A Multicenter, Single-blind, Randomized, Controlled Study of the Safety and Effectiveness of JUVÉDERM VOLUMA® XC Injectable Gel for Cheek Augmentation Using Cannula
Phase: NA
Conditions: Age-related Volume Deficit in the Mid-face
Sponsor: Allergan

NCT03438266 
 
 
 
Study ID: 1650‐801‐008 
 
 
 
Title: A Multicenter, Single‐blind, Randomized, Controlled Study of the Safety and Effectiveness of 
JUVÉDERM VOLUMA® XC Injectable Gel for Cheek Augmentation Using Cannula 
 
 
Protocol Date: 19 October 2017 
 
 
 

 
 
Approval Date: 
 
19-Oct-2017
Allergan Confidential 
Protocol 1650-801-008 
 
 
Page 1 of 46 
 
 
Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
Study Title: 
A multicenter, single-blind, randomized, controlled study 
of the safety and effectiveness of JUVÉDERM 
VOLUMA® XC injectable gel for cheek augmentation 
using cannula 
Protocol Number: 
1650-801-008 
Product Name: 
JUVÉDERM VOLUMA® XC injectable gel 
Development Phase: 
Post-market 
Sponsor: 
Allergan 
2525 Dupont Drive 
Irvine, CA 92612 
 
Manufacturer: 
Allergan 
Safety reporting: 
 
 
 
Names and contact information of Allergan study personnel are provided in the 
supplementary Study Contacts page.

 
 
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Protocol 1650-801-008 
 
 
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INVESTIGATOR SIGNATURE PAGE 
Study Title: 
A multicenter, single-blind, randomized, controlled 
study of the safety and effectiveness of JUVÉDERM 
VOLUMA® XC injectable gel for cheek 
augmentation using cannula 
Protocol Number: 
1650-801-008 
Product Name: 
JUVÉDERM VOLUMA® XC injectable gel 
Investigator: 
 
Study Location: 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with this protocol, 
good clinical practices (GCP), and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Ethics Committee (EC), or another 
group, it will be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 
 
RETURN TO ALLERGAN 

 
 
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Synopsis 
NUMBER AND TITLE OF STUDY: 
1650-801-008: A multicenter, single-blind, randomized, controlled study of the safety and effectiveness of 
JUVÉDERM VOLUMA® XC injectable gel for cheek augmentation using cannula 
DEVELOPMENT PHASE: Postmarket 
STUDY CENTERS: Up to 7 United States sites 
NUMBER OF SUBJECTS: Up to 75 subjects will be enrolled in order to have 60 subjects treated 
OBJECTIVES: The objective of this study is to evaluate the safety and effectiveness of JUVÉDERM 
VOLUMA XC (hereafter VOLUMA XC) injectable gel using cannula in subjects seeking correction of age-
related volume deficit in the mid-face. 
STUDY DESIGN: 
This is a multicenter, evaluator-blind, randomized, within-subject controlled, paired-comparison study of the 
safety and effectiveness of VOLUMA XC injectable gel using a cannula and needle for cheek augmentation to 
correct age-related volume deficit in the mid-face. 
At screening, after written informed consent has been obtained, the Treating Investigator (TI) will document the 
subject’s demographics, Fitzpatrick skin phototype, height, weight, vital signs, and medical, surgical, cosmetic, 
and dental procedures history. Female subjects of childbearing potential will undergo urine pregnancy testing. 
All subjects will complete the validated 5-item Satisfaction with Cheeks module of the FACE-Q questionnaire. 
The blinded Evaluating Investigator (EI) will rate the subject's mid-face deficit for the overall mid-face area,
 
 on the validated 6-point photonumeric Mid-
Face Volume Deficit Scale (MFVDS) (0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = significant, 
5 = severe) to determine eligibility for the study. 
On the randomization/treatment day, subjects will have 1 cheek treated with VOLUMA XC injectable gel using 
a 
 cannula and the contralateral cheek treated using a 
 with a goal to achieve at 
least a 1-grade improvement. In the cheek randomized for cannula use, a maximum treatment with cannula 
should be attempted. 
 
 The side of treatment (ie, side of face for needle or cannula) will be randomized. The left 
side of face will be treated first for all subjects. For the cheek treated with cannula, an anesthetic agent must be 
used on the treatment area prior to making the entry point with the introductory needle; use of anesthesia is 
optional for the cheek treated with needle only. The TI will inject VOLUMA XC in the mid-face to correct mid-
face volume deficit. 
 
 
At 1 and 3 months after treatment, subjects will return for a visit during which the EI will rate subjects on the 
MFVDS for the overall mid-face area, 
 
the TI will record any adverse events (AEs), and subjects will complete the Satisfaction with 
Cheeks module of the FACE-Q questionnaire. Subjects will be exited from the study at the end of the Month 3 
visit. 
DIAGNOSIS AND CRITERIA FOR INCLUSION/EXCLUSION: 
Adults with age-related volume deficit in the mid-face who are seeking to increase facial volume in the mid-
face. 
INCLUSION: 
1. 35 to 65 (inclusive) years of age and in good general health 
2. Has overall mid-face severity of Moderate (3) for both cheeks, Significant (4) for both cheeks, or 
Severe (5) for both cheeks on the 6-point photonumeric MFVDS as assessed by the EI 
 
 
 
 
 
 

 
 
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EXCLUSION: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. Has experienced trauma to the mid-face area within 6 months before enrollment or has residual 
deficiencies, deformities, or scarring 
 
 
10. Has a history of anaphylaxis or allergy to lidocaine (or any amide-based anesthetics), HA products, or 
Streptococcal protein, or is planning to undergo allergen desensitization therapy during the term of the 
study 
11. Has active autoimmune disease 
12. Has current cutaneous or mucosal inflammatory or infectious processes (eg, acne, herpes, gum 
disease), abscess, an unhealed wound, or a cancerous or precancerous lesion, above the subnasale 
 
 
 
 
 
 
 
 
 
 
 
 
TEST PRODUCT, DEVICE VOLUME, AND MODE OF ADMINISTRATION: 
VOLUMA® XC (a hyaluronic acid injectable gel with lidocaine) will be administered via 
 cannula 
and 
 needle to the mid-face to correct mid-face volume deficit. Appropriate injection volume for the 
mid-face will be determined by the TI
 
DURATION OF STUDY: Treatment period: 1 day. Follow-up period: 3 months 

 
 
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RESPONSE MEASURES: 
Effectiveness: The primary effectiveness measure is the blinded EI’s assessment of the subject’s overall mid-
face volume deficit for each cheek on the MFVDS. The timepoint for the primary effectiveness endpoint is 
Month 1. The secondary effectiveness measure is the FACE-Q Satisfaction with Cheeks questionnaire evaluated 
by the subject. 
Safety: Safety measures include the presence and severity of injection site responses (ISRs), which will be 
recorded by the subject in the subject diary for 30 days after treatment, procedural pain assessments, and any 
adverse events (AEs). Location of these assessments will be noted as being on the right and/or left cheek or not 
applicable. 
STATISTICAL METHODS: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Effectiveness analyses: For the primary effectiveness analysis of change from baseline (screening) to Month 1 
in overall mid-face MFVDS, the mean paired difference between treatment with cannula and treatment with 
needle and its 95% CI based on paired t-test will be calculated. If the upper confidence limit is < 0.5, statistical 
non-inferiority will be concluded. 
 
 
 
 
 
 
 
Safety analyses: ISRs, procedural pain assessment, and AEs will be summarized using descriptive statistics. 
ISRs and, separately, AEs will be summarized by the percentage (and 95% CI) of subjects who have the ISR (or 
AE) on both sides, by the percentage (and 95% CI) of subjects who have the ISR (or AE) on the cannula side 
and not on the needle side, and by the percentage (and 95% CI) of subjects who have the ISR (or AE) on the 
needle side and not on the cannula side. Also, the within-treatment percentage (and 95% CI) of subjects who 
have the ISR (or AE) will be summarized for the cannula side and, separately, for the needle side. 
 

 
 
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Table of Contents 
Synopsis .................................................................................................................................... 3 
Table of Contents ...................................................................................................................... 6 
List of Tables ............................................................................................................................. 9 
List of Figures ........................................................................................................................... 9 
1. 
Abbreviations and Terms ................................................................................................. 11 
 
 
 
 
 
 
2.3 
Clinical Rationale ................................................................................................... 13 
3. 
Study Objectives and Clinical Hypotheses ...................................................................... 13 
3.1 
Study Objectives .................................................................................................... 13 
3.2 
Clinical Hypotheses ............................................................................................... 14 
4. 
Study Design .................................................................................................................... 14 
4.1 
Structure ................................................................................................................. 14 
4.2 
Duration ................................................................................................................. 14 
4.3 
Treatment Groups and Treatment Regimen ........................................................... 14 
4.3.1  Study Treatment ......................................................................................... 14 
4.3.2  Control Treatment ...................................................................................... 14 
4.3.3  Methods for Blinding ................................................................................. 14 
4.4 
Permissible and Prohibited Medications/Treatments ............................................. 15 
4.4.1  Permissible Medications/Treatments ......................................................... 15 
4.4.2  Prohibited Medications/Treatments ........................................................... 15 
4.4.3  Special Diet or Activities ........................................................................... 16 
4.5 
Treatment Allocation Ratio and Stratification ....................................................... 16 
5. 
Study Population .............................................................................................................. 16 
5.1 
Number of Subjects ................................................................................................ 16 
5.2 
Study Population Characteristics ........................................................................... 16 
5.3 
Inclusion Criteria .................................................................................................... 17 
5.4 
Exclusion Criteria................................................................................................... 17 
 
 
 
 

 
 
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6.3 
Instructions for the Subjects ................................................................................... 22 
6.4 
Unscheduled Visits ................................................................................................. 23 
6.5 
Early Discontinuation of Subjects .......................................................................... 23 
6.6 
Withdrawal Criteria ................................................................................................ 24 
7. 
Response Measures and Summary of Data Collection Methods ..................................... 24 
7.1 
Effectiveness Measures .......................................................................................... 24 
7.1.1  Primary Effectiveness Measure .................................................................. 24 
7.1.2  Secondary Effectiveness Measure .............................................................. 25 
7.2 
Safety Measures ..................................................................................................... 25 
7.3 
Demographics and Baseline Characteristics .......................................................... 26 
7.4 
Treatment Characteristics ....................................................................................... 26 
7.5 
Summary of Methods of Data Collection .............................................................. 26 
8. 
Statistical Procedures ....................................................................................................... 26 
8.1 
Analysis Populations .............................................................................................. 27 
8.2 
Collection/Derivation of Primary and Secondary Effectiveness Assessments ...... 27 
8.2.1  Primary Effectiveness Variable .................................................................. 27 
8.2.2  Secondary Effectiveness Variables ............................................................. 27 
8.3 
Hypothesis and Methods of Analysis ..................................................................... 28 
8.3.1  Primary Effectiveness Analyses ................................................................. 28 
8.3.2  Secondary Effectiveness Analyses ............................................................. 28 
 
 
8.3.4  Safety Analyses .......................................................................................... 29 
8.4 
Subgroup Analyses ................................................................................................. 29 
 
 
8.6 
Interim Analyses..................................................................................................... 30 
9. 
Materials .......................................................................................................................... 30 
9.1 
Study Treatment ..................................................................................................... 30 
 
 

 
 
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9.1.2  Instructions for Use and Administration .................................................... 30 
9.1.3  Treatment Regimen Adjustments ............................................................... 31 
9.2 
Other Study Supplies ............................................................................................. 31 
10.  Study Administration Procedures .................................................................................... 31 
10.1  Subject Entry Procedures ....................................................................................... 31 
10.1.1  Overview of Entry Procedures ................................................................... 31 
10.1.2  Informed Consent and Subject Privacy ...................................................... 32 
10.1.3  Method for Assignment to Treatment Groups ............................................ 32 
10.2  Compliance with Protocol ...................................................................................... 33 
10.3  Pregnancy ............................................................................................................... 33 
10.4  Study Termination .................................................................................................. 33 
11.  Adverse Events ................................................................................................................ 34 
11.1  Definitions .............................................................................................................. 35 
11.1.1  Adverse Event ............................................................................................ 35 
11.1.2  Serious Adverse Event ............................................................................... 36 
11.1.3  Adverse Device Effect ............................................................................... 36 
11.1.4  Serious Adverse Device Effect ................................................................... 37 
11.1.5  Unanticipated Adverse Device Effect ........................................................ 37 
11.1.6  Device Deficiency ...................................................................................... 37 
11.1.7  Severity ...................................................................................................... 37 
11.1.8  Relationship to Treatment .......................................................................... 38 
11.2  Timelines for Reporting ......................................................................................... 38 
11.3  Procedures for Reporting an AE or ADE ............................................................... 38 
11.4  Procedures for Reporting an SAE or SADE .......................................................... 38 
12.  Administrative Issues ....................................................................................................... 39 
12.1  Protection of Human Subjects ................................................................................ 39 
12.1.1  Compliance with Informed Consent Regulations ...................................... 39 
12.1.2  Compliance with IRB Regulations............................................................. 39 
12.1.3  Compliance with Good Clinical Practice ................................................... 40 
12.1.4  Financial Disclosure/Certification Form .................................................... 40 
12.1.5  Compliance with Electronic Records and Signature Regulations .............. 40 
12.2  Changes to the Protocol ......................................................................................... 40 
12.3  Subject Confidentiality and Privacy....................................................................... 41 
12.4  Documentation ....................................................................................................... 41 
12.4.1  Source Documents ..................................................................................... 41 

 
 
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12.4.2  Case Report Form Completion................................................................... 42 
12.4.3  Investigator Reports ................................................................................... 42 
12.4.4  Retention of Documentation ...................................................................... 43 
12.5  Labeling, Packaging, Storage, and Return of Study Devices ................................ 43 
12.5.1  Labeling/Packaging .................................................................................... 43 
12.5.2  Storage of Study Devices ........................................................................... 44 
12.5.3  Study Device Accountability...................................................................... 44 
12.5.4  Return of Study Devices ............................................................................ 44 
12.6  Monitoring by Allergan .......................................................................................... 45 
12.7  Testing of Biological Specimens ............................................................................ 45 
12.8  Publications ............................................................................................................ 45 
13.  References ........................................................................................................................ 45 
 
List of Tables 
 
 
Table 2 
Midface Volume Deficit Scale ........................................................................ 24 
 
 
 
 
 

 
 
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1. 
Abbreviations and Terms 
Term/Abbreviation 
Definition 
ADE 
Adverse device effect 
AE 
Adverse event 
BMI 
Body mass index 
BOCF 
Baseline observation carried forward 
CFR 
US Code of Federal Regulations 
eCRF 
Electronic case report form 
EI 
Evaluating Investigator 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HA 
Hyaluronic acid 
HIPAA 
Health Insurance Portability and Accountability Act 
IC(F) 
Informed consent (Form) 
ICH 
International Council on Harmonisation 
IDFU 
Investigational directions for use 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ISRs 
injection site responses 
IWRS 
Interactive web response system 
MFVDS 
Mid-Face Volume Deficit Scale 
MI 
Multiple imputation 
mITT 
Modified intent-to-treat 
PP 
Per-protocol 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SD 
Standard deviation 
TI 
Treating Investigator 
UADE 
Unanticipated Adverse Device Effect 
 

 
 
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2. 
Background, Risk and Benefit, and Clinical Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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2.3 
Clinical Rationale 
VOLUMA XC was designed specifically for volumizing and has demonstrated effectiveness 
in restoring age-related mid-face volume deficit (Jones 2013). The protocol is designed to 
collect safety and effectiveness data of VOLUMA XC injectable gel using cannula in 
subjects seeking correction of age-related volume deficit in the mid-face. 
3. 
Study Objectives and Clinical Hypotheses 
3.1 
Study Objectives 
The objective of this study is to evaluate the safety and effectiveness of VOLUMA XC 
injectable gel using cannula in subjects seeking correction of age-related volume deficit in 
the mid-face. 

 
 
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3.2 
Clinical Hypotheses 
The response to treatment in terms of the Mid-Face Volume Deficit Scale (MFVDS) change 
from baseline (screening) to Month 1 with cannula will be non-inferior to response to 
treatment with needle. 
4. 
Study Design 
4.1 
Structure 
This is a multicenter, evaluator-blind, randomized, within-subject controlled, paired-
comparison study. Up to 7 investigational sites in the United States will enroll and follow 
subjects who meet the study criteria. 
4.2 
Duration 
Each subject’s participation will encompass 1 day of treatment and 3 months of follow-up. 
4.3 
Treatment Groups and Treatment Regimen 
4.3.1 
Study Treatment 
VOLUMA XC injectable gel injected with a 
 cannula and an optional 
 
4.3.2 
Control Treatment 
VOLUMA XC injectable gel injected with a 
 needle 
4.3.3 
Methods for Blinding 
The Evaluating Investigator (EI) will be blinded to treatment. The EI will not be present 
during the injection procedures. The Treating Investigator (TI), study coordinator, and subject 
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 
blinded EI. The TI will not discuss the randomized treatment assignments with or in the 
presence of the EI. 

 
 
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4.4 
Permissible and Prohibited Medications/Treatments 
4.4.1 
Permissible Medications/Treatments 
For the cheek treated with cannula, an anesthetic agent must be used on the treatment area 
prior to making the entry point with the introductory needle. For the cheek treated with 
needle, use of anesthesia is optional, according to routine practice, but it must be limited to 
the treatment area only. Acceptable topical and injectable anesthetic agents are listed in the 
investigational directions for use (IDFU). 
 
 
 
The use of any concomitant medication, prescription or over-the-counter, is to be recorded on 
the subject’s electronic case report form (eCRF) at each visit along with the reason the 
medication is taken. 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
TI. If the permissibility of a specific medication/treatment is in question, please contact 
Allergan. 
4.4.2 
Prohibited Medications/Treatments 
Subjects must not initiate or be on an existing regimen of anti-coagulant medications 
(eg, warfarin, clopidogrel) 
 
 
 
During the course of the study, subjects must not: 
 
 
 
 
 
 
 
 
 
 

 
 
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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 
Special Diet or Activities 
Within the first 24 hours after treatment, it is recommended that subjects avoid strenuous 
exercise, extensive sun or heat exposure, and alcoholic beverages. Exposure to any of the 
above may cause temporary redness, swelling, and/or itching at the injection sites. 
For 2 days after treatment, it is recommended that subjects avoid unnecessary external 
compression of the treatment site that could cause displacement or indentation where the 
product has been placed.  
For 1 week after treatment, subjects will be advised not to have a massage, enter a hot spring 
or sauna, or go swimming. 
4.5 
Treatment Allocation Ratio and Stratification 
Subjects will be randomized in a 1:1 ratio to receive treatment on the first side with the 
cannula or needle. 
5. 
Study Population 
5.1 
Number of Subjects 
Up to 75 subjects will be enrolled at up to 7 sites in order to have 60 subjects treated. 
5.2 
Study Population Characteristics 
Adult subjects who are seeking correction of age-related volume deficit in the mid-face will 
be recruited. 

 
 
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5.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
1. 35 to 65 (inclusive) years of age and in good general health 
2. Has overall mid-face severity of Moderate (3) for both cheeks, Significant (4) for both 
cheeks, or Severe (5) for both cheeks on the 6-point photonumeric MFVDS as 
assessed by the EI 
3.
 
 
 
 
 
5.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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8. Has experienced trauma to the mid-face area within 6 months before enrollment or has 
residual deficiencies, deformities, or scarring 
 
10. Has a history of anaphylaxis or allergy to lidocaine (or any amide-based anesthetics), 
HA products, or Streptococcal protein, or is planning to undergo allergen 
desensitization therapy during the term of the study 
11. Has active autoimmune disease 
12. Has current cutaneous or mucosal inflammatory or infectious processes (eg, acne, 
herpes, gum disease), abscess, an unhealed wound, or a cancerous or precancerous 
lesion, above the subnasale 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6.3 
Instructions for the Subjects 
During each study visit, subjects will be required to remove all makeup to avoid interference 
with the assessments. 
 
 

 
 
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For at least 24 hours after treatment, it is recommended that subjects avoid strenuous 
exercise, extensive sun or heat exposure, and alcoholic beverages to reduce the risk of 
posttreatment redness, swelling, and/or itching. 
Subjects will also be instructed to contact the TI or his/her research staff to report any 
unexpected symptoms or to ask questions about the study. 
6.4 
Unscheduled Visits 
An unscheduled visit may occur for safety purposes (eg, evaluation of AEs or injection site 
responses [ISRs] as requested by the subject and/or TI). Applicable procedures will be 
performed and recorded on the eCRF. 
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. It is recommended that all follow-up procedures scheduled to be 
performed at the final site visit 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 a treatment-related AE is ongoing at the time of withdrawal, the TI will attempt to follow 
the subject until the AE has been resolved or follow-up is no longer possible. The TI shall ask 
for the subject’s permission to follow his/her status/condition outside the study. 
Randomized subjects who withdraw before treatment will not be replaced by another subject. 
The subject number and associated randomization number of the withdrawn subject must not 
be reassigned to a different subject. 
If a subject fails to return for 1 or more scheduled study visits, the TI (or designee) will 
attempt to contact the subject to determine and document the reason the subject has failed to 
return and to encourage compliance with the study visit schedule. 
At regular intervals, the TI (or designee) will record on the eCRF the reasons for which any 
subjects are discontinued from the study, including subjects who signed the ICF but do not 
proceed to randomization. 

 
 
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6.6 
Withdrawal Criteria 
The subject may withdraw at will at any time for any reason. 
If a subject has a positive urine pregnancy test prior to treatment, the subject will not be 
eligible for treatment and will be withdrawn from the study. If a subject has a positive urine 
pregnancy test after treatment, she will continue all scheduled visit procedures. The 
pregnancy will be followed as described in Section 10.3. 
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 blinded EI’s assessment at Month 1 of the subject’s 
overall mid-face volume deficit for each cheek on the validated 6-point photonumeric 
MFVDS described in Table 2. 
Table 2 
Midface Volume Deficit Scale 
Score 
Grade  
Description 
5 
Severe 
• Wasting 
• Severe concavity in the zygomaticomalar region, anteromedial region, and/or 
submalar region 
• Severe tear troughs and/or nasolabial folds 
• Significant nasojugal folds and/or prejowl sulcus 
• Significant prominence of bony landmarks 
• Significant visibility of underlying musculature 
 
4 
Significant 
• Significant concavity in the zygomaticomalar region, anteromedial region, and/or 
submalar region 
• Significant tear troughs and/or nasolabial folds 
• Moderate nasojugal folds and/or prejowl sulcus 
• Moderate prominence of bony landmarks 
• Moderate visibility of musculature 
 
3 
Moderate 
• Moderate concavity in the zygomaticomalar region, anteromedial region, and/or 
submalar region 
• Moderate tear troughs and/or nasolabial folds 
• Mild nasojugal folds and/or prejowl sulcus 
• Mild prominence of bony landmarks 
• Mild visibility of musculature 
 
2 
Mild 
• Mild concavity in the zygomaticomalar region, anteromedial region, and/or submalar 
region 
• Mild tear troughs and/or nasolabial folds 

 
 
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Score 
Grade  
Description 
 
1 
Minimal 
• Flattening in the zygomaticomalar region, anteromedial region, and/or submalar 
region 
 
0 
None 
• Moon face 
• Fullness (convexity) in the zygomaticomalar region, anteromedial region, and/or 
submalar region 
 
7.1.2 
Secondary Effectiveness Measure 
The secondary effectiveness measure is the validated 5-item Satisfaction with Cheeks module 
of the FACE-Q questionnaire evaluated by the subject (very dissatisfied, somewhat 
dissatisfied, somewhat satisfied, very satisfied). 
7.2 
Safety Measures 
Safety measures will include: 
• subject assessment of procedural pain during treatment on an 11-point scale 
 
 
• presence and severity (mild, moderate, or severe) of ISRs recorded by subjects in 
daily safety diaries for 30 days after treatment 
• AEs observed by the TI or reported to the TI by the subject 
The subject’s daily safety diary will list the following ISRs that have been reported 
previously with HA dermal filler injections: 
• redness 
• pain after injection 
• tenderness to touch 
• firmness 
• swelling 
• lumps/bumps 
• bruising 
• itching 
• discoloration 
AEs will be monitored continuously throughout the study and documented on an AE eCRF. 

 
 
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7.3 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics to be collected include sex, age, height, 
weight, vital signs, Fitzpatrick skin phototype, medical/surgical/cosmetic/dental procedure 
history, and prior medications. 
7.4 
Treatment Characteristics 
Treatment characteristics will be evaluated by collecting information on anesthesia usage 
injection volume, and injection ease
 
 
7.5 
Summary of Methods of Data Collection 
Electronic data capture and questionnaires will be used to collect study-specific information, 
such as subject and Investigator assessments. Completed eCRFs will be reviewed by the 
Investigator, 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. 
8. 
Statistical Procedures 
A separate statistical analysis plan will be prepared to provide specifications for all analyses. 
The plan will be finalized and approved prior to clinical database lock. 
Descriptive statistics will be presented for key outcome measures. Categorical variables will 
be summarized with response frequencies and percentages. Continuous variables will be 
summarized by number of subjects, mean, median, standard deviation, minimum, and 
maximum. Where appropriate, 2-sided 95% CIs for population mean, or population 
proportion, will be provided as part of the summary. 
Every attempt will be made to collect complete data and limit the occurrence of missing data. 
No imputation of missing data is planned, except for sensitivity analyses described in 
Section 8.3.1 and to account for days with missing reports during the ISR duration discussed 
in Section 8.3.4. 

 
 
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8.1 
Analysis Populations 
The following analysis populations will be used in the analyses for this study: 
• modified intent-to-treat (mITT) population: all randomized subjects who received 
treatment with cannula on 1 cheek and treatment with needle on the contralateral 
cheek 
• safety population: all randomized subjects who received at least 1 study treatment 
• per-protocol (PP) population: all mITT population subjects who did not have any 
significant protocol deviations that could affect the primary endpoint; a significant 
deviation that occurred after the primary endpoint would not lead to exclusion from 
the PP analysis 
Analyses of safety variables will be performed on the safety population. Unless specified 
otherwise, all other analyses will be performed on the mITT population. The PP population 
will be used to perform PP sensitivity analyses for the primary and secondary effectiveness 
variables. 
Analyses will be based on treatment received, regardless of randomization assignment 
(ie, “as treated” rather than “as randomized”), in order to prevent bias towards study success 
(non-inferiority) that would be due to randomization errors that reverse the direction of the 
paired comparison. In addition, the mITT population will be used to do an “as randomized” 
sensitivity analysis for the primary effectiveness variable. That will not be necessary for the 
PP population, since it will exclude subjects who were not treated as randomized. 
8.2 
Collection/Derivation of Primary and Secondary Effectiveness 
Assessments 
8.2.1 
Primary Effectiveness Variable 
The primary effectiveness variable is the change from baseline (screening) to Month 1 in 
overall MFVDS based on EI assessment at each timepoint. 
8.2.2 
Secondary Effectiveness Variables 
The secondary effectiveness variables include EI-assessed overall MFVDS responder rates 
and subject satisfaction score on the FACE-Q Satisfaction with Cheeks module at Month 1. 
An overall MFVDS responder is defined as a subject who improves at least 1 grade from 
baseline on the primary measure of overall MFVDS. 

 
 
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8.3 
Hypothesis and Methods of Analysis 
8.3.1 
Primary Effectiveness Analyses 
For the primary effectiveness analysis of change from baseline at Month 1 in EI-assessed 
overall MFVDS, the mean paired difference between treatment with cannula and treatment 
with needle, and its 95% CI based on the paired t-test will be calculated. If the upper 
confidence limit is less than 0.5, statistical non-inferiority will be concluded. 
If there are any mITT subjects with missing scores for the primary effectiveness endpoint, the 
following 2 missing-data handling methods are pre-specified to use for missing-data 
sensitivity analysis of the primary effectiveness endpoint. 
1) Multiple imputation 
 
 
 
 
2) Baseline observation carried forward (BOCF) to replace missing Month 1 scores 
8.3.2 
Secondary Effectiveness Analyses 
The following analyses will be performed for secondary effectiveness variables: 
• Within-treatment overall MFVDS responder rates at Month 1 (and 95% CI) for the 
cannula side and, separately, for the needle side will be displayed, with support from 
paired-comparison response categories
 
 
 
• FACE-Q Satisfaction with Cheeks module (subject self-assessment) change from 
baseline at Month 1 Visit will be summarized with descriptive statistics. 
 
 
 
 
 

 
 
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8.3.4 
Safety Analyses 
ISRs, procedural pain assessment, and AEs will be summarized using descriptive statistics. 
The primary safety analysis of ISRs and AEs will be summarized by the percentage (and 
95% CI) of subjects who have the ISR (or AE) on both sides, by the percentage (and 95% CI) 
of subjects who have the ISR (or AE) on the cannula side and not on the needle side, and by 
the percentage (and 95% CI) of subjects who have the ISR (or AE) on the needle side and not 
on the cannula side. Also, the within-treatment percentage (and 95% CI) of subjects who 
have the ISR (or AE) will be summarized for the cannula side and, separately, for the needle 
side. 
ISRs reported by subjects will be summarized by symptom, maximum reported severity, 
maximum reported duration (ie, calendar days from first occurrence to last reported 
occurrence during the 30-day ISR period), and number of ISR days (ie, calendar days with 
non-zero severity, after accounting for days with missing reports during the ISR duration). 
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. AEs 
that occur before treatment will be listed, but not summarized. 
8.4 
Subgroup Analyses 
The primary effectiveness endpoint will be summarized by baseline overall MFVDS score 
and investigational site. Details will be provided in the statistical analysis plan. 
 
 
 

 
 
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8.6 
Interim Analyses 
No interim analysis is planned. 
9. 
Materials 
9.1 
Study Treatment 
 
 
 
 
 
 
 
9.1.2 
Instructions for Use and Administration 
For investigational use in this clinical study, VOLUMA XC dermal filler will be injected to 
the cheek area using the supplied 
 cannulas or needles 
 and aseptic 
injection technique. The TI will inject the treatment slowly using gentle, even pressure on the 

 
 
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syringe in accordance with the randomization scheme and the IDFU, which will be provided 
to the TI. 
9.1.3 
Treatment Regimen Adjustments 
The TI will determine the appropriate volume of VOLUMA XC to inject based on his/her 
clinical experience, 
 
9.2 
Other Study Supplies 
The investigational site is responsible for urine pregnancy tests (sensitivity ≥ 50 mIU/mL for 
human chorionic gonadotropin), routine supplies related to device storage, administration, 
and follow-up visits (eg, antiseptics, drapes, gloves, gauze, anesthesia, ice packs, blood 
pressure cuff, and internet connection for eCRF completion and IWRS). 
10. 
Study Administration Procedures 
The clinical study shall not begin until the required approvals from the appropriate regulatory 
authorities and IRBs have been obtained. 
10.1 
Subject Entry Procedures 
10.1.1 
Overview of Entry Procedures 
Prospective subjects as defined by the criteria in Sections 5.3 and 5.4 (inclusion/exclusion 
criteria) will be considered for entry into this study. A subject is considered to have entered 
the study upon signing the ICF, which will occur prior to any screening procedures. 
Screening procedures include: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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10.1.2 
Informed Consent and Subject Privacy 
The purpose, procedures, risks, benefits, and alternatives to study participation will be 
discussed with each potential subject. The subject must also give Authorization for Use and 
Release of Health and Research Study Information, including digital images and other 
written documentation in accordance with the relevant country and local privacy 
requirements (where applicable) prior to any study-related procedures or change in treatment. 
The TI or his/her authorized designee conducts the informed consent (IC) discussion and will 
document in the subject’s medical records the acquisition of IC and the subject’s agreement 
or refusal to notify his/her primary care physician about the study. The IC shall include all 
aspects of the study that are relevant to the subject’s decision to participate throughout the 
study. The IC process is to avoid any coercion or undue influence on, or inducement of, the 
subject to participate. The subject is to personally sign and date the ICF. The TI or his/her 
authorized designee 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 study number and site 
identification number for unique identification of each subject. The TI is to ensure important 
new information is provided to new or existing subjects throughout the study. Arrangements 
shall be made to inform the subject or legally authorized representative, as soon as possible, 
about the subject’s inclusion in the study and about all aspects of the study. The subject shall 
be asked to provide IC for continued participation as soon as his/her medical condition 
allows. 
10.1.3 
Method for Assignment to Treatment Groups 
All subjects will have 1 cheek treated with VOLUMA XC injectable gel using a 
 
cannula and the contralateral cheek treated using a 
 needle. The side of treatment 
(ie, side of face for needle or cannula) will be randomized based on a central randomization 
schedule. An automated IWRS will be used to manage the randomization assignment based 
on a randomization scheme prepared by Allergan. Study treatments will be labeled with kit 
numbers. The IWRS will provide the site with the specific kit number(s) for each randomized 
subject at the time of randomization. Sites will dispense treatment according to the IWRS 
instructions provided by the system. Kit numbers used for actual injection should be recorded 
on eCRFs in order to determine “as-treated” versus “as-randomized” treatment association. 

 
 
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10.2 
Compliance with Protocol 
The TI is responsible for compliance with the protocol at the investigational site. A 
representative of Allergan will make frequent contact with the TI and his/her research staff 
and will conduct regular monitoring visits at the site to review subject and device 
accountability records for compliance with the protocol. Any protocol deviations will be 
discussed with the TI upon identification. The use of the data collected for the subject will be 
discussed to determine if the data is to be included in the analysis. All protocol deviations 
will be reported to the IRB according to the IRB’s reporting requirements. 
10.3 
Pregnancy 
If a female subject becomes pregnant after treatment, the TI will notify Allergan immediately 
after the pregnancy is confirmed. The TI will (1) instruct the subject to notify her physician 
of the presence of the investigational device and (2) will follow the pregnancy to term. Best 
practices are to be followed in order to ensure the welfare of the subject and the fetus. The 
Medical Safety Physician will contact the TI to obtain information about the pregnancy 
outcome. The subject will continue to be followed for safety, and the pregnancy will be 
documented as a protocol deviation. 
Pregnancy by itself will not be considered an AE or serious adverse event (SAE). 
Hospitalization for a normal delivery or elective abortion of a normal fetus does not 
constitute an SAE. However, the occurrence of an adverse pregnancy outcome for the mother 
or child may constitute an AE or SAE, and these are to be reported as described in 
Section 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, the TI, monitor, IRB, and/or regulatory agencies will discuss the 
situation and take appropriate action after consultation. Conditions that may warrant 
termination of the study or site include, but are not limited to: 
• the discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in 
the study 
• the decision on the part of Allergan to suspend or discontinue testing, evaluation, or 
development of the study device 
• failure of the TI to comply with pertinent national or state regulations, IRB-imposed 
conditions, or protocol requirements 

 
 
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• TI submission of knowingly false information to Allergan, a study monitor, the IRB, 
or any regulatory agency 
 
 
 
 
 
 
 
 
 
Per International Organization for Standardization (ISO) 14155, if a study is prematurely 
terminated or suspended due to safety issues, Allergan shall inform all Investigators and the 
regulatory authorities of the termination or suspension and the reason(s) for the termination 
or suspension. The IRB is also to be informed promptly and provided the reason(s) for the 
termination or suspension by Allergan or by the Investigator, as specified by the applicable 
regulatory requirements. If a premature termination or suspension occurs, Allergan shall 
remain responsible for providing resources to fulfill the protocol obligations and existing 
agreements for follow-up of subjects enrolled in the study, and each Investigator or 
authorized designee shall promptly inform enrolled subjects, if applicable. 
11. 
Adverse Events 
Throughout the course of the study, all AEs will be monitored and reported on an AE eCRF, 
including seriousness, severity, action taken and relationship to study treatment. If AEs occur, 
the first concern will be the safety of the study subjects. 
Although the risk of developing a serious complication is small, the TI and the research staff 
will monitor each subject closely, and, if a complication occurs, they will use their medical 
judgment to do whatever is necessary to treat the problem. If subjects have any ongoing 
treatment-related AE at the time of the final visit, they must continue to be followed up until 
resolution of these events or the subject condition is considered stable by the TI. After the 
final visit, the subject will resume receiving the standard medical care according to the 
standard care of the clinic. 
Typical or expected AEs 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 VOLUMA XC. 

 
 
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11.1 
Definitions 
11.1.1 
Adverse Event 
An AE is defined in accordance with ISO 14155 as “any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory 
findings) in subjects, users, or other persons, whether or not related to the investigational 
medical device.” This definition includes events related to the investigational medical device 
or comparator and events related to the procedures involved except for events in users or 
other persons, which only include events related to investigational medical devices. 
Disease signs and symptoms that existed prior to the study treatment are not considered AEs 
unless the condition recurs after the subject has recovered from the pre-existing condition or 
the condition worsens in intensity or frequency during the study. 
AEs will be monitored throughout the study beginning with signing of the ICF. At each 
postscreening visit, the TI (or designee) will begin querying for AEs by asking each subject a 
general, non-directed questions, “Have you had any changes to your condition since your last 
visit?” Previous AEs and changes in therapy/concomitant medications are to be updated. 
Directed questioning and examination will then be done as appropriate. All reportable AEs 
and clinically significant abnormal laboratory findings will be documented on the appropriate 
eCRF. 
The following is a list of known potential AEs: 
• redness, swelling, or a rash, which may be associated with itching, pain on pressure, 
after the injection 
• pain at injection site 
• bruising 
• nodules or “lumpiness” at the injection site 
• discoloration of the injection site 
• rare cases of allergy, severe sensitivity, localized inflammation and abscesses 
• very occasionally, delayed side effects can occur many months after the treatment. 
These side effects may appear as red lumps showing up underneath the skin, or 
intermittent episodes of swelling. 
• in rare circumstances, facial fillers have been injected into blood vessels causing 
blockage and embolization which can result in skin necrosis, ulceration, or vision 
changes. Risks to vision include complete blindness, partial blindness, blurred vision, 
double vision, loss of peripheral vision, loss of a portion of the visual field or anterior 

 
 
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segment ischemia (characterized by decreased vision and pain). These effects can be 
temporary or permanent but are rare. 
• swelling or edema around the eye following an injection can result in a temporary 
decrease of vision. 
• in rare circumstances, facial fillers have been associated with granulomas, which are 
small inflammatory nodules under the skin. 
Unforeseeable risks or results are also a possibility. The risk of developing a serious 
complication is small. If a complication occurs, subjects will be advised to contact the TI 
who will use his/her medical judgment to do whatever is necessary to treat the subject. 
11.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is defined in accordance with ISO 14155 as an AE that: 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either resulted in 
1. A life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or 
4. medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered an SAE. Allergan 
considers all cancer AEs as SAEs. Abortion is also considered an SAE except for elective 
abortion of a normal fetus. 
See Section 11.4 for procedures for reporting an SAE/SADE. 
11.1.3 
Adverse Device Effect 
An adverse device effect (ADE) is defined in accordance with ISO 14155 as “an adverse 
event related to the use of an investigational medical device.” This definition includes any 
adverse events resulting from insufficient or inadequate instructions for use, deployment, 

 
 
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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 procedures for reporting an ADE. 
11.1.4 
Serious Adverse Device Effect 
A serious adverse device effect (SADE) is defined in accordance with ISO 14155 as “an 
adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event.” 
See Section 11.4 for procedures for reporting a SADE. 
11.1.5 
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) is defined in accordance with 21 CFR 812.3 
as “any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects.” 
11.1.6 
Device Deficiency 
A device deficiency is defined in accordance with ISO 14155 as “inadequacy of a medical 
device with respect to its identity, quality, durability, reliability, safety, or performance.” 
Device deficiencies include malfunctions, use errors, and inadequate labeling. 
If a device deficiency occurs, the TI will notify Allergan using the fax number or email on 
the front page of the protocol. Device deficiencies shall be documented throughout the study 
and appropriately managed by Allergan. Allergan shall review all device deficiencies and 
determine and document in writing whether they could have led to an SADE. These shall be 
reported to the regulatory authorities and IRBs 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 AE is to be completed using the following definitions as guidelines: 

 
 
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Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort affecting daily activity 
Severe 
Disabling with inability to do usual daily activities 
11.1.8 
Relationship to Treatment 
Relationship to a treatment refers to a determination of the relationship (if any) between an 
AE and the device or treatment procedure. A causal relationship is present if the TI 
determines that there is a reasonable possibility that the AE may have been caused by the 
device or is associated with the procedure, such as an event that can be attributed to other 
products, surgical techniques, or medications required specifically for the procedure. 
Relationship to the treatment must be determined by the TI and cannot be delegated to other 
study staff. 
11.2 
Timelines for Reporting 
The TI (or designee) is to adhere to the following schedule in reporting different types of 
AEs. 
Adverse Event Type 
Reporting to Allergan 
Start of Collection 
End of Collection 
AEs, ADEs 
Record on AE eCRF upon awareness 
for review by the Clinical Monitor 
Signing ICF 
Last subject visit 
SAEs, SADEs 
Record on SAE Form and fax/email to 
Allergan within 24 hours of awareness 
Signing ICF 
Last subject visit 
 
11.3 
Procedures for Reporting an AE or ADE 
All AEs or ADEs occurring during the study period (after signing ICF) are to be recorded on 
the appropriate eCRF by the TI. Any AE that is ongoing at the exit visit must be followed up 
as appropriate. 
11.4 
Procedures for Reporting an SAE or SADE 
All SAEs and SADEs occurring during the study period (after signing ICF) or through the 
last subject visit are to be immediately reported to an Allergan representative at the fax 
number/email address listed on the cover page and recorded on the appropriate eCRF. All 
subjects with an SAE/SADE must be followed up and the outcomes reported. The TI is to 
supply Allergan and the IRB with any additional requested information (eg, hospital 

 
 
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discharge summary, autopsy reports and terminal medical reports). Allergan will evaluate all 
SADEs and determine and document in writing whether they meet the definition of a UADE. 
These shall be reported to all participating TIs, the regulatory authorities, and IRBs as 
required by national regulations. 
In the event of an SAE/SADE, the TI must: 
1. Notify Allergan immediately by fax/email using the SAE/SADE reporting forms. For 
the SAE/SADE fax number/email 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 IRB of the event, if it is treatment-related. For other 
SAEs, notify the governing IRB as required by the IRB, local regulations, and the 
governing health authorities. 
12. 
Administrative Issues 
12.1 
Protection of Human Subjects 
12.1.1 
Compliance with Informed Consent Regulations 
Written IC is to be obtained from each subject prior to enrollment into the study, and/or from 
the subject’s legally authorized representative according to 21 CFR 50. 
12.1.2 
Compliance with IRB Regulations 
This study is to be conducted in accordance with IRB regulations (21 CFR 56). The TI must 
obtain approval from a properly constituted IRB prior to initiating the study and re-approval 
or review at least annually. Allergan is to be notified immediately if the responsible IRB has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all IRB 
correspondence with the TI are to be provided to Allergan. 

 
 
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12.1.3 
Compliance with Good Clinical Practice 
This protocol is to be conducted in compliance with GCP guidelines and with ethical 
principles for clinical research. 
12.1.4 
Financial Disclosure/Certification Form 
In accordance with 21 CFR 54.4, the Investigator and any subinvestigators who are directly 
involved in the treatment or evaluation of subjects must complete the Financial Disclosure 
Form disclosing completely and accurately any financial interests or arrangements that apply 
to themselves, their spouse, or their dependent children. 
• Any financial arrangement entered into between Allergan and the Investigator 
involved in the conduct of a covered clinical trial, whereby the value of the 
compensation to the Investigator for conducting the study could be influenced by the 
outcome of the study 
• Any significant payments of other sorts from Allergan, such as a grant to fund 
ongoing research, compensation in the form of equipment, retainer for ongoing 
consultation, or honoraria 
• Any proprietary interest in the tested product held by any Investigator involved in a 
study 
• Any significant equity interest in Allergan held by any Investigator involved in any 
clinical study 
• Any steps taken to minimize the potential for bias resulting from any of the disclosed 
arrangements, interests, or payments. 
The Investigator shall provide to Allergan accurate financial information on an annual basis, 
with prompt updates if any relevant changes occur over the course of the investigation, and at 
1 year following completion of this study. 
12.1.5 
Compliance with Electronic Records and Signature 
Regulations 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
12.2 
Changes to the Protocol 
The TI is not to implement any deviation from or changes to the protocol without approval 
by Allergan and prior review and documented approval/favorable opinion from the IRB of a 
protocol amendment, except where necessary to eliminate immediate hazards to study 

 
 
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subjects, or when the changes involve only logistical or administrative aspects of the study 
(eg, change in monitors, change of telephone numbers). Allergan may amend the protocol 
during the course of the study. The amended protocol shall be distributed to the TIs and IRBs 
upon approval by regulatory authorities. 
12.3 
Subject Confidentiality and Privacy 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study device may ultimately be marketed, but the 
subject’s name will not be disclosed in these documents. The subject’s name may be 
disclosed to Allergan, the governing health authorities, or the FDA, if they inspect the study 
records. Appropriate precautions will be taken to maintain confidentiality of medical records 
and personal information. 
Written Authorization and other documentation in accordance with the relevant country and 
local privacy requirements (where applicable) are to be obtained from each subject prior to 
enrollment into the study, and/or from the subject’s legally authorized representative in 
accordance with the applicable privacy requirements (eg, the Health Insurance Portability 
and Accountability Act Standards for Privacy of Individually Identifiable Health Information 
[HIPAA]). 
In accordance with HIPAA requirements, additional purposes of this study include the 
following: to publish anonymous subject data from the study and to create and maintain a 
data repository. 
12.4 
Documentation 
12.4.1 
Source Documents 
Source documents may include a subject’s medical records, hospital charts, laboratory notes, 
device accountability records, investigator MFVDS assessments, subject questionnaires and 
diaries, clinic charts, the TI’s subject study files, results of pregnancy tests, and results of any 
other diagnostic tests such as X-rays, laboratory tests, and magnetic resonance imaging. The 
SAE Form and Pregnancy Surveillance Form are also considered source documents. The TI’s 
copies of the eCRFs serve as part of the TI’s record of a subject’s study-related data. 
The following information is to be entered into the subject’s medical record: 
• Subject’s name 

 
 
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• Subject’s contact information 
• Date that the subject entered the study and subject number assigned from IWRS 
• Study title and/or the protocol number and study sponsor 
• A statement that informed consent was obtained, including the date and a statement 
that HIPAA Authorization or other country and local subject privacy required 
documentation for this study has been obtained, including the date 
• Details of the injection procedure including anesthetic used, volume injected, ease of 
injection, details regarding molding and massage, kit numbers of study device 
injected, subject’s assessment of procedural pain 
• Dates of all subject visits 
• All concurrent medications (List all prescription and non-prescription medications 
being taken at the time of enrollment. At each subsequent visit, changes to the list of 
medications are to be recorded.) 
• Occurrence and status of any AEs 
• Date the subject exited the study, and a notation as to whether the subject completed 
the study or reason for discontinuation 
• Results of laboratory tests performed by the site (eg, urine pregnancy tests) 
12.4.2 
Case Report Form Completion 
The TI is responsible for ensuring that data are properly recorded on each subject’s eCRFs 
and related documents. A TI who has signed the protocol signature page or his/her authorized 
designee is to personally sign the eCRFs (as indicated on the eCRF) to validate that the 
observations and findings are recorded on the eCRFs correctly and completely. The eCRFs 
are to be submitted to Allergan in a timely manner at the completion of the study, or as 
otherwise specified by Allergan. 
The data reported on the eCRFs shall be derived from source documents and be consistent 
with these source documents, and any discrepancies shall be explained in writing. Any 
change or correction to data reported on an eCRF shall be dated, initialed and explained, if 
necessary, and shall not obscure the original entry (ie, an audit trail shall be maintained); this 
applies to both written and electronic changes or corrections. 
12.4.3 
Investigator Reports 
In accordance with 21 CFR 812.150, the TI shall prepare and submit complete, accurate, and 
timely reports as follows: report to Allergan within 5 working days a withdrawal of IRB 
approval, study progress reports to Allergan and IRB at least annually, and a final report to 
Allergan and IRB within 3 months after study termination or completion. 

 
 
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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 the TI wishes to store study documents off-site or 
to relinquish the study data records so that mutually agreed-upon arrangements can be made 
for transfer of the data records to a suitably qualified, responsible person. Notification is to 
go to Allergan, Attn: Clinical Research Dept., 2525 Dupont Drive, Irvine, CA 92612. 
12.5 
Labeling, Packaging, Storage, and Return of Study Devices 
12.5.1 
Labeling/Packaging 
VOLUMA XC will be provided sterile in plastic syringes. An investigational caution label, 
such as the following, will appear on the individual syringe package and the outer box: 
Study 1650-801-008 Kit# VVVVV 
Lot# VVVVVV 
Allergan 
Irvine, CA 92612 
 
CAUTION - Investigational Device. 
Limited by Federal (or United States) law to Investigational Use 
 
Use as directed by protocol 
 
 
VOLUMA XC will be packaged into 2 kit types: 
1. 
 
 

 
 
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2. 
 
 
 
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. 
VOLUMA XC must be stored at room temperature 
) with a continuous 
temperature monitoring device. Use of the temperature monitoring 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 TI (or designee) must keep an accurate accounting of the number of study devices 
received from Allergan, dispensed to subjects, and returned to Allergan during and at the 
completion of the study. A detailed inventory must be completed for the study devices 
including subject identification number, device serial/lot number, date of implantation, and 
date of explantation if applicable. Study device accountability will be performed within 
IWRS according to the instructions provided by the system. The study product must be 
dispensed to study subjects by an appropriately qualified person and is to be used in 
accordance with the protocol under the direct supervision of a study TI. 
12.5.4 
Return of Study Devices 
Upon completion of the treatment period, the quantities of all used and unused study devices 
will be reconciled. Used syringes, cannulas, and needles will be disposed of onsite. Unused 
syringes will be returned to Allergan unless other disposition arrangements are agreed upon 
in writing with Allergan. 
Devices that are damaged during shipment or at the site or that malfunction during use 
(eg, faulty syringe or plunger) must be accounted for and returned. The TI will promptly 

 
 
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notify Allergan’s Clinical Research department of any device malfunction. The Clinical 
Research or Product Support representative will provide instruction for the return of any 
faulty syringe or evaluation. 
12.6 
Monitoring by Allergan 
Appropriately trained representatives of Allergan will monitor the conduct of the trial at each 
investigational site, including visits to the site to review, audit, and retrieve copies of study-
related documents. It is the responsibility of the TI to be present or available for consultation 
and to assure that Allergan has access to all study-related records during scheduled 
monitoring visits. 
Allergan will review device accountability records and completed eCRFs to ensure 
completeness and consistency with the source records and compliance with the protocol 
requirements. 
Allergan representatives will meet with the TI(s) and appropriate staff at mutually convenient 
times to discuss study-related data and questions. 
12.7 
Testing of Biological Specimens 
At screening and before study treatment, a trained research staff member will perform 
pregnancy testing on urine samples of female subjects of childbearing potential. The test 
employed must have a sensitivity of at least 50 mIU/mL for human chorionic gonadotropin. 
12.8 
Publications 
This study will be registered and results posted on www.clinicaltrials.gov. Allergan, as the 
Sponsor, has proprietary interest in this study. Authorship and manuscript composition will 
reflect joint cooperation between study TIs and Allergan personnel. Authorship will be 
established prior to the writing of the manuscript. As this study involves multiple centers, no 
individual publications will be allowed prior to completion of the final report of the 
multicenter study except as agreed with Allergan. 
13. 
References 
Bass LS. Injectable filler techniques for facial rejuvenation, volumization, and augmentation. 
Facial Plast Surg Clin N Am. 2015;23:479–488. 

 
 
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soft-tissue fillers. Aesthet Surg J. 2013;33(6):862–877. 
Tan M, Kontis T. Midface volumization with injectable fillers. Facial Plast Surg Clin N Am. 
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Vanaman M, Fabi SG, Carruthers J. Complications in the cosmetic dermatology patient: A 
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