Clinical trial NCT04609020
Conditions: Facial Rhytides Skin Folds Loss of Volume and Skin Quality
Sponsor: Allergan
Start date: 2023-02-15; Completion date: 2024-05-10
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to quantify the psychological, social, and emotional impact of comprehensive aesthetic treatment with a portfolio of the Sponsor's products by measuring the change in subject's satisfaction with facial appearance from baseline (before any treatment) to the final study visit

Detailed description:

Arms: arm 1: All treatments will be administered according to the respective label and according to an agreed upon treatment plan between the subject and Health Care Provider. If required: HarmonyCA Lidocaine will be administered at Visit 1, Juvéderm filler injections (JUVÉDERM VOLBELLA with Lidocaine, and/or JUVÉDERM VOLIFT with Lidocaine, and/or JUVÉDERM VOLUMA with Lidocaine, and/or JUVÉDERM VOLITE with Lidocaine and/or JUVÉDERM VOLUX with Lidocaine) will be administered at Visit 3, BOTOX will be administered at Visit 5. Touch-ups may be performed as required by subject's treatment plan after each study visit.
Interventions: intervention 1: JUVÉDERM intervention 2: BOTOX intervention 3: HArmonyCA Lidocaine
Intervention descriptions: intervention 1: JUVÉDERM VOLBELLA with Lidocaine Treatment of any fine lines and medium-sized skin depressions. Can also be used for enhancement and pouting of the lips to correct structural defects such as asymmetry, contour deformities, volume loss. JUVÉDERM VOLIFT with Lidocaine Intended for the treatment of any deep skin depressions due to conditions such as premature aging. Can also be used for face contouring and volume restoration to correct facial structural defects such as asymmetry, contour deformities, volume loss in the lips, cheeks, chin, lower face. JUVÉDERM VOLUMA with Lidocaine Intended to restore volume of the face JUVÉDERM VOLITE with Lidocaine Intended for treatment, by filling, of superficial cutaneous depressions such as fine lines and for additional improvement of skin quality attributes such as hydration and elasticity. JUVÉDERM VOLUX with Lidocaine Intended to restore and generate facial volume in chin and mandible areas intervention 2: Indicated for the treatment of hyperkinetic facial lines. intervention 3: HArmonyCa Lidocaine injectable gel is a dermal filler intended for facial soft tissue augmentation.

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Study Protocol 
HARMONY Brazil: Prospective, Multi-site, Study to Evaluate 
Subject Satisfaction with Facial Appearance Overall and the 
Aesthetic and Psychosocial Impact of Combined Facial 
Treatment 
CMO-MA-FAS-0580 
Version 2 
 
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Drug Development Phase: 
Phase 4, Post marketing 
Investigational Products: 
BOTOX®, JUVÉDERM® VOLITE® 
 
, JUVÉDERM® VOLBELLA® with 
Lidocaine, JUVÉDERM® VOLIFT® with 
Lidocaine, JUVÉDERM® VOLUMA® with 
Lidocaine, JUVÉDERM® VOLUX® with 
Lidocaine; HArmonyCa  Lidocaine 
Indications: 
Hyperkinetic Facial Lines, Deep Skin 
Depressions, Face Contouring, Volume 
Restoration, Superficial Cutaneous Depressions,  
Improvement of Skin Hydration and Elasticity, 
Facial Soft Tissue Augmentation 
Sponsor: 
AbbVie Inc. 
1 North Waukegan Road 
North Chicago, IL 60064 
USA  
Version and Date 
Version 2, 18-Oct-2021 
Conduct: In accordance with the ethical principles that originate from the Declaration of 
Helsinki and that are consistent with International Council for Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. 
CONFIDENTIAL INFORMATION 
This document is the sole property of the Sponsor. 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 the Sponsor. 
 
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Protocol Approval Signature Page 
Sponsor: AbbVie Inc.  
 
I have read and understand the contents of this clinical protocol for Study No. 
CMO-MA-FAS-0580 dated 18-Oct-2021 and agree to meet all obligations of the Sponsor as 
detailed in all applicable regulations and guidelines. In addition, I will inform the Principal 
Investigator and all other investigators of all relevant information that becomes available 
during the conduct of this study. 
Approved By: 
 
 
October 18, 2021 
Signature 
 
Date 
 
 
Global Aesthetic Medical Affairs 
 
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Principal Investigator
 
I have read and understand the contents of this clinical protocol for Study No. CMO-MA-FAS-
0580 dated 18-Oct-2021 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 (the Sponsor has certified GCP training completed) and all applicable 
laws and regulations. 
 Maintain all information supplied by the Sponsor in confidence and, when this information 
is submitted to a Research Ethics Board (REB) 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: 
 
Clinic:  
 
Address: 
 
 
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on schedule for V7. A subject not receiving Juvéderm (V5) touch-up would continue with 
BOTOX treatment (and all study procedures) outlined for V5. 
To reduce the number of subject visits, V0 can be combined with the initial treatment visit 
(V1), if judged by the investigator to be appropriate and acceptable for the subject. Identical 
study procedures will not be repeated where the visits are combined. 
All adverse events (AEs) and injection site reactions (ISRs) will be collected from when the 
ICF is signed through to the last study visit. Serious adverse events (SAEs) will be reported 
directly to the Sponsor within 24 hours.  
Criteria for Evaluation: 
Primary Endpoint 
The primary endpoint is the change from baseline in the overall Rasch-transformed score of 
the FACE-Q Satisfaction with Facial Appearance Scale to the final study visit (V7).  
Key Secondary Endpoints 
 
-related facial appearance as measured by the change from 
baseline before any treatment in the Rasch-transformed score of the FACE-Q Aging 
Appraisal to final study visit (V7)  
 
ological well-being as measured by the change from 
baseline before any treatment in the Rasch-transformed score of the FACE-Q 
Psychological Function Scale to final study visit (V7) 
 
line before 
any treatment in the Rasch-transformed score of the FACE-Q Social Function Scale to 
final study visit (V7)  
 
baseline before any treatment in the Rasch-transformed score of the FACE-Q Satisfaction 
with Skin to final study visit (V7) 
 
-related facial appearance as measured by self-perception of 
age (SPA) at baseline before any treatment to final study visit (V7); responders are defined 
as having achieved a younger category. 
Other Secondary Endpoints 
 
5-point global aesthetic improvement scale (GAIS) at final study visit (V7) 
 
facial aesthetic improvement as measured by the 5-point 
GAIS at final study visit (V7) 
 
periorbital aesthetic appearance questionnaire (PAAQ) from baseline to final study visit 
(V7) 
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Table of Contents 
LIST OF APPENDICES ................................................................................................................15 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
LIST OF ABBREVIATIONS ........................................................................................................16 
1 INTRODUCTION ...................................................................................................................17 
2 STUDY RATIONALE ............................................................................................................19 
3 STUDY OBJECTIVES ............................................................................................................20 
3.1 
Primary Objective ........................................................................................................20 
3.2 
Secondary Objectives...................................................................................................20 
4 STUDY DESIGN.....................................................................................................................21 
4.1 
Study Design Overview ...............................................................................................21 
4.2 
Study Endpoints ...........................................................................................................22 
4.2.1 
Primary Endpoint .............................................................................................22 
4.2.2 
Key Secondary Endpoints ................................................................................22 
4.2.2.1 
FACE-Q Questionnaires ..........................................................................22 
4.2.2.2 
Self-Perception of Age Questionnaire .....................................................22 
4.2.3 
Other Secondary Endpoints .............................................................................22 
4.2.3.1 
Global Aesthetic Improvement Scale ......................................................22 
4.2.3.2 
Periorbital Aesthetic Appearance Questionnaire .....................................22 
4.3 
Safety ...........................................................................................................................23 
4.4 
Blinding and Randomization .......................................................................................23 
5 SELECTION OF SUBJECTS..................................................................................................24 
5.1 
Inclusion Criteria .........................................................................................................24 
5.2 
Exclusion Criteria ........................................................................................................26 
5.3 
Summary of Required Washout Periods ......................................................................28 
5.4 
Other Restrictions and Precautions ..............................................................................29 
5.4.1 
Prohibited Medications and/or Treatments ......................................................29 
5.4.2 
Definition of Females of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods ....................................................................................29 
5.4.3 
Special Diet or Activities .................................................................................29 
6 STUDY PLAN AND PROCEDURES ....................................................................................30 
6.1 
Study Subject Number .................................................................................................30 
6.2 
Description of Study Days ...........................................................................................30 
6.2.1 
Study Procedures for Screening Visit (V0) .....................................................33 
6.2.2 
Visit V1 and V2 (HArmonyCa Lidocaine) ......................................................33 
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6.2.3 
Visit V3 and V4 (Juvéderm) ............................................................................34 
6.2.4 
Visit V5 (Juvéderm Touch-up and BOTOX) ...................................................35 
6.2.5 
Visit V6 (BOTOX Touch-up, if needed) .........................................................35 
6.2.6 
Visit V7 (Final Study Visit) .............................................................................35 
6.2.7 
Unscheduled/Missed Visits ..............................................................................36 
7 METHODS OF ASSESSMENT AND ENDPOINTS .............................................................37 
7.1 
Clinical Scales for Treatment Inclusion Only ..............................................................37 
7.2 
Efficacy Endpoint Measurements ................................................................................37 
7.2.1 
FACE-Q ...........................................................................................................37 
7.2.2 
Self-Perception of Age Questionnaire .............................................................37 
7.2.3 
Global Aesthetic Improvement Scale ..............................................................37 
7.2.4 
Periorbital Aesthetic Appearance Questionnaire .............................................37 
8 DISCONTINUATION CRITERIA .........................................................................................38 
8.1 
Early Discontinuation of the Study ..............................................................................38 
8.2 
Early Discontinuation of Individual Subjects ..............................................................38 
9 TREATMENTS .......................................................................................................................40 
9.1 
Rescue Medications .....................................................................................................41 
9.2 
Treatment Compliance .................................................................................................41 
10 ADVERSE EVENTS ...............................................................................................................42 
10.1 
Drug Adverse Events ...................................................................................................42 
10.2 
Medical Device Adverse Events ..................................................................................42 
10.3 
Injection Site Reactions ...............................................................................................42 
10.4 
Unusual Failure in Efficacy .........................................................................................43 
10.5 
Serious Adverse Events ...............................................................................................43 
10.5.1 
Serious Adverse Events Definition ..................................................................43 
10.5.2 
Serious Adverse Event Reporting Requirements .............................................43 
10.5.3 
Serious Adverse Event Contact Information ...................................................44 
10.6 
Unanticipated Serious Adverse Device Effects ...........................................................44 
10.7 
Assessment of Adverse Events ....................................................................................45 
10.7.1 
Severity ............................................................................................................45 
10.7.2 
Relationship to Study Product .........................................................................45 
10.7.3 
Adverse Event Follow-up ................................................................................46 
10.8 
Exposure to Investigational Product during Pregnancy ...............................................46 
10.8.1 
Female Subjects Who Become Pregnant .........................................................47 
10.8.2 
Male Subjects with Partners Who Become Pregnant ......................................47 
11 STATISTICAL METHODS ....................................................................................................48 
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11.1 
General Statistical Considerations ...............................................................................48 
11.1.1 
Analysis Populations ........................................................................................48 
11.1.2 
Subgroups ........................................................................................................48 
11.2 
Demographics and Baseline Characteristics ................................................................49 
11.3 
Exposure and Concomitant Therapies .........................................................................49 
11.4 
Efficacy Analyses ........................................................................................................49 
11.4.1 
Primary Efficacy Analysis ...............................................................................49 
11.4.2 
Analysis of All Other Efficacy Endpoints .......................................................49 
11.4.3 
Missing Data ....................................................................................................49 
11.5 
Adverse Events ............................................................................................................49 
11.6 
Interim Analyses and Data Monitoring........................................................................49 
11.7 
Determination of Sample Size .....................................................................................50 
11.8 
Changes in the Conduct of the Study or Planned Analysis .........................................50 
11.9 
Exploratory Imaging Analysis .....................................................................................50 
12 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS ...............................................51 
12.1 
Declaration of Helsinki ................................................................................................51 
12.2 
Good Clinical Practice .................................................................................................51 
12.3 
Research Ethics Board .................................................................................................51 
12.4 
Regulatory Authority Approval ...................................................................................51 
12.5 
Informed Consent.........................................................................................................51 
12.6 
Subject Confidentiality and Disclosure .......................................................................51 
12.7 
Sponsor Monitoring of Study Documentation .............................................................52 
12.8 
Study Documents .........................................................................................................52 
12.9 
Collection of Study Data ..............................................................................................52 
12.10 Disclosure of Information ............................................................................................52 
12.11 Discontinuation of the Study .......................................................................................53 
12.12 Archiving of Study Documents ...................................................................................53 
13 REFERENCES ........................................................................................................................54 
14 APPENDICES .........................................................................................................................56 
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List of Appendices 
Appendix 1 
Self-Perception of Age........................................................................................57 
Appendix 2 
FACE-Q : Satisfaction with Facial Appearance ...............................................58 
Appendix 3 
FACE-Q : Expectations .....................................................................................59 
Appendix 4 
FACE-Q : Aging Appraisal ...............................................................................60 
Appendix 5 
FACE-Q : Psychological Function ....................................................................61 
Appendix 6 
FACE-Q : Social Function ................................................................................62 
Appendix 7 
FACE-Q : Satisfaction with Skin ......................................................................63 
Appendix 8 
Chemical Ingredients of the Study Products.......................................................64 
Appendix 9 
Periorbital Aesthetic Appearance Questionnaire .................................................65 
Appendix 10 
Facial Wrinkle Scale Glabellar Line ...................................................................68 
Appendix 11 
 ................................................................................77 
Appendix 12 
Facial Wrinkle Scale Forehead Lines .................................................................86 
Appendix 13 
Global Aesthetic Improvement Scale .................................................................95 
Appendix 14 
Protocol Amendment Summary of Changes Table ............................................96 
 
List of Tables 
Table 5.1 
Summary of Inclusion Criteria by Facial Area for Potential Subjects for Filler 
Treatments ..........................................................................................................25 
Table 5.2 
Products and Procedures with Washout Periods Taken by Potential Subjects 
Prior to Study Enrollment ...................................................................................28 
Table 6.1 
Schedule of Study Procedures, Treatments, and Assessments ...........................31 
Table 10.1 
Classification of Adverse Events by Intensity ....................................................45 
Table 10.2 
Guidelines for Determining the Relationship Between Adverse Event and the 
Study Product ......................................................................................................46 
 
List of Figures 
Figure 4.1 
 Overall Study Design .........................................................................................21 
 
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List of Abbreviations 
Abbreviation 
Definition 
AR 
adverse reaction 
AE 
adverse event 
BMI 
body mass index 
CaHA 
calcium hydroxyapatite 
CFL 
 (also known as lateral canthal lines in BOTOX product 
literature)  
eCRF 
electronic case report form 
FHL 
forehead lines 
FWS 
facial wrinkle scale 
GAIS 
global aesthetic improvement scale 
GCP 
Good Clinical Practice 
GLs 
glabellar lines 
HA 
hyaluronic acid 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ISR 
injection site reaction 
MAH 
Marketing Authorization Holder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
N/A 
not applicable 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
PAAQ 
periorbital aesthetic appearance questionnaire 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SPA 
self-perception of age 
USADE 
unanticipated serious adverse device effect 
 
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1 
Introduction 
The negative psychosocial impact of facial aging has been well characterized from a variety of 
perspectives (Foos 2011, Zebrowski 2008, Sobanko 2015). Facial attractiveness is a factor 
perceived to be important in many social interactions. These concerns by the aging population 
have economic, legal, social, and psychological implications for achieving overall satisfaction 
with life in general. Therefore, the motivation for seeking minimally invasive cosmetic 
intervention is multi-faceted and potentially strong for those who are conscious of their 
appearance and have concerns about their perceived age. 
The acceptance and use of minimally invasive procedures to reduce the visible signs of aging 
have increased in recent years (American Society of Plastic Surgeons 2012). Signs of aging can 
be observed in multiple regions of the face and affect all tissues. Reduced and disorganized 
collagen and elastin result in a loss of elasticity and thinning of the skin, which can manifest as 
dynamic and static facial rhytides and/or sagging, in addition to folds and wrinkles. Redistribution 
of subcutaneous fat may hollow some areas while increasing local fat deposits in others. Bony 
remodeling may alter the surface for support for all of the overlying soft tissues, which can 
accentuate sagging of the skin and other signs of aging (Farkas 2013, Kahn 2010, Yaar 2002).  
Minimally invasive strategies to improve the signs of aging include the use of botulinum toxins to 
address the presence of dynamic wrinkles as well as dermal fillers to correct skin depressions or 
folds and to restore underlying structural or fat deficiencies. Botulinum toxins have been 
approved by the Brazilian Health Regulatory Agency (Anvisa) for the treatment of hyperkinetic 
facial lines (BOTOX® Product Monograph). Onabotulinumtoxin A (BOTOX) is widely used to 
treat undesirable static and dynamic facial lines (Binder 1998, Blitzer 1993, Carruthers 1994, 
Carruthers 2004b, Fagien 2003, Sommer 2003, Stotland 2007). Hyaluronic acid (HA) based 
fillers are approved by the Brazilian Health Regulatory Agency (Anvisa) to restore volume of the 
face (Jones 2013, JUVÉDERM VOLUMA® with Lidocaine Directions for Use, Lupo 2008, 
Pinsky 2008). In addition, HArmonyCa Lidocaine contains a synthetic calcium hydroxyapatite 
(CaHA) active ingredient. CaHA has been used in the dermal filler market for more than 10 years. 
It acts via its osteoconductive potential and supports ingrowth of fibrous and vascular tissue 
(Berlin 2006). Based on the various compositions of each HA filler product and the approved 
indications, filler injections are targeted to fill wrinkles and folds in specific facial areas. 
The Brazilian Health Regulatory Agency has approved the following filler products as indicated: 
 JUVÉDERM VOLBELLA with Lidocaine is indicated for the treatment of any fine lines and 
medium-sized skin depressions due to conditions such as premature aging and for 
enhancement and pouting of the lips to correct structural defects such as asymmetry, contour 
deformities, and volume loss. 
 JUVÉDERM VOLIFT with Lidocaine is indicated for the treatment of any deep skin 
depressions due to conditions such as premature aging and for face contouring and volume 
restoration to correct facial structural defects such as asymmetry, contour deformities, and 
volume loss in the lips, cheeks, chin, and lower face. 
 JUVÉDERM VOLUMA with Lidocaine is indicated to restore volume of the face.  
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 JUVÉDERM VOLITE 
 is indicated for the treatment, by filling, of superficial 
cutaneous depressions such as fine lines and for additional improvement of skin quality 
attributes such as hydration and elasticity. 
 JUVÉDERM VOLUX with Lidocaine is an injectable implant intended to restore and 
generate facial volume in chin and mandible areas. 
 HArmonyCa Lidocaine injectable gel is a dermal filler intended for facial soft tissue 
augmentation. 
In clinical trials, each Juvéderm product mentioned above has been demonstrated to be safe and 
effective for its approved indication (Carruthers 2004a, Jones 2013, Lupo 2008, Pinsky 2008). 
Studies of implants containing CaHA, both in vitro and in vivo, showed minimal or no 
inflammatory response, foreign body or giant cell granulomatous reaction, and no systemic 
toxicity (Lemperle 2003). Subject satisfaction or a psychological benefit has been reported 
following individual product treatments in several studies (Sommer 2003, Stotland 2007, 
Ogilvie 2017). In clinical practice, however, it is more common that patients seeking aesthetic 
enhancement will receive treatment for multiple areas of concern, as deemed appropriate by their 
physician. Given the multiple, distinct signs of facial aging, a variety of modalities may be 
administered as part of an integrated treatment plan agreed upon by patient and physician. 
Few studies have characterized the humanistic benefits resulting from improvement in the signs 
of aging. A recent study investigated the impact of fillers and botulinum toxin in a pan-facial 
approach and demonstrated subject satisfaction, improved self-esteem, and a modest 
improvement in quality of life (Molina 2015). 
A more comprehensive trial, the HARMONY Study, evaluated the impact of facial treatments 
using onabotulinum A toxin (BOTOX), dermal fillers, and bimatoprost (LATISSE) for 
inadequate eyelash length 
-image, self-esteem, and overall quality of life. Using 
validated patient-reported outcome measures, the study assessed the impact of a personalized, 
multimodal, minimally invasive treatment approach in 93 subjects. The results showed 
statistically significant physical, social, and psychological benefits following treatment, 
including a 
Dayan 2016). 
The results of these studies support the potential benefits of aesthetic treatment that extends 
beyond treating lines, folds, and volume deficiencies. With the increase in the availability of 
minimally invasive tools to address signs of aging, it has become possible to take a holistic 
approach to facial rejuvenation. A pan-facial approach to treatment may yield greater overall 
benefit to patients, as it allows for a more balanced rejuvenation addressing multiple concerns. 
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2 
Study Rationale 
As often occurs, clinical practice has moved beyond what has been demonstrated in clinical trials. 
To date, no studies have evaluated the safety and impact of treatment with multiple approved 
aesthetic products. The objective of the initial HARMONY USA study was to observe overall 
aesthetic impact of treating subjects with several modalities in an attempt to achieve 
 
desired clinical outcome. The HARMONY Brazil study will expand upon the products tested, the 
facial areas treated, and the quantification of the psychological and emotional impact of the 
comprehensive aesthetic treatment provided and will ultimately be global in scope. 
In the HARMONY Brazil study, subjects will be evaluated by the investigator to receive 
BOTOX, HArmonyCa Lidocaine facial filler, and Juvéderm facial fillers (JUVÉDERM VOLITE 
, JUVÉDERM VOLBELLA with Lidocaine, JUVÉDERM VOLIFT with 
Lidocaine, JUVÉDERM VOLUMA with Lidocaine, and JUVÉDERM VOLUX with Lidocaine). 
Selected subjects will receive staged treatment with the multiple products and will be evaluated 
using validated patient-reported outcome measurements to determine the psychological and 
emotional impact of an integrated treatment approach to reduce visible signs of aging. 
The clinical hypothesis of this study is that subjects treated with a combination of BOTOX, 
HarmonyCa Lidocaine facial filler, and JUVÉDERM facial fillers will be satisfied with their 
overall facial appearance at the final study visit as measured by the change from baseline on the 
FACE-Q Satisfaction with Facial Appearance Overall Scale.  
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3 
Study Objectives 
3.1 Primary Objective 
The primary objective of this study is to quantify the psychological, social, and emotional impact 
of comprehensive aesthetic treatment with a portfolio of 
 products by measuring 
the change in subject s satisfaction with facial appearance from baseline (before any treatment) 
to the final study visit (Appendix 4 FACE-Q : Satisfaction with Facial Appearance). These 
products include BOTOX, HArmonyCa Lidocaine, and Juvéderm HA facial fillers, as described 
in Section 9. 
3.2 
Secondary Objectives 
Secondary objectives are: 
 To determine the subject s self-appraisal of  age-related facial appearance (Appendix 4 
FACE-Q©: Aging Appraisal), psychological function (Appendix 5 FACE-Q : Psychological 
Function), social function (Appendix 6 FACE-Q : Social Function) and overall satisfaction 
with skin (Appendix 7 FACE-Q  Satisfaction with Skin Questionnaire).  
 To quantify the investigator s and subject s assessment of aesthetic improvement. 
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Study Design
4.1 Study Design Overview
This Phase 4 study is a prospective, interventional, multicenter, combination medical device and
drug post marketing study. Each subject will be in the study for up to approximately 5 months
and act as his/her own control. All products will be used as per their license only. The 
investigators will perform all treatments and evaluations.
The study is planned to enroll 60 subjects consecutively at approximately 7 study sites in Brazil. 
Recruitment will also target men, who are typically under-represented in aesthetic studies. 
Detailed descriptions of all study procedures by study visit and study treatment are presented in
Table 6.1 and Section 6.
All subjects will sign an informed consent form (ICF) and begin at the screening visit (V0). 
Subjects will enter the study at V1 to begin treatment with facial fillers and will receive BOTOX 
starting at V3, as indicated in the study design diagram (Figure 4.1). In order to reduce the 
number of subject visits, Visit 0 can be combined with the initial treatment visit, if judged by the 
investigator to be appropriate and acceptable for the subject. Identical study procedures will not 
be repeated where the visits are combined.
Figure 4.1
Overall Study Design
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4.2 
Study Endpoints 
4.2.1 
 Primary Endpoint 
The primary endpoint is the change from before any treatment (baseline, V0) in the 
Rasch-transformed score of the FACE-Q Satisfaction with Facial Appearance Overall Scale to 
the final study visit (V7).  
4.2.2 
 Key Secondary Endpoints 
4.2.2.1 FACE-Q Questionnaires 
 
-related facial appearance as measured by the change from 
baseline before any treatment in the Rasch-transformed score of the FACE-Q Aging 
Appraisal to final study visit (V7)  
 
-being as measured by the change from baseline 
before any treatment in the Rasch-transformed score the FACE-Q Psychological Function 
Scale to final study visit (V7) 
 
 the change from baseline before any 
treatment in the Rasch-transformed score of the FACE-Q Social Function scale to final study 
visit (V7)  
 Subject s assessment of overall satisfaction with skin as measured by the change from 
baseline before any treatment in the Rasch-transformed score of the FACE-Q Satisfaction 
with Skin to final study visit (V7) 
4.2.2.2 Self-Perception of Age Questionnaire 
-related facial appearance by the self-perception of age (SPA) 
measure at baseline before any treatment to final study visit (V7); responders are defined as 
having achieved a younger category. 
4.2.3 
Other Secondary Endpoints  
4.2.3.1 Global Aesthetic Improvement Scale 
 Investigator
-point 
global aesthetic improvement scale (GAIS) at final study visit (V7). 
 S
improvement as measured by the 5-point 
GAIS at final study visit (V7). 
4.2.3.2  Periorbital Aesthetic Appearance Questionnaire 
 Change in subject  satisfaction with appearance of periorbital area as measured by the 
periorbital aesthetic appearance questionnaire (PAAQ) from baseline to final study visit 
(V7). 
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4.3 
Safety 
All adverse events (AEs) including injection site reactions (ISRs) will be collected from when 
the ICF is signed through to the last study visit (V7). Serious adverse events (SAEs) will be 
reported within the specified time and format directly to the Sponsor as described in 
Section 10.5. 
4.4 
Blinding and Randomization 
Blinding and randomization are not applicable. This is an open-label, single-arm study. Subjects 
are enrolled consecutively based upon subject need and all subjects are intended to receive all 
treatments. Investigators will perform all treatments and evaluations.  
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5 
Selection of Subjects 
Approximately 60 subjects will be enrolled at approximately 7 sites in Brazil. Subjects will be 
assigned to study treatment only if they meet all of the inclusion criteria and none of the 
exclusion criteria. Subjects who discontinue treatment will not be replaced. 
5.1 
Inclusion Criteria 
The following are requirements for entry into the study. 
1. 35 to 65 years of age, inclusive, at screening (male or female) 
2. Accept the obligation not to receive any other facial procedures or treatments at any time 
during the study that are not related to the study 
3. Women of childbearing potential must have a negative urine pregnancy test before each 
injectable treatment and practice a reliable method of contraception throughout the study 
4. Willing to avoid direct and prolonged sun exposure to the facial skin, which includes 
tanning beds, for the duration of the study  
5. Must qualify to receive BOTOX treatments, in at least one area, as per the approved 
Product Monograph including treatment of hyperkinetic lines for the glabellar, crow
feet, and forehead lines: 
 Glabellar injection: glabellar rhytides characterized as 2 (moderate) or 3 (severe) 
during maximum muscle contraction on the evaluation of the facial wrinkle scale 
(FWS) 
 CFLs characterized as 2 (moderate) or 3 (severe) during maximum smile on the 
evaluation of the FWS  
 FHLs of 2 (moderate) to 3 (severe) rating at maximum eyebrow elevation as 
assessed using the FWS  
6. Must qualify to receive Juvéderm dermal filler treatments as per the approved Directions 
for Use. Subjects must use at least two different Juvéderm filler products in at least two 
different aesthetic anatomic areas. A summary of inclusion criteria by facial area for 
potential subjects for filler treatments is presented in Table 5.1. 
 
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Product 
Indication 
Contra-indications 
 
in patients with impaired wound healing due to 
systemic disorders, medicinal drugs, or unhealthy or 
poorly-vascularized tissue. 
 
in patients suffering from prolonged bleeding or tissue 
healing due to medical conditions or medicinal drugs. 
 
in patients with a history of anaphylactic reactions 
and/or multiple severe allergies. 
 
in patients with a known sensitivity to steroids, or who 
are contraindicated to be treated with steroids. 
 
for injection into the glabellar or periocular areas. 
 
for injection into the lips and perioral region. 
 
for injection into regions containing foreign bodies. 
 
in patients presenting with herpes. 
 
in patients with autoimmune diseases. 
 
for injection into blood vessels and to highly 
vascularized areas. 
 
for injection into the epidermis or superficial dermis. 
 
in breastfeeding or pregnant women. 
 
in patients below the age of 18. 
 
The investigator should not inject greater than 20 mL of filler (Juvéderm and 
HArmonyCa) per 60 kg (130 lbs.) body mass per year for a single subject.   
5.2 Exclusion Criteria 
The following criteria exclude potential subjects from participating in the study: 
1. Body mass index (BMI) > 30 kg/m2 
2. Known allergy or sensitivity to the study products or their components  
3. Pregnant, lactating, or planning to become pregnant at any time during the study 
4. Received BOTOX or treatment with any other botulinum toxin product for any condition 
within 6 months before enrollment 
5. Received (or is planning to receive) anticoagulation, antiplatelet or thrombolytic 
medications (e.g., warfarin) or other substances known to increase coagulation time from 
10 days prior to injection and up to 3 days post-injection 
6. Undergone plastic surgery of the face and/or neck, tissue grafting, or tissue augmentation 
with silicone, fat, or other permanent dermal fillers, or be planning to undergo any of 
these procedures at any time during the study 
7. Has undergone temporary or semi-permanent facial or neck dermal filler treatment (e.g., 
hyaluronic acid, calcium hydroxylapatite, poly-L-lactic acid) within 12 months before 
enrollment  
8. Received mesotherapy, skin resurfacing (laser, photomodulation, intense pulsed light, 
radio frequency, dermabrasion, chemical peel, or non-ablative procedures) in the face or 
neck within 6 months prior to study enrollment 
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9. Marked facial asymmetry, brow or eyelid ptosis, excessive dermatochalasis, deep dermal 
scarring, thick sebaceous skin, or an inability to substantially lessen the resting GLs and 
CFLs/facial rhytides by physically spreading them apart 
10. Lip tattoos, facial hair or scars that would interfere with visualization of the lips and 
perioral area for the effectiveness assessments 
11. At any proposed injection site, presence of inflammation, infection at any injection site or 
systemic infection (study entry may be postponed until one week following recovery), 
noticeable acne scarring, cancerous or pre-cancerous lesion, or unhealed wound or have 
undergone radiation treatment in the area to be treated 
12. Received any investigational product within 60 days prior to study enrollment or 
planning to participate in another investigation during the course of this study 
13. An employee (or a relative of an employee) of the investigators, the Sponsor, or 
representative of the Sponsor 
14. Condition or in a situation that, in the investigator s opinion, may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject s participation in the study 
15. Current use of oral corticosteroids  
16. Current use of nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen), 
from 10 days prior to injection up to 3 days post-injection 
17. Prescription topical retinoid therapy and/or topical hormone cream applied to the face, for 
potential subjects who have not been on a consistent dose regimen for at least 6 months 
prior to enrollment and who are unable to maintain regimen for the study  
18. Systemic retinoid therapy within one year prior to study enrollment 
19. History or current symptoms of dysphagia 
20. Medical condition that may increase the risk of exposure to botulinum toxin including 
diagnosed myasthenia gravis, Eaton-Lambert Syndrome, amyotrophic lateral sclerosis, or 
any other disease that might interfere with neuromuscular function 
21. Current use of aminoglycoside antibiotics, curare-like agents, or agents that might 
interfere with neuromuscular (skeletal) function  
22. Profound atrophy/excessive weakness of muscles in target areas of injection 
23. History of facial nerve palsy 
24. Anticipated need for treatment with botulinum toxin of any serotype for any reason 
during the study (other than study treatment) 
25. Very thin skin in the mid-facial region 
26. Tendency to accumulate fluid in the lower eyelids, or large infraorbital fat pads, i.e., 
significant convexity or projection from the infraorbital fat pads 
27. Mid-face volume deficit due to congenital defect, trauma, abnormalities in adipose tissue 
related to immune-mediated diseases such as generalized lipodystrophy (e.g., juvenile 
dermatomyositis), partial lipodystrophy (e.g., Barraquer-Simons syndrome), inherited 
disease, or human immunodeficiency virus related disease  
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5.4 Other Restrictions and Precautions 
5.4.1 
Prohibited Medications and/or Treatments 
Subjects must not undergo any type of facial plastic or reconstructive surgery or cosmetic 
procedure (e.g., plastic surgery; tissue grafting; tissue augmentation with silicone, fat, or other 
permanent, semi-permanent, or temporary dermal fillers; neuromodulator injections; or 
mesotherapy; or ablative procedures) at any time during this study. 
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 the Sponsor
representative should be notified before a prohibited medication/treatment is administered. Prior 
to attending study visits, subjects must not apply facial cosmetics. 
investigator, including but not limited to medications for other conditions (i.e., hypertension, 
diabetes, etc.), treatment of AEs, estrogens, androgens, anti-androgenic agents, vitamins, iron 
supplements, folate, and herbal supplements. Medications should be taken consistently 
 
Concomitant medications as defined for this study include dietary supplements, over-the counter 
medications, and oral herbal preparations, as well as changes in dosages of current prescription 
medications. Concomitant medications will be documented for each subject at each scheduled 
visit. A detailed history of medications will be documented at screening. Subsequently, at each 
study visit, subjects will be asked what medication, if any, they have taken since the previous 
visit. All concomitant medications will be recorded on electronic case report forms (eCRFs). 
5.4.2 
Definition of Females of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods 
Women of childbearing potential must have a negative urine pregnancy test before any injections 
or other treatments are given. A reliable method of contraception must be practiced throughout 
the study. Women of childbearing potential comprises women who have experienced menarche 
and who have not undergone successful surgical sterilization (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy) or who are not post-menopausal. The investigator and 
each subject will determine the appropriate method of contraception for the subject during the 
participation in the study. 
5.4.3 
Special Diet or Activities  
Within the first 24 hours after any filler treatment (HArmonyCa or Juvéderm) 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. 
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6 
Study Plan and Procedures 
6.1 Study Subject Number 
Subjects who meet all inclusion/exclusion criteria will be assigned a subject enrollment number 
via the electronic data system that will serve as the subject identification number on all study 
documents. 
6.2 Description of Study Days 
Study procedures, treatments, and assessments will be performed at the study visits as listed 
below and as shown in Table 6.1. 
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6.2.1 
Study Procedures for Screening Visit (V0)  
 Provide subject information; review / verify study criteria. 
 Collect ICF. 
 Collect subject demographics, including age and gender.  
 Collect medical history, including a detailed history of prior cosmetic procedures, with start 
and stop dates, if applicable, as well as any discontinuations due to intolerability or toxicity. 
 Confirm that inclusion/exclusion criteria are met; document status of all washout periods that 
apply. 
 Measure body weight and height and calculate BMI. Body mass index > 30 kg/m2 is 
exclusionary. 
 Perform urine pregnancy test for women of childbearing potential. 
 Record concomitant medications. 
 Perform 2D facial photography. 
 Perform standardized digital video. 
 Determine Fitzpatrick Skin Phototype 
 Record adverse events (AEs) occurring since signing consent. 
 Perform the following study assessments: 
- 
SPA 
- 
FACE-Q 
- 
PAAQ 
- 
FWS (GLs, CFLs, FHLs) 
6.2.2 
Visit V1 and V2 (HArmonyCa Lidocaine) 
Screening Visit (V0) and first study treatment (V1) may occur on the same day if all screening 
procedures are completed, results received, and all eligibility criteria (inclusion and exclusion) 
are confirmed prior to treatment administration.  But the subject must be in agreement to do this 
and must have had sufficient time to understand the study, and the investigator also must judge 
that the subject had enough time to consider the study.  It will be a subject and investigator 
decision together - in the event of any doubt, the subject should not be treated on the same day. 
Subjects who have successfully completed screening (V0) will enter the study at V1. If no 
HArmonyCa will be administered to the subject, please proceed with study activities for V3 as 
outlined in Section 6.2.3 and Table 6.1. 
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The following activities will be performed at V1 if HArmonyCa Lidocaine is administered: 
 Record concomitant medications. 
 Perform urine pregnancy test for women of childbearing potential. 
 Record AEs.  
 Dispense subject diary to record AEs; counsel subject on diary entries that are needed during 
the next 30 days. 
 Perform facial HArmonyCa Lidocaine injections into areas that the subject desires and 
qualified for per the inclusion/exclusion criteria and within the approved clinical indications 
(Section 5.1 and Section 5.2, respectively). 
 
At V2, HArmonyCa Lidocaine touch-up treatment may be performed. If touch-up is not 
performed, please proceed with study activities for V3 as outlined in Section 6.2.3 and Table 6.1. 
If touch-up for HArmonyCa Lidocaine is performed, perform the following activities: 
 Record concomitant medications. 
 Perform urine pregnancy test for women of childbearing potential. 
 Record AEs.  
 Dispense subject diary to record AEs; counsel subject on diary entries that are needed during 
the next 30 days. 
 Perform facial HArmonyCa Lidocaine touch-up injections into areas that the subject desires 
and qualified for per the inclusion/exclusion criteria and within the approved clinical 
indications (Section 5.1 and Section 5.2, respectively). 
 
6.2.3 
Visit V3 and V4 (Juvéderm) 
V3 will occur 30 ± 7 days after previous treatment. If HArmonyCa is not given to the subject, the 
subject may begin with Juvéderm filler injections and V3 activities as outlined in this section and 
in Table 6.1. If no HArmonyCa is administered, please see guidance regarding screening and 
first treatment occurring on the same day outlined in Section 6.2.2. V3 and V4 are mandatory 
regardless of whether further filler treatment is expected. The following study procedures and 
treatments will be performed at V3 and V4: 
 Record concomitant medications. 
 Perform urine pregnancy test for women of childbearing potential. 
 Record AEs.  
 Dispense subject diary to record AEs; counsel subject on diary entries that are needed during 
the next 30 days 
 Perform facial Juvéderm filler injections.  
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- 
Facial filler injections (JUVÉDERM VOLBELLA with Lidocaine, and/or  JUVÉDERM 
VOLIFT with Lidocaine, and/or JUVÉDERM VOLUMA with Lidocaine, and/or  
JUVÉDERM VOLITE 
 and/or JUVÉDERM VOLUX with Lidocaine) will 
be administered into areas that the subject desires and qualified for per the 
inclusion/exclusion criteria and within the approved clinical indications (Section 5.1 and 
Section 5.2, respectively). 
 
6.2.4 
Visit V5 (Juvéderm Touch-up and BOTOX) 
V5 will occur 30 ± 7 days following V4. 
 Record concomitant medications. 
 Perform urine pregnancy test for women of childbearing potential. 
 Record AEs. 
 If Filler touch up is given, dispense subject diary to record AEs; counsel subject on diary 
entries that are needed during the next 30 days 
 Administer BOTOX treatment. 
 
6.2.5 
Visit V6 (BOTOX Touch-up, if needed) 
V6 will occur 15 + 7 days following V5. 
 Collect diary from V5, if Filler treatment was given. 
 Record concomitant medications. 
 Record AEs. 
 Perform urine pregnancy test for women of childbearing potential (omit if no BOTOX touch 
up required at V6). 
 Administer touch up BOTOX treatment if needed. 
 
6.2.6 
Visit V7 (Final Study Visit) 
V7 will occur 15 ± 7 days following V6. 
 Measure body weight and calculate BMI.  
 Record concomitant medications. 
 Perform 2D facial photography. 
 Perform standardized digital video. 
 Record AEs. 
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 Perform the following study assessments for all subjects: 
- 
SPA 
- 
PAAQ 
- 
FACE-Q (except for Expectations subscale) 
- 
Investigator GAIS 
- 
Subject GAIS 
 
If a subject discontinues the study before V7, the subject will be asked to have this final study 
visit for collecting all clinical data required during this visit. 
6.2.7 
Unscheduled/Missed Visits 
Each time the subject returns to the study site, the investigator (or designee) will solicit and 
record information about ISRs, other AEs, and concomitant medications. An interim or 
unscheduled visit may replace a scheduled visit if it occurs within the acceptable time window 
for a scheduled visit or if the scheduled visit was missed. All applicable procedures should be 
performed. 
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7 
Methods of Assessment and Endpoints  
7.1 
Clinical Scales for Treatment Inclusion Only 
 Investigator
photonumeric guide (Appendix 10) 
 Investigator
CFLs at maximum smile using the FWS with 
photonumeric guide (Appendix 11) 
 Investigator
FWS with photonumeric guide (Appendix 12) 
 
-Q 
Expectations Scale (Appendix 3) 
7.2 
Efficacy Endpoint Measurements 
7.2.1 
FACE-Q 
 
-Q Satisfaction with 
Facial Appearance Scale (Appendix 2) 
 
-related facial appearance as measured by the FACE-Q Aging 
Appraisal (Appendix 4) 
 
-being as measured by the FACE-Q Psychological 
Function Scale (Appendix 5) 
 
-Q Social Function Scale 
(Appendix 6) 
 
-Q 
Satisfaction with Skin Questionnaire (Appendix 7) 
7.2.2 
Self-Perception of Age Questionnaire 
 
-related facial appearance as measured by the SPA Questionnaire 
(Appendix 1) 
7.2.3 
Global Aesthetic Improvement Scale  
 Investigator
-point 
GAIS (Appendix 13) 
 Subject  assessment of global facial aesthetic improvement as measured by the 5-point 
GAIS (Appendix 13) 
7.2.4 
Periorbital Aesthetic Appearance Questionnaire  
 
periorbital area as measured by the PAAQ (Appendix 9) 
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8 
Discontinuation Criteria  
8.1 
Early Discontinuation of the Study 
An investigator may stop the study at his/her study site at any time. The Sponsor may discontinue 
the study (and/or participation of a single study site) for any reason with appropriate notification. 
If conditions arise during the study that indicate that the study or an investigational site should be 
terminated, the Sponsor, the investigator, the study monitor, REB, and/or regulatory agencies will 
take appropriate action after consultation.  Conditions that may warrant termination of the study 
or investigational site include, but are not limited to: 
 Discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the study 
 The decision on the part of the Sponsor to suspend or discontinue testing or evaluation of the 
study treatment  
 Failure of an investigator to comply with pertinent national or state regulations, REB-imposed 
conditions, or protocol requirements 
 Submission of knowingly false information to the Sponsor, study monitor, the REB, or any 
regulatory agency by the investigator 
If the study is prematurely terminated or suspended due to safety issues, the Sponsor will inform 
all investigators and applicable regulatory authorities of the termination or suspension and the 
reason(s) for the termination or suspension. The REB is also to be informed promptly and 
provided the reason(s) for the termination or suspension by the Sponsor or by the investigator, as 
specified by the applicable regulatory requirements. If a premature termination or suspension 
occurs, the Sponsor shall remain responsible for providing resources to fulfill the protocol 
obligations and existing agreements for follow-up of subjects enrolled in the study, and each 
investigator or authorized designee will promptly inform enrolled subjects, if applicable. 
8.2 
Early Discontinuation of Individual Subjects 
A subject may voluntarily withdraw from the study at any time. Notification of early subject 
discontinuation from the study and the reason for discontinuation will be made to the sponsor and 
will be clearly documented on the appropriate eCRF. In the event of subject discontinuation, 
every effort should be made to have the subject complete the primary endpoint FACE-Q 
Satisfaction with Facial Appearance Overall questionnaire. 
It is the right and responsibility of the investigator to discontinue a 
 participation when 
the 
 health or well-being is threatened by continuation in the study. In the event of 
premature discontinuation, the investigator should determine the primary reason for 
discontinuation. 
A subject who is withdrawn from the study prior to initiation of treatment may be replaced. 
Discontinued subjects will not be replaced. 
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The following are circumstances that could result in a 
 discontinuation from the study: 
 AEs or SAEs that render the subject unable to continue study participation 
 Protocol violation  
 Subject voluntarily withdraws consent  
 Non-compliance with study requirements  
 Discretion of investigator (must document reason on eCRF)  
 Progressive injury (at the discretion of the investigator)  
 Changes in the subject s condition that render the subject unacceptable for further 
participation, in the judgment of the investigator  
 Pregnancy (required discontinuation) 
 Lost to follow-up  
 Unable to physically or mentally tolerate the use of the test treatment  
 Exclusion criterion met 
 
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9 
Treatments 
The study treatments are:  
 BOTOX: The dose and the number of injection points may be adapted to the needs of the 
subject, based on their characteristics and location of the muscles to be treated. Subjects will 
receive at least one BOTOX treatment in the following areas: GLs, CFLs, and FHLs.) 
 HArmonyCa Lidocaine:The investigator will determine the appropriate volume to be 
injected during initial and touch-up treatments based on his/her clinical experience. The 
maximum total volume of HArmonyCa Lidocaine allowed per subject for the initial and 
touch-up treatment combined is 4 syringes (5 mL). 
 JUVÉDERM: The investigator will determine the appropriate volume to be injected during 
initial and touch-up treatments based on his/her clinical experience 
- 
JUVÉDERM VOLITE 
: The maximum total volume of JUVÉDERM 
VOLITE 
 allowed per subject for the initial and touch-up treatments 
combined is 4 syringes (4 mL). 
- 
JUVÉDERM VOLBELLA with Lidocaine: The maximum combined total volume 
allowed per subject for all facial areas treated for both the initial and touch-up treatments 
combined is 2 syringes (2 mL). 
- 
JUVÉDERM VOLIFT with Lidocaine: The maximum total volume of JUVÉDERM 
VOLIFT with Lidocaine allowed per subject for the initial and touch-up treatments 
combined is 4 syringes (4 mL). 
- 
JUVÉDERM VOLUMA with Lidocaine: The maximum total volume of JUVÉDERM 
VOLUMA with Lidocaine allowed per subject for the initial and touch-up treatments 
combined is 4 syringes (4 mL). 
- 
JUVÉDERM VOLUX with Lidocaine: The maximum total volume of JUVÉDERM 
VOLUX with Lidocaine allowed per subject for the initial and touch-up treatments 
combined is 4 syringes (4 mL). 
 
The investigator should not inject greater than 20 mL of filler (Juvéderm and HArmonyCa) per 
60 kg (130 lbs.) body mass per year for a single subject. 
The chemical compositions for each of the study products intended for subject treatment are 
provided in Appendix 8. 
All study drugs/devices must be stored in a secure area, accessible only to study personnel. The 
sponsor will provide each study site with sufficient study treatments (study drugs and devices) for 
all study subjects, including back-up study treatments. 
The sponsor will provide the most recent country-specific Directions for Use and Product 
Monographs for each product to each investigator to be used in study treatment. Details of 
formulation, storage, and handling, and complete instructions for administration of treatments 
can be found in the respective product information for each study drug/device. 
All unused study treatments should be retained for return to the sponsor. 
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All products will be used as per their license only. Further details on the products can also be 
found in the currently approved Directions for Use and Product Monographs. 
9.1 
Rescue Medications 
No product licensed in Brazil is approved as a rescue medication. Administration of 
hyaluronidase is considered to be 
-
 and it has not been provided as a part of the study 
regimen. It should only be used if in the investigator  judgment it is deemed to be necessary to 
inject hyaluronidase for the safety of the subject, in that situation, the investigator may inject at 
his/her discretion as a concomitant medication, capturing relevant information. 
9.2 
Treatment 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 REB 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 drug and device accountability records for compliance with the 
protocol, e.g., subject eligibility criteria, volume of product injected, procedures performed, and 
follow-up visit schedule. 
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10 Adverse Events 
Throughout the course of the study (from the date of informed consent), all AEs will be 
monitored and recorded 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 or until follow-up is no longer possible.  
10.1 
Drug Adverse Events 
An AE from a drug is defined as any undesired medical occurrence in a subject receiving a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable sign 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. 
Adverse events 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 
AEs by asking each subject a general, non-
. All 
reported AEs will be documented on the AE eCRF.  
10.2 
Medical Device Adverse Events 
An AE from a medical device 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 considered related to the procedure or the product. Adverse events 
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.  
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. 
10.3 
Injection Site Reactions 
Injection site reactions following treatment with dermal fillers include redness, pain after 
injection, tenderness to touch, firmness, swelling, lumps/bumps, bruising, itching, and 
discoloration. Subjects will maintain a diary record of the presence, location, frequency, severity, 
and duration of any ISR for 30 days after each filler treatment.  
Subjects will indicate the occurrence of an ISR and severity (none, mild, moderate, severe) of the 
event. NOTE: ISRs that persist longer than 30 days should be recorded and followed to 
resolution on the AE eCRF. If an ISR is ongoing or appears after the 
 last study visit, it 
will be followed up by the sponsor Product Surveillance separate from this study protocol. 
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10.4 
Unusual Failure in Efficacy 
Unusual Failure in Efficacy is defined as failure of a health product to produce the 
expected/intended effect, which may result in an adverse outcome for the patient, including an 
exacerbation of the condition for which the health product is being used. One example of unusual 
failure in efficacy is a previously well-stabilized condition that deteriorates when the patient 
changes to a different brand or receives a new prescription.  Another example of a case that 
should be reported on an expedited basis is a life-threatening infection where the failure in 
efficacy seems to be due to the development of a newly resistant strain of bacterium previously 
regarded as susceptible. 
Any unusual failure in efficacy reported during the conduct of the study should be immediately 
reported to a sponsor representative and recorded in the appropriate eCRFs.   
The Investigator must: 
1. Notify the sponsor immediately.  For Emergency Phone Numbers see front of protocol. 
Fax completed Unusual Failure in Efficacy reporting form to: 1-714-796-9504. 
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. 
 
10.5 
Serious Adverse Events 
10.5.1 
Serious Adverse Events Definition 
An SAE is any AE that either led to death; resulted in a life-threatening illness or injury; resulted 
in a permanent impairment of a body structure or a body function; required in-patient 
hospitalization or prolongation of existing hospitalization; resulted in medical or surgical 
intervention to prevent permanent impairment to body structure or a body function; led to fetal 
distress, fetal death or a congenital abnormality or birth defect. 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
subject requires hospitalization are not reportable as an SAE. Any pre-planned surgery or 
procedure should be clearly documented in the site source documents by the investigator at the 
time of the subject
 
NOTE: the sponsor considers all cancer AEs as SAEs.  Pregnancy by itself is not generally 
considered an AE. 
10.5.2 
Serious Adverse Event Reporting Requirements 
Any SAE occurring during the study period (beginning with informed consent) and through 30 
days after study exit must be reported within 24 hours to the sponsor on 2 SAE forms. The drug, 
and device SAE forms must be recorded and e-mailed per this protocol section. All subjects with 
an SAE must be followed up and the outcomes reported.  
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The principal investigator must supply the sponsor and the REB with any additional requested 
information (e.g., hospital discharge summary, autopsy reports and terminal medical reports) 
only upon request. The sponsor will evaluate all SAEs for both drug and device. Device SAEs 
will be documented in writing as to whether they meet the definition of an USADE. These will 
be reported to all participating investigators, the regulatory authorities, and the REB. 
In the event of an SAE, the investigator must: 
1. Notify the sponsor immediately (within 24 hours) using the SAE reporting forms. 
Emergency phone numbers and relevant sponsor personnel contacts are below. 
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. 
Provide the sponsor with a complete, written case history (AE report form), including copies of 
supporting reports (e.g., progress notes, laboratory reports), upon request 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. 
Promptly inform the governing REB of the SAE, if it is device-related, as required by the REB, 
local regulations, and the governing health authorities. 
10.5.3 
Serious Adverse Event Contact Information 
SAE Reporting Information: BOTOX®  
Fax: 1-714-796-9504 
Back-up fax: 1-714-246-5295 
Email: IR-Clinical-SAE@abbvie.com 
SAE Reporting Information:  JUVÉDERM® 
VOLBELLA® with Lidocaine, 
JUVÉDERM® VOLIFT with Lidocaine, 
JUVÉDERM® VOLUMA® with Lidocaine, 
and JUVÉDERM® VOLITE® 
 
 and JUVÉDERM® VOLUX®, 
HArmonyCa Lidocaine 
Fax: 1-714-796-9567 
Email: LC-Medical_Safety@abbvie.com 
Fax: +1 (877) 605-4524 or 
Back-up Fax +1 (714) 796-9567 
 
10.6 
Unanticipated Serious Adverse Device Effects 
An unanticipated serious adverse device effect (USADE) 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 
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expeditiously reported to the Sponsor. Some examples of pregnancy related SAEs are, but not 
limited to, the following conditions: placental abruption, placenta previa, pre-eclampsia, 
prematurity, fetal death, congenital anomaly, or birth defects. 
10.8.1 
Female Subjects Who Become Pregnant  
 The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the 
participant will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on the subject and the neonate, and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. A spontaneous abortion or elective termination is always 
considered to be an SAE and will be reported as such. Any post-study pregnancy-related 
SAE considered reasonably related to the study intervention by the investigator will be 
reported to the sponsor as described in Section 10.5.2. While the investigator is not obligated 
to actively seek this information in former study subjects, he or she may learn of an SAE 
through spontaneous reporting.  
10.8.2 
Male Subjects with Partners Who Become Pregnant  
 The investigator will attempt 
partner who becomes pregnant while the male subject is in this study. This applies only to 
male subjects who receive study product. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
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11 Statistical Methods 
11.1 
General Statistical Considerations 
A brief summary of the general statistical analysis methods is 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). 
Hypothesis testing will be performed at 0.025 significance level (1-sided). Conclusions related to 
study outcomes will be focused on the overall results of each outcome. 
Two critical time points, baseline and end of study, 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, V7 
(after approximately 5 months of treatment). Subjects who discontinue prematurely will be asked 
to return for the last clinical visit for end-of-study data collection. 
11.1.1 
Analysis Populations 
The following analysis populations will be used: 
 mITT (modified Intent-to-Treat) Population - all subjects who enrolled and had at least one 
post-baseline efficacy assessment. 
 Evaluable Population  all subjects as defined in the mITT Population who have received 
both study products as treatments in this study, had at efficacy assessment at the final visit 
(V7) and no major protocol violations or deviations. 
 Safety Population  all subjects who received any product used as treatment in this study. 
 
The mITT Population will be used for subject disposition, demographics and baseline 
characteristics summary, efficacy and the Safety Population will be used for safety analyses. The 
Evaluable Population will be used on key efficacy endpoints.  
11.1.2 
Subgroups  
Subgroup analysis will be performed by: 
 Gender: As male and female subjects may have differing expectations/perceptions of 
aesthetic improvement; they will be examined separately.  
 Treatment touch-ups: subjects with no touch-ups, Juvéderm only, Botox only, Juvéderm and 
Botox 
 
Additional subgroup analysis will be discussed in the SAP. 
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11.2 
Demographics and Baseline Characteristics 
Subject disposition, demographics and baseline characteristics will be summarized using 
descriptive statistics. 
11.3 
Exposure and Concomitant Therapies 
Subject study product exposure and compliance will be summarized using descriptive statistics 
for each product, combination of multiple products, and overall exposure respectively. 
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.  
11.4 
Efficacy Analyses 
Unless stated otherwise, all efficacy analyses will be based on the mITT and Evaluable 
Populations. 
11.4.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from baseline in the overall Rasch-transformed 
scores of the FACE-Q Satisfaction with Facial Appearance Scale to the final study visit (V7). 
This will be analyzed using one sample t-test (or sign test if normality assumptions are not met).  
11.4.2 
Analysis of All Other Efficacy Endpoints 
The same analysis procedures and methods used for the primary efficacy endpoint will be used 
for the other FACE-Q efficacy endpoints (FACE-Q Aging Appraisal, FACE-Q Psychological 
Function Scale, FACE-Q Social Function Scale, FACE-Q Satisfaction with Skin). Details will be 
documented in the SAP. 
11.4.3 
Missing Data 
The missing data strategy will be documented in the SAP.  
11.5 
Adverse Events 
Device-related AEs will be captured with TrackWise Enterprise Quality Management Software 
and coded using AE term codes. Treatment-emergent AEs will also be summarized by serious 
AEs (SAEs), AE severity, AE leading to treatment or study early termination, and relationship to 
study drugs/devices and procedures. SAEs will be coded using MedDRA version 21.0 or higher 
and presented by system organ class and preferred term. 
11.6 
Interim Analyses and Data Monitoring 
No formal interim analyses are planned for this study. 
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11.7 
Determination of Sample Size 
A sample size of 48 subjects will provide 90% power to detect if change from baseline to end-of-
study visit in the FACE-Q Satisfaction with Facial Appearance Overall Scale Rasch-transformed 
score is different from zero, assuming a mean change of 12.0 and a standard deviation of 25.0. 
This calculation is based on a one-sample, 1-sided t-test at 0.025 significance level. The 
assumptions of mean and standard deviation are based on FACE-Q results from the HARMONY 
Study GMA-CMB-14-001. Anticipating a potential 20% drop-out rate (for early withdrawals 
and/or subjects who failed to duly complete the FACE-Q Satisfaction with Facial Appearance 
Overall Scale assessment at end of study), 60 subjects will be enrolled. 
PASS 2008 software was used to calculate the sample size. 
11.8 
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.  
11.9 
Exploratory Imaging Analysis  
Exploratory analysis may be performed on the collected video and photographs as part of this 
study only.  This could include lay panel review of photographs and videos on specific variables 
such as age, health, and attractiveness.  In addition, more advanced facial mapping of wrinkles 
may be performed.  Analysis will be detailed in the statistical analysis plan. 
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12 Regulatory, Ethical, and Legal Obligations 
12.1 
Declaration of Helsinki 
The investigator will ensure that this study is conducted in accordance with the most recent 
revision of the Declaration of Helsinki. 
12.2 
Good Clinical Practice 
The study will be conducted according to the study protocol and to Standard Operating 
Procedures that meet ICH GCP guidelines for clinical studies.  
12.3 
Research Ethics Board 
Before implementing this study, the protocol, the proposed subject ICFs, and other information 
for the subjects must be reviewed by a properly constituted committee or committees responsible 
for approving clinical studies. The REB-written and -signed approval letter/form must contain 
approval of the designated investigator, the protocol (identifying protocol title, date, and version 
number), and of the subject ICF (date, version).  
12.4 
Regulatory Authority Approval 
The study is utilizing all products as per their licensed usage and indications. No regulatory 
approval will be required.  
12.5 
Informed Consent  
Written informed consent is to be obtained from the subject prior to enrollment into the study. 
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. No 
protocol-specific procedures, including screening procedures, will be performed until the subject 
has signed and dated an REB-approved ICF. Study participation will start with the signing and 
dating of the ICF.  
The investigator must ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, and 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. 
In case of a clinical trial protocol amendment, the subject information sheet and ICF need to be 
revised to reflect the changes, if needed. Also, if the subject information sheet and ICF are 
revised, they must be reviewed and approved by the responsible REB and signed by all subjects 
subsequently enrolled in the clinical trial as well as those currently enrolled in the clinical trial. 
12.6 
Subject Confidentiality and Disclosure 
A report of the results of this study may be published or sent to the appropriate health authorities 
be disclosed to the sponsor or the 
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governing health authorities including the Brazilian Health Regulatory Agency if they inspect the 
study records. Appropriate precautions will be taken to maintain confidentiality of medical 
records and personal information. 
In accordance with Brazilian privacy requirements, additional purposes of this study include the 
following: to publish anonymous subject data from the study, and to create and maintain a data 
repository. 
12.7 
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 the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study. This will be detailed in 
the study monitoring plan.  
Authorized representatives of the sponsor 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. 
12.8 
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 ICF. All 
information on the eCRFs must be traceable to these source documents in the subject s file. Data 
without a written or electronic record will be defined before study start and will be recorded 
directly on the eCRFs which will be documented as being the source data. 
12.9 
Collection of Study Data 
This study will be conducted in compliance with Brazilian Health Regulatory Agency 
requirements. 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 should personally sign for the eCRFs (as indicated in the eCRFs) to ensure that 
the observations and findings are recorded on the eCRFs correctly and completely. The eCRFs 
are to be submitted to the sponsor in a timely manner at the completion of the study, or as 
otherwise specified by the sponsor. 
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. 
12.10 Disclosure of Information 
This study will be registered, and results posted on www.ClinicalTrials.gov. The sponsor has 
proprietary interest in this study. Authorship and manuscript composition will reflect joint 
cooperation between study investigators and the sponsor personnel. Authorship will be 
established prior to the writing of the manuscript. As this study involves multiple centers, no 
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individual publications will be allowed prior to completion of the final report of the multicenter 
study except as agreed with the sponsor. 
12.11 Discontinuation of the Study 
It is agreed that, for reasonable cause, either the investigator or the sponsor may terminate the 
investigator
ation in this study after submission of a written notice. The sponsor may 
terminate the study at any time upon immediate notice for any reason, including the sponsor
belief that discontinuation of the study is necessary for the safety of subjects. 
12.12 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. Essential documents specific to the sponsor 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 the sponsor. 
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13 References 
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JUVÉDERM® VOLBELLA® with Lidocaine [directions for use]; Pringy, France: Allergan, Inc.; 
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Sobanko JF, Taglienti AJ, Sarwer DB, Margolis DJ, Dai J, Percec I. Motivation for seeking 
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Stotland MA, Kowalski JW, Ray BB. Patient-reported benefit and satisfaction with botulinum 
toxin type A treatment of moderate to severe glabellar rhytides: results from a prospective open-
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APPENDIX 8 
Chemical Ingredients of the Study Products  
 
 BOTOX (onabotulinumtoxinA) purified neurotoxin complex  
 
 JUVÉDERM® VOLITE® is a sterile non-pyrogenic physiological solution of cross-linked 
hyaluronic acid which is not of animal origin. It consists of cross-linked HA produced by 
Streptococcus of bacteria, formulated to a concentration of 12 mg/mL and 0.3% w/w 
lidocaine, HCl, in a phosphate buffer.  
 JUVÉDERM® VOLBELLA® with Lidocaine injectable gel is a sterile, biodegradable, non-
pyrogenic, viscoelastic, clear, colorless, homogeneous gel implant. It consists of cross-linked 
HA produced by Streptococcus of bacteria, formulated to a concentration of 15 mg/mL and 
0.3% w/w lidocaine, HCl, in a phosphate buffer. 
 JUVÉDERM® VOLIFT® with Lidocaine is a sterile non-pyrogenic physiological solution of 
cross-linked hyaluronic acid which is not of animal origin. It consists of cross-linked HA 
produced by Streptococcus of bacteria, formulated to a concentration of 17.5 mg/mL and 
0.3% w/w lidocaine, HCl, in a phosphate buffer.   
 JUVÉDERM® VOLUMA® with Lidocaine is a sterile, biodegradable, non-pyrogenic, 
viscoelastic, clear, colorless, homogenized, HA gel implant (dermal filler). It consists of 
crosslinked HA formulated to a concentration of 20 mg/ml, suspended in a physiological 
buffer. The HA is mixed with phosphate buffer and 0.3% lidocaine, HCl, and crosslinked by 
adding BDDE to form a 3-dimensional HA gel. 
 JUVÉDERM® VOLUX® with Lidocaine is a sterile, pyrogenic physiological solution of 
cross-linked hyaluronic acid that is not of animal origin. It consists of crosslinked HA gel 25 
mg and 3 mg lidocaine, HCl, in a phosphate buffer.  
 HArmonyCa Lidocaine  is a dermal filler consisting of synthetic calcium hydroxyapatite 
microspheres, formulated to a concentration of 55.7% (w/w), embedded in a cross-linked 
sodium hyaluronate gel (0.886% [w/w] HA) from a non-animal source with 0.3% (w/v) 
lidocaine HCl. 
 
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APPENDIX 14 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Version 2 
October 2021 
Version 1 (Original Protocol) 
May 2020 
 
Version 2 (October 2021) 
Overall Rationale for the Amendment: 
HArmonyCa Lidocaine was approved for use in Brazil in April 2020. This provides the 
opportunity to include HArmonyCa Lidocaine in Study CMO-MA-FAS-0580 that evaluates 
combined facial treatment in subjects. All changes in the table below reflect the addition of 
HArmonyCa lidocaine to this study design. 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Addition of HArmonyCa 
Lidocaine to the study 
design. 
Per the overall rationale for the 
amendment to include HArmonyCa 
Lidocaine in this post market study, 
several sections throughout the protocol 
were updated, including study design, 
inclusion/exclusion criteria, study plan 
and procedures, etc. 
Global 
Editorial changes 
Editorial changes throughout 
 
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SAP_001.pdf: 
HARMONY Brazil 
CMA-MA-FAS-0580 – Statistical Analysis Plan
Version 3.0 – 05 June 2024
1 
Statistical Analysis Plan for Study CMA-MA-FAS-0580
HARMONY Brazil: Prospective, Multi-site, Study to 
Evaluate Subject Satisfaction with Facial Appearance 
Overall and the Aesthetic and Psychosocial Impact of 
Combined Facial Treatment
Date: 05 June 2024
Version 3.0
NCT04609020


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Table of Contents
1.0
Introduction .......................................................................................4
2.0
Study Design and Objectives............................................................4
2.1
Objectives and Hypotheses ................................................................................... 4
2.2
Study Design Overview ........................................................................................ 5
2.3
Treatment Assignment and Blinding .................................................................. 10
2.4
Sample Size Determination ................................................................................ 11
3.0
Endpoints .........................................................................................11
3.1
Primary Efficacy Endpoint ................................................................................. 11
3.2
Secondary Efficacy Endpoints ........................................................................... 11
3.2.1
Key Secondary Efficacy Endpoints .................................................................... 11
3.2.2
Other Secondary Efficacy Endpoints ................................................................. 12
3.3
Safety Endpoints ................................................................................................. 12
4.0
Analysis Populations and Subgroup..............................................13
4.1
Analysis Populations .......................................................................................... 13
4.1.1
Modified Intent-to-Treat (mITT) Population ..................................................... 13
4.1.2
Evaluable Population .......................................................................................... 13
4.1.3
Safety Population ................................................................................................ 13
4.2
Subgroup ............................................................................................................. 13
5.0
Subject Disposition and Treatment Disposition...........................13
6.0
Treatment Exposure and Administration.....................................15
7.0
Demographics, Baseline Characteristics, Medical History, 
and Prior/Concomitant Medications/Procedures ........................15
7.1
Demographics and Baseline Characteristics ...................................................... 15
7.2
Medical, Surgical and Cosmetic Procedure History ........................................... 16
7.3
Prior and Concomitant Medications ................................................................... 16
7.4
Concomitant Procedures ..................................................................................... 16
8.0
Efficacy Analyses.............................................................................16
8.1
General Considerations ...................................................................................... 16
8.2
Handling of Missing Data .................................................................................. 17
8.3
Primary Efficacy Endpoint and Analyses ........................................................... 18
8.3.1
Primary Efficacy Endpoint ................................................................................. 18
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint ........................... 18
8.3.3
Primary Efficacy Analyses ................................................................................. 19
8.3.4
Additional Analyses of the Primary Efficacy Endpoints ................................... 19
8.4
Secondary Efficacy Endpoints and Analyses ..................................................... 19


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8.4.1
Secondary Efficacy Endpoints ........................................................................... 19
8.4.2
Secondary Efficacy Analyses ............................................................................. 20
8.5
Subgroup Analyses ............................................................................................. 23
9.0
Safety Analyses ................................................................................23
9.1
General Considerations ...................................................................................... 23
9.2
Adverse Events ................................................................................................... 24
9.2.1
Treatment-Emergent Adverse Events ................................................................. 24
9.2.2
Adverse Event Overview .................................................................................... 25
9.2.1
Treatment-Emergent Adverse Events by SOC and PT, and/or Severity ............ 26
9.2.2
SAEs (Including Deaths) and Adverse Events Leading to Study 
Discontinuation ................................................................................................... 28
9.2.3
Adverse Events of Special Interest ..................................................................... 29
9.3
Analysis of Laboratory Data .............................................................................. 29
9.4
Analysis of Vital Signs ....................................................................................... 29
9.5
Injection Site Response ...................................................................................... 29
9.6
Procedural Pain ................................................................................................... 29
9.7
Safety Subgroup Analyses .................................................................................. 29
9.8
Other Safety Analyses ........................................................................................ 30
10.0
Other Analyses.................................................................................30
11.0
Interim Analyses..............................................................................30
12.0
Overall Type-I Error Control........................................................30
13.0
SAP Version History Summary.....................................................30
14.0
Reference..........................................................................................31
Appendix A.
Protocol Deviations and Violations .................................................................... 32
Appendix B.
List of Abbreviations .......................................................................................... 33
Appendix C.
Changes to Protocol-planned Analyses .............................................................. 35


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1.0
Introduction
This Statistical Analysis Plan (SAP), based on Protocol Amendment 1 Version 2, 18-Oct-2021, 
describes the statistical analyses for AbbVie Study CMA-MA-FAS-0580 HARMONY Brazil: 
Prospective, Multi-site, Study to Evaluate Subject Satisfaction with Facial Appearance Overall 
and the Aesthetic and Psychosocial Impact of Combined Facial Treatment. Specifications of 
tables, figures, and data listings are contained in a separate document. 
Study CMA-MA-FAS-0580 is a prospective, interventional, multicenter, combination filler 
medical device and drug post marketing study. Approximately 60 subjects will be enrolled 
consecutively at approximately 7 study sites in Brazil. Recruitment will also target men, who are 
typically under-represented in aesthetic studies. Each subject will be in the study for up to 
approximately 5 months and act as his/her own control. Subjects will be evaluated by the 
investigator to receive BOTOX, HArmonyCa Lidocaine facial filler, and Juvéderm facial fillers 
(JUVÉDERM VOLITE 
, JUVÉDERM VOLBELLA with Lidocaine, 
JUVÉDERM VOLIFT with Lidocaine, JUVÉDERM VOLUMA with Lidocaine, and 
JUVÉDERM VOLUX with Lidocaine). Selected subjects will receive staged treatment with the 
multiple products and will be evaluated using validated patient-reported outcome measurements 
to determine the psychological and emotional impact of an integrated treatment approach to 
reduce visible signs of aging. All products will be used as per their license only.
The SAP will not be updated in case of administrative changes or amendments to the protocol 
unless the changes impact the analysis. 
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS Institute 
Inc., Cary, NC  27513) or later. 
This SAP includes changes to analyses described in the protocol. Details are outlined in 
Appendix C. 
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The primary objective of this study is to quantify the psychological, social, and emotional impact 
of comprehensive aesthetic treatment with a portfolio of AbbVie’s products by measuring the 
change in subject’s satisfaction with facial appearance from baseline to the final study visit 


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(Statistical Programming Plan [SPP] Appendix C FACE-QTM: Satisfaction with Facial 
Appearance). These products include BOTOX, HArmonyCa Lidocaine, and Juvéderm facial 
fillers, as described in Section 1.0 and Section 2.3. 
The secondary objectives are: 
•
To determine the subject’s self-appraisal of aging appraisal (SPP Appendix D FACE-
QTM: Aging Appraisal), psychological function (SPP Appendix E FACE-QTM: 
Psychological Function), social function (SPP Appendix F FACE-QTM: Social Function) 
and satisfaction with skin (SPP Appendix G FACE-QTM: Satisfaction with Skin).
•
To quantify the investigator’s and subject’s assessment of aesthetic improvement. 
The clinical hypothesis of this study is that subjects treated with a combination of BOTOX, 
HArmonyCa Lidocaine facial filler, and Juvéderm facial fillers will be satisfied with their overall 
facial appearance at the final study visit as measured by the change from baseline on the FACE-
QTM Satisfaction with Facial Appearance Overall Scale.
2.2
Study Design Overview
This Phase 4 study is a prospective, interventional, multicenter, combination medical device and 
drug post marketing study. Each subject will be in the study for up to approximately 5 months 
and act as his/her own control. All products will be used as per their license only. The 
investigators will perform all treatments and evaluations.
The study is planned to enroll 60 subjects consecutively at approximately 7 study sites in Brazil. 
Recruitment will also target men, who are typically under-represented in aesthetic studies.
All subjects will sign an informed consent form (ICF) and begin the study at the screening visit 
(V0). Subjects following screening (V0) will enter the study and receive an initial treatment of 
HArmonyCa Lidocaine at Visit 1 (V1), followed by Juvéderm fillers at Visit 3 (V3), and 
BOTOX at Visit 5 (V5) as indicated in the study design diagram (Figure 1). If the decision is 
made to not treat with HArmonyCa Lidocaine, the subject may begin with Juvéderm fillers at 
V1. As indicated in the diagram, touch-ups of HArmonyCa at Visit 2 (V2), Juvéderm at Visit 5
(V5), and BOTOX at Visit 6 (V6) are optional. If a touch-up of HArmonyCa (V2) is not 
performed, the subject may advance in the study timeline to the next study visit procedures. If a 
touch-up of BOTOX is not performed, the subject will return on schedule for Visit 7 (V7). A 


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subject not receiving Juvéderm touch-up would continue with BOTOX treatment (and all study 
procedures) outlined for V5. To reduce the number of subject visits, V0 can be combined with 
the initial treatment visit (V1), if judged by the investigator to be appropriate and acceptable for 
the subject. End of study is the last clinical visit an enrolled subject has in this study, V7 (after 
approximately 5 months of treatment). Subjects who discontinue prematurely will be asked to 
return for the last clinical visit for end-of-study data collection.  Identical study procedures will 
not be repeated where the visits are combined. The schedule of activities is shown in Table 1.  
Figure 1. Study Design


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Table 2. 
Schedule of Activities (SOA)
      


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Abbreviation: BMI, body mass index; CFLs, crow’s feet lines; FHLs, forehead lines; FWS, facial wrinkle scale; GAIS, global aesthetic improvement scale; 
GLs, glabellar lines; PAAQ, periorbital aesthetic apperance questionnaire; SPA, self-perception of age.


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2.3
Treatment Assignment and Blinding
Approximately 60 subjects will be enrolled consecutively at approximately 7 study sites in 
Brazil. Recruitment will also target men, who are typically under-represented in aesthetic 
studies. Study treatments include: 
•
BOTOX: The dose and the number of injection points may be adapted to the needs of the 
subject, based on their characteristics and location of the muscles to be treated. Subjects 
will receive at least one BOTOX treatment in the following areas: glabellar lines (GLs), 
crow’s feet lines (CFLs), and forehead lines (FHLs). 
•
HArmonyCa Lidocaine: The investigator will determine the appropriate volume to be 
injected during initial and touch-up treatments based on his/her clinical experience. The 
maximum total volume of HArmonyCa Lidocaine allowed per subject for the initial and 
touch-up treatment combined is 4 syringes (5 milliliter [mL]).
•
JUVÉDERM: The investigator will determine the appropriate volume to be injected 
during initial and touch-up treatments based on his/her clinical experience. 
o
JUVÉDERM VOLITE 
: The maximum total volume of JUVÉDERM
VOLITE 
 allowed per subject for the initial and touch-up treatments
combined is 4 syringes (4 mL). 
o
JUVÉDERM VOLBELLA with Lidocaine: The maximum combined total volume of 
JUVÉDERM VOLBELLA with Lidocaine allowed per subject for all facial areas 
treated for both the initial and touch-up treatments combined is 2 syringes (2 mL). 
o
JUVÉDERM VOLIFT with Lidocaine: The maximum total volume of JUVÉDERM
VOLIFT with Lidocaine allowed per subject for the initial and touch-up treatments
combined is 4 syringes (4 mL). 
o
JUVÉDERM VOLUMA with Lidocaine: The maximum total volume of 
JUVÉDERM VOLUMA with Lidocaine allowed per subject for the initial and touch-
up treatments combined is 4 syringes (4 mL). 


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o
JUVÉDERM VOLUX with Lidocaine: The maximum total volume of JUVÉDERM
VOLUX with Lidocaine allowed per subject for the initial and touch-up treatments
combined is 4 syringes (4 mL). 
The investigator should not inject greater than 20 mL of filler (Juvéderm and HArmonyCa 
Lidocaine) per 60 kg (130 lbs.) body mass per year for a single subject.    
Blinding and randomization are not applicable. This is an open-label, single-arm study. Subjects 
are enrolled consecutively based upon subject need and all subjects are intended to receive all 
treatments. Investigators will perform all treatments and evaluations. 
2.4
Sample Size Determination
A sample size of 48 subjects will provide 90% power to detect if change from baseline to end of 
study visit in the FACE-QTM: Satisfaction with Facial Appearance Overall Scale Rasch-
transformed score is different from zero, assuming a mean change of 12.0 and a standard 
deviation of 25.0. 
This calculation is based on a one-sample, 1-sided t-test at 0.025 significance level. The 
assumptions of mean and standard deviation are based on FACE-QTM results from the 
HARMONY Study GMA-CMB-14-001. Anticipating a potential 20% drop-out rate (for early 
withdrawals and/or subjects who failed to duly complete the FACE-QTM: Satisfaction with Facial 
Appearance Overall Scale assessment at end of study), 60 subjects will be enrolled. 
PASS 2008 software was used to calculate the sample size.
3.0
Endpoints
3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in the overall Rasch-transformed 
score of the FACE-QTM: Satisfaction with Facial Appearance Scale to the final study visit (V7).
3.2
Secondary Efficacy Endpoints
3.2.1 Key Secondary Efficacy Endpoints
•
Subject’s assessment of aging appraisal as measured by the change from baseline in the 
Rasch-transformed score of the FACE-QTM: Aging Appraisal to final study visit (V7) 


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•
Subject’s assessment of psychological function as measured by the change from baseline 
in the Rasch-transformed score of the FACE-QTM: Psychological Function Scale to final 
study visit (V7) 
•
Subject’s assessment of social function as measured by the change from baseline in the 
Rasch-transformed score of the FACE-QTM: Social Function Scale to final study visit 
(V7)
•
Subject’s assessment of satisfaction with skin as measured by the change from baseline in 
the Rasch-transformed score of the FACE-QTM: Satisfaction with Skin to final study visit 
(V7)
•
Subject’s assessment of age-related facial appearance by the Self-Perception of Age (SPA)
measure at baseline to final study visit (V7); responders are defined as having achieved a 
younger category. 
3.2.2 Other Secondary Efficacy Endpoints
•
Investigator’s assessment of global facial aesthetic improvement as measured by the 5-
point Global Aesthetic Improvement Scale (GAIS) at final study visit (V7)
•
Subject’s assessment of global facial aesthetic improvement as measured by the 5-point 
GAIS at final study visit (V7)
•
Change in subject’s satisfaction with appearance of periorbital area as measured by the 
change from baseline in the Periorbital Aesthetic Appearance Questionnaire (PAAQ) to 
final study visit (V7) 
3.3
Safety Endpoints 
The safety endpoints will include the number and percentage of subjects who have any adverse 
events (AEs), injection site reactions (ISRs) or device deficiencies.
All AEs and injection site reactions (ISRs) will be collected from when the ICF is signed through 
to the last study visit (V7). Serious adverse events (SAEs) will be reported within the specified 
time and format directly to the Sponsor. 


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4.0
Analysis Populations and Subgroup
4.1
Analysis Populations
4.1.1 Modified Intent-to-Treat (mITT) Population
The mITT Population is defined as all subjects who enrolled and had at least one post-baseline 
efficacy assessment at V7. 
4.1.2 Evaluable Population
The Evaluable Population is defined as all subjects in the mITT Population who received study 
products (JUVÉDERM and BOTOX) as treatments in this study, had at least one efficacy 
assessment at the final visit (V7), and had no significant protocol violations or deviations that 
will affect any efficacy endpoint. Such significant protocol violations or deviations will be 
determined during data review. 
4.1.3 Safety Population
The Safety Population is defined as all subjects who received any product as treatment in this 
study. 
Unless otherwise specified, all efficacy analyses will be based on the Evaluable Population. The 
mITT Population will be used for demographics and baseline characteristics summary. The 
Safety Population will be used for the protocol deviation and violation, treatment exposure, all 
safety analyses, and listings unless otherwise specified. 
4.2
Subgroup
Subgroup analysis will be performed for the primary efficacy analysis by gender, as male and 
female subjects may have differing expectations/perceptions of aesthetic improvement; they will 
be examined separately.
5.0
Subject Disposition and Treatment Disposition
The number and percentage of subjects who are in the mITT Population, Evaluable Population, 
and Safety Population will be summarized by treatment group (HArmonyCA, Non-
HArmonyCA), gender (male, female), and overall, for all eligible subjects (subjects who signed 
the informed consent and met all eligibility criteria). Screen failure subjects and the reasons for 
screen failure will also be summarized by overall, for all screened subjects. 


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A listing of screen failure subjects, inclusion/exclusion criteria assessment and all analysis 
populations will be presented for all screened subjects. 
The number and percentage of subjects who complete the study and who discontinue from the 
study will be presented by treatment group, gender, and overall, for all screened subjects. The 
number and percentage of subjects who complete all treatments (HArmonyCA, JUVÉDERM, 
and BOTOX) and discontinue from any of the treatments (HArmonyCA, JUVÉDERM, and 
BOTOX) as collected on the CRF will also be presented by treatment group, gender, and overall, 
for all screened subjects. The primary reason for study discontinuation and treatment 
discontinuation will be presented as collected on the eCRF. Reasons for discontinuation include: 
•
Adverse Event
•
Lost to Follow-Up
•
Pregnancy
•
Withdrawal by Subject
•
Study Terminated by Sponsor 
•
Physician Decision
•
Protocol Deviation 
•
Other
A listing of study disposition and treatment disposition will be provided for the Safety
Population. 
The duration in study (days) will be summarized by treatment group, gender, and overall, for the 
Safety Population. It is calculated as (Last Assessment Date in the Study – First Assessment Date 
in the Study) + 1. 
A listing of study visits will be provided for the Safety Population. 


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6.0
Treatment Exposure and Administration
Treatment exposure of HArmonyCa Lidocaine, JUVÉDERM VOLITE, JUVÉDERM 
VOLBELLA, JUVÉDERM VOLIFT, JUVÉDERM VOLUMA, JUVÉDERM VOLUX will be 
summarized by visit, point of injection (region/MD code), side, gender, and overall, for the 
Safety Population. The summaries will include the number of injections and total volume of 
injections (mL), and average volume of injections (mL). 
The average volume of injections (mL) is calculated as total volume of injections (mL) / number 
of injections. 
Treatment exposure of BOTOX will be summarized by visit, point of injection (MD code), side, 
number of injections, gender, and overall, for the Safety Population. 
The investigator is responsible for ensuring that study data is properly recorded in compliance 
with the protocol at the investigational site.
All treatment exposure data will be listed for the Safety Population.
7.0
Demographics, Baseline Characteristics, Medical History, and 
Prior/Concomitant Medications/Procedures
7.1
Demographics and Baseline Characteristics
Demographic parameters will be summarized descriptively by treatment group, gender, and 
overall, for the mITT Population. Demographic parameters include age (years) and sex (if 
female, childbearing potential). 
Baseline characteristics will be summarized descriptively by treatment group, gender, and 
overall, for the mITT Population. Baseline parameters include height (m), weight (kg), body 
mass index (BMI) (kg/m2), and Fitzpatrick Skin Type (I, II, III, IV, V, VI). 
Demographics and baseline characteristics will be provided in a listing for the Safety Population. 
Facial wrinkle scale (FWS) will be collected for glabellar lines (GLs), crow’s feet lines (CFLs), 
and forehead lines (FHLs) at Screening visit. The FWS will be summarized by the severity of 
each question, by treatment group, gender, and overall, for the Safety Population.  FWS data will 
be provided in a listing for the Safety Population. 


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7.2
Medical, Surgical and Cosmetic Procedure History
Medical, surgical, and cosmetic procedural history data will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The actual version of the MedDRA will be 
noted in the statistical tables/listings and clinical study report. 
All medical, surgical, and cosmetic procedural history data will be listed for the Safety 
Population. 
7.3
Prior and Concomitant Medications
A prior medication is defined as any medication started before the date of first study treatment.
A concomitant medication is defined as any medication taken on or after the date of first 
treatment.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD). The actual version of the WHO DD will be noted in the statistical 
tables/listings and clinical study report. 
All prior and concomitant medications will be listed for the Safety Population. 
7.4
Concomitant Procedures
All concomitant procedures will be listed for the Safety Population. 
8.0 
Efficacy Analyses
8.1
General Considerations
•
All efficacy analyses will be conducted in the Evaluable Population. 
•
Day 1 is defined as the day on which the study treatment is first received.  
•
Baseline for efficacy is defined as the last non-missing assessment on or prior to Day 1. 
•
Study day is relative to Day 1. 
•
Change from baseline will be computed as post-baseline minus baseline. 


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•
Categorical variables will be summarized descriptively using number of subjects with 
observed values or events (n) and the percentage of subjects with observed values or 
events. 
•
Continuous variables will be summarized descriptively using number of subjects with 
observed values (n), mean, standard deviation (SD), standard error of mean (SEM), 
median, minimum (min), and maximum (max). 
•
Unless otherwise specified, the estimated mean and median for a set of values will be 
printed out to 1 more significant digit than the original values; the SD and SEM will be 
printed out to 2 more significant digits than the original values; the min and max will 
report the same significant digits as the original values.
•
Shapiro-Wilks test will be used to check the normality assumption. If the normality 
assumption is met, the statistical hypothesis test will be performed based on one-sample, 
one-sided t-test at 0.025 significance level. If the normality assumption is not met, 
Wilcoxon signed-rank test will be used instead and a 97.5% confidence interval (CI) for 
the median will be presented using the Hodges Lehmann method. Shapiro-Wilks and 
Wilcoxon signed-rank test will be performed by proc univariate procedure, and Hodges 
Lehmann CI of the median for paired samples will be performed based on a SAS macro
by Han (2008) [1] as specified in SPP Section 3.3. 
•
All CIs will be 1-sided 97.5% CIs, and will be printed to 2 decimal places, unless stated 
otherwise. P-values output will be in the format: ‘0.xxxx’, where xxxx is the value 
rounded to 4 decimal places. Every p-value less than 0.0001 will be presented as 
<0.0001. If the p-value is returned as >0.9999, then present it as it is. 
•
Unless otherwise specified, the summaries will be provided by treatment group, gender, 
and overall. 
8.2
Handling of Missing Data
For all FACE-QTM questionnaires, the sum of the items will be calculated and converted into an 
overall score (also known as the Rasch-transformed score) ranging from 0 (worst) to 100 (best). 
If the number of missing items (which includes selection of more than 1 response for an item, a 
response of non-applicable (N/A) or skipping a question) is at most 50% of all the items, then 
insert the unrounded mean of the completed items into the total sum score. Inversely, if the 


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number of missing items is more than 50%, then the overall score will be missing. The total 
score will not be calculated in this case and the particular visit will be excluded from the Rasch-
transformed score calculation and summary. 
For PAAQ questionnaire, all items will be transformed to a scale from 0 (no negative impact) to 
100 (high negative impact). Domain scores will be calculated as the average of transformed scale 
scores using the 50% rule given below: 
If the domain has at least 50% non-missing item responses it will be scored as the average of the 
non-missing responses (with reverse scoring and rescaling as appropriate). If the domain is 
missing more than 50% of item responses, then the domain score will be set to missing. 
For all other questionnaires as specified below, no imputation will be performed. 
•
Self-Perception of Age Questionnaire 
•
Global Aesthetic Improvement Scale
8.3
Primary Efficacy Endpoint and Analyses
8.3.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in the overall Rasch-transformed 
score of the FACE-QTM: Satisfaction with Facial Appearance Scale to the final study visit (V7). 
8.3.2 Handling of Missing Data for the Primary Efficacy Endpoint
For the FACE-QTM: Satisfaction with Facial Appearance questionnaire, if the number of missing 
items (which includes selection of more than 1 response for an item, a response of non-
applicable (N/A) or skipping a question) is at most 50% of all the items (i.e., at least 5 items have 
been answered), then insert the unrounded mean of the completed items into the total sum score. 
Inversely, if the number of missing items is more than 50% (i.e., less than 5 items have been 
answered), then the overall score will be missing.  The total score will not be calculated in this 
case and the particular visit will be excluded from the Rasch-transformed score calculation and 
summary.  


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8.3.3 Primary Efficacy Analyses
The FACE-QTM: Satisfaction with Facial Appearance questionnaire will be given at the 
Screening visit and the final study visit (V7). Change from baseline in the overall Rasch-
transformed score to the final study visit will be summarized descriptively by treatment group 
and overall and will be analyzed using a one-sample t-test (or Wilcoxon signed-rank test if the 
normality assumption is not met) for the Evaluable Population. See SPP Appendix C for the 
calculation of the overall Rasch-transformed score.
The number and percentage of subjects who provide responses to the FACE-QTM Satisfaction 
with Facial Appearance questionnaire will also be summarized descriptively by treatment group 
and overall based on the following categories for each FACE-QTM question: 
•
1. Very Dissatisfied
•
2. Somewhat Dissatisfied
•
3. Somewhat Satisfied
•
4. Very Satisfied
A listing for FACE-QTM Satisfaction with Facial Appearance will be provided for the Safety 
Population. 
8.3.4 Additional Analyses of the Primary Efficacy Endpoints
Not applicable.
8.4
Secondary Efficacy Endpoints and Analyses
8.4.1 Secondary Efficacy Endpoints
The key secondary efficacy endpoints are: 
•
Subject’s assessment of aging appraisal as measured by the change from baseline in the 
Rasch-transformed score of the FACE-QTM: Aging Appraisal to final study visit (V7) 
•
Subject’s assessment of psychological function as measured by the change from baseline 
in the Rasch-transformed score of the FACE-QTM: Psychological Function Scale to final 
study visit (V7) 


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•
Subject’s assessment of social function as measured by the change from baseline in the 
Rasch-transformed score of the FACE-QTM: Social Function Scale to final study visit 
(V7)
•
Subject’s assessment of satisfaction with skin as measured by the change from baseline in 
the Rasch-transformed score of the FACE-QTM: Satisfaction with Skin to final study visit 
(V7)
•
Subject’s assessment of age-related facial appearance by the Self-Perception of Age (SPA) 
measure at baseline to final study visit (V7); responders are defined as having achieved a 
younger category. 
Other secondary efficacy endpoints are: 
•
Investigator’s assessment of global facial aesthetic improvement as measured by the 5-
point GAIS at final study visit (V7) 
•
Subject’s assessment of global facial aesthetic improvement as measured by the 5-point 
GAIS at final study visit (V7)
•
Change in subject’s satisfaction with appearance of periorbital area as measured by the 
change from baseline in the Periorbital Aesthetic Appearance Questionnaire (PAAQ) to 
final study visit (V7) 
8.4.2 Secondary Efficacy Analyses
Change from baseline in the Rasch-transformed score of FACE-QTM questionnaires (FACE-QTM: 
Aging Appraisal, FACE-QTM: Psychological Function, FACE-QTM: Social Function, FACE-
QTM: Satisfaction with Skin) will be summarized descriptively by treatment group, gender, and 
overall and will be analyzed using a one sample t-test (or Wilcoxon signed-rank test if normality 
assumptions are not met) for the Evaluable Population. See SPP Appendix D, Appendix E, 
Appendix F, and Appendix G for the calculation of the overall Rasch-transformed score for each 
FACE-QTM questionnaire. 
The number and percentage of subjects who provide responses to each FACE-QTM questionnaire 
will also be summarized descriptively by treatment group, gender, and overall, for the Evaluable 
Population, based on the following categories for each questionnaire: 


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•
FACE-QTM Aging Appraisal 
o
1. Definitely Agree
o
2. Somewhat Agree 
o
3. Somewhat Disagree
o
4. Definitely Disagree
•
FACE-QTM Psychological Function, FACE-QTM Social Function 
o
1. Definitely Disagree 
o
2. Somewhat Disagree
o
3. Somewhat Agree 
o
4. Definitely Agree
•
FACE-QTM Satisfaction with Skin
o
1. Very Dissatisfied
o
2. Somewhat Dissatisfied
o
3. Somewhat Satisfied
o
4. Very Satisfied
For the Self-Perception of Age (SPA) questionnaire, the number and percentage of subjects who
look their current age will be summarized for baseline and the final study visit  by treatment 
group, gender, and overall, for the Evaluable Population. The change from baseline in the 
number of years look younger and older to the final study visit will be summarized descriptively 
by treatment group, gender, and overall, for the Evaluable Population. 
A shift table to summarize the changes into an improvement category from the baseline to the 
final study visit will be provided in frequency and percentage. No statistical testing for the shift 
table will be performed.


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There are two assessment categories in GAIS at the final study visit: subject rating and 
investigator rating. Descriptive summaries will be provided in frequency and percentage of the 
scales at the final study visit, in the 5-point scale from -2 to +2 by treatment group, gender, and 
overall, for the Evaluable Population. The scales include: 
•
2: Much Improved  
•
1: Improved 
•
0: No Change 
•
-1: Worse
•
-2: Much Worse 
Descriptive summaries will be provided in frequency and percentage for nine questions of 
PAAQ at baseline and the final study visit by treatment group, gender, and overall, for the 
Evaluable Population, with five categories of answers for each question. Five categories of 
answer include:
•
   0. Never
•
   1. Rarely
•
   2. Some of the Time
•
   3. Most of the Time
•
   4. All of the Time
The PAAQ will also be summarized in the transformed total score and three domains, using 
descriptive statistics by treatment group, gender, and overall and will be analyzed using a one-
sample t-test (or Wilcoxon signed-rank test if normality assumption is not met) for the Evaluable 
Population. 
The transformed scale score is calculated as [(actual raw score – lowest possible raw score) / 
possible raw score range] * 100. This formula can be simplified as [(actual raw score – 0) / 4] * 
100. 


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The transformed total score is calculated as [(actual total raw score - lowest possible total raw 
score) / (possible total raw score range)] * 100. This formula can be simplified as [(actual total 
raw score - 0) / 36] *100. 
Three domains include psychological domain, appearance domain, and coping domain. The 
psychological domain is defined as (sum of transformed scale score in PAAQ questions of 2, 4, 
6, 7, and 8) / (number of questions). This formula can be simplified as (sum of transformed scale
score in PAAQ questions of 2, 4, 6, 7 and 8) / 5. 
Similar manner will be applied to the appearance domain and the coping domain, but with 
different number of PAAQ questions included for each domain. The appearance domain includes 
PAAQ questions of 1, 3 and 5. The coping domain contains only PAAQ question 9. See SPP 
Appendix H for the details of domain score calculation and missing data imputation. 
Listings will be provided for FACE-QTM: Aging Appraisal, FACE-QTM: Psychological Function, 
FACE-QTM: Social Function, FACE-QTM: Satisfaction with Skin, SPA, GAIS, and PAAQ for the 
Safety Population. 
A figure will be provided for the change from baseline of each FACE-QTM questionnaires 
(Satisfaction with Facial Appearance, Aging Appraisal, Psychological Function, Social Function, 
and Satisfaction with Skin) in the Rasch-transformed score by treatment group and gender, for 
the Evaluable Population. 
8.5
Subgroup Analyses
A subgroup analysis on the primary efficacy endpoints (change from baseline in the overall 
Rasch-transformed score of the FACE-QTM: Satisfaction with Facial Appearance Scale to the 
final study visit) will be performed by gender and overall. 
9.0
Safety Analyses
9.1
General Considerations
•
All safety analyses will be conducted by treatment group, gender, and overall, for the 
Safety Population. 


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•
Adverse events (AEs) will be coded using the medical dictionary for Regulatory 
Activities (MedDRA). The actual version of the MedDRA coding dictionary will be 
noted in the statistical outputs and clinical study report. 
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System Organ 
Classes (SOCs) and preferred terms (PTs).
An AE will be considered a JUVÉDERM injection related AE if it has a reasonable possibility 
(Possible, Probable, or Causal relationship) that the JUVÉDERM injections caused the event.
The JUVÉDERM injections include JUVÉDERM VOLITE, JUVÉDERM VOLBELLA, 
JUVÉDERM VOLIFT, JUVÉDERM VOLUMA, and JUVÉDERM VOLUX.
An AE will be considered a BOTOX related AE if it has a reasonable possibility (Reasonable 
Possibility) that the BOTOX cosmetic caused the event.
An AE will be considered a study procedure related AE if it has a reasonable possibility 
(Possible, Probable, or Causal relationship) that the study procedure caused the event.  
An AE will be considered a device related AE if it is related to a device malfunction/deficiency. 
If the causal relationship to the study treatment/device/procedure is missing for an AE that 
occurred on or after the date of the first study treatment, then a causal relationship will be 
imputed for analysis. The imputed values for relationship to study treatment/device/procedure 
will be used for the incidence summary; the actual values will be presented in data listings.
If severity is missing for an AE that occurred before the date of first study treatment, then a 
severity of mild will be imputed for analysis. If the severity is missing for an AE that occurred 
on or after the date of the first study treatment, then a severity of severe will be imputed. The 
imputed values for severity will be used for the incidence summary; the actual values will be 
presented in data listings. 
9.2.1 Treatment-Emergent Adverse Events
Treatment-emergent adverse event (TEAE) is defined as any AE with the onset on or after the 
date (and time, if known) of the first study treatment. A TEAE will be considered a treatment-


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emergent serious adverse event (TESAE) if it is a TEAE that additionally meets any SAE 
criterion.
All AEs will be included in a listing. Only TEAEs will be included for summaries, unless 
otherwise specified. Subjects with any TEAEs, TESAEs, severe TEAEs, TEAEs related to study 
treatment, TEAEs related to study procedure, TEAES related to device, TEAEs leading to study 
discontinuation, TEAEs leading to death, TESAEs related to study treatment, TESAEs related to 
study procedure, TESAEs related to device, TESAEs leading to study discontinuation, and 
TESAEs leading to death will be summarized. 
9.2.2 Adverse Event Overview
Overall summaries of TEAEs will include:
•
The number and percentage of subjects with any TEAE 
•
The number and percentage of subjects with any TESAE
•
The number and percentage of subjects with any severe TEAE
•
The number and percentage of subjects with any TEAE related to JUVÉDERM VOLITE
•
The number and percentage of subjects with any TEAE related to JUVÉDERM
VOLBELLA
•
The number and percentage of subjects with any TEAE related to JUVÉDERM VOLIFT
•
The number and percentage of subjects with any TEAE related to JUVÉDERM
VOLUMA
•
The number and percentage of subjects with any TEAE related to JUVÉDERM VOLUX
•
The number and percentage of subjects with any TEAE related to BOTOX cosmetic
•
The number and percentage of subjects with any TEAE related to study procedure 
•
The number and percentage of subjects with any TEAE related to device
•
The number and percentage of subjects with any TEAE leading to study discontinuation 


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•
The number and percentage of subjects with any TEAE leading to death 
•
The number and percentage of subjects with any TESAE related to JUVÉDERM
VOLITE
•
The number and percentage of subjects with any TESAE related to JUVÉDERM
VOLBELLA
•
The number and percentage of subjects with any TESAE related to JUVÉDERM
VOLIFT
•
The number and percentage of subjects with any TESAE related to JUVÉDERM
VOLUMA
•
The number and percentage of subjects with any TESAE related to JUVÉDERM
VOLUX
•
The number and percentage of subjects with any TESAE related to BOTOX cosmetic
•
The number and percentage of subjects with any TESAE related to study procedure 
•
The number and percentage of subjects with any TESAE related to device 
•
The number and percentage of subjects with any TESAE leading to study discontinuation 
•
The number and percentage of subjects with any TESAE leading to death 
o
Before BOTOX Treatment
o
On or After BOTOX Treatment
9.2.1 Treatment-Emergent Adverse Events by SOC and PT, and/or Severity
The number and percentage of subjects will be summarized by SOC and PT, and by maximum 
severity, SOC, and PT as follow: 
•
TEAEs by SOC and PT 
•
TEAEs by maximum severity, SOC, and PT 


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•
TEAEs related to study treatment (JUVÉDERM VOLITE, JUVÉDERM VOLBELLA, 
JUVÉDERM VOLIFT, JUVÉDERM VOLUMA, JUVÉDERM VOLUX, and BOTOX 
cosmetic) by SOC and PT 
•
TEAEs related to study treatment (JUVÉDERM VOLITE, JUVÉDERM VOLBELLA, 
JUVÉDERM VOLIFT, JUVÉDERM VOLUMA, JUVÉDERM VOLUX, and BOTOX 
cosmetic) by maximum severity, SOC, and PT 
•
TEAEs related to study procedure by SOC and PT 
•
TEAEs related to study procedure by maximum severity, SOC, and PT 
•
TEAEs related to device by SOC and PT
•
TEAEs related to device by maximum severity, SOC, and PT 
•
TEAEs leading to study discontinuation by SOC and PT 
•
TEAEs leading to death by SOC and PT 
The TEAE summary tables will be presented with SOC in alphabetical order and in decreasing 
frequency within each SOC. If more than 1 AE is coded to the same SOC or PT for the same 
subject, the subject will be counted only once for that SOC or PT using the most severe 
occurrence for the summarization by severity. 
In addition, the duration of TEAEs will be summarized by SOC and PT. The duration of a TEAE 
will be calculated as (AE End Date – AE Start Date) + 1, and summarized as:
•
1 – 3 Days 
•
4 – 7 Days 
•
8 – 14 Days 
•
15 – 30 Days 
•
>= 30 Days


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The duration summary table will be presented with SOC in alphabetical order and in decreasing 
frequency within each SOC. If more than 1 AE is coded to the same SOC or PT for the same 
subject, the subject will be counted only once for that SOC or PT under the maximum duration. 
9.2.2 SAEs (Including Deaths) and Adverse Events Leading to Study 
Discontinuation
An SAE is defined as any AE that: 
•
led to death
•
led to serious deterioration in the health of the subject, that either resulted in 
o
a life-threatening illness or injury; or 
o
a permanent impairment of a body structure or a body function; or 
o
in-patient hospitalization or prolongation; or 
o
medical or surgical intervention to prevent permanent impairment to body structure or 
a body function; or 
•
led to fetal distress, fetal death or a congenital abnormality or birth defect.
TESAEs, TESAEs related to study drug, TESAEs related to study procedure, TESAEs related to 
device, TESAEs leading to study discontinuation, and TESAEs leading to death will be 
summarized in the overall summary table, and by SOC and PT as follow: 
•
TESAE by SOC and PT 
•
TESAEs related to study treatment (JUVÉDERM VOLITE, JUVÉDERM VOLBELLA, 
JUVÉDERM VOLIFT, JUVÉDERM VOLUMA, JUVÉDERM VOLUX, and BOTOX 
cosmetic) by SOC and PT 
•
TESAEs related to study procedure by SOC and PT 
•
TESAEs related to device by SOC and PT 
•
TESAEs leading to study discontinuation by SOC and PT 


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•
TESAEs leading to death by SOC and PT 
9.2.3 Adverse Events of Special Interest
Not applicable.
9.3
Analysis of Laboratory Data
Not Applicable. 
9.4
Analysis of Vital Signs
Not Applicable. 
9.5
Injection Site Response
Subjects will maintain a diary record of the presence, location, frequency, severity (mild, 
moderate, and severe), and duration of any injection site response (ISR) for 30 days after each 
filler treatment.
At each visit, the duration of each IRS symptom (redness, pain after injection, tenderness to 
touch, firmness, swelling, lumps/bumps, bruising, itching, discoloration, and other) will be
calculated as Last Occurrence Date in eDiary – First Occurrence Date in eDiary + 1. It will be 
summarized descriptively using number and percentage of subjects with observed symptom, 
mean, SD, SEM, median, min, and max, and by categories 1-3 days, 4-7 days, 8-14 days, and 15-
30 days. 
The number and percentage of subjects with any ISR will be summarized by visit, ISR symptom 
and maximum severity.
A listing of ISRs will be provided for the Safety Population. 
9.6
Procedural Pain
Not Applicable. 
9.7
Safety Subgroup Analyses
Not Applicable. 


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9.8
Other Safety Analyses
The numbers and percentage of subjects with device deficiencies will be summarized by suspect 
device type.
A listing will be provided for device deficiencies for the Safety Population. 
10.0 Other Analyses
Not applicable.
11.0 Interim Analyses
Not applicable.
12.0 Overall Type-I Error Control
Not applicable.
13.0 SAP Version History Summary
SAP Version
Date
Summary
0.1
10 May 2023
First draft
0.2 
28 June 2023
Second draft
1.0 
05 September 2023
Final version
1.1 
28 March 2024
Revision to modify the summaries for treatment 
exposure and ISR based on the data collected. 
2.0 
03 April 2024
Revised final version
2.1 
04 June 2024 
Revision with modifications below: 
1. Remove Appendix D through Appendix I. 
2. Add Hodges Lehmann method for the 
confidence interval for the median of 
paired samples. 
3. Modify the missing data imputation for 
FACE-Q and PAAQ questionnaires. 
3.0 
05 June 2024
Revised final version


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14.0 Reference
[1] Lingling Han, Merck & Co., Inc., North Wales, PA. Calculating the point estimate and 
confidence interval of Hodges-Lehmann's median using SAS® software.Paper ST-154, SESUG 
Proceedings. Available from http://analytics.ncsu.edu/sesug/2008/ST-154.pdf (access on May 
28, 2024). 


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Appendix A. Protocol Deviations and Violations
A protocol deviation (PD) is any non-adherence to study procedures that does not result in 
additional risk to the subject. Protocol deviations will be reviewed and documented before 
database lock.
A protocol violation (PV) is any non-adherence to the protocol that may result in significant 
additional risk to the subject (e.g., enrollment of a subject who does not meet the study criteria). 
A protocol violation can also be an event of non-adherence to Good Clinical Practice (GCP) that 
may impact subject safety (e.g., failure to obtain proper consent before performing study 
procedures). Violations should be reported to the study sponsor and the Institutional Review 
Board (IRB) within 5 working days if they occur.
Significant PDs/PVs (equivalent to major PDs/PVs as collected in data) will be identified before 
database lock. Significant PDs/PVs which impact the study conduct, data validity or integrity for 
the study outcomes will be summarized by the following categories:
•
Inclusion or exclusion criteria 
•
Withdrawal Criteria
•
Treatment
•
Concomitant Medications 
•
Timeframe Deviation
The number and percentage of subjects with significant PDs/PVs will be summarized for the 
Safety Population by gender and total, and by treatment group and overall, for the Safety 
Population. 
All PDs/PVs will be listed for the Safety Population.


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Appendix B. List of Abbreviations
Abbreviation
Definition 
AE
Adverse Event
BMI
Body Mass Index
CFL
Crow’s Feet Line
CI
Confidence Interval
DD
Drug Dictionary
eCRF
Electronic Case Report Form
FHL
Forehead Line
FWS
Facial Wrinkle Scale
GAIS
Global Aesthetic Improvement Scale
GCP
Good Clinical Practice
GL
Glabellar Line
ICF
Informed Consent Form
IRB
Institutional Review Board
ISR
Injection Site Response
max
Maximum
min
Minimum
mITT
Modified Intent-to-treat 
mL
Milliliter
MedDRA
Medical Dictionary for Regulatory Activities
PAAQ
Periorbital Aesthetic Appearance Questionnaire
PD
Protocol Deviation
PT
Preferred Term
PV
Protocol Violation
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SEM
Standard Error of Mean
SOA
Schedule of Activities
SOC
System Organ Class
SPA
Self-Perception of Age
SPP
Statistical Programming Plan


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Abbreviation
Definition 
TEAE
Treatment-emergent Adverse Event
TESAE
Treatment-emergent Serious Adverse Event
WHO 
World Health Organization 


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Appendix C. Changes to Protocol-planned Analyses
Protocol Planned Analysis 
Modified Analysis
All efficacy analyses will be based on the 
mITT and Evaluable Populations. 
All efficacy analyses will be based on the
Evaluable Populations. 
Subgroup analysis by gender and treatment 
touch-ups.  
Subgroup analysis by gender only. 
mITT (modified Intent-to-Treat) Population - 
all subjects who enrolled and had at least one 
post-baseline efficacy assessment.
mITT (modified Intent-to-Treat) Population - 
all subjects who enrolled and had at least one 
post-baseline efficacy assessment at V7.
Evaluable Population– all subjects as defined 
in the mITT Population who have received 
both study products as treatments in this 
study, had at efficacy assessment at the final 
visit (V7) and no major protocol violations or 
deviations. 
Evaluable Population– all subjects as defined 
in the mITT Population who have received 
both study products as treatments in this 
study, had at efficacy assessment at the final 
visit (V7) and no major protocol violations or 
deviations that will affect any efficacy 
endpoint. 
Exploratory efficacy analysis may be 
performed on the collected video and 
photographs. 
Removed.