Prospective, Multicenter, Controlled, Evaluator-blind, Randomized Study to Investigate the Effectiveness and Safety of Diluted RADIESSE® for Treatment of Décolleté Wrinkles
Phase: NA
Conditions: Décolleté Wrinkles
Sponsor: Merz North America, Inc.



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r ef err e d t o a n o p ht hal m olo gist f or e valuatio n. 
 
  
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Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
M930521003 
Version 5.0, 10-MAR-2022 
CONFIDENTIAL AND PROPRIETARY 
Page i of ii 
2  SYNOPSIS 
Title of Study 
Prospective, multicenter, controlled, evaluator-blind, randomized study to 
investigate the effectiveness and safety of diluted RADIESSE® for 
treatment of décolleté wrinkles. 
Study Identifier 
M930521003 
Investigators, 
Study Sites 
This study will be conducted at up to ten study sites in the United States. 
Investigational 
Medical Device 
RADIESSE® 
Objectives 
Effectiveness 
• 
Confirm the effectiveness of treatment with diluted Radiesse for 
correction of moderate to severe décolleté wrinkles by demonstrating 
superiority versus untreated-control. 
Safety 
• 
Demonstrate the safety of repeat treatment with diluted Radiesse for 
correction of décolleté wrinkles. 
Effectiveness 
Evaluation 
Primary endpoint 
• 
Proportion of responders at Week 24 on Merz Aesthetic Scale (MAS) 
Décolleté Wrinkles-At Rest as assessed live by a blinded evaluator, 
where response is defined as at least 1-point improvement from 
baseline. 
Secondary endpoint 
• 
Proportion of responders at Week 24 on MAS Décolleté 
Wrinkles-Dynamic as assessed live by a blinded evaluator, where 
response is defined as at least 1-point improvement from baseline. 
• 
Proportion of subjects with any improvement, defined as a rating of + 
1, + 2 or + 3 on Subject Global Aesthetic Improvement Scale (GAIS) 
at Week 24. 
• 
Proportion of subjects with any improvement, defined as a rating of 
+ 1, + 2 or + 3 on Investigator GAIS at Week 24. 
Safety Evaluation 
Secondary endpoint 
• 
Incidence of treatment-emergent adverse events (TEAEs) related to 
treatment with diluted Radiesse, as reported by the treating investigator 
throughout the study. 
Study Design 
Overview, and 
Methodology 
This is a prospective, multicenter, randomized, evaluator-blinded, 
parallel-group study designed to evaluate the effectiveness and safety of 
diluted Radiesse in healthy adult females desiring correction of moderate to 
severe décolleté wrinkles. 
All eligible subjects will be randomized at a 3:1 ratio to treatment with 
diluted Radiesse (Group A) or to untreated control followed by delayed 
treatment with diluted Radiesse (Group B). 

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T A B L E O F C O N T E N T S  
1  
TI T L E P A G E  ...................................................................................................... 1 
2  
S Y N O P SI S  ............................................................................................................ i 
3  
T A B L E O F C O N T E N T S ..................................................................................... 6 
4  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ..................... 1 0  
5  
E T HI C S ............................................................................................................. 1 3  
5. 1  
Et hic al C o n d uct of t he St u d y  ............................................................................ 1 3  
5. 2  
I nf or me d C o ns e nt ............................................................................................ 1 3  
5. 3  
S u bje ct Pri va c y  ................................................................................................ 1 4  
5. 4  
C o nfi de ntia lit y of S u bje ct I nf or mati o n  .............................................................. 1 4  
6  
I N T R O D U C TI O N ............................................................................................. 1 6  
6. 1  
Ba c k gr o u n d  ..................................................................................................... 1 6  
6. 2  
St u d y Ratio na l e ................................................................................................ 1 7  
6. 3  
P ote ntial Be nefits a n d Ris ks  ............................................................................. 1 7  
7  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  ...................................................... 2 0  
7. 1  
O bje cti ves ........................................................................................................ 2 0  
7. 2  
E n d p oi nts  ........................................................................................................ 2 0  
7. 2. 1  
Effe ctive ness E n d p oints .............................................................................. 2 0  
7. 2. 1. 1  
Pri mar y Eff e ctive ness En d p oi nt ............................................................ 2 0  
7. 2. 1. 2  
S e c o n d ary Effe ctiv e n ess E n d p oi nt ........................................................ 2 0  
7. 2. 2  
Safet y E n d p oi nts  ........................................................................................ 2 4  
7. 2. 2. 1  
S e c o n d ary S af ety E n d p oints  ................................................................. 2 4  
8  
C LI NI C A L I N V E S TI G A TI O N P L A N .............................................................. 2 6  
8. 1  
O ver vie w of St u d y D esi g n ................................................................................ 2 6  
8. 2  
Dis c uss io n of St u d y D esi g n, I nc lu di n g t he C h oic e of C o ntr ol Gr o u ps  ................ 2 7  
9  
S T U D Y P O P U L A TI O N
............................................ 2 8  
9. 1  
N u m ber of S u bje cts a n d Sites  ........................................................................... 2 8  
9. 2  
Sele ctio n of S u bje ct P o p ulati o n  ........................................................................ 2 8  
9. 2. 1  
I nc l us io n Cr ite r ia........................................................................................ 2 8  
9. 2. 2  
E xc l us io n Cr ite r ia  ...................................................................................... 2 9  
9. 2. 4  
S u bje ct E nr oll me nt a n d Ra n d o mizati o n ....................................................... 3 2  
9. 2. 5  
Scre e n Failures ........................................................................................... 3 3  
9. 2. 6  
Re m o va l of S u bje cts fr o m T hera p y or Ass ess me nt  ...................................... 3 3  
9. 2. 6. 1  
Tr e at me nt Dis c o nti n u ati o n  ................................................................... 3 3  
9. 2. 6. 2  
S u bje ct Wit h dra w al or Dis c o nti n u ati o n  ................................................ 3 3  
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Pr o visi o n of C are f or S u bj ects after Stu d y Dis c o nti n u ati o n  ................... 3 4  
9. 2. 7  
S us pe ns i o n or Pre mat ure Ter mi natio n of a St u d y Site  .................................. 3 4  
9. 2. 8  
S us pe ns i o n or Pre mat ure Ter mi natio n of t he St u d y ...................................... 3 5  
9. 2. 9  
E n d of St u d y  .............................................................................................. 3 6  
1 0  S T U D Y D E VI C E A N D T R E A T M E N T O F S U B J E C T S ................................... 3 7  
1 0. 1  
D es criptio n of St u d y D e vic e  ............................................................................. 3 7  
1 0. 2  
I nstr uctio ns f or Us e a n d A d mi nistrati o n ............................................................ 3 7  
1 0. 3  
Met h o ds of Assi g ni n g S u bje cts t o Tre at me nt Gr o u ps  ........................................ 3 7  
1 0. 4  
Bli n di n g Pr oc e d ures  ......................................................................................... 3 8  
1 0. 5  
St u d y Tre at me nt ............................................................................................... 3 8  
1 0. 5. 1  
Pla n ne d Tre at me nt Re gi me n  ....................................................................... 3 8  
1 0. 5. 1. 1  
D é c olleté Tr e at me nt Re g i o n  ................................................................. 3 8  
1 0. 5. 1. 2  
I nstr ucti o ns f or Pre p ar ati o n ................................................................. 3 9  
1 0. 5. 1. 3  
Tr e at me nt Ar e a .................................................................................... 4 1  
1 0. 5. 1. 4  
Tr e at me nt A d mi nistr ati o n Pr oc e d ure  .................................................... 4 2  
1 0. 5. 1. 5  
M a xi mu m I nj e cti o n Vol u me .................................................................. 4 2  
1 0. 5. 2  
Sele ctio n a n d Ti mi n g of Tre at me nt f or Ea c h S u bje ct  ................................... 4 3  
1 0. 6  
Prior a n d C o nc o mita nt T hera p y  ........................................................................ 4 3  
1 0. 7  
St u d y S u p plies a n d P a c ka gi n g of Tre at me nt S u p plies  ........................................ 4 3  
1 0. 8  
Re c eipt, St ora ge , D is pe ns i n g, a n d Ret ur n .......................................................... 4 4  
1 0. 9  
D e vic e A c c o u nta bilit y Pr oc e d ures  .................................................................... 4 5  
1 0. 1 0  Tre at me nt C o m plia nc e  ..................................................................................... 4 6  
1 0. 1 1  D urati o n of St u d y ............................................................................................. 4 6  
1 1  S T U D Y P R O C E D U R E S .................................................................................... 4 7  
1 1. 2  
St u d y Ass ess me nts a n d D efi niti o ns ................................................................... 4 8  
1 1. 2. 1  
Effe ctive ness Ass ess me nts .......................................................................... 4 8  
1 2  S A F E T Y D E FI NI TI O N S A N D R E P O R TI N G R E Q UI R E M E N T S  .................. 6 0  
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D efiniti o n of a n A d vers e E ve nt ( A E)  ................................................................ 6 0  
1 2. 1. 1  
D etails of a n A E  ......................................................................................... 6 0  
1 2. 1. 2  
Re p ortin g a n d H a n dlin g of a n A E  ............................................................... 6 0  
1 2. 1. 3  
Se verit y Gra din g f or a n A E  ........................................................................ 6 1  
1 2. 1. 4  
Ca us al Relati o ns hip of a n A E wit h a n I n vesti gatio nal Me dic al D e vic e  ......... 6 1  
1 2. 1. 5  
O utc o me Cate g ories f or a n A E  ................................................................... 6 2  
1 2. 2  
D efiniti o n of a Seri o us A d vers e E ve nt ( S A E) .................................................... 6 2  
1 2. 2. 1  
D etails of a n S A E ....................................................................................... 6 2  
1 2. 2. 2  
Re p ortin g a n d H a n dlin g of a n S A E  ............................................................. 6 3  
1 2. 3  
D efiniti o n of a n A d vers e D e vic e Effe ct ( A D E)  ................................................. 6 4  
1 2. 4  
D efiniti o n of a Seri o us A d vers e D e vic e Effe ct ( S A D E)  ..................................... 6 4  
1 2. 4. 1  
D efiniti o n of a n A ntici pate d Seri o us A d vers e D e vic e Effe ct ( A S A D E)  ........ 6 4  
1 2. 4. 2  
D efiniti o n of a n U na ntici pate d A d vers e D e vic e Effe ct ( U A D E)  ................... 6 4  
1 2. 5  
D efiniti o n of D e vic e D eficie nc y  ....................................................................... 6 5  
1 2. 6  
D e fin it i o n of Te c h n ic a l C o m p la i nt .................................................................... 6 5  
1 2. 6. 1  
Re p ortin g  a n d H a n dlin g  of D e vic e D eficie ncies  a n d Te c h nic al 
C o m p la ints ................................................................................................. 6 5  
1 2. 7  
Vis ua l D ist ur ba nc es a n d Ot her E ve nts of I nterest  .............................................. 6 6  
1 2. 9  
Re p ortin g of Pre g na nc y  .................................................................................... 6 7  
1 3  S T A TI S TI C A L M E T H O D S  .............................................................................. 6 8  
1 3. 1  
Esti matio n of Sa  m ple Size ................................................................................ 6 8  
1 3. 2  
Ra n d o mizatio n ................................................................................................. 7 0  
1 3. 3  
P o p ulati o ns f or A na lys is ................................................................................... 7 0  
1 3. 4  
A nal ys is of St u d y D ata ..................................................................................... 7 0  
1 3. 4. 1  
Effe ctive ness A nalys es  ............................................................................... 7 1  
1 3. 4. 1. 1  
Pri mar y Eff e ctive ness En d p oi nt ............................................................ 7 1  
1 3. 4. 1. 2  
S e c o n d ary Effe ctiv e n ess E n d p oi nt ........................................................ 7 3  
1 3. 4. 2  
Safet y A nal ys es .......................................................................................... 7 5  
1 3. 4. 2. 1  
S e c o n d ary S af ety E n d p oints  ................................................................. 7 5  
1 3 . 4. 3 
Ot her S u bje ct D ata  ..................................................................................... 7 7  
1 3. 5  
S pe c ia l Sta t ist ic a l/ A na l yt ic a l Iss ue s  ................................................................. 7 7  
1 3. 5. 1  
S u bje ct D is c o nti n uatio n a n d Miss i n g D ata  .................................................. 7 7  
1 3. 5. 2  
E xa mi natio n of S u b gr o u ps .......................................................................... 7 8  
1 3. 5. 3  
P o olin g of Sites  .......................................................................................... 7 9  
1 4  A D MI NI S T R A TI V E P R O C E D U R E S ............................................................... 8 0  
1 4. 1  
St u d y M o nit ori n g  ............................................................................................. 8 0  
1 4. 2  
D ata Q u alit y Ass ura nc e  .................................................................................... 8 0  
1 4. 2. 1  
Sta n dar dizati o n Pr oc e d ures ......................................................................... 8 1  
1 4. 2. 2  
D ata Ma na ge me nt  ...................................................................................... 8 1  
1 4. 2. 3  
D ata Re vie w a n d Clarific atio n Pr oc e d ures ................................................... 8 1  
1 4. 2. 4  
A u diti n g ..................................................................................................... 8 2  
1 4. 3  
Re c or d Rete nti o n  ............................................................................................. 8 3  
1 4. 4  
P u blic ati o n P olic y  ............................................................................................ 8 4  
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Pa g e 9 of 1 0 7  
1 4. 5  
F ina nc ia l D is c l os ure ......................................................................................... 8 4  
1 4. 6  
I n vestigat or C o m plia nc e................................................................................... 8 4  
1 5  R E F E R E N C E LI S T ........................................................................................... 8 6  
1 6  A P P E N DI C E S  ................................................................................................... 9 0  
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C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 1 1  of 1 0 7  
I E C 
I n de pe n de nt et hics c o m mitte e 
I F U 
I nstr uctio ns  f or us e 
i G AI S 
I n vestigat or  Glo bal  A est hetic I m pr o ve me nt Sc ale  
I M D 
I n vestigatio nal  me dic al de vic e 
I R B 
I nstit utio nal  Re vie w B oar d 
I T T 
I nte nt-t o-tre at 
I T T-O C  
I T T o bs er ve d c as es  
M A S  
Merz A est hetic Sc ale  
Me d D R A  
Me dic al Dictio nar y f or Re g ulat or y A ctivities  
MI  
M ultiple  I m p utatio n  ( S A S  Pr oc e d ure)  
N S AI D  
N o n -ster oidal a nti-infla m mat or y  dr u g 
P HI  
Pr ote cte d he alt h inf or matio n 
P P S  
P er pr ot oc ol  s et  
P T  
Preferre d ter m  
S A D E  
Serio us  a d vers e de vic e  effe ct  
S A E  
Serio us  a d vers e e ve nt  
S A P  
Sta tistic a l a na lysis  pla n  
S A R S -C o V - 2 
Se vere  a c ute  res pirat or y s y n dr o me  c or o na vir us 2  
S A S  
Sta tistic a l A na lysis  S yste m  
S E S  
Safet y e valuatio n  s et 
s G AI S 
S u bje ct Glo bal A est hetic I m pr o ve me nt Sc ale  
S O C  
S yste m or ga n class  
S O P  
Sta n dar d o peratin g pr oc e d ure  
T E A E  
Tre at me nt -e mer ge nt a d vers e e ve nt 
T E S A E  
Tre at me nt -e mer ge nt s erio us a d vers e e ve nt  
T x  
Tre at me nt  
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Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
M930521003 
Version 5.0, 10-MAR-2022 
CONFIDENTIAL AND PROPRIETARY 
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UADE 
Unanticipated adverse device effect 
UDI 
Unique device identifier 
US 
United States 
UV 
Ultraviolet 
 
 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
M930521003 
Version 5.0, 10-MAR-2022 
CONFIDENTIAL AND PROPRIETARY 
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5 ETHICS 
5.1 
Ethical Conduct of the Study 
This study will be performed in accordance with the principles outlined in the Declaration 
of Helsinki and in compliance with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use’s Good Clinical Practice 
(ICH-GCP), EN ISO 14155, the Code of Federal Regulations (CFR), 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 
Independent Ethics Committee (IEC), Institutional Review Board (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. 
In the event of a pandemic disease outbreak (e.g., new COVID-19 public health 
emergency) procedures that prioritize the reporting of protocol deviations that could impact 
subject safety will be defined and communicated to the appropriate IEC/IRB. In addition, 
changes in protocol conduct necessary to promptly ensure subject safety, such as 
conducting telephone or virtual visits for safety monitoring rather than on-site visits, can 
be implemented immediately with subsequent communication and review by the 
appropriate IEC/IRB and notification to regulatory authorities. 
5.2 
Informed Consent 
Verbal and written informed consent must be obtained from every subject 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, local-language translation of the informed consent form (ICF) 
will be provided. 
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. Ongoing subjects will be required to re-confirm consent by 
signing the amended form. 
The original and any amended signed and dated ICF(s) must be retained at the study site, 
and a copy of the signed and dated ICF(s) must be given to the subject. 
During the study, the subject will be informed if information becomes available that may 
be relevant to the subject’s willingness to continue participation in the study. Each ICF will 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
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Version 5.0, 10-MAR-2022 
CONFIDENTIAL AND PROPRIETARY 
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include contact information (with a phone number) the subject should use to communicate 
any medical concerns 24 hours a day. The subject, however, is free to withdraw consent at 
any time and for any reason, whether expressed or not. 
In the event of a pandemic disease outbreak (e.g., new COVID-19 public health 
emergency), if re-confirming subjects’ consent is deemed necessary due to significant 
changes made to the protocol and/or monitoring plan that could impact subjects, then: 
• Alternative ways of obtaining consent will be defined as subjects should not visit sites 
for the sole purpose of re-confirming consent. For example, subjects will be contacted 
via phone or video calls and verbal consent will be obtained, supplemented with written 
confirmation (e.g., via e-mail). 
• IEC/IRB approved updated subject information sheets and ICFs will be provided to 
subjects by e-mail, mail or courier when re-confirming consent. 
• All instances of re-confirming consent that are obtained through alternative ways will 
be documented. 
The subjects’ consent will be re-confirmed through regular consent procedures at the 
earliest opportunity once/if the subjects are able to return to the sites, if applicable. 
5.3 
Subject Privacy 
The subject will be informed of procedures to protect subject privacy. Under U.S. federal 
law (the Privacy Rule) any protected health information (PHI) that is created or obtained 
during this study cannot be used or disclosed without permission. The currently designated 
statistical CRO processes subject data in accordance with the data-protection provisions 
set forth in the German Federal Data Protection Act (Bundesdatenschutzgesetz), 
specifically in the version applicable as of 25-MAY-2018, and in the European-focused 
General Data Protection Regulation law (GDPR). Informed consent on data processing will 
be obtained in writing directly from the subject before recording of any data. Authorization 
to use and disclose PHI will be obtained in writing directly from the subject before 
recording of any data. Recorded data will be pseudonymized before transferring to 
authorized individuals. The investigator will maintain source documents that link unique 
subject numbers with subject names (e.g., in case of emergencies). 
At the conclusion of the study, subject photographs will be stored and archived 
electronically by the sponsor and the study site. Photographs allowing identification of the 
subject will be published only if the subject has given written permission. 
5.4 
Confidentiality of Subject Information 
Subject pseudo-anonymity is to be maintained during the study. Subjects will be identified 
by a unique subject number on all study documentation. Health information that could 
identify the subject (i.e., PHI) must be maintained in strict confidence by the investigator 
to the extent permitted by applicable laws and regulations. Subjects must sign an 

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authorization to allow PHI to be disclosed to the sponsor and anyone working on behalf of 
the sponsor, the IRB/IEC, or regulatory authorities. 
Confidentiality will also be maintained for any medical information obtained from the 
subject during study participation. At a subject’s request, the subject’s medical information 
may be provided to the subject’s personal physician or other appropriate medical personnel. 
If the results of the investigation are published, the subject’s identity will remain 
confidential. 

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CLINICAL STUDY PROTOCOL 
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6 INTRODUCTION 
6.1 
Background 
Many factors contribute to the natural aging process during which an individual’s skin 
gradually loses its youthful appearance. Aging skin is characterized by loss of volume, 
decreased elasticity, and increased laxity. Various aesthetic techniques are used in an 
attempt to reverse or slow the aging process. As such, individuals are increasingly 
undergoing rejuvenation procedures of the face. After facial procedures, they often notice 
that the improved appearance of the face is discordant with that of the untreated aging neck 
and chest. The chest and neck are exposed to substantial ultraviolet (UV) radiation and 
both regions tend to demonstrate photoaging. Additionally, the chest skin of females is 
vulnerable to the mechanical stress of the weight and movement of breasts.[1] 
Moreover, women are more prone to aging in this area as a result of hormonal changes 
relating to menopause and estrogen deficiency. These changes result in an accelerated 
breakdown of collagen and elastin, leading to skin thinning and laxity, and worsening of 
lines and wrinkles.[1] Aging of the skin in the décolleté region manifests as atrophy, laxity, 
wrinkles, and dyspigmentation. 
Special anatomic considerations exist when treating the skin of the décolleté. The skin in 
this area is thinner than some areas of the face [2] as well as the arms and legs.[1] 
Additionally, there are over 13 times fewer hair follicles on the chest than on the lateral 
forehead.[3] This difference in pilosebaceous units contributes to slower healing and 
increased risk of scarring after aesthetic treatments of the décolleté region, particularly with 
ablative treatments.[4] Modalities used to treat signs of aging in the décolleté region 
include neurotoxins, fillers, chemical peels, intense pulsed light, non-ablative and ablative 
lasers[4] and microfocused ultrasound with visualization.[5] 
Physicians use a variety of topical cosmeceuticals, energy-based devices, and injectable 
implants (including Radiesse®) to rejuvenate the décolleté region. In most cases, the use of 
energy-based devices and injectable implants is off-label use. Injectable implants, or 
dermal fillers, are primarily classified as permanent (i.e., non-biodegradable) and non-
permanent (i.e., biodegradable) products. Permanent dermal fillers are now seldom used 
for this indication given the documented higher risk of severe and persistent adverse 
effects.[6] Non-permanent (i.e., biodegradable) dermal fillers include: hyaluronic acid 
(HA); collagen (bovine, porcine, and human); poly-L-lactic acid; calcium hydroxylapatite 
(CaHA; as in Radiesse); subject's own body fat (autologous fatty tissue); and dextran beads 
in HA.[6-8] Non-permanent dermal fillers are safer than permanent fillers and are usually 
associated with a low incidence of complications.[9] 
Radiesse in its original undiluted form is indicated for aesthetic procedures, including deep 
dermal and subdermal soft tissue augmentation of the facial area and is also intended for 
restoration and correction of facial volume loss (see the current version of the Radiesse 
Instructions for Use [IFU]). Moreover, diluted Radiesse has been proven to improve skin 
texture and skin thickness.[1] Radiesse diluted with either lidocaine 
or saline 
(Radiesse:solvent, from 1:1 up to 1:6) has been shown to induce remodeling of the 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 1 7  of 1 0 7  
e xtra c ellular matrix after  s u b der mal  inje ctio n,   res ultin g  in  s kin  tig hte nin g   a n d  incre as e d  
s kin t hic k ness.[ 1, 1 0] T hes e alteratio ns ha ve be e n hist olo g ic a ll y  ass oc iate d wit h incre as e d 
c olla ge n a n d elastin pr o d uctio n.[ 1 0,  1 1] M ore o ver,  t he tre at me nt wit h  dilute d Ra diess e  has 
s h o w n t o be s afe a n d w as o nly ass ociate d wit h min or  side -effe cts t hat  are m ostly  tra nsie nt 
a n d  e asily  ma na ge d  [ 1 2],  t h us re pres e ntin g  a n a de q uate  inje cta ble   t o a d dress dé c ollet é 
wrin kle s.  Dilutio n  a p pe ars t o allo w  a m ore h o m o ge ne o us  distrib uti o n  of t he material  t hat 
ma y help t o a v oid c o m plic atio ns  s uc h as gra n ulo ma  f or matio n .[ 1 3] 
6. 2  
St u d y R ati o n al e  
T he  c urre nt  st u d y  is  desig ne d   t o  de m o nstrate  t he  s afet y  a n d  effe ctive ness  of  dilu t e d  
Ra diess e f or t he c orre ctio n  of m o derate t o s e vere wrin kle s  in t he dé c olleté. 
C urre nt  a vaila ble  s cie ntific,  pre -c linic a l,  c linic a l,  a n d  p ost -mar ketin g  s ur veilla nc e  data  of  
Ra diess e  in  a n o n-dilute d  f or m s u p p ort a n d de m o nstrate t he effe ctive ness  a n d s afet y of t he 
pr o d uct .[ 1 4-1 7]  Hig hly
 vis c oe la stic ,  Ra diess e  is  w e ll-s uite d  f or s u pra perioste a l, 
s u b der mal,  a n d de e p-der mal pla c e me nt  a n d  c a n deliver  a c o nsidera ble  v olu miz in g  e ffe c t.  
H o w e ver, it is c o m m o n pra ctic e  a m o n g p h ysicia ns  t o us e  Ra diess e  in  a dilute d  f or m t o 
a d dress s kin wrin klin g  in  are as wit h  a br oa der  s urfa c e s uc h as ha n ds,  ne c k, a n d dé c olleté. [ 1, 
1 8]  Dilutio n  re n ders t he pr o d uct  less vis c o us  a n d t heref ore m ore s uita ble  f or reju ve nati o n 
tre at me nts of lar ger are as wit h o ut its v olu mizin g  effe ct. Dilute d  Ra diess e has be e n s h o w n 
t o
 be
 effe ctive
 a n d
 s afe
 f or
 t he
 tre at me nt
 of
 atr o p hic
 ha n ds.[ 1 8,
 1 9] 
N otic e a ble  i m pr o ve me nts  in  s kin  fir m ness   a n d a p pe ara nc e  after inje ctio n of Ra diess e 
dilute d   wit h  s mall a m o u nts  of  lid oc aine  ha ve be e n re p orte d  in t he  ar ms, a b d o me n,  a n d  
t hig hs.[ 2 0,  2 1] Sti m ulatio n   of  der mal re ge ne ratio n  has  als o  be e n  esta blis he d  in  s e veral  
c linic a l  st u die s .[ 1 0,  2 2, 2 3]  I m pr o ve me nt  in  s kin  elasticit y  a n d  plia bilit y, a n d incre as e d 
der mal t hic k ness c orrelate wit h visible  a est hetic i m pr o ve me nts  a n d s u bje ct s atisfa ctio n.  
Be c a us e of t he wides pre a d interest of p h ysicia ns  t o us e Ra diess e  off -la be l in a dilute d  f or m,  
c o ns e ns us  r e c o m me n datio ns 
w ere 
esta blis he d  in  2 0 1 8  inc lu din g fa c e,  ne c k,  a n d  
dé c olleté. [ 2 4] T he  c urre nt st u d y  will  atte m pt t o c o nfir m  t he  effe ctive ness  a n d s afet y of 
dilute d Ra diess e inje ctio n  in t he dé c olleté.  
6. 3  
P ot e nti al B e n efit s a n d R i s k s 
T he p ote ntial  be nefit ass ociate d wit h  t he us e  of Ra diess e  is t he c orre ctio n of m o derate t o 
s e vere wrin kle s  in t he  dé c olleté. Ra diess e  tre at me nt of t he  dé c olleté  c o ntrib utes  t o  a n  
i m pr o ve me nt   of  s kin  elasticit y,   t hic k ness,  de nsit y,   a n d  micr ostr uct ure  in  t he  dé c olleté . 
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 1 9  of 1 0 7  
  N o A Es w ere ide ntifie d t hat w ere u ne x pe cte d or at y pic al wit h Ra diess e  us e . N o 
e ve nts ass ociate d wit h vas c ular  oc clusio n , or  p ul m o nar y  e m b olis m  or p ne u m ot h ora x  w ere 
re p orte d. 
I n  t his c urre nt st u d y,  dilute d  Ra diess e  will  be  inje cte d  in  t he  s u b der mal  pla ne  in  t he  
dé c olleté  are a usin g  a blu nt -tip,  2 2  ga u ge,  fle xible  2″  c a n n ula. As s h o w n b y t he  la c k of 
re p orts  in  t he  pilot   st u d y,  t he  likeli h o o d   of  intra vas c ular  inje ctio ns   le a din g  t o  pr o d uc t  
e m b olizati o n  t o t he p ul m o nar y  vas c ulat ure is e xc e ptio nally  lo w  w he n dilute d  Ra diess e is  
inje cte d in t he  s u b der mal pla ne  wit h a  c a n n ula. Si milarl y,  t he likelih o o d  of pe netratin g  t he 
t h ora cic  w all a n d c a usin g a  p ne u m ot h ora x  wit h a fle xible   c a n n ula  is  mini ma l . Ris ks will 
be  f urt her mini mize d  or re d uc e d b y m o nit orin g  t he s u bje ct d urin g  t he tre at me nt pr oc e d ure  
a n d f or at le ast 3 0 min utes  p ost-tre at me nt. 
A d ditio nal  ris ks t hat ma y aris e  in t he  e ve nt of  a pa n de mic  dis e as e o ut bre a k  (e. g. , ne w 
C O VI D- 1 9 p u blic   he alt h e mer g e nc y) ma y  affe ct  clinic al  st u d y  c o n d uct.  T he  s p o ns or’ s  
pri mar y  g oal is t o e ns ure t he pr ote ctio n  of t he s afet y a n d w ell-bein g  of t he participa ti n g 
s u bje cts. P ote ntia l  c halle n ges ass ociate d wit h  a pa n de mic  dis e as e o ut bre a k ma y inclu d e: 
q uara ntines,   site  clos ures,  tra vel  li mitatio ns,   interr u ptio ns   t o  t he  s u p ply   c hain  f or  t he  
in vestigatio na l  pr o d uct, or  ot her  c o nsideratio ns  (e. g., if  site  pers o n nel  or  trial  s u bje cts  
be c o me infe cte d  wit h S A R S-C o V - 2). T hes e c halle n ges ma y le a d t o diffic ulties  in me etin g 
pr ot oc ol-s pe cifie d   pr oc e d ures  a n d  re s ult  in pr ot oc ol  m o dific atio ns .   T his  has  be e n  
a d dress e d f or t his  st u d y in S e ctio n 1 1. 1. 3 . 
C o nsiderin g  all ris ks a n d be nefits, t he p ote ntial  be nefits t o s u bje cts s e e kin g tre at me nt wit h  
dilute d Ra diess e o ut w eig h   t he  p ote ntial   ris ks.  T he  be nefit/ris k  ratio  of  t he  de vic e  is  
c o nsidere d  a c c e pta ble w he n us e d o n s u bje cts s e e kin g  i m pr o ve me nt  in t he a p pe ara nc e of 
dé c olleté wrin kles.  
A d ditio nal  inf or mat io n  o n de vic e- a n d pr oc e d ure -relate d c o ntrain dic atio ns ,  w ar nin gs, a n d  
pre c a utio ns   c a n  be  f o u n d  in  t he  c urre nt  versio n  of  t he c o m mercially  a p pr o ve d  
Ra diess e  I F U. 
 
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7 STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Objectives 
Effectiveness 
• Confirm the effectiveness of treatment with diluted Radiesse for correction of moderate 
to severe décolleté wrinkles by demonstrating superiority versus untreated-control. 
Safety 
• Demonstrate the safety of repeat treatment with diluted Radiesse for correction of 
décolleté wrinkles. 
7.2 
Endpoints 
7.2.1 
Effectiveness Endpoints 
All endpoints will be assessed separately for the diluted Radiesse treatment group and the 
untreated-control/delayed-treatment with diluted Radiesse group, if not otherwise specified 
in Section 13. An overview of effectiveness endpoints is provided in Table 1. 
7.2.1.1 
Primary Effectiveness Endpoint 
• Proportion of responders at Week 24 on Merz Aesthetic Scale (MAS) Décolleté 
Wrinkles-At Rest, as assessed live by a blinded evaluator, where response is defined as 
at least 1-point improvement from baseline. 
7.2.1.2 
Secondary Effectiveness Endpoint 
• Proportion of responders at Week 24 on MAS Décolleté Wrinkles-Dynamic, as 
assessed live by a blinded evaluator, where response is defined as at least 1-point 
improvement from baseline. 
• Proportion of subjects with any improvement, defined as a rating of + 1, + 2 or + 3 on 
Subject Global Aesthetic Improvement Scale (GAIS) at Week 24. 
• Proportion of subjects with any improvement, defined as a rating of + 1, + 2 or + 3 on 
Investigator GAIS at Week 24. 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 2 2  of 1 0 7  
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 2 4  of 1 0 7  
7. 2. 2  
S af et y E n d p oi nt s  
7. 2. 2. 1  
S e c o n d ar y S af et y E n d p oi nt s  
•  I ncide nc e  of  T E A Es relate d t o tre at me nt wit h  dilute d  Ra diess e, as  re p orte d  b y  t he  
tre atin g  in vestigat or  t hr o u g h o ut  t he st u d y. 
7. 2. 2. 2  
 
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 2 9  of 1 0 7  
9. 2. 2  
E x c l u si o n Crit eri a 
S u bje cts  me etin g  a n y of t he f ollo win g  criteria  are n ot eligible  t o participate  in t he st u d y:  
5.  A n y pre vi o us  s ur ger y, inclu din g  plastic  s ur ger y or per ma ne nt s ur gic al i m pla nt  in t he  
tre at me nt are a. 
7.  Pre vio us tre at me nt wit h c olla ge n fillers,  Ca H A (e. g. , Ra diess e), a n d/ or lo n g -la stin g  H A  
fillers  (e. g., Beloter o®  I nte ns e/ V olu me,  J u vé der m®  V olift/ V olbe lla )   in t he  dé c olle t é  
wit hin  t he past 2 4 m o nt hs.  
9.  Pre vio us
 tre at me nt
 wit h
 b ot ulin u m
  t o xin,
  a blative
 or
 fra ctio nal
 las er,
 
micr o der ma brasio n,   micr o ne e dlin g,   c he mic al  pe els,  a n d/ or  n o n -in vasive
 s ki n 
                                                             
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 0  of 1 0 7  
tig hte nin g  (e. g., ultras o u n d,   ra diofre q ue nc y,  inte n s e  p uls e d  lig ht   tre at me nt)  in  t he  
dé c olleté  wit hin  t he past 6 m o nt hs.  
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 1  of 1 0 7  
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 2  of 1 0 7  
9. 2. 4  
S u bj e c t E nr oll m e nt a n d R a n d o mi z ati o n 
S u bje cts are c o nsidere d t o be e nr olle d  w he n t he y pr o vide inf or me d  c o ns e nt  (i. e., sig n  t he  
I C F) a nd me et all eligibilit y  criteria. Eligible  s u bje cts will  be ra n d o mize d  at t he s cre e nin g 
visit.  
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Screen failures are defined in Section 9.2.5. 
9.2.5 
Screen Failures 
Subjects who provide informed consent but who do not meet eligibility criteria or who 
withdraw consent prior to being randomized 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. 
9.2.6 
Removal of Subjects from Therapy or Assessment 
9.2.6.1 
Treatment Discontinuation 
If study treatment is discontinued at any time during the study, the investigator will record 
the reason for treatment discontinuation in the study records. Potential reasons for 
discontinuation of treatment may include refusal by the subject to receive additional 
treatments or physician’s decision. The investigator may request that a subject 
discontinuing treatment continue to participate in the study and complete all remaining 
visits and assessments for safety follow-up. For subjects who decline to continue study 
participation after treatment discontinuation, additional information regarding subject 
withdrawal is provided in Section 9.2.6.2. 
9.2.6.2 
Subject Withdrawal or Discontinuation 
Each subject will be followed to the end of the study, or until the sponsor decides to 
terminate the study, whichever comes first. The only reasons a subject will not be followed 
for all scheduled visits include withdrawal of consent, continuous non-compliance with 
protocol requirements, or loss to follow-up (e.g., moving away from study site; 
unresponsive to attempts to contact the subject). Additionally, the investigator can 
discontinue any subject, at any time, if medically necessary. 
A subject has the right to withdraw from the study at any time at her own request without 
prejudice. In cases of withdrawn consent, data collected until the date consent was 
withdrawn will be analyzed as recorded. 
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. 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 4  of 1 0 7  
•  If atte m pts t o c o nta ct t he s u bje ct are n ot s uc c essf ul, t he n t he s u bje ct will  be c o nsidere d 
lost t o f ollo w-u p  a n d dis c o ntin ue d  fr o m t he st u d y.  
T he re as o n f or t he s u bje ct’s dis c o ntin uati o n s h o uld  be d oc u me nte d in t he ele ctr o nic c ase 
re p ort  f or m  (e C R F).  T he  in vestigat or   s h o uld   ma ke  e ver y  atte m pt  t o  c om plete  t he  
re c o m me n de d  f ollo w-u p   ass ess me nts  s pe cifie d  f or  t he  E n d of St u d y/ Early  Ter minati o n  
visit  s pe cifie d  in t he  Sc he d ule   of E ve nts (Se ctio n  1 1. 1  a n d 
 w hile  f ull y  
res pe ctin g t he s u bje ct’s rig hts. 
If a n o n-s erio us  A E is u nres olve d  at t he ti me of t he s u bje ct’s final  st u d y visit,  a n eff ort will 
be ma de t o f ollo w  t he s u bje ct u ntil  t he A E is res olve d or sta bilize d,  t he s u bje ct is lost t o 
f ollo w-u p,  or s o me  ot her res olutio n  of t he  e ve nt  oc c urs . T he  in vestigat or  s h o uld  ma ke  
e ver y atte m pt  t o f ollo w  all s erio us a d vers e e ve nts (S A Es ) a n d u na nticipate d  a d vers e de vic e  
effe cts ( U A D Es ) t o res olutio n.  I nf or matio n  o n pre g na nc y a n d t he o utc o me f or a n y fe male  
w h o be c o mes pre g na nt d urin g  t he st u d y will  be c olle cte d.  
9. 2. 6. 3  
Pr o vi si o n of C ar e f or S u bj e ct s aft er  St u d y Di s c o nti n u ati o n  
T he in vestigat or  is res p o nsible  f or e ns urin g  t he a de q uate a n d s afe me dic al  c are of s u bje cts  
d urin g  t he st u d y.  After e n d of t he st u d y  or after s u bje ct  dis c o ntin uatio n ,  t he s p o ns or will 
f ollo w   all   a p plic a ble   loc al  or  inter natio nal   re g ulatio ns   a n d  g uidelines  wit h   re gar d  t o  
f ollo w-u p  c are f or s u bje cts. T he in vestigat or  will  e ns ure t hat a p pr o priate  c o nsideratio n  is  
give n  t o a s u bje ct’s p ost -st u d y c are. 
9. 2. 7  
S u s p e n si o n  or Pr e m at ur e T er mi n ati o n of a St u d y Sit e  
St u d y participatio n  b y in divi d ua l  sites ma y be s us pe n de d or  pre mat urely ter minate d b y t he 
s p o ns or. Re as o ns f or t he s us pe nsio n  or pre mat ure ter minatio n  of st u d y sites inclu de,  b ut 
are n ot li mite d  t o, t he f ollo win g: 
•  I n vestigat or re q uest; 
•  Serio us or persiste nt n o nc o m plia nc e  wit h t he pr ot oc ol,  loc al re g ulatio ns,  a n d/ o r G C P; 
•  S us picio n  of fra u d;  
•  Failure  t o a c cr ue s u bje cts at a n a c c e pta ble rate; a n d/ or  
•  
Et hic a l iss ue s.  
T he  s p o ns or will  pr o vide  t he  in vestigative   site  wit h writte n n otific atio n  d oc u me ntin g  t he  
re as o n f or s us pe nsio n  or pre mat ure ter minatio n.  T he s p o ns or will  inf or m  t he res p o nsible  
re g ulat or y  a ut h orit y,  as a p pr o priate,  a n d e ns ure t he I E C/I R B is n otifie d.  If t he s us pe nsi o n 
or pre mat ure  ter minatio n  w as in t he  interest of s afet y, t he  s p o ns or will  inf or m  all ot her  
principal  in vestigat ors.  
I n  c as es  of  te m p orar y  s us pensio n  at a n in vestigative   site,  t he  s p o ns or  will  c o n d uct  a n 
a nalysis of t he re as o n(s) f or s us pe nsio n.  After c o m pletin g  t his a nalysis a n d i m ple me nti n g 
ne c ess ar y c orre ctive  a ctio ns, a  te m p orar y site  s us pe nsio n ma y be  lifte d. T he  s p o ns or will 
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inform the principal investigators, the IEC/IRB, and, where appropriate, the regulatory 
authority of the rationale, providing relevant data supporting this decision. Concurrence 
must be obtained from the IEC/IRB and, where appropriate, regulatory authorities before 
the investigative site resumes trial activities. If subjects were informed of the suspension, 
the principal investigator or authorized designee will inform them of the reasons for 
resumption. 
In cases of premature termination, the investigator will conduct site-closure activities in 
accordance with all applicable sponsor, local, and international guidelines and regulations. 
In the event of a pandemic disease outbreak, (e.g., new COVID-19 public health 
emergency), it might not be feasible for a study site to continue participation. In this 
scenario, consideration will be given to the effect of the study site closure on the safety and 
well-being of participating subjects. Additionally, the impact on and maintenance of data 
validity should be considered in the event of study site closure(s). 
9.2.8 
Suspension or Premature 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. 
Reasons for the suspension or premature termination of the study include, but are not 
limited to, the following: 
• Determination of a potential safety risk to subjects, including intravascular injection, 
necrosis, vision loss, stroke, pneumothorax, pulmonary embolism, and/or myocardial 
infarction; 
• Inadequate subject enrollment; 
• Decision by the IEC/IRB to suspend or terminate approval/favorable opinion for the 
study; and/or 
• Sponsor decision. 
If suspicion of an unacceptable risk to subjects arises during the trial or if instructed by the 
IEC/IRB or regulatory authorities, the sponsor will temporarily suspend enrollment and 
treatment at the investigative site where the risk was identified. A root cause investigation 
will be conducted to determine the cause of the event and whether the risk could have been 
anticipated (e.g., lack of compliance with planned treatment) or if the identified risk was 
unanticipated. If the risk is determined to be unanticipated, the sponsor will suspend the 
entire trial while the risk is further assessed and preventive, correcting measures are 
designed and implemented. If the analysis determines that implementing necessary 
corrective actions is sufficient, a temporary trial suspension may be lifted. If an 
unacceptable risk is confirmed, the sponsor will terminate the trial. 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 6  of 1 0 7  
I n t he e ve nt of pre mat ure st u d y s us pe nsio n or ter minatio n  f or a n y re as o n, t he s p o ns or  will 
inf or m  all  in vestigat ors  a n d  rele va nt  re g ulat or y  a ut h orities   pr o m ptly   of  t he  st u d y  
s us pe nsio n/ter minati o n   a n d  re as o n  f or  t he  a ctio n,   as  detaile d   in  Se ctio n  9. 2. 7 . 
T he  in vestigat or  will  c o n d uct  site-clos ure  a ctivities  in  a c c or da nc e  wit h  all  a p plic a ble  
s p o ns or, loc al, a n d inter natio nal  g uidelines  a n d re g ulatio ns.  
I n t he  e ve nt of a  p u blic   he alt h e mer ge nc y t he  s p o ns or will  inf or m  all in vestigat ors,  t he  
I E C/I R B, a n d t he  rele va nt re g ulat or y a ut h orities  pr o m ptly  of a n y plan ne d  mitigatio ns   t o  
pr ote ct t he s afet y a n d w ell-bein g  of s u bje cts. T his c a n inclu de  b ut is n ot li mite d  t o: p utti n g 
t he  st u d y  re cr uit me nt   o n  h old,  st o p pin g   or  p ost p o nin g   f urt her  tre at me nts  or  c ha n gi n g  
o n -site visits t o visits b y p h o ne or at a n ot her clinic al site  (e. g., if t he pri mar y site is clos e d 
d ue t o q uara ntine).  
9. 2. 9  
E n d of St u d y  
T he  e n d of t he  st u d y is define d as w he n t he  last s u bje ct c o m pletes t he  last visit  a n d t he  
data bas e  is clos e d 
 
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 7  of 1 0 7  
1 0  S T U D Y D E VI C E A N D T R E A T M E N T O F S U B J E C T S 
1 0. 1  D e s cri pti o n of St u d y  D e vi c e  
Ra diess e  inje c ta ble   i m pla nt  (U niq ue   de vic e  ide ntifier   [ U DI ]: M 2 1 3 8 0 7 1 C 0 K 1 5 ) is  a  
ste rile ,  n o n-p yr o ge nic ,  s e mi-s olid,  c o hesive  i m pla nt,  w h os e  principal  c o m p o ne nt  is   
s y nt hetic 
Ca H A 
s us pe n de d  in  a  gel  c arrier  c o nsistin g  of 
glyc erin,
 s o di u m
 
c ar b o x y met h ylc ellul os e  a n d  sterile  w ater f or  inje ction .  Ra diess e  inje cta ble  i m pla nt ( 1. 5 c c) 
has a Ca H A particle  size ra n ge of 2 5  t o 4 5 μ m . 
Ra diess e is in dic ate d  f or s u b der mal  i m pla ntatio n  f or t he c orre ctio n of m o derate t o s e vere 
fa cial wrin kles  a n d f olds, s uc h as nas ola bial  f olds, f or ha n d a u g me ntatio n  t o c orre ct v olu m e  
loss in t he d ors u m  of t he ha n ds a n d is als o inte n de d  f or rest oratio n a n d/ or c orre ctio n  of t he 
sig ns of fa cial fat loss (lip oatr o p h y)  in pe o ple wit h h u ma n i m m u n o defic ie nc y  vir us  ( HI V). 
I n  t he  c urre nt  st u d y,  t he  inte n de d   us e  of  Ra diess e  is  s u b der mal  i m pla ntati o n  f or t he 
c orre ctio n  of m o derate t o s e vere dé c olleté  wrin kles.  
1 0. 2  I n str u cti o n s  f or U s e a n d A d mi ni str ati o n 
Ra diess e  s h o uld  be us e d in t he dé c olleté  tre at me nt re gio n  a c c or din g t o t he inf or matio n  a n d 
instr uctio ns  pres e nte d in Se ctio n  1 0. 5 . A d ditio na l  inf or matio n  o n pr o d uct  us a ge is pr o vid e d 
in t he pr o d uct  la belin g  (c urre nt versio n  of t he c o m mercially  a p pr o ve d Ra diess e  I F U). 
Ra diess e  s h o uld   o nly   be  a d ministere d   b y  t he  tre atin g  i n ve stiga t ors.   All  tre a tin g   
in vestigat ors   t hat  will  participate  in  t he  st u d y  are  b oar d-c ertifie d  der mat olo gists  a n d/ or  
plastic  s ur ge o ns.  
1 0. 3  M et h o d s of As si g ni n g  S u bj e ct s t o Tr e at m e nt Gr o u p s  
S u bje cts  w h o  pr o vide  inf or me d  c o ns e nt,  c o m plete  all s cre e nin g  ass ess me nts, me et all 
eligibilit y  criteria,  a n d  are a c c e pte d f or e nr oll me nt  int o  t he st u d y  will  be assig ne d  a s u bje ct 
ide ntific a tio n n u m ber.  
Tre at me nt gr o u p assig n me nts  will  be  ma de  bas e d o n t he  st u d y  ra n d o mizatio n  s c he me. 
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 8  of 1 0 7  
Ple as e s e e Se ctio n  1 3. 2  f or  a d ditio nal  ra n d o mizatio n  details. 
1 0. 4  
 
1 0. 5  St u d y Tr e at m e nt  
All  pr ot oc ol -s pe cific  criteria f or t he a d ministratio n  of st u d y tre at me nt m ust be met a nd 
d oc u me nte d prior t o a d ministratio n  of a n y st u d y tre at me nt. All de vic e a d ministratio n  will 
be  perf or me d  o n  site  b y  t he  tre atin g   in vestigat or.   S u bje cts  will  n ot  be  dis pe ns e d  a n y  
in ve stiga tio na l  ma te ria l. 
1 0. 5. 1  
Pl a n n e d  Tr e at m e nt R e gi m e n  
1 0. 5. 1. 1  
D é c oll et é Tr e at m e nt R e gi o n  
S u bje cts  will  re c eive tre at me nt wit h dilute d  Ra diess e wit h  a c a n n ula  f or t he c orre ctio n  of 
m o derate  t o s e vere dé c olleté  wrin kles . 
 illustra te s t he dé c olleté  tre at me nt re gio n t hat c o m pris es  a p pr o xi mately  1 0 0 c m 2, 
a n d is deline ate d  s u periorly  b y t he  ster n ocla vic ular  n otc h, laterally  b y t he  midcla vic ula r  
line  a n d inferiorly  b y t he  s u perior p oint  of t he  inter ma m mar y  cleft. N o  inje ctio ns  are t o 
oc c ur in a n are a o verlyin g  or inclu din g  bre ast tiss ue. 
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 3 9  of 1 0 7  
1 0. 5. 1. 2  
 
1 0. 5. 1. 2. 1  
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C CI
C CI
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 4 0  of 1 0 7  
1 0. 5. 1. 2. 2  
 
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 4 1  of 1 0 7  
1 0. 5. 1. 3  
Tr e at m e nt   Ar e a 
After e ns urin g  t hat t he tre at me nt are a has be e n t h or o u g hly  cle a ns e d,  t he are a s h o uld  be 
s w a b be d wit h alc o h ol or ot her a ntis e ptic. S u p ple me ntar y  t o pic al or intra der mal a nest hesia  
ma y be us e d f or  a d ditio nal  pain ma na ge me nt  bef ore t he inje ctio n  at t he dis cretio n  of t he 
tre atin g in vestigat or. 
Dilute d  Ra diess e will  be a d ministere d  s u b der mally  via a 2 2 G  2-inc h  ( 5 0 m m) blu nt -t y p e d 
c a n n ula utilizi n g  t he line ar  t hre a din g a n d/or fa n nin g retr o gra de te c h niq ue  
 
C CI
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 4 2  of 1 0 7  
1 0. 5. 1. 4  
 
1 0. 5. 1. 5  
 
C CI
C CI
C CI
C CI
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 4 3  of 1 0 7  
1 0. 5. 2  
S el e cti o n  a n d Ti mi n g of Tr e at m e nt f or E a c h S u bj e ct  
F or s u bje cts ra n d o mize d  t o t he tre at me nt gr o u p  ( Gr o u p  A), tre at me nt will  oc c ur at D a y  1, 
We e k  6, a n d We e k  1 2. S u bje cts  in  Gr o u p   A  ma y  re c eive  a n  o ptio nal retre at me nt at 
We e k  3 6 t o a c hie ve o pti mal  c os metic res ults, at t he dis creti o n  of t he tre atin g  in vestiga t or 
a n d t he s u bje ct.  
F or s u bje cts ra n d o mize d  t o t he dela ye d -tre at me nt  gr o u p ( Gr o u p  B), tre at me nt will  oc c ur at 
We e ks  2 4, 3 0 a n d 3 6.  
I n t he e ve nt of a p u blic  he alt h  e mer ge nc y , f urt her tre at me nts ma y be halte d  or p ost p o ne d. 
1 0. 6  Pri or a n d C o n c o mit a nt  T h er a p y  
Pre vio us  t hera pies  re c eive d  prior  t o  e nr oll me nt   a n d  c o nc o mita nt   t hera pies ,  inclu di n g  
pre - a n d p ost-tre at me nt pain me as ures, s h o uld be  d oc u me nte d in t he  e C R F. 
Restrictio ns  re gar din g  c o nc o mita nt  t hera p y  are  dis c uss e d  in  detail  in  Se ct io ns 9. 2. 2  
( E xclusio n  Criteria) a n d 9. 2. 3  ( Restrictio ns  d urin g  t he  St u d y). 
1 0. 7  St u d y  S u p pli e s a n d P a c k a gi n g  of Tr e at m e nt S u p pli e s  
Ra diess e  will  be  pr o vide d  b y t he  s p o ns or. T he  s p o ns or  or  desig ne e  will  pa c ka ge st u d y 
materials  a c c or din g  t o  a p plic a ble  re g ulat or y  re q uire me nts.  T he  s p o ns or  will  pr o vide  all  
pertine nt  la belin g  inf or matio n  as w ell  as a des criptio n  of t he s pe cif ic  de vic e-pa c ka gi n g 
c o n ditio ns.  
Ra diess e  is t o be us e d e xclusively  f or tre at me nt of s u bje cts ra n d o mize d in t his st u d y a n d  
will  be  la be le d  a s f ollo ws:  “ C A U TI O N - I n vestigatio na l  D e vic e. Li mite d  b y Fe deral ( or 
U nite d  States) La w t o  I n vestigatio nal  Us e. ” D e vi c e la bels  will  als o n ote t he ma n ufa ct urer 
na me a n d a d dress a n d t he q ua ntit y  wit hin  t he pa c ka ge. A c o p y  of t he c urre nt versio n  of t he 
c o m mercially a p pr o ve d Ra diess e  I F U will be  pr o vide d  wit h  e a c h  I M D.  
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 4 4  of 1 0 7  
I n t he  e ve nt of  a  pa n de mic   dis e as e  o ut bre a k  (e. g. , ne w  C O VI D -1 9  p u blic   he alt h  
e mer ge nc y) ,  c o nsideratio ns   ma y  be  ma de  t o  s u p ply  st u d y  sites wit h  s ufficie nt  st u d y  
s u p plies  t o  pre ve nt s u p plyin g  disr u ptio ns  d urin g  t he o ut bre a k.  
1 0. 8  R e c ei pt, St or a g e, Di s p e n si n g, a n d R et ur n  
U p o n re c eipt, t he site pers o n nel will  verif y t he c o nte nts of all st u d y s u p plies  re c eive d a n d 
pr o m ptly  n otif y  t he a p pr o priate c o nta cts of a n y dis cre pa ncies or da ma ges. T he  in vestiga t or 
is  res p o nsible   f or  e ns urin g   t hat  a n  a c c urate  re c or d  of  in ve nt or y   is  maintaine d.   
T he  in vestigat or or desig ne e  will  ke e p a c urre nt re c or d of t he st u d y  de vic e deliver y  t o t he 
st u d y site, in ve nt or y,  a n d dis pe nsin g,  a n d t his re c or d will  be ma de a vaila ble  t o t he s p o ns or 
u p o n  re q uest. St u d y sites will  be q uerie d a b o ut  a n y dis cre pa ncies.  
All  st u d y  de vic es m ust  be st ore d in  a s e c ure, e n vir o n me ntally  c o ntr olle d,  m o nit ore d  area  
in  a c c or da nc e wit h  t he la bele d  st ora ge c o n ditio ns (s e e Se ctio n  1 0. 1  a n d t he c urre nt versio n 
of t he Ra diess e I F U ). 
O nly a ut h orize d  st u d y pers o n ne l ma y s u p ply,  dis pe ns e, a n d/ or a d minister st u d y tre at me nt, 
a n d o nly  s u bje cts ra n d o mize d in t he st u d y ma y re c eive st u d y tre at me nt. T he in vestigat or  is  
res p o nsible  f or maintainin g  a c urre nt, a c c urate re c or d of all  st u d y-tre at me nt dis pe ns atio n. 
A n y  us e d  c a n n ula s s h o uld   be  dis c ar de d  per  t he  a p pr o priate   ha n dlin g   a n d  dis p os a l  
pr oc e d ures at t he  site. A n y us e d, partially  us e d or u n o pe ne d I M D, u n o pe ne d  c a n n ulas , 
a n d/ or
 o uter
 pa c ka gin g
 s h o uld
  be
 retaine d
 s o
 t he
 m o nit or
  c a n
 perf or m
 
de vic e -a c c o u nta bilit y  pr oc e d ures.  
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Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
M930521003 
Version 5.0, 10-MAR-2022 
CONFIDENTIAL AND PROPRIETARY 
Page 45 of 107 
At the end of the study and after verification of study device accountability, it is the 
investigator’s responsibility to return all unused study supplies, as directed by the sponsor. 
Appropriate records of return must be maintained for accountability purposes. 
All device-accountability procedures must be completed before the study is considered 
complete. 
10.9 Device Accountability Procedures 
The sponsor will provide the investigator with all necessary study supplies after approvals 
of the study protocol and ICF have been received from the IEC/IRB. Accountability for 
study supplies at the study site is the responsibility of the investigator. 
Access to the IMD will be controlled, and the IMD will be used only in the clinical 
investigation and according to the clinical study protocol (CSP). The sponsor will keep 
records to document the physical location of all IMDs from shipment to the study sites 
until return. The investigator or an authorized designee is responsible for ensuring that 
accurate records of receipt, use, and return of the IMD, are maintained and include: 
• The date of receipt and quantity of units received. 
• Identification of each IMD (batch number/serial number or unique code). 
• The expiry date (if applicable). 
• The names of all persons who received each device. 
• The dates and time of injection. 
• Unique subject number. 
• Date and quantity of units returned (if applicable). Include reason for return, if 
applicable. 
• The date of return of unused, expired, or malfunctioning IMDs (if applicable). 
All unused investigational products must be returned to the sponsor or designee 
immediately after the study is completed. Products accidentally destroyed during shipment 
or at a study site should be accounted for and documented. All clinical supplies must be 
accounted for at the termination of the study and a written explanation provided for 
discrepancies. 
In the event of a pandemic disease outbreak (e.g., new COVID-19 public health 
emergency), performing study-accountability procedures remotely should be considered 
and return of unused supplies may be delayed until return procedures can be safely 
performed by study site personnel. 

Merz North America, Inc. 
CLINICAL STUDY PROTOCOL 
M930521003 
Version 5.0, 10-MAR-2022 
CONFIDENTIAL AND PROPRIETARY 
Page 46 of 107 
10.10 Treatment Compliance 
The three required study treatments will be administered by the treating investigator. 
Potential deviations from the defined study-treatment administration will be reported as 
protocol deviations. 
10.11 Duration of Study 
Subjects will have a screening period of up to 10 days. All enrolled subjects will participate 
for a maximum duration of 84 weeks (± 14 days). 
In the event of a public health emergency the study might be halted, recruitment 
interrupted, and/or study processes and flow might be modified impacting the study 
duration and/or visit schedule depending on the study status at the time of the event. 
Mitigations may include, but are not limited to, extending visit windows, performing visits 
by phone or video, and/or performing effectiveness assessments remotely (see 
Section 11.1.3). 
 
 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 4 8  of 1 0 7  
1 1. 1. 1  
S c h e d ul e d Vi sit s  
All s c he d ule d visits a n d a p plic a ble  st u d y ass ess me nts m ust oc c ur as n ote d in Se ctio n  1 1. 1  
a n d t he Sc he d ule  of E ve nts  
 
1 1. 1. 2  
U n s c h e d ul e d Vi sit s  
T o e ns ure  s u bje ct s afet y, a n y s u bje ct w h o, f or a n y re as o n, re q uires a d ditio nal  f ollo w -u p 
t hat  d oes  n ot  c oincide  wit h  a  s c he d ule d  st u d y  visit  s h o uld  ha ve  t hat visit re c or de d as a n 
u ns c he d ule d  visit,  d urin g  w hic h  c o nc o mita nt  me dic atio n/ pr oc e d ures,   s kin  e xa minati o n,  
a n d A Es m ust be ass ess e d a n d re c or de d.  
A n u ns c he d ule d  visit  m ust be  s c he d ule d if e ntries in t he  s u bje ct diar y re q uire  a d diti o n a l 
f ollo w -u p  as deter mine d  b y  t he in vestigat or.  
A n u ns c he d ule d  visit m ust be  s c he d ule d if inf or matio n  a c q uire d fr o m a  s u bje ct d urin g a 
p ost -tre at me nt p h o ne c all re q uires a d ditio nal  f ollo w -u p  as deter mine d  b y  t he in vestigat or.  
1 1. 1. 3  
M o difi e d V i sit S c h e d ul e  d uri n g a P a n d e mi c  
I n t he  e ve nt  of  a  pa n de mic   dis e as e  o ut bre a k  (e. g. , ne w  C O VI D -1 9  p u blic   he alt h  
e mer ge nc y), t he  s p o ns or’s pri mar y  g oal  is t o  e ns ure  t he  s afet y  a n d  w ell-bein g  of  
participatin g  s u bje cts.  I n  ge neral,  t he  f ollo win g   re c o m me n datio ns  a p ply  if a  pa n de mic  
dis e as e o ut bre a k oc c urs: 
•  I n ge neral,  li mit  s c he d uled visits  t o t h os e ne c ess ar y f or s u bje ct s afet y, clinic al  c are, or 
f ollo w-u p  of  A Es . 
•  U s e p h o ne or virt ual  st u d y visits f or r o utine,  ma n date d s afet y f ollo w-u p  visits  as 
des cribe d in t he st u d y pr ot oc ol.  
•  D eter mine if effe ctive ness data c a n be c olle cte d  re m otely.  
•  E xercis e  fle xibilit y w he n ne c ess ar y a n d p ossible t o  c o ntin ue  perf or min g  pr ot oc ol 
re q uire d pr oc e d ures (e. g. , s u bje ct i ma gin g,  p h ot o gra p h y,  if a p plic a ble). 
1 1. 2  St u d y As s e s s m e nt s  a n d D efi niti o n s  
1 1. 2. 1  
Eff e cti v e n e s s  A s s e s s m e nt s  
T he  effe ctive ness  of s u b der mal  i m pla ntati o n   of  d ilute d  Ra diess e  f or t he  c orre ctio n   of  
m o derate t o s e ver e wrin kles  in t he dé c olleté will  be e valuate d wit h s e veral ass ess me nts. 
Refer t o t he res pe ctive e n d p oints  ( Se ctio n  7. 2 ), visit s c he d ule (Se ctio n  1 1. 1 ), a n d Sc he d ule  
of  E ve nts  
 f or  a d ditio nal   inf or matio n   o n  t he  met h o ds  a n d  ti min g   of  
effe ctive ness ass ess me nts.  
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 4 9  of 1 0 7  
1 1. 2. 1. 1  
 
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 0  of 1 0 7  
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 1  of 1 0 7  
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 2  of 1 0 7  
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 3  of 1 0 7  
1 1. 2. 1. 9  
 
1 1. 2. 2  
S af et y A s s e s s m e nt s  
Sta n dar d s afet y ass ess me nts, inclu di n g  d oc u me ntatio n  of A Es a n d S A Es re p orte d b y t he  
in vestigat or  t hr o u g h o ut  t he st u d y,  will  be e valuate d. 
Refer t o t he res pe ctive e n d p oint s  (Se ctio n  7. 2. 2 ), t he Sc he d ule of E ve nts 
 
a n d t he s afet y definitio ns  ( Se ctio n  1 2 ) f or a d ditio nal  inf or matio n  o n t he s afet y ass ess me nts. 
1 1. 2. 2. 1  
A d v er s e E v e nt s ( A E s)/ S eri o u s A d v er s e E v e nt s ( S A E s) 
All A Es / S A Es re p orte d b y st u d y  s u bje cts,  in vestigat ors,  or ot her st u d y  staff after t he ti m e  
of  inf or me d   c o ns e nt  t hr o u g h   e n d  of  st u d y  will   be  re c or de d ,  re gar dless  of  c a us alit y. 
T he  perio d  of o bs er vatio n  f or a n A E e xte n ds fr o m sig nin g  of t he I C F t hr o u g h  t he s u bje ct’s  
last st u d y visit. A d ditio nal  inf or matio n  (e. g., definitio ns ,  re p ortin g  re q uire me nts) re gar din g 
A Es a n d S A Es is pr o vide d  in Se ctio n  1 2. 1  a n d Se ctio n  1 2. 2 , res pe ctively. 
S t u d y  s u bje cts will  be q uerie d f or t he pres e nc e or a bs e nc e of a n y vis ual  s y m pt o ms at e a c h 
f ollo w-u p  visit  
 If vis ual  s y m pt o ms  are re p orte d at a f ollo w-u p  vis it,  
s u bje cts will  u n der g o vis ual f u nctio n  ass ess me nts t o  p ote ntially  ide ntif y  o p ht hal mic  sig ns  
a n d/ or  s y m pt o ms   t hat  ma y  re pres e nt  o p ht hal mic-arter y  oc clusio n  as  detaile d  i n  
Se ctio n  1 1. 2. 2. 2. 3 . 
1 1. 2. 2. 2  
 
1 1. 2. 2. 2. 1  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 4  of 1 0 7  
1 1. 2. 2. 2. 2  
 
1 1. 2. 2. 2. 3  
 
C CI
C CI
C CI
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 5  of 1 0 7  
1 1. 2. 2. 2. 3. 1  
 
C CI
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 6  of 1 0 7  
1 1. 2. 2. 2. 3. 2  
 
1 1. 2. 2. 2. 3. 3  
 
1 1. 2. 2. 2. 3. 4  
 
C CI
C CI
C CI
C CI
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 7  of 1 0 7  
1 1. 2. 2. 2. 4  
 
C CI
C CI
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 8  of 1 0 7  
1 1. 2. 3  
A d diti o n a l D at a C oll e ct e d 
D ata f or ot her  ass ess me nts will  be c olle cte d  as f ollo ws:  
•  D e m o gra p hics a n d ot her bas eline c hara cteristics;  
•  Me dic al  hist or y/c o nc o mita nt  dis e as es; a n d  
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 5 9  of 1 0 7  
•  Pre vio us a n d c o nc o mita nt  me dic atio ns  a n d n o n -dr u g  tre at me nts.  
F or ti me p oints of all ot her ass ess me nts, refer t o 
 
1 1. 2. 4  
A p pr o pri at e n e s s of A s s e s s m e nt s  
T he M A S D é c olleté Wrin kles  s c ales are c urre ntly  t he o nly  clinic al  instr u me nts  s h o w n t o 
be  valid  a n d  hig hly  relia ble  in clinic al  gra din g of dé c olleté  wrin kles in b ot h t he  “ At Rest”  
a n d “ D y na mic ”  p ositio ns.[ 3 8] Usin g a  ps yc h o metric  e valuatio n  pr oc ess, 1 3 e x pert raters  
s c ore d  t w o  s ets  of  p h ot o gra p hs  fr o m  s u bje cts pres e ntin g  wit h  a br oa d  s pe ctr u m  of  
a ge -relate d dé c olleté  c ha n ges (e. g., wrin klin g). 
T his a nalysis  de m o nstrate d  t hat  s u bje ct 
s c ores o n b ot h  M A S D é c olleté  Wrin kles  s c ales w ere p ositive ly  c orrelate d wit h s u bje ct a ge 
(a ct ual a n d esti mate d) a n d t he  esti mate d de gre e  of tre at me nt eff ort ne e de d t o pr o d uc e  
a est hetic  i m pr o ve me nt.  F urt her , b ot h   M A S  D é c olleté  Wrin kles   s c ales  de m o nstrate d  
s u bsta ntial   de gre es  of  intra- a n d  inter-ra te r  re lia bilit y in  t he  p o ol   of  e x pert  raters. 
T hes e  fin din gs  de m o nstrate t hat t he M A S D é c olleté Wrin kles  s c ales are valid  in ter ms of 
c o nte nt a n d str uct ure a n d esta blis h  a t hres h old  f or tre at me nt be nefit.  
C CI
C CI

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12 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
12.1 Definition of an Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical sign (including abnormal laboratory findings) in subjects, users, or other persons, 
whether or not related to the IMD. 
Note: 
1. This definition includes events related to the IMD. 
2. This definition includes events related to the procedures involved. 
3. For users or other persons, this definition is restricted to events related to the IMD. 
12.1.1 
Details of an AE 
The period of observation for an AE extends from when the ICF is signed until the subject’s 
last study visit. Any medical occurrence between the time the ICF is signed and the first 
treatment with the IMD is an AE and has to be documented in the subject’s file and in the 
AE eCRF. Any observed AE will be fully investigated, documented, and followed until the 
event is either resolved or adequately explained. In cases of surgical or diagnostic 
procedures, the condition/illness leading to such a procedure is considered the AE rather 
than the procedure itself. New AEs reported to the investigator during the observational 
period, after the last treatment with the IMD, must be documented, treated, and followed 
like all other AEs. 
Pre-existing conditions noted in the medical history should not be reported as an AE, unless 
the condition worsens or the disease reoccurs during the reporting period. To determine 
whether a condition has worsened, it is compared to the subject’s condition at screening. 
Elective treatments planned before screening, and which are documented in the subject’s 
source data, are usually not regarded as AEs. However, elective procedures should be 
postponed, if possible, until the subject completes their participation in the trial. 
12.1.2 
Reporting and Handling of an AE 
Data pertaining to AEs will be collected during each clinical study visit based on the 
subject’s spontaneous description, through investigator inquiry, or upon discovery in the 
course of examinations completed during the visit. The investigator will assess and record 
any AE in detail in the subject file and on the AE eCRF. The following information must 
be recorded: 
• AE diagnosis or main symptom; 
• Affected treatment area: In case of a local reaction, the corresponding area should be 
reported; 

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• Date of onset; 
• Intensity (maximum observed using the Severity Grading scale; see Section 12.1.3); 
• Causal relationship to IMD (not related, related); 
• Causal relationship to procedure (not related, related); 
• Serious (yes or no), date serious since, and reason for seriousness; 
• Outcome (see Section 12.1.5); 
• AE leading to discontinuation of the clinical study (yes or no); 
• Action taken with medical device; and 
• Stop date. 
In cases of a SAE (defined in Section 12.2), the investigator must also complete an SAE 
Report Form and report it to the sponsor within 24 hours, as described in Section 12.2.2. 
12.1.3 
Severity Grading for an AE 
The clinical severity (i.e., intensity) of an AE will be classified as: 
Mild: 
Signs and symptoms that can be easily tolerated. Symptoms can be ignored 
and disappear when the subject is distracted. 
Moderate: Signs and symptoms that cause discomfort and interfere with normal 
functioning but are tolerable. They cannot be ignored and do not disappear 
when the subject is distracted. 
Severe: 
Signs and symptoms that affect usual daily activity and incapacitate the 
subject, thereby interrupting her daily activities. 
The investigator is required to grade the severity (i.e., intensity) of each AE. 
12.1.4 
Causal Relationship of an AE with an Investigational Medical 
Device 
An AE is considered to be “related” to IMD or the treatment procedure if a causal 
relationship between the IMD or the treatment procedure and an AE is at least reasonably 
possible (i.e., the relationship cannot be ruled out). In this case, the non-serious event is 
considered an adverse device effect (ADE; Section 12.3). If the event is serious, it is a 
serious adverse device effect (SADE; Section 12.4). 
The expression “reasonable causal relationship” is meant to convey that there are facts 
(evidence) or arguments to suggest a causal relationship. Otherwise, the relationship should 
be considered as “not related”. 

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12.1.5 
Outcome Categories for an AE 
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; or 
• Unknown. 
If there is more than one AE, only the AE leading to death will be attributed with a “fatal” 
outcome. 
12.2 Definition of a Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
• led to death; 
• led to serious deterioration in the health of the subject, that either resulted in: 
o a life-threatening illness or injury; 
o a permanent impairment of a body structure or a body function, including chronic 
diseases; 
o inpatient or prolonged hospitalization; or 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• led to fetal distress, fetal death, or a congenital abnormality or birth defect, including 
physical or mental impairment. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the 
CSP, without serious deterioration in health, is not considered an SAE. 
12.2.1 
Details of an SAE 
In cases of fatality, the cause of death is considered the AE, and the death is considered its 
outcome. In this case, the primary cause of death (i.e., the event leading to death) should 
be recorded and reported as an SAE. “Death” will be recorded as the outcome of this 
respective event; death will not be recorded as a separate event. Only if no cause of death 
can be reported (e.g., sudden death, unexplained death), the death per se might be reported 
as an SAE. In cases of death, an autopsy report should be submitted (if available). The date 
and cause of death should be recorded. 

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Planned hospitalization for a pre-existing condition is not considered an SAE. If a subject 
experiences an additional AE that prolongs a pre-planned hospitalization, this event is 
considered an SAE and should be reported as such. Hospitalizations for elective treatments 
planned before screening and which are documented in the subject’s source data are not 
regarded as SAEs. 
In addition, device deficiencies, as defined in Section 12.5, that might have led to an SAE 
if: 
• suitable action had not been taken; or 
• intervention had not been made; or 
• if circumstances had been less fortunate 
should be categorized as an SAE and reported accordingly. 
12.2.2 
Reporting and Handling of an SAE 
All SAEs that occur during the clinical study period, whether considered to be related to 
an IMD or not, must be reported via fax, telephone, or e-mail, and an SAE Report Form 
should be submitted to the sponsor immediately upon knowledge of the event. 
Further reporting details will be outlined in a separate document. 
Although all information required for completion of an SAE Report Form may not be 
available within the specified time period, an initial report should be submitted if the 
following minimal information is available: 
• An identifiable subject (unique subject number); 
• A suspect product and how the treatment relates to the SAE; 
• An identifiable reporting source (investigator/study site identification); and/or 
• An event or outcome that can be identified as serious. 
The investigator must report SAEs to Merz as defined in Section 12.2 and the site’s 
IEC/IRB per their reporting guidelines. Within 10 working days after Merz first receives 
notice of the SAE, Merz Product Safety will conduct an evaluation of the SAE and report 
the results of such evaluation to regulatory agencies, IECs/IRBs, and investigators, as 
applicable. 
The investigator must supply further supporting information, and a detailed SAE 
description is an integral part of this supporting information. Follow-up SAE reports should 
be sent without delay to the sponsor as an SAE Report Form (marked as a “follow-up” 
report), and the eCRF has to be updated accordingly to avoid discrepancies. The SAE has 
to be followed until the SAE is resolved/recovered or a plausible explanation is available. 
The SAE will be followed-up only in the Global Product Safety database after final SAE 
reconciliation is completed. 

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An SAE occurring after the end of the observational period would need to be reported if 
the investigator considers the event to be related to IMD. These reports generally will not 
be entered into the investigation database. Following database close (including main and 
safety follow-up periods), any ongoing SAEs will be followed until resolution or 
stabilization under the responsibility of the investigator per his/her standard of care. 
The investigator should complete and send any SAE Report Forms (including any 
follow-up forms) to Merz North America Product Safety via the email provided below: 
Merz North America, Inc. Product Safety 
6501 Six Forks Road 
Raleigh, NC 27615 
US 
Product Safety Email: AxUS-adverse.events@merz.com 
12.3 Definition of an Adverse Device Effect (ADE) 
An ADE is defined as an AE related to the use of an IMD. 
Note: 
1. This definition includes AEs resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation or any malfunction of the 
IMD. 
2. This definition includes any event resulting from use error or from intentional misuse 
of the IMD. 
12.4 Definition of a Serious Adverse Device Effect (SADE) 
A SADE is defined as an adverse device effect that has resulted in any of the consequences 
characteristic of an SAE (Section 12.2). 
12.4.1 
Definition of an Anticipated Serious Adverse Device Effect 
(ASADE) 
An ASADE is a serious adverse device effect which by its nature, incidence, severity, or 
outcome has been identified in the current version of the risk-analysis report. 
12.4.2 
Definition of an Unanticipated Adverse Device Effect (UADE) 
A UADE is defined as follows: 
• 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 investigationa l 

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plan or application (including a supplementary plan or application), risk analysis report, 
or IFU. 
• Any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
12.5 Definition of Device Deficiency 
A device deficiency is defined as an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. 
Note: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
12.6 Definition of Technical Complaint 
A technical complaint, also referred to as a product complaint, is an apparent or suspected 
deficiency of a product in which the product does not meet its specification (e.g., leaking 
tube, incorrect consistency, cracked vial). 
12.6.1 
Reporting and Handling of Device Deficiencies and Technical 
Complaints 
All device deficiencies and technical complaints shall be documented and reported by the 
investigator throughout the clinical investigation and appropriately managed by Merz 
North America, Inc. 
The investigator will attempt to evaluate if the deficiency or complaint might have led to 
an AE if suitable action had not been taken, intervention had not been made, or 
circumstances had been less fortunate. A device deficiency that could have led to a SADE 
(Section 12.4) is to be reported in the same way as an SAE. 
For reporting of device deficiencies and technical complaints: 
• A device deficiency/technical complaint eCRF must be completed and submitted 
within 24 hours by the investigational site, irrespective of the seriousness of the case. 
• A device deficiency/technical complaint eCRF must be completed and submitted by 
the investigational site, irrespective of whether the complaint led to an AE. 
• If a technical complaint or device deficiency is associated with an SAE, the 
investigational 
site must also complete and submit an SAE Report Form 
(Section 12.2.2) in addition to the device deficiency/technical complaint eCRF. 
• If a technical complaint or device deficiency is not related to a specific subject 
(e.g., damaged packaging occurring prior to the subject’s visit), the investigator should 
complete a paper device deficiency/technical complaint form, instead of the eCRF 
page, and send to the sponsor within 24 hours to both their clinical study representative 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 6 6  of 1 0 7  
as w ell  as t o t he  Merz Te c h nic al  C o m plaint   D e part me nt  f or  pr oc essin g  usin g  t he  
f ollo win g  e ma il a d dre ss: c o m plaints 2 @ merz. c o m. 
T he in vestigat or  s h o uld  retain t he de vic e in q uestio n  f or f ut ure ins pe ctio n  a n d in vestiga ti o n 
b y t he s p o ns or,  if  ne c ess ar y.  T he Merz Te c h nic al  C o m plaint  D e part me nt will  de cide if t he 
de vic e a n d/ or s u p plies in q uestio n  ne e d t o be ret ur ne d a n d t o w h o m t he y s h o uld  be s e nt f or 
in vestigatio n. 
1 2. 7  
 
1 2. 8  
 
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12.9 Reporting of Pregnancy 
Any pregnancy that starts during the clinical study must be reported, using the Pregnancy 
Form, by the investigator to the sponsor within 24 hours of learning of its occurrence. 
Pregnancies and pregnancy follow-up should be reported on a Pregnancy 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 to the IMD. In addition, each pregnancy has to be reported on the AE eCRF  (i.e., as 
a non-serious AE due to device exposure before or during pregnancy). Pregnancy Forms 
(including any follow-up forms) should be submitted to the contacts referenced in 
Section 12.2.2. 
If a subject becomes pregnant during the study, the subject must not receive further 
treatments (i.e., additional treatments or optional retreatment); however, the subject will 
remain in the study. 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 6 9  of 1 0 7  
a p pro xi m a te ly 1 5 2  s u bje cts,  1 1 4 s u bje cts in t he  
tre at me nt Gr o u p  A a n d 3 8  s u bje cts in  t he  u ntre ate d -c o ntr ol/dela ye d -tre at me nt  Gr o u p  B, 
will  be ra n d o mize d  f or t his  st u d y.  Re gar din g  t he s afet y e valuatio n,  in  a s a m ple  size  of 
1 5 2  s u bje cts a n a d vers e e ve nt wit h  a tr ue incide nc e  of 1. 5 % will  be o bs er ve d at le ast o nc e 
wit h a pr o ba bilit y  of 8 9. 9 %.    
C CI
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 7 2  of 1 0 7  
1 3. 4. 1. 1. 1  
 
C CI
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 7 4  of 1 0 7  
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 7 5  of 1 0 7  
1 3. 4. 2  
S af et y A n al y s e s  
All s afet y a nalys es will  be perf or me d o n t he S E S.  
All A Es a n d S A Es will  be liste d, inclu di n g  t y pe, d uratio n,  s e verit y, a n d relatio ns hip  t o t he 
I M D. 
O nly  T E A Es will  be s u m marize d 
 
  usin g  Me d D R A preferre d ter ms ( P Ts) wit hin  t he s yste m or ga n 
class es  ( S O Cs). Safet y a nalys es re gar din g  T E A Es will  be perf or me d o verall,  f or tre at me nt 
Gr o u p  A a n d Gr o u p  B ( dela ye d -tre at me nt c o ntr ol) w here  a p pr o priate. 
Tre at me nt -e mer ge nt A Es ( T E A Es)  are define d  as A Es wit h  o ns et or w ors e nin g at or after 
t he  first  a d ministratio n   of  st u d y  tre at me nt. I n  t his   re gar d, a n  A E  wit h   o ns et  prior   t o  
tre at me nt  t hat  w ors e ns at  or  after  first  a d ministratio n   of  st u d y   tre at me nt  m ust  be  
d oc u me nte d  as a ne w T E A E wit h o ns et at t he ti me of w ors e nin g.  
All  ot her A Es t hat d o n ot f ollo w  t he prior  definitio ns  will be  c o nsidere d n o n-T E A Es.  
1 3. 4. 2. 1  
S e c o n d ar y S af et y E n d p oi nt s  
I ncide nc es of T E A Es relate d t o t he tre at me nt wit h dilute d Ra diess e  will be  s u m marize d b y  
tre at me nt gr o u p  a n d t otal,  o verall  a n d b y st u d y  perio d  b y P T a n d S O C. 
C CI
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 7 6  of 1 0 7  
1 3. 4. 2. 2  
 
C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 7 7  of 1 0 7  
1 3. 4. 3  
Ot h er S u bj e ct D at a  
St u d y s u bje cts will  be c hara cterize d b y des criptive  statistics f or:  
•  Dis p ositio n  of s u bje cts;  
•  D e m o gra p hics a n d ot her bas eline  c hara cteristics;  
•  Me dic al hist or y a n d c o nc o mita nt dis e as es;  
•  Prior  a n d  c o nc o mita nt  t hera pies  ( me dic atio n,  n o n -dr u g  tre at me nts, a n d pr oc e d ures); 
a n d 
•  E xte nt of e x p os ure . 
Dis p ositio n  of s u bje cts,  de m o gra p hic  data, a n d bas eline  c hara cteristics  will  be pres e nte d 
usin g  sta n dar d  des criptive  statistics.  D e m o gra p hic  data  will be  s u m marize d  f or  S E S, I T T, 
a n d P P S; re mainin g  bas eline  data will  be s u m marize d  des criptively  o nly  f or t he I T T a n d 
P P S.  
1 3. 5  S p e ci al S t ati sti c al/  An al yti c al Is s u e s  
1 3. 5. 1  
 
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C CI
C CI

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 7 8  of 1 0 7  
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M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 7 9  of 1 0 7  
1 3. 5. 3  
 
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14 ADMINISTRATIVE PROCEDURES 
14.1 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: 
• Data authenticity, accuracy, and completeness; 
• Protection of subject rights and safety; and 
• 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 5.3 and Section 5.4). 
Further details of monitoring activities will be set forth in the monitoring manual. 
In the event of a pandemic disease outbreak (e.g., new COVID-19 public health 
emergency), and by this, if on-site visits are not possible due to site closures, travel 
limitations, or other considerations (e.g., if site personnel or trial subjects become infected 
with SARS-CoV-2), the following mitigations should be considered and assessed in an 
updated monitoring plan: 
• On-site monitoring visits might be cancelled and/or the period between monitoring 
visits extended. When planned on-site monitoring visits are not possible, the reason 
should be clearly documented and made available for review during audits and/or 
inspections. 
• Phone and/or video visits will be implemented when feasible, considering site closures, 
reduced staff, and any other circumstances. 
• Remote monitoring or central monitoring could substitute on-site monitoring, when 
technically feasible. 
• Protocol deviations will be tracked and documented if deviations occurred due to the 
public health emergency. 
• Current local regulations, including data privacy regulations, will be considered when 
accessing source data remotely. 
14.2 Data Quality Assurance 
Inspections by regulatory authority representatives and IECs/IRBs are possible at any time, 
even after the end of the study. The investigator is to notify the sponsor immediately of any 
such inspection. The investigator and institution will permit study-related monitoring, 
audits, reviews by the IEC/IRB and/or regulatory authorities, and will allow direct access 
to source data and source documents for such monitoring, audits, and reviews. 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 8 1  of 1 0 7  
1 4. 2. 1  
St a n d ar di z ati o n P r o c e d ur e s 
Sta n dar dizatio n  pr oc e d ures will  be i m ple me nte d  t o e ns ure a c c urate, c o nsiste nt,  c o m plet e , 
a n d relia ble  data, inclu din g  met h o ds t o e ns ure sta n dar dizatio n  a m o n g sites (e. g., traini n g, 
ne wsletters,  in vestigat or  me etin gs,  m o nit orin g,  e valuatio ns,  a n d  validatio n  met h o ds).  
Sta n dar dize d  p h ot o gra p h y  met h o ds  will  be detaile d  in  a s e parate p h ot o gra p h y  us er ma n ual.  
T his st u d y will  be m o nit ore d  re g ularly  b y a q ualifie d  m o nit or  fr o m t he  C R O a c c or din g  t o 
G C P g uidelines  a n d t he res pe ctive sta n dar d o peratin g  pr oc e d ures (S O Ps ; s e e Se ctio n  1 4. 1 ). 
1 4. 2. 2  
D at a M a n a g e m e nt  
D ata  re q uire d  a c c or din g  t o  t his  pr ot oc ol  a re  t o  be  re c or de d  in  t he  w e b-bas e d e C R Fs  
pr o vide d   b y  a  C R O.  All  us ers  w h o  will  e nter  data  int o   t he  e C R F  m ust  s uc c essf ull y  
c o m plete trainin g  bef ore s yste m a c c ess is gra nte d. P articipa nt trainin g  will  be d oc u me nte d.  
A c c ess t o t he e C R F will  be pass w or d  c o ntr o lle d  a n d  will c o nf or m  wit h  2 1  C F R P art  1 1.  
D ata - pla usibilit y   c he c ks  will   be  perf or me d  a c c or din g   t o  a  data  validatio n   pla n.   
I nc o nsiste ncies  in t he data will  be q uerie d t o t he in vestigat ors  via t he E D C s yste m; a ns w ers 
t o q ueries or c ha n ges t o t he  data  will  als o be  d oc u me nte d  in t his s yste m dire ctly  b y a n 
a ut h orize d  me m ber  of t he in vestigat or’s st u d y pers o n nel.  T he a u dit  trail  in  t he E D C s yste m 
will d oc u me nt all c ha n ges. E dit c he c ks ge nerate  a ut o matic  q ueries d urin g data  e ntr y w he n 
a  field  is n ot p o p ulate d  a c c or din g  t o s pe cific atio ns  define d in  t he  data  validatio n  pla n.  
Ma n ual  q ueries  t o  be  a ns w ere d  b y  st u d y  pers o n nel c a n  be  rais e d  d urin g   s o urc e  data  
verific atio n  a n d/ or d urin g  me dic al,  s afet y, a n d/ or data ma na ge me nt re vie w.  
P h ot o gra p hs  will  be arc hive d b y t he c e ntral p h ot o gra p h y  ve n d or  in a s yste m s e parate fro m 
t he data bas e (s e e Se ctio n  1 4. 3 ). e Diar y data will  be tra nsferre d ele ctr o nic ally  t o t he data 
ma na ge me nt C R O. C he c ks will  be perf or me d t o e ns ure pla usibilit y  a n d c o m plete ness  of  
t hes e  data.  T he  data  ma na ge me nt  a ctivities  a n d  p h ot o gra p hs  pr oc essin g  will be  dele gate d  
t o t he C R Os liste d  in 
F or a nalysis of t he  main pe rio d, t he data bas e of t he 
main perio d  will  be  clos e d after all  data of t he main  perio d  are e ntere d a n d all  q ueries 
c o nc er nin g  t hes e data are s olve d. F or t he a nalysis  at t he e n d of t he s afet y f ollo w-u p  perio d, 
after all  data fr o m  t he s afet y f ollo w-u p  perio d are e ntere d a n d all q ueries are s olve d,  t he 
data bas e clos e (inclu din g  main a n d s afet y f ollo w-u p  pe rio ds) will  be  perf or me d . If a n y data 
c ha n ges are re q uire d  after data bas e clos e,  t hes e c ha n ges will  be d oc u me nte d  a c c or din g  t o 
t he res pe ctive S O P. 
F urt her details  of t he data ma na ge me nt  pr oc ess will  be des cribe d in  t he data ma na ge me nt 
pla n.  
1 4. 2. 3  
D at a R e vi e w a n d C l arifi c ati o n P r o c e d ur e s 
B y ele ctr o nic ally  sig nin g  t he e C R F wit h  a n a ut o mate d  ti me  sta m p, t he in vestigat or  will 
c o nfir m  t hat all  in vestigatio ns  ha ve be e n c o m plete d a n d c o n d ucte d in c o m plia nc e  wit h t he  
C S P  a n d t hat relia ble  a n d c o m plete  data ha ve be e n e ntere d int o  t he e C R F.  
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All data required by this CSP are to be recorded in the eCRF as soon as possible. However, 
direct entries are not allowed; data must be transcribed from the source documentation 
(e.g., subject file, scales) to the eCRF. 
All data required by this study protocol are to be entered into a validated database of 
eCRFs. 
If corrections are necessary, an authorized member of the investigator’s study personnel 
will enter the correct data into the web-based eCRF. The audit trail in the EDC system 
documents all changes. 
The CRO’s and sponsor’s data management functions will be responsible for data 
processing, in accordance with the CRO’s and sponsor’s data management procedures. 
Database close will occur only after quality assurance procedures have been completed. 
Entries from questionnaires completed by the subject will be entered into the eCRF by 
study personnel. 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. 
In the event of a pandemic disease outbreak (e.g., new COVID-19 public health 
emergency), and by this, if data entry and cleaning is limited or not possible due to site 
closures, travel limitations, or other considerations (e.g., if site personnel become infected 
with SARS-CoV-2), the following mitigations should be considered for data cleaning 
processes: 
• Data entry and response to data clarifications will proceed depending on availability of 
study site personnel and investigators. 
• Depending on the content of the response to data clarifications, the need for source data 
review will be assessed by the sponsor. 
• If applicable, a risk-based assessment for closing long opened data clarifications will 
be applied considering their impact on trial conclusion and data validity. 
• The need for data clarifications and/or eCRF pages to be signed by staff that is not yet 
on the delegation log will be assessed. The delegation log is to be updated, if applicable. 
14.2.4 
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. 

M erz N ort h A meric a, In c.  
C LI NI C A L S T U D Y P R O T O C O L  
M 9 3 0 5 2 1 0 0 3  
Versi o n 5 . 0, 1 0 -M A R -2 0 2 2 
C O N FI D E N T I A L  A N D P R O P RI E T A R Y  
Pa g e 8 3  of 1 0 7  
1 4. 3  R e c or d R et e nti o n  
Ess e ntial d oc u me nts s h o uld be  retaine d per a p plic a ble  re g ulatio ns  a n d as instr ucte d  b y t he 
st u d y s p o ns or. Ess e ntial d oc u me nts at t he  in vestigatio na l  site  inclu de , b ut are n ot  li mit e d 
t o: 
•  S o urc e d oc u me ntatio n  (e. g. , su bje c t  file s ); 
•  S u bje c t  ide ntific a tio n  c o de  list  (i. e., pr o vide d  b y te mplate  t o t he in vestigat or,  alo n g  wit h 
t he I n vestigat or  Site File,  at t he be gin nin g  of t he in vestigatio n),  w hic h ide ntifies  t he 
s u bje ct b y n u m ber, na me, a n d date of birt h; 
•  A c o p y of t he st u d y pr ot oc ol  a n d a n y a me n d me nts ; 
•  A C D/ D V D wit h  e C R F data a n d a n y ass ociate d s u bje ct-relate d  s o urc e data ( or, w here 
a p plic a ble,  a ut h orize d  c o pies of s o urc e data) ; 
•  Sig ne d I C Fs ; 
•  C o pies of site in vestigat ors’  a n d c o -w or kers' c urric ula  vita e ; 
•  C o pies  of  all   dire ct  c orres p o n de nc e  wit h  t he  I E C/I R B  a n d  wit h  t he  re g ulat or y  
a ut h orit y(ie s); 
•  C o pies  of all  rele va nt c orres p o n de nc e bet w e e n t he in vestigat or  a n d t he m o nit or,  a n d 
bet w e e n t he in vestigat or  a n d t he s p o ns or ; 
•  
 
•  C o pies of  I M D re c eipt f or ms a n d de vic e in ve nt or y  f or ms; a n d 
•  C o pies  of s afet y inf or matio n  re p o rte d d urin g  t he  in vestigatio n  a n d s u b mitte d  b y t he  
s p o ns or. 
St u d y  d oc u me nts  ma y  n ot  be  destr o ye d  b y  st u d y -site  pers o n nel  prior  t o t he  e n d of t he  
re q uire d  rete ntio n  perio d  as  s pe cifie d  b y  loc al  re g ulatio ns.   T he  in vestigat or   or  t he  
instit utio n   m ust  inf or m  t he  s p o ns or  in  d ue  ti me  if  t he  in vestigat or   le a ves  t he  instit uti o n  
d urin g  t he  rete ntio n perio d. T his r ule  als o a p plies  w he n t he  instit utio n  clos es wit hin  t he  
rete ntio n perio d. 
U p o n clos ure of t he st u d y,  t he in vestigat or  m ust maintain  all st u d y -site  re c or ds in  a s afe 
a n d s e c ure loc atio n.  T he in vestigat or  is res p o nsible  f or t he inte grit y,  rete ntio n,  a n d s e c urit y 
of all  st u d y -relate d re c or ds. T he  in vestigat or  m ust e ns ure  t hat a n y re pr o d uctio ns  of t he  
original   re c or ds  are  le gible   a n d  pr o vide   a  tr ue  a n d  a c c urate  c o p y  of  t he  origin a l.  
A c c urate,  c o m plete,  a n d c urre nt re c or ds m ust be st ore d in s uc h a w a y as t o per mit e as y a n d 
ti mely  retrie val  f or t he s p o ns or  or a n y a p plic a ble  re g ulat or y  a ut h orities. 
T he s p o ns or will  inf or m  t he in vestigat or  of t he ti me  perio d f or retai nin g  t hes e re c or ds t o 
c o m ply wit h all a p plic a ble  re g ulat or y re q uire me nts, wit h t he mini m u m  rete ntio n ti me bein g 
t he lo n gest of t h os e ti mes dictate d b y instit utio na l  re q uire me nts,  loc al la ws or re g ulatio ns , 
or t he s p o ns or’s sta n dar d pr oc e d ures. T he in vestig at or  m ust n otif y t he s p o ns or in t he e ve nt 
of  a n y  c ha n ges  t o  arc hival  arra n ge me nts  d ue  t o  wit h dra w al   of  t he  in vestigat or’ s  
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responsibility for keeping study records to ensure that suitable arrangements for the 
retention of study records are made. 
14.4 Publication Policy 
The results of this study and any discoveries related to this study, regardless of whether 
they have technical or medical character, are the property of the sponsor. 
The CSP, 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 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 SOP. 
The sponsor will ensure that a description of this clinical study is registered, and study 
results are disclosed on http://www.ClinicalTrials.gov, 
as required by U.S. law. 
Study registration may include a list of study sites, as applicable. 
14.5 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 
year after its completion if necessary. 
14.6 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 or assigned CRO, if possible, to 

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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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15 REFERENCE LIST 
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G Casabona,D Nogueira Teixeira. Microfocused ultrasound in combination with 
diluted calcium hydroxylapatite for improving skin laxity and the appearance of lines in 
the neck and decolletage. J Cosmet Dermatol. 2018;17(1):66-72. 
2. 
JD Peterson,MP Goldman. Rejuvenation of the aging chest: a review and our 
experience. Dermatol Surg. 2011;37(5):555-71. 
3. 
N Otberg, H Richter, H Schaefer, U Blume-Peytavi, W Sterry,J Lademann. 
Variations of hair follicle size and distribution in different body sites. The Journal of 
investigative dermatology. 2004;122(1):14-9. 
4. 
R Fitzgerald,D Vleggaar. Using poly-L-lactic acid (PLLA) to mimic volume in 
multiple tissue layers. Journal of drugs in dermatology : JDD. 2009;8(10 Suppl):s5-14. 
5. 
SG Fabi, MP Goldman, SH Dayan, MH Gold, SL Kilmer,CS Hornfeldt. A 
prospective multicenter pilot study of the safety and efficacy of microfocused ultrasound 
with visualization for improving lines and wrinkles of the decollete. Dermatol Surg. 
2015;41(3):327-35. 
6. 
U Wollina,A Goldman. Dermal fillers: facts and controversies. Clinics in 
dermatology. 2013;31(6):731-6. 
7. 
DR Jordan,B Stoica. Filler Migration: A Number of Mechanisms to Consider. 
Ophthalmic plastic and reconstructive surgery. 2015;31(4):257-62. 
8. 
DL Sachs,JJ Voorhees. Age-reversing drugs and devices in dermatology. Clinical 
pharmacology and therapeutics. 2011;89(1):34-43. 
9. 
F Urdiales-Galvez, NE Delgado, V Figueiredo, JV Lajo-Plaza, M Mira, A Moreno, 
et al. Treatment of Soft Tissue Filler Complications: Expert Consensus Recommendations. 
Aesthetic Plast Surg. 2018;42(2):498-510. 
10. 
YA Yutskovskaya,EA Kogan. Improved Neocollagenesis and Skin Mechanical 
Properties After Injection of Diluted Calcium Hydroxylapatite in the Neck and 
Decolletage:A Pilot Study. Journal of drugs in dermatology : JDD. 2017;16(1):68-74. 
11. 
N Zerbinati,A Calligaro. Calcium hydroxylapatite treatment of human skin: 
evidence of collagen turnover through picrosirius red staining and circularly polarized 
microscopy. Clin Cosmet Investig Dermatol. 2018;11:29-35. 
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O Hevia. A retrospective review of calcium hydroxylapatite for correction of 
volume loss in the infraorbital region. Dermatol Surg. 2009;35(10):1487-94. 
13. 
MH Devoto, FP Bernardini, A Cetinkaya,A Zambelli. Reply re: "Calcium 
hydroxylapatite (Radiesse) for the correction of periorbital hollows, dark circles, and lower 
eyelid bags". Ophthalmic plastic and reconstructive surgery. 2014;30(5):440-1. 

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LS Bass, S Smith, M Busso,M McClaren. Calcium hydroxylapatite (Radiesse) for 
treatment of nasolabial folds: long-term safety and efficacy results. Aesthet Surg J. 
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PF Jacovella. Aesthetic nasal corrections with hydroxylapatite facial filler. Plast 
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T Pavicic. Calcium hydroxylapatite filler: an overview of safety and tolerability. 
Journal of drugs in dermatology : JDD. 2013;12(9):996-1002. 
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TL Tzikas. A 52-month summary of results using calcium hydroxylapatite for facial 
soft tissue augmentation. Dermatol Surg. 2008;34 Suppl 1:S9-15. 
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J Emer,H Sundaram. Aesthetic applications of calcium hydroxylapatite volumizing 
filler: an evidence-based review and discussion of current concepts: (part 1 of 2). Journal 
of drugs in dermatology : JDD. 2013;12(12):1345-54. 
19. 
MP Goldman, A Moradi, MH Gold, DP Friedmann, K Alizadeh, JM Adelglass, et 
al. Calcium Hydroxylapatite Dermal Filler for Treatment of Dorsal Hand Volume Loss: 
Results From a 12-Month, Multicenter, Randomized, Blinded Trial. Dermatol Surg. 
2018;44(1):75-83. 
20. 
M Amselem. Radiesse((R)): a novel rejuvenation treatment for the upper arms. Clin 
Cosmet Investig Dermatol. 2016;9:9-14. 
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V Cogorno Wasylkowski. Body vectoring technique with Radiesse((R)) for 
tightening of the abdomen, thighs, and brachial zone. Clin Cosmet Investig Dermatol. 
2015;8:267-73. 
22. 
G Casabona,P Marchese. Calcium Hydroxylapatite Combined with Microneedling 
and Ascorbic Acid is Effective for Treating Stretch Marks. Plastic and reconstructive 
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