A Multicenter, Double-Blind, Randomized, Split-Face Study to Evaluate the Safety and Efficacy of Revanesse® Ultra + (With Lidocaine) Versus Revanesse® Ultra for the Correction of Nasolabial Folds (NLF)
Phase: NA
Conditions: Nasolabial Fold Correction
Sponsor: Prollenium Medical Technologies Inc.

Clinical Study Report SYM 2016-02 
Prollenium Medical Technologies Inc. 
Revanesse® Ultra + 
 
 
 
 
Appendix 16.1.1 Protocol and Protocol Amendments 
 
Protocol SYM 2016-02, Version 1.0 (08 July 2016) 
 
 
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1 
TITLE PAGE 
 
Title: 
A Multicenter, Double-Blind, Randomized, Split-Face Study 
to Evaluate the Safety and Efficacy of Revanesse® Ultra + 
(with Lidocaine) versus Revanesse® Ultra for the Correction 
of Nasolabial Folds 
Protocol No.: 
SYM 2016-02 
Sponsor: 
Prollenium Medical Technologies Inc. 
138 Industrial Parkway North  
Aurora Ontario 
L4G 4C3 
Canada 
Protocol Version: 
1.0 
Current Protocol Version 
Date:  
08 July 2016 
 
The information contained in this document is privileged and confidential and is the 
property of Prollenium Medical Technologies Inc.  Nothing herein is to be reproduced, 
published or disclosed to others, in any form, without the prior express written consent of 
Prollenium Medical Technologies Inc.  Persons to whom this, or any information related to 
the contents of this document, is to be disclosed must be informed that the information is 
privileged and confidential and must not be further disclosed by them. 
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DocuSign Envelope 10: 2AF49880-02B9-43A6-9B7B-7F 1701 B 1 EECO 
Prollenium Medical Technologies Inc. 
SYM 2016-02 
Revanesse® Ultra+ 
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Version: 1.0 
08 July 2016 
2 
SPONSORICRO SIGNATURE PAGE 
PROTOCOL NUMBER: 
SYM 2016-02 
PROTOCOL VERSION: 
PROTOCOL DATE: 
PROTOCOL TITLE: 
1.0 
08 July 2016 
A Multicenter Double-Blind Randomjzed, Split-Face Study to 
Evaluate the Safety and fficacy of Revanesse® Ultra + (with 
Lidocaine) versus Revanesse® Ultra for the Correction of 
Nasolabial Folds 
Signatures of the following individuals indicate that all agree this version is final. 
f
OocuSigncd by: 
Mr. Ario Khoshbin 
Managing Director 
Prollenium Medical Technologies Inc. 
Debra A. Dow, PharrnD 
Vice President, Scientific Affairs 
Symbio, LLC 
7/8/2016 
Date 
I f 
cf0}---2o 
Date 
Confidential 
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3 
SYNOPSIS AND STUDY FLOW CHART 
3.1 
Synopsis 
Title of Study:  A Multicenter, Double-Blind, Randomized, Split-Face Study to Evaluate the 
Safety and Efficacy of Revanesse® Ultra + (with Lidocaine) versus Revanesse® Ultra for the 
Correction of Nasolabial Folds 
Name of Sponsor:  Prollenium Medical Technologies Inc. 
Name of Finished Products:  Revanesse® Ultra +, Revanesse® Ultra 
Device Composition:  Hyaluronic acid gel with lidocaine (0.3% w/w); hyaluronic acid gel  
Objectives:  To compare the safety and efficacy profiles of Revanesse® Ultra + (with 
lidocaine, hereafter referred to as Revanesse Ultra +) to Revanesse Ultra for subjects 
undergoing correction of nasolabial folds (NLFs) 
Study Design:  This is a randomized, multicenter, double-blind, split-face study in subjects 
seeking nasolabial fold correction.  Subjects will be treated with Revanesse Ultra + in the NLF 
on one side of the face and Revanesse Ultra in the NLF on the other side of the face.  The side 
of the face for each study product will be randomly assigned.  The investigator and the subject 
will be blinded to the treatment; injections of the study product will be performed by an 
unblinded injecting investigator. 
At each visit, investigator and subject evaluations of the treated areas will be performed and 
recorded.  Visits will occur at: 
Visit 1/Week 0 (Day 1) – baseline and treatment 
Visit 2/Week 2 – interim visit, touch-up if the iGAI score = 3 or 4 
Visit 3/Week 4 – interim visit 
Visit 4/Week 12 – interim visit 
Visit 5/ Week 24 –End of Study  
 
Evaluations include: 
Pain assessment using a visual analog scale (VAS) 
Wrinkle Severity Rating Scale (WSRS) 
Patient Global Aesthetic Improvement (pGAI) 
Investigator Global Aesthetic Improvement (iGAI) 
Safety will be assessed by monitoring adverse events (AEs) at all study visits.  
Other evaluations include Investigator Ease of Use Assessment. 
 
Number of Study Centers:  Approximately 5 sites in the United States  
Duration of Participation:  Subjects will participate in the study for approximately 24 weeks 
from the time they sign the informed consent form (ICF) through the final contact.   
Duration of Study:  The study will require approximately 12 months from the beginning to 
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the end of the study (first subject signing the ICF to last contact with last subject). 
Number of Subjects:  Approximately 100 subjects will be randomized.  
Inclusion Criteria 
1. Men or women 22 years of age or older seeking augmentation therapy for correction of 
bilateral nasolabial folds. 
2. Two fully visible bilateral nasolabial folds each with a Wrinkle Severity Rating Scale 
Score (WSRS) of 3 or 4 that may be corrected with an injectable dermal filler.  The 
NFLs should be symmetrical, i.e., WSRS scores at NLFs on both sides should be the 
same (both Moderate [3] or both Severe [4]). 
3. If female and of childbearing potential, a negative urine pregnancy test and agree to use 
adequate contraception.  
4. Ability to understand and comply with the requirements of the study. 
5. Willingness and ability to provide written informed consent. 
6. Agree to refrain from seeking other treatment for this condition during the study. 
Note: Where possible, subjects currently enrolled in the ongoing retreatment study 
SYM2014-02 entitled “A Multicenter, Double-Blind, Randomized, Split-Face Study to 
Evaluate the Safety and Efficacy of Revanesse® Ultra versus Restylane for the Correction of 
Nasolabial Folds” (G140120) will be invited to participate in this study. 
Exclusion Criteria 
1. Wrinkle Severity Rating Scale Score of ≤ 2 on the right or left nasolabial fold. 
2. Women who are pregnant or lactating. 
3. Received prior dermabrasion, facelift, or Botox under the orbital rim, had undergone 
procedures based on active dermal response (e.g. laser or chemical peeling procedures) 
within 6 months (180 days) prior to study entry. 
4. Use of any facial tissue augmenting therapy with non-permanent filler or aesthetic 
facial surgical therapy within 9 months prior to study entry. 
5. Has ever received semi-permanent fillers or permanent facial implants anywhere in the 
face or neck, or is planning to be implanted with these products during the study. 
6. Has a permanent implant placed in the NLF area. 
7. Evidence of scar-related disease or delayed healing activity within the past 1 year. 
8. Scars at the intended treatment sites. 
9. History of keloid formation or hypertrophic scars. 
10. Any infection or unhealed wound on the face. 
11. Allergic history including anaphylaxis, multiple severe allergies, atopy, or allergies to 
natural rubber latex, lidocaine or any amide based anesthetic, hyaluronic acid products, 
or Streptococcal proteins or have plans to undergo desensitization therapy during the 
term of the study.   
12. Aspirin or nonsteroidal anti-inflammatory drugs within 1 week (7 days) prior to 
treatment. 
13. Concomitant anticoagulant therapy, antiplatelet therapy, or history of bleeding 
disorders, coagulation defects or connective tissue disorders. 
14. Over-the-counter (OTC) wrinkle products or prescription wrinkle treatments within 
4 weeks (28 days) prior to treatment and throughout the study. 
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15. Immunocompromised or immunosuppressed. 
16. Clinically significant organic disease including clinically significant cardiovascular, 
hepatic, pulmonary, neurologic, or renal disease or other medical condition, serious 
intercurrent illness, or extenuating circumstance that, in the opinion of the investigator, 
preclude participation in the trial. 
17. Received any investigational product within 30 days. 
18. Facial tattoo that may interfere with diagnosis. 
19. Systemic (oral/injectable) corticosteroids or immunosuppressive medications within 
30 days prior to treatment and topical steroids on the face within 14 days prior to 
treatment start and throughout the study. 
20. Acne and/or other inflammatory diseases of the skin  
21. Acute or chronic skin disease, inflammation or related conditions, cancerous or pre-
cancerous lesion on or near the injection sites 
 
Products 
Test product:  Revanesse Ultra +: a clear, colorless gel in 1.0 mL pre-filled syringes with 
25 mg/mL of stabilized hyaluronic acid and lidocaine 0.3% w/w.   
Comparator product:  Revanesse Ultra: a clear, colorless gel in 1.0 mL pre-filled syringes 
with 25 mg/mL of stabilized hyaluronic acid. 
The injection will be given intradermally and for best results should be injected in the 
mid-dermis. 
Statistical Methods:   
Sample Size Determination:  To detect the difference between the null hypothesis proportion 
of responders of 50% and the alternative proportion of responders of 70% via a two-sided 
exact binomial test with a 0.05 significance level, 80 modified intent-to-treat (mITT) subjects 
will supply a power of 94.1%.  For the alternative proportion of responders of 68%, 80 mITT 
subjects will supply a power of 87.8%. A responder is defined as a subject who had a within-
subject difference (Revanesse Ultra minus Revanesse Ultra +) in VAS pain score of at least 
10 mm immediately after injection.  
A total of 100 subjects will be randomized to obtain 80 mITT subjects and to provide adequate 
data for monitoring safety of the study product. 
 
Analysis Populations:   
Intent-to-treat (ITT) (safety) population:  All randomized subjects who received study product. 
Modified intent-to-treat (mITT):  All randomized subjects who met the inclusion/exclusion 
criteria, were randomized, received both study products, and had VAS pain score immediately 
post injection from both sides of the face. 
Per-protocol (PP):  All randomized subjects who met all inclusion/exclusion criteria; received 
both study products; completed Visit 5/Week 24 within the specified window; had data on 
pain score from both sides of the face immediately post injection and at 15, 30, 45, and 
60 minutes post injection at Visit 1/Day1; had data on pain score at 2 weeks post injection 
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(prior to touch-up); and had no significant protocol violations that would affect the treatment 
evaluation.  
Efficacy analyses will be performed on the mITT and PP populations.  Safety analyses will be 
performed on the ITT population. 
Efficacy Analysis: 
The primary efficacy variable is the proportion of responders immediately after injection, 
where a responder is defined as a subject who had a within-subject difference (Revanesse 
Ultra minus Revanesse Ultra +) in VAS pain score of at least 10 mm on a 100-mm scale.  
Summary statistics include mean, standard deviation (SD), minimum, median, and maximum 
for VAS score for each treatment and for the within-subject difference.  The proportion of 
responders will be summarized with frequency and percentage with a 95% confidence interval 
(CI) constructed using a one-sample binomial exact test.  If the lower bound of this 95% CI is 
greater than 50%, the test product will be claimed to be superior to the comparator product. 
The primary endpoint will be summarized by site descriptively. 
The secondary efficacy endpoints are the proportion of responders at 15, 30, 45, and 
60 minutes post injection and at 2 weeks post injection (prior to touch-up).  Upon the 
significance of the primary efficacy outcome, secondary endpoints will be analyzed using a 
hierarchical approach will be used.  If success is achieved at 15 minutes, 30 minutes will be 
evaluated; if success is achieved at 30 minutes, 45 minutes will be evaluated; if success is 
achieved at 45 minutes, 60 minutes will be evaluated; and if success is achieved at 60 minutes, 
2 weeks post-injection will be evaluated.   
Other efficacy variables include change in WSRS score from baseline, pGAI, and iGAI at each 
scheduled post-baseline visit.  Descriptive summaries will be provided for each treatment and 
for within-subject difference. 
All efficacy analyses will be performed for both the PP and mITT populations.  For the 
primary endpoint, the results from mITT are considered definitive and those from PP 
supportive. 
Safety Analysis:   
Adverse events will be coded to system organ class and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA, Version 15.1 or higher).  
Frequency and percent of subjects reporting treatment-emergent adverse events (TEAEs) of 
injection site reactions will be tabulated for each treatment by preferred terms, and further by 
severity.  In summaries of severity, subjects reporting more than one event in a treatment arm 
that are mapped to the same preferred term will be counted only once in that treatment arm 
under the strongest severity.  
For other AEs where an association with either treatment may not be clearly identified, 
including systemic TEAEs, frequency and percent of subjects will be tabulated to treated 
subjects as one group by preferred terms and system organ class, and further by severity and 
relationship to study device.  In summaries of severity and relationship, subjects who reported 
more than one event that are mapped to the same preferred term will be counted only once 
under the strongest severity and relationship.  
Adverse events will be summarized using the ITT population.  
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Interim Analysis:  One interim analysis is planned after all subjects have completed Visit 3 or 
discontinued prior to Visit 3.  The purpose is to determine the safety and pain relief of 
Revanesse Ultra + to support regulatory submissions outside the US that are currently under 
review for products containing lidocaine. The sponsor does not plan to change the protocol or 
stop the study based on the results of the interim analysis. 
 
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3.2 
Study Flow Chart  
 
 
 
 
 
 
 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
 
Scheduled 
Day 
(Week) 
Day 1 
(Week 0) 
Day 14 
(Week 2) 
Day 28 
(Week 4) 
Day 84 
(Week 
12) 
Day 168 
(Week 24) 
Unsched 
Visit 
Scheduling Window 
none 
± 2 days 
± 2 days 
± 4 days 
± 7 days 
 
Informed consent 
X 
 
 
 
 
 
Medical history/ demographics 
X 
 
 
 
 
 
Physical examination (including vital signs) 
X 
 
 
 
 
 
Concomitant medication/treatment 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria review 
X 
 
 
 
 
 
Urine pregnancy testa 
X 
 
 
 
 
 
Wrinkle Severity Rating Scale (WSRS) 
X 
X 
X 
X 
X 
Xb 
Randomization 
X 
 
 
 
 
 
Treatment with study products 
X 
Xc 
 
 
 
 
Pain score (VAS) 
0, 15, 30, 45, 60 mind 
Xe 
Xc 
 
 
 
Investigator Ease of Use 
X 
 
 
 
 
 
Evaluation for touch-up 
 
X 
 
 
 
 
Patient GAI (pGAI) 
 
X 
X 
X 
X 
Xb 
Investigator GAI (iGAI) 
 
X 
X 
X 
X 
Xb 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
Subject Diary 
Dispense 
Review/ 
Dispenseb 
Collect 
Collectb 
 
 
Schedule/confirm next visit 
X 
X 
X 
X 
X 
Xb 
a 
For women of childbearing potential, to be completed prior to enrollment. 
b 
If applicable. 
c 
For subjects who receive a touch-up treatment (iGAI = 3 or 4) 
d 
To be administered to the subject immediately after injection and 15, 30, 45, and 60 minutes post injection. 
e 
To be administered to subjects who will receive a touch-up treatment prior to touch-up, immediately after injection and 15, 30, 45, and 60 minutes post injection, and to be administered during the 
visit to subjects who do not receive a touch-up treatment. 
 
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4 
TABLE OF CONTENTS 
1 
TITLE PAGE ..........................................................................................................................1 
2 
SPONSOR/CRO SIGNATURE PAGE .................................................................................2 
3 
SYNOPSIS AND STUDY FLOW CHART ..........................................................................3 
3.1 
Synopsis ..............................................................................................................................3 
3.2 
Study Flow Chart ................................................................................................................8 
4 
TABLE OF CONTENTS ........................................................................................................9 
5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................12 
6 
INTRODUCTION .................................................................................................................14 
6.1 
Background .......................................................................................................................14 
6.2 
Rationale for the Study and Study Design ........................................................................14 
7 
STUDY OBJECTIVES .........................................................................................................14 
8 
INVESTIGATIONAL PLAN ...............................................................................................14 
8.1 
Overall Study Design ........................................................................................................14 
8.2 
Beginning and End of Study .............................................................................................15 
8.3 
Study Population ...............................................................................................................15 
8.3.1 
Inclusion Criteria .......................................................................................................16 
8.3.2 
Exclusion Criteria ......................................................................................................16 
8.3.3 
Subject Withdrawal Criteria ......................................................................................17 
8.3.4 
Replacement of Subjects ............................................................................................18 
8.4 
Treatments .........................................................................................................................18 
8.4.1 
Dosage and Formulations ..........................................................................................18 
8.4.2 
Method of Treatment Assignment, Randomization, and/or Stratification .................18 
8.4.3 
Administration of Dose for Each Subject ..................................................................19 
8.4.4 
Blinding of Study Product .........................................................................................20 
8.4.5 
Method of Packaging, Labeling, Storage, and Dispensing ........................................21 
8.4.6 
Study Product Accountability ....................................................................................21 
8.4.7 
Prior and Concomitant Medications/Treatments .......................................................21 
8.4.7.1 
Medications, Supplements, and Other Substances Prohibited Before Study Entry 
and During the Study ..................................................................................................... 21 
8.4.7.2 
Concomitant Medications, Supplements, and Other Substances Allowed During 
the Study ........................................................................................................................ 22 
8.4.8 
Assessment of Compliance ........................................................................................22 
8.5 
Study Schedule ..................................................................................................................22 
8.6 
Study Procedures ..............................................................................................................22 
8.6.1 
Study Initiation...........................................................................................................23 
8.6.2 
Written Informed Consent .........................................................................................23 
8.6.3 
Significant Medical History/Demographic Information ............................................23 
8.6.4 
Physical Examination (Including Vital Signs) ...........................................................23 
8.6.5 
Prior and Concomitant Medication/Treatment Review .............................................23 
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8.6.6 
Urine Pregnancy Test and Acceptable Contraceptive Methods ................................24 
8.6.7 
Visual Analog Scale for Pain (VAS) .........................................................................24 
8.6.8 
Wrinkle Severity Rating Scale (WSRS) ....................................................................24 
8.6.9 
Review Inclusion/Exclusion Criteria .........................................................................25 
8.6.10 Investigator Ease of Use Assessment ........................................................................25 
8.6.11 Evaluation for Touch-up ............................................................................................25 
8.6.12 Patient Global Aesthetic Improvement (pGAI) Score ...............................................25 
8.6.13 Investigator Global Aesthetic Improvement (iGAI) Score ........................................25 
8.6.14 Subject Diary Card .....................................................................................................26 
8.6.15 Adverse Events and Serious Adverse Events Assessment ........................................26 
8.6.16 Concomitant Medication/Treatment Review .............................................................26 
8.7 
Visit-Specific Procedures ..................................................................................................26 
8.7.1 
Visit 1/Day 1:  Baseline and Treatment .....................................................................26 
8.7.2 
Visit 2/Day 14 (± 2 days), Visit 3/Day 28 (± 2 days), and Visit 4/Day 84 
(± 4 days):  Interim Visits .........................................................................................27 
8.7.3 
Visit 5/Day 168 (Week 24) (± 7 days):  Final Visit/Early Termination ....................27 
8.7.4 
Unscheduled Visit ......................................................................................................27 
8.8 
Efficacy Assessments ........................................................................................................28 
8.8.1 
Primary Efficacy Endpoint ........................................................................................28 
8.8.2 
Secondary Efficacy Endpoints ...................................................................................28 
8.8.3 
Other Efficacy Endpoints ...........................................................................................28 
8.9 
Assessment of Safety ........................................................................................................28 
8.9.1 
Safety Endpoints ........................................................................................................28 
8.9.2 
Definitions of Terms ..................................................................................................28 
8.9.2.1 
Adverse Event ................................................................................................................ 28 
8.9.2.2 
Suspected Adverse Reaction .......................................................................................... 28 
8.9.2.3 
Unexpected Adverse Event ............................................................................................ 29 
8.9.2.4 
Serious Adverse Event ................................................................................................... 29 
8.9.2.5 
Planned Hospitalization ................................................................................................. 29 
8.9.2.6 
Pregnancy ...................................................................................................................... 29 
8.9.2.7 
Monitoring ..................................................................................................................... 30 
8.9.3 
Monitoring Adverse Events and Laboratory Evaluations ..........................................30 
8.9.4 
Assessment of Adverse Events ..................................................................................30 
8.9.4.1 
Assessment of Severity .................................................................................................. 30 
8.9.4.2 
Assessment of Causality ................................................................................................ 30 
8.9.4.3 
Reference Safety Information for Assessing Expectedness of Adverse Events ............ 31 
8.9.5 
Reporting Safety Observations ..................................................................................31 
8.9.6 
Withdrawal, Treatment Interruption, and Unblinding of Blinded Treatment Due 
to Safety Observations ..............................................................................................32 
8.9.6.1 
Withdrawal .................................................................................................................... 32 
8.9.6.2 
Unblinding Treatment for a Subject During the Study .................................................. 32 
8.10 Criteria for Early Termination of the Study ......................................................................33 
9 
STATISTICAL METHODS ................................................................................................34 
9.1 
Analysis Populations .........................................................................................................34 
9.2 
General Considerations .....................................................................................................34 
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9.3 
Comparability of Subjects at Baseline (or Demographics, Medical History, Baseline 
Characteristics, and Concomitant Medications) ...............................................................35 
9.4 
Efficacy Evaluations .........................................................................................................35 
9.4.1 
Handling of Missing Data ..........................................................................................35 
9.4.2 
Interim Analysis .........................................................................................................36 
9.5 
Safety Analyses .................................................................................................................36 
9.6 
Sample Size Determination ...............................................................................................37 
10 ETHICS ..................................................................................................................................38 
10.1 Informed Consent ..............................................................................................................38 
10.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........................38 
10.3 Subject Confidentiality .....................................................................................................38 
10.4 Study Registration .............................................................................................................39 
11 DATA HANDLING AND RECORDKEEPING ................................................................39 
11.1 Site Regulatory Documents Required for Initiation .........................................................39 
11.2 Maintenance and Retention of Records ............................................................................39 
11.2.1 Case Report Forms (CRFs) ........................................................................................39 
11.2.2 Primary Source Documents .......................................................................................40 
11.3 Study Monitoring ..............................................................................................................41 
11.4 Audits and Inspections ......................................................................................................41 
11.5 Modifications to the Protocol ............................................................................................41 
11.6 Completion of the Study ...................................................................................................42 
12 CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION ....................42 
13 LIST OF REFERENCES .....................................................................................................42 
14 INVESTIGATOR AGREEMENT ......................................................................................43 
15 APPENDICES .......................................................................................................................44 
15.1 Revanesse Ultra + (with Lidocaine) Instructions for Use .................................................45 
15.2 Revanesse Ultra Instructions for Use ................................................................................51 
 
 
List of Tables 
Table 1 
Fitzpatrick Classification Scale..............................................................................23 
Table 2 
Subjects with at Least a 10 mm Difference in VAS (Restylane – Restylane-L) ....37 
Table 3 
Sample Size Calculations .......................................................................................37 
 
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5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
DCF 
data correction form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HA 
hyaluronic acid 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
iGAI 
Investigator Global Aesthetic Improvement 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
min 
minimum 
mITT 
modified intent-to-treat 
NI 
non-inferiority 
NLF 
nasolabial fold 
OTC 
over-the-counter 
pGAI 
Patient Global Aesthetic Improvement 
PI 
principal investigator 
PP 
per-protocol 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SD 
standard deviation 
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Term 
Definition 
TEAE 
treatment-emergent adverse event 
US 
United States 
VAS 
visual analog scale 
WHO 
World Health Organization 
WSRS 
Wrinkle Severity Rating Scale 
w/w 
weight/weight 
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6 
INTRODUCTION 
6.1 
Background 
Revanesse Ultra + (with lidocaine, hereafter referred to as Revanesse Ultra +) is a stabilized 
hyaluronic acid (HA) dermal filler with lidocaine 0.3% w/w and Revanesse Ultra is a stabilized 
HA dermal filler.  Both products are commercially available in Canada and several European 
countries.  The purpose of this study is to compare the efficacy and safety of these two products. 
Details about specific benefits and risks for subjects participating in this study may be found in 
the Appendix (product labeling) and consent documents for this study.   
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
all applicable regulatory requirements. 
6.2 
Rationale for the Study and Study Design 
This study is a randomized, double-blind prospective, comparative study of the efficacy and 
safety of Revanesse Ultra + versus Revanesse Ultra in the cutaneous correction of nasolabial 
folds (NLFs).  Randomization will follow a 1:1 within-subject control model of augmentation 
correction of NLFs.  Given that the implants have been shown to not migrate, the within-subject 
model is ideal and has already been shown in previous studies to detect differences.  Subjects 
with signs of NLFs who meet the entry criteria will be enrolled.  All subjects will be followed for 
efficacy and safety for 6 months.  The study design is appropriate for the indication studied.  
Validated methods of data collection, analysis, and evaluation will be used. 
7 
STUDY OBJECTIVES 
The objectives of this study are to compare the safety and efficacy profiles of Revanesse Ultra + 
to Revanesse Ultra for subjects undergoing correction of NLFs. 
8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design 
This is a randomized, multicenter, double-blind, split-face study in subjects seeking NLF 
correction.  Subjects will be treated with Revanesse Ultra + (test product) in the NLF on one side 
of the face and Revanesse Ultra (comparator product) in the NLF on the other side of the face.  
The side of the face for each product will be randomly assigned.  The investigator performing the 
evaluations and the subject will be blinded to the treatment; injections of the study product will 
be performed by an unblinded injecting investigator. 
Approximately 100 subjects will be randomized at approximately 5 study sites in the United 
States (US).  Where possible, subjects currently enrolled in the ongoing retreatment study 
SYM2014-02 entitled “A Multicenter, Double-Blind, Randomized, Split-Face Study to Evaluate 
the Safety and Efficacy of Revanesse® Ultra versus Restylane for the Correction of Nasolabial 
Folds” (G140120) will be invited to participate in this study.  Those subjects will receive a third 
treatment with Revanesse Ultra. 
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At each visit, investigator and subject evaluations of the treated areas will be performed and 
recorded.  Visits will occur at: 
Visit 1/Week 0 (Day 1) – baseline and treatment 
Visit 2/Week 2 (± 2 days) – interim visit, touch-up if the iGAI score = 3 or 4 
Visit 3/Week 4 (± 2 days) – interim visit 
Visit 4/Week 12 (± 4 days) – interim visit 
Visit 5/ Week 24 (± 7 days) – End of Study  
 
Evaluations include pain assessment by a visual analog scale (VAS) , Wrinkle Severity Rating 
Scale (WSRS), Patient Global Aesthetic Improvement (pGAI), and Investigator Global Aesthetic 
Improvement (iGAI).  Safety will be assessed by monitoring adverse events (AEs) at all study 
visits.  Other evaluations include the Investigator Ease of Use Assessment.  A diary card will be 
dispensed to each enrolled subject at Visit 1/Day 1.  The subject will be instructed to complete 
the diary card to record the occurrence and extent of symptoms experienced for the first 2 weeks 
after treatment. 
8.2 
Beginning and End of Study 
A subject is considered to be enrolled in the study when he/she has provided written informed 
consent and has been randomized to treatment. 
A subject is considered to have completed the study after he/she has completed Visit 5/Week 24.   
A subject is considered to have withdrawn after he/she has withdrawn consent or has been 
withdrawn under the conditions specified in Section 8.3.3. 
A subject is considered to have been lost to follow-up if he/she cannot be contacted by the 
investigator.  The investigator will document efforts to attempt to reach the subject twice by 
telephone and will send a certified letter before considering the subject lost to follow-up.  The 
end of participation for a subject lost to follow-up is documented as the date of the certified 
letter. 
Each subject will be monitored for the occurrence of AEs, including serious adverse events 
(SAEs), starting immediately after the subject has signed the informed consent form (ICF).  Each 
subject will be followed for safety monitoring until he/she is discharged from the study.  
Follow-up procedures related to pregnancy, AEs, or SAEs may continue beyond the end of the 
study. 
Each subject will participate in the study for approximately 24 weeks from the time he/she signs 
the ICF through the final contact.  After determination of eligibility at Visit 1/Day 1, each subject 
will be treated with Revanesse Ultra + and Revanesse Ultra. 
It is anticipated that the duration of this study will be 12 months. 
8.3 
Study Population 
Approximately 100 healthy males and females at least 22 years of age and with NLFs will be 
selected to participate in the study. 
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Where possible, subjects currently enrolled in the ongoing retreatment study SYM2014-02 
entitled “A Multicenter, Double-Blind, Randomized, Split-Face Study to Evaluate the Safety and 
Efficacy of Revanesse® Ultra versus Restylane for the Correction of Nasolabial Folds” 
(G140120) will be invited to participate in this study.   
8.3.1 Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Men or women 22 years of age or older seeking augmentation therapy for correction of 
bilateral nasolabial folds. 
2. Two fully visible bilateral nasolabial folds each with a Wrinkle Severity Rating Scale 
Score (WSRS) of 3 or 4 that may be corrected with an injectable dermal filler.  The NFLs 
should be symmetrical, i.e., WSRS scores at NLFs on both sides should be the same 
(both Moderate [3] or both Severe [4]). 
3. If female and of childbearing potential, a negative urine pregnancy test and agree to use 
adequate contraception.  Female subjects of childbearing potential (excluding women 
who are surgically sterilized or postmenopausal for at least 2 years) must have a negative 
urine pregnancy test and must be willing to use a medically accepted method of 
contraception during the study.  The following are considered acceptable methods of 
birth control for the purpose of this study:  oral contraceptives, contraceptive patches, 
contraceptive implant, vaginal contraceptive, double barrier methods (e.g., condom and 
spermicide), contraceptive injection (Depo-Provera®), intrauterine device (IUD), 
hormonal IUD (Mirena®), and abstinence with a documented second acceptable method 
of birth control if the subject becomes sexually active.  Subjects entering the study who 
are on hormonal contraceptives must have been on the method for at least 90 days prior 
to the study and continue the method for the duration of the study.  Subjects who had 
used hormonal contraception and stopped must have stopped no less than 90 days prior to 
Visit 1/Day 1. 
4. Ability to understand and comply with the requirements of the study. 
5. Willingness and ability to provide written informed consent. 
6. Agree to refrain from seeking other treatment for this condition during the study. 
8.3.2 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Wrinkle Severity Rating Scale Score of ≤ 2 on the right or left nasolabial fold.  
2. Women who are pregnant or lactating.  
3. Received prior dermabrasion, facelift, or Botox below the orbital rim, or had undergone 
procedures based on active dermal response (e.g., laser or chemical peeling procedures) 
within 6 months (180 days) prior to study entry. 
4. Use of any facial tissue augmenting therapy with non-permanent filler or aesthetic facial 
surgical therapy within 9 months prior to study entry. 
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5. Has ever received semi-permanent fillers anywhere in the face or neck, or is planning to 
be implanted with these products during the study. 
6. Has a permanent implant placed in the NLF area. 
7. Evidence of scar-related disease or delayed healing activity within the past 1 year. 
8. Scars at the intended treatment sites. 
9. History of keloid formation or hypertrophic scars. 
10. Any infection or unhealed wound on the face. 
11. Allergic history including anaphylaxis, multiple severe allergies, atopy, or allergies to 
natural rubber latex, lidocaine or any amide-based anesthetic, hyaluronic acid products, 
or Streptococcal proteins or have plans to undergo desensitization therapy during the term 
of the study.   
12. Aspirin or nonsteroidal anti-inflammatory drugs within 1 week (7 days) prior to 
treatment. 
13. Concomitant anticoagulant therapy, antiplatelet therapy, or history of bleeding disorders, 
coagulation defects or connective tissue disorders. 
14. Over-the-counter (OTC) wrinkle products or prescription wrinkle treatments within 
4 weeks (28 days) prior to treatment and throughout the study. 
15. Immunocompromised or immunosuppressed. 
16. Clinically significant organic disease including clinically significant cardiovascular, 
hepatic, pulmonary, neurologic, or renal disease or other medical condition, serious 
intercurrent illness, or extenuating circumstance that, in the opinion of the investigator, 
preclude participation in the trial. 
17. Received any investigational product within 30 days of signing the Informed Consent 
Form. 
18. Facial tattoo that may interfere with diagnosis. 
19. Systemic (oral/injectable) corticosteroids or immunosuppressive medications within 
30 days prior to treatment and topical steroids on the face within 14 days prior to 
treatment start and throughout the study. 
20. Acne and/or other inflammatory diseases of the skin. 
21. Acute or chronic skin disease, inflammation or related conditions, cancerous or 
precancerous lesions on or near the injection sites. 
8.3.3 Subject Withdrawal Criteria 
A subject may withdraw from the study at any time for any reason. 
A subject will be withdrawn from the study if his/her safety or well-being is determined to be at 
risk.  Withdrawal will be made at the discretion of the investigator or at the subject’s request. 
A subject must withdraw from the study for any of the following reasons: 
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• The subject or legal representative withdraws consent 
• The subject’s product code is unblinded 
• There is a significant protocol violation  
A subject may be withdrawn from the study for any of the following reasons: 
• Lost to follow-up 
• Investigator discretion 
Withdrawal is permanent; after a subject has been withdrawn, he/she will not be allowed to 
enroll again. 
If a subject is withdrawn from the study for any reason, the End of Study or Early Termination 
procedures (Visit 5/Week 24) should be completed and any outstanding data and study product 
should be collected.  Data, including the date and primary reason for withdrawal, must be 
documented on the End of Study case report form (CRF) and source document.   
If a subject withdraws from the study at any time due to an AE, the reason for withdrawal, the 
nature of the AE, and its clinical course must be fully documented.  The investigator must strive 
to follow the subject until the AE has resolved, become clinically insignificant, is stabilized, or 
the subject is lost to follow-up.  For any SAE, follow procedures provided in Section 8.9.5 
8.3.4 Replacement of Subjects 
A subject who withdraws from the study will not be replaced. 
8.4 
Treatments 
The investigator will take responsibility for and will take all steps to maintain appropriate 
records and ensure appropriate supply, handling, storage, distribution, and use of study materials 
in accordance with the protocol and any applicable laws and regulations. 
8.4.1 Dosage and Formulations 
The test and comparator products will be provided by the sponsor as follows. 
Test product:  Revanesse Ultra +:  a clear, colorless gel in 1.0 mL pre-filled syringes with 
25 mg/mL of stabilized hyaluronic acid and lidocaine 0.3% w/w. 
Comparator product:  Revanesse Ultra: a clear, colorless gel in 1.0 mL pre-filled syringes with 
25 mg/mL of stabilized hyaluronic acid. 
8.4.2 Method of Treatment Assignment, Randomization, and/or Stratification 
Every subject will receive Revanesse Ultra + on one side of the face and Revanesse Ultra on the 
other side of the face.  The side of the face treated with either product will vary from subject to 
subject based on the randomization assignment made at Visit 1/Day 1.   
Subjects who satisfy all of the inclusion and none of the exclusion criteria will be randomized 
with respect to which side of the face receives which treatment.  Randomization will be 
performed according to a computer-generated randomization scheme.  The randomization 
scheme will be generated and maintained by an independent third party.  A sealed copy of the 
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randomization scheme should be retained at each site and should be available to regulatory 
authorities at the time of site inspection to allow for verification of the treatment identity for each 
subject. 
A unique subject number will be assigned to each subject.  Each site will receive a list of 
randomization code numbers and corresponding study product boxes.  Each eligible subject will 
be assigned a unique randomization code number in ascending order.   
No stratification based on age, sex, or other characteristics will be performed.   
8.4.3 Administration of Dose for Each Subject  
Subjects are physically masked (blindfolded) just prior to and during all injection procedures to 
prevent observation of the syringes containing study product. 
Injections of the study product are performed by the unblinded injecting investigator.  The 
blinded evaluator is not allowed to retrieve study supplies or to be present during opening of the 
study supplies or during the injections.  The injecting investigator is not to have any discussion 
with the blinded evaluator or subjects regarding the treatments. 
Up to a maximum of 2.0 mL (2 pre-filled syringes) will be used per treatment on each nasolabial 
fold similar to the comparator agent based on previous studies and common clinical practice.   
The injection will be given intradermally and for best results should be injected in the 
mid-dermis.  The treatment technique and the volume per treatment should be as similar as 
possible on both sides of the face. 
For many subjects with moderate NLFs, one syringe will be adequate per NLF.  Based on the 
iGAI score at that time, a touch-up treatment may be administered at Visit 2/Week 2.   
For this study, topical anesthetic will not be used.  Ice may be applied before the treatment if the 
injecting investigator deems it necessary.  The same technique should be used on both sides of 
the face.  Using the nondominant hand to apply gentle downward traction to the inferiormost 
aspect of the fold to immobilize it, the dominant hand is used to inject filler.  Steadying the 
injecting hand on the mandible or the other hand, the linear threading technique is most easily 
used to deposit the filler beneath the fold and efface it. 
The peri-alar sulcus, a triangular shaped concavity at the upper end of the fold, may be more 
effectively filled with the fanning technique of implantation, where two or three threads are 
deposited in a fan-like array.  Wide portions of the fold may require several threads placed side 
by side, with gentle massage after each thread is placed. 
Treatment of this area is generally easy and straightforward.  Notice that the fold is partially 
formed by prominent cheek tissue that is lateral to it, with the fold becoming more prominent as 
the cheek becomes more protuberant.  Therefore, injections should stay medial to the fold to fill 
it.  Injecting lateral to the fold, in the excessive cheek tissue, can actually tend to accentuate the 
fold. 
Bruising is the most common side effect in this area and usually resolves in 5 to 7 days.  The 
facial artery runs below the fold and necrosis is possible, although rare. 
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Implantation Technique 
After removing any make-up, the area to be treated should be cleansed with an alcohol prep pad 
or some other antiseptic.  It is useful to avoid having the subject completely recline as the 
contours of some facial folds change in the supine position. 
The viscosity of stabilized HA gel fillers decreases with increasing temperature.  The syringe 
should be warmed in the hand for a few minutes prior to injection.  Use the syringes labeled 
LEFT to treat the left NLF and the syringe labeled RIGHT to treat the right NLF.   
Before injecting the subject, push the plunger forward to feel the intrinsic resistance of the filler 
moving through the needle, until a small droplet appears at the needle tip.  Wipe off the droplet 
with a sterile pad and begin injection. 
The linear threading technique is probably the most commonly used.  Holding the syringe 
parallel to the length of the NLF to be treated, pierce the skin and advance the needle to its fullest 
extent.  Then, while slowly withdrawing the needle, apply even pressure on the plunger to 
dispense material into dermis.  Relieve pressure just before withdrawing the needle from the skin 
to avoid leakage.  Several successive “threads” below, above, or beside previous injections may 
be required to fill larger folds. 
Enter the skin with a needle angle of 30°, 45°, or parallel to the skin.  It is recommended to keep 
the needle bevel up so the tip of the needle is seen and more precisely controlled where the skin 
is pierced.  Keep the tip of the needle at constant depth during implantation, depositing all filler 
material within the same plane to get even results.  The depth of needle placement (and thus filler 
implantation) should be mid-dermis for NLFs, where the needle’s contour should be visible 
through the subject’s skin, but the needle’s color is not visible. 
After injection, manually massage the area gently to smooth out any nodular or uneven areas, 
and ensure the implanted material conforms to the contour of surrounding tissues.  Using an ice 
pack or other cold compress can help to minimize swelling and alleviate post injection 
discomfort.   
The subject should be injected so that an optimal correction is achieved.  If overcorrected, 
massage firmly between fingers or against underlying bone to obtain optimal results.  
Approximately 20% overcorrection can be massaged out; more will lead to a persistent unwanted 
cosmetic result. 
8.4.4 Blinding of Study Product 
Injections of the study product prior to Week 24 are performed by the unblinded injecting 
investigator.  The blinded evaluator is not allowed to retrieve study supplies or to be present 
during opening of the study supplies or during the injections.  The injecting investigator is not to 
have any discussion with the blinded evaluator or subjects regarding the treatments. 
Subjects are blinded to treatment assignment of each NLF.  Subjects are physically masked 
(blindfolded) just prior to and during all injection procedures to prevent observation of the 
syringes containing study product. 
Subjects, investigators, the sponsor’s staff conducting the study, and members of the 
administrative team will not have access to individual subjects’ treatment assignments.  In the 
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event of an emergency that requires breaking of the study blind, randomization code envelopes 
will be maintained by each investigator that can be opened to reveal the study product. 
See Section 8.9.6.2 for a description of the method of unblinding a subject during the study if 
such action is warranted. 
8.4.5 Method of Packaging, Labeling, Storage, and Dispensing 
Study products will be supplied to the sites in their standard packaging.  A label that includes the 
protocol number and Sponsor name will be attached to each pouch of the Revanesse Ultra + and 
Revanesse Ultra study products.  Investigators will be instructed to follow instructions regarding 
storage in accordance with the products’ Instructions for Use. 
All study products will be stored in a climate-controlled, limited access area. 
The investigator agrees to store and administer the study products only at the site(s) listed on 
Form FDA 1572 (or investigator agreement/statement).  The investigator, sub-investigator(s), or 
qualified designees also agree that the study products will be administered only to subjects who 
have provided written informed consent and have met all entry criteria.  Study products may not 
be used for any purpose other than as stated in the protocol. 
8.4.6 Study Product Accountability 
Study products will be available on site for each subject.  Receipt of study products will be 
documented and confirmed via the Investigational Product Receipt Form.  All study products 
must be kept in a locked area with access restricted to designated study personnel in a climate-
controlled, limited access area.  The administration of study products will be recorded on the 
Study Product Dispensing Log.  The site monitor will periodically check the supply of study 
products held by the investigator or pharmacist to ensure accountability.  At study conclusion, all 
unused study products will be returned to the sponsor and documented using the Investigational 
Product Return Form. 
Inventory records must be readily available for inspection by the study monitor and/or auditor, 
and open to inspection by regulatory authorities at any time. 
8.4.7 Prior and Concomitant Medications/Treatments 
All medications and other treatments taken by the subject within 6 months before Visit 1/Day 1 
and during the study are to be recorded on the CRF using their generic name, if known, with the 
corresponding indication.  The medications to be recorded include prescription and OTC 
medications and dietary supplements.  All medications taken on a regular basis, including 
vitamins, aspirin, and acetaminophen, should be recorded prior to first use of the study 
medication.   
The use of any concomitant medication must relate to the subject’s documented medical history, 
prophylaxis, or an AE. 
8.4.7.1 
Medications, Supplements, and Other Substances Prohibited Before Study Entry and 
During the Study 
The medications prohibited prior to Visit 1/Day 1 are listed in the exclusion criteria 
(Section 8.3.2). 
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Subjects will be advised to avoid the following for the duration of the study: 
• Botox® in the study treatment areas 
• Any chemical peel (light, medium or deep) in the study treatment areas 
• Soft tissue augmentation anywhere on the face 
• Dermabrasion or laser abrasion anywhere on the face 
• Silicone injections or implants anywhere on the face 
• Facial wrinkle therapies, including Accutane® and Renova® 
• Aesthetic facial surgery (i.e., facelift) 
• Oral corticosteroids or immunosuppressive medications 
• Topical corticosteroids on the face  
• Treatment with intense pulsed light 
8.4.7.2 
Concomitant Medications, Supplements, and Other Substances Allowed During the 
Study 
Permitted medications/treatments include any concomitant medication/treatment not listed in the 
exclusion criteria (Section 8.3.2). 
8.4.8 Assessment of Compliance 
Administration of the study product by the investigator is documented on the CRF.   
8.5 
Study Schedule 
The visit-by-visit schedule of study activities is provided in the Study Flow Chart in Section 3.2.  
The timing of each visit is relative to Day 1, which is defined as the day the subject is 
randomized and treated. 
All visits should be performed within the windows specified on the Study Flow Chart.  Every 
attempt should be made to have each subject attend each visit as scheduled.  If a subject is unable 
to attend a visit within the specified window the visit should be scheduled as closely as possible 
to the applicable window. 
8.6 
Study Procedures 
The Study Flow Chart in Section 3.2 summarizes the study procedures to be performed at each 
visit.  Individual study procedures are described below. 
All clinical assessments (WSRS, pain VAS, and iGAI) must be conducted by qualified 
investigators listed on the Form FDA 1572 who have been delegated these tasks by the principal 
investigator (PI).  The PI may delegate this task to physicians, physician assistants, or nurse 
practitioners who have documented training and past experience conducting the assessment. 
The WSRS, pain VAS, and iGAI evaluations are to be performed by a research team member 
who does not participate in treatment and who is blinded to the treatment assignment of each 
NLF (blinded evaluator).   
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To minimize variability of evaluations, the same investigator/sub-investigator should perform 
these assessments for any given subject and anticipate evaluating the subject at each visit, to the 
extent possible. 
8.6.1 Study Initiation 
The investigational staff may not enroll any subjects prior to completion of a site initiation visit.  
This visit will include, but is not limited to, an inventory of study supplies (if present) and a 
detailed review of the protocol, CRFs, and the investigator’s responsibilities as outlined on Form 
FDA 1572. 
8.6.2 Written Informed Consent 
The study personnel will review the ICF with each subject and give the subject an opportunity to 
have all questions answered before proceeding with any study procedures.  A copy of the signed 
ICF will be given to every subject and the original will be maintained with the subject’s records. 
8.6.3 Significant Medical History/Demographic Information 
Medical history and demographic information will be obtained at Visit 1/Day 1.  The medical 
history will include a complete review of all current diseases and their respective durations and 
treatments.  Demographic information will include date of birth, sex, race, ethnicity, and 
Fitzpatrick skin type (Table 1). 
Table 1 
Fitzpatrick Classification Scale 
Skin Type 
Skin Color 
Characteristics 
I 
White; very fair; red or blond hair; blue eyes; freckles 
Always burns, never tans 
II 
White; fair; red or blond hair; blue, hazel, or green 
eyes 
Usually burns, tans with difficulty 
III 
Cream white; fair with any eye or hair color; very 
common 
Sometimes mild burn, gradually tans 
IV 
Brown; typical Mediterranean Caucasian skin 
Rarely burns, tans with ease 
V 
Dark Brown; mid-eastern skin types 
very rarely burns, tans very easily 
VI 
Black 
Never burns, tans very easily 
 
8.6.4 Physical Examination (Including Vital Signs) 
An abbreviated physical examination including height, weight, and vital signs will be recorded.  
Vital signs will include sitting blood pressure, oral temperature, heart rate, and respiratory rate.  
This physical examination will be performed at Visit 1/Day 1 to determine that the subject is 
healthy enough to participate in the study.   
8.6.5 Prior and Concomitant Medication/Treatment Review 
Prior medications/treatments, including the necessary washout times, and concomitant 
medications will be reviewed with the subject.  A record of prior medications/treatments taken or 
used by the subject within 6 months before signing the ICF and concomitant 
medications/treatments will be obtained at Visit 1/Day 1.  Concomitant medications or 
treatments will be reviewed with the subject at each study visit. 
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8.6.6 Urine Pregnancy Test and Acceptable Contraceptive Methods 
Women of childbearing potential, in addition to having a negative urine pregnancy test at Visit 1/ 
Day 1, must be willing to use an acceptable form of birth control during the study.  The 
following are considered acceptable methods of birth control for the purpose of this study:  oral 
contraceptives, contraceptive patches, contraceptive implant, vaginal contraceptive, double 
barrier methods (e.g., condom and spermicide), contraceptive injection (Depo-Provera®), IUD, 
hormonal IUD (Mirena®), and abstinence with a documented second acceptable method of birth 
control if the subject becomes sexually active.  Subjects entering the study who are on hormonal 
contraceptives must have been on the method for at least 90 days prior to the study and continue 
the method for the duration of the study.  Subjects who had used hormonal contraception and 
stopped must have stopped no less than 90 days prior to Visit 1/Day 1. 
8.6.7 Visual Analog Scale for Pain (VAS) 
Pain from the injection will be assessed at each NLF by the subject using a 100-mm VAS scale 
from 0 = no pain to 100 = worst possible pain (Figure 1) at Visit 1/Day 1 immediately after the 
injection and 15, 30, 45, and 60 minutes post injection.  At Visit 2/Day 14, this assessment will 
be performed for subjects who do not have a touch-up treatment and prior to touch-up, 
immediately after the injection and 15, 30, 45, and 60 minutes post injection for subjects who do 
have a touch-up treatment.  Subjects will be asked the question “How would you rate your pain 
from the injection of study material?” and will respond by placing a mark on the VAS. 
Figure 1 
Visual Analog Scale for Subject Assessment of Pain Following Injection 
 
 
8.6.8 Wrinkle Severity Rating Scale (WSRS) 
1. 
Absent - No visible fold; continuous skin line. 
2. 
Mild - Shallow but visible fold with a slight indentation; minor facial feature; 
implant is expected to produce a slight improvement in appearance. 
3. 
Moderate - Moderately deep folds; clear facial feature visible at normal 
appearance but not when stretched; excellent correction is expected from 
injectable implant. 
4. 
Severe - Very long and deep folds; prominent facial feature; less than 2 mm 
visible when stretched; significant improvement is expected from injectable 
implant. 
5. 
Extreme - Extremely deep and long folds, detrimental to facial appearance; 2 to 
4 mm visible V-shaped fold when stretched; unlikely to have satisfactory 
correction with injectable implant alone. 
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The WSRS score will be assessed for each NLF at every study visit through Visit 5/Week 24 
(Visit 1/Day 1, Visit 2/Week 2, Visit 3/Week 4, Visit 4/Week 12, and Visit 5/Week 24 [End of 
Study/Early Termination]) by an evaluator blinded to the treatment assignment of each NLF.   
8.6.9 Review Inclusion/Exclusion Criteria 
The inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the study. 
8.6.10 Investigator Ease of Use Assessment 
The Investigator will assess overall ease of use by the device by circling the appropriate number 
on the Numerical Rating Scale (NRS) from 0 being not easy to 10 being most easy at 
Visit 1/Day 1.   
8.6.11 Evaluation for Touch-up 
If the iGAI score = 3 or 4 at Visit 2/Week 2, a touch-up treatment will be administered.   
8.6.12 Patient Global Aesthetic Improvement (pGAI) Score 
The pGAI score is a 5-point scale used to assess the subject’s satisfaction with the visual 
appearance of their NLF correction after treatment by assessment of wrinkle improvement using 
the following categories: 
1. 
Worse – the appearance is worse than the original condition. 
2. 
No change – the appearance is the same as the original condition. 
3. 
Improved – obvious improvement in appearance from the initial condition.  A 
touch-up might further improve the result. 
4. 
Much improved – marked improvement in appearance from the initial condition, 
but not completely optimal.  A touch-up might slightly improve the result 
5. 
Very much improved – optimal cosmetic result. 
The GAIS score will be assessed for each NLF at Visit 2/Week 2, Visit 3/Week 4, 
Visit 4/Week 12, and Visit 5/Week 24 (End of Study/Early Termination).  Subjects will be asked 
the question “How would you rate improvement in your appearance compared to your initial 
condition using the scale below?”  Treatment success is defined as at least a 1-grade 
improvement from pre-treatment. 
8.6.13 Investigator Global Aesthetic Improvement (iGAI) Score 
The iGAI score is a 5-point scale with the following categories: 
1. 
Worse – the appearance is worse than the original condition. 
2. 
No change – the appearance is the same as the original condition. 
3. 
Improved – obvious improvement in appearance from the initial condition.  
A touch-up might further improve the result. 
4. 
Much improved – marked improvement in appearance from the initial condition, 
but not completely optimal.  A touch-up might slightly improve the result. 
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5. 
Very much improved – optimal cosmetic result. 
The iGAI score will be assessed for each NLF at Visit 2/Week 2, Visit 3/Week 4, 
Visit 4/Week 12, and Visit 5/Week 24 (End of Study/Early Termination) by a blinded evaluator 
(blinded to the treatment assignment of each NLF).   
8.6.14 Subject Diary Card 
A diary card will be dispensed to each enrolled subject at Visit 1/Day 1.  The subject will be 
instructed to complete the diary card to record any AEs experienced during the 2 weeks after 
receiving treatment.  The diary card will be collected at Visit 3/Week 4.  A diary card will be 
dispensed at Visit 2/ Week 2 if a touch-up treatment is administered.  The diary card will be 
collected at Visit 4/Week 12. 
8.6.15 Adverse Events and Serious Adverse Events Assessment 
See Section 8.9 for instructions on the assessment and reporting of AEs and SAEs and 
Section 8.9.5 for instructions on reporting SAEs to the sponsor or designee. 
8.6.16 Concomitant Medication/Treatment Review 
Medications, including prescription, over-the-counter, and dietary supplements taken and other 
treatments and cosmetic products used by the subject during the study will be reviewed at each 
study visit.   
8.7 
Visit-Specific Procedures 
The following sections outline the procedures required at each visit. 
8.7.1 Visit 1/Day 1:  Baseline and Treatment 
1. Obtain written informed consent (Section 8.6.2) 
2. Obtain medical history and demographic information, including Fitzpatrick skin type 
classification (Section 8.6.3) 
3. Perform physical examination, including height, weight, and vital signs (temperature, 
heart rate, blood pressure, and respiratory rate) (Section 8.6.4) 
4. Obtain/record prior and concomitant medications/treatments (Section 8.6.5) 
5. Perform urine pregnancy test for all women of childbearing potential (Section 8.6.6) 
6. WSRS assessment (Section 8.6.8) 
7. Evaluate inclusion/exclusion criteria (Section 8.3) 
8. Randomization (Section 8.4.2) 
9. Treatment administration (Section 8.4.3) 
10. Pain assessment immediately following injection and 15, 30, and 60 minutes post 
injection (Section 8.6.7) 
11. Investigator Ease of Use assessment (Section 8.6.10)  
12. Assess AEs (Section 8.9) 
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13. Dispense subject diary card (Section 8.6.14) 
14. Schedule next visit 
15. Complete CRFs (Section 11.2.1) 
8.7.2 Visit 2/Day 14 (± 2 days), Visit 3/Day 28 (± 2 days), and Visit 4/Day 84 (± 4 days):  
Interim Visits 
1. WSRS assessment (Section 8.6.8) 
2. At Visit 2/Day 14 only, evaluation for touch-up (Section 8.6.11) and administration of 
touch-up if iGAI score = 3 or 4  
3. At Visit 2/Day 14, pain assessment if a touch-up treatment is not administered and pain 
assessment prior to touch-up, immediately following injection and 15, 30, and 60 minutes 
post injection if a touch-up treatment is administered. Pain assessment at Visit 3/Day 28 
only for subjects who had a touch-up treatment administered at Visit 2/Day 14 
(Section 8.6.7) 
4. pGAI assessment (Section 8.6.12) 
5. iGAI assessment (Section 8.6.13) 
6. Assess AEs (Section 8.9) 
7. Assess concomitant medications (Section 8.6.16)  
8. Collect subject diary card at Visit 3/Day 28; dispense subject diary card at Visit 2/Day 
14, if applicable and collect subject diary card at Visit 4/ Week 12 if applicable 
(Section 8.6.14) 
9. Schedule next visit 
10. Complete CRFs (Section 11.2.1) 
8.7.3 Visit 5/Day 168 (Week 24) (± 7 days):  Final Visit/Early Termination 
1. WSRS assessment (Section 8.6.8) 
2. pGAI assessment (Section 8.6.12) 
3. iGAI assessment (Section 8.6.13) 
4. Assess AEs (Section 8.9) 
5. Assess concomitant medications (Section 8.6.16) 
6. Complete CRFs (Section 11.2.1) 
8.7.4 Unscheduled Visit 
An unscheduled visit is allowed at any time if in the investigator’s opinion it is warranted.  The 
following procedures may be performed at the Unscheduled Visit if required. 
1. WSRS assessment (Section 8.6.8) 
2. pGAI assessment (Section 8.6.12) 
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3. iGAI assessment (Section 8.6.13) 
4. Assess AEs (Section 8.9) 
5. Assess concomitant medications (Section 8.6.16) 
6. Complete CRFs (Section 11.2.1) 
8.8 
Efficacy Assessments 
8.8.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of responders immediately after injection, where 
a responder is defined as a subject who had a within-subject difference (Revanesse Ultra – 
Revanesse Ultra +) in VAS pain score of at least 10 mm. 
8.8.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are the proportion of responders at 15, 30, 45, and 60 minutes 
post injection and at 2 weeks post injection (prior to touch-up).   
8.8.3 Other Efficacy Endpoints 
Other efficacy endpoints include change in WSRS score from baseline, pGAI, and iGAI at each 
scheduled post-baseline visit. 
8.9 
Assessment of Safety 
8.9.1 Safety Endpoints 
Safety of the study products will be compared by evaluating the nature, severity, and frequency 
of treatment-emergent adverse events (TEAEs).  All AEs that occur during the study will be 
recorded whether or not they are considered to be related to treatment.  A description of the AE 
will be recorded with the date of onset, date of resolution, severity of the AE, relationship to the 
study product, action taken, and the outcome. 
8.9.2 Definitions of Terms  
8.9.2.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related (21 Code of Federal Regulations [CFR] 
312.32 (a)).  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a drug, without any judgment about causality. 
Expected adverse events are defined as the events that appeared at injection site subsequent to 
the first injection.  Expected adverse events may include but are not limited to bruising, swelling, 
erythema, edema, inflammation at injection site. 
8.9.2.2 
Suspected Adverse Reaction 
A suspected adverse reaction (SAR) is defined as any AE for which there is reasonable 
possibility that the drug caused the AE (21 CFR 312.32 (a)). 
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8.9.2.3 
Unexpected Adverse Event 
An AE or SAR is considered unexpected if it is not consistent with the risk information 
described in the labeling for the study products. 
8.9.2.4 
Serious Adverse Event 
An SAE is defined as any AE or SAR that, in the view of the investigator or sponsor, results in 
any of the following outcomes (21 CFR 312.32 (a)): 
• Death 
• Life-threatening AE (Note: the term “life-threatening” as used here refers to an event that 
in the view of the investigator or sponsor places the subject at immediate risk of death at 
the time of the event; it does not include an AE or SAE that, had it occurred in a more 
severe form, might have caused death [21 CFR 312.32(a)]) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/birth defect 
• Any “other” important medical event.  Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
8.9.2.5 
Planned Hospitalization  
A hospitalization planned by the subject prior to signing the ICF is considered a therapeutic 
intervention and not the result of a new SAE and should be recorded as medical history.  If the 
planned hospitalization or procedure occurs as planned, the record in the subject’s medical 
history is considered complete.  However, if the event/condition worsens during the study, it 
must be reported as an AE. 
8.9.2.6 
Pregnancy 
Pregnancies occurring after the administration of study product require immediate reporting.  
They must be reported within 24 hours after the investigator has become aware of the pregnancy.  
A pregnancy report will be completed and sent by fax to Symbio within 24 hours of becoming 
aware of the pregnancy.  The investigator will collect follow-up information regarding the 
outcome of the pregnancy and any postnatal sequelae in the infant that must also be reported to 
the sponsor or designee.  Upon awareness of the outcome of the pregnancy, the PI or designee 
must forward a follow-up Pregnancy Report with any relevant information to Symbio.  
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If the outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the investigator will 
report the event by faxing a completed SAE report form to Symbio within 24 hours of being 
notified of the pregnancy report. 
The subject should immediately be withdrawn from the study.   
8.9.2.7 
Monitoring 
8.9.3 Monitoring Adverse Events and Laboratory Evaluations 
Each subject will be monitored for the occurrence of AEs, including SAEs, immediately after 
treatment initiation.  Each subject will be followed for safety monitoring until discharged from 
the study.  Follow-up procedures related to pregnancy or AEs or SAEs may continue beyond the 
end of the study. 
Subjects will be questioned and/or examined by the investigator or a qualified designee for 
occurrence of AEs throughout the study.  The presence or absence of specific AEs should not be 
elicited from subjects.  In addition, subjects will be instructed to record AEs on the subject diary 
card during the 2 weeks after treatment.  Subjects having AEs will be monitored with relevant 
clinical assessments and laboratory tests, as determined by the investigator. 
AEs, actions taken as a result of AEs, and follow-up results must be recorded on the CRF, as 
well as in the subject’s source documentation.   
For all AEs that require the subject to be withdrawn from the study and SAEs, relevant clinical 
assessments and laboratory tests will be repeated as clinically appropriate until final resolution or 
stabilization of the event(s). 
8.9.4 Assessment of Adverse Events 
8.9.4.1 
Assessment of Severity 
Severity of AEs will be graded according to the following definitions: 
Mild:  AE that was easily tolerated 
Moderate: AE sufficiently discomforting to interfere with daily activity 
Severe: AE that prevented normal daily activities 
8.9.4.2 
Assessment of Causality 
A medically-qualified investigator must assess the relationship of any AE (including SAEs) to 
the use of the study product, as unlikely related, possibly related, or probably related, based on 
available information, using the following guidelines:   
Unlikely related:  no temporal association, or the cause of the event has been identified, 
or the drug, biological, or device cannot be implicated based on available information 
Possibly related:  temporal association but other etiologies are likely to be the cause; 
however, involvement of the drug, biological, or device cannot be excluded based on 
available information 
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Probably related:  temporal association, other etiologies are possible, but unlikely based 
on available information 
8.9.4.3 
Reference Safety Information for Assessing Expectedness of Adverse Events 
The reference safety information for assessing the expectedness of an AE for the study product 
in this study is the Revanesse Plus Instructions for Use and the Revanesse Ultra Instructions for 
Use.   
8.9.5 Reporting Safety Observations 
Any SAE, whether deemed product-related or not, must be reported to Symbio by telephone or 
fax as soon as possible after the investigator or coordinator has become aware of its occurrence.  
The investigator/coordinator must complete a Serious Adverse Event (SAE) Form and fax it to 
Symbio along with the subject’s Adverse Events Log and Concomitant Medications Log within 
24 hours of notification of the event.  Symbio will notify the sponsor immediately upon 
notification of the event from a study site to allow for reporting to the United States Food and 
Drug Administration (FDA) in a timely fashion.  The sponsor will notify the FDA of device-
related SAEs. 
Symbio contact details: 
Evyan Cord-Cruz, MD 
Medical Monitor 
Direct:  516/338-0647 or 
631/474-8531 ext 5126 
Cell:  516/982-0677 
Fax: 631/474-8534 
Shanna Smith 
Director, Clinical Operations 
Direct:  631-474-8531 ext 
2456 
Cell: 215-817-0175 
Symbio, LLC 
21 Perry Street 
Port Jefferson, NY  11777 
Tel:  631/474-8531 
Fax:  631/474-8534 
 
Sponsor contact details: 
Mr. Ario Khoshbin 
Managing Director 
Prollenium Medical Technologies Inc. 
138 Industrial Parkway North  
Aurora Ontario 
L4G 4C3 
CANADA 
Tel: 905/508-1469 
Fax: 905/508-6716 
Colin Eric Hall, Ph.D. 
Director of Quality Assurance & 
Regulatory Affairs 
Prollenium Medical Technologies Inc. 
138 Industrial Parkway North  
Aurora Ontario 
L4G 4C3 
CANADA 
Tel: 905/508-1469 ext 225 
Fax: 905/508-6716 
 
 
 
The investigator must be prepared to supply the medical monitor with the following information: 
1. Investigator name and site number 
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2. Protocol number 
3. Subject ID (screening/randomization) number 
4. Subject initials and date of birth 
5. Subject demographics 
6. Clinical event 
a. description 
b. date of onset 
c. severity 
d. treatment (including hospitalization) 
e. relationship to study product 
f. action taken regarding study product 
g. if the AE was fatal or life-threatening: 
i. cause of death (whether or not the death was related to study product) 
ii. autopsy findings (if available) 
The Sponsor must submit a written summary of the clinical course of any life-threatening SAE 
and related subject information to the FDA within 7 days.  Serious and unexpected AEs that are 
not life-threatening must be reported to the FDA within 15 calendar days.  Any serious and 
unexpected AE (including all deaths) must also be reported to the IRB/IEC by the investigator 
according to IRB reporting requirements and documentation of this report sent to Symbio. 
The investigator must provide a follow-up written report within 5 calendar days of reporting the 
event to the medical monitor.  The written report must contain a full description of the event and 
any sequelae.  Subjects who have had an SAE must be followed clinically until all parameters 
(including laboratory) have either returned to normal or are stabilized. 
8.9.6 Withdrawal, Treatment Interruption, and Unblinding of Blinded Treatment Due to 
Safety Observations 
8.9.6.1 
Withdrawal 
See Section 8.3.3 for the criteria for withdrawing a subject.  If a subject is withdrawn from the 
study, the activities specified for Visit 6/Week 24 on the Study Flow Chart (Section 3.2) should 
be completed if possible. 
8.9.6.2 
Unblinding Treatment for a Subject During the Study 
Unblinding by the investigator should occur only in the event of an AE or SAE for which it is 
necessary to know the study treatment to determine an appropriate course of therapy for the 
subject.  In the event of an emergency that requires breaking of the study blind, randomization 
code envelopes will be maintained by each investigator that can be opened to reveal the study 
product. 
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Envelopes that have been opened at the study site must be returned to the sponsor accompanied 
by a written explanation of the reason why the blind was broken. 
If unblinding occurs, the subject must be withdrawn from the study. 
8.10 
Criteria for Early Termination of the Study 
The trial may be terminated because of safety concerns. Where termination is deemed 
appropriate, there will be timely communication with FDA in accordance with the regulation 
(21 CFR 812.150 (devices)). The sponsor, Prollenium Medical Technologies, will initiate 
discussion as soon as possible about the appropriate course of action for the trial in question and 
for the investigational product. There will be immediate follow up by the company to investigate 
any potential safety concern.  
The clinical study may be stopped if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In the event of an unanticipated serious adverse event or death, the sponsor, 
Prollenium Medical, will submit to the agency, and to the reviewing IRB, a report as soon as 
possible, but in no event later than 10 working days after the investigator / sponsor first learns of 
the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as 
FDA requests.  
The following conditions are considered as cause for termination of the study: 
Any death related to the study treatment 
Unanticipated treatment emergent related AEs reported as severe in the opinion of the 
Investigator in > 7 of the subjects 
Unanticipated treatment emergent related AEs reported as moderate in the opinion of the 
Investigator in > 43 of the subjects 
 
Unanticipated treatment emergent related AEs reported as mild in the opinion of the 
Investigator and unresolved at 14 days in > 98 of the subjects 
 
Duration of AEs lasting more than 4 weeks 
Increased incidence of Physician diagnosed unexpected AEs 
Increased occurrence of extreme swelling of the face, hypersensitivity 
reactions/anaphylaxis 
Anticipated Adverse Effects:  Injection-related reactions might occur, such as transient erythema, 
swelling, pain, itching, discoloration, or tenderness at the injection site.  These reactions may last 
for 1 week.  Nodules or induration are also possible at the injection site. Glabellar necrosis, 
abscess formation, granulomas, and hypersensitivity have all been reported with injections of HA 
products.  Reactions thought to be of hypersensitivity in nature have been reported in less than 1 
in every 1,500 treatments.  These have consisted of prolonged erythema,  swelling, and 
induration at the implant site. 
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Unanticipated adverse events related to the injection will be evaluated as they occur by the 
sponsor and physician (these may include injection site adverse events not listed above, such as 
hyperpigmentation, pruritus, papule, burning, hypopigmentation, and injection site scab). These 
events will be evaluated based on their severity and duration, and if deemed necessary, the study 
will be stopped. 
Any serious adverse event, and / or systemic response, or condition, that requires hospitalization 
following injection, in particular those deemed related to the injection, will be evaluated based 
on their severity and duration, and if deemed necessary, the study will be stopped. 
All reported events will be reviewed on a weekly basis during the clinical study team meeting. 
In addition, further recruitment in the study or at (a) particular site(s) may be stopped due to 
insufficient compliance with the protocol, GCP, and/or other applicable regulatory requirements, 
procedure-related problems, or the number of discontinuations for administrative reasons is too 
high.  
9 
STATISTICAL METHODS 
Prior to the database lock, a detailed, finalized Statistical Analysis Plan will be completed and 
placed on file.  The Statistical Analysis Plan will contain a more comprehensive explanation than 
that provided here of the methodology used in the statistical analyses, as well as the rules and 
data handling conventions used to perform the analyses and the procedure used to account for 
missing data. 
9.1 
Analysis Populations 
Three populations are defined for the analyses. 
• Intent-to-treat (ITT) (safety population):  All randomized subjects who received study 
product. 
• Modified intent-to-treat (mITT):  All randomized subjects who met the 
inclusion/exclusion criteria, were randomized, received both study products, and returned 
for at least 1 post-injection assessment of pain score immediately post injection from both 
sides of the face.   
• Per-protocol (PP):  All randomized subjects who met all inclusion/exclusion criteria; 
received both study products; completed Visit 5/Week 24 within the specified window; 
had data on pain score from both sides of the face immediately post injection and at 15, 
30, 45, and 60 minutes post injection at Visit 1/Day1; had data on pain score at 2 weeks 
post injection (prior to touch-up); and had no significant protocol violations that would 
affect the treatment evaluation. 
Efficacy analyses will be performed on the mITT and PP populations.  Safety analyses will be 
performed on the ITT population. 
9.2 
General Considerations 
Two-sided hypothesis testing will be conducted for all tests.  Resulting p-values less than 0.05 
will be considered statistically significant unless noted otherwise.  No adjustments of p-values 
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for multiple comparisons will be made.  SAS software (version 9.1.3) will be used for all data 
analyses and tabulations. 
Missing efficacy data will be imputed via the last observation carried forward (LOCF) method in 
the mITT analysis. For the PP population, efficacy analysis will be performed using all the 
available data without imputation for the missing values. 
For demographic and baseline characteristics and the safety profile, each variable will be 
analyzed using the existing data. Subjects with missing data will be excluded only from the 
analyses for which data are not available. 
9.3 
Comparability of Subjects at Baseline (or Demographics, Medical History, 
Baseline Characteristics, and Concomitant Medications) 
Baseline and demographic characteristic variables (including date of birth, sex, race, ethnicity, 
and Fitzpatrick skin type) will be tabulated using descriptive statistics. For each continuous 
variable, the summary will include the mean, standard deviation, median, minimum and 
maximum.  For each categorical variable, the summary will include frequencies and percentages. 
9.4 
Efficacy Evaluations 
The primary efficacy variable is the proportion of responders immediately after injection, where 
a responder is defined as a subject who had a within-subject difference (Revanesse Ultra minus 
Revanesse Ultra +) in VAS pain score of at least 10 mm on a 100-mm scale.  The VAS score 
will be summarized for each treatment and for the within-subject difference with mean, standard 
deviation (SD), minimum, median, and maximum.  The proportion of responders will be 
summarized with frequency and percentage.  A 95% CI for proportion of responders will be 
constructed using a one-sample binomial exact test.  If the lower bound of this 95% CI is greater 
than 50%, the test product will be claimed to be superior to the comparator product.  The primary 
endpoint will be summarized by site descriptively. 
The secondary efficacy endpoints are the proportion of responders at 15, 30, 45, and 60 minutes 
post injection and at 2 weeks post injection (prior to touch-up).  Upon the significance of the 
primary efficacy outcome, secondary endpoints will be analyzed using a hierarchical approach 
will be used.  If success is achieved at 15 minutes, 30 minutes will be evaluated; if success is 
achieved at 30 minutes, 45 minutes will be evaluated; if success is achieved at 45 minutes, 60 
minutes will be evaluated; and if success is achieved at 60 minutes, 2 weeks post-injection will 
be evaluated. 
Other efficacy variables include change in WSRS score from baseline, pGAI, and iGAI at each 
scheduled post-baseline visit.  Descriptive summaries will be provided for each treatment and for 
within-subject difference. 
All efficacy analyses will be performed for both the PP and mITT populations.  For the primary 
endpoint, the results from mITT are considered definitive and those from PP supportive. 
9.4.1 Handling of Missing Data 
There will not be missing data for the primary efficacy endpoint for the mITT and PP based on 
the definitions of these analysis populations (Section 9.1). 
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For the mITT analysis of the secondary efficacy endpoints, missing VAS scores will be replaced 
using the multiple imputation (MI) method.  To evaluate the robustness of MI method, subjects 
with missing VAS scores will be considered in two different ways: (1) as non-responders to the 
test product (worse case scenario), and (2) as responders to the test product (best case scenario). 
Other efficacy endpoints will be tabulated using the observed data; no missing values will be 
replaced in the analyses. 
9.4.2 Interim Analysis 
One interim analysis is planned after all subjects have completed Visit 3 or discontinued prior to 
Visit 3.  The purpose is to determine the safety and pain relief of Revanesse Ultra + to support 
regulatory submissions outside the US that are currently under review for products containing 
lidocaine. The sponsor does not plan to change the protocol or stop the study based on the results 
of the interim analysis. 
To maintain the integrity of the study, there will be a separate Statistical Analysis Plan for the 
interim analysis.  The interim analysis will be performed by an independent group that is not 
involved in the day-to-day trial activities.  Access to the interim analysis results will be strictly 
limited to people who are not directly involved in the study conduct. 
Because no change in the study conduct is planned based on the results of the interim analysis, 
the Haybittle-Peto method will be used to guard the overall Type 1 error rate, with a 0.001 level 
of significance for the interim analysis and a 0.05 level of significance for the final analysis. 
9.5 
Safety Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, 
Version 15.1 or higher).  
TEAEs are defined as events that appear subsequent to the first injection or that were present 
prior to the first injection but worsened in intensity after the first injection.  TEAEs may include, 
but are not limited to, injection site bruising, injection site discoloration, injection site edema, 
injection site erythema, injection site inflammation, injection site pain, and injection site 
swelling. 
Frequency and percent of subjects reporting TEAEs of injection site reactions will be tabulated 
for each treatment by preferred terms, and further by severity.  In summaries of severity, subjects 
who reported more than one event in a treatment arm that are mapped to the same preferred term 
will be counted only once in that treatment arm under the strongest severity.  
For other AEs where an association with either treatment may not be clearly identified, including 
systemic TEAEs, frequency and percent of subjects will be tabulated to treated subjects as one 
group by preferred terms and system organ class, and further by severity and relationship to 
study device.  In summaries of severity and relationship, subjects who reported more than one 
event that are mapped to the same preferred term will be counted only once under the strongest 
severity and relationship.  
Adverse events will be summarized using the ITT population. 
SAEs will be discussed within the clinical study report.  Data collected pertaining to SAEs will 
be presented in data listings. 
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Concomitant medications will be classified according to the World Health Organization (WHO) 
Drug Dictionary (March 2013 edition) and will be presented in data listings. 
9.6 
Sample Size Determination 
Restylane-L Injectable Gel was approved in supplement P040024/S039 on January 29, 2010 for 
mid-to-deep dermal implantation for the correction of moderate to severe facial wrinkles and 
folds such as NLFs.  For the supplement study (MA-1100-001), the primary endpoint was the 
proportion of subjects who had a within-subject difference in VAS (Restylane minus 
Restylane-L) pain assessment of at least 10 mm at injection. The objective was to show that the 
95% confidence interval for the within-subject difference lay above 50%.  The key study results 
are shown in Table 2 (Source: Summary of Safety and Effectiveness Data (SSED), for 
Restylane-L Injectable Gel). 
Table 2 
Subjects with at Least a 10 mm Difference in VAS (Restylane – Restylane-L) 
 
The following sample size is calculated based on the data from the above Restylane-L study, 
assuming that similar statistics and the same criterion will be applicable for Revanesse Ultra + vs 
Revanesse Ultra.  
Table 3 
Sample Size Calculations 
Proportion of 
Responders 
Power by N (Number of mITT subjects) 
N=90 
N=80 
70% 
97.2% 
94.1% 
68% 
93.3% 
87.8% 
 
To detect the difference between the null hypothesis proportion of responders of 50% and the 
alternative proportion of responders of 70% via a two-sided exact binomial test with a 
0.05 significance level, 80 mITT subjects will supply a power of 94.1%. For the alternative 
proportion of responders of 68%, 80 mITT subjects will supply a power of 87.8%. 
A total of 100 subjects will be randomized to obtain 80 mITT subjects and to provide adequate 
data for monitoring safety of the study product.  
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10 
ETHICS 
10.1 
Informed Consent 
The principles of informed consent, according to Food and Drug Administration (FDA) 
regulations and International Conference on Harmonization (ICH) guidelines on GCP, will be 
followed.  A copy of the proposed ICF must be submitted with the protocol to the IRB/IEC for 
approval. 
The informed consent process must be conducted and the ICF must be signed before each subject 
undergoes any Visit 1 procedures that are performed solely for the purpose of determining 
eligibility for the study, in compliance with 21 CFR Part 50.  Each subject’s signed ICF must be 
kept on file by the investigator for inspection by regulatory authorities at any time.  A copy of 
the signed ICF will be given to the subject.  A notation will be made in the subject’s medical 
record indicating the date and time informed consent was obtained. 
10.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)  
The study protocol and ICF must be approved in writing by an appropriate IRB/IEC as defined 
by FDA regulations and other applicable requirements prior to enrollment of any study subjects.   
Any changes to the protocol or a change of investigator approved by the sponsor must also be 
approved by the site’s IRB/IEC and documentation of that approval provided to the sponsor or 
designee.  Records of the IRB/IEC review and approval of all documents pertaining to this study 
must be kept on file by the investigator and are subject to inspection by regulatory authorities 
during or after completion of the study.  SAEs must also be reported to the IRB/IEC. 
Periodic status reports must be submitted to the IRB/IEC at least annually, as well as notification 
of completion of the study and a final report within 1 month of study completion or termination.  
A copy of all reports submitted to the IRB/IEC must be sent to the sponsor or designee. 
The investigator will ensure that an IRB/IEC that complies with the requirements set forth in 
21 CFR Part 56 will be responsible for the initial and continuing review and approval of the 
study. 
10.3 
Subject Confidentiality 
All subject data will be identified only by a subject identification number and subject initials.  
However, in compliance with federal guidelines regarding the monitoring of clinical studies and 
in fulfillment of his/her obligations to the sponsor, the investigator must permit the study 
monitor, sponsor representative or auditor, and/or FDA representative or other regulatory 
authority to review the portion of the subject’s medical record that is directly related to the study.  
This shall include all study-relevant documentation including medical history to verify 
eligibility, admission/discharge summaries for hospital stays occurring while the subject is 
enrolled in the study, and autopsy reports if a death occurs during the study. 
As part of the required content of informed consent, each subject must be informed that his or 
her medical chart may be reviewed by the sponsor, the sponsor’s authorized representatives, 
FDA or other regulatory authority.  If access to the medical record requires a separate waiver or 
authorization, it is the investigator’s responsibility to obtain such permission from the subject in 
writing before the subject is entered into the study. 
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10.4 
Study Registration 
The study will be registered by the sponsor on an appropriate free public web site such as 
clinicaltrials.gov, which is a service of the United States National Institutes of Health. 
11 
DATA HANDLING AND RECORDKEEPING 
11.1 
Site Regulatory Documents Required for Initiation 
The sponsor or designee will receive the following documents prior to the initiation of the study: 
• Completed, signed Form FDA 1572  
• Current curricula vitae, signed and dated, for the principal investigator (PI) and 
co-investigators named on Form FDA 1572 
• Current license(s) of the PI and co-investigators named on Form FDA 1572 
• Documentation of IRB/IEC approval of the study protocol, investigator, and ICF 
• Current IRB/IEC membership list 
• A copy of the protocol signature page signed by the PI 
• Original Non-disclosure Agreements for the PI and co-investigators named on Form FDA 
1572 
• Debarment Certification for the PI and co-investigators named on Form FDA 1572 
• Financial Disclosure Statement for all individuals named on Form FDA 1572 
11.2 
Maintenance and Retention of Records 
The study will be conducted according to GCP as outlined in ICH guidelines by the FDA.  It is 
the responsibility of the investigator to maintain a comprehensive and centralized filing system 
of all relevant documentation.  Investigators will be instructed to retain all study records required 
by the sponsor and the regulations in a secure and safe facility with limited access.  Regulations 
require retention for a period of at least 2 years after marketing approval and notification from 
the sponsor.  These regulatory documents should be retained for a longer period if required by 
local regulatory authorities.   
These records include documents pertaining to the receipt and return of medical device supplies, 
IRB/IEC, informed consent, source documents, and final signed CRFs.  No documents shall be 
transferred from the site or destroyed without first notifying the sponsor. 
11.2.1 Case Report Forms (CRFs)  
CRFs for individual subjects will be provided by Symbio.  CRFs must be legible and complete.  
CRFs for this study will be maintained in a study binder and data recorded on 2-part NCR paper.  
One copy will be kept by the investigator and the other copy will be collected by the study 
monitor.  All forms should be completed using a black ballpoint pen.  Errors should be lined out, 
but not obliterated, and the correction inserted, initialed, and dated by designated study 
personnel.  Further data corrections will be performed on special “data correction forms” (DCFs) 
that will be provided to the investigator in case of erroneous or unclear data.  The investigator 
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will make the correction on the DCF and sign the DCF.  The original will be given to the study 
monitor and a copy retained with the CRFs. 
A CRF must be completed and signed by the investigator for each subject enrolled, including 
those withdrawn from the study for any reason.  The reason for withdrawal must be noted on a 
subject’s study termination form. 
CRFs must be kept current to reflect the subject’s status at each phase during the course of the 
study.  Subjects are not to be identified on CRFs by name; appropriately coded identification and 
the subject’s initials must be used.  The investigator must keep a separate log of the subjects’ 
names and addresses. 
Source documents such as the clinic chart are to be maintained separately from the CRF to allow 
data verification.  Because of the potential for errors, inaccuracies, and illegibility in transcribing 
data onto CRFs, originals of laboratory and other test results must be kept on file with the 
subject’s CRF.  CRFs, source documents, and copies of test results must be available at all times 
for inspection by the study monitor.  The following should also be available for review: 
• Subject Screening Log, which should reflect the reason any subject screened for the study 
was found to be ineligible 
• Delegation of Authority Log, which will list all site personnel with their responsibilities 
as delegated by the PI and their signatures.  This log will be maintained at the site 
throughout the study. 
• Monitoring Log, which will list the date and purpose of all monitoring visits by the 
sponsor or designee 
• Enrollment Log, which will list subject initials and start and end dates for all enrolled 
subjects 
• Product Inventory/Packing Slip, which will list the total amount of study product shipped 
to the site and received and signed for by the investigator 
• Study Product Dispensing Log, which will list the lot number and total amount of study 
product used for each NLF for each subject 
• ICF which must be available for each subject and be verified for proper documentation 
• All correspondence 
11.2.2 Primary Source Documents 
The investigator must maintain primary source documents supporting significant data for each 
subject’s medical notes.  These documents, which are considered “source data,” should include 
documentation of: 
• Demographic information 
• Evidence supporting the diagnosis/condition for which the subject is being studied 
• General information supporting the subject’s participation in the study 
• General history and physical findings 
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• Hospitalization or Emergency Room records (if applicable) 
• Each study visit by date, including any relevant findings/notes by the investigator(s), 
occurrence (or lack) of AEs, and changes in medication usage 
• Any additional visits during the study 
• Any relevant telephone conversations with the subject regarding the study or possible 
AEs 
• An original, signed ICF for study participation 
The investigator must also retain all subject-specific printouts/reports of tests and procedures 
performed as a requirement of the study.  During monitoring visits the monitor will validate CRF 
entries against these sources of data. 
11.3 
Study Monitoring 
Symbio will be responsible for monitoring the study according to GCP and applicable 
regulations.  The study will be monitored by a Clinical Research Associate (CRA) in compliance 
with GCP, ICH guidelines, and applicable regulations.  The investigator will be visited by a CRA 
prior to the study and at regular intervals during the course of the study.  These visits are to 
verify adherence to the protocol.  The CRA will review the ICFs and verify CRF entries by 
comparing them with the source documents (hospital/clinic/office records) that will be made 
available for this purpose.  The CRA will review the maintenance of regulatory documentation 
and product accountability.  The monitor will review the progress of the study with the 
investigator and other site personnel on a regular basis.  CRFs may be collected during these 
visits.  At the end of the study, a closeout monitoring visit will be performed.  Monitoring visits 
will be arranged with site personnel in advance at a mutually acceptable time.  Sufficient time 
must be allowed by the site personnel for the monitoring of CRFs and relevant source 
documents.  The coordinator and/or investigator should be available to answer questions or 
resolve data clarifications.  Adequate time and space for these visits should be made available by 
the investigator and study staff. 
11.4 
Audits and Inspections 
During the course of the study and/or after it has been completed, 1 or more sites may be audited 
by authorized representatives of the sponsor.  The purpose of the audit is to determine whether or 
not the study is being conducted and monitored in compliance with recognized GCP/ICH 
guidelines and regulations. 
Additionally, the study may be inspected by regulatory authorities.  These inspections may take 
place at any time during or after completion of the study and are based on local regulations. 
11.5 
Modifications to the Protocol 
The procedures defined in the protocol and CRFs will be carefully reviewed to ensure that all 
parties involved with the study fully understand the protocol.  To ensure the validity of the data, 
no deviations from the protocol (with minimal exceptions) may be made unless the issue is broad 
enough to warrant revision of the protocol.  Such revisions must be submitted to and have 
documented approval from the sponsor and IRB/IEC prior to implementation.  The only 
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circumstance in which an amendment may be initiated without prior IRB/IEC approval is to 
eliminate an apparent immediate hazard to a subject or subjects.  In such a case, however, the 
investigator must notify the sponsor immediately and the IRB/IEC within 5 working days after 
implementation. 
11.6 
Completion of the Study 
The investigator is required to forward CRFs and all other relevant data and records to Symbio.  
The investigator will complete and report (submission of CRFs) his/her study in satisfactory 
compliance with the protocol as soon as possible after the completion of the study. 
The investigator must submit a final report to the IRB and the sponsor within 1 month of study 
completion or early termination. 
12 
CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION 
All information related to this study that is supplied by the sponsor and not previously published 
is considered confidential information.  This information includes but is not limited to data, 
materials (protocol, CRFs), equipment, experience (whether of a scientific, technical, 
engineering, operational, or commercial nature), designs, specifications, know-how, product 
uses, processes, formulae, costs, financial data, marketing plans and direct selling systems, 
customer lists, and technical and commercial information relating to customers or business 
projections used by the sponsor in its business.  Any data, inventions, or discoveries collected or 
developed as a result of this study are considered confidential.  This confidential information 
shall remain the sole property of the sponsor, shall not be disclosed to any unauthorized person 
or used in any unauthorized manner without written consent of the sponsor, and shall not be used 
except in the performance of the study. 
The information developed during the course of this study is also considered confidential and 
will be used by the sponsor in the development of the study product.  The information may be 
disclosed as deemed necessary by the sponsor.  To allow the use of the information derived from 
this study, the investigator is obliged to provide the sponsor with complete test results and all 
data developed in the study.  The information obtained during this study may be made available 
to other investigators who are conducting similar studies. 
The investigator shall not make any publication related to this study without the express written 
permission of the sponsor.  If the investigator wants to publish or present the results of this study, 
he or she agrees to provide the sponsor with an abstract, manuscript, and/or presentation for 
review 60 days prior to submission for publication or presentation.  The sponsor retains the right 
to delete confidential information and to object to suggested publication/presentation and/or its 
timing (at the sponsor’s sole discretion). 
 
13 
LIST OF REFERENCES  - NONE
 
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14 
INVESTIGATOR AGREEMENT 
Protocol Number: 
SYM 2016-02 
Protocol Title: 
A Multicenter, Double-Blind, Randomized, Split-Face Study to Evaluate 
the Safety and Efficacy of Revanesse® Ultra + versus Revanesse® Ultra 
for the Correction of Nasolabial Folds 
 
I have carefully read and understand the foregoing protocol and agree that it contains all the 
necessary information for conducting this study safely.  I will conduct this study in strict 
accordance with this protocol, ICH guidelines for Good Clinical Practice, the Code of Federal 
Regulations, the Health Insurance Portability and Accountability Act (HIPAA), and local 
regulatory guidelines.  I will attempt to complete the study within the time designated.  I will 
ensure that the rights, safety, and welfare of subjects under my care are protected.  I will ensure 
control of the devices under investigation in this study.  I will provide copies of the protocol and 
all other study-related information supplied by the sponsor to all personnel responsible to me 
who participate in the study.  I will discuss this information with them to assure that they are 
adequately informed regarding the device and conduct of the study.  I agree to keep records on 
all subject information (case report forms, shipment and device return forms, and all other 
information collected during the study) and device disposition in accordance with FDA 
regulations.  I will not enroll any subjects into this protocol until IRB approval and sponsor 
approval are obtained. 
 
 
 
 
 
 
 
 
 
 
 
Investigator Name (Print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Signature  
 
 
 
 
Date 
 
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15 
APPENDICES 
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15.1 
Revanesse Ultra + (with Lidocaine) Instructions for Use 
 
COMPOSITION 
Cross-linked hyaluronic acid (High Viscosity) 25 mg/mL 
Lidocaine 0.3% w/w 
In phosphate buffered saline 
[Cross-linked with Butanediol-diglycidylether (BDDE)] 
 
DESCRIPTION 
Revanesse® Ultra + is a colorless, odorless, transparent and aqueous gel of synthetic 
origin. The gel is stored in a pre-filled disposable syringe. Each box contains two 1ml 
syringes of Revanesse® Ultra + along with two sterilized needles. The product is being 
evaluated to compare the safety and efficacy profiles of Revanesse® Ultra + 
(with lidocaine, hereafter referred to as Revanesse Ultra +) to Revanesse Ultra for 
subjects undergoing correction of nasolabial folds (NLFs). The product is not currently 
approved by US FDA. 
 
APPLICATION RANGE / INDICATIONS 
Revanesse® Ultra + is intended for nasolabial fold correction. The product is intended 
for injection into the mid to deep dermis for correction of moderate to severe facial 
wrinkles and folds (such as nasolabial folds). 
 
ANTICIPATED SIDE EFFECTS 
Physicians must inform patients that with every injection of Revanesse® Ultra + there 
are potential adverse reactions that may be delayed or occur immediately after the 
injection. These include but are not limited to: 
 
• Injection-related reactions might occur, such as transient erythema, swelling, 
pain, itching, discoloration or tenderness at the injection site. These reactions may 
last for one week. 
 
• Nodules or induration are also possible at the injection site. 
 
• Poor product performance due to improper injection technique. 
 
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• Glabellar necrosis, abscess formation, granulomas and hypersensitivity have all 
been reported with injections of hyaluronic acid products. It is important for 
physicians to take these reactions into account on a case by case basis. 
 
Reactions thought to be of hypersensitivity in nature have been reported in less than 
one in every 1500 treatments. These have consisted of prolonged erythema, 
swelling and induration at the implant site. 
 
These reactions have started either shortly after injection or after a delay of 2 – 4 
weeks and have been described as mild or moderate, with an average duration of 2 
weeks. Typically, this reaction is self-limiting and resolves spontaneously with time. 
However, it is imperative that patients with hypersensitivity type reactions contact 
their physician immediately for assessment. Patients with multiple allergic reactions 
should be excluded from the treatment. 
 
CONTRAINDICATIONS 
• Contains lidocaine and is contraindicated for patients with a history of allergies to 
such material. 
 
• Do not inject Revanesse® Ultra + into eye contours (into the eye circle or eyelids). 
 
• Pregnant women, or women during lactation should not be treated with 
Revanesse® Ultra +. 
 
• Revanesse® Ultra + is only intended for intradermal use and must not be injected 
into blood vessels. This may occlude and could cause an embolism. 
 
• Patients who develop hypertrophic scarring or keloid formation should not be 
treated with Revanesse® Ultra +, or has evidence of scars at the intended 
treatment sites. 
 
• Contains trace amounts of gram positive bacterial proteins, and is 
contraindicated for patients with a history of allergies to such material, or patients 
who are Immunocompromised or immunosuppressed. 
 
• Never use Revanesse® Ultra + in conjunction with a laser, intense pulsed light, 
chemical peeling or dermabrasion treatments, or with Over-the-counter (OTC) 
wrinkle products or prescription wrinkle treatments within 4 weeks (28 days) prior 
to treatment and throughout the study. 
 
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• Use of any facial tissue augmenting therapy with non-permanent filler or 
aesthetic facial surgical therapy within 9 months, or a permanent implant placed in 
the NLF area, or has ever received semi-permanent fillers anywhere in the face or 
neck, or is planning to be i mplanted with these products during the study, or a 
facial tattoo that would interfere with the NLF correction. 
 
• Clinically significant organic disease including clinically significant cardiovascular, 
hepatic, pulmonary, neurologic, or renal disease or other medical condition, 
serious intercurrent illness, or extenuating circumstance that, in the opinion of the 
investigator, preclude participation in the trial. 
 
• People under the age of 22 should not be treated with Revanesse® Ultra +. 
 
• Patients with acne and / or other inflammatory diseases of the skin should not be 
treated with Revanesse® Ultra +. 
 
• Patients with unattainable expectations. 
 
• Patients with multiple severe allergies, or with allergic history including 
anaphylaxis, multiple severe allergies, atopy, or allergies to natural rubber latex, 
lidocaine or any amide-based anaesthetic, hyaluronic acid products, or 
Streptococcal proteins or have plans to undergo desensitization therapy during the 
term of the study 
 
• Patients with acute or chronic skin disease in or near the injection sites, or 
with any infection or unhealed wound of the face. 
 
• Coagulation defects or under anti-coagulation therapy, or Aspirin or 
nonsteroidal anti- inflammatory drugs within 1 week (7 days) prior to treatment. 
Individuals who are under Concomitant anticoagulant therapy, antiplatelet therapy, 
or history of bleeding disorders, coagulation defects or connective tissue disorders 
should not use this product. 
 
• Patients with sensitivity to hyaluronic acid. 
 
It is imperative that patients with adverse inflammatory reactions that persist for 
more than one week report this immediately to their physician. These conditions 
should be treated as appropriate {ie: corticosteroids or antibiotics}. All other types of 
adverse reactions should be reported directly to the investigational site of the 
Revanesse Ultra + clinical study directly. 
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ADMINISTRATION & DOSAGE 
• Revanesse® Ultra + should only be injected by or under the direct supervision of 
qualified physicians who have been trained on the proper injection technique for 
filling facial wrinkles. 
 
• Before patients are treated they should be informed of the indications of the 
device as well as its contraindications and potential undesirable side effects. 
 
• The area to be treated must be thoroughly disinfected. Be sure to inject only 
under sterile conditions. 
 
• Revanesse® Ultra + and needles packaged with it are for single use only. Do 
not re- use. If re-used, there is a risk of infection or transmission of blood born 
diseases. 
 
• Keep the product at room temperature for 30 minutes prior to injection. 
 
• The depth of injection is at the discretion of the practitioner/physician and i s 
dependent on the severity of the wrinkle/depression and the level of correction 
desired. 
 
• If the skin turns a w hite color (blanching), the injection should be s topped 
immediately and the area should be massaged until the skin returns to its normal 
color. 
 
• Before injecting, press on the plunger of the syringe until a small drop is visible 
at the tip of the needle. 
 
PRECAUTIONS 
• Revanesse® Ultra + should not be injected into an ar ea that already contains 
another filler product as there is no available clinical data on possible reactions. 
 
• Revanesse® Ultra + should not be injected into an area where there is a 
permanent filler or implant. 
 
• Hyaluronic acid products have a known incompatibility with quaternary 
ammonium salts such 
as 
benzalkonium 
chloride. 
Please 
ensure 
that 
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Revanesse® Ultra + never comes into contact with this substance or medical 
instrumentation that has come into contact with this substance. 
 
• Revanesse® Ultra + should never be used for breast enlargement, or for 
implantation into bone, tendon, ligament or muscle. 
 
• Avoid touching the treated area for 12 hours after injection and avoid prolonged 
exposure to sunlight, UV, as well as extreme cold and heat. 
 
• Until the initial swelling and redness have resolved, do not expose the treated 
area to intense heat (e.g. solarium and sunbathing) or extreme cold. 
 
• If you have previously suffered from facial cold sores, there is a risk that the 
needle punctures could contribute to another eruption of cold sores. 
 
• Individuals using aspirin, non-steroidal anti-inflammatory medications, St. John’s 
Wort or high doses of Vitamin E supplements prior to treatment or any similar 
medications be aware that these may increase bruising and bl eeding at the 
injection site. 
 
• Based on a toxicological risk assessment for lidocaine, patients should be limited 
to 20 mL per 60 kg (130 lbs) body mass per annum. The safety of injecting 
greater amounts has not been established. 
 
• The safety for use in patients under 22 y ears has not been established, and 
treatment must not be used. 
 
• Patients who are visibly ill, with bacterial or viral infections, influenza, or active 
fever should not be treated until a resolution of their symptoms. 
 
WARNINGS 
Confirm that the seal on the box has not been broken and sterility has not been 
compromised. Confirm that the product has not expired. Product is for single use 
only; do not re-use. If re-used, there is a risk of infection or transmission of blood 
borne diseases. 
The Revanesse family of products should not be used in areas that have high 
vascularity. Use in these areas such as the glabella and nose region has resulted in 
cases of vascular embolization and symptoms consistent with ocular vessel 
occlusion (i.e.: blindness). 
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Physicians should take extra precautions when treating patients with auto immune 
disorder, HIV, AIDS or who are under immuno-therapy as these patients are at 
higher risk of adverse events. 
 
SHELF LIFE & STORAGE 
Expiry is indicated on each individual package. Store between 2°-25° C, and protect 
from direct sun light and freezing. 
 
NOTE: The correct injection technique is crucial to treatment success & patient 
satisfaction. Revanesse® Ultra + should only be injected by a practitioner qualified 
according to FDA laws and standards. 
 
The graduation on the syringe is not precise and should be used as a guide only. 
The amount of material to be injected is best determined by visual and tactile 
assessment by the user. 
 
MANUFACTURER 
Prollenium Medical Technologies, Inc. 138 Industrial Parkway North, Aurora, ON L4G 
4C3, Canada 
 
CLINICAL RESEARCH ORGANIZATION 
Symbio LLC 21 Perry 
Street 
Port Jefferson, NY 11777 Tel: 
(631) 474-8531 
Fax: (631) 474-8534 
 
 
 
 
 
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15.2 
Revanesse Ultra Instructions for Use 
 
Revanesse Ultra  
 
COMPOSITION 
Cross-linked hyaluronic acid (High Viscosity) 
25 mg/mL 
In phosphate buffered saline 
[Cross-linked with Butanediol-diglycidylether (BDDE)] 
 
DESCRIPTION 
Revanesse Ultra is a colorless, odorless, transparent and aqueous gel of synthetic origin. The gel is 
stored in a pre-filled disposable syringe. Each box contains two 1ml syringes of Revanesse Ultra along 
with two sterilized needles. The product is being evaluated to compare the safety and efficacy profiles of 
Revanesse Ultra + (with lidocaine, hereafter referred to as Revanesse Ultra +) to Revanesse Ultra for 
subjects undergoing correction of nasolabial folds (NLFs). The product is not currently approved by US 
FDA. 
 
APPLICATION RANGE / INDICATIONS 
Revanesse Ultra is intended for nasolabial fold correction. The product is intended for injection into the 
mid to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial 
folds). 
 
ANTICIPATED SIDE EFFECTS 
Physicians must inform patients that with every injection of Revanesse® Ultra there are potential adverse 
reactions that may be delayed or occur immediately after the injection. These include but are not limited 
to: 
 
• Injection-related reactions might occur, such as transient erythema, swelling, pain, itching, discoloration 
or tenderness at the injection site. These reactions may last for one week. 
 
• Nodules or induration are also possible at the injection site. 
 
• Poor product performance due to improper injection technique. 
 
• Glabellar necrosis, abscess formation, granulomas and hypersensitivity have all been reported with 
injections of hyaluronic acid products. It is important for physicians to take these reactions into account on 
a case by case basis.  
 
Reactions thought to be of hypersensitivity in nature have been reported in less than one in every 1500 
treatments. These have consisted of prolonged erythema, swelling and induration at the implant site.  
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These reactions have started either shortly after injection or after a delay of 2 – 4 weeks and have been 
described as mild or moderate, with an average duration of 2 weeks. Typically, this reaction is self-limiting 
and resolves spontaneously with time. However, it is imperative that patients with hypersensitivity type 
reactions contact their physician immediately for assessment. Patients with multiple allergic reactions 
should be excluded from the treatment.  
 
CONTRAINDICATIONS 
 
• Do not inject Revanesse® Ultra into eye contours (into the eye circle or eyelids). 
 
• Pregnant women, or women during lactation, should not be treated with Revanesse Ultra. 
 
• Revanesse Ultra is only intended for intradermal use and must not be injected into blood vessels.  This 
may occlude and could cause an embolism.   
 
• Patients who develop hypertrophic scarring or keloid formation should not be treated with Revanesse 
Ultra, or has evidence of scars at the intended treatment sites. 
 
• Contains trace amounts of gram positive bacterial proteins, and is contraindicated for patients with a 
history of allergies to such material, or patients who are Immunocompromised or immunosuppressed. 
 
• Never use Revanesse Ultra in conjunction with a laser, intense pulsed light, chemical peeling or 
dermabrasion treatments, or with Over-the-counter (OTC) wrinkle products or prescription wrinkle 
treatments within 4 weeks (28 days) prior to treatment and throughout the study. 
 
• Use of any facial tissue augmenting therapy with non-permanent filler or aesthetic facial surgical therapy 
within 9 months, or a permanent implant placed in the NLF area, or has ever received semi-permanent 
fillers anywhere in the face or neck, or is planning to be implanted with these products during the study, or 
a facial tattoo that would interfere with the NLF correction.  
 
• Clinically significant organic disease including clinically significant cardiovascular, hepatic, pulmonary, 
neurologic, or renal disease or other medical condition, serious intercurrent illness, or extenuating 
circumstance that, in the opinion of the investigator, preclude participation in the trial. 
 
• People under the age of 22 should not be treated with Revanesse® Ultra. 
 
• Patients with acne and / or other inflammatory diseases of the skin should not be treated with 
Revanesse Ultra. 
 
• Patients with unattainable expectations. 
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• Patients with multiple severe allergies, or with allergic history including anaphylaxis, multiple severe 
allergies, atopy, or allergies to natural rubber latex, hyaluronic acid products, or Streptococcal proteins or 
have plans to undergo desensitization therapy during the term of the study 
 
• Patients with acute or chronic skin disease in or near the injection sites, or with any infection or 
unhealed wound of the face. 
 
• Coagulation defects or under anti-coagulation therapy, or Aspirin or nonsteroidal anti-inflammatory 
drugs within 1 week (7 days) prior to treatment. Individuals who are under Concomitant anticoagulant 
therapy, antiplatelet therapy, or history of bleeding disorders, coagulation defects or connective tissue 
disorders should not use this product. 
 
• Patients with sensitivity to hyaluronic acid. 
 
It is imperative that patients with adverse inflammatory reactions that persist for more than one week 
report this immediately to their physician. These conditions should be treated as appropriate {ie: 
corticosteroids or antibiotics}. All other types of adverse reactions should be reported directly to the 
investigational site of the Revanesse Ultra clinical study directly. 
 
ADMINISTRATION & DOSAGE 
• Revanesse Ultra should only be injected by or under the direct supervision of qualified physicians who 
have been trained on the proper injection technique for filling facial wrinkles. 
 
• Before patients are treated they should be informed of the indications of the device as well as its 
contraindications and potential undesirable side effects. 
 
• The area to be treated must be thoroughly disinfected. Be sure to inject only under sterile conditions. 
 
• Revanesse Ultra and needles packaged with it are for single use only. Do not re-use. If re-used, there is 
a risk of infection or transmission of blood borne diseases. 
  
• Keep the product at room temperature for 30 minutes prior to injection. 
 
• The depth of injection is at the discretion of the practitioner/physician and is dependent on the severity 
of the wrinkle/depression and the level of correction desired. 
 
• If the skin turns a white color (blanching), the injection should be stopped immediately and the area 
should be massaged until the skin returns to its normal color. 
 
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Prollenium Medical Technologies Inc. 
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SYM 2016-02 
Version:  1.0  
Revanesse® Ultra + 
08 July 2016 
 
Confidential 
• Before injecting, press on the plunger of the syringe until a small drop is visible at the tip of the needle. 
 
PRECAUTIONS 
• Revanesse Ultra should not be injected into an area that already contains another filler product as there 
is no available clinical data on possible reactions. 
 
• Revanesse Ultra should not be injected into an area where there is a permanent filler or implant. 
 
• Hyaluronic acid products have a known incompatibility with quaternary ammonium salts such as 
benzalkonium chloride. Please ensure that Revanesse Ultra never comes into contact with this substance 
or medical instrumentation that has come into contact with this substance. 
 
• Revanesse Ultra should never be used for breast enlargement, or for implantation into bone, tendon, 
ligament or muscle. 
 
• Avoid touching the treated area for 12 hours after injection and avoid prolonged exposure to sunlight, 
UV, as well as extreme cold and heat. 
 
• Until the initial swelling and redness have resolved, do not expose the treated area to intense heat (e.g. 
solarium and sunbathing) or extreme cold. 
 
• If you have previously suffered from facial cold sores, there is a risk that the needle punctures could 
contribute to another eruption of cold sores. 
 
• Individuals using aspirin, non-steroidal anti-inflammatory medications, St. John’s Wort or high doses of 
Vitamin E supplements prior to treatment or any similar medications be aware that these may increase 
bruising and bleeding at the injection site. 
 
• The safety for use in patients under 22 years  has not been established, and treatment must not be 
used. 
 
• Patients who are visibly ill, with bacterial or viral infections, influenza, or active fever should not be 
treated until a resolution of their symptoms. 
 
WARNINGS 
Confirm that the seal on the box has not been broken and sterility has not been compromised. Confirm 
that the product has not expired. Product is for single use only; do not re-use. If re-used, there is a risk of 
infection or transmission of blood borne diseases. 
The Revanesse family of products should not be used in areas that have high vascularity. Use in these 
areas such as the glabella and nose region has resulted in cases of vascular embolization and symptoms 
consistent with ocular vessel occlusion (i.e.: blindness). 
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Prollenium Medical Technologies Inc. 
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SYM 2016-02 
Version:  1.0  
Revanesse® Ultra + 
08 July 2016 
 
Confidential 
Physicians should take extra precautions when treating patients with auto immune disorder, HIV, AIDS or 
who are under immuno-therapy as these patients are at higher risk of adverse events. 
 
SHELF LIFE & STORAGE 
Expiry is indicated on each individual package. Store between 2°-25° C, and protect from direct sun light 
and freezing. 
 
NOTE: The correct injection technique is crucial to treatment success & patient satisfaction. Revanesse 
Ultra should only be injected by a practitioner qualified according to FDA laws and standards.  
 
The graduation on the syringe is not precise and should be used as a guide only.  The amount of material 
to be injected is best determined by visual and tactile assessment by the user. 
 
 
 
MANUFACTURER 
Prollenium Medical Technologies, Inc. 
138 Industrial Parkway North, Aurora, ON 
L4G 4C3, Canada 
 
CLINICAL RESEARCH ORGANIZATION 
Symbio LLC 
21 Perry Street 
Port Jefferson, NY 11777 
Tel: (631) 474-8531 
Fax: (631) 474-8534 
 
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