Evaluation of Effectiveness and Safety of Radiesse (+) to Improve the Contour of Jawline by Adding Volume to the Jawline
Phase: NA
Conditions: Improvement of Jawline Contour
Sponsor: Merz North America, Inc.

Clinical Study Protocol 
Evaluation of Effectiveness and Safety of Radiesse (+) to 
Improve the Contour of Jawline by Adding Volume to the 
Jawline 
Study protocol number: 
M900391004 
Protocol amendment date: 
20-JUL-2018 (replaces Version 3.0, 18-JUN-2018) 
Development phase: 
Device Pre-Market - Pivotal study 
Investigational product: 
Radiesse (+) Injectable Implant 
Indication: 
Deep (subdermal and/or supraperiosteal) injection to 
improve the contour of jawline by adding volume to the 
jawline  
Sponsor: 
Merz North America, Inc. 
6501 Six Forks Road 
Raleigh, NC 27615 
Telephone: (919) 582-8000 
Authors: 
Clinical Project Director: 
 
Medical Expert: 
 
Scientific Expert/Senior Medical Writer: 
 
 
Senior 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. 
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NCT03583359, redacted 
version v1.0, 02May2022

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 sponsor, 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 
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 Ever been treated with fat injections or permanent fillers (e.g., 
silicone, polymethylmethacrylate (PMMA)) in the lower face 
and/or jawline area or plans to receive such treatments during 
participation in the study. 
 Been treated with semi-permanent dermal fillers (e.g., poly L-
lactic acid) in the lower face and/or jawline area in the past 5 
years or plans to receive such treatments during participation in 
the study. 
 
 
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4.2 
Inclusion criteria ....................................................................................................40 
4.3 
Exclusion criteria ...................................................................................................41 
4.4 
 
4.5 
Screen failures ........................................................................................................44 
4.6 
Subject withdrawal criteria ....................................................................................44 
5 
Study procedures ......................................................................................................45 
5.1 
Schedule of events by visit ....................................................................................45 
5.1.1 
Schedule of events by visit for subjects randomized to the treatment 
group only ........................................................................................................45 
5.1.2 
Schedule of events by visit for the control/delayed-treatment group ..............52 
5.1.3 
Scheduled visits ...............................................................................................59 
5.1.4 
Unscheduled visits ...........................................................................................59 
5.2 
Stopping rules ........................................................................................................59 
5.2.1 
Criteria for treatment discontinuation ..............................................................59 
5.2.2 
Premature suspension or termination of study .................................................60 
5.2.3 
Study site discontinuation ................................................................................60 
5.2.4 
Discontinuation criteria for a subject ...............................................................61 
5.2.5 
Provision of care for subjects after study discontinuation ...............................61 
6 
Study device and treatment of subjects ..................................................................62 
6.1 
Description of the study device..............................................................................62 
6.2 
Usage......................................................................................................................62 
6.3 
Study treatment ......................................................................................................62 
6.3.1 
Planned treatment procedure and administration .............................................62 
6.3.1.1 
Jawline region and treatment area ............................................................64 
6.3.1.2 
Injection procedure ....................................................................................65 
6.4 
 
6.5 
Packaging of treatment supplies ............................................................................69 
6.6 
Receipt, storage, dispensing, and return/disposal ..................................................70 
6.7 
Accountability procedures .....................................................................................70 
6.8 
 
7 
Safety and adverse events ........................................................................................72 
7.1 
Definitions..............................................................................................................72 
7.1.1 
Investigational medical device .........................................................................72 
7.1.2 
Adverse event (AE)..........................................................................................72 
7.1.3 
Adverse device effect (ADE) ...........................................................................73 
7.1.4 
Serious adverse events (SAE) ..........................................................................73 
7.1.5 
Serious ADE (SADE) ......................................................................................74 
7.1.6 
Unanticipated adverse device effect (UADE) ..................................................74 
7.1.7 
Anticipated serious adverse device effect (ASADE) .......................................74 
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7.1.8 
 
7.1.9 
Device deficiency.............................................................................................75 
7.1.10 
Malfunction ......................................................................................................75 
7.2 
Reporting requirements ..........................................................................................75 
7.2.1 
Determining severity/intensity .........................................................................75 
7.2.2 
Determining causal relationship ......................................................................76 
7.2.3 
Determining outcome.......................................................................................76 
7.2.4 
Procedures for reporting specific events ..........................................................76 
7.2.4.1 
Adverse event (AE) and adverse device effect (ADE) ................................76 
7.2.4.2 
Serious adverse event (SAE) and serious adverse device effect 
(SADE) .......................................................................................................77 
7.2.4.3 
Technical device complaints ......................................................................78 
7.2.4.4 
Pregnancy ..................................................................................................79 
7.3 
Submission procedure ............................................................................................79 
7.4 
 
8 
Statistical methods ....................................................................................................80 
8.1 
Estimation of sample size ......................................................................................80 
8.2 
Randomization .......................................................................................................81 
8.3 
Populations for analysis .........................................................................................81 
8.4 
Statistical analyses .................................................................................................82 
8.4.1 
Effectiveness analyses .....................................................................................82 
8.4.1.1 
Primary effectiveness endpoint ..................................................................82 
8.4.1.2 
Secondary effectiveness endpoints .............................................................83 
8.4.1.3 
 
8.4.2 
Safety analyses and endpoints .........................................................................90 
8.5 
Special statistical / analytical issues ......................................................................90 
8.5.1 
 
8.5.2 
Interim data reporting ......................................................................................91 
8.6 
 
9 
Ethics and administrative procedures ....................................................................92 
9.1 
Ethical considerations ............................................................................................92 
9.2 
Informed consent ...................................................................................................92 
9.3 
Confidentiality of subject information ...................................................................93 
9.4 
Study monitoring ...................................................................................................93 
9.5 
Data quality assurance ...........................................................................................93 
9.5.1 
Standardization procedures ..............................................................................93 
9.5.2 
Data management.............................................................................................94 
9.5.3 
Data review and clarification procedures ........................................................94 
9.5.4 
Study auditing ..................................................................................................95 
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9.6 
Record retention .....................................................................................................95 
9.7 
Publication policy ..................................................................................................95 
9.8 
Financial disclosure ...............................................................................................96 
9.9 
Investigator compliance .........................................................................................96 
10 References ..................................................................................................................97 
11 Appendices.................................................................................................................99 
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List of Abbreviations 
Abbreviation/Term 
Definition 
ADE 
Adverse device effect 
AE 
Adverse event 
ASADE 
Anticipated serious adverse device effect 
ASAPS 
American Society for Aesthetic Plastic Surgery 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
eCRF 
Electronic case report form 
ET 
Early termination 
FDA 
Food and Drug Administration, US 
FIRS 
Functional Impairment Rating Scale 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good clinical practice 
HA 
Hyaluronic acid 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MJAS 
Merz Jawline Assessment Scale 
MNAR 
Missing not at random 
MVTF 
Missing value treated as failure 
OC 
Observed cases 
OR 
Odds ratio 
PI 
Principal investigator 
PLLA 
Poly L-lactic acid 
PMMA 
Polymethylmethacrylate 
PP 
Per protocol population 
PT 
Preferred term 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
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Abbreviation/Term 
Definition 
Tx 
Treatment 
UADE 
Unanticipated adverse device effects 
UV 
Ultraviolet 
Wk 
Week 
 
 
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1 INTRODUCTION 
1.1 Background and rationale 
As part of the natural aging process, multiple factors lead to a decreased level of volume 
or noticeable contour of the jawline, including loss of bony structures, atrophy (volume 
loss) and descent of fat [1]. Volume loss in relation to the attachment points of the skin to 
the underlying superficial muscular aponeurotic system and/ or bone results in specific 
patterns of deflation, pseudoptosis, and shadowing – all of which characterize the aging 
face. As soft tissue fullness shifts from the upper face to the lower face, the aging face 
loses its youthful heart-shaped appearance and takes on a heavy, rectangular shape [2]. A 
surgical facelift is the standard treatment used to address these signs of aging and aid in 
redefining the jawline. However, it is, by definition, an invasive procedure and thus 
deemed less safe than other non-invasive alternatives, including radiofrequency/ 
ultrasonic skin tightening or the use of dermal fillers. As the demographics of aesthetic 
patients evolve, patients are seeking increasingly less invasive procedures with visible 
results and reduced downtime [3]. 
Dermal fillers have been identified as a treatment option to straighten and reestablish 
volume and contour of the jawline; fillers also provide an opportunity to enhance the size 
of the jaw by adding volume in the front at the chin and/or on the sides of the jaw. This 
enhancement can be achieved through filling volume and contour deficits, resulting in the 
enhancement of ptotic superficial compartments, repositioning of superficial fat, and/or 
tightening the skin around the jawline [3][4]. In order to reestablish or correct the 
mandibular angle and to achieve a satisfactory filling effect, a dermal filler with high 
elasticity and viscosity provides the best volumizing capacity [2]. 
Over a decade of clinical experience, multiple published reports have documented the use 
of dermal fillers, including Radiesse, to improve the jawline [4][5][6][7][8][9][10][11]. 
The available literature supports both the effectiveness and safety of Radiesse when used 
in the jawline, from the mentum through the mandibular angle. Multiple authors report 
favorable results at 6 and 12 months following placement of the product, noting both 
physician and patient satisfaction. A low number of procedure-related adverse events, 
such as pain, erythema, edema, and bruising, were reported – most of which were mild 
and resolved quickly without intervention. Overall, the safety profile of jawline treatment 
is favorable and comparable to other established treatment indications. 
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The published literature on the effectiveness and safety of Radiesse used in the jawline 
justifies the need for Merz North America, Inc. to conduct a large, robust randomized 
clinical trial among subjects who desire improvement of jawline volume and contour 
using Radiesse (+). 
1.2 Potential benefits and risks 
The potential benefit of Radiesse (+) when used in the jawline is to improve contour by 
adding volume to the jawline. 
In a European observational study using calcium hydroxylapatite (CaHA) for the 
treatment of the jawline in a routine setting, the findings showed improvements in jawline 
contour compared with baseline, and these findings were statistically significant at each 
visit, with scores of 2.42 (moderate to severe sagging) at baseline, 1.02 (mild) at Day 30 
(p<0.0001), 1.11 at Day 180 (p<0.0001), and 1.45 at Day 360 (p<0.0015). Overall, CaHA 
was found to be very effective for restoring jawline contour in clinical practice with high 
levels of physician and subject satisfaction [12]. 
The potential risks associated with the use of Radiesse (+) for deep (subdermal and/or 
supraperiosteal) injection into the jawline are similar to other lidocaine-containing, 
commercially available, cosmetic dermal fillers. No new risks have been identified for 
use of Radiesse (+) in the jawline, including product placement in deep (subdermal 
and/or supraperiosteal) injection planes. 
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2.2.4 
Safety endpoints 
2.2.4.1 
Primary safety endpoints 
• Incidence and nature of device- and/or injection-related AEs and SAEs observed 
during the study. 
2.2.4.2 
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3.2.1.3 
Treating Investigator Global Aesthetic Improvement Scale (GAIS) 
The treating investigator will use the GAIS to assess global aesthetic improvement 
among treated subjects 
. 
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Refer to the study endpoints (see Section 2.2) and visit schedules (see Sections 5.1.1 and 
5.1.2 
) for additional information regarding the GAIS 
assessments and the associated reference time points. 
3.2.1.4 
Subject Global Aesthetic Improvement Scale (GAIS) 
Treated subjects will evaluate their overall aesthetic improvement on the subject GAIS 
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3.2.2 
 
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Subjects must be informed that, at any time over the study interval, if they experience any 
signs or symptoms of a stroke, they must call 911 immediately. If they experience any 
changes in vision associated with vascular occlusion, they must contact the site identified 
Ophthalmologist prior to contacting the site investigator. If any other new or unusual 
symptoms related to a potential vascular occlusion (e.g., tissue necrosis), 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. 
A list of symptoms related to potential vascular occlusion will be provided to all subjects 
in a separate Study Safety Information Guide and in the Informed Consent Form (ICF) 
for the subject’s reference.  
If any change to vision is reported over the study interval (e.g., during a telephone 
follow-up, scheduled or unscheduled visit), the subject may be asked to come in 
immediately for an examination or referred immediately to an ophthalmologist for further 
evaluation. 
Additional information on safety assessments and procedures is discussed in Section 7. 
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3.2.4 
Definitions 
3.2.4.1 
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. 
3.2.4.2 
Subject completion 
Subjects are considered to have completed the study if they are randomized and 
completed all visits defined in the Schedule of Events (see Section 5.1 and Appendices 
11.1 and 11.2). 
3.2.4.3 
End of study 
The end of the study is defined as when the last subject completes the last visit and the 
database is locked. 
3.2.5 
Duration of study 
Subjects are screened and enrolled at the baseline visit. For subjects randomized to the 
treatment group, treatment will occur at the baseline visit. For subjects randomized to the 
control/delayed-treatment group, treatment will occur at Week 12. The time from the 
baseline visit to the end of study is 60 weeks (± 10 days) for all subjects. 
 
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4.3 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible to participate in the study: 
 Ever been treated with fat injections or permanent fillers (e.g., silicone, poly-
methylmethacrylate (PMMA)) in the lower face and/or jawline area or plans to 
receive such treatments during participation in the study. 
 Been treated with semi-permanent dermal fillers (e.g., poly L-lactic acid (PLLA)) 
in the lower face and/or jawline area in the past 5 years or plans to receive such 
treatments during participation in 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 system for screen failures, such as date of informed consent, 
demographics, and reason for screen failure. 
Individuals who do not meet the eligibility 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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• Treating physician confirms that the subject meets all eligibility criteria prior to 
randomization. 
Randomization: 
• Randomize subject to either the treatment group or control/delayed-treatment 
group
. 
Injection (initial treatment): 
o Administer treatment injections (see Section 6.3.1 for injection instructions). 
o Review and record any AEs (since the time of signing the Informed Consent 
Form (ICF). 
o Schedule 72-hour follow-up phone call. 
Follow-up phone call (72-hours post-treatment): Day 4 (± 1 day) 
• Discuss and record any changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Discuss and record any AEs. 
• If subject reports a safety concern, arrange an unscheduled visit. 
• Ask whether the subject is experiencing any new or unusual symptoms related to 
a vascular occlusion (e.g., signs of a stroke, changes in vision, tissue necrosis) as 
noted in the Study Safety Information Guide for Subjects. 
• If the subject reports any such symptoms, they should be assessed and referred for 
immediate medical treatment as deemed necessary per best medical practices. If 
any change to vision is reported, the subject may be asked to come in immediately 
for an examination or referred immediately to an ophthalmologist for further 
evaluation. 
Visit 2 (Week 2 post-treatment): Day 14 (± 3 days) 
• Review and record changes in any concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
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• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
Visit 6 (Week 24 post-treatment): Day 168 (± 10 days) 
• Review and record changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
• 
 MJAS assessment. 
• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
Visit 7 (Week 36 post-treatment): Day 252 (± 10 days) 
• Review and record changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
• 
 MJAS assessment. 
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• Have subject complete the Subject GAIS. 
• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
Visit 8 (Week 48 post-treatment): Day 336 (± 10 days) 
• Review and record changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
•  
MJAS assessment. 
• Have subject complete the Subject GAIS. 
• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
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Visit 10 (Week 60 post-treatment)/ End of Study/Early Termination: Day 420 (± 10 days) 
• Review and record changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
• Record height and weight for BMI. 
• Perform urine pregnancy test (if female of childbearing potential). 
• 
 MJAS assessment. 
• Have subject complete the Subject GAIS. 
• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
5.1.2 
Schedule of events by visit for the control/delayed-treatment 
group 
Visit 1 – Pre-Treatment Baseline (Screening/Enrollment) 
The following procedures will be performed at baseline for subjects randomized to the 
control/delayed-treatment group: 
• Obtain written informed consent. A subject must be informed of the study 
requirements, including the risks and benefits of participation. An IEC/IRB-
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• If the subject reports any such symptoms, they should be assessed and referred for 
immediate medical treatment as deemed necessary per best medical practices. If 
any change to vision is reported, the subject may be asked to come in immediately 
for an examination or referred immediately to an ophthalmologist for further 
evaluation.  
Visit 4 - Week 14 (2 weeks post-treatment): Day 14 (± 3 days) 
• Review and record changes in any concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
Visit 5 – Week 16 (4 weeks post-treatment): Day 29 (+ 3 days) 
• Review and record changes in any concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
• 
 MJAS assessment. 
• Have subject complete the Subject GAIS.  
• Administer FACE-Q assessments to subject. 
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• Review and record any AEs. 
• Record height and weight for BMI. 
• 
 MJAS assessment. 
• Have subject complete the Subject GAIS. 
• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
Visit 8- Week 36 (24 weeks post-treatment): Day 168 (± 10 days) 
• Review and record changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
• 
 MJAS assessment. 
• Have subject complete the Subject GAIS. 
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• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
Visit 9- Week 48 (36 weeks post-treatment): Day 252 (± 10 days) 
• Review and record changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
• 
 MJAS assessment. 
• Have subject complete the Subject GAIS. 
• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
Visit 10- Week 60 (48 weeks post-treatment)/End of Study/Early Termination: Day 336 
(± 10 days) 
• Review and record changes in concomitant medications/procedures. Confirm 
subject remains compliant with any applicable study restrictions. 
• Review and record any AEs. 
• Record height and weight for BMI. 
• Perform urine pregnancy test (if female of childbearing potential). 
• 
 MJAS assessment. 
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• Have subject complete the Subject GAIS. 
• Administer FACE-Q assessments to subject. 
• Administer Treating Investigator GAIS. 
5.1.3 
Scheduled visits 
All scheduled visits and applicable study assessments must occur as noted in Section 5.1 
and the Schedule of Events table (Appendices 11.1 and 11.2). 
5.1.4 
Unscheduled visits 
To ensure subject safety, any subject who requires additional follow-up during the study 
for safety (that does not fall on a scheduled study visit) should be seen for an unscheduled 
visit and the following safety assessments completed: review of adverse events/ 
concomitant 
medications/procedures, 
if applicable. An unscheduled for a reason other 
than safety, will be done at the discretion of the investigator and documented 
appropriately. 
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 
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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 end of study assessments specified in the Schedule of Events (Section 5.1 and 
Appendices 11.1 and 11.2). 
5.2.2 
Premature suspension or termination of study 
Should the investigator, the sponsor, the Food and Drug Administration (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, a root-cause investigation will be conducted to determine the cause, the outcome 
of the event and status of subject. The investigator and Merz will conduct a thorough 
evaluation of the event. Merz will then immediately make a determination if the study 
should be suspended. 
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 
• 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: 
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• 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 loss 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 End of study/early termination visit. If a non-serious AE is 
unresolved at the time of the subject’s early termination visit, an effort will be made to 
follow-up until the AE is resolved or stabilized, the subject is lost to follow-up, or there is 
some other resolution of this event. The investigator should make every attempt to follow 
all SAEs/SADEs to resolution. Information on pregnancy and the outcome for any 
woman who becomes pregnant during the study will be collected. Additional information 
on subject withdrawal criteria is provided in Section 4.6. 
5.2.5 
Provision of care for subjects after study discontinuation 
The investigator is responsible for ensuring the adequate and safe medical care of 
subjects during the study. After completion of the study, the sponsor will follow all 
applicable local or international regulations and guidelines with regard to follow-up care 
for subjects. The investigator will ensure that appropriate consideration is given to a 
subject’s post-study care. 
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6.4 
6.5 
Packaging of treatment supplies 
Radiesse (+) kits 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. 
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6.6 
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, 
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 Radiesse (+) 
 should be discarded per the 
appropriate handling and disposal procedures at the site. Any unused/unopened product, 
 and/or outer packaging 
 should be retained so the monitor 
can perform device-accountability procedures. 
At the end of the study and after verification of study device 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 
All study-accountability procedures must be completed before the study is considered 
complete. 
6.7 
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. 
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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: 
1. The date of receipt. 
2. Identification of each investigational medical device (batch number/serial number 
or unique code). 
3. The expiry date (if applicable). 
4. The date of use. 
5. Subject identification number. 
6. Date on which the investigational medical device was returned. 
7. The date of return of unused, expired, or malfunctioning investigational medical 
devices (if applicable). 
6.8 
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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. 
• 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 events (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, 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 or product labeling. 
7.1.8 
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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 adverse event, but could have 
led to a medical occurrence if either 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 on a Device Technical Complaint Form 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 instructions for 
use or the protocol. 
All malfunctions shall be documented on a Device Technical Complaint Form 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 AE eCRF). 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. 
For all randomized subjects, the period of observation for AEs and ADEs extends from 
signing of the 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, malfunction and/or device deficiency observed during study conduct will 
be fully investigated, documented, and followed until the event is either resolved, until 
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the 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 AE eCRF. 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 
• Seriousness (yes or no) 
• Outcome 
• Action taken with investigational medical device 
• AE resulting in subject discontinuation  
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 and designee, via the designated 
safety email address or other means of contact, as defined in Section 7.3 and the site’s 
IEC/IRB per their reporting guidelines. 
Although all information required for completing an SAE report form may not be 
available within the specified time period, an initial report should be submitted and the 
following minimal information should be provided: 
• An identifiable subject number; 
• Adverse event; 
• Investigational device name; 
• Causality or relationship of investigational device; and/or 
• Investigator/investigational site name. 
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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 Week 60 would need to be reported to Merz Product Safety 
if the investigator considers the event to be related to the investigational medical device. 
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 and/or whether the 
complaint led to an AE. All AEs that occur as a result of a technical complaint 
must be reported in the AE eCRF. 
• 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 
Technical Complaint Department for processing using the following email address: 
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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. Pregnancy will be reported in the 
eCRF. Subjects who become pregnant during the course of the study should not be 
retreated (i.e. touch-up, optional retreatment), but will remain in the study.  
7.3 
Submission procedure 
The investigator should complete and send any SAE forms or the 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 
7.4 
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8 STATISTICAL METHODS 
This section describes the statistical analyses foreseen at the time of study planning. 
Further details on the statistical and analytical aspects will be presented in the statistical 
analysis plan (SAP) that will be prepared and completed prior to database lock. 
Any deviations from planned analyses, the reasons for such deviation, and all alternative 
or additional statistical analyses that may be performed before database close will be 
described in amendments to the clinical study protocol and/or the SAP. All deviations 
and/or alterations will also be summarized in the clinical study report. 
8.1 
Estimation of sample size 
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endpoints will be summarized using the ITT population. Additional information related to 
the usage of the analysis populations as it relates to the statistical analyses of study results 
will be described in the SAP. 
8.4 
Statistical analyses 
Effectiveness and safety endpoints are provided in Sections 2.2.1 to 2.2.4. 
The sponsor will finalize the SAP prior to database lock. Deviations from the analyses 
outlined in this protocol will be documented in the SAP within a section discussing 
changes to the planned analyses. 
8.4.1 
Effectiveness analyses 
8.4.1.1 
Primary effectiveness endpoint 
The primary effectiveness endpoint is the proportion of responders with ≥ 1-grade 
improvement of both jawlines on the MJAS from baseline to Week 12.  
Two hypothesis tests will be performed for the primary endpoint, in a sequential order.  
The first hypothesis is to demonstrate at least 50% of treated subjects are responders and 
the second hypothesis is to compare the treatment group with the control group. Each 
hypothesis test is a one-sided test at a significance level of 0.025. 
Hypothesis test 1: 
H01:  Ptreatment  ≤  50%      
H11:  Ptreatment  >  50% 
Hypothesis test 2: 
H02:  Ptreatment  ≤  Pcontrol     H12:  Ptreatment  >  Pcontrol 
For hypothesis testing of at least 50% of treated subjects are responders (H01 versus H11), 
the binomial test will be utilized and for testing the statistical superiority of treatment 
over control (H02 versus H12), the Fisher’s exact test will be used. 
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8.5.2 
Interim data reporting 
Data listings pertaining to annual reporting updates to the FDA will be produced as 
necessary. The annual reports will contain enrollment updates (i.e., number of subjects 
recruited at each site, number screened and enrolled, number randomized, etc.), subject 
disposition, and safety listings. 
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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 into the relevant local language will be provided. The original and any 
amended signed and dated ICF must be retained at the study site; and a copy must be 
given to the subject or subject’s legally authorized representative(s). 
It is not anticipated that members of a vulnerable population will participate in this study. 
If the ICF is amended during the study, the investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IEC/IRB and 
use of the amended form (including for ongoing subjects). 
During the course of the study, the subject will be informed in a timely manner if 
information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study. In case of AEs, the subject should inform the 
investigator, who then will make a judgment whether continuing in the study serves the 
subject’s best interests. The subject, however, is free to withdraw consent at any time and 
for any reason, whether expressed or not. 
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Each ICF will include contact information (with a phone number) the subject should use 
to communicate any medical concerns 24 hours a day. Each ICF will also include the 
contact information for an ophthalmologist and an oral surgeon, who are identified by the 
Investigator, for instances in which a subject requires evaluation by an ophthalmologist 
(e.g., subjects experiences sudden visual changes following treatment injections) and/or 
referral to an oral surgeon. 
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, 
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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). 
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 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 
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• Copies of investigational device disposition records 
Study documents may not be destroyed by study site personnel prior to the end of the 
required retention period as specified by local regulations. The PI or the institution must 
inform the sponsor in due time if the PI leaves the institution during the retention period. 
This rule also applies when the institution closes within the retention period. 
9.5.4 
Study auditing  
To ensure compliance with applicable standards and regulations, the sponsor, IEC/IRB, 
or regulatory authorities may conduct a quality assurance assessment or audit of site 
records at any time during or after completion of the study. In the event of an audit, 
investigators must grant access to all relevant documents (including source documents, 
electronic records, and other applicable study documentation) and provide support at all 
times for auditing activities. 
9.6 
Record retention 
Upon closure of the study, the investigator must maintain all study site records in a safe 
and secure location. The investigator is responsible for the integrity, retention, and 
security of all study-related records. The investigator must ensure that any reproductions 
of the original records are legible and provide a true and accurate copy of the original. 
Accurate, complete, and current records must be stored in such a way as to permit easy 
and timely retrieval for the sponsor or any applicable regulatory authorities. 
The sponsor will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements, with the minimum retention time 
being the longest of those times dictated by institutional requirements, local laws or 
regulations, or the sponsor’s standard procedures. The investigator must notify the 
sponsor in the event of any changes to archival arrangements due to withdrawal of the 
investigator’s responsibility for keeping study records to ensure that suitable 
arrangements for the retention of study records are made. 
9.7 
Publication policy 
The study protocol, study data, and information related the study or the sponsor’s 
products or research programs are to be kept confidential and may not be disclosed 
without the consent of the sponsor. The investigators have the responsibility to provide 
complete study data, records, and reports for inspection by the appropriate regulatory 
authorities, the sponsor, or the IEC/IRB, as appropriate. 
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The investigator agrees that the results of this study may be used for submission to 
national or international registration and supervising authorities. The sponsor may 
disclose the information obtained during the study to regulatory authorities or other 
personnel as required. If necessary, the sponsor may disclose the names, contact 
information, and qualifications of all investigators as well as their roles in the study. 
Upon completion of the study, publication or disclosure of the study results is to follow 
the terms contained in the sponsor’s publication policy. 
9.8 
Financial disclosure 
The US FDA Financial Disclosure by Clinical Investigators (21 CFR 54) regulations 
require sponsors to obtain certain financial information from investigators participating in 
covered clinical studies. By participating in the study, the investigator agrees to provide 
the required financial information and to promptly update the sponsor with any relevant 
changes to this financial information throughout the course of the study and for up to 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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10 REFERENCES 
 
[1] 
Loghem JV, Yutskovskaya YA, Werschler P. Calcium Hydroxylapatite – Over a 
Decade of Clinical Experience. J Clin Aesthetic Derm. 2016;8(1):38-49. 
[2] 
Lorenc ZP, Lee JC. Composite Volumization of the Aging Face: Supra-Periosteal 
Space as the Foundation for Optimal Facial Rejuvenation. J Drugs Dermatol. 
2016;15(9):1136-44. 
[3] 
Pavicic T, Few JW, Huber-Vorlander J. A Novel, Multistep, Combination Facial 
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IncobotulinumtoxinA, and Two Dermal Fillers – Calcium Hydroxylapatite and a 
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[4] 
Dallara JM, et al. Calcium hydroxylapatite for jawline rejuvenation: consensus 
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[5] 
Sclafani AP, Kwak E. Alternative management of the aging jawline and neck. 
Facial Plast Surg. 2005;21(1):47-54. 
[6] 
Graivier MH, et al. Calcium hydroxylapatite (Radiesse) for correction of the mid- 
and lower face: consensus recommendations. Plast Reconstr Surg. 2007;120(6 
Suppl):55S-66S. 
[7] 
Dayan SH, Lieberman BS, Larimer K. High Volume Calcium Hydroxylapatite 
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147. 
[8] 
Hamilton DG. Calcium Hydroxylapatite for Augmentation of the Posterior 
Mandibular Angle in Men. Cosmetic Derm. 2009;22(9):474-78. 
[9] 
Bartus CL, et al. The tower technique: a novel technique for the injection of 
hyaluronic acid fillers. J Drugs Dermatol. 2011;10(11):1277-80. 
[10] Braz A, Humphrey S, Weinkle S, et al. Lower Face: Clinical Anatomy and 
Regional Approaches with Injectable Fillers. Plast Reconstr Surg. 2015;136(5 
Suppl):235S-257S. 
[11] Buckingham ED, et al. Volume rejuvenation of the facial upper third. Facial Plast 
Surg. 2015;31(1):43-54. 
[12] Baspeyras M, Dallara JM, Cartier H, et al. Restoring Jawline Contour with Calcium 
Hydroxylaptite: A Prospective, Observational Study. J Cosmet Dermatol. 
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[13] The American Society for Aesthetic Plastic Surgery. 2016 Cosmetic Surgery 
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[14] Sudheesh KM, Desai R, Bharani KSN, Katta N. Assessment of Mandibular 
Function using Mandibular Function Impairment Questionnaire after Closed 
Treatment of Unilateral Mandibular Condyle Fracture. International Journal of 
Oral Health and Medical Research. 2016; 3(1): 28-30. 
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[15] Stegenga B, Bont L, Leeuw R, et al. Assessment of Mandibular Function 
Impairment Associated with Temporomandibular Joint Osteoarthrosis and Internal 
Derangement. Journal of Orofacial Pain. 1993; 7:183-195. 
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11 APPENDICES 
 
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