Evaluation of Pain With Belotero® Balance With Integral Lidocaine for Correction of the Nasolabial Folds
Phase: NA
Conditions: Correction of Moderate to Severe Nasolabial Folds
Sponsor: Merz North America, Inc.

Clinical Study Protocol 
Evaluation of Pain with Belotero® Balance with Integral 
Lidocaine for Correction of the Nasolabial Folds 
Study protocol number: 
M930021001 
Protocol amendment date: 
24-JUL-2017 (replaces Version 1.0, 26-APR-2017)
Development phase: 
Device Pre-Market 
Investigational product: 
Belotero® Balance with integral lidocaine 
Indication: 
Injection into the mid-to-deep dermis for correction of 
moderate-to-severe facial wrinkles and folds, such as 
nasolabial folds 
Sponsor: 
Merz North America, Inc. 
6501 Six Forks Road 
Raleigh, NC 27615 
Telephone: (919) 582-8000 
Authors: 
Clinical Project Director:
Medical Expert: 
Medical Writer:
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. 
Merz North America, Inc.  
Belotero Balance with Lidocaine
CLINICAL STUDY PROTOCOL 
Protocol #: M930021001; Version 2.0, 24-JUL-2017
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Page 1 of 103
NCT03319719, redacted 
version v1.0, 11Sep2019

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). Provide written disclosure of any financial interest, in accordance 
with 21 CFR Part 54, and 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-year) 
 
Signature 
Merz North America, Inc.  
Belotero Balance with Lidocaine
CLINICAL STUDY PROTOCOL 
Protocol #: M930021001; Version 2.0, 24-JUL-2017
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PROTOCOL SYNOPSIS 
Protocol Title 
Evaluation of Pain with Belotero® Balance with Integral Lidocaine for 
Correction of the Nasolabial Folds 
Protocol Number 
M930021001 
Active Product 
Belotero® Balance with integral lidocaine 
Comparator Product 
Belotero® Balance 
Study Phase 
Device Pre-Market 
Indication 
Injection into the mid-to-deep dermis for correction of moderate-to-severe 
facial wrinkles and folds, such as nasolabial folds (NLF) 
Number of Sites and 
Countries 
This study will be conducted at up to three (3) study centers in the United 
States.  
Number of Study Subjects 
Approximately fifty-two (52) subjects will be enrolled and treated. Each 
NLF (i.e., right and left NLFs) will be analyzed separately for the primary 
and secondary endpoints, resulting in approximately 104 discrete units of 
measure. 
Objectives 
Effectiveness 
• 
Demonstrate the effectiveness of Belotero Balance with lidocaine 
(Test group) for the reduction of injection-related pain in 
comparison to Belotero Balance without lidocaine (Control 
group) for the correction of NLFs. 
Safety 
• 
Identify and describe adverse events (AEs) and serious adverse 
events (SAEs) during the course of the study. Additionally, 
common treatment site responses (CTRs) will be assessed. 
Key Endpoints 
Primary 
• 
Demonstrate a statistically significant, mean reduction in pain, 
measured using a 10-cm visual analogue scale (VAS), in the Test 
NLF compared to the Control NLF immediately after split-face 
NLF treatment (i.e., at time zero) on Day 1. Time zero will be 
defined as the time the last injection needle is removed from each 
NLF, separately, after a full correction on Day 1. 
Secondary 
• 
Compare the responder rates between the Test and Control NLFs, 
separately, at Week 6, as assessed live by the blinded evaluator 
and according to the Merz NLF Scale. Response is defined as ≥ 
1-point improvement on the Merz NLF Scale for each NLF 
compared to baseline. Each NLF is to be assessed separately. 
Safety 
• 
Evaluate the incidence and nature of device- and/or injection-
related AEs and SAEs observed during the study. Additionally, 
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the incidence, severity, and duration of pre-specified CTRs will 
be evaluated using subject diaries. 
Study Design Overview 
This is a 6-week, prospective, randomized, split-face, double-blind, 
multicenter, pre-market study to demonstrate the effectiveness of Belotero 
Balance with integral lidocaine (Test) for reduction of injection-related 
pain when compared to Belotero Balance without lidocaine (Control) for 
the correction of NLFs.  
The split-face study consists of two treatment arms. Approximately 52 
subjects will be randomized to receive treatment with Belotero Balance 
with integral lidocaine (Test product) in one NLF and Belotero Balance 
without lidocaine (Control product) in the contralateral NLF on Day 1. 
Randomization will also determine which NLF (subject’s right or left) will 
be injected first. Subjects will be eligible for an optional touch-up 
treatment, at the investigator’s discretion and to achieve optimal 
correction, at Week 2. Subjects will be followed for at least 4 weeks after 
the last injection.  
Subjects enrolled will have a baseline rating of moderate to severe (i.e., 
rating of 2 or 3) on the Merz NLF Scale. Subjects must have the same 
Merz NLF Scale rating in both NLFs at the time of enrollment. A 
minimum of 20% of the enrolled subjects will be Fitzpatrick skin type IV, 
V, or VI. Subjects from the Fitzpatrick skin type IV, V, and VI group will 
be approximately evenly distributed within the IV, V, and VI categories. 
The planned duration of participation for individual subjects is 6 weeks. 
For all subjects randomized at baseline, the study will consist of three 
office visits and a 72-hour post-treatment phone call. Additional 
effectiveness assessments include the blinded-evaluator Global Aesthetic 
Improvement Scale (GAIS), the subject GAIS, and two (2) FACE-Q 
assessments. 
Key Inclusion/ 
Exclusion Criteria 
To be eligible for the study, each subject must meet all of the following 
criteria:  
1. Has right and left NLF ratings of 2 or 3 (moderate or severe) on 
the Merz NLF Scale, as determined by the blinded evaluator. 
2. Has the same Merz NLF Scale rating on both NLFs (i.e., 
symmetrical NLFs). 
3. Is at least 18 years of age. 
4. Understands and accepts the obligation not to receive any other 
procedures (i.e., dermal fillers, toxin treatments, facial ablative or 
fractional laser, microderm abrasion, chemical peels, non-
invasive skin-tightening [e.g., Ultherapy, Thermage], or surgical 
procedures) below the orbital rim on the face during study 
participation. 
Patients meeting any of the following criteria are not eligible to participate 
in the study: 
1. Had prior surgery in the mid- and/or lower-face area, including 
the nasolabial fold(s), or has a permanent implant or graft in the 
mid- and/or lower-face area that could interfere with effectiveness 
assessments. (NOTE: Rhinoplasty is permitted if the procedure 
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was ≥ 12 months prior to study enrollment.) 
2. Has skin or fat atrophy, beyond typical for the subject’s age, in 
the mid- to lower-facial region or has been diagnosed with a 
connective tissue disorder. 
3. Has unphysiological skin laxity or sun damage, beyond typical 
for the subject’s age, or subject plans to tan during the study 
period. 
4. Has undergone oral surgery (e.g., orthodontia, extraction, 
implants) in the past 30 days or plans to receive such surgery 
during participation in the study. 
5. Has received mid- and/or lower-facial region treatments with 
porcine-based collagen fillers, Belotero® Volume, JUVÉDERM 
VOLUMA®, Restylane® Lyft, RADIESSE®, poly L-lactic acid 
(PLLA), or mesotherapy within the past 24 months and/or with 
other hyaluronic acid (HA) products within the past 12 months or 
plans to receive such treatment during participation in the study. 
6. Has ever been treated with fat injections or permanent and/or 
semi-permanent dermal fillers in the mid- and/or lower-facial 
region or plans to receive such treatment during participation in 
the study. 
7. Has received immunosuppressive medications or systemic 
steroids (except intranasal/inhaled steroids) in the past 2 months 
or plans to receive such treatment during participation in the 
study. 
8. Has an acute inflammatory process or infection at the injection 
site (e.g., skin eruptions such as cold sores, cysts, pimples, acne, 
eczema, hives, streptococcus infections) or history of chronic or 
recurrent infection or inflammation with the potential to interfere 
with study results or increase the risk of AEs. 
9. Has a history of allergic/anaphylactic reactions, including 
hypersensitivity to lidocaine or anesthetics of the amide type, 
hyaluronic acid preparations, gram positive bacterial proteins, or 
any of the device components. 
10. Has a known bleeding disorder or has received or is planning to 
receive 
anti-coagulation, 
anti-platelet, 
or 
thrombolytic 
medications 
(e.g., 
warfarin), 
anti-inflammatory 
drugs 
(oral/injectable 
corticosteroids 
or 
NSAIDs 
[e.g., 
aspirin, 
ibuprofen]), or other substances known to increase coagulation 
time (e.g., vitamins or herbal supplements, i.e., Vitamin E, garlic, 
gingko) from 10 days before injection to 3 days after injection. 
11. Has any other medical condition with the potential to interfere 
with study outcome assessments or compromise subject safety 
(i.e., increase the risk of adverse events). 
 
 
Merz North America, Inc.  
Belotero Balance with Lidocaine
CLINICAL STUDY PROTOCOL 
Protocol #: M930021001; Version 2.0, 24-JUL-2017
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Table of Contents 
1 
Introduction...............................................................................................................14 
1.1 
Background ............................................................................................................14 
1.2 
Study rationale .......................................................................................................14 
1.3 
Potential benefits and risks ....................................................................................15 
2 
Study objectives and endpoints ...............................................................................17 
2.1 
Objectives ..............................................................................................................17 
2.1.1 
Effectiveness ....................................................................................................17 
2.1.2 
Safety ...............................................................................................................17 
2.2 
Endpoints ...............................................................................................................17 
2.2.1 
Primary endpoint ..............................................................................................17 
2.2.2 
Secondary endpoint ..........................................................................................17 
2.2.3 
 
2.2.4 
Safety endpoints ...............................................................................................18 
3 
Investigational plan ..................................................................................................19 
3.1 
Overview of study design ......................................................................................19 
3.2 
Study assessments and definitions .........................................................................20 
3.2.1 
Effectiveness assessments ................................................................................20 
3.2.1.1 
Evaluation of pain ......................................................................................20 
3.2.1.2 
Evaluation of aesthetic effectiveness .........................................................21 
3.2.2 
Safety assessments ...........................................................................................25 
3.2.2.1 
Adverse events and common treatment responses .....................................25 
3.2.3 
Definitions........................................................................................................26 
3.2.3.1 
Subject enrollment and randomization ......................................................26 
3.2.3.2 
Subject completion.....................................................................................26 
3.2.3.3 
End of study ...............................................................................................26 
3.3 
Duration of study ...................................................................................................26 
4 
Study population and restrictions ...........................................................................27 
4.1 
Number of subjects and sites .................................................................................27 
4.2 
Inclusion criteria ....................................................................................................27 
4.3 
Exclusion criteria ...................................................................................................28 
4.4 
Subject restrictions during the study ......................................................................30 
4.5 
Screen failures ........................................................................................................32 
4.6 
Subject withdrawal criteria ....................................................................................32 
5 
Study procedures ......................................................................................................33 
5.1 
Schedule of events by visit ....................................................................................33 
5.1.1 
Scheduled visits ...............................................................................................35 
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5.1.2 
Unscheduled visits ...........................................................................................36 
5.2 
Stopping rules ........................................................................................................36 
5.2.1 
Criteria for treatment discontinuation ..............................................................36 
5.2.2 
Premature suspension or termination of the study ...........................................36 
5.2.3 
Study site discontinuation ................................................................................37 
5.2.4 
Discontinuation criteria for a subject ...............................................................37 
5.2.5 
Provision of care for subjects after study discontinuation ...............................38 
6 
Study device and treatment of subjects ..................................................................39 
6.1 
Description of the study devices ............................................................................39 
6.1.1 
Test product .....................................................................................................39 
6.1.2 
Control product ................................................................................................39 
6.2 
Usage......................................................................................................................40 
6.3 
Study treatment ......................................................................................................40 
6.3.1 
Planned treatment procedure and administration .............................................40 
6.3.1.1 
Injection procedure ....................................................................................43 
6.3.1.2 
Maximum injection volume .......................................................................45 
6.4 
Packaging of treatment supplies ............................................................................45 
6.5 
Receipt, storage, dispensing, and return/disposal ..................................................45 
6.6 
Accountability procedures .....................................................................................46 
6.7 
Level and method of blinding ................................................................................47 
7 
Safety and adverse events ........................................................................................48 
7.1 
Definitions..............................................................................................................48 
7.1.1 
Investigational medical device .........................................................................48 
7.1.2 
Adverse event (AE)..........................................................................................48 
7.1.3 
Adverse device effect (ADE) ...........................................................................49 
7.1.4 
Serious adverse event (SAE) ...........................................................................49 
7.1.5 
Serious ADE (SADE) ......................................................................................50 
7.1.6 
Unanticipated adverse device effect (UADE) ..................................................50 
7.1.7 
Anticipated serious adverse device effect (ASADE) .......................................50 
7.1.8 
Common treatment site responses (CTRs) ......................................................50 
7.1.9 
Device deficiency.............................................................................................51 
7.1.10 
Malfunction ......................................................................................................51 
7.2 
Reporting requirements ..........................................................................................51 
7.2.1 
Determining severity/intensity .........................................................................51 
7.2.2 
Determining causal relationship ......................................................................52 
7.2.3 
Determining outcome.......................................................................................52 
7.2.4 
Procedures for reporting specific events ..........................................................52 
7.2.4.1 
Adverse event (AE) and adverse device effect (ADE) ..............................52 
7.2.4.2 
Serious adverse event (SAE) and serious adverse device effect 
(SADE) ......................................................................................................53 
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7.2.4.3 
Technical device complaints ......................................................................54 
7.2.4.4 
Pregnancy ...................................................................................................55 
7.3 
Submission procedure ............................................................................................55 
7.4 
Procedures for unblinding ......................................................................................55 
8 
Statistical methods ....................................................................................................56 
8.1 
Estimation of sample size ......................................................................................56 
8.2 
Randomization .......................................................................................................56 
8.3 
Populations for analysis .........................................................................................56 
8.4 
Statistical analyses .................................................................................................57 
8.4.1 
Effectiveness analyses .....................................................................................57 
8.4.1.1 
Primary effectiveness endpoint ..................................................................57 
8.4.1.2 
Secondary effectiveness endpoint ..............................................................58 
8.4.1.3 
 
8.4.2 
Safety analyses .................................................................................................59 
8.4.2.1 
Safety endpoints .........................................................................................59 
8.4.3 
Other variables .................................................................................................60 
8.5 
Subject discontinuation and missing data ..............................................................60 
8.6 
Imputation of effectiveness data ............................................................................60 
8.7 
Imputation of safety data .......................................................................................61 
9 
Ethics and administrative procedures ....................................................................62 
9.1 
Ethical considerations ............................................................................................62 
9.2 
Informed consent ...................................................................................................62 
9.3 
Confidentiality of subject information ...................................................................63 
9.4 
Study monitoring ...................................................................................................63 
9.5 
Data quality assurance ...........................................................................................63 
9.5.1 
Standardization procedures ..............................................................................63 
9.5.2 
Data management.............................................................................................64 
9.5.3 
Data review and clarification procedures ........................................................64 
9.5.4 
Study auditing ..................................................................................................65 
9.6 
Record retention .....................................................................................................65 
9.7 
Publication policy ..................................................................................................65 
9.8 
Financial disclosure ...............................................................................................66 
9.9 
Investigator compliance .........................................................................................66 
10 References ..................................................................................................................67 
11 Appendices.................................................................................................................69 
 
 
 
 
Merz North America, Inc.  
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Merz North America, Inc.  
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CLINICAL STUDY PROTOCOL 
Protocol #: M930021001; Version 2.0, 24-JUL-2017
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List of Tables 
 
 
List of Figures 
Figure 1: Study design .......................................................................................................20 
Figure 2: Example of a visual analog scale (VAS) for the right NLF at time zero 
on Day 1 .....................................................................................................21 
Figure 3: Merz Nasolabial Fold Scale: At rest ...................................................................23 
 
Figure 5: Nasolabial fold region ........................................................................................42 
Figure 6: Treatment area ....................................................................................................42 
Figure 7: Alar-tragus line ...................................................................................................42 
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1 INTRODUCTION 
1.1 
Background 
Belotero Balance (Control product) was approved by the U.S. FDA in November 2011 
(PMA Number: P090016) to help smooth moderate-to-severe facial wrinkles and folds, 
such as nasolabial folds (NLF), by temporarily adding volume to facial tissue and 
restoring a smoother appearance to the face. At present, the approved Belotero Balance 
formulation does not contain lidocaine hydrochloride. The investigational device (Test 
product) is a change to the approved Belotero Balance formulation to integrate 0.3% 
lidocaine hydrochloride for the purpose of pain reduction. 
Notably, a formulation similar to Belotero Balance with lidocaine has been registered in 
approximately 32 countries worldwide since 2013 (brand names: Esthelis Basic 
Lidocaine, Belotero Basic Lidocaine). 
1.2 
Study rationale 
During the administration of dermal fillers, pain is one of the most consistent patient 
complaints [1]. To mitigate patient pain and discomfort, lidocaine hydrochloride 
(C14H23ClN2O x H2O, herein, lidocaine) is frequently used by healthcare providers prior 
to dermal filler injection or alternatively lidocaine is mixed directly into the product 
[2][3][4]. 
Lidocaine is one of the most widely used anaesthetic drugs in the world. Although its 
activity as a membrane-stabilizing agent has made it useful as an anti-arrhythmic drug, 
the most common application of lidocaine is as a local anaesthetic. It is available as 
injectable solution and in topical formulations. The compound was first synthesized in 
1943 and commercialized by Astra AB in 1948; this amide type anaesthetic has a long 
history of safe and effective use [5]. 
The safety profile of lidocaine is well characterized [6]. Toxicity is modest, with cited 
LD50 values from 159-773 mg/kg in rats and 105 mg/kg (intraperitoneal injection) in 
mice. The recommended maximum dosage in adults or children is 4.5 mg/kg or 300 
mg/session. While serious side effects, including respiratory failure and cardiac arrest, 
have been observed at high doses, especially following intravenous administration, side 
effects following peripheral injection at the recommended dosage are modest and include 
dizziness, tinnitus, drowsiness, and sensation of heat, cold, or numbness. Although 
allergic reactions to lidocaine have been documented, they have been reported as being 
“extremely rare”. Buffering the pH of lidocaine solutions near physiological pH, but 
below pKa of ~7.85, improves both safety and efficacy, since lidocaine hydrochloride is 
more soluble than lidocaine base, and buffered lidocaine solutions are less painful at 
injection than unbuffered solutions [7][8]. 
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The pharmacokinetics profile of lidocaine has been extensively studied in both humans 
and animal models. In humans, the majority (up to 70%) of lidocaine is metabolized in 
the liver, with the metabolites excreted in the urine. Lidocaine levels in the blood follow 
a biphasic exponential curve, with an initial half-life of 8 to 17 minutes in the first 10 to 
15 minutes after intravenous injection followed by a half-life of 87 to 108 minutes for the 
remainder of the degradation time in humans. Lidocaine diffuses rapidly through tissue, 
reaching peak plasma concentration only 17 minutes after intranasal administration in 
rats. 
Pairing its efficacy with an extensive physician experience, lidocaine is frequently the 
anaesthetic of choice in facial aesthetic applications and has been incorporated into 
products such as Artefill®, Prevelle® Silk, Restylane-L®, Radiesse® (+), and 
JUVÉDERM® Ultra, all at the 0.3% concentration. 
Literature on the effectiveness and safety of lidocaine in various facial aesthetic 
applications, accompanied by its use in other similar products, justifies the need for Merz 
North America, Inc. to conduct a robust randomized clinical trial to demonstrate the 
effectiveness of Belotero Balance with lidocaine (Test product) for reduction of injection-
related pain when compared to FDA-approved Belotero Balance without lidocaine 
(Control product) for the correction of nasolabial folds. The investigational device (Test 
product) is a change to the approved Belotero Balance formulation to integrate 0.3% 
lidocaine hydrochloride for the purpose of pain reduction. 
1.3 
Potential benefits and risks 
The potential benefit of Belotero Balance with integral lidocaine (Test product) is the 
reduction of injection-related pain when using dermal fillers to correct the NLFs. 
Adverse events have been identified during post-approval use of Belotero Balance 
(Control product); 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 adverse events associated with the use of Belotero Balance Lidocaine (Test 
product) include: induration (transient or permanent); bump (transient or permanent); 
nodule (transient or permanent); lump (transient or permanent); blister; edema/swelling; 
erythema/redness; rash; bleeding; hematoma; pain; itching/pruritus; tingling; numbness; 
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burning sensation; hyperpigmentation; hypopigmentation; Tyndall effect; inflammation; 
Type I allergy; Type IV allergy; superficial local infection; severe deep local infection; 
severe systemic infection; chronic infection; necrosis; scarring; severe vascular 
compromise; transmissible severe systemic disease; fever; granuloma; cardiovascular 
compromise (e.g., loss of consciousness, palpitations, nausea, vomiting); embolization; 
sweating; nausea; paralysis; organ damage; nervous system impairments (e.g., dizziness, 
paraesthesia); worsening of a pre-existing condition; headache/cephalgia; severe visual 
impairment/blindness; nonthrombotic embolism; discoloration; scarring; transient 
vascular compromise; and/or death. 
For both the test and control products, an additional harm or risk, which is not an adverse 
event, includes disappointment due to lack of or reduced performance and/or undesirable 
aesthetic effect. 
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; 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. 
Lidocaine is commercially available and frequently used as a local and regional 
anesthetic agent. Potential side effects anticipated with its use include: lightheadedness; 
nervousness; apprehension; euphoria; confusion; dizziness; drowsiness; ringing noise in 
the ears; blurred or double vision; vomiting; sensations of heat, cold or numbness; 
twitching; tremors; convulsions; unconsciousness; respiratory depression and arrest; slow 
heartbeat; hypotension; and/or cardiovascular collapse, which may lead to cardiac arrest. 
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Protocol #: M930021001; Version 2.0, 24-JUL-2017
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3 INVESTIGATIONAL PLAN 
3.1 
Overview of study design 
This is an 6-week, prospective, randomized, split-face, double-blind, multicenter, pre-
market study to demonstrate the effectiveness of Belotero Balance with integral lidocaine 
(Test product) for reduction of injection-related pain when compared to Belotero Balance 
without lidocaine (Control product) for the correction of NLFs. Approximately 52 
subjects will be enrolled at approximately 3 investigational sites in the United States; a 
minimum of 20% of the enrolled subjects will be Fitzpatrick skin type IV, V, or VI. 
Subjects from the Fitzpatrick skin type IV, V, and VI group will be approximately evenly 
distributed within the IV, V, and VI categories. Subjects enrolled will have right and left 
NLF ratings of 2 or 3 (i.e., moderate or severe) on the Merz NLF Scale, as determined by 
the blinded evaluator. Both NLFs must have the same rating (i.e., symmetrical NLFs) at 
baseline. 
In this split-face design, a single randomization scheme will determine which NLF 
(subject’s right or left) will be assigned to Test product or Control product and which 
NLF (subject’s right or left) will be injected first. The treating investigator, the Merz NLF 
Scale evaluator, and the subject will be blinded to which NLF is randomized to Test and 
which NLF is randomized to Control. 
Study subjects will receive treatment with Belotero Balance with integral lidocaine in one 
NLF (Test) and Belotero Balance without lidocaine in the contralateral NLF (Control) on 
Day 1. All subjects without ongoing, treatment-related, investigator-reported AEs will be 
eligible for an optional touch-up treatment, at the investigator’s discretion and to achieve 
optimal correction, at Week 2. Each treatment session will consist of multiple mid- to 
deep-dermal injections of 0.1 to 0.2 milliliters (mL) Belotero Balance with and without 
lidocaine (up to a maximum of 3 mL per NLF over the two treatment sessions) into the 
left or right NLF according to the randomization assignment and the instructions for use. 
Subjects not receiving the optional, touch-up injection will be followed for six (6) weeks 
after their initial injection, while touch-up subjects will be followed for four (4) weeks 
after their last injection. Subjects will be evaluated at screening/enrollment, by phone at 
72 hours after treatment, at Week 2 (optional touch-up treatment), and Week 6 (end of 
study). If subjects report a safety concern at the 72-hour phone call, an unscheduled visit 
will be scheduled to address safety concerns. Of the 52 estimated subjects enrolled, each 
NLF will be analyzed as a separate unit of measure (i.e., either Test or Control NLF) for 
the primary and secondary effectiveness endpoints, resulting in approximately 104 
evaluable NLFs (52 Test, 52 Control). Pain levels, between the Test NLF and Control 
NLF, will be compared using a 10-cm VAS. Pain assessments will be evaluated at time 
zero (i.e., time the last injection needle is removed from each NLF, separately, after a full 
correction)
. 
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Standard safety endpoints, including documentation of AEs and SAEs, will be assessed. 
Furthermore, several, pre-defined common treatment site responses (CTRs) will be 
evaluated via subject diaries. 
Figure 1 illustrates the visit schedule associated with the split-face design. Section 5.1 
and Appendix 11.1 detail a full schedule of study events and a schedule of events for 
each visit. 
Figure 1: Study design 
 
NLFs: Nasolabial folds; N: sample size; V: Visit; Wk: Week; R: Randomization; HR: hour 
3.2 
Study assessments and definitions 
3.2.1 
Effectiveness assessments 
3.2.1.1 
Evaluation of pain 
Pain will be assessed using a visual analog scale (VAS) [9][10][11]; this VAS includes 
21-numbered circles at 0.5 cm increments, spanning 10 cm total, and is anchored by word 
descriptors (see Figure 2). The level of pain will be evaluated for each NLF 
independently immediately upon completion of injection (time zero)
 
 on Day 1. Time zero will be defined as the time the last injection 
needle is removed from each NLF, separately, after a full correction on Day 1. At time 
zero, the subject will be asked to rate the pain experienced throughout the injection 
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for the assessment of NLF severity. In this study, the left and right NLFs of each subject 
are assessed independently with the Merz NLF Scale. 
Study subjects will be evaluated at the screening/enrollment visit and at Week 6 with the 
Merz NLF Scale; the scale assessor is a trained evaluator who is blinded to the subject’s 
treatment assignment and who will perform the scale assessment independently from any 
study staff. In addition to the Merz NLF Scale assessment, the blinded evaluator will 
evaluate the subject using a GAIS at Week 6 (see Section 3.2.1.2.3). The blinded 
evaluator should not be present for any study procedures other than the Merz NLF Scale 
assessment (at baseline and Week 6) and the Week 6 GAIS assessment, and he/she 
should not have access to subject study records. Further, subjects will be instructed not to 
discuss aspects of their treatment with the blinded evaluator.  
Prior to study enrollment, at least one blinded evaluator at each site will be trained by the 
study sponsor to perform NLF ratings using the Merz NLF Scale. Training will consist of 
an instructional session, followed by the blinded-evaluator trainees scoring two sets of 
photographs, at least 2 weeks apart for inter- and intra-evaluator weighted Kappa 
analyses prior to study enrollment. Any blinded evaluator who does not achieve the 
minimal weighted Kappa point estimate value of ≥ 0.70 will be retrained and requalified. 
If sites have multiple blinded evaluators identified, the evaluator with the highest Kappa 
statistics will be chosen as the primary blinded evaluator. In the event the primary 
blinded evaluator is unavailable, the qualified backup evaluator may be used. Efforts will 
be made to maintain the same evaluator for all assessments throughout the study. If 
evaluator retention (e.g., change in personnel) becomes an issue during the study, new 
blinded evaluators must be qualified by the sponsor and the Kappa analyses must be re-
run according to the criteria above. The qualification and training of the evaluators will 
be documented. 
The treating investigator will also attend a Merz NLF Scale instructional session to 
ensure understanding of the subject-eligibility criteria of moderate-to-severe nasolabial 
folds, defined as a Merz NLF Scale rating of 2 or 3 at study entry.  
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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. 
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, and completed all visits defined in the Schedule of Events (see Section 5.1 and 
Appendix 11.1). 
3.2.3.3 
End of study 
The end of the study is defined as when the last subject completes the last visit and the 
database is locked. 
3.3 
Duration of study 
Subjects are screened and enrolled at the baseline visit. Treatment will occur at the 
screening/enrollment (baseline) visit. The time between baseline and end of study is 42 
days (+ 3 day window). 
 
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4 STUDY POPULATION AND RESTRICTIONS 
4.1 
Number of subjects and sites 
Approximately fifty-two (52) subjects will be enrolled and treated. Each NLF (i.e., right 
or left NLF) will be analyzed separately, resulting in approximately 104 discrete units of 
measure for the primary and secondary effectiveness endpoints. Subjects will be enrolled 
from up to 3 sites in the United States. A minimum of 20% of the enrolled subjects will 
be Fitzpatrick skin type IV, V, or VI. Subjects from the Fitzpatrick skin type IV, V, and 
VI group will be approximately evenly distributed within the IV, V, and VI categories. 
Additional information regarding subject enrollment is provided within the sample size 
justification in Section 8.1. 
4.2 
Inclusion criteria 
In order to be eligible for study participation, each subject must meet all of the following 
criteria: 
1. 
Has right and left NLF ratings of 2 or 3 (moderate or severe) on the Merz NLF 
Scale, as determined by the blinded evaluator (i.e., a qualified healthcare 
practitioner delegated by the treating investigator). 
2. 
Has the same Merz NLF Scale rating on both NLFs (i.e., symmetrical NLFs). 
3. 
Is a candidate for bilateral NLF treatment with Belotero Balance. 
4. 
Is at least 18 years of age at the time of screening. 
5. 
Has an adequate understanding (reading, speaking, and writing) of the local/ 
regional language. 
6. 
Is willing and able to give written informed consent after having been informed of 
the requirements and the restrictions of the study. 
7. 
Understands and accepts the obligation not to receive any other procedures (i.e., 
dermal fillers, toxin treatments, facial ablative or fractional laser, microderm 
abrasion, chemical peels, non-invasive skin-tightening [e.g., Ultherapy, 
Thermage], or surgical procedures) below the orbital rim on the face during study 
participation. 
8. 
Is willing to comply with all requirements of the study, including being 
photographed, following post-treatment care instructions, and attending all study 
visits. 
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4.3 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible to participate in the study: 
1. 
Has skin or fat atrophy, beyond typical for the subject’s age, in the mid- to lower-
facial region or has been diagnosed with a connective tissue disorder. 
2. 
Has unphysiological skin laxity or sun damage, beyond typical for the subject’s 
age, or subject plans to tan during the study period. 
3. 
Has an acute inflammatory process or infection at the injection site (e.g., skin 
eruptions such as cold sores, cysts, pimples, acne, eczema, hives, streptococcus 
infections) or history of chronic or recurrent infection or inflammation with the 
potential to interfere with study results or increase the risk of AEs. 
4. 
Had prior surgery in the mid- and/or lower-face area, including the nasolabial 
fold(s), or has a permanent implant or graft in the mid- and/or lower-face area that 
could interfere with effectiveness assessments. (NOTE: Rhinoplasty is permitted 
if the procedure was ≥ 12 months prior to study enrollment.) 
5. 
Had lower-lid blepharoplasty within 6 months prior to enrollment. 
6. 
Has ever been treated with fat injections or permanent and/or semi-permanent 
dermal fillers in the mid- and/or lower-facial region or plans to receive such 
treatment during participation in the study. 
7. 
Has received mid- and/or lower-facial region treatments with porcine-based 
collagen fillers, Belotero® Volume, JUVÉDERM VOLUMA®, Restylane® Lyft, 
RADIESSE®, poly L-lactic acid (PLLA), or mesotherapy within the past 24 
months and/or with other hyaluronic acid (HA) products within the past 12 
months or plans to receive such treatment during participation in the study. 
8. 
Has undergone oral surgery (e.g., orthodontia, extraction, implants) in the past 30 
days or plans to receive such surgery during participation in the study. 
9. 
Has begun use of any new over-the-counter or prescription, oral or topical, skin 
products on the face within 90 days prior to enrollment or is planning to begin use 
of such products during participation in the study. 
NOTE: Use of sunscreens and continued therapy with some cosmeceuticals 
(e.g., alpha hydroxyl acids, glycolic acids, skin-bleaching agents, retinol, or 
retinoic acids) are allowed if the regimen was established > 90 days prior to 
enrollment and the subject agrees to continue the same regimen throughout 
the study. 
10. Has used any prescription topical steroids or skin-irritating preparations on the 
face in the past 2 weeks or plans to receive such treatment during participation in 
the study. 
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11. Had prolonged exposure to natural or artificial sources of UV radiation (e.g., 
sunlight or tanning booth) on the face in the past 7 days or plans for prolonged 
UV-radiation exposure during participation in the study. 
12. Has received facial dermal therapies (e.g., facial ablative or fractional laser, 
microderm abrasion, chemical peels, non-invasive skin-tightening [e.g., 
Ultherapy, Thermage], or surgical procedures) in the mid-face region within the 
past 12 months or plans to receive such treatment during participation in the 
study. 
13. Has received neurotoxin treatment in the midface within the past 4 months or 
plans to receive such treatment during participation in the study. 
14. Has received immunosuppressive medications or systemic steroids (except 
intranasal/inhaled steroids) in the past 2 months or plans to receive such treatment 
during participation in the study. 
15. Has a history of allergic/anaphylactic reactions, including hypersensitivity to 
lidocaine or anesthetics of the amide type, hyaluronic acid preparations, gram 
positive bacterial proteins, or any of the device components. 
16. Has facial nerve palsy or a history of facial nerve palsy. 
17. Has volume deficit in the mid- and/or lower-face area due to medical conditions 
such as congenital defect, trauma, and abnormalities in adipose tissue related to 
immune-mediated diseases such as generalized lipodystrophy (e.g., juvenile 
dermatomyositis), partial lipodystrophy (e.g., Barraquer-Simons-Syndrome), 
inherited disease, or HIV-related disease. 
18. Has active or a history of recurrent or chronic edema or rosacea in the mid- and/or 
lower-face area. 
19. A history or documented evidence of an autoimmune disease (e.g., scleroderma, 
lupus erythematosus, rheumatoid arthritis). 
20. Has a known bleeding disorder or has received or is planning to receive anti-
coagulation, anti-platelet, or thrombolytic medications (e.g., warfarin), anti-
inflammatory drugs (e.g., oral/injectable corticosteroids or NSAIDs [e.g., aspirin, 
ibuprofen]), or other substances known to increase coagulation time (e.g., 
vitamins or herbal supplements, e.g., Vitamin E, garlic, gingko) from 10 days 
before injection to 3 days after injection. 
21. Has a propensity toward pigmentary skin changes, such as hyper- or hypo-
pigmentation in the face, keloid formation, or hypertrophic scarring. 
22. Has lost ≥ 2 body mass index (BMI) units within the previous 90 days or has the 
intention to lose a significant amount of weight during the course of the study. 
23. Has a history of recurrent herpetic eruption in the midfacial region, excluding the 
lips, within 12 months. 
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24. Is a female of childbearing potential1 and not using medically effective birth 
control2 or is pregnant or lactating. (NOTE: Urine pregnancy tests will be used in 
female subjects of childbearing potential.) 
25. Has facial hair (i.e., beards, sideburns, etc.) that would interfere with study 
assessments and/or create inconsistency in required study photography. 
26. Has congenital methemoglobinemia, with glucose-6-phosphate dehydrogenase 
deficiencies, or is receiving concomitant treatment with methemoglobin-inducing 
agents. 
27. Has any other medical condition with the potential to interfere with study 
outcome assessments or compromise subject safety (i.e., increase the risk of 
adverse events). 
28. Refusal to refrain from any anesthesia or other methods to minimize pain (e.g., 
Tylenol®, ice or ice compress, topical anesthetic, local nerve block) before NLF 
injection on Day 1. That is, no pre-treatment forms of facial pain reduction are 
allowed on Day 1. 
NOTE: After completion of the 60-minute VAS pain assessment (see Section 
3.2.1.1), ice, cold compresses, and/or other medication(s) to minimize 
swelling and bruising are permitted at the discretion of the treating 
investigator. 
29. Has participated in a study in the last 30 days or is enrolled or plans to enroll in 
any other interfering investigational study during participation in this study. 
30. Is an employee or direct relative of an employee of the investigational department 
of the site or of the study sponsor. 
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: 
− Application of any new over-the-counter or prescription, oral or topical, skin 
products in the mid- or lower-facial region. 
1 Childbearing potential is defined as NOT premenarche, permanently sterilized, bilateral tubal ligation, or 
postmenopausal (i.e., 12 months with no menses without an alternative medical cause). 
2 Defined as a highly effective method that results in a low-failure rate (i.e., less than 1% per year) when 
used consistently and correctly, such as implants, injectables, combined oral contraceptives, IUDs, sexual 
abstinence, or vasectomized partner. Hormonal methods and IUD must be in use at least 30 days prior to 
first study product administration; barrier methods must be in use at least 14 days prior to study product 
administration; vasectomy must be completed 3 months prior to first study product administration, or as an 
alternative, a zero (0) sperm count will suffice. 
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o NOTE: Use of sunscreens and continued therapy with some 
cosmeceuticals (e.g., alpha hydroxyl acids, glycolic acids, skin-bleaching 
agents, retinol, or retinoic acids) are allowed if the regimen was 
established > 90 days prior to enrollment. 
− Cosmetic facial plastic surgery or oral surgery procedures (e.g., orthodontia, 
extraction, implants). 
− Facial treatments with permanent and/or semi-permanent dermal fillers (e.g., 
collagen, fat, hyaluronic-acid products, calcium-hydroxylapatite products, etc.). 
− Additional dermal therapies other than the investigational treatment (e.g., dermal 
fillers, neurotoxin treatments, facial ablative or fractional laser, microderm 
abrasion, chemical peels, non-invasive skin-tightening [e.g., Ultherapy, 
Thermage], or surgical procedures) on the face. 
− Prescription topical steroids or skin-irritating preparations on the face. 
− Immunosuppressive medications or systemic steroids (except intranasal/inhaled 
steroids). 
− Prolonged exposure to natural or artificial sources of UV radiation (e.g., sunlight 
or tanning booth) on the face. 
− Exposure to extreme cold or heat (e.g., sauna, Turkish bath). 
− Loss of a significant amount of body weight (i.e., ≥ 2 BMI units).  
Subjects are also prohibited from the following activities post treatment: 
− Touching/pressing treated parts of the face for 12 hours post treatment. 
− Applying makeup to treated parts of the face for 12 hours post treatment. 
− Exercising strenuously for 24 hours after treatment. 
− Consuming alcoholic beverages for 24 hours after treatment. 
− Taking anti-coagulation, anti-platelet, or thrombolytic medications (e.g., 
warfarin), anti-inflammatory drugs (e.g., oral/injectable corticosteroids or 
NSAIDs [e.g., aspirin, ibuprofen]), or other substances known to increase 
coagulation time (e.g., vitamins or herbal supplements, e.g., Vitamin E, garlic, 
gingko) for 3 days after treatment. 
Finally, if the subject is a female of childbearing potential, she must commit to not 
becoming pregnant during the study. 
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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, and reason for screen failure. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. 
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 eCRFs. 
 
 
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5.1.2 
Unscheduled visits 
To ensure subject safety during the study, any subject who requires additional follow-up 
during the study for any reason (that does not fall on a scheduled study visit) should have 
that visit recorded as an unscheduled visit; additionally, all applicable eCRFs for that 
unscheduled visit should be completed (e.g., AEs, concomitant medications/ procedures). 
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 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 (Section 5.1 and Appendix 
11.1). 
5.2.2 
Premature suspension or termination of the study 
Should the investigator, 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 reported 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 entire study will be immediately 
suspended and no subjects will be enrolled 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; 
• Sponsor decision; and/or 
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• 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 or lost to follow-up (e.g., 
moving away from study site; unresponsive to attempts to contact the subject). 
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 
the event. The investigator should make every attempt to follow all SAEs/UADEs to 
resolution. Information on pregnancy and the outcome for any female who becomes 
pregnant during the study will be collected. Additional information on subject withdrawal 
criteria is provided in Section 4.6. 
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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 care 
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 devices 
6.1.1 
Test product 
The investigational device is a change to the Belotero Balance formulation to integrate 
0.3% lidocaine hydrochloride for the purpose of pain reduction. Belotero® Balance with 
integral lidocaine is a sterile, bioresorbable, non-pyrogenic, viscoelastic, clear, colorless, 
homogeneous gel device. It 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. 
Belotero Balance with integral lidocaine injectable implant will be supplied by the study 
sponsor. This product should be stored at room temperature (up to 25°C/77°F), away 
from heat, and should not be refrigerated. The test product has a clear, colorless 
(transparent) appearance. In the event that the syringe contains material that is not clear, 
do not use the syringe and notify the study sponsor. 
6.1.2 
Control product 
Belotero® Balance is a sterile, bioresorbable, non-pyrogenic, viscoelastic, clear, colorless, 
homogeneous gel device. It 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. Belotero® Balance is indicated for 
injection into the mid-to-deep dermis for correction of moderate-to-severe facial wrinkles 
and folds, such as nasolabial folds. The Belotero Balance Premarket Approval (PMA) 
submission (P090016) was approved November 14, 2011 by the Food and Drug 
Administration (FDA). Belotero filler had been previously approved for aesthetic use in 
the United Kingdom, Germany, Italy, Russia, Austria, and Switzerland. Currently, the 
approved Belotero Balance formulation does not contain lidocaine hydrochloride. The 
Belotero Balance package insert is included in Appendix 11.2. 
Belotero Balance injectable implant will be supplied by the study sponsor. This product 
should be stored at room temperature (up to 25°C/77°F), away from heat, and should not 
be refrigerated. Belotero Balance has a clear, colorless (transparent) appearance. In the 
event that the syringe contains material that is not clear, do not use the syringe and notify 
the study sponsor. 
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6.2 
Usage 
Test and control products should be used in the NLF treatment region according to the 
information and injection instructions presented in Section 6.3. Test and control products 
are packaged and designed for single use only. Syringes are not to be re-sterilized. 
Products should not be used if the package is opened or damaged or beyond the 
expiration date provided to the investigational site. Please refer to the study-site binder 
for the expiry date memorandum from Anteis SA (manufacturer); this memo indicates the 
clinical trial material (CTM) lot number, the expiration date of the lot, and a statement 
indicating the product meets its release specifications. Do not use CTM lots beyond the 
expiration date indicated by the manufacturer. 
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. All device administration 
(injection) will be performed on site by the principal investigator (PI); only the PI can 
inject. The PI is also described as the treating investigator in this document. 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 
Subjects will receive treatment with Belotero Balance with integral lidocaine (Test 
product) and Belotero Balance without lidocaine (Control product). 
At baseline, approximately 52 subjects will be randomized in this split-face study. Prior 
to injection, one NLF will be randomized to receive Belotero Balance with integral 
lidocaine (Test), and the contralateral NLF will receive Belotero Balance without 
lidocaine (Control). 
A single randomization scheme will determine which NLF (subject’s right or left) will be 
assigned to Test product or Control product and which NLF (subject’s right or left) will 
be injected first. Randomization will be provided by an electronic randomization system, 
which site personnel must access following confirmation that the subject meets all 
eligibility criteria. 
Care must be taken to follow the subject’s randomization assignment – ensuring the 
Test product and Control product syringes are injected according to their assigned 
order (Test first or Control first) and into the NLF that is randomly assigned to be 
injected first (subject’s right NLF first or subject’s left NLF first). Accurate 
documentation of (1) which product (Test or Control) is injected into which NLF 
(subject’s right or left) and (2) in the order assigned by the randomization system 
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(subject’s right NLF first or subject’s left NLF first) is of critical importance in this 
study. 
During the screening/enrollment visit, randomized subjects will receive Belotero Balance 
(Test and Control) in both NLFs per the administration instructions below. Each NLF of 
each subject will be treated until, in the agreement of the treating investigator and the 
subject, an optimal result is achieved, defined as “optimal cosmetic result” for the 
implant in that subject; however, treatment is not to exceed the maximum allowable 
injection volume of 3 mL per NLF over two treatment sessions (Day 1 and optional 
touch-up at Week 2). The same injection technique (i.e., serial puncture and/or linear 
threading) must be used for both NLFs on Day 1. Subjects will be eligible for a single, 
optional touch-up treatment, at the investigator’s discretion and to achieve optimal 
correction, at the Week 2 visit. 
Color-coded subject labels, packaged in the kit tray with the syringe and needles, will be 
used to document which NLF was injected with which blinded product. After receiving 
the randomization assignment and preparing the products for injection, these labels 
should be affixed to the subject’s source documents. The site personnel shall write the 
following on each label: 
1. (R)ight or (L)eft (corresponding to the subject’s right or left NLF) and 
2. #1 or #2 (corresponding to which NLF was treated first or second). 
This information will remain in the subject’s source documents and made available for 
verification of the proper randomization sequence by the sponsor or designee during 
monitoring visits. 
Injection volumes, depth, and technique will be recorded for each NLF injection location. 
Observed AEs will also be recorded. 
The NLF region and treatment area are shown in Figure 5 and Figure 6, respectively. 
 
 
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Figure 5: Nasolabial fold region 
Crease formed lateral to the mouth from the 
alar-tragus to the oral commissure 
 
Figure 6: Treatment area 
Injection in the nasolabial fold from the 
alar-tragus line to the oral commissure 
 
 
Figure 7: Alar-tragus line 
 
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6.3.1.1 
Injection procedure 
Injection occurs for all subjects at Visit 1 (baseline). 
1. Prepare the pre-filled syringes of Belotero Balance (Test and Control) and the 
injection needle(s) before the percutaneous injection as described below. To 
assure proper needle attachment, use only needles provided with the clinical trial 
product. 
2. To attach needle to syringe, open the needle packaging to expose the needle hub. 
Remove the Luer-syringe cap from the distal end of the syringe prior to attaching 
the needle. 
3. Holding the Luer-lock fitting of the syringe, twist the needle onto the glass 
syringe provided in the kit, taking care not to contaminate the needle. Discard 
needle packaging. The needle must be tightened securely to the syringe and 
primed with Belotero Balance (Test and Control) injectable implant. Do not 
over-tighten as this may break the needle and/or dislodge the syringe. 
4. Pull off the needle guard to expose needle. If excess implant is on the surface of 
the Luer-lock fittings, 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 
needle. 
5. If leakage is noted at the Luer fitting, it may be necessary to remove the needle, 
and clean the surfaces of the Luer fitting or, in extreme cases, replace both the 
pre-filled syringe and the needle. 
6. Prepare subject for percutaneous injection using standard aseptic methods (e.g., 
alcohol, Betadine, chlorhexidine).  
NOTE: In this trial, no anesthesia or other methods to minimize pain (e.g., 
Tylenol®, ice or ice compress, topical anesthetic, local nerve block) are 
allowed in either NLF before device injection through the end of the 60-
minute pain assessment on Day 1 (see Section 3.2.1.1). 
7. According to the subject’s randomization assignment (i.e., Test or Control 
product injected first and subject’s right or left NLF injected first), Belotero 
Balance (Test and Control) is to be injected into the mid to deep dermis using a 30 
gauge x ½ inch needle. The injection technique (i.e., angle and orientation of the 
bevel, depth of injection, and quantity administered) may vary. A linear-threading 
technique, tunneling technique, serial puncture injections, or a combination of 
these have been used to achieve optimal results. Care must be used to avoid 
intravascular injection, with particular attention given to the region superior to the 
alar-tragus line (see Figure 7), regardless of technique used. 
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NOTE: In this trial, the maximum allowable injection volume of Belotero 
Balance (Test or Control) is not to exceed 3 mL per NLF over the two 
treatment sessions. In addition, the same injection technique (i.e., serial 
puncture or linear threading) must be used for both NLFs at Day 1. 
8. The number of NLF injection locations and volume (not to exceed 3 mL per NLF 
over the two treatment sessions) of dermal filler injected are at the discretion of 
the treating investigator until, in the agreement of the treating investigator and the 
subject, an optimal result is achieved, defined as “optimal cosmetic result” for the 
implant in that subject. Augment to optimal 1:1 correction. Do not overcorrect. 
9. For the linear-threading technique and/or tunneling technique, the needle is 
inserted at an approximate angle of 30° parallel to the length of the NLF. The 
injection can be performed with a constant low-to-moderate pressure on the 
plunger while slowly and gradually withdrawing the needle. 
10. For the serial puncture technique, the needle is inserted at multiple sites along the 
NLF as per the provider’s clinical discretion. 
11. With both injection techniques, slight elevation of the skin should be observed 
without significant blanching of the skin. To avoid visible lumps and/or 
discoloration, avoid injection of Belotero Balance (Test and Control) into the 
superficial dermis when removing the needle. 
12. If immediate blanching occurs, the injection should be stopped and the area 
massaged until it returns to a normal color. Blanching may represent a vessel 
occlusion. If normal skin coloring does not return, do not continue with the 
injection. Treat in accordance with the American Society for Dermatologic 
Surgery guideline, which includes possible hyaluronidase injection. 
13. When the injection is complete, the site may be gently massaged, if necessary. 
NOTE: In this trial, after completion of the 60-minute VAS pain assessment 
(see Section 3.2.1.1), ice, cold compresses, and/or other medication(s) to 
minimize swelling and bruising are permitted at the discretion of the treating 
investigator. 
14. Immediately stop the injection if a study subject exhibits any of the following 
symptoms: changes in vision; signs of a stroke; blanching of the skin; or unusual 
pain during or shortly after the procedure. Subjects should receive prompt medical 
attention and possibly evaluation by an appropriate healthcare practitioner 
specialist should an intravascular injection occur. 
Subjects must be also be informed that, at any time over the study interval, if 
they experience signs or symptoms of an intravascular injection, similar to 
those noted above, or symptoms listed on the first page of the study diary 
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card or within the informed consent form, they must seek immediate medical 
attention and notify the study doctor immediately. The study doctor must 
refer the subject to a specialist if additional medical attention is deemed 
necessary. 
6.3.1.2 
Maximum injection volume 
In this study, the maximum injection volume of Belotero Balance (Test or Control) is not 
to exceed 3 mL per NLF over the two treatment sessions (Day 1 and optional touch-up 
injection at Week 2). Subjects should not receive more than 6 mL of Belotero Balance 
per year. The safety of injecting greater amounts has not been established. 
6.4 
Packaging of treatment supplies 
Belotero Balance with integral lidocaine (Test product) and Belotero Balance without 
integral lidocaine (Control product) will be provided by the study sponsor. The sponsor 
will package study materials according to applicable regulatory requirements. The 
sponsor will provide all pertinent labeling information, as well as a description of the 
specific device-packaging conditions. 
The sponsor will provide a blinded, bulk supply of both Test product and Control 
product. The product kits, including syringe and needles, will be distinguished only by 
different colored labels. Only the unblinded sponsor will have the product lot number key 
(i.e., code break). 
Product kits will include: 
• One sterile 1-mL prefilled glass syringe of Belotero Balance with integral 
lidocaine (Test) or 
• One sterile 1-mL prefilled glass syringe of Belotero Balance without integral 
lidocaine (Control); 
• Two sterile 30 gauge, ½ inch needle(s) with Luer-lock fittings; and 
• Color-coded subject labels (provided in the kit tray) for appropriate source 
documentation. 
6.5 
Receipt, storage, dispensing, and return/disposal 
Upon receipt, the site personnel will verify the contents of all study supplies received and 
promptly notify the appropriate contacts of any discrepancies or damages. The 
investigator is responsible for ensuring that an accurate record of inventory is maintained. 
The investigator will keep a current record of the study product delivery to the study site, 
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inventory, and dispensing, and this record will be made available to the sponsor upon 
request. Study sites will be queried about any discrepancies. 
All study devices must be stored in a secure, environmentally controlled, monitored area 
in accordance with the labelled storage conditions. 
Only authorized study personnel may supply, dispense, and/or administer study 
treatment, and only subjects enrolled in the study may receive study treatment. The 
investigator is responsible for maintaining a current, accurate record of all study 
treatment dispensation. 
Any used syringes of Belotero Balance (Test and Control) and needles should be 
discarded per the appropriate handling and disposal procedures at the site. Any 
unused/unopened product, needles, and/or outer packaging (of used kits) should be 
retained so the monitor can perform device-accountability procedures. 
At the end of the study and after verification of study device/kit accountability, it is the 
investigator’s responsibility to return or destroy all unused study supplies, as directed by 
the sponsor. Appropriate records of return or disposal must be maintained for 
accountability purposes. For the return of supplies, the following address shall be used: 
 
To: Merz North America, Inc. 
Attn: Receiving 
1340 Grandview Parkway, Suite 2 
Sturtevant, WI 53177-1261 
 
Phone: (866) 862-1211 
Fax: (866) 862-1212 
All study-accountability procedures must be completed before the study is considered 
complete. 
6.6 
Accountability procedures 
The sponsor will provide the investigator with all 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 PI or an authorized designee will keep records documenting the receipt, 
use, return, and disposal of the investigational medical devices, which will include the 
following: 
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1. The date of receipt. 
2. Identification of each investigational medical device (batch number/serial number 
or unique code). 
3. The expiry date (see Section 6.2 for additional information). 
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). 
6.7 
Level and method of blinding 
In this split-face design, the treating investigator, the Merz NLF Scale evaluator (i.e., 
person responsible for assessing aesthetic effectiveness), and the study subject will be 
blinded to treatment assignment. The blinded evaluator cannot be the treating investigator 
or the study coordinator. 
 
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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 AEs 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 event (SAE) 
A SAE is any adverse event 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 an SAE. 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 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 ADE (SADE) 
A SADE is defined as a serious adverse event related to the use of an investigational 
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’s Brochure (IB), or product 
labeling, 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 site 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 diary cards provided to them. The treating investigator will review and initial 
the diary and determine if any entries should be reported 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, SAE, ADE, SADE, and/or UADE. 
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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 
severity/intensity of an AE will be classified as follows: 
• 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. 
• 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. 
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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 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Fatal 
• Unknown 
NOTE: If a subject experiences 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 
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 
eCRF. 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 during study conduct will be fully 
investigated, documented, and followed until the event is either resolved, until the 
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condition stabilizes, until the event is otherwise explained, or the subject is lost to follow-
up. 
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 
• AE resulting in subject discontinuation (yes or no) 
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. 
The investigator must report SAEs and SADEs to Merz or designee as defined in Section 
7.2 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. 
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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, IECs/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 the 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 his/her 
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. 
• A Device Technical Complaint form must be completed and submitted by the 
investigative site, irrespective of the seriousness of the case. 
• A Device Technical Complaint form must be completed and submitted by the 
investigative site, irrespective of whether the complaint led to an AE. 
• If a technical complaint is associated with an SAE, the investigative site must also 
complete and submit an SAE form (see Section 7.2.4.2) in addition to the Device 
Technical Complaint form. SAE forms for device clinical trials should be sent to 
Merz Product Safety for processing (as defined in Section 7.3). 
Any technical complaints should be reported to the sponsor. The investigator will 
complete the Device Technical Complaint form and send within 24 hours to the Merz 
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Technical Complaint Department for processing using the following email address: 
complaints2@merz.com. 
7.2.4.4 
Pregnancy 
Any female subject who experiences pregnancy during the study must be reported by the 
investigator to Merz Product Safety or designee upon learning of the pregnancy. 
Pregnancies and pregnancy follow-up should be reported on a Pregnancy Report Form. 
Pregnancy follow-up should describe the outcome of the pregnancy, including any 
voluntary or spontaneous discontinuation; details of the birth; the presence or absence of 
any congenital abnormalities, birth defects, maternal or newborn complications, and their 
relation, if any, to the investigational medical device. Each pregnancy must be reported 
on the end of study eCRF. 
7.3 
Submission procedure 
The investigator should complete and send any SAE forms or pregnancy forms (including 
any follow-up forms) to Merz North America Product Safety via the fax number and/or 
email provided below: 
Merz North America, Inc. Product Safety 
6501 Six Forks Road 
Raleigh, NC 27615 
USA 
Product Safety Fax: 336-458-5983 
Product Safety Email: adverse.events@merz.com 
7.4 
Procedures for unblinding 
Only the sponsor, the monitor, and the designee managing the electronic randomization 
system are unblinded in this study. 
In the event of a medical emergency, where unblinding is determined to be necessary by 
the treating investigator, the medical monitor at the sponsor or designee will be contacted 
immediately to facilitate the identification of the Belotero Balance product (Test or 
Control) that was randomized to the NLF in question. In the event that unblinding 
becomes necessary, the treating investigator must adequately document the circumstances 
in the subject’s source documents. 
 
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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 or 
unblinding, respectively, 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 
Sample size calculation was performed using the nQuery+nterim version 4.0 statistical 
software. Based on a review of comparable clinical literature [2][3][4][12][13][14][15], it 
is assumed for this power calculation that a change of 3.8 cm on a 10-cm VAS represents 
a clinically meaningful difference in pain as experienced between lidocaine-treated and 
non-lidocaine-treated NLFs. Assuming a statistical power, 1–β of 95%, a one-sided level 
of significance of α = 0.025, and a conservative estimate of standard deviation of 
difference of 7, a total of 47 subjects will be required. To account for possible subject 
dropout after randomization and prior to treatment (up to 10% attrition), a total of 52 
subjects will be enrolled, yielding approximately 104 total NLFs (52 Test and 52 
Control). Additionally, a minimum of 20% of the enrolled total sample size will consist 
of subjects in the Fitzpatrick Skin Types IV, V, or VI group. Subjects from the 
Fitzpatrick skin type IV, V, and VI group will be approximately evenly distributed within 
the IV, V, and VI categories. 
8.2 
Randomization 
Randomization will be performed within blocks using a random allocation schedule that 
will assign one side of each subject’s NLF to Belotero Balance with integral lidocaine 
(Test product) and the contralateral NLF to Belotero Balance without lidocaine (Control 
product) or vice versa. The blocks will be created in such a way that the proportion of 
subjects in both sequences (Test/Control – L/R or Control/Test – L/R) will be 
approximately equally distributed within each site. 
8.3 
Populations for analysis 
The following analysis sets will be defined for the statistical analysis of this study: 
• The Safety Evaluation Set (SES) will comprise subjects who are enrolled into the 
study, randomized, and receive an injection. 
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• The Full Analysis Set (FAS) is the subset of subjects in the SES for whom the 
primary effectiveness variable is available (i.e., all subjects who have a VAS 
assessment value for both left and right NLFs at time zero on Day 1). 
• The Per Protocol Set (PPS) is a subset of subjects in the FAS without major 
protocol deviations. Final determination of what constitutes major or minor 
protocol deviations will be made prior to database lock. 
The usage of the analysis populations as it pertains statistical analyses of study results 
will be described in the SAP. 
8.4 
Statistical analyses 
Effectiveness and safety endpoints are provided in Sections 2.2.1 to 2.2.4. 
Statistical tests will be two-sided at α = 0.05 except for the primary effectiveness analysis 
where a one-sided α = 0.025 will be used. Two-sided confidence limits (95%) and p-
values associated with the appropriate test statistic will be provided where necessary. 
Primary and secondary effectiveness data will be summarized using the FAS and PPS. 
Other effectiveness endpoints will be summarized using only the FAS. All safety data 
will be summarized using the SES. 
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. 
8.4.1 
Effectiveness analyses 
8.4.1.1 
Primary effectiveness endpoint 
The assessment of a statistically significant, mean reduction in pain, measured using a 
10-cm VAS, in the Test NLF compared to the Control NLF at time zero on Day 1 will be 
analyzed using a paired t-test to test the one-sided hypothesis that the mean of the 
differences in VAS scores between Test (μT) and Control (μC) folds is either greater 
than/equal to zero (≥ 0) or less than zero (< 0), as equivalently assessed using the 
following hypothesis-testing notation(s): 
H0 (null): μR ≤ μT, (i.e. ∆ = µT - µR ≥ 0) versus 
Ha: (alternate): μR > μT, (i.e. ∆ = µT - µR < 0) 
For testing this hypothesis using the t distribution, H0 will be rejected if the upper limit of 
the 95% confidence interval (CI) around ∆ is < 0 using a one-sided p-value < (α = 0.025), 
otherwise H0 will not be rejected. 
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data will be summarized descriptively and separately by left or right NLF. 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. 
8.4.3 
Other variables  
Subject disposition, demographic characteristics and baseline characteristics will be 
presented using standard descriptive statistics for continuous variables (i.e., n, mean, SD, 
median, minimum, and maximum) and for qualitative variables (absolute and percent 
frequencies (i.e., n, %). Demographic and baseline characteristics will be summarized for 
the SES, the FAS, and the PPS. 
Prior and concomitant treatments as well as non-pharmacological concomitant 
procedures will be listed. Prior and concomitant medications will be coded using WHO 
Drug Dictionary. 
Frequencies of concomitant medications will be given based on different ATC code 
levels as well as by generic name for the SES. Indications for concomitant procedures 
will be coded and only listed. Medical history and concomitant diseases will be 
summarized based on MedDRA system organ class (SOC) and preferred term (PT) levels 
for the SES. 
8.5 
Subject discontinuation and missing data 
8.6 
Imputation of effectiveness data 
Observed Cases (OC) 
• For the OC method, there will be no missing value imputations conducted. All 
effectiveness data will be analyzed as observed data. 
Last Observation Carried Forward (LOCF) 
• For the LOCF, in the analysis of the secondary effectiveness variable the subjects 
who have a missing score on the Merz NLF scale at Week 6, as well as who have 
an Early Discontinuation of unscheduled assessments will have their latest 
available post-baseline assessment carried forward and imputed into the missing 
Week 6 assessment.  
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8.7 
Imputation of safety data 
Details regarding imputation rules and analyses of safety data will be provided in the 
statistical analysis plan and finalized prior to data base 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, 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 (ICF) 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 the 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 interest. The subject, however, is free to withdraw consent at any time and 
for any reason, whether expressed or not. 
Each ICF will include contact information (with phone number) the subject should use to 
communicate any medical concerns 24 hours a day. 
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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 is in accordance with the currently approved protocol and all 
applicatory regulatory requirements and guidelines. 
Investigators agree to grant 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). 
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). 
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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 eCRFs 
should be derived from source documents and must be consistent with the sources from 
which they derive. Investigators will sign and date the eCRFs 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 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 subject diary or 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. 
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 
• 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 
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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, or 
sponsor’s designee, 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. 
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. 
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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 U.S. 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 one 
(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. 
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