A Randomized, Blinded, No-Treatment Control, Multicenter, Prospective Clinical Study of TEOSYAL RHA® Redensity for the Treatment of Moderate to Severe Dynamic Perioral Rhytids
Phase: NA
Conditions: Perioral Rhytids, Aging, Wrinkle
Sponsor: Teoxane SA

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 72 
 
 
 
 
 A Randomized, Blinded, No-Treatment Control, Multicenter, 
Prospective Clinical Study of TEOSYAL® RHA Redensity  
for the Treatment of Moderate to Severe Perioral Rhytids 
 
 
IDE Pivotal Study 
Protocol:   TEO-RHA-1501 
Version:   v.1.2 
Date:   27-Oct-2017 
(Previous version: v1.1, 25-Jul-2016) 
 
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-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 72 
PROTOCOL APPROVAL SIGNATURE PAGE 
 
The following individuals approve this version of Protocol TEO-RHA-1501. 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: 
___________________________  ______________________________  
Printed Name 
Title 
___________________________  ______________________________   
Signature 
Date 
 
 
Accepted for the Clinical Research Organization - ethica CRO Inc: 
___________________________  ______________________________  
Printed Name 
Title 
___________________________  ______________________________   
Signature 
Date 
 
 
 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 72 
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-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 72 
SYNOPSIS 
Protocol 
Version 
Version 1.2 
27-Oct-2017 
Investigational 
Device: 
TEOSYAL® RHA Redensity 
Study Number 
TEO-RHA-1501 
Phase 
IDE Pivotal 
Control Device: 
No-Treatment 
Indication 
Injection in the dermis and superficial 
dermis of the face for correction of 
moderate to severe perioral rhytids 
Study Sites:  
Multicenter, up to 10 sites 
2 Canadian sites with the 
remainder being US sites 
Title 
A Randomized, Blinded, No-Treatment control, Multicenter, Prospective Clinical Study of 
TEOSYAL® RHA Redensity for the Treatment of Moderate to Severe Perioral Rhytids 
Sponsor 
TEOXANE SA, Rue de Lyon 105, CH - 1203 Genève, Switzerland. 
Study 
Duration 
52 to 58 weeks for subjects randomized 
to TEOSYAL® RHA Redensity 
treatment group, and  
60 to 66 weeks for subjects randomized 
to the “No-Treatment” control group 
Number of 
Subjects 
At least 200 subjects, 150 treated 
and 50 No-Treatment controls 
Treatment 
Groups 
Subjects will be randomized (3:1 ratio) to one of the following groups: 
• 
TEOSYAL® RHA Redensity 
• 
No-Treatment control 
Study Design 
This is a randomized, blinded, No-Treatment control, multicenter, prospective clinical study, to 
identify whether TEOSYAL® RHA Redensity is more effective than No-Treatment in the 
correction of moderate to severe perioral rhytids at Week 8 after last treatment. 
The Treating Investigator (TI) at screening will evaluate the subject’s perioral rhytids severity 
using the Perioral Rhytids Severity Rating Scale (PR-SRS) for eligibility of the subject for the 
study. 
The Blinded Live Evaluator (BLE) at screening will evaluate the subject’s perioral rhytids severity 
using the PR-SRS in order to confirm eligibility and to establish a pre-treatment score for 
assessment of effectiveness. This will be done independently of the TI, and exact concordance 
between the BLE and the TI is not necessary for eligibility of the subject for the study. 
Enrolled subjects will be randomized to either the TEOSYAL® RHA Redensity treatment group 
or the “No-Treatment” control group. The TI will administer study device, and if necessary, 
subjects will receive a touch-up treatment 14 days following the initial treatment to optimize the 
results. The TI will conduct safety and effectiveness evaluations at study visits, which will occur 
at Week 4, 8, 12, 16, 24, 36, and 52 after the last treatment, and 4 weeks after a repeat treatment. 
A Blinded Live Evaluator (BLE) will conduct assessments of efficacy during the trial, including 
assessment of the primary endpoint at Week 8 after the last treatment. The BLE will conduct 
effectiveness evaluations at Week 8, 12, 16, 24, 36, and 52 after the last treatment. 
All subjects will be followed for 52 weeks after initial treatment or touch-up, at which point they 
will be offered retreatment (provided that the TI deems the treatment to be appropriate and the 
subject agrees) and will then be followed for 4 weeks after retreatment before exiting the study. If 
a subject has returned to his pre-treatment PR-SRS score at Week 12 or Week 16 or Week 24 or 
Week 36 after initial treatment or touch up (as assessed by the TI), subject will be eligible for 
optional early retreatment if necessary at 12 or 16 or 24 or 36 weeks after baseline (provided that 
the TI deems the treatment to be appropriate, and the subject agrees). The subject will then be 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 5 of 72 
followed for an additional 4 weeks after repeat treatment and for all subsequent scheduled visits.  
Subjects receiving optional early retreatment at Week 12 or Week 16 or Week 24 or Week 36 after 
the after initial treatment or touch-up, will be offered retreatment at Week 52. 
Subjects randomized to the “No-Treatment” control group will receive their first treatment after 
the primary endpoint evaluation (Week 8 after randomization) and will then follow the same 
schedule as the initial treatment group. 
Hypothesis 
TEOSYAL® RHA Redensity will be superior to No-Treatment control for the correction of 
moderate to severe perioral rhytids as determined by the PR-SRS at Week 8 after the last treatment. 
An improvement in the PR-SRS of ≥1-grade compared to pre-treatment will be considered 
clinically meaningful.  
Objectives 
To establish the safety and effectiveness of TEOSYAL® RHA Redensity in the treatment of 
moderate to severe perioral rhytids.  
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 perioral rhytids of grade 2 or 3 on the four point PR-SRS (ranging from 
0-3). BLE and TI must independently assess and agree that the criterion is met; however, 
concordance of severity is not required. 
3. Willing to abstain from facial aesthetic procedures/therapies that could interfere with study 
evaluations (e.g., other fillers, botulinum toxin injections, laser or chemical resurfacing, etc.) 
for the duration of the study (see Section 7.5.1 for the medications/procedures which have 
either restrictions for usage, or are prohibited during the course of the study). 
4. Able to follow study instructions and complete all required visits. 
5. Sign the IRB-approved ICF, Photographic Release Form and the Authorization for Use and 
release of Health and Research Study Information (HIPAA) form prior to any study-related 
procedures being performed. 
Exclusion 
Criteria 
1. Female subjects that 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 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 within 6 months prior to study entry (TI discretion). 
7. History of active chronic debilitating systemic disease. 
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. 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 6 of 72 
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 (eg non-steroidal anti-inflammatory, anti-
coagulant, fish oil), wait 14 days or until bleeding times return to normal before injecting. 
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 
(TI discretion). 
18. Have 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 administrated into the dermis, including the superficial 
dermis. 
Injection technique:  The injection technique (e.g., linear threading, cross hatching, fan like 
administration, multiple puncture, etc.), injection direction (e.g., retro-grade, or ante-grade), and 
how the wrinkle was injected (e.g., following the wrinkle, right angle to the wrinkle, etc.), will be 
at the discretion of the TI, and will be recorded. 
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. 
Amount of device to administer:  The maximum volume per administration of the study device 
into the perioral rhytids (upper and lower) is 6.0 mL per treatment session (max 3.0 mL for upper, 
and max 3.0 mL for lower).  
Blinding 
The BLE will be blinded to the treatment allocation. Furthermore, to ensure that they remain 
masked and unbiased when making their assessments throughout the study, the BLE, TI and 
subject will not be allowed to refer to each other’s efficacy assessments. 
All subjects will be instructed to not discuss their study treatment, AEs, or CTRs with the BLE. 
Visit 
Procedures 
Refer to the Study Summary Tables and the Study Schematic for a schedule of activities. 
Efficacy 
Evaluations 
• Perioral Rhytids Severity Rating Scale (PR-SRS) - a validated 4-point static scale for 
assessing perioral rhytids severity. 
• FACE-Q scale - a validated Patient Reported Outcome Measure. 
• Global Aesthetic Improvement (GAI) scale - a subjective, balanced, 5-point dynamic scale 
assessing cosmetic improvement. 
• Subject Satisfaction Scale - a subjective, balanced, 5-point scale assessing subject satisfaction 
with study treatment. 
• Treatment Volume - the number of treatment sessions and total volume to obtain Optimal 
Correction Result. 
• Modified Glogau Classification Scale - a 4-point classification to measure the severity of 
wrinkling. 
• Natural look and natural feel of the perioral area, assessed by the subjects on a 11-point scale  
Safety 
Evaluations 
• Adverse Events. 
• Post-injection common treatment response (14-day patient CTR diary). 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 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 Injection Site Pain (100 mm Visual Analog Scale -VAS).  
Primary 
Endpoint 
The primary endpoint will be a co-primary endpoint. A responder will be defined as a subject who 
has a ≥1-grade improvement on the PR-SRS as assessed by the BLE before initial treatment and 
at Week 8 after initial treatment or touch-up.  Only data from the first 8-week phase will be taken 
into account.  The No-Treatment control group after treatment will not be pooled for the primary 
endpoint. 
The effectiveness of TEOSYAL® RHA Redensity will be demonstrated if: 
• 
The responder rate for subjects treated with TEOSYAL® RHA Redensity is statistically 
superior to the responder rate for the No-Treatment control, and; 
• 
The responder rate for subjects treated with TEOSYAL® RHA Redensity is ≥70%, and; 
• 
The difference between the responder rate for subjects treated with TEOSYAL® RHA 
Redensity and the No-Treatment group must be ≥50 points. 
Secondary 
Endpoints 
For the Secondary Endpoints, like for the Primary Endpoint, only data from the first 8-week phase 
will be taken into account, and will compare TEOSYAL® RHA Redensity to No-Treatment (the 
No-Treatment control group after treatment will not be pooled): 
• 
FACE-Q at Week 4 and Week 8 after last treatment 
• 
Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as assessed 
by subject at Week 8 after last treatment, using the GAI scale. 
• 
Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as assessed 
by BLE at Week 8 after last treatment, using the GAI scale. 
• 
Proportion of subjects “satisfied” or “very satisfied” at Week 8 after initial treatment or 
touch-up, using the Subject Satisfaction Scale. 
Sample Size 
The estimated responder rate for subjects treated for perioral rhytids is set at 70%. First level risk 
error alpha will be set to 2.5%. 
In order to have the study able to detect any AE that has an incident rate of 2.5% or more in the 
sub-population of subjects of Fitzpatrick skin type IV to VI, at least 160 subjects should be enrolled 
and treated with the investigational device in the two pooled arms. With an anticipated 20% drop-
out rate throughout the entire study, a minimum total sample of 200 subjects (160 / 0.8 = 200), 
who will each receive TEOSYAL® RHA Redensity are required in order to detect a sufficient AE 
rate. 
Using an unbalanced 3:1 ratio, a sample size of a minimum of 150 subjects in the treatment group, 
and a minimum of 50 subjects in the control group, assuming a 20% drop-out rate throughout the 
entire study, will provide a >99.9% power for a 1-sided 2-group Fisher’s exact test at the 2.5% 
significance level to demonstrate statistical superiority of the treatment group over the control 
group, assuming a rate of responders in the treatment group of 70% and a rate of responders in the 
No-Treatment control group of 20%. 
Statistical 
Methods 
Primary Endpoint: The primary endpoint will be analyzed in a superiority statistical model using 
the PR-SRS as rated by the BLE. A responder is defined as a subject with a ≥1-grade improvement 
on the PR-SRS as assessed by the BLE at Week 8 after initial or touch-up compared with the pre-
treatment assessment (baseline) by the BLE. Only data from the first 8-week phase will be taken 
into account (the No-Treatment control group after treatment will not be pooled for the primary 
endpoint). 
The efficacy analysis will be based on a co-primary end-point: 

TEOXANE SA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 8 of 72 
• The rate of responders treated with TEOSYAL® RHA Redensity will be compared to the rate 
of responders in the No-Treatment group, using an independent-testing based on a 2-group, 1-
sided, Fisher’s exact statistic. For achieving superiority, the observed p-value must be ≤ 0.05; 
• At least 70% of the subjects treated with TEOSYAL® RHA Redensity must be responders; 
• The difference between the responder rate for subjects treated with TEOSYAL® RHA 
Redensity and the No-Treatment group must be ≥50 points. 
 
A two-sided 95.0% Confidence Interval will be calculated for the estimated responder rates.  
Analysis will be performed on the Intent-To-Treat (ITT) population. 
Secondary Endpoints:  For the Secondary Endpoints, like for the Primary Endpoint, only data 
from the first 8-week phase will be taken into account and will compare treatment to No-Treatment 
(the No-Treatment control group after treatment will not be pooled for the secondary endpoint): 
Secondary effectiveness analysis will be performed only if the primary endpoint analysis is 
significant. Each test will be performed at the same significance level () of 0.025, using one-sided 
tests. For achieving superiority of the treatment group over the group without treatment, each of 
the observed p-value must be ≤ 0.025.  
For categorical variables, the two groups will be compared using an independent-testing based on 
a 2-group, 1-sided, Fisher’s exact statistic.  For continuous variables, the two groups will be 
compared using an independent Student t-test. 
Safety Analysis:  Safety population will be used to summarize the safety of TEOSYAL® RHA 
Redensity and will consist of all treated subjects. The primary safety analysis is the calculation of 
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. 
The safety data of the two groups will be pooled, which will increase the power to observe AEs 
after treatment with the investigational device, and a separate analysis will be provided to compare 
the safety profile between the investigational group and the No-Treatment control group with 
delayed treatment once they have been treated. 
The study will be able to detect any AE that has an incident rate of <1.0% (0.625%) or more 
(assuming 160 subjects will be treated with the investigational device in the two pooled arms, and 
taking account of an anticipated 20% drop-out rate). 
When performing the analysis for the sub-group of subjects of Fitzpatrick skin type IV to VI (40 
subjects, or 25% of subjects who received treatment), the study will have the power to detect an 
AE with an incident rate of 2.5% or more. 
Safety results after repeat treatment (4 week follow up period) will also be compared between the 
initial treatment group and the No-Treatment control group, then if appropriate, the repeat 
treatment CTR, AE and SAE data will be pooled. 
 
 
 

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Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 9 of 72 
 
STUDY SUMMARY – TABLE 1 
 
PHASE 1a 
Groups:  RHA / Ø-tx 
PHASE 1b 
PHASE 2   Groups:  RHA / Ø-tx 
Visit 
V1 
BL 
i-Tx 
 
V2 
2W 
 
V3 
4W 
from last Tx 
V4 
8W 
from last Tx 
 
 
 
 
 
 
V5 to V9 
12W - 36W from last Tx 
Assessments and Procedures 
phone f/u 
3d post-Tx 
 
TU phone f/u 
3d post-TU 
ICF, Incl/excl, Demog, Med/surg hist* 
X 
 
 
 
 
 
 
*   = Procedures indicated may be performed up to 14 days prior to D0 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
RHA Redensity group 
 
 
 
 
 
 
 
 
Ø-tx = No-Treatment Group 
RHA = RHA Redensity Group 
i-Tx = Initial Treatment 
Tx = Treatment 
TU = Touch-Up Tx 
BL = Baseline 
BLE = Blinded Live Evaluator 
TI = Treating Investigator 
CTR = Common Treatment Reaction 
PR-SRS = Perioral Rhytids Severity Rating Scale 
GAI = Global Aesthetic Improvement 
b = before treatment 
a = after treatment 
b / a = before and after treatment 
(X), (b), (a), (b / a) = if treatment is administered 
† = V4 and V1(b) occur on same day 
 
UPT (if applicable) 
b 
 
 
(b) 
 
 
 
 
Injection 
X 
 
 
(X) 
 
 
 
 
14-day CTR diary & Pain VAS 
a 
 
 
(a) 
 
 
 
 
Adverse events 
b / a 
X 
X (a) 
(X) 
X 
X 
 
Conmeds * 
X 
X 
X 
 
(X) 
X 
X 
 
PR-SRS (BLE) 
b 
 
 
 
 
 
X 
 
PR-SRS (TI) 
b / a 
 
X (a) 
 
X 
X 
Proceed to Study Summary 
– Table 2 
Patient satisfaction 
 
 
 
 
 
X 
X 
GAI (BLE) 
 
 
 
 
 
 
X 
GAI (TI & subject) 
 
 
X 
 
 
X 
X 
 
FACE-Q  
b 
 
X 
 
 
X 
X 
 
Glogau (BLE) 
b 
 
 
 
 
 
X 
 
Glogau (TI) 
b 
 
X 
 
 
X 
X 
 
Natural look and feel (subject) 
b 
 
X 
 
 
X 
X 
 
Lip functionality (subject) 
b / a 
 
X (a) 
 
X 
X 
 
Photography 
b / a 
 
X (a) 
 
X 
X 
 
PR-SRS (IPR) 
b 
 
 
 
 
 
X 
 
No-Treatment (Ø-Tx) group 
 
 
 
 
 
 
PHASE 1b            Group:  Ø-tx 
 
 
V1 
BL 
 
 
V2 
2W 
 
 
V3 
4W 
 
V4† 
8W 
 
V1(b)† 
BL 
i-Tx 
 
V2(b) 
2W 
 
V3(b) 
4W 
from last Tx 
V4(b) 
8W 
from last Tx 
 
phone f/u 
3d post-Tx 
 
TU phone f/u 
3d post-Tx 
UPT (if applicable) 
X 
 
 
 
 
 
b 
 
 
(b) 
 
 
 
 
Injection 
 
 
 
 
 
 
X 
 
 
(X) 
 
 
 
 
14-day CTR diary & Pain VAS 
 
 
 
 
 
 
a 
 
 
(a) 
 
 
 
 
Adverse events 
 
 
X 
 
X 
X 
a 
X 
X (a) 
(X) 
X 
X 
 
Conmeds * 
X 
 
X 
 
X 
X 
 
X 
X 
 
(X) 
X 
X 
 
PR-SRS (BLE) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
PR-SRS (TI) 
X 
 
X 
 
X 
X 
a 
 
X (a) 
 
X 
X 
 
Patient satisfaction 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
GAI (BLE) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
GAI (TI & subject) 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
FACE-Q  
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
Glogau (BLE) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Glogau (TI) 
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
Natural look and feel (subject) 
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
Lip functionality (subject) 
 
 
 
 
 
X 
a 
 
X (a) 
 
X 
X 
 
Photography 
X 
 
 
 
 
X 
a 
 
X (a) 
 
X 
X 
 
PR-SRS (IPR) 
 
 
 
 
 
b 
 
 
 
 
 
 
X 
 

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Protocol  TEO-RHA-1501 
CONFIDENTIAL 
v.1.2; 27-Oct-2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 10 of 72 
STUDY SUMMARY – TABLE 2 
 
PHASE 2 
                   All Subjects 
Visit 
V5 
12W from last Tx 
 
V6§ - V5(x) 
16W from last Tx 
 
V7 
24W from last Tx 
 
V8 
36W from last Tx 
 
V9 
   52W from last Tx 
 
Assessments and Procedures 
 
 
re-Tx† 
 
phone f/u 
3d post-Tx 
 
 
re-Tx† 
 
phone f/u 
3d post-Tx 
V6(x) 
4W from 
re-Tx 
 
 
re-Tx† 
 
phone f/u 
3d post-Tx 
V7(x) 
4W from 
re-Tx 
 
 
re-Tx† 
 
phone f/u 
3d post-Tx 
V8(x) 
4W from 
re-Tx 
 
 
re-Tx 
 
phone f/u 
3d post-Tx 
V9(x) 
4W from 
re-Tx 
UPT (if applicable) 
 
(b) 
 
 
(b) 
 
 
 
(b) 
 
 
 
(b) 
 
 
 
(b) 
 
 
Early retreatment (conditional) 
 
(X) 
 
 
(X) 
 
 
 
(X) 
 
 
 
(X) 
 
 
 
 
 
 
Retreatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
 
 
14-day CTR diary & Pain VAS 
 
(a) 
 
 
(a) 
 
 
 
(a) 
 
 
 
(a) 
 
 
 
(a) 
 
 
Adverse events 
X 
(a) 
(X) 
X 
(a) 
(X) 
(X) 
X 
(a) 
(X) 
(X) 
X 
(a) 
(X) 
(X) 
X 
(a) 
(X) 
(X) 
Conmeds 
X 
 
(X) 
X 
 
(X) 
(X) 
X 
 
(X) 
(X) 
X 
 
(X) 
(X) 
X 
 
(X) 
(X) 
PR-SRS (BLE) 
X 
(a) 
 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
PR-SRS (TI) 
X 
(a) 
 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
Patient satisfaction 
X 
 
 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
GAI (BLE) 
X 
 
 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
GAI (TI & subject) 
X 
 
 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
FACE-Q  
X 
 
 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
Glogau (BLE) 
X 
 
 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
Glogau (TI) 
X 
 
 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
Natural look and feel (subject) 
X 
 
 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
X 
 
 
(X) 
Lip functionality (subject) 
X 
(a) 
 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
Photography 
X 
(a) 
 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
X 
(a) 
 
(X) 
PR-SRS (IPR) 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Exit Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
(X**) 
re-Tx = retreatment 
b = before treatment 
† = early re-Tx may be provided only ONCE: at V5 or V6 or V7 or V8.  
Subjects receiving re-Tx at V5 or V6 or V7 or V8 will continue study 
participation and will be offered re-Tx at V9.  . 
* =   Exit study if re-Tx not administered at V9 
** = Exit study if re-Tx administered at V9 
§ = V6 and V5(x) occur on same day 
Tx = Treatment 
a = after treatment 
BLE = Blinded Live Evaluator 
(X), (b), (a) = if treatment is administered 
TI = Treating Investigator 
 
CTR = Common Treatment Reaction 
 
PR-SRS = Perioral Rhytids Severity Rating Scale 
 
GAI = Global Aesthetic Improvement 
 
 
 

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STUDY SCHEMATIC 
 
 
1. 
Subjects could be eligible for a Touch-Up (TU) if deemed necessary by the Treating Investigator. 
2. 
Subjects offered early repeat treatment if PR-SRS returns to baseline at W12 after last treatment (if the Treating Investigator deems treatment to be 
appropriate).  
3. 
Subjects offered early repeat treatment if PR-SRS returns to baseline at W16 after last treatment, and if retreatment not provided at W12 after initial or touch-
up (and if the Treating Investigator deems treatment to be appropriate). 
4. 
Subjects offered early repeat treatment if PR-SRS returns to baseline at W24 after initial or touch-up, and if he/she has not yet received repeat treatment at 
W12, or W16 after last treatment (and if the Treating Investigator deems treatment to be appropriate). 
5. 
Subjects offered early repeat treatment if PR-SRS returns to baseline at W36 after initial or touch-up, and if he/she has not yet received repeat treatment at 
W12, W16, or W24 after initial or touch-up (and if the Treating Investigator deems treatment to be appropriate. 
6. 
Subjects offered repeat treatment at W52 after initial or touch-up , if the Treating Investigator deems treatment to be appropriate. The subject will then be 
followed for 4 weeks before exiting the study 
7. 
Subjects will be followed until the resolution of any clinically significant Treatment Related Adverse Events.  

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TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ............................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE .............................................................................................................. 3 
SYNOPSIS .............................................................................................................................................................. 4 
STUDY SCHEMATIC ........................................................................................................................................ 11 
TABLE OF CONTENTS ..................................................................................................................................... 12 
CONTACT LIST ................................................................................................................................................. 15 
ABBREVIATIONS .............................................................................................................................................. 16 
1 
INTRODUCTION ....................................................................................................................................... 17 
1.1 
Background ........................................................................................................................................... 17 
1.2 
Rationale for Study ................................................................................................................................ 17 
1.3 
Hypothesis ............................................................................................................................................. 17 
2 
STUDY OBJECTIVES ................................................................................................................................ 18 
3 
COMPLIANCE STATEMENT .................................................................................................................. 19 
3.1 
Variations to the Protocol ..................................................................................................................... 19 
3.2 
Investigational Sites .............................................................................................................................. 19 
3.3 
Training and certification on the Perioral Rhytids Severity Rating Scale (PR-SRS) ............................ 19 
3.4 
Independent Panel Review (Photographs) ............................................................................................ 20 
3.5 
Medical Monitor ................................................................................................................................... 20 
3.6 
Photography .......................................................................................................................................... 20 
4 
OVERVIEW OF STUDY DESIGN ............................................................................................................ 21 
4.1 
Study Design ......................................................................................................................................... 21 
4.2 
Study Design Rationale ......................................................................................................................... 21 
4.2.1 
Study Population ............................................................................................................................................. 21 
4.2.2 
Primary Effectiveness Outcome Measurement ............................................................................................... 22 
5 
STUDY POPULATION .............................................................................................................................. 23 
5.1 
Inclusion Criteria .................................................................................................................................. 23 
5.2 
Exclusion Criteria ................................................................................................................................. 23 
6 
TREATMENT ALLOCATION AND RANDOMIZATION .................................................................... 25 
7 
DEVICE APPLICATION ........................................................................................................................... 26 
7.1 
Study Devices ........................................................................................................................................ 26 
7.2 
Injection of Study Devices ..................................................................................................................... 26 
7.2.1 
Initial Treatment (Visit 1) ............................................................................................................................... 26 
7.2.2 
Touch-up Treatment (Visit 2; Week 2) ........................................................................................................... 26 
7.2.3 
Optional Early Retreatment (Visit 5, 6, 7 or 8; Weeks 12, 16, 24 or 36)......................................................... 27 
7.2.4 
Retreatment (Visit 9; Week 52) ....................................................................................................................... 27 
7.2.5 
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 ....................................................................................................................................... 29 
7.5 
Concomitant Medications and Procedures ........................................................................................... 29 
7.5.1 
Prohibited Treatment and Procedures ............................................................................................................. 29 
8 
DATA COLLECTION ................................................................................................................................ 31 
8.1 
Electronic Case Report Form ............................................................................................................... 31 
8.2 
Subject Diary and Questionnaires ........................................................................................................ 31 
8.3 
Photography .......................................................................................................................................... 31 
9 
STUDY EVALUATIONS ............................................................................................................................ 32 
9.1 
Informed Consent .................................................................................................................................. 32 

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9.2 
Phase 1a – Visit Procedures ................................................................................................................. 32 
9.2.1 
Visit 1 (Screening / Enrolment / Initial Treatment) ......................................................................................... 32 
9.2.2 
Visit 2 (14 days from V1; ±3 days) ................................................................................................................. 33 
9.2.3 
Visit 3 (Week 4 from last treatment - V1/V2; ±3 days) .................................................................................. 34 
9.2.4 
Visit 4 (Week 8 from last treatment - V1/V2; ±7 days) .................................................................................. 35 
9.3 
Phase 1b – Visit Procedures ................................................................................................................. 36 
9.3.1 
Visit 1b (Study Treatment) .............................................................................................................................. 36 
9.3.2 
Visit 2b (14 days from V1b; ±3 days) ............................................................................................................. 36 
9.3.3 
Visit 3b (Week 4 from last treatment - V1b/V2b; ±3 days)............................................................................. 36 
9.3.4 
Visit 4b (Week 8 from last treatment - V1b/V2b; ±7 days)............................................................................. 37 
9.4 
Phase 2 – Visit Procedures ................................................................................................................... 37 
9.4.1 
Visit 5 (Week 12 from last treatment – V1/V1b/V2/V2b; ±7 days) ................................................................ 37 
9.4.2 
Visit 6 (Week 16 from last treatment – V1/V1b/V2/V2b; ± 7days) ................................................................ 38 
9.4.3 
Visit 7 (Week 24 from last treatment – V1/V1b/V2/V2b; ±7 days) ................................................................ 39 
9.4.4 
Visit 8 (Week 36 from last treatment – V1/V1b/V2/V2b; ±7 days) ................................................................ 41 
9.4.5 
Visit 9 (Week 52 from last treatment – V1/V1b/V2/V2b; ±7 days) ................................................................ 42 
9.4.6 
Study Exit ........................................................................................................................................................ 43 
9.5 
Efficacy ................................................................................................................................................. 43 
9.5.1 
Primary Efficacy Variable ............................................................................................................................... 43 
9.5.2 
Secondary Efficacy Variables ......................................................................................................................... 43 
9.6 
Safety ..................................................................................................................................................... 45 
9.6.1 
14-Day Patient Common Treatment Response Diary ...................................................................................... 45 
9.6.2 
72-Hour Telephone Follow-up ........................................................................................................................ 46 
9.6.3 
Assessment of Injection Site Pain ................................................................................................................... 46 
9.6.4 
Lip Functionality ............................................................................................................................................. 46 
9.6.5 
Pregnancy ........................................................................................................................................................ 47 
9.6.6 
Adverse Events ............................................................................................................................................... 47 
9.6.7 
Adverse Event Reporting ................................................................................................................................ 50 
10 SUBJECT COMPLETION / WITHDRAWAL ......................................................................................... 52 
10.1 
Completion ............................................................................................................................................ 52 
10.2 
Discontinuation of Treatment................................................................................................................ 52 
10.3 
Withdrawal ............................................................................................................................................ 52 
11 STATISTICAL METHODS ....................................................................................................................... 54 
11.1 
Primary Endpoint .................................................................................................................................. 54 
11.2 
Secondary Endpoints ............................................................................................................................. 54 
11.3 
Exploratory Endpoints .................................................................................. Erreur ! Signet non défini. 
11.4 
Analysis Populations ............................................................................................................................. 56 
11.4.1 
Intent-to-Treat (ITT) Population ..................................................................................................................... 56 
11.4.2 
Per Protocol (PP) Population ........................................................................................................................... 56 
11.4.3 
Safety (SAFT) Population ............................................................................................................................... 56 
11.5 
Sample Size Considerations .................................................................................................................. 56 
11.6 
General Considerations ........................................................................................................................ 57 
11.7 
Efficacy Analysis ................................................................................................................................... 58 
11.8 
Safety Analysis ...................................................................................................................................... 59 
11.8.1 
Adverse Events (AEs) ..................................................................................................................................... 60 
11.8.2 
Injection Site Pain ........................................................................................................................................... 61 
11.8.3 
Lip Functionality ............................................................................................................................................. 61 
12 ETHICAL ASPECTS .................................................................................................................................. 62 
12.1 
Informed Consent .................................................................................................................................. 62 
12.2 
Health Authorities and IRBs ................................................................................................................. 62 
12.3 
Confidentiality Regarding Study Subjects ............................................................................................. 62 
13 STUDY MANAGEMENT & ADMINISTRATIVE REQUIREMENTS ................................................. 63 
13.1 
Protocol Amendments ........................................................................................................................... 63 
13.2 
Monitoring and Quality Assurance ....................................................................................................... 63 

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13.2.1 
Information to Study Personnel ....................................................................................................................... 63 
13.2.2 
Study Monitoring ............................................................................................................................................ 63 
13.2.3 
Audit and Inspection ....................................................................................................................................... 64 
13.3 
Protocol Deviations .............................................................................................................................. 64 
14 DATA HANDLING AND RECORD KEEPING ....................................................................................... 65 
14.1 
Source Data........................................................................................................................................... 65 
14.2 
Case Report Form ................................................................................................................................. 66 
14.3 
Archiving of Study Documentation ....................................................................................................... 66 
15 FINANCING AND INSURANCE .............................................................................................................. 68 
16 REPORTING AND PUBLICATION OF RESULTS ................................................................................ 69 
17 REFERENCES ............................................................................................................................................ 70 
18 APPENDICES .............................................................................................................................................. 71 
APPENDIX A: PROTOCOL VERSION HISTORY ........................................................................................ 72 
 

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CONTACT LIST 
Medical Monitor 
Stacy Smith, MD 
561 Saxony Place,  
Suite 102,  
Encinitas, CA 92024 
Phone:  619.787.5723 
Fax:   
619.342.7428 
ssmith@stacyrsmithmd.com 
 
Sponsor Contacts 
Mathilde Chenet (Clinical Project Manager) 
Sandra Chennoufi (Clinical Operation Manager) 
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 
s.chennoufi@teoxane.com 
 
Catherine Gloster 
Gloster Biomedical International 
577 North Hope Ave 
Santa Barbara, CA 93110 USA 
Phone: 805.679.1258 
Fax:  
805.682.1250 
c.gloster@GlosterBiomedical.com 
 
CRO Project Manager 
Murray Jensen, MSc 
ethica CRO Inc. 
8555 Transcanada Hwy, Suite 201 
Montreal, Quebec, H4S 1Z6 
Phone: 514.337.0442 ext. 208 
Fax:  
514.336.1142 
mjensen@ethicaCRO.com 
 
24-Hour Emergency Phone Number 
ethica CRO Inc.  
514.262.9398 
 
 
NOTE: Changes in the names, addresses or telephone numbers of these contacts will be considered 
administrative and will not require a protocol amendment before being implemented. 

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ABBREVIATIONS 
AE 
Adverse Event 
BLE 
Blinded Live Evaluator  
BL 
Baseline 
CFR 
U. S. Code of Federal Regulations 
CTR 
Common Treatment Response 
CRO 
Clinical Research Organization 
DHHS 
Department of Health and Human Services 
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 
IPR 
Independent Panel Review 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LLT 
Lowest Level Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-steroidal anti-inflammatory drug 
OCR 
Optimal Correction Result 
PI 
Principle Investigator 
PMA 
Premarket Approval 
PP 
Per protocol 
PR-SRS 
Perioral Rhytids Severity Rating Scale 
PT 
Preferred Term 
RHA 
Resilient Hyaluronic Acid 
SAE 
Serious Adverse Event 
SAFT 
Safety 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SDs 
Source Documents 
SOC 
System Organ Class 
TAN 
Treatment Assignment Number 
TRAE 
Treatment Related Adverse Event 
UADE 
Unexpected Adverse Device Effects 
TI 
Treating Investigator 
TU 
Touch-up Injection 
Tx 
Treatment 
UPT 
Urine Pregnancy Test 
 
 

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1 
INTRODUCTION 
1.1 
Background 
Hyaluronic acid (HA) is a long-chain, repeated dimer, N-acetyl glucosamine and D-glucuronic 
acid polymer and is a major component of the extracellular matrix. HA is widely present in all 
animal species and does not differ from one species to another. Due to this extended compatibility, 
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 
TEOSYAL® RHA Redensity dermal filler is a device containing colorless, biodegradable, sterile, 
biocompatible, crosslinked HA of non-animal origin (i.e., bacterial fermentation using 
Streptococcus zooepidemicus). Crosslinking is performed using 1,4-butanediol diglycidyl ether 
(BDDE) to form a gel. This RHA device contains 0.3% w/w of lidocaine hydrochloride, a drug 
substance widely used in dermatology for its anesthetic properties (i.e., it blocks the origin and 
transmission of nervous influx at the point of injection by stabilizing the neuronal membrane).  
TEOSYAL® RHA Redensity is indicated for injection in the dermis and superficial dermis of the 
face to correct moderate to severe perioral rhytids. 
Table 3.  Characteristics of TEOSYAL® RHA Redensity 
 
RHA Redensity 
Molecular weight of crosslinked HA 
4 MDa 
Total HA concentration 
15 mg/g 
Concentration of lidocaine hydrochloride by mass 
0.3% 
Syringe volume 
1mL volume per syringe 
Gauge needle for injection 
30G ½ inch needle 
1.2 
Rationale for Study 
TEOSYAL® RHA Redensity is an investigational device that has not yet been approved by the 
FDA. In the current study, this device is being compared to a No-Treatment control in a superiority 
pivotal study designed to support a PMA application (FDA) for TEOSYAL® RHA Redensity. 
1.3 
Hypothesis 
TEOSYAL® RHA Redensity will be superior to No-Treatment control for the correction of 
moderate to severe perioral rhytids as determined by the PR-SRS at 8 weeks after initial or touch-
up treatment. An improvement in the PR-SRS of ≥1-grade from pre-treatment will be considered 
clinically meaningful. 

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2 
STUDY OBJECTIVES 
The study objectives are to establish the safety and effectiveness of TEOSYAL® RHA Redensity 
in the treatment of moderate to severe perioral rhytids: 
1. To demonstrate the superiority of TEOSYAL® RHA Redensity versus the No-Treatment 
control at 8 weeks for the correction of moderate to severe perioral rhytids.  Assessment 
of superiority will be based on the Perioral Rhytids Severity Rating Scale (PR-SRS) as 
rated by the Blinded Live Evaluator (BLE) at each investigative site. 
 
2. To evaluate the safety of TEOSYAL® RHA Redensity for the treatment of moderate to 
severe perioral rhytids. Safety will be determined by the rates of Adverse Events (AEs) 
associated with the use of the study device. Subjects will be observed for up to 
approximately 52 weeks following initial treatment or touch-up treatment with the study 
device. Safety will also be evaluated for 4 weeks following any retreatment. 

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3 
COMPLIANCE STATEMENT 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) and Good Clinical Practice (GCP), the Declaration of Helsinki, 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 and in Canada. 
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 trained in its proper use are immediately 
available in case of a medical emergency. The Investigators (BLE and 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. The ethica CRO Inc. 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, Health Canada, 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 
Up to ten (10) U.S. and Canadian 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 protocol, and approved 
by the reviewing IRB.  
Each site will have at least one TI who will be responsible for administering all study treatments, 
assessing safety, and conducting live assessments of efficacy secondary endpoints, and a single 
BLE who will conduct live PR-SRS, GAI and Glogau assessments at selected visits. 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. 
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 appearance of perioral 
rhytids. All assessors (BLEs, TIs, and IPRs) 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 severity. An assessor (BLEs, TIs, and IPRs) will be considered 
certified once his/her percentage of agreement with the true values is ≥80%. 

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There will be a single BLE for each site; however, an additional BLE(s) may be certified at a given 
site to ensure continuity of subject follow-up in cases of sickness or unavoidable absence. 
3.4 
Independent Panel Review (Photographs) 
Three independent experts, that are not Investigators in the clinical study, will be selected and 
trained to conduct PR-SRS assessments on photographs. Prior to conducting the Independent Panel 
Review (IPR), each member of the panel will be certified regarding the conduct of PR-SRS 
assessments as described in Section 3.3. 
3.5 
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 monthly, 
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 with the Sponsor. 
3.6 
Photography 
Set-up of photographic equipment, as well as training and quality control processes, will be 
provided and will be managed by a dedicated professional third party (i.e., Canfield Scientific 
Inc.). 

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4 
OVERVIEW OF STUDY DESIGN 
4.1 
Study Design 
This is a randomized, blinded, No-Treatment control, multicenter, prospective clinical study, to 
identify whether TEOSYAL® RHA Redensity is more effective than No-Treatment in the 
correction of moderate to severe perioral rhytids at Week 8 after initial or touch-up treatment. 
The Treating Investigator (TI) will evaluate subjects for eligibility of the subject for the study. 
The Blinded Live Evaluator (BLE) at screening will evaluate the subject’s perioral rhytids 
severity using the Perioral Rhytids Severity Rating Scale (PR-SRS) in order to confirm eligibility 
and to establish a pre-treatment score. This will be done independently of the TI, and exact 
concordance between the BLE and the TI is not necessary. 
Enrolled subjects will be randomized to either the TEOSYAL® RHA Redensity treatment group 
or the “No-Treatment” control group. The TI will administer study device, and if necessary, 
subjects will receive a touch-up treatment 14 days following the initial treatment to optimize the 
results. The TI will conduct safety and effectiveness evaluations at study subject visits, which will 
occur at Week 4, 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment, and 4 weeks after a 
repeat treatment. 
The BLE will conduct assessments of efficacy during the trial, including assessment of the primary 
endpoint at Week 8 after initial or touch up treatment. The BLE will conduct effectiveness 
evaluations at Week 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment. 
Subjects will be followed for 52 weeks from initial or touch up treatment, at which point they will 
be offered a repeat treatment (provided that the TI deems the treatment to be appropriate, and if 
the subject agrees). The subject will then be followed for an additional 4 weeks after the treatment 
before exiting the study. 
Should a subject return to his/her pre-treatment PR-SRS level before Week 52, as assessed by the 
TI, he/she will be eligible to receive an early repeat treatment (provided that the TI deems the 
treatment to be appropriate, and if the subject agrees) at Week 12, or Week 16, or Week 24, or 
Week 36 after initial or touch-up treatment. . 
Subjects randomized to the “No-Treatment” control group will receive their first treatment after 
the primary endpoint evaluation (8 weeks after randomization) and will then follow the same 
schedule as the initial treatment group. 
4.2 
Study Design Rationale 
4.2.1 
Study Population 
At least 200 subjects will be enrolled and randomized.  At least 150 subjects will receive treatment 
with TEOSYAL® RHA Redensity, and at least 50 subjects will be enrolled as No-Treatment 
controls. 
The study population includes female and male subjects that are 22 years old.   
The study will ensure that subjects meeting the inclusion criteria will be representative of the U.S. 
population that may use TEOSYAL® RHA Redensity.  Specifically, enrolment will be comprised 
of at least 25% subjects of Fitzpatrick skin IV to VI. The randomization algorithm will ensure an 

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overall minimal demographic sample of subjects in the active treatment group as per the following: 
• ≥25% of subjects with Fitzpatrick Skin Type IV to VI 
- 
≥18% of subjects with Fitzpatrick Skin Type IV (i.e., ≥36 subjects); 
- 
≥7% of subjects with Fitzpatrick Skin Type V or VI (i.e., ≥14 subjects). 
A full description of the inclusion and exclusion criteria can be found in Section 5. 
4.2.2 
Primary Effectiveness Outcome Measurement 
The primary endpoint will be a co-primary endpoint. A responder will be defined as a subject who 
has a ≥1-grade improvement on the PR-SRS as assessed by the BLE before initial treatment 
(baseline) and at Week 8 after initial or touch-up treatment.  The effectiveness of TEOSYAL® 
RHA Redensity will be demonstrated if: 
• The responder rate for subjects treated with TEOSYAL® RHA Redensity is statistically 
superior to the responder rate for the No-Treatment control, and; 
• The responder rate for subjects treated with TEOSYAL® RHA Redensity is ≥70%, and; 
• The difference between the responder rate for subjects treated with TEOSYAL® RHA 
Redensity and the No-Treatment group must be ≥50 points. 
 
 
 
 

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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
1. Outpatient, male or female of any race, 22 years of age or older. 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 or intrauterine device in use >90 days prior to study treatment administration; 
- barrier methods plus spermicide in use at least 14 days prior to study treatment administration; or 
- vasectomized partner.  
[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 perioral rhytids of grade 2 or 3 on the four point PR-SRS (ranging from 
0-3). BLE and TI must independently assess and agree that the criterion is met; however, 
concordance of severity is not required. 
3. Willing to abstain from facial aesthetic procedures/therapies below the orbital rim that could 
interfere with study evaluations (e.g., other fillers, lip augmentation, botulinum toxin 
injections, laser or chemical resurfacing, etc.) for the duration of the study (see Section 7.5.1 
for the medications/procedures have either restrictions for usage, or are prohibited during the 
course of the study). 
4. Be able to follow study instructions and likely to complete all required visits; 
5. Sign the IRB-approved ICF, Photographic Release Form and the Authorization for Use and 
release of Health and Research Study Information (HIPAA) form prior to any study-related 
procedures being performed. 
5.2 
Exclusion Criteria 
1. Female subjects that 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 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 within 6 months prior to study entry (TI discretion). 

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7. History of active chronic debilitating systemic disease that, in the opinion of the investigator, 
would make the subject a poor candidate for participation 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 (eg non-steroidal anti-inflammatory, anti-
coagulant, fish oil), wait 14 days or until bleeding times return to normal before injecting. 
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 
(TI discretion). 
18. Have 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 prior to study entry. 
21. Clinically significant alcohol or drug abuse, or history of poor cooperation or unreliability. 

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6 
TREATMENT ALLOCATION AND RANDOMIZATION 
All subjects who have signed an ICF will receive a 4-digit subject number, starting at 0001. 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 to a study group utilizing a 
randomization algorithm embedded into the electronic Case Report Form (eCRF).  
Subjects will be randomized (3:1 ratio) to one of the following groups: 
• TEOSYAL® RHA Redensity; 
• No-Treatment (untreated control). 
The TI will secure the treatment allocation and any other record of study treatment from potential 
discovery by the BLE. Any instance where the blind is opened to the BLE will be documented in 
writing. 
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. 
 

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7 
DEVICE APPLICATION 
7.1 
Study Devices 
TEOSYAL® RHA Redensity: 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 study device, please refer to TEO-RHA-1501 Investigator’s 
Brochure. 
7.2 
Injection of Study Devices 
TEOSYAL® RHA Redensity will be administrated into the dermis, including the superficial 
dermis.  The injection technique (e.g., linear threading, cross hatching, fan like administration, 
multiple puncture, etc.), injection direction (e.g., retro-grade, or ante-grade), and how the wrinkle 
was injected (e.g., following the wrinkle, right angle to the wrinkle, etc.), will be at the discretion 
of the TI, and will be documented and recorded.  
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. 
TEOSYAL® RHA Redensity contains lidocaine. Treating Investigators may select the additional 
pre-procedure aesthesia to be used for pain or discomfort (e.g., EMLA), and its use must be 
recorded in the eCRF, if any. Any topical anesthesia should be on label, and no compounding 
formulation will be used. Post-procedure ice packs shall be applied to the treatment area as per the 
Investigator’s standard of care. Use of ice will be recorded as a concomitant treatment on the 
Concomitant Treatment eCRF. 
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 moderate to severe perioral lines, and there will be no 
augmentation of the lips.  TI may inject at the level of the vermilion border when they feel it is 
required to achieve a satisfactory result of the treatment of the perioral rhytids. 
7.2.1 
Initial Treatment (Visit 1) 
Each subject randomized to treatment will receive injections of TEOSYAL® RHA Redensity.  
Subjects randomized to the No-Treatment control arm of the study will not receive any injection. 
Subjects randomized to the “No-Treatment” control group will receive their first treatment after 
the primary endpoint evaluation (i.e., Visit 4; 8 weeks after randomization) and will then follow 
the same schedule as the initial treatment group. 
7.2.2 
Touch-up Treatment (Visit 2; Week 2) 
If deemed necessary by the TI, additional touch-up correction with TEOSYAL® RHA Redensity 
will be performed after 2 weeks.  

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If a touch-up injection is not administered, the scheduling of subsequent study visits will be based 
on Visit 1 (i.e., from the last study treatment). If a touch-up injection is administered, the 
scheduling of subsequent study visits will be based on Visit 2. 
7.2.3 
Optional Early Retreatment (Visit 5, 6, 7 or 8; Weeks 12, 16, 24 or 36) 
In order to reduce subject dissatisfaction, optional* early retreatment will be offered at Visit 5 
(Week 12) or Visit 6 (Week 16) or Visit 7 (Week 24) or Visit 8 (Week 36) in case of significant 
loss of correction as per the following criteria: 
• Correction of perioral rhytids has returned to pre-treatment levels. 
Any optional retreatment will be performed with TEOSYAL® RHA Redensity to achieve optimal 
correction. 
Subjects who receive optional early retreatment at Visit 5 may not receive additional early optional 
retreatment at Visit 6, Visit 7, or Visit 8. 
Subjects who receive optional early retreatment at Visit 6 may not receive additional early optional 
retreatment at Visit 7, or Visit 8. 
Subjects who receive optional early retreatment at Visit 7 may not receive additional early optional 
retreatment at Visit 8. 
Subjects that receive optional early retreatment at either Visit 5 or Visit 6 or Visit 7 or Visit 8 are 
eligible to receive retreatment at Visit 9.  
Subjects who receive optional retreatment at Visit 5 or Visit 6 or Visit 7 or Visit 8 will be followed 
up by telephone at 3 days after retreatment, complete a 14-day patient CTR diary and will return 
for safety evaluations 4 weeks after optional early retreatment (Visit 5x = Visit 6 or Visit 6x, Visit 
7x or Visit 8x). 
* “Optional early retreatment” ≠ “retreatment”.  “Optional early retreatment” is reserved for subjects dissatisfied by loss of effect 
and at high risk of study d/c prior to attaining 1-year (52 weeks) post-treatment safety follow-up.  “Retreatment” is provided to all 
subjects at Visit 9/Week 52 to encourage subject participation and to evaluate the safety of retreatment.  All subjects who will have 
received optional early retreatment will continue with all following visits, up and included Visit 9/Week 52.. 
7.2.4 
Retreatment (Visit 9; Week 52) 
Subjects will be followed for 52 weeks from initial or touch up treatment), at which point they will 
be offered a repeat treatment, provided that the TI deems the treatment to be appropriate, and the 
subject agrees. The subject will then be followed for an additional 4 weeks before exiting the study. 
7.2.5 
Treatment Volume Allowance 
The maximum volume per administration of the study device into the perioral rhytids (upper and 
lower) is 6.0 mL per treatment session (max 3.0 mL for upper, and max 3.0 mL for lower). 
7.3 
Labeling, Packaging and Storage 
Open-label packaged supplies of TEOSYAL® RHA Redensity will be provided to the sites in bulk 

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(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-1501 
• IDE number: e.g., G160123 
• Name and address of the Sponsor/Manufacturer (i.e., TEOXANE S.A.) 
• Name of product (i.e., TEOSYAL® RHA Redensity) 
• Quantity of syringes (n=1) 
• Quantity of 30G ½ inch needles (n=2) 
• Batch number 
• Manufacturing date 
• Expiry date 
• The CAUTION statement mentioned above 
There will be no study specific labeling applied directly to the device syringe. 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 area with restricted 
access. 
7.3.1 
Relabeling 
Real-time aging testing is in progress for TEOSYAL® RHA Redensity. As new test data will 
become available throughout the course of the study, the shelf life of TEOSYAL® RHA Redensity 
may be extended through the course of the study. The site monitor will be responsible for 
relabeling the Tyvek lid with the new expiry date. The site monitor 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. TEOSYAL® RHA 
Redensity may also be returned to the Sponsor to be relabeled. When TEOSYAL® RHA Redensity 
has reached the expiry date as indicated on its label, the PI should segregate them and follow the 
instructions from the site monitor as to awaiting for relabeling by the site monitor or 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 TEOSYAL® RHA Redensity will be approximately 6 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 initial treatments, touch-up treatments, and for retreatments. It is forbidden to use a 
study device for purposes other than defined in this protocol. 

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Study devices must be kept in a locked area with access restricted to designated study personnel. 
The Principal Investigator or designate will inventory and acknowledge receipt of all study device 
shipments, and to 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 disposed of according to each site’s standard 
procedures. 
7.4.1 
Other Study Supplies 
Supplies that are unique to the study will be provided by the Sponsor (e.g., UPTs, photographic 
equipment, paper study diaries, source document worksheets, etc.). The site is responsible for 
routine supplies related to pre-/post-treatment care (e.g., alcohol wipes, gauze, EMLA, 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 (including No-Treatment controls) must not undergo any type of facial procedure below 
the orbital rim, including but not limited to dental, plastic or reconstructive surgery; non-ablative 
procedures; botulinum toxin injections; laser resurfacing; facial laser hair removal, 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: 
• 
Clinically significant oral or maxillofacial surgery that may interfere with 
study 
assessments 
or 
procedures 
(e.g., 
craniofacial 
surgery, 
reconstructive therapy, implants, dentoalveolar surgery, etc.). 
≥12 months 
Investigational drugs/devices: 
• 
Exposure to any other investigational drug/device 
≥90 days 
Additionally, subjects should be advised to not use make-up below the infraorbital rim during the 
12 hours following injection and not to use lip plumping cosmetics or devices for the duration of 

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the study. Subjects should be advised to avoid extreme temperatures (intense cold, sauna, 
hammam, etc.) during the week following treatment. Wax or chemical hair removal around the 
lips is prohibited for 7 days before treatment and 14 days after treatment. 
All treatment/procedures received by the subject within 30 days prior to the baseline visit and 
throughout the treatment period, including the name of the treatment/procedure, must be recorded 
in the eCRF with end dates, if applicable. Use of prohibited treatment/procedures must be recorded 
in the eCRF up to the extent of the prohibited time period indicated above. Furthermore, previous 
use of facial aesthetic treatment/procedures must be recorded for up to 1 year prior to the baseline 
visit. 
In the event such prohibited therapies are administered during the study period, the Medical 
Monitor will be contacted to discuss the details of the event. Subject participation will not 
automatically be discontinued. At a minimum, the event will be documented by the site staff as a 
protocol deviation, as instructed by the Medical Monitor. Depending upon the nature of the 
prohibited therapy and the timing relative to the determination of the primary endpoint, the 
Medical Monitor may make a decision to discontinue the subject. 
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. If the permissibility of a specific medication/treatment is 
in question, the Medical Monitor should be contacted before the prohibited medication/treatment 
is administered. 
 

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8 
DATA COLLECTION 
8.1 
Electronic Case Report Form 
Treatment and follow-up of subjects will be recorded in a 21 CFR part 11 compliant eCRF. Data 
will be first recorded into the medical record and study specific source document worksheets prior 
to entry into the eCRF. 
A paper CRF will be used to capture additional demographics and social history. 
Two sets of worksheets will be used to capture study specific information (i.e., efficacy 
assessments, injection volumes, injection technique, etc.); one set for the BLE and study 
coordinator, and one set for the TI and study coordinator. This will allow the BLE and TI to remain 
blinded to each other’s assessments. The study coordinator will refer to these worksheets in 
conjunction with the medical record in order to complete data entry into the eCRF. Study 
Investigators will not disclose their opinion regarding treatment outcomes with subjects in order 
to, 1) prevent subjects from sharing such opinions between the TI and the BLE, and 2) avoid 
biasing subject reported outcomes. 
In order to review and electronically sign the eCRF, the BLE and TI will have individual login 
passwords that will allow them to view only the data that they have generated. The BLE and TI 
must ensure that they electronically sign for completed eCRFs on a timely basis. 
8.2 
Subject Diary and Questionnaires 
Subjects will complete paper-based subject 14-day diaries and questionnaires. Data recorded in 
these documents will be entered into the eCRF by the study coordinator. 
8.3 
Photography 
Calibrated photographs will be taken at each in-clinic study visit (and if applicable, before and 
after study treatment), according to a standardized protocol incorporating appropriate quality 
control processes (i.e., Canfield Scientific Inc.). 

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9 
STUDY EVALUATIONS 
9.1 
Informed Consent 
The Principal Investigator (or designate) will explain the benefits and risks of participation in the 
study to each subject and will obtain written informed consent. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study related procedure 
and injection of study devices). 
(*) To ensure the unbiased assessment, the perioral rhytids severity rating scale (PRS-RS) assessment will be performed 
first at all visits that require PRS-RS evaluations.  Once this evaluation is complete, then the forms will be removed 
and the materials will be brought in for the investigator to perform the dynamic evaluations such as the GAI 
assessment. 
9.2 
Phase 1a – Visit Procedures 
9.2.1 
Visit 1 (Screening / Enrolment / Initial 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+ 
• Randomization to study treatment allocation 
- 
If subject randomized to treatment with Redensity, go to Section 9.2.1.1 
- 
If subject randomized to No-Treatment, go to Section 9.2.1.2 
9.2.1.1 
Redensity Treatment Group 
• BLE Assessments 
- 
PR-SRS* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
Glogau 
- 
AEs from time of consent 
- 
PR-SRS (post-injection) 
- 
AEs (post-injection) 
- 
Lip functionality (pre and post injection) 
• Subject Assessments 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Injection site pain 
• Facial photography (pre- and post-injection) 
• Injection of study devices 
• Dispense CTR diary 

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• Contact subject by phone at 72 hours (3d from V1; ±1d) and query regarding health status 
and AEs 
9.2.1.2 
No-Treatment Group 
• BLE Assessments 
- 
PR-SRS* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
Glogau 
• Subject Assessments 
- 
FACE-Q 
- 
Natural Look/Feel 
• Facial Photography 
9.2.2 
Visit 2 (14 days from V1; ±3 days) 
9.2.2.1 
Redensity Treatment Group 
• Concomitant medications/treatments 
• BLE Assessments 
- 
Not applicable 
• TI Assessments 
- 
PR-SRS* 
- 
PR-SRS post-TU (if applicable) 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs) 
- 
AEs post-TU (if applicable) 
- 
Lip functionality (pre and post if TU – or just once if no TU) 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Injection site pain (if TU injection) 
• Facial photography 
• Touch-up injections (TI discretion) 
- 
If TU administered: 
▪ 
UPT (if female subject of childbearing potential) 
▪ 
Facial photography post-TU 
▪ 
Dispense CTR diary 
▪ 
Phone subject at 72 hours (3d from V2; ±1d) and query regarding health status and AEs 

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9.2.2.2 
No-Treatment Group 
• Concomitant medications/treatments 
• BLE Assessments 
- 
Not applicable 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
9.2.3 
Visit 3 (Week 4 from last treatment - V1/V2; ±3 days) 
9.2.3.1 
Redensity Treatment Group 
• Concomitant medications/treatments 
• BLE Assessments 
- 
Not applicable 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs, if applicable) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
9.2.3.2 
No-Treatment Group 
• Concomitant medications/treatments 
• BLE Assessments 
- 
Not applicable 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 

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- 
Natural Look/Feel 
9.2.4 
Visit 4 (Week 8 from last treatment - V1/V2; ±7 days) 
9.2.4.1 
Redensity Treatment Group 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
• Proceed to Phase 2 of the study (Section 9.4) 
9.2.4.2 
No-Treatment Group 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
• Proceed immediately to Phase 1b (Visit 1b) of the study (Section 9.3.1) 
- 
No-Treatment Group subjects will receive treatment with Redensity 
- 
Visit 4 (Phase 1a) and Visit 1b (Phase 1b) are to be combined into a single visit 

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9.3 
Phase 1b – Visit Procedures 
9.3.1 
Visit 1b (Study Treatment) 
Phase 1b to be conducted with No-Treatment group subjects only 
• UPT (if female subject of childbearing potential) 
• TI Assessments 
- 
PR-SRS (post-injection) 
- 
AEs (post-injection) 
- 
Lip functionality (post injection) 
• Subject Assessments 
- 
Injection site pain 
• Injection of study device 
- 
Facial photography (post-injection) 
- 
Dispense CTR diary 
- 
Phone subject at 72 hours (3d from V1b; ±1d) and query regarding health status and AEs 
9.3.2 
Visit 2b (14 days from V1b; ±3 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
Not applicable 
• TI Assessments 
- 
PR-SRS* 
- 
PR-SRS post-TU (if applicable) 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs) 
- 
AEs post-TU (if applicable) 
- 
Lip functionality (pre and post injection if TU) 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Injection site pain (if TU injection) 
• Facial photography 
• Touch-up injections (TI discretion) 
- 
If TU administered: 
▪ 
UPT (if female subject of childbearing potential) 
▪ 
Facial photography (post-TU) 
▪ 
Dispense CTR diary 
▪ 
Phone subject at 72 hours (3d from V2b; ±1d) and query regarding health status and AEs 
9.3.3 
Visit 3b (Week 4 from last treatment - V1b/V2b; ±3 days) 
• Concomitant medications/treatments 
• BLE Assessments 

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- 
Not applicable 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs, if applicable) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
9.3.4 
Visit 4b (Week 8 from last treatment - V1b/V2b; ±7 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
• Proceed to Phase 2 of the study (Section 9.4) 
9.4 
Phase 2 – Visit Procedures 
* “Optional early retreatment” ≠ “retreatment”.  “Optional early retreatment” is reserved for subjects dissatisfied by loss of 
effect and at high risk of study d/c prior to attaining 1-year (52 weeks) post-treatment safety follow-up.  “Retreatment” is 
provided to all subjects at Visit 9/Week 52 to encourage subject participation and to evaluate the safety of retreatment.  All 
subjects who will have received optional early retreatment will continue with all following visits, up and included Visit 9/Week 
52. 
9.4.1 
Visit 5 (Week 12 from last treatment – V1/V1b/V2/V2b; ±7 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 

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- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
- 
AEs 
- 
AEs post-injection (if applicable) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
- 
Injection site pain (if applicable) 
• Facial photography 
• Early Retreatment 
- 
TI will determine if early retreatment is warranted as per Section 7.2.3 
- 
If Early Retreatment IS NOT administered 
▪ 
Proceed to Visit 6 
- 
If Early Retreatment IS administered 
▪ 
UPT (if female subject of childbearing potential) 
▪ 
Facial photography (post-injection) 
▪ 
Dispense CTR diary 
▪ 
Lip functionality (post injection) 
▪ 
Phone subject at 72 hours (3d from V5; ±1d) and query regarding health status and AEs 
▪ 
Proceed to Visit 6 
9.4.2 
Visit 6 (Week 16 from last treatment – V1/V1b/V2/V2b; ± 7days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs) 
- 
AE post-injection (if applicable) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 

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- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
- 
Injection site pain (if applicable) 
• Facial photography 
• Early Retreatment 
- 
TI will determine if early retreatment is warranted as per Section 7.2.3 
- 
If Early Retreatment IS NOT administered 
▪ 
Proceed to Visit 7 
- 
If Early Retreatment IS administered 
▪ 
UPT (if female subject of childbearing potential) 
▪ 
Facial photography (post-injection) 
▪ 
Dispense CTR diary 
▪ 
Lip functionality (post injection) 
▪ 
Phone subject at 72 hours (3d from V6; ±1d) and query regarding health status and AEs 
▪ 
Proceed to Visit 6x 
9.4.2.1 
Visit 6x (4 weeks from V6; ±7 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
• Proceed to Visit 7 
9.4.3 
Visit 7 (Week 24 from last treatment – V1/V1b/V2/V2b; ±7 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 

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- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
- 
AEs 
- 
AEs post-injection (if applicable) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
- 
Injection site pain (if applicable) 
• Facial photography 
• Early Retreatment 
- 
TI will determine if early retreatment is warranted as per Section 7.2.3 
- 
If Early Retreatment IS NOT administered 
▪ 
Proceed to Visit 8 
- 
If Early Retreatment IS administered 
▪ 
UPT (if female subject of childbearing potential) 
▪ 
Facial photography (post-injection) 
▪ 
Dispense CTR diary 
▪ 
Lip functionality (post injection) 
▪ 
Phone subject at 72 hours (3d from V7; ±1d) and query regarding health status and AEs 
▪ 
Proceed to Visit 7x 
9.4.3.1 
Visit 7x (4 weeks from V7; ±7 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 

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• Facial photography 
• Proceed to Visit 8 
9.4.4 
Visit 8 (Week 36 from last treatment – V1/V1b/V2/V2b; ±7 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
- 
AEs 
- 
AEs post-injection (if applicable) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
- 
Injection site pain (if applicable) 
• Facial photography 
• Early retreatment 
- 
TI will determine if retreatment is warranted as per Section 7.2.3 
- 
If Early Retreatment IS NOT administered 
▪ 
Proceed to Visit 9  
- 
If Early Retreatment IS administered 
▪ 
UPT (if female subject of childbearing potential) 
▪ 
Facial photography (post-injection) 
▪ 
Dispense CTR diary 
▪ 
Lip functionality (post injection) 
▪ 
Phone subject at 72 hours (3d from V8; ±1d) and query regarding health status and AEs 
▪ 
Proceed to Visit 8x 
9.4.4.1 
Visit 8x (4 weeks from V8; ± 7days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
• TI Assessments 

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- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
• Proceed to Visit 9 
9.4.5 
Visit 9 (Week 52 from last treatment – V1/V1b/V2/V2b; ±7 days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
PR-SRS post-injection (if applicable) 
- 
GAI* 
- 
Glogau 
- 
AEs 
- 
AEs post-injection (if applicable) 
- 
Lip functionality  
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
- 
Injection site pain (if applicable) 
• Facial photography 
• Retreatment 
- 
TI will determine if retreatment is warranted as per Section 7.2.4 
- 
If Retreatment IS NOT administered 
▪ 
Study Exit 
- 
If Retreatment IS administered 
▪ 
UPT (if female subject of childbearing potential) 
▪ 
Facial photography (post-injection) 
▪ 
Dispense CTR diary 
▪ 
Lip functionality (post injection) 
▪ 
Phone subject at 72 hours (3d from V9; ±1d) and query regarding health status and AEs 

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▪ 
Proceed to Visit 9x 
9.4.5.1 
Visit 9x (4 weeks from V9; ± 7days) 
• Concomitant medications/treatments 
• BLE Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
• TI Assessments 
- 
PR-SRS* 
- 
GAI* 
- 
Glogau 
- 
AEs (including review of CTR diary for potential AEs) 
- 
Lip functionality 
• Subject Assessments 
- 
GAI 
- 
FACE-Q 
- 
Natural Look/Feel 
- 
Patient Satisfaction 
• Facial photography 
• Study Exit 
9.4.6 
Study Exit 
• To verify resolution of ongoing clinically significant AE, a visit may be held within 4W 
9.5 
Efficacy 
9.5.1 
Primary Efficacy Variable 
The primary efficacy variable will be assessed at rest by the BLE at Visit 4 (Week 8 after initial 
or touch-up treatment) using the validated 4-grade PR-SRS photo-numeric scale and text as 
detailed in Table 4 below: 
Table 4.  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 
To qualify for the study, a subject must have PR-SRS grades of 2 or 3 (at rest by the BLE and the 
TI). Half-point grades will not be accepted. 
9.5.2 
Secondary Efficacy Variables 
9.5.2.1 
Perioral Rhytids Severity Rating Scale 

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The PR-SRS as assessed by the BLE at visits other than Visit 4 (Week 8 after initial or touch-up 
treatment), as well as assessed by the TI at all study visits, will serve as secondary and exploratory 
efficacy variables. 
9.5.2.2 
Modified Glogau Classification Scale 
The severity of wrinkling will be assessed by the BLE and TI using the Modified Glogau 
Classification scale as detailed in Table 5 below: 
Table 5.  Modified Glogau Classification Scale 
Group 
Classification 
Description 
I 
Mild 
No Wrinkles while the subject is at rest or while moving 
II 
Moderate 
Wrinkles only in motion, visible when the person is talking, laughing, frowning, and so on 
III 
Advanced 
Wrinkles at rest; you see the wrinkles when the person is not moving 
IV 
Severe 
Wrinkles as predominant characteristic; you see only wrinkles 
 
9.5.2.3 
Global Aesthetic Improvement 
GAI will be assessed by the TI, BLE and the subject using the Visit 1 pre-injection photograph 
and the subjective 5-grade scale as detailed in Table 6 below. Subjects will be instructed: 
“Compare the baseline photograph of your lips to the current photograph of your lips and rate the 
degree of aesthetic improvement by using the following scale”. The TI and BLE will complete the 
assessment using the same pre-injection photograph. 
Table 6.  Global Aesthetic Improvement Scale 
Grade 
Description 
1 
Much improved 
2 
Improved 
3 
No change 
4 
Worse 
5 
Much worse 
 
9.5.2.4 
FACE-Q 
Subjects will complete the Perioral Rhytids domain of the validated FACE-Q scale. 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 7 below: 
Table 7.  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 

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f. 
How the lines around your lips look when your lips are 
puckered? 
1 
2 
3 
4 
 
9.5.2.5 
Subject Satisfaction 
Subject Satisfaction will be assessed by the subject using the following subjective 5-grade scale 
as detailed below in Table 8.  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 8.  Subject Satisfaction Scale 
Grade 
Description 
1 
Very satisfied 
2 
Satisfied 
3 
Neither satisfied nor dissatisfied 
4 
Dissatisfied 
5 
Very dissatisfied 
 
9.5.2.6 
Natural look and natural feel 
Natural look and natural feel of the perioral area will be assessed by the subjects using 11-point 
scale (ranging from 0 to 10) as detailed below in Table 9. 
Table 9.  Natural look and natural fell of the perioral area 
Grade 
Description 
0 
Unnatural 
10 
Natural 
9.5.2.7 
Treatment Volume 
The number of treatment sessions and total volume to obtain OCR will be collected for 
TEOSYAL® RHA Redensity. Treatment volume will be measured to an accuracy of 0.1 mL. 
9.6 
Safety 
Safety will be evaluated through a 14-day patient Common Treatment Response (CTR) diary 
capturing post-injection signs/symptoms following study injections (including touch-up treatments 
and retreatments), and AE assessments at each visit.  
9.6.1 
14-Day Patient Common Treatment Response Diary 
The subject will receive a diary booklet and instructions for recording his/her observations of the 
Common Treatment Responses (CTRs) of the study treatments for the first 14 days after each 
treatment (initial, touch-up, retreatment(s)). The diary will be dispensed 30 minutes after each 
treatment and will be discussed during each telephone follow-up visit. 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, 

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itching, discoloration, and “other (e.g: fever, headache, changes in vision)”. Subjects will record 
the presence and the severity of each observed sign/symptom as: none, mild, moderate, or severe. 
The 14-day patient CTR will capture the daily occurrence of each CTR.  The 14-day patient CTR 
diary will include a detailed glossary describing all signs/symptoms listed in the diary. 
9.6.2 
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 should attempt at least twice to contact 
the subject. All failed attempts will also be documented in the study notes. 
9.6.3 
Assessment of Injection Site Pain 
Pain at the injection sites will be self-assessed by the subject using a Visual Analog Scale (VAS). 
The VAS is a straight, 100 mm long line with the left end representing “no pain” and the right end 
representing “worst pain”. Subjects will be asked to mark the location on the line that represented 
their level of pain. The distance along the line from the no pain end to the marked location will be 
measured and expressed in units of mm. 
Injection site pain is typical following the administration of a dermal filler. 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. 
9.6.4 
Lip Functionality 
Lip functionality testing will be conducted by the TI at each follow-up visit and pre and post 
injection at each injection. The lip functionality testing will include the following Yes/No 
evaluations: 
• Lip function: Ability to suck liquid through a straw. TI 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 the upper lip and three points on the 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 the upper lip and three points on the lower lip). 
The 6 different points 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 will be asked to capture 

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Yes or No with the following question: “Can the subject effectively pronounce the 
following words?”  
o Member 
o Simmering 
o Drab 
o Babble 
o Spear 
o Peep 
o Fire 
o Staff 
o Verse 
o Liver 
9.6.5 
Pregnancy 
A female of childbearing potential must present a negative UPT prior to any injection (initial, 
touch-up, retreatment) 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, or diaphragm). Male 
subjects have no contraceptive restrictions. 
9.6.6 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship to 
the study device(s) will be recorded in the eCRF. Subjects will be questioned for the occurrence 
of any new or worsening signs or symptoms at each visit by the following methods: 
• Information volunteered by the subject 
• Open ended and non-leading questions such as: Have you had any health problems since 
your last visit? 
• Observation by the investigational team, other care providers or relatives 
9.6.6.1 
Adverse Event Reporting 
Throughout the course of the study, all AEs will be monitored and reported through the AE eCRF.  
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. 
If a Device Related AE(s) is ongoing at the final study visit, the TI will determine which action 
should be taken and should schedule a clinic visit (if appropriate; i.e., if the event is clinically 
significant) within 4 weeks to verify that the AE has resolved. 
9.6.6.2 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered the study device and which does not necessarily have to have a causal relationship 

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with the device. An AE can therefore be any unfavorable or unintended sign (for example an 
abnormal laboratory finding), a 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 Adverse Events unless the duration and/or severity are in excess of 
that typically observed following injection of a dermal filler and are clinically significant as 
determined by the TI.  CTRs that persist longer than 14 days will be recorded as AEs (Device 
Related AE) and followed to resolution. CTRs will be reviewed by TI to ensure that CTRs are 
elevated to the status of an AE as appropriate.  The severity of each AE that is the result of a CTR 
persisting beyond 14 days will be determined by the TI. The subject assessment of CTR severity 
will NOT be used to determine AE severity.   
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. 
Clinically significant abnormal clinical 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. 
9.6.6.3 
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. 
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 

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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. 
9.6.6.4 
Causality Assessment 
The TI’s assessment of an AE’s relationship to the study device is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event will be reported. The TI will assign 
the causality assessment according to his/her clinical experience and the subject’s description of 
the event. The Sponsor will be responsible for the final causality judgment.  The causal relationship 
should be classified according to the following criteria (not all variables need to be present to be 
indicative of relationship to the device): 
Definitely related: 
• The temporal sequence of AE onset relative to injection of study device is reasonable. 
• The AE is more likely explained by the study device or procedure than by another cause. 
• The AE shows a pattern consistent with previous knowledge of the study device. 
Probably related: 
• The temporal sequence of AE onset relative to injection of study device is reasonable. 
• The AE is more likely explained by the study device or procedure than by another cause. 
Possibly related: 
• The temporal sequence of AE onset relative to injection of study device is reasonable. 
• The AE could have been due to another equally likely cause. 
Probably not related: 
• There is another more likely cause of the AE. 
Definitely not related: 
• The temporal sequence of AE onset relative to injection of study device is not reasonable. 
• There is another obvious cause of the AE. 
9.6.6.5 
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): 

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• 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.  
9.6.7 
Adverse Event Reporting 
9.6.7.1 
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 1 month following the last 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. The Sponsor is responsible for reporting AEs to the relevant 
governing authorities in the time frame applicable according to international and local law. 
9.6.7.2 
Serious Adverse Events (SAEs) and Unexpected Adverse Device Effects (UADEs) 
All SAEs and UADEs that occur after the time of informed consent through to 7 days after a 
subject’s completion of study participation, or within 1 month following the last study treatment, 
must be reported to the ethica CRO Inc. within 24 hours of awareness. Initial reports must be made 
by contacting ethica CRO Inc. as per the following: Contact the ethica CRO Inc. ethica Clinical 
Project Manager by telephone and complete the SAE/UADE Form and submit by fax (514-336-
1142). If outside of office hours, or if unable to contact the ethica CRO Inc. 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 Inc. 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 Inc., 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 the UADE to ethica CRO Inc. within 24 hours of becoming 
aware of the event. Within 24 hours of receiving the UADE report from the site, ethica CRO 
Inc. must report the UADE to the Sponsor.  As required by 21 CFR 812.46 (US) and 
Subsection 59(1) of the Medical Device Regulations (SOR/98-282) (Canada), the Sponsor 

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must investigate the UADE and report the results to the FDA, Health Canada and IRB within 
10 working days† of receiving the report from ethica CRO Inc. 
• SAEs: The site must report the SAE to ethica CRO Inc. within 24 hours of becoming aware 
of the event. Within 24 hours of receiving the SAE report from the site, ethica CRO Inc. 
should report the SAE to the Sponsor.  The Medical Monitor will investigate the SAE. SAEs 
will be reported to the IRB as per the regulations of the IRB. SAEs will be reported to FDA 
in study annual and final reports. 
† note:, Health Canada to be notified within 72 hours after the qualified investigator becoming aware of the 
information if the event has led to the death or a serious deterioration in the state of health of a patient, user 
or other person, or could do so were it to recur.. 
 
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, Health Canada and FDA approval. 
9.6.7.3 
Pregnancy 
Pregnancy is not considered an SAE or AE. The site will inform ethica CRO Inc. 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 not receive further treatments with the study device(s), but 
will continue to be followed up for scheduled efficacy and safety assessments for the duration of 
the study. All pregnancies should be followed to term and the outcome reported to ethica CRO Inc 
to determine the outcome of pregnancy. 
 

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10 SUBJECT COMPLETION / WITHDRAWAL 
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 
Discontinuation of Treatment 
A subject will be discontinued from further applications of the study devices if they become 
pregnant; however, they will continue all other assessments as per protocol. 
10.3 
Withdrawal 
A subject will be withdrawn from the study for any of the following reasons: 
- Loss 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. 
Should a subject decide to decline repeat treatment, this will not be considered as a withdrawal, 
but the reason will be documented. 
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 

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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. 

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11 STATISTICAL METHODS 
11.1 
Primary Endpoint 
The primary endpoint will be a co-primary endpoint. A responder will be defined as a subject who 
has a ≥1-grade improvement on the PR-SRS as assessed by the BLE at Week 8 after initial or 
touch-up treatment, compared with the pre-treatment assessment (baseline) by the BLE.  Only data 
from the first 8-week phase will be taken into account.  The No-Treatment control group after 
treatment will not be pooled for the primary endpoint. 
The effectiveness of TEOSYAL® RHA Redensity will be demonstrated if: 
• The responder rate for subjects treated with TEOSYAL® RHA Redensity is statistically 
superior to the responder rate for the No-Treatment control, and; 
• The responder rate for subjects treated with TEOSYAL® RHA Redensity is ≥70%, and; 
• The difference between the responder rate for subjects treated with TEOSYAL® RHA 
Redensity and the No-Treatment group is ≥50 points. 
11.2 
Secondary Endpoints 
For the Secondary Endpoints, like for the Primary Endpoint, only data from the first 8 week phase 
will be taken into account, and will compare TEOSYAL® RHA Redensity to No-Treatment (the 
No-Treatment control group after treatment will not be pooled for the secondary endpoints): 
• FACE-Q at Week 4 and Week 8 after initial or touch-up treatment. 
• Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as 
assessed by subject at Week 8 after initial or touch-up treatment, using the 5-grade Global 
Aesthetic Improvement (GAI) scale. 
• Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as 
assessed by BLE at Week 8 after initial or touch-up treatment, using the 5-grade Global 
Aesthetic Improvement (GAI) scale. 
• Proportion of subjects “satisfied” or “very satisfied” at Week 8 after initial or touch-up 
treatment, using the 5-point scale assessing subjects’ satisfaction with study treatment. 
11.3 
Exploratory Endpoints 
For the following Exploratory Endpoints, like for the Primary Endpoint, only data from the first 8 
week phase will be taken into account and will compare TEOSYAL® RHA Redensity to No-
Treatment (the No-Treatment control group after treatment will not be pooled for these exploratory 
endpoints): 
• Proportion of subjects with ≥1-grade improvement from pre-treatment on the PR-SRS as 
assessed by the Treating Investigator, at Week 4 and Week 8 after initial or touch-up 
treatment, compared with the pre-treatment assessment (baseline) by the Treating 
Investigator. 
• Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as assessed 
by Treating Investigator at Week 4 and Week 8 after initial or touch-up treatment, using the 
5-grade Global Aesthetic Improvement (GAI) scale. 

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• Proportion of subjects with ≥1-grade improvement from pre-treatment of dynamic perioral 
rhytids on the 1-4 Modified Glogau classification of wrinkling as assessed by the BLE at 
Week 8 after initial or touch-up treatment, compared with the pre-treatment assessment 
(baseline) by the BLE.  
• Proportion of subjects with ≥1-grade improvement from pre-treatment of dynamic perioral 
rhytids on the 1-4 Modified Glogau classification of wrinkling as assessed by the Treating 
Investigator at Week 4 and Week 8 after initial or touch-up treatment, compared with the pre-
treatment assessment (baseline) by the Treating Investigator. 
• Proportion of subjects with ≥1-grade improvement from pre-treatment on the PR-SRS, as 
evaluated by the Independent Photographic Reviewers (IPR) at Week 8 after initial or touch-
up treatment, compared with the pre-treatment assessment (baseline) by the IPR. For a given 
subject to be considered a responder, at least 2 of the 3 readers must have confirmed a 1-point 
improvement for that subject. 
For the following Exploratory Endpoints, unlike for the Primary and Secondary Endpoints, data 
from the TEOSYAL® RHA Redensity group and from the No-Treatment control group after 
treatment will be pooled (if deemed comparable). 
• Proportion of subjects with ≥1-grade improvement of their dynamic perioral rhytids on the 1-
4 Modified Glogau classification of wrinkling as assessed by the BLE at Week 8, 12, 16, 24, 
36, and 52 after initial or touch-up treatment, compared with the pre-treatment assessment 
(baseline) by the BLE. 
• Proportion of subjects with ≥1-grade improvement of dynamic perioral rhytids on the 1-4 
Modified Glogau classification of wrinkling as assessed by the Treating Investigator at Week 
4, 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment, compared with the pre-treatment 
assessment (baseline) by the Treating Investigator. 
• Subject satisfaction at Weeks 4, 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment, 
using the 5-point scale assessing subjects’ satisfaction with study treatment. 
• FACE-Q at Week 4, 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment 
• Proportion of subjects with a ≥1-grade improvement based on the PR-SRS assessed by the 
Treating Investigator at Weeks 4, 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment, 
compared with the pre-treatment assessment (baseline) by the Treating Investigator. 
• Proportion of subjects with a ≥1-grade improvement based on the PR-SRS assessed by the 
BLE at Weeks 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment, compared with the 
pre-treatment assessment (baseline) by the BLE. 
• Proportion of subjects with a ≥1-grade improvement, based on the PR-SRS as evaluated by 
the Independent Photographic Reviewers (IPR) at Week 8, 12, 16, 24, 36, and 52 after initial 
or touch-up treatment, compared with the pre-treatment assessment (baseline) by the IPR. For 
a given subject to be considered a responder, at least 2 of the 3 readers must have confirmed 
a 1-point improvement for that subject 
• Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as assessed 
by subjects at Week 4, 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment, using the 
5-grade Global Aesthetic Improvement (GAI) scale. 

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• Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as assessed 
by Treating Investigators at Week 4, 8, 12, 16, 24, 36, and 52 after initial or touch-up 
treatment, using the 5-grade Global Aesthetic Improvement (GAI) scale. 
• Proportion of subjects with a Global Aesthetic “improved” or “much improved”, as assessed 
by BLE at Week 8, 12, 16, 24, 36, and 52 after initial or touch-up treatment, using the 5-grade 
Global Aesthetic Improvement (GAI) scale. 
• Proportion of subjects with a natural look ≥7, and proportion of subjects with a natural feel 
≥7, both assessed by subjects at Week 4, 8, 12, 16, 24, 36, and 52 after initial or touch-up 
treatment, using a 11-point scale. 
11.4 
Analysis Populations 
Three subject analysis populations are defined: Per Protocol (PP) Population, Intent-to-Treat (ITT) 
Population, and Safety (SAFT) Population. All analysis populations will be defined and 
determined prior to unblinding and database closure 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 in the treatment group to which they were randomized, 
whether or not they received treatment. 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 efficacy analyses. 
11.4.2 
Per Protocol (PP) Population 
The PP Population will consist of all study subjects who met all inclusion/exclusion criteria and 
who completed 8 weeks of post-treatment follow-up (i.e., up to Visit 4) with no major protocol 
violations/deviations that could affect efficacy assessments. The decision whether a protocol 
violation/deviation is relevant for the exclusion of subjects from the PP Population will be made 
prior to breaking the study blind on a case-by-case basis 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 at least 
one treatment with the study device. 
11.5 
Sample Size Considerations 
The estimated responder rate for subjects treated for moderate to severe perioral rhytids is set at 
70%.  First level risk error alpha has been set to 2.5%. 
The study will ensure that enrolled subjects are representative of U.S. population ethnicity and will 
be comprised of at least 25% subjects of Fitzpatrick skin IV to VI.  In order to be able to detect a 
sufficient AE rate (i.e., maximum 2.5% in the sub-population of subjects of Fitzpatrick skin type 
IV to VI), the number of subjects must be increased beyond that required for achieving statistical 
power for the primary efficacy outcome; specifically: 
 
𝐴𝐸% =
100
𝑛× 0.25 ↔𝑛= 400
𝐴𝐸% ↔𝑛= 400
2.5 = 160 

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Where: 
• AE% is the AE threshold detection in the subpopulation of Fitzpatrick skin type IV to VI 
• n is the number of subjects needed in the overall population to be included in the study (n 
x 0.25 is the number of subjects of Fitzpatrick skin type IV to VI) 
In order to have the study able to detect any AE that has an incident rate of 2.5% or more in the 
sub-population of subjects of Fitzpatrick skin type IV to VI, at least 160 subjects should be enrolled 
and treated with the investigational device in the two pooled arms. With an anticipated 20% drop-
out rate throughout the entire study, a minimum total sample of 200 subjects (160 / 0.8 = 200), 
who will each receive TEOSYAL® RHA Redensity are required in order to detect a sufficient AE 
rate (i.e., 2.5% or more in the sub-population of subjects of Fitzpatrick skin type IV to VI, and 
<1.0% (0.625%) or more in the overall population). 
Using an unbalanced 3:1 ratio, a sample size of a minimum of 150 subjects in the treatment group 
and a minimum of 50 subjects in the control group, assuming a 20% drop-out rate throughout the 
entire study, will provide a >99.9% power for a 1-sided 2-group Fisher’s exact test at the 2.5% 
significance level to demonstrate statistical superiority of the treatment group over the control 
group, assuming a rate of responders in the treatment group of 70% and a rate of responders in the 
No-Treatment control group of 20%. 
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 values, tables, 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). All programs for data output and analyses will be written in SAS version 9.3 
or higher (SAS Institute, Inc., Cary, NC). 
Missing Values 
For subjects lost-to-follow-up (LTFU), or not present at a visit, missing data will be imputed using 
last observation carried forward (LOCF) for the primary endpoint (PR-SRS, ITT population).  
Various statistical procedures to confirm the impact of missing data (e.g., Tipping Point Analysis) 
will be detailed in the Statistical Analysis Plan. No imputations will be performed for secondary 
endpoints; 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 efficacy analysis. 
Poolability Between Countries 

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Due to the potential impact on safety and effectiveness, the variation in data across baseline 
demographics will be accounted, and heterogeneity across the two countries (US and Canada) will 
be investigated to establish if the data for safety and effectiveness can be combined.   
To assess the homogeneity of the baseline characteristics across the two countries, and to 
determine if data from both countries could be pooled, statistical hypothesis tests will be performed 
with their null hypotheses as the absence of difference between US and Canada. All observed two-
sided p-value must be >0.05 to pool data from the two countries.  If the two-sided p-value is less 
or equal to 0.05, then, data collected from subjects of both countries will not be pooled. Percentages 
of each characteristic of the demographics will be compared using a Fischer’s Exact test, and 
continuous data will be compared using a Student t test.  The full details will be provided in the 
Statistical Analysis Plan. 
11.7 
Efficacy Analysis 
Primary Endpoint: The primary endpoint will be analyzed in a superiority statistical model using 
the PR-SRS as rated by the BLE. A responder is defined as a subject with a ≥1-grade improvement 
on the PR-SRS at 8 weeks after initial or touch-up treatment, as rated by the BLE, compared with 
the pre-treatment assessment (baseline) by the BLE. Only data from the first 8-week phase will be 
taken into account (the No-Treatment control group after treatment will not be pooled for the 
primary endpoint).  The efficacy analysis will be based on a co-primary end-point: 
• The rate of responders treated with TEOSYAL® RHA Redensity will be compared to the 
rate of responders in the No-Treatment group, using an independent-testing based on a 2-
group, 1-sided, Fisher’s exact statistic. For achieving superiority, the observed p-value 
must be ≤ 0.025; 
• At least 70% of the subjects treated with TEOSYAL® RHA Redensity must be responders; 
• A difference of at least 50 points in TEOSYAL® RHA Redensity and no-treatment control 
group responders must be observed to demonstrate a clinically significant difference in 
product performance 
A two-sided 95.0% Confidence Interval will be calculated for the estimated responder rates.  
Analysis will be performed on the Intent-To-Treat (ITT) population. 
Secondary Endpoints:  For the Secondary Endpoints, like for the Primary Endpoint, only data 
from the first 8 week phase will be taken into account and will compare treatment to No-Treatment 
(the No-Treatment control group after treatment will not be pooled for the secondary endpoint). 
Secondary effectiveness analysis will be performed only if the primary endpoint analysis is 
significant. Each test will be performed at the same significance level () of 0.05, using one-sided 
tests. For achieving superiority of the treatment group over the group without treatment, each of 
the observed p-value must be ≤ 0.025.  
For categorical variables, the two groups will be compared using an independent-testing based on 
a 2-group, 1-sided, Fisher’s exact statistic. For continuous variables, the two groups will be 
compared using an independent Student t-test. 
Exploratory Endpoints: Exploratory effectiveness analysis will be descriptive, and statistical test 

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will be informative only.  
For the Exploratory Endpoints to be compared between the two groups, only data from the first 8-
week phase will be taken into account (the No-Treatment control group after treatment will not be 
pooled for these exploratory endpoints). For categorical variables, the two groups will be compared 
using an independent-testing based on a 2-group, 1-sided, Fisher’s exact statistic. For continuous 
variables, the two groups will be compared using an independent Student t-test. 
For the other exploratory Endpoints, unlike for the Primary and Secondary Endpoints, data from 
the TEOSYAL® RHA Redensity treatment group and from the No-Treatment control group after 
treatment will be pooled (if deemed comparable). To determine if data from both groups could be 
pooled, groups will be compared using a test of homogeneity at the significance level () of 0.05. 
Each observed p-value must be >0.05 to pool data from the two groups for the considered variable. 
If a p-value is ≤0.05, it will indicate a learning curve, and data from the two groups will not be 
pooled and presented separately for the considered variable. Methods will be detailed in the 
Statistical Analysis Plan. 
11.8 
Safety Analysis 
The SAFT Population will be used to summarize the safety of TEOSYAL® RHA Redensity and 
will consist of all treated subjects. The primary safety analysis is the calculation of 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. 
The safety data of the two groups will be pooled, which will increase the power to observe AEs 
after treatment with the investigational device, and separate analysis will be provided to compare 
the safety profile between the investigational group and the No-Treatment control group with 
delayed treatment once they have been treated. 
The study will be able to detect any AE that has an incident rate of <1.0% (0.625%) or more 
(assuming 200 subjects will be treated with the investigational device in the two pooled arms and 
taking account of a 20% drop-out rate throughout the entire study): 
𝐴𝐸% =
100
𝑛× 𝐷𝑂% ↔𝐴𝐸% =
100
200 × 0.8 ↔𝐴𝐸% = 100
160 = 0.625% 
 
Where: 
• AE% is the AE threshold detection in the overall treated population 
• n is the number of subjects needed  to be included in the study 
• DO% is the drop-out rate throughout the entire study 
When performing the analysis for the sub-group of subjects of Fitzpatrick skin type IV to VI (40 
subjects, or 25% of subjects who received treatment, taking account of a 20% drop-out rate 
throughout the entire study), the study will have the power to detect an AE with an incident rate 
of 2.5% 

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Safety results after repeat treatment (4 week follow up period) will also be compared between the 
initial treatment group and the No-Treatment control group, then if appropriate, the repeat 
treatment CTR, AE and SAE data will be pooled. 
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. All safety data will be tabulated with descriptive group statistics 
(mean, standard deviation, minimum, maximum, number of valid cases). 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 AEs sorted by seriousness criterion 
• SAEs: All and possibly* related AEs sorted by SOC 
• UADEs: All and possibly* related AEs sorted by SOC 
• Death: All and possibly* related AEs sorted by SOC 
• Discontinuation: All and possibly* related AEs sorted by SOC 
* definitely, probably, possibly 
AE incidence rates with exact 95% confidence intervals will be calculated for each safety variable 
at each post-treatment; confidence intervals will be used to confirm whether distribution of 
subjects with events is homogeneous between the study arms. 
Statistical analysis will also be performed to evaluate the potential impact of the injection 
technique on the safety data.  
 
 

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11.8.2 
Injection Site Pain 
Injection site pain, as measured using a 100 mm VAS, at each post-treatment time point (i.e., 
during injection, and 15 minutes), at each injection session, will be analyzed using descriptive 
statistics (mean, standard deviation, minimum and maximum). 
11.8.3 
Lip Functionality 
Lip Function, Lip Sensation, and Lip Movement assessments, at each follow-up visit, will be 
analyzed using descriptive statistics (frequency and percent). It will also be analyzed each time 
pre and post injection. 
 

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12 ETHICAL ASPECTS 
12.1 
Informed Consent 
This study will be conducted in compliance with 21 CFR Part 50 for informed consent. Written 
informed consent will be obtained from each subject before any procedures or assessments are 
done and after the aims, methods, anticipated benefits, and potential hazards are explained. It will 
also be explained to the subject that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment. 
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. 
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. 
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, Health Canada and to the 
central IRB for evaluation. As required, the study will not start before the IRB, and the local Health 
Authority (FDA for US sites and Health Canada for Canadian sites) give approval. 
12.3 
Confidentiality Regarding Study Subjects 
The Principal Investigator must assure that the privacy of the subjects, including their personal 
identity and all personal medical information, will be maintained at all times. In eCRFs and other 
documents submitted to the Sponsor, subjects will not be identified by their names, but by an 
identification code (e.g., subject or screen number).  
The site monitor, properly authorized persons on behalf of the Sponsor’s quality assurance unit, 
or competent authorities may scrutinize personal medical information for the purpose of verifying 
data recorded on the eCRF. Personal medical information will always be treated as confidential, 
according to local privacy regulations. 

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13 STUDY MANAGEMENT & ADMINISTRATIVE REQUIREMENTS 
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, Health Canada 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 Inc., 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 Inc. site monitor is responsible for initiating the site, for ensuring site compliance 
with the protocol and for 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 
Clinical monitors of ethica CRO Inc. will visit the study site periodically to ensure adherence to 
the protocol and applicable regulations, to ensure compliance with ICH-GCP, to ensure safety of 
the subjects, and to ensure 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 seven 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 BLE or 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 

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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. 
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 Inc. no later than 24 hours upon notification of being audited by the FDA, Health 
Canada 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, the Blinded Live Evaluator, 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 Inc. 
All deviations from the protocol must be addressed in study subject source documents. A 
completed copy of the ethica CRO Inc. 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 (i.e., BLE or TI).  
 

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14 DATA HANDLING AND RECORD KEEPING 
14.1 
Source Data  
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.  
The site is required to prepare and maintain adequate and accurate medical records designed to 
record all observations and other data pertinent to the study for each study subject. 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 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 informed consent process and the date that informed consent and HIPAA; 
f. Records of previous and current dermatological treatments and/or therapies; 
g. Dates of all subject visits; 
h. PR-SRS, GAI, Glogau, FACE-Q, satisfaction assessments, and pain during injection; 
i. 14-day patient CTR diaries and questionnaires; 
j. Study device injection volumes and injection techniques; 
k. All prescription and non-prescription concurrent medications, therapies, and treatments (up 
to 1 month prior to enrollment through the final visit of the study) and any changes to the 
list of medications; 
l. Occurrence and status of any AEs; 
m. Lip functionality assessments 
n. The date the subject exited the study, and a notation as to whether the subject completed the 
study or reason for discontinuation; 
o. The results of urine pregnancy testing, if performed. 
Two sets of worksheets will be used to capture study specific information (i.e., efficacy 
assessments, injection volumes, injection technique, etc.); one set for the BLE and study 
coordinator, and one set for the TI and study coordinator. This will allow the BLE and TI to remain 
blinded to each other’s assessments. The study coordinator will refer to these worksheets in 
conjunction with the medical record in order to complete data entry into the eCRF. 
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 Principal Investigator will protect the 

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confidentiality of all subjects’ records within applicable federal, state, provincial and local laws. 
A subject identification code list will be maintained in order to allow unambiguous identification 
of each subject included in the study. This list should contain the subject’s full name, date of birth, 
dates of participation and identification number as per local regulations. 
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 the subject’s medical records pertinent to the study will be reviewed by ethica CRO 
Inc., representatives from TEOXANE SA, the IRB and regulatory bodies such as the FDA and 
Health Canada 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 Inc. and with no remaining queries) should then be reviewed and 
electronically signed by the appropriate Investigator (i.e., BLE or TI). In order to review and 
electronically sign the eCRF, the BLE and TI will each have their 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 all TEOSYAL® RHA Redensity, and copies of eCRFs should be retained 
and available for audit by the Sponsor’s auditor and regulatory authorities until at least 2 years 
(US Sites) or 25 years (Canadian Sites) 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 
TEOSYAL® RHA Redensity. These documents should be retained for a longer period, however, 

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if mandated by the applicable regulatory requirements, by conditions imposed by the IRB, or by 
an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Principal 
Investigator when these documents no longer need to be retained.  
The Sponsor must be notified in writing if the Principal Investigator chooses to store the records 
at a different physical address than the site address or if the Principal Investigator wishes to 
relinquish ownership of the data so that mutually agreed-upon arrangements can be made for 
transfer of ownership to a suitably qualified, responsible person. 

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15 FINANCING AND INSURANCE 
A separate financial agreement (Clinical 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. 

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16 REPORTING AND PUBLICATION OF RESULTS 
TEOXANE SA, as the Sponsor, has a proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation among multiple Principal Investigators and sites and 
TEOXANE SA personnel. Authorship will be established prior to the writing of the manuscript. 
As this study involves multiple sites, no individual publications will be allowed prior to completion 
of the final report of the multicenter study except as agreed with TEOXANE SA. 
All information, including but not limited to information regarding TEOSYAL® RHA Redensity 
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 designate is responsible for preparing a clinical study report. 
The Sponsor or its designate is responsible for publically registering this study on 
http://www.clinicaltrials.gov/ prior to initiating enrolment. 
 
 

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

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18 APPENDICES 
 
Appendix A: Protocol Version History 
 
 
 

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APPENDIX A: PROTOCOL VERSION HISTORY 
 
Version and Date 
Description 
Version 1.0, 04-May-2016 
Final 
Version 1.1, 25-Jul-2016 
Implemented 
changes 
to 
reflect 
FDA 
approval conditions and Study Design 
Considerations.  
Version 1.2, 23-Oct-2017 
Implemented changes listed in Administrative 
Letter dated 23-Nov-2016 as well as other 
administrative 
changes. 
Modify 
section 
9.6.7.2: remove reporting SAEs to FDA prior 
to annual and final reports as this is not a 
requirement per 21 CFR 812.150 and 21 CFR 
812.46.