Pilot Study to Assess the Effectiveness and Safety of Belotero Balance® Injection for Volume Augmentation of the Infraorbital Hollow
Phase: NA
Conditions: Correction of Volume Loss in the Infraorbital Hollow Area
Sponsor: Merz North America, Inc.

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 1 of 85 
Clinical Study Protocol 
A Pilot Study to Assess the Effectiveness and Safety of Belotero Balance® 
Injection for Volume Augmentation of the Infraorbital Hollow 
Study protocol number: 
M930121001 
Date of original clinical study 
protocol and all previous 
amendments: 
08-NOV-2018 (Amendment no. 4.0, Version 5.0)
04-OCT-2018 (Amendment no. 3.0, Version 4.0)
05-DEC-2017 (Amendment no. 2.0, Version 3.0)
09-AUG-2017 (Amendment no. 1.0, Version 2.0)
13-MAR-2017 (original protocol, Version 1.0)
Development phase: 
Device pre-market 
Investigational product: 
Belotero Balance® 
Indication: 
Correction of volume loss in the infraorbital hollow area 
Sponsor: 
Merz North America Inc. 
6501 Six Forks Road 
Raleigh, NC 27615 
Telephone: (919) 582-8000 
Authors: 
Clinical Project Director: 
 
Medical Expert: 
 
Scientific Expert/Sr. Medical Writer: 
 
Sr. Biostatistician: 
 
CONFIDENTIAL AND PROPRIETARY 
The contents of this document are confidential and proprietary of Merz North America, Inc 
Unauthorized use, disclosure or reproduction is strictly prohibited. This document or parts thereof may not 
be disclosed to parties not associated with the clinical investigation without the prior written consent of 
Merz North America, Inc. 
NCT03777917, redacted 
version v1.0, 15Mar2022

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 3 of 85 
Statement of Compliance and Investigator Signature 
I have thoroughly read and reviewed the clinical study protocol and assume responsibility 
for the proper conduct of the study and all investigational device testing at this site.  
Having understood the requirements and conditions of the clinical study protocol, I agree 
to conduct the study in compliance with this protocol, any future amendments, and any 
other study conduct procedures provided by the sponsor. I will follow the principles of 
International Conference on Harmonization’s Good Clinical Practice (ICH-GCP), all 
applicable regulatory authority requirements, and conditions of approval imposed by any 
reviewing or regulatory bodies when conducting this study. In addition, I agree to: 
• Sign this clinical study protocol before the study formally starts. 
• Wait until I have received approval from the appropriate Institutional Ethics 
Committee (IEC)/Institutional Review Board (IRB) before enrolling any subject in 
this study. 
• Start the study only after all legal requirements in my country have been fulfilled. 
• Obtain informed consent for all subjects prior to performing any study-related 
action. 
• Permit study-related monitoring, audits, IEC/IRB review, and regulatory 
inspections and provide direct access to all study-related records, source documents, 
subject files, and case report forms for the monitor, auditor, IEC/IRB, or regulatory 
authority upon request. 
• Use all study materials only as specified in the clinical study protocol. 
• Report to the responsible product safety officer, within 24 hours, any serious 
adverse event (SAE) and serious adverse device effect (SADE), whether considered 
related or not related to the investigational device. 
• Provide to the sponsor, prior to initiating the study, my curriculum vitae, including 
details of relevant experience and an explanation of any prior terminated research 
(if applicable). Agree to provide written disclosure of any financial interest, in 
accordance with 21 CFR Part 54, and will promptly update this information if 
changes occur during or within one year after study completion.  
Furthermore, I understand that: 
• Changes to this protocol must be made in the form of an amendment that has the 
prior written approval of Merz and any applicable IEC/IRB or regulatory authority. 
• The content of the clinical study protocol is confidential and proprietary to Merz.  
• Any deviation from the clinical study protocol may lead to early termination of the 
study site. 
 
 
 
 
 
Principal Investigator (print name) 
 
Date (dd-MMM-yyyy) 
 
Signature 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 4 of 85 
PROTOCOL SYNOPSIS 
Protocol Title 
A pilot study to assess the effectiveness and safety of Belotero Balance® Injection 
for Volume Augmentation of the Infraorbital Hollow 
Protocol Number 
M930121001 
Active Product 
Belotero Balance® 
Study Phase 
Device pre-market 
Indication 
Correction of volume loss in the infraorbital hollow area 
Number of Sites and 
Countries 
The study will be conducted in the United States at approximately 3 sites.  
Number of Study 
Subjects 
Approximately 66 subjects will be enrolled and randomized, with approximately 
44 subjects assigned to the treatment group and 22 subjects assigned to the 
untreated control group. 
Objective 
The pilot study aims to define safety, effectiveness, and patient-reported outcomes 
for Belotero Balance use in the infraorbital hollow (IOH) in order to utilize the 
results to inform the design of a future pivotal study.   
Key Endpoints 
Primary 
• 
Comparison of the responder rate between the treatment group and the 
untreated control group at Month 2, according to the Merz Infraorbital 
Hollow Assessment Scale (MIHAS) 
. 
For subjects randomized to treatment, if no touch-up is performed, the 
primary effectiveness MIHAS assessment will occur at Month 2 post 
baseline injection. If a touch-up is performed, the primary effectiveness 
MIHAS assessment will be at 2-months post touch-up. For subjects 
randomized to the untreated control group, the primary effectiveness 
assessment will be at Month 2 from the baseline visit.    
Treatment response is defined as ≥ 1-point improvement on both IOHs 
compared to baseline.  
Secondary 
• 
Summary of the FACE-Q satisfaction with eyes scores for treated 
subjects at baseline and Month 2 post last injection (i.e., either baseline 
treatment or touch-up, if applicable) and for control subjects at baseline 
and Month 2. The subject’s assessment is based on taking into 
consideration both eyes. 
• 
Descriptive summary of Global Aesthetic Improvement Scale (GAIS) 
scores for treated subjects at Month 2 post last injection (i.e., either 
baseline treatment or touch-up, if applicable), as completed by the 
treating investigator. This assessment is a measure of aesthetic 
improvement relative to the baseline pre-treatment condition, as assessed 
from photographs. 
• 
Descriptive summary of GAIS scores for treated subjects at Month 2 post 
last injection (i.e., either baseline treatment or touch-up, if applicable), as 
completed by the subject. This assessment is a measure of aesthetic 
improvement relative to the baseline pre-treatment condition, as assessed 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 7 of 85 
 Ever been treated with fat injections or permanent and/or semi-permanent 
dermal fillers in the midfacial region or plans to receive such treatments 
during participation in the study.  
 Received lower eyelid and/or malar region treatments with any 
absorbable or temporary fillers such as porcine-based collagen fillers, 
hyaluronic acid (HA) products, RADIESSE®, poly L-lactic acid (PLLA) 
or received mesotherapy treatment to the area within the past 24 months 
or plans to receive such treatments during participation in the study. 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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Table of Contents 
1 
Introduction ...............................................................................................................15 
1.1 
Background and rationale .................................................................................... 15 
1.2 
Potential benefits and risks .................................................................................. 16 
2 
Study objectives and endpoints ...............................................................................17 
2.1 
Objectives ............................................................................................................ 17 
2.1.1 
Effectiveness ................................................................................................. 17 
2.1.2 
Safety ............................................................................................................. 18 
2.2 
Endpoints ............................................................................................................. 18 
2.2.1 
Primary endpoint ........................................................................................... 18 
2.2.2 
Secondary endpoints ...................................................................................... 19 
2.2.3 
 
2.2.4 
Safety endpoints ............................................................................................ 21 
3 
Investigational plan ..................................................................................................22 
3.1 
Overview of study design .................................................................................... 22 
3.2 
Study assessments and definitions ....................................................................... 23 
3.2.1 
Effectiveness assessments.............................................................................. 23 
3.2.1.1 
Merz Infraorbital Hollow Assessment Scale (MIHAS) ..............................23 
3.2.1.2 
Photographs ...............................................................................................25 
3.2.1.3 
Treating investigator Global Aesthetic Improvement Scale (GAIS) ..........26 
3.2.1.4 
Subject Global Aesthetic Improvement Scale (GAIS) ................................27 
3.2.1.5 
FACE-Q instruments 
28 
3.2.2 
Safety assessments ......................................................................................... 30 
3.2.2.1 
Adverse events and common treatment responses .....................................30 
3.2.2.2 
Visual safety assessments ...........................................................................30 
3.2.3 
Definitions ..................................................................................................... 32 
3.2.3.1 
Subject enrollment and randomization ......................................................32 
3.2.3.2 
Subject completion .....................................................................................33 
3.2.3.3 
End of study and Total Study Duration......................................................33 
4 
Study population and restrictions ...........................................................................34 
4.1 
Number of subjects and sites ............................................................................... 34 
4.2 
Inclusion criteria .................................................................................................. 34 
4.3 
Exclusion criteria ................................................................................................. 35 
4.4 
Subject restrictions during the study .................................................................... 37 
4.5 
Screen failures ..................................................................................................... 39 
4.6 
Subject withdrawal criteria .................................................................................. 39 
5 
Study procedures ......................................................................................................40 
5.1 
Schedule of events by visit .................................................................................. 40 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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5.1.1 
Scheduled visits ............................................................................................. 45 
5.1.2 
Unscheduled visits ......................................................................................... 45 
5.2 
Stopping rules ...................................................................................................... 46 
5.2.1 
Criteria for treatment discontinuation ............................................................ 46 
5.2.2 
Premature suspension or termination of study ............................................... 46 
5.2.3 
Study site discontinuation .............................................................................. 47 
5.2.4 
Discontinuation criteria for a subject ............................................................. 47 
5.2.5 
Provision of care for subjects after study discontinuation .............................. 48 
6 
Study device and treatment of subjects ..................................................................49 
6.1 
Description of the study device ........................................................................... 49 
6.2 
Usage ................................................................................................................... 49 
6.3 
Study treatment.................................................................................................... 49 
6.3.1 
Planned treatment procedure and administration ........................................... 49 
6.3.2 
Infraorbital hollow treatment region .............................................................. 49 
6.3.3 
Injection procedure ........................................................................................ 50 
6.3.3.1 
Preparation of the injection region............................................................50 
6.3.3.2 
Directions for use of cannula .....................................................................50 
6.3.3.3 
Depth of injection and injection technique ................................................52 
6.3.3.4 
Additional injection information ................................................................53 
6.3.3.5 
Post-treatment care/pain management ......................................................53 
6.3.4 
 
6.3.5 
Packaging of treatment supplies .................................................................... 54 
6.3.6 
Receipt, storage, dispensing, and return/disposal ........................................... 54 
6.3.7 
Accountability procedures ............................................................................. 55 
6.3.8 
 
7 
Safety and adverse events ........................................................................................57 
7.1 
Definitions ........................................................................................................... 57 
7.1.1 
Investigational medical device ....................................................................... 57 
7.1.2 
Adverse event (AE) ....................................................................................... 57 
7.1.3 
Adverse device effect (ADE) ......................................................................... 58 
7.1.4 
Serious adverse events (SAE) ........................................................................ 58 
7.1.5 
Serious adverse device effect (SADE) ........................................................... 59 
7.1.6 
Unanticipated adverse device effect (UADE) ................................................ 59 
7.1.7 
Anticipated serious adverse device effect (ASADE) ..................................... 59 
7.1.8 
Common treatment responses (CTRs) ........................................................... 59 
7.1.9 
Device deficiency .......................................................................................... 60 
7.1.10 
Malfunction ................................................................................................... 60 
7.2 
Reporting requirements ....................................................................................... 60 
7.2.1 
Determining severity/intensity ....................................................................... 60 
7.2.2 
Determining causal relationship .................................................................... 61 
7.2.3 
Determining outcome .................................................................................... 61 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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7.2.4 
Procedures for reporting specific events ........................................................ 61 
7.2.4.1 
Adverse event (AE) and adverse device effect (ADE) ................................61 
7.2.4.2 
Serious adverse event (SAE) and serious adverse device effect 
(SADE) .......................................................................................................62 
7.2.4.3 
Technical device complaints ......................................................................63 
7.2.4.4 
Pregnancy ..................................................................................................64 
7.3 
Submission procedure ......................................................................................... 64 
7.4 
Procedures for unblinding.................................................................................... 65 
8 
Statistical methods ....................................................................................................66 
8.1 
Estimation of sample size .................................................................................... 66 
8.2 
Randomization .................................................................................................... 67 
8.3 
Populations for analysis ....................................................................................... 67 
8.4 
Statistical analyses ............................................................................................... 67 
8.4.1 
Effectiveness analysis .................................................................................... 68 
8.4.1.1 
Primary effectiveness endpoint ..................................................................68 
8.4.1.2 
Secondary effectiveness endpoint ..............................................................68 
8.4.1.3 
 
8.4.2 
Safety analysis and endpoints ........................................................................ 71 
8.4.3 
 
8.5 
Timing of statistical analyses ............................................................................... 72 
8.6 
Special statistical/ analytical issues ..................................................................... 72 
8.6.1 
Subject discontinuation and missing effectiveness data ................................. 72 
8.6.2 
Imputation of safety data ............................................................................... 72 
9 
Ethics and administrative procedures ....................................................................73 
9.1 
Ethical considerations .......................................................................................... 73 
9.2 
Informed consent ................................................................................................. 73 
9.3 
Confidentiality of subject information ................................................................. 74 
9.4 
Study monitoring ................................................................................................. 74 
9.5 
Data quality assurance ......................................................................................... 74 
9.5.1 
Standardization procedures ............................................................................ 74 
9.5.2 
Data management .......................................................................................... 75 
9.5.3 
Data review and clarification procedures ....................................................... 75 
9.5.4 
Study auditing ................................................................................................ 76 
9.6 
Record retention .................................................................................................. 76 
9.7 
Publication policy ................................................................................................ 76 
9.8 
Financial disclosure ............................................................................................. 77 
9.9 
Investigator compliance ....................................................................................... 77 
10 Appendices .................................................................................................................78 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 11 of 85 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 12 of 85 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 13 of 85 
List of Abbreviations 
Abbreviation/Term 
Definition 
ADE 
Adverse device effects  
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical classification system 
BDDE 
1,4-butanediol diglycidyl ether 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTR  
Common treatment site response or common treatment response 
eCRF 
Electronic case report form  
EDC 
Electronic data capture 
FACE-Q 
Set of subject-reported questionnaire modules 
FDA 
Food and Drug Administration, US  
G 
Gauge  
GAIS 
Global Aesthetic Improvement Scale  
GCP 
Good clinical practice  
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee  
IFU  
Instructions for use  
IOH 
Infraorbital hollow  
IRB 
Institutional review board  
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram  
MIHAS 
Merz Infraorbital Hollow Assessment Scale  
mL 
Milliliter  
mm 
Millimeter 
N 
Number of non-missing observations 
PI 
Principal investigator 
PLLA 
Poly-L-lactic acid 
PP 
Per protocol population 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SP 
Safety population 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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Abbreviation/Term 
Definition 
UADE 
Unanticipated adverse device effects  
US 
United States 
UV 
Ultraviolet 
 
 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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1.2 Potential benefits and risks 
The potential benefit of Belotero Balance is the correction of volume loss in the 
infraorbital hollow area. 
Adverse events have been identified during post-approval use of Belotero Balance; 
however, because the events are reported voluntarily, from a population of uncertain size, 
it is not always possible to reliably estimate their frequency or establish a causal 
connection to Belotero Balance. The following adverse events have been chosen for 
inclusion due to a combination of their seriousness, frequency of reporting, or potential 
causal connection to Belotero Balance: allergic reactions including Quincke’s edema, 
anaphylaxis, rash, hives, necrosis, inflammation, granuloma, indurations, and/or nodules; 
hematoma; Tyndall effect; Cordon-like effect; bumps; pustule; scarring; swelling; 
erythema; pain; edema; bruising; lumps; discoloration; infection; migration/displacement; 
asymmetry; numbness; vascular occlusion; and/or visual disturbance. 
Potential risks associated with the use of Belotero Balance are similar to those of other 
commercially available, deep soft-tissue fillers. Previously reported injection-site 
responses to Belotero Balance consisted mainly of short-term inflammatory symptoms 
including: swelling; induration; bruising; redness; erythema; pain; nodule formation; 
coloration or discoloration; pruritus; and rash. These observations started early after 
treatment and resolved in 7 days or less.  
Rare but serious adverse events associated with the intravascular injection of soft-tissue 
fillers in the face have been reported and include: temporary or permanent vision 
impairment; blindness; cerebral ischemia or cerebral hemorrhage leading to stroke; skin 
necrosis; abscesses; granulomas; eyelid muscle degeneration and damage to the 
underlying facial structures. Implantation of Belotero Balance into the vasculature may 
lead to embolization, occlusion of the vessels, ischemia, or infarction. 
An additional risk includes disappointment due to lack of or reduced performance and/or 
undesirable aesthetic effect. 
The use of cannula may increase the duration of local site irritation or erythema by 1-2 
days in comparison to the use of a needle. 
Currently, there are no approved dermal fillers for volume correction around the 
eyes. Alternative options may include various surgical, non-invasive procedural and 
potentially topical therapy interventions or no treatment at all. 
Additional information on product- and injection-related contraindications, warnings, and 
precautions can be found in the Instructions for Use (see Appendix 10.3). 
 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
The pilot study aims to define safety, effectiveness, and patient-reported outcomes for 
Belotero Balance use in the IOH in order to utilize the results to inform the design of a 
future pivotal study.  
2.1.1 
Effectiveness 
The effectiveness and relevance of aesthetically pleasing outcomes following Belotero 
Balance injection will be established in the following manner: 
• The primary endpoint (see Section 2.2.1) will establish effectiveness by using the 
MIHAS to demonstrate that clinically relevant changes of ≥ 1-point on both IOHs 
can be detected 2-months post-treatment. 
• The secondary endpoints (See Section 2.2.2) including the validated FACE-Q 
satisfaction with eyes, the investigator GAIS, and the subject GAIS will be 
utilized to substantiate aesthetically pleasing outcomes. The GAIS assessments 
will be used in the treated subjects only. Improvements in the FACE-Q 
satisfaction with eyes scores from baseline to 2-months post-treatment will 
indicate that subjects are satisfied with treatment effects observed on their IOHs 
and such changes are considered to be clinically relevant from the subject’s 
perspective. Responses for FACE-Q satisfaction with eye scores in the control 
group will be compared to that of the treatment group in order to show that 
changes in satisfaction post-treatment are clinically relevant to the subject.  
Additionally, the investigator and subject GAIS scores at Month 2 post last 
injection will be utilized to demonstrate the level of improvement, when 
compared to baseline photographs, resulting from treatment in the IOHs.  

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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• The level of agreement in treated subjects between the MIHAS responders 
(≥ 1-point improvement on both IOHs), 
 and 
the level of improvement (score of ≥ 1) on the treating investigator- and 
subject-GAIS assessments will be obtained. Aesthetically pleasing outcomes 
that are clinically relevant will be established if the agreement between the 
MIHAS responders and the level of improvement on the investigator- and 
subject-GAIS scores, respectively, are met as per the pre-defined endpoints in 
Section 2.2.3.  
In totality, the results from the MIHAS, as well as the supportive outcomes obtained 
from the treating investigator and subject perspectives regarding aesthetic 
improvements, will be used to establish that Belotero Balance injections in the IOH 
region are effective in producing clinically relevant and aesthetically pleasing 
outcomes.  
2.1.2 
Safety 
The safety objectives include the identification and description of adverse events (AEs) 
and serious adverse events (SAEs) during the course of the study. In addition to standard 
safety assessments, eye assessments (including visual acuity, visual field, ocular motility, 
and undilated fundoscopic exam) will be evaluated. Common treatment responses 
(CTRs) will also be assessed. 
2.2 Endpoints 
2.2.1 
Primary endpoint 
 

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The primary endpoint is a comparison of the responder rate between the treatment group 
and the untreated control group at Month 2, according to the MIHAS 
 
. For subjects randomized to treatment, if no touch-up is performed, 
the primary effectiveness MIHAS assessment will occur at Month 2 post baseline 
injection. If a touch-up is performed, the primary effectiveness MIHAS assessment will 
be at 2-months post touch-up. For subjects randomized to the untreated control group, the 
primary effectiveness assessment will be at Month 2 from the baseline visit.   
Treatment response is defined as ≥ 1-point improvement on both IOHs compared to 
baseline.  
2.2.2 
Secondary endpoints 
 
• Summary of the FACE-Q satisfaction with eyes scores for treated subjects at baseline 
and Month 2 post last injection (i.e., either baseline treatment or touch-up, if 
applicable) and for control subjects at baseline and Month 2. The subject’s 
assessment is based on taking into consideration both eyes. 
• Descriptive summary of GAIS scores for treated subjects at Month 2 post last 
injection (i.e., either baseline treatment or touch-up, if applicable), as completed by 
the treating investigator. This assessment is a measure of aesthetic improvement 
relative to the baseline pre-treatment condition, as assessed from photographs. 
• Descriptive summary of GAIS scores for treated subjects at Month 2 post last 
injection (i.e., either baseline treatment or touch-up, if applicable), as completed by 
the subject. This assessment is a measure of aesthetic improvement relative to the 
baseline pre-treatment condition, as assessed from photographs. 
• Summary of the responder rates in the treatment group and the control group at 
Month 2, according to the MIHAS,
 
using subject photographs. In addition to baseline photograph assessments, for 
subjects randomized to treatment, if no touch-up is performed, the photographs 
assessed will be those taken at 2-months post baseline injection. If a touch-up is 
performed, the photographs assessed will be those taken at 2-months post touch-up. 
For subjects randomized to the untreated control group, the photographs assessed will 
be taken at 2-months from the baseline visit.  
 
Treatment response is defined as ≥ 1-point improvement on both IOHs when 
comparing the change from baseline to Month 2. A subject will be considered a 
responder if a treatment response of at least 1-point change on both IOHs is 
determined 
. 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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2.2.4 
Safety endpoints  
• Incidence and nature of device- and/or injection-related AEs and SAEs observed 
during the study. 
• Incidence, severity, and duration of pre-specified CTRs reported in subject diaries. 
 
 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
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Figure 1: Merz Infraorbital Hollow Assessment Scale (MIHAS) 
3.2.1.2 
Photographs 
Subject photographs will serve as an accurate record of the subject’s appearance and the 
subject’s appearance after IOH injection and may reflect any relevant safety concerns. 
Standardized photographs will be taken for treated subjects at the baseline visit, Week 2 
and Months 1, 2, 3, 6, 9, and 12 after the last injection (i.e., either baseline treatment or 
touch-up, if applicable). If subjects receive a touch-up 1-month after baseline injection, 
these subjects will also have standardized photographs taken 2-weeks and 1 month after 
the touch-up injection. Baseline photographs will be used for pre-treatment 
comparison/reference in the Month 2 post last injection (i.e., either baseline injection or 
touch-up, if applicable) GAIS assessments conducted by the treating investigator and the 
study subject (see Sections 3.2.1.3 to 3.2.1.4, respectively). Standardized photographs 
will be taken for control subjects at the baseline visit and Month 2. Every effort should be 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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Table 1: Treating Investigator Global Aesthetic Improvement Scale (GAIS) 
3.2.1.4 
Subject Global Aesthetic Improvement Scale (GAIS) 
Treated subjects will evaluate their overall facial aesthetic improvement on the subject 
GAIS using photographs from Month 2 after the last injection (i.e., either baseline 
treatment or touch-up, if applicable) and baseline pre-treatment photos for comparison 
(see Table 2). GAIS will not be completed for subjects randomized to the control group. 
The subject will be asked: “Considering both IOHs, what is your overall impression of 
change of your aesthetic result due to treatment, compared to the condition before the 
injection? Please tick the one option that best fits your overall impression of change.” 
The following 7-point scale will be used: 
Table 2: Subject Global Aesthetic Improvement Scale (GAIS) 
 
 
 
 
 
 

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3.2.2 
Safety assessments 
3.2.2.1 
Adverse events and common treatment responses 
All AEs reported by study subjects, investigators, or other study staff after the time of 
informed consent through end of study will be recorded. Events will be recorded 
regardless of causality. Note: End of study will be 13-months from baseline treatment for 
subjects who receive a touch-up, 12-months from baseline treatment for subjects who do 
not receive a touch-up, and Month 2 for control subjects. 
A subject diary will be dispensed on the day of treatment to collect CTR information as 
well as specific safety concerns. The diary will be collected daily for 4-weeks post-
treatment. Another 4-week diary will be distributed and completed following touch-up 
treatment at Month 1, if applicable.  
Subjects will be asked to record daily on the diary any pre-defined CTRs and other safety 
events that may occur. The treating investigator will review and determine if any entries 
should be captured as AEs. Subjects assigned to the control group will not be provided or 
asked to complete the diary.  
After the baseline treatment, treated subjects will receive a 72-hour post-treatment phone 
call and return to the clinic for a 2-weeks post-injection visit. During these safety checks, 
the subject diary will be reviewed for potential AEs. Subjects will continue their diary for 
1-month after baseline treatment. If a subject receives an optional touch-up 1-month after 
baseline treatment, the subject will receive a 72-hour post touch-up phone call and return 
to the clinical 2-weeks post touch-up. Touch-up diaries will be reviewed for potential 
AEs and subjects will continue to complete the diary for 1-month after the touch-up 
injection.  
Additional information on safety assessments and procedures is discussed in Section 7. 
3.2.2.2 
Visual safety assessments 
Although the incidence of SAEs associated with retinal artery occlusion is very low, 
treated subjects will undergo visual examinations to potentially identify several 
associated ophthalmic signs and/or symptoms that may represent ophthalmic artery 
occlusion. 
All injecting physicians will be oculoplastic surgeons. In addition to plastic surgery 
expertise, these physicians have all completed ophthalmology training and have the 
knowledge and skill set specifically suited to injecting and treating issues in this anatomic 
area. 

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For subjects assigned to the treatment group, prior to injection, each subject will undergo 
a series of bilateral, visual safety assessments. These assessments will also be completed 
post injection at Week 2 and Months 1, 2, 3, 6, 9, and 12 after the last injection (i.e., 
either baseline treatment or touch-up, if applicable). If subjects received a touch-up 1-
month after the baseline injection, a visual assessment will be performed immediately 
post touch-up. Visual assessments will include a visual acuity test (using a Snellen chart), 
a visual field test and an ocular motility exam. The investigator will also perform an 
undilated fundoscopic exam with an ophthalmoscope. 
For subjects assigned to the control group visual safety assessments will be performed at 
baseline and Month 2. 
3.2.2.2.1 
Visual acuity 
Visual acuity will be determined using the Snellen chart. Each site is equipped with a 
Snellen chart. The lane and distance from the chart will be confirmed by the monitor.  
The site will follow standard directions for using the Snellen chart in determining visual 
acuity. The subject will be asked to cover one eye (if the subject wears glasses/contacts 
for distance vision they will be asked to keep them on/in). The examiner will point to 
each line as the subject reads the letters out loud. The smallest line where the subject 
identified the majority of letters correctly (i.e., if he/she could read 5 out of 8 letters on 
line 8, the visual acuity would be 20/20.) Visual acuity is expressed as a fraction. The top 
number refers to the distance the subject stands from the chart while the bottom number 
indicates the distance at which a person with normal eyesight could read the same line. 
The visual acuity per eye will be recorded in the electronic case report form (eCRF). 
3.2.2.2.2 
Visual field test 
The Visual field test will measure how sensitive the vision is in different parts of the 
visual axis. To measure the visual field, the examiner will use the standard finger test 
according to the American Academy Ophthalmology. 
3.2.2.2.3 
Ocular motility exam 
The examiner should determine if the subject’s motility is intact in each direction of gaze. 
The subject should be instructed to voice if they have any double vision in any of these 
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3.2.2.2.4 
Undilated central retinal fundoscopic exam using an 
ophthalmoscope 
In this procedure, the oculoplastic surgeon will perform a focused exam of the central 
retina and blood vessels to evaluate for any evidence of vascular occlusion. 
After the injection of the first IOH (either baseline treatment or touch-up, if applicable), 
subjects will be asked to wait 30 minutes and then repeat the visual safety assessments 
for the already treated side. The subsequent side will then be injected once these 
assessments are completed on the first side and the investigator confirms that it is safe to 
proceed with treatment on the second IOH. The subject will then receive the Belotero 
Balance to treat the second IOH, wait 30 minutes, and then repeat the visual safety 
assessments for that side. When the subject returns for the 2-week safety follow-up visit 
and any subsequent visits, these visual assessments will be repeated and compared to 
baseline for any changes that could indicate a safety signal or concern. 
NOTE: If only injecting one side for touch-up, only the side being injected will need the 
visual safety assessments 30-minutes post-treatment.  
A local retinal specialist will be identified in advance to address any visual changes and 
potential retinal artery occlusion (i.e., investigator-determined, clinically significant 
changes in vision, such as blindness, blurriness, double vision, pain in or around the eye 
[other than typical injection-induced pain], blind spots, or restriction of eye motility). 
3.2.2.2.5 
Directions for intravascular injection or embolic event 
In the event of intravascular injection or embolic event, the treating physician will 
provide prompt medical attention and follow the proper protocol for handling these 
symptoms. If in progress, best practices should be used to stop the injection. The treating 
physician should consider the following: an immediate referral to the retinal specialist, 
injection of hyaluronidase in the anatomic area of treatment and/or retrobulbar, and 
consideration of active reduction of intraocular pressure. The investigator should treat in 
accordance with the American Society for Dermatologic Surgery guidelines. The subject 
will be closely monitored by the treating investigator, and if applicable, a retinal 
specialist. 
3.2.3 
Definitions 
3.2.3.1 
Subject enrollment and randomization 
Subjects are considered to be enrolled after they sign informed consent, meet all 
eligibility criteria, and are randomized in the electronic randomization system. 

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Screen failures are defined in Section 4.5. 
3.2.3.2 
Subject completion 
Subjects are considered to have completed the study if they are randomized, received 
treatment (for treatment group), and completed all visits defined in the Schedule of 
Events (see Section 5.1 and Appendices 10.1 and 10.2). Control group subjects are 
considered to have completed the study after all Month 2 assessments have been 
completed. 
3.2.3.3 
End of study and Total Study Duration 
Subjects will be screened and enrolled/randomized at the first study visit. For subjects 
randomized to the treatment group, treatment will occur at this baseline visit. The time 
from the baseline visit to the end of study is 13 months for subjects who receive a 
touch-up, 12 months for treated subjects, and 2 months for control subjects.  
The primary effectiveness endpoint is at Month 2 after the last injection (i.e., either 
baseline treatment or touch-up, if applicable); however, treated subjects will continue to 
be followed-up for safety after the effectiveness endpoint via clinical visits at Months 3, 
6, 9,  and 12 after the last injection received (i.e., either baseline treatment or touch-up, if 
applicable). Additional details regarding the timing of database lock and statistical 
analyses are provided in Section 8.5.  
 

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4.3 Exclusion criteria 
Subjects meeting any of the following criteria are not eligible to participate in the study: 
 Ever been treated with fat injections or permanent and/or semi-permanent dermal 
fillers in the midfacial region or plans to receive such treatments during participation 
in the study. 
 Received lower eyelid and/or malar region treatments with any absorbable or 
temporary fillers such as porcine-based collagen fillers, hyaluronic acid (HA) 
products, RADIESSE®, poly L-lactic acid (PLLA) or received mesotherapy treatment 
to the area within the past 24 months or plans to receive such treatments during 
participation in the study. 

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4.4 Subject restrictions during the study 
By providing informed consent, subjects commit to refrain from receiving any of the 
following therapies, procedures, and/or exposures during the study interval (through 13 

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months for subjects who receive a touch-up, 12 months for treated subjects, or 2 months 
for control subjects): 

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4.5 Screen failures 
Subjects who sign informed consent but who do not meet eligibility criteria or who 
withdraw consent prior to being randomized in the electronic randomization system will 
be defined as screen failures. The investigator will maintain all source documentation for 
all subjects who are considered screen failures. Minimal information will be collected in 
the electronic data capture (EDC) system for screen failures, such as date of informed 
consent, demographics, reason for screen failure. 
Individuals who do not initially meet the criteria for participation in this study (screen 
failure) may be rescreened one time. A subject is eligible for rescreening only if the 
reason for failure is due to inclusion/exclusion criteria other than his/her MIHAS rating 
(i.e., baseline MIHAS rating of 0, 1, or 4 or asymmetrical MIHAS scores). Subjects who 
are screen failures due to MIHAS ratings are not eligible for rescreening. 
4.6 Subject withdrawal criteria 
A subject may withdraw from the study at any time at his/her own request without 
prejudice to future medical care. Subjects may also be withdrawn at any time at the 
discretion of the investigator for safety, compliance, or administrative reasons. 
If a subject does not attend a required study visit, the following actions will be taken: 
• The site will attempt to contact the subject at least twice and reschedule the 
missed visit as soon as possible. Every effort to regain contact with the subject 
will be made (e.g., telephone contact on different dates/times, registered mail). All 
contact attempts will be documented. 
• If attempts to contact the subject are not successful, then the subject will be 
considered lost to follow up and withdrawn from the study. The reason for early 
withdrawal will be documented in the case report form (CRF). 
 

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5 STUDY PROCEDURES 
5.1 Schedule of events by visit 
The Schedule of Events is presented in Appendices 10.1 (treated subjects) and 10.2 
(control subjects). 
Day 0 (-28 Day) – Baseline Treatment (BT) / No Treatment (Control) includes Screening, 
Enrollment, and Baseline Assessments 
The following procedures will be performed at this visit in the following order: 
• Obtain written informed consent. A subject must be informed of the study 
requirements, including the risks and benefits of participation. An IEC/IRB-
approved informed consent must be signed and dated by the subject prior to any 
study related activities or procedures being performed, including discontinuation 
of any prohibited medications. 
• Assign subject identification. 
• Collect demographic information. 
• Collect height and weight. Height will be collected at the baseline visit only. 
• Record medical history. 
• Record ocular history. 
• Review and record concomitant medications/therapies. 
• Perform urine pregnancy test (if female of childbearing potential). Negative test 
required prior to randomization. 
• Confirm subject meets all eligibility criteria. 
• Treating physician confirms that the subject meets all eligibility criteria prior 
to randomization. 
• Take standardized baseline IOH photographs. 
• 
 perform the MIHAS assessment. 
• Visual safety assessments on both eyes. 
• Visual acuity test (using a Snellen chart); 

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• Visual field test; 
• Ocular motility exam; and  
• Fundoscopic (opthalmoscopic) view of the eye (not dilated). 
• Administer FACE-Q assessments to subject.  
• Satisfaction with eyes 
• Randomize subject. 
NOTE: Subjects randomized to the control group (no treatment) have completed this visit 
and will be scheduled for the Month 2 visit. 
• Injection (for subjects randomized to the treatment group): 
• Administer treatment injection to first IOH. 
• Wait 30 minutes. 
• Perform visual safety assessments on first eye (where IOH area was treated). 
• Administer treatment injection to second IOH if treating investigator agrees 
that it is safe to proceed with injecting the second IOH. 
• Wait 30 minutes. 
• Perform visual safety assessments on other eye (where second IOH area was 
treated). 
• Dispense subject diary and discuss completion instructions. 
• Review and record AEs.  
• Schedule 72-hour follow-up phone call and Week 2 visit. 
Follow-up Phone call (72-hours ±1 day post treatment)  
NOTE: This phone call is only for subjects assigned to the treatment group. 
• Review and record changes in concomitant medications/therapies. Confirm 
subject remains compliant with any applicable study restrictions (see Section 4.4). 
• Review and record AEs. Site staff will review subject diary responses to identify 
any safety concerns. 

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• If subject reports a safety concern, the subjects will be scheduled for an 
unscheduled visit, referred to a specialist, or be provided means of emergency 
medical care as determined by the investigator. 
• Remind subject to continue the diary.  
• Schedule and/or confirm Week 2 visit. 
Week 2: Day 14 (+3 days) 
NOTE: This visit is only for subjects assigned to the treatment group. 
• Review and record changes in concomitant medications/therapies. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review subject diary for potential AEs. Remind subject to continue to record in 
the diary until Month 1 visit. 
• Review and record AEs. 
• Take standardized IOH photographs. 
• Visual Safety Assessments on both eyes. 
• Visual acuity test (using a Snellen chart);  
• Visual field test; 
• Ocular motility exam; and  
• Fundoscopic (opthalmoscopic) view of the eye (not dilated). 
• Schedule and/or confirm Month 1 visit. 
Month 1: Day 28 (+3 days) Safety and assessment for Touch-up (TU)  
NOTE: This visit is only for treated subjects  
• Review and record changes in concomitant medications/therapies. Confirm 
subject remains compliant with any applicable study restrictions. 
• Take standardized IOH photographs. 
• Review and collect subject diary. The investigator will review the diary and 
determine if any diary entries should be recorded as AEs on the AE eCRF. 
• Visual Safety Assessments on both eyes. 
• Visual acuity test (using a Snellen chart);  
• Visual field test; 

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• Ocular motility exam; and  
• Fundoscopic (opthalmoscopic) view of the eye (not dilated). 
• Review and record AEs.  
• Schedule and/or confirm Month 2 visit.  
• Asymmetry assessment based on a visual assessment completed by the treating 
investigator. 
NOTE: Subjects who don’t receive a touch up to address asymmetry based on the 
treating investigator’s assessment have completed this visit and will be scheduled for the 
Month 2 visit.  
Month 1: Touch-up (TU) 
If the treating investigator determines a touch-up is needed to address asymmetry the 
following procedures will be done: 
• Perform urine pregnancy test (if female of childbearing potential and for treated 
subjects only). Negative test required prior to touch-up injection. 
• Injection (only if treating investigator notes asymmetry): 
• Administer touch-up injection to first IOH. 
• Wait 30 minutes. 
• Perform visual safety assessments on first eye (where IOH area was treated). 
• Administer treatment injection to second IOH if treating investigator agrees 
that it is safe to proceed with injecting the second IOH. 
• Wait 30 minutes. 
• Perform visual safety assessments on other eye (where second IOH area was 
treated). 
NOTE: If only injecting one side, only the side being injected will need the visual safety 
assessment 30 minutes post treatment.  
• Dispense subject diary and discuss completion instructions. 

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• Review and record AEs.  
• Schedule 72-hour follow-up phone call and Week 2 visit. 
NOTE: For subjects receiving a touch-up refer to the Follow-up 72 hour Phone Call, 
Week 2 and Month 1 (safety) assessments as described above. Then subject will continue 
with Month 2 assessments. 
Month 2: Day 56 (+3 days) ALL SUBJECTS 
Visit to occur 2 months after last injection (either baseline treatment or touch-up, if 
applicable) or 2 month after baseline visit for control subjects. 
• Review and record changes in concomitant medications/therapies. Confirm 
subject remains compliant with any applicable study restrictions. 
• Perform urine pregnancy test (if female of childbearing potential and for treated 
subjects only). 
• Take standardized IOH photographs. 
• Collect weight. 
• Review and collect subject diary (touch-up subjects only). The investigator will 
review the diary and determine if any entries should also be recorded as AEs on 
the AE eCRF. 
• Visual Safety Assessments on both eyes. 
• Visual acuity test (using a Snellen chart);  
• Visual field test; 
• Ocular motility exam; and  
• Fundoscopic (opthalmoscopic) view of the eye (not dilated). 
• 
 perform MIHAS assessment. 
• Have the treating investigator complete the investigator GAIS (treated subjects 
only). 
NOTE: Standardized photographs, previously taken during the baseline visit, will be 
available for the treating investigator to reference when completing the Month 2 
GAIS assessment. 
• Have subjects complete the subject GAIS (treated subjects only). 

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NOTE: Standardized photographs, previously taken during the baseline visit, will be 
available for the subject to reference when completing his/her Month 2 GAIS 
assessment. 
• Administer FACE-Q assessments to subject.  
• Satisfaction with eyes  
• Review and record AEs.  
• Schedule and/or confirm Month 3 visit (treated and touch-up subjects only).  
Note: This is the last visit for subjects assigned to the control group. 
Month 3 (Day 84), 6 (Day 168), 9 (Day 252), and 12 (Day 336) (± 7 days)  
• Review and record changes in concomitant medications/therapies. Confirm 
subject remains compliant with any applicable study restrictions. 
• Take standardized IOH photographs. 
• Visual Safety Assessments on both eyes. 
• Visual acuity test (using a Snellen chart); 
• Visual field test; 
• Ocular motility exam; and 
• Fundoscopic (opthalmoscopic) view of the eye (not dilated). 
• Review and record AEs.  
• Schedule and/or confirm the next visit. Study participation ends after Month 12 
visit. 
5.1.1 
Scheduled visits  
All scheduled visits and applicable study assessments must occur as noted in Sections 5.1 
and the Schedule of Events (Appendices 10.1 (treated subjects) and 10.2 (control 
subjects)). 
5.1.2 
Unscheduled visits 
To ensure subject safety during the study, any subject who requires additional follow-up 
during the study for any reasons (that does not fall on a scheduled study visit) should 

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have that visit recorded as an unscheduled visit and all applicable CRFs for that 
unscheduled visit completed. Treated subjects will be followed at 72 hours via a safety 
follow up phone call. These phone calls may result in an unscheduled visit if any safety 
concerns are identified. Treated subjects will be completing a diary for 28 days post 
baseline injection and for 28 days post touch-up injection, which may alert site staff to 
schedule an unscheduled visit if any safety concerns are identified. 
5.2 Stopping rules 
5.2.1 
Criteria for treatment discontinuation 
If study treatment is discontinued at any time during the treatment administration, the 
investigator will record the reason for treatment discontinuation in the study records. The 
investigator may request that a subject discontinuing treatment will continue to 
participate in the study and complete all remaining visits and assessments. If a subject 
declines to continue study participation, the investigator will make every effort to 
perform the appropriate assessments specified in the Schedule of Events (Appendices 
10.1 (treated subjects) and 10.2 (control subjects). 
5.2.2 
Premature suspension or termination of study 
Should the investigator, the sponsor, the FDA, or local regulatory authorities become 
aware of conditions arising during the conduct of this study that may warrant the 
cessation of the study, such action may be taken. Prior to such action, consultation 
between the sponsor, the investigator, and, as appropriate, the FDA and/or local 
regulatory authorities will occur. 
In the case of a treatment related vascular embolic event leading to skin necrosis, vision 
loss, or stroke, the study will be suspended and a root-cause investigation will be 
conducted to determine the cause of the embolic event and whether the outcome was 
anticipated or unanticipated. If the latter situation is observed, the study will be 
immediately suspended and no subjects will be enrolled or treated until the event can be 
properly characterized and an appropriate treatment strategy to avoid this unanticipated 
event can be devised. 
Reasons for the premature suspension or termination of the study include, but are not 
limited to, the following: 
• Determination of a potential safety risk to subjects; 
• Inadequate subject enrollment;  
• Decision by the IEC/IRB to suspend or terminate approval/favorable opinion for 
the study; 

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• Sponsor decision; and/or 
• Other. 
In the event of premature study suspension or termination for safety reasons, the sponsor 
will inform all investigators and relevant regulatory authorities promptly of the study 
suspension/termination and reason for the action. The investigator will conduct site 
closure activities in accordance with all applicable sponsor and local/international 
guidelines and regulations. 
5.2.3 
Study site discontinuation  
Study participation by individual sites may be discontinued by the sponsor for any of the 
reasons listed in Section 5.2.2. Additional reasons for the premature discontinuation of 
study sites include, but are not limited to, the following: 
• Investigator request; 
• Serious or persistent noncompliance with the protocol, local regulations and/or 
GCP; 
• Failure to accrue subjects at an acceptable rate; 
• Ethical issues; and/or 
• Other 
In the event of study site discontinuation, the sponsor will provide to the study site 
written notification documenting the reason for discontinuation. The investigator will 
conduct site closure activities in accordance with all applicable sponsor and 
local/international guidelines and regulations. 
5.2.4 
Discontinuation criteria for a subject  
Each subject will be followed to the end of the study, or/if when the sponsor decides to 
terminate the study, whichever comes first. The only reasons a subject will not be 
followed for all scheduled visits are withdrawal of consent, lost to follow-up (e.g., 
moving away from study site; unresponsive to attempts to contact the subject), any AE or 
adverse device effect (ADE). 
If a subject withdraws consent to continue in the study, the investigator should make 
every attempt to complete the final study visit. If a non-serious AE is unresolved at the 
time of the subject’s final study visit, an effort will be made to follow-up until the AE is 
resolved or stabilized, the subject is lost to follow-up, or there is some other resolution of 
this event. The investigator should make every attempt to follow all serious adverse 
events (SAEs)/unanticipated adverse drug effects (UADEs) to resolution. Information on 

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pregnancy and the outcome for any woman who becomes pregnant during the study will 
be collected. Additional information on subject withdrawal criteria is provided in 
Section 4.6. 
5.2.5 
Provision of care for subjects after study discontinuation 
The investigator is responsible for ensuring the adequate and safe medical care of 
subjects during the study. After completion of the study, the sponsor will follow all 
applicable local or international regulations and guidelines with regard to follow-up 
treatment for subjects. The investigator will ensure that appropriate consideration is given 
to a subject’s post-study care. 
 

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6 STUDY DEVICE AND TREATMENT OF SUBJECTS 
6.1 Description of the study device 
Belotero Balance is a sterile, bioresorbable, non-pyrogenic, viscoelastic, clear, colorless, 
homogeneous gel device. Belotero Balance is a bacterially fermented, injectable, 
hyaluronic-acid-based dermal filler. After extraction and purification, hyaluronic acid 
manufactured from streptococcal cultures is cross-linked with a binding agent 1,4-
butanediol diglycidyl ether (BDDE) in two consecutively executed reactions and 
reconstituted in a physiologic buffer at pH 7 and concentration of 22.5 mg/mL. 
6.2 Usage 
Belotero Balance should be used in the IOH treatment region according to the 
information and injection instructions presented in Section 6.3.3. Additional information 
on product usage is provided in Appendix 10.3. 
6.3 Study treatment 
All protocol-specific criteria for the administration of study treatment must be met and 
documented prior to administration of any study treatment. Study treatment (injection) 
will be administered only to eligible subjects by a qualified oculoplastic surgeon. 
Subjects will not be dispensed any investigational material. Any noncompliant subject or 
site may be discontinued from the study (Section 5.2). 
6.3.1 
Planned treatment procedure and administration 
Approximately 44 subjects will be randomized to receive treatment and 22 subjects will 
serve as the controls. Subjects will be randomized using a 2:1 allocation ratio for 
treatment to control. 
For subjects randomized to the treatment group, both right and left IOHs will receive 
treatment with Belotero Balance per the administration instructions specified below. 
6.3.2 
Infraorbital hollow treatment region 
Belotero Balance is to be deposited in the supraperiosteal plane. Injection volume will be 
recorded. Figure 3 illustrates the region of the IOH that may be treated. The infraorbital 
treatment area is at the junction of the lower eyelid and mid-face where a volume deficit 
has formed. The area is bordered by the nasal sidewall medially, the temporal region of 
the bony orbit laterally, the bulk of the lower eyelid superiorly, and the superior aspect of 
the mid-face inferiorly. 

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Figure 3: Treatment region 
6.3.3 
Injection procedure 
6.3.3.1 
Preparation of the injection region 
• Any makeup in the IOH area should be removed.  
• As with all transcutaneous procedures, Belotero Balance injection carries a risk of 
infection and should be conducted with aseptic technique. 
• Only topical anesthetic, at the preference of the treating physician, or ice may be 
applied. Any medication or therapy must be recorded in the CRF. 
6.3.3.2 
Directions for use of cannula 
1. To attach the cannula to the syringe, open the cannula packaging to expose the hub. 
Use only the cannula provided with the clinical trial supply. 
2. Remove the Luer lock syringe cap from the distal end of the syringe prior to attaching 
the cannula (see Figure 4). 

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Figure 4: Removing the Luer lock syringe cap from the syringe 
 
3. Holding the Luer lock fitting of the syringe, twist the cannula onto the syringe. The 
cannula must be tightened securely to the syringe. Do not over-tighten as this may 
break the cannula and/or dislodge the syringe (see Figure 5). 
Figure 5: Placing the needle or cannula onto the syringe 

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4. Pull off the cannula guard to expose cannula (see Figure 6). 
Figure 6: Removing the cannula guard 
5. Prime the cannula with Belotero Balance. 
6. If excess implant is on the surface of the Luer lock fitting, it will need to be wiped 
clean with sterile gauze. Slowly push the syringe plunger until the implant material 
exudes from the end of the cannula. If leakage is noted at the Luer lock fitting, it may 
be necessary to remove the cannula, clean the surfaces of the Luer lock fitting, and 
reattach the cannula. In extreme cases, replace both the syringe and the cannula. 
6.3.3.3 
Depth of injection and injection technique 
Standard precautions associated with injectable materials should be followed. 
• The cannula injection technique of Belotero Balance with regard to the angle and 
orientation of the bevel, the depth of injection, and the quantity administered may 
vary. Fewer injection points are usually used when a cannula is utilized instead of 
a needle. Insertion sites will typically be at the malar and zygomatic regions. For 
insertion of the cannula, first a skin puncture should be made at the desired 
insertion point using the provided needle. The needle will be of slightly larger 
gauge then the cannula. After the needle is withdrawn the cannula will be inserted 
through the established skin puncture. Subsequently, a tunneling, fanning, or 
combination injection technique will be used to achieve optimal results. Care 
must be used to avoid intravascular injection regardless of technique used. 
• In general, when the needle and then cannula are inserted, it will be at an 
approximate angle of 30° or less parallel to the skin. Belotero Balance will be 
placed at the junction of the lower eyelid and midface along the inferior orbital 
rim in the supraperiosteal plane. The injection should be performed with a 
constant low-to-moderate pressure on the plunger, while slowly and gradually 
withdrawing the cannula. Slight elevation of the skin should be observed without 
significant blanching of the skin. To avoid visible lumps and/or discoloration, 

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avoid injection of Belotero Balance superficially when removing the cannula. 
When the injection is complete, the site may be gently massaged, if necessary. 
6.3.3.4 
Additional injection information 
• If blanching occurs, the injection should be stopped and the area massaged until it 
returns to a normal color. Blanching may be a sign of a vascular occlusion. If 
normal skin coloring does not return, do not continue with the injection. Treat in 
accordance with the American Society for Dermatologic Surgery guidelines, 
which include possible hyaluronidase injection. 
• Correct to the desired volume effect. Do not overcorrect. The degree and duration 
of the correction depend on the character of the defect treated, the tissue stress at 
the implant site, the depth of the implant in the tissue, and the injection technique. 
Markedly indurated defects may be difficult to correct. 
• Follow national, local, or institutional guidelines for use and disposal of medical 
sharp devices. To help avoid needle or cannula breakage, do not attempt to 
straighten a bent needle or cannula Discard it and complete the procedure with a 
replacement needle from the clinical supply. Do not reshield used needles and 
cannulas. Recapping by hand is a hazardous practice and should be avoided. 
Discard unshielded needles and cannulas in approved sharps containers. For 
additional product handling information, see Section 6.2. 
6.3.3.5 
Post-treatment care/pain management 
• To manage pain, once the injection is complete ice may be applied as needed. 
• Acetaminophen may be taken if instructed by the physician. Any medication or 
therapy used by the subject must be recorded in the CRF. 
• The following information should be shared with subjects: 
o Within the first 24 hours, subjects should avoid lower eyelid makeup, 
strenuous exercise, extensive sun, or heat exposure, aspirin or non-steroidal 
anti-inflammatory drugs and alcoholic beverages. Exposure to any of the 
above may cause temporary redness, swelling and/or itching at the injection 
site. 
o Any and all medications used throughout study participation should be 
reported by the subject to site personnel for recording in the CRF. 
6.3.4 

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To: Merz North America, Inc. 
Attn: Receiving 
1340 Grandview Parkway, Suite 2 
Sturtevant, WI 53177-1261 
All study-accountability procedures must be completed before the study is considered 
complete. 
6.3.7 
Accountability procedures 
The sponsor will provide the investigator with necessary study supplies. Accountability 
for study supplies at the study site is the responsibility of the investigator. 
Access to investigational medical devices will be controlled, and the investigational 
medical devices will be used only in the clinical investigation and according to the 
clinical study protocol. The sponsor will keep records to document the physical location 
of all investigational medical devices from shipment to the investigation sites until return 
or disposal. The Principal Investigator or an authorized designee will keep records 
documenting the receipt, use, return, and disposal of the investigational medical devices, 
which will include: 
1. The date of receipt. 
2. Identification of each investigational medical device (batch number/serial number 
or unique code). 
3. The expiry date (if applicable). 
4. The date or dates of use. 
5. Subject identification number. 
6. Date on which the investigational medical device was returned/explanted from 
subject, if applicable. 
7. The date of return of unused, expired, or malfunctioning investigational medical 
devices (if applicable). 

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7 SAFETY AND ADVERSE EVENTS 
7.1 Definitions 
7.1.1 
Investigational medical device 
An investigational medical device is defined as a medical device being assessed for 
safety or effectiveness in a clinical investigation. This definition includes medical devices 
already on the market that are being evaluated for new intended uses, new populations, 
new materials, and/or design changes. In this protocol, the terms “investigational medical 
device” and “investigational device” are used interchangeably. 
7.1.2 
Adverse event (AE) 
An AE is defined as an untoward medical occurrence, which does not necessarily have a 
causal relationship to the investigational medical device. An AE can therefore be any 
unfavorable, unintended, or untoward clinical sign (including an abnormal laboratory 
finding), unintended disease or injury, and/or a symptom or disease temporally associated 
with the use of the investigational medical device, whether or not considered related to 
that investigational medical device.  
• Definition includes events related to the investigational medical device or the 
comparator. 
• Definition includes events related to the procedures involved.  
• AEs may include, but are not limited to, subjective or objective symptoms 
spontaneously offered by the subject, uncovered by review of concomitant 
medications or therapies, and/or observed by the investigation-site staff. The 
investigator will determine the description (sign, symptom, or diagnosis), onset, 
outcome, seriousness, severity, cause, and action taken for any event. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a 
procedure is considered as the AE, rather than the procedure itself. 
Pre-existing conditions that do not worsen during the course of the clinical investigation 
are not reportable as AEs. Recurring symptoms associated with pre-existing conditions 
are not considered AEs unless they have a clinically significant increase in severity 
and/or frequency. To determine whether a condition has worsened, it is compared to the 
condition of the subject at screening. 
Elective treatments planned before screening, which are documented in the subject’s 
source data, are not typically regarded as AEs. The subject’s course must be monitored 

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until the event has subsided, or in a case of permanent impairment, until the event 
stabilizes and the overall clinical outcome has been ascertained. 
7.1.3 
Adverse device effect (ADE) 
An ADE is defined as an adverse event related to the use of an investigational medical 
device.  
• Definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device. 
• Definition includes any event resulting from use error or from intentional misuse 
of the investigational medical device. 
7.1.4 
Serious adverse events (SAE) 
A SAE is any AE that results in: 
• Death 
• Life-threatening illness or injury (or places the subject at immediate risk of death 
from this event as it occurred) or 
• Hospitalization or prolonged hospitalization, or 
• Disability/incapacity or permanent impairment of a body structure or a body 
function, or 
• An important medical event for which medical or surgical intervention is required 
to prevent life-threatening illness or injury, or permanent impairment of a body 
structure or body function, or 
• Fetal distress, fetal death, or a congenital abnormality/birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by 
the protocol, without serious deterioration in health, is not considered a serious adverse 
event. Pre-planned admissions must be recorded in the subject’s source documentation. 
If a subject experiences an additional AE that prolongs a pre-planned hospitalization, this 
event is considered to be an SAE and should be reported as an SAE. 
In the case of a fatality, the primary cause of death (the event leading to death) is 
considered as the SAE, and death is considered the outcome. “Fatal” will be recorded as 
the outcome. Death may be reported as an SAE only when no cause of death can be 
determined (e.g., sudden death, unexplained death). 

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7.1.5 
Serious adverse device effect (SADE) 
A SADE is defined as an SAE related to the use of an investigation medical device.  
• Definition includes SAEs resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation or any malfunction of the 
investigational medical device. 
• Definition includes any SAE resulting from use error or from intentional misuse 
of the investigational medical device. 
7.1.6 
Unanticipated adverse device effect (UADE) 
A UADE is defined as: 
• Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or 
application), risk analysis report, Investigator Brochure (IB), or Instructions for 
Use (IFU), or 
• Any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. 
7.1.7 
Anticipated serious adverse device effect (ASADE) 
An ASADE is defined as: 
• Any serious adverse effect which by its nature, severity, or degree of incidence or 
outcome has been identified in the risk analysis report, IB, or product labeling. 
7.1.8 
Common treatment responses (CTRs) 
CTRs are common clinical presentations and/or side effects that a study subject may 
experience following treatment. Subjects will self-report CTRs, as defined a priori in the 
protocol, on a diary provided to them. The treating investigator will review the diary and 
determine if any diary entries should be captured as AEs. A CTR that is more severe than 
what is generally expected and/or is not resolving should also be evaluated by the 
investigator as a possible AE or SAE. CTRs include the following: swelling; visible 
lumps; bumps you can feel; bruising or discoloration; redness; rash; pain/discomfort 
(including burning/stinging); itching; blistering/peeling skin; and/or scabby/crusty skin. 
Treated subjects will be instructed (within the diary) to seek immediate medical attention 
if any of the following symptoms are observed: changes in vision; fever; dizziness; 

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confusion; weakness in arms/legs; changes in alertness/consciousness; difficulty 
speaking; face droop; change in skin color comparing one side to the other; a blue or 
white spot of skin; and/or a headache that is more intense or longer than you usually 
experience. They will also have the opportunity to self-report any unforeseen/ 
unanticipated events on the diary. 
7.1.9 
Device deficiency 
A device deficiency is defined as any inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequate labeling. 
Device deficiencies include events that did not lead to an AE, but could have led to a 
medical occurrence if suitable action had not been taken, if intervention had not been 
made, or if circumstances had been less fortunate. 
All device deficiencies shall be documented and reported by the PI throughout the 
clinical investigation and appropriately managed by Merz North America, Inc. in 
accordance with Sections 7.2.4.3 and 7.3. 
7.1.10 
Malfunction 
Malfunction is defined as failure of an investigational medical device to perform in 
accordance with its intended purpose, when used in accordance with the product labeling 
or the protocol. 
All device malfunctions shall be documented and reported by the PI throughout the 
clinical investigation and appropriately managed by Merz North America, Inc. in 
accordance with Sections 7.2.4.3 and 7.3. 
7.2 Reporting requirements 
7.2.1 
Determining severity/intensity 
The investigator is required to grade the severity/intensity of each AE. The clinical 
intensity of an AE will be classified as: 
• Mild: Signs and symptoms that can be easily tolerated. Symptoms can be ignored 
and disappear when the subject is distracted. 
• Moderate: Signs and symptoms that cause discomfort and interfere with normal 
functioning, but are tolerable. They cannot be ignored and do not disappear when 
the subject is distracted. 

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• Severe: Signs and symptoms that affect usual daily activity and incapacitate the 
subject, thereby interrupting his/her daily activities. 
The definitions above are difficult to apply for some data (e.g., clinically relevant 
laboratory values that are documented and evaluated on the eCRF AE report form). In 
such situations, the investigator should exercise medical and scientific judgment. 
7.2.2 
Determining causal relationship 
An AE is considered to be “related” to the investigational medical device if a causal 
relationship between the investigational medical device and the AE is at least a 
reasonable possibility (i.e., the relationship cannot be ruled out). 
NOTE: The expression “reasonable causal relationship” is intended to convey that there 
are facts (evidence) or arguments to suggest a causal relationship. Otherwise, the 
relationship should be considered as “not related”. 
7.2.3 
Determining outcome 
The reportable outcomes and/or sequelae of an AE may include the following: 
• Recovered/resolved 
• Recovering/resolving 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Fatal 
• Unknown 
NOTE: If there is more than one AE, only the AE leading to death will be attributed with 
a “fatal” outcome. 
7.2.4 
Procedures for reporting specific events 
7.2.4.1 
Adverse event (AE) and adverse device effect (ADE) 
Subjects will be carefully monitored during the clinical investigation for possible AEs 
and ADEs. 
The period of observation for AEs and ADEs extends from signing of the informed 
consent form (ICF) until the subject’s last visit. Any medical occurrence between the 

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time the ICF is signed and the first treatment with the investigational medical device is 
classified as an AE or ADE and must be documented in the subject’s file and in the 
eCRFs. New AEs or ADEs reported to the investigator during the observational period 
(i.e., after the start of treatment with the investigational medical device) must also be 
documented, treated, and followed. 
Any AE, ADE, and/or device deficiency observed will be fully investigated, documented, 
and followed until the event is either resolved or adequately explained at the End of 
Study visit. 
The investigator will assess and record any AE or ADE in detail in the subject’s file 
(medical record) and in the eCRF AE report form. At a minimum the following 
information will be recorded: 
• AE diagnosis or main symptom 
• Location of AE: systemic or restricted to injection area. In case of local reaction, 
the corresponding area should be reported. 
• Start and stop dates 
• Severity/Intensity 
• Causal relationship 
• Serious (yes or no) 
• Outcome 
• Action taken with investigational medical device 
In this study, any adverse event of visual disturbance (including, but not limited to, any 
loss of vision, blurry vision, double vision, pain in or around eye (other than typical 
injection-induced pain), blind spot or shadow in the visual field, trouble moving eyes, 
etc.) will be reported. The investigator will be instructed to report any AE of visual 
disturbance within 24 hours. The incident will then be reported to the Agency within 10 
business days of receipt by the sponsor. These reports will be generated by the sponsor or 
designee and will include injection volume, symptoms observed, time to onset and 
resolution, and any interventions implemented. 
7.2.4.2 
Serious adverse event (SAE) and serious adverse device effect 
(SADE) 
The investigator must report all SAEs and SADEs that occur during the observational 
period on the SAE form within 24 hours, whether considered related or not related to the 
investigational device.  

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The investigator must report SAEs and SADEs to Merz or designee as defined in Section 
7.3 and the site’s IEC/IRB per their reporting guidelines. 
Although all information required for completing an SAE report form may not be 
available within the specified time period, an initial report should be submitted and the 
following minimal information should be provided: 
• An identifiable subject number; 
• Adverse event; 
• Investigational device name; 
• Causality or relationship of investigational device; and/or 
• Investigator/investigational site name 
Within 10 working days after Merz first receives notice of the SAE/SADE, Merz Product 
Safety will conduct an evaluation of the SAE/SADE and report the results of such 
evaluation to regulatory agencies, IRBs and investigators, as applicable. 
Follow-up SAE/SADE reports should be sent without delay to the sponsor, or designee, 
as an SAE form (marked as a “follow-up” report). The SAE/SADE has to be followed 
until the SAE/SADE is resolved/recovered or a plausible explanation is available.  
In the case of a reportable death, the investigator shall make every effort to obtain a copy 
of the autopsy report and/or death certificate. The investigator will be required to review 
any post-mortem findings, including histopathology, and provide a synopsis of all 
pertinent findings by updating the SAE form. 
SAEs/SADEs occurring after the end of the observational period would need to be 
reported if the investigator considers the event to be related to investigational medical 
device. These reports generally will not be entered into the investigation database. 
Following the database lock for the study, all ongoing SAEs/SADEs will be followed 
until resolution or stabilization under the responsibility of the investigator per their 
standard of care. 
7.2.4.3 
Technical device complaints 
For device deficiencies or device malfunctions, the investigator will attempt to evaluate if 
the deficiency or malfunction might have led to an AE if suitable action had not been 
taken, intervention had not been made, or circumstances had been less fortunate. 
Complaints are defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, or performance 
of a medical device. 

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8 STATISTICAL METHODS 
This section describes the statistical analyses foreseen at the time of study planning. 
Further details on the statistical and analytical aspects will be presented in the statistical 
analysis plan (SAP) that will be prepared and completed prior to database lock. 
Any deviations from planned analyses, the reasons for such deviation, and all alternative 
or additional statistical analyses that may be performed before database close, will be 
described in amendments to the clinical study protocol and/or the SAP. All deviations 
and/or alterations will also be summarized in the clinical study report. 
8.1 Estimation of sample size 
In order to assess the ability of the planned sample size to provide power for a statistical 
comparison of the treatment and control groups success proportions (based on a ≥ 1-point 
improvement on both IOHs using the MIHAS from baseline to Month 2), a power 
calculation using a Fisher’s exact test with a binomial distribution was performed using 
the following assumptions: 
• Type I error rate: 0.05 (two-sided) 
• Control group success proportion: 0.20  
• Treatment group success proportion: 0.60 
• Allocation ratio (control: treatment): 1:2 
• Total N (number of evaluable subjects): 60 (40 subjects in the treatment group 
and 20 subjects in the control group). 
Based on the above assumptions, the study power is approximately 80%. To account for 
possible missing data, attrition, and/or study deviations (up to 10%), a total of 66 subjects 
will be enrolled (44 subjects in the treatment arm and 22 subjects in the no treatment 
control arm).  
Approximately 70% of the total sample size will consist of subjects with a Fitzpatrick 
skin type of I, II, or III, and approximately 30% of the subjects will consist of subjects 
with a Fitzpatrick skin type IV, V, or VI. Subjects from the Fitzpatrick skin type IV, V, 
and VI group will be distributed as follows: ≥ 6 subjects will be enrolled in the 
Fitzpatrick skin type group IV and ≥ 12 subjects will be enrolled in the Fitzpatrick Skin 
Type group V and VI. Each clinical site will enroll a minimum of 6 subjects with 
Fitzpatrick skin types IV, V, VI. At least 5 males will be enrolled into the study.  
In the event that the sample size accounting for missing data, attrition, and/or deviations 
is attained (i.e., 44 treated subjects and 22 untreated/control subjects), using the 
assumptions above, the study power would be approximately 84%. 

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nQuery Advisor 7.0 was used for the power calculation. 
8.2 Randomization 
The randomization procedure for this study will be a block randomization stratified per 
site which will be computer-generated independently of the study team. Block 
randomization will control for potential deviations from the intended allocation ratio 
between treated and control subjects. Accordingly, a 2:1 allocation ratio will be utilized 
with approximately 44 subjects randomized to treatment and 22 subjects to control. 
8.3 Populations for analysis 
The following analysis sets will be defined for the statistical analysis of this study: 
• The Intent-to-Treat (ITT) population will consist of all randomized subjects. This 
will be the primary population used for the effectiveness analyses. All 
effectiveness endpoints will be analyzed as randomized.  
• The Per Protocol Population (PP) is a subset of subjects in the ITT population 
without major protocol deviations. Final determination of what constitutes major 
or minor protocol deviations will be made prior to database lock. 
• The Safety Population (SP) will consist of all enrolled/randomized subjects who 
received at least one study treatment.  
The primary and secondary effectiveness endpoints will be summarized using the ITT 
population, and additionally, for sensitivity purposes, on the PP population. 
 
 All safety 
endpoints will be summarized using the SP. Additional information related to the usage 
of the analysis populations as it relates to the statistical analyses of study results will be 
described in the SAP. 
8.4 Statistical analyses 
The sponsor will finalize the formal SAP prior to database lock. Deviations from the 
analyses outlined in this protocol will be documented in the SAP. 
Effectiveness and safety endpoints are provided in Sections 2.2.1 to 2.2.4.  
Adequate descriptive statistics will be provided for each endpoint. Continuous variables 
will be summarized by number of observations, number of missing, mean, standard 
deviation, minimum, median, maximum. Categorical data will be summarized by counts 
(n) and percentages (%). Ordered categorical data will be summarized by both. 

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8.4.1 
Effectiveness analysis 
8.4.1.1 
Primary effectiveness endpoint 
The primary effectiveness endpoint, the proportion of subjects with ≥ 1-grade 
improvement of both IOHs on the MIHAS from baseline to Month 2 will be summarized 
as percentages for the treatment (ptreatment) and control (pcontrol) subjects and inferentially 
compared according to the following hypothesis: 
H0 (null): ptreatment ≤ pcontrol  
Ha (alternate): ptreatment > pcontrol 
For this hypothesis testing, the Fisher’s exact test will be used to compare both 
proportions in order to test for the superiority of treatment over control. If the two-sided 
p-value obtained from this test statistic is < 0.05 H0 will be rejected in favor of Ha. 
8.4.1.2 
Secondary effectiveness endpoint 
• For the FACE-Q satisfaction with eyes, sum scores and the equivalent Rasch-
transformed scores will be analyzed descriptively for baseline and Month 2 for 
treatment and control groups.  The FACE-Q scale will be scored using a look-up 
conversion table approach. The scale ranges from 0 to 100 with higher numbers 
indicating greater satisfaction. The FACE-Q user manual is included in Appendix 
10.4, and additional information related to the scoring of the FACE-Q satisfaction 
with eyes scale will be included in the SAP. 
• The investigator GAIS categories will be analyzed descriptively at Month 2 post 
last injection (i.e., either baseline treatment or touch-up, if applicable) among 
treated subjects using counts (n) and percentages (%) for each GAIS category 

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8.4.2 
Safety analysis and endpoints 
Nature, frequency, and severity of AEs will be recorded. All AEs, SAEs, and device 
effects will be stratified by treatment and summarized descriptively including type, 
duration, severity, relationship to study device. 
The assessment of safety will be based mainly on the frequency of AEs and SAEs. Only 
treatment-emergent AEs (TEAEs) will be summarized for each group (as applicable) by 
the incidence of at least one event, the number of events, and the incidence using Medical 
Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) within the system 
organ classes (SOCs). AEs will be coded according to MedDRA. 
Treated subjects will be asked to record any CTRs that may occur in a subject diary. CTR 
results from the subject diaries will be summarized descriptively. The treating 
investigator will review all CTRs; he/she will determine whether any CTR qualifies as an 
AE and needs to be added to the CRF. CTRs that are deemed AEs will be presented in 
the AE tables and coded. 

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8.5 Timing of statistical analyses 
The time from the baseline visit to the end of study is thirteen months. The primary 
effectiveness endpoint is at Month 2 post last injection (i.e. either baseline treatment or 
touch-up, if applicable); however, treated subjects will continue to be followed for safety 
via in clinic visits at Months 3, 6, 9, and 12 after the last injection (i.e., either baseline 
treatment or touch-up, if applicable). For the purposes of the clinical study report (CSR), 
statistical analyses will be performed after all subjects have completed the Month 2 post 
last injection visit. At this time, the data will be cleaned and the database temporarily 
locked for all effectiveness and safety analyses corresponding to the Month 2 primary 
effectiveness endpoint. A CSR will be written for these data and an addendum will be 
made to the report based on additional safety analyses associated with the safety 
monitoring for treated subjects up to 12 months after the last injection (i.e., either 
baseline treatment of touch-up, if applicable). 
8.6 Special statistical/ analytical issues 
8.6.1 
Subject discontinuation and missing effectiveness data 
To account for missing effectiveness data for the primary endpoint, missing MIHAS data 
will be imputed as no change (i.e. subject is considered as non-responder). This approach 
is conservative because it assumes that missing values are attributable to lack of 
treatment benefit. Furthermore, given that the primary effectiveness is only performed at 
baseline and Month 2 post last injection (i.e., either baseline treatment or touch-up, if 
applicable), the only observation that can be imputed for a missing Month 2 after the last 
injection time point is the baseline value, which assumes no change. Additionally, 
analyses will also be performed using the observed case (OC) method where no missing 
value imputations will be conducted. All other effectiveness and safety data will be 
analyzed as observed. 
8.6.2 
Imputation of safety data 
Details regarding imputation rules and analyses of safety data (i.e., CTRs) will be 
provided in the statistical analysis plan and finalized prior to database lock. 

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9 ETHICS AND ADMINISTRATIVE PROCEDURES 
9.1 Ethical considerations 
This study will be performed in accordance with the principles outlined in the 
Declaration of Helsinki and in compliance with the standards for Good Clinical Practice 
described in ISO 14155, the Code of Federal Regulations, and any applicable regional or 
national laws and regulations. The study will adhere to all applicable subject privacy 
requirements. 
All required approvals, favorable opinions, or additional requirements of the appropriate 
IEC/EC, IRB, or other regulatory authority will be obtained prior to initiation of the trial.  
The investigator and all study personnel will conduct the study in compliance with this 
protocol. The investigator will ensure that all personnel involved in the conduct of this 
study are qualified to perform the assigned study responsibilities. Investigators will 
adhere to all applicable study reporting requirements. 
9.2 Informed consent 
Written informed consent must be obtained from every subject or his/her legal 
representative prior to the initiation of any screening or study procedures. The 
investigator will follow a standard process for obtaining consent that complies with all 
applicable regulatory requirements. If applicable, a certified translation of the informed 
consent form into the relevant local language will be provided. The original and any 
amended signed and dated ICF must be retained at the study site; and a copy must be 
given to the subject or subject’s legally authorized representative(s). 
It is not anticipated that members of a vulnerable population will participate in this study. 
If the ICF is amended during the study, the investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IEC/IRB and 
use of the amended form (including for ongoing subjects). 
During the course of the study, the subject will be informed in a timely manner if 
information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study. In case of AEs, the subject should inform the 
investigator, who then will make a judgment whether continuing in the study serves the 
subject’s best interests. The subject, however, is free to withdraw consent at any time and 
for any reason, whether expressed or not. 
Each ICF will contain contact information with a phone number the subject should 
contact if they have medical concerns 24 hours a day. Each ICF will also include the 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
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Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
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contact information for a retinal specialist, who is identified by the Investigator, for 
instances in which a subject requires evaluation by a retinal specialist (e.g., subject 
experiences sudden visual changes following treatment injections). 
9.3 Confidentiality of subject information 
Subject anonymity is to be maintained during the study. Subjects will be identified by an 
assigned number on all study documentation. Documents that identify the subject must be 
maintained in strict confidence by the investigator to the extent permitted by applicable 
laws and regulations, unless their disclosure is necessary to allow auditing by regulatory 
authorities, the sponsor, or the sponsor’s designee. 
Subject medical information obtained during the study is confidential. At a subject’s 
request, the subject’s medical information may be provided to the subject’s personal 
physician or other appropriate medical personnel. Disclosure of subject medical 
information to third parties other than those noted above is not permitted. 
9.4 Study monitoring 
Study monitoring will conform to all applicable regulatory standards and guidelines. The 
sponsor or designee will monitor the study through periodic site visits to verify the 
following: 
• Data authenticity, accuracy, and completeness. 
• Protection of subject rights and safety. 
• Conduct of the study in accordance with the currently approved protocol and all 
applicatory regulatory requirements and guidelines. 
Investigators agree to grant direct access to all relevant documents and provide support at 
all times for study monitoring activities. Study monitoring activities will be performed in 
a manner that ensures maintenance of subject confidentiality (Section 9.3). 
9.5 Data quality assurance 
9.5.1 
Standardization procedures 
Standardization procedures will be implemented to ensure accurate, consistent, complete, 
and reliable data, including methods to ensure standardization among sites (e.g., training, 
newsletters, investigator meetings, monitoring, centralized evaluations, and validation 
methods). Standardized photography methods are detailed in the separate photography 
user manual. 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
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This study will be monitored regularly by a qualified monitor from the sponsor, or its 
designee according to GCP guidelines and the respective SOPs (see Section 9.4). 
9.5.2 
Data management 
The investigator will prepare and maintain complete and accurate eCRFs recording all 
observations and data pertinent to the study for each subject. Data reported on case report 
forms should be derived from source documents and must be consistent with the sources 
from which they derive. Investigators will sign and date the case report forms as 
appropriate to verify the accuracy of the reported data. It is the responsibility of the 
Investigator to ensure that all data are submitted to the sponsor in a timely manner. 
9.5.3 
Data review and clarification procedures 
All data required by this clinical study protocol are to be entered into a validated 
database. Individual subject data is to be recorded in electronic case report forms (eCRFs) 
within 5 days of each study visit. 
By signing and dating the eCRFs, the investigator is confirming that all investigations 
have been completed and conducted in compliance with the clinical study protocol, and 
that reliable and complete data have been entered into the eCRFs. 
If corrections in the questionnaires are necessary, the subject should be instructed to 
make a correction by drawing only a single line through the error, leaving the incorrect 
entry legible. The subject should date and initial the correction. The investigator should 
not make any changes to these documents. 
Subjects will enter data into their electronic diaries and site staff will review the diary as 
required per protocol Sections 3.2.2.1 and 5.1. 
Essential documents should be retained per applicable regulations and as instructed by 
the study sponsor. Essential documents at the investigational site include but are not 
limited to: 
• Subject files 
• Subject identification code list  
• A copy of the study protocol and any amendments 
• Investigator’s copies of the eCRFs and any associated subject-related source data 
• Signed ICFs 
• Copies of all direct correspondence with the IEC/IRB and with the regulatory 
authority(ies), and with the sponsor 

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CLINICAL STUDY PROTOCOL 
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• Copies of any photographs 
• Copies of investigational device disposition records 
Study documents may not be destroyed by study site personnel prior to the end of the 
required retention period as specified by local regulations. The PI or the institution must 
inform the sponsor in due time if the PI leaves the institution during the retention period. 
This rule also applies when the institution closes within the retention period. 
9.5.4 
Study auditing 
To ensure compliance with applicable standards and regulations, the sponsor, IEC/IRB, 
or regulatory authorities may conduct a quality assurance assessment or audit of site 
records at any time during or after completion of the study. In the event of an audit, 
investigators must grant access to all relevant documents (including source documents, 
electronic records, and other applicable study documentation) and provide support at all 
times for auditing activities. 
9.6 Record retention 
Upon closure of the study, the investigator must maintain all study site records in a safe 
and secure location. The investigator is responsible for the integrity, retention, and 
security of all study-related records. The investigator must ensure that any reproductions 
of the original records are legible and provide a true and accurate copy of the original. 
Accurate, complete, and current records must be stored in such a way as to permit easy 
and timely retrieval for the sponsor or any applicable regulatory authorities. 
The sponsor will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements, with the minimum retention time 
being the longest of those times dictated by institutional requirements, local laws or 
regulations, or the sponsor’s standard procedures. The investigator must notify the 
sponsor in the event of any changes to archival arrangements due to withdrawal of the 
investigator’s responsibility for keeping study records to ensure that suitable 
arrangements for the retention of study records are made. 
9.7 Publication policy 
The study protocol, study data, and information related the study or the sponsor’s 
products or research programs are to be kept confidential and may not be disclosed 
without the consent of the sponsor. The investigators have the responsibility to provide 
complete study data, records, and reports for inspection by the appropriate regulatory 
authorities, the sponsor, or the IEC/IRB, as appropriate. 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
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The investigator agrees that the results of this study may be used for submission to 
national or international registration and supervising authorities. The sponsor may 
disclose the information obtained during the study to regulatory authorities or other 
personnel as required. If necessary, the sponsor may disclose the names, contact 
information, and qualifications of all investigators as well as their roles in the study. 
Upon completion of the study, publication or disclosure of the study results is to follow 
the terms contained in the sponsor’s publication policy. 
9.8 Financial disclosure 
The US FDA Financial Disclosure by Clinical Investigators (21 CFR 54) regulations 
require sponsors to obtain certain financial information from investigators participating in 
covered clinical studies. By participating in the study, the investigator agrees to provide 
the required financial information and to promptly update the sponsor with any relevant 
changes to this financial information throughout the course of the study and for up to 
1 year after its completion if necessary. 
9.9 Investigator compliance 
The investigator will conduct the study in compliance with the protocol provided by the 
sponsor and in accordance with all relevant regulatory guidelines and requirements. 
Modifications to the protocol should not be made without the agreement of the 
investigator and sponsor. The sponsor will submit all protocol modifications to the 
appropriate regulatory authority in accordance with applicable regulations. All protocol 
modifications require written IEC/IRB approval/favorable opinion, except in the case of 
an immediate hazard to subjects. 
If an immediate deviation from the protocol is required to eliminate an immediate hazard 
to subjects, the investigator must contact the sponsor, if possible, to discuss the planned 
course of action. The investigator must thoroughly document any departure from the 
protocol and submit appropriate documentation to the sponsor without delay. 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
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10 APPENDICES

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CLINICAL STUDY PROTOCOL 
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Merz North America, Inc.  
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 81 of 85 

Merz North America, Inc.  
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 82 of 85 

Merz North America, Inc.  
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 83 of 85 

Merz North America, Inc.  
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 84 of 85 

Merz North America, Inc.  
CLINICAL STUDY PROTOCOL 
Belotero Balance® 
Protocol #: M930121001; Amendment no. 4.0, Version 5.0; 08-NOV-2018 
CONFIDENTIAL AND PROPRIETARY 
Page 85 of 85