Open-label, Multicenter, Uncontrolled, Rater-blinded, Post-market Clinical Follow-up [PMCF] Study to Confirm Performance and Safety of RADIESSE® (+) Lidocaine in the Treatment of Nasolabial Folds, Marionette Lines, and/or Cheek Volume Loss
Phase: NA
Conditions: Signs of Facial Aging With Volume Loss in the Upper Cheeks, Nasolabial Folds and Marionette Lines
Sponsor: Merz North America, Inc.

- confidential -
Merz Pharmaceuticals GmbH         
    M900391005/RaLido  
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 1 / 94 
File name: M900391005_CP_1.0_20180618_final 
Open-label, multicenter, uncontrolled, rater-blinded, post-market clinical 
follow-up [PMCF] study to confirm performance and safety of 
RADIESSE® (+) Lidocaine in the treatment of nasolabial folds, marionette 
lines, and/or cheek volume loss 
Study identifier: 
M900391005, RaLido 
IDE number 
Not applicable 
Indications: 
Nasolabial folds, marionette lines, and/or cheek volume 
loss 
Planned study period: 
First subject first visit: Q3 2018 
Last primary outcome visit: Q2 2020 
Last subject last visit: Q2 2020 
Medical device: 
RADIESSE® (+) Lidocaine 
Sponsor: 
Merz Pharmaceuticals GmbH 
Eckenheimer Landstraße 100 
60318 Frankfurt am Main 
Telephone: +49-69-1503-0 
Telefax: +49-69-1503-200 
Responsible for the clinical 
protocol content at the sponsor: 
Clinical project manager: 
Medical expert: 
Biostatistician: 
Safety Officer: 
Clinical study sites: 
15-20 sites in Germany 
Statement: 
This clinical protocol is defined in accordance with DIN 
EN ISO 14155:2012 / ICH GCP / MEDDEV 2.12/2 rev. 
2- January 2012
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 study without the prior written consent of Merz Pharmaceuticals. 
NCT03650387, redacted 
version v1.0, 03May2021

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 2 / 94 
File name: M900391005_CP_1.0_20180618_final 
SIGNATURE PAGE 
The study will be conducted in compliance with the clinical protocol [CP], DIN EN ISO 
14155:2012, the Declaration of Helsinki, and regulatory authority requirements. 
The following individuals are responsible for the content of the CP: 
 
 
 
 
Clinical project manager 
Date 
 
Signature 
 
 
 
 
Medical expert 
Date 
 
Signature 
 
 
 
 
Biostatistician 
Date 
 
Signature 
 
 
 
 
Program Manager 
Date 
 
Signature 
 
 
 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 3 / 94 
File name: M900391005_CP_1.0_20180618_final 
Statement of Compliance 
Study Site(s) 
I have thoroughly read and reviewed the CP. Having understood the requirements and 
conditions of the CP, I agree to perform the clinical study according to the CP, the 
electronic Case Report Form [eCRF], DIN EN ISO 14155:2012, the Declaration of 
Helsinki, and regulatory authority requirements. 
I have received the current instructions for use [IFU 2017] leaflet and have been 
adequately informed about the study medical device [SMD] development to date, I also 
agree to: 
 Sign this CP before the study formally starts. 
 Wait until I have received approval from the appropriate ethics committee [EC] 
before enrolling any subject in this study. 
 Obtain informed consent for all subjects prior to any study-related action performed. 
 Start the study only after all legal requirements in my country have been fulfilled. 
 Permit study-related monitoring, audits, EC review, and regulatory inspections. 
 Provide direct access to all study-related records, source documents, and subject files 
for the monitor, auditor, EC, or regulatory authority upon request. 
 Use the SMD and all study materials only as specified in the CP. 
 Report to the responsible medical device safety officer, within 24 hours, any adverse 
event [AE] that is serious, whether considered treatment-related or not. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 4 / 94 
File name: M900391005_CP_1.0_20180618_final 
Furthermore, I understand that: 
 Changes to the CP 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 CP is confidential and proprietary to Merz.  
 Any deviation from the CP may lead to early termination of the study site. 
 
 
 
 
Principal investigator 
Date 
 
Signature 
 
 
 
 
 
 
 
Print Name 
 
 
 
 
Study site stamp: 
 
 
 
 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 5 / 94 
File name: M900391005_CP_1.0_20180618_final 
List of Abbreviations and Definitions of Terms 
AE 
Adverse event 
ADE 
Adverse device effect 
APAC 
Asia Pacific 
ASADE 
Anticipated serious adverse device effect 
ATC 
Anatomical Therapeutic Chemical classification system of the World Health 
Organization 
CaHA 
Calcium hydroxylapatite 
CE 
Conformité Européenne 
CIP 
Clinical Investigation Plan (term is synonymous with CP, Clinical Protocol) 
CP 
Clinical protocol 
CRO 
Contract research organization 
eCRF 
Electronic case report form 
EC 
Ethics committee 
EU 
European Union 
FAS 
Full analysis set 
FDA 
American Food and Drug Administration 
GCP 
Good clinical practice  
HA 
Hyaluronic acid 
IFU 
Instructions for use 
iGAIS 
Investigator Global Aesthetic Improvement Scale 
IMD 
Investigational Medical Device (term is synonymous with SMD, study medical 
device) 
ISF 
Investigator’s site file 
ISO 
International Organization for Standardization 
LATAM 
Latin America 
MAS 
Merz Aesthetic Scale  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMLS 
Merz Marionette Lines Scale 
MNLFS 
Merz Nasolabial Folds Scale 
MUCFS 
Merz Upper Cheek Fullness Scale  
N 
Number of non-missing observations 
PMCF 
Post-market clinical follow-up 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 6 / 94 
File name: M900391005_CP_1.0_20180618_final 
PPS 
Per protocol set 
SAE 
Serious adverse event 
SADE 
Serious adverse device effect 
SAP 
Statistical analysis plan 
SES 
Safety evaluation set 
sGAIS 
Subject Global Aesthetic Improvement Scale 
SMD 
Study medical device 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event 
TC 
Telephone contact 
USADE 
Unanticipated serious adverse device effect 
UV 
Ultraviolet 
V 
Visit 
VAS 
Visual analogue scale 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 7 / 94 
File name: M900391005_CP_1.0_20180618_final 
Table of Contents 
1 
SYNOPSIS .................................................................................................................12 
2 
STUDY ADMINISTRATIVE STRUCTURE ........................................................19 
2.1 
Internal responsibilities ..........................................................................................19 
2.2 
External responsibilities .........................................................................................20 
3 
ETHICS .....................................................................................................................21 
3.1 
Ethics committee ....................................................................................................21 
3.2 
Ethical conduct of the study ...................................................................................21 
3.3 
Subject information and informed consent ............................................................21 
3.3.1 
Subject information ..........................................................................................21 
3.3.2 
Informed consent .............................................................................................22 
3.3.3 
Subject card ......................................................................................................22 
3.3.4 
Subject privacy.................................................................................................22 
3.4 
Insurance ................................................................................................................23 
3.5 
Financing................................................................................................................23 
4 
INTRODUCTION ....................................................................................................24 
4.1 
Study background ..................................................................................................24 
4.2 
Study rationale .......................................................................................................25 
4.3 
Risk analysis and risk-benefit assessment .............................................................26 
5 
STUDY OJECTIVES ...............................................................................................30 
6 
STUDY PLAN ...........................................................................................................31 
6.1 
Overall study design ..............................................................................................31 
6.1.1 
End of study .....................................................................................................32 
6.1.2 
Study flow chart ...............................................................................................33 
6.2 
Discussion of study design, including choice of control groups ...........................34 
7 
STUDY POPULATION ...........................................................................................35 
7.1 
Selection of study population.................................................................................35 
7.2 
Inclusion criteria ....................................................................................................35 
7.3 
Exclusion criteria ...................................................................................................37 
7.4 
Removal of subjects from treatment or assessment ...............................................40 
7.4.1 
Discontinuation of subjects ..............................................................................40 
7.4.2 
Premature termination or suspension of the study or a study site ....................41 
7.4.3 
Provision of care for subjects after study discontinuation ...............................41 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 8 / 94 
File name: M900391005_CP_1.0_20180618_final 
8 
TREATMENTS ........................................................................................................42 
8.1 
Study medical device .............................................................................................42 
8.1.1 
Description of study medical device ................................................................42 
8.1.1.1 
Instructions for preparation .......................................................................42 
8.1.1.2 
Instructions for administration ..................................................................42 
8.1.2 
Packaging and labelling ...................................................................................43 
8.1.3 
Storage of study medical device ......................................................................44 
8.1.4 
Accountability for study medical device .........................................................44 
8.1.5 
Destruction of study medical device ................................................................44 
8.2 
Treatments administered ........................................................................................45 
8.2.1 
Methods of assigning subjects to treatment groups .........................................45 
8.2.2 
Selection of doses in the study .........................................................................45 
8.2.3 
Selection and timing of doses for each subject ................................................45 
8.2.4 
Duration of treatment per subject ....................................................................45 
8.2.5 
Treatment compliance ......................................................................................45 
8.2.6 
Treatment of overdose .....................................................................................46 
8.3 
Previous and concomitant therapies/procedures ....................................................46 
8.4 
Blinding..................................................................................................................47 
8.5 
Restrictions during the study .................................................................................47 
8.6 
Precautions during and after the study ...................................................................48 
9 
STUDY ASSESSMENTS AND VISIT SCHEDULE ............................................49 
9.1 
Clinical evaluations ................................................................................................49 
9.2 
Performance assessments .......................................................................................49 
9.2.1 
2D photographs ................................................................................................49 
9.2.2 
Merz Aesthetic Scales ......................................................................................50 
9.2.2.1 
Merz Nasolabial Folds – At Rest Scale......................................................50 
9.2.2.2 
Merz Marionette Lines – At Rest Scale ......................................................50 
9.2.2.3 
Merz Upper Cheek Fullness Scale – At Rest Scale ....................................51 
9.2.3 
Investigator Global Aesthetic Improvement Scale ..........................................53 
9.2.4 
Subject Global Aesthetic Improvement Scale .................................................54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3 
Safety assessments .................................................................................................58 
 
 
9.5 
Visit schedule .........................................................................................................59 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 9 / 94 
File name: M900391005_CP_1.0_20180618_final 
10 SAFETY ASSESSMENTS .......................................................................................65 
10.1 
Definition of an adverse event (AE) ......................................................................65 
10.1.1 
Adverse event details .......................................................................................65 
10.1.2 
Adverse event handling and reporting .............................................................66 
10.1.3 
Adverse event severity grading scale ...............................................................66 
10.1.4 
Causal relationship with medical device ..........................................................67 
10.1.5 
Categories of outcome .....................................................................................67 
10.2 
Definition of a serious adverse event (SAE) ..........................................................68 
10.2.1 
Serious adverse event details ...........................................................................68 
10.2.2 
Reporting and handling of SAEs .....................................................................69 
10.3 
Definition of an adverse device effect (ADE) .......................................................70 
10.4 
Definition of a serious adverse device effect (SADE) ...........................................70 
10.4.1 
Definition of an anticipated serious adverse device effect (ASADE) .............70 
10.4.2 
Definition of an unanticipated serious adverse device effect (USADE) .........71 
10.5 
Pregnancy ...............................................................................................................71 
10.6 
Definition of device deficiency ..............................................................................71 
10.6.1 
Reporting and handling of device deficiencies ................................................71 
11 DATA QUALITY ASSURANCE ............................................................................73 
11.1 
Standardization procedures ....................................................................................73 
11.2 
Source documentation requirements ......................................................................73 
11.3 
Data management...................................................................................................74 
11.4 
Monitoring .............................................................................................................74 
11.5 
Auditing .................................................................................................................75 
12 STATISTICAL METHODS ....................................................................................76 
12.1 
Determination of sample size .................................................................................76 
12.2 
Analysis sets...........................................................................................................76 
12.3 
Variables for analysis .............................................................................................77 
12.3.1 
Performance variables ......................................................................................77 
12.3.1.1 
Primary performance variable ..................................................................77 
12.3.1.2 
Secondary performance variables .............................................................79 
 
 
12.3.2 
Safety variables ................................................................................................81 
12.3.2.1 
Primary safety variable..............................................................................81 
12.3.2.2 
Secondary safety variables ........................................................................81 
 
 
 
 
12.4 
Statistical analysis methods ...................................................................................82 
12.4.1 
Performance variables ......................................................................................82 
12.4.1.1 
Primary performance variable ..................................................................82 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 10 / 94 
File name: M900391005_CP_1.0_20180618_final 
12.4.1.2 
Secondary performance variables .............................................................83 
 
 
12.4.2 
Safety variables ................................................................................................84 
12.4.2.1 
Primary safety variable..............................................................................84 
12.4.2.2 
Secondary safety variables ........................................................................84 
 
 
 
 
12.4.4 
Special statistical/analytical issues ..................................................................85 
12.4.4.1 
Discontinuations and missing data ............................................................85 
12.4.4.2 
Interim analyses .........................................................................................85 
12.4.4.3 
Data monitoring committee .......................................................................86 
12.4.4.4 
Multiple comparisons/multiplicity .............................................................86 
12.4.4.5 
Examination of subgroups .........................................................................86 
13 DATA HANDLING AND RECORDKEEPING....................................................88 
13.1 
Corrections to data .................................................................................................88 
13.2 
Recordkeeping .......................................................................................................88 
13.3 
Destruction of study documents.............................................................................89 
14 PUBLICATION POLICY ........................................................................................90 
15 REFERENCES .........................................................................................................91 
16 APPENDICES ...........................................................................................................94 
 
 
 
 
List of Figures 
Figure 1: Study Flow Chart................................................................................................33 
Figure 2: Merz Nasolabial Folds Scale ..............................................................................50 
Figure 3: Merz Marionette Lines Scale .............................................................................51 
Figure 4: Merz Upper Cheek Fullness Scale .....................................................................52 
 
 
List of Tables 
Table 1: Investigator Global Aesthetic Improvement Scale ..............................................54 
Table 2: Subject Global Aesthetic Improvement Scale .....................................................54 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 11 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
 
 
 
 
 
 
 
Table 7: Overview of study activities/visit schedule .........................................................63 
Table 8: Visits to be used for calculation of the primary variables changes from 
baseline to primary follow up visit ............................................................79 
 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 12 / 94 
File name: M900391005_CP_1.0_20180618_final 
1 SYNOPSIS 
Study title  
Open-label, multicenter, uncontrolled, rater-blinded, post-market clinical follow-up 
[PMCF] study to confirm performance and safety of RADIESSE® (+) Lidocaine in the 
treatment of nasolabial folds, marionette lines, and/or cheek volume loss. 
Indications 
Nasolabial folds, marionette lines, and/or cheek volume loss. 
Study objectives 
Primary objective(s) 
The primary objective of this post-market clinical follow-up study is to collect clinical 
data to confirm performance and safety for the injectable medical device 
RADIESSE® (+) Lidocaine, when used in accordance with its labelling in the treatment 
of nasolabial folds, marionette lines and/or cheek volume loss. The primary objective 
time point will be at Week 12/16 (depending on touch up). 
Secondary objective(s) 
The secondary objective is to analyse performance at all objective time point(s) other 
than the primary ones. 
Subject population, diagnosis, and main criteria for in- and exclusion 
Main inclusion criteria: 
1. Male or female ≥18 years old. 
2. Subjects seeking for dermal filler/volumising treatment in at least two of the 
following indications:  
o 
Nasolabial folds; 
o 
Marionette lines; 
o 
Cheek volume loss. 
3. Nasolabial folds volume deficit of moderate to very severe intensity (grade 2-4) 
on the Merz Nasolabial Folds Scale with symmetrical rating at Day 1 as 
determined by the blinded rater and confirmed by the treating investigator 
afterwards. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 13 / 94 
File name: M900391005_CP_1.0_20180618_final 
4. Marionette lines volume deficit of moderate to very severe intensity (grade 2-4) 
on the Merz Marionette Lines Scale with symmetrical rating at Day 1 as 
determined by the blinded rater and confirmed by the treating investigator 
afterwards. 
5. Upper cheek volume deficit of moderate to very severe intensity (grade 2-4) on 
the Merz Upper Cheek Fullness Scale with symmetrical rating at Day 1 as 
determined by the blinded rater and confirmed by the treating investigator 
afterwards. 
At least two of the inclusion criteria 3, 4, and 5 must be fulfilled. Depending on the 
fulfilled criteria, the respective indications will be treated. 
Main exclusion criteria: 
1. Any prior treatment with silicone, polymethyl methacrylate, fat injections, poly 
L-lactic acid or permanent dermal fillers in the face. 
2. Any prior facial surgery, including facial plastic surgery, thread lift, any unknown 
treatment, or any surgical permanent implant that could interfere with 
performance assessments. 
3. Prior treatment within the past 24 months with porcine based collagen fillers or 
with volumisers (e.g., Belotero® Volume or others) in the area to be treated. 
4. Prior treatment within the past 18 months with calcium hydroxylapatite in the area 
to be treated. 
5. Prior treatment within the past 12 months with hyaluronic acid in the area to be 
treated. 
6. Prior treatment within the past 6 months with facial dermal therapies (e.g. 
epilation, ultraviolet irradiation, radiofrequency, facial ablative or non-ablative 
laser treatment, microderm abrasion, mechanical or chemical peels, non-invasive 
skin-tightening [e.g., Ultherapy, Thermage] or surgical procedures) or plans to 
receive this during participation in the study. 
Medical device 
RADIESSE® (+) Lidocaine is CE-marked in Europe since 02-JUN-2016. It is a sterile, 
non-pyrogenic, semi-solid, cohesive implant. The principle component is synthetic 
calcium hydroxylapatite suspended in a gel carrier that consists primarily of water (sterile 
water for injection USP), glycerin (USP), sodium carboxymethylcellulose (USP), and 
0.3% lidocaine hydrochloride. The gel is dissipated in vivo and replaced with soft tissue 
growth, while the calcium hydroxylapatite remains at the site of injection. The lidocaine 
provides short-term local anesthetic effect. The result is long-term yet non-permanent 
restoration and augmentation. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 14 / 94 
File name: M900391005_CP_1.0_20180618_final 
RADIESSE® (+) Lidocaine has a calcium hydroxylapatite particle size range of 25-45 
microns. It is indicated for plastic/reconstructive procedures, including deep dermal and 
subdermal soft tissue augmentation of the facial area and is also intended for restoration 
and correction of facial volume loss. 
Study design 
This study is an open-label multicenter post-market clinical follow-up study with rater-
blinded1 live evaluation. There will be no control group as the objective is to confirm 
safety and performance in “real-life”.  
RADIESSE® (+) Lidocaine will be injected as per its current approved labelling and 
investigator’s usual practice at Day 1 with an optional touch up treatment after 4 weeks. 
The subject will be injected at Day 1 with appropriate quantity for each area to be treated, 
using injection techniques based on investigator’s judgement, skin condition, safety and 
subject’s expectations. A minimum of two and a maximum of three indications 
(nasolabial folds, marionette lines, and/or upper cheeks) per subject can be treated. An 
optional touch-up can be performed after 4 weeks (Visit 2) in one or more indications 
treated at Day 1, to obtain an optimal aesthetic outcome. 
An interim analysis report is planned on 6 months data (Week 24/28 respectively, 
depending on the touch-up).  
Planned study period 
First subject first visit: Q3 2018 
Last primary outcome visit: Q2 2020 
Last subject last visit: Q2 2020 
Duration of treatment per subject 
The duration of the study per subject will be approximately 18 months (in case of no 
touch-up performed at Visit 2) and 19 months (in case of touch-up at Visit 2).  
Variables for analysis 
The primary performance variables are: 
 Responder 
rate 
for 
nasolabial 
folds 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the Merz 
                                                          
1 The blinded rater does not know which indications were treated. He/she performs the Merz Aesthetic 
Scales live ratings and is also involved into the Merz Aesthetic Scales ratings at subject inclusion. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 15 / 94 
File name: M900391005_CP_1.0_20180618_final 
Nasolabial Folds Scale. Response defined as improvement of ≥ 1 point in both 
folds (left and right) from Day 1 pre-injection to Week 12/16 (depending on 
touch-up). 
 Responder 
rate 
for 
marionette 
lines 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the Merz 
Marionette Lines Scale. Response defined as improvement of ≥ 1 point in both 
marionette lines (left and right) from Day 1 pre-injection to Week 12/16 
(depending on touch-up). 
 Responder 
rate 
for 
cheek 
fullness 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the Merz 
Upper Cheek Fullness Scale. Response defined as improvement of ≥ 1 point in 
both cheeks (left and right) from Day 1 pre-injection to Week 12/16 (depending 
on touch-up). 
The primary safety variable is: 
 The occurrence of treatment emergent adverse events. 
The secondary performance variables are: 
 Responder 
rate 
for 
nasolabial 
folds 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the Merz 
Nasolabial Folds Scale prior to optional touch-up at Visit 2 (Week 4), at 
Week 24/28, at Week 48/52, and at Week 72/76 (depending on touch-up 
performed). Response for nasolabial folds defined as improvement of ≥ 1 point in 
both folds (left and right) compared to Day 1 pre-injection.  
 Responder 
rate 
for 
marionette 
lines 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the Merz 
Marionette Lines Scale prior to optional touch-up at Visit 2 (Week 4), at 
Week 24/28, at Week 48/52, and at Week 72/76 (depending on touch-up 
performed). Response for marionette lines defined as improvement of ≥ 1 point in 
both marionette lines (left and right) compared to Day 1 pre-injection. 
 Responder 
rate 
for 
cheek 
fullness 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the Merz 
Upper Cheek Fullness Scale prior to optional touch-up at Visit 2 (Week 4), at 
Week 24/28, at Week 48/52, and at Week 72/76 (depending on touch-up 
performed). Response for cheek fullness defined as improvement of ≥ 1 point in 
both cheeks (left and right) compared to Day 1 pre-injection. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 16 / 94 
File name: M900391005_CP_1.0_20180618_final 
 Treating investigator’s evaluation of the global aesthetic improvement on the 
investigator Global Aesthetic Improvement Scale from Day 1 pre-injection photos 
to Visit 2 (Week 4) prior to optional touch-up, to Week 12/16, to Week 24/28, to 
Week 48/52, and to Week 72/76 (depending on touch-up performed). 
 Subject’s evaluation of the global aesthetic improvement on the subject Global 
Aesthetic Improvement Scale from Day 1 pre-injection photos to Visit 2 (Week 4) 
prior to optional touch-up, to Week 12/16, to Week 24/28, to Week 48/52, and to 
Week 72/76 (depending on touch-up performed).  
Total number of subjects and number of countries 
A total number of 210 subjects in one country (Germany).  
Number of study sites 
A total of 15-20 study sites. 
Number of visits 
Six visits (if no touch-up is performed), six visits plus one telephone contact (if touch-up 
is performed in all indications that were treated at Day 1), or seven visits plus one 
telephone contact (if partial [i.e. in at least one, but not in all indications that were treated 
at Day 1] touch-up treatment is performed) in total. 
Medical device, dose, and route of administration 
RADIESSE® (+) Lidocaine will be injected as per its current approved labelling and 
investigator’s usual practice.  
Volume to be injected, techniques of injections and depths of injections are at the 
investigator’s discretion according to the area to be treated, as well as the subject’s 
expectations. Overcorrection should be avoided. Investigators should use only the needles 
provided in the SMD packaging, however, investigators are allowed to use cannulas at 
their own choice instead of the supplied needles, if cannulas instead of needles are 
usually being used in their daily practice.  
Statistical analysis methods 
All performance analyses will be based primarily on the full analysis set and additionally, 
for the primary performance analyses, on the per protocol set. Statistical tests will be 
one-sided hypothesis tests for responder rates. The Bonferroni Holm alpha correction will 
be used for three statistical tests to adhere to the global significance level of 0.025. 
Continuous variables (values and changes from baseline) will be summarized by number 
of non-missing values, mean, standard deviation, median, quartiles, minimum and 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 17 / 94 
File name: M900391005_CP_1.0_20180618_final 
maximum. For qualitative variables, absolute and percent frequencies (N, %) will be 
displayed.  
Primary performance variables 
Responder rates will be summarized as absolute and percent frequencies (N, %). The aim 
of primary performance analyses is to show that there are: 
 significantly more than 60% of responders in treatment of nasolabial folds; 
 significantly more than 60% of responders in treatment of marionette lines; 
 significantly more than 60% of responders in treatment of cheek volume loss. 
A confirmatory exact one-sample binomial test will be used to test probability of being a 
responder (p) is above 60% separately for each indication: 
 H0 nasolabial folds: p ≤ 0.6  
vs. 
H1 nasolabial folds: p > 0.6 
 H0 marionette lines: p ≤ 0.6   
vs. 
H1 marionette lines: p > 0.6 
 H0 cheek volume loss: p ≤ 0.6  
vs. 
H1 cheek volume loss: p > 0.6 
Secondary performance variable 
No additional key secondary hypotheses will be tested under control of the global type I 
error level.  All secondary variables will be analysed descriptively as follows: responder 
rates for nasolabial folds, for marionette lines, and for cheek fullness of the remaining 
visits will be summarized as frequency tables with absolute and percent frequencies (N, 
%). Investigator and subject Global Aesthetic Improvement Scales will be displayed 
using descriptive summary statistics for continuous variables and as frequency tables 
with absolute and percent frequencies (N, %). Subgroup analysis will be done per 
indication (subjects treated for nasolabial folds, for marionette lines, and for cheek 
volume loss).  
Manufacturer of the medical device(s) 
Merz North America, Inc. 
4133 Courtney St., Suite 10 
Franksville WI 53126 U.S.A. 
Telephone: 844.469.6379 
E-Mail: mymerzsolutions@merz.com 
(Manufacturer of RADIESSE® [+] Lidocaine) 
Terumo Europe N.V. 
Interleuvenlaan 40 
3001 Leuven 
Belgium 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 18 / 94 
File name: M900391005_CP_1.0_20180618_final 
Tel.: +32 16 38 12 11 
(Manufacturer of needles) 
 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 19 / 94 
File name: M900391005_CP_1.0_20180618_final 
2 STUDY ADMINISTRATIVE STRUCTURE 
2.1 
Internal responsibilities 
Name 
Function 
Address 
Merz North America, Inc.,  
 
Legal manufacturer of the 
device 
4133 Courtney St., Suite 10 
Franksville, WI 53126, U.S.A. 
Telephone: +1 844 469 6379 
Merz Pharmaceuticals GmbH 
 
Sponsor  
Eckenheimer Landstraße 100 
60318 Frankfurt am Main 
Telephone: +49-69-1503-0 
 
Clinical project manager 
Telephone: 
 
Telefax: 
 
Email: 
 
 
Medical expert 
Telephone: 
 
Telefax: 
 
Email: 
 
 
Biostatistician 
Telephone: 
 
Telefax: 
 
Email: 
 
  
Medical device safety 
officer 
Telephone: 
 Telefax:
 
 
Email:           
 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 20 / 94 
File name: M900391005_CP_1.0_20180618_final 
2.2 
External responsibilities 
The administrative structure for external responsibilities includes, but is not limited to, 
the following participants: 
 
Name 
Function 
Address 
 
 
 
 
 
CRO for clinical conduct 
 
 
Germany 
Telephone: 
 
Telefax: 
 
Email: 
 
 
  
 
 
CRO for data 
management and 
biostatistics 
 
 
Germany  
Telephone: 
 
Telefax:             
 
Email: 
 
For this study, the sponsor will maintain a list of all principal investigators. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 21 / 94 
File name: M900391005_CP_1.0_20180618_final 
3 ETHICS 
3.1 
Ethics committee 
The following documents must be submitted to the responsible EC and approval should 
be obtained: 
 The CP.  
 Any amendment to the CP that is not solely of an administrative nature. 
 The IFU and all updates. 
 Subject information and informed consent forms, as well as updates (if applicable). 
 All subject recruitment procedures and any advertisement used to recruit subjects (if 
applicable). 
 Any other required documents.  
If applicable, and in accordance with local legal requirements, the above documents also 
may be submitted to the respective regulatory authority(ies) for separate approval. 
3.2 
Ethical conduct of the study 
This study will be conducted in accordance with the ethical principles that have their 
origin 
in 
the 
Declaration 
of 
Helsinki 
and 
are 
consistent 
with 
DIN EN ISO 14155:2012/MEDDEV 2.12/2 rev. 2 – January 2012/ICH-GCP and 
applicable regulatory requirements.  
3.3 
Subject information and informed consent 
3.3.1 
Subject information 
Prior to study 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 study. 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, ICH GCP, DIN EN ISO 14155:2012 (chap. 4.7), and MEDDEV 
2.12/2 rev. 2 – January 2012. The obligations of the investigator are set forth in the CP, 
DIN EN ISO 14155:2012, and the respective national regulations governing medical 
research and experimentation on humans. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 22 / 94 
File name: M900391005_CP_1.0_20180618_final 
Each subject will have the opportunity to question the investigator (or authorized 
designee) about the study prior to giving consent. 
3.3.2 
Informed consent 
Informed consent will be obtained in accordance with DIN EN ISO 14155:2012 (chap. 
4.7) in writing directly from the subject. 
The consent must be confirmed by the investigator (or authorized designee) who 
conducted the informed consent process. The informed consent process must be traceable 
from the available documentation. At a minimum, this documentation should include 
information regarding when the subject was first informed about the study and who 
supplied the information. The subject will be given a copy of the signed and dated written 
informed consent form as well as all consent form updates (if applicable). 
During the course of the study, the subject will be informed in a timely manner if data 
becomes available that might be relevant to the subject’s willingness to continue 
participation in the study. In case of AEs or poor tolerability to the SMD, the subject 
should inform the investigator, who then will make a judgement whether continuing in 
the study serves the subject’s best interests. The subject, however, is free to withdraw 
consent at any time and for any reason, whether expressed or not. 
3.3.3 
Subject card  
This is not applicable for the current study.  
3.3.4 
Subject privacy 
The subject will be informed of procedures that protect the subject privacy. Although 
recorded data will be passed on in a coded manner to authorized individuals only, re-
identification by the investigator (e.g., in case of emergencies) will be possible using the 
subject number assigned to the subject. Access to non-coded data will be allowed solely 
to check validity, and such access will be limited strictly to authorized individuals (e.g., 
the sponsor or individuals authorized by the sponsor, auditors, regulatory authorities, or 
members of ECs who have been bound to confidentiality. If the results of the study are 
published, the subject’s identity will remain confidential. 
Photographs will be used by the site staff only for support of evaluations and will not be 
published or otherwise disclosed. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 23 / 94 
File name: M900391005_CP_1.0_20180618_final 
3.4 
Insurance  
From the beginning of the study until its termination, each subject is insured against any 
health impairment occurring as a result of participation in the study, 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, if requested. Any medical 
deviation from the CP that is deemed to have occurred through the subject’s own fault is 
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 CP. The sponsor is also 
usually not liable for events resulting from negligence of the investigator, clinical study 
staff, including failure to act according to DIN EN ISO 14155:2012 or to comply strictly 
with the agreed CP. 
3.5 
Financing 
The financial aspects of the study will be documented in an agreement between the 
sponsor, the Contract research organization [CRO] and each investigator or any other 
involved party and must be confirmed in writing before the study commences. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 24 / 94 
File name: M900391005_CP_1.0_20180618_final 
4 INTRODUCTION 
4.1 
Study background 
Facial aging 
Facial aging is the result of innate (chronological) aging and external (e.g., sun-induced) 
damage that share the loss of normal elastic fiber functions and the loss of hyaluronic 
acid [HA] as key common features. Innate aging comprises the atrophy and sagging of 
facial fat compartments and the remodeling of the underlying bone, manifested by 
flattening or indentation of normally convex contours [Fitzgerald 2014, Truswell 2013] . 
Tissue ptosis and/or atrophy and are most commonly seen in the mid to lower face. The 
aging process differs between individuals and depends on genetic predisposition, on 
exposure to ultra-violet [UV] radiation, deleterious environmental factors, and nicotine 
and alcohol consumption [Thurstan 2012]. 
Soft tissue augmentation 
Soft tissue augmentation with dermal fillers is a popular, minimally invasive aesthetic 
procedure to counteract the signs of aging [Carruthers 2009]. Unwanted wrinkles can be 
corrected by a variety of methods depending on their nature and causation. To select a 
suitable method, it is necessary to accurately define the wrinkles (depth, classification 
into dynamic folds, gravity-induced folds etc.) and evaluate the facial fat distribution.  
Facial anatomy is complex since the three-dimensional aspect of the face must be 
considered in relation to functional anatomical components. These components are in 
permanent motion and muscle contractions result in facial expression. The thickness, 
color, mobility and texture of facial skin are variable and the fat layer, which is located in 
subcutaneous tissue layers between the skin and muscles, also varies in thickness. Many 
signs of aging are due to the loss of subcutaneous fat and so the use of fillers can help to 
create a more youthful appearance, thereby reducing many signs of aging [Carruthers 
2008b]. 
A very effective method of treating facial folds and volume loss is the augmentation 
procedure in which absorbable or non-absorbable filler materials of various types are 
implanted or injected. If permanent implants (non-absorbable silicone or substances 
containing polyacrylamide or acrylates) are used, the effect can only be reversed with 
difficulties. This means that all the adverse effects of permanent implants such as 
slippage, allergy induction and nodule formation either remain for years or the implants 
must be removed surgically. 
Biodegradable substances that are currently used are the subject's own body fat 
(autologous fatty tissue), polylactic acid, calcium hydroxylapatite [CaHA], and HA 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 25 / 94 
File name: M900391005_CP_1.0_20180618_final 
produced by biotechnology methods. In 2016, most non-surgical augmentation treatments 
performed with a dermal filler in the US used a product based on HA, followed by CaHA 
[ASAPS 2017]. 
RADIESSE® (+) Lidocaine 
RADIESSE® (+) Lidocaine is Conformité Européenne [CE]-marked in Europe since 
02-JUN-2016. It is a sterile, non-pyrogenic, semi-solid, cohesive implant. The principle 
component is synthetic CaHA suspended in a gel carrier that consists primarily of water 
(sterile water for injection USP), glycerin (USP), sodium carboxymethylcellulose (USP), 
and 0.3% lidocaine hydrochloride. Itis formulated to augment volume and, subsequently, 
to stimulate collagen production [Marmur 2004]. It consists 30% of CaHA microspheres 
and 70% of sodium carboxymethylcellulose gel. The microspheres are composed of a 
synthetic form of a natural substance found in the bones and teeth with a particle size 
range of 25-45 microns. Carboxymethylcellulose is a derivative of cellulose and acetic 
acid. The substance is frequently applied as a thickening agent and stabilizer of emulsions 
in certain foods and nonfood products, and to increase the viscosity in liquid 
pharmacological preparations. After injection, the carboxymethylcellulose gel is rapidly 
broken down while CaHA microspheres act as a sort of platform for newly synthesized 
collagen. This means that the filler is slowly replaced by autologous connective tissue 
[Kadouch 2017]. 
As a deep dermal to subdermal implant, RADIESSE® (+) Lidocaine it is indicated for 
plastic and reconstructive surgery of the facial area, including the correction of moderate 
to severe facial wrinkles and folds, and restoration and/or correction of the signs of facial 
fat loss [Jacovella 2008]. The formulation without lidocaine has already received 
CE-certification in 2003 and was approved by the American Food and Drug 
Administration [FDA] in 2006. Since then, it has been investigated in many studies in 
different indications, demonstrating high effectiveness, subject satisfaction and a 
favorable safety profile [Kadouch 2017]. The new formulation with lidocaine was 
introduced in 2016 to enhance patient comfort during treatment [Schachter 2016]. 
The SMD used in this clinical study is a CE-marked dermal filler and approved for the 
indications that will be treated (see current version of the [IFU 2017]). 
4.2 
Study rationale 
Essential features of safe and effective dermal fillers include facility of use, longevity of 
results, and minimization of adverse effects.  
The purpose of this PMCF study is to collect clinical data on RADIESSE® (+) Lidocaine 
when used simultaneously in multiple indications and in accordance with the approved 
labelling, to confirm its clinical performance and safety, and to detect potential emerging 
risks based on factual evidence.  

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 26 / 94 
File name: M900391005_CP_1.0_20180618_final 
Current available scientific data, clinical data, and post-marketing surveillance data of the 
SMD itself and its version without lidocaine support and demonstrate the clinical 
performance and safety of the product when injected as per its IFU (see current version of 
[IFU 2017]) [Bass 2010, Graivier 2007, Jacovella 2008, Pavicic 2013, Tzikas 2008]. 
Although it is common practice to inject more than one indication in one treatment 
session (holistic approach), only few clinical data following combination treatment of 
more than one indication at the same time are available so far. It is therefore desirable 
that post-market clinical data of good quality is generated to investigate the safety and 
performance of the SMD when used according to its current IFU. 
4.3 
Risk analysis and risk-benefit assessment 
Benefits 
 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 2017, 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 2017, Sadick 2007]. The risk to 
develop an allergic reaction to lidocaine is also considered low [Fathi 2016]. 
 The addition of lidocaine to CaHA provides better patient comfort during treatment 
[Schachter 2016]. 
 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 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 SMD is CE-marked in Europe and approved in US and several LATAM- and APAC 
countries.Risks: 
In occasional cases, one or more of the events described below may occur either 
immediately or as a delayed reaction: 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 27 / 94 
File name: M900391005_CP_1.0_20180618_final 
 For any implant material, possible adverse reactions that may occur include, but 
are not limited to, the following: inflammation, infection, fistula formation, 
extrusion, hematoma/ecchymosis, seroma, induration formation, inadequate 
healing, skin discoloration/blanching of the skin, inadequate or excessive 
augmentation, contour irregularity, lumps, granulomas, hardening of the tissue at 
the injection site. Irregularity of the implant may require a surgical procedure to 
correct. In extreme cases, overcorrection can lead to site rupture. Overcorrection 
is not allowed in this study. 
 An important untoward occurrence for any implant material is the introduction of 
the product into the blood vessels, which may lead to embolization, occlusion of 
the vessels (vascular compromise), ischemia, or infarction which can lead to 
necrosis, cerebral ischemia or cerebral hemorrhage, leading to stroke, and damage 
to underlying facial structures. In rare cases, such embolization can lead to 
blindness, especially when the dorsum of the nose is treated [Rayess 2017]. In this 
study, nose correction is not allowed and only well trained and experienced 
physicians with a deep knowledge of the facial anatomy will be included in this 
study. The investigator is advised to take extra care during the procedure. He/she 
needs to inject the SMD slowly and apply the least amount of pressure necessary. 
If some subject exhibits symptoms of blanching of the skin or unusual pain during 
or shortly after the procedure, subjects should receive prompt medical attention 
and evaluation by an appropriate health care practitioner specialist. 
 
Adverse Events recorded in the studies with RADIESSE® (+) Lidocaine 
 
 Adverse events seen in a clinical trial with RADIESSE® (+) Lidocaine injectable 
implant were generally expected, mild in nature, and short in duration.  In a multi-
center, randomized, controlled trial for the treatment of nasolabial folds by subdermal 
injection, one fold was injected with the RADIESSE® injectable implant and the 
other fold was injected with the RADIESSE® (+) Lidocaine injectable implant.  The 
most common adverse events reported were swelling and redness.  There was no 
significant difference in adverse event rates between the nasolabial folds injected with 
RADIESSE® and those injected with RADIESSE® (+) Lidocaine.  Needle jams 
occurred during RADIESSE® (+) Lidocaine injections in three (3/101, 3%) subjects.  
In all cases, the needle was replaced and the RADIESSE® (+) Lidocaine injections 
were completed without further sequelae.  Of 13 blanching events described, one was 
associated with a vascular compromise event.  There were two (2/102, 2%) vascular 
compromises that occurred in nasolabial folds injected with RADIESSE® and none 
that occurred in nasolabial folds injected with RADIESSE® (+) Lidocaine.  Both 
occurrences of vascular compromise were treated and resolved. The following 
adverse events were reported during clinical trials performed with the RADIESSE® 
injectable implant (without lidocaine): ecchymosis, edema, erythema, nodule, pain, 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 28 / 94 
File name: M900391005_CP_1.0_20180618_final 
pruritus, soreness, tenderness, numbness, contour irregularity, lumps, irritation, rash, 
needle jamming, discoloration, hardness, headache, scab, tightness, blood shot eyes, 
black eye, abrasion, spot, nerve sensitivity, dry, burning sensation, warm, stretched, 
pimple, flushed, feverish, ear running, backed-up salivary gland, firmness, hearing 
loss, and puffiness. 
 
Post market surveillance for equivalent product, RADIESSE®.   
 The following adverse events have been identified during post-approval use of 
RADIESSE®.  Because they are reported voluntarily from a population of uncertain 
size, it is not always possible to reliably estimate their frequency or establish a causal 
relationship to RADIESSE®.  These events have been chosen for inclusion  due to a 
combination of their seriousness, frequency of reporting, or potential causal 
connection to RADIESSE®: infection, cellulitis, impetigo, loss of effect, product 
displacement/migration, allergic reaction, anaphylaxis, hives, rash, pruritus, urticaria, 
angioedema, inflammation, necrosis, granuloma, nodules, induration, erythema, skin 
discoloration, pustule, skin pallor, hair loss, paresthesia, ptosis, pain, headache, 
swelling, asymmetry, abscess, herpetic infection including herpes simplex and herpes 
zoster, hematoma, blanching, blistering, dizziness, festoons, flu-like symptoms, 
Guillain-Barre syndrome, tachypnea, ischemic reaction, lymphoid hyperplasia, 
nausea, pericarditis, scarring, sensitivity to cold, vascular occlusion/ obstruction, 
vascular compromise, ocular ischemia, diplopia, visual impairment/blindness, facial 
muscle paralysis, Bell’s palsy. 
The CaHA particles are radio-opaque and are clearly visible on computer tomogram 
scans and may be visible in standard, plain radiography. Subjects need to be informed of 
the radio-opaque nature of the SMD, so that they can inform their primary care health 
professionals and/or radiologists. In a radiographic study of 58 patients, there was no 
indication of RADIESSE® (without lidocaine) potentially masking abnormal tissues or 
was interpreted as tumors in computer tomogram scans [Carruthers 2008a].  
During injection, needle/cannula jam can occur in rare cases that can make 
needle/cannula change necessary. 
Subjects using anti-coagulant or thrombolytic substances like aspirin may have increased 
reactions of bruising hematomas, nodules or bleeding at the injection site. Special care 
should apply in subjects suffering from severe bleeding disorders [DeLorenzi 2014]. In 
accordance with RADIESSE® (+) Lidocaine IFU, subjects with bleeding disorders or 
receiving therapy with anti-coagulation, anti-platelet, or thrombolytic medications (e.g., 
warfarin, heparin, clopidogrel), anti-inflammatory drugs (e.g., aspirin), or other 
substances known to increase coagulation time from ten days before to three days 
post-injection with the SMD are excluded from this clinical study. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 29 / 94 
File name: M900391005_CP_1.0_20180618_final 
Since the product investigated in this study is biodegradable, regular follow-up treatment 
may be necessary if a visible enhancement effect (optimal cosmetic correction) continues 
to be desired. 
Conclusion: 
The SMD is marketed for aesthetic treatments in the target indications for several years 
across different countries worldwide. Since then 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.  
Considering all risks and benefits of the SMD the potential benefits outweigh the 
potential risks. The risk/benefit ratio of the device is considered as acceptable when used 
on subjects according to the current manufacturer’s IFU. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 30 / 94 
File name: M900391005_CP_1.0_20180618_final 
5 STUDY OBJECTIVES  
Primary objective(s) 
The primary objective of this PMCF study is to collect clinical data to confirm 
performance and safety for the injectable medical device RADIESSE® (+) Lidocaine, 
when used in accordance with its labelling in the treatment of nasolabial folds, marionette 
lines and/or cheek volume loss. The primary objective time point will be at Week 12/16 
(depending on touch-up). 
Secondary objective(s) 
The secondary objective is to analyse performance at all objective time point(s) other 
than the primary ones.   

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 31 / 94 
File name: M900391005_CP_1.0_20180618_final 
6 STUDY PLAN 
6.1 
Overall study design 
This study is an open-label multicenter PMCF study with rater-blinded2 live evaluation. 
There will be no control group as the objective is to confirm safety and performance in 
“real-life”. 
Approximately 
175 subjects 
per 
indication 
seeking 
for 
dermal 
filler/volumising treatment in the face who agree to participate by signing the written 
informed consent form and who are fulfilling inclusion/exclusion criteria will be enrolled 
at approximately 15-20 sites. Since subjects must be treated for at least two and up to 
three indications, selected out of nasolabial folds, marionette lines and cheek volume 
loss, about 210 subjects in total are planned to be enrolled to collect data from about 
175 subjects per separate indication (it is assumed that 50% of subjects will be treated for 
two and 50% for three indications, respectively). 
At least 105 subjects will be treated in all of the three indications (i.e. nasolabial folds, 
marionette lines, and cheek volume). In addition, 35 subjects will be treated for each of 
the three treatment combinations: 
 Nasolabial folds + marionette line; 
 Nasolabial folds + cheek volume; 
 Marionette lines + cheek volume. 
If the number of subjects treated in all of the three indications is higher than 105, the 
number of the subjects treated for only two indications may be reduced so that the total 
number of all treated subjects will be 210. 
The SMD is CE-marked in Europe since 02-JUN-2016 and will be injected as per its 
current approved labelling and investigator’s usual practice at Day 1 with an optional 
touch-up treatment after 4 weeks. 
The duration of the study per subject will be approximately 18 months (in case of no 
touch-up performed at Visit [V] 2) and 19 months (in case of touch-up performed at V2).  
The subject will be injected at Day 1 with volume for each area to be treated, using 
injection techniques based on investigator’s judgement, skin condition, safety and 
subject’s expectations. A minimum of two and a maximum of three indications 
(nasolabial folds, marionette lines, cheeks) per subject can be treated. An optional touch-
                                                          
2 The blinded rater does not know which indications were treated. He/she performs the Merz Aesthetic 
Scales [MAS] live ratings and is also involved into the MAS ratings at subject inclusion. 

 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 32 / 94 
File name: M900391005_CP_1.0_20180618_final 
up can be performed after four weeks at V2 in the indications that were treated at Day 1, 
to obtain an optimal aesthetic outcome, as appropriate. 
 
If the subject fulfills the inclusion criteria and agrees to participate, he/she will attend six 
visits (if no touch-up is performed), six visits plus one telephone contact [TC] (if touch-
up is performed in all indications that were treated at Day 1), or seven visits plus one TC 
(if partial [i.e. in at least one, but not in all indications that were treated at Day 1] touch-
up treatment is performed) in total. If any serious AE [SAE] related to the injection or the 
SMD is not resolved by the end of the study, the subject will be followed until the 
resolution of the SAE by the Merz Pharmaceuticals Department of Product Safety. 
An interim analysis report is planned on 6 months data (Week 24/28 respectively, 
depending on touch-up). 
6.1.1 
End of study 
The end of study will be defined as the last visit of the last subject. 
 
 

 
- confidential - 
Merz Pharmaceuticals GmbH                                                                                                           M900391005/RaLido     
 
Clinical Protocol for post market clinical follow-up studies (PMCF) 
Version 1.0 
 18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 33 / 94 
File name: M900391005_CP_1.0_20180618_final 
6.1.2 
Study flow chart                                      
 Figure 1: Study Flow Chart 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 34 / 94 
File name: M900391005_CP_1.0_20180618_final 
6.2 
Discussion of study design, including choice of control groups 
The prospective, open label multicenter PMCF study design was chosen to adequately 
investigate the performance and safety of the SMD as per the current practice. 
In general, prospective designs can achieve a higher data quality as compared to 
retrospective designs. 
In order to collect “real-life” data, it has been decided not to interfere with investigators’ 
usual practice and therefore employ a PMCF design. This design will allow evaluation of 
performance and safety of the SMD while used as per its current approved IFU. 
Using several study sites increases the representativeness of the study results and 
decreases study site-related biases. 
The observational period of approximately 18 to 19 months (if touch-up has been 
performed) was chosen to allow assessment of late-onset reactions. 
The volume of the SMD to be injected as well as the choice of the injection technique are 
at the discretion of the investigator. This reflects the common use of fillers among 
physicians because the volume is adapted to the depths and the size of the areas to be 
treated as well as to the quality/thickness of the skin in these areas. Moreover, it depends 
on the desired cosmetic outcome which is usually a collective decision of both the 
treating physician and the subject. 
Investigators should use only the needles provided in the SMD packaging, however, 
investigators are allowed to use cannulas at their own choice instead of the supplied 
needles, if cannulas instead of needles are usually being used in their daily practice. As 
this is a PMCF study with the main focus on performance and safety under real life 
conditions in daily practice, a control group that will be left untreated is not foreseen. 
A blinded rater at each study site not otherwise involved in study procedures was chosen 
to assess the primary endpoint. The blinded rater does not know which indications were 
treated, which helps minimize the possible effects of evaluator bias.  

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 35 / 94 
File name: M900391005_CP_1.0_20180618_final 
7 STUDY POPULATION 
7.1 
Selection of study population 
A total of approximately 210 adult subjects of both genders will be enrolled if they meet 
all of the inclusion and none of the exclusion criteria.  
Investigators may recruit subjects from their existing pool of subjects, new subjects that 
are seeking facial aesthetic treatment, by word-of-mouth recommendation (e.g., satisfied 
subjects that formerly have received aesthetic treatment in the practice or clinic) or by 
advertisement. 
Each of the three subpopulations, i.e. subject treated for nasolabial folds, marionette 
lines, and cheek volume loss, will contain approximately 175 subjects. Each subject will 
belong to at least two of these subpopulations. At least 50% of the subjects will be treated 
in all of the three indications and as consequence these subjects will belong to all of these 
three subpopulations (i.e. nasolabial folds, marionette lines, and cheek volume loss). 
7.2 
Inclusion criteria 
Only subjects meeting the following inclusion criteria will be considered for study 
enrollment: 
Inclusion criteria   
Rationale 
1. Written informed consent obtained from the subject. 
Administrative 
2. Understanding of study procedures and willingness to abide by all 
procedures during the course of the study. 
Administrative 
3. Male or female ≥18 years old. 
Administrative 
4. Subjects seeking for dermal filler/volumising treatment in at least 
two of the following indications: 
o Nasolabial folds; 
o Marionette lines; 
o Cheek volume loss. 
Performance 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 36 / 94 
File name: M900391005_CP_1.0_20180618_final 
Inclusion criteria   
Rationale 
5. Nasolabial folds volume deficit of moderate to very severe intensity 
(grade 2-4) on the Merz Nasolabial Folds Scale [MNLFS] with 
symmetrical rating at Day 1 as determined by the blinded rater and 
confirmed by the treating investigator afterwards. 
Performance 
6. Marionette lines volume deficit of moderate to very severe intensity 
(grade 2-4) on the Merz Marionette Lines Scale [MMLS] with 
symmetrical rating at Day 1 as determined by the blinded rater and 
confirmed by the treating investigator afterwards. 
Performance 
7. Upper cheek volume deficit of moderate to very severe intensity 
(grade 2-4) on the Merz Upper Cheek Fullness Scale [MUCFS] with 
symmetrical rating at Day 1 as determined by the blinded rater and 
confirmed by the treating investigator afterwards. 
Performance 
8. Subject understands and accepts the obligation to follow study 
instructions and is logistically able to present for all scheduled study 
visits and meets all study requirements. 
Administrative 
9. 
Subject is willing to abide from all procedures (e.g., dermal fillers 
outside of this study, toxin treatments, facial ablative or fractional 
laser, microdermabrasion, chemical peels, non-invasive 
skin-tightening [e.g., Ultherapy, Thermage], and surgical 
procedures) in the face during participation in the study. 
Safety concern 
10. Subject will be compliant with contra-indications, precautions for 
use and warnings mentioned in the IFU of the injectable device to 
be injected (for details see exclusion criteria). 
Safety concern 
11. Women of childbearing potential3 must be using a highly effective 
method of birth control.4 
Safety concern 
At least two of the inclusion criteria 5, 6, and 7 must be fulfilled depending on which 
indication will be treated. 
 
 
                                                          
3 Childbearing potential is defined as NOT premenarche, permanently sterilized or postmenopausal (i.e., 
12 months with no menses without an alternative medical cause). 
4 Defined as a method that results in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual 
abstinence, or vasectomized partner. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 37 / 94 
File name: M900391005_CP_1.0_20180618_final 
7.3 
Exclusion criteria 
Subjects having any of the following criteria will not be included in the study: 
Exclusion criteria 
Rationale 
1. Any prior treatment with silicone, polymethyl methacrylate, fat 
injections, poly L-lactic acid or permanent dermal fillers in the face. 
Safety concern 
2. Any prior facial surgery, including facial plastic surgery, thread lift, 
any unknown treatment, or any surgical permanent implant that 
could interfere with performance assessments. 
Safety concern 
3. Prior treatment within the past 24 months with porcine based 
collagen fillers or with volumisers (e.g., Belotero® Volume or 
others) in the area to be treated. 
Safety concern 
4. Prior treatment within the past 18 months with CaHA in the area to 
be treated. 
Safety concern 
5. Prior treatment within the past 12 months with HA in the area to be 
treated. 
Safety concern 
6. Prior treatment within the past 6 months with facial dermal therapies 
(e.g., epilation, UV irradiation, radiofrequency, facial ablative or 
non-ablative laser treatment, microdermal abrasion, mechanical or 
chemical peels, non-invasive skin-tightening [e.g., Ultherapy, 
Thermage], surgical procedures) or plans to receive this during 
participation in the study. 
Safety concern 
7. Prior treatment within the past 4 months with botulinum toxin in the 
area to be treated or plans to receive it during participation in the 
study. 
Safety concern 
8. Use of any new over-the-counter or prescription, oral or topical, 
anti-wrinkle products within 3 months prior to study inclusion or 
intention to use such products along the study duration. 
NOTE: Use of sunscreens and continued therapy with 
some cosmeceuticals, e.g., alpha hydroxyl acids, glycolic 
acids, skin-bleaching agents, retinol, or retinoic acids, 
are allowed if the regimen was established > 3 months 
prior to enrollment. 
Safety concern 
9. Prior treatment within the past 2 months with immunosuppressive 
medications or systemic steroids (except intranasal/inhaled steroids) 
or plans to receive them during participation in the study. 
Safety concern 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 38 / 94 
File name: M900391005_CP_1.0_20180618_final 
Exclusion criteria 
Rationale 
10. 
Prior cosmetic treatment (e.g., facials) within the past 30 days in 
the area to be treated or plans to receive it during participation in the 
study. 
Safety concern 
11. 
Prior oral surgery (e.g., orthodontia, extraction, implants) within 
the past 30 days or plans to undergo it during participation in the 
study. 
Safety concern 
12. 
Any known bleeding disorder, intake or planned intake of anti-
coagulation, anti-platelet, or thrombolytic medications (e.g., aspirin, 
warfarin, heparin, clopidogrel), anti-inflammatory drugs (e.g., 
aspirin), or other substances known to increase coagulation time 
ten days prior and up to three days post SMD application. 
Safety concern 
13. 
Facial hair (e.g., beard) or other conditions (e.g., sideburns, etc.) 
that might interfere with study assessments. 
Performance 
14. 
Actinic damaged skin, premature aging skin, or poor 
vascularized tissue in the area to be treated. 
Performance 
15. 
History of allergic/anaphylactic reactions including 
hypersensitivity to lidocaine or anesthetics of the amide type, or any 
other components of the SMD. 
Safety concern 
16. 
Congenital methemoglobinemia, with glucose-6-phosphate 
dehydrogenase deficiencies, or concomitant treatment with 
methemoglobin-inducing agents. 
Safety concern 
17. 
Acute or chronic inflammation or infection at the injection site 
(e.g., acne). 
Safety concern 
18. 
History of chronic or recurrent infection or inflammation with 
the potential to interfere with the study results or increase the risk of 
AEs. 
Safety concern 
19. 
Tendency to accumulate fluid in the lower eyelids, or large 
infraorbital fat pads. 
Safety concern 
20. 
History of recurrent or chronic infraorbital edema. 
Safety concern 
21. 
Ectropium of the lower eyelid or eye diseases that lead to 
reddening and tendency of watering of the eye. 
Safety concern 
22. 
Facial nerve palsy or history of facial nerve palsy. 
Safety concern 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 39 / 94 
File name: M900391005_CP_1.0_20180618_final 
Exclusion criteria 
Rationale 
23. 
Facial skin and/or lipoatrophy other than age-related, due to 
medical conditions (e.g., congenital defect, trauma), or 
abnormalities in adipose tissue related to immune-mediated 
diseases, such as generalized lipodystrophy (e.g., juvenile 
dermatomyositis), partial lipodystrophy (e.g., Barraquer-Simons-
Syndrome), inherited disease or HIV-related disease. 
Safety concern 
24. 
A propensity towards pigmentary skin changes such as hyper- or 
hypopigmentation in the face, inflammatory skin conditions, keloid 
formation, or hypertrophic scarring. 
Safety concern 
25. 
History or documented evidence of an autoimmune disease 
(e.g., scleroderma, lupus erythematosus, rheumatoid arthritis). 
Safety concern 
26. 
History of recurrent herpetic eruption in the facial region. 
Safety concern 
27. 
Systemic disorders which cause poor wound healing or will lead 
to tissue deterioration over the treated areas. 
Safety concern 
28. 
Present or uncontrolled malignant disease. 
Safety concern 
29. 
Any medical condition with the potential to interfere with the 
study or compromise subject safety, or increase the risk of AEs 
(e.g., epilepsy, impaired cardiac conditions, severely impaired 
hepatic function, severe renal dysfunction, porphyria, severe 
psychic, neurological or mental disease, current or history of drug or 
alcohol abuse, general infection). 
Safety concern 
30. 
Pregnant, breast-feeding women, or women who are of 
childbearing potential and not practicing a reliable method of birth 
control. 
Safety concern 
31. 
Subject who is imprisoned or is lawfully kept in an institution. 
Administrative 
32. 
Employee or direct relative of an employee of the CRO, the 
study site, or Merz. 
Administrative 
33. 
Participation in a clinical study within the last 4 weeks prior to 
Day 1 and in parallel to this investigation. 
Administrative 
34. 
Previous participation in this clinical study. 
Administrative 
Exclusion criteria 12, 17, and 30 must be confirmed at V2 if touch-up treatment is 
planned. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 40 / 94 
File name: M900391005_CP_1.0_20180618_final 
In case that any of the exclusion criteria, e.g., history or presence of a disease, disorder, 
allergy, etc. might be unknown or questionable, the subject should not be included in the 
study until the respective exclusion criterion has been clarified. 
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 study at any time without any penalty or loss of benefits to 
which the subject is otherwise entitled (see Section 7.4.3). Both the discontinuation of 
study and the reason(s) why the study was prematurely discontinued must be recorded in 
the subject file and the eCRF. Date and discontinuation circumstances should be stated. 
Subjects must be discontinued from the study by the investigator at any time for any of 
the following reasons: 
 Withdrawal of informed consent. 
 Pregnancy (no further administration of SMD will be performed). 
 Any AEs for which treatment continuation would constitute an unacceptably high risk 
for the subject. 
 Subject is lost to follow-up. 
Clinical protocol deviations or conditions arising from the exclusion criteria established 
in Section 7.3, may (but will not necessarily) lead to the subject’s discontinuation. All 
such conditions should be properly documented. 
Subjects who are discontinued from the study due to AEs will be treated according to 
standard clinical strategies and will be followed-up until the final study visit/safety visit 
as described in Section 10. All pertinent information concerning the AE will be 
documented in the subject file as well as in the eCRF AE report form. 
In case of study discontinuation of a subject the final study visit according to Table 7 
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 TC, copies of letters). Discontinued subjects will not 
be replaced. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 41 / 94 
File name: M900391005_CP_1.0_20180618_final 
7.4.2 
Premature termination or suspension of the study or a 
study site 
The study or a study site can be prematurely terminated or suspended by the sponsor. 
Reasons for termination of the study or a study site may include, but are not limited to, 
the following: 
 Subject enrollment is unsatisfactory. 
 The risks and benefits of continuing the study have been reassessed, and the risks 
outweigh any potential benefits. 
 In particular if an increase in the frequency or severity of expected AEs or newly 
identified harms, currently not regarded in the risk analysis, according to ISO 
14971:2012 could have a significant impact on the benefit-risk analysis and which 
may lead to risks to the health or safety of subjects, users or other persons that are 
unacceptable when weighed against the intended benefits. 
 New scientific data on the SMD do not justify a continuation of the study. 
 The investigator or study site exhibit serious and/or persistent non-adherence to the 
CP, the Declaration of Helsinki, DIN EN ISO 14155:2012, and/or applicable 
regulatory requirements. 
 The sponsor decides to terminate the study at any time for any other reason. 
Furthermore, the study may be prematurely ended if the regulatory authority or the EC 
has decided to terminate or suspend approval for the study, the study site, or the 
investigator. 
If the study 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 investigators, study 
sites, the EC, and regulatory authorities of the termination or suspension of the study, as 
well as provide reasons for the action. 
7.4.3 
Provision of care for subjects after study 
discontinuation 
After study discontinuation, the subjects will be treated by their physician according to 
their medical condition and standard treatments. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 42 / 94 
File name: M900391005_CP_1.0_20180618_final 
8 TREATMENTS 
8.1 
Study medical device 
The SMD RADIESSE® (+) Lidocaine is CE-marked in Europe since 02-JUN-2016 and 
will be injected as per its current approved labelling and investigator’s usual practice.  
8.1.1 
Description of study medical device 
RADIESSE® (+) Lidocaine is a sterile, non-pyrogenic, semi-solid, cohesive implant. The 
principle component is synthetic CaHA suspended in a gel carrier that consists primarily 
of 
water 
(sterile 
water 
for 
injection 
USP), 
glycerin 
(USP), 
sodium 
carboxymethylcellulose (USP), and 0.3% lidocaine hydrochloride. The gel is dissipated 
in vivo and replaced with soft tissue growth, while the CaHA remains at the site of 
injection. The lidocaine provides short-term local anesthetic effect. The result is 
long-term yet non-permanent restoration and augmentation. 
RADIESSE® (+) Lidocaine has a CaHA particle size range of 25-45 microns. It is 
indicated for plastic/reconstructive procedures, including deep dermal and subdermal soft 
tissue augmentation of the facial area and is also intended for restoration and correction 
of facial volume loss. 
The SMD is provided sterile and non-pyrogenic in a syringe packaged in a foil pouch and 
boxed for convenient storage. Each syringe only unit consists of one pre-filled syringe 
containing 1.5 ml of RADIESSE® (+) Lidocaine and a Terumo K-Pack II with two 
27 gauge thin wall injection needles.  
8.1.1.1 
Instructions for preparation 
The instructions for preparation of RADIESSE® (+) Lidocaine (e.g., the correct 
assembling of the needle to the syringe) are to be followed as described in the current 
version of the IFU. The treating investigator should check the integrity of the inner 
packaging and the expiry date for both the syringes and the needles prior to use. The 
products must not be used if the expiry date has lapsed or if the packaging has been 
opened or damaged or if the syringe end cap or syringe plunger is not intact. 
8.1.1.2 
 Instructions for administration 
For successful treatment, it is essential that the treating investigator has experience with 
the injection techniques for treating nasolabial folds, marionette lines, and upper cheek 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 43 / 94 
File name: M900391005_CP_1.0_20180618_final 
volume loss and has a deep knowledge of the facial anatomy. The treatment must be 
carried out under appropriate aseptic conditions.  
The treating investigator determines the appropriate treatment area, depth, needle/cannula 
and injection technique based on clinical experience and preference in accordance with 
the current version of the IFU of the SMD. The SMD must be injected into a healthy, 
non-inflamed and previously rigorously disinfected skin. It should be injected into the 
deep dermal and/or subdermal soft tissue. 
Injection volume of the SMD will be at the investigator’s judgement based on subject’s 
expectations, skin conditions and safety considerations and depends on the area to be 
treated and the extent of the volume loss/deficit. The optimal cosmetic outcome and an 
expected ≥ 1point improvement on the respective MAS in each treated area should be 
achieved. However, over-correction should be avoided. 
The SMD should be injected slowly with the least amount of pressure necessary. It 
should not be injected into blood vessels, into areas presenting cutaneous problems of an 
inflammatory or infectious type (e.g., acne, herpes) or into an area previously treated with 
a permanent dermal filler. For full exclusion criteria, please refer to Section 7.3. Only the 
nasolabial folds, the marionette lines, and the upper cheek should be treated, other 
regions of the face must not be treated in this study. 
If the needle/cannula becomes obstructed during the procedure and the injection pressure 
is too high, the treating investigator should stop the injection and change the 
needle/cannula. 
After injection of SMD, the treated area can be gently massaged to distribute the product 
uniformly. 
The investigator will use the SMD and all study materials only within the framework of 
the clinical study and in accordance with this CP. 
8.1.2 
Packaging and labelling  
The packaging will be that of the commercialized products with additional labelling of 
“Studiennummer: M900391005“, and „Medizinproduktenummer: XXXX“ (SMD number 
with sequential numbering). 
The SMD will be provided directly to each study site. If necessary during the course of 
the study, the study sites will be replenished with further study material. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 44 / 94 
File name: M900391005_CP_1.0_20180618_final 
8.1.3 
Storage of study medical device 
Storage of the SMD should be in accordance with the instruction leaflet (see current 
version of the [IFU 2017]). 
8.1.4 
Accountability for study medical device 
It is the responsibility of the investigator to ensure that a current record of inventory 
accountability per site and per study subject is maintained. Inventory records must be 
readily available for the study monitor and are open to inspection by regulatory 
authorities at any time. Each shipment of materials for the study will contain an SMD 
supply and return form to assist the investigator in maintaining current and accurate 
inventory records. This form includes the following information: study number, dates, 
quantities, SMD number, and expiry date. 
Upon receipt of the SMD, the investigator or his designated and authorized site staff will 
visually inspect the shipment and verify the number and condition of the SMD. The SMD 
supply and return form will be completed and signed by the investigator or authorized 
site staff. The completed form should be sent back to the sponsor, and the original signed 
form should be filed with the inventory accountability records. 
To ensure proper storage and to verify inventory, a supply inspection will be conducted 
by the monitor. The results of the inspection will be made available to the authorized 
individuals (e.g., monitor, auditor, and regulatory authorities) on request throughout the 
study. 
For subject device accountability and treatment compliance, see Section 8.2.5. 
8.1.5 
Destruction of study medical device  
Upon the completion or termination of the study, all unused products will be returned to 
the sponsor. The sponsor will destroy the unused MD(s) after completion of the clinical 
investigation report. Destruction of MD(s) at the investigation site may be possible if 
written authorization is provided by the sponsor. If destruction at the investigation site is 
agreed upon, then a certificate of destruction must be given to the sponsor. 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 45 / 94 
File name: M900391005_CP_1.0_20180618_final 
8.2 
Treatments administered 
The SMD will be applied according to the administration method and volumes described 
in the current IFU and in Section 8.2.2.  
The treatment plan will consist of one injection session at Day 1 and an optional touch-up 
treatment after 4 weeks.  
The following treatment order is recommended (depending on the indications the 
investigator considers for treatment): 
 Progress from cranial to caudal (upper cheek augmentation before nasolabial folds 
and marionette lines). 
 Nasolabial folds after upper cheek augmentation and before marionette lines. 
 Marionette lines at the end. 
8.2.1 
Methods of assigning subjects to treatment groups 
This is not applicable for the current study. 
8.2.2 
Selection of doses in the study 
The volume to be injected is at the investigator’s discretion according to the area to be 
treated as well as subject’s expectations in order to achieve a desired improvement on the 
respective MAS in each treated area. Overcorrection must be avoided.  
8.2.3 
Selection and timing of doses for each subject 
This is not applicable for the current study. 
8.2.4 
Duration of treatment per subject 
The SMD will be injected at Day 1. An optional touch-up for one or more areas that were 
injected at Day 1 can be performed after 4 weeks +/- 7 days if deemed necessary by the 
investigator and the subject to achieve the optimal cosmetic correction. 
8.2.5 
Treatment compliance 
At the beginning of the investigation, the site will receive device accountability forms to 
document how and when MD is dispensed to subjects, or returned unused. These forms 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 46 / 94 
File name: M900391005_CP_1.0_20180618_final 
will be made available to the authorized individuals (e.g., monitor, auditor) and include 
the following information: study number, dates, quantities, and the SMD number 
assigned to the MD and study subjects. 
8.2.6 
Treatment of overdose 
As treatment with SMD is performed exclusively in a clinical setting under the 
supervision of trained medical personnel, the risk of overdose in this study is estimated to 
be low. However, in the case an overdose occurred (i.e., over-correction), it must be 
recorded in the source documents and the SMD section of the eCRF and recorded as an 
AE. Any case of overdose leading to an SAE(s) must be reported to the sponsor in an 
expedited manner using the appropriate reporting form. Usually, overcorrection is an 
aesthetic issue and harmless for health. It resolves within 6 to 12 months without 
intervention. 
The SMD, once implanted, cannot be easily removed, and a chirurgical intervention 
might be necessary in case of overcorrection. 
8.3 
Previous and concomitant therapies/procedures 
After signature of the informed consent and prior to enrollment, the subject’s previous 
and concomitant therapies and procedures should be reported in the eCRF. Previous and 
concomitant 
therapies/procedures 
should 
include 
a 
detailed 
list 
of 
all 
medications/non-drug therapies the subject was taking for a period of at least 
three months previous to Day 1. Facial treatments (such as surgery, aesthetic procedures) 
should be recorded regardless of time frame. For drug therapies, the record should 
include the drug name (trade or generic), route of administration (e.g., intravenous, oral), 
total daily dose and unit (expressed in mg, ml, or IU), indication, the start and stop date 
(day, month, and year), and whether the medication is ongoing at the end of the study. 
For non-drug therapies, the record should include the therapy name, body site and the 
start and stop date (day, month, and year).  
Contra-indications and precautions for use mentioned in the SMD leaflet are to be 
checked prior to any injection and should be strictly respected.  
Therapy changes (including changes of regimen) during the study are to be documented 
in the subject file and in the eCRF. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 47 / 94 
File name: M900391005_CP_1.0_20180618_final 
8.4 
Blinding 
A blinded rater who is not otherwise involved in any study procedures and who is not 
aware of the indications that will be treated will assess the primary and some of the other 
endpoints. 
8.5 
Restrictions during the study 
The following restrictions to concomitant therapies will have to be observed during the 
study: 
 No application of any new over-the-counter or prescription, oral or topical, anti-
wrinkle products in the area to be treated during participation in this study.  
 No cosmetic facial plastic surgery or oral surgery procedures (e.g., orthodontia, 
extraction, implants) during participation in the study.  
 No dermal therapies (e.g., dermal fillers, toxin treatments, facial ablative or 
fractional laser, microdermabrasion, chemical peels, non-invasive skin-tightening, 
epilation, and surgical procedures) in the area to be treated during participation in 
the study. 
 No immunosuppressive medications or systemic steroids region during 
participation in the study (except intranasal/inhaled steroids). 
 No anti-coagulation, anti-platelet, or thrombolytic medications (e.g., aspirin, 
warfarin, heparin, clopidogrel), anti-inflammatory drugs (e.g., aspirin), from ten 
days before up to three days post SMD application. 
 Use of sunscreens and continued therapy with some cosmeceuticals, e.g., alpha 
hydroxyl acids, glycolic acids, skin-bleaching agents, retinol, or retinoic acids, are 
allowed if the regimen was established > 3 months prior to enrollment. 
The following actions and treatments are prohibited until the initial skin 
reddening/swelling has subsided: 
 Application of makeup and touching/pressing of the treated parts of the face for at 
least 12 hours after treatment. 
 Skin irritating agents (e.g., keratolytic, antiseborrheic, anti-acne agents) for at 
least three days after treatment in the treated area. 
 Pigmenting and depigmenting agents for at least three days after treatment in the 
treated area. 
 Promote facial rest for one week by encouraging subjects to limit talking, smiling 
and laughing. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 48 / 94 
File name: M900391005_CP_1.0_20180618_final 
 Extreme cold or heat (e.g., sauna, hot spring water, steam rooms) for at least 
14 days after treatment. 
 UV-exposure (sun or other UV ray emitters) for at least 14 days after treatment. 
8.6 
Precautions during and after the study 
 The CaHA particles in the SMD are radio-opaque and are clearly visible on 
computer tomogram scans and may be visible in standard, plain radiography. 
Subjects need to be informed of the radio-opaque nature of the SMD, so that they 
can inform their primary care health professionals and/or radiologists. 
 The investigator should council the subject to apply cool compresses to treated 
areas for approximately 24 hours. 
 The investigator should council to massage the treatment area gently if palpable 
nodules become present. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 49 / 94 
File name: M900391005_CP_1.0_20180618_final 
9 STUDY ASSESSMENTS AND VISIT SCHEDULE 
9.1 
Clinical evaluations 
At the beginning of the study, the subject’s relevant medical history and all current and 
concomitant medications, treatments and procedures planned during the study as well as 
previous aesthetic procedures undertaken on the face will be recorded (see Section 8.3). 
A review of this information will allow the investigator to assess whether the subject 
should be enrolled. Treatment areas will be determined by the investigator. Other data 
will be collected as required, including complete information obtained from the 
examination of the treatment areas. If counseling of subjects is deemed necessary, either 
prior to enrollment or during the study, the investigator and/or subject might schedule an 
additional visit as necessary or clarify all issues during a planned study visit. 
For time points of these assessments, please refer to Table 7. 
9.2 
Performance assessments 
All assessments at a given study site should be performed by the same investigator for an 
individual subject enrolled at this site, if possible. A blinded rater, who is not otherwise 
involved in this study and who is also not aware of the treatment areas of the respective 
subject, will perform the MAS endpoint assessments by live rating. All assessments for 
an individual subject should be scored by the same blinded rater throughout the study, if 
possible. Subjects and the treating investigator will be instructed not to discuss the 
treatment areas with the blinded rater. The blinded rater must not have access to the 
subject`s file and the source data of the study.  
It is strongly recommended that treating investigator and the blinded rater remain the 
same for each patient throughout the study, to ensure consistency in assessment.    
Assessment collection time points are detailed in Table 7. 
9.2.1 
2D photographs 
Three 2D photographs will be captured at baseline prior to SMD injection to serve as 
reference pictures for treating investigators and subjects for evaluation of iGAIS and 
sGAIS. The investigator will use his/her own photo equipment which he/she uses in daily 
practice. One full-face photograph from front view, and one full-face-photograph from 
45° degree of each side per subjects should be taken with appropriate display of the 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 53 / 94 
File name: M900391005_CP_1.0_20180618_final 
9.2.3 
Investigator Global Aesthetic Improvement Scale 
The iGAIS (see Table 1) will be used to assess aesthetic improvement in the subjects. 
The assessment will be performed by the treating investigator by live rating using 
baseline photographs for comparison. For time points of this assessment, please refer to 
Table 7.  
The treating investigator will be asked: “Based on your clinical experience, what is your 
overall impression of change of the subject´s aesthetic result due to treatment, compared 
to the condition before the first treatment (baseline)? Please check the one option that 
best fits your overall impression of change based on your comparison of the baseline visit 
photographs.”  
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 54 / 94 
File name: M900391005_CP_1.0_20180618_final 
Table 1: Investigator Global Aesthetic Improvement Scale 
Score 
Rating 
+3 
Very much improved 
+2 
Much improved 
+1 
Improved 
0 
No change 
-1 
Worse 
-2 
Much worse 
-3 
Very much worse 
9.2.4 
Subject Global Aesthetic Improvement Scale 
The sGAIS (see Table 2) will be used to assess aesthetic improvement in the subjects. 
The assessment will be performed by the subject by live rating using baseline 
photographs for comparison. For time points of this assessment, please refer to Table 7. 
The subject will be asked: “What is your overall impression of change of your aesthetic 
result due to treatment, compared to the condition before the injection? Please tick the 
one option that best fits your overall impression of change based on your comparison of 
the baseline visit photographs.” 
Table 2: Subject Global Aesthetic Improvement Scale 
Score 
Rating 
+3 
Very much improved 
+2 
Much improved 
+1 
Improved 
0 
No change 
-1 
Worse 
-2 
Much worse 
-3 
Very much worse 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 55 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 57 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 58 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
 
 
 
 
 
  
 
9.3 
Safety assessments 
Detailed information regarding the safety assessments is comprised in Section 10.  
. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 59 / 94 
File name: M900391005_CP_1.0_20180618_final 
9.5 
Visit schedule 
The purpose of the baseline visit is to determine the subjects’ eligibility for study 
participation. Subjects who are diagnosed with a medical condition during the screening 
process will be notified and referred for medical care. The screening evaluation must be 
completed prior to baseline. 
 
Baseline is defined as V1/Day 1 (enrollment pre-injection), which is the day of injection 
of SMD in at least two out of three treatment regions (i.e., nasolabial folds, marionette 
lines, and/or cheek volume loss). 
The study activities and the visit schedule are shown in Table 7. The study allows a time 
window of ±7 or ±14 days, depending on the visit. V6 (Week 72/76) is the final study 
visit. 
If the subject meets the inclusion and exclusion criteria and agrees to participate, he/she 
will attend six or seven visits, depending on whether and in how many indications a 
touch-up treatment is done at V2 or not.  
The primary endpoint for each treatment area will be evaluated 12 weeks after the last 
treatment, whether the last treatment occurred at V1 or as touch-up. Safety follow-up will 
occur up to 72/76 weeks post-treatment. Subjects who had the optional touch-up 
treatment will be contacted by telephone 4 weeks later and may have additional 
unscheduled visits if indicated by AEs or other safety issues. Unscheduled visits may be 
required in the case of premature discontinuation of the study. In this case, a final 
assessment will be performed. If additional safety follow-up is necessary after this 
assessment, subjects may be contacted by telephone or assessed in the practice/clinic, 
depending on the nature of the follow-up required. 
Study Visits: - V1/Injection visit (Day 1): At this visit, the following procedures will be 
performed: 
Before injection of SMD: 
 Obtain written informed consent from the subject. 
 Assessment of eligibility criteria. 
 Assessment of demographic data (age, gender, race), previous and concomitant 
therapies, previous cosmetic procedures on the face, relevant medical history, and 
concomitant diseases. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 60 / 94 
File name: M900391005_CP_1.0_20180618_final 
 Based on the list of areas to be investigated, determination of subjects’ face areas 
to be treated by the treating investigator (i.e., nasolabial folds, marionette lines, 
cheek volume loss) according to subjects’ expectations. 
 Assessment of baseline severity of each region according to the corresponding 
MAS by the blinded rater and the treating investigator.  
 Full face photographs will be taken to have a comparison to later time points for 
global impression assessments. 
 
 
 
 Injection of the SMD as per its approved labelling (see current version of IFU) in 
a minimum of two treatment areas in order to achieve a ≥ 1point improvement on 
the respective MAS in each treated area. 
After injection of SMD: 
 
 
 
 Assessment of AEs/SAEs/technical device deficiencies/complaints. 
- V2/Follow-up visit with optional touch-up (Week 4 +/- 7 days): At this visit, the 
following procedures will be performed: 
Before possible touch-up for area(s) injected at Day 1: 
 Assessment of exclusion criteria N°12, 17, and 30. 
 Assessment of concomitant medication/cosmetic procedures on the face and non-
drug treatments. 
 Assessment of AEs/SAEs/technical device deficiencies/complaints. 
 
 
 
 Assessment of iGAIS and sGAIS. 
 Assessment of severity of each investigated region according to the corresponding 
MAS by the blinded rater.  
 Injection of the SMD as per its approved labelling (see current version of IFU) (if 
touch-up is deemed necessary by the investigator and the subject) to achieve the 
optimal aesthetic correction.  
After possible injection of SMD: 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 61 / 94 
File name: M900391005_CP_1.0_20180618_final 
 Assessment of AEs/SAEs/technical device deficiencies/complaints.  
 Inform the subject that he/she will be called by phone for safety evaluation and 
concomitant diseases and therapies. 
- V2A/Follow-up TC (Week 8 +/- 7 days; subjects with touch-up only):  
Four weeks after the touch-up injections, all subjects that had a touch-up treatment in at 
least one region, will be called by phone for safety evaluation and concomitant 
diseases/therapies.  
- V3/Follow-up visit/Primary endpoint visit (Week 12 /Week 16 +/- 7 days): If no 
touch-up was performed, V3 occurs at Week 12. Subject will come back to the site to 
evaluate performance and safety as well as to document investigator’s and subject’s 
global impression assessments. Follow-up visits will be performed further at Week 24, 
Week 48 and Week 72 (there will be no Week 16 visit for these subjects).   
If touch-up was performed in at least one, but not in all indications treated at V1, V3 
occurs at Week 12. Subject will come back to the site to evaluate performance and safety 
as well as to document investigator’s and subject’s global impression assessments. 
Additionally, subject performs V3a at Week 16. Follow-up visits will be performed 
further on Week 28, Week 52, Week 76.  
 
If touch-up was performed at V2 in all indications treated at V1, V3 occurs at Week 16. 
Follow-up visits will be performed further at Week 28, Week 52, Week 76 (there will be 
no Week 12 visit for these subjects). 
 
 Assessment of concomitant medication/cosmetic procedures on the face and non-
drug treatments. 
 Assessment of AEs/SAEs. 
 
 
 
 Assessment of iGAIS and sGAIS. 
 Assessment of severity of each investigated region according to the corresponding 
MAS by the blinded rater.  
- V3A/Follow-up visit/optional primary endpoint visit (Week 16 +/- 7 days):  
 
This visit occurs in addition to V3, only if touch-up was performed at V2 for some but 
not all indications treated at V1. Sixteen weeks after the first injections at V1, the subject 
will come back to the site to evaluate performance and safety as well as to document 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 62 / 94 
File name: M900391005_CP_1.0_20180618_final 
investigator’s and subject’s global impression assessments. This visit will serve as 
primary endpoint for the respective indication(s), i.e., nasolabial folds, marionette lines, 
or cheek volume loss, in which a touch-up was performed, provided that not all 
indications have been treated with touch-up. Follow-up visits will be performed further 
on at Week 28, Week 52, Week 76. 
 
 Assessment of concomitant medication/cosmetic procedures on the face and non-
drug treatments. 
 Assessment of AEs/SAEs. 
 
 
 
 Assessment of iGAIS and sGAIS. 
 Assessment of severity of each investigated region according to the corresponding 
MAS by the blinded rater.  
- V4/Follow-up visit (Week 24/Week 28 +/- 14 days),  
- V5/Follow-up visit (Week 48/Week 52 +/- 14 days), and  
- V6/Follow-up visit/End of study visit (Week 72/Week 76 +/- 14 days): At these 
visits, the following procedures will be performed: 
 Assessment of concomitant medication/cosmetic procedures on the face and non-
drug treatments. 
 Assessment of AEs/SAEs. 
 
 
 
 Assessment of iGAIS and sGAIS. 
 Assessment of severity of each investigated region according to the corresponding 
MAS by the blinded rater. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 64 / 94 
File name: M900391005_CP_1.0_20180618_final 
assessed at Week 12 and for the indications that received touch-up will be assessed during the additional visit V3A at 
Week 16, follow-up visits will occur at Weeks 28, 52, and 76; 
d  
 if all indications treated at V1 are also treated at the optional touch-up, V3, 4, 5, and 6 will be at Weeks 16, 28, 52 and 76, 
respectively; 
e  
in case of premature study discontinuation a final study visit has to be performed for the subject.  

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 65 / 94 
File name: M900391005_CP_1.0_20180618_final 
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 investigational medical device. 
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 study 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 SMD 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 SMD, must be 
documented, treated, and followed up like all other AEs. 
AEs will not be followed up after the final visit, which is scheduled 72 or 76 weeks 
(depending on optional touch up) after first treatment with the SMD. 
Treatment emergent adverse events (TEAEs) are defined as adverse events with onset or 
worsening at or after the first administration of study treatment. 
Pre-existing conditions noted in the medical history and previous to SMD administration 
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. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 66 / 94 
File name: M900391005_CP_1.0_20180618_final 
10.1.2 
Adverse event handling and reporting 
Data pertaining to AEs will be collected during each investigation visit based on the 
subject’s spontaneous description, through investigator inquiry, or discovered in the 
course of examinations done during the visit. The investigator will assess and record any 
AE in detail in the subject file and on the eCRF AE report form. The following 
information must be recorded: 
 AE diagnosis or main symptom. 
 Location of AE: systemic or restricted to injection area. In case of local reaction, 
the corresponding area should be reported. 
 Date of onset. 
 Date of worsening. 
 Severity (maximum observed; see Section 10.1.3). 
 Causal relationship (not related, related). 
  Serious (yes or no). 
 Outcome (see Section 10.1.5). 
 Action taken with SMD  
 AE leading to discontinuation of the investigation (yes or no). 
 Stop date. 
After completion of all scheduled visit assessments the investigator must document any 
AEs arising from these assessments. 
In case of an serious adverse event (defined in section 10.2), the investigator must also 
complete an SAE report form and report it to 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: 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 67 / 94 
File name: M900391005_CP_1.0_20180618_final 
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 medical device 
An AE is considered to be “related” to SMD if a causal relationship between the SMD 
and an AE is at least reasonably possible (i.e., the relationship cannot be ruled out). In 
this case the event is considered an “adverse device effect” (see Section 10.3). If the 
event is serious (see above), it is a “serious adverse device effect”(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. 
If there is more than one AE, only the AE leading to death will be attributed with a 
“fatal” outcome. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 68 / 94 
File name: M900391005_CP_1.0_20180618_final 
10.2 Definition of a serious adverse event (SAE) 
A 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. 
10.2.1 
Serious adverse event details 
In case of a fatality, the cause of death is considered as the adverse event, and the death is 
considered as its outcome. In this case, the primary cause of death (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 case 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 as an SAE. If a 
subject experiences an additional AE that prolongs a pre-planned hospitalization, this is 
considered to be an SAE and should also be reported as an SAE. Hospitalizations for 
elective treatments planned before screening and which are documented in the subject’s 
source data are usually not regarded as SAEs. 
Device deficiencies that might have led to an SAE if  
a) suitable action had not been taken, or  

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 69 / 94 
File name: M900391005_CP_1.0_20180618_final 
b) intervention had not been made, or 
c) if circumstances had been less fortunate  
are handled under the SAE reporting system. 
10.2.2 
Reporting and handling of SAEs 
All SAEs that occur during the investigation period, whether considered to be related to a 
SMD or not, must be reported via SAE report form to the CRO within 24 hours of 
knowledge of the event. The CRO will report the SAE to the sponsor. Further reporting 
details will be outlined in a separate document. 
Although all information required for completion of an SAE report form may not be 
available within the specified time period, an initial report should be submitted if the 
following minimal information is available: 
 An identifiable subject (number). 
 A suspect product and how the treatment relates to the SAE. 
 An identifiable reporting source (investigator/investigation site identification). 
 An event or outcome that can be identified as serious. 
The report must be delivered to the individual(s) listed below. 
The address for SAE reporting is: 
 
  
Merz Pharmaceuticals GmbH  
Global Product Safety Department  
Eckenheimer Landstrasse 100  
D – 60318 Frankfurt/Main  
E-Mail: product.safety@merz.de in cc to MD-team@merz.de  
Telephone: 
  
Fax: 
  
Mobile: 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 70 / 94 
File name: M900391005_CP_1.0_20180618_final 
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 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 SMD.  
As 
this 
study 
is 
considered 
as 
PMCF 
study 
based 
on 
§23b 
German 
“Medizinproduktegesetz”, serious adverse device effects (see Section 10.4) need to be 
reported as incidents as well as near incidents by the sponsor accordingly based on the 
timelines defined in the current “Medizinproduktesicherheitsplanverordnung”. 
10.3 Definition of an adverse device effect (ADE) 
An ADE is defined as an adverse event related to the use of an investigational medical 
device. 
NOTE 1: This definition includes adverse events 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 investigational medical device. 
10.4 Definition of a serious adverse device effect (SADE) 
A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of an SAE (see Section 10.2). 
10.4.1 
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. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 71 / 94 
File name: M900391005_CP_1.0_20180618_final 
10.4.2 
Definition of an unanticipated serious adverse device 
effect (USADE) 
An USADE is a serious adverse device effect 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 investigation must be reported by the investigator 
via Pregnancy report form within 24 hours of learning of its occurrence. Pregnancies and 
pregnancy 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 SMD. 
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 performance. 
NOTE Device deficiencies include malfunctions, use errors, and inadequate labelling. 
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: 
 
 
Merz Pharma & Co. KGaA 
Global Quality 
Eckenheimer Landstrasse 100 
D – 60318 Frankfurt/Main 
E-Mail: complaints@merz.de in cc. to MD-team@merz.de 
Telephone: 
 
Fax: 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 72 / 94 
File name: M900391005_CP_1.0_20180618_final 
The Global Quality department will decide if the concerned sample needs to be returned 
and to whom the product should be sent for investigation. 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 73 / 94 
File name: M900391005_CP_1.0_20180618_final 
11  DATA QUALITY ASSURANCE 
Inspections by regulatory authority representatives and ECs are possible at any time, even 
after the end of study. The investigator is to notify the sponsor immediately of any such 
inspection. The investigator and institution will permit study-related monitoring, audits, 
reviews by the 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, monitoring, centralized evaluations, and validation methods).  
This study will be monitored regularly by a qualified monitor from the CRO according to 
DIN EN ISO 14155:2012, 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 study should be retained 
in the respective source documentation (e.g., subject file). 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 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. Subjects, investigators and blinded raters’ 
assessments must be filed in subject files. 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 and source data worksheet, if applicable). 
If a study site is using an electronic system for documenting source data, a member of the 
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 site staff who can confirm the accuracy and 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 74 / 94 
File name: M900391005_CP_1.0_20180618_final 
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’s Site 
File [ISF] or in separate binders for the study. 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.  
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 study subjects), then no 
such paper print-outs are required.   
11.3 Data management 
Data required according to this protocol is to be recorded in the web-based eCRFs 
(electronic data capture system) provided by the CRO. All users who will enter data into 
the eCRF will be previously trained. After the successful completion of the training all 
participants will receive a training certificate, which will be a pre-requisite for the access 
to the eCRF. The access to the eCRF is password-controlled and conforms with the Code 
of Federal Regulations part 11. 
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 investigator’s 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 site staff) can be raised during 
source data verification, medical or safety review and data management review. 
After all data up to Week 24/28 are entered and all queries are solved, the database will 
be closed for interim analysis (1st database close). Data will be exported and archived at 
SAS data sets. A second database close will take place after all remaining data have been 
entered and cleaned. Changes to data after 1st database close are documented exclusively 
in the audit trail of the electronic data capture system. The audit trail will be archived at 
the end of the study. In case of any changes to the data after 2nd database close, these 
changes will be documented according to respective SOP. 
11.4 Monitoring 
This study will be monitored regularly by a qualified monitor of the CRO according to 
DIN EN ISO 14155:2012 (chap. 8.2.4) and the respective SOPs. During these visits, the 
monitor will prepare the study site for the conduct of the study, check for subject 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 75 / 94 
File name: M900391005_CP_1.0_20180618_final 
eligibility, for completion of the entries in the source data and on the eCRFs; for 
compliance with the CP, DIN EN ISO 14155:2012, the Declaration of Helsinki, and 
regulatory authority requirements; and for the integrity and verification of the source data 
with the eCRF entries. Monitoring also will be aimed at detecting any misconduct or 
fraud. 
In addition, the monitor will check whether all AEs/ADEs and SAEs/SADEs have been 
reported appropriately within the time periods required. 
The investigator and all 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 units of SMD dispensed in the eCRF and the device inventory records. 
All subjects who are screened, but not included into the study, will be listed on the 
subject enrollment log. 
Further details of monitoring activities, if applicable, will be set forth in the monitoring 
plan. 
11.5 Auditing 
Audits will be performed according to the corresponding audit program, including the 
possibility that a member of the sponsor’s quality assurance function may arrange to visit 
the investigator in order to audit the performance of the study at the study site, as well as 
all study documents originating there. Auditors conduct their work independently of the 
observational study and its performance. 
Audits may also be performed by contract auditors. In this case, the sponsor’s quality 
assurance function will agree with the contract auditor regarding the timing and extent of 
the audit(s). In case of audits at the study site, the monitor will usually accompany the 
auditor(s). 
In addition, standard routine quality control procedures will be employed according to the 
sponsor’s SOPs.  

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 76 / 94 
File name: M900391005_CP_1.0_20180618_final 
12 STATISTICAL METHODS  
This section describes the statistical analyses intended at the time of study planning. 
Further details on the statistical and analytical aspects will be presented in the statistical 
analysis plan [SAP]. 
Any deviations from planned analyses, the reasons for such deviations, and all alternative 
or additional statistical analyses that may be performed before database close will be 
described in amendments to the CP or the SAP. All deviations and/or alterations will be 
summarized in the clinical study report. 
12.1 Determination of sample size 
The sample size estimation is based on the primary performance analyses, i.e., on three 
one-sided exact one-sample binomial tests (one test for each indication). Under the 
following assumptions 140 subjects are required per indication to reach a global power of 
80%:  
 Global significance level: 0.025 (one-sided) 
 Local significance levels for tests per indication: α1=0.0083, α2=0.0125, α3=0.025 
(Bonferroni Holm adjusted alpha)  
 Proportion of responders under the null hypothesis 0.6  
 Expected responder rate under test treatment: 0.75 
 Power for each single test: 89.6% (for α1), 92.6% (for α2), 96.6% (for α3) 
 Global power for all tests under independence 80.1% 
In order to have sufficient subjects for safety analysis the sample size is increased to 
175 subjects per indication so that a minimum of 161 subjects per indication will 
complete the study. In 161 subjects per indication an AE with a true incidence of 1% will 
be observed at least once per indication with a probability of 80%. The total number of 
210 subjects to be treated was chosen to have approximately 175 subjects treated per 
indication. 
12.2 Analysis sets 
The following analysis sets will be defined for the statistical analysis of this study: 
Safety Evaluation Set [SES] 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 77 / 94 
File name: M900391005_CP_1.0_20180618_final 
The SES is the subset of all subjects who were exposed to the SMD at least once.  
Full Analysis Set [FAS] 
The FAS is the subset of subjects in the SES for whom at least one of the primary 
performance variables is available (i.e., all subjects who have a baseline and a post-
baseline primary performance value of at least one treated indication).  
Per Protocol Set [PPS] 
The PPS is the subset of subjects in the FAS without major deviations. Major protocol 
deviations will be defined during the data review meeting. 
12.3 Variables for analysis 
12.3.1 
Performance variables 
12.3.1.1 
Primary performance variable 
The primary performance variables of this study are: 
 Responder 
rate 
for 
nasolabial 
folds 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the 
MNLFS. Response defined as improvement of ≥ 1point in both folds (left and 
right) from Day 1 pre-injection to Week 12/16 (depending on touch-up). 
o V3 visit at Week 12 after first injection at Day 1, if no touch-up is done for 
nasolabial folds 
o V3 visit at Week 16 after first injection at Day 1, if a touch-up is done for 
nasolabial folds and for all further indications treated at V1 
o V3A visit at Week 16 after first injection at Day 1, if a touch-up is done for 
nasolabial folds, but not for all indications treated at V1 
 Responder 
rate 
for 
marionette 
lines 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the MMLS. 
Response defined as improvement of ≥ 1point in both marionette lines (left and 
right) from Day 1 pre-injection to Week 12/16 (depending on touch-up). 
o V3 visit at Week 12 after first injection at Day 1, if no touch-up is done for 
marionette lines 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 78 / 94 
File name: M900391005_CP_1.0_20180618_final 
o V3 visit at Week 16 after first injection at Day 1, if a touch-up is done for 
marionette lines and for all further indications treated at V1 
o V3A visit at Week 16 after first injection at Day 1, if a touch-up is done for 
marionette lines, but not for all indications treated at V1 
 Responder 
rate 
for 
cheek 
fullness 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the 
MUCFS. Response defined as improvement of ≥ 1point in both cheeks (left and 
right) from Day 1 pre-injection to Week 12/16 (depending on touch-up). 
o V3 visit at Week 12 after first injection at Day 1, if no touch-up is done for 
cheek fullness 
o V3 visit at Week 16 after first injection at Day 1, if a touch-up is done for 
cheek fullness and for all further indications treated at V1 
o V3A visit at Week 16 after first injection at Day 1, if a touch-up is done for 
cheek fullness, but not for all indications treated at V1 
Table 8 displays which visits will be used to for calculation of the primary variables 
depending on touch-up treatment.  

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 80 / 94 
File name: M900391005_CP_1.0_20180618_final 
 Responder 
rate 
for 
cheek 
fullness 
after 
treatment 
with 
RADIESSE® (+) Lidocaine based on the blinded rater’s evaluation on the 
MUCFS prior to optional touch-up at V2 (Week 4), at Week 24/28, at 
Week 48/52, and at Week 72/76 (depending on touch-up performed). Response 
for cheek fullness defined as improvement of ≥ 1point in both cheeks (left and 
right) compared to Day 1 pre-injection. 
 Treating investigator’s evaluation of the global aesthetic improvement on the 
iGAIS from Day 1 pre-injection photos to V2 (Week 4) prior to optional 
touch-up, to Week 12/16, to Week 24/28, to Week 48/52, and to Week 72/76 
(depending on touch-up performed).  
 Subject’s evaluation of the global aesthetic improvement on the sGAIS from 
Day 1 pre-injection photos to V2 (Week 4) prior to optional touch-up, to 
Week 12/16, to Week 24/28, to Week 48/52, and to Week 72/76 (depending on 
touch-up performed). 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 81 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
 
12.3.2 
Safety variables 
12.3.2.1 
Primary safety variable 
The primary safety variable is: 
 Occurrence of treatment emergent adverse events [TEAEs]. 
12.3.2.2 
Secondary safety variables 
Not applicable for the current study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 82 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
 
 
 
 
 
 
 
 
12.4 Statistical analysis methods 
12.4.1 
Performance variables 
All performance analyses will be based primarily on the FAS and additionally for the 
primary performance analyses on the PPS. Where applicable subgroup analysis will be 
performed on the following subpopulation “nasolabial folds”, “marionette lines” and 
“cheek volume loss” (for details see section 12.4.4.5). 
Statistical tests will be one-sided hypothesis tests for responder rates. The Bonferroni 
Holm alpha correction will be used for three statistical tests to adhere to the global 
significance level of 0.025. Continuous variables (values and changes from baseline) will 
be summarized by number of non-missing values, mean, standard deviation, median, 
quartiles, minimum, and maximum. For qualitative variables, absolute and percent 
frequencies (N, %) will be displayed. 
12.4.1.1 
Primary performance variable 
Responder rates for nasolabial folds, for cheek volume loss, and for marionette lines will 
be summarized as absolute and percent frequencies (N, %). Only the subjects of the FAS 
treated for the corresponding indication will be included into the analyses of responder 
rates (for details see section 12.4.4.5).  
The aim of primary performance analyses is to show that there are: 
 significantly more than 60% of responders in treatment of nasolabial folds 
 significantly more than 60% of responders in treatment of marionette lines 
 significantly more than 60% of responders in treatment of cheek volume loss 
A confirmatory exact one-sample binomial test will be used to test probability of being a 
responder (p) is above 60% separately for each indication: 
 H0 nasolabial folds: p ≤ 0.6  
vs. 
H1 nasolabial folds: p > 0.6 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 83 / 94 
File name: M900391005_CP_1.0_20180618_final 
 H0 marionette lines: p ≤ 0.6   
vs. 
H1 marionette lines: p > 0.6 
 H0 cheek volume loss: p ≤ 0.6  
vs. 
H1 cheek volume loss: p > 0.6 
Using the Bonferroni Holm alpha correction with global significance level of 0.025 for 
the test with lowest p-value the local significance level α1 is 0.0083. For the test with the 
second lowest p-value α2 is 0.0125. For the test with the highest p-value α3 is 0.025. If the 
lowest p-value of a single (one-sided) hypothesis is below 0.0083 it is shown that the 
responder rate lies significantly above 60% for this indication. In this case performance is 
shown for this indication. If additionally the second p-value of a single (one-sided) 
hypothesis is below 0.0125 it is shown that the responder rate lies significantly above 
60% also for this indication. If additionally the highest p-values of the single sub-
hypothesis are below 0.025, the primary objective regarding performance (i.e., 
performance shown for all three indications) can be concluded. The procedure is stopped 
if a p-value is higher than the corresponding local significance level. In this case no 
subsequent null hypothesis will be rejected.  
Point estimates of the rates will be provided with exact one-sided 97.5% Clopper-Pearson 
confidence intervals.  
12.4.1.2 
Secondary performance variables 
No additional key secondary hypotheses will be tested under control of the global type I 
error level. All secondary variables will be analysed descriptively as follows: Responder 
rates for nasolabial folds, for marionette lines, and for cheek fullness of the remaining 
visits will be summarized as frequency tables with absolute and percent frequencies (N, 
%). iGAIS and sGAIS will be displayed using descriptive summary statistics for 
continuous variables and as frequency tables with absolute and percent frequencies (N, 
%). Subgroup analysis for iGAIS and sGAIS will be done per indication (subjects treated 
for nasolabial folds, for marionette lines, and for cheek volume loss). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 84 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
 
 
 
 
 
12.4.2 
Safety variables 
All safety analyses will be performed on the SES in total and by the subpopulations of 
each indication (subjects treated for nasolabial folds, for marionette lines, and for cheek 
volume loss). AEs will be coded according to the Medical Dictionary for Regulatory 
Activities [MedDRA] version in effect at the time the database is closed. Only TEAEs 
will be analysed which are defined as AEs with onset or worsening at or after the first 
administration of the SMD. 
12.4.2.1 
Primary safety variable 
The main analysis for the primary safety variable will be the overall TEAE incidence 
rate(s). Further incidences will be calculated for TEAEs on the system organ class level 
and on the preferred term level (i.e., total, by intensity, and by relationship, by outcome, 
and by injection site area). Listings and, if applicable, tables displaying incidences for 
TEAEs leading to discontinuation, serious TEAEs, and deaths will also be provided.  
12.4.2.2 
Secondary safety variables 
Not applicable for the current study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 85 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.4.4 
Special statistical/analytical issues 
12.4.4.1 
Discontinuations and missing data 
Discontinued subjects will not be replaced.  
For responder analyses missing values will be evaluated as non-responder (worst case 
replacement). 
 
 
 
 
 
 
 
 analyses except responder analysis 
 
 
will be performed on observed cases only. 
12.4.4.2 
Interim analyses  
An interim analysis for the SES and the FAS will be performed including all data (safety, 
performance and other data) up to Week 24/28 respectively, depending on touch-up. The 
analyses of the subpopulations “nasolabial folds”, “marionette lines” and “cheek volume 
loss” is also part of the interim analysis (for details see section 12.4.4.5). The PPS 
analysis is not part of the interim analysis and will be done for the final analysis at the 
end of the study in addition to SES and FAS. A combined SAP containing interim 
analysis and end of study analysis will be written. Tables to be created for the interim 
analysis and data to be included will be described in detail in the SAP. The interim 
analysis will be done for obtaining the performance and safety data  up to Week 24/28 as 
early as possible. Therefore, the purpose of this interim analysis is not to perform any 
adaptions on the study design, statistical analysis, sample size or for stopping the study, 
as this is not a study with an adaptive design.  

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 86 / 94 
File name: M900391005_CP_1.0_20180618_final 
Since this is an open label study, the interim analysis will not have any influence on the 
integrity of the study data and it will not bias the data collected after interim analysis. 
12.4.4.3 
Data monitoring committee 
Not applicable for the current study. 
12.4.4.4 
Multiple comparisons/multiplicity 
Three confirmatory tests will be performed in the primary analysis, one for each primary 
performance variable of the corresponding indication. Bonferroni Holm correction will 
be used to counteract the problem of multiple comparisons. For the three statistical test 
the local significance levels α1=0.025/3, α2=0.025/2 and α3=0.025 will be applied to 
obtain the global significance level of 0.025. 
12.4.4.5 
Examination of subgroups 
The subpopulation “nasolabial folds” will contain all subjects treated for nasolabial folds, 
regardless if they have been treated for one or both other indications as well. The 
subpopulation “marionette lines” will contain all subjects treated for marionette lines, 
regardless if they have been treated for only one or for two other indications as well. The 
subpopulation “cheek volume loss” will contain all subjects treated for cheek volume 
loss, regardless if they have been treated for one or both other indications as well. Each of 
these three subpopulations will contain approximately 175 subjects. Each subject will 
belong to at least two of these subpopulations. At least 50% of the subjects will be treated 
in all of the three indications and as consequence these subjects will belong to all of these 
three subpopulations (i.e., nasolabial folds, marionette lines, and cheek volume loss).  
For the performance variables iGAIS, sGAIS, 
 
 
 
 for subject dispositions, 
demographic data, and for all safety analyses (analysis of TEAEs), subgroup analyses 
will be performed for each indication (subjects treated for nasolabial folds, for marionette 
lines and/or for cheek volume loss) in addition to the total population.  
Responder analysis of MNLFS, MUCFS, and MMLS will only be performed for the 
subpopulations and not for the total population. 
 
 
 
 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 87 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 88 / 94 
File name: M900391005_CP_1.0_20180618_final 
13 DATA HANDLING AND RECORDKEEPING 
By signing and dating the eCRF, the investigator will confirm that all studies have been 
completed and conducted in compliance with the CP, and that reliable and complete data 
have been entered into the eCRF. 
13.1 Corrections to data 
All data required by this CP are to be recorded in the eCRF as soon as possible. However, 
direct entries are not allowed; data must be transcribed from the source documentation 
(e.g., subject file, scales) to the eCRF.  
All data required by this CP are to be entered into a sponsor-validated database of eCRFs. 
If corrections are necessary, an authorized member of the investigator’s site staff will 
enter the correct data into the web-based eCRF. The audit trail in the electronic data 
capture system documents all changes.  
The CRO´s/sponsor’s data management function will be responsible for data processing, 
in accordance with the CRO`s/sponsor’s data management procedures. Database close 
will occur only after quality assurance procedures have been completed.  
13.2 Recordkeeping 
Essential documents should be retained for a period of at least 10 years. Destruction of 
the documents after this period is only allowed after written agreement with the sponsor.  
Essential documents at the study site include (among other documents): 
 Source documentation (e.g., subject files, photos, scales). 
 Subject identification code list (i.e., provided by template to the investigator, along 
with the ISF, at the beginning of the study), which identifies the subject by number, 
name, and date of birth. 
 A signed copy of the final CP and any amendment. 
 Investigator’s compact disc/digital versatile disc with eCRF data, data clarification 
forms, and any associated subject-related source data (or, where applicable, 
authorized copies of source data). 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 89 / 94 
File name: M900391005_CP_1.0_20180618_final 
 Signed informed consent forms.  
 Copies of site investigators’ and co-worker’s curricula vitae. 
 Copies of all direct correspondence with the EC (submission and approval letters). 
 Copies of study supply receipt forms and device inventory forms. 
 Copies of all essential correspondence between the investigator and the monitor, and 
between the investigator and the sponsor.  
 Copies of safety information reported during the study and submitted by the sponsor. 
13.3 Destruction of study documents 
Study documents may not be destroyed by study site personnel prior to the retention 
period specified above without the prior written consent of the sponsor. The study 
institution must inform the sponsor in due time if the principle investigator leaves the 
institution during the retention period. This rule also applies when the institution closes 
within the retention period. 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 90 / 94 
File name: M900391005_CP_1.0_20180618_final 
14 PUBLICATION POLICY 
The study results should be published in the public domain, and publishing details will be 
given in the clinical study agreement. Publications concerning study results must be 
approved in advance by the sponsor in writing.  
The results of this study and any discoveries related to this study, regardless of whether 
they have technical or medical character, are the property of the sponsor. 
The sponsor ensures that the study is registered, and study results are disclosed in at least 
one public clinical study registry, in accordance with national/international regulations 
and other requirements. Study registration may include a list of the study sites, as 
applicable. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 91 / 94 
File name: M900391005_CP_1.0_20180618_final 
15 REFERENCES 
Cosmetic Surgery National Data Bank Statistics [Internet]. 2017 [cited 2017]. 
 
Bass LS, Smith S, Busso M, McClaren M. Calcium hydroxylapatite (Radiesse) for 
treatment of nasolabial folds: long-term safety and efficacy results. Aesthetic surgery 
journal / the American Society for Aesthetic Plastic surgery. 2010;30(2):235-8. 
 
Carruthers A, Liebeskind M, Carruthers J, Forster BB. Radiographic and computed 
tomographic studies of calcium hydroxylapatite for treatment of HIV-associated facial 
lipoatrophy and correction of nasolabial folds. Dermatol Surg. 2008a;34 Suppl 1:S78-84. 
 
Carruthers J, Cohen SR, Joseph JH, Narins RS, Rubin M. The science and art of dermal 
fillers for soft-tissue augmentation. J Drugs Dermatol. 2009;8(4):335-50. 
 
Carruthers J, Flynn TC, Geister TL, et al. Validated assessment scales for the mid face. 
Dermatol Surg. 2012;38(2 Spec No.):320-32. 
 
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. 2008b;121(5 Suppl):5S-30S. 
 
DeLorenzi C. Complications of injectable fillers, part 2: vascular complications. 
Aesthetic surgery journal / the American Society for Aesthetic Plastic surgery. 
2014;34(4):584-600. 
 
Fakhre GP, Perdikis G, Shaddix KK, Terkonda SP, Waldorf JC. An evaluation of calcium 
hydroxylapatite (Radiesse) for cosmetic nasolabial fold correction: a meta-analysis and 
patient centric outcomes study. Ann Plast Surg. 2009;63(5):486-9. 
 
Fathi R, Serota M, Brown M. Identifying and Managing Local Anesthetic Allergy in 
Dermatologic Surgery. Dermatol Surg. 2016;42(2):147-56. 
 
Fitzgerald R, Rubin AG. Filler placement and the fat compartments. Dermatol Clin. 
2014;32(1):37-50. 
 
Graivier MH, Bass LS, Busso M, Jasin ME, Narins RS, Tzikas TL. Calcium 
hydroxylapatite (Radiesse) for correction of the mid- and lower face: consensus 
recommendations. Plast Reconstr Surg. 2007;120(6 Suppl):55S-66S. 
 
IFU, Merz Aesthetics. IFU RADIESSE (+) Lidocaine. 2017:1-124. 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 92 / 94 
File name: M900391005_CP_1.0_20180618_final 
 
Jacovella PF. Use of calcium hydroxylapatite (Radiesse) for facial augmentation. Clinical 
interventions in aging. 2008;3(1):161-74. 
 
Kadouch JA. Calcium hydroxylapatite: A review on safety and complications. J Cosmet 
Dermatol. 2017. 
 
 
 
 
 
Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic and electron microscopic 
findings after injection of a calcium hydroxylapatite filler. J Cosmet Laser Ther. 
2004;6(4):223-6. 
 
Narins RS, Carruthers J, Flynn TC, et al. Validated assessment scales for the lower face. 
Dermatol Surg. 2012;38(2 Spec No.):333-42. 
 
 
 
 
 
 
Pavicic T. Calcium hydroxylapatite filler: an overview of safety and tolerability. J Drugs 
Dermatol. 2013;12(9):996-1002. 
 
Pavicic T. Complete biodegradable nature of calcium hydroxylapatite after injection for 
malar enhancement: an MRI study. Clinical, cosmetic and investigational dermatology. 
2015;8:19-25. 
 
 
 
 
 
Rayess HM, Svider PF, Hanba C, et al. A Cross-sectional Analysis of Adverse Events 
and Litigation for Injectable Fillers. JAMA facial plastic surgery. 2017. 
 
Sadick NS, Katz BE, Roy D. A multicenter, 47-month study of safety and efficacy of 
calcium hydroxylapatite for soft tissue augmentation of nasolabial folds and other areas 
of the face. Dermatol Surg. 2007;33 Suppl 2:S122-6; discussion S6-7. 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 93 / 94 
File name: M900391005_CP_1.0_20180618_final 
Schachter D, Bertucci V, Solish N. Calcium Hydroxylapatite With Integral Lidocaine 
Provides Improved Pain Control for the Correction of Nasolabial Folds. J Drugs 
Dermatol. 2016;15(8):1005-10. 
 
Thurstan SA, Gibbs NK, Langton AK, Griffiths CE, Watson RE, Sherratt MJ. Chemical 
consequences of cutaneous photoageing. Chemistry Central journal. 2012;6(1):34. 
 
Truswell WHt. Aging changes of the periorbita, cheeks, and midface. Facial Plast Surg. 
2013;29(1):3-12. 
 
Tzikas TL. A 52-month summary of results using calcium hydroxylapatite for facial soft 
tissue augmentation. Dermatol Surg. 2008;34 Suppl 1:S9-15. 
 
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. 
 
Zerbinati N. CALCIUM hydroxylapatite treatment of human skin: evidence of collagen 
turnover through picrosirius red staining and circularly polarized microscopy. Dove 
Medical Press 
Clinical, Cosmetic and Investigational Dermatology. 2018;11:29-35. 
 
 
 
 

 
 
 
- confidential - 
Merz Pharmaceuticals GmbH                                      M900391005/RaLido    
 
Clinical Protocol for post market clinical follow-up 
studies (PMCF) 
Version 1.0 
18-Jun-2018 
 
F01/ PMCF/ 11119/ EN/ 01/ valid from: 2016-07-26/ p. 94 / 94 
File name: M900391005_CP_1.0_20180618_final 
16 APPENDICES