Evaluation of the Effectiveness and Safety of Radiesse for the Correction of Moderate to Severe Nasolabial Folds
Phase: NA
Conditions: Correction of Moderate to Severe Nasolabial Folds (NLFs)
Sponsor: Merz North America, Inc.



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2  SYNOPSIS 
Title of Trial 
Evaluation of the Effectiveness and Safety of Radiesse for the Correction 
of Moderate to Severe Nasolabial Folds 
Trial Identifier 
M900311009 
Investigative 
Sites 
This trial will be conducted at approximately seven investigative sites in 
China. 
Investigational 
Medical Device 
(generic name) 
RADIESSE® or Radiesse® (calcium hydroxylapatite (CaHA) injectable 
implant) 
Comparator 
Medical Device   
(generic name) 
Restylane® (hyaluronic acid (HA) dermal filler gel) 
Indication 
Correction of moderate to severe nasolabial folds (NLFs) 
Objectives 
Effectiveness: To demonstrate non-inferiority of Radiesse (CaHA) to 
Restylane (HA) following subdermal implantation for the correction of 
moderate to severe facial wrinkles and folds, such as NLFs. 
Safety: To evaluate the incidence and type of adverse events and serious 
adverse events. 
Effectiveness 
Evaluation 
All endpoints will be assessed separately for the Radiesse and Restylane 
treatments, if not otherwise specified. 
Primary endpoint 
− 
Change from baseline to Week 24 after last injection on the Wrinkle 
Severity Rating Scale (WSRS)
 
. 
Secondary endpoints 
− 
Proportion of subjects with any improvement, defined as a rating of 
+ 1, + 2, or + 3, on the Investigator Global Aesthetic Improvement 
Scale (iGAIS) for each NLF at Week 24 after last injection, as 
assessed by the treating investigator. 
− 
Proportion of subjects with any improvement, defined as a rating of 
+ 1, + 2, or + 3, on the Subject Global Aesthetic Improvement Scale 
(sGAIS) for each NLF at Week 24 after last injection, as assessed 
by the masked subject. 
Safety 
Evaluation 
Secondary endpoint 
− 
Incidence of treatment-emergent adverse events related to Radiesse, 
as reported by the treating investigator throughout the trial. 
Trial Design 
Overview and 
Methodology 
This is a 48-week, prospective, randomized, multicenter, split-face, active-
comparator, blinded 
trial designed to 
evaluate the effectiveness and safety of Radiesse compared to Restylane 
for the correction of moderate to severe NLFs in healthy adults. 
Subjects will be enrolled from participating investigative sites in China. 
 

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9 
TRIAL POPULATION AND RESTRICTIONS ..................................... 29 
9.1 
Number of Subjects and Sites ................................................................. 29 
9.2 
Selection of Subject Population .............................................................. 29 
9.2.1 
Inclusion Criteria .............................................................................. 29 
9.2.2 
Exclusion Criteria............................................................................. 30 
 
 
9.2.4 
Subject Enrollment and Randomization ............................................ 33 
9.2.5 
Screen Failures ................................................................................. 33 
9.2.6 
Removal of Subjects from Therapy or Assessment ........................... 34 
9.2.6.1 
Treatment Discontinuation ......................................................... 34 
9.2.6.2 
Subject Withdrawal or Discontinuation ...................................... 34 
9.2.6.3 
Provision of Care for Subjects after Trial Discontinuation ......... 35 
9.2.7 
Suspension or Premature Termination of an Investigative Site .......... 35 
9.2.8 
Suspension or Premature Termination of the Trial ............................ 36 
9.2.9 
End of Trial ...................................................................................... 36 
10 TRIAL DEVICES AND TREATMENT OF SUBJECTS ....................... 37 
10.1 
Description of Trial Devices .................................................................. 37 
10.1.1 
Investigational Medical Device - Radiesse ....................................... 37 
10.1.2 
Comparator Device - Restylane ........................................................ 37 
10.3 
Methods of Assigning Subjects to Treatment Groups ............................. 38 
10.4 
Blinding Procedures ............................................................................... 39 
10.4.1 
Blinding ........................................................................................... 39 
10.4.2 
Planned Unblinding .......................................................................... 39 
10.5 
Trial Treatment ...................................................................................... 39 
10.5.1 
Planned Treatment Regimen ............................................................. 40 
10.5.1.1 
NLF Treatment Region ............................................................... 40 
10.5.1.2 
Treatment Administration Procedure .......................................... 41 
 
 
10.5.2 
Selection and Timing of Treatment for Each Subject ........................ 47 
10.5.3 
Treatment Interruption and Modification .......................................... 47 
10.6 
Prior and Concomitant Therapy .............................................................. 47 
10.7 
Trial Supplies and Packaging of Treatment Supplies .............................. 48 
10.8 
Receipt, Storage, Dispensing, and Return/Disposal ................................ 49 
10.9 
Device Accountability Procedures .......................................................... 49 
10.10 Treatment Compliance ........................................................................... 50 
10.11 Duration of Trial .................................................................................... 50 
11 TRIAL PROCEDURES ........................................................................... 51 
11.1 
Visit Schedule ........................................................................................ 51 
11.1.1 
Scheduled Visits ............................................................................... 52 
11.1.2 
Unscheduled Visits ........................................................................... 52 
11.2 
Trial Assessments and Definitions.......................................................... 52 
11.2.1 
Effectiveness Assessments ............................................................... 52 
11.2.1.1 
Wrinkle Severity Rating Scale (WSRS) ........................................ 52 
 
 

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13.5 
Special Statistical/Analytical Issues ....................................................... 71 
 
 
13.5.2 
Multiple Comparisons/Multiplicity ................................................... 71 
 
 
14 ADMINISTRATIVE PROCEDURES ..................................................... 72 
14.1 
Trial Monitoring .................................................................................... 72 
14.2 
Data Quality Assurance and Standardization Procedures ........................ 72 
14.3 
Source Documentation Requirements ..................................................... 72 
14.3.1 
Data Management ............................................................................ 73 
14.3.2 
Data Review and Clarification Procedures ........................................ 73 
14.3.3 
Direct Access to Source Data/Documents ......................................... 74 
14.3.4 
Auditing ........................................................................................... 74 
14.4 
Protocol Deviations and Amendments .................................................... 75 
14.4.1 
Protocol Deviations .......................................................................... 75 
14.4.2 
Protocol Amendments ...................................................................... 75 
14.5 
Record Retention ................................................................................... 76 
14.6 
Clinical Trial Report .............................................................................. 77 
14.7 
Publication of Trial Results .................................................................... 77 
14.8 
Financial Disclosure ............................................................................... 77 
14.9 
Investigator Compliance ........................................................................ 77 
15 REFERENCE LIST.................................................................................. 78 
16 APPENDICES .......................................................................................... 80 

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Responsibilities of All Parties 
Sponsor’s Statement 
The sponsor should perform duties according to Article 6 of “State Food and Drug 
Administration National Health and Family Planning Commission” (No. 25, People’s 
Republic of China, National Health and Family Planning Commission, National Medical 
Products Administration). The clinical trial institution and the investigators should perform 
duties according to Article 7 of “State Food and Drug Administration, National Health and 
Family Planning Commission” (No. 25, People’s Republic of China, National Health and 
Family Planning Commission, National Medical Products Administration). 
Investigator’s Statement 
I agree that: 
1. I will conduct this clinical trial in strict compliance with the Declaration of Helsinki, 
current laws and regulations of China, and the requirements of the protocol. 
2. I will record all required data accurately and in a timely manner on the Case Report 
Form (CRF) and complete the final report of the clinical trial on time. 
3. The investigational medical devices will be used only for this clinical trial, and the 
receipt and use of the investigational medical devices will be recorded completely and 
accurately, and the records will be retained during the process of the clinical trial. 
4. The monitor and verifier, as authorized or designated by the sponsor, and the regulatory 
authorities are allowed to conduct monitoring, verification, and inspection for the 
clinical trial. 
5. The clinical trial should be conducted in strict compliance with contract/articles of 
agreement signed by all parties. 
I have already read the clinical trial protocol, including the above statement, and I fully 
agree to all the above requirements.

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Comments from the sponsor: 
Signature (stamp): 
Date (MM/DD/YYYY): 
 
Comments from the investigator: 
Signature (stamp): 
Date (MM/DD/YYYY): 
 
Comments from the medical device clinical trial institution: 
Signature (stamp): 
Date (MM/DD/YYYY): 

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5 ETHICS 
5.1 
Ethical Conduct of the Trial 
This trial will be performed in accordance with the principles outlined in the Declaration 
of Helsinki and in compliance with the standards for Good Clinical Practice (GCP) 
described in International Organization for Standardization as adopted by the European 
Union (EN ISO) 14155 and in China’s GCP for Medical Devices (Chinese GCP; No. 25 
Order of China National Medical Products Administration (NMPA) and National Health 
and Family Planning Commission of the People’s Republic of China (NHFPC)), Notice on 
Issue of Guidelines for the Design of Medical Device Clinical Trials (CFDA 2018 No. 6), 
and any applicable regional or national laws and regulations. The trial will adhere to all 
applicable subject privacy requirements. Regulatory authorities will be notified and 
consulted as required prior to, during, and after the conduct of the trial. 
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 trial personnel will conduct the trial in compliance with this 
protocol. The investigator will ensure that all personnel involved in the conduct of this trial 
are qualified to perform the assigned trial responsibilities. Investigators will adhere to all 
applicable trial-reporting requirements. 
5.2 
Informed Consent 
A subject will provide verbal and written informed consent to the investigator (or 
authorized designee) according to the provisions set forth in the Declaration of Helsinki, 
EN ISO 14155 (Chapter 4.7), and Chinese GCP. The obligations of the investigator are set 
forth in the clinical trial protocol (CTP), the Declaration of Helsinki, EN ISO 14155, 
Chinese GCP, and local Chinese requirements governing medical research and 
experimentation on humans. Consent must be obtained from every subject prior to the 
initiation of any screening or trial procedures. The informed consent process must be 
traceable from the available documentation. At a minimum, this documentation should 
include information about when the subject was first informed about the investigation and 
who supplied the information. 
If the informed consent form (ICF) is amended during the trial, the investigator and the 
contract research organization (CRO) 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. 
One original, and any amended, signed and dated ICF(s) must be retained at the 
investigative site; a second original signed and dated ICF(s) must be given to the subject. 

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During the trial, the subject will be informed if information becomes available that may be 
relevant to the subject’s willingness to continue participation in the trial. In the case of an 
adverse event (AE) or poor tolerability to the trial device(s), the subject should inform the 
investigator, who will then make a judgment whether continuing in the investigation serves 
the subject’s best interest. The subject, however, is free to withdraw consent at any time 
and for any reason, whether expressed or not. 
5.3 
Subject Privacy 
The subject will be informed of procedures to protect subject privacy. The CRO, the 
sponsor, or an authorized vendor will process subject data only 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 Regulation (European Union or EU) 2016/679 (General Data Protection Regulation). 
Informed consent on data processing will be obtained in writing directly from the subject 
before recording of any data. Authorization to use and disclose health information that 
could identify the subject (referred to as protected health information or 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). 
5.4 
Confidentiality of Subject Information 
Subject pseudo-anonymity is to be maintained during the trial. Subjects will be identified 
by a unique, assigned number on all trial 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 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 trial participation. At a subject’s request, the subject’s medical information 
may be provided to other appropriate medical personnel. 
If the results of the investigation are published, the subject’s identity will remain 
confidential. 

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5.5 
Insurance 
The trial sponsor will provide insurance. From the beginning of the investigation until its 
termination, each subject is insured against any health impairment occurring as a result of 
participation in the investigation in accordance with Chinese laws and regulations. 
The subject will be informed by the investigator and through the ICF about the existence 
of this insurance and the resulting obligations. The insurance conditions will be distributed 
to the subject if requested or if required by local Chinese requirements. 
Any medical deviation from the CTP that is deemed to have occurred through the subject’s 
own fault is not covered by this insurance. 
Relatedness of potential injury to trial devices and/or procedures should be assessed by the 
treating investigator. The sponsor is usually not liable for injuries or deaths that occur 
solely because of the subject’s pre-existing medical condition(s) or from diagnostic or 
therapeutic measures not specifically required by the agreed CTP. The sponsor is also 
usually not liable for events resulting from negligence of the investigator, trial personnel, 
and/or CRO, including failure to act according to EN ISO 14155 principles and/or 
Chinese GCP or to comply strictly with the agreed CTP. 
The terms of the insurance will be kept in the trial files. 
5.6 
Financing 
The financial aspects of the investigation will be documented in an agreement between the 
sponsor, the CRO, and each investigator or any other involved party, and must be 
confirmed in writing before the investigation commences. 

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6.2 
Trial Rationale 
Radiesse first received EU approval in 2003 for plastic and reconstructive surgery, 
including deep dermal and subdermal soft-tissue augmentation of the facial area [14]. In 
2006, Radiesse received USA FDA approval for the correction of moderate to severe facial 
wrinkles and folds, such as NLFs, and for the correction of mid-facial lipoatrophy in people 
with human immunodeficiency virus (HIV). Marketed in more than 50 countries [14], 
Radiesse has become a very effective filler agent, providing soft-tissue augmentation for 
many areas of the face, while maintaining an excellent safety and patient satisfaction 
profile. 
6.2.1 
Justification of Proposed Trial Design and Primary Effectiveness 
Endpoint 
This current trial is designed to demonstrate the effectiveness and safety of Radiesse in a 
split-face trial that compares this CaHA dermal filler to an HA dermal filler, Restylane, for 
treatment of NLFs. The safety and effectiveness of Radiesse for use as a soft-tissue filler 
in the NLFs, hands, and face has been demonstrated in other studies, resulting in extensive 
use worldwide [10-15]. Although Radiesse, as a CaHA, differs from HA fillers in its 
ultimate mechanism of action, proposed use of a split-face trial design and an active 
comparator follows China’s Center of Medical Device Evaluation (CMDE) guidelines for 
NLF treatment with dermal fillers. The primary effectiveness endpoint has been chosen to 
demonstrate that Radiesse will be non-inferior to Restylane for correction of moderate to 

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shivering, lymphadenopathy, burning sensation, injection-site sore/warmth, induration, 
fever, cellulitis, impetigo, loss of effect, product displacement/migration, allergic reaction, 
anaphylaxis, hives, rash, pruritus, urticaria, angioedema, inflammation, necrosis, 
granuloma, blister, vesicle, papule, lump/bump (visible and/or palpable material) or 
nodules, erythema, ecchymosis/bruising, skin discoloration, hyper- or hypo-pigmentation, 
pustule, skin pallor, hair loss, tingling, numbness, hypoesthesia, paresthesia, ptosis, 
headache, edema/swelling, asymmetry, abscess, temporary scabs, needle marks, urticaria, 
transient bleeding, hematoma, telangiectasia, herpetic infection (including herpes simplex 
and herpes zoster), hematoma, blanching, blistering, headache/cephalgia, dizziness, flu-
like symptoms, Guillain-Barre syndrome, tachypnea, ischemic reaction, lymphoid 
hyperplasia, nausea, vomiting, pericarditis, scarring, sensitivity to cold, vascular 
occlusion/obstruction, vascular compromise, embolization, necrosis, ocular ischemia, 
diplopia, visual impairment/blindness, facial muscle paralysis, Bell’s palsy, impairment of 
the otorhinolaryngological system (e.g.,  nasal congestion, oropharyngeal pain, dysgeusia, 
rhinorrhea, epistaxis, sinusitis, transient hearing loss) mastication pain, muscle twitching, 
muscle injury, anxiety caused by trypanophobia and disappointment (i.e., due to lack of or 
reduced product performance, decreased firmness/response, undesirable aesthetic effect, 
injection-site discharge, injection-site indentation, superficial vein prominence, patient 
dissatisfaction)
). 
Vascular occlusion, resulting in ischemia/necrosis, and vision disturbances, including 
blindness, have been reported following injection of soft-tissue fillers in the face especially 
when injected in the nose, glabella, periorbital areas, NLFs, and cheek; time to onset may 
range from immediate to a few weeks following injection. Vascular compromise may occur 
due to an inadvertent intravascular injection or as a result of vascular compression 
associated with implantation of any injectable product. This condition may manifest as 
blanching, discoloration, necrosis, or ulceration at the implant site or in the area supplied 
by the blood vessels affected, or rarely, as ischemic events in other organs due to 
embolization. Isolated, rare cases of ischemic events affecting the eye, leading to visual 
loss, and affecting the brain, resulting in cerebral infarction, following facial aesthetic 
treatments have been reported. 
Additional information on product- and treatment administration-related contraindications, 
warnings, and precautions can be found in the applicable investigational device and 
comparator device IFUs
 

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7 TRIAL OBJECTIVES AND ENDPOINTS 
7.1 
Objectives 
Effectiveness 
The primary objective is to demonstrate non-inferiority of Radiesse (CaHA) to Restylane 
(HA) following subdermal implantation for the correction of moderate to severe facial 
wrinkles and folds, such as NLFs. 
Safety 
The safety objective includes an evaluation of the incidence and type of adverse events 
(AEs) and serious adverse events (SAEs). 
7.2 
Endpoints 
All endpoints will be assessed separately for Radiesse and Restylane treatments, if not 
otherwise specified. 
 
7.2.1 
Effectiveness Endpoints 
7.2.1.1 
Primary Effectiveness Endpoint 
• Change from baseline to Week 24 after last injection on the Wrinkle Severity Rating 
Scale (WSRS)
. 
7.2.1.2 
Secondary Effectiveness Endpoints 
• Proportion of subjects with any improvement, defined as a rating of + 1, + 2, or + 3, on 
the Investigator Global Aesthetic Improvement Scale (iGAIS) for each NLF at Week 
24 after last injection, as assessed by the treating investigator. 
• Proportion of subjects with any improvement, defined as a rating of + 1, + 2, or + 3, on 
the Subject Global Aesthetic Improvement Scale (sGAIS) for each NLF at Week 24 
after last injection, as assessed by the masked subject. 

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7.2.2 
Safety Endpoints 
7.2.2.1 
Secondary Safety Endpoint 
• Incidence of treatment-emergent AEs (TEAEs) related to Radiesse, as reported by the 
treating investigator throughout the trial. 

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9 TRIAL POPULATION AND RESTRICTIONS 
9.1 
Number of Subjects and Sites 
Approximately 118 subjects will be randomized at up to seven investigative sites in China. 
Enrolled subjects will sign and date the ICF before any trial-related procedures are 
undertaken. At each of seven sites, the number of subjects treated should not exceed 20 to 
ensure a reasonable distribution of subjects across all investigative sites (see Section 13.1.2 
for additional information). 
Any treated subject who does not complete the trial will not be replaced. 
Additional information regarding the estimation of sample size, including the numbers of 
randomized subjects projected for trial sites, is reported in Section 13.1. Further 
information related to subject randomization is provided in Section 13.2. 
9.2 
Selection of Subject Population 
Assessment for eligibility criteria is based on the subject’s medical records, an interview 
with the candidate subject, and investigator judgment. Selection criteria have been chosen 
to identify a suitable subject population to investigate the trial objectives and to minimize 
safety concerns in this population. 
9.2.1 
Inclusion Criteria 
To be eligible for trial participation, each subject must meet all of the following criteria at 
screening (V1; Day −10 to 1) and/or baseline (V2; Day 1): 
 Has symmetrical NLFs, with the same WSRS score of 3 or 4 (moderate or severe) for 
both right and left NLFs
. 
 Is ≥ 22 and ≤ 65 years of age. 
 Is willing to abstain from all other aesthetic treatments on ANY part of the face, 
including but not limited to injectable fillers, implants, neurotoxin, skin peels, laser 
treatments, surgical treatments, etc. for the trial’s duration. 

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9.2.4 
Subject Enrollment and Randomization 
Subjects are considered to be enrolled once the ICF is signed and dated. Eligible subjects 
will be randomized at baseline (V2). 
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 trial (i.e., 
screen failure) may not be rescreened. 

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9.2.6 
Removal of Subjects from Therapy or Assessment 
9.2.6.1 
Treatment Discontinuation 
In the current trial design, potential reasons for discontinuation of treatment may include 
refusal by the subject to receive a required or recommended touch-up injection (i.e., 
necessary to achieve optimal correction) or a treating investigator’s decision that the risk 
of continued treatment (i.e., touch-up injection) is greater than the subject’s potential 
benefit. 
If treatment is discontinued, the investigator will record the reason for treatment 
discontinuation in the trial records. The investigator may request that a subject 
discontinuing treatment continue to participate in the trial and complete all remaining visits 
and assessments for safety follow-up. For subjects who decline to continue trial 
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 trial, or until the sponsor decides to terminate 
the trial, whichever comes first. The only reasons a subject will not be followed for all 
scheduled visits include withdrawal of consent, continuous noncompliance with protocol 
requirements, or loss to follow-up (e.g., moving away from trial 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 trial at any time at his/her own request without 
any penalty or loss of benefits to which the subject is otherwise entitled. 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 trial visit, the following actions will be taken: 
• The site will make every reasonable attempt to contact the subject and reschedule the 
missed visit as soon as possible. Every effort to regain contact with the subject will be 
made (e.g., phone contact on different dates/times, registered mail). All contact 
attempts will be documented. 
• If attempts to contact the subject are not successful, the subject will be considered lost 
to follow-up and discontinued from the trial. 
The reason for the subject’s discontinuation should be documented in the electronic case 
report form (eCRF). The investigator should make every attempt to complete the 
recommended follow-up assessments specified for the End of Trial (EOT) visit specified 
in the Schedule of Events (Section 11.1
) while fully respecting the 
subject’s rights. If appropriate, according to local regulations, IEC/IRB and Competent 
Authorities should be informed. 

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If a non-serious AE is unresolved at the time of the subject’s final trial visit, an effort will 
be made to follow the subject until the AE is resolved or stabilized, the subject is lost to 
follow-up, or some other resolution of the event occurs. The investigator should make 
every attempt to follow all SAEs/unanticipated serious adverse device effects (USADEs) 
to resolution. Information on pregnancy and the outcome for any female who becomes 
pregnant during the trial will be collected. 
9.2.6.3 
Provision of Care for Subjects after Trial Discontinuation 
The investigator is responsible for ensuring the adequate and safe medical care of subjects 
during the trial. At the end of the trial or after subject discontinuation, the investigator will 
ensure that appropriate consideration is given to a subject’s after-trial care. Subjects will 
be treated by their physician according to their medical condition and standard treatments 
in China. Additionally, the sponsor will follow all applicable local or international 
regulations and guidelines regarding follow-up care for subjects. 
9.2.7 
Suspension or Premature Termination of an Investigative Site  
Trial participation by individual sites may be suspended or prematurely terminated by the 
sponsor. Reasons for the suspension or premature termination of sites include, but are not 
limited to, the following: 
• Investigator request; 
• Serious or persistent noncompliance with the protocol, local regulations, and/or 
Chinese GCP; 
• Suspicion of fraud; 
• Failure to accrue subjects at an acceptable rate; and/or 
• Ethical issues. 
The sponsor will provide the investigative site with written notification documenting the 
reason for suspension or premature termination. The sponsor will inform the responsible 
regulatory authority, as appropriate, and ensure the IEC/IRB is notified. If the suspension 
or premature termination was in the interest of safety, the sponsor will inform all other 
principal investigators. 
In cases of temporary suspension at an investigative site, the sponsor will conduct an 
analysis of the reason(s) for suspension. After completing this analysis and implementing 
necessary corrective actions, a temporary site suspension may be lifted. The sponsor will 
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. 

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In cases of premature termination, the investigator will conduct site-closure activities in 
accordance with all applicable sponsor, local, and international guidelines and regulations. 
9.2.8 
Suspension or Premature Termination of the Trial 
Should the investigator, sponsor, the NMPA, or local regulatory authorities become aware 
of conditions arising during the conduct of this trial that may warrant the cessation of the 
trial, such action may be taken. Prior to such action, consultation between the sponsor, the 
investigator, and, as appropriate, the NMPA and/or local regulatory authorities will occur. 
Reasons for the suspension or premature termination of the trial include, but are not limited 
to, the following: 
• Anticipated benefit cannot justify the risk; 
• New scientific data do not justify a continuation of the trial; 
• Determination of a potential safety risk to subjects; 
• Inadequate subject enrollment; 
• Decision by the regulatory authority or IEC/IRB to suspend or terminate approval/ 
favorable opinion for the trial; 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 suspend the trial while the risk is 
assessed. 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. 
If the trial is suspended or prematurely terminated for any reason, the sponsor will inform 
all 
investigators 
and 
relevant 
regulatory 
authorities 
promptly 
of 
the 
trial 
suspension/termination and reason for the action, as detailed in Section 9.2.7. The 
investigator will conduct site-closure activities in accordance with all applicable sponsor 
and local/international guidelines and regulations. 
9.2.9 
End of Trial 
The end of the trial is defined as when the database is closed for the final (Week 48 after 
last injection) analyses. 

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needles. Restylane will be supplied by the trial sponsor and will be marked for trial-specific 
clinical use only. Restylane must be used prior to the expiration date printed on the 
package. It should be stored at a temperature of up to 25° C (77° F). Do not freeze. Protect 
from sunlight. Do not resterilize Restylane as it may damage or alter the product. Do not 
use if the package is damaged. 
Restylane is intended to be used for facial-tissue augmentation by injection into the mid-
dermis to correct moderate to severe NLFs. Restylane should be injected into the middle 
part of the dermis layer of the facial skin. This product is only intended for use as an 
intradermal implant, and should not be used for breast injection. Restylane will degrade 
gradually in the body, typically 6 to 12 months after injection. With degradation, the filler 
effect will disappear. Patients preferring to maintain the filler effect can receive follow-up 
injection when the filler effect disappears. [Note: No retreatment injection will be provided 
under 
this 
CTP.] 
As 
reported 
 
 
 
 
 
, the filler effect remains for longer than six months in the 
majority of patients as shown in the Chinese study, where the patients were injected in the 
NLFs. 
10.3 Methods of Assigning Subjects to Treatment Groups 
Subjects who complete all screening assessments and meet all eligibility criteria will be 
randomized 1:1 to one of the following groups prior to injection: 
− Group 1: left NLF: Radiesse, right NLF: Restylane 
− Group 2: left NLF: Restylane, right NLF: Radiesse 
Care must be taken to follow the subject’s randomization assignment, ensuring that the 
Radiesse and Restylane syringes are injected in the randomly assigned NLF (left NLF or 
right NLF). Accurate documentation of which product (Radiesse or Restylane) is injected 
into which NLF (subject’s right or left) is of critical importance in this trial. 
This information will remain in the subject’s source documents and be made available for 
verification of the proper randomization sequence by the sponsor or designee during 
monitoring visits. 

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5. Do not apply excessive pressure to the syringe at any time. If resistance is encountered 
the needle should be partially withdrawn and repositioned or fully withdrawn and 
checked for function.  
6. The correction site should be massaged to conform to the contour of the surrounding 
tissues. 
7. If the product is injected too superficially this may result in visible lumps and / or bluish 
discoloration. 
10.5.1.2.2.4 
After-Injection Procedures 
When the injection is complete, the treatment site may be gently massaged, if 
necessary. 
Subjects may have mild to moderate injection-site reactions, which typically resolve in 
< 7 days. 
Use the device once and discard in accordance with local safety standards. 
 

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10.5.2 
Selection and Timing of Treatment for Each Subject 
Subjects will have an initial injection at baseline (V2) on Day 1, as well as the option for a 
touch-up injection in one or both NLFs at Week 4 (V3). If a touch-up is performed, the 
same randomized product assigned for the initial injection must be used for touch-up 
injection. A touch-up treatment will only be administered if there are no medical 
contraindications or existing AEs of concern, as determined by the treating investigator. 
 
10.5.3 
Treatment Interruption and Modification 
In the current trial design, treatment interruption or modification is not expected. 
However, if immediate blanching occurs in the treatment area, the injection should be 
stopped and the area massaged until it returns to a normal color. Blanching may represent 
a vessel occlusion. If normal skin coloring does not return, do not continue with the 
injection. Treat in accordance with American Society of Dermatologic Surgery guideline 
[18]. 
The treating investigator should immediately stop the injection if a trial subject exhibits 
any of the following symptoms: changes in vision, signs of stroke, blanching of the skin, 
difficulty walking, or atypical pain during or shortly after the procedure. Subjects should 
receive prompt medical attention and possibly evaluation by an appropriate healthcare 
practitioner (specialist) should an intravascular injection occur. 
The treating investigator must inform all subjects that, at any time over the trial interval, if 
the subject experiences any new or unusual symptoms, including signs related to a possible 
vascular event, including any atypical pain, changes in vision, irregularities in skin color 
and/or skin texture 
, or 
scabby/crusty skin, the subject must seek immediate medical attention and notify the 
treating investigator immediately. The treating investigator must refer the subject to a 
specialist if additional medical attention is deemed necessary. 
10.6 Prior and Concomitant Therapy 
Medical history and concomitant therapy that is deemed relevant for study conduct by the 
investigator (e.g., chronic diseases, previous aesthetic treatments) should be documented 

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in the eCRF. Restrictions regarding concomitant therapy are discussed in detail in 
Section 9.2.2 (Exclusion Criteria)
. 
10.7 Trial Supplies and Packaging of Treatment Supplies 
Radiesse and Restylane will be provided by the sponsor. The sponsor will package trial 
materials according to applicable regulatory requirements. The sponsor will provide all 
pertinent labeling information, as well as a description of the specific device-packaging 
conditions. 
Radiesse and Restylane are to be used exclusively for treatment of subjects enrolled in this 
trial and will be labeled as follows: “CAUTION – Investigational Device. Limited to 
Investigational Use Only.” Device labels will also note the manufacturer name and address 
and the quantity within the package. The IFUs for the respective products will be provided 
to the investigative sites. Clinical trial supply should be stored in a controlled area with 
limited access and stored separately from any commercial supplies. 
Parts of the trial devices may be subject to reduced labeling according to the applicable 
regulations. Records about production date, serial number (as applicable), test record 
related to product quality and stability, and records of transportation, maintenance, and 
delivery must be kept with the trial devices. 

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11 TRIAL PROCEDURES 
11.1 Visit Schedule 
The investigation activities and visit schedule are detailed in the Schedule of Events 
(Appendix 16.1) and the Trial Design figure (Appendix 16.2). 
The screening visit (V1) is required to determine subject eligibility for trial participation; 
this visit must be completed no more than 10 days prior to baseline (V2) or on the same 
day of the baseline visit (i.e., baseline and screening can occur on the same day if all 
screening procedures, 
and 
laboratory results, have been obtained prior to trial device injection). 
The baseline visit (V2) is the day of subject randomization and first administration of the 
investigational and comparator products. A touch-up injection may be administered 
(Visit 3, Week 4) to ensure the subject achieves optimal aesthetic correction (Section 10.2). 
All treatments will be administered at the investigative site 
, 
occurring only after completion of all required pre-injection procedures and assessments. 
The primary endpoint visit (PEV) will occur at Week 24 (± 7 days) after last injection, and 
the EOT visit will occur at Week 48 (± 7 days) after last injection. In the case of a subject’s 
premature discontinuation of the trial, a final assessment (EOT visit) should be performed. 

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11.2.2 
Safety Assessments 
Standard safety assessments, including documentation of AEs and SAEs reported by the 
investigator throughout the trial, will be evaluated. 
Refer to the respective endpoints (Section 7.2.2) 
 
for additional information on the safety assessments. 
11.2.2.1 
Adverse Events (AEs) / Serious Adverse Events (SAEs) 
All AEs/SAEs reported by trial subjects, investigators, or other trial staff after the time of 
informed consent through the last trial follow-up visit will be recorded. All AEs/SAEs will 
be recorded regardless of causality. 
Additional information (e.g., definitions, reporting requirements) is provided in 
Section 12. All AEs/SAEs will be assessed throughout the trial, including on-site trial 
visits and during follow-up phone calls. 
Any AE/SAE must be documented in the subject’s file and on the AE eCRF page. 
Any AE/SAE observed will be fully investigated, documented, and followed until the 
AE/SAE is either resolved or adequately explained, until the EOT visit (Section 12.2.2). 
Serious AEs occurring after the end of the observational period only need to be reported if 
the investigator considers the SAE to be related to the trial devices. These reports generally 
will not be entered into the investigation database. 

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11.2.3 
Additional Data Collected 
Other data collected are as follows: 
− Demographics and other baseline characteristics, including height and weight; 
− Injection technique, location, and depth; 
− Relevant medical history/concomitant diseases; 

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− Concomitant therapies; and 
− Vital signs. 
 
11.2.3.1 
Laboratory Assessments 
Non-fasting clinical laboratory tests will be performed at screening (V1) and Week 24 after 
last injection. These lab tests include clinical chemistry, hematology, and urinalysis to rule 
out underlying disease that may exclude the subject from participation or require initiation 
of medical care during the trial 
. 
 

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11.2.3.2 
Vital Signs 
Vital signs will be measured on subjects after they have been seated for approximately 
five minutes. Resting heart rate and blood pressure (systolic and diastolic, preferably on 
the same arm each time) will be measured at screening (V1) and Week 24 after last 
injection. 
 
11.2.4 
Appropriateness of Assessments 
Appropriateness of the selected trial assessments is detailed in the respective Effectiveness 
Assessments (Section 11.2.1) and Safety Assessments (Section 11.2.2). 

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record any AE in detail in the subject’s file and on the AE eCRF. The following information 
must be recorded: 
• AE diagnosis or main symptom; 
• AE localization (restricted to treatment area, systemic). If a local reaction, the 
corresponding area should be reported; 
• Date of onset; 
• Intensity (maximum observed using the Severity Grading scale; Section 12.1.3); 
• Causal relationship (not related, related) to investigational device and study procedure; 
• Causal relationship (not related, related) to comparator device; 
• Serious (yes, no), date serious since, and reason for seriousness; 
• Outcome (Section 12.1.5); 
• AE leading to discontinuation of the clinical trial (yes, no); 
• Action taken with medical device; 
• Action taken related to the AE; and 
• Stop date. 
In cases of an SAE (defined in Section 12.2), the investigator must also complete an SAE 
Report Form and report it to the sponsor and CRO immediately 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 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 to the treatment procedure if a causal 
relationship between the IMD or the treatment procedure and an AE is at least reasonably 

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possible (i.e., the relationship cannot be ruled out). In this case, the non-serious event is 
considered an “adverse device effect” (Section 12.3). If the event is serious, it is a “serious 
adverse device effect” (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”. 
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: 
a) led to death; 
b) led to serious deterioration in the health of the subject, that either resulted in: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function including 
chronic diseases, or 
3) inpatient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
c) led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the 
CTP, without serious deterioration in health, is not considered an SAE. 

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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. 
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 usually 
not regarded as SAEs. 
In addition, device deficiencies, as defined in Section 12.5, that might have led to an SAE 
if: 
a) suitable action had not been taken; or 
b) intervention had not been made; or 
c) 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 trial period, whether considered to be related to the 
IMD or not, must be reported via fax, phone, or e-mail, and an SAE Report Form should 
be submitted to the sponsor and the CRO immediately upon knowledge of the event. The 
investigator will report the SAE to the clinical trial management departments of the clinical 
trial institution and the CRO. Further reporting details will be outlined in the Safety 
Management Plan. 
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/investigative site identification); and/or 
• An event or outcome that can be identified as serious. 
The investigator must report SAEs to the sponsor and the CRO, as defined in Section 12.2 
and in compliance with Chinese GCP (Article 71), and to the site’s IEC/IRB, through the 
medical device clinical trial management department, per their reporting guidelines. 

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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) 
An 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 Serious Adverse Device Effect 
(USADE) 
A USADE 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 investigational 
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 Reporting of Pregnancy 
Any pregnancy that starts during the clinical trial must be reported by the investigator to 
the sponsor and CRO immediately. 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 page (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 trial, the subject must not receive further 
treatments (i.e., touch-up treatment); however, the subject will remain in the trial. In cases 
of pregnancy, clinical laboratory tests will not be performed. 

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12.7 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 effectiveness. 
Note: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
12.7.1 
Reporting and Handling of Device Deficiencies 
All device deficiencies shall be documented and reported by the investigator throughout 
the clinical investigation and appropriately managed by the sponsor. 
The investigator should retain the device and/or needle in question for future inspection 
and investigation by the sponsor, if necessary. 
The investigator will attempt to evaluate if the deficiency 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: 
• A Device Deficiency eCRF page must be completed and submitted by the investigator, 
irrespective of the seriousness of the case. 

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13.4.2 
Safety Analyses 
All safety endpoints will be analyzed for the SES. 
Adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version that is in effect at the time the database is closed. 
Only TEAEs will be analyzed, which are defined as AEs with onset at or after the first 
administration of Radiesse or Restylane. If an AE starts prior to treatment but worsens at 
or after treatment, the investigator records this observation as a new AE with onset = time 
of worsening. new AE with onset = time of worsening. 
Similarly, only those device deficiencies that are reported to be associated with devices 
that were used to treat subjects will be analyzed. 
Non-TEAEs and device deficiencies reported for devices not used for treatment but 
documented in the eCRF will be listed only. 
For public disclosure, incidences of non-serious TEAEs regardless of relationship will be 
calculated at the system organ class (SOC) level and at the preferred term (PT) level and 
will be presented by treatment (where applicable) and overall. 
In case of a missing causal relationship of an AE, the worst-case principle will be applied 
(i.e., a missing causal relationship will be set to “related”). 
13.4.2.1 
Secondary Safety Endpoints 
Incidences of TEAEs related to Radiesse will be calculated at the SOC level and at the PT 
level and will be presented by treatment (where applicable) and overall. 

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13.5 Special Statistical/Analytical Issues 
13.5.2 
Multiple Comparisons/Multiplicity 
No multiplicity adjustments are required. Only one confirmatory analysis of the primary 
effectiveness endpoint will be performed. All other analyses are for exploratory or 
sensitivity purposes. 

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14 ADMINISTRATIVE PROCEDURES 
14.1 Trial Monitoring 
Trial monitoring will conform to all applicable regulatory standards and guidelines. 
The sponsor or designee will monitor the trial through periodic site visits to verify: 
• Data authenticity, accuracy, and completeness. 
• Protection of subject rights and safety. 
• Conduct of the trial is in accordance with the currently approved protocol and all 
applicatory regulatory and IEC/IRB requirements and guidelines. 
Investigators agree to grant access to all relevant documents and provide support at all 
times for trial-monitoring activities. These 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 provided in the monitoring manual. 
14.2 Data Quality Assurance and Standardization Procedures 
Inspections by regulatory-authority representatives and institutions are possible at any 
time, even after the end of trial. The investigator is to notify the sponsor immediately of 
any such inspection. The investigator and institution will permit trial-related monitoring, 
audits, and/or reviews by the regulatory authorities and will allow direct access to source 
data and source documents for such monitoring, audits, and reviews. 
Standardization procedures will be implemented to ensure accurate, consistent, complete, 
and reliable data, including methods to ensure standardization among sites (e.g., training, 
newsletters, investigator meetings, monitoring, evaluations, and validation methods). 
 
This trial will be monitored regularly by a qualified monitor from the CRO according to 
EN ISO 14155, Chinese GCP, Chinese regulatory authority requirements, and the 
respective standard operating procedures 
. 
14.3 Source Documentation Requirements 
All data collected from a subject during the course of a clinical investigation should be 
retained in the respective source documentation (e.g., subject file). Although not an 
exhaustive list, this information should include a descriptive statement on the informed 
consent procedure (Section 5.2). The investigator must also confirm by written statement 
in the source documentation that all inclusion criteria and all exclusion criteria were 
checked prior to inclusion of the subject. In addition to this statement, the subject’s meeting 
or non-meeting of the in- and exclusion criteria and eligibility criteria must be traceable in 
the source documentation. The childbearing potential of female subjects must be 

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documented in the file. The site will keep a source-data location list, which will outline for 
the different data categories, including electronic data (e.g., demographics, relevant 
medical history, and AEs, etc.), which document serves as its source
 
. 
Further information (e.g., procedures for verification, validation, and securing of 
applicable electronic clinical data systems) will be described in the data management plan. 
14.3.1 
Data Management 
Data required according to this protocol are to be recorded in the web-based eCRFs (EDC 
system). All users who have access to the EDC system will be trained for their respective 
roles, and their training will be documented. After successful completion of the training, 
participants will receive a training certificate, which will be a pre-requisite for access to 
the eCRF. Access to the eCRF will be password controlled. 
Data-plausibility checks will be performed according to a data validation plan. 
Inconsistencies in the data will be queried to the investigators via the EDC system; answers 
to queries or changes to the data will also be documented in this system directly by an 
authorized member of the investigator’s trial personnel. The audit trail in the EDC system 
will document all changes. Edit checks generate automatic queries during data entry when 
a field is not populated according to specifications defined in the data validation plan. 
Manual queries to be answered by trial personnel can be raised during source data 
verification and/or during medical, safety, and/or data management review. After all data  
are entered and all queries are solved, the database will be closed and unblinding will take 
place. If any data changes are required after database close, these changes will be 
documented according to the respective SOP. 
14.3.2 
Data Review and Clarification Procedures 
By electronically signing the eCRF with an automated time stamp, the investigator will 
confirm that all investigations have been completed and conducted in compliance with the 
CTP and that reliable and complete data have been entered into the eCRF. 

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All data required by this CTP 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. 
If eCRF corrections are necessary, an authorized member of the investigator’s trial 
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 trial 
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. Per Chinese GCP, clinical trial records, 
as the original materials, must not be changed without authorization. If such a change is 
required, the reason shall be explained, and the explanation shall be signed and dated. 
14.3.3 
Direct Access to Source Data/Documents 
As stated in Section 14.1, investigators agree to grant access to all relevant documents and 
to provide support for monitoring activities. 
Subjects providing informed consent (Section 5.2) agree to allow the sponsor or designee 
access and copying rights to pertinent information in their medical records concerning their 
participation in this trial. The investigator will obtain, as part of the informed consent, 
permission for trial monitors or regulatory authorities to review, in confidence, any records 
identifying the subjects in this trial. This information may be shared with regulatory 
agencies; however, the sponsor undertakes not to otherwise release the subject’ s personal 
and/or private information. 
14.3.4 
Auditing 
Audits shall be conducted by qualified auditors to evaluate compliance with the CTP, 
sponsor’s current written procedures, and any applicable regulatory requirements. These 
audits may cover all involved parties, systems, and facilities and are independent of, and 
separate from, routine monitoring or quality-control functions. 
An audit can be conducted: 
• as a routine part of the sponsor’s quality-assurance program; 
• to assess the conduct of the monitoring activity; 
• whenever there are serious or repeated CTP deviations or suspicion of fraud; 

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• to bring an investigative site into “inspection readiness” (i.e., to prepare the 
investigative site for a potential regulatory inspection), and/or 
• when requested or suggested by a regulatory authority. 
Audit results shall be documented and communicated to relevant parties, if applicable. 
14.4 Protocol Deviations and Amendments 
14.4.1 
Protocol Deviations 
Investigators will not deviate from or alter the CTP without written agreement between the 
principal investigator and the sponsor and written approval by the IEC/IRB based on prior 
review. Exceptionally, in case of urgent clinical need (e.g., to minimize emergent risk to a 
subject), the principal investigator may deviate from the protocol without this written 
agreement. After mitigating the immediate risk, the investigator must contact the sponsor 
and the CRO without delay to report the incident. 
In the event that an investigator does not comply with the Clinical Trial Agreement or the 
CTP, the sponsor will be notified of the site’s noncompliance. 
In the event of repeated noncompliance, as determined by the sponsor, a sponsor’s monitor 
or company representative will attempt to secure compliance by one or more (and not 
limited to) of the following: 
• Visiting the investigator; 
• Telephoning the investigator; and/or 
• Corresponding with the investigator. 
Repeated noncompliance with the signed Clinical Trial Agreement, the CTP, or any other 
conditions of the trial may result in further escalation in accordance with the sponsor’s 
written procedures, including securing compliance or, at its sole discretion, the sponsor 
may terminate the investigator’s participation in the trial. 
If CTP deviations occur at the investigation site, these will be detected during routine 
monitoring visits and reported in the visit report. In addition, a list containing all deviations 
reported from monitoring visits will be maintained by the CRO, analyzed for frequency 
and severity, and discussed with the sponsor on a regular basis. Depending on the type of 
deviation, corrective and preventive actions will be defined and implemented accordingly. 
14.4.2 
Protocol Amendments 
Approved CTP amendments will be provided to investigators by the sponsor. The principal 
investigator is responsible for notifying the IRB/IEC of the CTP amendment (if 
administrative changes) or obtaining IRB/IEC’s approval of the CTP amendment (if 
changes in subject care or safety), according to instructions provided by the sponsor. 

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Acknowledgement/approval by the IRB/IEC must be documented in writing prior to 
implementation of the CTP amendment. Copies of this documentation must also be 
provided to the sponsor. 
14.5 Record Retention 
Essential documents should be retained per applicable regulations and as instructed by the 
sponsor. Essential documents at the investigative site include, but are not limited to: 
• Source documentation (e.g., subject files); 
• Subject identification code list (i.e., provided by template to the investigator, along 
with the Investigator Site File, at the beginning of the investigation), which identifies 
the subject by number, name, and date of birth; 
• A copy of the CTP and any amendments; 
• A CD/DVD with eCRF data and any associated subject-related source data (or, where 
applicable, authorized copies of source data); 
• Signed ICFs; 
• Copies of site investigators’ and co-workers’ curricula vitae; 
• Copies of all direct correspondence with the IEC/IRB and with the regulatory 
authority(ies); 
• Copies of all relevant correspondence between the investigator and the monitor and 
between the investigator and the sponsor; 
• Copies of investigational device disposition records; 
• Copies of safety information reported during the investigation and submitted by the 
sponsor. 
Trial documents may not be destroyed by site personnel prior to the end of the required 
retention period, as specified by local regulations. The investigator or the institution must 
inform the sponsor in due time if the investigator leaves the institution during the retention 
period. This rule also applies when the institution closes within the retention period. 
Upon closure of the trial, the investigator must maintain all trial-site records in a safe and 
secure location. The investigator is responsible for the integrity, retention, and security of 
all trial-related records. The investigator must ensure that any reproductions of the original 
records are legible and provide a true and accurate copy of the original. Accurate, complete, 
and current records must be stored in a manner to permit easy and timely retrieval for the 
sponsor or any applicable regulatory authorities. 
The sponsor will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements, with the minimum retention time being 
the longest of those times dictated by institutional requirements, local laws or regulations, 

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or the sponsor’s standard procedures. The investigator must notify the sponsor in the event 
of any changes to archival arrangements due to withdrawal of the investigator’s 
responsibility for keeping trial records to ensure that suitable arrangements for the retention 
of trial records are made. 
14.6 Clinical Trial Report 
A clinical trial report containing effectiveness and safety analyses will be generated after 
all subjects have completed the trial. The content of the report will meet China CMDE 
requirements. 
14.7 Publication of Trial Results 
The results of this trial and any discoveries related to this trial, regardless of whether they 
have technical or medical character, are the property of the sponsor. 
The CTP, trial data, and information related to the trial 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 trial may be used for submission to national 
or international registration and supervising authorities. Upon completion of the trial, 
publication or disclosure of trial results is to follow the terms contained in the sponsor’s 
publication policy. 
The sponsor will ensure the clinical trial is registered, and results are reported in public 
registries, at minimum in case one or both is required by law and/or other applicable 
requirements (e.g., on ClinicalTrials.gov if required by U.S law and/or on Chinese Clinical 
Trial registry (ChiCTR)). Trial registration may include a list of investigative sites, as 
applicable. 
14.8 Financial Disclosure 
Financial aspects of the investigation will be documented in an agreement between the 
sponsor, the CRO, and each investigator or any other involved party, and must be 
confirmed in writing before the investigation commences. 
14.9 Investigator Compliance 
The investigator will conduct the trial in compliance with the CTP, EN ISO 14155, Chinese 
GCP, the Declaration of Helsinki, and Chinese regulatory authority requirements. 
Additional information is reported in Section 14.4.1. 

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15 REFERENCE LIST 
1. Carruthers JD, Glogau RG, Blitzer A. Advances in facial rejuvenation: botulinum toxin 
type a, hyaluronic acid dermal fillers, and combination therapies--consensus 
recommendations. Plast Reconstr Surg. 2008;121(5 Suppl):5S-30S; quiz 1S-6S. 
2. Finn CJ, Cox SE, Earl ML. Social implications of hyperfunctional facial lines. 
Dermatol Surg. 2003;29(5):450-5. 
3. Fisher GJ. The pathophysiology of photoaging of the skin. Cutis. 2005;75(2 Suppl):5-
8; discussion -9. 
4. Freiman A, Bird G, Metelitsa AI, Barankin B, Lauzon GJ. Cutaneous effects of 
smoking. J Cutan Med Surg. 2004;8(6):415-23. 
5. Honigman R, Castle DJ. Aging and cosmetic enhancement. Clin Interv Aging. 
2006;1(2):115-9. 
6. James J, Carruthers A, Carruthers J. HIV-associated facial lipoatrophy. Dermatol Surg. 
2002;28(11):979-86. 
7. Rexbye H, Petersen I, Johansens M, Klitkou L, Jeune B, Christensen K. Influence of 
environmental factors on facial ageing. Age Ageing. 2006;35(2):110-5. 
8. Tan SR, Glogau RG. Filler esthetics. In: Carruthers J, Carruthers A, editors. Procedures 
in cosmetic dermatology series: soft tissue augmentation. Philadelphia: Saunders; 
2005. p. 23-5. 
9. Lorenc ZP, Fagien S, Flynn TC, Waldorf HA. Review of key Belotero Balance safety 
and efficacy trials. Plast Reconstr Surg. 2013;132(4 Suppl 2):33s-40s. 
10. Moers-Carpi M, Vogt S, Santos BM, Planas J, Vallve SR, Howell DJ. A multicenter, 
randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for 
treatment of nasolabial folds. Dermatol Surg. 2007;33 Suppl 2:S144-51. 
11. Smith S, Busso M, McClaren M, Bass LS. A randomized, bilateral, prospective 
comparison of calcium hydroxylapatite microspheres versus human-based collagen for 
the correction of nasolabial folds. Dermatol Surg. 2007;33 Suppl 2:S112-21; discussion 
S21. 
12. Yutskovskaya Y, Kogan E, Leshunov E. A randomized, split-face, histomorphologic 
study comparing a volumetric calcium hydroxylapatite and a hyaluronic acid-based 
dermal filler. J Drugs Dermatol. 2014;13(9):1047-52. 
13. Jacovella PF. Calcium hydroxylapatite facial filler (Radiesse): indications, technique, 
and results. Clin Plast Surg. 2006;33(4):511-23. 

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CLINICAL TRIAL PROTOCOL 
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14. Loghem JV, Yutskovskaya YA, Philip Werschler W. Calcium hydroxylapatite: over a 
decade of clinical experience. J Clin Aesthet Dermatol. 2015;8(1):38-49. 
15. Bass LS, Smith S, Busso M, McClaren M. Calcium hydroxylapatite (Radiesse) for 
treatment of nasolabial folds: long-term safety and efficacy results. Aesthet Surg J. 
2010;30(2):235-8. 
16. Li D, Sun J, Wu S. A multi-center comparative efficacy and safety study of two 
different hyaluronic acid fillers for treatment of nasolabial folds in a Chinese 
population. J Cosmet Dermatol. 2019;18(3):755-61. 
17. Summary of Safety and Effectiveness Data (SSED) for Radiesse (Injectable Dermal 
Filler) (P050052). 2006. 
18. Alam M, Gladstone H, Kramer EM, Murphy JP, Jr., Nouri K, Neuhaus IM, et al. ASDS 
guidelines of care: injectable fillers. Dermatol Surg. 2008;34 Suppl 1:S115-48. 
19. Day DJ, Littler CM, Swift RW, Gottlieb S. The wrinkle severity rating scale: a 
validation study. Am J Clin Dermatol. 2004;5(1):49-52. 
 

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16 APPENDICES