Prospective, Multicenter, Parallel-group, Evaluator-blind, Randomized Study to Investigate the Effectiveness and Safety of MRZF111 in the Treatment of décolleté Wrinkles
Phase: NA
Conditions: Décolleté Wrinkles
Sponsor: Merz Aesthetics GmbH

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Prospective, multicenter, parallel-group, evaluator-blind, 
randomized study to investigate the effectiveness and safety of 
MRZF111 in the treatment of décolleté wrinkles 
Investigation identifier: 
M930521001 
IDE number: 
Not applicable 
Date 
of 
original 
clinical 
investigation plan and all 
previous amendments: 
CIP Version 3.0 29-AUG-2019 
Indication: 
Improvement of décolleté wrinkles and skin quality 
Planned investigation period: 
First subject first visit: Dec-2019 
Last primary outcome visit: Oct-2020 
Last subject last visit: Feb-2021 
Investigational medical 
device: 
MRZF111 
Sponsor: 
Merz Pharmaceuticals GmbH 
Eckenheimer Landstr. 100 
60318 Frankfurt/Main Germany 
Telephone: 
+49 69 1503 0 
Telefax: 
+49 69 1503 200 
Responsible for the clinical 
investigation plan content at 
the sponsor: 
Clinical Project Manager: 
 
Medical Expert: 
  
Biostatistician: 
 
Product Safety Officer: 
 
Coordinating Investigator: 
Clinical investigation sites: 
 
 
 Germany 
Statement: 
This clinical investigation plan is defined in 
accordance with EN ISO 14155:2011 
 
 
 
NCT04177212, redacted 
version v1.0, 05Sep2023

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CONFIDENTIAL AND PROPRIETARY 
The contents of this document are confidential and proprietary to Merz Pharmaceuticals. 
Unauthorized use, disclosure or reproduction is strictly prohibited. This document or parts thereof may 
not be disclosed to parties not associated with the clinical investigation without the prior written consent 
of Merz Pharmaceuticals. 
 

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Statement of Compliance 
Investigation Site(s) 
I have thoroughly read and reviewed the CIP. Having understood the requirements and 
conditions of the CIP, I agree to perform the clinical investigation according to the CIP, 
the electronic case report form (eCRF), EN ISO 14155, the Declaration of Helsinki, and 
regulatory authority requirements. 
I have received the current investigators brochure (IB) and have been adequately informed 
about the investigational medical device (IMD) development to date, I also agree to: 
Sign this CIP before the investigation formally starts. 
Wait until I have received approval from the appropriate ethics committee (EC) before 
enrolling any subject in this investigation. 
Obtain informed consent for all subjects prior to any investigation-related action 
performed. 
Start the investigation only after all legal requirements in my country have been fulfilled. 
Permit investigation-related monitoring, audits, EC review, and regulatory inspections. 
Provide direct access to all investigation-related records, source documents, and subject 
files for the monitor, auditor, EC, or regulatory authority upon request. 
Use the IMD and all investigational materials only as specified in the CIP. 
Report to the responsible product safety officer, immediately, any adverse event that is 
serious, whether considered treatment-related or not, and any device deficiency that could 
have led to a SADE. 

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Furthermore, I understand that: 
• Changes to the CIP must be made in the form of an amendment that has the prior 
written approval of Merz and – as applicable – of the appropriate EC and regulatory 
authority. 
• The content of the CIP is confidential and proprietary to Merz.  
• Any deviation from the CIP may lead to early termination of the investigation site. 
 
 
 
 
Principal investigator 
Date 
 
Signature 
 
 
 
 
 
 
 
Print Name 
 
 
 
Investigation site stamp  
 

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List of Abbreviations and Definitions of Terms 
 
AE 
Adverse event 
ADE 
Adverse device effect 
ASADE 
Anticipated serious adverse device effect 
ASAPS 
American Society for Aesthetic Plastic Surgery 
ATC 
Anatomical Therapeutic Chemical classification system of the World Health 
Organization 
BfArM 
Bundesinstitut für Arzneimittel; German Regulatory Authority 
CaHA 
Calcium Hydroxylapatite 
CE 
Communauté Européenne 
CIP 
Clinical investigation plan 
COVID-19 
Coronavirus disease 2019  
CRO 
Contract research organization 
DRM 
Data review meeting 
EC 
Ethics committee 
eCRF 
Electronic case report form 
EU 
European Union 
FAS 
Full analysis set 
G 
Gauge 
GAIS 
Global Aesthetic Improvement Scale  
GAIS-Skin 
Quality  
Global Aesthetic Improvement Scale on Skin Quality 
GCP 
Good clinical practice  
HA 
Hyaluronic acid 
IB 
Investigator’s brochure 
I.D. 
Internal Diameter 
IDE 
Investigational Device Exemption 
IU 
International unit 
iGAIS-Wrinkles 
Investigator’s Global Aesthetic Improvement Scale on Décolleté Wrinkles 
iGAIS-Skin 
Quality 
Investigator’s Global Aesthetic Improvement Scale on Skin Quality 
IMD 
Investigational medical device  
ISO 
International Organization for Standardization 

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LOCF 
Last observation carried forward 
MAS 
Merz Aesthetic Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPSV 
German Ordinance on the Medical Device Safety Plan 
(Medizinproduktesicherheitsplanverordnung) 
N 
Number of non-missing observations 
PPS 
Per protocol set 
PT 
Preferred term 
SAE 
Serious adverse event 
SADE 
Serious adverse device effect 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SES 
Safety evaluation set 
sGAIS-Wrinkles 
Subject’s Global Aesthetic Improvement Scale on Décolleté Wrinkles 
sGAIS - Skin 
Quality 
Subject’s Global Aesthetic Improvement Scale on Skin Quality 
SOC 
System organ class 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event 
UTW 
Ultra-Thin Wall 
US 
United States 
USA 
United States of America 
USADE 
Unanticipated serious adverse device effect 
UV 
Ultraviolet 
 

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Table of Contents 
SIGNATURE PAGE ..........................................................................................................3 
Statement of Compliance ..................................................................................................5 
List of Abbreviations and Definitions of Terms ..............................................................7 
Definitions ...........................................................................................................................9 
Table of Contents .............................................................................................................10 
1 
SYNOPSIS .................................................................................................................14 
2 
INVESTIGATION ADMINISTRATIVE STRUCTURE .....................................21 
2.1 
Internal Responsibilities.........................................................................................21 
2.2 
External Responsibilities .......................................................................................22 
3 
ETHICS .....................................................................................................................23 
3.1 
Ethics Committee ...................................................................................................23 
3.2 
Ethical Conduct of the Investigation......................................................................23 
3.3 
Subject Information and Informed Consent ...........................................................23 
3.3.1 
Subject Information .........................................................................................23 
3.3.2 
Informed Consent.............................................................................................24 
3.3.3 
Subject Privacy ................................................................................................24 
3.3.4 
Contact Point ....................................................................................................25 
3.4 
Insurance ................................................................................................................25 
3.5 
Financing................................................................................................................25 
4 
INTRODUCTION ....................................................................................................26 
4.1 
Investigational Background ...................................................................................26 
4.2 
Investigational Rationale .......................................................................................29 
4.3 
Risk Analysis and Benefit-Risk Assessment .........................................................33 
4.3.1 
Anticipated Clinical Benefits ...........................................................................33 
4.3.2 
Anticipated Adverse Device Effects ................................................................33 
4.3.3 
Residual Risks Associated with the Investigational Device, as 
Identified in the Risk Analysis .........................................................................36 
4.3.4 
Risks Associated with Participation in the Clinical Investigation ...................36 
4.3.5 
Possible Interactions with Concomitant Medical Treatments .........................36 
4.3.6 
Steps that will be Taken to Control or Mitigate the Risks ...............................36 
4.3.7 
Benefit-to-Risk Rationale ................................................................................39 
5 
INVESTIGATION OBJECTIVES .........................................................................41 
6 
DESIGN OF THE CLINICAL INVESTIGATION ..............................................42 
6.1 
General ...................................................................................................................42 
6.1.2 
End of Investigation .........................................................................................44 
6.2 
Discussion of Investigational Design, Including Choice of Control Groups .........44 

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7 
INVESTIGATION POPULATION ........................................................................46 
7.1 
Selection of Investigation Population ....................................................................46 
7.2 
Inclusion Criteria ...................................................................................................46 
7.3 
Exclusion Criteria ..................................................................................................47 
7.4 
Removal of Subjects from Treatment or Assessment ............................................51 
7.4.1 
Discontinuation of Subjects .............................................................................51 
7.4.2 
Premature Termination or Suspension of the Investigation or an 
Investigation Site .............................................................................................52 
7.4.3 
Provision of Care for Subjects after Investigation Discontinuation ................53 
8 
TREATMENTS ........................................................................................................54 
8.1 
Investigational Medical Device(s) .........................................................................54 
8.1.1 
Description of Investigational Medical Device(s) and its Intended 
Purpose in the Present Clinical Investigation ..................................................54 
8.1.2 
Instructions for Preparation..............................................................................56 
8.1.3 
Instructions for Application .............................................................................58 
8.1.4 
Packaging and Labeling ...................................................................................60 
8.1.5 
Storage of Investigational Medical Device ......................................................60 
8.1.6 
Accountability for Investigational Medical Device .........................................61 
8.1.7 
Destruction of Investigational Medical Device ...............................................61 
8.2 
Treatments Administered .......................................................................................61 
8.2.1 
Methods of Assigning Subjects to Treatment Groups .....................................62 
8.2.3 
Selection and Timing of Exposure for Each Subject .......................................62 
8.2.4 
Duration of Treatment per Subject ..................................................................62 
8.2.5 
Treatment Compliance .....................................................................................62 
8.2.6 
Treatment of Overdose ....................................................................................63 
8.3 
Previous and Concomitant Therapies/Procedures .................................................63 
8.4 
Blinding Procedures ...............................................................................................65 
8.4.1 
Blinding............................................................................................................65 
8.4.2 
Planned Unblinding Procedures .......................................................................65 
8.4.3 
Emergency Unblinding ....................................................................................65 
9 
INVESTIGATION ASSESSMENTS AND VISIT SCHEDULE .........................66 
9.1 
Clinical Evaluations ...............................................................................................66 
9.2 
Effectiveness Assessments.....................................................................................66 
9.2.3 
Biophysical Skin Quality Parameters ..............................................................68 
9.2.4 
Merz Aesthetics Scales for Décolleté Wrinkles ...............................................69 
9.2.5 
Treatment Satisfaction Assessments ................................................................70 
9.2.6 
Global Aesthetic Improvement Scales on Décolleté Wrinkles ........................70 
9.2.7 
Global Aesthetic Improvement Scales on Décolleté Skin Quality ..................71 
9.4 
Laboratory Evaluations ..........................................................................................73 
9.5 
Visit Schedule ........................................................................................................74 

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10 SAFETY ASSESSMENTS .......................................................................................77 
10.1 
Definition of an Adverse Event (AE) ....................................................................77 
10.1.1 
Adverse Event Details......................................................................................77 
10.1.2 
Adverse Event Handling and Reporting ..........................................................78 
10.1.3 
Adverse Event Severity Grading Scale ............................................................79 
10.1.4 
Causal Relationship with Investigational Medical Device ..............................79 
10.1.5 
Categories of Outcome ....................................................................................79 
10.2 
Definition of a Serious Adverse Event (SAE) .......................................................80 
10.2.1 
Serious Adverse Event Details.........................................................................81 
10.2.2 
Reporting and Handling of Serious Adverse Events .......................................81 
10.3 
Definition of an Adverse Device Effect (ADE) .....................................................83 
10.4 
Definition of a Serious Adverse Device Effect (SADE) .......................................83 
10.4.1 
Definition of an Anticipated Serious Adverse Device Effect (ASADE) .........83 
10.4.2 
Definition of an Unanticipated Serious Adverse Device Effect 
(USADE)..........................................................................................................83 
10.5 
Pregnancy ...............................................................................................................83 
10.6 
Definition of Device Deficiency ............................................................................84 
10.6.1 
Reporting and Handling of Device Deficiencies .............................................84 
11 DATA QUALITY ASSURANCE ............................................................................85 
11.1 
Standardization Procedures ....................................................................................85 
11.2 
Source Documentation Requirements....................................................................85 
11.3 
Data Management ..................................................................................................86 
11.4 
Monitoring .............................................................................................................87 
11.5 
Auditing .................................................................................................................88 
12 STATISTICAL METHODS ....................................................................................89 
12.1 
Determination of Sample Size ...............................................................................89 
12.2 
Analysis Sets ..........................................................................................................90 
12.3 
Endpoints for Analysis ...........................................................................................90 
12.3.1 
Effectiveness Endpoints ...................................................................................90 
12.3.2 
Safety Endpoints ..............................................................................................92 
12.4 
Statistical Analysis Methods ..................................................................................93 
12.4.1 
Effectiveness Endpoints ...................................................................................93 
12.4.2 
Safety Endpoints ..............................................................................................96 
12.4.4 
Special Statistical/Analytical Issues ................................................................97 
13 DATA HANDLING AND RECORDKEEPING....................................................99 
13.1 
Corrections to Data ................................................................................................99 
13.2 
Recordkeeping .......................................................................................................99 
13.3 
Destruction of Investigation Documents .............................................................100 
14 PUBLICATION POLICY ......................................................................................101 
15 REFERENCES .......................................................................................................102 
16 APPENDICES .........................................................................................................108 

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1 SYNOPSIS 
Investigation title 
Prospective, multicenter, parallel-group, evaluator-blind, randomized study to investigate 
the effectiveness and safety of MRZF111 in the treatment of décolleté wrinkles. 
Indication 
Improvement of décolleté wrinkles and skin quality. 
Investigation objectives 
Primary objectives 
• To evaluate the effectiveness and safety of MRZF111 treatment for improvement of 
décolleté wrinkles as assessed on the Merz Aesthetic Scale (MAS) Décolleté 
Wrinkles-At Rest.  
Secondary objectives 
• To evaluate the effectiveness of MRZF111 treatment for improvement of décolleté 
wrinkles as assessed on the MAS Décolleté Wrinkles-Dynamic.  
• To evaluate the subjects and physician’s treatment satisfaction assessment after 
MRZF111 treatment of the décolleté.  
• To evaluate the subjects and physician’s global aesthetic improvement on Décolleté 
Wrinkles (GAIS-Wrinkles) after MRZF111 treatment of the décolleté.  
Subject population, diagnosis, and main criteria for in- and exclusion 
A total of approximately 112 adult females will be enrolled if they meet all of the inclusion 
and none of the exclusion criteria. The enrolment period will be 12 weeks in total.   
Main inclusion criteria 
• Female between ≥18 and ≤65 years old. 
• Décolleté wrinkles with a rating of moderate to severe (grade 2 to 3) on the MAS 
Décolleté Wrinkles-At Rest as determined
and confirmed by 
the treating investigator afterwards. 
Main exclusion criteria 
• Any previous treatment with fat injections, poly L-lactic acid or permanent dermal 
fillers (e.g., silicone, polymethyl methacrylate) in the décolleté. 
• Any previous surgery, including plastic surgery, or surgical permanent implant in the 
décolleté or in the breasts that could interfere with effectiveness and safety. 

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First subject first visit: Dec-2019 
Last primary outcome visit: Oct-2020 
Last subject last visit: Feb-2021 
Duration of treatment per subject 
The duration of treatment is approximately 4 months per subject. 
Endpoints for analysis 
Primary Effectiveness Endpoint 
Proportion of subjects with ≥ 1-point improvement on the MAS Décolleté Wrinkles-At 
Rest scale at 16 weeks after last treatment compared to baseline (Day 1). 
Secondary Effectiveness Endpoints 
• Proportion of subjects with ≥ 1-point improvement on the MAS Décolleté Wrinkles 
– Dynamic scale at 16 weeks after last treatment compared to baseline (Day 1).  
• Treating investigators treatment satisfaction assessment of aesthetic improvement in 
the subject after the décolleté treatments 16 weeks after last treatment. 
• Subjects treatment satisfaction assessment of aesthetic improvement after the 
décolleté treatments 16 weeks after last treatment. 
• Treating investigator’s evaluation of the global aesthetic improvement on the 
investigator GAIS-Wrinkles (iGAIS-Wrinkles) from baseline (Day 1) 
 
to 16 weeks after last treatment.  
• Subject’s evaluation of the global aesthetic improvement on the subject GAIS-
Wrinkles (sGAIS-Wrinkles) from baseline (Day 1) 
to 
16 weeks after last treatment. 
Secondary Safety Endpoints 
• Incidence of TEAEs related to the treatment with the IMD. 
Total number of subjects and number of countries 
A total of approximately 112 adult females will be enrolled in Germany. 
Number of investigation sites 
Up to 10 sites. 
Number of visits 
Subjects are assigned to attend overall 6 visits
 
 24 or at latest 48 hours post-injection telephone contacts.  

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The primary analysis will be based on a one-sided binomial test at the one-sided type I 
error level of α = 0.025 for the pooled data from both treatment groups to test the null-
hypothesis that the response rate is ≤ 50% versus the alternative that response rate is >50%: 
As further supportive explorative analyses, the effectiveness for the different time points 
of treatments with a 16 weeks post-treatment period in both treatment groups will be 
analyzed on the observed cases in the modified FAS as for the primary endpoint: 
• Proportion of responders (response rate) defined as subjects with ≥ 1-point 
improvement on the MAS Décolleté Wrinkles-At Rest from last treatment 
application to 16 weeks after last treatment as assessed
 
 in treatment group A. 
• Proportion of responders (response rate) defined as subjects with ≥ 1-point 
improvement on the MAS Décolleté Wrinkles-At Rest from last treatment 
application to 16 weeks after last treatment as assessed
 
 treatment group B. 
• Proportion of responders (response rate) defined as subjects with ≥ 1-point 
improvement on the MAS Décolleté Wrinkles-At Rest from baseline to 16 weeks 
after first treatment as assessed 
in treatment group B. 
In addition, two-sided 95% Wilson score confidence intervals will be provided overall, and 
for each treatment group in the supportive analyses.  
Secondary Effectiveness Endpoints 
One secondary effectiveness endpoint is the proportion of responders (response rate) 
defined as subjects with ≥ 1-point improvement on the MAS Décolleté Wrinkles-Dynamic 
from baseline to 16 weeks after last treatment as assessed 
. Same 
analyses as for the primary endpoint will be performed on this endpoint. 
Number and percentage of subjects with any levels of treatment satisfaction of the aesthetic 
improvement in subject’s décolleté at 16 weeks after last treatment assessed by investigator 
and subject will be calculated and the according 2-sided 95% confidence intervals for the 
percentage of subjects with any level of treatment satisfaction will be provided for the 
pooled treatments (overall). 
Number and percentage of subjects with improvement in iGAIS-Wrinkles defined in a 
rating of 1, 2 or 3 at 16 weeks after last treatment will be summarized and 2-sided 95% 
confidence intervals be provided overall. Analogous methods will be used for sGAIS-
Wrinkles. 
Secondary Safety Endpoints 
All safety analyses will be performed on the Safety Evaluation Set (SES). 

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Only TEAEs will be analyzed, which are defined as AEs with onset on or after date of first 
injection of the IMD. 
Incidences of TEAEs and SAEs will be provided by System Organ Class (SOC) and 
preferred term (PT). They will be provided overall and by worst intensity, by worst causal 
relationship and by worst outcome.  

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2.2 
External Responsibilities 
The administrative structure for external responsibilities includes, but is not limited to, the 
following participants: 
 
Name 
Function 
Address 

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3 ETHICS 
3.1 
Ethics Committee 
The following documents must be submitted to and approved by the responsible EC: 
• CIP,  
• Amendments to CIP with a significant impact on the safety of the subjects or the 
scientific value of the investigation (if applicable), 
• IB including its updates/amendments (if applicable), 
• Subject information and informed consent forms, as well as updates (if applicable), 
• All subject recruitment procedures and advertisements used to recruit subjects (if 
applicable), 
• Any other required documents.  
If applicable, and in accordance with local legal requirements, the above listed documents 
may also be submitted to the respective regulatory authority (ies) for separate approval. 
3.2 
Ethical Conduct of the Investigation 
This investigation will be conducted in accordance with the ethical principles of the 
Declaration of Helsinki, that are consistent with EN ISO 14155:2011 and the applicable 
regulatory requirements. Regulatory authorities will be notified and consulted as required 
prior to, during, and after the conduct of the investigation. 
The clinical investigation shall not begin until the required approval/favorable opinion 
from the EC or regulatory authority has been obtained, if appropriate. Any additional 
requirements imposed by the EC or regulatory authority shall be followed, if appropriate. 
3.3 
Subject Information and Informed Consent 
3.3.1 
Subject Information 
Prior to investigation enrollment, the subject will be given full verbal and written 
information on the nature, objective, significance, potential benefits, potential risks, 
alternative therapy, confidentiality, compensation, the right to question and terminate 
participation, and expected consequences of the investigation. This verbal and written 
information will be provided by the investigator (or authorized designee) according to the 
provisions set forth in the Declaration of Helsinki and EN ISO 14155:2011 (chap. 4.7). The 

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3.3.4 
Contact Point 
A contact address where subjects may obtain further general information regarding clinical 
investigations will be provided in the informed consent form. 
3.4 
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 German laws and regulations.  
The subject will be informed by the investigator and through the subject’s informed consent 
form about the existence of this insurance and the resulting obligations. The insurance 
conditions will be handed out to the subject.  
Any medical or non-medical deviation from the CIP that is deemed to have occurred 
through the subject’s own fault may not covered by this insurance. 
The sponsor is usually not liable for injuries/cases of death that occur solely as a 
consequence of the subject’s underlying disease or condition, or from diagnostic or 
therapeutic measures not specifically required by the agreed CIP. The sponsor is also 
usually not liable for events resulting from negligence of the investigator, clinical 
investigational staff, and CRO, including failure to act according to EN ISO 14155:2011 
or to comply strictly with the agreed CIP. 
3.5 
Financing 
The financial aspects of the investigation will be documented in an agreement between the 
sponsor, the CRO, each investigator, any other involved party, and must be confirmed in 
writing before the investigation commences. 

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4.3 
Risk Analysis and Benefit-Risk Assessment 
4.3.1 
Anticipated Clinical Benefits  
• According to clinical studies, the treatment will lead to an improvement of décolleté 
wrinkles.  
• CaHA is a biodegradable material [Pavicic 2015]; undesirable effects such as 
overcorrection of the treated area or dissatisfaction with the outcome of the 
corrective procedure subside spontaneously after a few months. 
• AEs seen in clinical trials with CaHA were generally expected, mild in nature, and 
short in duration [Kadouch 2017, Rayess 2018, Sadick 2007]. Long-term follow-up 
studies showed the favorable safety profile of CaHA with mostly injection-related 
mild side-effects [Bass 2010]. 
• Allergies and immunological reactions due to CaHA occur very rarely compared to 
permanent filler materials [Kadouch 2017, Rayess 2018, Sadick 2007].  
• CaHA has some additional benefits over HA fillers such as longer lasting results 
and enhanced cellular end extracellular matrix proliferation [Yutskovskaya 2014, 
Zerbinati 2018]. 
• Treatment with CaHA provides a high long-term patient satisfaction [Fakhre 2009].  
• Treatment with injectable devices is usually performed on an ambulatory basis. No 
special preparations for the procedure are required. 
• Injection with CaHA is less invasive and less permanent than available invasive 
treatment options via plastic surgery. 
• The RADIESSE® in its original un-diluted form is marketed for aesthetic 
since 2003 in the European Union (EU) and is also registered and marketed in over 
50 countries worldwide. Since then, over 5 million units had been sold. As it has 
already been used in a variety of subject populations.   
4.3.2 
Anticipated Adverse Device Effects  
Study subjects must be informed that as with any implant material possible adverse 
reactions may occur: 
• Swelling, edema, festoons, angioedema  
• Induration, mass, nodules, lumpiness and granulomas at the injection site, calcium 
deposits 

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• Erythema, redness 
• Pain, tenderness, soreness 
• Loss of effect, reduced effect (undercorrection, under injection), overcorrection 
(over injection), superficial injection, delayed reaction 
• Discoloration, hyperpigmentation, depigmentation, blanching 
• Bruising, ecchymosis 
• Embolia cutis medicamentosa, skin necrosis, vascular occlusion (obstruction), 
ischemia 
• Numbness, hypoaesthesia, hyperaesthesia, parasthesia (tingling), burning 
sensation 
• Inflammation, foreign body inflammation 
• Product migration/displacement, tissue plane migration 
• Itching, pruritus 
• Haematoma, bleeding, petechiae, 
• Allergy, allergic reaction, hypersensitivity, anaphylaxia 
• Infection (e.g., impetigo), abscess, pus, cellulitis 
• Rash, urticaria (hives), contact dermatitis 
• Dizziness, blurred vision, headache, nausea, hyperventilating, syncope, malaise 
(flu-like symptoms, shakes/chills), tachypnea, pericarditis 
• Warmth 
• Exfoliation, scab, abrasion 
• Pustules, papules, pimples 
• Contour irregularity, asymmetry, unevenness, uneven contours 
• Paralysis 
• Blisters, vesicles 
• Herpes reactivation (herpes simplex, herpes zoster) 
• Fever 
• Lymphadenopathy, lymphoedema 
• Irritation 
• Scarring 
• Dryness, hair loss, ptosis 
• Tightness 
• Muscle twitching 
• Guillain-Barre syndrome 
• Veins look more prominent, broken capillaries 
• Sarcoidosis 
• Sensitivity to cold 
• Extrusion 
• Granulomatosis with Polyangiitis 

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• Stroke 
• Introduction of the IMD into the vasculature may lead to embolization, occlusion 
of the vessels, ischemia, or infarction. Rare but serious adverse events associated 
with the intravascular injection of soft tissue fillers in the face have been reported 
and include temporary or permanent vision impairment, blindness, cerebral 
ischemia or cerebral hemorrhage, leading to stroke, skin necrosis, and damage to 
underlying skin structures. This complication is more likely when the IMD is 
injected into the lips, nose, glabellar or ocular area. In a large cross-sectional 
review, this risk was considered low (<0.01%) [DeLorenzi 2014, Rayess 2018]. 
• The following adverse events were reported during clinical studies performed with 
RADIESSE® Injectable Implant: ecchymosis, edema, erythema, granuloma, 
nodule, pain, pruritus, soreness, tenderness, numbness, contour irregularity, lumps, 
rash, discoloration, hardness, headache, scab, tightness, abrasion, burning 
sensation, papule/pustule, firmness, hearing loss, swelling and, nausea. For cases 
where information was available, patients had recovered or were recovering with 
minimal to no scarring at last contact. Few cases required consultation with a plastic 
surgeon and possible excision and revision surgery to correct the defect resulting 
from the necrosis (see current IB and Risk Analysis [IB, Risk Analysis]). 
• A detailed list of adverse events obtained from Post Marked Surveillance for 
RADIESSE® Injectable Implant can be found in the current IB [IB]. The nature, 
intensity, and duration were comparable to those reported during studies.  
• Since the IMD is biodegradable, regular follow-up treatment may be necessary if a 
visible enhancement effect (optimal cosmetic correction) continues to be desired. 
• 
As with any other medical treatment, injection with the IMD may be associated 
with unforeseen and/or unanticipated AEs. For further information see current 
version of the IB [IB]. 
Investigators must be informed that as with any medical device the following Adverse 
Device Effects (ADEs) may occur: 
• Needle breakage 
• Leakage of material 
• Resistance during injection, needle jamming 
• Injury of third persons (e.g., during detachment of needle after treatment 
procedure). 

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• As the IMD can interact with other implantable materials, it is only allowed to inject 
the IMD when potential injectable material in the décolleté has completely resorbed 
at baseline; it is not allowed to inject the IMD in the area previously treated with 
permanent dermal fillers. 
• The investigator is obliged to discuss all potential risks of IMD injection with the 
subjects prior to treatment and to ensure that the subjects are aware of signs and 
symptoms of potential complications. 
• As the subject may experience slight discomfort during and following the 
procedure, anesthetic techniques like topical anesthetics or cooling are allowed in 
this investigation.  
• The components of the MRZF111 kit should be carefully examined to verify that 
neither the packaging nor the devices have been damaged during shipment. The 
MRZF111 kit must not be used if the packaging of any of the components is 
compromised or if any of the devices have been damaged or if the syringe end cap 
or syringe plunger is not in place. 

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• The usual aseptic practices and precautions associated with percutaneous injection 
procedures should be followed to prevent infection. 
• To avoid needle breakage, the investigator will be advised to not attempt to 
straighten a bent needle but to replace it.  
• Infection requiring treatment may occur at the injection site. It generally results 
from natural skin flora being introduced through the injection site. These infections 
often respond to oral antibiotics [Rayess 2018]. If such infection cannot be 
corrected, it may become necessary to perform an invasive medical procedure. 
• Irregularities of the skin may occur after the treatment which may require a surgical 
procedure to correct. 

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• As the injection with the IMD may be associated with unforeseen and/or 
unanticipated AEs, regular safety follow-up visits will be scheduled, and the 
subjects will be instructed to contact the site without delay in any case he/she 
suspects an ADE. 
• Used and partially used syringes and injection needles should not be recapped and 
be handled and disposed in an appropriate sharps or biohazard container.  
4.3.7 
Benefit-to-Risk Rationale 
The RADIESSE® in its original un-diluted form is marketed for aesthetic treatments and is 
indicated for plastic and reconstructive surgery, including deep dermal and sub-dermal soft 
tissue augmentation of the facial area, and is also intended for restoration and/or correction 
of the signs of facial fat loss (lipoatrophy) in people with human immunodeficiency virus 
since 2003 in the EU, and is also registered and marketed in over 50 countries worldwide. 
Since then, over 5 million units had been sold. As it has already been used in a variety of 
subject populations, it is likely that this experience would have identified any rare 
complications or problems that may become apparent only after widespread device use. By 
diluting the original product, side effects will probably not occur more often. Some side 
effects, such as nodules and granuloma, might occur less often.  
Clinical data collected from available publications on RADIESSE® Injectable Implant 
diluted with normal saline solution at various dilution ratios demonstrate: 

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5 INVESTIGATION OBJECTIVES  
Primary objectives 
• To evaluate the effectiveness and safety of MRZF111 treatment for improvement 
of décolleté wrinkles as assessed on the MAS Décolleté Wrinkles-At Rest.  
Secondary objectives 
• To evaluate the effectiveness of MRZF111 treatment for improvement of décolleté 
wrinkles as assessed on the MAS Décolleté Wrinkles-Dynamic.  
• To evaluate the subjects and physician’s treatment satisfaction assessment after 
MRZF111 treatment of the décolleté.  
• To evaluate the subjects and physician’s global aesthetic improvement (GAIS-
Wrinkles) after MRZF111 treatment of the décolleté.  

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7.3 
Exclusion Criteria 
Subjects having any of the following criteria, either at screening or at baseline, will not be 
included in the investigation: 
Exclusion Criteria 
Rationale 
Any previous treatment with fat injections, poly L-
lactic acid or permanent dermal fillers (e.g., silicone, 
polymethyl methacrylate) in the décolleté. 
Safety concern 
Any previous surgery, including plastic surgery, or 
surgical permanent implant in the décolleté or in the 
breasts that could interfere with effectiveness and 
safety. 
Safety concern 
Effectiveness 
Any previous thread lifting in the décolleté. 
Safety concern 
Previous treatment with collagen fillers, CaHA, and/or 
with long lasting HA fillers (e.g., Belotero® 
Intense/Volume, Juvéderm® Volift/Volbella) in the 
décolleté within the past 24 months before baseline. 
Safety concern 
 

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Exclusion Criteria 
Rationale 
Previous treatment with other HA fillers in the décolleté 
within the past 12 months before baseline. 
Safety concern 
 
Previous treatment with botulinum toxin, ablative or 
fractional laser, microdermabrasion, microneedling, 
chemical peels and/or non-invasive skin-tightening (e.g. 
ultrasound, radiofrequency, intense pulsed light 
treatment) in the décolleté within the past 6 months 
before baseline. 
Safety concern 
 

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7.4 
Removal of Subjects from Treatment or Assessment 
7.4.1 
Discontinuation of Subjects 
In accordance with the Declaration of Helsinki and the informed consent form, the subject 
may discontinue the investigation at any time without any penalty or loss of benefits to 
which the subject is otherwise entitled (see Section 7.4.3). Premature discontinuation of 
the investigation with its reason(s) must be recorded in the subject file and the eCRF. Date 
and discontinuation circumstances should be stated. 
Subjects must be discontinued from the investigation by the investigator at any time for 
any of the following reasons: 
• Withdrawal of informed consent. 

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• Pregnancy (no further injection of IMD, or any other interventional procedure will be 
performed). 
• Any AEs for which treatment continuation would constitute an unacceptably high risk 
for the subject. 
CIP deviations or conditions arising from the exclusion criteria established in Section 7.3, 
may lead to the subject’s discontinuation. All such conditions should be properly 
documented.  
Subjects who are discontinued from the investigation due to AEs will be treated according 
to standard clinical strategies and will be followed-up until the final investigational 
visit/safety visit. All pertinent information concerning the AE will be documented in the 
subject file as well as in the eCRF AE report form. 
Following discontinuation, a final examination should be performed for safety reasons. The 
investigator is required to make every effort to contact subjects lost to follow-up, and all 
such efforts should be documented in the subject file (e.g., times and dates of telephone 
contact, copies of letters).  
7.4.2 
Premature Termination or Suspension of the Investigation or an 
Investigation Site 
The investigation or an investigation site can be prematurely terminated or suspended by 
the sponsor. Reasons for termination of the investigation or an investigation site may 
include, but are not limited to, the following: 
• Subject enrollment is unsatisfactory. 
• The benefits and risks of continuing the investigation have been reassessed, and the 
risks outweigh any potential benefits. 
• The incidence of AEs constitutes a potential health hazard to the subjects. 
• New scientific data on the IMD do not justify a continuation of the investigation. 
• The investigator or investigation site exhibit serious and/or persistent non-adherence 
to the CIP, Declaration of Helsinki, EN ISO14155:2011, and/or applicable regulatory 
requirements. 
• The sponsor decides to terminate the investigation at any time for any other reason. 
Furthermore, the investigation may be prematurely ended if the regulatory authority or the 
EC has decided to terminate or suspend approval for the investigation, the investigation 
site, or the investigator. 
If the investigation is prematurely terminated or suspended for any reason, the investigator 
must inform the subjects and assure appropriate follow-up treatment. Within the 
timeframes noted in applicable regulations, the sponsor will promptly inform the 

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investigators, investigation sites, the EC, and regulatory authorities of the termination or 
suspension of the investigation, as well as provide reasons for the action. 
7.4.3 
Provision of Care for Subjects after Investigation Discontinuation 
Plans for treatment or care after investigational discontinuation are not foreseen, as this is 
an investigation without therapeutic relevance. 

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8 TREATMENTS 
8.1 
Investigational Medical Device(s) 
8.1.1 
Description of Investigational Medical Device(s) and its Intended 
Purpose in the Present Clinical Investigation 
8.1.1.1 
Investigational Medical Device(s) 
The final applied IMD MRZF111 is RADIESSE® Volume Advantage 1.5 mL Injectable 
Implant
. The injection of 
MRZF111 needs to be done directly after dilution.  

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The intended purpose of the IMD in the present clinical investigation is the 
 
injection of the IMD in the décolleté. For further details on the injection technique, please 
refer to Section 8.1.3. Only physicians who are highly experienced in the treatment of the 
décolleté with injectable fillers (preferably with CaHA) are allowed to conduct this 
investigation.   

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Following treatment, manual massage of the entire treatment area can be performed by the 
treating investigator in order to promote even distribution of MRZF111. 
The investigator will use the IMD and all investigational materials only within the 
framework of the clinical investigation and in accordance with this CIP.  
8.1.4 
Packaging and Labeling  
The packaging and labeling will be according to regulatory requirements and specifications 
in Germany. The labelling that of the outer box is with additional labelling of 
“Studiennummer: M930521001“, and „Medizinproduktenummer: XXXX“(MRZF111 kit 
number with sequential numbering). 
MRZF111 kits will be provided directly to the investigation sites at the beginning of the 
investigation. Replenishments will be provided during the investigation, if necessary. 
8.1.5 
Storage of Investigational Medical Device 
Storage temperature (a controlled room temperature between 15°C and 32°C) will be 
controlled once a week and the minimum/maximum temperature will be recorded in a 
temperature log.  

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• For ten days prior to and three days after treatment (applies to all injection cycles): 
The following concomitant non-drug treatments are forbidden during the investigation:  
• During the whole course of the investigation:  
• For at least 24 hours after treatment (applies to all injection cycles): 

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9.2.3 
Biophysical Skin Quality Parameters 
 

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9.4 
Laboratory Evaluations 
A urine pregnancy dip stick test will be performed before each injection visit in women of 
childbearing potential3. For time points of this assessment please refer to Table 2.  
                                                          
3 Childbearing potential is defined as NOT premenarche, permanently sterilized or postmenopausal (i.e., 12 
months with no menses without an alternative medical cause). 

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preferably on or around the initially planned date for that visit. Study subjects need to 
provide prior verbal agreement to this procedure. 
 

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10 SAFETY ASSESSMENTS 
10.1 Definition of an Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (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 investigational medical device or the 
comparator. 
NOTE 2 This definition includes events related to the procedures involved. 
NOTE 3 For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
10.1.1 
Adverse Event Details 
The period of observation for an AE extends from when the informed consent form was 
signed until the last investigational visit of the subject. Any medical occurrence that 
happens between the time when the informed consent form 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 eCRF AE 
report form. Any AE observed will be fully investigated, documented and followed up 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 as the adverse 
event 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 up like all other AEs. 
  
TEAEs are defined as AEs with onset or worsening at or after the first injection of the IMD. 
Pre-existing conditions noted in the medical history and previous to IMD injection 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 
condition of the subject at screening. 
In case of a positive COVID-19 result, the “COVID-19 infection” has to be documented 
as an AE in the eCRF. All individual symptoms related to the confirmed COVID-19 
infection should be recorded as separate AEs attributable to COVID-19 using the following 
descriptions e.g. “cough due to confirmed COVID-19 infection”. 

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After completion of all scheduled visit assessments the investigator must document any 
AEs arising from these assessments.  
In case of an SAE (defined in section 10.2), the investigator must also complete an SAE 
report form and report it to Merz and the CRO immediately, as described in Section 10.2.2. 
10.1.3 
Adverse Event Severity Grading Scale 
The clinical severity 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 his/her daily activities. 
The Investigator is required to grade the severity/intensity of each AE. 
10.1.4 
Causal Relationship with Investigational Medical Device 
An AE is considered to be “related” to IMD or the injection procedure if a causal 
relationship between the IMD or the injection procedure and an AE is at least reasonably 
possible (i.e., the relationship cannot be ruled out). In this case the event is considered an 
ADE (see Section 10.3). If the event is serious it is a “serious ADE” (SADE) (see Section 
10.4). 
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.” 
10.1.5 
Categories of Outcome 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Fatal 
• Unknown 

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If there is more than one AE, only the AE leading to death will be attributed with a “fatal” 
outcome. 
10.2 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, or 
3) in-patient 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 foetal distress, foetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the 
CIP, without serious deterioration in health, is not considered a serious adverse event. 
Based on MPSV the definition for a SAE additionally comprises any unintended event 
which occurred in the scope of the clinical investigation, and directly or indirectly led, 
might lead to or might have led to death or to a serious deterioration of the state of health 
of a subject, user or any other person regardless whether the event is related to the IMD. 

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The address for SAE reporting is: 
MERZ contact 
CRO contact 
Merz Pharmaceuticals GmbH  
Global Product Safety Department  
Eckenheimer Landstrasse 100 
D – 60318 Frankfurt/Main 
The investigator must supply further supporting information within 3 days of knowledge 
of the SAE, and a detailed SAE description is an integral part of this supporting 
information. Follow-up reports should be sent to the CRO without delay as an SAE report 
form (marked as a “follow-up” report) and accompanied by appropriate supporting 
documentation (e.g., hospital reports). The SAE has to be followed-up until the SAE is 
recovered/resolved 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. 
SAEs occurring after the end of the observational period need only be reported if the 
investigator considers the event to be related to IMD.  
As this clinical investigation is performed in Germany, Merz is responsible to report SAEs 
as well device deficiencies that could have led to a SADE 
 
to the German Regulatory Authority BfArM based on §3 paragraph (5) of 
the current German Ordinance on the Medical Device Safety Plan (Medizinprodukte-
Sicherheitsplanverordnung, MPSV). 
In accordance with MPSV §5 paragraph (2), SAEs shall be reported to the BfArM 
immediately using the SAE reporting form for Germany if a causal relationship to the IMD 
cannot be ruled out. All other SAEs shall be documented completely and reported quarterly 
or upon request by the BfArM as summary using the MEDDEV 2.7/3 SAE report table. 
Furthermore, the SAE assessment form provided by the BfArM shall be used. Should no 
SAEs occur within a defined reporting period, a report shall nonetheless be submitted. 
The address for SAE reporting to BfArM is MPSAE@bfarm.de. 

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In order to ensure reporting of SAEs immediately to the BfArM, the Medical Devices 
Safety Officer at Merz provides 24 hours availability. 
A copy of submitted reports will be provided to the CRO for submission to EC and 
dissemination to all investigators. 
In accordance with MPSV 14 paragraph (1,2), the sponsor and the investigator will take 
immediately all necessary safety measures to protect immediate or indirect danger in case 
that circumstances can affect the safety of the subjects, users or third parties. The Medical 
Devices Safety Officer at Merz will immediately inform the BfArM about these new 
circumstances and submit the information in addition to the responsible ethics committee. 
10.3 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 investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional 
misuse of the IMD. 
10.4 Definition of a Serious Adverse Device Effect (SADE) 
A SADE is defined as an ADE that has resulted in any of the consequences characteristic 
of an SAE (see Section 10.2). 
10.4.1 
Definition of an Anticipated Serious Adverse Device Effect 
(ASADE)  
An anticipated SADE (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. 
10.4.2 
Definition of an Unanticipated Serious Adverse Device Effect 
(USADE) 
An unanticipated SADE (USADE) is a SADE which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis report. 
10.5 Pregnancy 
Each pregnancy that starts during the clinical investigation must be immediately reported 
by the investigator via pregnancy report form to the CRO. Pregnancies and pregnancy 

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follow-up should be reported on a pregnancy monitoring 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. 
10.6 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. 
10.6.1 
Reporting and Handling of Device Deficiencies 
A device deficiency that could have led to a SADE (see Section 10.4) is to be reported in 
the same way as an SAE. 
Device deficiencies must be reported to the following address: 
The Global Quality department will decide if the concerned sample needs to be returned 
and to whom the product should be sent for investigation. 
 

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11 DATA QUALITY ASSURANCE 
Inspections by regulatory authority representatives and EC are possible at any time, even 
after the end of investigation. The investigator is to notify the sponsor immediately of any 
such inspection. The investigator and institution will permit investigation-related 
monitoring, audits, reviews by the EC and/or regulatory authorities, and will allow direct 
access to source data and source documents for such monitoring, audits, and reviews. 
11.1 Standardization Procedures 
Standardization procedures will be implemented to ensure accurate, consistent, complete, 
and reliable data, including methods to ensure standardization among sites (e.g., training, 
newsletters, investigator meetings, monitoring, centralized evaluations, and validation 
methods).  
This investigation will be monitored regularly by a qualified monitor from the CRO 
according to EN ISO 14155:2011 and the respective Standard Operating Procedures 
(SOPs) (see Section 11.4). 
11.2 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/medical records). The 
source documentation must also contain a descriptive statement on the informed consent 
procedure (see Section 3.3.2). 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 have to be traceable on the 
basis of the documentation in the subjects file. The childbearing potential of female 
subjects must be noted in the source documentation. Details to the injection treatment have 
to be entered in the source data
 
. The site will keep a source data location list which will outline for the 
different data categories including electronic data (e.g., demographics, medical history, and 
AEs etc.) which document serves as source for this data (e.g., subject file, subject eDiary, 
questionnaires). 
During the study period, the COVID-19 outbreak occurred. Subjects might get tested for 
SARS-CoV-2; however, this is not a general procedure foreseen in the study protocol. 
Nevertheless, according to national and international guidance documents, collection of 
specific information which might explain the basis for e.g. missing data, is 
important. Therefore, any relevant circumstances related to the COVID-19 outbreak should 
be documented in the source data, e.g. reason for visit not performed / visit performed via 
phone. A COVID-19 infection itself has to be documented as an adverse 
event. Corresponding documentation in the eCRF should be done as follows:  
• In case of a positive COVID-19 result, the “COVID-19 infection” has to be 
documented as an AE in the eCRF. In case of symptoms related to the confirmed 

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COVID-19 infection, all individual symptoms should be recorded as separate AEs 
attributable to COVID-19 using the following descriptions e.g. “cough due to 
confirmed COVID-19 infection”. 
• All changes to visits or premature terminations due to COVID-19 should be 
documented in the source data as well as in the eCRF.  
• Visits not done regularly on site due to COVID-19 pandemic will be marked in eCRF 
as visit not done or done virtually via phone contact.  
If an investigation site is using an electronic system for documenting source data, a member 
of the investigation site staff must print out the source data after each visit. The paper print-
outs must be overlapping, if possible (i.e., must contain at least the last row of data from 
the subject’s previous visit). If it is not possible to obtain overlapping paper print-outs, the 
completeness of source data must be ensured by other suitable means. The print-out must 
be signed and dated by a member of the investigation site staff who can confirm the 
accuracy and completeness of data in the paper print-out. The monitor should also sign and 
date after verifying the source data. The paper print-out should be stored in the Investigator 
Site File or in the medical records (information must be visible that the subject was in a 
clinical investigation/investigation number). If source data information is entered 
retrospectively, this must be done directly on the paper print-out and should be initialed 
and dated. The same applies to any corrections of initial data. Further details are described 
in the Monitoring Plan.  
If the site is using a validated computer system including audit trail with a separate access 
for the monitor (i.e., the monitor can only access the data of the investigational subjects), 
then no such paper print-outs are required. 
11.3 Data Management 
Data required according to this CIP is to be recorded in the web-based eCRFs (electronic 
data capture system) provided by the CRO Metronomia.  
All users who will enter data into the eCRF will be previously trained. The successful 
completion of the training of all participants will be documented in a listing, or participants 
will receive a training certificate, which will be a prerequisite for the access to the eCRF. 
The access to the eCRF is password-controlled and conforms with CFR part 11.  
Patient reported outcome data will be collected by a web based electronic data capture 
system called “Clincase ePRO” which is a separate module of the eCRF with write access 
restricted to the respective subject. All data collected from ePRO are synchronized in real 
time mode with the Clincase server via Internet (e.g. Wi-Fi, 3G). This means, that data are 
submitted directly to EDC and no local data are stored on the subjects’ own device 
(smartphone/tablet/computer). Subjects will get access to the ePRO web portal through 
personal invitation by investigator (personal web-link for registration). The access to the 
subject’s eDiary itself is password-controlled and requires a separate PIN. Investigators or 
the delegated site staff will have read only permissions to view the data of their respective 
subjects. This guarantees that subjects data entries cannot be changed.  

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Plausibility checks will be performed according to a data validation plan. Inconsistencies 
in the data will be queried to the investigators via the electronic data capture system; 
answers to queries or changes to the data will also be documented in this system directly 
by an authorized member of the investigation site staff. The audit trail in the electronic data 
capture system documents 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 investigation site staff) can be raised during source 
data verification, medical or safety review and data management review. 
Validated systems are used for electronic data capture. 
After all data are entered and all queries are solved, the database will be closed. In case of 
any changes to the data after database close, these changes will be documented according 
to the respective SOP. Further details are described in the Data Management Plan.  
11.4 Monitoring 
This investigation will be monitored regularly by a qualified monitor of the CRO according 
to EN ISO 14155:2011 (chap. 8.2.4) and the respective SOPs. During these visits, the 
monitor will prepare the investigation site for the conduct of the investigation, check for 
subject eligibility, for completion of the entries in the source data and on the eCRFs, 
including completeness and content of the patients’ eDiaries; for compliance with the CIP, 
EN ISO 14155:2011, Declaration of Helsinki, and regulatory authority requirements; for 
the integrity and verification of the source data with the eCRF entries; and for subject 
eligibility. Monitoring will also be aimed at detecting any misconduct or fraud. 
In addition, the monitor will check whether all AEs/ADEs, SAEs/SADEs 
have 
been reported appropriately within the time periods required. 
The investigator and all investigation site staff will be expected to cooperate with the 
monitor by providing any missing information whenever possible. The investigator must 
be available to answer questions arising during regular monitoring visits. In addition, the 
investigator is required to: 
• Have all data properly recorded in the source documentation and the eCRF prior to 
each monitoring visit. 
• Have the source documentation available at the monitoring visits. 
• Record all IMDs dispensed in the eCRF and the device inventory records. 
All subjects who are screened, but not included into the investigation, will be listed on the 
subject screening/enrollment log. 

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11.5 Auditing 
Audits shall be conducted by qualified auditors to evaluate compliance with the CIP, 
sponsor’s current written procedures, ISO14155:2011 and the 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: 
a) as a routine part of the sponsor's quality assurance program, 
b) to assess the conduct of the monitoring activity, 
c) whenever there are serious or repeated CIP deviations or suspicion of fraud, 
d) to bring an investigation site into “inspection readiness”, i.e., to prepare the investigation 
site for a potential regulatory inspection, and 
e) when requested or suggested by a regulatory authority. 
The audit results shall be documented and communicated to relevant parties, if applicable. 

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Calculations to determine the required sample size were performed using the software 
nQuery Version 8.1.2.0, Statistical Solutions Ltd. 2017, and validated by double 
programming with proc power on SAS 9.4, SAS Institute Inc., Cary, NC, USA, 2016. 
12.2 Analysis Sets 
The following analysis sets will be defined for the statistical analysis of this investigation: 
Safety Evaluation Set 
The SES is the subset of all randomized subjects who were exposed to the IMD at least 
once. Subjects will be analyzed as treated. 
Full Analysis Set 
The FAS is the subset of subjects in the SES for whom at least the baseline value of the 
primary effectiveness variable is available (i.e., all subjects who have a baseline value on 
the MAS Décolleté Wrinkles-At Rest scale). In contrast to the SES, subjects will be 
analyzed as randomized. 
Modified Full Analysis Set 
The modified FAS is the subset of subjects in the SES for whom at least the baseline value 
of the primary effectiveness variable is available (i.e., all subjects who have a baseline 
value on the MAS Décolleté Wrinkles-At Rest scale). Subjects will be analyzed as treated. 
Per Protocol Set 
The PPS is the subset of subjects in the modified FAS without major deviations. Subjects 
of treatment group A switching to treatment group B will be excluded from the PPS. 
Further major protocol deviations and other reasons leading to exclusion will be defined 
prior to database lock during a data review meeting. 
12.3 Endpoints for Analysis 
12.3.1 
Effectiveness Endpoints 
12.3.1.1 
Primary Effectiveness Endpoint 
The primary effectiveness endpoint is the proportion of subjects with at least 1-point 
(≥ 1-point) improvement on the MAS Décolleté Wrinkles-At Rest scale at 16 weeks after 
last treatment compared to baseline (Day 1). 
 
A response is defined as ≥ 1-point improvement on MAS Décolleté 
Wrinkles-At Rest scale at 16 weeks after treatment compared to baseline (Day 1). 

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12.3.1.2 
Secondary Effectiveness Endpoints 
• Proportion of subjects with at least 1-point (≥ 1-point) improvement on the MAS 
Décolleté Wrinkles-Dynamic scale at 16 weeks after last treatment compared to 
baseline (Day 1). 
A 
response is defined as ≥ 1-point improvement on MAS Décolleté Wrinkles – 
Dynamic scale at 16 weeks after treatment compared to baseline (Day 1). 
• Treating investigators treatment satisfaction assessment of aesthetic improvement in 
the subject after the décolleté treatments 16 weeks after last treatment. 
• Subjects treatment satisfaction assessment of aesthetic improvement after the 
décolleté treatments 16 weeks after last treatment. 
• Treating investigator’s evaluation of the global aesthetic improvement on the iGAIS-
Wrinkles from baseline (Day 1) 
to 16 weeks after last 
treatment.  
• Subject’s evaluation of the global aesthetic improvement on the sGAIS-Wrinkles 
from baseline (Day 1) 
to 16 weeks after last treatment. 

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12.3.2 
Safety Endpoints 
12.3.2.1 
Secondary Safety Endpoints 
• Incidence of TEAEs related to the treatment with the IMD. 

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from baseline to 16 weeks after last treatment as assessed
. Same 
analyses as for the primary endpoint will be performed on this endpoint. 
Number and percentage of subjects with any level of treatment satisfaction of the aesthetic 
improvement in subject’s décolleté at 16 weeks after last treatment assessed by investigator 
and subject will be calculated and the according 2-sided 95% confidence intervals for the 
percentage of subjects with any level of treatment satisfaction will be provided for the 
pooled treatments (overall). 
Number and percentage of subjects with improvement in iGAIS-Wrinkles defined in a 
rating of 1, 2 or 3 at 16 weeks after last treatment will be summarized and 2-sided 95% 
confidence intervals be provided overall. Analogous methods will be used for sGAIS-
Wrinkles. 

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12.4.2 
Safety Endpoints 
All safety analyses will be performed on the SES. 
AEs will be coded according to the MedDRA version in effect at the time the database is 
closed. Only TEAEs will be analyzed, which are defined as AEs with onset on or after date 
of first injection of the IMD. 
12.4.2.1 
Secondary Safety Endpoints 
Incidences of related TEAEs will be provided by SOC and PT. 

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• Copies of IMD receipt forms and device inventory forms. 
• Copies of all relevant correspondence between the investigator and the monitor, and 
between the investigator and the sponsor.  
• Copies of safety information reported during the investigation and submitted by the 
sponsor. 
13.3 Destruction of Investigation Documents 
Investigation documents may not be destroyed by investigation site personnel prior to the 
retention period specified above without the prior written consent of the sponsor. The party 
who signed the investigator contract must inform the sponsor in due time if the principal 
investigator leaves the institution during the retention period. This rule also applies when 
the institution closes within the retention period. 

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14 PUBLICATION POLICY 
The investigational results should be published in the public domain, and publishing details 
will be given in the clinical study agreement. Publications concerning investigational 
results must be approved in advance by the sponsor in writing.  
The results of this investigation and any discoveries related to this investigation, regardless 
of whether they have technical or medical character, are the property of the sponsor. 

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