Clinical trial NCT03425253
Conditions: Contour
Keywords: Lower Face Contouring
Sponsor: Allergan
Start date: 2018-02-02; Completion date: 2019-12-05
Enrollment: 58 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study has been designed to evaluate the safety and effectiveness of sequential treatment with BELKYRA® (for the treatment of convexity and fullness associated with submental fat) and VOLUMA™ (to restore volume along the mandibular border) to enhance the overall contour of the jawline.

Detailed description:
Participants may be treated with up to 6 treatments with Belkyra, followed by treatment with Voluma. Participants will have opportunity to participation in a skin biopsy sub-study.

Arms: arm 1: BELKYRA® was injected into subcutaneous preplatysma fat tissue in the submental area (at least 1 plus up to 5 optional treatments, for maximum of 6 treatments 8 weeks apart). When the investigator and participant agreed that no further intervention was required to achieve the desired result, participants were eligible to receive VOLUMA™ treatment. VOLUMA™ was injected along the mandibular border, with an optional touch-up visit 2 weeks later if applicable.
Interventions: intervention 1: BELKYRA® intervention 2: Juvéderm® VOLUMA™ with Lidocaine
Intervention descriptions: intervention 1: BELKYRA® was injected into preplatysma fat tissue in the submental area (at least 1 plus up to 5 optional treatments, for maximum of 6 treatments 8 weeks apart). intervention 2: Juvéderm® VOLUMA™ with Lidocaine VOLUMA™ was injected along the mandibular border.

Protocol documents:
Prot_001.pdf: 
NCT03425253 
 
Study ID: CMO-MA-FAS-0513 
 
 
Title:  A Prospective, Open-label Study to Evaluate Sequential Treatment with BELKYRA® and Juvéderm® 
VOLUMA™ with Lidocaine for Overall Improvement in Jawline Contour 
 
Protocol Date: 21Mar2018 


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Clinical Study Protocol 
A Prospective, Open-label Study to Evaluate Sequential 
Treatment with BELKYRA® and Juvéderm® VOLUMA™ 
with Lidocaine for Overall Improvement in Jawline Contour 
Protocol Number: 
CMO-MA-FAS-0513 
Drug Development Phase: 
Phase IV, Post-marketing 
Investigational Product: 
BELKYRA® / Juvéderm® VOLUMA™ with 
Lidocaine 
Sponsor: 
Allergan Pharmaceuticals International Limited 
Clonshaugh Industrial Estate 
Coolock, Dublin 17, Ireland 
Version and Date 
Version 2.0 21-March-2018 
Serious Adverse Event Reporting 
Information - Drug:  BELKYRA® 
 
 
 
 
 
Serious Adverse Event Reporting 
Information - Device:  JUVÉDERM® 
VOLUMA™ 
 
 
 
 
 
Allergan Medical Safety Physician 
Contact Information 
 
 
 
 
 
 
 
 
 
 
 
 


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Conduct: In accordance with the ethical principles that originate from the Declaration of 
Helsinki and that are consistent with International Conference on Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. 
 
CONFIDENTIAL INFORMATION 
This document is the sole property of Allergan.  This document and any and all information 
contained herein has to be considered and treated as strictly confidential.  This document 
shall be used only for the purpose of the disclosure herein provided.  No disclosure or 
publication shall be made without the prior written consent of Allergan. 


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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol for Study No. CMO-MA-
FAS-0513 Version 2.0, 21-March-2018 and will adhere to the study requirements as 
presented, including all statements regarding confidentiality. 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the 
protocol, good clinical practices (Sponsor has certified GCP training completed) 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), 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. 
 
 
 
 
Signature 
 
Date 
 
Name of Principal Investigator: 
<Enter Name and Title> 
 
 
 


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PROTOCOL SUMMARY 
Sponsor: 
Allergan Pharmaceuticals 
International Limited, 
Clonshaugh Industrial 
Estate, Coolock,  
Dublin 17, Ireland 
Investigational Products: 
BELKYRA® / Juvéderm® VOLUMA™ 
with Lidocaine 
Developmental 
Phase: 
Phase IV, Post-
marketing 
Title of Study:  A Prospective, Open-label Study to Evaluate Sequential Treatment with 
BELKYRA® and Juvéderm® VOLUMA™ with Lidocaine for Overall Improvement in 
Jawline Contour  
Protocol Number:  CMO-MA-FAS-0513 
Number of Subjects: Approximately 50 subjects in main study, approximately 
10 subjects in the Biopsy Sub-study. 
Indication:  Reduction of submental fat and restoration of facial volume for overall 
improvement in the contour of the jawline. 
Primary Study Objective: 
To evaluate the combined effectiveness of sequential BELKYRA® treatments of convexity 
or fullness associated with submental fat and Juvéderm® VOLUMA™ with Lidocaine 
(hereafter referred to as VOLUMA™) to restore volume along the mandible in enhancing 
the overall contour of the jawline. 
Secondary Study Objectives: 
• To evaluate the Investigator’s and subject’s assessment of aesthetic improvement 
of the lower face and jawline. 
• To evaluate histological changes from baseline to after BELKYRA® treatment(s). 
Methodology: 
This Phase IV trial is a prospective, open-label, multi-center, interventional, drug and 
medical device, post-marketing study.  Each subject will act as his/her own control.  All 
subjects will sign an informed consent form at the Screening Visit (Visit 1).  Eligible 
subjects will undergo treatment with BELKYRA® injected into subcutaneous pre-
platysmal fat tissue in the submental area (Visit 2.1/Day 0).  Seven days after the initial 
BELKYRA® treatment (Visit 3.1), the subject will return to the clinic for a safety 
evaluation.  Eight weeks after BELKYRA® treatment, the submental profile will be 
evaluated by the Investigator and subject.  If the Investigator and subject agree that no 
further intervention is required to achieve the desired result, subjects may receive 
VOLUMA™ treatment (Visit 4).  If further intervention is required to achieve the desired 
result, subjects may receive up to 5 optional BELKYRA® treatments (Visits 2.2 to 2.6).  
Optional BELKYRA® treatments will be administered at least 8 weeks apart, for a 
maximum of 6 treatments (including initial BELKYRA® treatment at Visit 2.1/Day 0).  
Subjects who receive optional BELKYRA® treatments will be contacted by telephone 


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7 days after treatment for safety evaluation (Visits 3.2 to 3.6).  Eight weeks after each 
BELKYRA® treatment, the submental profile will be assessed as described above and a 
decision made whether further BELKYRA® treatments are desired.  When it is determined 
that further BELKYRA® intervention is not required or the maximum number (6) of 
BELKYRA® treatments have been administered, the subject receives VOLUMA™ 
treatment (Visit 4).  Fourteen days after VOLUMA™ treatment, subjects will return to the 
clinic and the Investigator will assess whether a VOLUMA™ Touch-up treatment is to be 
performed (Visit 5).  All subjects will attend a final exit-visit 4 weeks after the last 
VOLUMA™ treatment (Visit 6). 
Subjects will have the option of participating in a Biopsy Sub-study.  Participation in the 
sub-study is voluntary and will not affect the subject’s eligibility to participate in the main 
study.  Biopsy samples will be collected from the submental region at Visit B1 and B2.  
Samples will be collected at 2 timepoints: Visit B1 will occur at least 4 weeks before the 
first BELKYRA® treatment (at Visit 2.1); Visit B2 will occur 8 weeks after the last 
BELKYRA® treatment and at least 4 weeks prior to VOLUMA™ treatment (at Visit 4).  
The initial BELKYRA® treatment (Visit 2.1) will not occur until the initial biopsy site has 
healed (at least 4 weeks after biopsy); if not healed by 4 weeks, BELKYRA® treatment 
will be postponed until healed.  The VOLUMA™ treatment (Visit 4) will not occur until 
the second biopsy site has healed (at least 4 weeks after biopsy); if not healed by 4 weeks, 
VOLUMA™ treatment will be postponed until healed.  Histological changes from baseline 
to after BELKYRA® treatment(s) will be evaluated. 
Data will be collected at each clinic visit for all relevant parameters per the Schedule of 
Visits and Procedures (Table 1.1). 
All adverse events (AEs) will be collected from the signing of the informed consent form 
(Visit 1) through to the last study visit (Visit 6).  Serious adverse events (SAEs) will be 
reported directly to Allergan within the specified time, format, and procedure described in 
Section 9: Adverse Events.  Injection site reactions (ISRs) recorded during the 
VOLUMA™ treatment period will be collected in an ISR Diary as described in Section 
7.1.8: Injection Site Reaction (ISR) Diary. 


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Criteria for Evaluation: 
Primary Endpoint 
The primary endpoint will be the responder rate for jawline improvement on the Allergan 
Loss of Jawline Definition Scale (ALJDS), which is defined as the proportion of subjects 
who show ≥ 1-point improvement from baseline on the ALJDS at the final study visit 
(after last VOLUMA™ treatment received), as assessed by the Investigator. 
Secondary Endpoints 
• Change from baseline to last BELKYRA® treatment for ALJDS 
• Change from baseline to final study visit for FACE-Q™ Satisfaction with lower face 
and jawline score 
• Change from baseline to final study visit for FACE-Q™ Appraisal of Neck  
• Change from baseline to final study visit for FACE-Q™ Appraisal of Area under Chin  
• Change from baseline to final study visit for CR (Clinician-Reported) and PR 
(Patient-reported) Submental Fat Rating Scale (SMFRS) scores 
• Change from baseline to final study visit for Submental Skin Laxity Grade (SMSLG) 
score 
• Change from baseline to final study visit in jawline definition based on Independent 
Reviewer assessment using the ALJDS and photographic images 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Key Criteria for Inclusion:  
1. 
Male and females 18 to 65 years of age inclusive on the day of initial BELKYRA® 
treatment  
2. 
Sign the Independent Ethics Committee (IEC)/Institutional Review Board (IRB)-
approved informed consent form (ICF) prior to any study-related procedures being 
performed 
3. 
Grade 2 or above on the ALJDS 
 
 
 
4. 
Submental fat graded by the Investigator as 2 or 3 using the CR-SMFRS 
 
 
 
5. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
9. 
Accept the obligation to forego any treatment or behavior (e.g., unshaven facial hair; 
significant changes to dietary or exercise habits) during the subject’s participation in 
the study that may affect the assessments of the submental area 
 
 
. 


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Key Criteria for Exclusion:  
1. 
 
2. 
A grade of 4 on the SMSLG 
 
 
 
 
 
3. 
Grade 4 on the Allergan Jowl Fat Rating Scale (AJFRS) (See Appendix 13:  Allergan 
Jowl Fat Rating Scale) 
4. 
Body mass index (BMI) > 35 kg/m2 as determined at Screening 
5. 
 
 
6. 
History of, or current symptoms of dysphagia. 
7. 
 
 
8. 
History of temporary, semi-permanent or permanent facial or neck dermal filler 
injections (
 
below the medial canthi at any time prior to treatment, or within 52 weeks before 
Screening for treatment above the medial canthi, o
 
 
9. 
History of facial and/or neck plastic surgery, tissue grafting or permanent facial 
implants 
) anywhere in 
the face or neck, 
 
 
10. History of any intervention (e.g., liposuction, surgery, or lipolytic agents) to treat 
submental fat (SMF) 
11. Evidence of any cause of enlargement in the submental area (e.g., thyroid 
enlargement, cervical adenopathy, ptotic submandibular gland) other than localized 
SMF 
12. History of mesotherapy or ablative procedures to the face and/or neck 52 weeks before 
Screening 
13. History of skin resurfacing 
 
 in the neck or 
submental area within 26 weeks before Screening 
14. Treatment with botulinum toxin injections in the neck or submental area within 
26 weeks before Screening 
15. Subjects on prescription topical retinoid therapy and/or topical hormone cream applied 
to the face, who have not been on a consistent dose regimen for at least 26 weeks 
before Screening and who are unable to maintain regimen for the study  
16. Systemic retinoid therapy within 52 weeks before Screening 
17. Current use of oral corticosteroids 


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18. Is on a regimen of anticoagulation therapy (eg, warfarin, clopidogrel) 
 
 
 
 
20. Has current injection site inflammatory or infectious processes, abscess, an unhealed 
wound, or a known cancerous or precancerous lesion in chin, masseter, or submental 
region 
 
 
22. Planned oral surgery or other dental procedures (e.g., tooth extraction, orthodontia, or 
implantation) within 2 weeks prior to and after VOLUMA™ treatment  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Products, Dose, and Mode of Administration:  
BELKYRA® (deoxycholic acid) is a clear, colorless, sterile solution supplied in 2 mL vials 
intended for single subject use.  Each milliliter of the solution contains 10 mg of 
deoxycholic acid. 
BELKYRA® is injected into subcutaneous fat tissue in the submental area using an 
area-adjusted dose of 2 mg/cm2. 
• A single treatment consists of up to a maximum of 50 injections, 0.2 mL each 
(up to a total of 10 mL), and injected 1 cm apart 
• Up to 6 single treatments may be administered at intervals no less than 8 weeks 
apart 
VOLUMA™ injectable gel is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, 
colorless, homogeneous gel implant.  It consists of cross-linked HA produced by 


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Streptococcus species of bacteria, formulated to a concentration of 20 mg/mL, and 0.3% 
lidocaine in a physiological buffer.  It is supplied in prefilled syringes containing 1 mL of 
product at a concentration of 20mg/mL. 
The Investigator will determine the appropriate volume of VOLUMA™ to be injected for 
restoring volume along the mandibular border and enhancement of the overall contour of 
the jawline.  The maximum total volume allowed for an individual subject for the initial 
and touch-up treatments combined is 6.0 mL, 3 mL per side. 
Concomitant Medications:  Throughout the study, Investigators can prescribe any 
concomitant medications or treatments deemed necessary, with the exception of 
investigational drugs.  
Study Duration: 
Duration of subject participation will be a minimum of 12 weeks and up to approximately 
64 weeks, depending on the number of BELKYRA® injections needed and participation in 
the Biopsy Sub-study. 
Statistical Methods: 
Two analysis populations will be used for analysis of efficacy:  the Full Analysis Set (FAS) 
population, defined as all subjects enrolled and who have at least treatment and one 
post-treatment efficacy assessment - this population will be used for analysis of all  
endpoints; and Evaluable Set (ES) population, defined as subjects who received both study 
treatments (i.e., both BELKYRA® and VOLUMA™) and one post-treatment efficacy 
assessment – this population will be used for analysis of the primary endpoint.  The Safety 
Analysis Set (SAS), defined as all subjects who consented to participation - this population 
will be used for safety analyses. 
 
The primary efficacy endpoint is the responder rate for jawline improvement on the 
ALJDS, which is defined as the proportion of subjects who show ≥ 1-point improvement 
from baseline on the ALJDS at the final study visit (after last VOLUMA™ treatment 
received), as assessed by the Investigator.  Descriptive statistics will be used to summarize 
the responder rate and 95% confidence intervals will be provided. 
Details of the analyses for all other efficacy endpoints will be documented in the Statistical 
Analysis Plan (SAP). 


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TABLE OF CONTENTS 
PROTOCOL SUMMARY .........................................................................................................4 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................19 
1 INTRODUCTION .............................................................................................................20 
1.1 
Background ............................................................................................................20 
1.2 
Rationale for the Study ..........................................................................................21 
2 STUDY OBJECTIVES AND CLINICAL HYPOTHESIS ...............................................21 
2.1 
Study Objectives ....................................................................................................21 
2.1.1 
Primary Study Objective ............................................................................21 
2.1.2 
Secondary Study Objectives ......................................................................21 
2.2 
Clinical Hypothesis ................................................................................................21 
3 STUDY DESIGN...............................................................................................................21 
3.1 
Biopsy Sub-Study ..................................................................................................23 
3.2 
BELKYRA® Treatment .........................................................................................23 
3.3 
VOLUMA™ Treatment .........................................................................................24 
4 STUDY POPULATION AND ENTRY CRITERIA .........................................................24 
4.1 
Number of Subjects................................................................................................24 
4.2 
Inclusion Criteria ...................................................................................................24 
4.3 
Exclusion Criteria ..................................................................................................25 
4.4 
Permissible and Prohibited Medications/Treatments.............................................27 
4.4.1 
Permissible Medications and/or Treatments ..............................................27 
4.4.1.1 
Anesthesia ..........................................................................................27 
4.4.1.2 
Rescue Medications ...........................................................................27 
4.4.1.3 
Acceptable Contraceptive Methods ...................................................27 
4.4.2 
Prohibited Medications/Treatments ...........................................................28 
4.4.2.1 
Anticoagulant Medications ................................................................28 
4.4.2.2 
Facial Procedures/Treatments ............................................................28 
4.4.2.3 
Special Diet or Activities ...................................................................29 
4.4.2.4 
Weight Loss Medications ..................................................................29 
5 TREATMENT ...................................................................................................................29 
5.1 
Investigational Product ..........................................................................................29 
5.1.1 
BELKYRA® ...............................................................................................29 
5.1.2 
VOLUMA™ ..............................................................................................29 


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5.1.3 
Blinding and Randomization .....................................................................30 
5.1.4 
Treatment Assignment ...............................................................................30 
5.2 
Storage, Handling and Destruction ........................................................................30 
5.2.1 
Storage .......................................................................................................30 
5.2.1.1 
BELKYRA® .......................................................................................30 
5.2.1.2 
VOLUMA™ ......................................................................................30 
5.2.2 
Handling .....................................................................................................30 
5.2.2.1 
BELKYRA® .......................................................................................30 
5.2.2.2 
VOLUMA™ ......................................................................................31 
5.2.3 
Destruction .................................................................................................31 
5.3 
Treatment Administration ......................................................................................31 
5.3.1 
BELKYRA® ...............................................................................................31 
5.3.2 
VOLUMA™ ..............................................................................................32 
6 STUDY VISIT SCHEDULE AND PROCEDURES ........................................................33 
6.1 
Subject Entry Procedures .......................................................................................33 
6.1.1 
Informed Consent.......................................................................................33 
6.1.2 
Subject Number .........................................................................................33 
 
 
6.1.4 
Subject Enrollment.....................................................................................34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.3 
Post-treatment Instructions for Subjects ................................................................42 
6.3.1 
BELKYRA® Treatment Period ..................................................................42 
6.3.2 
Biopsy Sub-Study ......................................................................................42 
6.3.3 
VOLUMA™ Treatment Period .................................................................43 
7 METHODS OF ASSESSMENT AND ENDPOINTS .......................................................43 
7.1 
Study Procedures ...................................................................................................43 
7.1.1 
Demographic Data .....................................................................................43 
7.1.2 
Medical History .........................................................................................43 
7.1.3 
Concomitant Medications/Procedures .......................................................43 
7.1.4 
Fitzpatrick Skin Type .................................................................................44 
7.1.5 
Urine Pregnancy Test .................................................................................44 
7.1.6 
Photographic Imaging ................................................................................44 
7.1.7 
Biopsy ........................................................................................................44 
7.1.8 
Injection Site Reaction (ISR) Diary ...........................................................44 
7.2 
Efficacy Measures ..................................................................................................45 
7.2.1 
Allergan Loss of Jawline Definition Scale ................................................45 
7.2.2 
Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) ................45 
7.2.3 
Patient-Reported Submental Fat Rating Scale (PR-SMFRS) ....................45 
7.2.4 
Submental Skin Laxity Grade (SMSLG) ...................................................45 
7.2.5 
FACE-Q™ Questionnaires ........................................................................45 
7.2.5.1 
Appraisal of Area Under Chin ...........................................................45 
7.2.5.2 
Appraisal of Neck ..............................................................................46 
7.2.5.3 
Satisfaction of Lower Face and Jawline ............................................46 
7.2.6 
Global Aesthetic Improvement Scale (GAIS) Questionnaires ..................46 
7.2.6.1 
GAIS Investigator ..............................................................................46 
7.2.6.2 
GAIS Subject .....................................................................................46 
 
 
8 DISCONTINUATION CRITERIA ...................................................................................46 
8.1 
Discontinuation of the Study .................................................................................46 
8.2 
Discontinuation of Subjects ...................................................................................46 
8.2.1 
Withdrawal Criteria ...................................................................................47 


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9 ADVERSE EVENTS .........................................................................................................47 
9.1 
Definitions..............................................................................................................48 
9.1.1 
Adverse Events (AE) .................................................................................48 
9.1.1.1 
Drug ...................................................................................................48 
9.1.1.2 
Medical Device ..................................................................................48 
9.1.1.3 
Injection Site Reaction (ISR) .............................................................48 
9.1.2 
Serious Adverse Events (SAE) ..................................................................49 
9.1.3 
Unanticipated Adverse Device Effects (UADE) .......................................49 
9.1.4 
Severity ......................................................................................................49 
9.1.5 
Relationship to Study Medication or Study Device ...................................50 
9.2 
Procedure for Reporting Adverse Events ..............................................................50 
9.3 
Procedures for Reporting an SAE ..........................................................................50 
9.4 
Procedures for Reporting Pregnancy .....................................................................51 
10 STATISTICAL METHODS ..............................................................................................51 
10.1 
General Statistical Considerations .........................................................................51 
10.1.1 
Analysis Populations ..................................................................................52 
10.1.2 
Subgroups ..................................................................................................52 
10.2 
Demographics and Baseline Characteristics ..........................................................52 
10.3 
Exposure and Concomitant Therapies ...................................................................52 
10.4 
Study Endpoints .....................................................................................................53 
10.4.1 
Primary Endpoint .......................................................................................53 
10.4.2 
Secondary Endpoints .................................................................................53 
10.4.2.1 
FACE-Q Questionnaires ....................................................................53 
10.4.2.2 
Clinician-Reported and Patient-Reported Submental Fat Rating 
Scale (CR-SMFRS and PR-SMFRS) .............................................53 
10.4.2.3 
Submental Skin Laxity Grade (SMSLG) Score .................................53 
 
 
10.5 
Efficacy Analyses ..................................................................................................54 
10.5.1 
Primary Efficacy Analysis .........................................................................54 
10.5.2 
Secondary Efficacy Analysis .....................................................................54 
 
 
10.5.4 
Missing Data ..............................................................................................54 
10.5.5 
Adverse Events ..........................................................................................54 
10.6 
Interim Analyses and Data Monitoring..................................................................54 
10.7 
Determination of Sample Size ...............................................................................54 
10.8 
Changes in the Conduct of the Study or Planned Analysis ...................................55 


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11 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS .........................................55 
11.1 
Declaration of Helsinki ..........................................................................................55 
11.2 
Good Clinical Practice ...........................................................................................55 
11.3 
Independent Ethics Committees ............................................................................55 
11.4 
Regulatory Authority Approval .............................................................................55 
11.5 
Protocol Compliance ..............................................................................................56 
11.6 
Informed Consent...................................................................................................56 
11.7 
Subject Confidentiality and Disclosure .................................................................56 
11.8 
Sponsor Monitoring Of Study Documentation ......................................................56 
11.9 
Study Documents ...................................................................................................57 
11.10 Collection of Study Data ........................................................................................57 
11.11 Archiving of Study Documents .............................................................................57 
11.12 Disclosure of Information ......................................................................................57 
12 REFERENCES ..................................................................................................................59 
13 APPENDICES ...................................................................................................................61 
 
LIST OF IN-TEXT TABLES 
 
 
 
 
Table 9.1 
Classification of Adverse Events by Severity ...............................................50 
 
LIST OF IN-TEXT FIGURES 
Figure 3.1 
Study Design .................................................................................................22 
LIST OF APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 14 
Version History .............................................................................................94 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALJDS 
Allergan Loss of Jawline Definition Scale 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CR-SMFRS 
Clinician-Rated Submental Fat Rating Scale 
eCRF 
electronic case report form 
ES 
Evaluable Set 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good Clinical Practice 
HA 
hyaluronic acid 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
NSAIDs 
non-steroidal anti-inflammatory drugs 
PR-SMFRS 
Patient-Rated Submental Fat Rating Scale 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SMF 
submental fat 
SMSLG 
Submental Skin Laxity Grade 
UADE 
unanticipated adverse device effect 
US 
United States 
VOLUMA™ 
Juvéderm® VOLUMA™ with Lidocaine 


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1 
INTRODUCTION 
1.1 
BACKGROUND 
The defining feature of the lower face is the jawline, or mandible (Shire, 2008).  Its shape 
affects the mouth, chin, and neck.  Factors affecting jawline definition are jowling, the 
development of the prejowl notch or sulcus, and marionette lines (Shire, 2008).  The chin is 
also important to overall facial appearance.  If the chin is of less than ideal size, it will cause 
other areas of the face to appear too large or too small.  If the chin projection or width is 
inadequate, the adjacent neck and jowl soft tissues appear prematurely aged (Sykes and 
Fitzgerald, 2016).  As in other areas of the face, changes in the jawline are products of soft 
tissue and bony changes (Bass, 2015). 
Submental fullness associated with the accumulation of submental fat (SMF) can lead to an 
unappealing submental profile/convexity and may blunt the definition of the jawline.  Further, 
it negatively affects the satisfaction and well-being of a substantial proportion of the 
population (Schlessinger et al, 2013; Rohrich et al, 2006).  Current treatment options for SMF 
reduction include traditional aesthetic surgical procedures performed under general anesthesia, 
or targeted liposuction which may be performed under general or local anesthesia.  However, 
not all patients are suitable candidates for, or willing to undergo, these invasive procedures 
and the potential complications (Patel, 2006; Koehler, 2009; Kamer and Minoli, 1993; Wong 
et al, 2012; Pelosi and Pelosi, 2010; Mejia et al, 2009).  Because the jawline and chin play a 
strong role in the facial profile, there has been an increasing desire for safe and effective tools 
that can contour the area nonsurgically.  The use of energy-based devices for lipolysis has 
been investigated as a less invasive approach (Coleman et al, 2009) but may still require 
accompanying surgery in more severely affected cases (Leclère et al, 2014) and safety 
concerns remain (Ersek, 2011). 
Recently, BELKYRA® (deoxycholic acid solution for injection) was approved for the 
treatment of moderate to severe convexity or fullness associated with SMF in adults 
([Appendix 1: BELKYRA® Product Information).  When injected into subcutaneous fat tissue, 
BELKYRA® physically disrupts the cell membrane of adipocytes and causes adipocytolysis, 
the destruction of fat cells.  Notably, the activity of BELKYRA® is attenuated by protein, 
making protein-poor tissues such as subcutaneous fat more sensitive to its cytolytic effects.  
As a result, when injected into fat tissue, nearby protein-rich tissues such as skin and muscle 
are largely unaffected (Thuangtong et al, 2010). 
While treatment with BELKYRA® has been shown to be safe and effective in reducing SMF 
in patients who desire a minimally invasive treatment for their condition (Humphrey et al, 
2016; Jones et al, 2016), it may only address one aspect of the overall contour of the jawline. 
Further definition may be gained by subsequent treatment with a dermal filler such as a 
hyaluronic acid (HA) injectable gel placed along the jawline.  HA fillers have become a 
primary treatment for facial rejuvenation, with an established record of safety and 
effectiveness (Jones and Flynn, 2010).  Juvéderm® VOLUMA™ with Lidocaine (hereafter 
referred to as VOLUMA™) is a member of the Juvéderm® family of HA-based dermal fillers 
that has been specifically developed for volumizing by injection into deeper tissue, e.g., to 
augment facial volume for aesthetic improvement.  It is currently approved for restoring 
volume of the face by deep (subcutaneous and/or supraperiosteal) injection and has been 


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increasingly utilized for structural support of the chin and for the angle of the jaw and jawline 
(and other areas) in the aging patient (Goodman, 2015). 
1.2 
RATIONALE FOR THE STUDY 
This study has been designed to evaluate the safety and effectiveness of sequential treatment 
with BELKYRA® (for the treatment of convexity and fullness associated with submental fat) 
and VOLUMA™ (to restore volume along the mandibular border) to enhance the overall 
contour of the jawline.  While each of these treatments may individually produce 
improvements in the definition of the jawline, a comprehensive treatment approach may be 
required to more fully address a patient’s aesthetic concerns. 
In addition, a subset of patients will participate in a Biopsy Sub-study that will investigate 
changes in histopathology of tissue taken from the submental area, including collagen 
formation, between baseline (pre-treatment) and after the last BELKYRA® treatment 
(post-treatment). 
2 
STUDY OBJECTIVES AND CLINICAL HYPOTHESIS 
2.1 
STUDY OBJECTIVES 
2.1.1 
Primary Study Objective 
To evaluate the combined effectiveness of sequential BELKYRA® treatments of convexity or 
fullness associated with submental fat and VOLUMA™ to restore volume along the 
mandible in enhancing the overall contour of the jawline. 
2.1.2 
Secondary Study Objectives 
• To evaluate the Investigator’s and subject’s assessment of aesthetic improvement of 
the lower face and jawline. 
• To evaluate histological changes from baseline to after BELKYRA® treatment(s). 
2.2 
CLINICAL HYPOTHESIS 
The clinical hypothesis of this study is that a significant proportion of subjects sequentially 
treated with BELKYRA® and VOLUMA™ will achieve at least a 1-point improvement in 
the Allergan Loss of Jawline Definition Scale (ALJDS) following completion of the 
BELKYRA® and VOLUMA™ sequence at study exit, as compared to baseline. 
3 
STUDY DESIGN 
This Phase IV trial is a prospective, open-label, multi-center, interventional, drug and 
medical device, post-marketing study.  Each subject will act as his/her own control.  Subjects 
will attend a minimum of 6 and maximum of 18 visits (see Figure 3.1)


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Approximately 50 subjects will be enrolled.  Approximately 10 subjects are expected to 
participate in the Biopsy Sub-study. 
3.1 
BIOPSY SUB-STUDY 
Eligible subjects will have the option of participating in a Biopsy Sub-study.  Participation in 
the sub-study is voluntary and will not affect the subject’s eligibility to participate in the 
main study.  The Biopsy Sub-study will evaluate changes in tissue samples taken from the 
submental area.  Samples will be collected at least 4 weeks before BELKYRA® treatment 
(Visit B1) and again (at Visit B2) 8 weeks following the final BELKYRA® treatment and at 
least 4 weeks prior to VOLUMA™ treatment (at Visit 4).  See Section 6.2.2: Biopsy - Visit 
B1, Section 6.2.7 Biopsy – visit B2, Section 7.1.7: Biopsy, and Figure 3.1. 
3.2 
BELKYRA® TREATMENT 
Subjects will undergo treatment with BELKYRA® injected into subcutaneous fat tissue in the 
submental area (Visit 2.1/Day 0) (note: Screening and Visit 2.1/Day 0 may occur the same 
day if all eligibility criteria are confirmed prior to treatment and the subject is not 
participating in the Biopsy Sub-study).  Seven days after the initial BELKYRA® treatment 
(Visit 3.1), the subject will return to the clinic for a safety evaluation.  Eight weeks after 
BELKYRA® treatment, the submental profile will be evaluated by the Investigator and 
subject.  If the Investigator and subject agree that no further intervention is required to 
achieve the desired result, subjects may receive VOLUMA™ treatment (Visit 4).  If further 
intervention is required to achieve the desired result, subjects may receive up to 5 optional 
BELKYRA® treatments (Visits 2.2 to 2.6).  Optional BELKYRA® treatments will be 


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administered at least 8 weeks apart, for a maximum of 6 treatments (including initial 
BELKYRA® treatment at Visit 2.1/Day 0).  Subjects who receive optional BELKYRA® 
treatments will be contacted by telephone 7 days after each treatment for safety evaluation 
(Visits 3.2 to 3.6).  Eight weeks after each BELKYRA® treatment, the submental profile will 
be assessed, as described above, and a decision made whether further BELKYRA® 
treatments are desired.  When it is determined that further BELKYRA® intervention is not 
required or the maximum number (6) of BELKYRA® treatments have been administered, the 
subject receives VOLUMA™ treatment (Visit 4). 
NOTE:  Subjects participating in the Biopsy Sub-study will have an additional visit (Visit 
B2) between the final BELKYRA® treatment and the first VOLUMA™ treatment.  See 
Figure 3.1 and Section 3.1: Biopsy Sub-Study. 
3.3 
VOLUMA™ TREATMENT  
The initial VOLUMA™ treatment will occur at Visit 4, either 8 weeks after the final 
BELKYRA® treatment or, if the subject is participating in the Biopsy Sub-study, after the 
biopsy site has healed.  Fourteen days after initial VOLUMA™ treatment, subjects will 
return to the clinic and the Investigator and subject will assess whether a VOLUMA™ 
Touch-up treatment is to be performed (Visit 5).  The optional Touch-up treatment will occur 
at Visit 5.  All subjects will attend a final Exit Visit 4 weeks after the last VOLUMA™ 
treatment (Visit 6). 
NOTE:  If the Investigator and the subject agree that following BELKYRA® treatment, 
VOLUMA™ treatment is no longer desired or necessary, the subject may exit the study at 
this time.  The subject will be considered as an early discontinuation, and procedures for 
Visit 6 (Exit Visit) will be performed instead of Visit 4 procedures. 
4 
STUDY POPULATION AND ENTRY CRITERIA 
4.1 
NUMBER OF SUBJECTS 
Approximately 50 subjects will be treated in this study.  Approximately 10 subjects will 
participate in the Biopsy Sub-study.  Subjects who discontinue after receiving treatment on 
Day 0 will not be replaced. 
4.2 
INCLUSION CRITERIA 
The following are requirements for entry into the study. 
1. 
Male and females 18 to 65 years of age inclusive on the day of initial BELKYRA® 
treatment  
2. 
Sign the Independent Ethics Committee (IEC)/Institutional Review Board (IRB)-
approved informed consent form (ICF) prior to any study-related procedures being 
performed 
3. 
Grade 2 or above on the ALJDS 
 
 
 


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4. 
Submental fat graded by the Investigator as 2 or 3 using the Clinician-Rated Submental 
Fat Rating Scale (CR-SMFRS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3 
EXCLUSION CRITERIA 
 
 
2. 
A grade of 4 on the Submental Skin Laxity Grade (SMSLG) 
 
 
 
 
 
3. 
Grade 4 on the Allergan Jowl Fat Rating Scale (AJFRS) (See Appendix 13:  Allergan 
Jowl Fat Rating Scale) 
4. 
Body mass index (BMI) > 35 kg/m2 as determined at Screening 
 
 
 
6. 
History of, or current symptoms of dysphagia 
 
 
 
8. 
History of temporary, semi-permanent or permanent facial or neck dermal filler 
injections 
) below the medial canthi 
at any time prior to treatment, or within 52 weeks before Screening for treatment above 
the medial canthi, 
 
 
9. 
History of facial and/or neck plastic surgery, tissue grafting or permanent facial implants 
) anywhere in the face 
 
 
10. History of any intervention (e.g., liposuction, surgery, or lipolytic agents) to treat SMF 


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11. Evidence of any cause of enlargement in the submental area (e.g., thyroid enlargement, 
cervical adenopathy, ptotic submandibular gland) other than localized SMF 
12. History of mesotherapy or ablative procedures to the face and/or neck 52 weeks before 
Screening  
13. History of skin resurfacing 
 
 in the neck or 
submental area within 26 weeks before Screening 
14. Treatment with botulinum toxin injections in the neck or submental area within 
26 weeks before Screening 
15. Subjects on prescription topical retinoid therapy and/or topical hormone cream applied 
to the face, who have not been on a consistent dose regimen for at least 26 weeks before 
Screening and who are unable to maintain regimen for the study  
16. Systemic retinoid therapy within 52 weeks before Screening 
17. Current use of oral corticosteroids 
18. Is on a regimen of anticoagulation therapy (eg, warfarin, clopidogrel) 
 
 
 
 
20. Has current injection site inflammatory or infectious processes, abscess, an unhealed 
wound, or a known cancerous or precancerous lesion in chin, masseter, or submental 
region 
 
 
22. Planned oral surgery or other dental procedures (e.g., tooth extraction, orthodontia, or 
implantation) within 2 weeks prior to and after VOLUMA™ treatment  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.4 
PERMISSIBLE AND PROHIBITED MEDICATIONS/TREATMENTS 
4.4.1 
Permissible Medications and/or Treatments 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
Investigator, including but not limited to medications for other conditions (i.e., hypertension, 
diabetes, etc.), and treatment of adverse events (AEs).  Medications should be taken consistently 
throughout the study and at the Investigator’s discretion.  All therapies administered, 
prescription or over-the-counter, will be recorded at each visit along with the reason the 
medication is taken. 
4.4.1.1 
Anesthesia 
Oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs), topical and/or injectable 
local anaesthesia (e.g., lidocaine), and/or cooling using cool packs may be applied to the area 
of injection (for treatment or biopsy) at the discretion of the Investigator/Injector.  The type 
of anesthesia (topical, local injectable, etc), anesthesia medication used and dose of anesthesia 
during the treatment is at the clinical judgment of the Investigator/Injector.  Use of injectable 
anesthesia during the treatment will be limited to the area of injection only.  Anesthesia use 
elsewhere is prohibited. 
The type, drug, dose and administration method of anesthesia shall be recorded.  Anesthesia is 
to be administered according to local site practice.  It must be confirmed that the subject is not 
allergic to the anesthetic drug to be used prior to administration. 
4.4.1.2 
Rescue Medications 
Although it has been reported that hyaluronidase is effective in reversing the effects of 
misplaced or excess HA-based dermal fillers, no product has been approved for this 
indication.  Administration of hyaluronidase is considered to be “off-label” and has not 
been provided as a part of the study regimen.  If in the Investigator’s judgment it is deemed 
to be necessary to inject hyaluronidase for the safety of the subject, then the Investigator may 
inject at his/her discretion, capturing this information as a concomitant medication.  Note 
that the use of hyaluronidase for aesthetic purposes (e.g., to reverse overcorrection) is not 
permitted. 
4.4.1.3 
Acceptable Contraceptive Methods 
Women of childbearing potential are required to practice a reliable method of contraception 
throughout the study.  The following methods of contraception, if properly used, are 
generally considered reliable:  oral contraceptives, patch contraceptives, injection 
contraceptives, male condom with intra-vaginal spermicide, diaphragm or cervical cap with 
spermicide, vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral 
tubal ligation), vasectomized partner, or sexual abstinence. 
Men, whose sexual partners are women of childbearing potential are required to practice a 
reliable method of contraception throughout the study.  The following methods of 
contraception, if properly used, are generally considered reliable:  male condom with intra-
vaginal spermicide, vasectomy or sexual abstinence. 


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The Investigator and each subject will determine the appropriate method of contraception for 
the subject during the participation in the study.  The method of contraception will be 
recorded for all female participants of childbearing potential. 
4.4.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/treatment will be made with the safety of 
the study participant as the primary consideration. When possible, the Sponsor or Sponsor’s 
representative should be notified before a prohibited medication/treatment is administered.  
Subjects must not be enrolled in another study and may not receive another investigational 
product during the course of this study. 
Prior to attending study visits, subjects must not apply facial cosmetics. 
For information regarding medications/treatments requiring washout prior to treatment, see 
Section 6.1.3: Washout of Prohibited Medications/Treatments. 
4.4.2.1 
Anticoagulant Medications 
Subjects on a regimen of anticoagulation therapy (eg, warfarin, clopidogrel) should not be 
enrolled in this study.  NSAID use is permitted to improve patient comfort during 
BELKYRA® treatment. 
Subjects who receive VOLUMA™ and who are taking NSAIDs must be warned of the 
potential increased risk of bleeding and hematomas during injection. 
Use, discontinuation and resumption, as applicable, of anticoagulant medication will be 
recorded as concomitant medication. 
4.4.2.2 
Facial Procedures/Treatments 
During the study, subjects must not: 
• Receive permanent facial implants (eg, polymethylmethacrylate, silicone, 
polytetrafluoroethylene) anywhere in the face or neck 
• Undergo fat injections in the malar, chin, or jawline area 
• Undergo any piercing or tattooing procedures below the subnasale 
• Undergo semi-permanent dermal fillers (eg, calcium hydroxylapatite, L-polylactic 
acid) below the subnasale 
• Undergo mesotherapy or cosmetic treatment (laser, photomodulation, intense pulsed 
light, radio frequency, dermabrasion, moderate or greater depth chemical peel, 
liposuction, lipolysis, or other ablative procedures) anywhere in the face or neck  
• Receive botulinum toxin injections in the chin, masseter, periorial area, or platysmal 
bands 


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4.4.2.3 
Special Diet or Activities 
Within the first 24 hours after filler treatment with VOLUMA™, at Visit 4, and if a Touch-up 
treatment is performed at Visit 5, subjects should avoid strenuous exercise, extensive sun or 
heat exposure and alcoholic beverages.  Exposure to any of the above may cause temporary 
redness, swelling, and/or itching at the injection sites. 
4.4.2.4 
Weight Loss Medications 
Subject should not be prescribed medication with the purpose of inducing weight loss during 
the course of the study.  Additionally, subjects should not be prescribed other medications for 
which significant weight loss is a known common side effect without consulting with the 
Sponsor. 
5 
TREATMENT 
5.1 
INVESTIGATIONAL PRODUCT 
Commercial grade product will be provided by Allergan for use in this study.  The product will be 
labeled as investigational and shall be used only for subjects enrolled in this trial, at no cost to the 
subject, in accordance with the conditions specified in the protocol.  Commercial grade product 
obtained by any other method shall not be used for subjects in this study.  Allergan will provide 
each study site with sufficient study treatment/devices for all study subjects. 
5.1.1 
BELKYRA® 
BELKYRA® is a clear, colorless, sterile solution supplied in 2 mL vials, 4 vials in each kit.  
The vials are intended for single subject use.  Each milliliter of the solution contains 10 mg 
of deoxycholic acid. 
BELKYRA® is injected into subcutaneous fat tissue in the submental area using an 
area-adjusted dose of 2 mg/cm2. 
• A single treatment consists of up to a maximum of 50 injections, 0.2 mL each (up to a 
total of 10 mL), and injected 1 cm apart. 
• Up to 6 single treatments may be administered at intervals no less than 8 weeks apart. 
BELKYRA® should be administered by a licensed healthcare professional. 
5.1.2 
VOLUMA™ 
VOLUMA™ injectable gel is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, 
colorless, homogeneous gel implant. It consists of cross-linked HA produced by 
Streptococcus species of bacteria, formulated to a concentration of 20 mg/mL, and 0.3% 
lidocaine in a physiological buffer. VOLUMA™ injectable gel is supplied in 1 mL syringes, 
2 syringes per kit.  The maximum total volume allowed for an individual subject for the 
initial and touch-up treatments combined during the study is 6 mL (3 mL per side). 


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5.1.3 
Blinding and Randomization 
This is an open-label, single-arm study.  Thus, blinding and randomization methods will not 
be implemented. 
5.1.4 
Treatment Assignment 
Sequentially numbered investigational product (IP) will be provided to each investigative 
site.  IP will be assigned sequentially to eligible subjects beginning with the lowest numbered 
unassigned IP at the site.  Each kit will be assigned to one subject.  Unopened vials/syringes 
in an assigned kit may be used for subsequent treatments for the assigned subject.   Kits shall 
not be shared between subjects. 
The assigned IP will be labelled with the subject’s initials, subject’s study number and date 
of assignment.  The IP number(s) assigned to a specific subject will be recorded in that 
subject’s source document and on the site’s inventory list as described in Section 5.2.1: 
Storage. 
BELKYRA® will be provided in kits containing 4 vials, each vial containing 2 mL of 
product.  Each kit will be labeled as investigational product and will be sequentially 
numbered.  A maximum of 5 vials (10 mL) may be used per treatment. Partially used 
vials/kits shall not be shared between individuals. 
VOLUMA™ will be provided in kits containing 2 syringes, each syringe containing 1 mL of 
product.  Each kit will be labeled as investigational product and will be sequentially 
numbered.  The maximum of 3 kits (total volume 6 mL) is allowed per subject for the initial 
and touch-up treatments combined. Partially used syringes/kits shall not be shared between 
individuals. 
5.2 
STORAGE, HANDLING AND DESTRUCTION 
5.2.1 
Storage 
All study drug/devices must be stored in a locked, secure area accessible only to study 
personnel.  The study site shall keep an inventory of all kits received, used and not used.  The 
disposition of each vial/syringe contained in the kit will also be inventoried. 
5.2.1.1 
BELKYRA® 
The vials of BELKYRA® should be stored at room temperature in a locked, limited-access 
storage area. 
5.2.1.2 
VOLUMA™ 
VOLUMA™ is to be stored at room temperature in a locked, limited-access storage area. 
5.2.2 
Handling 
5.2.2.1 
BELKYRA® 
BELKYRA® is clear, colorless and free of particulate matter.  BELKYRA® vials should be 
visually inspected for particulate matter and/or discoloration.  If the solution is discolored 


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and/or contains particulate matter, the vial is to be labeled as “DAMAGED” and a new vial 
obtained for the subject.  Document the reason the original vial was considered damaged.  
Record the vial number for the damaged vial and the vial number for the replacement vial 
that was used.  Used, partially used or damaged vials should be handled per Section 5.2.3 
Destruction. 
Detailed instructions for BELKYRA® handling are in the BELKYRA® Summary of Product 
Characteristics.  
5.2.2.2 
VOLUMA™ 
VOLUMA™ is an injectable gel with a clear appearance.  If a syringe contains material that 
is not clear, do not use the syringe.  If either one or both syringes in a kit is defective (e.g., gel 
is not clear, plunger does not work, etc.), the entire kit is considered damaged.  Label the kit 
as “DAMAGED” and obtain a new kit for the subject.  Document the reason the original kit 
was considered damaged.  Record the kit number for the damaged kit and the kit number for 
the replacement kit that was used. All syringes (unused, partially-used or used) should be 
returned to the kit. Used, partially used or damaged kits should be handled per Section 5.2.3 
Destruction. 
Detailed instructions for VOLUMA™ handling are provided in the JUVÉDERM® 
VOLUMA™ WITH LIDOCAINE Directions for Use (Appendix 2). 
5.2.3 
Destruction 
All vials/kits shall be retained in a secure location for audit by the Sponsor.  Partially-used and 
unused kits will be shipped for destruction by the site monitor.  Used kits shall be destroyed at 
the site following local site practices and regulations after the kit has been audited by the site 
monitor. 
5.3 
TREATMENT ADMINISTRATION 
5.3.1 
BELKYRA® 
The safe and effective use of BELKYRA® depends on the use of the correct number and 
locations for injections, proper needle placement, and administration techniques. A brief 
summary of the method of use is provided below; full details of treatment administration will 
be provided in Appendix 1: BELKYRA® Product Information. 
BELKYRA® is injected into subcutaneous fat tissue in the submental area using an 
area-adjusted dose of 2 mg/cm2.  The Investigator will determine the appropriate area of 
submental tissue to be treated. 
• A single treatment consists of up to a maximum of 50 injections, 0.2 mL each (up to a 
total of 10 mL), and injected 1 cm apart. 
• Up to 6 single treatments may be administered at intervals no less than 8 weeks apart. 
The planned treatment area should be outlined with a surgical pen and a 1 cm injection grid 
applied to mark the injection sites.  Injections near the area of the marginal mandibular nerve 


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should be avoided.  Similarly, injection into the platysma should also be avoided. 
BELKYRA® should not be injected outside the defined parameters. 
• Using a large bore needle, draw 1 mL of BELKYRA® into a sterile 1 mL syringe and 
expel any air bubbles in the syringe barrel. 
• Have the subject tense the platysma. Pinch the submental fat and, using a 30 gauge (or 
smaller) 0.5-inch needle, inject 0.2 mL of BELKYRA® into the pre-platysmal fat next to 
each of the marked injection sites by advancing the needle perpendicular to the skin. 
• Injections that are too superficial (into the dermis) may result in skin ulceration. Do not 
withdraw the needle from the subcutaneous fat during injection as this could increase the 
risk of intradermal exposure and potential skin ulceration. 
• Avoid injecting into the post-platysmal fat by injecting BELKYRA® into fat tissue at the 
depth of approximately mid-way into the subcutaneous fat layer. 
• If at any time resistance is met as the needle is inserted, indicating the possibility of 
contact with fascial or nonfat tissue, the needle must be withdrawn to an appropriate 
depth before the injection is administered. 
• Avoid injecting into other tissues such as the muscle, salivary glands and lymph nodes. 
• Upon needle withdrawal, pressure may be applied to each injection site as necessary to 
minimize bleeding; an adhesive dressing may be applied. 
For information on use of local anesthesia and use of rescue medications, refer to 
Section 4.4.1.1: Anesthesia and Section 4.4.1.2: Rescue Medications, respectively.  For 
information on prohibited medications/treatments refer to Section 4.4.2: Prohibited 
Medications/Treatments. 
5.3.2 
VOLUMA™ 
The Investigator will determine the appropriate volume of VOLUMA™ to be injected for 
restoring volume along the mandibular border and enhancement of the overall contour of the 
jawline.  Two weeks following the initial VOLUMA™ treatment (Visit 4), touch up 
treatment may be administered at Visit 5. The maximum total volume allowed for an 
individual subject for the initial and touch-up treatments combined is 6 mL (3 mL per side). 
A brief summary of the method of use is provided below; full details for the injection of 
VOLUMA™ will be provided in Appendix 2: Juvéderm® VOLUMA™ with Lidocaine 
Directions For Use. 
Use of needle or cannula for the procedure is per investigator judgement.  If the Investigator 
opts to use a cannula for the procedure, the specific cannula to be used will be per Allergan 
guidance.   
• Prior to the injection, the area to be treated should be disinfected thoroughly.   
• Confirm that the product flows out of the needle or cannula upon depressing the plunger 
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• After needle or cannula insertion and before injection, it is recommended to slightly 
withdraw the plunger to aspirate and verify the needle or cannula is not intravascular. 
• The product should be injected slowly, applying the least amount of pressure necessary. 
• If the needle or cannula becomes blocked, pressure on the plunger rod should not be 
increased; instead, the injection should be stopped and the needle or cannula replaced.   
• If immediate blanching occurs at any time during the injection, the injection should be 
stopped and appropriate action taken such as massaging the area until its return to a 
normal color.   
• After the injection, it is important to massage the area treated in order to ensure that the 
substance has been uniformly distributed. 
For information on use of local anesthesia and use of rescue medications, refer to 
Section 4.4.1.1: Anesthesia and Section 4.4.1.2: Rescue Medications, respectively.  For 
information on prohibited medications/treatments refer to Section 4.4.2: Prohibited 
Medications/Treatments. 
6 
STUDY VISIT SCHEDULE AND PROCEDURES 
6.1 
SUBJECT ENTRY PROCEDURES 
Prospective subjects as defined by the criteria in Section 4.2: Inclusion Criteria and 
Section 4.3: Exclusion Criteria will be considered for entry into this study. 
6.1.1 
Informed Consent 
The study will be discussed with the subject.  The subject must give written informed consent 
prior to the performance of any study-related procedures, inclusive of screening procedures, 
or change(s) in treatment, e.g. washout of medications.  The subject must give patient privacy 
authorization in accordance with relevant country and applicable local privacy requirements. 
The Biopsy Sub-study is optional for all eligible subjects.  Subjects will indicate on the 
written informed consent whether or not they agree to participate in the sub-study.  
Participation in the core study will not be contingent on participating in the sub-study. 
See Section 11.6: Informed Consent for additional information and requirements regarding 
informed consent. 
6.1.2 
Subject Number 
All subjects who provide informed consent will be assigned a subject number that will be used 
as the subject identifier on all study documentation throughout the study. 
 
 
 
 
 
 


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6.1.4 
Subject Enrollment 
An individual who provides written informed will be assigned a subject number and will 
undergo screening for participation.  Subjects who meet eligibility criteria (See Section 4.2 
and 4.3) will receive BELKYRA® treatment.  Subjects who meet eligibility criteria and 
consent to participate in the Biopsy Sub-study will have a biopsy sample collected prior to 
the treatment with BELKYRA®.  
Eligible subjects who withdraw after undergoing biopsy and before receiving BELKYRA® 
treatment may be replaced by another suitable subject in order that 50 subjects are treated 
with BELKYRA® and are included in the Full Analysis Set for analysis (see Section 10.1.1).  
The subject number will not be reassigned to a different subject.  Subjects who have received 
BELKYRA® treatment will not be replaced. 
 
 
 
 
 
 
 
  
 
 
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6.3 
POST-TREATMENT INSTRUCTIONS FOR SUBJECTS 
Prior to leaving the study site, the subject’s next study visit should be scheduled and a 
reminder card provided to the subject.  The subject’s contact information should be verified 
to enable reminder phone call, text and/or email(s). 
6.3.1 
BELKYRA® Treatment Period 
During the BELKYRA® treatment period, subjects will be instructed prior to leaving the site 
to: 
• Contact the study site (or have a family member or friend contact the study site) to report 
any hospitalizations. 
• Report any adverse events to the Investigator at the next study visit 
• Maintain the dose of any concomitant medication.  If there are any changes to 
medications, dosages, or frequency, the changes must be reported to the Investigator at 
the next study visit. 
• Maintain the frequency of any concomitant procedure.  If there are any changes to 
concomitant procedures, the changes must be reported to the Investigator at the next 
study visit. 
• Contact the study site as soon as possible if the subject cannot make the next scheduled 
study visit in order to reschedule. 
6.3.2 
Biopsy Sub-Study 
For subjects who consent to participate in the Biopsy Sub-study, instructions on care of the 
biopsy lesion will be provided. 


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6.3.3 
VOLUMA™ Treatment Period 
During the VOLUMA™ treatment period (Visits 4 to 6), subjects will additionally be 
instructed to: 
• Within the first 24 hours after study treatment, avoid strenuous exercise, extensive sun or 
heat exposure, and alcoholic beverages. 
• Complete the ISR Diary: every day, one page per day, around the same time of the day as 
the treatment. 
• Bring the ISR Diary to the next study visit. 
7 
METHODS OF ASSESSMENT AND ENDPOINTS 
7.1 
STUDY PROCEDURES 
7.1.1 
Demographic Data 
Subject demographic data will be collected at the Screening Visit. 
These data include date of birth, age, gender, race, and ethnicity.  Height and weight 
measurements will also be collected for use in calculating BMI. 
7.1.2 
Medical History 
Medical history will be obtained from each subject at the Screening Visit. 
Medical history includes pertinent surgical history and a detailed history of prior facial 
aesthetic procedures with start and stop dates, if applicable, as well as any discontinuations 
due to intolerability or toxicity.  
7.1.3 
Concomitant Medications/Procedures 
Concomitant medication/procedure status shall be collected at all visits.  Concomitant 
medications include prescription medications, dietary supplements, over-the-counter 
medications, and oral herbal preparations. 
A list of concomitant medications/procedures will be collected at the Screening visit.  Data 
collected shall be medication/treatment name, dose, frequency, start date, stop date (if 
applicable).  All medications or treatments received within 4 weeks before the Screening visit 
shall be recorded.  Medications/procedures received more than 4 weeks before Screening and 
in the Investigator’s judgment is pertinent to this study, should also be recorded. 
Following treatment at Day 0, subjects will be asked at each subsequent study visit whether 
any new medication/procedures have been administered or if any changes in dosage or 
frequency, have occurred since the previous visit.  All concomitant medications and 
procedures will be recorded on eCRFs. 


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7.1.4 
Fitzpatrick Skin Type 
The subject’s Fitzpatrick skin type will be determined at the Screening visit using the 
parameters listed in Appendix 12. 
7.1.5 
Urine Pregnancy Test 
The urine pregnancy test will be performed at the Screening visit and prior to administration 
of any study treatment.  The urine pregnancy test will be performed only for women of 
childbearing potential.  The woman’s childbearing status must be clearly reported in the 
source documentation. 
The pregnancy test will be performed by urine dipstick.  Positive pregnancy test results must 
be repeated to confirm the result.  Women of childbearing potential must have a negative 
pregnancy test before any study treatments are given. 
7.1.6 
Photographic Imaging 
Standardized facial photographic images will be captured prior to each study treatment and 
within 60 minutes of VOLUMA treatment. Equipment and training for the capturing of 
images will be provided by a vendor selected by Allergan.  Captured images will be 
transferred to the imaging vendor for archiving.  Instructions for image capture, transmission 
and central assessment will be contained in the procedure manual. 
7.1.7 
Biopsy 
Subjects who consent to participate in the optional Biopsy Sub-study will have a biopsy 
sample collected at least 4 weeks prior to the first BELKYRA® treatment at Visit B1.  Biopsy 
sample collection may occur on the same day as Screening (Visit 1) if all eligibility criteria 
are confirmed prior to performing the biopsy. A second biopsy sample will be collected 8 
weeks following the last BELKYRA® treatment at Visit B2.  When the second biopsy lesion 
is healed (at least 4 weeks), VOLUMA™ treatment may occur (see Figure 3.1). 
Biopsy samples, approximately 2 mm, will be excised from the submental area 
approximately 1.5 cm left and right of midline (baseline and post-treatment, respectively). 
Biopsy samples will be transferred to 10% neutral buffered formalin and shipped to a central 
laboratory for histopathology. 
Additional details on biopsy logistics (e.g. sample collection, fixative, shipping) will be 
available in the Biopsy Manual. 
7.1.8 
Injection Site Reaction (ISR) Diary 
The ISR Diary will be completed by the subject beginning on the day of treatment with 
VOLUMA™ and for daily for 4weeks.   
If Touch-up treatment is received at Visit 5, the initial ISR Diary provided at Visit 4 will be 
collected. A new ISR Diary will be dispensed and started at touch-up treatment.  Four weeks 
of ISR will be collected after the last VOLUMA™ treatment.  An example of the ISR Diary 
is available in Appendix 11. 


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7.2 
EFFICACY MEASURES 
7.2.1 
Allergan Loss of Jawline Definition Scale 
The ALJDS is an Investigator assessment of jawline contour measured by a 5-point scale (see 
Appendix 3).  The Investigator will use the ALJDS to perform a live assessment of the 
subject at the visits specified in Table 1.1: Schedule of Visits and Procedures.  Photographic 
images will be collected to capture the subject status at the time of the live assessments. 
A third party Independent Reviewer (IR) will use the photographic images collected during 
the subject visits to evaluate jawline definition using the ALJDS. 
7.2.2 
Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) 
The CR-SMFRS is an Investigator assessment measured on a 5-point scale (see Appendix 4).  
The Investigator will use the CR-SMFRS to perform a live assessment of the subject at the 
visits specified in Table 1.1: Schedule of Visits and Procedures.  Photographic images will be 
collected to capture the subject status at the time of the live assessments. 
7.2.3 
Patient-Reported Submental Fat Rating Scale (PR-SMFRS) 
The PR-SMFRS is a subject assessment measured on a 5-point scale (see Appendix 5).  The 
subject is instructed to position his or her head as described for the CR-SMFRS assessment 
and is asked to complete a questionnaire about the area under their chin using a mirror to 
help them.  The subject completes a live assessment at the visits specified in Table 1.1: 
Schedule of Visits and Procedures.  Photographic images will be collected to capture the 
subject status at the time of the live assessments. 
7.2.4 
Submental Skin Laxity Grade (SMSLG) 
The SMSLG is based on the Investigator’s clinical evaluation of the subject, including 
palpation of the chin and neck area, oblique and profile views of the chin and neck, as well as 
observation of the pronation, supination, and lateral movement of the head (see Appendix 6).  
The Investigator will use the SMSLG to perform a live assessment of the subject at the visits 
specified in Table 1.1: Schedule of Visits and Procedures.  Photographic images will be 
collected to capture the subject status at the time of the live assessments. 
7.2.5 
FACE-Q™ Questionnaires 
The FACE-Q™ modules were designed to assess the impact of treatment from the subject’s 
perspective, specifically the impact of treatment from the subject’s appraisal of the area 
under their chin (see Appendix 7), neck (see Appendix 8), and satisfaction with lower face 
and jawline (see Appendix 9). 
7.2.5.1 
Appraisal of Area Under Chin 
The subject will assess satisfaction using the 5 items on the Appraisal of Area Under Chin 
module of the FACE-Q™ questionnaire.  The responses to the 5 items are combined to create 
a scale score that ranges from 0 (worst) to 100 (best).   


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7.2.5.2 
Appraisal of Neck 
The subject will assess satisfaction using the 10items on the Neck module of the FACE-Q™ 
questionnaire.  The responses to the 10 items are combined to create a scale score that ranges 
from 0 (worst) to 100 (best). 
7.2.5.3 
Satisfaction of Lower Face and Jawline 
The subject will assess satisfaction using the 5 items on the Satisfaction of Lower Face and 
Jawline module of the FACE-Q™ questionnaire.  The responses to the 5 items are combined 
to create a scale score that ranges from 0 (worst) to 100 (best). 
7.2.6 
Global Aesthetic Improvement Scale (GAIS) Questionnaires 
7.2.6.1 
GAIS Investigator 
Investigator’s assessment of global facial aesthetic improvement as measured by the 5-point 
GAIS (see Appendix 10). 
7.2.6.2 
GAIS Subject 
Subject’s assessment of global facial aesthetic improvement as measured by the 5-point 
GAIS (see Appendix 10). 
 
 
 
 
 
 
 
 
 
 
 
8 
DISCONTINUATION CRITERIA 
8.1 
DISCONTINUATION OF THE STUDY 
The Investigator or Allergan, may terminate the Investigator’s participation in this study after 
submission of a written notice.  Allergan may terminate the study at any time for any reason. 
8.2 
DISCONTINUATION OF SUBJECTS 
A subject may voluntarily withdraw or the Investigator may withdraw the subject at any time 
without prejudice to the subject’s future medical care by the Investigator or institution.  It is 
the responsibility of the site Investigator to discontinue a subject’s participation when the 
subject’s health or wellbeing is threatened by continuation in the study. 


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For any subjects who withdraw from the study, the date and reason for withdrawal will be 
recorded on the eCRF.  If an AE or ISR is ongoing at the time of the withdrawal, the 
Investigator will attempt to follow the subject until the AE or ISR has resolved or stabilized.  
8.2.1 
Withdrawal Criteria 
The following circumstances shall result in a subject’s discontinuation from the study:  
• If a subject becomes pregnant,  
• Subject is lost to follow-up.  Subjects may be withdrawn if they do not return for 
follow-up visits.  If a subject fails to return for one or more scheduled study visits, the 
Investigator 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. 
The following circumstances may result in a subject’s discontinuation from the study. 
Investigator should contact Allergan prior to withdrawal of the subject. 
• AEs or serious adverse events (SAEs) that render the subject unable to continue study 
participation 
• Protocol violation 
• Non-compliance with study requirements  
• During the study, the subject meets any of the Exclusion Criteria listed in section 4.3 
• Progressive injury (at the discretion of the Investigator)  
• There are changes in the subject’s condition that render the subject unacceptable for 
further participation in the judgment of the Investigator  
• A subject is unable to physically or mentally tolerate the use of the test treatment 
• Discretion of Investigator 
 
The reason for withdrawal shall be documented in the source documents and in the eCRF. 
9 
ADVERSE EVENTS 
Throughout the course of the study (from the date of informed consent), all AEs will be 
monitored and recorded in source documents and on the AE eCRF.  If an AE occurs, the first 
concern will be the safety of the study participant.  All AEs related to study treatments or 
procedures will be followed until resolved or stabilized based on the Investigator’s clinical 
judgment or until follow-up is no longer possible. 


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9.1 
DEFINITIONS 
9.1.1 
Adverse Events (AE) 
9.1.1.1 
Drug 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have a causal relationship with this treatment.  An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
AEs will be assessed and documented, as appropriate, throughout the study (i.e., after 
informed consent has been obtained).  At each visit, the Investigator will begin by querying 
for adverse events by asking each subject a general, non-directed question such as “How 
have you been feeling since the last visit?”  Directed questioning and examination will then 
be done as appropriate.  All reported adverse events will be documented on the AE eCRF.   
9.1.1.2 
Medical Device 
An AE is defined as any undesirable physical, psychological or behavioral effect experienced 
by a subject during his/her participation in a study, in conjunction with the use of the device, 
whether or not it is considered related to the procedure or the product.  AEs may include, but 
are not limited to, subjective or objective symptoms spontaneously offered by the subject, 
solicited via subject interviews, uncovered by review of concomitant medications, therapies, 
and treatments and/or observed by the Investigator.  The Investigator will record the 
description (sign, symptom and diagnosis), location, onset, resolution, seriousness, severity, 
cause, and action taken for any event on the AE eCRF.  To maintain study blind, the 
Evaluating Investigator must not be present during the safety evaluations.  
Disease signs and symptoms that existed prior to the study injections 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. 
9.1.1.3 
Injection Site Reaction (ISR) 
ISRs following treatment with dermal fillers include redness, pain after injection, tenderness 
to touch, firmness, swelling, lumps/bumps, bruising, itching, discoloration, and other 
specified events.  Subjects will maintain a diary record of the presence, location, frequency, 
severity, and duration of any ISR for 4 weeks after treatment with VOLUMA™ (initial 
treatment at Visit 4 and Touch-up at Visit 5, if applicable).  (See Section 7.1.8: Injection Site 
Reaction (ISR) Diary for further details). 
Subjects will indicate the occurrence of an ISR and severity (none, mild, moderate, severe) of 
the event.  ISRs that persist longer than 4 weeks (i.e., ongoing at the end of the diary period) 
will be reported as AEs and followed as described in Section 9.2: Procedure for Reporting 
Adverse Events.  If an ISR is ongoing or appears 4 weeks after the subject’s last study visit, it 
will be followed up by Allergan Product Surveillance separate from this study protocol. 


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9.1.2 
Serious Adverse Events (SAE) 
An SAE is any AE occurring at any dose that results in any of the following outcomes:  
death, a life-threatening AE, subject hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect.  Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  (See Section 9.3: Procedures for Reporting an 
SAE). 
Note:  Allergan considers all cancer AEs as SAEs.  In addition, Allergan considers any 
abortion (spontaneous or not spontaneous) as an SAE. 
9.1.3 
Unanticipated Adverse Device Effects (UADE) 
An Unanticipated Adverse Device Effect (UADE) is any device-related SAE that meets one 
or more of the following criteria: 
• Is not identified in nature, severity, or frequency in current literature on the product 
• Is life-threatening, even if temporary in nature 
• Results in permanent impairment of a body function or permanent damage to a body 
structure 
• Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure. 
Also considered an UADE is any device malfunction that would be likely to cause or 
contribute to a death or serious injury if the malfunction were to recur.  The Investigator will 
notify the Allergan Medical Affairs Department within 24 hours of any device malfunction 
and the Clinical Research representative will provide instruction for the return of any faulty 
syringe for evaluation. 
As required by United States (US) Code of Federal Regulation (CFR) 21 §812.46(b)(2), if 
the Sponsor determines that an UADE presents an unreasonable risk to study subjects, the 
Sponsor will terminate the investigation within 5 working days of the unreasonable risk 
determination. 
9.1.4 
Severity 
Definitions for classification of severity appear below in Table 9.1.  The Investigator will 
review these definitions with the subject for use when completing the subject diary.  For 
events reported on the AE eCRF, e.g., ISRs that persist beyond the diary period and other 
AEs, the Investigator will determine the severity classification based on these definitions, 
his/her experience in the use of dermal fillers, and/or the subject’s description of the event.  
Note: A “severe” AE is not the same as an “SAE”, which is defined above.  Seriousness of 
AEs is defined in Section 9.1.2: Serious Adverse Events (SAE). 


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Table 9.1 
Classification of Adverse Events by Severity 
Mild: 
Symptoms are barely noticeable or do not make the subject uncomfortable.  The 
AE/ISR does not interfere with performance or functioning.  Prescription drugs 
are not ordinarily needed for relief of symptoms. 
Moderate: 
Symptom are of sufficient severity to make the subject uncomfortable. 
Performance of daily activities is influenced.  Treatment of symptom(s) with 
prescription drugs/therapies may be needed. 
Severe: 
Symptoms are of such sufficient severity to cause the subject severe discomfort.  
Performance of daily activities is compromised.  Treatment of symptom(s) with 
prescription drugs/therapies may be needed. 
Not applicable: 
In some cases, an AE/ISR may be an “all or nothing” finding that cannot be 
graded. 
 
9.1.5 
Relationship to Study Medication or Study Device 
A determination will be made, by the Investigator, of the relationship (if any) between an AE 
and the study drug, anesthesia employed, the study device, or the injection procedure, as 
applicable.  A causal relationship is present if a determination is made that there is a 
reasonable possibility that the AE may have been caused by the drug, device, or study 
procedure. 
9.2 
PROCEDURE FOR REPORTING ADVERSE EVENTS 
All AEs must be recorded in source documents and on the appropriate eCRF.  All AEs that 
are drug-related and unexpected (not listed as treatment-related in the current Package Insert 
or Directions for Use) must be reported to the governing IRB as required by the IRB, local 
regulations, and the governing health authorities.  Any adverse event that is marked 
“ongoing” at the Exit Visit must be followed-up as appropriate. 
9.3 
PROCEDURES FOR REPORTING AN SAE 
Any SAE occurring during the study period (beginning with informed consent) and through 
30 days after study exit must be immediately reported on 2 SAE forms.  Both drug and 
device SAE fax forms must be recorded and faxed to the appropriate numbers on the front 
page of the protocol.  All subjects with an SAE must be followed up and the outcomes 
reported.  The Principal Investigator must supply the Sponsor and the IRB with any 
additional requested information (e.g., hospital discharge summary, autopsy reports and 
terminal medical reports) if required.  The Sponsor shall evaluate all SAEs for both drug and 
device.  Device SAEs will be documented in writing as to whether they meet the definition of 
an UADE.  These shall be reported to all participating Investigators, the regulatory 
authorities, and the IRB. 
In the event of a serious adverse event, the Investigator must: 
1. Notify Allergan immediately (within 24 hours) using the SAE reporting forms (for 
information see page 1 of the protocol).  Emergency phone numbers and relevant 
Allergan personnel contacts are also on the front page of protocol. 


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2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the subject. 
3. Provide Allergan with a complete, written case history (SAE report form) including 
copies of supporting reports (e.g., progress notes, laboratory reports) and a statement 
from the Investigator as to whether the event was or was not related to the use of the 
investigational drug or device. 
4. Promptly inform the governing IRB/IEC of the SAE, if it is device-related, as 
required by the IEC/IRB, local regulations, and the governing health authorities. 
9.4 
PROCEDURES FOR REPORTING PREGNANCY 
If a female of childbearing potential becomes pregnant during the study, the Investigator will 
notify the Sponsor immediately by completing the Pregnancy Surveillance Form after the 
pregnancy is confirmed.  The subject will be withdrawn from the study per Section 8.2.1: 
Withdrawal Criteria.  The Investigator shall (1) notify the subject’s physician that the subject 
was being treated with BELKYRA® or BELKYRA® plus VOLUMA™, as appropriate, and 
(2) follow the progress of the pregnancy.  The Investigator must document the outcome of 
the pregnancy and provide a copy of the documentation to Allergan. 
Pregnancy by itself will not be considered an AE or SAE.  Hospitalization for a normal 
delivery 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 should be reported 
as described in Section 9.2: Procedure for Reporting Adverse Events.  Allergan considers any 
abortion (spontaneous or not spontaneous) as an SAE and should be reported as described in 
Section 9.3: Procedures for Reporting an SAE. 
10 STATISTICAL METHODS 
10.1 GENERAL STATISTICAL CONSIDERATIONS 
General statistical analysis methods are provided below; full details will be provided in a 
separate Statistical Analysis Plan (SAP), which will be finalized prior to database lock. 
Data will be summarized using descriptive statistics (number of observations (n), mean, 
standard deviation, median, minimum, and maximum for continuous variables; and n and 
percent for categorical variables).  Confidence intervals (95%) will be provided for the 
efficacy endpoints.  
Three critical time points, baseline (Visit 2.1/Day 0), Visit 4 (end of BELKYRA® treatment, 
prior to VOLUMA™ treatment), and end of study (Exit/Visit 6; end of VOLUMA™ 
treatment), will be referenced in most of statistical analyses for this study. 
Baseline is defined as the latest assessment prior to any study treatments for each subject.  
End of study is the last clinical visit an enrolled subject has in this study.  For subjects who 
complete this study, the end of study visit will be their Visit 6 visit; for subjects who drop out 


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early, they will be asked to come back for the last clinical visit for end of study data 
collection. 
10.1.1 
Analysis Populations 
The following analysis populations will be used: 
• Full Analysis Set (FAS) – Consists of all subjects who received BELKYRA® 
• Evaluable Set (ES) – Consists of subjects in the Full Analysis Set who received 
BELKYRA® and VOLUMA™ and a post-treatment efficacy assessment at Visit 6 (Exit 
Visit). 
• Safety Analysis Set (SAS) – Consists of all subjects who consented to participation.  
Includes subjects who are defined as Full Analysis Set as well as subjects who were 
biopsied but did not receive BELKYRA® 
The FAS population will be used for summary of subject disposition, demographics, baseline 
characteristics and efficacy analyses of endpoints assessed up to end of BELKYRA® 
treatment; the ES population will be used for the efficacy analyses of endpoints assessed at 
the final study visit, and the SAS population will be used for safety analyses. 
10.1.2 
Subgroups  
As males and females may have differing expectations / perceptions of aesthetic 
improvement, data will be analyzed by gender separately. 
Additional subgroup analysis will be discussed in the study SAP. 
10.2 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Subject disposition, demographics and baseline characteristics will be summarized using 
descriptive statistics. 
10.3 EXPOSURE AND CONCOMITANT THERAPIES 
Subject study treatment exposure and compliance will be summarized using descriptive 
statistics. 
The latest version of the World Health Organization Drug Dictionary will be used to classify 
prior and concomitant medications and therapies by therapeutic class and drug/device name. 
Prior medication/therapy is defined as those started by enrolled subjects before the date of 
first study treatment.  Concomitant medication/therapy is defined as those taken on or after 
the date of first treatment.  Prior and concomitant medications/therapies will be summarized 
using descriptive statistics. 


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10.4 STUDY ENDPOINTS 
10.4.1 
Primary Endpoint 
The primary endpoint will be the responder rate for jawline improvement on the ALJDS, 
which is defined as the proportion of subjects who show ≥ 1-point improvement from 
baseline on the ALJDS at the final study visit (after last VOLUMA™ treatment received), as 
assessed by the Investigator. 
10.4.2 
Secondary Endpoints 
10.4.2.1 
Allergan Loss of Jawline Definition Scale (ALJDS) 
• Change from baseline to last BELKYRA® treatment on ALJDS  
• Change from baseline to final study visit in jawline definition based on Independent 
Reviewer assessment using the ALJDS and photographic images 
10.4.2.2 
FACE-Q Questionnaires 
• Change from baseline to final study visit on the FACE-Q™ Satisfaction with Lower Face 
and Jawline module at the final study visit. 
• Change from baseline to final study visit on the FACE-Q™ Appraisal of Neck  
• Change from baseline to final study visit on the FACE-Q™ Appraisal of Area Under 
Chin  
10.4.2.3 
Clinician-Reported and Patient-Reported Submental Fat Rating Scale 
(CR-SMFRS and PR-SMFRS) 
Change from baseline to final study visit for CR-SMFRS and PR-SMFRS scores. 
10.4.2.4 
Submental Skin Laxity Grade (SMSLG) Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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. 
10.5 EFFICACY ANALYSES 
Unless stated otherwise, all efficacy analyses will compare post-treatment assessment values 
to the subject’s corresponding baseline assessment value. 
10.5.1 
Primary Efficacy Analysis 
Responder rate for jawline severity, which is defined as the proportion of subjects who show 
≥ 1-point improvement from baseline on the ALJDS compared to baseline assessment at the 
final study visit (after last VOLUMA™ treatment received) will be summarized by the 
number and percentage of subjects and exact 95% confidence interval will be provided.   
10.5.2 
Secondary Efficacy Analysis 
The secondary efficacy endpoints will be analyzed similar to the primary efficacy endpoint. 
The change from baseline to the exit visit in each of the FACE-Q™ modules overall Rasch-
transformed scores will be analyzed using paired t-test (or Wilcoxon signed-rank test if 
normality assumptions are not met). 
 
 
 
 
 
10.5.4 
Missing Data 
Missing data strategy will be documented in the study SAP. 
10.5.5 
Adverse Events 
AEs will be coded using MedDRA version 17.0 or higher, and presented by system organ 
class and preferred term.  Treatment-emergent AEs will also be summarized by SAEs, AE 
severity, AE leading to treatment or study early termination, and relationship to study 
drugs/devices.  Summary tables will be presented by the study treatment drug. 
10.6 INTERIM ANALYSES AND DATA MONITORING 
No interim analysis is planned. 
10.7 DETERMINATION OF SAMPLE SIZE 
In the 2 US pivotal trials for BELKYRA® (ATX-101-11-22 and ATX-101-11-23), 79.1% and 
77.9% of subjects, respectively, demonstrated a ≥ 1 grade improvement in the CR-SMFRS 12 
weeks following the final treatment.  In the VOLUMA-002 study, the responder rate defined 
as the percentage of subjects whose overall mid-face volume deficit improved (i.e., decreased) 
by ≥ 1 point from baseline based on the average of the 2 blinded Evaluating Investigators’ 


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assessments at Month 6 using the 6-point Mid-Face Volume Deficit Scale, was 85.6% at 
Month 6. 
In this study, as BELKYRA® and VOLUMA™ will be administered sequentially, the 
estimated responder rate for the jawline severity is set lower at 78.0%. 
The sample size will provide reasonable precision of the estimations of the parameters of 
interests. With 40 subjects, the half-width of the 95% confidence interval for the proportion of 
subjects who show ≥ 1-point improvement from baseline on the ALJDS compared to baseline 
assessment at the final study visit (after last VOLUMA™ treatment received) is 14.0% 
assuming the improvement rate is 78%. To account for 20% study drop-out rate and/or 
subjects who may not continue for the VOLUMA™ treatment, 50 subjects will be enrolled. 
 
The sample size calculation was performed using the PASS 2008 software for one single 
proportion. 
10.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS 
Any changes to the conduct or planned analyses will be handled via protocol or SAP 
amendment, respectively. 
11 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS 
11.1 DECLARATION OF HELSINKI 
The Investigator will ensure that this study is conducted in accordance with the most recent 
revision of the Declaration of Helsinki. 
11.2 GOOD CLINICAL PRACTICE  
The study will be conducted according to the study protocol and to Standard Operating 
Procedures that meet the guidelines provided by the International Conference on 
Harmonization (ICH) for Good Clinical Practice in clinical studies.  
11.3 INDEPENDENT ETHICS COMMITTEES 
Before implementing this study, the protocol, the proposed subject informed consent forms, 
and other information for the subjects must be reviewed by a properly constituted committee 
or committees responsible for approving clinical studies.  The IEC/IRB written, signed 
approval letter/form must contain approval of the designated Investigator, the protocol 
(identifying protocol title, date and version number), the subject informed consent form 
(date, version), and any other subject facing documents. 
11.4 REGULATORY AUTHORITY APPROVAL 
The study is utilizing all products as per their licensed usage and indications.  No regulatory 
approval will be required.  


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11.5 PROTOCOL COMPLIANCE 
The Investigator is responsible for compliance with the protocol at the investigational site. 
The Investigator is also responsible for reporting all issues of protocol non-compliance to the 
respective IEC/IRB and to the Sponsor.  A representative of the Sponsor 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 study device accountability records for compliance with 
the protocol, e.g., subject eligibility criteria, volume of product injected, procedures 
performed, and follow-up visit schedule. 
11.6 INFORMED CONSENT 
Written informed consent is to be obtained from the subject prior to any study-related 
procedures or change in treatment.  Privacy-related documentation will also be obtained from 
each subject prior to enrollment into the study, in accordance with relevant country and 
applicable local privacy requirements. 
All subjects will be required to participate in the consent process.  During the consent 
process, the person obtaining consent will inform the subject of all elements of informed 
consent.  The Investigator must ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the clinical trial.  
Subjects must also be notified that they are free to withdraw from the clinical trial at any time 
without prejudice to future care.  The subject should be given the opportunity to ask 
questions and allowed time to consider the information provided.   
If the ICF is revised for any reason (e.g., protocol amendment or new safety data), the revised 
ICF must be reviewed and approved by the IEC/IRB.  The revised ICF is not considered 
effective until approved by the IEC/IRB.  All subjects currently enrolled in the clinical trial 
must sign the revised ICF.  Subjects enrolled in the clinical trial after the revised ICF has 
been approved by the IEC/IRB will sign the revised version. 
11.7 SUBJECT CONFIDENTIALITY AND DISCLOSURE 
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 drug may ultimately be marketed, but the 
subject’s name will not be disclosed in these documents.  The subject’s name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the US 
Food and Drug Administration (FDA) if they inspect the study records.  Appropriate 
precautions will be taken to maintain confidentiality of medical records and personal 
information. 
In accordance with Health Insurance Portability and Accountability Act 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. 
11.8 SPONSOR MONITORING OF STUDY DOCUMENTATION 
A representative of the Sponsor will monitor the study on a periodic basis.  The 
determination of the extent and nature of monitoring will be based on considerations such as 


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the objective, purpose, design, complexity, size, and endpoints of the study.  This will be 
detailed in the Study Monitoring Plan.  
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the Investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
11.9 STUDY DOCUMENTS 
The Investigator must maintain source documents for each subject in the study, including all 
demographic and medical information etc., and keep a copy of the signed and dated informed 
consent forms.  All information on the eCRFs must be traceable to these source documents in 
the subject’s file. 
11.10 COLLECTION OF STUDY DATA 
This study will be conducted in compliance with the US FDA Code of Federal Regulations (21 
CFR Part 11).  The Investigator is responsible for ensuring that study data are properly 
recorded on each subject’s eCRFs and related documents.  An Investigator who has signed 
the protocol signature page shall sign for the eCRFs to attest 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 (i.e., an audit trail shall be maintained); 
this applies to both written and electronic changes and corrections. 
11.11 ARCHIVING OF STUDY DOCUMENTS 
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 should 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. 
11.12 DISCLOSURE OF INFORMATION 
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 


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centers, no individual publications will be allowed prior to completion of the final report of 
the multicenter study except as agreed with Allergan. 


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12 REFERENCES 
1. Bass LS. Injectable filler techniques for facial rejuvenation, volumization, and 
augmentation. Facial Plast Surg Clin North Am 2015;23:479-488. 
2. Coleman KM, Coleman WP III, Benchetrit A. Non-invasive, external ultrasonic lipolysis. 
Semin Cutan Med Surg 2009;28:263–267. 
3. Ersek RA. Evaluation of new ultrasound technologies should include assessments of 
peripheral nerve function. Aesthet Surg J 2011;31:837. 
4. Goodman GJ. An interesting reaction to high- and low-molecular weight combination 
hyaluronic acid. Dermatol Surg 2015;41 Suppl 1;S164-S166. 
5. Humphrey S, Sykes J, Kantor J, Bertucci V, Walker P, Lee DR et al. ATX-101 for 
reduction of submental fat: a phase III randomized controlled trial. J Am Acad Dermatol 
2016;75(4):788-797. 
6. Jones D, Flynn T. Hyaluronic acids: clinical applications. In: Jones D, editor. Injectable 
fillers: principles and practice. Oxford, UK: Wiley-Blackwell; 2010. p. 158-174. 
7. Jones DH, Carruthers J, Joseph JH, Callender VD, Walker P, Lee DR et al. REFINE-1, a 
multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with ATX-101, 
an injectable drug for submental fat reduction. Dermatol Surg 2016;42:38-49. 
8. Kamer FM, Minoli JJ. Postoperative platysmal band deformity. A pitfall of submental 
liposuction. Arch Otolaryngol Head Neck Surg 1993;119:193–196. 
9. Koehler J. Complications of neck liposuction and submentoplasty. Oral Maxillofac Surg 
Clin N Am 2009; 21:43–52, vi 
10. Leclère FM, Moreno-Moraga J, Alcolea JM, Casoli V, Trelles MA. Laser Assisted 
Lipolysis for Neck and Submental Remodeling in Rohrich Type IV Patient: Fact or 
Fiction? J Cosmet Laser Ther 2014 Oct 6:1-20. [Epub ahead of print]  
11. Mejia JD, Nahai FR, Nahai F, Momoh AO. Isolated management of the aging neck. 
Semin Plast Surg 2009;23:264–273. 
12. Patel BCK. Aesthetic surgery of the aging neck: options and techniques. Orbit 
2006;25:327–356  
13. Pelosi MA III, Pelosi MA II. Liposuction. Obstet Gynecol Clin North Am 2010;37:507–
519. 
14. Rohrich RJ, Rios JL, Smith PD, Gutowski KA. Neck rejuvenation revisited. Plast 
Reconstr Surg 2006;118(5):1251-1263. 
15. Schlessinger J, Weiss SR, Jewell M, et al. Perceptions and practices in submental fat 
treatment: a survey of physicians and patients. Skinmed 2013;11(1):27-31. 


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16. Shire JR. The importance of the prejowl notch in face lifting: the prejowl implant. Facial 
Plast Surg Clin North Am 2008;16:87-97. 
17. Sykes JM, Fitzgerald R. Choosing the best procedure to augment the chin: is anything 
better than an implant? Facial Plast Surg 2016;32:507-512. 
18. Thuangtong R, Bentow JJ, Knopp K, Mahmood NA, David NE, Kolodney MS. Tissue-
selective effects of injected deoxycholate. Dermatol Surg 2010;36(6):899-908. 
19. Wong SS, Wong SC, Yuen KY. Infections associated with body modification. J Formos 
Med Assoc 2012;111:667–681. 
 


 
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APPENDIX 14 
VERSION HISTORY 
Version 
Number 
Version 
Date 
Author 
Changes Made 
1.0 
26Jul2017 
 
Original version 
1.1 
17Aug2017 
 
Non-substantial changes: 
 
 
 
 
 
 
 
 
 
2. Sections 5.1.1, BELKYRA – added 
statements regarding number of vials 
contained in kits 
3. Sections 5.1.4, Treatment Assignments – 
added statements regarding partially used kits 
and unopened vials/syringes; added 
statements regarding number of vials 
contained in kits  
4. Section 5.2.1 Storage – added instruction for 
inventory at vial and syringe level 
5. Section 5.3.2 VOLUMA – specified that 
cannula used for VOLUMA treatment is per 
Allergan guidance. 
 
1.2 
26Sep2017 
 
Non-substantial changes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1.3 
21Nov2017 
 
Non-substantial changes: 
1. Protocol Summary (Secondary Endpoints) 
and Sections 7.2.1 and 10.4.2.1 Allergan 
Loss of Jawline Definition Scale– added 
Independent Reviewer assessment for the 
ALJDS 
2. Section 4.4.1.1 Anesthesia – clarified “area 
of injection” such that anesthetic 
interventions apply to treatment or biopsy 
3. Section 7.1.6 Photographic Imaging – 
specified imaging to also be completed 
“within 60 minutes after VOLUMA 
treatment” for consistency with Table 1.1 
4. Section 7.1.7 Biopsy – changed biopsy 
sample size from “3-4mm” to “2mm”.  
Changed location of biopsy excision site 
from “2cm” to “approximately 1.5cm” 
 
 
 
 
2.0 
xxFeb2018 
 
Substantial Changes: 
 
 
 
 
 
 
 
 
 
 
3. Section 6.1.4 Subject Enrollment – deleted 
subject status terms and definitions 
 
 
 
 
 
  
6. Section 10.1.1 Analysis Populations; 
Protocol Summary, Statistical Methods – 
modified analysis set titles and definitions to 
be consistent with non-randomized trials. 
Non-substantial Changes: 
 
 
 
 
 
 
 
 

SAP_000.pdf: 
NCT03425253 
 
Study ID: CMO-MA-FAS-0513 
 
 
Title:  A Prospective, Open-label Study to Evaluate Sequential Treatment with BELKYRA® and Juvéderm® 
VOLUMA™ with Lidocaine for Overall Improvement in Jawline Contour 
 
Statistical Analysis Plan Version 3.0 Date: 21Feb2020 


Version 3.0, 21-February-2020 
 
Page 1 of 31 
 
Allergan 
Biostatistics 
Statistical Analysis Plan  
 
Study ID: 
CMO-MA-FAS-0513 
 
Study Title: 
A Prospective, Open-label Study to Evaluate Sequential Treatment with 
BELKYRA® and Juvéderm® VOLUMA™ with Lidocaine for Overall Improvement in 
Jawline Contour 
 
Version 3.0 
Date: 21-February-2020 
 
Prepared by: 
 
 
 
 
 
.  
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CMO-MA-FAS-0513 
Statistical Analysis Plan 
Version 3.0, 21-February-2020 
 
Page 2 of 31 
 
Contents 
Summary of Changes ............................................................................................ 4 
1.  Introduction ..................................................................................................... 5 
2.  Primary Study Objectives and Design ............................................................ 5 
2.1  Study Design ......................................................................................... 5 
2.2  Primary Objective .................................................................................. 7 
2.3  Secondary Objectives ............................................................................ 7 
2.4  Exploratory Objectives .......................................................................... 7 
3.  Analysis Populations and Data Conventions .................................................. 7 
3.1  Analysis Populations ............................................................................. 7 
 
3.3  Data Conventions .................................................................................. 9 
3.3.1  Study Day ..................................................................................... 9 
3.3.2  Imputation for Missing Measurement or Assessment Data ......... 9 
3.3.3  Imputation for Missing or Partially Missing Dates ..................... 9 
3.3.4  Study End Date for Individual Subject ...................................... 10 
3.3.5  Other Conventions ..................................................................... 11 
4.  Subject Disposition and Exit Status ............................................................. 12 
4.1  Screening Log Data ............................................................................. 12 
4.2  Disposition and Withdrawals .............................................................. 12 
5.  Demographics and Other Baseline Characteristics ...................................... 12 
5.1  Demographics ...................................................................................... 12 
5.2  Prior Medications and Therapies ......................................................... 12 
5.3  Concomitant Medications and Therapies ............................................ 13 
5.4  Medical History ................................................................................... 14 
6.  Efficacy Analyses ......................................................................................... 14 
6.1  Collection of Efficacy Measurements and Derivation of Efficacy 
Variables .............................................................................................. 15 
6.2  Efficacy Analyses ................................................................................ 16 


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6.2.1  Primary Efficacy Analysis ......................................................... 16 
6.2.2  Secondary Efficacy Analyses ..................................................... 16 
 
6.3  SubGroup Analyses ............................................................................. 19 
7.  Safety Analyses ............................................................................................. 19 
7.1  Exposure to Study Treatment(s) .......................................................... 19 
7.2  Adverse Events .................................................................................... 20 
7.3  Serious Adverse Events ....................................................................... 21 
7.4  Other Safety Analysis .......................................................................... 22 
7.5  Pregnancy ............................................................................................ 22 
7.6  Subgroup Analyses for Safety Variables ............................................. 22 
8.  Pharmacokinetic, Biomarker, Genomic, or Immunogenicity Data Analyses
 ...................................................................................................................... 22 
9.  Health Outcomes Data Analyses .................................................................. 22 
10. Interim Analyses ........................................................................................... 22 
11.  Data Collected but not Analyzed .................................................................. 23 
12. References ..................................................................................................... 23 
13. Appendices ................................................................................................... 24 
 
 
 
 
 
 
 


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Version 3.0, 21-February-2020 
 
Page 4 of 31 
 
Summary of Changes 
Version 
Number 
Version 
Date 
Author 
Changes Made 
1.0 
14-Jan-2019 
 
Initial Version 
2.0 
29-Aug-2019 
 
Changes from V1.0 to V2.0 include:  
 Revisions to section 6.2.3.3 - Image 
Analysis 
 Revisions to section 7.4 - Other Safety 
Analysis 

 
 
 
 
3.0 
21-Feb2020 
 
Changes from V2.0 to V3.0 include:  
 Addition of section 6.3 - SubGroup 
Analyses 

 
 
 
 
 
 
 
 


CMO-MA-FAS-0513 
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Version 3.0, 21-February-2020 
 
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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the data analyses 
as outlined in the study protocol dated on March 21, 2018 and titled “A Prospective, Open-
label Study to Evaluate Sequential Treatment with BELKYRA® and Juvéderm® VOLUMA 
with Lidocaine (VOLUMA) for Overall Improvement in Jawline Contour”. 
 
This SAP should be reviewed in conjunction with the study protocol.  In case of any 
discrepancies in the statistics section between the protocol and the SAP, the SAP will 
supersede the protocol, as the SAP is intended to be more precise and specific.  Any 
amendment to the SAP will be made prior to database lock.  Any additional analyses 
performed but not described in the final SAP or deviations from the final SAP will be 
documented in the clinical study report. 
 
This study is a Phase IV, post-marketing study sponsored by Allergan.  It is a prospective, 
open-label, multi-center, interventional, drug and medical device study to evaluate the 
combined effectiveness of sequential BELKYRA treatments of convexity or fullness 
associated with submental fat and VOLUMA to restore volume along the mandible in 
enhancing the overall contour of the jawline.  This post-marketing study includes an 
exploratory endpoint for a Biopsy Sub-study to evaluate histological changes from baseline 
to after the final BELKYRA treatment. 
 
Approximately 50 male and female subjects will be treated in the study, out of which 
approximately 10 subjects are expected to participate in the Biopsy Sub-study.  Data 
collection on participants may continue from a minimum of 12 weeks and up to 
approximately 64 weeks, depending on the number of BELKYRA injections needed and 
participation in the Biopsy Sub-study. 
 
There will be no interim analysis.  One final analysis is planned for this study.  The final 
analysis will be performed upon the completion of the study.  Database lock will be executed 
for the final analysis. 
2. 
Primary Study Objectives and Design 
2.1 
Study Design 
This Phase IV trial is a prospective, open-label, multi-center, interventional, drug and 
medical device, post-marketing study.  Each subject will act as his/her own control.  Subjects 
will attend a minimum of 6 and maximum of 18 visits. 
 


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Approximately 50 male and female subjects will be treated.  Approximately 10 of them are 
expected to participate in the Biopsy Sub-study. 
 
All subjects will sign an informed consent form (ICF) at the Screening Visit (Visit 1).  
Eligible subjects will undergo treatment with BELKYRA injected into subcutaneous pre-
platysma fat tissue in the submental area (Visit 2.1/Day 0).  Seven days after the initial 
BELKYRA treatment (Visit 3.1), the subject will return to the clinic for a safety evaluation.  
Eight weeks after BELKYRA treatment, the submental profile will be evaluated by the 
investigator and the subject. If further BELKYRA intervention is required to achieve the 
desired result, subjects may receive up to 5 optional BELKYRA treatments (Visits 2.2 to 
2.6), for a maximum of 6 treatments including the initial required treatment.   Subjects who 
receive optional BELKYRA treatments will be contacted by telephone 7 days after treatment 
for safety evaluation (Visits 3.2 to 3.6).  The submental profile will be assessed as described 
8 weeks after each BELKYRA treatment, and a decision made if further BELKYRA 
treatments are desired.  
 
When the investigator and the subject agree that no further BELKYRA intervention is 
required to achieve the desired result, the subject may receive VOLUMA treatment (Visit 4).  
Fourteen days after VOLUMA treatment, subjects will return to the clinic (Visit 5) and the 
investigator will assess whether a VOLUMA touch up treatment is to be performed.  All 
subjects will attend a final exit visit (Visit 6) which is 4 weeks after the last VOLUMA 
treatment (Visit 4 if no touch-up done or Visit 5, if touch-up was performed). 
 
Subjects will have the option of participating in a Biopsy Sub-study. Participation in the sub-
study is voluntary and will not affect the subject’s eligibility to participate in the main study.  
Biopsy samples will be collected from the submental region at 2 time points: Visit B1 will 
occur at least 4 weeks before the first BELKYRA treatment (at Visit 2.1); Visit B2 will occur 
8 weeks after the last BELKYRA treatment and at least 4 weeks prior to VOLUMA treatment 
(at Visit 4).  Histological changes from baseline to after final BELKYRA treatment(s) will be 
evaluated. 
 
 
 
 
 
 
 


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2.2 
Primary Objective 
The primary objective of the study is to evaluate the combined effectiveness of sequential 
BELKYRA treatments on submental fat (SMF) and VOLUMA on restoring mandible volume 
to enhance the overall contour of the jawline. 
 
2.3 
Secondary Objectives 
 To evaluate the investigator’s and subject’s assessment of aesthetic improvement of 
the lower face and jawline. 
 
 
 
 
3. 
Analysis Populations and Data Conventions 
3.1 
Analysis Populations 
To adequately describe the statistical analyses, three analysis populations are defined as 
follows: 
 Full Analysis Set (FAS): Consists of all subjects who received BELKYRA. 
 Evaluable Set (ES): Consists of the FAS subjects who received both BELKYRA and 
VOLUMA and a post-treatment efficacy assessment at Visit 6 (Exit Visit). 
 Safety Analysis Set (SAS): Consists of all subjects who consented to participation. 
Includes subjects who are defined as FAS subjects and those subjects who underwent 
biopsy procedure but did not receive the BELKYRA treatment.  This population will 
be used for safety analyses. 
 
Unless specified otherwise, the FAS will be used for summary of subject disposition, 
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assessed up to the end of BELKYRA treatment; the Evaluable Set will be used for the 
efficacy analyses of endpoints that are assessed at the final study visit, and the Safety 
Analysis Set will be used for safety analyses.  
 
Note that in the context of the SAP (including the TFL mockup shells), subjects in the safety 
analysis set are called safety subjects, and subjects in the evaluable set are called evaluable 
subjects.  Also, the terms of full analysis set, safety analysis set and evaluable set mentioned 
in the protocol are used interchangeably with full analysis population, safety analysis 
population and evaluable population respectively.  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3 
Data Conventions 
3.3.1 Study Day 
For each subject, the reference start date (also referred to as Day 0 per the protocol) is the 
date when the subject receives his/her first injection of BELKYRA treatment at Visit 2.1.  
Study day will be calculated using visit date and the reference start date as follows: (1) study 
day = (visit date – reference start date + 1), for any visit date ≥ reference start date.  (2) study 
date = (visit date – reference start date), for any visit/time point date < reference start date. 
 
3.3.2 Imputation for Missing Measurement or Assessment Data 
There is no imputation for missing values for post-baseline measurements or assessments.  
All data summaries and analyses of post-baseline data will be conducted using observed 
cases. 
 
3.3.3 Imputation for Missing or Partially Missing Dates 
Any partial or missing dates occurring between the enrollment date and the exit date will be 
queried to obtain the full date prior to imputation. 
 
3.3.3.1 
For assigning treatment-emergent AEs (TEAEs), and prior and concomitant 
medications 
The followings rules will be applied for partial or missing start dates:  
 If the day is missing, the first day of the given month will be used unless the month 
and year are the same as the month and year of enrollment, in which case the date of 
enrollment will be used. Note that the enrollment date for the subjects of the biopsy 
sub-study is at Visit B1, instead of Visit 2.1.  
 If the day and month are missing, the 1st of January will be used unless the year is the 
same as the year of enrollment, in which case the date of enrollment will be used.  
 If the whole date is missing, the date of enrollment will be used. 
 


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3.3.3.2 
For calculating durations of treatments, adverse events (AEs), and 
medications 
The followings rules will be applied for partial or missing start dates:  
 If the day is missing, the 15th day of the given month will be used unless the month 
and year are the same as the month and year of enrollment, in which case the date of 
enrollment will be used. 
 If the day and month are missing, the 1st of July will be used unless the year is the 
same as the year of enrollment, in which case the date of enrollment will be used.  
 If the whole date is missing, the date of enrollment will be used. 
 
The followings rules will be applied for partial or missing end dates: 
 If the day is missing, the 15th day of the given month will be used unless: 
o the month and year are the same as the month and year of date of last contact, 
in which case the date of last contact will be used. 
o the imputed date is earlier that the start date, in which case the start date will 
be used. 
 If the day and month are missing, the 1st of July will be used unless: 
o the year is the same as the year of last contact, in which case the date of last 
contact will be used.  
o the imputed date is earlier that the start date, in which case the start date will 
be used. 
 If the whole date is missing, the date of last contact will be used. 
 
Under those circumstances where missing data components will make the imputation of 
missing values problematic for calculating relevant time intervals, decisions will be made on 
a case by case basis for the pertinent analysis. 
 
No other dates will be imputed. 
3.3.4 Study End Date for Individual Subject 
Study end date for individual subject is defined as the date of his/her exit visit.  Note that a 
subject who exits early from the study for whatever reasons will be invited to attend exit visit 
for data collection.   
 


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3.3.5 Other Conventions 
Summary statistics (used interchangeably with the term “descriptive statistics”) for 
continuous data include sample size (N), mean, standard deviation (SD), median, minimum, 
and maximum.  Categorical variables will be summarized using sample size (N), frequency 
and percentages of patients.  In calculating the percentage, unless specified otherwise, the 
count of subjects “at risk” will be used as denominator.  Ordinal variables will be handled as 
categorical variables in terms of presenting summary statistics.   
 
Subject’s demographic and baseline characteristics, including height, weight, Fitzpatrick skin 
type and Allergan Jowl Fat Rating Scale (AJFRS) will be collected at Visit 1 (Screening) and 
the value at Visit 1 (Screening) will be used as baseline value.  For efficacy parameters, such 
as Allergan Loss of Jawline Definition Scale (ALJDS), CR (Clinician-Reported) and PR 
(Patient reported) Submental Fat Rating Scale (SMFRS) scores, Submental Skin Laxity 
Grade (SMSLG) score, FACE-Q™ satisfaction with lower face and jawline score; FACE-
Q™ appraisal of neck; and FACE-Q™ appraisal of area under chin, baseline value is defined 
as the assessment outcome taken at Visit 1 (Screening).  
 
 
). 
 
Change from baseline is calculated as ‘visit value minus baseline value’.  Percentage change 
from baseline is calculated as change from baseline divided by baseline value, then 
multiplied by 100.  If baseline value is zero, percentage change from baseline will be 
undefined or not evaluable (NE).  If baseline value is missing, percentage change from 
baseline will be missing.   
 
Data will be pooled across clinical sites/centers for all analyses. 
 
The International System of Units (Système international d'unités or SI) is the current 
international standard metric system.  The SI units will be used for the reporting in all 
Tables/Figures/Listings for this study. 
 
All statistical analysis and reporting will be performed using 
. 
 


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4. 
Subject Disposition and Exit Status 
4.1 
Screening Log Data 
Subject eligibility criteria (including both inclusion and exclusion criteria) and date of 
informed consent will be listed for all the subjects screened.  Note that date of informed 
consent will be included in the subject disposition listing. 
 
4.2 
Disposition and Withdrawals 
The number of subject enrolled and the number and percentage of subjects completed and 
discontinued together with the reasons for discontinuation will be summarized for FAS.  The 
number and percentage of subjects included, and reasons for exclusion, from each of the 
analysis sets will be presented as well. 
 
Subject disposition (including date of and reasons for early discontinuation from study) will 
be listed for the FAS.  
 
5. 
Demographics and Other Baseline Characteristics 
5.1 
Demographics 
All subject demographic and baseline characteristic data will be summarized using 
descriptive statistics for the full analysis population and/or the evaluable population 
whenever appropriate. 
 
Age (years) captured at screening visit will be summarized as a continuous variable.  Other 
continuous variables to be presented include weight, height and body mass index.  
Categorical or ordinal variables to be presented include sex, race, AJFRS on right and left 
sides, and Fitzpatrick skin type. 
 
All demographic data will be listed.  
 
5.2 
Prior Medications and Therapies 
Prior medications/therapies are defined as any medication/therapy which is administered any 
time prior to the first BELKYRA treatment at Visit 2.1 (Day 0) regardless of when the 
medication stops. 
 


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Partial or missing medication start dates will be handled as per Section 3.3.3 of the SAP.  
 
Prior medications/therapies will be coded by the Anatomical Therapeutic Chemical (ATC) 
classification system according to the latest World Health Organization (WHO) Drug 
Dictionary Enhanced WHODDE.  Medications/therapies will be summarized by ATC class 
(level 2) and subclass preferred term (PT) for all patients in the safety population.  
 
Summary tables will show the frequency count and percentage of patients with at least 1 
usage of medication/therapy on the subclass level within each ATC class, sorted 
alphabetically.  Percentages will be calculated using the number of patients in the safety 
population as the denominator. 
 
All prior medications/therapies will be listed. 
 
5.3 
Concomitant Medications and Therapies 
Concomitant medication/therapy is defined as any medication/therapy which is administered 
any time on or after the initial BELKYRA treatment at Day 0, regardless of when the 
medication starts or stops.  An episode of medication can be classified into both of prior and 
concomitant medication/therapy based on how the start and stop date of the medication are 
relative to the first BELKYRA treatment visit.  
 
Partial or missing medication start and end dates will be handled as per Section 3.3.3. 
 
Any concomitant medication will be recorded collected at each visit, including the 
medication name, dose, unit, frequency, route of administration, indication, and medication 
start and end dates. 
 
Concomitant medications/therapies will be coded by the ATC classification system according 
to the latest WHODDE.  Medications will be summarized by ATC class (level 2) and 
subclass (PT) for all subjects in the safety population.  
 
Summary tables will show the frequency count and percentage of patients with at least 1 
usage of medication on the subclass level within each ATC class, sorted alphabetically.  
Percentages will be calculated using the number of patients in the safety population as the 
denominator. 
 
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5.4 
Medical History 
Descriptions of medical history findings will be coded using latest Medical Dictionary for 
Regulatory Activities (MedDRA).  Medical history will be summarized for the safety 
population by the number and percentage of patients within each system organ class (SOC) 
and PT, sorted descending by overall frequency. 
 
Medical history will be listed for all patients in the safety population.  Medical history data 
listings will be sorted by patient number, start date, SOC, PT and verbatim term. 
 
6. 
Efficacy Analyses 
For this post-marketing study, efficacy data are collected at three critical time points, namely, 
Baseline (prior to Visit 2.1/Day 0), Visit 4 (end of BELKYRA treatment, prior to VOLUMA 
treatment), and final study visit (Exit Visit 6; end of VOLUMA treatment). The three critical 
time points will be referenced in most of the statistical analyses for this study.  
 
 
 
Efficacy analyses will be conducted to evaluate the combined effectiveness of sequential 
treatments with BELKYRA and Juvéderm VOLUMA on the following parameters: Allergan 
Loss of Jawline Definition Scale (ALJDS), CR (Clinician-Reported) and PR (Patient 
reported) Submental Fat Rating Scale (SMFRS) scores, Submental Skin Laxity Grade 
(SMSLG) score, FACE-Q™ satisfaction with lower face and jawline score; FACE-Q™ 
appraisal of neck; and FACE-Q™ appraisal of area under chin, and investigator and subject 
 
  
 
Efficacy analyses to evaluate the effect of BELKYRA treatment will be conducted at  
 Visit 4 (after last BELKYRA treatment) from baseline on ALJDS score, SMSLG 
score, FACE-Q™ satisfaction with lower face and jawline score; FACE-Q™ 
appraisal of neck score; FACE-Q™ appraisal of area under chin score.  
 Visit 2.x (after each treatment of BELKYRA) from baseline on CR and PR SMFRS 
scores; 
 Visit B2 (after the last BELKYRA treatment) from Visit B1 (before the first 
BELKYRA treatment) for histological changes in the submental tissue  
 


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All efficacy analyses will be based on the evaluable population (for combined effectiveness 
assessments); and on the full analysis population (for BELKYRA treatment evaluation). 
 
6.1 
Collection of Efficacy Measurements and Derivation of Efficacy 
Variables 
The following measurements and variables are of the efficacy interests.  Data on Submental 
convexity or fullness and Jawline contour assessments, including ALJDS (investigator and 
independent reviewer), CR-SMFRS, PR-SMFRS, SMSLG and FACE-Q™ Satisfaction with 
lower face and jawline score/Appraisal of Neck/Appraisal of Area under Chin are collected at 
baseline (Visit 2.1/Day 0), Visit 4 (end of BELKYRA treatment, prior to VOLUMA 
treatment), and final study visit (Visit 6; end of VOLUMA treatment).  
 
 
). 
 
 Measurement: ALJDS by investigator and by independent reviewer;  
Variables: Change on ALJDS from baseline (numeric variable on the value of right 
side; and value of left side); and having had at least 1-point improvement from 
baseline (binary variable).  Improvement is defined as having had negative change 
from baseline.  
 
 Measurement: CR-SMFRS;  
Variables: Change on CR-SMFRS from baseline (numeric variable).  Improvement is 
defined as having had negative change from baseline.  
 
 Measurement: PR-SMFRS;  
Variables: Change on PR-SMFRS from baseline (numeric variable).  Improvement is 
defined as having had negative change from baseline.  
 
 Measurement: SMSLG;  
Variables: Change on SMSLG from baseline (numeric variable).  Improvement is 
defined as having had negative change from baseline.   
 


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 Measurement: FACE-Q™ lower face and jawline;  
Variables: Change on FACE-Q™ lower face and jawline from baseline (numeric 
variable on combined scores).  Improvement is defined as having had positive change 
from baseline.   
 
 Measurement: FACE-Q™ Neck;  
Variables: Change on FACE-Q™ Neck from baseline (numeric variable on combined 
scores).  Improvement is defined as having had positive change from baseline.   
 
 Measurement: FACE-Q™ Chin;  
Variables: Change on FACE-Q™ Chin from baseline (numeric variable on combined 
scores).  Improvement is defined as having had positive change from baseline.   
 
 
  
 
  
 
 
  
 
  
6.2 
Efficacy Analyses 
6.2.1 Primary Efficacy Analysis 
The primary endpoint will be the responder rate for jawline improvement on the ALJDS, 
which is defined as the proportion of subjects who show ≥ 1-point improvement from 
baseline on the ALJDS at the final study visit (after last VOLUMA™ treatment received), as 
assessed by the Investigator. It will be summarized by the number and percentage of subjects 
together with exact 95% confidence interval. The analysis of primary efficacy endpoint will 
be based on evaluable population.  
6.2.2 Secondary Efficacy Analyses 
Secondary efficacy endpoints include followings: 
6.2.2.1 
Allergan Loss of Jawline Definition Scale (ALJDS) 
 
Change from baseline to last BELKYRA® treatment on ALJDS  
 
Change from baseline to final study visit in jawline definition based on Independent Reviewer 
assessment using the ALJDS and photographic images 


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6.2.2.2 
FACE-Q Questionnaires 
• Change from baseline to final study visit on the FACE-Q™ Satisfaction with Lower Face and 
Jawline module at the final study visit. 
• Change from baseline to final study visit on the FACE-Q™ Appraisal of Neck  
• Change from baseline to final study visit on the FACE-Q™ Appraisal of Area Under Chin  
6.2.2.3 
Clinician-Reported and Patient-Reported Submental Fat Rating Scale 
(CR-SMFRS and PR-SMFRS) 
Change from baseline to final study visit for CR-SMFRS and PR-SMFRS scores. 
6.2.2.4 
Submental Skin Laxity Grade (SMSLG) Score 
The change from baseline in ALJDS, CR-SMFRS, PR-SMFRS, and SMSLG will be 
analyzed using paired t-test (or Wilcoxon signed-rank test if normality assumptions are not 
met). Descriptive statistics and 95% confidence intervals will be presented. As exploratory 
endpoints, CR- and PR SMFRS will be summarized at each Belkyra treatment visit beside 
those mentioned three critical visits’ 
 
For FACE-Q™ satisfaction with lower face and jawline score, appraisal of neck, and 
appraisal of area under chin, descriptive statistics of the Rasch transformed scale score will 
be provided.  The Rasch transformed scale score, ranging from 0 (worst) to 100 (best), is 
derived for the responses for each of the three FACE-Q™ items. The change from baseline in 
Rasch transformed scale score will be analyzed using paired t-test and 95% confidence 
intervals will be presented. 
 
The distribution-free 95% CI for the estimate of median (or median change) will be 
calculated using SAS® procedure Proc Univariate.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2.3.2 
Biopsy Sub-study 
Subjects who consent to participate in the optional Biopsy Sub-study will have a biopsy 
sample collected at least 4 weeks prior to the first BELKYRA treatment at Visit B1.  A 
second biopsy sample will be collected 8 weeks following the last BELKYRA treatment at 
Visit B2.  Biopsy samples, approximately 2 mm, will be excised from the submental area 
approximately 1.5 cm from the submental crease and 1.5 cm left and right of midline. 
 Objective: Evaluate changes from baseline to last BELKYRA® treatment based on 
histological evaluation of the submental tissue biopsies. 
 Analysis: For each biopsy sample, mean levels of pro-collagen I, collagen I, collagen 
III, and elastin will be evaluated.  For each subject, changes in expression from 
baseline to after final BELKYRA® treatment will be calculated for each marker.  The 
mean change across all subjects for each marker will be determined. Statistical 
comparisons from baseline to after final BELKYRA® treatment (based on mean 
change) may be performed to determine the significance of these observations. 
 
Refer to Appendix I for Analysis Plan of Biopsy Data 
 
6.2.3.3 
Image Analysis 
Standardized facial photographic images using the VECTRA M3 camera system will be 
captured at the investigative sites prior to each study treatment (BELKYRA and VOLUMA), 
within 60 minutes of VOLUMA treatment and at the end of study visit.  Once the images are 
submitted to and received at Canfield Scientific, the images will be staged into its digital monitoring 
system (DMS) and available for review by the Clinical Services Project Management Team 
(CSPMT).  The CSPMT member assigned to monitor the study will review all the images for 
photographic quality. 
 
All images selected for analysis will be assigned a random tracking number by the CSPMT 
which will blind the Image Analysis Technicians (IATs) to information such as Subject 
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Image Analysis (IA) using Canfield Scientific software or scripts will be performed on two 
dimensional (2D) and three dimensional (3D) images by the IAT(s) on a rolling basis. to 
provide left and right jawline and submental volume, submental surface area, submental 
strain, and submental direction movement as well as facial angle measurements on the frontal 
view image.  The 3D image analysis data will measure major and minor strain, displacement 
in the x, y, and z-directions, and surface area within the submental area of interests (AOI); 
while the 2D image analysis data will measure subject’s two facial angles and submental 
angle. 
 
Descriptive statistics will be provided for the 3D and 2D image analysis data. 
 
Refer to Appendix II for Analysis Plan of Imaging Data 
6.3 
SubGroup Analyses 
As males and females may have differing expectations and perceptions of aesthetic 
improvement, assessment outcomes of efficacy data will be analyzed by gender. 
 
7. 
Safety Analyses  
All safety analyses will be based on the safety population.  Safety will be assessed primarily 
in terms of the frequency count and the binominal incidence rate of the AEs of interest.  The 
binomial incidence rate for a given event of interest during a certain period is defined as the 
number of unique patients who have experienced the event of interest in the period divided 
by the number of patients in the safety population, then multiplied by 100.  Note that, for the 
calculation of the incidence rate, the numerator will be counted at subject level.  Specifically, 
if a subject has experienced the event(s) of interest (at a given summarization level) more 
than once during the period, he/she will be counted only once into the numerator.  The total 
number of events will also be presented. The 95% confidence intervals (CIs) for binomial 
incidence rate per the Clopper and Pearson exact method (via SAS procedure Proc Freq) will 
also be calculated and presented.   
7.1 
Exposure to Study Treatment(s) 
Treatment duration in days will be calculated as: (Date of the last treatment session – Date of 
the first treatment + 1) for study drugs BELKYRA and/or VOLUMA.  Treatment duration 
will be summarized using descriptive statistics.  The number of the sessions of BELKYRA 
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descriptive statistics.  The total injection volume (mL) of BELKYRA and VOLUMA will be 
calculated and summarized, as well as treatment specific injection volumes.  
 
Partial or missing start/end dates will be handled as per Section 3.3.3.2. 
 
All treatment data will be listed. 
 
7.2 
Adverse Events 
Adverse events (AE) will be coded using MedDRA v20.1 or later to give a PT and a SOC 
term for each event. 
 
An AE is defined as any untoward medical occurrence in a clinical investigational patient 
administered a pharmaceutical (investigational) product or any undesirable physical, 
psychological or behavioral effect experienced by a subject during his/her participation in a 
study, in conjunction with the use of the device  and which does not necessarily have to have 
a causal relationship with this treatment.   
 
All AEs will be included in by-subject AE listings.  A separate listing will be created with all 
the distinct levels of SOC and PT, and the verbatim investigator description reported in the 
study.  Sorting will be by earliest observed SOC, PT within SOC and then verbatim 
description. 
 
A treatment-emergent adverse event (TEAE) is a post-baseline AE where (i) there is no pre-
treatment AE of the same MedDRA primary SOC and PT; or (ii) the maximum severity 
during the post-baseline period is greater than the maximal severity of any pre-treatment AE 
of the same MedDRA primary SOC and PT during the enrollment visit.  Note that the post-
baseline period of the study starts upon the initiation of the BELKYRA treatment at Visit 
2.1/Day 0.  
 
Partial or missing AE start dates will be handled as per Section 3.3.3.1. 
 
An overall summary of frequency count and the binomial incidence rate with associated 95% 
CIs will be presented to describe the incidents of TEAEs.  Note that 95% CIs of the binomial 
incidence rate will be presented for the overall summary analyses of TEAEs, but not for the 
by-visit analyses.  Percentages and corresponding 95% CIs will be displayed to 1 decimal 
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Each type of AE will be tabulated by SOC and PT within SOC.  The SOC and PT within 
SOC will be sorted by descending frequency.  Number of subjects with percentage and 
number of events will be presented based on SOC and PT.   
 
The incidence of all TEAEs by SOC and PT will be presented for the following categories: 
 Any TEAE 
 Any TEAE related to BELKYRA 
  Any TEAE related to VOLUMA 
 Any TEAE related to anesthesia 
 Any TEAE related to study procedure 
 Any TEAE related to BELKYRA/VOLUMA and leading to discontinuation of 
treatment with BELKYRA/VOLUMA 
 Any TEAE by maximum severity 
 
The following listing will be provided: 
 Listing of all TEAE 
7.3 
Serious Adverse Events 
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect.  While an unanticipated adverse device effect (UADE) is any device-
related SAE that meets one or more of the criteria listed in the Sec. 9.1.3 of the Protocol in 
page 49.   
 
An overall summary of frequency count and the binomial incidence rate with associated 95% 
CIs will be presented to describe the incidents of treatment emergent SAEs.  Note that 95% 
CIs presented are for the overall summary analyses of SAE, but not for the by-visit analyses.  
Percentages and corresponding 95% CIs will be displayed to 1 decimal place.   
 
The incidence of all treatment-emergent SAEs by SOC and PT within SOC will be presented 
for the following categories: 
 Any SAE 
 Any SAE related to BELKYRA 
 Any SAE related to VOLUMA 
 Any SAE related to anesthesia 
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 Any SAE related to BELKYRA/VOLUMA treatment and leading to discontinuation 
of treatment 
 Any SAE by maximum severity 
 
7.4 
Other Safety Analysis 
Injection Site Reactions (ISR) following treatment with dermal fillers (VOLUMA) will be 
analyzed using the AE terms captured in the patient diary (i.e.  ISR Diary).  
ISR events will be tabulated by PT and sorted by descending frequency.   If a subject has 
multiple occurrences (start and stop) of an event associated with a specific SOC and PT, a 
patient will only be counted once in the incidence count. The total number of events will also 
be presented. 
 
An overall summary of frequency count and the binomial incidence rate with its associated 
95% CIs will be presented to describe ISRs. 
 
The 95% CIs for the binominal incidence rate will be calculated using the Clopper and 
Pearson exact method. 
 
7.5 
Pregnancy 
All positive results of pregnancy tests will be listed. 
 
7.6 
Subgroup Analyses for Safety Variables 
Not applicable. 
 
8. 
Pharmacokinetic, Biomarker, Genomic, or Immunogenicity Data Analyses 
Not applicable. 
 
9. 
Health Outcomes Data Analyses 
There are no health outcomes analyses planned for this study.  
 
10. 
Interim Analyses 
There is no interim analysis planned for this study. 
 


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11. 
Data Collected but not Analyzed 
Not Applicable. 
 
12. 
References 
 
 
 
Allergan’s Study Protocol 
Study Number 
Study Title 
CMO-MA-FAS-0513 
A Prospective, Open-label Study to Evaluate Sequential 
Treatment with BELKYRA® and Juvéderm® VOLUMA™ 
with Lidocaine for Overall Improvement in Jawline Contour 
 
 
 


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13. 
Appendices 
 
 


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