effectiveness Analysis ......................................................................................................................... 47 
11.7.1 
Primary Endpoint ............................................................................................................................ 47 
11.7.2 
Secondary Endpoints....................................................................................................................... 48 
11.8 
Safety Analysis .................................................................................................................................... 48 
11.8.1 
Adverse Events (AEs) ..................................................................................................................... 48 
12 ETHICAL ASPECTS ................................................................................................................... 49 
12.1 
Informed Consent ................................................................................................................................ 49 
12.2 
Health Authorities and IRBs ................................................................................................................ 49 
12.3 
Confidentiality Regarding Study Subjects ........................................................................................... 49 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 12 of 57 
13 STUDY MANAGEMENT & ADMINISTRATION ........................................................................... 50 
13.1 
Protocol Amendments.......................................................................................................................... 50 
13.2 
Monitoring and Quality Assurance ...................................................................................................... 50 
13.2.1 
Information to Study Personnel ...................................................................................................... 50 
13.2.2 
Study Monitoring ............................................................................................................................ 50 
13.2.3 
Audit and Inspection ....................................................................................................................... 51 
13.3 
Protocol Deviations.............................................................................................................................. 51 
14 DATA HANDLING AND RECORD KEEPING ................................................................................ 52 
14.1 
Source Data .......................................................................................................................................... 52 
14.2 
Case Report Form ................................................................................................................................ 53 
14.3 
Archiving of Study Documentation ..................................................................................................... 53 
15 FINANCING AND INSURANCE ................................................................................................. 54 
16 REPORTING AND PUBLICATION OF RESULTS ........................................................................... 55 
17 REFERENCES .......................................................................................................................... 56 
18 APPENDICES .......................................................................................................................... 57 
APPENDIX A: Protocol Version History .................................................................................................. 57 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 13 of 57 
CONTACT LIST 
Medical Monitor 
Stacy Smith, MD 
561 Saxony Place,  
Suite 102,  
Encinitas, CA 92024 - USA 
Phone:  619.787.5723 
Fax:   
619.342.7428 
ssmith@stacyrsmithmd.com 
 
Sponsor Contacts 
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 
 
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 Project Manager 
Tania Mete 
ethica CRO Inc. 
8555 Transcanada Hwy, Suite 201 
Montreal, Quebec, H4S 1Z6 - 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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 14 of 57 
ABBREVIATIONS 
AE 
Adverse Event 
BL 
Baseline 
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 
PI 
Principle Investigator (typically functions as the Treating Investigator) 
PMA 
Premarket Approval 
PP 
Per protocol 
PR-SRS 
Perioral Rhytids Severity Rating Scale 
RHA 
Resilient Hyaluronic Acid 
SAE 
Serious Adverse Event 
SAFT 
Safety 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
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 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 15 of 57 
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 
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 2018 were extracted from the ASPS website in June 2019 
(https://www.plasticsurgery.org/news/plastic-surgery-statistics): 
• 15.9 M cosmetic minimally invasive procedures, up 2% from previous year 
• 2.68 M procedures with any dermal filler, up 2% from previous year 
• 2.13 M procedures with HA, up 2% 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, such as lip augmentation. 
RHA® 1 and RHA® 1-M dermal fillers are devices 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® 1 product contains 0.3% w/w of lidocaine hydrochloride, and RHA® 
1-M contains 0.3% w/w of MEPIVACAINE hydrochloride. Both lidocaine and MEPIVACAINE 
are drug substances widely used for their anesthetic properties (i.e., they block the origin and 
transmission of nervous influx at the point of injection by stabilizing the neuronal membrane).  

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 16 of 57 
RHA® 1 and RHA® 1-M are intended for injection in the dermis and superficial dermis of the face 
to correct moderate to severe perioral rhytids. RHA® 1 is an investigational device that has not yet 
been approved by the FDA. TEOXANE S.A. has recently completed a pivotal clinical study (IDE 
number G160123) investigating RHA® 1 for the treatment of perioral rhytids that is intended to 
secure a Premarket Approval (PMA) from the FDA for this device. All subjects in this study have 
completed their final visits, there were no UADEs or Treatment-Related SAEs, and data analysis 
is in progress. The primary endpoint was achieved. 
1.2 
Rationale for Study 
Similar to lidocaine, MEPIVACAINE is a local anesthetic of the amide type. A new formulation 
of RHA® 1, substituting MEPIVACAINE for lidocaine, has been developed for specific 
commercial reasons. RHA® 1-M is identical to RHA® 1 except that the 0.3% w/w of lidocaine 
hydrochloride has been replaced with another anesthetic agent, 0.3% w/w of MEPIVACAINE 
hydrochloride. In the current study, a non-inferiority pivotal study designed to support a PMA 
application (FDA) for RHA® 1-M with MEPIVACAINE, RHA® 1 with lidocaine (control) will be 
compared to RHA® 1-M with MEPIVACAINE. 
1.3 
Hypothesis 
The anesthetic effect of RHA® 1-M with MEPIVACAINE will be non-inferior to RHA® 1 with 
lidocaine in terms of injection site pain felt by the subject during injection into the upper perioral 
rhytids assessed immediately after injection of each upper quadrant using a 100 mm Visual Analog 
Scale (VAS). 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 17 of 57 
2 
STUDY OBJECTIVE 
The study objective is to demonstrate the non-inferiority of RHA® 1-M with MEPIVACAINE 
versus the control (RHA® 1 with lidocaine) in terms of reducing pain during device injection into 
the upper perioral rhytids. Injection pain during injection will be based on the 100 mm Visual 
Analog Scale (VAS), as assessed by subjects immediately after injection of each upper perioral 
quadrant. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 18 of 57 
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 
Maximum three (3) 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. TIs 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. 
Each site will have identified a local retina specialist 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 Perioral Rhytids Severity Rating Scale (PR-SRS) 
The study will use a validated 4-grade photonumeric scale measuring the severity of perioral 
rhytids. All assessors (i.e., TIs) will be certified on the use of the PR-SRS. Specifically, all 
assessors will be trained on the scale then tested using a photo booklet with a broad range of 
perioral rhytids severities. An assessor will be considered certified once his/her percentage of 
agreement with the true values is ≥80%. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 19 of 57 
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 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, and visual disturbance AEs 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.). 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 20 of 57 
4 
OVERVIEW OF STUDY DESIGN 
4.1 
Study Design 
This is a randomized, controlled, double-blinded, within-subject (split-face), multicenter, 
prospective study to investigate whether RHA® 1-M with MEPIVACAINEis non-inferior to 
RHA® 1 with lidocaine in terms of injection site pain felt by the subject during injection. 
At screening, the Treating Investigator (TI) will evaluate subjects’ perioral rhytid severity (using 
the Perioral Rhytid Severity Rating Scale; PR-SRS) to confirm eligibility and to establish a pre-
treatment score for assessing aesthetic improvement. 
At Visit 1, RHA® 1-M with MEPIVACAINEwill be administered in a random sequence (first or 
second injection) and side of the mouth and RHA® 1 with lidocaine will be administered to the 
other side. Study subjects and the TI injecting study devices will be blinded. 
To minimize potential interference between the effect of the anesthetic agents of each study device, 
left and right perioral areas will be separated by a “no treatment zone” defined as the area between 
the philtral columns (approximately 8 mm). Similarly, a no treatment zone of the lower perioral 
area will be defined as the ~8 mm area directly below the upper perioral no treatment zone (See 
Section 7.2.4). 
The perioral area will be divided into 4 quadrants (upper right, upper left, lower right, lower left) 
and the sequence of injections will be performed by quadrant as follows: 
1. Inject upper right (or left) then immediately assess injection pain during injection; 
2. Inject upper left (or right) then immediately assess injection pain during injection; 
3. Inject lower right (or left) only if needed to improve cosmetic results; 
4. Inject lower left (or right) only if needed to improve cosmetic results. 
Immediately after injection of an upper perioral quadrant, subjects will rate injection site pain 
experienced during injection using a 100 mm Visual Analog Scale (VAS). Injection site pain in 
each side of the mouth will also be assessed at 15, 30, 45 and 60 minutes after the upper quadrant 
was injected. 
Additionally, subjects will assess anesthetic sensation, on each side of their mouth, every hour 
until normal sensation returns. Should the anesthetic effect continue into the following day, the 
subject, upon waking, will continue to assess the anesthetic sensation every hour until they return 
to normal sensation; the time for return to normal sensation for each side will be recorded. 
Safety evaluation will consist of AE assessments, lip functionality assessments, visual 
assessments, a 30-day CTR diary, and a follow-up call performed by the study site at 72 hours 
after injection. 
Subjects will attend Visit 2 (30 days post-injection) during which efficacy and safety assessments 
will be conducted. Subjects who present with an unresolved clinically significant device related 
AE at Visit 2 will receive the optional follow-up phone call no later than 30 days after Visit 2. If 
the clinically significant AE remains unresolved, the Investigator will request that the subject 
attend the optional in-clinic follow-up visit (i.e., Visit 3) within 5 working days. Follow-up of the 
clinically significant AE will continue until the AE is resolved or the TI determines that additional 
follow-up is not necessary. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 21 of 57 
At study exit (i.e., Visit 2, optional follow-up phone call, or Visit 3), subjects will be offered 
treatment with a commercially available dermal filler approved for injection into the perioral 
rhytids if they present wrinkles/lines in the no-treatment zone. 
4.2 
Study Design Rationale 
4.2.1 
Study Population 
Maximum 30 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., 6 subjects) presenting Fitzpatrick skin types IV to VI including at least 
10% of subjects (i.e., 3 subjects) with Fitzpatrick Skin Type V-VI. See Section 5 for a full 
description of the inclusion and exclusion criteria. 
4.2.2 
Primary Endpoint 
The primary endpoint is injection site pain during injection into the upper perioral rhytids assessed 
immediately following injection with RHA® 1-M with MEPIVACAINE(using a 100 mm VAS) 
compared to the injection site pain felt during injection into the contralateral upper perioral rhytids 
assessed immediately following injection(s) with RHA® 1 with lidocaine. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 22 of 57 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
1. Outpatient, male or female of any race, 22 years of age or older. 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 the site’s Principal 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.] 
2. Moderate to severe bilateral perioral rhytids (grade 2 or 3 on the four point PR-SRS). 
3. Perioral rhytids of the same PR-SRS grade on the left and right sides of the mouth. 
4. Willing to abstain from facial aesthetic procedures/therapies that could interfere with the study 
evaluations (e.g., other fillers, botulinum toxin injections [frontalis and glabella complex 
treatment allowed], laser or chemical resurfacing, etc.) for the duration of the study (see 
Section 7.5.1 for prohibited/restricted medication/procedures). 
5. Able to follow study instructions and complete all required visits. 
6. 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. Female subjects who are pregnant, breast-feeding, or of childbearing potential and not 
practicing reliable birth control. 
2. Known hypersensitivity or previous allergic reaction to any component of the study devices. 
3. Use of a prohibited treatment/procedure within time periods defined in Section 7.5.1. 
4. Known sensitivity to local anesthetics of the amide type, history of multiple severe allergies, 
or history of anaphylactic shock. 
5. Known susceptibility to keloid formation, hypertrophic scarring or clinically significant skin 
pigmentation disorders (TI discretion). 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 23 of 57 
6. Clinically significant active skin disease or infection in the perioral area within 6 months prior 
to study entry (TI discretion). 
7. History of active chronic debilitating systemic disease that, in the opinion of the investigator, 
would make the subject a poor candidate in the study. 
8. History of connective tissue disease. 
9. Malignancy (excluding non-melanoma skin cancer) within the past 5 years. 
10. Need for clinically significant (TI discretion) and continuous medical treatment within 2 weeks 
prior to Visit 1. 
11. History or presence of condition or feature that may confound the interpretation of the results 
in the perioral region, for example, tattoo, significant facial hair, acne scaring, prior surgery in 
the area, potential for active disease or infection flare up such as herpes simplex. 
12. Herpes simplex lesion flare-ups greater than 6 per year. 
13. History of skin cancer in the treatment area. 
14. Elective, clinically significant facial procedures that may confound the interpretation of the 
results in the perioral region (TI discretion), prior to study enrollment. 
15. Clinically active disease or infection in the perioral area or mouth (e.g., dental abscess). 
16. Subjects with known prolonged bleeding times because of disease or medication. 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 14 days or until bleeding 
times return to normal before injecting. (Note: low dose 81mg/day ASA is permitted). 
17. 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. 
18. Dentures or any device covering all or part of the upper palate, and/or severe malocclusion, 
dentofacial or maxillofacial deformities, or significant asymmetry of the perioral area (TI 
discretion). 
19. Subjects seeking lip augmentation. 
20. Exposure to any other investigational drug/device within 90 days of entering the study. 
21. Clinically significant alcohol or drug abuse, or history of poor cooperation or unreliability. 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 24 of 57 
6 
TREATMENT ALLOCATION, RANDOMIZATION AND BLINDING 
All subjects who have signed an ICF 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. 
Upon qualifying for treatment, subjects will be randomized for the side of mouth and the order of 
injection of study devices (i.e., left or right / 1st or 2nd order). If needed to improve cosmetic results, 
the lower perioral quadrant of a side will be injected only after both upper perioral quadrants have 
been injected. 
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. 
This is a double-blinded study in which subjects and TIs will be blinded to treatment allocation. 
Designated site personnel will secure the randomization/treatment allocation information and any 
other record of study treatment from potential discovery by the TI or the subject. Any instance 
where the blind is opened to the TI or subject will be documented in writing. 
If it is medically imperative to know what device was injected into the left and right perioral 
rhytids, the TI or study coordinator will contact ethica CRO to confirm the rationale for unblinding. 
If appropriate, ethica CRO and/or the Sponsor will approve unblinding and treatment assignments 
for that particular subject will be disclosed. The rationale for breaking the code must be recorded 
in subjects’ medical record and eCRF. 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 25 of 57 
7 
DEVICE APPLICATION 
7.1 
Study Devices 
RHA® 1-M with MEPIVACAINE: A sterile, biodegradable, biocompatible, viscoelastic, clear, 
colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by 
fermentation of Streptococcus zooepidemicus, formulated to a concentration of 15 mg/g and 0.3% 
w/w MEPIVACAINEin a physiologic buffer. It is supplied in individual treatment syringes with 
30G ½ inch disposable sterile needles. 
RHA® 1 with lidocaine: A sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, 
homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation 
of Streptococcus zooepidemicus, formulated to a concentration of 15 mg/g and 0.3% w/w 
lidocaine in a physiologic buffer. It is supplied in individual treatment syringes with 30G ½ inch 
disposable sterile needles. 
For additional information regarding RHA 1-M, please refer to TEO-RHA-1801 Investigator’s 
Brochure. 
7.2 
Injection of Study Devices 
At Visit 1, each enrolled and randomized subject will receive injections of RHA® 1-M with 
MEPIVACAINEinto the perioral rhytids of the upper left quadrant or the upper right quadrant, 
and injections of the control device (i.e., RHA® 1 with lidocaine) into the contralateral upper 
quadrant. Using the same device as the upper quadrant for that side, the lower perioral quadrant of 
a side will be injected only after both upper perioral quadrants have been injected and only if 
needed. 
The study devices will not be injected in the “no treatment zone” as defined in Section 7.2.4.  
7.2.1 
Injection Depth 
Study devices will be administered into the dermis, including the superficial dermis, at the 
discretion of the TI. 
7.2.2 
Injection Technique 
The injection technique (e.g., linear threading, cross hatching, fan like administration, multiple 
puncture, etc.) will be at the discretion of the TI, and will be recorded. The same injection 
technique will be used on both sides of the mouth. While injecting on either side of the mouth, 
using any of the techniques mentioned above, the needle should not cross or inject into the no 
treatment zone. 
For the purposes of this study, the lip will be defined as the structures within the vermilion border. 
The focus of this study is to treat perioral rhytids, and there will be no augmentation of the lips, 
but the vermilion border may be treated to ensure a satisfactory result of the treatment of the 
perioral rhytids. 
Devices will be injected using the needle that is provided within the standard packaging of the 
device; the TI is not permitted to use a needle of different gauge or length. 
7.2.3 
Supplementary Anesthesia 
Both study devices contain an anesthetic. 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 mouth have been 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 26 of 57 
completed (i.e., at 60 minutes post-injection). 
7.2.4 
No Treatment Zone 
In order to minimize potential interference between the anesthetic agents of each study device, left 
and right perioral areas will be separated by a “no treatment zone”. The no treatment zone of the 
upper perioral area will be defined as the area between the philtral columns (approximately 8mm). 
Similarly, a no treatment zone of the lower perioral area will be defined as the ~8mm area directly 
below the no treatment zone of the upper perioral area (see Figure 2 below). 
Optional treatment with a commercially available product approved for injection into the perioral 
rhytids will be offered to subjects at study exit (i.e., at Visit 2, optional follow-up phone call, or 
Visit 3) in order to provide correction within the no treatment zone should the TI and subject agree 
it is desirable. 
 
Figure 2. No Treatment Zone 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 27 of 57 
7.2.5 
Visual Assessment 
The subject will undergo three visual assessment tests to detect rare and unintentional injection 
into a blood vessel. Subjects should be instructed to wear the same corrective eyewear (if 
applicable) at each visit. 
The following assessments will be performed 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 
• Visit 3 if the AE in question is a suspected vascular event 
7.2.6 
Injection Sequence 
Using a non-permanent marker, divide the perioral area into 4 quadrants (i.e., upper right, upper 
left, lower right, lower left), and delineate the “no-treatment zone” as defined in Section 7.2.4. 
Upon qualifying for treatment, subjects will be randomized for the side of mouth and the order of 
injection (i.e., left or right / 1st or 2nd order). Both upper perioral rhytids will be injected prior to 
injection of either lower perioral rhytid. The sequence of injections will be performed by quadrant 
as follows: 
1. Inject upper right (or left) then immediately assess injection pain during injection; 
2. Inject upper left (or right) then immediately assess injection pain during injection; 
3. Inject lower right (or left) only if needed improve cosmetic results; 
4. Inject lower left (or right) only if needed improve cosmetic results. 
7.2.7 
Treatment Volume Allowance 
The maximum volume per administration of a study device into the perioral rhytids (upper and 
lower) is 6.0 mL (max 3.0 mL for right side, and max 3.0 mL for left side). 
7.3 
Labeling, Packaging and Storage 
Supplies of RHA® 1-M with MEPIVACAINEand RHA® 1 with lidocaine 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. The Tyvek lid on the blister will include:  
• Study number: TEO-RHA-1801 
• IDE number: e.g., G190055 
• Name and address of the Sponsor/Manufacturer (i.e., TEOXANE S.A.) 
• Quantity of syringes (n=1) 
• Quantity of 30G ½ inch needles (n=2) 
• Batch number and Manufacturing date 
• Expiry date 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 28 of 57 
• 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. 
7.3.1 
Relabeling 
Real-time aging testing is in progress for the study devices. As new test data will become available 
throughout the course of the study, the shelf life of the study devices may be extended through the 
course of the study. The site monitor and/or study coordinator will be responsible for relabeling 
the Tyvek lid with the new expiry date. The site monitor and/or study coordinator will follow a 
specific procedure to perform and verify the product relabeling with the extended expiry date (to 
be provided in a separate guidance document). The relabeling process will be documented. The 
study devices may also be returned to the Sponsor to be relabeled. When the study devices have 
reached the expiry date as indicated on its label, the TI should segregate them and follow the 
instructions from the site monitor as to relabeling by the site monitor and/or study coordinator or 
for returning the devices to the Sponsor.  
It is the responsibility of the TI to verify that a device is within its expiry date before being used. 
The initial shelf life of the study devices will be approximately 9 months; however, as devices 
being subjected to real time aging are being tested periodically, the shelf-life could be extended. 
7.4 
Study Device Supply and Accountability 
The study Sponsor will ensure that participating sites are provided with a sufficient supply of study 
devices 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.  
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 will be returned to the Sponsor at the end of the study unless other arrangements 
are agreed upon in writing. Used syringes 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, paper study diaries, 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 
Any medication or procedure, including over-the-counter preparations, that the subject takes 
during the study protocol period is considered concomitant medication and will be captured on the 
Concomitant Medications and Procedures page of the eCRF. 
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 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 29 of 57 
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 
Procedures below the orbital rim: 
• 
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, 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). 
≥14 days before treatment 
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 and to avoid extreme temperatures (intense 
cold, sauna, hammam, etc.) during the week following treatment. 
Subjects will be instructed to not use laser hair removal around the lip during study. Additionally, 
subjects will be instructed to not use any hair removal products around the lip (e.g. waxing, 
bleaching, hair removal creams) for 7 days before a study treatment and until V2 is complete.  
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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 30 of 57 
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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 31 of 57 
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 will have an individual login password 
that will allow them to view only the data that they have generated. The TI must ensure that they 
electronically sign for completed eCRFs on a timely basis. 
8.2 
Subject Diaries 
Subjects will record Common Treatment Responses (CTRs) for 30 days post-injection using 
paper-based diaries. Data recorded in this diary will be entered into the eCRF by the study 
coordinator. 
The 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 also record “duration of anesthetic effect” using paper-based diaries. Data recorded 
in this diary will be entered into the eCRF by the study coordinator. 
8.3 
Photography 
Calibrated photographs will be taken at Visit 1 (pre-injection and post-injection) and Visit 2 
according to a standardized protocol incorporating appropriate quality control processes (i.e., 
Canfield Scientific Inc.). 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 32 of 57 
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) 
• Photography (pre-injection and post-injection) 
• Injection of study devices 
• TI Assessments 
- 
PR-SRS (pre-injection and post-injection) 
- 
GAI (post-injection) 
- 
Lip functionality (pre and post injection) 
- 
AE Review (post-injection) 
• Subject Assessments 
- 
FACE-Q (pre-injection) 
- 
Injection site pain VAS (immediately after injection of each upper perioral quadrant, and in each 
side of the mouth at 15, 30, 45 and 60 after the upper quadrant for that side was injected. 
- 
GAI (post-injection) 
- 
Patient Satisfaction (post-injection) 
• CTR Diary and “Duration of Anesthetic Effect” Diary  
- 
Dispense diaries to subject and train subject on proper completion 
- 
Train subjects 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  
9.2.2 
Follow-up Phone Call (72 hours post-injection) 
• CTR diary review 
• Anesthetic effect duration diary review 
• Concomitant medications/treatments review 
• AE review 
9.2.3 
Visit 2 (30 days from V1; ±3 days) 
• Concomitant medications/treatments 
• Photography  
• Visual assessment by trained evaluator 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 33 of 57 
- 
Ocular motility test 
• TI Assessments 
- 
PR-SRS 
- 
GAI 
- 
Lip functionality 
- 
AE Review* 
* Subject presenting with an unresolved device related clinically significant AE at V2 will receive a 
f/u call not later than 30 days after V2. 
• Subject Assessments 
- 
FACE-Q 
- 
GAI 
- 
Patient Satisfaction 
• Collect and review CTR Diary and “Duration of Anesthetic Effect” Diary 
• Next Study Visit 
- 
If Subject presents with an unresolved device related clinically significant AE, proceed to Follow-
up Phone Call. 
- 
If Subject does not present with an unresolved device related clinically significant AE, the subject 
will exit the study and optional treatment with a commercially available product approved for 
injection into the perioral rhytids will be offered to subjects with remaining lines and/or wrinkles in 
the no-treatment zone. 
9.2.4 
Follow-up Phone Call – Optional (no later than 30 days from V2) 
• Concomitant medications/treatments review 
• AE review 
- 
Confirm if subject is still experiencing the unresolved clinically significant device related AE(s) 
▪ If yes, the site will request that the subject attend the optional in-clinic within 5 working days. 
▪ If no, the subject will exit the study and optional treatment with a commercially available product 
approved for injection into the perioral rhytids will be offered to subjects with remaining lines 
and/or wrinkles in the no-treatment zone. Treatment should be scheduled within 1 month 
following this call. 
9.2.5 
Visit 3 - Optional (Within 5 working days of the previous follow-up phone call) 
• Concomitant medications/treatments review 
• Visual assessment by trained evaluator (only if unresolved AE is related to a suspected 
vascular event) 
- 
Snellen visual acuity (letter chart) 
- 
Confrontational visual field test 
- 
Ocular motility test 
• AE review 
- 
Follow-up of the clinically significant device related AE will continue until the AE is resolved or the 
TI determines that additional follow-up it is not necessary. 
• Optional treatment with a commercially available product approved for injection into the 
perioral rhytids will be offered to subjects with remaining lines and/or wrinkles in the no-
treatment zone 
• Study Exit 
9.3 
Effectiveness Variables  
9.3.1 
Anesthetic Effectiveness Variables 
9.3.1.1 
Injection Site Pain - Primary Effectiveness Variable 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 34 of 57 
Injection pain will be self-assessed by the subject using a Visual Analog Scale (VAS) Pain Scale 
Ruler (see Figure 3 below). 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 3.  VAS Ruler 
 
Immediately after injection of an upper perioral quadrant, subjects will rate injection site pain 
during injection. Injection site pain in each side of the mouth will also be assessed at 15, 30, 45 
and 60 minutes after the upper quadrant for that side was injected. 
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). 
9.3.1.2 
Duration of Anesthetic Effect 
Subjects will complete a self-assessment of the duration of anesthetic effect on each side of the 
mouth (right and left, every hour until returning to normal sensation) using a paper-based diary. 
The subject will respond to the following question in their diary regarding the treatment on the left 
side and the right side of their mouth: “Indicate the time at which you evaluate sensation and check 
the box to report if you still feel numbness (i.e., "YES" or "NO").” 
Subjects who go to sleep prior to returning to normal sensation will re-assess anesthetic effect 
upon waking. If the anesthetic effect is absent upon waking, subjects should use the time they 
woke as the time anesthetic effect returned to normal. 
9.3.2 
Aesthetic Effectiveness Variables 
9.3.2.1 
Perioral Rhytids Severity Rating Scale 
The PR-SRS will be assessed at rest by the TI at Baseline (Visit 1 pre-treatment and post-injection) 
and Visit 2 (30 days after study treatment) using the validated 4-grade PR-SRS photo-numeric 
scale and text as detailed in Table 2 below: 
Table 2.  Perioral Rhytids Severity Rating Scale (PR-SRS) 
Category 
Grade 
Description 
Absent 
0 
No lines 
Mild 
1 
Shallow lines 
Moderate 
2 
Deeper lines 
Severe 
3 
Deepest lines 
Left side and right side of the mouth will be assessed individually. NOTE: To qualify for the study, 
a subject must have PR-SRS grades of 2 or 3 (at rest as determined by the TI). Half-point grades 
will not be accepted. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 35 of 57 
9.3.2.2 
FACE-Q 
Subjects will complete the Perioral Rhytids domain of the validated FACE-Q scale, once for the 
left perioral side, and once for the right perioral side. The subject will be instructed as follows: 
“These questions ask about how you look right now. For each question, circle only one answer. 
With the area around your lips in mind, in the past week, how much have you been bothered 
by:”, and will provide response as per Table 3 below: 
Table 3.  FACE-Q – Perioral Rhytids domain 
Not at All 
A Little 
Moderately 
Extremely 
a. 
The number of lines around your lips?  
1 
2 
3 
4 
b. How deep the lines around your lips are? 
1 
2 
3 
4 
c. 
How noticeable the lines around your lips are? 
1 
2 
3 
4 
d. How the lines around your lips look compared with other people your age?  
1 
2 
3 
4 
e. 
How old the lines around your lips make you look?  
1 
2 
3 
4 
f. 
How the lines around your lips look when your lips are puckered? 
1 
2 
3 
4 
 
9.3.2.3 
Global Aesthetic Improvement 
GAI will be assessed by the TI and the subject using the Visit 1 pre-injection photograph and the 
subjective 5-grade scale as detailed in Table 4 below. Left side and right side of the mouth 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 will complete the assessment using the same pre-injection photograph (photograph 
will be labeled with “left side” and “right side"). 
Table 4.  Global Aesthetic Improvement Scale 
Grade 
Description 
1 
Much improved 
2 
Improved 
3 
No change 
4 
Worse 
5 
Much worse 
9.3.2.4 
Patient Satisfaction 
Patient Satisfaction will be assessed by the subject using the following subjective 5-grade scale as 
detailed in Table 5 below. Left side and right side of the mouth will be assessed individually. 
Subject will be instructed: “Rate your level of satisfaction with the effect of study treatment on 
your perioral rhytids by using the following scale”: 
Table 5.  Patient Satisfaction Scale 
Grade 
Description 
1 
Very satisfied 
2 
Satisfied 
3 
Neither satisfied nor dissatisfied 
4 
Dissatisfied 
5 
Very dissatisfied 
 
9.3.2.5 
Treatment Volume 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 36 of 57 
The total volume injected in each upper quadrant will be collected for each study device. 
Additionally, total volume required injected in each lower quadrant will be collected. Treatment 
volume will be measured to an accuracy of 0.1 mL. 
9.4 
Safety 
Safety will be evaluated through a 30-day patient Common Treatment Response (CTR) diary that 
captures post-injection signs/symptoms and AE reporting based on phone follow-ups and clinic 
visits. Safety assessments will also include lip functionality tests performed at Visit 1 (pre and 
post-injection) and at Visit 2 as well as visual assessment tests performed at Visit 1 (before and 30 
minutes post-injection, including referral to a retina specialist if a visual disturbance is noted post 
injection), Visit 2, and at Visit 3 (if the unresolved AE is related to a vascular event). 
9.4.1 
30-Day Patient Common Treatment Response Diary 
The subject will receive a diary booklet and instructions for recording his/her observations of the 
CTRs of the study treatments for the first 30 days after treatment. The diary will be dispensed after 
treatment and will be discussed during the 72-hour 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”. 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 heart beat  
• Sensitivity to hot/cold liquids and foods 
The 30-day patient CTR diary will capture the daily occurrence of each CTR. The 30-day patient 
CTR diary will include a detailed glossary describing all signs/symptoms listed in the diary. 
9.4.2 
72-Hour Telephone Follow-up 
The subject will be contacted by telephone by the investigational site approximately 72 hours 
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 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 37 of 57 
the subject. All failed attempts will also be documented in the study notes. 
9.4.3 
Lip Functionality 
Lip functionality testing will be conducted by the TI or study coordinator pre- and post-injection 
and at each follow-up visit. The lip functionality testing will include the following Yes/No 
evaluations: 
• Lip function: Ability to suck liquid through a straw. TI or study coordinator will be asked 
to capture Yes or No with the following question: “Can the subject drink/suck through a 
straw effectively?” 
• Lip Sensation: Ability to feel the change in the lip sensation to touch, using the two 
following tests: 
1) the monofilament test (i.e., a subject’s ability to feel the sensation of a 0.4G 
monofilament at three points on each the left and right upper lip and three points on 
each the left and right lower lip) and  
2) the cotton wisp test (i.e., a subject’s ability to feel the sensation of a cotton wisp at 
three points on each the left and right upper lip and three points on each the left and 
right lower lip). 
The 6 different points on each side of the mouth will be randomly tested for each of the 
two tests. Subjects will wear a blindfold and will be asked to acknowledge sensation at 
each of the points by answering Yes or No. 
• Lip Movement: Ability to pronounce specific letters and words. TI or study coordinator 
will be asked to capture Yes or No with the following question: “Can the subject effectively 
pronounce the following words?”  
o Member, Simmering, Drab, Babble, Spear, Peep, Fire, Staff, Verse, Liver 
9.4.4 
Visual Assessments 
Subjects will undergo three visual 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 
• Confrontational visual fields tests 
• Ocular motility 
9.4.5 
Pregnancy and Contraception 
A female of childbearing potential must present a negative UPT prior to injection of the study 
device. Subjects who are pregnant are excluded from the study. 
Female subjects of childbearing potential are expected to prevent pregnancy occurring whilst on 
treatment by using effective birth control methods (e.g., oral contraceptive, condom, IUD, 
injectable contraceptive, diaphragm or vasectomized partner). Male subjects have no contraceptive 
restrictions. 
9.4.6 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship to 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 38 of 57 
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 30 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. 
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 
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 retina specialist.  
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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 39 of 57 
9.4.8 
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. 
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. 
9.4.9 
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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 40 of 57 
• 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. 
9.4.10 
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. 
9.4.11 
Adverse Event Reporting 
9.4.11.1 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 study treatment. The TI will assess all AEs and 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. 
9.4.11.2 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 30 days following the study treatment, must be reported to ethica 
CRO within 24 hours of awareness. Initial reports must be made by contacting ethica CRO as per 
the following: Contact the ethica CRO Clinical Project Manager by telephone and complete the 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 41 of 57 
SAE/UADE Form and submit by fax (514-336-1142) or by email. If outside of office hours, or 
if unable to contact the ethica CRO Clinical Project Manager, use the 24-hour number (514-262-
9398). 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 ethica CRO 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. 
Reporting Timelines 
UADEs: The site must report UADEs to ethica CRO within 24 hours of awareness of the event. 
Within 24 hours of receiving the UADE report from the site, ethica CRO must report the UADE 
to the Sponsor. As per 21 CFR 812.46 (US), the Sponsor must investigate the UADE and report 
the results to the FDA and IRB within 10 working days of receiving the report from ethica CRO. 
• SAEs: The site must report the SAE to the ethica CRO within 24 hours of becoming aware 
of the event. Within 24 hours of receiving the SAE report from the site, ethica CRO must 
report the SAE to the Sponsor. Sponsor must investigate the SAE and, if it is device related, 
will report the results to the FDA and IRB within 10 working days of receiving the report 
from ethica CRO. 
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. 
9.4.11.3 Reporting of Adverse Events Associated with Visual Disturbances 
One of the rare risks of dermal fillers is the unintentional injection into a blood vessel which may 
lead to stroke or blindness. The actual risk is unknown; however, the perioral rhytid area is highly 
vascularized. Therefore, any incidence of visual disturbance should be reported as follows: 
• Any incidence of 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.) should be reported to ethica CRO within 24 hours 
of becoming aware of the event. 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. Within 24 hours of receiving the report of this 
category of AE, ethica CRO must report the event to the Sponsor and the IRB(s).  
• Sponsor must investigate the AE and report the results to FDA within 10 working days of 
receiving the report from ethica CRO. 
9.4.11.4 Pregnancy 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 42 of 57 
Pregnancy is not considered an SAE or AE. The site will inform ethica CRO immediately of any 
case of pregnancy and collect information on any subject who becomes pregnant during the study 
using the Unexpected Problems Report Form. 
Subjects who become pregnant will continue to be followed up for scheduled efficacy and safety 
assessments for the duration of the study. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 43 of 57 
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 significant 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: 
• Vascular embolic event leading to skin necrosis, any clinically significant change in vision 
and/or stroke. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 44 of 57 
If the cause of the event was anticipated (e.g., the Investigator did not properly follow the study 
protocol), the study 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, the entire study must be immediately suspended, and 
subject enrolment and/or treatment will be stopped. The study will remain on-hold until the event 
can be properly characterized and an appropriate treatment strategy to avoid this unanticipated 
event be devised. 
In case of a UADE, the TI will follow the procedure as noted in Section 9.4.11.2. 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 9.4.11.2. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 45 of 57 
11 STATISTICAL METHODS 
11.1 
Primary Endpoint 
The primary endpoint will be the injection site pain felt during injection of the upper perioral 
quadrants assessed by the subject immediately following injection with RHA® 1-M with 
MEPIVACAINE, compared to the injection site pain felt during injection of the contralateral upper 
perioral quadrant assessed immediately following injection with RHA® 1 with lidocaine. 
The effectiveness of RHA® 1-M with MEPIVACAINEwill be demonstrated if the injection site 
pain during injection of the upper perioral quadrant assessed by subjects immediately following 
injection with RHA® 1-M with MEPIVACAINEis statistically non-inferior to the injection site 
pain felt during injection of the contralateral upper perioral quadrant assessed by subjects 
immediately following injection with RHA® 1 with lidocaine. 
The primary endpoint will use a paired design and will be analyzed using hypothesis test.  
For achieving non-inferiority, the observed p value must be ≤0.05, taking account of the non-
inferiority margin. 
In case of non-inferiority, for achieving superiority of RHA® 1-M with MEPIVACAINEover 
RHA® 1 with lidocaine in terms of reducing pain, the observed p-value must be ≤0.05.  
11.2 
Secondary Endpoints 
The following secondary effectiveness endpoints will be explored: 
1) Injection Site Pain in each side of the mouth at 15, 30, 45 and 60 minutes after the upper 
quadrant was injected. 
2) Duration of anesthetic effect in each side of the mouth, as assessed by subjects, commencing 
after the time of the final Injection Site Pain assessments (i.e., at 60 minutes post-injection). 
3) Perioral Rhytids Rating Scale (PR-SRS) of each side of the mouth, as assessed by the TI at 
Visit 1 (pre- and post-injection) and at Visit 2 on a subjective 4-grade scale comprised of 
“absent, mild, moderate, and severe”. 
4) Perioral Rhytids domain of the validated FACE-Q scale, as assessed by the subject at Visit 1 
(pre-injection) and at Visit 2. Each side of the mouth will be assessed independently. 
5) Global aesthetic improvement (GAI) on each side of the mouth, as assessed by the TI at Visit 
1 (post-injection) and at Visit 2, on a subjective 5-grade scale comprised of “much improved, 
improved, no change, worse, and much worse”. 
6) Global aesthetic improvement (GAI) on each side of the mouth, as assessed by the subject at 
Visit 1 (post-injection) and at Visit 2, on a subjective 5-grade scale comprised of “much 
improved, improved, no change, worse, and much worse”. 
7) Patient Satisfaction for each side of the mouth, as assessed by the subject at Visit 1 (post-
injection) and at Visit 2 using a subjective 5-grade scale comprised of “very satisfied, satisfied, 
neither satisfied nor dissatisfied, dissatisfied, and very dissatisfied.” 
8) Volume injected in each upper quadrant. 
9) Volume injected in each side of the mouth. 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 46 of 57 
11.3 
Safety Endpoints 
The following safety endpoints will be explored: 
1) Occurrence of Common Treatment Responses (CTRs) 
2) Occurrence of Adverse Events (AEs) 
3) Lip functionality testing 
4) Visual assessments 
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 that were randomized. The ITT principle will be 
followed in that subjects will be analyzed according to the treatment assigned to each side of the 
mouth as per the randomization schedule. Furthermore, all subjects in the ITT Population will be 
included in the analysis, regardless if they have missing data at the time point of interest. The ITT 
Population will be the primary population used for effectiveness analyses. 
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 assessments of injection site pain felt during injection (i.e., recorded at 
Visit 1 immediately after injection(s) of each upper perioral region, and 3) who experienced no 
major protocol violations/deviations that could affect assessments of injection site pain felt during 
injection. Subjects will be analyzed according to the treatment actually received on each side of 
the mouth. 
The decision whether a protocol violation/deviation results in the exclusion of subjects from the 
PP Population will be made prior to breaking the study blind in a data review meeting.  
11.4.3 
Safety (SAFT) Population 
The SAFT Population will consist of all study subjects that were randomized and received 
treatment with the study device. 
11.5 
Sample Size Considerations 
Using a balance ratio, a minimum sample size of 10 subjects who will receive RHA®1-M with 
MEPIVACAINEon one side, and the control device on the other side, are required to detect a 
10mm non-inferiority with a power of 80%. As the primary endpoint will be assessed at the first 
study visit, no drop-outs are anticipated. The estimated number of subjects needed was computed 
using the following assumptions: 
• A unilateral approach 
• A first level risk α = 0.05 
• A standard deviation S = 19.74 (*) 
• A non-inferiority margin –Δ = 10 
• A left-right correlation r = 0.83306 (**) 
• Balanced groups 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 47 of 57 
• No lost to follow-up anticipated as the primary endpoint (i.e., injection pain) occurs 
during the initial study visit 
(*) Standard deviation of pain was determined using data from the ongoing TEO-RHA-1501 clinical study of RHA® Redensity (i.e., 
RHA®1, with lidocaine) for the treatment of perioral rhytids, during first injection (G160123). 
(**) Correlation of pain felt during injection between sides was determined using data from split-face TEO-RHA-1302 and TEO-
RHA-1402 clinical studies of RHA® Global Action, RHA Deep Lines, and RHA Ultra Deep (aka RHA®2, RHA®3, and RHA®4, 
respectively, with lidocaine) for the treatment of nasolabial folds, at all timepoints (G140028 and G140106). Data from G160123 
were not applicable as 1) it was a not a split-face design, and 2) it used a no-treatment control group. 
Due to the small number of subjects needed according to this simulation and the variability in 
human pain tolerance, the Sponsor increased the sample size to 30 subjects. 
11.6 
General Considerations 
Data will be listed by treatment group and subject number. The safety and efficacy data will be 
summarized by treatment allocation. Descriptive statistics will consist of mean, standard deviation, 
minimum and 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 data imputation performed for missing data. 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 the ITT 
analysis. Subject disposition will be summarizing the number of subjects enrolled in the study and 
those that discontinued the study and their reason. 
Interim Analysis 
There will be no interim effectiveness analysis. 
11.7 
Effectiveness Analysis 
11.7.1 
Primary Endpoint 
Effectiveness of RHA® 1-M with MEPIVACAINEversus control will first be analyzed in a non-
inferiority statistical model using the pain felt by the subject during injection. If non-inferiority is 
achieved, pain felt by the subject during injection will be tested for superiority (i.e., to confirm if 
RHA® 1-M is superior to RHA® 1 for reducing pain). 
The primary endpoint will use a paired-design and will be analyzed using a one-sided parametric 
or non-parametric test for paired data, as appropriate. Due to the small sample size, normality of 
the observed distribution will be visually confirmed. 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. 
A difference of 10mm between the two treatment groups will be used as the non-inferiority margin, 
as half of the clinically significant difference of pain felt by a subject on a 100 mm VAS pain scale, 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 48 of 57 
identified as 20mm.4,5 
11.7.2 
Secondary Endpoints 
Secondary endpoint statistical analysis will be performed if the non-inferiority of the primary 
endpoint is achieved. 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. Due to the small sample 
size, normality of the observed distribution will be visually confirmed. 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 
relationship to study treatment. Severity and relationship to study treatment will be assessed and 
recorded. 
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 safety data. 
 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 49 of 57 
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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 50 of 57 
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 two 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. 
Monitoring functions will be performed in compliance with recognized GCP and as per 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. Approximately two on-site interim monitoring visits will be conducted at each site, 
and a dedicated close-out visit will also be conducted at each site. 
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, 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 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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 51 of 57 
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.  
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 52 of 57 
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. PR-SRS, FACE-Q, GAI, satisfaction assessments, and pain at time of injection (and at 15, 
30, 45 and 60 minutes after injection); 
i. 30-day patient CTR diaries; 
j. Anesthetic effect duration diaries; 
k. Study device injection volumes and injection techniques; 
l. 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; 
m. Lip functionality assessments 
n. Visual assessments 
o. Occurrence and status of any AEs; 
p. The date the subject exited the study, and a notation as to whether the subject completed the 
study or reason for discontinuation; 
q. 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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 53 of 57 
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. 
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 hardcopy 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® 1-M with MEPIVACAINEor RHA® 1 with lidocaine. 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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 54 of 57 
15 FINANCING AND INSURANCE 
A separate financial agreement (Clinical Study 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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 55 of 57 
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® 1-M with 
MEPIVACAINE, RHA® 1 with lidocaine, 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 
www.clinicaltrials.gov prior to initiating enrolment. 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 56 of 57 
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. 
4. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in 
chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001, Vol. 
94, 2, pp. 149-58. 
5.  Rowbotham MC. What is a "clinically meaningful" reduction in pain? Pain. 2001, Vol. 94, 2, 
pp. 131-2. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol TEO-RHA-1801 
CONFIDENTIAL 
v.1.5; 10-Sep-2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 57 of 57 
18 APPENDICES 
 
APPENDIX A: PROTOCOL VERSION HISTORY 
 
Version and Date 
Description 
v.1.0; 03-Jan-2019 
Initial 
v. 1.1; 29-Mar-2019 
Updates following FDA’s feedback 
v. 1.2; 14-May-2019 
Updates following FDA’s feedback 
v.1.3; 20-Jun-2019 
Updates following FDA’s feedback 
v.1.4; 23-Aug-2019 
Updates following Sponsor’s feedback 
v.1.5; 10-Sep-2019 
Updates following IRB’s feedback