Clinical trial NCT03460158
Conditions: Cosmetic Techniques
Keywords: facial filler Retylane aesthetic improvement volumizing fillers
Sponsor: University of Pennsylvania
Start date: 2020-08-21; Completion date: 2024-05-29
Enrollment: 101 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A prospective, trial to quantitatively and qualitatively compare the dermal fillers for the treatment of age related aesthetic changes.

Detailed description:
Dermal fillers have been approved for the treatment of age related aesthetic changes, including facial volume loss, and attenuation of the static and dynamic rhytid. Despite widespread use of volumizing fillers there is little data quantifying the subjective benefit of these minimally invasive treatments from the patient perspective. Furthermore, there is little data comparing the subjective benefit with true objective volumetric results. Such data will provide much needed information for patient counselling and treatment optimization for patient perceived outcomes.

This study is to determine the patient reported outcomes of three different dermal fillers and establish the volumetric changes over 90 days. Screening will be performed during the patient's office visit. Approximately 100 patients will be enrolled. Patients will participate up to 90 days (Day 1, 14 days, 28 days, and 90 days).

Arms: arm 1: Hyaluronic acid
Interventions: intervention 1: Restylane-L® intervention 2: Restylane-L® Lyft intervention 3: Restylane Silk®
Intervention descriptions: intervention 1: Restylane-L® for the indication for mid-to-deep dermal implantation for moderate to severe facial wrinkles and folds, such as nasolabial folds. intervention 2: Restylane-L® Lyft is for the indication of implantation into the deep dermis to superficial subcutis for the correction of moderate to severe facial folds and wrinkles, such as nasolabial folds and malars (cheek/cheek bone area). intervention 3: Restylane Silk® is for the indication for submucosal implantation for lip augmentation and dermal implantation for correction of perioral rhytids in patients over the age of 21.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Prospective Evaluation of Minimally Invasive Facial  
Cosmetic Procedures through Measured Volumetric Changes  
and Patient Reported Outcomes 
 
 
 
 
Protocol Number: 
 
IRB Number: 
827003  
 
ClinicalTrials.gov Number        
 
NCT03460158. 
 
 
 
 
 
 
 
 
 
 
Initial version 
07.31.2017 A3 
Amended 
11.06.2019 
 
 


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Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS ........................................................................................................................ IV 
STUDY SUMMARY ....................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ............................................................................................... 3 
1.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT .................................................................... 3 
2 
STUDY OBJECTIVES .......................................................................................................................... 3 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................ 3 
2.2 
SECONDARY OBJECTIVES ......................................................................................................................... 3 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 3 
3.1 
GENERAL DESIGN .................................................................................................................................... 4 
3.1.1 
Screening Phase ............................................................................................................................... 4 
3.1.2 
Study Intervention Phase .................................................................................................................. 4 
3.1.3 
Follow Up Phase................................................................................................................................ 4 
3.1.4 
Primary Study Endpoints ................................................................................................................... 4 
3.1.5 
Secondary Study Endpoints .............................................................................................................. 4 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ......................................................... 4 
4.1 
INCLUSION CRITERIA ................................................................................................................................ 4 
4.2 
EXCLUSION CRITERIA ............................................................................................................................... 4 
4.3 
SUBJECT RECRUITMENT ........................................................................................................................... 5 
4.4 
DURATION OF STUDY PARTICIPATION ........................................................................................................ 5 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES .................................................................................................. 5 
5 
STUDY INTERVENTION ...................................................................................................................... 5 
5.1 
DESCRIPTION ........................................................................................................................................... 5 
5.2 
INTERVENTION REGIMEN ........................................................................................................................... 6 
5.2.1 
Study Group ....................................................................................................................................... 6 
5.3 
RECEIPT .................................................................................................................................................. 6 
5.4 
STORAGE ................................................................................................................................................. 6 
5.5 
PREPARATION AND PACKAGING................................................................................................................. 6 
5.6 
ADMINISTRATION AND ACCOUNTABILITY ..................................................................................................... 6 
5.7 
RETURN OR DESTRUCTION OF INVESTIGATIONAL PRODUCT ........................................................................ 6 
6 
STUDY PROCEDURES ....................................................................................................................... 6 
TABLE 4  SCHEDULE OF STUDY PROCEDURES .................................................................................... 6 
6.1 
STUDY INTERVENTION PHASE ................................................................................................................... 7 
6.1.1 
Screening/Baseline Visit (Day 1) ....................................................................................................... 7 
6.1.2 
Intervention (Day 1) ........................................................................................................................... 7 
6.2 
FOLLOW UP PHASE OF THE STUDY ............................................................................................................ 7 
6.2.1 
Follow-up Visits.................................................................................................................................. 7 
• 
Visit 1 (Day 14 ± 3) ................................................................................................................................ 7 
6.3 
UNSCHEDULED VISITS .............................................................................................................................. 8 
6.4 
SUBJECT WITHDRAWAL ............................................................................................................................ 8 
6.4.1 
Data Collection and Follow-up for Withdrawn Subjects .................................................................... 8 
6.5 
EARLY TERMINATION VISITS ...................................................................................................................... 8 
7 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 8 


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7.1 
EFFICACY EVALUATIONS ........................................................................................................................... 8 
8 
STATISTICAL PLAN............................................................................................................................ 8 
8.1 
PRIMARY ENDPOINT ................................................................................................................................. 8 
8.2 
SECONDARY ENDPOINTS .......................................................................................................................... 8 
8.3 
SAMPLE SIZE AND POWER DETERMINATION ............................................................................................... 8 
8.4 
STATISTICAL METHODS............................................................................................................................. 8 
8.4.1 
Baseline Data .................................................................................................................................... 8 
8.4.2 
Efficacy Analysis ................................................................................................................................ 8 
8.5 
SUBJECT POPULATION(S) FOR ANALYSIS ................................................................................................... 9 
9 
SAFETY AND ADVERSE EVENTS ..................................................................................................... 9 
9.1 
DEFINITIONS ............................................................................................................................................ 9 
9.1.1 
Adverse Event ................................................................................................................................... 9 
9.1.2 
Serious Adverse Event ...................................................................................................................... 9 
9.2 
RECORDING OF ADVERSE EVENTS ............................................................................................................ 9 
9.3 
RELATIONSHIP OF AE TO STUDY ............................................................................................................. 10 
9.4 
REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ............... 10 
9.4.1 
Follow-up report ............................................................................................................................... 10 
9.4.2 
Investigator reporting: notifying the study sponsor .......................................................................... 10 
9.4.3 
Investigator reporting: notifying the Penn IRB ................................................................................. 11 
9.4.4 
Sponsor reporting: Notifying Participating Investigators ................................................................. 11 
9.5 
MEDICAL MONITORING............................................................................................................................ 11 
9.6 
CONFIDENTIALITY ................................................................................................................................... 11 
9.7 
DATA COLLECTION AND MANAGEMENT .................................................................................................... 11 
9.8 
RECORDS RETENTION ............................................................................................................................ 12 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 12 
10.1 
STUDY MONITORING PLAN ...................................................................................................................... 12 
10.2 
AUDITING AND INSPECTING ..................................................................................................................... 12 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 12 
11.1 
RISKS .................................................................................................................................................... 12 
11.2 
BENEFITS ............................................................................................................................................... 13 
11.3 
RISK BENEFIT ASSESSMENT ................................................................................................................... 13 
11.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ........................................................................ 13 
12 
STUDY FINANCES ............................................................................................................................ 13 
12.1 
FUNDING SOURCE .................................................................................................................................. 13 
12.2 
CONFLICT OF INTEREST .......................................................................................................................... 13 
12.3 
SUBJECT STIPENDS OR PAYMENTS ......................................................................................................... 13 
13 
PUBLICATION PLAN ........................................................................................................................ 13 
14 
REFERENCES ................................................................................................................................... 13 
ATTACHMENTS ......................................................................................................................................... 13 
15 
APPENDIX ......................................................................................................................................... 14 
15.1 
REFERENCE FOR SAFETY REPORTING SECTION- COMMON DEFINITIONS FOR DEVELOPING AND ADVERSE 
EVENT TRACKING AND SERIOUS ADVERSE EVENT REPORTING PROTOCOL ............................................................ 14 
15.2 
EXPEDITED FDA REPORTING REQUIREMENTS ......................................................................................... 14 
15.3 
DSMB REFERENCE: THE FOLLOWING SECTION OF GUIDANCE LANGUAGE DRAWS FROM: THE FDA GUIDANCE 
DOCUMENT: “GUIDANCE FOR CLINICAL TRIAL SPONSORS ON THE ESTABLISHMENT OF CLINICAL TRIAL DATA 
MONITORING COMMITTEES” ................................................................................................................................. 14 
15.4 
SOURCE DOCUMENTS ............................................................................................................................ 14 
15.5 
CASE REPORT FORMS (CRFS) ............................................................................................................... 14 
 
 


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List of Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse Event 
CDC 
Center for Disease Control 
CRF 
Case Report Forms 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Record 
FACE-Q 
Face Image Quality of Life Inventory 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HA 
Hyaluronic Acid 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
PHI 
Protect Health Information 
PI  
Principal Investigator 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
UPHS 
University of Pennsylvania Health System 
 


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Study Summary 
 
Title 
Prospective evaluation of minimally invasive facial cosmetic procedures 
through measured volumetric changes and patient reported outcomes 
Short Title 
Galderma - Prospective 
IRB Number 
827003 
Protocol Number 
NCT 03460158 
Phase 
Post-market Study 
Methodology 
 Prospective comparison of the dermal fillers for the treatment of age related 
aesthetic changes.   
Study Duration 
The active portion of the study will be the baseline visit and observational 
follow-up will occur approximately at baseline visit, 14 days, 28 days, and 90 
days for a total of 90 day of patient participation.   
Study Center(s) 
 University of Pennsylvania Health System (Penn Medicine) 
Objectives 
Primary: 
• 
Determine patient satisfaction with minimally invasive volume 
correction using patient reported outcomes and satisfaction with the 
validated survey FACE-Q 
• 
Determine the volumetric changes over 90 days 
Secondary: 
• 
Correlate degree of patient satisfaction with 3-dimensinal image 
analysis. 
Number of Subjects 
100 subjects 
Main Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
• 
Female patients 
• 
Between the age of 40 - 65 
Exclusion Criteria 
• 
Male patients 
• 
Prior surgical facial rejuvenation procedures 
• 
Prior minimally invasive rejuvenation procedure ≤ 12 months 
• 
Known contraindications to devices or drugs used in this study 
• 
Facial paralysis 
• 
Congenital facial asymmetry  
• 
Pregnant women 
• 
Patient actively taking blood thinners 


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Investigational 
Product (drug, 
biologic, device, etc.) 
For Device include 
the planned use 
For Drug, food, 
cosmetic, etc. 
include the dose, 
route of 
administration and 
dose regiment 
Restylane-L® used in the nasolabial folds and marionette lines up to a total of 
4cc injections 
Restylane-L® Lyft used in the nasolabial folds and marionette lines up to a 
total of 2 cc injections 
Up to 1cc injections of Restylane® Silk may be placed in the lips and 
cutaneous vermillion (up to 2 cc total) 
Up to a total of 4cc injections of Restylane-L® Lyft may be placed in the 
malar region  
 
Duration of 
administration  
Injections to be placed during clinic visit. 
Reference therapy 
None 
Statistical 
Methodology 
Standard descriptive statistics will be used to summarize baseline 
characteristics and study outcome measures at each visit, both overall, and 
within each arm.  
 
The validated FACE-Q will be used to determine patient satisfaction for each 
arm.  Mean and standard deviation calculation with regression analysis will be 
performed for all survey variables.  Analysis of variance will also be performed.  
 
The baseline and post treatment measurements from the Vectra 3D images 
will determine volumetric changes of the injections over time.  The average 
volume change will be calculated.  A correlation between patient satisfaction 
and volumetric changes will be calculated. 
 
 
 
  
 


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Prospective evaluation of minimally invasive facial cosmetic procedures through 
measured volumetric changes and patient reported outcomes 
 
This study will be conducted in full accordance with all applicable University of Pennsylvania Research 
Policies and Procedures and all applicable Federal and state laws and regulations including [as applicable 
include the following regulations as they apply 45 CFR 46, 21 CFR Parts 50, 54, 56, 312, 314 and 812 and 
Good Clinical Practice: Consolidated Guidelines approved by the International Conference on 
Harmonisation (ICH). Note: Only include ICH compliance if the study will actually comply with these 
requirements.] All episodes of noncompliance will be documented. 
 
1 
Introduction 
 
1.1 
Background and Relevant Literature  
 
Dermal fillers have been approved for the treatment of age related aesthetic changes, including facial 
volume loss, and attenuation of the static and dynamic rhytid. Despite widespread use of volumizing fillers 
there is little data quantifying the subjective benefit of these minimally invasive treatments from the patient 
perspective. Furthermore, there is little data comparing the subjective benefit with true objective volumetric 
results. Such data will provide much needed information for patient counselling and treatment optimization 
for patient perceived outcomes.  
1.2 
Name and Description of the Investigational Product  
Three different dermal fillers will be utilized in this study.  All products are FDA approved.  Restylane-L® 
has FDA 510(k) approval for the indication for mid-to-deep dermal implantation for moderate to severe 
facial wrinkles and folds, such as nasolabial folds and marionette lines. Restylane-L® Lyft is FDA approved 
for the indication of implantation into the deep dermis to superficial subcutis for the correction of moderate 
to severe facial folds and wrinkles, such as nasolabial folds and marionette lines and malars (cheek/cheek 
bone area).  Restylane Silk has FDA approval for the indication indicated for submucosal implantation for 
lip augmentation and dermal implantation for correction of perioral rhytids in patients over the age of 21.      
2 
Study Objectives 
The primary object of the study is to evaluate patient reported outcomes following minimally invasive 
rejuvenation using FDA approved dermal fillers.    
2.1 
Primary Objective 
•  To determine and compare patient reported outcomes and satisfaction with the validated survey 
FACE-Q over 90 days. 
•  To determine and compare the volumetric changes over 90 days 
2.2 
Secondary Objectives  
• Determine facial volumetric changes after treatment and correlate to patient reported outcomes. 
3 
Investigational Plan  
Screening will be completed during the clinic visit, and then the patient will be approached for informed 
consent process.  Once the patient is consented, the baseline data will be collected.  3-D Vectra imaging 
will occur before and after the injections at the initial visit and then again at 14 days, 28 days and 90 days 
post injection with the FACE-Q survey.    


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3.1 
General Design 
This is a prospective study to evaluate the efficacy and to determine patient reported outcomes of dermal 
fillers.  Screening will be performed during the patient’s office visit. Approximately 100 patients will be 
enrolled. Patients will participate up to 90 days (Day 1, 14 days, 28 days, and 90 days).   
 
Treatment – Restylane-L® or Restylane-L® Lyft, and Restylane Silk® 
3.1.1 
Screening Phase 
Eligible subjects will be identified from all the principal investigators’ clinical schedules, as well as recruiting 
local population including employees.  Potential subjects will be screened by a member of the study team 
for eligibility using the electronic medical record (EMR) according to the inclusion/exclusion criteria.  A 
member of the study team will give a written informed consent and will answer any questions the patients 
many have.  Eligible patients may be contacted at home through a phone call by a member of the study 
team to introduce the study.  A member of the study team will answer any questions the patient may have 
before and after the informed consent form is signed.  The informed consent form will be documented in 
the subject’s medical record or comparable source document.  
3.1.2 
Study Intervention Phase  
Intervention will occur during the patient’s previously scheduled office visit.  The patient will be seen by the 
PI for the originally scheduled consultation.  After the initial consultation, proper screening, and informed 
consent of the patient is completed the patient will answer one survey and undergo 3-D photography and 
standard digital photography.  After injections the patient will have photographs and the survey administered 
again before the initial visit is complete. 
3.1.3 
Follow Up Phase 
The follow-up phase of a patient is approximately 90 ± 7 days.  Follow-up will begin after treatment is 
administered.  Required visits occur at 14 ± 3 days, 28 ± 3 days and 90 ± 7 days.  At each required follow-
up visit one questionnaire will be administered, the FACE-Q in addition to the 3-D Vectra imaging.   
3.1.4 
Primary Study Endpoints 
The primary endpoint will be to quantify patient satisfaction with minimally invasive volume correction.  
 
• Determine patient reported outcomes and satisfaction with the validated survey FACE-Q  
• Determine the volumetric changes at each time point up to 90 days 
3.1.5 
Secondary Study Endpoints 
• 
Correlate degree of patient satisfaction with volumetric measurements from 3-D analysis after 
treatment over the 90 day period  
4 
Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
• 
Female patients 40 – 65 years of age 
4.2 
Exclusion Criteria 
• 
Male patients 
• 
Prior surgical facial rejuvenation procedures 
o 
Facelift 
o 
Neck lift 
o 
Blepharoplasty 
o 
Facial fat grafting 
• 
Prior minimally invasive rejuvenation procedure ≤ 12 months 
• 
Known contraindications to devices or drugs used in this study 


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• 
Facial paralysis 
• 
Congenital facial asymmetry  
• 
Pregnant women 
• 
Patient actively taking blood thinners 
4.3 
Subject Recruitment  
Eligible subjects will be identified from principal investigator’s clinic schedule and recruited from local area 
including employees.  Potential subjects will be screened by a member of the study team for eligibility, using 
the electronic medical record (EMR), according to the inclusion and exclusion criteria listed above.  In clinic, 
the principal investigator will introduce the study to eligible patients.  A member of the study team will give 
a written informed consent, and will answer any questions the patients may have. Eligible patients may be 
contacted at home through a phone call by a member of the study team to introduce the study to assess 
interest in participation.  A member of the study team will answer any questions the patients may have 
before and after the informed consent is signed.  The informed consent process will be documented in the 
subject’s medical record or comparable source document. 
4.4 
Duration of Study Participation 
Subject participation will begin during the office when the informed consent is signed.  Once the patient is 
confirmed to be a study candidate by the participating physician, they can be enrolled.   Patients will be 
asked to return for 3 follow-up visits over the next 90 ± 7 days.   
4.5 
Total Number of Subjects and Sites  
Total accrual will be 100 patients.  The aim will be to enroll all subjects at the University of Pennsylvania 
Health System (UPHS).   
5 
Study Intervention  
The initial consultation by the principal investigator will determine the injection area and the volume of the 
injections.  Injections of the fillers will be used according to the FDA approval indicated use.  All three areas 
will be injected (nasolabial folds, marionette lines, and lips).   
 
Restylane-L® used for the nasolabial folds and/or marionette lines up to a total of 4 cc (2 cc/side).  
Restylane-L® Lyft used for severe nasolabial folds and or marionette lines up to a total of 2 cc (1 cc/side) 
Restylane-L® Lyft used for malar deflation will receive up to a total of 4 cc of (2 cc/side) 
  Restylane® Silk in the lips and cutaneous vermillion used for perioral volume loss will receive up to 1cc 
per lip.   
5.1 
Description 
Restylane-L® is indicated for mid-to-deep dermal implantation for moderate to severe facial wrinkles and 
folds, such as nasolabial folds.  It is indicated for submucosal implantation for lip augmentation in patients 
over the age of 21.  Restylane-L® consists of stabilized, hyaluronic acid (HA) generated by streptococcal 
bacteria and formulated to a concentration of 20 mg/ml, suspended in physiological buffer of pH7 with 0.3% 
lidocaine.  Restylane-L® is a transparent viscous and sterile gel, supplied in disposable glass syringes 
contain 0.4 or 0.7 ml gel.   
 
Restylane-L® Lyft is indicated for implantation into the deep dermis to superficial subcutis for the correction 
of severe facial folds and wrinkles, such as nasolabial folds and for subcutaneous to supraperiostal 
implantation for check augmentation correction of age-related midface contour deficiencies in patients >21 
years of age.  Restylane-L® Lyft is a sterile gel of stabilized hyaluronic acid generated by staphylococcus 
species of bacteria, suspended in phosphate buffer saline at pH 7 at a concentration of 20 mg/ml with 0.3% 
lidocaine. 
 
Restylane® Silk is indicated for submucosal implantation for lip augmentation and dermal implantation for 
correction of perioral rhytids in patients >21 years of age.  Restylane® Silk is a gel of hyaluronic acid 
generated by streptococcus species of bacteria stabilized and suspended in phosphate buffered saline at 
pH 7 at a concentration of 20 mg/ml with 0.3%.   


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5.2 
Intervention Regimen 
5.2.1 
Study Group  
The patient will receive the injections of the fillers in all three areas the nasolabial folds, marionette lines, 
and lips as recommended by the PI during the initial consultation of the regularly scheduled appointment. 
5.3 
Receipt  
Galaderma the manufacturer of Restylane-L®, Restylane-L® Lyft, and Restylane® Silk, will provide the 
fillers for the study.  The products will be shipped directly to the PI and stored in a drug labeled refrigerator.  
The products will be inventoried when they arrive and designated as used per patient.   
5.4 
Storage 
The products will be shipped directly to the PI and stored in a drug labeled refrigerator in the PI’s office. 
Restylane-L®, Restylane-L® Lyft and Restylane® Silk must be used prior to expiration date printed on the 
package and stored at a temperature ≤ 77° F ≥ 36°F, protected from sunlight.  Do NOT freeze.   
5.5 
Preparation and Packaging 
Restylane-L®, Restylane-L® Lyft and Restylane® Silk come prepared in sterile disposable glass syringes 
with luer-lock fitting.  Restylane products are co-packed with sterilized needles (needle gauge specified on 
package).  Sterile syringes will be used for each vial assigned to each subject.         
5.6 
Administration and Accountability    
Restylane® products come supplied with a patient record label as a part of the syringe label. Remove it by 
pulling the flap marked with three small arrows. This label is to be attached to patient records to ensure 
traceability of the product. The extra label will also be placed on the device accountability log.   
5.7 
Return or Destruction of Investigational Product 
The unused products will be disposed in the fashion of biohazard material.   
 
6 
Study Procedures 
  
TABLE 4  SCHEDULE OF STUDY PROCEDURES  
 
Baseline 
Visit  
Intervention 
 
Follow-up Visit  1 
Day 14 
Follow-up Visit 2 
Day 28 
Follow-up Visit 3 
Day 90 
Visit Window 
Day 1 
Day 1 
Day 14  ± 3 
Day 28 ± 3 
Day 90 ± 7 
Eligibility 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Demographic 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Consultation 
X 
 
 
 
 
Vectra Photography  
 
X 
X 
X 
X 
FACE-Q  
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
 


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6.1 
Study Intervention Phase 
6.1.1 
Screening/Baseline Visit (Day 1)  
Electronic medical records from the most recent office visit will be used to initially screen according to the 
inclusion/exclusion criteria in Section 4.1 and 4.2. The current office visit will be used to confirm the patient’s 
eligibility, if confirmed the patient will be approached to consent to participate in the study.  When the patient 
is consented the screening/baseline documentation will take place.  The screening and baseline data 
collection will include demographic information, medical history, and surgical history. The screening and 
baseline visit and intervention can occur in the same office visit.   
 
 
• 
Medical Record Review 
Variables abstracted from the electronic medical record 
o 
Date of Birth 
o 
Height  
o 
Weight 
o 
Race  
o 
Gender 
o 
Any history of disease 
o 
Surgical facial rejuvenation history 
 
• 
Consultation 
The patient will undergo the initial consultation with the PI. The consultation will be documented in 
the patient’s EMR.    
6.1.2 
Intervention (Day 1) 
• 
If patient is concerned of child bearing potential, a urine pregnancy test will be administered. 
• 
FACE-Q survey will be administered prior to injections 
• 
Photographs with the Vectra 3D camera will be administered prior to injections 
• 
Injections 
o 
The patient will receive the fillers injectors as suggested in the consultation in all three 
areas of the face. 
• 
Photographs with the Vectra 3D camera will be administered 30 minutes after injections 
6.2 
Follow Up Phase of the Study 
6.2.1 
Follow-up Visits  
• 
Visit 1 (Day 14 ± 3) 
o 
Photographs with the Vectra 3D camera  
o 
FACE-Q will be administered 
 
• 
Visit 2 (Day 28 ± 3) 
o 
Photographs with the Vectra 3D camera  
o 
FACE-Q will be administered 
 
• 
Visit 3 (Day 90 ± 7) 
o 
Photographs with the Vectra 3D camera  
o 
FACE-Q will be administered 


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6.3 
Unscheduled Visits 
An unscheduled visit or extra visit will be defined as a visit scheduled outside of the protocol due to any 
concern of the patient’s treatment related to the injections.  If an unscheduled visit occurs, it is preferred to 
collect the information during the visit for example any adverse event.  If an unscheduled visit is missed a 
follow-up phone interview is adequate if more information is required than is available in the patient’s EMR.  
6.4 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care.  The Investigator may also 
withdraw subjects who violate the study plan, or to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the clinical study.  
6.4.1 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdraw consent to participate in the study may be asked for one final visit or phone interview 
to collect any study endpoints or adverse events at that time.   
6.5 
Early Termination Visits   
If a subject decides to leave the study early or is asked by the investigator to cease participation in the 
study the subject’s participation is complete.  
7 
Study Evaluations and Measurements  
7.1 
Efficacy Evaluations 
To quantify the subjective benefit using the FACE-Q to determine the patient’s satisfaction and comparing 
it with true objective volume changes measured with the Vectra 3D camera. 
8 
Statistical Plan 
8.1 
Primary Endpoint 
The primary endpoint is to quantify patient satisfaction with minimally invasive volume correction and to 
measure the volume metric changes with fillers over time.   
8.2 
Secondary Endpoints  
The secondary endpoints will correlate degree of patient satisfaction with the volumetric measurements 
from 3-dimensional image analysis.  
8.3 
Sample Size and Power Determination 
The sample size was deemed appropriate to power the study based on previous literature in this area of 
research. 
8.4 
Statistical Methods 
8.4.1 
Baseline Data 
Standard descriptive statistics will be used to summarize baseline characteristics and study outcome 
measures at each visit, both overall, and within each arm.  
8.4.2 
Efficacy Analysis  
The validated FACE-Q will be used to determine patient satisfaction for each arm.  The Mirror Software 3D 
software (Canfield Scientific Inc, Fairfield, New Jersey) will calculate the volumetric changes by comparing 
the treated area after filler injection to the baseline images.  The baseline and post treatment measurements 
from the Vectra 3D images will determine volumetric changes of the injections over time.  All volumetric 
measurements will be recorded in milliliters, and the average volume change will be calculated.  A 
correlation between patient satisfaction and volumetric changes will be calculated. 
 


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Statistical tests will be performed as determined by the study team.  Mean and standard deviation 
calculation with regression analysis will be performed for all survey variables.  Analysis of variance will also 
be performed.   
8.5 
Subject Population(s) for Analysis 
Per-protocol population: Any eligible patients randomized and adhered with their assigned treatment 
throughout the course of the trial.  
9 
Safety and Adverse Events 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
For FDA regulated studies the FDA defines an adverse event as the following:  
 
Adverse event means any untoward medical occurrence associated with the use if a drug in humans 
whether or not considered drug related.  
9.1.2 
Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
9.2 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should be 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study intervention or 


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participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
will be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study intervention or study participation will be 
recorded and reported immediately. 
9.3 
Relationship of AE to Study  
The relationship of each adverse event to the study procedures should be characterized. The PI or medical 
monitor will determine how the relationship of the AE will be classified as: 
• likely related – a well-known effect of the device or clearly not related to the subject or 
environmental factors 
• probably related – is known or suspected effect of device or cannot be readily explained by 
subject or study procedures  
• possibly related – is a possible effect of the device or can be explained by the subject or study 
procedures 
• unlikely related – is not a suspected effect of the device or can readily be explained by the 
subject or environmental factors  
• unrelated – is not a known effect of the device and can readily be readily and easily explained 
by the subject or environmental factors 
9.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
Investigators and the protocol sponsor (which may or may not be a Penn Investigator) must conform to the 
adverse event reporting timelines, formats and requirements of the various entities to which they are 
responsible,  
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes: 
 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study intervention was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study intervention 
 
 
Additionally, all other events (unanticipated problems, adverse reactions, unanticipated adverse device 
effects and subject complaints will be recorded and reported with respect to institutional and federal policies.  
 
9.4.1 
Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) should be submitted to the IRB. The investigator 
is responsible for ensuring that all SAE are followed until either resolved or stable.  
9.4.2 
Investigator reporting: notifying the study sponsor 
Investigators from all participating sites should report all unexpected and related adverse events, regardless 
of whether they are serious or not, and all unanticipated problems to the sponsor. 
 
Any study-related unanticipated problem posing risk to subjects or others, and any type of serious adverse 
event, will be reported to the study sponsor by telephone within 24 hours of the event.  To report such 
events, a Serious Adverse Event (SAE) form will be completed by the investigator and emailed to the study 
sponsor within 24 hours.  The investigator will keep a copy of this SAE form on file at the study site.  Report 
serious adverse events by sending via email to: 
 


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[Galderma Laboratories, L.P.,   
email: WELLS Sara <Sara.WELLS@galderma.com>] 
 
Within the following 48 hours, the investigator will provide further information on the serious adverse event 
or the unanticipated problem in the form of a written narrative.  This should include a copy of the completed 
Serious Adverse Event form, and any other diagnostic information that will assist the understanding of the 
event.  Significant new information on ongoing serious adverse events should be provided promptly to the 
study sponsor. 
9.4.3 
Investigator reporting: notifying the Penn IRB 
For single and multi-site studies each site PI will need to follow their local IRB reporting requirements in 
addition to the protocol outlined reporting.  
9.4.4 
Sponsor reporting: Notifying Participating Investigators  
For clinical trials, in addition to reporting certain unanticipated problems and adverse events noted above 
to the FDA, it is the responsibility of the study sponsor to report those same adverse events or findings to 
participating investigators. 
9.5 
Medical Monitoring 
It is the responsibility of the site Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above. The lead PI will monitor all AEs reported.   
9.6 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
9.7 
Data Collection and Management  
REDCap will be used to store and maintain the primary study records.  The data entered into REDCap will 
be obtained from the study-relevant patient EMRs.  Study personnel will be granted access to this project 
created in REDCap with each user obtaining individual access authenticated by a login system.  Minimal 
patient identifiers will be collected and stored in the REDCap database.  Patient name and date of birth will 
be collected in REDCap.   
 
Source data will mainly be from the patient’s EMR.  When the study requires data not normally collected in 
the patient’s EMR, the case report forms will also be the source document.  Data from source documents 
(Appendix15.4, case report forms (case report forms definition- Appendix 15.5), will be entered into an 
electronic data capturing system.  All source documents should be secure in private spaces with restricted 
access.   
 
During procurement of data charts will be reviewed in private spaces to ensure the confidentiality of 
acquired data.   Data will be stored for up to 7 years after completion of the last follow-up visit of the last 
patient randomized.  Data may be collected for up to two years following the treatment.     


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9.8 
Records Retention  
The Principal Investigator at each site is responsible for storing regulatory documents, subject files and 
financial records for the period specified by law.  The time period for maintaining research records is defined 
first by HIPAA regulations that require any HIPAA-regulated information, authorizations, waivers, etc. must 
be maintained for at least 6 years subsequent to the Institutional Review Board (IRB) acknowledgement of 
the termination of the research project and secondly by DHHS regulations (45 CFR 46.115) and FDA 
regulations (21 CFR 56.115) state that IRB records relating to research shall be retained for at least 3 years 
after completion of the research.   
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be closely monitored by the PI and the project manager.  The PI will be participating and the 
data will be collected by the PI and one other study steam member from the patient’s EMR.  The study 
team member will enter the data into the REDCap and the project manager will monitor the entry to verify 
the compliance with respect to the protocol, data collection and source documents.     
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  This consent 
form will be submitted with the protocol for review and approval by the EC/IRB for the study.  The formal 
consent of a subject, using the EC/IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent. 
11.1 Risks 
All treatments used in this protocol will be used according to the FDA approved intended use.  No 
unexpected risks should occur.  Risks that may be experienced from any injection are swelling bruising, 
redness, itching, infection, or pain.   
 
All HA containing products have the risk of potential tissue loss if there is unrecognized intravascular 
injection of the fillers.  All HA  fillers are dissolvable and if you are strongly dissatisfied with the treatment 
filler or if there is evidence of tissue threat, HA can be removed with hyaluronidase (Vitrase)®.  Restylane 
Silk carries an extra risk of hyperpigmentation to the risks from injection listed above.  A risk related to all 
injectables used in this study is unevenness or lumps.   
 


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Reproductive risks: If patient is of child-bearing potential, a urine pregnancy test may be administered prior 
to injection to confirm negative pregnancy status.  The effects of this drug/device, there could be serious 
harm to unborn children or children who are breast-feeding. These effects could also harm the mother.   
11.2 Benefits 
Subjects participating in this trial will not directly benefit participating in this study.  If assigned to the 
treatment group, the patient will receive the treatment described in the initial consultation. If assigned to the 
control group, they may not receive the desired benefits of the requested consultation. 
11.3 Risk Benefit Assessment 
Subjects participating in this trial will unlikely experience an increase in risk as both groups receive 
injections.  This study is designed to minimally change patient’s care.  Subjects participating in this trial are 
chosen due to the clinic consultation scheduled.  No change in patient care will happen if the subject is 
consented.  All subjects will be asked to return for three follow-up visits for observation and surveys.  
11.4 Informed Consent Process / HIPAA Authorization  
Eligible subjects will be identified from the practice of the PI.  Potential subjects will be screened by a 
member of the study team for eligibility, using the electronic medical record (EMR), according to the 
inclusion and exclusion criteria listed above.  In clinic, the participating investigator will introduce the study 
to eligible patients during the consultation visit.  A member of the study team, identified to consent, will give 
a written informed consent and answer any questions the patients may have. Eligible patients may be 
contacted at home through a phone call by a member of the study team to introduce the study followed by 
presenting the consent form during the consultation visit.  A member of the study team will answer any 
questions the patients may have before and after the informed consent is signed.  It will be emphasized to 
the potential subject that three visits are required which are not considered standard of care.  The informed 
consent process will be documented in the subject’s medical record or comparable source document.  
12 Study Finances 
12.1 Funding Source 
All product used in this study will be provided by the manufacturer, Galderma.   
12.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
12.3 Subject Stipends or Payments 
Subjects will not be compensated when they return to the clinic for the follow-up visits.    
13 Publication Plan 
The manuscript for this trial will contain the overall study results and be submitted to a peer-review journal.  
The final contents will be at the discretion of the PI.   All results of the study performed under this protocol, 
or any of the information provided by the PI for the purposes of performing the study, will not be published 
or passed on to any third party without the consent of the PI.  Any investigator involved with this study is 
obligated to provide the PI with complete test results and all data derived from the study. 
14 References 
Attachments 
Investigator will attach sample Investigator Agreement and ICF prior to study activation 
• Investigator Agreement (for any investigator, other than sponsor-investigator, who participates in 
the study) 
• Sample Consent Form 


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15 Appendix 
15.1 Reference for Safety Reporting Section- Common Definitions for Developing and Adverse 
Event Tracking and Serious Adverse Event Reporting Protocol 
15.2 Expedited FDA Reporting Requirements  
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND/ IDE safety reports.  
 
The following describes the IDE safety reporting requirements by timeline for reporting and associated type 
of event: 
 
• Within 10 working days 
Any study event that is all: 
– associated with the use of the study drug, and 
– unexpected, 
regardless of the seriousness of the event. 
 
• Within 5 working days 
– Protocol deviation to protect the life of the subject in emergency 
– Withdrawal of IRB approval 
– Lack of informed consent 
 
Additional reporting requirements 
Sponsors are also required to identify in IND/IDE safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Applicable events can be reported to the FDA using Form FDA3500A or in narrative format. The report 
must be sent to the correct division. Specific information that must be included in the reports can be found 
in 21 CFR 312.32 or in 21 CFR 812.150. 
15.3 DSMB Reference: The following section of guidance language draws from: the FDA Guidance 
Document: “Guidance for Clinical Trial Sponsors on the Establishment of Clinical Trial Data 
Monitoring Committees” 
15.4 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
15.5 Case Report Forms (CRFs) 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the item, then initial 
and date it.