Clinical trial NCT03712449
Conditions: Facial Rhytides, Skin Folds, Loss of Volume and Skin Quality
Sponsor: Allergan
Start date: 2019-01-22; Completion date: 2020-07-29
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to quantify the psychological and emotional impact of comprehensive aesthetic treatment with a portfolio of Allergan products by measuring the change in participant's satisfaction with facial appearance from baseline to the final study visit.

Detailed description:

Arms: arm 1: BELKYRA was injected into the subcutaneous fat for maximum of 6 treatments, 1 month apart from Month 0 to Month 5. Maximum dose did not exceed 100 milligrams (mg) \[10 milliliters (mL)\] in a single treatment.

SkinMedica products: (Facial Cleanser, TNS Essential Serum®, Rejuvenative Moisturizer, Optional: Total Defense + Repair Broad Spectrum Sunscreen SPF34), applied daily from Month 6 to Month 11.

Facial filler injectable treatment (JUVÉDERM VOLBELLA with Lidocaine and/or JUVÉDERM VOLIFT with Lidocaine and/or JUVÉDERM VOLUMA with Lidocaine and/or JUVÉDERM VOLITE with Lidocaine) from Month 6 to Month 8. The volume of filler injected at initial and touch-up treatments was determined by the investigator.

BOTOX Cosmetic 20 units (U) to glabellar lines and/or 2-6 U injected bilaterally to crow's feet lines and/or 24 U total injected to forehead lines at Month 9 and Month 10. arm 2: Participants who did not receive BELKYRA.

SkinMedica products: (Facial Cleanser, TNS Essential Serum®, Rejuvenative Moisturizer, Optional: Total Defense + Repair Broad Spectrum Sunscreen SPF34), applied daily from Month 0 to Month 5.

Facial filler injectable treatment (JUVÉDERM VOLBELLA with Lidocaine and/or JUVÉDERM VOLIFT with Lidocaine and/or JUVÉDERM VOLUMA with Lidocaine and/or JUVÉDERM VOLITE with Lidocaine) from Month 0 to Month 2. The volume of filler injected at initial and touch-up treatments was determined by the investigator.

BOTOX Cosmetic 20 units (U) to glabellar lines and/or 2-6 U injected bilaterally to crow's feet lines and/or 24 U total injected to forehead lines at Month 3 and Month 4.
Interventions: intervention 1: JUVÉDERM® intervention 2: BOTOX Cosmetic® intervention 3: BELKYRA® intervention 4: SkinMedica
Intervention descriptions: intervention 1: Facial filler injection (JUVÉDERM VOLBELLA with Lidocaine, and/or JUVÉDERM VOLIFT with Lidocaine, and/or JUVÉDERM VOLUMA with Lidocaine, and/or JUVÉDERM VOLITE with Lidocaine) from Month 6 to Month 8 (BELKYRA Treatment) and Month 0 to Month 2 (Non-BELKYRA Treatment). intervention 2: BOTOX Cosmetic, 20 U to glabellar lines and/or 2-6 U injected bilaterally to crow's feet lines and/or 24 U injected to forehead lines at Month 9 and Month 10 (BELKYRA Treatment) and at Month 3 and Month 4 (Non-BELKYRA Treatment). intervention 3: BELKYRA, subcutaneous injection for maximum of 6 treatments, 1 month apart from Month 0 to Month 5. Maximum dose = 100 mg (10mL). intervention 4: SkinMedica products (Facial Cleanser, TNS Essential Serum®, Rejuvenative Moisturizer, Optional: Total Defense + Repair Broad Spectrum Sunscreen SPF34), applied daily from Month 6 to Month 11 (BELKYRA Treatment) and Month 0 to Month 5 (Non-BELKYRA Treatment).

Protocol documents:
Prot_000.pdf: 
NCT03712449 
 
Study ID: CMO-MA-FAS-0579 
 
 
Title:  Canada Global HARMONY: Prospective, Multi-site, Study to Evaluate Subject Satisfaction 
With Facial Appearance Overall and the Aesthetic and Psychosocial Impact of Combined Facial 
Treatment 
 
Protocol Date: 24Oct2018 


 
Clinical Study Protocol 
Canada Global HARMONY: 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-0579 
Drug Development Phase: 
Phase 4, Postmarketing 
Investigational Products: 
BOTOX Cosmetic®, BELKYRA®, 
JUVÉDERM® VOLITE®, JUVÉDERM® 
VOLBELLA® with Lidocaine, JUVÉDERM® 
VOLIFT® with Lidocaine, JUVÉDERM® 
VOLUMA® with Lidocaine  
Indications: 
Glabellar Lines, Crow’s Feet Lines, Forehead 
Lines, Nasolabial Folds, Facial Volume Loss, Lip 
Augmentation, Perioral Rhytides, Submental Fat, 
and/or Forehead/Cheek/Neck Cutaneous 
Depressions or Fine Lines 
Sponsor: 
Allergan Inc. 
85 Enterprise Boulevard, Suite 500 
Markham, Ontario, Canada L6G 0B5 
Tel:  905-940-1660 
Version and Date 
Version 2, 24th October 2018  
 
 
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. 


Canada Global HARMONY Protocol 
Allergan 
CMO-MA-FAS-0579 
 
 24th October 2018 
 
VERSION 2 
 
Page 2 
Protocol Approval Signature Page 
Sponsor: Allergan  
I have read and understand the contents of this clinical protocol for Study No.  
CMO-MA-FAS-0579 dated  24th October 2018 and agrees to meet all obligations of 
Allergan 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: 
 
Associate Director, Phase IV 
 
 
 
 


Canada Global HARMONY Protocol 
Allergan 
CMO-MA-FAS-0579 
 
 24th October 2018 
 
VERSION 2 
 
Page 3 
 
Principal Investigator’s Agreement 
I have read and understand the contents of this clinical protocol for Study No. 
CMO-MA-FAS-0579 dated 24th October 2018 and will adhere to the study requirements as 
presented, including all statements regarding confidentiality. 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the 
protocol, good clinical practices (Allergan has certified GCP training completed) and all 
applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this 
information is submitted to 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 
 
 
 


Canada Global HARMONY Protocol 
Allergan 
CMO-MA-FAS-0579 
 
 24th October 2018 
 
VERSION 2 
 
Page 4 
PROTOCOL SYNOPSIS 
Sponsor: 
Allergan Inc.  85 
Enterprise Blvd., Suite 
500, Markham, Ontario, 
Canada 
 
Investigational Products: 
BOTOX Cosmetic®, BELKYRA®, 
JUVÉDERM® VOLITE®, JUVÉDERM® 
VOLBELLA® with Lidocaine, 
JUVÉDERM® VOLIFT® with Lidocaine, 
JUVÉDERM® VOLUMA® with Lidocaine  
Developmenta
l Phase: 
Phase 4, 
Postmarketing 
Title of Study: Canada Global HARMONY: Prospective, Multi-site Study to Evaluate 
Subject Satisfaction with Facial Appearance Overall and the Aesthetic and Psychosocial 
Impact of Combined Facial Treatment 
Protocol Number: CMO-MA-FAS-0579 
Number of Subjects and Study Center(s): 60 subjects at 7 study centers in Canada 
Indication:  
1. BOTOX Cosmetic is indicated for the treatment of upper facial rhytides, including 
forehead, lateral canthus, and glabellar lines. 
2. BELKYRA® is indicated for the improvement in the appearance of moderate to severe 
convexity or fullness associated with submental fat (SMF) in adults. 
3. JUVÉDERM® VOLITE® is indicated for the treatment, by filling, of superficial 
cutaneous depressions such as fine lines. 
4. JUVÉDERM® VOLBELLA® with Lidocaine is indicated for enhancement and pouting 
of the lips to correct volume loss and to treat perioral lines and oral commissures, and 
infraorbital area 
5. JUVÉDERM® VOLIFT® with Lidocaine is indicated for the treatment of nasolabial 
folds. 
6. JUVÉDERM® VOLUMA® with Lidocaine is indicated to restore volume of the face 
(i.e. cheek, chin, and malar area).  
 
Primary Study Objective: 
To quantify the psychological and emotional impact of comprehensive aesthetic treatment 
with a portfolio of Allergan products by measuring the change in subject’s satisfaction 
with facial appearance from baseline (before any treatment) to the final study visit.  
Secondary Study Objectives: 
• To determine the subject’s self-appraisal of age-related facial appearance, 
psychological function, and overall satisfaction with skin modules.  
• To quantify the investigator’s and subject’s assessment of aesthetic improvement. 
Methodology: 
This Phase 4 study is a prospective, interventional, multicenter, combination medical 
device, drug, and skin care postmarketing study. Each subject will be in the study for up to 


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Canada Global HARMONY Protocol 
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 24th October 2018 
 
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The primary endpoint is the change from screening (V0) before treatment in the 
Rasch-transformed score of the FACE-Q Satisfaction with Facial Appearance Overall 
Scale to the final study visit (V12).  
Key Secondary Endpoints 
• Subject’s assessment of expectations of life change as measured by the mean change 
from baseline before any treatment in the Rasch-transformed score of the FACE-Q 
Expectations scale to final study visit (V12)  
• Subject’s assessment of age-related facial appearance as measured by the mean change 
from baseline before any treatment in the Rasch-transformed score of the FACE-Q 
Aging Appraisal to final study visit (V12)  
• Subject’s assessment of psychological well-being as measured by the mean change 
from baseline before any treatment in the Rasch-transformed score of the FACE-Q 
Psychological Function Scale to final study visit (V12) 
• Subject’s assessment of social function as measured by the mean change from baseline 
before any treatment in the Rasch-transformed score of the FACE-Q Social Function 
Scale to final study visit (V12)  
• Subject’s assessment of overall satisfaction with skin as measured by the mean change 
from baseline before any treatment in the Rasch-transformed score of the FACE-Q 
Satisfaction with Skin to final study visit (V12) 
• Subject’s assessment of age-related facial appearance as measured by self-perception 
of age (SPA) at baseline before any treatment to final study visit (V12); responders are 
defined as having achieved a younger category. 
Other Secondary Endpoints 
• Change in investigator’s assessment of global facial aesthetic improvement as 
measured by the 5-point global aesthetic improvement scale (GAIS) at final study visit 
(V12) 
• Change in subject’s assessment of global facial aesthetic improvement as measured by 
the 5-point GAIS at final study visit (V12) 
• Change in subject’s satisfaction with appearance of periorbital area as measured by the 
periorbital aesthetic appearance questionnaire (PAAQ) 


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Key Inclusion Criteria:  
1. 30 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. Mild to moderate facial photo damage based on a score of 1 to 9 on the SkinMedica 
overall photodamage scale (SOPS) 
5. Willing to avoid direct and prolonged sun exposure to the facial skin, which includes 
tanning beds, for the duration of the study  
6. Must qualify to receive BOTOX Cosmetic as per the approved Product Monograph:is 
indicated: for the treatment of upper facial rhytides, including forehead, lateral 
canthus, and glabellar 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  


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- 
FHLs of 2 (moderate) to 3 (severe) rating at maximum eyebrow elevation as 
assessed using the FWS  
7. Must qualify to receive facial filler treatments as per the approved Directions for Use 
Key Exclusion Criteria:  
2. Body mass index (BMI) > 30 
3. Known allergy or sensitivity to any study products or their components  
4. Pregnant, lactating, or planning to become pregnant at any time during the study 
5. Received BOTOX Cosmetic or treatment with any other botulinum toxin product for 
any condition within 6 months before enrollment 
6. Received (or is planning to receive) anti-coagulation, anti-platelet or thrombolytic 
medications (eg, warfarin) or other substances known to increase coagulation time 
from 10 days prior to injection and up to 3 days post-injection 
7. 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 
8. 
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  
9. 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 
11. Lip tattoos, facial hair, or scars that would interfere with visualization of the lips and 
perioral area for the effectiveness assessments 


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12. 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 
13. Received any investigational product within 60 days prior to study enrollment or 
planning to participate in another investigation during the course of this study 
14. An employee (or a relative of an employee) of the investigators, Allergan, or 
representative of Allergan 
15. 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 
16. Current use of oral corticosteroids 
17. Current use of nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, aspirin, 
ibuprofen), from 10 days prior to injection up to 3 days post-injection  
18. 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  
19. Systemic retinoid therapy within one year prior to study enrollment 
21. 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 
22. Current use of aminoglycoside antibiotics, curare-like agents, or agents that might 
interfere with neuromuscular (skeletal) function  
23. Profound atrophy/excessive weakness of muscles in target areas of injection 
24. History of facial nerve palsy 
25. Anticipated need for treatment with botulinum toxin of any serotype for any reason 
during the study (other than study treatment) 
26. Very thin skin in the mid-facial region  
27. Tendency to accumulate fluid in the lower eyelids, or large infraorbital fat pads, ie, 
significant convexity or projection from the infraorbital fat pads 
28. Mid-face volume deficit due to congenital defect, trauma, abnormalities in adipose 
tissue related to immune-mediated diseases such as generalized lipodystrophy (eg, 
juvenile dermatomyositis), partial lipodystrophy (eg, Barraquer-Simons syndrome), 
inherited disease, or human immunodeficiency virus–related disease  
29. Undergone oral surgery or other dental procedures (eg, tooth extraction, orthodontia, 
or implantation) within 30 days prior to enrollment or planning to undergo any of these 
procedures during the study 
30. Subjects with neuromuscular disorders including generalized muscle weakness, 
diplopia, ptosis, dysphonia, dysarthria, severe dysphagia, and respiratory compromise  
31. Subjects with a history of allergies or hypersensitivity to HA or lidocaine 
 
 


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Products, Dose, and Mode of Administration:  
BELKYRA 
Inject 0.2 mL in each site, 1 cm apart, up to 50 injections into the subcutaneous fat. The 
planned treatment area should be outlined with a surgical pen and a 1 cm injection grid applied 
to mark the injection sites. The maximum dose should not exceed 100 mg (10 mL) in a 
single treatment. The number of treatment sessions needed to achieve a satisfactory 
response depends on the individual patient. Up to 6 treatments spaced at intervals of no 
less than 1 month apart. are recommended based on the clinical trial efficacy and safety 
data.  Patients should receive the minimum number of injections over a minimum number 
of treatment sessions to achieve a satisfactory result. More frequent dosing with 
BELKYRA has not been clinically evaluated for safety and effectiveness and is not 
recommended. The investigator will determine the number of treatment sessions based on 
his/her clinical experience and the subject’s aesthetic goals. 
 
SkinMedica Products 
 
During Visit 7 to Visit 12, all subjects will receive a combination of the following 
SkinMedica products, to be applied daily for approximately 4 months, as per the 
investigator’s discretion:  
• Facial Cleanser 
• TNS Essential Serum® 
• Rejuvenative Moisturizer 
• Optional: Total Defence + Repair Broad Spectrum Sunscreen SPF34 may be used at 
the subjects’ discretion 
 
BOTOX Cosmetic  
Subjects will receive at least one of the following BOTOX Cosmetic dosing regimens: 
• 20 U total to GLs area consisting of 5 injection sites (2 in each corrugator and one in 
the procerus), and/or 
• CFLs: 2-6 U should be injected bilaterally at each of 1-3 injection sites and/or 
• 24U total to FHLs area consisting of 4 injection sites in the frontalis muscle. 
 
Facial Fillers  
JUVÉDERM VOLBELLA with Lidocaine  
The investigator will determine the appropriate volume of JUVÉDERM VOLBELLA to 
inject at initial and touch-up treatments based on his/her clinical experience and the 
subject’s aesthetic goals. The maximum volume that may be injected for initial and top-up 
treatments combined is 2 mL for lips injection, 1.5 mL for oral commissure injection, 1.2 
mL for perioral line injection and 1.5 mL per eye for infraorbital injection. 


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JUVÉDERM VOLIFT with 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 
JUVÉDERM VOLIFT with Lidocaine allowed per subject for the initial and touch-up 
treatments combined is 4 syringes (4.0 mL). 
JUVÉDERM VOLUMA with Lidocaine 
The investigator will determine the appropriate volume to be injected during initial and 
touch-up treatments based on his/her clinical experience.  Do not inject more than 2 mL 
per treatment area during each session.  
 
JUVÉDERM VOLITE with 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 
JUVÉDERM VOLITE with Lidocaine allowed per subject for the initial and touch-up 
treatments combined is 4 syringes (4.0 mL).  
 
The investigator should not inject greater than 20 mL of filler per 60kg (130 lbs) body 
mass per year for a single subject.   
Concomitant Medications: 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
investigator, including but not limited to medications for other conditions (ie, hypertension, 
diabetes, etc.), treatment of AEs, estrogens, androgens, anti-androgenic agents, vitamins, 
iron supplements, folate, and herbal supplements. Medications should be taken consistently 
throughout the study and at the investigator’s discretion. 
All medications or treatments received by the subject within 30 days before the baseline 
visit and throughout the study, including the name of the drug or procedure, must be 
recorded in the study source documents and electronic case report form (eCRF) with end 
dates, if end dates are available. 


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Study Duration: Each subject will participate in the study for approximately 11 months 
depending on the treatments they receive. 
Statistical Methods: 
Three analysis populations are defined in Section 11. Unless otherwise specified in the 
SAP, efficacy analyses will be based on the Evaluable Population, safety analyses will be 
based on the Safety Analysis Population, and all other analyses will be based on the Full 
Analysis Population 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from baseline to the final visit in the overall 
Rasch-transformed scores of the FACE-Q Satisfaction with Facial Appearance Scale. This 
will be analyzed using paired t-test (or Wilcoxon signed-rank test if normality assumptions 
are not met). 


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Table of Contents 
PROTOCOL SYNOPSIS ..........................................................................................................4 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................17 
1 INTRODUCTION .............................................................................................................18 
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 ...............................................23 
4.2.3 
Other Secondary Endpoints .......................................................................23 
4.2.3.1 
Global Aesthetic Improvement Scale ................................................23 
4.2.3.2 
Periorbital Aesthetic Appearance Questionnaire ...............................23 
4.2.4 
Exploratory Endpoints ...............................................................................23 
4.3 
Safety .....................................................................................................................23 
4.4 
Blinding and Randomization .................................................................................24 
5 SELECTION OF SUBJECTS............................................................................................25 
5.1 
Inclusion Criteria ...................................................................................................25 
5.2 
Exclusion Criteria ..................................................................................................26 
5.3 
Summary of Required Washout Periods ................................................................29 
6 STUDY PLAN AND PROCEDURES ..............................................................................31 
6.1 
Study Subject Number ...........................................................................................31 
6.2 
Description of Study Days .....................................................................................31 
6.2.1 
Study Procedures for Screening Visit (V0) for All Subjects .....................35 
6.2.2 
Study Procedures for BELKYRA Subjects ...............................................35 
6.2.2.1 
Visits V1 to V6 ..................................................................................35 
6.2.2.2 
Visit V7 (Month 6, a Minimum of 30 Days After Previous 
Treatment) ......................................................................................36 
6.2.3 
Visit V8 (Juvéderm HA Facial Fillers and SkinMedica as Applicable) .....36 


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6.2.3.1 
Visit V9 (Juvéderm HA Facial Fillers and SkinMedica as 
Applicable) .....................................................................................37 
6.2.3.2 
Visit V10 (BOTOX Cosmetic and SkinMedica as Applicable) .........37 
6.2.3.3 
Visit V11 (BOTOX Cosmetic and SkinMedica as Applicable ) .......37 
6.2.3.4 
Visit V12 (Final Study Visit/Early Termination) ..............................38 
6.2.4 
Unscheduled/Missed Visits ........................................................................38 
6.2.5 
Restrictions and Precautions ......................................................................38 
6.2.5.1 
Prohibited Medications and/or Treatments ........................................38 
6.2.5.2 
Special Diet or Activities ...................................................................39 
7 METHODS OF ASSESSMENT AND ENDPOINTS .......................................................40 
7.1 
Demographic Data .................................................................................................40 
7.2 
Medical History .....................................................................................................40 
7.3 
Concomitant Medications ......................................................................................40 
7.4 
Pregnancy ...............................................................................................................40 
7.5 
Clinical Scales for Treatment Inclusion Only ........................................................40 
7.6 
Efficacy Endpoint Measurements ..........................................................................41 
7.6.1 
FACE-Q .....................................................................................................41 
7.6.2 
Self-Perception of Age Questionnaire .......................................................41 
7.6.3 
Global Aesthetic Improvement Scale ........................................................41 
7.6.4 
Periorbital Aesthetic Appearance Questionnaire .......................................41 
8 DISCONTINUATION CRITERIA ...................................................................................43 
8.1 
Early Discontinuation of the Study ........................................................................43 
8.2 
Early Discontinuation of Individual Subjects ........................................................43 
9 TREATMENTS .................................................................................................................45 
9.1 
Rescue Medications and Concomitant Treatments ................................................45 
9.2 
Treatment Compliance ...........................................................................................45 
10 ADVERSE EVENTS .........................................................................................................46 
10.1 
Drug .......................................................................................................................46 
10.2 
Medical Device ......................................................................................................46 
10.3 
Injection Site Reactions .........................................................................................46 
10.4 
Unusual Failure in Efficacy ...................................................................................47 
10.5 
Serious Adverse Events .........................................................................................47 
10.6 
Unanticipated Serious Adverse Device Effects .....................................................48 
10.7 
Assessment of Adverse Events ..............................................................................48 


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10.7.1 
Severity ......................................................................................................48 
10.7.2 
Relationship to Study Product ...................................................................49 
10.8 
Adverse Events and Pregnancy ..............................................................................49 
10.8.1 
Adverse Event Follow-up ..........................................................................50 
10.8.2 
Pregnancies ................................................................................................50 
10.9 
Serious Adverse Event Reporting ..........................................................................51 
10.9.1 
Reporting Requirements ............................................................................51 
10.9.2 
Serious Adverse Event Contact Information .............................................51 
11 STATISTICAL METHODS ..............................................................................................53 
11.1 
General Statistical Considerations .........................................................................53 
11.1.1 
Analysis Populations ..................................................................................53 
11.1.2 
Subgroups ..................................................................................................53 
11.2 
Demographics and Baseline Characteristics ..........................................................54 
11.3 
Exposure and Concomitant Therapies ...................................................................54 
11.4 
Efficacy Analyses ..................................................................................................54 
11.4.1 
Primary Efficacy Analysis .........................................................................54 
11.4.2 
Analysis of All Other Efficacy Endpoints .................................................54 
11.4.3 
Missing Data ..............................................................................................54 
11.4.4 
Adverse Events ..........................................................................................55 
11.5 
Interim Analyses and Data Monitoring..................................................................55 
11.6 
Determination of Sample Size ...............................................................................55 
11.7 
Changes in the Conduct of the Study or Planned Analysis ...................................55 
12 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS .........................................56 
12.1 
Declaration of Helsinki ..........................................................................................56 
12.2 
Good Clinical Practice ...........................................................................................56 
12.3 
Research Ethics Board ...........................................................................................56 
12.4 
Regulatory Authority Approval .............................................................................56 
12.5 
Informed Consent...................................................................................................56 
12.6 
Subject Confidentiality and Disclosure .................................................................57 
12.7 
Sponsor Monitoring of Study Documentation .......................................................57 
12.8 
Study Documents ...................................................................................................57 
12.9 
Collection of Study Data ........................................................................................57 
12.10 Disclosure of Information ......................................................................................58 
12.11 Discontinuation of the Study .................................................................................58 


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12.12 Archiving of Study Documents .............................................................................58 
13 REFERENCES ..................................................................................................................59 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
BMI 
body mass index 
CFLs 
crow’s feet lines (also known as lateral canthal lines in BOTOX product 
literature)  
DCA 
deoxycholic acid 
eCRF 
electronic case report form 
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 Harmonisation 
ISR 
injection site reaction 
LFS 
lip fullness score 
MITT 
modified intent-to-treat 
NLF 
nasolabial fold 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
OTC 
over-the-counter 
PAAQ 
periorbital aesthetic appearance questionnaire 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMF 
submental fat 
SMFRS 
submental fat rating scale 
SOPS 
SkinMedica overall photodamage scale 
SPA 
self-perception of age 
SSRS 
subject self-rating scale 
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 interactionsThese 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 including use of botulinum toxin as well as hyaluronic acid fillers 
are used to improve the signs of aging such as addressing presence of both static and dynamic 
wrinkles, myomodulation  
In addition, a recently approved injectable agent, BELKYRA, has been demonstrated as safe and 
effective in the reduction of undesirable excess submental fat (SMF) (McDiarmid 2014, Jones 
2016, Ascher 2014, Humphrey 2016). SMF may cause an unappealing fullness, which can affect 
overall facial appearance. Before the approval of BELKYRA, the procedures used to cure the 
SMF were surgical, eg, liposuction or fat excision, which may lead to serious complications 
(Jones 2016, Wollina 2015). 
BELKYRA contains an injectable proprietary formulation of synthetically derived deoxycholic 
acid (DCA), a cytolytic agent that can induce adipocytolysis when injected directly into fat. 
Multiple treatment sessions spaced at least a month apart are generally needed for full response, 
with most subjects requiring 3 to 5 treatments (BELKYRATM Product Monograph). 
Botulinum toxins have been approved by Health Canada for the treatment of moderate to severe 
glabellar lines, lateral canthal rhytides, and forehead lines (BOTOX Cosmetic® Product 
Monograph). Onabotulinumtoxin A (BOTOX Cosmetic) 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 Health  
Canada–approved to temporarily treat facial wrinkles and volume loss (Jones 2013, JUVÉDERM 
VOLUMA® with Lidocaine Directions for Use, Lupo 2008, Pinsky 2008). 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.  
Health Canada has approved the following filler products as indicated: 


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• 
JUVÉDERM VOLBELLA with Lidocaine is indicated for enhancement and pouting 
of the lips to correct volume loss and to treat perioral lines and oral commissures and 
correction of infraorbital skin depressions. 
• 
JUVÉDERM VOLIFT with Lidocaine is indicated for the treatment of nasolabial 
folds. 
• 
JUVÉDERM VOLUMA with Lidocaine is indicated to restore volume of the face 
(ie, cheek, chin, and malar area).  
• 
JUVÉDERM VOLITE is indicated for the treatment of face (cheek and forehead) 
and neck, by filling of superficial cutaneous depressions such as fine lines and for 
additional improvement of hydration 
In clinical trials, each product mentioned above has been demonstrated to be safe and effective 
for its approved indication (Carruthers 2004a, Jones 2013, Lupo 2008, Pinsky 2008, Wollina 
2015, Ascher 2014). 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 onabotulinumA toxin (BOTOX Cosmetic), dermal fillers, and bimatoprost (LATISSE) for 
inadequate eyelash length on subjects’ self-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 substantial improvement in subjects’ perceived age (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.  
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 Health 
Canada–approved aesthetic products. The objective of the initial USA HARMONY study was to 
observe the safety and overall aesthetic impact of treating subjects with several modalities in an 
attempt to achieve subjects’ desired clinical outcome. The Canada Global HARMONY study will 


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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 Global HARMONY study, subjects will be evaluated by the investigator to receive 
BOTOX Cosmetic, BELKYRA, Juvéderm facial fillers (JUVÉDERM VOLITE, JUVÉDERM 
VOLBELLA with Lidocaine, JUVÉDERM VOLIFT with Lidocaine, and JUVÉDERM 
VOLUMA with Lidocaine), and SkinMedica products. 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 
Cosmetic, BELKYRA, JUVÉDERM facial fillers, and SkinMedica products will have a 
significantly higher satisfaction with their overall facial appearance at the final study visit when 
compared with baseline, pre-treatment satisfaction scores, as measured by the mean change from 
baseline on the FACE-Q Satisfaction with Facial Appearance Overall Scale.  
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 Allergan products by measuring the 
change in subject’s satisfaction with facial appearance from baseline (before any treatment) to 
the final study visit (
 FACE-Q™: Satisfaction with Facial Appearance). These 
Allergan products include BOTOX Cosmetic, BELKYRA, Juvéderm HA facial fillers, and 
SkinMedica® topical nonprescription skin care products, as described in Section 9.  
3.2 
Secondary Objectives 
Secondary objectives are: 
• To determine the subject’s self-appraisal of expectations of life change (
 
FACE-Q™: Expectations), age-related facial appearance 
 FACE-Q©: Aging 
Appraisal), psychological function (
 FACE-Q™: Psychological Function), 
social function (
 FACE-Q™: Social Function) and overall satisfaction with 
skin (
 FACE-Q™ Satisfaction with Skin Questionnaire).  
• To quantify the investigator’s and subject’s assessment of aesthetic improvement. 


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4 
Study Design 
4.1 Study Design Overview 
This Phase 4 study is a prospective, interventional, multicenter, combination medical device, 
drug, and skin care postmarketing study. Each subject will be in the study for up to 11 months 
depending on the treatments given, 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 6 study sites in 
Canada. The ratio of subjects treated with BELKYRA to subjects without BELKYRA treatment 
will be approximately 1:2 (ie, approximately 20 BELKYRA subjects and 40 subjects without 
BELKYRA) based on clinical indication and the decision of the subject and investigator. Thus 
approximately one-third of all subjects will receive BELKYRA treatment. 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 receiving BELKYRA treatment will enter the study at V1 continuing on to V12. There 
will be at least 1 month between repeat BELKYRA treatments and the final BELKYRA 
treatment. 
Subjects not receiving BELKYRA following screening (V0) will enter the study at V7 to begin 
treatment with Juvéderm HA facial fillers, SkinMedica, and BOTOX Cosmetic, as indicated in 
the study design diagram (Figure 4.1).  
 
 


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• Subject’s assessment of overall satisfaction with skin as measured by the mean change from 
screening before any treatment in the Rasch-transformed score of the FACE-Q Satisfaction 
with Skin to final study visit (V12) 
4.2.2.2 Self-Perception of Age Questionnaire 
Subject’s assessment of age-related facial appearance by the self-perception of age (SPA) 
measure at baseline before any treatment to final study visit (V12); responders are defined as 
having achieved a younger category. 
4.2.3 
Other Secondary Endpoints  
4.2.3.1 Global Aesthetic Improvement Scale 
• Change in investigator’s assessment of global facial aesthetic improvement as measured by 
the 5-point global aesthetic improvement scale (GAIS) at final study visit (V12) 
• Change in subject’s assessment of global facial aesthetic improvement as measured by the 
5-point GAIS at final study visit (V12) 
4.2.3.2  Periorbital Aesthetic Appearance Questionnaire 
• Change in subject’s satisfaction with appearance of periorbital area as measured by the 
periorbital aesthetic appearance questionnaire (PAAQ)  
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 (V12). Serious adverse events (SAEs) will be 
reported within the specified time and format directly to Allergan and SkinMedica as described 
in Section 10.8.1. 


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4.4 
Blinding and Randomization 
Blinding and randomization are not applicable. This is an open-label, single-arm study. Subjects 
are enrolled consecutively into study groups based upon subject need. 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 Canada. 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. 
Applies to BELKYRA Subjects Only 
1. Clinical report of Grade 2 or 3 on the submental fat rating scale (SMFRS; 
).  
2. Subject report of dissatisfaction with submental area; rating of 0, 1, or 2 using the subject 
self-rating scale (SSRS; 
). 
Applies to All Subjects  
1. 30 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 
5. Willing to avoid direct and prolonged sun exposure to the facial skin, which includes tanning 
beds, for the duration of the study  


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5.2 Exclusion Criteria 
The following criteria exclude potential subjects from participating in the study: 
Applies to BELKYRA Subjects Only  
1. History of any intervention to treat SMF (eg, liposuction, surgery, or lipolytic agents) 
2. History of trauma associated with the chin or neck areas that in the judgment of the 
investigator may affect evaluation of safety or efficacy of treatment 
3. An anatomical feature (eg, predominant subplatysmal fat, loose skin in the neck or chin 
area, prominent platysmal bands) for which reduction in SMF may, in the judgment of 
the investigator, result in an aesthetically unacceptable outcome 


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4. Evidence of any cause of enlargement in the submental area (eg, thyroid enlargement, 
cervical adenopathy, ptotic submandibular gland) other than localized SMF 
5. Any medical condition (eg, respiratory, cardiovascular, hepatic, neurological disease, or 
thyroid dysfunction) that would interfere with assessment of safety or efficacy or 
compromise the subject’s ability to undergo study procedures or give informed consent 
 
 


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Applies to All Subjects  
2. Body mass index (BMI) > 30 
3. Known allergy or sensitivity to the study products or their components  
4. Pregnant, lactating, or planning to become pregnant at any time during the study 
5. Received BOTOX Cosmetic or treatment with any other botulinum toxin product for any 
condition within 6 months before enrollment 
6. Received (or is planning to receive) anticoagulation, antiplatelet or thrombolytic 
medications (eg, warfarin) or other substances known to increase coagulation time from 
10 days prior to injection and up to 3 days post-injection 
7. 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 
8. 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  
9. 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 
11. Lip tattoos, facial hair or scars that would interfere with visualization of the lips and 
perioral area for the effectiveness assessments 
12. 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 
13. Received any investigational product within 60 days prior to study enrollment or 
planning to participate in another investigation during the course of this study 
14. An employee (or a relative of an employee) of the investigators, Allergan, or 
representative of Allergan 
15. 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 
16. Current use of oral corticosteroids 
17. Current use of nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, aspirin, ibuprofen), 
from 10 days prior to injection up to 3 days post-injection 
18. 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  
19. Systemic retinoid therapy within one year prior to study enrollment 


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21. 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 
22. Current use of aminoglycoside antibiotics, curare-like agents, or agents that might 
interfere with neuromuscular (skeletal) function  
23. Profound atrophy/excessive weakness of muscles in target areas of injection 
24. History of facial nerve palsy 
25. Anticipated need for treatment with botulinum toxin of any serotype for any reason 
during the study (other than study treatment) 
26. Very thin skin in the mid-facial region 
27. Tendency to accumulate fluid in the lower eyelids, or large infraorbital fat pads, ie, 
significant convexity or projection from the infraorbital fat pads 
28. Mid-face volume deficit due to congenital defect, trauma, abnormalities in adipose tissue 
related to immune-mediated diseases such as generalized lipodystrophy (eg, juvenile 
dermatomyositis), partial lipodystrophy (eg, Barraquer-Simons syndrome), inherited 
disease, or human immunodeficiency virus–related disease  
29. Undergone oral surgery or other dental procedures (eg, tooth extraction, orthodontia, or 
implantation) within 30 days prior to enrollment or be planning to undergo any of these 
procedures during the study 
30. Subjects with neuromuscular disorders including generalized muscle weakness, diplopia, 
ptosis, dysphonia, dysarthria, severe dysphagia, and respiratory compromise  
31. Subjects with a history of allergies or hypersensitivity to HA or lidocaine 
5.3 Summary of Required Washout Periods 
Potential study subjects may have used the following products and procedures (Table 5.2) 
that have specified washout periods prior to baseline visits for all subjects. 
 
 


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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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Table 6.1  
Schedule of Study Procedures, Treatments, and Assessments 


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6.2.4 
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. 
6.2.5 
Restrictions and Precautions 
6.2.5.1 
Prohibited Medications and/or Treatments 
Subjects must not undergo any type of facial plastic or reconstructive surgery or cosmetic 
procedure (eg, 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, Allergan or Allergan’s 


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representative should be notified before a prohibited medication/treatment is administered. 
Prior to attending study visits, subjects must not apply facial cosmetics. 
6.2.5.2 
Special Diet or Activities 
Within the first 24 hours after filler treatment, on V7, and if a touch-up treatment is 
performed on V8 and V9, 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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7 
Methods of Assessment and Endpoints 
7.1 
Demographic Data 
At the Screening Visit (V0), subject demographic data will be collected. These data include 
age and gender. 
7.2 
Medical History 
At the Screening Visit (V0), a medical history will be obtained from each subject. Medical 
history includes a detailed history of prior cosmetic procedures, with start and stop dates, if 
applicable, as well as any discontinuations due to intolerability or toxicity.  
7.3 
Concomitant Medications 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
investigator, including but not limited to medications for other conditions (ie, hypertension, 
diabetes, etc.), treatment of AEs, estrogens, androgens, anti-androgenic agents, vitamins, iron 
supplements, folate, and herbal supplements. Medications should be taken consistently 
throughout the study and at the investigator’s discretion. 
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).  
7.4 
Pregnancy  
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. 
7.5 
Clinical Scales for Treatment Inclusion Only 
• Investigator’s assessment of the severity of GLs at maximum frown using the FWS with 
photonumeric guide (
) 
• Investigator’s assessment of the severity of CFLs at maximum smile using the FWS with 
photonumeric guide (
 
• Investigator’s assessment of the severity of FHLs at maximum eyebrow elevation using 
the FWS with photonumeric guide (
) 


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• Investigator’s assessment of the subject’s facial photodamage severity using the 10-point 
SOPS (
 
• Investigator’s assessment of the subject’s SMF using the 5-point SMFRS 
 
• Subject’s assessment of self-appearance using the 7-point SSRS (
 
7.6 
Efficacy Endpoint Measurements 
7.6.1 
FACE-Q 
• Subject’s assessment overall facial appearance as measured by the FACE-Q Satisfaction 
with Facial Appearance Scale 
 
• Subject’s assessment of expectations of life change as measured by the FACE-Q 
Expectations Scale (
 
• Subject’s assessment of age-related facial appearance as measured by the FACE-Q Aging 
Appraisal (
 
• Subject’s assessment of psychological well-being as measured by the FACE-Q 
Psychological Function Scale (
 
• Subject’s assessment of social function as measured by the FACE-Q Social Function 
Scale (
 
• Subject’s assessment of overall satisfaction with skin as measured by the FACE-Q 
Satisfaction with Skin Questionnaire (
 
7.6.2 
Self-Perception of Age Questionnaire 
• Subject’s assessment of age-related facial appearance as measured by the SPA 
Questionnaire (
 
7.6.3 
Global Aesthetic Improvement Scale  
• Investigator’s assessment of global facial aesthetic improvement as measured by the 
5-point GAIS (
 
• Subject’s assessment of global facial aesthetic improvement as measured by the 5-point 
GAIS (
 
7.6.4 
Periorbital Aesthetic Appearance Questionnaire  
• Subject’s assessment of periorbital area as measured by the PAAQ (
 


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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. Allergan, as 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, Allergan, 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 Allergan 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 Allergan, study monitor, the REB, or any 
regulatory agency by the investigator 
If the study is prematurely terminated or suspended due to safety issues, Allergan 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 Allergan or by the investigator, 
as specified by the applicable regulatory requirements. If a premature termination or 
suspension occurs, Allergan shall remain responsible for providing resources to fulfill the 
protocol obligations and existing agreements for follow-up of subjects enrolled in the study, 
and each investigator or authorized designee 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 Allergan 
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 subject’s participation 
when the subject’s 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. 
The following are circumstances that could result in a subject’s discontinuation from the 
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• 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  
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9 
Treatments 
The study treatments are:  
• BOTOX Cosmetic 
• BELKYRA 
• JUVÉDERM VOLITE, JUVÉDERM VOLBELLA with Lidocaine, JUVÉDERM 
VOLIFT with Lidocaine, and/or JUVÉDERM VOLUMA with Lidocaine 
• SkinMedica products  
All study drugs/devices must be stored in a secure area, accessible only to study personnel. 
Allergan will provide each study site with sufficient study treatments (study drugs, devices 
and SkinMedica) for all study subjects, including back-up study treatments. 
Allergan 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 Allergan. 
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 and Concomitant Treatments 
No product licensed in Canada is approved as a rescue medication. Administration of 
hyaluronidase is considered to be “off-label” and has not been provided as a part of the study 
regimen and should only be used if in the investigator’s judgment it is deemed to be 
necessary to inject hyaluronidase for the safety of the subject, then the investigator may inject 
at his/her discretion 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 Allergan. A representative of Allergan will make frequent contact 
with the investigator and his/her research staff and will conduct regular monitoring visits at the 
site to review subject and study drug and device accountability records for compliance with 
the protocol, eg, subject eligibility criteria, volume of product injected, procedures performed, 
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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 
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 temporarily 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 (ie, 
after informed consent has been obtained). At each visit, the investigator will begin by 
querying for AEs by asking each subject a general, non-directed question such as “How have 
you been feeling since the last visit?” Directed questioning and examination will then be 
done as appropriate. All reported AEs will be documented on the AE eCRF.  
The daily skin care products (SkinMedica) utilized by subjects are not considered to be 
investigational products in this study. SkinMedica-related AEs will be handled per 
SkinMedica Standard Operating Procedures for Postmarketing Safety. 
10.2 
Medical Device 
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 it is 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, 
discoloration, and other. Subjects will maintain a diary record of the presence, location, 
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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 be recorded and followed to 
resolution on the AE eCRF. If an ISR is ongoing or appears 30 days after the subject’s last 
study visit, it will be followed up by Allergan Product Surveillance separate from this study 
protocol. 
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 an Allergan Inc. representative and recorded in the appropriate 
CRFs.   
The Investigator must: 
1.     Notify Allergan Inc. immediately.  For Emergency Phone Numbers see front of 
protocol. Fax completed Unusual Failure in Efficacy reporting form to:
 
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 
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’s entry into the study.  
NOTE: Allergan considers all cancer AEs as SAEs. Pregnancy by itself is not generally 
considered an AE.  The occurrence of an adverse pregnancy outcome may constitute an SAE, 
making the collection of pregnancy-related data and pregnancy outcomes valuable. Inpatient 
hospitalization for a normal vaginal delivery or elective abortion of a normal fetus does not 
constitute a SAE. If no serious injury occurred to the mother or fetus, then there is no reason 
to qualify pregnancy in the setting of hospitalization as a SAE. Accidental, therapeutic, or 


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spontaneous abortion should always be classified as a SAE and 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.   
10.6 
Unanticipated Serious Adverse Device Effects 
An unanticipated 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 
• Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure 
Also considered an USADE is any device malfunction that would be likely to cause or 
contribute to a death or serious injury if the malfunction were to recur. The investigator will 
notify Allergan within 24 hours of any device malfunction and a representative will provide 
instruction for the return of any faulty syringe for evaluation. 
10.7 
Assessment of Adverse Events 
10.7.1 
Severity 
Assessment of severity of an AE will be rated according to the definitions in Table 10.1 and 
the worst grade documented. The investigator will review these definitions with the subject 
for use when completing the subject diary. For events reported on the AE eCRF, eg, ISRs 
that persist beyond the diary period and other AEs, the investigator will determine the 
severity classification based on these definitions, his/her experience in the use of dermal 
fillers and/or the subject’s description of the event.  
The term “severe” is used to describe the intensity of an AE; the event itself could be of 
relatively minor clinical significance (eg, “severe headache”). This is not the same as 
“serious.” Seriousness of AEs is based on the outcome of an AE and usually associated with 
events that pose a threat to a subject’s life or functioning. 


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Table 10.1 
Classification of Adverse Events by Intensity 
Grade 1 (Mild) 
The symptom is barely noticeable to the study subject and does not 
influence performance or functioning. Concomitant medication is not 
ordinarily indicated for relief of mild AEs. 
Grade 2 (Moderate) 
The symptom is of sufficient severity to make the study subject 
uncomfortable and to influence performance of daily activities. 
Concomitant medication may be indicated for relief of moderate AEs. 
Grade 3 (Severe) 
The symptom causes severe discomfort, sometimes of such severity 
that the study subject cannot continue in the study. Daily activities are 
significantly impaired or prevented by the symptom. Concomitant 
medication may be indicated for relief of severe AEs. 
Not applicable 
In some cases, an AE/ISR may be an “all-or-nothing” finding that 
cannot be graded. 
Abbreviations: AE = adverse event, ISR = injection site reaction. 
10.7.2 
Relationship to Study Product 
A determination will be made, by the investigator, of the relationship, if any, between an AE 
and any study product, anesthesia employed, the study device, or the injection procedure, as 
applicable, using the guidelines presented in Table 10.2. 
Table 10.2 
Guidelines for Determining the Relationship Between Adverse Event and 
the Study Product 
Highly 
Probable 
This causal relationship is assigned if the AE starts a reasonable time after the 
administration of study product, stops/improves when the study product is 
stopped, and could reasonably be explained by known characteristics of the 
study product. 
Probable 
This causal relationship is assigned when the AE starts a reasonable time after 
the administration of study product, stops/improves when the study product is 
stopped, and could not be reasonably explained by known characteristics of the 
subject’s clinical state. 
Possible 
This causal relationship is assigned when the AE starts a reasonable time after 
the administration of study product, but could be produced by the subject’s 
clinical state or other modes of therapy administered to the subject. 
Not Related 
This causal relationship is assigned when the time association or the subject’s 
clinical state is such that the study product was not likely to have had an 
association with the observed AE. 
Abbreviations: AE = adverse event. 
10.8 
Adverse Events and Pregnancy 
MAHs are expected to follow up all pregnancy reports from health professionals and 
consumers where the embryo/fetus could have been exposed to one of its health products. 
For consumer reports, it is appropriate to seek permission to only follow up with the health 
professional. The MAH must apply all principles outlined in this guidance document and the 
Regulations pertaining to reporting requirements, including determination of seriousness and 


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minimal criteria for submitting an AR report. Reports of pregnancy exposure with no 
associated adverse reactions should not be reported as ARs. When an active substance, or one 
of its metabolites, has a long half-life, this should be taken into account when considering 
whether a fetus could have been exposed (e.g., if health products taken before the gestational 
period should be considered). 
10.8.1 
Adverse Event Follow-up 
All AEs (including SAEs) must be recorded on the appropriate eCRF. All AEs that are 
treatment-related and unexpected (not listed as treatment-related in the current package insert 
or directions for use) must be reported to the governing REB as required by the REB, local 
regulations, and the governing health authorities. Any AE that is marked “ongoing” at the 
exit visit must be followed up as appropriate. 
10.8.2 
Pregnancies 
The investigator and each subject will determine the appropriate method of contraception for 
the subject during the participation in the study. 
Male Subjects with Partners Who Become Pregnant  
• The investigator will attempt to collect pregnancy information on any male subject’s 
female 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 submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female 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. 
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 sponsor within 24 hours of learning of a 
subject’s pregnancy. 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 or elective abortion is 
always considered to be an SAE and will be reported as such. Any poststudy 
pregnancy-related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the sponsor as described in Section 8.3.4. While the 


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investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of an SAE through spontaneous reporting.  
10.9 
Serious Adverse Event Reporting 
10.9.1 
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 Allergan on 2 SAE forms. The 
drug, and device SAE forms must be recorded and e-mailed per this protocol section 
(including to the SkinMedica Safety Contact below from V7 to V12). All subjects with an 
SAE must be followed up and the outcomes reported.  
The principal investigator must supply Allergan and the REB with any additional requested 
information (eg, hospital discharge summary, autopsy reports and terminal medical reports) 
only upon request. Allergan 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 Allergan immediately (within 24 hours) using the SAE reporting forms. 
Emergency phone numbers and relevant Allergan personnel contacts are below. 
2. Obtain and maintain in his/her files of all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject. 
3. Provide Allergan with a complete, written case history (AE report form), including copies 
of supporting reports (eg, 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. 
4. 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. 
10.9.2 
Serious Adverse Event Contact Information 
SAE Reporting Information: BOTOX® 
Cosmetic, and BELKYRA 
SAE Reporting Information:  
JUVÉDERM® VOLBELLA® with 
Lidocaine, JUVÉDERM® VOLIFT with 
Lidocaine, JUVÉDERM® VOLUMA® 
with Lidocaine, and JUVÉDERM® 
VOLITE®, BELKYRA Skin Grid 


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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 a 0.05 significance level (2-sided). In this study, 
BELKYRA and without BELKYRA is the major treatment difference between enrolled 
subjects. Hence, unless specified, all endpoints will be summarized by those two groups 
(BELKYRA and without BELKYRA) and overall respectively. However, this study is not 
designed to compare the efficacy and safety outcomes between subjects treated with 
BELKYRA and those treated without BELKYRA. All discussion and interpretation related 
to study outcomes will be mainly focused on the overall results. 
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. For BELKYRA subjects who complete this study, the final visit will be their V12 
visit; for subjects who will not be treated with BELKYRA, this visit will also be the V12 
visit after approximately 5 months of treatment. Subjects who discontinue 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: 
• Full Analysis Population – all subjects who have met all eligibility criteria at the 
screening visit (V0) and received any product used as treatment in this study.  
• Safety Population – defined the same as Full Analysis Population. 
• Evaluable Population– all subjects as defined in the Safety Population who have had at 
least one post-treatment efficacy assessment at the final visit (V12). 
 
The Full Analysis Population will be used for subject disposition, demographics and baseline 
characteristics summary, and the Safety Population will be used for safety analyses. The 
Evaluable Population will be used on key efficacy endpoints.  
11.1.2 
Subgroups  
Two subgroups will be examined separately: 


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• Gender: As male and female subjects may have differing expectations/perceptions of 
aesthetic improvement, they will be examined separately.  
• BELKYRA: As it is expected that approximately two-thirds of the enrolled population 
will not be treated with BELKYRA, subjects treated and not treated with BELKYRA will 
be examined separately. 
Additional subgroup analysis will be discussed in the SAP. 
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 compare post-treatment assessment values 
to the subject’s corresponding baseline assessment value, and will be based on the Evaluable 
Population. 
11.4.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from baseline to the final visit (V12) in the 
overall Rasch-transformed scores of the FACE-Q Satisfaction with Facial Appearance Scale. 
This will be analyzed using paired t-test (or Wilcoxon signed-rank test if normality 
assumptions are not met).  
11.4.3 
Missing Data 
Missing data strategy will be documented in the SAP.  


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11.4.4 
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. SAEs will be coded using MedDRA version 17.0 or 
higher, and presented by system organ class and preferred term. 
11.5 
Interim Analyses and Data Monitoring 
No formal interim analyses are planned for this study. 
11.6 
Determination of Sample Size 
A sample size of 48 subjects will provide 90% power to detect whether 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 20.0. This calculation is based on a 1-sample, 2-sided t-test at 5% 
significance level. The assumptions of mean and standard deviation are based on FACE-Q 
results from Allergan HARMONY Study GMA-CMB-14-001. With a 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. 
From the 60 subjects planned to enroll in this study, approximately 20 subjects will be treated 
with BELKYRA. 
PASS 2008 software was used to calculate the sample size. 
11.7 
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.  


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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. 


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12.6 
Subject Confidentiality and Disclosure 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
subject’s name will not be disclosed in these documents. The subject’s name may be 
disclosed to the sponsor, Allergan, or the governing health authorities including Health 
Canada if they inspect the study records. Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
In accordance with Canadian 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 Allergan 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 Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents. These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
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 Health Canada 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 Allergan in a timely manner at the completion of the study, or 
as otherwise specified by Allergan. 
The data reported on the eCRFs shall be derived from source documents and be consistent 
with these source documents, and any discrepancies shall be explained in writing. Any 
change or correction to data reported on an eCRF shall be dated, initialed and explained, if 
necessary, and shall not obscure the original entry (ie, an audit trail shall be maintained); this 
applies to both written and electronic changes and corrections. 


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12.10 Disclosure of Information 
This study will be registered and results posted on www.ClinicalTrials.gov. Allergan, as the 
sponsor, has proprietary interest in this study. Authorship and manuscript composition will 
reflect joint cooperation between study investigators and Allergan personnel. Authorship will 
be established prior to the writing of the manuscript. As this study involves multiple centers, 
no individual publications will be allowed prior to completion of the final report of the 
multicenter study except as agreed with Allergan. 
12.11 Discontinuation of the Study 
It is agreed that, for reasonable cause, either the investigator or Allergan may terminate the 
investigator’s participation in this study after submission of a written notice. Allergan may 
terminate the study at any time upon immediate notice for any reason, including the 
Allergan’s 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. Allergan-specific essential documents are to be 
retained until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents are to be retained for a longer 
period, however, if required by the applicable regulatory requirements or if needed by 
Allergan. 


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13 References 
Ascher B, Hoffmann K, Walker P, Lippert S, Wollina U, Havlickova B. Efficacy, patient-
reported outcomes and safety profile of ATX-101 (deoxycholic acid), an injectable drug for 
the reduction of unwanted submental fat: results from a Phase III, randomized, placebo-
controlled study. J Eur Acad Dermatol Venereol. 2014;28(12):1707-15. 
American Society of Plastic Surgeons. 2012 Plastic Surgery Statistics Report. 
https://d2wirczt3b6wjm.cloudfront.net/News/Statistics/2012/plastic-surgery-statistics-full-
report-2012.pdf. Accessed 19 December 2016. 
BELKYRATM [product monograph]. Markham, Ontario: Allergan, Inc.; March 2016. 
Binder WJ, Blitzer A, Brin MF. Treatment of hyperfunctional lines of the face with 
botulinum toxin A. Dermatol Surg. 1998;24(11):1198-205. 
Blitzer A, Brin MF, Keen JS, Aviv JE. Botulinum toxin for the treatment of hyperfunctional 
lines of the face. Arch Otolaryngol Head Neck Surg. 1993;119(9):1018-22. 
BOTOX Cosmetic® [product monograph]; Markham, Ontario: Allergan, Inc.; October 2014. 
Carruthers A, Carruthers JDA. The use of botulinum toxin to treat glabellar frown lines and 
other facial wrinkles. Cosmet Dermatol. 1994;7:11-15. 
Carruthers A, Carruthers J, Lowe, NJ, Menter A, Gibson J, Nordquist M, Mordaunt J. One-
year randomised, multicenter, two-period study of the safety and efficacy of repeated 
treatments with botulinum toxin type A in patients with glabellar lines. J Clin Res. 2004a;7:1-
20. 
Carruthers J, Fagien S, Matarasso SL. Consensus recommendations on the use of botulinum 
toxin type a in facial aesthetics. Plast Reconstr Surg. 2004b;114(6 Suppl):1S-22S. 
Dayan S, Weinkle S, Cohen JL, Kaminer MS, Narurkar V, Rivkin A, et al. Improvement in 
aging appearance, social confidence, and psychological well-being with combined facial 
aesthetic treatment comprising onabotulinumtoxinA, dermal fillers, and bimatoprost: 
HARMONY Study Outcomes. Poster presented at the 2016 American Academy of 
Dermatology Annual Meeting; 4-8 March 2016; Washington, DC. 
Fagien S. Botulinum toxin type A for facial aesthetic enhancement: role in facial shaping. 
Plast Reconstr Surg. 2003;112(5 Suppl):6S-18S. 
Farkas JP, Pessa JE, Hubbard B, Rohrich RJ. The science and theory behind facial aging. Plas 
Recon Surg. 2013;1(1):1-8. 
Foos PW, Clark MC. Adult age and gender differences in perceptions of facial attractiveness: 
beauty is in the eye of the older beholder. J Genetic Psychol. 2011;172(2): 162-75. 
Humphrey S, Sykes J, Kantor J, Bertucci V, Walker P, Lee DR, et al. ATX-101 for reduction 
of submental fat: a phase III randomized controlled trial. J Am Acad Dermatol. 
2016;75(4):788-97. 


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Jones DH, Carruthers J, Joseph JH, Callender VD, Walker P, Lee DR, et al. REFINE-1, a 
multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an 
injectable drug for submental fat reduction. Dermatol Surg. 2016;42(1):38-49. 
Jones D, Murphy DK. Volumizing hyaluronic acid filler for midface volume deficit: 2-year 
results from a pivotal single-blind randomized controlled study. Dermatol Surg. 
2013;39(11):1602-12. 
JUVÉDERM® VOLUMA® with Lidocaine [directions for use]; Pringy, France: Allergan, Inc.; 
April 2016. 
JUVÉDERM® VOLIFT® with Lidocaine [directions for use]; Pringy, France: Allergan, Inc.; 
April 2016.  
JUVÉDERM® VOLBELLA® with Lidocaine [directions for use]; Pringy, France: Allergan, 
Inc.; February 2017 
JUVÉDERM® VOLITE® [directions for use]; Pringy, France: Allergan, Inc.; January 2018 
Kahn DM, Shaw RB. Overview of current thoughts on facial volume and aging. Facial Plast 
Surg. 2010;26(5):350-5. 
Lupo M, Smith SR, Thomas JA, Murphy DK, Beddingfield FC. Effectiveness of Juvéderm 
Ultra Plus dermal filler in the treatment of severe nasolabial folds. Plast Reconstr Surg 
2008;121(1):289-97. 
McDiarmid J, Ruiz JB, Lee D, Lippert S, Hartisch C, Havlickova B. Results from a pooled 
analysis of two European, randomized, placebo-controlled, phase 3 studies of ATX-101 for 
the pharmacologic reduction of excess submental fat. Aesth Plast Surg. 2014;38(5):849-60. 
Molina B, David M, Jain R, Amselem M, Ruiz-Rodriguez R, Ma MY, Kerrouche N, 
Georgantopoulos SP, Radeau T, Boineau D. Patient Satisfaction and Efficacy of Full-Facial 
Rejuvenation Using a Combination of Botulinum Toxin Type A and Hyaluronic Acid Filler. 
Dermatol Surg. 2015 Dec;41 Suppl 1:S325-32.  
Ogilvie P, Safa M, Marx A, Hopfinger R. Satisfaction with treatment of facial fine lines with 
VYC-12 injectable gel: patient-reported outcomes from a prospective study. Poster presented 
at the AMEC and VISAGE Joint Meeting, 15 to 17 September, 2017, Monte Carlo, Monaco. 
Pinsky MA, Thomas JA, Murphy DK, Walker PS; Juvéderm vs. Zyplast Nasolabial Fold 
Study Group. Juvéderm injectable gel: a multicenter, double-blind, randomized study of 
safety and effectiveness. Aesthetic Surg J 2008;28(1):17-23. 
Sobanko JF, Taglienti AJ, Sarwer DB, Margolis DJ, Dai J, Percec I. Motivation for seeking 
minimally invasive cosmetic procedures in an academic outpatient setting. Aesthet Surg J. 
2015;35(8):1014-20. 
Sommer B, Zschocke I, Bergfeld D, Sattler G, Augustin M. Satisfaction of subjects after 
treatment with botulinum toxin for dynamic facial lines. Dermatol Surg. 2003;29(5):456-60. 


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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-label study. Plast Reconstr Surg. 2007;120(5):1386-93. 
Wollina U, Goldman A. ATX-101 for reduction of submental fat. Expert Opin Pharmacother. 
2015;16(5):755-62. 
Yaar M, Eller MS, Gilchrest BA. Fifty years of skin aging. J Investig Dermatol Symp Proc. 
2002;7(1):51-8. 
Zebrowski LA, Montepare JM. Social psychological face perception: why appearance 
matters. Soc Personal Psychol Compass. 2008;2(3):1497. 

SAP_001.pdf: 
NCT03712449 
 
Study ID: CMO-MA-FAS-0579 
 
 
Title:  Canada Global HARMONY: Prospective, Multi-site, Study to Evaluate Subject Satisfaction 
With Facial Appearance Overall and the Aesthetic and Psychosocial Impact of Combined Facial 
Treatment 
 
Statistical Analysis Plan Date: 25Aug2020 


1
TITLE PAGE
Canada Global HARMONY: Prospective, Multi-site Study to Evaluate Subject Satisfaction 
with Facial Appearance Overall and the Aesthetic and Psychosocial Impact of Combined 
Facial Treatment
STATISTICAL ANALYSIS PLAN - Clinical Study Report
Version: 2.0
Draft 0.1: 08/25/2020


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Canada Global HARMONY
August 26, 2020
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Confidentiality Statement
This document is the property of Allergan plc and may notin full or partbe passed on,
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan plc


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Canada Global HARMONY
August 26, 2020
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SIGNATURE PAGE
Written by:
Date (DD/MM/YYYY)
Medical Science Statistics
Allergan Pharmaceutical
Reviewed and Approved at Allergan Pharmaceutical by:
Date (DD/MM/YYYY)
AVP, Medical Science Statistics
Allergan Pharmaceutical
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TABLE OF CONTENTS
1 TITLE PAGE.......................................................................................................................1 
2 TABLE OF CONTENTS.....................................................................................................4 
3 LIST OF ABBREVIATIONS..............................................................................................6 
4 INTRODUCTION ...............................................................................................................7 
5 OBJECTIVES......................................................................................................................9 
5.1 
Primary Objective....................................................................................................9 
5.2 
Secondary Objectives...............................................................................................9 
6 PATIENT POPULATIONS...............................................................................................10 
6.1 
Full Analysis Populations ......................................................................................10 
6.2 
Evaluable Population .............................................................................................10 
6.3 
Subgroups ..............................................................................................................10 
7 SUBJECT DISPOSITION.................................................................................................11 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ..........................12 
8.1 
Demographics ........................................................................................................12 
8.2 
Baseline characteristics..........................................................................................12 
8.3 
Medical History .....................................................................................................12 
8.4 
Concomitant Medications......................................................................................12 
8.5 
Clinical Scales for Treatment Inclusion Only........................................................12 
9 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ..................................13 
10 EFFICACY ANALYSES ..................................................................................................14 
10.1 
FACE-QTM: Description ........................................................................................14 
10.2 
Primary Efficacy Parameter...................................................................................15 
10.3 
Secondary Efficacy Parameters .............................................................................15 
10.3.1 
Self-Perception of Age Questionnaire .......................................................15 
 
 
 
 
11 SAFETY ANALYSES.......................................................................................................18 
11.1 
Adverse Events ......................................................................................................18 
12 HEALTH OUTCOMES ANALYSES...............................................................................20 
13 INTERIM ANALYSIS......................................................................................................21 
14 DETERMINATION OF SAMPLE SIZE..........................................................................22 
15 STATISTICAL SOFTWARE............................................................................................23 
16 DATA HANDLING CONVENTIONS.............................................................................24 


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16.1 
Visit Time Windows..............................................................................................24 
16.2 
Handling of dropouts missing data ........................................................................24 
16.2.1 
Handling of missing or incomplete dates...................................................24 
16.3 
Missing Severity Assessment for Adverse Events.................................................24 
17 DATA COLLECTED BUT NOT ANALYZED...............................................................25 
18 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................26 
19 REFERENCES ..................................................................................................................27 
1. 
Development and Psychometric Evaluation of the FACE-Q Satisfaction with 
Appearance Scale A New Patient-Reported Outcome Instrument for Facial 
Aesthetics Patients, Andrea L. Pusic, MD, MD, MHS, FRCSC, Anne F. 
Klassen...................................................................................................................27 
2. 
Improving the evaluation of therapeutic interventions in multiple sclerosis: 
the role of new psychometric methods, Health Technology Assessment 2009; 
Vol. 12 No. 12, J Hobart and S Cano ....................................................................27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
BMI
body mass index
CFLs
crow’s feet lines (also known as lateral canthal lines in BOTOX product 
literature)
DCA
deoxycholic acid
eCRF
electronic case report form
EOS
End of Study
FACE-Q
A clinically useful, patient-reported outcome measure (PROM) of 
satisfaction and quality of life following elective surgical and 
nonsurgical facial rejuvenation.
FWS
facial wrinkle scale
GAIS
global aesthetic improvement scale
GLs
glabellar lines
ICF
informed consent form
ISR
injection site reaction
PAAQ
periorbital aesthetic appearance questionnaire
SAE
serious adverse event
SAP
statistical analysis plan
SMF
submental fat
SMFRS
submental fat rating scale
SOPS
SkinMedica overall photodamage scale
SPA
self-perception of age
SSRS
subject self-rating scale
USADE
unanticipated serious adverse device effect


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INTRODUCTION
The objective of the initial USA HARMONY study was to observe the safety and overall
aesthetic impact of treating subjects with several modalities in an attempt to achieve subjects’
desired clinical outcome. The Canada Global HARMONY 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 Global HARMONY study, subjects will be evaluated by the investigator to receive
BOTOX Cosmetic, BELKYRA, Juvéderm facial fillers (JUVÉDERM VOLITE, JUVÉDERM 
VOLBELLA with Lidocaine, JUVÉDERM VOLIFT with Lidocaine, and JUVÉDERM
VOLUMA with Lidocaine), and SkinMedica products. 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 
Cosmetic, BELKYRA, JUVÉDERM facial fillers, and SkinMedica products will have a 
significantly higher satisfaction with their overall facial appearance at the final study visit when 
compared with baseline, pre-treatment satisfaction scores, as measured by the mean change from 
baseline on the FACE-Q Satisfaction with Facial Appearance Overall Scale. 
Overall Study Design 
V1                  V2                  V3                   V4                  V5                   V6                 V7               V8                 V9               V10              V11               V12
      
SkinMedica Daily
BOTOX
BELKYRA
KEY INJECTIONS
Subjects being 
treated with 
BELKYRA start here 
Subjects not being 
treated with  
BELKYRA start here 
FILLERS
VO
VO
All subjects will sign an informed consent form (ICF), and begin the study at the screening visit 
(V0). Subjects receiving BELKYRA treatment will enter the study at V1 continuing on through 
V12. There will be no less than 1 month between repeat BELKYRA treatments and the final 
BELKYRA treatment. Subjects not receiving BELKYRA following screening (V0) will enter the 


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study at V7 to begin treatment with fillers, SkinMedica, and BOTOX Cosmetic as indicated in 
the study design diagram above. 
All adverse events (AEs) including 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 Allergan and SkinMedica within 24 hours.


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OBJECTIVES
5.1 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 Allergan products by 
measuring the change in subject’s satisfaction with facial appearance from baseline (before 
any treatment) to the final study visit (FACE-Q™: Satisfaction with Facial Appearance). 
These Allergan products include BOTOX® Cosmetic, BELKYRA®, Juvéderm HA facial 
fillers, and SkinMedica® topical nonprescription skin care products, as described in Section 9.
5.2
Secondary Objectives
Secondary objectives are:
x
To determine the subject’s self-appraisal of expectations of life change FACE-Q™:
Expectations), age-related facial appearance (FACE-Q™: Aging Appraisal),
psychological function (FACE-Q™: Psychological Function), social function (FACE-
Q™: Social Function) and overall satisfaction with skin (FACE-Q™Satisfaction with 
Skin Questionnaire).
x
To quantify the investigator’s and subject’s assessment of aesthetic improvement.


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PATIENT POPULATIONS
6.1 Full Analysis Populations
Full analysis population is defined as all subjects who have met all eligibility criteria at 
the screening visit (V0) and received any product used as treatment in this study. 
6.2 Evaluable Population
Evaluable population is defined as all subjects as defined in the Full Analysis 
Population who have had at least one post-treatment efficacy assessment at the final 
visit (V12).
The Full Analysis Population will be used for subject disposition, demographics and 
baseline characteristics summary will be used for safety analyses. The Evaluable
Population will be used on demographics and key efficacy endpoints as well.
6.3 Subgroups 
Two subgroups will be examined separately:
1. Gender: As male and female subjects may have differing 
expectations/perceptions of aesthetic improvement, they will be examined 
separately. 
2. BELKYRA: As it is expected that approximately two-thirds of the enrolled
population will not be treated with BELKYRA, subjects treated and not 
treated with BELKYRA will be examined separately.


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SUBJECT DISPOSITION
The number and percentage of subjects of the Full Analysis Population will be
summarized by treatment group and overall. The number and percentage of patients for the 
following categories will be displayed: 
Enrolled
Treated
BELKYRA
Non-BELKYRA
Completed the Study
Yes
No
Primary Reason for Discontinuation:   
Adverse Event
Termination by Investigator/Sponsor
Lost to Follow-Up
Personal Reasons
Protocol Violation
Other
Screen-failure patients (i.e., patients screened but not treated) and the associated reasons 
for failure to enroll will be tabulated overall for the all screened patients. The number and 
percentage of patients who complete the V12 and of patients who prematurely discontinue 
during the same period will be presented for each treatment group and pooled across 
treatment groups for the Full Analysis Population. The reasons for premature 
discontinuation from the V12 as recorded on the termination pages of the electronic case 
report forms will be summarized (number and percentage) by treatment group for the Full 
Analysis Population. All patients who prematurely discontinue during the V12 will be listed 
by discontinuation reason for the Full Analysis Population.


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DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
8.1 Demographics
Age, Fitzpatrick skin type, height, weight, BMI at baseline will be summarized descriptively 
with Full Analysis population. 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. Number and percentage of female subjects of childbearing potential and in 
pregnancy are reported.
The demographic information will be listed.
8.2 Baseline characteristics
All FACE-Qs, SPA, PAAQ will be reported. 
8.3 Medical History
A summary of medical history will be presented by system organ class (SOC) and preferred 
term (PT) using Medical Dictionary for Regulatory Affairs® (MedDRA) Version 21.0 or 
higher.
In addition, medical and surgical history will be listed.
8.4 Concomitant Medications
Therapy considered necessary for the subject’s welfare may be given at the discretion of the
investigator, including but not limited to medications for other conditions (i.e., hypertension, 
diabetes, etc.), treatment of AEs, estrogens, androgens, anti-androgenic agents, vitamins, iron
supplements, folate, and herbal supplements. Medications should be taken consistently
throughout the study and at the investigator’s discretion.
Concomitant medications encompass all medicinal products that the subject was taking prior 
to the day 0 visit that are ongoing at the visit, in addition to all medications that have a start 
date on or after the day 0 visit date.
Concomitant medications will be summarized descriptively using frequency tables by ATC 
class and preferred name by treatment group and overall.
In addition, individual listing will be generated for all medication.
8.5
Clinical Scales for Treatment Inclusion Only
FWS, SMFRS and other inclusion/exclusion criteria will not be reported.


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EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
Subject study product exposure and compliance will be summarized using descriptive 
statistics for each product, combination of multiple products, and overall exposure 
respectively during the treatment period.


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EFFICACY ANALYSES
The primary efficacy endpoint is the change from baseline to the final visit in the overall 
Rasch-transformed scores of the FACE-QTM Satisfaction with Facial Appearance Scale. The
scale data will be analyzed by using paired t-test. If normality is unmet, Wilcoxon signed-
rank test is used to replace paired t-test. If skewness of FACE-Q change from baseline is not 
close to zero, the change data of FACE-Q is not considered as normally distributed. In this 
case, one-way nonparametric procedure with Wilcoxon option will be used to replace paired 
t-test.
One-sample paired t-test is performed on changes at end of study. The following statistics 
will be provided; 
Label of Statistics
Description
N
Number of subjects of overall or a subgroup
Mean
Mean change of FACE-QTM Scale
SD
Standard deviation of Mean Change
SEM
Standard error of Mean Change
Median
Median of Changes
Minimum, Maximum
Minimum, Maximum (of Changes)
Pr > |t|
p value of Mean Change through paired t-test, or that of 
Wilcoxon signed-rank test
95% CIs
95% Confidence Intervals of the Mean, lower and upper limits
The efficacy analyses will be based on the Evaluable population. Baseline for efficacy is 
defined as the last nonmissing assessment before the first dose of study treatment. All 
statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects. All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise.
Hypothesis testing will be performed at a 0.05 significance level (2-sided). Since BELKYRA 
and without BELKYRA are the major treatment cohorts, unless specified, all endpoints will 
be summarized by those two groups (BELKYRA and without BELKYRA) and overall 
respectively. However, this study is not designed to compare the efficacy and safety 
outcomes between subjects treated with BELKYRA and those treated without BELKYRA. 
All discussion and interpretation related to study outcomes will be mainly focused on the 
overall results.
10.1 FACE-QTM: Description
The FACE-QTM was developed in response to a lack of well-defined and reliable PRO 
instruments for facial aesthetic patients. It is made up of a set of more than 40 independently 
functioning scales and checklists measuring concepts and symptoms important to facial 


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aesthetic patients in relation to different facial areas. The FACE-QTM can be used with any 
facial aesthetic patient (surgical and nonsurgical) to measure what patient’s think about their 
appearance, quality of life, adverse effects, and process of care. Each scale provides a 
standalone score from 0 to 100, with higher scores indicating a better outcome. Depending on 
the surgical or nonsurgical procedure, only those FACE-QTM scales and/or checklists relevant 
to a patient or procedure(s) need be completed.
Primary Efficacy Endpoint is FACE-QTM Satisfaction with Facial Appearance.
The other efficacy endpoints include the following FACE-QTM questionnaires;
1. FACE-QTM Expectations Scale
2. FACE-QTM Aging Appraisal
3. FACE-QTM Psychological Function Scale
4. FACE-QTM Social Function Scale
5. FACE-QTM Satisfaction with Skin
10.2 Primary Efficacy Parameter
The primary endpoint is the change from baseline in the Rasch-transformed score of the 
FACE-QTM Satisfaction with Facial Appearance Overall Scale to the final study visit.
The primary efficacy parameter will be summarized by treatment group and overall, as well 
as by subgroup being defined in Section 6.3 Subgroup. Two treatment groups are defined as 
BELKYRA and without-BELKYRA. Overall efficacy is summarized by both groups.
Subgroups of gender and treatment are treated as separate cohorts. There is no between 
groups analysis to be performed.
10.3 Secondary Efficacy Parameters
The same analysis procedures and methods used for the primary efficacy endpoint will be 
applied for the secondary efficacy endpoints, which include FACE-Q Expectations, FACE-Q
Aging Appraisal, FACE-Q Psychological Function Scale, FACE-Q Social Function scale and
FACE-Q Satisfaction with Skin. 
10.3.1 Self-Perception of Age Questionnaire
Subject’s assessment of age-related facial appearance by the self-perception of age (SPA)
measure at baseline before any treatment to final study visit (V12); responders are defined as 
having achieved a younger category. No statistical testing will be performed for SPA data 
distribution.
Summaries of responders are provided in frequency and percentage at baseline and final visit 
for all three questions (a. I look my current age, b. I look years younger and c. I look years 
older). A shift table to summarize changes into an improvement category from baseline to the 
study end is provided in frequency and percentage. No statistical testing for shift tables is 
performed.


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Subgroups in analysis are treated as individual cohorts. No comparison between treatments is 
performed.
10.3.2 Other Efficacy Endpoints
In general, summaries are provided in frequency and percentage for both of assessments by
investigators and subjects, and by subgroups at V12. No statistical testing will be performed
for other efficacy endpoints.
10.3.2.1 Global Aesthetic Improvement Scale (GAIS)
There are two assessment categories in GAIS at V12; Subject rating and Investigator rating. 
Descriptive statistics in frequency and percentage of scales at end of the study, in the 5-point 
scale from -2 to +2 are provided for both of assessments by investigators and subjects, and by 
subgroups as well.
10.3.2.2 Periorbital Aesthetic Appearance Questionnaire (PAAQ)
Descriptive summaries are provided in frequency and percentage for nine (9) questions by 
treatment and subgroups at baseline and end of the study, with five categories of answers for 
each question. Change in subject’s satisfaction with appearance of periorbital area as 
measured by the periorbital aesthetic appearance questionnaire (PAAQ). Transformed PAAQ 
scores are summarized in the same manner of the primary endpoint.
 
 
 
 
 
 


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11
SAFETY ANALYSES
The safety analysis will be performed using the Full Analysis Population. The safety 
parameters will include adverse events (AEs). The last nonmissing safety assessment before
the first dose of study treatment will be used as the baseline for all analyses of that safety 
parameter. 
Categorical variables will be summarized by number and percentage of patients. No 
statistical test will be performed.
11.1 Adverse Events
All Adverse events (AEs) will be classified by Primary System Organ Class (SOC) and 
Preferred Term (PT) according to the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.0 or newer. 
TEAE is defined as an AE that was not present prior to treatment with investigational 
products but appeared following treatment or was present at treatment initiation but worsened 
after treatment or become SAE. 
An SAE is defined as 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.
AE summary tables will be presented for TEAEs only and will include the following: 
x
All TEAEs 
x
TEAEs related to study drug 
x
TEAEs leading to study discontinuation 
x
Serious/Severe TEAEs 
x
Serious/Severe TEAEs related to study drugs
x
TEAEs leading to death. 
All TEAEs will be summarized by SOC, PT and treatment group using frequency counts and 
percentages (i.e., number and percentage of subjects with an event). In addition, an overall 
summary for the categories above will be prepared by treatment group and overall. 
All TEAEs will be summarized by SOC, PT, maximum severity, and treatment group using 
frequency counts and percentages (i.e., number and percentage of subjects with an event)
An AE will be considered as related if the event is Possibly, Probably or Definitely related. If 
the relationship to study drug is missing, the AE will be treated as related. For AE with 
severity missing, the missing severity will be imputed as severe. 


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For the incidence at the subject level by SOC and PT, if a subject experiences more than one 
event within the same SOC and PT, only one occurrence will be included in the incidence.  
For the incidence at the subject level by SOC, PT, and severity, if a subject experiences more 
than one event within the same SOC and PT, only the most severe occurrence will be 
included in the incidence. 
For the incidence at the subject level by SOC, PT, and relationship to investigational product, 
if a subject experiences more than one event within the same SOC and PT, only the most 
related occurrence will be included in the incidence. 
For the summary of number of events, if a subject experiences more than one event within 
the same SOC and PT, all events will be counted. 
All AEs will be listed, and additional listings will be presented for AEs leading to 
discontinuation, serious AEs and AEs resulted in deaths.


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12
HEALTH OUTCOMES ANALYSES
Health outcome analysis is not applicable to this study.


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INTERIM ANALYSIS
Interim analysis is not applicable to this study.


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DETERMINATION OF SAMPLE SIZE
A sample size of 48 subjects will provide 90% power to detect whether 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 20.0. This calculation is based on a 1-sample, 2-sided t-test at 5% 
significance level. The assumptions of mean and standard deviation are based on FACE-Q
results from Allergan HARMONY Study GMA-CMB-14-001. With a 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. 
From the 60 subjects planned to enroll in this study, approximately 20 subjects will be treated 
with BELKYRA.
Subjects will be assigned to study treatment only if they meet the inclusion criteria and none 
of the exclusion criteria. Subjects who discontinue treatment will not be replaced.
EXACT software (version 6) was used to confirm the sample size in the protocol.


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STATISTICAL SOFTWARE
Statistical analyses will be performed using 


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DATA HANDLING CONVENTIONS
16.1 Visit Time Windows
All subjects will sign an informed consent form (ICF), and begin the study at the screening 
visit (V0).
Subjects receiving BELKYRA treatment will enter the study at V1 and continuing through 
V12. There will be no less than 1 month between repeat BELKYRA treatments and the final 
BELKYRA treatment. Subjects not receiving BELKYRA following screening (V0) will 
enter the study at V7 to begin treatment with fillers, SkinMedica, and BOTOX Cosmetic as 
indicated in the study design diagram above. 
16.2 Handling of dropouts missing data
After the subjects exit the study, the values for missed future visits will not be imputed.
For subjects who discontinued from the study, the efficacy data collected on the exit visit will 
be mapped to scheduled visit. 
16.2.1 Handling of missing or incomplete dates
Missing or incomplete dates will not to be imputed. There are cases where dates are missing 
for which visits and results are also missing, imputation will only be done on visits and 
results, but not on dates.
16.3 Missing Severity Assessment for Adverse Events
If severity is missing for an AE that started before the date of the first dose of study 
treatment, an intensity of mild will be assigned. If severity is missing for an AE that started 
on or after the date of the first dose of study treatment, an intensity of severe will be 
assigned. The imputed values for severity assessment will be used for the incidence 
summary; the values will be shown as missing in the data listings.


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DATA COLLECTED BUT NOT ANALYZED
This section is not applicable to this study.


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CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
Change to analyses specified in protocol is not applicable to this study.


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REFERENCES
1. Development and Psychometric Evaluation of the FACE-Q Satisfaction with 
Appearance Scale A New Patient-Reported Outcome Instrument for Facial Aesthetics 
Patients, Andrea L. Pusic, MD, MD, MHS, FRCSC, Anne F. Klassen.
2. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of 
new psychometric methods, Health Technology Assessment 2009; Vol. 12 No. 12, J 
Hobart and S Cano


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