A Randomized, Multicenter, No-treatment Controlled Study of the Safety and Effectiveness of JUVÉDERM® VOLBELLA® With Lidocaine for Lip Enhancement in Chinese Adults
Phase: NA
Conditions: Lip Enhancement
Sponsor: Allergan

NCT03519204 
 
Study ID: VOLBELLA-005 
 
Title: A randomized, multicenter, no-treatment-controlled study of the safety and effectiveness 
of JUVÉDERM® VOLBELLA® with Lidocaine for lip enhancement in Chinese adults 
 
Protocol Amendment 2 Date: 29‐July‐2015 
 
 
 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
Page 1 of 63 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information 
that is the property of Allergan 
Study Title: 
A randomized, multicenter, no-treatment-controlled study 
of the safety and effectiveness of JUVÉDERM® 
VOLBELLA® with Lidocaine for lip enhancement in 
Chinese adults 
Protocol Number: 
VOLBELLA-005 Amendment 2 
Protocol Date: 
29 July 2015 
Product Name: 
JUVÉDERM® VOLBELLA® with Lidocaine injectable 
gel 
Development Phase: 
Pivotal 
Sponsor: 
Allergan Information Consulting (Shanghai) Co., Ltd. 
Suite 5605 
56F, 1266 West Nanjing Road 
Jingan District 
Shanghai, China, 200040 
Manufacturer: 
Allergan 
Route de Proméry 
Zone Artisanale de Pré-Mairy 
74370 Pringy 
France 
Safety reporting: 
 
 
 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
Page 2 of 63 
GDD-TAD-T-002 v2013.1 
 
INVESTIGATOR SIGNATURE PAGE 
Study Title: 
A randomized, multicenter, no-treatment-controlled 
study of the safety and effectiveness of 
JUVÉDERM® VOLBELLA® With Lidocaine for lip 
enhancement in Chinese adults 
Protocol Number: 
VOLBELLA-005 Amendment 2 
Protocol Date: 
29 July 2015 
Product Name: 
JUVÉDERM® VOLBELLA® with Lidocaine 
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 Independent Ethics Committee (IEC) 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 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
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Synopsis 
 
NUMBER AND TITLE OF STUDY: 
VOLBELLA-005:  A randomized, multicenter, no-treatment-controlled study of the safety and effectiveness of 
JUVÉDERM® VOLBELLA® with Lidocaine for lip enhancement in Chinese adults 
DEVELOPMENT PHASE:  pivotal 
STUDY CENTERS:  up to 9 Chinese sites 
NUMBER OF SUBJECTS:  Up to 176 eligible subjects will be  randomized (approximately 132 subjects will 
be assigned to the JUVÉDERM® VOLBELLA® with Lidocaine [hereafter referred to as VOLBELLA with 
Lidocaine] group and approximately 44 subjects will be assigned to the no-treatment control group). 
OBJECTIVES:  The objective of this study is to evaluate the safety and effectiveness of VOLBELLA with 
Lidocaine for lip enhancement in a Chinese population. 
STUDY DESIGN: 
This is a prospective, multicenter, randomized, no-treatment-controlled study to evaluate the safety and 
effectiveness of VOLBELLA with Lidocaine for lip enhancement in a Chinese population. 
Subjects will be randomized at a 3:1 ratio either to have treatment with VOLBELLA with Lidocaine at the 
outset of the study (VOLBELLA with Lidocaine group, also referred to as the treatment group) or to have 
treatment delayed by 3 months (no-treatment control group).  Treatment and safety assessments of a subject 
throughout the study will be performed by the same Treating Investigator (maximum 2 Treating Investigators 
per site), and effectiveness assessments will be performed by the same Evaluating Investigator.  The Evaluating 
Investigator will remain blinded to treatment assignments throughout the duration of the study.  Subjects 
randomized to the treatment group should undergo treatment on the same day as randomization.  If initial 
treatment does not occur on the randomization day for subjects in the treatment group, it must occur within 30 
days after screening.  Subjects randomized to the no-treatment control group will attend study visits at months 1 
and 3 of the no-treatment control period at which they will undergo effectiveness measures also performed at 
randomization.  These measures include the Evaluating Investigator’s assessment of the subject’s lip fullness 
using the 5-point Lip Fullness Scale (LFS; 5 points:  Minimal, Mild, Moderate, Marked, and Very Marked) and 
facial 3-dimensional (3D) imaging.  
 
 
 
  In addition, vital signs 
will be collected.  After the completion of the control period, subjects randomized to the no-treatment control 
group will receive optional treatment for lip enhancement and follow the same schedule of visits and procedures 
in the treatment period as described below and in Table 1 for subjects randomized to the treatment group. 
On the initial treatment day, the trained Treating Investigator will inject VOLBELLA with Lidocaine into the 
lips, as needed for lip enhancement.  Allowable treatment areas are the vermilion body, vermilion border 
(including the Cupid’s bow), and philtral columns.  Prior to initial treatment, the Evaluating Investigator and the 
subject will rate the subject’s lip fullness by using the LFS, and the Evaluating Investigator will rate the 
subject’s philtral column definition by using a 5-point scale (Not Defined, Barely Defined, Somewhat Defined, 
Well-defined, and Very Well-defined).  On day 30 after initial treatment, the Evaluating Investigator will again 
rate the subject’s lip fullness and philtral column definition.  Subjects may undergo an optional touch-up 
treatment at the day 30 visit after initial treatment, if the Treating Investigator assesses that optimal correction 
was not achieved.  At each treatment visit, the subject will rate procedural pain on an 11-point scale immediately 
after receiving the injections, and the Treating Investigator will assess the ease of injection and the product 
moldability.  Subjects will complete a safety diary for 30 days after each treatment and will complete a safety 
follow-up telephone call at 3 days after each treatment.  Before treatment on each treatment day, the subject will 
undergo facial 3D imaging, which will also be performed 30 days after treatment. 
Routine follow-up visits for safety and effectiveness will occur at 1, 3, and 6 months after the last treatment for 
both groups.  At these visits, facial 3D imaging will be performed, 
 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
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Long-term safety data will be collected by telephone call at 9 months after the last treatment for the control 
group and at 9 and 12 months after the last treatment for the treatment group.  Throughout the study, the 
Treating Investigator (or designee) will monitor the subjects for safety. 
DIAGNOSIS AND CRITERIA FOR INCLUSION/EXCLUSION:  Chinese adults seeking lip enhancement 
INCLUSION: 
1. male or female, 18 years of age or older 
2. has an overall baseline score of Minimal, Mild, or Moderate on the 5-point LFS, as assessed by the 
Evaluating Investigator, and desires to achieve at least a 1-point improvement in overall LFS score after 
treatment 
 
 
4. has the ability to follow study instructions and is likely to complete all required visits 
 
 
EXCLUSION: 
1. has lip tattoos, piercings, facial hair, or scars that would interfere with visualization of the lips and 
perioral area for the effectiveness assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. is on an ongoing regimen of anti-coagulation therapy (eg, warfarin) 
 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
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14. has current cutaneous inflammatory or infectious processes (eg, acne or herpes), an abscess, an 
unhealed wound, or a cancerous or precancerous lesion in the mouth area (study treatment may be 
delayed so that subjects with a history of recurrent oral herpes can take prophylactic antiviral/herpes 
medication for 2 days) 
 
 
 
 
 
 
 
 
 
 
 
TEST PRODUCT, DEVICE VOLUME, AND MODE OF ADMINISTRATION: 
VOLBELLA with Lidocaine hyaluronic acid dermal filler will be injected into the lips and, if needed, the 
philtral columns using a 30 G x ½-inch needle.  The appropriate injection volume will be determined by the 
Treating Investigator but is not to exceed a maximum total of 4.0 mL for initial and touch-up treatments 
combined. 
DURATION OF STUDY:  treatment period:  1 to 30 days;  follow-up period:  up to 12 months 
RESPONSE MEASURES: 
Effectiveness:  The primary effectiveness measure is the Evaluating Investigator’s assessment of overall lip 
fullness using the 5-point LFS.  The secondary effectiveness measures are the subject’s assessment of overall lip 
fullness using the 5-point LFS, the volume of the overall lips measured from 3D images, and the lip surface area 
change measured from 3D images. 
 
 
. 
Safety:  Safety will be evaluated by subject assessment of procedural pain; by the severity and duration of 
injection site responses (ISRs), which will be reported in the subject safety diary for 30 days after each 
treatment; and by any reported adverse events at all follow-up visits throughout the study. 
STATISTICAL METHODS: 
Sample Size Calculation:  A sample size of 111 randomized subjects treated with VOLBELLA with Lidocaine 
and 37 randomized untreated control subjects will provide > 96% power to detect the superiority of 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
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VOLBELLA with Lidocaine over no treatment for responder rate at month 3.  Responder rate is the percentage 
of subjects who show at least a 1-point improvement compared with baseline on the 5-point LFS based on the 
Evaluating Investigator’s assessment of overall lip fullness.  A 2-sided Fisher’s Exact test with 5% significance 
level will be used to calculate the power, assuming responder rates of 79.0% for the VOLBELLA with 
Lidocaine group and up to 44.1% for the no-treatment control group at month 3.  The assumed responder rates 
are based on the results of a US study of JUVÉDERM® Ultra XC for the lips (Study JULIDO-002).  The power 
calculation was performed using an Inequality Test for 2 Independent Proportion [Difference] in PASS software 
(Version 2008).  The planned sample size is considered to be adequate for evaluation of long-term (ie, 12-
month) safety. 
Approximately 15% of subjects may drop out after receiving treatment or not provide data at month 3.  To 
accommodate this, 176 subjects will be randomized, with at least 132 subjects assigned to the VOLBELLA with 
Lidocaine group and approximately 44 subjects assigned to the no-treatment control group. 
Effectiveness:  The primary effectiveness variable is lip response based on the Evaluating Investigator’s 
assessment of overall lip fullness using the 5-point LFS.  A subject showing ≥ 1-point improvement (increase in 
fullness) compared with baseline will be considered to be a lip responder.  The primary evaluation timepoint is 
month 3 after last treatment for subjects in the VOLBELLA with Lidocaine group and month 3 after 
randomization for subjects in the no-treatment control group. 
The primary effectiveness analysis will test for superiority of VOLBELLA with Lidocaine over no treatment in 
the difference in overall lip fullness responder rate.  Two-sided Fisher’s exact test with 5% significance level 
will be used to compare treatment effects between VOLBELLA with Lidocaine group and the no-treatment 
control group.  If the 2-sided p-value is less than 0.05 and the responder rate is greater for the VOLBELLA with 
Lidocaine group than for the no-treatment control group, then VOLBELLA with Lidocaine will be considered 
superior to no-treatment. 
Secondary effectiveness analyses will include 1) responder rate and the corresponding 2-sided 95% exact CI 
based on the subject’s assessment of overall lip fullness at month 3 for the treatment group, 2) change from 
baseline to month 3 in volume of the overall lips, and 3) the percentage change from baseline to month 3 in lip 
surface area using t-test or Wilcoxon rank-sum test, as appropriate. 
 
All effectiveness analyses will be performed on the modified intent-to-treat (mITT) population, defined as all 
subjects who are randomized to study treatment (treatment group), receive at least 1 study device treatment, and 
have baseline and at least 1 posttreatment assessment of the primary variable, and subjects who are randomized 
to the no-treatment control group and have baseline and at least 1 follow-up assessment of the primary variable.  
Additional sensitivity analyses for the primary effectiveness variable will be performed on the per-protocol (PP) 
population, defined as all mITT subjects who do not have any significant protocol deviations that affect the 
primary effectiveness endpoint.  All analyses will be performed without data imputation. 
Safety:  Procedural pain will be summarized using descriptive statistics.  ISRs reported in subject diaries will be 
summarized by treatment (initial and touch-up), symptom, maximum reported severity, and maximum reported 
duration.  Summaries will include the incidence rate for each ISR. 
Adverse events will be summarized by System Organ Class and Preferred Term and will be tabulated by 
duration, severity, causality, action taken, relationship to treatment, and outcome.  The summary will include 
incidence rate as well as total number of events. 
 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
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Table of Contents 
Synopsis .................................................................................................................................... 3 
Table of Contents ...................................................................................................................... 7 
List of Tables ........................................................................................................................... 10 
1. 
Abbreviations and Terms ................................................................................................. 17 
2. 
Background, Risk and Benefit, and Clinical Rationale ................................................... 18 
2.1 
Background ............................................................................................................ 18 
2.2 
Risk and Benefit ..................................................................................................... 20 
2.3 
Clinical Rationale ................................................................................................... 21 
3. 
Study Objectives and Clinical Hypotheses ...................................................................... 22 
3.1 
Study Objectives .................................................................................................... 22 
3.2 
Clinical Hypotheses ............................................................................................... 22 
4. 
Study Design .................................................................................................................... 22 
4.1 
Structure ................................................................................................................. 22 
4.2 
Duration ................................................................................................................. 22 
4.3 
Treatment Groups and Treatment Regimen ........................................................... 22 
4.3.1  Study Treatment ......................................................................................... 22 
4.3.2  Control Treatments ..................................................................................... 22 
4.3.3  Methods for Blinding ................................................................................. 23 
4.3.4  Retreatment Criteria ................................................................................... 23 
4.4 
Permissible and Prohibited Medications/Treatments ............................................. 23 
4.4.1  Permissible Medications/Treatments ......................................................... 23 
4.4.2  Prohibited Medications/Treatments ........................................................... 24 
4.4.3  Escape Medications .................................................................................... 24 
4.4.4  Special Diet or Activities ........................................................................... 24 
4.5 
Treatment Allocation Ratio and Stratification ....................................................... 24 
5. 
Study Population .............................................................................................................. 25 
5.1 
Number of Subjects ................................................................................................ 25 
5.2 
Study Population Characteristics ........................................................................... 25 
5.3 
Inclusion Criteria .................................................................................................... 25 
5.4 
Exclusion Criteria .................................................................................................. 25 

 
 
Approval Date: 
 
29-Jul-2015
Allergan Confidential 
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JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
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6. 
Procedures ........................................................................................................................ 28 
6.1 
Washout or Run-In Intervals .................................................................................. 28 
6.1.1  Washout Intervals ....................................................................................... 28 
6.1.2  Run-in Intervals .......................................................................................... 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Instructions for the Subjects ................................................................................... 35 
6.4 
Unscheduled Visits ................................................................................................. 35 
6.5 
Early Discontinuation of Subjects .......................................................................... 36 
6.6 
Withdrawal Criteria ................................................................................................ 36 
7. 
Response Measures and Summary of Data Collection Methods ..................................... 36 
7.1 
Effectiveness Measures .......................................................................................... 36 
7.1.1  Primary Effectiveness Measure .................................................................. 36 
7.1.2  Secondary Effectiveness Measures ............................................................ 37 
 
 
7.2 
Safety Measures ..................................................................................................... 37 
7.3 
Demographics and Baseline Characteristics .......................................................... 38 
7.4 
Treatment Characteristics ....................................................................................... 38 
7.5 
Summary of Methods of Data Collection .............................................................. 38 
8. 
Statistical Procedures ....................................................................................................... 39 
8.1 
Analysis Populations .............................................................................................. 39 
8.2 
Collection/Derivation of Primary and Secondary Effectiveness Assessments ...... 39 
8.2.1  Primary Effectiveness Variable .................................................................. 39 
8.2.2  Secondary Effectiveness Variables ............................................................. 40 
8.3 
Hypothesis and Methods of Analysis ..................................................................... 40 
8.3.1  Primary Effectiveness Analyses ................................................................. 41 
8.3.2  Secondary Effectiveness Analyses ............................................................. 41 

 
 
Approval Date: 
 
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Allergan Confidential 
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29 July 2015 
 
 
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8.3.4  Safety Analyses .......................................................................................... 42 
8.4 
Subgroup Analyses ................................................................................................. 43 
8.5 
Sample Size Calculation ........................................................................................ 43 
8.6 
Interim Analyses .................................................................................................... 43 
9. 
Materials .......................................................................................................................... 43 
9.1 
Study Treatment ..................................................................................................... 43 
 
 
9.1.2  Instructions for Use and Administration .................................................... 44 
9.1.3  Treatment Regimen Adjustment ................................................................. 44 
9.2 
Other Study Supplies .............................................................................................. 44 
10.  Study Administration Procedures .................................................................................... 44 
10.1  Subject Entry Procedures ....................................................................................... 45 
10.1.1  Overview of Entry Procedures ................................................................... 45 
10.1.2  Informed Consent and Subject Privacy ...................................................... 45 
10.1.3  Method for Assignment to Treatment Groups ............................................ 46 
10.2  Compliance with Protocol ...................................................................................... 46 
10.3  Pregnancy ............................................................................................................... 47 
10.4  Study Termination .................................................................................................. 47 
11.  Adverse Events ................................................................................................................ 48 
11.1  Definitions .............................................................................................................. 49 
11.1.1  Adverse Event ............................................................................................ 49 
11.1.2  Serious Adverse Event ............................................................................... 49 
11.1.3  Adverse Device Effect ............................................................................... 50 
11.1.4  Serious Adverse Device Effect ................................................................... 50 
11.1.5  Unanticipated Serious Adverse Device Effect ........................................... 50 
11.1.6  Device Deficiency ...................................................................................... 51 
11.1.7  Severity ...................................................................................................... 51 
11.1.8  Relationship to Treatment .......................................................................... 51 
11.2  Timelines for Reporting ......................................................................................... 52 
11.3  Procedures for Reporting an Adverse Event or Adverse Device Effect ................. 52 
11.4  Procedures for Reporting an Serious Adverse Events or Serious Adverse Device 
Effects 52 
11.5  Procedures for Unblinding Study Treatments ........................................................ 53 

 
 
Approval Date: 
 
29-Jul-2015
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29 July 2015 
 
 
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12.  Administrative Issues ....................................................................................................... 53 
12.1  Protection of Human Subjects ................................................................................ 53 
12.1.1  Compliance with Informed Consent Regulations ...................................... 53 
12.1.2  Compliance with Independent Ethics Committee Regulations .................. 53 
12.1.3  Compliance with Good Clinical Practice ................................................... 54 
12.1.4  Compliance with Electronic Records and Signature Regulations ............. 54 
12.2  Changes to the Protocol ......................................................................................... 54 
12.3  Subject Confidentiality and Privacy ...................................................................... 54 
12.4  Documentation ....................................................................................................... 55 
12.4.1  Source Documents ..................................................................................... 55 
12.4.2  Case Report Form Completion .................................................................. 56 
12.4.3  Investigator Reports ................................................................................... 56 
12.4.4  Retention of Documentation ...................................................................... 57 
12.5  Labeling, Packaging, Storage, and Return of Study Devices ................................. 57 
12.5.1  Labeling/Packaging .................................................................................... 57 
12.5.2  Storage of Study Devices ........................................................................... 57 
12.5.3  Study Device Accountability ...................................................................... 58 
12.5.4  Return of Study Devices ............................................................................ 58 
12.6  Monitoring by Allergan .......................................................................................... 59 
12.7  Testing of Biological Specimens ............................................................................ 59 
12.8  Publications ............................................................................................................ 60 
12.9  Coordinating Investigator ...................................................................................... 60 
13.  References ........................................................................................................................ 60 
13.1  Study Report References ........................................................................................ 60 
13.2  Literature References ............................................................................................. 61 
14.  Protocol Amendment Summary ....................................................................................... 62 
 
List of Tables 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
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Allergan Confidential 
Protocol VOLBELLA-005 Amendment 2 
JUVÉDERM® VOLBELLA® with Lidocaine 
29 July 2015 
 
 
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Table 4 
5-Point Lip Fullness Scale .............................................................................. 37 
 
 
 

 
 
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Allergan Confidential 
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Approval Date: 
 
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29 July 2015 
 
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Approval Date: 
 
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29 July 2015 
 
 
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29 July 2015 
 
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29 July 2015 
 
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Approval Date: 
 
29-Jul-2015
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29 July 2015 
 
 
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1. 
Abbreviations and Terms 
Term/Abbreviation 
Definition 
3D 
3-dimensional 
BDDE 
1,4-butanediol diglycidyl ether 
CFDA 
Chinese Food and Drug Administration 
CI 
confidence interval 
eCRF 
electronic case report form 
EKG 
electrocardiogram 
FDA 
Food and Drug Administration 
 
 
HA 
hyaluronic acid 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDFU 
investigational directions for use 
IEC 
Independent Ethics Committee 
ISO 
International Organization for Standardization 
ITT 
intent-to-treat 
ISR 
injection site response 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LFS 
Lip Fullness Scale 
mITT 
modified intent-to-treat 
PP 
per-protocol 
QS 
quantity sufficient to make 
US 
United States 
 

 
 
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2. 
Background, Risk and Benefit, and Clinical Rationale 
2.1 
Background 
Lip augmentation to restore fullness and definition loss due to hypoplasia or aging has 
become a common use for hyaluronic acid (HA) dermal fillers (Eccleston and Murphy, 2012; 
Philipp-Dormston et al, 2014).  Treatment with temporary HA fillers can provide volume to 
the lips and perioral area, restoring fullness and the natural contour of the region to which it 
is applied. 
JUVÉDERM® VOLBELLA® with Lidocaine (hereafter referred to as VOLBELLA with 
Lidocaine), CE-marked in 2011 and included in the JUVÉDERM range of products, is a 
malleable gel that meets the physical constraints that would be experienced with injection 
and volume expansion of the lips.  VOLBELLA with Lidocaine is formulated using a 
combination of high and low molecular weight HA, which reduces the concentration of 
crosslinking reagent needed while increasing overall crosslinking efficiency.  The final 
formulation includes a small quantity of noncross-linked HA to decrease extrusion force 
during injection, and lidocaine (0.3% w/w) to increase patient comfort.  In a postmarketing 
study, JUVÉDERM VOLBELLA without Lidocaine (received European marking of 
conformity [CE mark] in 2007) was demonstrated to be safe and effective in providing 
smooth and natural improvement in lip fullness (Eccleston and Murphy, 2012).  VOLBELLA 
with Lidocaine represents an improvement with the addition of 0.3% (w/w) lidocaine 
hydrochloride to reduce procedural pain. 
In Europe and other countries, numerous fillers have been used in the lips and perioral area.  
In the US, Restylane® and Restylane-L® (with lidocaine) are the only dermal fillers currently 
approved for lip augmentation.  In China, no dermal fillers are approved for lip augmentation.  
As described below, investigations assessing the safety and effectiveness of HA-based 
dermal fillers for volume restoration of the lips have demonstrated treatment success and 
high patient satisfaction. 
• In a multicenter European postmarket study of the safety and effectiveness of 
JUVÉDERM VOLBELLA without Lidocaine, 60 subjects desiring lip enhancement 
were treated.  The filler was injected into the upper and lower lips, perioral lines, and 
oral commissures.  Three months after treatment, 93.2% of subjects displayed ≥ 1point 
improvement on the 4-point Lip Fullness Scale (LFS).  After treatment, 84.0% of 
subjects displayed ≥ 1-point improvement on the 4-point Perioral Lines Severity Scale 

 
 
Approval Date: 
 
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and 70.0% displayed ≥ 1-point improvement on the 4-point Oral Commissures 
Severity Scale.  At the end of the study (12 months), 94.1% of subjects were satisfied 
with the overall effects of the treatment (Eccleston and Murphy, 2012). 
• In the pivotal study evaluating the safety and effectiveness of Restylane for soft tissue 
augmentation of the lips, 92.6% of 134 treated subjects displayed ≥ 1-point 
improvement 8 weeks after treatment on the 5-point Medicis LFS compared with 
baseline assessment, and 90.1% of subjects displayed ≥ 1-point improvement 
12 weeks after treatment (Restylane Directions for Use, 2011). 
• In a multicenter, feasibility study of lip enhancement conducted in the United States 
(US), 50 subjects were injected with JUVÉDERM Ultra in the upper and lower lips, 
perioral lines, and oral commissures.  At 12 weeks after treatment, 71% of subjects 
improved by ≥ 1 point on the 4-point LFS, 51% of subjects improved by ≥ 1 point on 
the Perioral Lines Severity Scale, and 64% of subjects improved by ≥ 1 point on the 
Oral Commissures Severity Scale (all of which were evaluated by a blinded 
Evaluating Investigator).  Overall subject satisfaction at 12 weeks was 82% 
(Fagien et al, 2013) 
• In a large, non-randomized study, 1,446 subjects were treated with Restylane for lip 
augmentation and visible facial rhytides (2,242 treated areas).  Subject satisfaction was 
77.8% at 3 months, declining to 36.4% at 9 months.  The filling effect lasted longer in 
areas that were not subjected to animation (eg, glabellar lines), which was reflected in 
subject satisfaction trends (Bosniak et al, 2004). 
• Sixty-six subjects were treated with Restylane for lip augmentation in specific lip 
zones to allow for targeted volume enhancement in which the gel could easily be 
injected with a 30 G needle.  Mean satisfaction on a scale of 0 to 5 (5 being most 
satisfied) was 4.5.  Mean persistence until lips returned to preoperative appearance 
was 4.9 months.  No adverse events were observed (Jacono, 2008). 
• In an open-label pilot study assessing the effectiveness of Restylane for restoring lip 
fullness, lip volume changes were measured in 21 subjects at several timepoints 
through 12 weeks after treatment.  At 12 weeks after treatment, 79% of subjects had 
≥ 1-point improvement on a 5-point lip fullness scale, as rated by an independent 
evaluator (Solish and Swift, 2011). 

 
 
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• A postmarketing surveillance study assessed treatment comfort and aesthetic effect in 
57 patients treated with JUVÉDERM Ultra Smile.  The most common site for 
injection was the vermilion border, and 95% of injectors found the gel easy to inject.  
Furthermore, 99% of injectors rated an improved aesthetic compared to baseline.  
Patient satisfaction with the product was 96% (Lanigan, 2011). 
As with any dermal filler injection, pain during administration is a possible side effect and 
may compromise the physician’s ability to inject precisely (Segall and Ellis, 2007).  
Physicians typically use pain-relieving agents concomitant with injection, such as a nerve 
block, topical anesthetic, or a local anesthetic.  The inclusion of lidocaine in HA dermal 
fillers is intended to reduce the patient’s pain during the procedure and reduce or eliminate 
the need for additional pain-relieving agents.  Ninety-three percent of subjects, randomized to 
treatment with JUVÉDERM Ultra or Ultra Plus in 1 nasolabial fold and JUVÉDERM Ultra 
or Ultra Plus including 0.3% lidocaine in the other nasolabial fold, rated the lidocaine 
formulations less or slightly less painful than the JUVÉDERM Ultra or Ultra Plus 
(Weinkle et al, 2009).  As reviewed by Smith and Cockerham (2011), additional studies have 
demonstrated significantly less pain associated with dermal fillers containing lidocaine, 
allowing for a quick treatment, reduced recovery time, and high patient satisfaction.  
Furthermore, lidocaine in HA fillers has been shown not to affect the rheology, duration of 
effect, or frequency of adverse events (Andre, 2008; Gold, 2009; Raspaldo et al, 2010; 
Rivkin, 2009). 
2.2 
Risk and Benefit 
A risk analysis linked to the manufacturing, biocompatibility, and use of VOLBELLA with 
Lidocaine was conducted according to International Organization for Standardization (ISO) 
14971:2007 and is detailed in the risk management file.  An overview of these risks and 
additional risks related to the injection procedure is contained within the Investigational Plan 
Risk Analysis.  Each device contains 15 mg HA of nonanimal origin cross-linked with a 
minimal amount of 1,4-butanediol diglycidyl ether (BDDE), 3 mg lidocaine hydrochloride, 
and 1 mL QS phosphate buffer pH 7.2 supplied in a syringe composed of cyclic olefin 
copolymer.  Assessment of overall risks that could have a high severity of consequences 
revealed that preventative actions guaranteed residual risks graded “very low,” “low,” or 
“moderate,” with no risk graded as “unacceptable.” 
However, as with any skin or lip injection, risks exists with the injection procedure itself, the 
anesthetic agent, and the type of injection (in this case an HA facial injection).  Risks related 
to the injection procedure and/or the device include redness, pain, tenderness, swelling, 

 
 
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itching, firmness, lumps and bumps, and delayed adverse reactions.  These risks are common 
to all dermal filler injection procedures.  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 use of a 
small-gauge needle to deliver the experimental device used in this clinical study is intended 
to minimize tissue trauma.  The inclusion of 0.3% lidocaine in VOLBELLA with Lidocaine 
is meant to reduce pain during the injection and during the hours following injection as well 
as to provide consistency in anesthetic dosing.  It is advisable to take the potential risks into 
account.  Furthermore, the literature analysis and medical device reporting from US Food 
and Drug Administration (FDA) approved dermal filler products reveal that pre-existing 
pathological conditions of patients along with the contraindications and precautions for use 
as written in the investigational directions for use (IDFU) should be carefully reviewed. 
The benefit of using HA dermal fillers for lip enhancement has been demonstrated by the 
published literature showing the safety and effectiveness of treatment and by studies of 
JUVÉDERM products for equivalent indications.  Characteristics of VOLBELLA with 
Lidocaine potentially increase the benefit of use of HA dermal fillers for lip enhancement. 
2.3 
Clinical Rationale 
Although various materials have been investigated as potential candidate soft-tissue fillers, 
none have produced as consistent and optimal lip enhancement as HA dermal fillers.  HA can 
enhance lip volume (Sarnoff et al, 2012).  The safety and effectiveness of VOLBELLA 
(without lidocaine) for lip enhancement has been demonstrated in European subjects 
(Eccleston and Murphy, 2012).  However, European and Chinese ideals of beautiful lips 
differ; consequently, the use of dermal fillers and their safety and effectiveness for lip 
enhancement may differ. 
Risks associated with VOLBELLA with Lidocaine have been mitigated by the product’s 
formulation, and potential complications that may arise have been described in the literature 
and IDFU.  Therefore, VOLBELLA with Lidocaine is expected to be safe and effective.  
Study VOLBELLA-005 is intended to provide safety and effectiveness data on VOLBELLA 
with Lidocaine for lip enhancement to support a Chinese Food and Drug Administration 
(CFDA) pre-market application. 

 
 
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3. 
Study Objectives and Clinical Hypotheses 
3.1 
Study Objectives 
The objective of this study is to evaluate the safety and effectiveness of VOLBELLA with 
Lidocaine for lip enhancement in a Chinese population. 
3.2 
Clinical Hypotheses 
The percentage of subjects with a clinically significant change in lip fullness from baseline to 
month 3 will be significantly greater in subjects treated with VOLBELLA with Lidocaine 
than in untreated control subjects. 
4. 
Study Design 
4.1 
Structure 
This is a prospective, multicenter, randomized, no-treatment-controlled study.  Up to 
9 investigational sites will enroll and follow subjects who meet the study criteria. 
4.2 
Duration 
The study will span a total of approximately 22 months including an estimated 8 months for 
recruitment, up to 30 days between screening and randomization, up to 1 month for treatment, 
and up to 12 months for follow-up.  Participation for subjects randomized to the treatment 
group will encompass up to 1 month for treatment and 12 months of follow-up.  Participation 
for subjects randomized to the no-treatment control group will encompass a 3-month no-
treatment period, up to 1 month for optional treatment, and 9 months of follow-up. 
4.3 
Treatment Groups and Treatment Regimen 
4.3.1 
Study Treatment 
VOLBELLA with Lidocaine injectable gel 
4.3.2 
Control Treatments 
A no-treatment control group is included. 

 
 
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4.3.3 
Methods for Blinding 
The Evaluating Investigator will remain blinded to treatment assignments throughout the 
duration of the study.  The Evaluating Investigator will not be present during the injection 
procedures. 
The Treating Investigator will not discuss the randomized treatment assignments with or in 
the presence of the Evaluating Investigator. 
The Treating Investigators, 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 
prior study assessments) from potential discovery by the Evaluating Investigator. 
The device accountability log will include the kit numbers.  The Evaluating Investigator will 
not have access to the device accountability log. 
4.3.4 
Retreatment Criteria 
One month (30 days) after the initial treatment, the subject and Treating Investigator will 
discuss the results of the initial treatment and determine whether optimal correction has been 
achieved.  If optimal correction has not been achieved, the Treating Investigator may perform 
a touch-up treatment.  Moreover, if the Evaluating Investigator has determined that the 
subject’s LFS score has not improved by at least 1 point, the subject should receive a touch-
up injection. 
4.4 
Permissible and Prohibited Medications/Treatments 
4.4.1 
Permissible Medications/Treatments 
All medications and treatments are permitted with the exception of the restricted medications 
and treatments described in Section 4.4.2. 
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 
investigator.  If the permissibility of a specific medication/treatment is in question, please 
contact Allergan. 

 
 
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4.4.2 
Prohibited Medications/Treatments 
Concurrent enrollment in another clinical investigation for a medicinal product or device is 
prohibited.  Subjects must not be on an ongoing regimen of anti-coagulant medications 
(eg, warfarin).  Subjects must not be on an ongoing regimen of medications or other 
substances known to increase coagulation time (eg, aspirin; ibuprofen; high doses of Vitamin 
C or Vitamin E; herbal supplements with garlic, ginkgo biloba, or ginseng) within 10 days 
prior to and 3 days after study device injection. 
Subjects must not use lip plumping product or begin any new regimen of over-the-counter or 
prescription, oral or topical, antiwrinkle products for the lips or around the mouth.  Subjects 
must not undergo facial tissue augmentation with dermal fillers or fat injections, semi-
permanent fillers or permanent facial implants, botulinum toxin injections, mesotherapy, or 
cosmetic facial procedures (eg, face-lift, laser, photomodulation, intense pulsed light, radio 
frequency, dermabrasion, moderate or greater depth chemical peel, or other ablative 
procedures) below the inferior orbital rim at any time during the study. 
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. 
4.4.3 
Escape Medications 
Administration of hyaluronidase should not be performed during the 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 site. 
4.5 
Treatment Allocation Ratio and Stratification 
Subjects will be randomized at a 3:1 ratio either to have treatment with VOLBELLA with 
Lidocaine at the outset of the study (treatment group) or to have treatment delayed by 
3 months (no-treatment control group).  Randomization will be stratified by baseline LFS 
score (ie, LFS score rated as Minimal, Mild, or Moderate at the randomization visit by the 
Evaluating Investigator). 

 
 
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5. 
Study Population 
5.1 
Number of Subjects 
An estimated 176 subjects will be randomized in a 3:1 ratio resulting in 132 subjects 
assigned to the VOLBELLA with Lidocaine group and 44 subjects assigned to the no-
treatment control group.  Approximately 148 subjects including 111 treated subjects and 
37 untreated control subjects will complete the 3-month visit (primary endpoint) with an 
anticipated dropout rate of 15% by month 3.  An estimated 133 subjects will complete the 
12-month visit (end of study) based on an anticipated dropout rate of 10% after month 3. 
5.2 
Study Population Characteristics 
Subjects will be recruited from a population of healthy Chinese adults who desire lip 
enhancement. 
5.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
1. male or female, 18 years of age or older 
2. has an overall baseline score of Minimal, Mild, or Moderate on the 5-point LFS, as 
assessed by the Evaluating Investigator, and desires to achieve at least a 1-point 
improvement in overall LFS score after treatment 
 
4. has the ability to follow study instructions and is likely to complete all required visits 
 
5.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
 
 

 
 
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10. is on an ongoing regimen of anti-coagulation therapy (eg, warfarin) 

 
 
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14. has current cutaneous inflammatory or infectious processes (eg, acne or herpes), an 
abscess, an unhealed wound, or a cancerous or precancerous lesion in the mouth area 
(study treatment may be delayed so that subjects with a history of recurrent oral herpes 
can take prophylactic antiviral/herpes medication for 2 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6. 
Procedures 
6.1 
Washout or Run-In Intervals 
6.1.1 
Washout Intervals 
Washout Period 
Medication or Procedure 
10 days before 
treatment 
• 
medications known to increase coagulation time (eg, aspirin or ibuprofen) 
• 
other pharmaceutical, vitamin, or herbal preparations with clinically significant 
anticoagulation effects (eg, high doses of Vitamin C or Vitamin E, herbal 
supplements with garlic, gingko biloba, or ginseng) 
NOTE:  This 10-day washout period for anticoagulants must continue for 3 days after 
treatment is administered. 
10 days before 
enrollment 
• 
lip plumping products 
30 days before 
enrollment 
• 
any investigational product 
 
6.1.2 
Run-in Intervals 
Run-In Period 
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 for the lips or 
around the mouth 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 Treating Investigator (or designee) will discuss routine alternative 
treatments that may be available with any subject who is interested in participating in the 
study.  The available alternative treatments include plastic surgery, autologous fat injection, 
etc; he/she will counsel the subject regarding his/her treatment goals, and the potential 
benefit and limitations of study treatment.  After counseling, if the subject’s expectations are 
not realistic, the Treating Investigator (or designee) will not proceed with obtaining the 
subject’s signature on the ICF and will discontinue the subject from the study. 
During each study visit, subjects will be required to remove all jewelry, make-up, and lipstick, 
and male subjects will not be allowed to have facial hair in the perioral area to avoid 
interference with the digital photographs. 
For 10 days before and 3 days after study treatment administration, subjects should avoid 
taking anti-coagulation, antiplatelet, or thrombolytic medications; nonsteroidal anti-
inflammatory drugs; supplements of Vitamin C or E, garlic, gingko biloba, or ginseng; or 
other supplements known to increase coagulation time.  These precautions are recommended 
to reduce the risk of posttreatment bleeding or bruising. 
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. 
Subjects will also be instructed to contact the Treating Investigator 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, if the subject needs to obtain 
information regarding adverse events or ISRs).  An unscheduled visit may also occur to 
repeat facial digital images if those obtained at the scheduled visit are poor quality images.  
Applicable procedures will be performed and recorded on the eCRF. 

 
 
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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.  All follow-up procedures scheduled to be performed at the final 
site visit should be performed at the subject’s last site 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 adverse event is ongoing at the time of withdrawal, the Treating Investigator will 
attempt to follow the subject until the adverse event has been resolved or follow-up is no 
longer possible.  The Treating Investigator shall ask for the subject’s permission to follow 
his/her status/condition outside the study. 
Randomized subjects who withdraw before treatment will not be replaced by another subject.  
The subject number and associated randomization number of the withdrawn subject should 
not be reassigned to a different subject. 
If a subject fails to return for 1 or more scheduled study visits, the Treating Investigator 
(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. 
At regular intervals, the Treating Investigator (or designee) will record on the eCRF and will 
report to Allergan and the Independent Ethics Committee (IEC) the reasons for which any 
subjects are discontinued from the study, including subjects who signed the ICF but do not 
proceed to randomization. 
6.6 
Withdrawal Criteria 
The subject may withdraw at will at any time for any reason. 
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 Evaluating Investigator’s assessment of overall lip 
fullness using the LFS described in Table 4. 

 
 
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Table 4 
5-Point Lip Fullness Scale 
Score 
Grade 
Description
4 
Very Marked 
Very significant red lip show, lower lip pout, and upper lip pout 
3 
Marked 
Significant red lip show and lower lip pout 
2 
Moderate 
Moderate red lip show with slight lower lip pout 
1 
Mild 
Some red lip show; no lower lip pout 
0 
Minimal 
Flat or nearly flat contour, minimal red lip show 
 
7.1.2 
Secondary Effectiveness Measures 
The secondary effectiveness measures are the subject’s assessment of overall lip fullness 
using the 5-point LFS, the volume of the overall lips measured from 3D images, and the lip 
surface area measured from 3D images. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 
Safety Measures 
Safety measures will include: 
• subject assessment of procedural pain (pain during injection) on an 11-point scale 
ranging from 0 (no pain) to 10 (worst pain imaginable) 
• severity and duration of ISRs, which will be obtained by a subject safety diary 

 
 
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• adverse events reported to and recorded by the investigators 
Vital sign measurements, including blood pressure (systolic and diastolic, while subject is 
seated), temperature, pulse, and respiratory rate, will be performed at screening, treatment 
visit, Month 1, Month 3 and Month 6 visits.  Urine pregnancy tests for women of 
childbearing potential (sexually active and not sterile, surgically sterilized, or 
postmenopausal for at least 1 year) will be performed at screening, treatment visit, and the 
month 6 posttreatment follow-up visit.  Routine hematology and blood chemistry testing and 
urinalysis will be performed at screening and at the months 1 and 6 posttreatment follow-up 
visit. 
7.3 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics to be collected include sex, age, 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 anesthesia usage, 
treatment area, injection ease, and volume injected. 
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 Treating or Evaluating 
Investigator 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 either complete the ISR diaries electronically, or they will complete them on 
paper, and responses will be entered into the clinical database.  Sites will save photographs 
onto supplied electronic media and send the storage device to 
.  
Alternatively, files containing the facial digital photographs may be directly uploaded to 
. 

 
 
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8. 
Statistical Procedures 
One database lock is planned after all subjects exit the study.  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. 
8.1 
Analysis Populations 
The following analysis populations will be used in the analyses for this study: 
• modified intent-to-treat (mITT) population:  subjects who are randomized to study 
treatment (treatment group) and receive at least 1 study device treatment and have 
baseline and at least 1 posttreatment assessment of the primary variable, and subjects 
who are randomized to the no-treatment control group and have baseline and at least 
1 follow-up assessment of the primary variable 
• per-protocol (PP) population:  all mITT subjects who do not have any significant 
protocol deviations affecting the primary effectiveness endpoint 
• safety population:  subjects who receive at least 1 study treatment  
Unless specified otherwise, effectiveness analyses will be conducted using the mITT 
population.  The PP population will be used to perform sensitivity analyses for the primary 
effectiveness variable.  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 lip response based on the Evaluating Investigator’s 
assessment of overall lip fullness using the 5-point LFS.  A subject showing ≥ 1-point 
improvement (increase in fullness) in LFS score compared with baseline will be considered 
to be a lip responder.  The primary evaluation timepoint is month 3 after last treatment for 
subjects in the VOLBELLA with Lidocaine group and month 3 after randomization for 
subjects in the no-treatment control group. 

 
 
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8.2.2 
Secondary Effectiveness Variables 
The 3 secondary effectiveness variables are: 
• subject’s lip response based on the subject’s assessments of overall lip fullness using 
the 5-point LFS 
o A subject showing ≥ 1-point improvement (increase in fullness) in 5-point 
LFS score compared with baseline will be considered to be a lip responder.  
The evaluation timepoint is month 3 after last treatment for subjects in the 
VOLBELLA with Lidocaine group. 
• percentage change from baseline to month 3 in overall lip volume 
o The evaluation timepoint is month 3 after last treatment for subjects in the 
VOLBELLA with Lidocaine group and month 3 after randomization for 
subjects in the no-treatment control group. 
• change from baseline to month 3 in lip surface area 
o The percentage change from baseline in lip surface area will be calculated 
as the difference (ie, month 3 lip surface area minus the baseline lip 
surface area) divided by baseline value.  Month 3 refers to 3 months after 
last treatment for subjects in the VOLBELLA with Lidocaine group and 
3 months after randomization for subjects in the no-treatment control 
group. 
8.3 
Hypothesis and Methods of Analysis 
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, during posttreatment follow-up visits (for both the VOLBELLA with 
Lidocaine group and the no-treatment control group), baseline refers to the last evaluation 
prior to initial treatment; during the no-treatment period (for the no-treatment control group), 
baseline refers to the last evaluation prior to the month 1 visit. 

 
 
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No imputation for missing data will be performed.  However, sensitivity analyses for the 
primary endpoint will be performed using applicable missing imputations to assess the 
potential effect of missing data. 
8.3.1 
Primary Effectiveness Analyses 
The primary effectiveness analysis will test for superiority of VOLBELLA with Lidocaine 
over no treatment in the difference in overall lip fullness responder rate based on the 
Evaluating Investigator’s assessment at month 3.  Month 3 refers to 3 months after the last 
treatment for subjects in the VOLBELLA with Lidocaine group and 3 months after 
randomization for subjects in the no-treatment control group. 
The null hypothesis is that the responder rate for VOLBELLA with Lidocaine group is equal 
to the responder rate for the no-treatment control group.  The alternative hypothesis is that 
the responder rates are not equal for the VOLBELLA with Lidocaine and the no-treatment 
control groups.  These hypotheses are stated as: 
Ηo:  Pv – Pc = 0 
Ηa:  Pv – Pc > 0 or Pv – Pc < 0 
where Pv and Pc denote the responder rates for the VOLBELLA with Lidocaine group at 
month 3 after last treatment and no-treatment control group at month 3 after randomization, 
respectively.  Two-sided Fisher´s exact test with 5% significance level will be used to 
compare treatment effects between VOLBELLA with Lidocaine and the no-treatment control 
group.  If the 2-sided p-value is less than 0.05 and the responder rate is greater for 
VOLBELLA with Lidocaine than for the no-treatment control group, then VOLBELLA with 
Lidocaine will be considered superior to the no-treatment 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: 
• For overall lip fullness based on the subject’s assessments using the 5-point LFS, 
responder rate and 95% exact CI will be presented only for the treatment group at month 
3. 

 
 
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• The overall lip volume change from baseline to month 3 will be summarized using 
descriptive statistics.  Treatment effect will be analyzed using t-test or Wilcoxon 
rank-sum test as appropriate. 
• The lip surface area percentage change from baseline to month 3 will be summarized 
descriptively.  Treatment effect for this endpoint will be analyzed using t-test or Wilcoxon 
rank-sum test, as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.4 
Safety Analyses 
Procedural pain will be summarized using descriptive statistics.  ISRs reported by subjects 
will be summarized by symptom, maximum reported severity, and maximum reported 
duration for initial and touch-up treatments, separately.  Summaries will include the 
incidence rate for each ISR. 
Adverse events will be summarized by System Organ Class and Preferred Term and will be 
tabulated by duration, severity, causality, action taken, relationship to treatment, and outcome.  
The summary will include incidence rate as well as total number of events. 
Adverse events that may occur before treatment (ie, the initial treatment for subjects 
randomized to the treatment group and the optional treatment at month 3 for subjects 
randomized to the no-treatment control group) will be listed but not summarized. 

 
 
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8.4 
Subgroup Analyses 
The primary effectiveness endpoint will be summarized by baseline lip LFS score, volume 
injected, and investigational site.  Details will be provided in the statistical analysis plan. 
8.5 
Sample Size Calculation 
A sample size of 111 randomized subjects treated with VOLBELLA with Lidocaine and 
37 randomized untreated control subjects will provide > 96% power to detect the superiority 
of VOLBELLA with Lidocaine over no treatment for responder rate at month 3.  Responder 
rate is the percentage of subjects who show at least a 1-point improvement compared with 
baseline on the 5-point LFS based on the Evaluating Investigator’s assessment of overall lip 
fullness.  A 2-sided Fisher’s Exact test with 5% significance level will be used to calculate 
the power, assuming responder rates of 79.0% for the VOLBELLA with Lidocaine group and 
up to 44.1% for the no-treatment control group at month 3 (based on interim data from 
Study JULIDO-002.  The power calculation was performed using an Inequality Test for 2 
Independent Proportion [Difference] procedure in PASS software (Version 2008).  The 
planned sample size is considered to be adequate for evaluation of long-term (ie, 12-month) 
safety. 
Allowing for attrition of 15% up to month 3 due to early discontinuations, missed visits, or 
out-of-analysis-window visits, 176 subjects will be randomized, with at least 132 subjects 
assigned to the VOLBELLA with Lidocaine group and approximately 44 subjects assigned to 
the no-treatment control group. 
8.6 
Interim Analyses 
No interim analysis is planned. 
9. 
Materials 
9.1 
Study Treatment 
 
 
 
 
 
  

 
 
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9.1.2 
Instructions for Use and Administration 
For investigational use in this clinical study, VOLBELLA with Lidocaine HA dermal filler 
will be injected into the lips mucosa and superficial or mid dermis using a 30 G x ½-inch 
needle and aseptic injection technique. 
The Treating Investigator should inject the treatment slowly using gentle, even pressure on 
the syringe into the vermilion body, vermilion border (including the Cupid’s bow), and 
philtral columns in accordance with the randomization scheme and the IDFU.  The IDFU 
will be provided to the Treating Investigator. 
Treating Investigators must be experienced in the use and administration of HA implants and 
be practicing in the field of aesthetic medicine, plastic/cosmetic/reconstructive surgery, or 
dermatology. 
9.1.3 
Treatment Regimen Adjustment 
Up to 2 treatment sessions 30 days apart are allowed.  The Treating Investigator will 
determine the appropriate volume of VOLBELLA with Lidocaine 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. 
9.2 
Other Study Supplies 
Allergan will provide urine pregnancy test kits, digital imaging equipment, shipping 
materials for shipment of laboratory samples to the central laboratory, explant kits, and other 
supplies specific to this study (eg, 30 G x ½-inch needles).  The investigational site is 
responsible for routine supplies related to device administration and follow-up visits 
(eg, antiseptics, drapes, gloves, gauze, anesthesia, ice packs, blood pressure cuff, internet 
connection for eCRF completion and IWRS, and telephone connection for IVRS). 
10. 
Study Administration Procedures 
The clinical study shall not begin until the required approvals from the appropriate regulatory 
authorities and IECs have been obtained. 

 
 
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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 informed consent, which will occur prior to any screening 
procedures.  Screening procedures include: 
• Evaluating Investigator assessment of the subject’s overall lip fullness using the 5-point 
LFS 
• evaluation of inclusion/exclusion criteria 
• collection of demographic information 
• collection of height; weight; and vital signs, including blood pressure (systolic and 
diastolic, while subject is seated), temperature, pulse, and respiratory rate 
• evaluation of Fitzpatrick skin phototype and sun exposure 
• collection of smoking history 
• collection of medical/surgical history 
• collection of cosmetic/dental procedures history 
• conduct EKG test 
• collection of blood for routine hematology and chemistry 
• collection of urine from all enrolled subjects for urinalysis 
• urine pregnancy test for women of childbearing potential (sexually active and not sterile, 
surgically sterilized, or postmenopausal for at least 1 year) 
• collection of adverse events and concurrent medications and procedures 
Subjects choosing not to participate in photos through checkbox selection on the ICF will be 
excluded from the study.  Allergan shall have full ownership rights to any photographs 
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 sign the ICF prior to any study-
related procedures or change in treatment. 
The Principal Investigator or his/her authorized designee conducts the informed consent 
discussion and will document in the subject’s medical records the acquisition of informed 

 
 
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consent and the subject’s agreement or refusal to notify his/her primary care physician about 
the study.  The informed consent shall include all aspects of the study that are relevant to the 
subject’s decision to participate throughout the study.  The informed consent 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 informed consent.  The Principal Investigator 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 Principal Investigator is to ensure important new information is provided to 
new or existing subjects throughout the study. 
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 randomly assigned to 1 of 2 treatment groups (treatment and no-
treatment control) in a 3:1 ratio to receive VOLBELLA with Lidocaine treatment 
immediately or to delay treatment by 3 months until the end of the no-treatment control 
period.  Subjects will be assigned to a treatment group based on a central randomization 
schedule.  An automated IVRS/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.  This number will be recorded on the appropriate 
eCRF.  The IVRS/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 IVRS/IWRS instructions provided by the 
system. 
10.2 
Compliance with Protocol 
The Principal Investigator is responsible for compliance with the protocol at the 
investigational site.  A representative of Allergan will make frequent contact with the 
investigator 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 investigator upon identification.  The use of 
the data collected for the subject will be discussed to determine if the data is to be included in 

 
 
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the analysis.  All protocol deviations will be reported to the IEC according to the IEC’s 
reporting requirements. 
10.3 
Pregnancy 
No VOLBELLA studies have been conducted in pregnant women.  Therefore, females who 
are of childbearing potential must have a negative result on a pregnancy test prior to 
receiving injection of products.  As stipulated in the exclusion criteria, all females of 
childbearing potential must be willing to use contraception and not become pregnant during 
the full course of the study to avoid potential risks to the pregnancy. 
If a female becomes pregnant during the study, the Treating Investigator (or designee) will 
notify Allergan immediately by completing the Pregnancy Surveillance Form after the 
pregnancy is confirmed and faxing or e-mailing it to the appropriate number on the front 
page of this protocol.  The Treating Investigator (or designee) 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.  Once the pregnancy has reached term, the second page of the 
Pregnancy Surveillance Form concerning outcome is to be completed.  The Medical Safety 
Physician will contact the Treating Investigator (or designee) 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.  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 adverse event or serious adverse event.  
Hospitalization for a normal delivery or elective abortion of a normal fetus does not 
constitute a serious adverse event.  However, the occurrence of an adverse pregnancy 
outcome for the mother or child may constitute an adverse event or serious adverse event, 
and these are to be reported as described in Sections 11.3 and 11.4. 
10.4 
Study Termination 
If conditions arise during the study that indicate that the study or an investigational site needs 
to be terminated, Allergan and the Principal Investigator, monitor, IEC, 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: 

 
 
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• 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 investigator to comply with pertinent national or state regulations, 
IEC-imposed conditions, or protocol requirements 
• investigator submission of knowingly false information to Allergan, a study monitor, the 
IEC, or any regulatory agency 
Per 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 IEC 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 adverse events will be monitored and reported on an 
adverse event eCRF, including seriousness, severity, action taken and relationship to study 
treatment.  If adverse events occur, the first concern will be the safety of the study 
participants. 
Although the risk of developing a serious complication is small, the Treating Investigator 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 problem.  Additional 
information is available in the IDFU. 
Typical or expected adverse events or risks include bruising, swelling, redness, tenderness, 
and/or itching at the treatment site.  Additional information about the possible side effects is 
available in the IDFU for VOLBELLA with Lidocaine. 

 
 
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11.1 
Definitions 
11.1.1 
Adverse Event 
An adverse event 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 
adverse events 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. 
Adverse events will be monitored throughout the study beginning with signing of the ICF.  At 
each postscreening visit, the Treating Investigator (or designee) will begin querying for 
adverse events by asking each subject a general, nondirected question such as “Have you had 
any changes to your condition since your last visit?”  Previous adverse events and changes in 
therapy/concomitant medications are to be updated.  Directed questioning and examination 
will then be done as appropriate.  All reportable adverse events and clinically significant 
abnormal laboratory findings will be documented on the appropriate eCRF. 
11.1.2 
Serious Adverse Event 
A serious adverse event is defined in accordance with ISO 14155 as an adverse event that: 
1. led to death 
2. led to serious deterioration in the health of the subject, that either resulted in: 
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or a body function, or 
c. in-patient or prolonged hospitalization, or 
d. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 

 
 
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3. led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE:  Planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered a serious adverse event. 
See Section 11.4 for procedures for reporting a serious adverse event/serious adverse device 
effect. 
11.1.3 
Adverse Device Effect 
An adverse device effect is defined in accordance with ISO 14155 as “an adverse event 
related to the use of an investigational medical device.”  This definition includes any adverse 
events 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 adverse device effect. 
11.1.4 
Serious Adverse Device Effect 
A serious adverse device effect 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 serious adverse device effect. 
11.1.5 
Unanticipated Serious Adverse Device Effect 
An unanticipated serious adverse device effect is defined in accordance with ISO 14155 as 
“any serious adverse device effect which by its nature, incidence, severity, or outcome has 
not been identified in the current version of the risk analysis report.”  The Principal 
Investigator is to consult the IDFU for anticipated risks or anticipated adverse events. 

 
 
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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 Treating Investigator (or designee) 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 an serious adverse device effect.  These shall be reported to the regulatory 
authorities and IECs as required by national regulations. 
11.1.7 
Severity 
Severity is a clinical determination of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event is to be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity 
Severe 
Incapacitating with inability to work or do usual activity 
11.1.8 
Relationship to Treatment 
Relationship to treatment refers to a determination of the relationship (if any) between an 
adverse event and the device or treatment procedure.  An adverse event could be considered 
treatment-related when, in the judgment of the Treating Investigator, it is reasonable to 
believe that the event 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. 
Relationship to treatment must be determined by the Treating Investigator and cannot be 
delegated to other study staff. 

 
 
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11.2 
Timelines for Reporting 
The Treating Investigator (and designees) is to adhere to the following schedule in reporting 
different types of adverse events. 
Adverse Event Type 
Reporting to Allergan 
Start of Collection 
End of Collection 
Adverse events, 
adverse device 
effects 
Record on adverse event eCRF upon 
awareness for review by the clinical 
monitor 
Signing of ICF 
Last subject visit 
Serious adverse 
events, serious 
adverse device 
effects 
Record on Serious Adverse Event 
Form and fax or e-mail to Allergan 
within 24 hours of awareness 
Signing of ICF 
Last subject visit 
ICF = informed consent form 
 
11.3 
Procedures for Reporting an Adverse Event or Adverse Device 
Effect 
All adverse events or adverse device effects occurring during the study period (beginning 
with signing of the ICF) are to be recorded on the appropriate eCRF.  Any adverse event that 
is ongoing at the exit visit must be followed up as appropriate. 
11.4 
Procedures for Reporting an Serious Adverse Events or Serious 
Adverse Device Effects 
All serious adverse events and serious adverse device effects occurring during the study 
period (beginning with signing of the ICF) are to be immediately reported to an Allergan 
representative at the fax number/e-mail address listed on the cover page and recorded on the 
appropriate eCRFs.  All subjects with an serious adverse event/serious adverse device effect 
must be followed up and the outcomes reported.  The Treating Investigator (or designee) is to 
supply Allergan and the IEC with any additional requested information (eg, hospital 
discharge summary, autopsy reports, and terminal medical reports).  Allergan shall evaluate 
all serious adverse device effects and determine and document in writing whether they meet 
the definition for “unexpected.”  These shall be reported to all participating Treating 
Investigators, the regulatory authorities, and IECs as required by national regulations. 

 
 
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In the event of a serious adverse event/serious adverse device effect, the Treating Investigator 
(or designee) must: 
1. Notify Allergan immediately by fax or by e-mail using the serious adverse 
event/serious adverse device effect reporting forms.  For the serious adverse 
event/serious adverse device effect fax number and e-mail address, see the front page 
of the protocol. 
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 IEC of the event, if it is device-related.  For other 
serious adverse events, notify the governing IEC as required by the IEC, local 
regulations, and the governing health authorities. 
11.5 
Procedures for Unblinding Study Treatments 
Evaluating Investigators may be become unblinded after the final database lock upon 
notification by Allergan or an Allergan representative. 
12. 
Administrative Issues 
12.1 
Protection of Human Subjects 
12.1.1 
Compliance with Informed Consent Regulations 
Written informed consent is to be obtained from each subject prior to enrollment into the 
study according to ethical principles contained in the World Medical Association Declaration 
of Helsinki, International Conference on Harmonisation (ICH) guidelines, applicable state 
and local laws and regulations, and IEC requirements. 
12.1.2 
Compliance with Independent Ethics Committee Regulations 
This study is to be conducted in accordance with applicable regulations of the IEC.  The 
Principal Investigator must obtain approval from a properly constituted IEC prior to initiating 

 
 
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the study and re-approval or review at least annually.  Allergan is to be notified immediately 
if the responsible IEC has been disqualified or if proceedings leading to disqualification have 
begun.  Copies of all IEC correspondence with the Principal Investigator are to be provided 
to Allergan. 
12.1.3 
Compliance with Good Clinical Practice 
This protocol is to be conducted in compliance with guidelines of good clinical practices, and 
with ethical principles for clinical research. 
12.1.4 
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 
No investigator is to implement any deviation from or changes to the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IEC 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.  Allergan may amend the protocol during the course of the study.  The amended 
protocol shall be distributed to all Principal, Treating, and Evaluating Investigators and IECs 
upon approval by regulatory authorities. 
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 or the governing health authorities if they inspect the study records.  
Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information. 

 
 
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12.4 
Documentation 
12.4.1 
Source Documents 
Source documents may include a subject’s medical records, hospital charts, laboratory notes, 
device accountability records, photographic negatives or digital images, video recordings, 
radiographs, clinic charts, the Treating Investigator’s subject study files, as well as the results 
of diagnostic tests such as X-rays, EKG data, laboratory tests, and magnetic resonance 
imaging.  Other source records include the subject safety diaries, LFS scores and GAIS 
scores from the Evaluating Investigator and the subject, and philtral column definition scores 
from the Evaluating Investigator.  The Serious Adverse Event Form and Pregnancy 
Surveillance Form are also considered source documents.  The investigators’ copies of the 
eCRFs serve as part of the investigators’ record of a subject’s study-related data. 
The following information is to be entered into the subject’s medical record: 
• subject’s name 
• subject’s contact information 
• date that the subject entered the study and subject number 
• study title and/or the protocol number and study Sponsor 
• a statement that informed consent was obtained, including the date; and a statement that 
country and local subject privacy required documentation for this study has been obtained, 
including the date 
• medical, surgical, dental, cosmetic, and smoking history 
• subject’s demographics, physical measurements, Fitzpatrick skin phototype, sun exposure 
estimate, and vital signs 
• details of the injection procedure including anesthesia use, injection procedure, volume 
injected, treatment areas, kit numbers, needle gauge, procedure characteristics, and 
product characteristics 
• dates of all subject visits and telephone calls 
• all current 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.) 
• all concomitant procedures and therapies 
• occurrence and status of any adverse events 
• the date the subject exited the study, and a notation as to whether the subject completed 
the study or reason for discontinuation 

 
 
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• EKG data 
• results of laboratory tests performed by the site (urine pregnancy tests) or central 
laboratory (blood chemistry, hematology, and urinalysis) 
12.4.2 
Case Report Form Completion 
Each investigator is responsible for ensuring that data are properly recorded on each subject’s 
eCRFs and related documents.  An investigator 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. 
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 and corrections. 
12.4.3 
Investigator Reports 
In accordance with ICH E6 4.10 and 4.13 and IEC requirements, the Principal Investigator is 
to submit written summaries of study status to the IEC annually (or more frequently if 
requested by the IEC) and promptly provide written reports to Allergan, the IEC, and, where 
required by applicable regulatory requirements, the institution regarding any changes 
significantly affecting the conduct of the study and/or increasing the risk to subjects.  Upon 
completion of the study and where required by the applicable regulatory requirements, the 
Principal Investigator is to inform the institution of the completion of the study.  The 
investigator/institution is to provide Allergan with all required reports, the IEC with a 
summary of the study outcome, and the regulatory authorities with any reports they require 
of the investigator/institution. 

 
 
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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 an investigator 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. 
12.5 
Labeling, Packaging, Storage, and Return of Study Devices 
12.5.1 
Labeling/Packaging 
VOLBELLA with Lidocaine will be provided sterile in syringes composed of cyclic olefin 
copolymer.  An investigational caution label, such as the following, will appear on the 
individual syringe package and the outer box: 
FOR CLINICAL TRIAL USE ONLY 
PROTOCOL VOLBELLA-005 
Each kit of VOLBELLA with Lidocaine contains 5 blisters, each containing 1 syringe 
prefilled to 1.0 mL and 2 single-use sterile needles, 30 G x ½-inch, specifically intended for 
injecting VOLBELLA with Lidocaine. 
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. 

 
 
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VOLBELLA with Lidocaine must be stored at 
 OR under refrigeration with a 
continuous temperature monitoring device (provided by Allergan).  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. 
12.5.3 
Study Device Accountability 
The Treating Investigator (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, and date of implantation.  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 Treating 
Investigator. 
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.  The blister/outer packaging of used syringes will be retained for 
verification against the eCRF by Allergan’s study monitor.  The used syringes will be 
destroyed appropriately at the site by following the site’s routine internal practices and China 
local regulations.  Unused syringes of VOLBELLA with Lidocaine will be returned to an 
Allergan-contracted local depot in China for destruction according to Allergan instructions. 
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 the nature of the malfunction will 
be recorded on the appropriate form.  The Treating Investigator will promptly notify 
Allergan’s Medical Safety Physician or Clinical Research Department of any device 
malfunction.  Any faulty syringe will be sent to an Allergan-contracted local depot in China 
for destruction. 

 
 
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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 the monitor has access to all study-related 
records during scheduled monitoring visits. 
The monitor 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 Treating Investigator(s) and appropriate staff at 
mutually convenient times to discuss study-related data and questions. 
12.7 
Testing of Biological Specimens 
At screening and at months 1 and 6 posttreatment, blood samples will be collected and 
prepared for routine hematology and chemistry testing by a central laboratory located in 
China. 
Routine hematology tests including: 
• levels of hemoglobin and hematocrit, concentration of red blood cells, mean cell 
volume, mean cell hemoglobin, mean cell hemoglobin concentration, red blood cell 
morphology, and the concentration of white blood cells, neutrophils (%, absolute), 
lymphocytes (%, absolute), monocytes (%, absolute), eosinophils (%, absolute), 
basophils (%, absolute), and platelets 
Chemistry tests including: 
• Hepatic function tests:  total bilirubin, direct bilirubin, alkaline phosphatase, alanine 
aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, total 
protein, and albumin 
• Renal function tests:  urea nitrogen, creatinine, uric acid, calcium, and phosphorous 
• Others: lactate dehydrogenase, glucose, triglycerides, cholesterol, and creatinine 
kinase 

 
 
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At screening and at months 1 and 6 posttreatment, urine samples will be collected for routine 
macro and micro panel of tests conducted by the central laboratory in China to assess color 
and clarity, specific gravity, pH, and concentration of protein, glucose, ketones, bilirubin, 
urobilinogen, blood, nitrite, and leukocyte esterase, and for microscopic analysis. 
At screening, on treatment days prior to injection, and at month 6 posttreatment, a trained 
research staff member at each investigational site will perform pregnancy testing on urine 
samples from women of child-bearing potential.  The urine pregnancy test employed will test 
for the presence of human chorionic gonadotropin and should have a sensitivity of at least 
50 mIU/mL. 
All blood and urine samples (ie, not including samples for urine pregnancy testing) will be 
stored at the central laboratory for the duration of the study.  All samples will be returned to 
Allergan or Allergan designee for destruction when the study sites have been closed.  
Allergan shall have full ownership rights to any biological specimens/samples derived from 
the study. 
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. 
12.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 

 
 
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13. 
References 
13.1 
Study Report References 
Data from the following study are on file at Allergan. 
Study Number 
Study Title 
JULIDO-002 
A multicenter, single-blind, randomized, controlled study of the safety and 
effectiveness of JUVÉDERM® Ultra XC Injectable Gel for lip augmentation 
13.2 
Literature References 
Andre P.  New trends in face rejuvenation by hyaluronic acid injections.  J Cosmet Dermatol.  
2008; 7:251-258. 
Bosniak S, Cantisano-Zilkha M, Glavas IP.  Nonanimal stabilized hyaluronic acid for lip 
augmentation and facial rhytid ablation.  Arch Facial Plast Surg.  2004; 6:379-383. 
Eccleston D, Murphy DK.  Juvéderm® Volbella™ in the perioral area:  a 12-month 
prospective, multicenter, open-label study.  Clin Cosmet Investig Dermatol.  2012; 5:167-172. 
Fagien S, Maas C, Murphy DK, Thomas JA, Beddingfield FC.  3rd; Juvéderm Lips Study 
Group.  Juvéderm® Ultra for lip enhancement:  An open-label, multicenter study.  Aesthet 
Surg J.  2013;33(3):414-420. 
Gold M.  The science and art of hyaluronic acid dermal filler use in esthetic applications.  J 
Cosmet Dermatol.  2009; 8(4):301-307. 
Jacono A.  A new classification of lip zones to customize injectable lip augmentation.  Arch 
Facial Plast Surg.  2008; 10(1):25-29. 
Lanigan S.  An observational study of a 24 mg/mL hyaluronic acid with pre-incorporated 
lidocaine for lip definition and enhancement.  J Cosmet Dermatol.  2011;10:11-14. 
Philipp-Dormston WG, Hilton S, Nathan M.  A prospective, open-label, multicenter, 
observational, postmarket study of the use of a 15 mg/mL hyaluronic acid dermal filler in the 
lips.  J Cosmet Dermatol.  2014;13(2):125-134. 
Raspaldo H, De Boulle K, Levy P.  Longevity of effects of hyaluronic acid plus lidocaine 
facial filler. J Cosmet Dermatol 2010;9:11-15. 

 
 
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Rivkin A.  New fillers under consideration:  What is the future of injectable aesthetics?  
Facial Plast Surg.  2009; 25:120-123. 
Sarnoff DS, Saini R, Gotkin RH.  Six steps to the “Perfect” lip.  J Drug Dermatol.  
2012;11(9):1081-1088. 
Segall L, Ellis D.  Therapeutic options for lip augmentation.  Facial Plast Surg Clin North 
Am.  2007;15:485-490. 
Smith L, Cockerham K.  Hyaluronic acid dermal fillers:  can adjunctive lidocaine improve 
patient satisfaction without decreasing efficacy or duration?  Patient Preference Adherence.  
2011; 5:133-139. 
Solish N, Swift A.  An open-label, pilot study to assess the effectiveness and safety of 
hyaluronic acid gel in the restoration of soft tissue fullness of the lips.  J Drugs Dermatol.  
2011; 10(2):145-149. 
Weinkle SH, Bank DE, Boyd CM, Gold MH, Thomas JA, Murphy DK.  A multi-center, 
double-blind, randomized controlled study of the safety and effectiveness of Juvéderm® 
injectable gel with and without lidocaine.  J Cosmet Dermatol 2009; 8:205-210. 
14. 
Protocol Amendment Summary 
Version 
Date/Amend. No. 
Changes to Protocol 
July 24, 2015/1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Updated Sponsor address on Title page 
 
 
 
 
 
 
 
 
 
 
• Clarification of Section 6.3 Instructions for the Subjects to discuss routine 
alternative treatments and to include available alternative treatments 
• Clarification of Section 10.3 Pregnancy to align with exclusion criteria 
• Updated Section 12.4.4 to remove Sponsor address 
• Updated Section 12.7 to remove the requirement for lactate dehydrogenase and 
glucose testing 

 
 
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July 29, 2015/2 
• Updated Section 7.2 to clarify timing of vital signs measurements and urine 
pregnancy tests 
• Updated Section 12.7 to clarify chemistry tests and storage of samples 
 
 

 
 
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Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol VOLBELLA-005 Amendment 2