A Multicenter, Single-blind, Randomized, Controlled Study of the Safety and Effectiveness of JUVÉDERM VOLUMA® XC Injectable Gel for Chin Augmentation
Phase: NA
Conditions: Chin Retrusion
Sponsor: Allergan

NCT02833077 
 
Study ID: VOLUMA‐006 
 
 
 
Title: A multicenter, single‐blind, randomized, controlled study of the safety and effectiveness of 
JUVÉDERM VOLUMA® XC injectable gel for chin augmentation 
 
Protocol Amendment 4 Date: 01 Mar 2017 
 
 

 
 
Approval Date: 
 
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Allergan Confidential 
Protocol VOLUMA-006 Amendment 4 
JUVÉDERM VOLUMA® XC 
 
 
 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information 
that is the property of Allergan 
Study Title: 
A multicenter, single-blind, randomized, controlled study 
of the safety and effectiveness of JUVÉDERM 
VOLUMA® XC injectable gel for chin augmentation 
Protocol Number: 
VOLUMA-006 Amendment 4 
Protocol Date 
01 Mar 2017 
Product Name: 
JUVÉDERM VOLUMA XC Injectable Gel 
Development Phase: 
Pivotal 
Sponsor: 
Allergan, Inc. 
2525 Dupont Drive 
Irvine, CA 92612 
 
 
 
 
 
 
 
 
 
 
Names and contact information of Allergan study personnel are provided in the 
supplementary Study Contacts page.

 
 
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INVESTIGATOR SIGNATURE PAGE 
Study Title: 
A multicenter, single-blind, randomized, controlled 
study of the safety and effectiveness of JUVÉDERM 
VOLUMA® XC injectable gel for chin augmentation 
 
Protocol Number: 
VOLUMA-006 Amendment 4 
Protocol Date: 
01 Mar 2017 
Product Name: 
JUVÉDERM VOLUMA XC Injectable Gel 
Investigator: 
 
Study Location: 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with this protocol, 
good clinical practices (GCP), and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Ethics Committee (EC), or another 
group, it will be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
RETURN TO ALLERGAN 

 
 
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Synopsis 
 
NUMBER AND TITLE OF STUDY: 
VOLUMA-006:  A multicenter, single-blind, randomized, controlled study of the safety and effectiveness of 
JUVÉDERM VOLUMA® XC injectable gel for chin augmentation 
DEVELOPMENT PHASE:  Pivotal 
STUDY CENTERS:  Up to 15 United States (US) centers 
NUMBER OF SUBJECTS:  Up to 224 subjects will be enrolled 
OBJECTIVES:  The objectives of this study are to evaluate the safety and effectiveness of JUVÉDERM 
VOLUMA XC injectable gel for chin augmentation to correct volume deficit in adult subjects seeking correction 
of chin retrusion. 
STUDY DESIGN: 
This is a prospective, multicenter, evaluator-blinded, randomized, controlled study to evaluate the safety and 
  
 
 
 
 
 
 
 
 
 
 
Treatment Group:  For subjects randomized to the treatment group, the TI will use
 
 
  
.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
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DIAGNOSIS AND CRITERIA FOR INCLUSION/EXCLUSION: 
Adults with chin retrusion who are seeking to increase facial volume in the chin area 
INCLUSION: 
1. Age 22 or over and in good general health 
 
 
 
3. Treating Investigator considers the subject’s chin retrusion to be amenable to temporary correction 
4. Ability to follow study instructions and likely to complete all required visits 
5. Written informed consent has been obtained 
EXCLUSION: 
1. Has ever received permanent facial implants (eg, polymethylmethacrylate, silicone, 
polytetrafluoroethylene) anywhere in the face or neck, or is planning to be implanted with any of these 
products during the study 
2. Has ever undergone fat injections below the subnasale or is planning to undergo this procedure during 
the study 
3. Has tattoos, piercings, facial hair (ie, beard, mustache), or scars below and including the subnasale that 
would interfere with visual assessment of the chin, jowls, or jawline 
4. Has undergone semipermanent dermal filler treatment (eg, calcium hydroxyapatite, poly-L-lactic acid) 
in the chin or jaw within 36 months before enrollment or is planning to undergo such treatment during 
the study 
5. Has undergone dermal filler injections, or has undergone any surgery in the chin or jaw area (including 
marionette lines, pre-jowl sulci, mandibular body, or masseter muscles) within 24 months before 
enrollment or is planning to undergo any of these procedures during the study 
6. Has undergone dermal filler injection in the lips or perioral area within 12 months before enrollment or 
is planning to undergo such treatment during the study 
 
 
 
 
 
 
 
10. Has undergone mesotherapy or cosmetic treatment (laser, photomodulation, intense pulsed light, radio 

 
 
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frequency, dermabrasion, moderate or greater depth chemical peel, liposuction, lipolysis, or other 
ablative procedures) anywhere in the face or neck, or botulinum toxin treatment below the subnasale 
(including injections to the masseter muscles) within 6 months before enrollment or is planning to 
undergo any of these procedures during the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TEST PRODUCT, DEVICE VOLUME, AND MODE OF ADMINISTRATION: 
 
 
 Appropriate injection volume for the chin and chin area will be determined by the Treating 
Investigator but is not to exceed a maximum total volume of 4.0 mL for initial and touch-up treatments 
combined, and 4.0 mL for repeat treatment. 

 
 
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DURATION OF STUDY:  Treatment Group:  Initial treatment period:  up to 30 days; Follow-up period:  
12 months following last treatment (initial or touch-up), and 1 month following optional repeat treatment.  
Control Group:  Control period:  6 months; Initial treatment period:  up to 30 days; Follow-up period:  6 months 
following last treatment (initial or touch-up) 
RESPONSE MEASURES: 
Effectiveness:  The primary effectiveness measure is the EI’s photo assessment of chin retrusion using the 
ACRS at month 6 based on 2D profile images of the left side of the chin rendered by the Canfield image analysis 
technician from the 3D images.  Secondary effectiveness measures include EI and subject assessments of global 
aesthetic improvement in the chin area using the 5-point GAIS, and subject responses on the Satisfaction with 
Chin module of the validated FACE-Q questionnaire. 
 
 
 
. 
 
 
 
 
 
STATISTICAL METHODS: 
Sample Size Calculation:  Sample size is determined to provide adequate power to demonstrate that the product 
is effective as well as safe.  A sample size of 120 subjects in the treatment group and 40 subjects in the control 
group will provide > 99% power to detect a difference of at least 40% in the responder rates between the groups.  
This calculation is based on a 2-sided Fisher’s exact test at the 5% level.  The treatment group is assumed to 
have at least 80% responder rate and the control group will have at most 40% responder rate.  Assuming a screen 
fail rate of 15% and a drop-out rate of 15% between randomization and the month 6 visit, up to 224 subjects will 
be enrolled, resulting in up to 168 subjects randomized to the treatment group and up to 56 subjects to the 
control group (3:1 ratio).  Assuming a screen fail rate of 15% and an overall drop-out rate of 20% between 
randomization and study completion, an estimated 152 subjects will complete the study. 
With up to 168 subjects randomized to the treatment group and an estimated screen fail rate of 15%, it is 
estimated that at least 143 subjects will be treated in the study.  With 143 treated subjects, there is at least an 
88% power to detect an AE related to treatment with an incidence rate of 1.5% in the population using a 1-sided 
exact binomial test at the 2.5% level. 
Due to an estimated 15% of subjects having a baseline photo assessment of 1 or 4, up to 36 additional subjects 
may be randomized to ensure sufficient power for sensitivity analyses, resulting in a total of up to 260 subjects 
enrolled. 
The commercial software,
 was used for the power calculation.  The sample size 
calculation used an inequality test for 2 proportions to demonstrate that the treatment group is superior to the 
control group.  The safety calculation used an inequality test for 1 proportion. 
Effectiveness:  The primary effectiveness endpoint will be met if the responder rate at month 6 for the treatment 
group is statistically greater than that for the control group at month 6 and the responder rate at month 6 for the 
treatment group is greater than 50%.  Responder rate is the percentage of subjects who show at least 1-point 
improvement on the ACRS from baseline based on EI assessment of 2D renderings of the chin profile.  Baseline 
is defined as the EI assessment of the 2D image at randomization (or screening if no usable randomization photo 
is available).  The primary effectiveness analysis will be performed on the modified intent-to-treat (mITT) 
population, which includes subjects who are randomized to study treatment (treatment group) and receive at 
least 1 study device treatment or are randomized to the control group.  A sensitivity analysis will be performed 
on the intent-to-treat (ITT) population, which includes all randomized subjects.  For the primary effectiveness 
analysis, a 2-sided, Fisher’s exact test at the 5% level will be used to test whether the responder rate from 
baseline for the treatment group is significantly greater than that for the control group at month 6 in the control 

 
 
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period. 
The secondary effectiveness analyses will include the responder rates with 95% confidence intervals for the 
treatment group based separately on the EI and subject assessments of GAIS, where a “responder” is a subject 
who shows improvement in the overall aesthetic assessment in the chin area (Improved or Much Improved on 
GAIS) at the month 6 visit and descriptive summary of the change in overall score of subject’s satisfaction with 
chin since baseline at the month 6 visit based on the treatment group subjects’ responses on Satisfaction With 
Chin FACE-Q questionnaire and a 2-sided paired t-test at the 5% level to demonstrate that the mean overall 
satisfaction score at month 6 visit is statistically greater than that at baseline for the treatment group.  Other 
effectiveness analyses will include
 
 
 
 
 
 
 

 
 
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Table of Contents 
Synopsis .................................................................................................................................... 3 
Table of Contents ...................................................................................................................... 8 
List of Tables ........................................................................................................................... 11 
List of Figures ......................................................................................................................... 12 
1. 
Abbreviations and Terms ................................................................................................. 18 
2. 
Background, Risk and Benefit, and Clinical Rationale ................................................... 19 
2.1 
Background ............................................................................................................ 19 
2.2 
Risk and Benefit ..................................................................................................... 20 
2.3 
Clinical Rationale ................................................................................................... 22 
3. 
Study Objectives and Clinical Hypotheses ...................................................................... 22 
3.1 
Study Objectives .................................................................................................... 22 
3.2 
Clinical Hypothesis ................................................................................................ 22 
4. 
Study Design .................................................................................................................... 23 
4.1 
Structure ................................................................................................................. 23 
4.2 
Duration ................................................................................................................. 23 
4.3 
Treatment Groups and Treatment Regimen ........................................................... 23 
4.3.1  Study Treatment ......................................................................................... 23 
4.3.2  Control Treatment ...................................................................................... 23 
4.3.3  Methods for Blinding ................................................................................. 23 
4.3.4  Retreatment Criteria ................................................................................... 24 
4.4 
Permissible and Prohibited Medications/Treatments ............................................. 24 
4.4.1  Permissible Medications/Treatments ......................................................... 24 
4.4.2  Prohibited Medications/Treatments ........................................................... 25 
4.4.3  Escape Medications .................................................................................... 26 
4.4.4  Special Diet or Activities ........................................................................... 26 
4.5 
Treatment Allocation Ratio .................................................................................... 26 
5. 
Study Population .............................................................................................................. 26 
5.1 
Number of Subjects ................................................................................................ 26 
5.2 
Study Population Characteristics ........................................................................... 26 
5.3 
Inclusion Criteria .................................................................................................... 26 

 
 
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5.4 
Exclusion Criteria................................................................................................... 27 
6. 
Procedures ........................................................................................................................ 29 
6.1 
Washout or Run-In Intervals .................................................................................. 29 
 
 
6.1.2  Run-in Intervals .......................................................................................... 29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Instructions for the Subjects ................................................................................... 37 
6.4 
Unscheduled Visits ................................................................................................. 38 
6.5 
Early Discontinuation of Subjects .......................................................................... 38 
6.6 
Withdrawal Criteria ................................................................................................ 39 
7. 
Response Measures and Summary of Data Collection Methods ..................................... 39 
7.1 
Effectiveness Measures .......................................................................................... 39 
7.1.1  Primary Effectiveness Measure .................................................................. 39 
7.1.2  Secondary Effectiveness Measures ............................................................ 40 
 
 
 
 
7.3 
Demographics and Baseline Characteristics .......................................................... 44 
7.4 
Treatment Characteristics ....................................................................................... 44 
7.5 
Summary of Methods of Data Collection .............................................................. 44 
8. 
Statistical Procedures ....................................................................................................... 45 
8.1 
Analysis Populations .............................................................................................. 45 
8.2 
Collection/Derivation of Primary and Secondary Effectiveness Assessments ...... 46 
8.2.1  Primary Effectiveness Variable .................................................................. 46 
8.2.2  Secondary Effectiveness Variables ............................................................. 46 

 
 
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8.3 
Hypothesis and Methods of Analysis ..................................................................... 47 
8.3.1  Primary Effectiveness Analyses ................................................................. 47 
8.3.2  Secondary Effectiveness Analyses ............................................................. 47 
 
 
 
 
8.4 
Subgroup Analyses ................................................................................................. 48 
8.5 
Sample Size Calculation ........................................................................................ 49 
8.6 
Interim Analyses..................................................................................................... 49 
9. 
Materials .......................................................................................................................... 49 
9.1 
Study Treatment ..................................................................................................... 49 
9.1.1  Product Description .................................................................................... 49 
9.1.2  Instructions for Use and Administration .................................................... 50 
9.1.3  Treatment Regimen Adjustments ............................................................... 50 
9.2 
Other Study Supplies .............................................................................................. 51 
10.  Study Administration Procedures .................................................................................... 51 
10.1  Subject Entry Procedures ....................................................................................... 51 
10.1.1  Overview of Entry Procedures ................................................................... 51 
10.1.2  Informed Consent and Subject Privacy ...................................................... 52 
10.1.3  Method for Assignment to Treatment Groups ............................................ 53 
10.2  Compliance with Protocol ...................................................................................... 53 
10.3  Pregnancy ............................................................................................................... 53 
10.4  Study Termination .................................................................................................. 54 
11.  Adverse Events ................................................................................................................ 54 
11.1  Definitions .............................................................................................................. 55 
11.1.1  Adverse Event ............................................................................................ 55 
11.1.2  Serious Adverse Event ............................................................................... 55 
11.1.3  Adverse Device Effect ............................................................................... 56 
11.1.4  Serious Adverse Device Effect ................................................................... 56 
11.1.5  Unanticipated Adverse Device Effect ........................................................ 57 
11.1.6  Device Deficiency ...................................................................................... 57 
11.1.7  Severity ...................................................................................................... 57 
11.1.8  Relationship to Treatment .......................................................................... 57 
11.2  Timelines for Reporting ......................................................................................... 58 
11.3  Procedures for Reporting an AE or ADE ............................................................... 58 

 
 
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11.4  Procedures for Reporting an SAE or SADE .......................................................... 58 
12.  Administrative Issues ....................................................................................................... 59 
12.1  Protection of Human Subjects ................................................................................ 59 
12.1.1  Compliance with Informed Consent Regulations ...................................... 59 
12.1.2  Compliance with IRB Regulations............................................................. 59 
12.1.3  Compliance with Good Clinical Practice ................................................... 59 
12.1.4  Financial Disclosure/Certification Form .................................................... 59 
12.1.5  Compliance with Electronic Records and Signature Regulations .............. 60 
12.2  Changes to the Protocol ......................................................................................... 60 
12.3  Subject Confidentiality and Privacy....................................................................... 61 
12.4  Documentation ....................................................................................................... 61 
12.4.1  Source Documents ..................................................................................... 61 
12.4.2  Case Report Form Completion................................................................... 62 
12.4.3  Investigator Reports ................................................................................... 63 
12.4.4  Retention of Documentation ...................................................................... 63 
12.5  Labeling, Packaging, Storage, and Return of Study Devices ................................. 64 
 
12.5.2  Storage of Study Devices ........................................................................... 64 
12.5.3  Study Device Accountability ...................................................................... 65 
12.5.4  Return of Study Devices ............................................................................ 65 
12.6  Monitoring by Allergan .......................................................................................... 65 
12.7  Testing of Biological Specimens ............................................................................ 66 
12.8  Publications ............................................................................................................ 66 
13.  References ........................................................................................................................ 66 
14.  Protocol Amendment Summary ....................................................................................... 68 
 
List of Tables 
 
 
 
 
 
 
 
 
 
 

 
 
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List of Figures 
Figure 1 
Lines Used in the ACRS Descriptors .............................................................. 40 
 

 
 
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1. 
Abbreviations and Terms 
Term/Abbreviation 
Definition 
2D 
2-dimensional 
3D 
3-dimensional 
ACRS 
Allergan Chin Retrusion Scale 
ADE 
adverse device effect 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
eCRF 
electronic case report form 
EI 
Evaluating Investigator 
DFU 
directions for use 
FDA 
Food and Drug Administration 
 
 
GAIS 
Global Aesthetic Improvement Scale 
HA 
hyaluronic acid 
HIPAA 
Health Insurance Portability and Accountability Act 
IC 
informed consent 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ISR 
injection site response 
ITT 
Intent-to-treat 
IWRS 
interactive web response system 
mITT 
modified intent-to-treat 
PP 
per-protocol 
PT 
preferred term 
SADE 
serious adverse device effect 
SOC 
system organ class 
TI 
Treating Investigator 
UADE 
unanticipated adverse device effect 
US 
United States 

 
 
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2. 
Background, Risk and Benefit, and Clinical Rationale 
2.1 
Background 
Hyaluronic acid (HA) injectable gels have become a primary treatment for facial 
rejuvenation, with an established record of safety and effectiveness (Jones and Flynn, 2010).  
A range of HA injectable gels is available for correction of wrinkles and folds.  However, the 
paradigm for achieving a more youthful looking face has moved away from the approach of 
treating discrete wrinkles and folds to one focused on panfacial volumizing.  One such 
product, JUVÉDERM VOLUMA® XC, was specifically designed for volumizing and has 
demonstrated effectiveness in restoring age-related volume deficit to the mid-face 
(Jones and Murphy, 2013).  JUVÉDERM VOLUMA XC can better achieve balanced facial 
proportions because it has improved qualities of lift and projection compared with HA gels 
designed for correction of wrinkles and folds.  Another area of the face where lift and 
projection are important aspects of volumizing includes the chin area. 
The shape and projection of the chin contribute to the proportional balance of the face that 
underlies attractiveness.  A chin lacking projection is commonly labeled a “weak chin” 
whereas prominent chins are labeled “strong chins” and imply strength of personality 
(Naini, 2011).  Several studies have suggested that faces with average proportions are viewed 
as the most attractive and that juvenile features including a small chin are interpreted as 
attractive in females while a strong chin and jaw are interpreted as attractive in males 
(Jones and Hill, 1993; Schact, 2005).  The appearance of the chin is a determinant of 
perceived attractiveness and can influence an individual’s psychosocial well-being 
(Naini et al, 2012). 
In a survey to understand the role of the nose, lips, and chin in achieving a balanced facial 
profile, 545 professionals viewed a series of silhouettes that varied in the size of the nose, 
lips, angle of facial convexity, and facial angle.  Both males and females least favored 
retrusive chin profiles.  Sagittal changes in the position of the chin formed by varying the soft 
tissue facial angle and resulting in a more pronounced chin were more favored, especially by 
males (Czarnecki et al, 1993). 
As the mandible and chin are the framework of the lower face, augmentation methods to treat 
chin retrusion and contour changes of the chin area or to treat microgenia have been explored 
for decades.  Where the approach in correcting chin retrusion is to add volume, treatment 
methods have included chin implants, genioplasty, and injection of silicone and semi-
permanent fillers, such as polymethylmethacrylate microspheres, and calcium 

 
 
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hydroxyapatite.  However, all of these treatment methods have drawbacks.  For example, 
chin implants and genioplasty involve painful surgery that may not result in correction of 
chin retrusion and aesthetic blending of the area.  This approach may exacerbate bone 
resorption and infection, resulting in the need for implant removal (Frodel, 2005; 
Rubin and Yaremchuk, 1997; Yaremchuk, 2003).  Injection of semi-permanent fillers has 
trade-offs between volumizing capacity and adverse events (AEs).  Temporary dermal fillers 
offer a better alternative. 
JUVÉDERM VOLUMA XC is a temporary HA dermal filler that is a structural gel 
manufactured specifically to provide a safe, minimally invasive method to restore and create 
facial volume.  JUVÉDERM VOLUMA XC is currently indicated in the United States (US) 
for injection into the subcutaneous and/or supraperiosteal space of the mid-face to add 
volume in the cheek area; and it is approved outside of the US for volumizing other areas of 
the face, including the chin and chin area.  As JUVÉDERM VOLUMA XC is moldable after 
injection, it allows for sculpting, contouring, and shaping across the injected areas to achieve 
the optimal aesthetic outcome.  As the chin and chin area is a high mobility areas where a 
structural filler is expected to be more effective, this area represents an excellent target for 
leveraging the volumizing and lifting capabilities of JUVÉDERM VOLUMA XC.  The 
current study will investigate the safety and effectiveness of JUVÉDERM VOLUMA XC in 
subjects seeking to correct volume deficit in the chin and chin area. 
2.2 
Risk and Benefit 
The injection procedure, anesthetic agents, or JUVÉDERM VOLUMA XC may cause some 
of the risks and/or discomforts listed below.  Unforeseeable risks or results are also a 
possibility.  The risk of developing a serious complication is small.  If a complication occurs, 
subjects will be advised to contact the Treating Investigator (TI) who will use his/her medical 
judgment to do whatever is necessary to treat the subject. 
For a more comprehensive review of the risk profile of JUVÉDERM VOLUMA XC, 
including Contraindications, Warnings, and Precautions, please refer to the VOLUMA-006 
directions for use (DFU). 
As with any skin injection, risks can be posed by the injection procedure itself, the anesthetic 
agent, and injection of JUVÉDERM VOLUMA XC Injectable Gel.  Risks related to the 
injection procedure include redness, itching, pain, tenderness, swelling, bruising, and lumps 
and bumps, which are common to dermal filler injection procedures, in general.  The use of a 
small gauge needle to deliver JUVEDERM VOLUMA XC in this study is intended to 

 
 
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minimize tissue trauma.  Risks associated with the anesthetic agent include allergic reactions 
that may manifest as an anaphylactic reaction, skin rash, redness, itching, hives, burning, 
stinging, swelling, tenderness, and transient loss of skin color.  The inclusion of 
0.3% lidocaine in the formulation is meant to reduce pain during the injection and this should 
be taken into account when administering concomitant additional anesthetics. 
Prior to administering any topical pretreatment anesthesia, the Investigator will thoroughly 
review the subject’s history to confirm the suitability of the planned anesthetic agent and 
route of administration.  Additionally, the VOLUMA-006 DFU must be carefully reviewed, 
and each individual subject’s medical history should be carefully considered, when 
evaluating a potential subject’s candidacy for study enrollment. 
The safety and effectiveness of JUVÉDERM VOLUMA XC has been established for 
increasing facial volume in the cheeks (Jones, 2013).  Since the injections will be in the same 
tissue planes, and the neurovascular structures of the cheeks and chin are similar, the safety 
and effectiveness profiles of JUVÉDERM VOLUMA XC in the chin are expected to be 
similar to the safety and effectiveness profiles of JUVÉDERM VOLUMA XC demonstrated 
in the cheeks. 
In a multicenter study of JUVÉDERM VOLUMA XC in the cheeks, safety and effectiveness 
information was collected for 270 subjects who received treatment.  The volume of treatment 
injected varied depending on the subject’s volume deficit and treatment goal, and ranged 
from 1.2 mL to 13.9 mL (median 4.8 mL).  After initial treatment with JUVEDERM 
VOLUMA XC, 98% of subjects reported experiencing a local treatment site response, 
predominantly mild or moderate in severity (80.7%), lasting 2 to 4 weeks.  The most frequent 
treatment site responses were tenderness (92.1%), swelling (85.7%), and firmness (82.3%).  
AEs were experienced less frequently (32.6%) than treatment site responses, and were also 
generally mild to moderate in severity.  Almost all (99%) of the reported AEs were at a 
treatment site, with the most frequently reported device- and injection-related AEs being 
treatment site mass (18.9%), treatment site induration (14.1%), and treatment site 
swelling (7.0%). 
A treatment responder was identified as having an improvement of ≥ 1-grade change on the 
validated 6-point photometric mid-face volume deficit scale (MFVDS) at 6 months after the 
initial treatment compared to baseline.  The responder rate of the treatment group was 85.6%, 
which was significantly greater (p < 0.0001) than the responder rate for the control group 
(38.9%), demonstrating that the vast majority of treatment group subjects experienced 

 
 
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improvement in their facial appearance at the primary timepoint of 6 months after treatment.  
When followed through 24 months after treatment, the responder rate was 67.1%. 
The benefits of the study treatment are expected to include greater lift capacity with a 
favorable tolerability profile compared with alternative available treatments.  Although there 
are risks associated with the injection procedure and with the product formulation (including 
HA, lidocaine, and crosslinker), the enhanced product characteristics of a viscous and 
cohesive gel are expected to result in significant advantages to the subject as they allow the 
investigator to treat a discrete area using a minimally invasive procedure with the ability to 
sculpt for optimal aesthetic augmentation of the chin and chin area. 
The safety and effectiveness after injection of study treatment to the chin area are expected to 
be similar to the profiles described for JUVÉDERM VOLUMA XC when injected in the 
cheeks. 
2.3 
Clinical Rationale 
JUVÉDERM VOLUMA XC was designed specifically for volumizing and has demonstrated 
effectiveness in restoring age-related mid-face volume deficit (Jones, 2013).  The protocol is 
designed as a pivotal study to collect safety and effectiveness data associated with the 
implantation of JUVÉDERM VOLUMA XC for the augmentation of chin retrusion in adult 
subjects seeking improvement in chin volume deficit. 
3. 
Study Objectives and Clinical Hypotheses 
3.1 
Study Objectives 
The objectives of this study are to evaluate the safety and effectiveness of JUVÉDERM 
VOLUMA XC injectable gel in augmentation of chin retrusion in adult subjects seeking 
improvement in chin volume deficit. 
3.2 
Clinical Hypothesis 
The clinical hypothesis is that the percentage of subjects with a clinically significant change 
(defined as at least a 1-point improvement in the Allergan Chin Retrusion Scale [ACRS] 
score as assessed by the Evaluating Investigator [EI] based on assessment of 2-dimensional 
[2D] renderings of 3-dimensional [3D] digital facial images) in chin retrusion from baseline 
to month 6 will be significantly greater in the JUVÉDERM VOLUMA XC treatment group 

 
 
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than in the untreated control group and the percentage of the treatment group with a clinically 
significant change in chin retrusion from baseline to month 6 will be greater than 50%. 
4. 
Study Design 
4.1 
Structure 
This is a prospective, multicenter, evaluator-blinded, randomized, controlled study.  Up to 
15 investigational sites will enroll and follow subjects who meet the study criteria. 
4.2 
Duration 
The study will span a total of approximately 23 months:  an estimated 9 months for 
recruitment, 1 month for treatment, and up to 13 months for follow-up.  Participation for each 
subject randomized to the treatment group will encompass up to 1 month for screening, up to 
1 month for treatment, 12 months of follow-up after the last treatment (initial or touch-up), 
and 1 month of follow-up after optional repeat treatment.  Participation for each subject in 
the control group will encompass up to 1 month for screening, 6 months for the no-treatment 
control period, up to 1 month for optional treatment, and 6 months of follow-up after the last 
treatment (initial or touch-up). 
4.3 
Treatment Groups and Treatment Regimen 
4.3.1 
Study Treatment 
JUVÉDERM VOLUMA XC injectable gel 
4.3.2 
Control Treatment 
No treatment 
4.3.3 
Methods for Blinding 
The EI and the Canfield image analysis technician will be blinded to treatment until after the 
month 6 visit when the control group subjects complete the control period.  The EI will not 
be present during the injection procedures.  The 2D images used for ACRS assessments will 
be cropped by the Canfield image technician to include only the lower face.  The EI will not 
be blinded to the timepoint at which photos were taken.  As the image files will be accessed 
by the blinded image analysis technician, the image files will not reveal subject treatment 

 
 
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randomization or the timepoint at which the image was captured.  The EI will access images 
through a web-based portal that can have additional information. 
The Treating Investigators (TIs), study coordinators, and subjects will not be blinded to 
treatment, but they will secure the randomization and other records (eg, records of study 
treatments and records of all prior study assessments, including scores and whether an 
assessment was performed) from potential discovery by the blinded EI.  The TI will not 
discuss the randomized treatment assignments with or in the presence of the EI. 
4.3.4 
Retreatment Criteria 
The subject may undergo a touch-up treatment 30 days after the initial treatment (ie, at the 
month 1 follow-up visit) if both the subject and TI determine that optimal correction has not 
been achieved and total treatment has been less than 4.0 mL.  The total injection volume for 
an individual subject for the initial and touch-up treatments combined cannot exceed 4.0 mL. 
Subjects in the treatment group may undergo repeat treatment 12 months after the last 
treatment (ie, at the month 12 follow-up visit after all procedures are completed).  The total 
injection volume for repeat treatment cannot exceed 4.0 mL. 
4.4 
Permissible and Prohibited Medications/Treatments 
4.4.1 
Permissible Medications/Treatments 
Topical anesthesia may be used during treatment according to routine practice, but it must be 
limited to the treatment areas only.  Examples of permitted topical anesthesia include:  ice, 
lidocaine cream, or both. 
If a subject is on a regimen of over-the-counter or prescription, oral or topical, anti-wrinkle 
products below the subnasale, the regimen must have been stable for at least 30 days prior to 
study enrollment and the subject must continue with the regimen throughout the study. 
The use of any concomitant medication, prescription or over-the-counter, is to be recorded on 
the subject’s electronic case report form (eCRF) at each visit along with the reason the 
medication is taken. 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
TI.  If the permissibility of a specific medication/treatment is in question, please contact 
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4.4.2 
Prohibited Medications/Treatments 
Subjects must not initiate or be on an existing regimen of anti-coagulant medications 
(eg, warfarin, clopidogrel) or other medications or substances known to increase coagulation 
time (eg, aspirin, ibuprofen, or herbal supplements) in the 10 days prior to undergoing study 
device injection and for 3 days afterward. 
During the course of the study, subjects must not: 
• be on an ongoing regimen of lidocaine or structurally-related local anesthetics 
• be on an ongoing regimen of drugs that reduce or inhibit hepatic metabolism 
(eg, cimetidine, beta-blockers) 
• be enrolled in another study and may not receive another investigational product in 
the 30 days prior to study enrollment 
• receive permanent facial implants (eg, polymethylmethacrylate, silicone, 
polytetrafluoroethylene) anywhere in the face or neck 
• receive facial tissue augmentation with fat injections below the subnasale; semi-
permanent dermal fillers (eg, calcium hydroxyapatite, poly-L-lactic acid) in the chin 
or jaw; or dermal filler injections in the glabellar area, nose, lips, or perioral area 
• receive botulinum toxin injections below the subnasale (including the masseter 
muscles) 
• undergo mesotherapy or receive cosmetic facial procedures (eg, face-lift, brow lift, 
facial reconstructive surgery, laser, photomodulation, intense pulsed light, radio 
frequency, dermabrasion, moderate or greater depth chemical peel, or other ablative 
procedures) anywhere in the face or neck 
• undergo allergen desensitization therapy 
• undergo any piercing or tattooing procedures below the subnasale 
• undergo any dental procedure (other than prophylaxis or dental fillings) 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, Allergan is to be notified 
before the prohibited medication/treatment is administered. 

 
 
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4.4.3 
Escape Medications 
Although several authors have reported that hyaluronidase (Vitrase™ or Amphadase®) is 
effective in reversing the effects of misplaced or excess HA-based dermal fillers, no 
hyaluronidase product has been approved for this indication.  Therefore, administration of 
hyaluronidase for this use should not be performed during this study. 
4.4.4 
Special Diet or Activities 
Within the first 24 hours after treatment, subjects should avoid strenuous exercise, extensive 
sun or heat exposure, and alcoholic beverages.  Exposure to any of the above may cause 
temporary redness, swelling, and/or itching at the injection sites. 
For 2 days after treatment, subjects should avoid unnecessary external compression of the 
treatment site that could cause displacement or indentation where the product has been 
placed.  Subjects will be advised not to have a massage, enter a hot spring or sauna, receive 
excessive sun exposure, or go swimming during the week following study treatment (initial, 
touch-up, or repeat). 
4.5 
Treatment Allocation Ratio 
Subjects are randomized at an allocation ratio of 3 treatment with JUVÉDERM VOLUMA 
XC to 1 control group. 
5. 
Study Population 
5.1 
Number of Subjects 
Up to 224 subjects will be enrolled at up to 15 sites. 
5.2 
Study Population Characteristics 
Adult subjects with chin retrusion who are seeking to increase facial volume in the chin area 
will be recruited. 
5.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
1. Age 22 or over and in good general health 

 
 
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3. Treating Investigator considers the subject’s chin retrusion to be amenable to 
temporary correction 
 
 
5.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
1. Has ever received permanent facial implants (eg, polymethylmethacrylate, silicone, 
polytetrafluoroethylene) anywhere in the face or neck, or is planning to be implanted 
with any of these products during the study 
2. Has ever undergone fat injections below the subnasale or is planning to undergo this 
procedure during the study 
3. Has tattoos, piercings, facial hair (ie, beard, mustache), or scars below and including 
the subnasale that would interfere with visual assessment of the chin, jowls, or jawline 
4. Has undergone semipermanent dermal filler treatment (eg, calcium hydroxyapatite, 
poly-L-lactic acid) in the chin or jaw within 36 months before enrollment or is 
planning to undergo such treatment during the study 
5. Has undergone dermal filler injections, or has undergone any surgery in the chin or 
jaw area (including marionette lines, pre-jowl sulci, mandibular body, or masseter 
muscles) within 24 months before enrollment or is planning to undergo any of these 
procedures during the study 
6. Has undergone dermal filler injection in the lips or perioral area within 12 months 
before enrollment or is planning to undergo such treatment during the study 
 
 
 
 
 
 

 
 
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10. Has undergone mesotherapy or cosmetic treatment (laser, photomodulation, intense 
pulsed light, radio frequency, dermabrasion, moderate or greater depth chemical peel, 
liposuction, lipolysis, or other ablative procedures) anywhere in the face or neck, or 
botulinum toxin treatment below the subnasale (including injections to the masseter 
muscles) within 6 months before enrollment or is planning to undergo any of these 
procedures during the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6. 
Procedures 
6.1 
Washout or Run-In Intervals 
6.1.2 
Run-in Intervals 
Run-in Intervals 
Medication or Procedure 
2 days before treatment 
• 
Prophylactic herpes treatment for subjects with a history of recurrent oral 
herpes lesions 
30 days before enrollment 
• 
Over-the-counter or prescription, oral or topical, anti-wrinkle products 
below the subnasale for subjects who will use such products during the 
study 
 
 
 
 

 
 
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6.3 
Instructions for the Subjects 
At the screening visit, the TI (or designee) will discuss alternative treatments that may be 
available with any subject who is interested in participating in the study; he/she will counsel 
the subject regarding his/her treatment goals and the potential benefits and limitations of 
study treatment.  After counseling, if the subject’s expectations are achievable within the 
parameters of the study, the TI (or designee) will proceed with obtaining the subject’s 
signature on the ICF and will continue the subject in the study. 

 
 
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During each study visit, subjects will be required to remove all jewelry, make-up, and 
lipstick, and male subjects must be clean-shaven below the subnasale to avoid interference 
with digital imaging and evaluations of the chin and chin area. 
To reduce the risk of posttreatment bleeding or bruising, subjects on a regimen of 
medications (eg, aspirin or ibuprofen) or other substances known to increase coagulation 
time (eg, herbal supplements with garlic or gingko biloba) must suspend the regimen for at 
least 10 days before and 3 days after study treatment (initial, touch-up, and repeat). 
For at least 24 hours after treatment, subjects should avoid strenuous exercise, consumption 
of alcoholic beverages, and extended exposure to sun or heat to reduce the risk of 
posttreatment redness, swelling, and/or itching. 
For 2 days after treatment, subjects should avoid unnecessary external compression to the 
treatment site that could cause displacement or indentation where the product has been 
placed.  Subjects should also avoid having a massage, entering a hot spring or sauna, 
receiving excessive sun exposure, or going swimming during the week following study 
treatment (initial, touch-up, and repeat). 
Subjects will also be instructed to contact the TI or his/her research staff to report any 
unexpected symptoms or to ask questions about the study. 
6.4 
Unscheduled Visits 
An unscheduled visit may occur for safety purposes (eg, evaluation of AEs or ISRs as 
requested by the subject and/or TI).  Applicable procedures will be performed and recorded 
on the eCRF. 
An unscheduled visit may also occur to repeat facial digital images if those obtained at the 
scheduled visit are poor quality images. 
6.5 
Early Discontinuation of Subjects 
Each subject reserves the right to withdraw from the study at any time without jeopardy to 
his/her future medical care.  The month 12/early exit procedures are to be performed at the 
final study visit.  Subjects may also be administratively withdrawn if they do not return for 
follow-up visits.  For any subject who withdraws from the study, the date and reason for 
withdrawal will be recorded on the eCRF.  If an AE is ongoing at the time of withdrawal and 
is related to the study treatment, the TI will attempt to follow the subject until the AE has 

 
 
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been resolved or follow-up is no longer possible.  The TI shall ask for the subject’s 
permission to follow his/her status/ condition outside the study. 
If a subject fails to return for 1 or more scheduled study visits, the TI (or designee) will 
attempt to contact the subject to determine and document the reason the subject has failed to 
return, and to encourage compliance with the study visit schedule. 
6.6 
Withdrawal Criteria 
If a subject has a positive urine pregnancy test at the time of the initial, touch-up, or repeat 
treatment visit, the subject will not be eligible for treatment and will be withdrawn from the 
study.  The pregnancy will be followed as described in Section 10.3. 
In addition, a subject must be withdrawn from the study if he or she: 
• receives any dermal filler or fat injection to the chin area 
• undergoes facelift or facial reconstructive surgery 
• receives treatment with hyaluronidase in the chin area 
7. 
Response Measures and Summary of Data Collection Methods 
7.1 
Effectiveness Measures 
7.1.1 
Primary Effectiveness Measure 
The primary effectiveness measure is the EI’s photo assessment of chin retrusion using the 
ACRS described in Table 6 and Figure 1.  The EI will assess 2D profile images of the left 
side of the chin rendered by the Canfield image analysis technician from the 3D images. 

 
 
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JUVÉ
 
 
 
Table
Score
0 
1 
2 
3 
4 
* 
Ch
 
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 6 
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Minimal 
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Moderate, 3 =
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Moderate c
Severe chin
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Retrusion Scal
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= Extreme). 
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e assessment
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tical 
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ss 
s 
ts by 
point 
ated 

 
 
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Table 7 
Global Aesthetic Improvement Scale 
Score 
Grade 
Description 
2 
Much Improved 
Marked improvement in appearance 
1 
Improved 
Improvement in appearance, but a touch-up or retreatment is indicated 
0 
No Change 
The appearance is essentially the same as the original condition 
-1 
Worse 
The appearance is worse than the original condition 
-2 
Much Worse 
The appearance is much worse than the original condition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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7.3 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics to be collected include sex, age, race, 
height, weight, Fitzpatrick skin phototype and sun exposure, smoking history, 
medical/surgical/cosmetic/dental procedure history, and prior medications. 
7.4 
Treatment Characteristics 
Treatment characteristics will be evaluated by collecting information on topical anesthesia 
usage, injection ease, product moldability, volume injected, needle/cannula usage, plane of 
injection, and treatment area. 
7.5 
Summary of Methods of Data Collection 
Electronic data capture will be used to collect study-specific information, such as subject and 
Investigator assessments.  Completed eCRFs will be reviewed by the TI or EI as applicable 
(or designee), and the designated monitor will verify the data.  Investigators will provide 
access to hospital files, medical records, and other source documents containing subject 
clinical/medical information.  Source document verification will be performed. 
Subjects will complete the ISR diaries.  FACE-Q questionnaires will be completed on paper 
and the data will be entered into the clinical database by a third party vendor.  Sites will save 
facial digital imaging onto supplied electronic media and send the storage device to Canfield 
Scientific.  Alternatively, files containing the facial digital imaging may be uploaded directly 
to Canfield Scientific from the Canfield Scientific equipment. 
The clinical database or a subset of the clinical database will be locked prior to initiation of 
statistical analysis.  All data review and verification procedures and resolution of queries 
must be completed prior to database lock. 
Allergan will permit trial-related monitoring, audits, Institutional Review Board (IRB) 
review, and regulatory inspections, and will provide direct access to source documents, 
which will be retained for at least 2 years after the last approval of a marketing application 
and until there are no pending or contemplated marketing applications in an International 
Conference on Harmonisation (ICH) region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. 

 
 
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8. 
Statistical Procedures 
A statistical analysis plan will be prepared to provide specifications for all analyses.  The 
plan will be finalized and approved prior to clinical database lock once all data are collected 
through the end of the study. 
In general, descriptive statistics will be presented.  Categorical variables will be summarized 
with frequency and percentage.  Continuous variables will be summarized by number of 
subjects, mean, median, standard deviation, minimum, and maximum.  Where appropriate, 
2-sided 95% confidence intervals (CIs) for mean or proportion will be provided as part of the 
descriptive summary. 
Unless otherwise noted, baseline refers to the EI assessment of the 2D renderings from the 
3D image taken at randomization (or screening if the randomization image is not usable). 
Every attempt will be made to collect complete data and limit the occurrence of missing data.  
No imputation of missing data will be performed.  Deviations from the analyses planned in 
the statistical plan will be documented in the clinical study report. 
8.1 
Analysis Populations 
The following analysis populations will be used in the analyses for this study: 
• intent-to-treat (ITT) population:  all randomized subjects 
• modified intent-to-treat (mITT) population:  subjects who are randomized to study 
treatment (treatment group) and receive at least 1 study device treatment or are 
randomized to the control group 
• per-protocol (PP) population:  all mITT subjects who do not have any significant 
protocol deviations affecting the primary effectiveness endpoint 
• safety population:  all subjects randomized to treatment (treatment group) who 
receive at least 1 study device treatment and all subjects randomized to control group 
Unless specified otherwise, all effectiveness analyses will be performed on the mITT 
population using the “as-randomized” assignment for each subject (ie, if a subject 
randomized to the control group is treated inadvertently at the start of the study, the 
assessments for that subject will nonetheless be included in the control group analysis).  The 
ITT and PP populations as well as missing data imputation will be used to perform sensitivity 

 
 
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analyses for the primary effectiveness variable.  Additionally, sensitivity analysis will be 
performed on mITT subjects with a baseline ACRS photo score of 2 or 3.  All safety analyses 
will be conducted using the safety population. 
8.2 
Collection/Derivation of Primary and Secondary Effectiveness 
Assessments 
8.2.1 
Primary Effectiveness Variable 
The primary effectiveness variable is defined as the change in the EI’s assessment of chin 
retrusion using the ACRS based on 2D renderings of 3D images.  A subject showing 
≥ 1-point improvement (decrease in retrusion) in ACRS score compared with baseline will be 
considered to be a responder.  The primary evaluation timepoint is month 6 after last 
treatment for subjects in the treatment group and month 6 after randomization for subjects in 
the control group. 
The primary effectiveness endpoint is the difference in mean scores on the ACRS between 
the treatment group and the control group at month 6. 
8.2.2 
Secondary Effectiveness Variables 
The 3 secondary effectiveness variables are: 
• Subject responses on the Satisfaction with Chin module of the FACE-Q questionnaire 
o Change from baseline in subjects’ score on the Satisfaction with Chin 
module of the FACE-Q questionnaire will be calculated for the subjects in 
the treatment group in 2 steps: 1) an overall score for this module on a 
100-point scale will be calculated by the conversion table created by the 
scale developers, and 2) the change from baseline will be calculated as 
month 6 score (since last treatment) minus the baseline score 
• GAIS responder based on EI assessment of global aesthetic improvement in the chin 
area using the GAIS where a responder is defined as “improved” or “much improved” 
on the GAIS 
• GAIS responder based on subject assessments of global aesthetic improvement in the 
chin area using the GAIS where a responder is defined as “improved” or “much 
improved” on the GAIS 

 
 
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8.3 
Hypothesis and Methods of Analysis 
8.3.1 
Primary Effectiveness Analyses 
The study device will be determined to be clinically effective if at least 50% (a point estimate 
of 50% or greater) of subjects treated with JUVÉDERM VOLUMA XC are observed to be 
responders (subjects who show clinically significant improvement [≥ 1-point decrease] on 
the ACRS compared with pretreatment) at month 6 and if the responder rate for treatment 
group is statistically superior to the responder rate for the control group at month 6.  The 
following hypothesis will be tested: 
Ηo:  Pv = Pc 
Ηa:  Pv ≠ Pc 
where Pv and Pc denote the responder rates for the treatment group at month 6 after last 
treatment and control group at month 6 after randomization, respectively.  Two-sided Fisher´s 
exact test with 5% significance level will be used to compare responder rates between the 
treatment and control groups.  If the 2-sided p-value is < 0.05, the responder rate is greater 
for treatment than for the control group, and the point estimate of the responder rater for the 
treatment group is greater than 50%, then treatment will be considered superior to the control 
group. 
The primary effectiveness analysis will be performed on the mITT population. 
8.3.2 
Secondary Effectiveness Analyses 
The following analyses will be performed for each of the secondary effectiveness endpoints: 
• responder rates with 95% exact CIs for the treatment group based on EI and subject 
assessments of GAIS, where a “responder” is a subject who shows improvement in 
the overall aesthetic assessment in the chin area (Improved or Much Improved on 
GAIS) at the month 6 visit 
• descriptive summary of the change from baseline to month 6 (since last treatment) in 
overall scores of the Satisfaction with Chin module of the FACE-Q questionnaire and 
a 2-sided paired t-test at the 5% level to demonstrate that the mean overall satisfaction 
score at month 6 visit is statistically greater than that at the baseline for the treatment 
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No multiplicity adjustment will be made for the 2 GAIS responder rates, since these 
endpoints are descriptive in nature.  The secondary effectiveness analysis for Satisfaction 
with Chin module of the FACE-Q questionnaire will be conducted only if the primary 
endpoint is met. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Subgroup Analyses 
The primary effectiveness endpoint will be summarized by baseline photo ACRS score, 
volume injected, and investigational site.  Subgroup analyses by injection with cannula 
versus without cannula will be conducted on the primary endpoint, ISRs collected via the 30-
day subject diaries, and treatment-related AEs.  The analyses will include count and percent 
along with exact binomial 95% CI.  Details will be provided in the statistical analysis plan. 

 
 
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8.5 
Sample Size Calculation 
A sample size of 120 subjects in the treatment group and 40 subjects in the control group will 
provide > 99% power to detect a difference of at least 40% in the responder rates between the 
groups.  This calculation is based on a 2-sided Fisher’s exact test at the 5% level.  The 
treatment group is assumed to have at least 80% responder rate and the control group will 
have at most 40% responder rate.  Assuming a screen fail rate of 15% and a drop-out rate of 
15% between randomization and the month 6 visit, up to 224 subjects will be enrolled, 
resulting in up to 168 subjects randomized to the treatment group and up to 56 subjects to the 
control group (3:1 ratio).  Assuming a screen fail rate of 15% and an overall drop-out rate of 
20% between randomization and study completion, an estimated 152 subjects will complete 
the study. 
With up to 168 subjects randomized to the treatment group and an estimated screen fail rate 
of 15%, it is estimated that at least 143 subjects will be treated in the study.  With 143 treated 
subjects, there is at least an 88% power to detect an AE related to treatment with an incidence 
rate of 1.5% in the population using a 1-sided exact binomial test at the 2.5% level. 
Due to an estimated 15% of subjects having a baseline photo assessment of 1 or 4, up to 36 
additional subjects may be randomized to ensure sufficient power for sensitivity analyses, 
resulting in a total of up to 260 subjects enrolled. 
The commercial software, PASS (2008, Version 8.0.13), was used for the power calculation.  
The sample size calculation used an inequality test for 2 proportions to demonstrate that the 
treatment group is superior to the control group.  The safety calculation used an inequality 
test for 1 proportion. 
8.6 
Interim Analyses 
No interim analysis is planned for this study. 
9. 
Materials 
9.1 
Study Treatment 
9.1.1 
Product Description 
JUVÉDERM VOLUMA XC is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, 
colorless, homogenized, HA gel implant (dermal filler).  JUVÉDERM VOLUMA XC 

 
 
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9.1.2 
Instructions for Use and Administration 
 
 
 
 
 
 
 
 
 
The TIs must be experienced in the use and administration of HA implants and be practicing 
in the field(s) of aesthetic medicine, plastic/cosmetic/reconstructive surgery, or dermatology.  
Before the study begins, the TIs will receive training in the administration of JUVÉDERM 
VOLUMA XC according to the technique specified for this study. 
 
.  The detailed 
recommended injection technique is provided in the VOLUMA-006 DFU included in the Site 
Study Binder. 
9.1.3 
Treatment Regimen Adjustments 
Up to 2 treatment sessions 30 days apart are allowed; repeat treatment is allowed 12 months 
after initial treatment.  The TI will determine the appropriate volume of JUVÉDERM 
VOLUMA XC to inject at the initial and touch-up treatments based on his/her clinical 
experience and the randomization assignment, but the maximum volume is not to exceed 
4.0 mL for initial and touch-up treatments combined.  The maximum volume for repeat 
treatment is not to exceed 4.0 mL. 

 
 
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9.2 
Other Study Supplies 
Allergan will provide urine pregnancy test kits, digital imaging equipment, and other supplies 
specific to this study 
  The investigational site 
is responsible for routine supplies related to device storage, administration, and follow-up 
visits (eg, antiseptics, drapes, gloves, gauze, topical anesthesia, ice packs, blood pressure 
cuff), and internet connection for eCRF completion and IWRS. 
10. 
Study Administration Procedures 
The clinical study shall not begin until the required approvals from the appropriate regulatory 
authorities and IRBs have been obtained. 
10.1 
Subject Entry Procedures 
10.1.1 
Overview of Entry Procedures 
Prospective subjects as defined by the criteria in Sections 5.3 and 5.4 (inclusion/exclusion 
criteria) will be considered for entry into this study.  A subject is considered to have entered 
the study upon signing the ICF, which will occur prior to any screening procedures.  
Screening procedures include: 
• collection of demographic information 
• collection of height, weight, and vital signs 
• evaluation of Fitzpatrick skin phototype and history of sun exposure 
• collection of smoking history 
• collection of medical/surgical/cosmetic/dental procedures history 
• administration of urine pregnancy test to female subjects of childbearing potential 
(women who are not of childbearing potential are considered as postmenopausal 
for at least 1 year or have no uterus) 
• capture of 3D facial digital images 
• evaluation by both the EI and the TI of the subject’s chin retrusion using the ACRS 

 
 
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• evaluation of inclusion/exclusion criteria 
• administration of FACE-Q questionnaire modules for Satisfaction with Chin and 
Psychological Well-Being 
• EI assessments of subject’s facial sensation and facial function 
• collection of AEs, concomitant medications, and concurrent procedures 
Subjects choosing not to participate in facial digital imaging through checkbox selection on 
the ICF will be excluded from the study.  Allergan shall have full ownership rights to any 
facial digital imaging derived from the study. 
10.1.2 
Informed Consent and Subject Privacy 
The purpose, procedures, risks, benefits, and alternatives to study participation will be 
discussed with each potential subject.  The subject must also give Authorization for Use and 
Release of Health and Research Study Information, including digital images and other 
written documentation in accordance with the relevant country and local privacy 
requirements (where applicable) prior to any study-related procedures or change in treatment. 
The TI or his/her authorized designee conducts the informed consent (IC) discussion and will 
document in the subject’s medical records the acquisition of IC and the subject’s agreement 
or refusal to notify his/her primary care physician about the study.  The IC shall include all 
aspects of the study that are relevant to the subject’s decision to participate throughout the 
study.  The IC process is to avoid any coercion or undue influence on, or inducement of, the 
subject to participate.  The subject is to personally sign and date the ICF.  The TI will retain 
the original copy of the signed form, and the subject will receive a copy.  Upon signing the 
ICF, the subject is considered to be enrolled in the study and receives a subject number that 
will be used on all documentation for the subject throughout the study.  Subject numbers will 
be assigned in ascending order, and numbers will not be omitted or reused.  The subject 
number is coupled with the site identification number for unique identification of each 
subject.  The TI is to ensure important new information is provided to new or existing 
subjects throughout the study. For studies involving emergency treatments, when prior IC of 
the subject is not possible because of the subject’s medical condition, the IC of the subject’s 
legally authorized representative shall be requested.  Arrangements shall be made to inform 
the subject or legally authorized representative, as soon as possible, about the subject’s 

 
 
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inclusion in the study and about all aspects of the study.  The subject shall be asked to 
provide IC for continued participation as soon as his/her medical condition allows. 
10.1.3 
Method for Assignment to Treatment Groups 
At the time of randomization (ie, at or within 30 days after screening/signing of the ICF), 
eligible subjects will be assigned to 1 of 2 treatment groups (treatment and control) in a 
3:1 ratio to receive JUVÉDERM VOLUMA XC or to the control group based on a central 
randomization schedule.  An automated IWRS will be used to manage the randomization and 
treatment assignment based on a randomization scheme prepared by Allergan.  Study 
treatments will be labeled with kit numbers.  The IWRS will provide the site with the specific 
kit number(s) for each randomized subject at the time of randomization and at each 
subsequent treatment visit.  Sites will dispense treatment according to the IWRS instructions 
provided by the system. 
10.2 
Compliance with Protocol 
The TI is responsible for compliance with the protocol at the investigational site.  A 
representative of Allergan will make frequent contact with the TI and his/her research staff 
and will conduct regular monitoring visits at the site to review subject and device 
accountability records for compliance with the protocol.  Any protocol deviations will be 
discussed with the TI upon identification.  The use of the data collected for the subject will 
be discussed to determine if the data is to be included in the analysis.  All protocol deviations 
will be reported to the IRB according to the IRBs reporting requirements. 
10.3 
Pregnancy 
If a female becomes pregnant after treatment, the TI will notify Allergan immediately after 
the pregnancy is confirmed.  The TI shall (1) instruct the subject to notify her physician of 
the presence of the investigational device and (2) follow the pregnancy to term.  Best 
practices are to be followed in order to ensure the welfare of the subject and the fetus.  The 
Medical Safety Physician will contact the TI to obtain information about the pregnancy 
outcome.  The subject will continue to be followed as part of the mITT Population, but the 
pregnancy will be documented as a protocol deviation, and the subject will not be evaluated 
as part of the PP Population for timepoints after the pregnancy is confirmed. 
Pregnancy by itself will not be considered an AE or serious adverse event (SAE).  
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constitute a SAE.  However, the occurrence of an adverse pregnancy outcome for the mother 
or child may constitute an AE or SAE, and these are to be reported as described in 
Sections 11.1.3 and 11.1.4. 
10.4 
Study Termination 
If conditions arise during the study that indicate that the study or an investigational site needs 
to be terminated, Allergan, TI, Monitor, IRB, and/or regulatory agencies will discuss the 
situation and take appropriate action after consultation.  Conditions that may warrant 
termination of the study or site include, but are not limited to: 
• the discovery of an unexpected, serious, or unacceptable risk to subjects enrolled 
in the study 
• the decision on the part of Allergan to suspend or discontinue testing, evaluation, 
or development of the study device 
• failure of the TI to comply with pertinent national or state regulations, 
IRB-imposed conditions, or protocol requirements 
• TI submission of knowingly false information to Allergan, a study monitor, the 
IRB, or any regulatory agency 
Per International Organization for Standardization (ISO) 14155, if a study is prematurely 
terminated or suspended due to safety issues, Allergan shall inform all investigators and the 
regulatory authorities of the termination or suspension and the reason(s) for the termination 
or suspension.  The IRB is also to be informed promptly and provided the reason(s) for the 
termination or suspension by Allergan or by the Investigator, as specified by the applicable 
regulatory requirements.  If a premature termination or suspension occurs, Allergan shall 
remain responsible for providing resources to fulfill the protocol obligations and existing 
agreements for follow-up of subjects enrolled in the study, and each Investigator or 
authorized designee shall promptly inform enrolled subjects, if applicable. 
11. 
Adverse Events 
Throughout the course of the study, all AEs will be monitored and reported on an AE eCRF, 
including seriousness, severity, action taken, and relationship to study treatment.  If AEs 
occur, the first concern will be the safety of the study participants. 

 
 
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The TI and the research staff will monitor each subject closely, and, if a complication occurs, 
they will use their medical judgment to do whatever is necessary to treat the subject.  
Additional information is available in the VOLUMA-006 DFU.  If subjects have any ongoing 
treatment-related SAEs at the time of the final visit, they should continue to be followed up 
until resolution of these events or the subject condition is considered stable by the TI.  After 
the final visit, the subject will resume receiving the standard medical care according to the 
standard care of the clinic. 
For a description of potential AEs, see Section 2.2 and the VOLUMA-006 DFU. 
11.1 
Definitions 
11.1.1 
Adverse Event 
An AE is defined in accordance with ISO 14155 as “any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory 
findings) in subjects, users, or other persons, whether or not related to the investigational 
medical device.”  This definition includes events related to the investigational medical device 
or comparator and events related to the procedures involved except for events in users or 
other persons, which only include events related to investigational medical devices. 
Disease signs and symptoms that existed prior to the study treatment are not considered AEs 
unless the condition recurs after the subject has recovered from the pre-existing condition or 
the condition worsens in intensity or frequency during the study. 
AEs will be monitored throughout the study beginning with signing of the ICF.  At each 
postscreening visit, the TI (or designee) will begin querying for AEs by asking each subject a 
general, non-directed question such as “Have you had any changes to your condition since 
your last visit?”  Previous AEs and changes in therapy/concomitant medications are to be 
updated.  Directed questioning and examination will then be done as appropriate.  All 
reportable AEs and clinically significant abnormal laboratory findings will be documented on 
the appropriate eCRF. 
11.1.2 
Serious Adverse Event 
A SAE is defined in accordance with ISO 14155 as an AE that: 
a) led to death, 

 
 
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b) led to serious deterioration in the health of the subject, that either resulted in 
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or 
4. medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE:  Allergan considers all cancer AEs as SAEs.  Abortion is also considered an SAE 
except for elective abortion of a normal fetus. 
NOTE:  Planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered an SAE. 
See Section 11.4 for procedures for reporting a SAE/serious adverse device effect (SADE). 
11.1.3 
Adverse Device Effect 
An adverse device effect (ADE) is defined in accordance with ISO 14155 as “an adverse 
event related to the use of an investigational medical device.”  This definition includes any 
AEs resulting from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device as well as 
any event resulting from use error (per ISO 62366) or from intentional misuse of the 
investigational medical device. 
See Section 11.3 for procedures for reporting an ADE. 
11.1.4 
Serious Adverse Device Effect 
A SADE is defined in accordance with ISO 14155 as “an adverse device effect that has 
resulted in any of the consequences characteristic of a serious adverse event.” 
See Section 11.4 for procedures for reporting a SADE. 

 
 
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11.1.5 
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) is defined in accordance with 21 Code of 
Federal Regulations (CFR) 812.3 as “any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in 
the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects.” 
11.1.6 
Device Deficiency 
A device deficiency is defined in accordance with ISO 14155 as “inadequacy of a medical 
device with respect to its identity, quality, durability, reliability, safety, or performance.”  
Device deficiencies include malfunctions, use errors, and inadequate labeling. 
If a device deficiency occurs, the TI will notify Allergan using the fax number or email on 
the front page of the protocol.  Device deficiencies shall be documented throughout the study 
and appropriately managed by Allergan.  Allergan shall review all device deficiencies and 
determine and document in writing whether they could have led to a SADE.  These shall be 
reported to the regulatory authorities and IRBs/ECs as required by national regulations. 
11.1.7 
Severity 
Severity is a clinical determination of the intensity of an AE.  The severity assessment for a 
clinical AE is to be completed using the following definitions as guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort affecting daily activity 
Severe 
Disabling with inability to do daily activities 
11.1.8 
Relationship to Treatment 
Relationship to a treatment refers to a determination of the relationship (if any) between an 
AE and the device or treatment procedure.  A causal relationship is present if the TI 
determines that there is a reasonable possibility that the AE may have been caused by the 
device or is associated with the procedure, such as an event that can be attributed to other 
products, surgical techniques, or medications required specifically for the procedure. 

 
 
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Relationship to the treatment must be determined by the TI and cannot be delegated to other 
study staff. 
11.2 
Timelines for Reporting 
The TI (or designee) is to adhere to the following schedule in reporting different types of 
AEs. 
Adverse Event 
Type 
Reporting to Allergan 
Start of 
Collection 
End of Collection 
AEs, ADEs 
Record on AE eCRF upon awareness for 
review by the Clinical Monitor 
Signing ICF 
Last subject visit 
SAEs, SADEs 
Record on SAE Form and fax/e-mail to 
Allergan within 24 hours of awareness 
Signing ICF 
Last subject visit 
 
11.3 
Procedures for Reporting an AE or ADE 
All AEs or ADEs occurring during the study period (beginning with signing ICF) are to be 
recorded on the appropriate eCRF.  Any AE that is ongoing at the exit visit must be followed 
up as appropriate. 
11.4 
Procedures for Reporting an SAE or SADE 
All SAEs and SADEs occurring during the study period (from signing ICF) through the last 
subject visit are to be immediately reported to an Allergan representative at a fax number/e-
mail address listed on the cover page and recorded on the appropriate eCRFs.  All subjects 
with an SAE/SADE must be followed up and the outcomes reported.  The TI is to supply 
Allergan and the IRB with any additional requested information (eg, hospital discharge 
summary, autopsy reports and terminal medical reports).  Allergan shall evaluate all SADEs 
and determine and document in writing whether they meet the definition of a UADE.  These 
shall be reported to all participating TIs, the regulatory authorities, and IRBs/ECs as required 
by national regulations. 
In the event of an SAE/SADE, the TI must: 
1. Notify Allergan immediately by fax/e-mail using the SAE/SADE reporting forms.  
For the SAE/SADE fax number/e-mail address, see the front page of the protocol. 

 
 
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2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the subject. 
3. Provide Allergan with a complete, written case history which includes a statement as 
to whether the event was or was not related to the use of the investigational device. 
4. Promptly inform the governing IRB of the event, if it is treatment-related.  For other 
SAEs, notify the governing IRB as required by the IRB, local regulations, and the 
governing health authorities. 
12. 
Administrative Issues 
12.1 
Protection of Human Subjects 
12.1.1 
Compliance with Informed Consent Regulations 
Written IC is to be obtained from each subject prior to enrollment into the study, and/or from 
the subject’s legally authorized representative according to 21 CFR 50. 
12.1.2 
Compliance with IRB Regulations 
This study is to be conducted in accordance with IRB regulations (21 CFR 56).  The TI must 
obtain approval from a properly constituted IRB prior to initiating the study and re-approval 
or review at least annually.  Allergan is to be notified immediately if the responsible IRB has 
been disqualified or if proceedings leading to disqualification have begun.  Copies of all IRB 
correspondence with the TI are to be provided to Allergan. 
12.1.3 
Compliance with Good Clinical Practice 
This protocol is to be conducted in compliance with Good Clinical Practice (GCP) guidelines 
and with ethical principles for clinical research. 
12.1.4 
Financial Disclosure/Certification Form 
In accordance with 21 CFR 54.4, the TI and any Sub-Investigators who are directly involved 
in the treatment or evaluation of subjects must complete the Financial Disclosure Form 
disclosing completely and accurately any financial interests or arrangements that apply to 
themselves, their spouse, or their dependent children. 

 
 
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• Any financial arrangement entered into between Allergan and the Investigator 
involved in the conduct of a covered clinical trial, whereby the value of the 
compensation to the Investigator for conducting the study could be influenced by the 
outcome of the study 
• Any significant payments of other sorts from Allergan, such as a grant to fund 
ongoing research, compensation in the form of equipment, retainer for ongoing 
consultation, or honoraria 
• Any proprietary interest in the tested product held by any Investigator involved in a 
study 
• Any significant equity interest in Allergan held by any Investigator involved in any 
clinical study 
• Any steps taken to minimize the potential for bias resulting from any of the disclosed 
arrangements, interests, or payments. 
The Investigator shall provide to Allergan accurate financial information on an annual basis, 
with prompt updates if any relevant changes occur over the course of the investigation, and at 
1 year following completion of this study. 
12.1.5 
Compliance with Electronic Records and Signature 
Regulations 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
12.2 
Changes to the Protocol 
The TI is not to implement any deviation from or changes to the protocol without approval 
by Allergan and prior review and documented approval/favorable opinion from the IRB of a 
protocol amendment, except where necessary to eliminate immediate hazards to study 
subjects, or when the changes involve only logistical or administrative aspects of the study 
(eg, change in monitors, change of telephone numbers).  Allergan may amend the protocol 
during the course of the study.  The amended protocol shall be distributed to the TIs and 
IRBs upon approval by regulatory authorities. 

 
 
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12.3 
Subject Confidentiality and Privacy 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study device may ultimately be marketed, but the 
subject’s name will not be disclosed in these documents.  The subject’s name may be 
disclosed to Allergan, the governing health authorities, or the FDA, if they inspect the study 
records.  Appropriate precautions will be taken to maintain confidentiality of medical records 
and personal information. 
Written Authorization and other documentation in accordance with the relevant country and 
local privacy requirements (where applicable) are to be obtained from each subject prior to 
enrollment into the study, and/or from the subject’s legally authorized representative in 
accordance with the applicable privacy requirements (eg, Health Insurance Portability and 
Accountability Act Standards for Privacy of Individually Identifiable Health Information 
[HIPAA]). 
In accordance with HIPAA requirements, additional purposes of this study include the 
following:  to publish anonymous subject data from the study and to create and maintain a 
data repository. 
12.4 
Documentation 
12.4.1 
Source Documents 
Source documents may include a subject’s medical records, hospital charts, laboratory notes, 
device accountability records, TI and EI assessments of chin retrusion, 
 
subject FACE-Q questionnaires, 
 
 
diaries, EI and subject assessments of global aesthetic improvement in the chin area using the 
GAIS, photographic negatives, digital images, or renderings, clinic charts, the TI’s subject 
study files, results of pregnancy tests, and any other diagnostic tests that may be performed, 
such as X-rays, laboratory tests, and magnetic resonance imaging.  If the Serious Adverse 
Event Form and Pregnancy Surveillance Form are used in this study, they are also considered 
source documents.  The TI’s copies of the eCRFs serve as part of the TI’s record of a 
subject’s study-related data. 
The following information is to be entered into the subject’s medical record: 
• Subject’s name 

 
 
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• Subject’s contact information 
• Date that the subject entered the study, subject number, and subject randomization 
number 
• Study title and/or the protocol number and study Sponsor 
• A statement that IC was obtained, including the date and a statement that HIPAA 
Authorization or other country and local subject privacy required documentation 
for this study has been obtained, including the date 
• Details of the injection procedure including anesthetic used, treatment areas 
injected, volume injected in each treatment area, ease of injection, details 
regarding molding and massage, kit and lot numbers of study device injected, 
subject’s assessment of procedural pain 
• Dates of all subject visits 
• All concurrent medications (List all prescription and non-prescription medications 
being taken at the time of enrollment.  At each subsequent visit, changes to the list 
of medications are to be recorded.) 
• Occurrence and status of any AEs 
• Date the subject exited the study, and a notation as to whether the subject 
completed the study or reason for discontinuation 
• Results of laboratory tests performed by the site (eg, results of urine pregnancy 
tests) 
12.4.2 
Case Report Form Completion 
The TI is responsible for ensuring that data are properly recorded on each subject’s eCRFs 
and related documents.  The TI who has signed the protocol signature page or his/her 
authorized designee is to personally sign the eCRFs (as indicated on the eCRF) to validate 
that the observations and findings are recorded on the eCRFs correctly and completely.  The 
eCRFs are to be submitted to Allergan in a timely manner at the completion of the study, or 
as otherwise specified by Allergan. 

 
 
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The data reported on the eCRFs shall be derived from source documents and be consistent 
with these source documents, and any discrepancies shall be explained in writing.  Any 
change or correction to data reported on an eCRF shall be dated, initialed and explained, if 
necessary, and shall not obscure the original entry (ie, an audit trail shall be maintained); this 
applies to both written and electronic changes or corrections. 
12.4.3 
Investigator Reports 
In accordance with 21 CFR 812.150, the TI shall prepare and submit complete, accurate, and 
timely reports as follows:  report to Allergan within 5 working days a withdrawal of IRB 
approval, study progress reports to Allergan and IRB at least annually, and a final report to 
Allergan and IRB within 3 months after study termination or completion. 
12.4.4 
Retention of Documentation 
All study related correspondence, subject records, consent forms, subject privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of eCRFs are to be maintained on file. 
Allergan-specific essential documents are to be retained until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents are to be retained for a longer period, however, if required by the applicable 
regulatory requirements or if needed by Allergan. 
Allergan requires notification in writing if the TI wishes to store study documents off-site or 
to relinquish the study data records so that mutually agreed-upon arrangements can be made 
for transfer of the data records to a suitably qualified, responsible person.  Notification is to 
go to Allergan, Attn: Clinical Research Dept., 2525 Dupont Drive, Irvine, CA 92612. 

 
 
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12.5 
Labeling, Packaging, Storage, and Return of Study Devices 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.5.2 
Storage of Study Devices 
The study device must be stored in a secure area accessible to delegated study personnel only 
and administered only to subjects entered into the clinical study, at no cost to the subject, in 
accordance with the conditions specified in this protocol. 
 
.  The temperature 
monitoring device has been pre-programmed by Allergan with temperature storage-range 
limits required to ensure study product stability during the study.  Use of the device is 
required to ensure that the study product is being maintained within the acceptable storage-
range conditions.  If the storage temperature varies from the programmed limits, the device 
alarm will trigger indicating an excursion that may impact the stability of the study product.  
Sites must report any alarmed temperature excursion to Allergan, and avoid administering the 
impacted study product, by isolating the product, until receiving further instructions from 
Allergan.  Do not freeze or expose to extreme heat.  Do not use if the package is open or 
damaged or if the product is not clear. 

 
 
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12.5.3 
Study Device Accountability 
The TI (or designee) must keep an accurate accounting of the number of study devices 
received from Allergan, dispensed to subjects, and returned to Allergan during and at the 
completion of the study.  A detailed inventory must be completed for the study devices 
including subject initials, device serial/lot number, date of implantation, and date of 
explantation if applicable.  The study product must be dispensed to study subjects by an 
appropriately qualified person and is to be used in accordance with the protocol under the 
direct supervision of a study TI. 
12.5.4 
Return of Study Devices 
Upon completion of the treatment period, the quantities of all used and unused study devices 
will be reconciled.  Used syringes will be disposed of onsite.  Unused syringes will be 
returned to Allergan unless other disposition arrangements are agreed upon in writing with 
Allergan. 
Devices that are damaged during shipment or at the site or that malfunction during use 
(eg, faulty syringe or plunger) must be accounted for and returned.  The TI will promptly 
notify Allergan’s Clinical Research department of any device malfunction.  The Clinical 
Research or Product Support representative will provide instruction for the return of any 
faulty syringe for evaluation. 
12.6 
Monitoring by Allergan 
Appropriately trained representatives of Allergan will monitor the conduct of the trial at each 
investigational site, including visits to the site to review, audit, and retrieve copies of study-
related documents.  It is the responsibility of the Principal Investigator to be present or 
available for consultation and to assure that Allergan has access to all study-related records 
during scheduled monitoring visits. 
Allergan will review device accountability records and completed eCRFs to ensure 
completeness and consistency with the source records and compliance with the protocol 
requirements. 
Allergan representatives will meet with the TI(s) and appropriate staff at mutually convenient 
times to discuss study-related data and questions. 

 
 
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12.7 
Testing of Biological Specimens 
At screening and before each study treatment (initial and touch-up), a trained research staff 
member will perform pregnancy testing on urine samples of women of childbearing 
potential.  The test employed should have a sensitivity of at least 50 mIU/mL for human 
chorionic gonadotropin. 
12.8 
Publications 
This study will be registered and results posted on www.clinicaltrials.gov.  Allergan, as the 
Sponsor, has proprietary interest in this study.  Authorship and manuscript composition will 
reflect joint cooperation between study Investigators and Allergan personnel.  Authorship 
will be established prior to the writing of the manuscript.  As this study involves multiple 
centers, no individual publications will be allowed prior to completion of the final report of 
the multicenter study except as agreed with Allergan. 
13. 
References 
Czarnecki ST, Nanda RS, Currier GF.  Perceptions of balanced facial profile.  Am J Orthod 
Dentofac Orthop. 1993;104:180-187. 
Frodel JL.  Evaluation and treatment of deformities of the chin.  Facial Plast Surg Clin North 
Am.  2005;13(1):73-84. 
Jones D, Flynn T.  Hyaluronic acids: clinical applications.  In: Jones D, editor.  Injectable 
fillers: principles and practice.  Oxford, UK: Wiley-Blackwell; 2010, 158-74. 
Jones D, Hill K.  Criteria of facial attractiveness in five populations.  Hum Nat. 
1993;4(3):271-296. 
Jones D, Murphy DK.  Volumizing hyaluronic acid filler for midface volume deficit: 2-year 
results from a pivotal single-blind randomized controlled study.  Dermatol Surg. 
2013;39(11):1602-1612. 
Naini FB.  Facial aesthetics:  concepts and clinical diagnosis.  Chichester, West Sussex: 
Wiley-Blackwell; 2011. 
Naini FB, Donaldson AN, McDonald F, Cobourne MT.  Assessing the influence of chin 
prominence on perceived attractiveness in the orthognathic patient, clinician, and layperson.  
Int J Oral Maxillofac Surg.  2012;41(7):839-846. 

 
 
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Rubin JP, Yaremchuk MJ.  Complications and toxicities of implantable biomaterials used in 
facial reconstructive and aesthetic surgery:  a comprehensive review of the literature.  Plast 
Reconstr Surg. 1997;100:1336-1353. 
Schact R.  Female and male perceptions of attractiveness:  what is attractive and why?  
Nebraska Anthropologist.  2005;8:63-69. 
Yaremchuk MJ.  Improving aesthetic outcomes after alloplastic chin augmentation.  Plast 
Reconstr Surg. 2003;112:1422-1432. 

 
 
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14. 
Protocol Amendment Summary 
Version Date/ 
Amend. No. 
Changes to Protocol 
28 Mar 2016/1 
 
• 
Synopsis, Tables 1, 3, and 5, and Section 12.4.1 - Changed e-diary to diary 
(paper diaries will be used) 
• 
Synopsis (Study design) - clarified timing of EI assessment as after the 
visits when the 3D images are made available. 
• 
Synopsis (Inclusion criteria) - Criterion #1 clarified subject age from “Over 
age 21” to “Age 22 or over”; Criterion #6 clarified from ...“within the first 3 
months after study treatment” to “during the study” 
• 
Synopsis (Response Measures) - added ...“2D profile images of the left side 
of the chin rendered by the Canfield image analysis technician from the 3D 
images.” 
• 
Synopsis (Statistical Methods) - clarified that 1) the responder rate is based 
on EI assessment of 2D images of the chin profile, and 2) baseline is 
defined as the EI assessment of the 2D image at randomization (or 
screening if no usable randomization photo is available). 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 1 - added abbreviation for 2-dimensional 
• 
Section 3.2 - clarified that the ACRS score as assessed by the EI is based on 
assessment of 2D renderings of 3D facial images 
• 
Section 4.3.3 - added that the 2D images used for ACRS assessments will 
be cropped by Canfield to include only the lower face, that the EI will not 
be blinded to the timepoint at which photos were taken, and that the EI will 
access images through a web-based portal that can have additional 
information. 
• 
Section 5.3 - Criterion #1 clarified subject age from “Over age 21” to “Age 
22 or over”;  
• 
Section 5.4 - Criterion #6 clarified from ...“within the first 3 months after 
study treatment” to “during the study” 
 
 
 
 
 

 
 
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. 
• 
 
• 
Section 7.1.1 - clarified primary effectiveness measure as the EI assessment 
of 2D profile images of the left side of the chin rendered from the 3D 
images by the Canfield image analysis technician 
• 
Section 8 - clarified baseline as EI assessment of the photo taken at 
randomization (or screening if the randomization image is not usable) 
• 
Section 8.2.1 - clarified the primary effectiveness variable as EI’s 
assessment of chin retrusion using the ACRS based on ACRS based on 2D 
renderings of 3D images 
• 
Section 8.3.2 (second bullet) - the timepoint for secondary effectiveness 
analysis was corrected from “month 3” to “month 6” 
• 
Section 8.5.1 - corrected to Section 4.4.2 
• 
 
• 
Section 13.1 - removed study report reference 
• 
Section 13.2 - subheading deleted 
24 May 2016/2 
 
 
 
. 
• 
Synopsis (Sample Size Calculation) - added “Assuming a drop-out rate of 
20% between randomization and study completion, an estimated 
170 subjects will complete the study.” 
• 
Section 8.5 - added “Assuming a drop out-rate of 20% between 
randomization and study completion, an estimated 170 subjects will 
complete the study.” 
 
 
11 Jan 2017/3 
• 
Synopsis (Number of Subjects) - Changed “212” to “224” 
• 
Synopsis (Study Design) - Treatment Group: Added “At the month 6 visit, 
the EI will conduct a live ACRS assessment.” 
• 
Synopsis (Study Design) - Control Group: Added “At the month 6 visit, the 
EI will conduct a live ACRS assessment.” 
• 
Synopsis (Inclusion criteria) - Criterion #2: Added the category “Extreme” 
to chin retrusion and grade “4” on the ACRS 
• 
Synopsis (Response Measures) - Effectiveness: Primary effectiveness 
measure added “photo” in front of “assessment of chin retrusion” 
 
 
 
• 
Synopsis (Statistical Methods) - Sample Size Calculation: Changed screen 
fail rate from “10%” to “15%”, number of subjects from “212” to “224”, 
number of subjects per treatment group from “159” to “168”, number of 
subjects in the control group from “53” to “56”, changed the number of 

 
 
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subjects who complete the study from “170” to “152” based on both the 
screen fail rate and the overall dropout rate. 
• 
Synopsis (Statistical Methods) - Sample Size Calculation: Deleted “and an 
inequality test for 1 proportion to demonstrate that the responder rate of the 
treatment group is > 50%” 
• 
Synopsis (Statistical Methods) - Effectiveness: Modified the definition of 
the mITT population to read “which includes subjects with a baseline photo 
assessment of 2, 3, or 4 who are randomized to study treatment (treatment 
group) and receive at least 1 study device treatment or are randomized to 
the control group.” 
• 
Synopsis (Statistical Methods) - Effectiveness: Added “A sensitivity 
analysis will be performed on the intent-to-treat (ITT) population, which 
includes all randomized subjects.” 
• 
Synopsis (Statistical Methods) - Effectiveness: Deleted “and” before 
“subject assessments” and added “and the EI’s live ACRS assessment” 
 
 
 
 
 
• 
Section 5.1 (Number of Subjects) - Changed “212” to “224” 
• 
Section 5.3 - Criterion #2 added the category “Extreme” to chin retrusion 
and grade “4” on the ACRS 
 
 
 
 
 
 
 
 
 
• 
Section 7.1.1 - Added “photo” in front of “assessment of chin retrusion” 
 
 
 
 
 
 
• 
Section 8.1 - Modified the definition of the mITT population to read 
“subjects with a baseline photo assessment of 2, 3, or 4 who are randomized 
to study treatment (treatment group) and receive at least 1 study device 
treatment or are randomized to the control group.” 
• 
Section 8.1 - Modified the definition of the safety population to read “all 
subjects randomized to treatment (treatment group) who receive at least 1 
study device treatment and all subjects randomized to the control group.” 
• 
Section 8.1 - Added “all” in front of “effectiveness analyses will be 
performed on the mITT population” 
• 
Section 8.1 - Added “ITT and” in front of “PP population will be used to 
perform sensitivity analyses”. Changed “population” to “populations”. 
• 
Section 8.1 - Deleted “Additionally, the ITT population will be used to 
assess the impact of missing data on the primary effectiveness endpoint.” 

 
 
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• 
Section 8.3.1 - Added “The primary effectiveness analysis will be 
performed on the  mITT population.” 
 
 
• 
Section 8.4 - Primary effectiveness endpoint added “photo” in front of 
ACRS 
• 
Section 8.5 (Sample Size Calculation) - Changed screen fail rate from 
“10%” to “15%”, number of subjects from “212” to “224”, number of 
subjects per treatment group from “159” to “168”, number of subjects in the 
control group from “53” to “56”, changed the number of subjects who 
complete the study from “170” to “152” based on both the screen fail rate 
and the overall dropout rate. 
• 
Section 8.5 (Sample Size Calculation) - Deleted “and an inequality test for 
1 proportion to demonstrate that the responder rate of the treatment group is 
> 50%” 
01 Mar 2017/4 
• 
Synopsis (Inclusion Criterion #2) - Deleted “extreme” and grade “4” 
• 
Synopsis (Statistical Methods, Sample Size Calculation) - Added “Due to 
an estimated 15% of subjects having a baseline photo assessment of 1 or 4, 
up to 36 additional subjects may be randomized to ensure sufficient power 
for sensitivity analyses, resulting in a total of up to 260 subjects enrolled”. 
• 
Synopsis (Statistical Methods, Effectiveness) - Deleted “with a baseline 
photo assessment of 2, 3, or 4” 
• 
Section 5.3 (Inclusion Criterion #2) - Deleted “extreme” and grade “4” 
 
 
• 
Section 8.1 (Analysis Populations, mITT) - Deleted “with a baseline photo 
assessment of 2, 3, or 4” 
• 
Section 8.1 (Analysis Populations) - Added “as well as missing data 
imputation” and “Additionally, sensitivity analysis will be performed on 
mITT subjects with a baseline ACRS photo score of 2 or 3.” 
• 
Section 8.5 (Sample Size Calculation) - Added “Due to an estimated 15% 
of subjects having a baseline photo assessment of 1 or 4, up to 36 additional 
subjects may be randomized to ensure sufficient power for sensitivity 
analyses, resulting in a total of up to 260 subjects enrolled”. 
• 
Section 11.1.2 (Serious Adverse Event) - Added “NOTE:  Allergan 
considers all cancer AEs as SAEs.  Abortion is also considered an SAE 
except for elective abortion of a normal fetus.” 
 

 
 
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Date (DD/MMM/YYYY)/Time (PT) 
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Protocol VOLUMA-006 Amd 4